Hospira Worldwide, Inc.

Hospira Worldwide, Inc. Drugs

• Cytarabine
  

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  Cytarabine

  

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  Cytarabine Injection is not active orally. The schedule and method of administration varies with the program of therapy to be used. Cytarabine Injection may be given by intravenous infusion or injection, subcutaneously, or intrathecally (preservative free preparation only).

  Thrombophlebitis has occurred at the site of drug injection or infusion in some patients, and rarely patients have noted pain and inflammation at subcutaneous injection sites. In most instances, however, the drug has been well tolerated.

  Patients can tolerate higher total doses when they receive the drug by rapid intravenous injection as compared with slow infusion. This phenomenon is related to the drug’s rapid inactivation and brief exposure of susceptible normal and neoplastic cells to significant levels after rapid injection. Normal and neoplastic cells seem to respond in somewhat parallel fashion to these different modes of administration and no clear-cut clinical advantage has been demonstrated for either.

  In the induction therapy of acute non-lymphocytic leukemia, the usual cytarabine dose in combination with other anti-cancer drugs is 100 mg/m2/day by continuous IV infusion (Days 1-7) or 100 mg/m2 IV every 12 hours (Days 1-7).

  The literature should be consulted for the current recommendations for use in acute lymphocytic leukemia.

  Intrathecal Use in Meningeal Leukemia

  Cytarabine injection has been used intrathecally in acute leukemia in doses ranging from 5 mg/m2 to 75 mg/m2 of body surface area. The frequency of administration varied from once a day for 4 days to once every 4 days. The most frequently used dose was 30 mg/m2 every 4 days until cerebrospinal fluid findings were normal, followed by one additional treatment. The dosage schedule is usually governed by the type and severity of central nervous system manifestations and the response to previous therapy.

  Cytarabine injection given intrathecally may cause systemic toxicity and careful monitoring of the hematopoietic system is indicated. Modification of other anti-leukemia therapy may be necessary. Major toxicity is rare. The most frequently reported reactions after intrathecal administration were nausea, vomiting and fever; these reactions are mild and self-limiting. Paraplegia has been reported. Necrotizing leukoencephalopathy occurred in 5 children; these patients had also been treated with intrathecal methotrexate and hydrocortisone, as well as by central nervous system radiation. Isolated neurotoxicity has been reported. Blindness occurred in two patients in remission whose treatment had consisted of combination systemic chemotherapy, prophylactic central nervous system radiation and intrathecal cytarabine injection.

  When cytarabine injection is administered both intrathecally and intravenously within a few days, there is an increased risk of spinal cord toxicity, however, in serious life-threatening disease, concurrent use of intravenous and intrathecal Cytarabine Injection is left to the discretion of the treating physician.

  Focal leukemic involvement of the central nervous system may not respond to intrathecal cytarabine injection and may better be treated with radiotherapy.

  Chemical Stability of Infusion Solutions

  Chemical stability studies were performed by ultraviolet assay on Cytarabine Injection in infusion solutions. These studies showed that when Cytarabine Injection was added to Water for Injection, 5% Dextrose in Water or Sodium Chloride Injection, 94 to 96 percent of the cytarabine was present after 192 hours storage at room temperature.

  Parenteral drugs should be inspected visually for particulate matter and discoloration, prior to administration, whenever solution and container permit. If a precipitate has formed as a result of exposure to low temperatures, redissolve by warming up to 55°C for no longer than 30 minutes and shake until the precipitate has dissolved. Allow to cool prior to use.

  HANDLING AND DISPOSAL

  Procedures for proper handling and disposal of anti-cancer drugs should be considered. Several guidelines on this subject have been published.1-7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

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• Carboplatin
  

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  Carboplatin

  

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  NOTE: Aluminum reacts with carboplatin causing precipitate formation and loss of potency, therefore, needles or intravenous sets containing aluminum parts that may come in contact with the drug must not be used for the preparation or administration of Carboplatin Injection.

  Single Agent Therapy: Carboplatin Injection, as a single agent, has been shown to be effective in patients with recurrent ovarian carcinoma at a dosage of 360 mg/m2 IV on day 1 every 4 weeks (alternatively see Formula Dosing). In general, however, single intermittent courses of Carboplatin Injection should not be repeated until the neutrophil count is at least 2000 and the platelet count is at least 100,000.

  Combination Therapy with Cyclophosphamide: In the chemotherapy of advanced ovarian cancer, an effective combination for previously untreated patients consists of:

  Carboplatin Injection - 300 mg/m2 IV on day 1 every four weeks for six cycles (alternatively see Formula Dosing).

  Cyclophosphamide - 600 mg/m2 IV on day 1 every four weeks for six cycles. For directions regarding the use and administration of cyclophosphamide please refer to its package insert. (See CLINICAL STUDIES.)

  Intermittent courses of Carboplatin Injection in combination with cyclophosphamide should not be repeated until the neutrophil count is at least 2000 and the platelet count is at least 100,000.

  Dose Adjustment Recommendations: Pretreatment platelet count and performance status are important prognostic factors for severity of myelosuppression in previously treated patients.

  The suggested dose adjustments for single agent or combination therapy shown in the table below are modified from controlled trials in previously treated and untreated patients with ovarian carcinoma. Blood counts were done weekly, and the recommendations are based on the lowest post-treatment platelet or neutrophil value.

  * Percentages apply to Carboplatin Injection as a single agent or to both Carboplatin Injection and cyclophosphamide in combination. In the controlled studies, dosages were also adjusted at a lower level (50% to 60%) for severe myelosuppression. Escalations above 125% were not recommended for these studies.

  Platelets

  Neutrophils

  Adjusted Dose* (From Prior Course)

  >100,000

  >2000

  125%

  50-100,000

  500-2000

  No Adjustment

  <50,000

  <500

  75%

  Carboplatin Injection is usually administered by an infusion lasting 15 minutes or longer. No pre- or post-treatment hydration or forced diuresis is required.

  Patients with Impaired Kidney Function: Patients with creatinine clearance values below 60 mL/min are at increased risk of severe bone marrow suppression. In renally-impaired patients who received single-agent Carboplatin Injection therapy, the incidence of severe leukopenia, neutropenia, or thrombocytopenia has been about 25% when the dosage modifications in the table below have been used.

  Baseline Creatinine Clearance

  Recommended Dose on Day 1

  41 - 59 mL/min

  16 - 40 mL/min

  250 mg/m2

  250 mg/m2

  The data available for patients with severely impaired kidney function (creatinine clearance below 15 mL/min) are too limited to permit a recommendation for treatment.

  These dosing recommendations apply to the initial course of treatment. Subsequent dosages should be adjusted according to the patient’s tolerance based on the degree of bone marrow suppression.

  Formula Dosing: Another approach for determining the initial dose of Carboplatin Injection is the use of mathematical formulae, which are based on a patient’s preexisting renal function or renal function and desired platelet nadir. Renal excretion is the major route of elimination for carboplatin. (See CLINICAL PHARMACOLOGY.) The use of dosing formulae, as compared to empirical dose calculation based on body surface area, allows compensation for patient variations in pretreatment renal function that might otherwise result in either underdosing (in patients with above average renal function) or overdosing (in patients with impaired renal function).

  A simple formula for calculating dosage, based upon a patient’s glomerular filtration rate (GFR in mL/min) and Carboplatin Injection target area under the concentration versus time curve (AUC in mg/mL•min), has been proposed by Calvert. In these studies, GFR was measured by 51Cr-EDTA clearance.

  CALVERT FORMULA FOR CARBOPLATIN DOSING

  Total Dose (mg) = (target AUC) x (GFR + 25)

  Note: With the Calvert formula, the total dose of Carboplatin Injection is calculated in mg, not mg/m2.

  The target AUC of 4-6 mg/mL•min using single agent Carboplatin Injection appears to provide the most appropriate dose range in previously treated patients. This study also showed a trend between the AUC of single agent Carboplatin Injection administered to previously treated patients and the likelihood of developing toxicity.

  % Actual Toxicity in PreviouslyTreated Patients

  Gr 3 or Gr 4

  Gr 3 or Gr 4

  AUC (mg/mL•min)

  Thrombocytopenia

  Leukopenia

  4 to 5

  16%

  13%

  6 to 7

  33%

  34%

  Geriatric Dosing: Because renal function is often decreased in elderly patients, formula dosing of Carboplatin Injection based on estimates of GFR should be used in elderly patients to provide predictable plasma Carboplatin Injection AUCs and thereby minimize the risk of toxicity.

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• Methotrexate
  

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  Methotrexate

  

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  Neoplastic Diseases

  Oral administration in tablet form is often preferred when low doses are being administered since absorption is rapid and effective serum levels are obtained. Methotrexate injection may be given by the intramuscular, intravenous or intra-arterial route. The preserved formulation contains Benzyl Alcohol and must not be used for intrathecal or high dose therapy. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  Choriocarcinoma and similar trophoblastic diseases: Methotrexate is administered orally or intramuscularly in doses of 15 to 30 mg daily for a five-day course. Such courses are usually repeated for 3 to 5 times as required, with rest periods of one or more weeks interposed between courses, until any manifesting toxic symptoms subside. The effectiveness of therapy is ordinarily evaluated by 24 hour quantitative analysis of urinary chorionic gonadotropin (hCG), which should return to normal or less than 50 IU/24 hr usually after the third or fourth course and usually be followed by a complete resolution of measurable lesions in 4 to 6 weeks. One to two courses of methotrexate after normalization of hCG is usually recommended. Before each course of the drug careful clinical assessment is essential. Cyclic combination therapy of methotrexate with other antitumor drugs has been reported as being useful.

  Since hydatidiform mole may precede choriocarcinoma, prophylactic chemotherapy with methotrexate has been recommended.

  Chorioadenoma destruens is considered to be an invasive form of hydatidiform mole. Methotrexate is administered in these disease states in doses similar to those recommended for choriocarcinoma.

  Leukemia: Acute lymphoblastic leukemia in pediatric patients and young adolescents is the most responsive to present day chemotherapy. In young adults and older patients, clinical remission is more difficult to obtain and early relapse is more common.

  Methotrexate alone or in combination with steroids was used initially for induction of remission in acute lymphoblastic leukemias. More recently corticosteroid therapy, in combination with other antileukemic drugs or in cyclic combinations with methotrexate included, has appeared to produce rapid and effective remissions. When used for induction, methotrexate in doses of 3.3 mg/m2 in combination with 60 mg/m2 of prednisone, given daily, produced remissions in 50% of patients treated, usually within a period of 4 to 6 weeks. Methotrexate in combination with other agents appears to be the drug of choice for securing maintenance of drug-induced remissions. When remission is achieved and supportive care has produced general clinical improvement, maintenance therapy is initiated, as follows: Methotrexate is administered 2 times weekly either by mouth or intramuscularly in total weekly doses of 30 mg/m2. It has also been given in doses of 2.5 mg/kg intravenously every 14 days. If and when relapse does occur, reinduction of remission can again usually be obtained by repeating the initial induction regimen.

  A variety of combination chemotherapy regimens have been used for both induction and maintenance therapy in acute lymphoblastic leukemia. The physician should be familiar with the new advances in antileukemic therapy.

  Meningeal Leukemia: In the treatment of prophylaxis of meningeal leukemia, methotrexate must be administered intrathecally. Preservative free methotrexate is diluted to a concentration of 1 mg/mL in an appropriate sterile, preservative free medium such as 0.9% Sodium Chloride Injection, USP.

  The cerebrospinal fluid volume is dependent on age and not on body surface area. The CSF is at 40% of the adult volume at birth and reaches the adult volume in several years.

  Intrathecal methotrexate administration at a dose of 12 mg/m2 (maximum 15 mg) has been reported to result in low CSF methotrexate concentrations and reduced efficacy in pediatric patients and high concentrations and neurotoxicity in adults. The following dosage regimen is based on age instead of body surface area:

  AGE (years)

  DOSE (mg)

  <1

  6

  1

  8

  2

  10

  3 or older

  12

  In one study in patients under the age of 40, this dosage regimen appeared to result in more consistent CSF methotrexate concentrations and less neurotoxicity. Another study in pediatric patients with acute lymphocytic leukemia compared this regimen to a dose of 12 mg/m2 (maximum 15 mg), a significant reduction in the rate of CNS relapse was observed in the group whose dose was based on age.

  Because the CSF volume and turnover may decrease with age, a dose reduction may be indicated in elderly patients.

  For treatment of meningeal leukemia, intrathecal methotrexate may be given at intervals of 2 to 5 days. However, administration at intervals of less than 1 week may result in increased subacute toxicity. Methotrexate is administered until the cell count of the cerebrospinal fluid returns to normal. At this point one additional dose is advisable. For prophylaxis against meningeal leukemia, the dosage is the same as for treatment except for the intervals of administration. On this subject, it is advisable for the physician to consult the medical literature.

  Untoward side effects may occur with any given intrathecal injection and are commonly neurological in character. Large doses may cause convulsions. Methotrexate given by the intrathecal route appears significantly in the systemic circulation and may cause systemic methotrexate toxicity. Therefore, systemic antileukemic therapy with the drug should be appropriately adjusted, reduced or discontinued. Focal leukemic involvement of the central nervous system may not respond to intrathecal chemotherapy and is best treated with radiotherapy.

  Lymphomas: In Burkitt’s tumor, Stages I-II, methotrexate has produced prolonged remissions in some cases. Recommended dosage is 10 to 25 mg/day orally for 4 to 8 days. In Stage III, methotrexate is commonly given concomitantly with other antitumor agents. Treatment in all stages usually consists of several courses of the drug interposed with 7 to 10 day rest periods. Lymphosarcomas in Stage III may respond to combined drug therapy with methotrexate given in doses of 0.625 to 2.5 mg/kg daily.

  Mycosis fungoides (cutaneous T cell lymphoma): Therapy with methotrexate as a single agent appears to produce clinical responses in up to 50% of patients treated. Dosage in early stages is usually 5 to 50 mg once weekly. Dose reduction or cessation is guided by patient response and hematologic monitoring. Methotrexate has also been administered twice weekly in doses ranging from 15 to 37.5 mg in patients who have responded poorly to weekly therapy. Combination chemotherapy regimens that include intravenous methotrexate administered at higher doses with leucovorin rescue have been utilized in advanced stages of the disease.

  Osteosarcoma: An effective adjuvant chemotherapy regimen requires the administration of several cytotoxic chemotherapeutic agents. In addition to high-dose methotrexate with leucovorin rescue, these agents may include doxorubicin, cisplatin, and the combination of bleomycin, cyclophosphamide and dactinomycin (BCD) in the doses and schedule shown in the table below. The starting dose for high-dose methotrexate treatment is 12 grams/m2. If this dose is not sufficient to produce a peak serum methotrexate concentration of 1,000 micromolar (10-3 mol/L) at the end of the methotrexate infusion, the dose may be escalated to 15 grams/m2 in subsequent treatments. If the patient is vomiting or is unable to tolerate oral medication, leucovorin is given IV or IM at the same dose and schedule.

  * Link MP, Goorin AM, Miser AW, et al: The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J of Med 1986; 314 (No.25): 1600-1606. † See each respective package insert for full prescribing information. Dosage modifications may be necessary because of drug-induced toxicity.

  Drug*

  Dose*

  Treatment Week After Surgery

  Methotrexate

  12 g/m2 IV as 4 hour infusion (starting dose)

  4,5,6,7,11,12,15,16,29,30,44,45

  Leucovorin

  15 mg orally every six hours for 10 doses starting at 24 hours after start of methotrexate infusion

  - - -

  Doxorubicin† as a single drug

  30 mg/m2 day IV x 3 days    

  8,17    

  Doxorubicin†

  Cisplatin†

  50 mg/m2 IV

  100 mg/m2 IV

  20,23,33,36

  20,23,33,36

  Bleomycin†

  Cyclophosphamide†

  Dactinomycin†

  15 units/m2 IV x 2 days

  600 mg/m2 IV x 2 days

  0.6 mg/m2 IV x 2 days

  2,13,26,39,42

  2,13,26,39,42

  2,13,26,39,42

  When these higher doses of methotrexate are to be administered, the following safety guidelines should be closely observed.

  GUIDELINES FOR METHOTREXATE THERAPY WITH LEUCOVORIN RESCUE

  1. Administration of methotrexate should be delayed until recovery if: • the WBC count is less than 1500/microliter • the neutrophil count is less than 200/microliter • the platelet count is less than 75,000/microliter • the serum bilirubin level is greater than 1.2 mg/dL • the SGPT level is greater than 450 U • mucositis is present, until there is evidence of healing • persistent pleural effusion is present; this should be drained dry prior to infusion. 2. Adequate renal function must be documented. a. Serum creatinine must be normal, and creatinine clearance must be greater than 60 mL/min, before initiation of therapy. b. Serum creatinine must be measured prior to each subsequent course of therapy. If serum creatinine has increased by 50% or more compared to a prior value, the creatinine clearance must be measured and documented to be greater than 60 mL/min (even if the serum creatinine is still within the normal range). 3. Patients must be well hydrated, and must be treated with sodium bicarbonate for urinary alkalinization. a. Administer 1,000 mL/m 2 of intravenous fluid over 6 hours prior to initiation of the methotrexate infusion. Continue hydration at 125 mL/m 2/hr (3 liters/m 2/day) during the methotrexate infusion, and for 2 days after the infusion has been completed. b. Alkalinize urine to maintain pH above 7.0 during methotrexate infusion and leucovorin calcium therapy. This can be accomplished by the administration of sodium bicarbonate orally or by incorporation into a separate intravenous solution. 4. Repeat serum creatinine and serum methotrexate 24 hours after starting methotrexate and at least once daily until the methotrexate level is below 5 x 10 -8 mol/L (0.05 micromolar). 5. The table below provides guidelines for leucovorin calcium dosage based upon serum methotrexate levels. (See table below. ‡)

  Patients who experience delayed early methotrexate elimination are likely to develop nonreversible oliguric renal failure. In addition to appropriate leucovorin therapy, these patients require continuing hydration and urinary alkalinization, and close monitoring of fluid and electrolyte status, until the serum methotrexate level has fallen to below 0.05 micromolar and the renal failure has resolved. If necessary, acute, intermittent hemodialysis with a high-flux dialyzer may also be beneficial in these patients.

  6. Some patients will have abnormalities in methotrexate elimination, or abnormalities in renal function following methotrexate administration, which are significant but less severe than the abnormalities described in the table below. These abnormalities may or may not be associated with significant clinical toxicity. If significant toxicity is observed, leucovorin rescue should be extended for an additional 24 hours (total 14 doses over 84 hours) in subsequent courses of therapy. The possibility that the patient is taking other medications which interact with methotrexate (e.g., medications which may interfere with methotrexate binding to serum albumin, or elimination) should always be reconsidered when laboratory abnormalities or clinical toxicities are observed.

  CAUTION: DO NOT ADMINISTER LEUCOVORIN INTRATHECALLY.

  Psoriasis, Rheumatoid Arthritis, and Juvenile Rheumatoid Arthritis

  Adult Rheumatoid Arthritis: Recommended Starting Dosage Schedules

  1. Single oral doses of 7.5 mg once weekly. † 2. Divided oral dosages of 2.5 mg at 12 hour intervals for 3 doses given as a course once weekly. †

              † Methotrexate Sodium Tablets for oral administration are available.

  Polyarticular-Course Juvenile Rheumatoid Arthritis: The recommended starting dose is 10 mg/m2 given once weekly.

  For either adult RA or polyarticular-course JRA, dosages may be adjusted gradually to achieve an optimal response. Limited experience shows a significant increase in the incidence and severity of serious toxic reactions, especially bone marrow suppression, at doses greater than 20 mg/wk in adults. Although there is experience with doses up to 30 mg/m2/wk in children, there are too few published data to assess how doses over 20 mg/m2/wk might affect the risk of serious toxicity in children. Experience does suggest, however, that children receiving 20 to 30 mg/m2/wk (0.65 to 1.0 mg/kg/wk) may have better absorption and fewer gastrointestinal side effects if methotrexate is administered either intramuscularly or subcutaneously.

  Therapeutic response usually begins within 3 to 6 weeks and the patient may continue to improve for another 12 weeks or more.

  The optimal duration of therapy is unknown. Limited data available from long-term studies in adults indicate that the initial clinical improvement is maintained for at least two years with continued therapy. When methotrexate is discontinued, the arthritis usually worsens within 3 to 6 weeks.

  The patient should be fully informed of the risks involved and should be under constant supervision of the physician. (See Information for Patients under PRECAUTIONS.)

  Assessment of hematologic, hepatic, renal, and pulmonary function should be made by history, physical examination, and laboratory tests before beginning, periodically during, and before reinstituting methotrexate therapy. (See PRECAUTIONS.) Appropriate steps should be taken to avoid conception during methotrexate therapy. (See PRECAUTIONS and CONTRAINDICATIONS.)

  All schedules should be continually tailored to the individual patient. An initial test dose may be given prior to the regular dosing schedule to detect any extreme sensitivity to adverse effects (See ADVERSE REACTIONS.) Maximal myelosuppression usually occurs in seven to ten days.

  Psoriasis: Recommended Starting Dose Schedule:

  1. Weekly single oral, IM or IV dosage schedule: 10 to 25 mg per week until adequate response is achieved. † 2. Divided oral dose schedule 2.5 mg at 12 hour intervals for three doses. †

              †Methotrexate Sodium Tablets for oral administration are available.

  Dosages in each schedule may be gradually adjusted to achieve optimal clinical response; 30 mg/week should not ordinarily be exceeded.

  Once optimal clinical response has been achieved, each dosage schedule should be reduced to the lowest possible amount of drug and to the longest possible rest period. The use of methotrexate may permit the return to conventional topical therapy, which should be encouraged.

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• Mupirocin Ointment
  

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  Mupirocin Ointment

  

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  Oxaliplatin should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of therapy and complications is possible only when adequate diagnostic and treatment facilities are readily available.

  2.1 Dosage

  Administer Oxaliplatin in combination with 5-fluorouracil/leucovorin every 2 weeks. For advanced disease, treatment is recommended until disease progression or unacceptable toxicity. For adjuvant use, treatment is recommended for a total of 6 months (12 cycles):

  Day 1: Oxaliplatin 85 mg/m2 intravenous infusion in 250-500 mL 5% Dextrose injection, USP and leucovorin 200 mg/m2 intravenous infusion in 5% Dextrose Injection, USP both given over 120 minutes at the same time in separate bags using a Y-line, followed by 5-fluorouracil 400 mg/m2 intravenous bolus given over 2 to 4 minutes, followed by 5-fluorouracil 600 mg/m2 intravenous infusion in 500 mL 5% Dextrose Injection, USP (recommended) as a 22-hour continuous infusion.

  Day 2: Leucovorin 200 mg/m2 intravenous infusion over 120 minutes, followed by 5-fluorouracil 400 mg/m2 intravenous bolus given over 2 to 4 minutes, followed by 5-fluorouracil 600 mg/m2 intravenous infusion in 500 mL 5% Dextrose Injection, USP (recommended) as a 22-hour continuous infusion.

  The administration of Oxaliplatin does not require prehydration. Premedication with antiemetics, including 5-HT3 blockers with or without dexamethasone, is recommended.

  For information on 5-fluorouracil and leucovorin, see the respective package inserts.

  2.2 Dose Modification Recommendations

  Prior to subsequent therapy cycles, patients should be evaluated for clinical toxicities and recommended laboratory tests [see Warnings and Precautions (5.6)]. Prolongation of infusion time for Oxaliplatin from 2 hours to 6 hours may mitigate acute toxicities. The infusion times for 5-fluorouracil and leucovorin do not need to be changed.

  Adjuvant Therapy in Patients with Stage III Colon Cancer

  Neuropathy and other toxicities were graded using the NCI CTC scale version 1 [see Warnings and Precautions (5.2)].

  For patients who experience persistent Grade 2 neurosensory events that do not resolve, a dose reduction of Oxaliplatin to 75 mg/m2 should be considered. For patients with persistent Grade 3 neurosensory events, discontinuing therapy should be considered. The infusional 5-fluorouracil/leucovorin regimen need not be altered.

  A dose reduction of Oxaliplatin to 75 mg/m2 and infusional 5-fluorouracil to 300 mg/m2 bolus and 500 mg/m2 22 hour infusion is recommended for patients after recovery from grade 3/4 gastrointestinal (despite prophylactic treatment) or grade 4 neutropenia or grade 3/4 thrombocytopenia. The next dose should be delayed until: neutrophils ≥1.5 x 109/L and platelets ≥75 x 109/L.

  Dose Modifications in Therapy in Previously Untreated and Previously Treated Patients with Advanced Colorectal Cancer

  Neuropathy was graded using a study-specific neurotoxicity scale [see Warnings and Precautions (5.2)]. Other toxicities were graded by the NCI CTC, Version 2.0.

  For patients who experience persistent Grade 2 neurosensory events that do not resolve, a dose reduction of Oxaliplatin to 65 mg/m2 should be considered. For patients with persistent Grade 3 neurosensory events, discontinuing therapy should be considered. The 5-fluorouracil/leucovorin regimen need not be altered.

  A dose reduction of Oxaliplatin to 65 mg/m2 and 5-fluorouracil by 20% (300 mg/m2 bolus and 500 mg/m2 22-hour infusion) is recommended for patients after recovery from grade 3/4 gastrointestinal (despite prophylactic treatment) or grade 4 neutropenia or grade 3/4 thrombocytopenia. The next dose should be delayed until: neutrophils ≥1.5 x 109/L and platelets ≥75 x 109/L.

  Dose Modifications in Therapy for Patients with Renal Impairment

  In patients with normal renal function or mild to moderate renal impairment, the recommended dose of Oxaliplatin is 85 mg/m2. In patients with severe renal impairment, the initial recommended Oxaliplatin dose should be reduced to 65 mg/m2 [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

  2.3 Preparation of Infusion Solution

  Do not freeze the concentrated solution. Protect from light (keep in outer carton until use).

  A final dilution must never be performed with a sodium chloride solution or other chloride-containing solutions.

  The solution must be further diluted in an infusion solution of 250-500 mL of 5% Dextrose Injection, USP.

  After dilution with 250-500 mL of 5% Dextrose Injection, USP, the shelf life is 6 hours at room temperature [20-25°C (68-77°F)] or up to 24 hours under refrigeration [2-8°C (36-46°F)]. After final dilution, protection from light is not required.

  Oxaliplatin Injection, USP is incompatible in solution with alkaline medications or media (such as basic solutions of 5-fluorouracil) and must not be mixed with these or administered simultaneously through the same infusion line. The infusion line should be flushed with 5% Dextrose Injection, USP prior to administration of any concomitant medication.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration and discarded if present.

  Needles or intravenous administration sets containing aluminum parts that may come in contact with Oxaliplatin Injection, USP should not be used for the preparation or mixing of the drug. Aluminum has been reported to cause degradation of platinum compounds.

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• Dacarbazine
  

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  Dacarbazine

  

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  Malignant Melanoma: The recommended dosage is 2 to 4.5 mg/kg/day for 10 days. Treatment may be repeated at 4 week intervals.

  An alternate recommended dosage is 250 mg/square meter body surface/day IV for 5 days. Treatment may be repeated every 3 weeks.

  Hodgkin’s Disease: The recommended dosage of Dacarbazine for Injection in the treatment of Hodgkin’s disease is 150 mg/square meter body surface/day for 5 days, in combination with other effective drugs. Treatment may be repeated every 4 weeks. An alternative recommended dosage is 375 mg/square meter body surface on day 1, in combination with other effective drugs, to be repeated every 15 days.

  Dacarbazine for Injection 200 mg/vial is reconstituted with 19.7 mL of Sterile Water for Injection, USP. The resulting solution contains 10 mg/mL of dacarbazine having a pH of 3.0 to 4.0. The calculated dose of the resulting solution is drawn into a syringe and administered only intravenously.

  The reconstituted solution may be further diluted with 5% dextrose injection, USP or sodium chloride injection, USP and administered as an intravenous infusion.

  After reconstitution and prior to use, the solution in the vial may be stored at 4°C for up to 72 hours or at normal room conditions (temperature and light) for up to 8 hours. If the reconstituted solution is further diluted in 5% dextrose injection, USP or sodium chloride injection, USP, the resulting solution may be stored at 4°C for up to 24 hours or at normal room conditions for up to 8 hours.

  Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published1-7. There is no general agreement that all the procedures recommended in the guidelines are necessary or appropriate.

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• Oxaliplatin
  

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  Oxaliplatin

  

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  Oxaliplatin should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of therapy and complications is possible only when adequate diagnostic and treatment facilities are readily available.

  2.1 Dosage

  Administer Oxaliplatin in combination with 5-fluorouracil/leucovorin every 2 weeks. For advanced disease, treatment is recommended until disease progression or unacceptable toxicity. For adjuvant use, treatment is recommended for a total of 6 months (12 cycles):

  Day 1: Oxaliplatin 85 mg/m2 intravenous infusion in 250-500 mL 5% Dextrose injection, USP  and leucovorin 200 mg/m2 intravenous infusion in 5% Dextrose Injection, USP both given over 120 minutes at the same time in separate bags using a Y-line, followed by 5-fluorouracil 400 mg/m2 intravenous bolus given over 2 to 4 minutes, followed by 5-fluorouracil 600 mg/m2 intravenous infusion in 500 mL 5% Dextrose Injection, USP (recommended) as a 22-hour continuous infusion.

  Day 2: Leucovorin 200 mg/m2 intravenous infusion over 120 minutes, followed by 5-fluorouracil 400 mg/m2 intravenous bolus given over 2 to 4 minutes, followed by 5-fluorouracil 600 mg/m2 intravenous infusion in 500 mL 5% Dextrose Injection, USP (recommended) as a 22-hour continuous infusion.

  Figure 1

  The administration of Oxaliplatin does not require prehydration. Premedication with antiemetics, including 5-HT3 blockers with or without dexamethasone, is recommended.

  For information on 5-fluorouracil and leucovorin, see the respective package inserts.

  2.2 Dose Modification Recommendations

  Prior to subsequent therapy cycles, patients should be evaluated for clinical toxicities and recommended laboratory tests [see Warnings and Precautions (5.6)]. Prolongation of infusion time for Oxaliplatin from 2 hours to 6 hours may mitigate acute toxicities. The infusion times for 5-fluorouracil and leucovorin do not need to be changed.

  Adjuvant Therapy in Patients with Stage III Colon Cancer

  Neuropathy and other toxicities were graded using the NCI CTC scale version 1 [see Warnings and Precautions (5.2)].

  For patients who experience persistent Grade 2 neurosensory events that do not resolve, a dose reduction of Oxaliplatin to 75 mg/m2 should be considered. For patients with persistent Grade 3 neurosensory events, discontinuing therapy should be considered. The infusional 5-fluorouracil/leucovorin regimen need not be altered.

  A dose reduction of Oxaliplatin to 75 mg/m2 and infusional 5-fluorouracil to 300 mg/m2 bolus and 500 mg/m2 22 hour infusion is recommended for patients after recovery from grade 3/4 gastrointestinal (despite prophylactic treatment) or grade 4 neutropenia or grade 3/4 thrombocytopenia. The next dose should be delayed until: neutrophils ≥ 1.5 x 109/L and platelets ≥ 75 x 109/L.

  Dose Modifications in Therapy in Previously Untreated and Previously Treated Patients with Advanced Colorectal Cancer

  Neuropathy was graded using a study-specific neurotoxicity scale [see Warnings and Precautions (5.2)]. Other toxicities were graded by the NCI CTC, Version 2.0.

  For patients who experience persistent Grade 2 neurosensory events that do not resolve, a dose reduction of Oxaliplatin to 65 mg/m2 should be considered. For patients with persistent Grade 3 neurosensory events, discontinuing therapy should be considered. The 5-flourouracil/leucovorin regimen need not be altered.

  A dose reduction of Oxaliplatin to 65 mg/m2 and 5-FU by 20% (300 mg/m2 bolus and 500 mg/m2 22-hour infusion) is recommended for patients after recovery from grade 3/4 gastrointestinal (despite prophylactic treatment) or grade 4 neutropenia or grade 3/4 thrombocytopenia. The next dose should be delayed until: neutrophils ≥ 1.5 x 109/L and platelets ≥ 75 x 109/L.

  2.3 Preparation of Infusion Solution

  Powder for solution for infusion

  Reconstitution or final dilution must never be performed with a sodium chloride solution or other chloride containing solutions.

  The lyophilized powder is reconstituted by adding 10 mL (for the 50 mg vial) or 20 mL (for the 100 mg vial) of Water for Injection, USP or 5% Dextrose Injection, USP. Do not administer the reconstituted solution without further dilution. The reconstituted solution must be further diluted in an infusion solution of 250-500 mL of 5% Dextrose Injection, USP.

  After reconstitution in the original vial, the solution may be stored up to 24 hours under refrigeration [2-8°C (36-46°F)]. After final dilution with 250-500 mL of 5% Dextrose Injection, USP, the shelf life is 6 hours at room temperature [20-25°C (68-77°F)] or up to 24 hours under refrigeration [2-8°C (36-46°F)].

  Oxaliplatin for Injection is not light sensitive.

  Concentrate for solution for infusion

  Do not freeze the concentrated solution.A final dilution must never be performed with a sodium chloride solution or other chloride-containing solutions.

  The solution must be further diluted in an infusion solution of 250-500 mL of 5% Dextrose Injection, USP.

  After dilution with 250-500 mL of 5% Dextrose Injection, USP, the shelf life is 6 hours at room temperature [20-25°C (68-77°F)] or up to 24 hours under refrigeration [2-8°C (36-46°F)]. After final dilution, protection from light is not required.

  Oxaliplatin Injection is incompatible in solution with alkaline medications or media (such as basic solutions of 5-fluorouracil) and must not be mixed with these or administered simultaneously through the same infusion line. The infusion line should be flushed with 5% Dextrose Injection, USP prior to administration of any concomitant medication.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration and discarded if present.

  Needles or intravenous administration sets containing aluminum parts that may come in contact with Oxaliplatin Injection should not be used for the preparation or mixing of the drug. Aluminum has been reported to cause degradation of platinum compounds.

  2.1 Dosage

  Administer Oxaliplatin in combination with 5-fluorouracil/leucovorin every 2 weeks. For advanced disease, treatment is recommended until disease progression or unacceptable toxicity. For adjuvant use, treatment is recommended for a total of 6 months (12 cycles):

  Day 1: Oxaliplatin 85 mg/m2 intravenous infusion in 250-500 mL 5% Dextrose injection, USP  and leucovorin 200 mg/m2 intravenous infusion in 5% Dextrose Injection, USP both given over 120 minutes at the same time in separate bags using a Y-line, followed by 5-fluorouracil 400 mg/m2 intravenous bolus given over 2 to 4 minutes, followed by 5-fluorouracil 600 mg/m2 intravenous infusion in 500 mL 5% Dextrose Injection, USP (recommended) as a 22-hour continuous infusion.

  Day 2: Leucovorin 200 mg/m2 intravenous infusion over 120 minutes, followed by 5-fluorouracil 400 mg/m2 intravenous bolus given over 2 to 4 minutes, followed by 5-fluorouracil 600 mg/m2 intravenous infusion in 500 mL 5% Dextrose Injection, USP (recommended) as a 22-hour continuous infusion.

  Figure 1

  The administration of Oxaliplatin does not require prehydration. Premedication with antiemetics, including 5-HT3 blockers with or without dexamethasone, is recommended.

  For information on 5-fluorouracil and leucovorin, see the respective package inserts.

  2.2 Dose Modification Recommendations

  Prior to subsequent therapy cycles, patients should be evaluated for clinical toxicities and recommended laboratory tests [see Warnings and Precautions (5.6)]. Prolongation of infusion time for Oxaliplatin from 2 hours to 6 hours may mitigate acute toxicities. The infusion times for 5-fluorouracil and leucovorin do not need to be changed.

  Adjuvant Therapy in Patients with Stage III Colon Cancer

  Neuropathy and other toxicities were graded using the NCI CTC scale version 1 [see Warnings and Precautions (5.2)].

  For patients who experience persistent Grade 2 neurosensory events that do not resolve, a dose reduction of Oxaliplatin to 75 mg/m2 should be considered. For patients with persistent Grade 3 neurosensory events, discontinuing therapy should be considered. The infusional 5-fluorouracil/leucovorin regimen need not be altered.

  A dose reduction of Oxaliplatin to 75 mg/m2 and infusional 5-fluorouracil to 300 mg/m2 bolus and 500 mg/m2 22 hour infusion is recommended for patients after recovery from grade 3/4 gastrointestinal (despite prophylactic treatment) or grade 4 neutropenia or grade 3/4 thrombocytopenia. The next dose should be delayed until: neutrophils ≥ 1.5 x 109/L and platelets ≥ 75 x 109/L.

  Dose Modifications in Therapy in Previously Untreated and Previously Treated Patients with Advanced Colorectal Cancer

  Neuropathy was graded using a study-specific neurotoxicity scale [see Warnings and Precautions (5.2)]. Other toxicities were graded by the NCI CTC, Version 2.0.

  For patients who experience persistent Grade 2 neurosensory events that do not resolve, a dose reduction of Oxaliplatin to 65 mg/m2 should be considered. For patients with persistent Grade 3 neurosensory events, discontinuing therapy should be considered. The 5-flourouracil/leucovorin regimen need not be altered.

  A dose reduction of Oxaliplatin to 65 mg/m2 and 5-FU by 20% (300 mg/m2 bolus and 500 mg/m2 22-hour infusion) is recommended for patients after recovery from grade 3/4 gastrointestinal (despite prophylactic treatment) or grade 4 neutropenia or grade 3/4 thrombocytopenia. The next dose should be delayed until: neutrophils ≥ 1.5 x 109/L and platelets ≥ 75 x 109/L.

  2.3 Preparation of Infusion Solution

  Powder for solution for infusion

  Reconstitution or final dilution must never be performed with a sodium chloride solution or other chloride containing solutions.

  The lyophilized powder is reconstituted by adding 10 mL (for the 50 mg vial) or 20 mL (for the 100 mg vial) of Water for Injection, USP or 5% Dextrose Injection, USP. Do not administer the reconstituted solution without further dilution. The reconstituted solution must be further diluted in an infusion solution of 250-500 mL of 5% Dextrose Injection, USP.

  After reconstitution in the original vial, the solution may be stored up to 24 hours under refrigeration [2-8°C (36-46°F)]. After final dilution with 250-500 mL of 5% Dextrose Injection, USP, the shelf life is 6 hours at room temperature [20-25°C (68-77°F)] or up to 24 hours under refrigeration [2-8°C (36-46°F)].

  Oxaliplatin for Injection is not light sensitive.

  Concentrate for solution for infusion

  Do not freeze the concentrated solution.A final dilution must never be performed with a sodium chloride solution or other chloride-containing solutions.

  The solution must be further diluted in an infusion solution of 250-500 mL of 5% Dextrose Injection, USP.

  After dilution with 250-500 mL of 5% Dextrose Injection, USP, the shelf life is 6 hours at room temperature [20-25°C (68-77°F)] or up to 24 hours under refrigeration [2-8°C (36-46°F)]. After final dilution, protection from light is not required.

  Oxaliplatin Injection is incompatible in solution with alkaline medications or media (such as basic solutions of 5-fluorouracil) and must not be mixed with these or administered simultaneously through the same infusion line. The infusion line should be flushed with 5% Dextrose Injection, USP prior to administration of any concomitant medication.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration and discarded if present.

  Needles or intravenous administration sets containing aluminum parts that may come in contact with Oxaliplatin Injection should not be used for the preparation or mixing of the drug. Aluminum has been reported to cause degradation of platinum compounds.

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• Multi Vitamin Infusion ...
  

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  Multi Vitamin Infusion Adult

  

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  2.1 Important Dosage and Administration Instructions

  M.V.I.-Adult™ is a combination product that contains the following vitamins: ascorbic acid, vitamin A, vitamin D, thiamine, riboflavin, pyridoxine, niacinamide, dexpanthenol, vitamin E, vitamin K, folic acid, biotin, and vitamin B12.

  M.V.I.-Adult is supplied as a single dose or as a pharmacy bulk package for intravenous use intended for administration by intravenous infusion after dilution:

  • M.V.I-Adult Single Dose consists of two vials which must be mixed prior to use. The mixed solution will provide a single 10 mL dose which must be diluted prior to intravenous administration [ see Dosage and Administration (2.3)]. • M.V.I-Adult Pharmacy Bulk Package consists of two pharmacy bulk vials which must be mixed prior to use. The mixed solution will provide ten 10 mL single doses which must be diluted prior to intravenous administration. Pharmacy bulk package of M.V.I-Adult is intended for dispensing of single doses to multiple patients in a pharmacy admixture program and is restricted to the preparation of admixtures for infusion [ see Dosage and Administration (2.3)].

  Do not administer M.V.I.-Adult™ as a direct, undiluted intravenous injection as it may cause dizziness, faintness, and tissue irritation.

  2.2 Dosage Information

  The recommended daily dosage volume is 10 mL. One daily dose (10 mL) is diluted by adding directly to a specified volume of an intravenous fluid [see Dosage and Administration (2.3)].

  Patients with multiple vitamin deficiencies or with increased vitamin requirements may need multiple daily dosages as indicated or additional doses of individual vitamins.

  2.3 Preparation and Administration Instructions

  M.V.I.-Adult supplied as a single dose:

  • M.V.I- Adult is to be used only in a suitable work area such as a laminar flow hood (or an equivalent clean air compounding area). • Transfer the contents of Vial 1 (5 mL of solution) into the contents of Vial 2 (5 mL of solution). The mixed solution (10 mL) will provide a single 10 mL dose. • Once the closure system has been penetrated, complete withdrawal of vial contents within 4 hours. Mixed solution may be stored for up to 4 hours refrigerated. • Visually inspect for particulate matter and discoloration prior to intravenous administration. • Utilizing a suitable sterile automated compounding device or dispensing pin for accuracy, aseptically transfer the 10 mL dose into a plastic or glass bottle containing at least 500 to 1000 mL intravenous parenteral nutrition solution containing dextrose or saline. • After M.V.I.-Adult™ is diluted in an intravenous infusion, refrigerate the resulting solution unless it is to be used immediately, and use the solution within 24 hours after dilution. • Minimize exposure to light because some of the vitamins in M.V.I.-Adult, particularly A, D and riboflavin, are light sensitive.

  M.V.I.-Adult supplied as a pharmacy bulk package:

  • M.V.I- Adult is to be used only in a suitable work area such as a laminar flow hood (or an equivalent clean air compounding area). • Transfer the contents of Vial 1 (50 mL) into Vial 2 (50 mL). The mixed solution (100 mL) will provide ten 10 mL single doses to patients in a pharmacy admixture program. • Each bulk vial closure shall be penetrated only one time with a suitable sterile transfer device or dispensing set that allows measured dispensing of the contents. • Once the closure system has been penetrated, complete dispensing from the pharmacy bulk vial within 4 hours. Mixed solution may be stored for up to 4 hours refrigerated. • Discard unused portion. • Visually inspect for particulate matter and discoloration prior to administration. • Utilizing a suitable sterile automated compounding device or dispensing pin for accuracy, aseptically transfer each 10 mL dose into a plastic or glass bottle containing at least 500 to 1000 mL intravenous parenteral nutrition solution containing dextrose or saline. • After M.V.I.-Adult™ is diluted in an intravenous infusion, refrigerate the resulting solution unless it is to be used immediately, and use the solution within 24 hours after dilution. • Minimize exposure to light because some of the vitamins in M.V.I.-Adult, particularly A, D and riboflavin, are light sensitive.

  2.4 Monitoring Vitamin Blood Levels

  Blood vitamin concentrations should be monitored to ensure maintenance of adequate levels, particularly in patients receiving parenteral multivitamins as the only source of vitamins for long periods of time.

  2.5 Drug Incompatibilities

  • M.V.I.-Adult™ is not physically compatible with moderately alkaline solutions such as a sodium bicarbonate solution and other alkaline drugs such as acetazolamide sodium, aminophylline, ampicillin sodium, and chlorothiazide sodium. • Folic acid is unstable in the presence of calcium salts such as calcium gluconate. • Vitamin A and thiamine in M.V.I.-Adult™ may react with bisulfite solutions such as sodium bisulfite or vitamin K bisulfite. Do not add M.V.I.-Adult™ directly to intravenous fat emulsions. • Consult appropriate references for listings of physical and chemical compatibility of solutions and drugs with the vitamin infusion. In such circumstances, admixture or Y-site administration with vitamin solutions should be avoided.

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• Multi Vitamin Infusion ...
  

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  Multi Vitamin Infusion Adult

  

  ---

  2.1 Important Dosage and Administration Instructions

  M.V.I.-Adult™ is a combination product that contains the following vitamins: ascorbic acid, vitamin A, vitamin D, thiamine, riboflavin, pyridoxine, niacinamide, dexpanthenol, vitamin E, vitamin K, folic acid, biotin, and vitamin B12.

  M.V.I.-Adult is supplied as a single dose or as a pharmacy bulk package for intravenous use intended for administration by intravenous infusion after dilution:

  • M.V.I-Adult Single Dose consists of two vials which must be mixed prior to use. The mixed solution will provide a single 10 mL dose which must be diluted prior to intravenous administration [ see Dosage and Administration (2.3)]. • M.V.I-Adult Pharmacy Bulk Package consists of two pharmacy bulk vials which must be mixed prior to use. The mixed solution will provide ten 10 mL single doses which must be diluted prior to intravenous administration. Pharmacy bulk package of M.V.I-Adult is intended for dispensing of single doses to multiple patients in a pharmacy admixture program and is restricted to the preparation of admixtures for infusion [ see Dosage and Administration (2.3)].

  Do not administer M.V.I.-Adult™ as a direct, undiluted intravenous injection as it may cause dizziness, faintness, and tissue irritation.

  2.2 Dosage Information

  The recommended daily dosage volume is 10 mL. One daily dose (10 mL) is diluted by adding directly to a specified volume of an intravenous fluid [see Dosage and Administration (2.3)].

  Patients with multiple vitamin deficiencies or with increased vitamin requirements may need multiple daily dosages as indicated or additional doses of individual vitamins.

  2.3 Preparation and Administration Instructions

  M.V.I.-Adult supplied as a single dose:

  • M.V.I- Adult is to be used only in a suitable work area such as a laminar flow hood (or an equivalent clean air compounding area). • Transfer the contents of Vial 1 (5 mL of solution) into the contents of Vial 2 (5 mL of solution). The mixed solution (10 mL) will provide a single 10 mL dose. • Once the closure system has been penetrated, complete withdrawal of vial contents within 4 hours. Mixed solution may be stored for up to 4 hours refrigerated. • Visually inspect for particulate matter and discoloration prior to intravenous administration. • Utilizing a suitable sterile automated compounding device or dispensing pin for accuracy, aseptically transfer the 10 mL dose into a plastic or glass bottle containing at least 500 to 1000 mL intravenous parenteral nutrition solution containing dextrose or saline. • After M.V.I.-Adult™ is diluted in an intravenous infusion, refrigerate the resulting solution unless it is to be used immediately, and use the solution within 24 hours after dilution. • Minimize exposure to light because some of the vitamins in M.V.I.-Adult, particularly A, D and riboflavin, are light sensitive.

  M.V.I.-Adult supplied as a pharmacy bulk package:

  • M.V.I- Adult is to be used only in a suitable work area such as a laminar flow hood (or an equivalent clean air compounding area). • Transfer the contents of Vial 1 (50 mL) into Vial 2 (50 mL). The mixed solution (100 mL) will provide ten 10 mL single doses to patients in a pharmacy admixture program. • Each bulk vial closure shall be penetrated only one time with a suitable sterile transfer device or dispensing set that allows measured dispensing of the contents. • Once the closure system has been penetrated, complete dispensing from the pharmacy bulk vial within 4 hours. Mixed solution may be stored for up to 4 hours refrigerated. • Discard unused portion. • Visually inspect for particulate matter and discoloration prior to administration. • Utilizing a suitable sterile automated compounding device or dispensing pin for accuracy, aseptically transfer each 10 mL dose into a plastic or glass bottle containing at least 500 to 1000 mL intravenous parenteral nutrition solution containing dextrose or saline. • After M.V.I.-Adult™ is diluted in an intravenous infusion, refrigerate the resulting solution unless it is to be used immediately, and use the solution within 24 hours after dilution. • Minimize exposure to light because some of the vitamins in M.V.I.-Adult, particularly A, D and riboflavin, are light sensitive.

  2.4 Monitoring Vitamin Blood Levels

  Blood vitamin concentrations should be monitored to ensure maintenance of adequate levels, particularly in patients receiving parenteral multivitamins as the only source of vitamins for long periods of time.

  2.5 Drug Incompatibilities

  • M.V.I.-Adult™ is not physically compatible with moderately alkaline solutions such as a sodium bicarbonate solution and other alkaline drugs such as acetazolamide sodium, aminophylline, ampicillin sodium, and chlorothiazide sodium. • Folic acid is unstable in the presence of calcium salts such as calcium gluconate. • Vitamin A and thiamine in M.V.I.-Adult™ may react with bisulfite solutions such as sodium bisulfite or vitamin K bisulfite. Do not add M.V.I.-Adult™ directly to intravenous fat emulsions. • Consult appropriate references for listings of physical and chemical compatibility of solutions and drugs with the vitamin infusion. In such circumstances, admixture or Y-site administration with vitamin solutions should be avoided.

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• Methotrexate
  

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  Methotrexate

  

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  Neoplastic Diseases

  Oral administration in tablet form is often preferred when low doses are being administered since absorption is rapid and effective serum levels are obtained. Methotrexate injection may be given by the intramuscular, intravenous or intra-arterial route. However, the preserved formulation contains Benzyl Alcohol and must not be used for intrathecal or high dose therapy. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  Choriocarcinoma and similar trophoblastic diseases: Methotrexate is administered orally or intramuscularly in doses of 15 to 30 mg daily for a five-day course. Such courses are usually repeated for 3 to 5 times as required, with rest periods of one or more weeks interposed between courses, until any manifesting toxic symptoms subside. The effectiveness of therapy is ordinarily evaluated by 24 hour quantitative analysis of urinary chorionic gonadotropin (hCG), which should return to normal or less than 50 IU/24 hr usually after the third or fourth course and usually be followed by a complete resolution of measurable lesions in 4 to 6 weeks. One to two courses of methotrexate after normalization of hCG is usually recommended. Before each course of the drug careful clinical assessment is essential. Cyclic combination therapy of methotrexate with other antitumor drugs has been reported as being useful.

  Since hydatidiform mole may precede choriocarcinoma, prophylactic chemotherapy with methotrexate has been recommended.

  Chorioadenoma destruens is considered to be an invasive form of hydatidiform mole.

  Methotrexate is administered in these disease states in doses similar to those recommended for choriocarcinoma.

  Leukemia: Acute lymphoblastic leukemia in pediatric patients and young adolescents is the most responsive to present day chemotherapy. In young adults and older patients, clinical remission is more difficult to obtain and early relapse is more common.

  Methotrexate alone or in combination with steroids was used initially for induction of remission in acute lymphoblastic leukemias. More recently corticosteroid therapy, in combination with other antileukemic drugs or in cyclic combinations with methotrexate included, has appeared to produce rapid and effective remissions. When used for induction, methotrexate in doses of 3.3 mg/m2 in combination with 60 mg/m2 of prednisone, given daily, produced remissions in 50% of patients treated, usually within a period of 4 to 6 weeks. Methotrexate in combination with other agents appears to be the drug of choice for securing maintenance of drug-induced remissions. When remission is achieved and supportive care has produced general clinical improvement, maintenance therapy is initiated, as follows: Methotrexate is administered 2 times weekly either by mouth or intramuscularly in total weekly doses of 30 mg/m2. It has also been given in doses of 2.5 mg/kg intravenously every 14 days. If and when relapse does occur, reinduction of remission can again usually be obtained by repeating the initial induction regimen.

  A variety of combination chemotherapy regimens have been used for both induction and maintenance therapy in acute lymphoblastic leukemia. The physician should be familiar with the new advances in antileukemic therapy.

  Meningeal Leukemia: In the treatment of prophylaxis of meningeal leukemia, methotrexate must be administered intrathecally. Preservative free methotrexate is diluted to a concentration of 1 mg/mL in an appropriate sterile, preservative free medium such as 0.9% Sodium Chloride Injection, USP.

  The cerebrospinal fluid volume is dependent on age and not on body surface area. The CSF is at 40% of the adult volume at birth and reaches the adult volume in several years.

  Intrathecal methotrexate administration at a dose of 12 mg/m2 (maximum 15 mg) has been reported to result in low CSF methotrexate concentrations and reduced efficacy in pediatric patients and high concentrations and neurotoxicity in adults. The following dosage regimen is based on age instead of body surface area:

  AGE (years)

  DOSE (mg)

  <1

  6

  1

  8

  2

  10

  3 or older

  12

  In one study in patients under the age of 40, this dosage regimen appeared to result in more consistent CSF methotrexate concentrations and less neurotoxicity. Another study in pediatric patients with acute lymphocytic leukemia compared this regimen to a dose of 12 mg/m2 (maximum 15 mg), a significant reduction in the rate of CNS relapse was observed in the group whose dose was based on age.

  Because the CSF volume and turnover may decrease with age, a dose reduction may be indicated in elderly patients.

  For treatment of meningeal leukemia, intrathecal methotrexate may be given at intervals of 2 to 5 days. However, administration at intervals of less than 1 week may result in increased subacute toxicity. Methotrexate is administered until the cell count of the cerebrospinal fluid returns to normal. At this point one additional dose is advisable. For prophylaxis against meningeal leukemia, the dosage is the same as for treatment except for the intervals of administration. On this subject, it is advisable for the physician to consult the medical literature.

  Untoward side effects may occur with any given intrathecal injection and are commonly neurological in character. Large doses may cause convulsions. Methotrexate given by the intrathecal route appears significantly in the systemic circulation and may cause systemic methotrexate toxicity. Therefore, systemic antileukemic therapy with the drug should be appropriately adjusted, reduced or discontinued. Focal leukemic involvement of the central nervous system may not respond to intrathecal chemotherapy and is best treated with radiotherapy.

  Lymphomas: In Burkitt’s tumor, Stages I-II, methotrexate has produced prolonged remissions in some cases. Recommended dosage is 10 to 25 mg/day orally for 4 to 8 days. In Stage III, methotrexate is commonly given concomitantly with other antitumor agents. Treatment in all stages usually consists of several courses of the drug interposed with 7 to 10 day rest periods. Lymphosarcomas in Stage III may respond to combined drug therapy with methotrexate given in doses of 0.625 to 2.5 mg/kg daily.

  Mycosis fungoides (cutaneous T cell lymphoma): Therapy with methotrexate as a single agent appears to produce clinical responses in up to 50% of patients treated. Dosage in early stages is usually 5 to 50 mg once weekly. Dose reduction or cessation is guided by patient response and hematologic monitoring. Methotrexate has also been administered twice weekly in doses ranging from 15 to 37.5 mg in patients who have responded poorly to weekly therapy. Combination chemotherapy regimens that include intravenous methotrexate administered at higher doses with leucovorin rescue have been utilized in advanced stages of the disease.

  Osteosarcoma: An effective adjuvant chemotherapy regimen requires the administration of several cytotoxic chemotherapeutic agents. In addition to high-dose methotrexate with leucovorin rescue, these agents may include doxorubicin, cisplatin, and the combination of bleomycin, cyclophosphamide and dactinomycin (BCD) in the doses and schedule shown in the table below. The starting dose for high-dose methotrexate treatment is 12 grams/m2. If this dose is not sufficient to produce a peak serum methotrexate concentration of 1,000 micromolar (10-3 mol/L) at the end of the methotrexate infusion, the dose may be escalated to 15 grams/m2 in subsequent treatments. If the patient is vomiting or is unable to tolerate oral medication, leucovorin is given IV or IM at the same dose and schedule.

  Drug*

  Dose*

  Treatment Week After Surgery

  Methotrexate

  Leucovorin

  12 g/m2 IV as 4 hour infusion (starting dose)

  15 mg orally every six hours for 10 doses starting at 24 hours after start of methotrexate infusion

  4,5,6,7,11,12,15,16,29,30,44,45

  - - -

  Doxorubicin† as a single drug

  30 mg/m2 day IV x 3 days

  8,17

  Doxorubicin†

  Cisplatin†

  50 mg/m2 IV

  100 mg/m2 IV

  20,23,33,36

  20,23,33,36

  Bleomycin†

  Cyclophosphamide†

  Dactinomycin†

  15 units/m2 IV x 2 days

  600 mg/m2 IV x 2 days

  0.6 mg/m2 IV x 2 days

  2,13,26,39,42

  2,13,26,39,42

  2,13,26,39,42

  *Link MP, Goorin AM, Miser AW, et al: The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J of Med 1986; 314 (No.25): 1600-1606.

  †See each respective package insert for full prescribing information. Dosage modifications may be necessary because of drug-induced toxicity.

  When these higher doses of methotrexate are to be administered, the following safety guidelines should be closely observed.

  GUIDELINES FOR METHOTREXATE THERAPY WITH LEUCOVORIN RESCUE

  1. Administration of methotrexate should be delayed until recovery if:

  • the WBC count is less than 1500/microliter

  • the neutrophil count is less than 200/microliter

  • the platelet count is less than 75,000/microliter

  • the serum bilirubin level is greater than 1.2 mg/dL

  • the SGPT level is greater than 450 U

  • mucositis is present, until there is evidence of healing

  • persistent pleural effusion is present; this should be drained dry prior to infusion.

  2. Adequate renal function must be documented.

  a. Serum creatinine must be normal, and creatinine clearance must be greater than 60 mL/min, before initiation of therapy.

  b. Serum creatinine must be measured prior to each subsequent course of therapy. If serum creatinine has increased by 50% or more compared to a prior value, the creatinine clearance must be measured and documented to be greater than 60 mL/min (even if the serum creatinine is still within the normal range).

  3. Patients must be well hydrated, and must be treated with sodium bicarbonate for urinary alkalinization.

  a. Administer 1,000 mL/m2 of intravenous fluid over 6 hours prior to initiation of the methotrexate infusion. Continue hydration at 125 mL/m2/hr (3 liters/m2/day) during the methotrexate infusion, and for 2 days after the infusion has been completed.

  b. Alkalinize urine to maintain pH above 7.0 during methotrexate infusion and leucovorin calcium therapy. This can be accomplished by the administration of sodium bicarbonate orally or by incorporation into a separate intravenous solution.

  4. Repeat serum creatinine and serum methotrexate 24 hours after starting methotrexate and at least once daily until the methotrexate level is below 5 x 10-8 mol/L (0.05 micromolar).

  5. The table below provides guidelines for leucovorin calcium dosage based upon serum methotrexate levels. (See table below.‡)

  Patients who experience delayed early methotrexate elimination are likely to develop nonreversible oliguric renal failure. In addition to appropriate leucovorin therapy, these patients require continuing hydration and urinary alkalinization, and close monitoring of fluid and electrolyte status, until the serum methotrexate level has fallen to below 0.05 micromolar and the renal failure has resolved. If necessary, acute, intermittent hemodialysis with a high-flux dialyzer may also be beneficial in these patients.

  6. Some patients will have abnormalities in methotrexate elimination, or abnormalities in renal function following methotrexate administration, which are significant but less severe than the abnormalities described in the table below. These abnormalities may or may not be associated with significant clinical toxicity. If significant toxicity is observed, leucovorin rescue should be extended for an additional 24 hours (total 14 doses over 84 hours) in subsequent courses of therapy. The possibility that the patient is taking other medications which interact with methotrexate (e.g., medications which may interfere with methotrexate binding to serum albumin, or elimination) should always be reconsidered when laboratory abnormalities or clinical toxicities are observed.

  CAUTION: DO NOT ADMINISTER LEUCOVORIN INTRATHECALLY.

  Psoriasis, Rheumatoid Arthritis, and Juvenile Rheumatoid Arthritis

  Adult Rheumatoid Arthritis: Recommended Starting Dosage Schedules

  Single oral doses of 7.5 mg once weekly.†

  Divided oral dosages of 2.5 mg at 12 hour intervals for 3 doses given as a course once weekly.†

  † Methotrexate Sodium Tablets for oral administration are available.

  Polyarticular-Course Juvenile Rheumatoid Arthritis: The recommended starting dose is 10 mg/m2 given once weekly.

  For either adult RA or polyarticular-course JRA, dosages may be adjusted gradually to achieve an optimal response. Limited experience shows a significant increase in the incidence and severity of serious toxic reactions, especially bone marrow suppression, at doses greater than 20 mg/wk in adults. Although there is experience with doses up to 30 mg/m2/wk in children, there are too few published data to assess how doses over 20 mg/m2/wk might affect the risk of serious toxicity in children. Experience does suggest, however, that children receiving 20 to 30 mg/m2/wk (0.65 to 1.0 mg/kg/wk) may have better absorption and fewer gastrointestinal side effects if methotrexate is administered either intramuscularly or subcutaneously.

  Therapeutic response usually begins within 3 to 6 weeks and the patient may continue to improve for another 12 weeks or more.

  The optimal duration of therapy is unknown. Limited data available from long-term studies in adults indicate that the initial clinical improvement is maintained for at least two years with continued therapy. When methotrexate is discontinued, the arthritis usually worsens within 3 to 6 weeks.

  The patient should be fully informed of the risks involved and should be under constant supervision of the physician. (See Information for Patients under PRECAUTIONS). Assessment of hematologic, hepatic, renal, and pulmonary function should be made by history, physical examination, and laboratory tests before beginning, periodically during, and before reinstituting methotrexate therapy. (See PRECAUTIONS). Appropriate steps should be taken to avoid conception during methotrexate therapy. (See PRECAUTIONS and CONTRAINDICATIONS).

  All schedules should be continually tailored to the individual patient. An initial test dose may be given prior to the regular dosing schedule to detect any extreme sensitivity to adverse effects (See ADVERSE REACTIONS). Maximal myelosuppression usually occurs in seven to ten days.

  Psoriasis: Recommended Starting Dose Schedule:

  Weekly single oral, IM or IV dosage schedule: 10 to 25 mg per week until adequate response is achieved.†

  Divided oral dose schedule 2.5 mg at 12 hour intervals for three doses.†

  †Methotrexate Sodium Tablets for oral administration are available.

  Dosages in each schedule may be gradually adjusted to achieve optimal clinical response; 30 mg/week should not ordinarily be exceeded.

  Once optimal clinical response has been achieved, each dosage schedule should be reduced to the lowest possible amount of drug and to the longest possible rest period. The use of methotrexate may permit the return to conventional topical therapy, which should be encouraged.

  HANDLING AND DISPOSAL

  Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

  DILUTION INSTRUCTIONS FOR LIQUID METHOTREXATE INJECTION PRODUCT

  Methotrexate Injection, USP, Isotonic Liquid, Contains Preservative

  If desired, the solution may be further diluted with a compatible medium such as Sodium Chloride Injection, USP. Storage for 24 hours at a temperature of 21°C to 25°C results in a product which is within 90% of label potency.

  Methotrexate Injection, USP, Isotonic Liquid, Preservative Free, for Single Use Only

  If desired, the solution may be further diluted immediately prior to use with an appropriate sterile, preservative free medium such as 5% Dextrose Solution, USP or Sodium Chloride Injection, USP.

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• Vinorelbine Tartrate
  

  ×

  Vinorelbine Tartrate

  

  ---

  2.1 Recommended Dose

  In Combination with Cisplatin 100 mg/m2

  • The recommended dose of Vinorelbine is 25 mg/m 2 administered as an intravenous injection or infusion over 6 to 10 minutes on days 1, 8, 15 and 21 of a 28 day cycle in combination with cisplatin 100 mg/m 2 on day 1 only of each 28 day cycle.

  In Combination with Cisplatin 120 mg/m2

  • The recommended dose of Vinorelbine is 30 mg/m 2 administered as an intravenous injection or infusion over 6 to 10 minutes once a week in combination with cisplatin 120 mg/m 2 on days 1 and 29, then every 6 weeks.

  Single-Agent

  • The recommended dose of Vinorelbine is 30 mg/m 2 administered intravenously over 6 to 10 minutes once a week.

  2.2 Dose Modifications

  Hematologic Toxicity

  [see Warnings and Precautions (5.1)].

  Hold or decrease the dose of Vinorelbine in patients with decreased neutrophil counts using the following schema.

  Neutrophils on Day of Treatment (Cells/mm3)

  Percentage of Starting Dose of Vinorelbine

  ≥ 1,500

  100%

  1,000 to 1,499

  50%

  < 1,000

  Do not administer Vinorelbine. Repeat neutrophil count in one week. If three consecutive weekly doses are held because Neutrophil count is < 1,000 cells/mm3, discontinue Vinorelbine

  Note: For patients who experience fever and/or sepsis while neutrophil count is < 1,500 or had 2 consecutive weekly doses held due to neutropenia, subsequent doses of Vinorelbine should be:

  > 1,500

  75%

  1,000 to 1,499

  37.5%

  < 1,000

  Do not administer Vinorelbine. Repeat neutrophil count in one week.

  Hepatic Impairment/Toxicity

  [see Warnings and Precautions (5.2) and Use in Specific Populations (8.6)].

  Reduce Vinorelbine dose in patients with elevated serum total bilirubin concentration according to the following schema:

  Serum total bilirubin concentration (mg/dl)

  Percentage of Starting Dose of Vinorelbine

  ≤ 2.0

  100%

  2.1 to 3.0

  50%

  > 3.0

  25%

  Concurrent Hematologic Toxicity and Hepatic Impairment

  In patients with both hematologic toxicity and hepatic impairment, administer the lower of the doses based on the corresponding starting dose of Vinorelbine determined from the above schemas.

  Neurologic Toxicity

  [see Warnings and Precautions (5.5)]

  Discontinue Vinorelbine for NCI CTCAE Grade 2 or higher peripheral neuropathy or autonomic neuropathy causing constipation.

  2.3 Preparation and Administration

  Vinorelbine Injection must be diluted in either a syringe or IV bag using one of the recommended solutions.

  Syringe

  The calculated dose of Vinorelbine should be diluted to a concentration between 1.5 and 3 mg/mL. The following solutions may be used for dilution:

  5% Dextrose Injection, USP0.9% Sodium Chloride Injection, USP

  IV Bag

  The calculated dose of Vinorelbine should be diluted to a concentration between 0.5 and 2 mg/mL. The following solutions may be used for dilution:

  5% Dextrose Injection, USP0.9% Sodium Chloride Injection, USP0.45% Sodium Chloride Injection, USP5% Dextrose and 0.45% Sodium Chloride Injection, USPRinger’s Injection, USPLactated Ringer’s Injection, USP

  Stability

  Unopened vials of Vinorelbine are stable until the date indicated on the package when stored under refrigeration at 2° to 8°C (36° to 46°F) and protected from light in the carton.

  Unopened vials of Vinorelbine are stable at temperatures up to 25°C (77°F) for up to 72 hours.

  This product should not be frozen.

  Administration

  The diluted Vinorelbine should be administered over 6 to 10 minutes into the side port of a free-flowing IV closest to the IV bag followed by flushing with at least 75 to 125 mL of one of the solutions.

  Vinorelbine must only be administered intravenously. It is extremely important that the intravenous needle or catheter be properly positioned before any Vinorelbine is injected.

  Parenteral drug products should be visually inspected for particulate matter and discoloration prior to administration whenever solution and container permit. If particulate matter is seen, Vinorelbine should not be administered.

  Management of Suspected Extravasation

  • If Vinorelbine leakage into surrounding tissue occurs or is suspected, immediately stop administration of Vinorelbine and initiate appropriate management measures in accordance with institutional policies [ see Warnings and Precautions (5.4)].

  2.4 Procedures for Proper Handling and Disposal

  Handle and dispose Vinorelbine consistent with recommendations for the handling and disposal of hazardous drugs.2

  Exercise caution in handling and preparing the solution of Vinorelbine. The use of gloves is recommended. If the solution of Vinorelbine contacts the skin or mucosa, immediately wash the skin or mucosa thoroughly with soap and water.

  Avoid contamination of the eye with Vinorelbine. If exposure occurs, flush the eyes with water immediately and thoroughly.

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• Multi Vitamin Infusion
  

  ×

  Multi Vitamin Infusion

  

  ---

  • M.V.I.-12™ is ready for immediate intravenous use in adults and children aged 11 years and above when added to intravenous infusion fluids. Do not administer M.V.I.-12™ as a direct, undiluted intravenous injection as it may cause dizziness, faintness, and tissue irritation.

  2.1 Starting Dose, Dose Range and Route of Administration

  The starting dose is one 10 mL daily dose added directly to an intravenous fluid. Patients with multiple vitamin deficiencies or with increased vitamin requirements may need multiple daily dosages as indicated. Some patients do not maintain adequate levels of certain vitamins when this formulation in recommended amounts is the only source of vitamins. 

  2.2 Monitoring

  Blood vitamin concentrations should be monitored to ensure maintenance of adequate levels, particularly in patients receiving parenteral multivitamins as the only source of vitamins for long periods of time.

  2.3 Instructions for Intravenous Administration

  The solution must be prepared prior to intravenous administration.

  •    Aseptically transfer the contents of the 50 mL Vial 1 into 50 mL Vial 2. The mixed solution will provide ten 10 mL single doses. Once closure system has been compromised, withdrawal of container contents should be completed within 4 hours. Mixed solution may be stored for up to 4 hours refrigerated. Discard unused portion.

  •    Do not administer M.V.I.-12™ as a direct, undiluted intravenous injection as it may cause dizziness, faintness, and tissue irritation.

  •    Utilizing a suitable sterile automated compounding device or dispensing pin for accuracy, aseptically transfer each 10 mL dose into a plastic or glass bottle containing at least 500 - 1000 mL intravenous total parenteral nutrition solution containing dextrose or saline. Discard unused portions. This infusion solution may be stored up to 24 hours refrigerated.

  •    Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  •    Handling of M.V.I.-12™ solution, including preparation of the Pharmacy Bulk Pack, should be restricted to a suitable work area, such as a laminar flow hood.

  2.4 Drug Incompatibilities

  •    M.V.I.-12™ (Multi-Vitamin Infusion without vitamin K) is not physically compatible with moderately alkaline solutions such as a sodium bicarbonate solution and other alkaline drugs such as acetazolamide sodium, aminophylline, ampicillin sodium, and chlorothiazide sodium.

  •    Folic acid is unstable in the presence of calcium salts such as calcium gluconate.

  •    Vitamin A and thiamine in M.V.I.-12™ may react with bisulfite solutions such as sodium bisulfite or vitamin K bisulfate. Patients should be monitored for vitamin A and thiamine deficiencies.

  •    Consult appropriate references for listings of physical and chemical compatibility of solutions and drugs with the vitamin infusion. In such circumstances, admixture or Y-site administration with vitamin solutions should be avoided.

  2.1 Starting Dose, Dose Range and Route of Administration

  The starting dose is one 10 mL daily dose added directly to an intravenous fluid. Patients with multiple vitamin deficiencies or with increased vitamin requirements may need multiple daily dosages as indicated. Some patients do not maintain adequate levels of certain vitamins when this formulation in recommended amounts is the only source of vitamins. 

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• Cytarabine
  

  ×

  Cytarabine

  

  ---

  Cytarabine Injection is not active orally. The schedule and method of administration varies with the program of therapy to be used. Cytarabine Injection may be given by intravenous infusion or injection, subcutaneously, or intrathecally (preservative free preparation only).

  Thrombophlebitis has occurred at the site of drug injection or infusion in some patients, and rarely patients have noted pain and inflammation at subcutaneous injection sites. In most instances, however, the drug has been well tolerated.

  Patients can tolerate higher total doses when they receive the drug by rapid intravenous injection as compared with slow infusion. This phenomenon is related to the drug’s rapid inactivation and brief exposure of susceptible normal and neoplastic cells to significant levels after rapid injection. Normal and neoplastic cells seem to respond in somewhat parallel fashion to these different modes of administration and no clear-cut clinical advantage has been demonstrated for either.

  In the induction therapy of acute non-lymphocytic leukemia, the usual cytarabine dose in combination with other anti-cancer drugs is 100 mg/m2/day by continuous IV infusion (Days 1-7) or 100 mg/m2 IV every 12 hours (Days 1-7).

  The literature should be consulted for the current recommendations for use in acute lymphocytic leukemia.

  Intrathecal Use in Meningeal Leukemia

  Cytarabine injection has been used intrathecally in acute leukemia in doses ranging from 5 mg/m2 to 75 mg/m2 of body surface area. The frequency of administration varied from once a day for 4 days to once every 4 days. The most frequently used dose was 30 mg/m2 every 4 days until cerebrospinal fluid findings were normal, followed by one additional treatment. The dosage schedule is usually governed by the type and severity of central nervous system manifestations and the response to previous therapy.

  Cytarabine injection given intrathecally may cause systemic toxicity and careful monitoring of the hematopoietic system is indicated. Modification of other anti-leukemia therapy may be necessary. Major toxicity is rare. The most frequently reported reactions after intrathecal administration were nausea, vomiting and fever; these reactions are mild and self-limiting. Paraplegia has been reported. Necrotizing leukoencephalopathy occurred in 5 children; these patients had also been treated with intrathecal methotrexate and hydrocortisone, as well as by central nervous system radiation. Isolated neurotoxicity has been reported. Blindness occurred in two patients in remission whose treatment had consisted of combination systemic chemotherapy, prophylactic central nervous system radiation and intrathecal cytarabine injection.

  When cytarabine injection is administered both intrathecally and intravenously within a few days, there is an increased risk of spinal cord toxicity, however, in serious life-threatening disease, concurrent use of intravenous and intrathecal Cytarabine Injection is left to the discretion of the treating physician.

  Focal leukemic involvement of the central nervous system may not respond to intrathecal cytarabine injection and may better be treated with radiotherapy.

  Chemical Stability of Infusion Solutions

  Chemical stability studies were performed by ultraviolet assay on Cytarabine Injection in infusion solutions. These studies showed that when Cytarabine Injection was added to Water for Injection, 5% Dextrose in Water or Sodium Chloride Injection, 94 to 96 percent of the cytarabine was present after 192 hours storage at room temperature.

  Parenteral drugs should be inspected visually for particulate matter and discoloration, prior to administration, whenever solution and container permit.

  HANDLING AND DISPOSAL

  Procedures for proper handling and disposal of anti-cancer drugs should be considered. Several guidelines on this subject have been published.1-7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

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• Cytarabine
  

  ×

  Cytarabine

  

  ---

  Cytarabine Injection (non-preserved) can be administered by intravenous injection or infusion, subcutaneously, or intrathecally. However, the intent of this Pharmacy Bulk Package is for the preparation of solutions for IV infusion only. Intrathecal use of cytarabine requires the use of single-dose, unpreserved solutions only.

  Cytarabine Injection is not active orally. The schedule and method of administration varies with the program of therapy to be used. While Cytarabine Injection may be given by intravenous infusion or injection, or subcutaneously or intrathecally, THE PURPOSE OF THE PHARMACY BULK PACKAGE IS FOR THE PREPARATION OF INTRAVENOUS INFUSIONS. Thrombophlebitis has occurred at the site of drug injection or infusion in some patients, and rarely patients have noted pain and inflammation at subcutaneous injection sites. In most instances, however, the drug has been well tolerated.

  Patients can tolerate higher total doses when they receive the drug by rapid intravenous injection as compared with slow infusion. This phenomenon is related to the drug’s rapid inactivation and brief exposure of susceptible normal and neoplastic cells to significant levels after rapid injection. Normal and neoplastic cells seem to respond in somewhat parallel fashion to these different modes of administration and no clear-cut clinical advantage has been demonstrated for either.

  In the induction therapy of acute non-lymphocytic leukemia, the usual cytarabine dose in combination with other anti-cancer drugs is 100 mg/m2/day by continuous IV infusion (Days 1-7) or 100 mg/m2 IV every 12 hours (Days 1-7).

  The literature should be consulted for the current recommendations for use in acute lymphocytic leukemia.

  Intrathecal Use in Meningeal Leukemia: Cytarabine has been used intrathecally in acute leukemia in doses ranging from 5 mg/m2 to 75 mg/m2 of body surface area. The frequency of administration varied from once a day for 4 days to once every 4 days. The most frequently used dose was 30 mg/m2 every 4 days until cerebrospinal fluid findings were normal, followed by one additional treatment. The dosage schedule is usually governed by the type and severity of central nervous system manifestations and the response to previous therapy.

  If used intrathecally, do not use a solution containing benzyl alcohol. This pharmacy bulk package is not intended to be used for the preparation of intrathecal doses.

  Cytarabine given intrathecally may cause systemic toxicity and careful monitoring of the hemopoietic system is indicated. Modification of other anti-leukemia therapy may be necessary. Major toxicity is rare. The most frequently reported reactions after intrathecal administration were nausea, vomiting and fever; these reactions are mild and self-limiting. Paraplegia has been reported. Necrotizing leukoencephalopathy occurred in 5 children; these patients had also been treated with intrathecal methotrexate and hydrocortisone, as well as by central nervous system radiation. Isolated neurotoxicity has been reported. Blindness occurred in two patients in remission whose treatment had consisted of combination systemic chemotherapy, prophylactic central nervous system radiation and intrathecal cytarabine.

  When cytarabine is administered both intrathecally and intravenously within a few days, there is an increased risk of spinal cord toxicity, however, in serious life-threatening disease, concurrent use of intravenous and intrathecal cytarabine is left to the discretion of the treating physician.

  Focal leukemic involvement of the central nervous system may not respond to intrathecal cytarabine and may better be treated with radiotherapy.

  Chemical Stability of Infusion Solutions: Chemical stability studies were performed by a stability indicating HPLC assay on Cytarabine Injection in infusion solutions. These studies showed that when Cytarabine Injection was diluted with Water for Injection, 5% Dextrose Injection or Sodium Chloride Injection, in both glass and plastic infusion bags, 97-100% of the cytarabine was present after 8 days storage at room temperature.

  This chemical stability information in no way indicates that it would be acceptable practice to infuse a cytarabine admixture well after the preparation time. Good professional practice suggests that administration of an admixture should be as soon after preparation as feasible.

  Parenteral drugs should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  Handling and Disposal: Procedures for proper handling and disposal of anti-cancer drugs should be considered. Several guidelines on this subject have been published.1-7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

  Direction for Dispensing From Pharmacy Bulk Package: The 50 mL Pharmacy Bulk Package is for use in the Pharmacy Admixtures Service only. The vials should be inserted into the plastic handling device provided, suspended as a unit in the laminar flow hood.

  A single entry through the vial closure should be made with a sterile dispensing set or transfer device. Transfer individual doses to appropriate intravenous infusion solutions. Use of a syringe with needle is not recommended. Multiple entries will increase the potential of microbial and particulate contamination.

  The above process should be carried out under a laminar flow hood using aseptic technique. Care should be exercised to protect personnel from aerosolized drug (see DOSAGE AND ADMINISTRATION, REFERENCES). Discard any unused portion within 4 hours after initial closure entry.

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• Cytarabine Solution
  

  ×

  Cytarabine Solution

  

  ---

  Cytarabine is not active orally. The schedule and method of administration varies with the program of therapy to be used. Cytarabine Injection may be given by intravenous infusion or injection or subcutaneously. Thrombophlebitis has occurred at the site of drug injection or infusion in some patients, and rarely patients have noted pain and inflammation at subcutaneous injection sites. In most instances, however, the drug has been well tolerated.

  Patients can tolerate higher total doses when they receive the drug by rapid intravenous injection as compared with slow infusion. This phenomenon is related to the drug’s rapid inactivation and brief exposure of susceptible normal and neoplastic cells to significant levels after rapid injection. Normal and neoplastic cells seem to respond in somewhat parallel fashion to these different modes of administration and no clear-cut clinical advantage has been demonstrated for either.

  In the induction therapy of acute non-lymphocytic leukemia, the usual cytarabine dose in combination with other anti-cancer drugs is 100 mg/m2/day by continuous IV infusion (Days 1-7) or 100 mg/m2 IV every 12 hours (Days 1-7).

  The literature should be consulted for the current recommendations for use in acute lymphocytic leukemia.

  Intrathecal Use in Meningeal Leukemia: DO NOT USE CYTARABINE INJECTION (which contains benzyl alcohol) INTRATHECALLY.

  The following dosage information regarding intrathecal use is included for informational purposes only.

  Cytarabine has been used intrathecally in acute leukemia in doses ranging from 5 mg/m2 to 75 mg/m2 of body surface area. The frequency of administration varied from once a day for 4 days to once every 4 days. The most frequently used dose was 30 mg/m2 every 4 days until cerebrospinal fluid findings were normal, followed by one additional treatment. The dosage schedule is usually governed by the type and severity of central nervous system manifestations and the response to previous therapy.

  Cytarabine given intrathecally may cause systemic toxicity and careful monitoring of the hemopoietic system is indicated. Modifications of other anti-leukemia therapy may be necessary. Major toxicity is rare. The most frequently reported reactions after intrathecal administration were nausea, vomiting and fever; these reactions are mild and self-limiting. Paraplegia has been reported. Necrotizing leukoencephalopathy occurred in 5 children; these patients had also been treated with intrathecal methotrexate and hydrocortisone, as well as by central nervous system radiation. Isolated neurotoxicity has been reported. Blindness occurred in two patients in remission whose treatment had consisted of combination systemic chemotherapy, prophylactic central nervous system radiation and intrathecal cytarabine.

  When cytarabine is administered both intrathecally and intravenously within a few days, there is an increased risk of spinal cord toxicity, however, in serious lifethreatening disease, concurrent use of intravenous and intrathecal cytarabine is left to the discretion of the treating physician.

  Focal leukemic involvement of the central nervous system may not respond to intrathecal cytarabine and may be better treated with radiotherapy.

  Chemical Stability in Infusion Solutions: Chemical stability studies were performed by a stability indicating HPLC assay on Cytarabine Injection in infusion solutions. These studies showed that when Cytarabine Injection was diluted with Water for Injection, 5% Dextrose Injection or Sodium Chloride Injection, 97-100% of the cytarabine was still present after 8 days storage at room temperature.

  This chemical stability information in no way indicates that it would be acceptable practice to infuse a cytarabine admixture well after the preparation time. Good professional practice suggests that administration of an admixture should be as soon after preparation as feasible.

  Parenteral drugs should be inspected visually for particulate matter and discoloration, prior to administration, whenever solution and container permit.

  Handling and Disposal: Procedures for proper handling and disposal of anti-cancer drugs should be considered. Several guidelines on this subject have been published.1-7 There is no general agreement that all of the procedures in the guidelines are necessary or appropriate.

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• Multi Vitamin Infusion
  

  ×

  Multi Vitamin Infusion

  

  ---

  M.V.I.–12™ is ready for immediate intravenous use in adults and children aged 11 years and above when added to intravenous infusion fluids. Do not administer M.V.I.-12™ as a direct, undiluted intravenous injection as it may cause dizziness, faintness, and tissue irritation.

  2.1 Starting Dose, Dose Range and Route of Administration

  The starting dose is one 10 mL daily dose added directly to an intravenous fluid. Patients with multiple vitamin deficiencies or with markedly increased requirements may need multiple daily dosages as indicated. Some patients do not maintain adequate levels of certain vitamins when this formulation in recommended amounts is the only source of vitamins.

  2.2 Monitoring

  Blood vitamin concentrations should be monitored to ensure maintenance of adequate levels, particularly in patients receiving parenteral multivitamins as the only source of vitamins for long periods of time.

  2.3 Instructions for Intravenous Administration

  The solution must be prepared prior to intravenous administration. 

        •     Remove the protective plastic cap, turn the plunger-stopper 90° and press down firmly to force liquid in the upper chamber and the center seal into the lower compartment. Gently agitate to mix solution. Disinfect the rubber stopper in the usual manner before inserting needle squarely through the center of the plunger-stopper until tip is just visible. Vial should be mixed just prior to use. Invert vial and withdraw a 10 mL dose in the usual manner.       •      Do not administer M.V.I.–12™ as a direct, undiluted intravenous injection as it may cause dizziness, faintness, and possible tissue irritation.       •     Aseptically transfer each sterile 10 mL dose into a plastic or glass bottle containing at least 500-1000 mL of intravenous dextrose or saline.       •     Withdraw container contents without delay.       •     After M.V.I.–12™ is diluted in an intravenous fluid, the resulting solution is ready for immediate use. Use the prepared solution within 4 hours after dilution.       •     Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.       •     Handling of M.V.I-12 solution should be performed in a suitable work area, such as a laminar flow hood.

   

  2.4 Drug Incompatibilities

       •     M.V.I.–12™ (Multi-Vitamin Infusion without vitamin K) is not physically compatible with moderately alkaline solutions such as a sodium bicarbonate solution and other alkaline drugs such as acetazolamide sodium, aminophylline, ampicillin sodium, and chlorothiazide sodium.      •     Folic acid is unstable in the presence of calcium salts such as calcium gluconate.      •     Vitamin A and thiamine in M.V.I.–12™ may react with bisulfite solutions such as sodium bisulfite or vitamin K bisulfate. Patients should be monitored for vitamin A and thiamine deficiencies.      •     Consult appropriate references for listings of physical and chemical compatibility of solutions and drugs with the vitamin infusion. In such circumstances, admixture or Y-site administration with vitamin solutions should be avoided.

   

  2.1 Starting Dose, Dose Range and Route of Administration

  The starting dose is one 10 mL daily dose added directly to an intravenous fluid. Patients with multiple vitamin deficiencies or with markedly increased requirements may need multiple daily dosages as indicated. Some patients do not maintain adequate levels of certain vitamins when this formulation in recommended amounts is the only source of vitamins.

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• Multi Vitamin Infusion ...
  

  ×

  Multi Vitamin Infusion Pediatric

  

  ---

  The single dose vial of M.V.I. Pediatric® is reconstituted by adding 5 mL of Sterile Water for Injection USP, Dextrose Injection USP 5%, or Sodium Chloride Injection to the 10 mL vial.

  The vial may be swirled gently after the addition of the water to hasten reconstitution. Use of this product is restricted to a suitable work area, such as a laminar flow hood. The reconstituted solution is ready within three minutes for immediate use. The withdrawal of container contents should be accomplished without delay. However, should this not be possible, a maximum time of 4 hours from initial closure entry is permitted to complete fluid transfer operations. The amount to be administered should be added to appropriate intravenous infusion fluids (see below).

  The reconstituted M.V.I. Pediatric® should not be given as a direct, undiluted intravenous injection as it may give rise to dizziness, faintness and possible tissue irritation.

  For a single dose, 5 mL of reconstituted M.V.I. Pediatric® should be added directly to not less than 100 mL of intravenous dextrose, saline or similar infusion solutions.

  Infants weighing less than 1 kg: The daily dose is 30% (1.5 mL) of a single full dose (5 mL). Do not exceed this daily dose.

  Infants weighing 1 to 3 kg: The daily dose is 65% (3.25 mL) of a single full dose (5 mL). Multiples of this recommended dose should not be given to infants weighing less than 3 kg. A supplemental vitamin A may be required for low birth weight infants.

  Infants and children weighing 3 kg or more up to 11 years of age: The daily dose is 5 mL unless there is clinical or laboratory evidence for increasing or decreasing the dosage.

  DISCARD ANY UNUSED PORTION.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  After M.V.I. Pediatric® is reconstituted it should be immediately diluted into the intravenous solution. The resulting solution should be administered immediately. Some of the vitamins in this product, particularly vitamins A and D and riboflavin, are light-sensitive and exposure to light should be minimized.

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• Irinotecan Hydrochlorid...
  

  ×

  Irinotecan Hydrochloride

  

  ---

  2.1 Colorectal Single Agent Regimens 1 and 2

  Administer Irinotecan Hydrochloride Injection, USP as a 90-minute intravenous infusion. The currently recommended regimens are shown in Table 1.

  A reduction in the starting dose by one dose level of Irinotecan Hydrochloride Injection, USP may be considered for patients with any of the following conditions: prior pelvic/abdominal radiotherapy, performance status of 2, or increased bilirubin levels. Dosing for patients with bilirubin >2 mg/dL cannot be recommended because there is insufficient information to recommend a dose in these patients.

  Table 1. Single-Agent Regimens of Irinotecan Hydrochloride Injection, USP and Dose Modifications a     Subsequent doses may be adjusted as high as 150 mg/m2 or to as low as 50 mg/m2 in 25 to 50 mg/m2 decrements depending upon individual patient tolerance.b     Subsequent doses may be adjusted as low as 200 mg/m2 in 50 mg/m2 decrements depending upon individual patient tolerance.c     Provided intolerable toxicity does not develop, treatment with additional cycles may be continued indefinitely as long as patients continue to experience clinical benefit.

  Regimen 1 (weekly)a

  125 mg/m2 intravenous infusion over 90 minutes, days 1, 8, 15, 22 then 2-week rest

  Starting Dose and Modified Dose Levelsc (mg/m2)

  Starting Dose

  Dose Level -1

  Dose Level -2

  125

  100

  75

  Regimen 2 (every 3 weeks)b

  350 mg/m2 intravenous infusion over 90 minutes, once every 3 weeksc

  Starting Dose and Modified Dose Levels (mg/m2)

  Starting Dose

  Dose Level -1

  Dose Level -2

  350

  300

  250

  Dose Modifications

  Based on recommended dose-levels described in Table 1, Single-Agent Regimens of Irinotecan Hydrochloride Injection, USP and Dose Modifications, subsequent doses should be adjusted as suggested in Table 2, Recommended Dose Modifications for Single-Agent Schedules. All dose modifications should be based on the worst preceding toxicity.

  Table 2. Recommended Dose Modifications for Single-Agent Schedulesa a     All dose modifications should be based on the worst preceding toxicityb     National Cancer Institute Common Toxicity Criteria (version 1.0)c     Pretreatmentd     Excludes alopecia, anorexia, asthenia

  A new cycle of therapy should not begin until the granulocyte count has recovered to ≥1500/mm3, and the platelet count has recovered to ≥100,000/mm3, and treatment-related diarrhea is fully resolved. Treatment should be delayed 1 to 2 weeks to allow for recovery from treatment-related toxicities. If the patient has not recovered after a 2-week delay, consideration should be given to discontinuing Irinotecan Hydrochloride Injection, USP.

  Worst Toxicity NCI Gradeb (Value)

  During a Cycle of Therapy

  At the Start of the Next Cycles of Therapy (After Adequate Recovery), Compared with the Starting Dose in the Previous Cyclea

  Weekly

  Weekly

  Once Every 3 Weeks

  No toxicity

  Maintain dose level

  ↑ 25 mg/m2 up to a maximum dose of 150 mg/m2

  Maintain dose level

  Neutropenia

   

   

   

  1 (1500 to 1999/mm3)

  Maintain dose level

  Maintain dose level

  Maintain dose level

  2 (1000 to 1499/mm3)

  ↓ 25 mg/m2 

  Maintain dose level

  Maintain dose level

  3 (500 to 999/mm3)

  Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m2 

  ↓ 25 mg/m2 

   

  ↓ 50 mg/m2

   

  4 (<500/mm3)

  Omit dose until resolved to ≤ grade 2, then ↓ 50 mg/m2

  ↓ 50 mg/m2

  ↓ 50 mg/m2 

  Neutropenic fever

  Omit dose until resolved, then ↓ 50 mg/m2 when resolved

  ↓ 50 mg/m2

  ↓ 50 mg/m2

  Other hematologic toxicities

  Dose modifications for leukopenia, thrombocytopenia, and anemia during a cycle of therapy and at the start of subsequent cycles of therapy are also based on NCI toxicity criteria and are the same as recommended for neutropenia above.

  Diarrhea

   

   

   

  1 (2-3 stools/day > pretxc)

  Maintain dose level

  Maintain dose level

  Maintain dose level

  2 (4-6 stools/day > pretx)

  ↓ 25 mg/m2 

  Maintain dose level

  Maintain dose level

  3 (7-9 stools/day > pretx)

  Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m2 

  ↓ 25 mg/m2

  ↓ 50 mg/m2 

  4 (≥10 stools/day > pretx)

  Omit dose until resolved to ≤ grade 2, then ↓ 50 mg/m2

  ↓ 50 mg/m2

  ↓ 50 mg/m2

  Other nonhematologicd toxicities

   

   

   

  1

  Maintain dose level

  Maintain dose level

  Maintain dose level

  2

  ↓ 25 mg/m2 

  ↓ 25 mg/m2 

  ↓ 50 mg/m2 

  3

  Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/m2 

  ↓ 25 mg/m2 

   

  ↓ 50 mg/m2 

   

  4

  Omit dose until resolved to ≤ grade 2, then ↓ 50 mg/m2 

  ↓ 50 mg/m2 

  ↓ 50 mg/m2 

  2.2 Dosage in Patients with Reduced UGT1A1 Activity

  When administered as a single-agent, a reduction in the starting dose by at least one level of Irinotecan Hydrochloride Injection, USP should be considered for patients known to be homozygous for the UGT1A1*28 allele [see Dosage and Administration (2.1) and Warnings and Precautions (5.3)]. However, the precise dose reduction in this patient population is not known, and subsequent dose modifications should be considered based on individual patient tolerance to treatment (see Tables 1-2).

  2.3 Premedication

  It is recommended that patients receive premedication with antiemetic agents. In clinical studies of the weekly dosage schedule, the majority of patients received 10 mg of dexamethasone given in conjunction with another type of antiemetic agent, such as a 5-HT3 blocker (e.g., ondansetron or granisetron). Antiemetic agents should be given on the day of treatment, starting at least 30 minutes before administration of Irinotecan Hydrochloride Injection, USP. Physicians should also consider providing patients with an antiemetic regimen (e.g., prochlorperazine) for subsequent use as needed.

  Prophylactic or therapeutic administration of atropine should be considered in patients experiencing cholinergic symptoms.

  2.4 Preparation of Infusion Solution

  Inspect vial contents for particulate matter and discoloration and repeat inspection when drug product is withdrawn from vial into syringe.

  Irinotecan Hydrochloride Injection, USP 20 mg/mL is intended for single use only and any unused portion should be discarded.

  Irinotecan Hydrochloride Injection, USP must be diluted prior to infusion. Irinotecan Hydrochloride Injection, USP should be diluted in 5% Dextrose Injection, USP, (preferred) or 0.9% Sodium Chloride Injection, USP, to a final concentration range of 0.12 mg/mL to 2.8 mg/mL. Other drugs should not be added to the infusion solution.

  The solution is physically and chemically stable for up to 24 hours at room temperature and in ambient fluorescent lighting. Solutions diluted in 5% Dextrose Injection, USP, and stored at refrigerated temperatures (approximately 2° to 8°C, 36° to 46°F), and protected from light are physically and chemically stable for 48 hours. Refrigeration of admixtures using 0.9% Sodium Chloride Injection, USP, is not recommended due to a low and sporadic incidence of visible particulates. Freezing Irinotecan Hydrochloride Injection, USP and admixtures of Irinotecan Hydrochloride Injection, USP may result in precipitation of the drug and should be avoided.

  The Irinotecan Hydrochloride Injection, USP solution should be used immediately after reconstitution as it contains no antibacterial preservative. Because of possible microbial contamination during dilution, it is advisable to use the admixture prepared with 5% Dextrose Injection, USP, within 24 hours if refrigerated (2° to 8°C, 36° to 46°F). In the case of admixtures prepared with 5% Dextrose Injection, USP, or Sodium Chloride Injection, USP, the solutions should be used within 4 hours if kept at room temperature. If reconstitution and dilution are performed under strict aseptic conditions (e.g. on Laminar Air Flow bench), Irinotecan Hydrochloride Injection, USP solution should be used (infusion completed) within 12 hours at room temperature or 24 hours if refrigerated (2° to 8°C, 36° to 46°F).

  2.5 Safe Handling

  Care should be exercised in the handling and preparation of infusion solutions prepared from Irinotecan Hydrochloride Injection, USP. The use of gloves is recommended. If a solution of Irinotecan Hydrochloride Injection, USP contacts the skin, wash the skin immediately and thoroughly with soap and water. If Irinotecan Hydrochloride Injection, USP contacts the mucous membranes, flush thoroughly with water. Several published guidelines for handling and disposal of anticancer agents are available.

  2.6 Extravasation

  Care should be taken to avoid extravasation, and the infusion site should be monitored for signs of inflammation. Should extravasation occur, flushing the site with sterile water and applications of ice are recommended.

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• Womens Laxative
  

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  Womens Laxative

  

  ---

  NOTE: Aluminum reacts with carboplatin causing precipitate formation and loss of potency, therefore, needles or intravenous sets containing aluminum parts that may come in contact with the drug must not be used for the preparation or administration of Carboplatin Injection.

  Single Agent Therapy: Carboplatin Injection, as a single agent, has been shown to be effective in patients with recurrent ovarian carcinoma at a dosage of 360 mg/m2 IV on day 1 every 4 weeks (alternatively see Formula Dosing). In general, however, single intermittent courses of Carboplatin Injection should not be repeated until the neutrophil count is at least 2000 and the platelet count is at least 100,000.

  Combination Therapy with Cyclophosphamide: In the chemotherapy of advanced ovarian cancer, an effective combination for previously untreated patients consists of:

  Carboplatin Injection - 300 mg/m2 IV on day 1 every four weeks for six cycles (alternatively see Formula Dosing).

  Cyclophosphamide - 600 mg/m2 IV on day 1 every four weeks for six cycles. For directions regarding the use and administration of cyclophosphamide please refer to its package insert. (See CLINICAL STUDIES.)

  Intermittent courses of Carboplatin Injection in combination with cyclophosphamide should not be repeated until the neutrophil count is at least 2000 and the platelet count is at least 100,000.

  Dose Adjustment Recommendations: Pretreatment platelet count and performance status are important prognostic factors for severity of myelosuppression in previously treated patients.

  The suggested dose adjustments for single agent or combination therapy shown in the table below are modified from controlled trials in previously treated and untreated patients with ovarian carcinoma. Blood counts were done weekly, and the recommendations are based on the lowest post-treatment platelet or neutrophil value.

  Platelets Neutrophils Adjusted Dose* (From Prior Course) *Percentages apply to Carboplatin Injection as a single agent or to both Carboplatin Injection and cyclophosphamide in combination. In the controlled studies, dosages were also adjusted at a lower level (50% to 60%) for severe myelosuppression. Escalations above 125% were not recommended for these studies.

  >100,000

  >2000

  125%

  50-100,000

  500-2000

  No Adjustment

  <50,000

  <500

  75%

  Carboplatin Injection is usually administered by an infusion lasting 15 minutes or longer. No pre- or post-treatment hydration or forced diuresis is required.

  Patients with Impaired Kidney Function: Patients with creatinine clearance values below 60 mL/min are at increased risk of severe bone marrow suppression. In renally-impaired patients who received single-agent Carboplatin Injection therapy, the incidence of severe leukopenia, neutropenia, or thrombocytopenia has been about 25% when the dosage modifications in the table below have been used.

  Baseline Creatinine Clearance Recommended Dose on Day 1

  41 - 59 mL/min

  250 mg/m2

  16 - 40 mL/min

  200 mg/m2

  The data available for patients with severely impaired kidney function (creatinine clearance below 15 mL/min) are too limited to permit a recommendation for treatment.

  These dosing recommendations apply to the initial course of treatment. Subsequent dosages should be adjusted according to the patient’s tolerance based on the degree of bone marrow suppression.

  Formula Dosing: Another approach for determining the initial dose of Carboplatin Injection is the use of mathematical formulae, which are based on a patient’s preexisting renal function or renal function and desired platelet nadir. Renal excretion is the major route of elimination for carboplatin. (See CLINICAL PHARMACOLOGY.) The use of dosing formulae, as compared to empirical dose calculation based on body surface area, allows compensation for patient variations in pretreatment renal function that might otherwise result in either underdosing (in patients with above average renal function) or overdosing (in patients with impaired renal function).

  A simple formula for calculating dosage, based upon a patient’s glomerular filtration rate (GFR in mL/min) and Carboplatin Injection target area under the concentration versus time curve (AUC in mg/mL•min), has been proposed by Calvert. In these studies, GFR was measured by 51Cr-EDTA clearance.

  CALVERT FORMULA FOR CARBOPLATIN DOSING

  Total Dose (mg) = (target AUC) x (GFR + 25)

  Note: With the Calvert formula, the total dose of Carboplatin Injection is calculated

  in mg, not mg/m2.

  The target AUC of 4-6 mg/mL•min using single agent Carboplatin Injection appears to provide the most appropriate dose range in previously treated patients. This study also showed a trend between the AUC of single agent Carboplatin Injection administered to previously treated patients and the likelihood of developing toxicity.

  % Actual Toxicity in Previously Treated Patients

  Gr 3 or Gr 4

  Gr 3 or Gr 4

  AUC (mg/mL•min)

  Thrombocytopenia

  Leukopenia

  4 to 5

  16%

  13%

  6 to 7

  33

  34%

  Geriatric Dosing: Because renal function is often decreased in elderly patients, formula dosing of Carboplatin Injection based on estimates of GFR should be used in elderly patients to provide predictable plasma Carboplatin Injection AUCs and thereby minimize the risk of toxicity.

  PREPARATION OF INTRAVENOUS SOLUTIONS

  Carboplatin Injection 10 mg/mL is supplied as a Ready To Use (RTU) sterile solution in 5 mL, 15 mL, 45 mL or 60 mL vials. Total content of carboplatin per vial is described in following table:

  Vial Strength Diluent Volume

  50 mg

  5 mL

  150 mg

  15 mL

  450 mg

  45 mL

  600 mg

  60 mL

  Carboplatin Injection can be further diluted to concentrations as low as 0.5 mg/mL with 5% Dextrose in Water (D5W) or 0.9% Sodium Chloride Injection, USP.

  When further diluted, Carboplatin Injection solutions are stable for 8 hours at room temperature (25°C). Since no antibacterial preservative is contained in the formulation, it is recommended that Carboplatin Injection solutions be discarded 8 hours after dilution.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

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• Fludarabine Phosphate
  

  ×

  Fludarabine Phosphate

  

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  Usual Dose:

  The recommended adult dose of Fludarabine Phosphate for Injection, USP is 25 mg/m2 administered intravenously over a period of approximately 30 minutes daily for five consecutive days. Each 5 day course of treatment should commence every 28 days. Dosage may be decreased or delayed based on evidence of hematologic or nonhematologic toxicity. Physicians should consider delaying or discontinuing the drug if neurotoxicity occurs.

  A number of clinical settings may predispose to increased toxicity from fludarabine phosphate, USP. These include advanced age, renal insufficiency, and bone marrow impairment. Such patients should be monitored closely for excessive toxicity and the dose modified accordingly.

  The optimal duration of treatment has not been clearly established. It is recommended that three additional cycles of fludarabine phosphate, USP be administered following the achievement of a maximal response and then the drug should be discontinued.

  Renal Insufficiency

  Adult patients with moderate impairment of renal function (creatinine clearance 30 to 70 mL/min/1.73 m2) should have a 20% dose reduction of fludarabine phosphate, USP. Fludarabine phosphate, USP should not be administered to patients with severely impaired renal function (creatinine clearance less than 30 mL/min/1.73 m2).

  Preparation of Solutions:

  Fludarabine Phosphate for Injection, USP should be prepared for parenteral use by aseptically adding Sterile Water for Injection, USP. When reconstituted with 2 mL of Sterile Water for Injection, USP, the solid cake should fully dissolve in 15 seconds or less; each mL of the resulting solution will contain 25 mg of fludarabine phosphate, USP, 25 mg of mannitol, and sodium hydroxide to adjust the pH to 7.7. The pH range for the final product is 7.2 to 8.2. In clinical studies, the product has been diluted in 100 cc or 125 cc of 5% Dextrose Injection, USP or 0.9% Sodium Chloride, USP.

  Reconstituted Fludarabine Phosphate for Injection, USP contains no antimicrobial preservative and thus should be used within 8 hours of reconstitution. Care must be taken to assure the sterility of prepared solutions. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

  Fludarabine Phosphate for Injection, USP should not be mixed with other drugs.

  Handling and Disposal:

  Procedures for proper handling and disposal should be considered. Consideration should be given to handling and disposal according to guidelines issued for cytotoxic drugs. Several guidelines on this subject have been published.1-4

  Caution should be exercised in the handling and preparation of Fludarabine Phosphate for Injection, USP solution. The use of latex gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If the solution contacts the skin or mucous membranes, wash thoroughly with soap and water; rinse eyes thoroughly with plain water. Avoid exposure by inhalation or by direct contact of the skin or mucous membranes.

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• Epirubicin Hydrochlorid...
  

  ×

  Epirubicin Hydrochloride

  

  ---

  When possible, to reduce the risk of developing cardiotoxicity in patients receiving Epirubicin Hydrochloride Injection after stopping treatment with other cardiotoxic agents, especially those with long half-lives such as trastuzumab, Epirubicin Hydrochloride Injection-based therapy should be delayed until the other agents have cleared from the circulation [see Warnings and Precautions (5.3)].

  Administer Epirubicin Hydrochloride Injection by intravenous infusion. Give Epirubicin Hydrochloride Injection in repeated 3- to 4-week cycles. The total dose of Epirubicin Hydrochloride Injection may be given on Day 1 of each cycle or divided equally and given on Days 1 and 8 of each cycle. The recommended dosages of Epirubicin Hydrochloride Injection are as follows:

  2.1 Recommended Dose

  The recommended dose of Epirubicin Hydrochloride Injection is 100 to 120 mg/m2. The following regimens are recommended:

  CEF-120:

  Cyclophosphamide

  75 mg/m2 PO D 1-14

  Epirubicin Hydrochloride Injection

  60 mg/m2 IV D 1, 8

  5-Fluorouracil

  500 mg/m2 IV D 1, 8

  Repeated every 28 days for 6 cycles

  FEC-100:

  5-Fluorouracil

  500 mg/m2 

  Epirubicin Hydrochloride Injection

  100 mg/m2 

  Cyclophosphamide

  500 mg/m2 

  All drugs administered intravenously on Day 1 and repeated every 21 days for 6 cycles

  Patients administered the 120-mg/m2 regimen of Epirubicin Hydrochloride Injection should receive prophylactic antibiotic therapy.

  2.2 Dose Modifications

  Epirubicin Hydrochloride Injection dosage adjustments for hematologic and non-hematologic toxicities within a cycle of treatment, is based on nadir platelet counts <50,000/mm3, absolute neutrophil counts (ANC) <250/mm3, neutropenic fever, or Grades 3/4 nonhematologic toxicity. Reduce Epirubicin Hydrochloride Injection Day 1 dose in subsequent cycles to 75% of the Day 1 dose given in the current cycle. Delay Day 1 chemotherapy in subsequent courses of treatment until platelet counts are ≥100,000/mm3, ANC ≥1500/mm3, and nonhematologic toxicities have recovered to ≤ Grade 1.

  Bone Marrow Dysfunction

  Consider administering a lower starting dose (75-90 mg/m2) for heavily pretreated patients, patients with pre-existing bone marrow depression, or in the presence of neoplastic bone marrow infiltration [see Warnings and Precautions (5)]. For patients receiving a divided dose of Epirubicin Hydrochloride Injection (Day 1 and Day 8), the Day 8 dose should be 75% of Day 1 if platelet counts are 75,000-100,000/mm3 and ANC is 1000 to 1499/mm3. If Day 8 platelet counts are <75,000/mm3, ANC <1000/mm3, or Grades 3/4 nonhematologic toxicity has occurred, omit the Day 8 dose.

  Hepatic Impairment

  Recommendations regarding use of Epirubicin Hydrochloride Injection in patients with hepatic impairment are not available because patients with hepatic abnormalities were not included in the adjuvant trials [see Warnings and Precautions (5.5) and Clinical Pharmacology (12.3)]. In patients with elevated serum AST or serum total bilirubin concentrations, the following dose reductions are recommended:

  • Bilirubin 1.2 to 3 mg/dL or AST 2 to 4 times upper limit of normal 1/2 of recommended starting dose • Bilirubin >3 mg/dL or AST > 4 times upper limit of normal 1/4 of recommended starting dose

  Renal Impairment

  While no specific dose recommendation can be made based on the limited available data in patients with renal impairment, consider lower doses in patients with severe renal impairment (serum creatinine >5 mg/dL) [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)].

  2.3 Preparation and Administration Precautions

  Storage of the solution for injection at refrigerated conditions can result in the formation of a gelled product. This gelled product will return to a slightly viscous to mobile solution after 2 to a maximum of 4 hours equilibration at controlled room temperature (15-25°C).

  Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Procedures for proper handling and disposal of anticancer drugs should be used when handling and preparing Epirubicin Hydrochloride Injection. Several guidelines on this subject have been published.1-4 [See References (15).]

  Protective Measures

  Take the following protective measures when handling Epirubicin Hydrochloride Injection:

  • Train personnel in appropriate techniques for reconstitution and handling. • Exclude pregnant staff from working with this drug. • Wear protective clothing: goggles, gowns, and disposable gloves and masks when handling Epirubicin Hydrochloride Injection. • Define a designated area for syringe preparation (preferably under a laminar flow system), with the work surface protected by disposable, plastic-backed, absorbent paper. • Place all items used for reconstitution, administration, or cleaning (including gloves) in high-risk, waste-disposal bags for high temperature incineration. • Treat spillage or leakage with dilute sodium hypochlorite (1% available chlorine) solution, preferably by soaking, and then water. Place all contaminated and cleaning materials in high-risk, waste-disposal bags for incineration. Treat accidental contact with the skin or eyes immediately by copious lavage with water, or soap and water, or sodium bicarbonate solution. However, do not abrade the skin by using a scrub brush. Seek medical attention. Always wash hands after removing gloves.

  Incompatibilities

  Avoid prolonged contact with any solution of an alkaline pH as it will result in hydrolysis of the drug. Do not mix Epirubicin Hydrochloride Injection with heparin or fluorouracil due to chemical incompatibility that may lead to precipitation.

  Epirubicin Hydrochloride Injection can be used in combination with other antitumor agents, but do not mix with other drugs in the same syringe.

  Preparation of Infusion Solution

  Administer Epirubicin Hydrochloride Injection into the tubing of a freely flowing intravenous infusion (0.9% sodium chloride or 5% glucose solution). Patients receiving initial therapy at the recommended starting doses of 100-120 mg/m2 should generally have Epirubicin Hydrochloride Injection infused over 15-20 minutes. For patients who require lower Epirubicin Hydrochloride Injection starting doses due to organ dysfunction or who require modification of Epirubicin Hydrochloride Injection doses during therapy, the Epirubicin Hydrochloride Injection infusion time may be proportionally decreased, but should not be less than 3 minutes. This technique is intended to minimize the risk of thrombosis or perivenous extravasation, which could lead to severe cellulitis, vesication, or tissue necrosis. A direct push injection is not recommended due to the risk of extravasation, which may occur even in the presence of adequate blood return upon needle aspiration. Venous sclerosis may result from injection into small vessels or repeated injections into the same vein [see Warnings and Precautions (5.9)]. Use Epirubicin Hydrochloride Injection within 24 hours of first penetration of the rubber stopper. Discard any unused solution.

  2.1 Recommended Dose

  The recommended dose of Epirubicin Hydrochloride Injection is 100 to 120 mg/m2. The following regimens are recommended:

  CEF-120:

  Cyclophosphamide

  75 mg/m2 PO D 1-14

  Epirubicin Hydrochloride Injection

  60 mg/m2 IV D 1, 8

  5-Fluorouracil

  500 mg/m2 IV D 1, 8

  Repeated every 28 days for 6 cycles

  FEC-100:

  5-Fluorouracil

  500 mg/m2 

  Epirubicin Hydrochloride Injection

  100 mg/m2 

  Cyclophosphamide

  500 mg/m2 

  All drugs administered intravenously on Day 1 and repeated every 21 days for 6 cycles

  Patients administered the 120-mg/m2 regimen of Epirubicin Hydrochloride Injection should receive prophylactic antibiotic therapy.

  2.2 Dose Modifications

  Epirubicin Hydrochloride Injection dosage adjustments for hematologic and non-hematologic toxicities within a cycle of treatment, is based on nadir platelet counts <50,000/mm3, absolute neutrophil counts (ANC) <250/mm3, neutropenic fever, or Grades 3/4 nonhematologic toxicity. Reduce Epirubicin Hydrochloride Injection Day 1 dose in subsequent cycles to 75% of the Day 1 dose given in the current cycle. Delay Day 1 chemotherapy in subsequent courses of treatment until platelet counts are ≥100,000/mm3, ANC ≥1500/mm3, and nonhematologic toxicities have recovered to ≤ Grade 1.

  Bone Marrow Dysfunction

  Consider administering a lower starting dose (75-90 mg/m2) for heavily pretreated patients, patients with pre-existing bone marrow depression, or in the presence of neoplastic bone marrow infiltration [see Warnings and Precautions (5)]. For patients receiving a divided dose of Epirubicin Hydrochloride Injection (Day 1 and Day 8), the Day 8 dose should be 75% of Day 1 if platelet counts are 75,000-100,000/mm3 and ANC is 1000 to 1499/mm3. If Day 8 platelet counts are <75,000/mm3, ANC <1000/mm3, or Grades 3/4 nonhematologic toxicity has occurred, omit the Day 8 dose.

  Hepatic Impairment

  Recommendations regarding use of Epirubicin Hydrochloride Injection in patients with hepatic impairment are not available because patients with hepatic abnormalities were not included in the adjuvant trials [see Warnings and Precautions (5.5) and Clinical Pharmacology (12.3)]. In patients with elevated serum AST or serum total bilirubin concentrations, the following dose reductions are recommended:

  • Bilirubin 1.2 to 3 mg/dL or AST 2 to 4 times upper limit of normal 1/2 of recommended starting dose • Bilirubin >3 mg/dL or AST > 4 times upper limit of normal 1/4 of recommended starting dose

  Renal Impairment

  While no specific dose recommendation can be made based on the limited available data in patients with renal impairment, consider lower doses in patients with severe renal impairment (serum creatinine >5 mg/dL) [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)].

  2.3 Preparation and Administration Precautions

  Storage of the solution for injection at refrigerated conditions can result in the formation of a gelled product. This gelled product will return to a slightly viscous to mobile solution after 2 to a maximum of 4 hours equilibration at controlled room temperature (15-25°C).

  Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Procedures for proper handling and disposal of anticancer drugs should be used when handling and preparing Epirubicin Hydrochloride Injection. Several guidelines on this subject have been published.1-4 [See References (15).]

  Protective Measures

  Take the following protective measures when handling Epirubicin Hydrochloride Injection:

  • Train personnel in appropriate techniques for reconstitution and handling. • Exclude pregnant staff from working with this drug. • Wear protective clothing: goggles, gowns, and disposable gloves and masks when handling Epirubicin Hydrochloride Injection. • Define a designated area for syringe preparation (preferably under a laminar flow system), with the work surface protected by disposable, plastic-backed, absorbent paper. • Place all items used for reconstitution, administration, or cleaning (including gloves) in high-risk, waste-disposal bags for high temperature incineration. • Treat spillage or leakage with dilute sodium hypochlorite (1% available chlorine) solution, preferably by soaking, and then water. Place all contaminated and cleaning materials in high-risk, waste-disposal bags for incineration. Treat accidental contact with the skin or eyes immediately by copious lavage with water, or soap and water, or sodium bicarbonate solution. However, do not abrade the skin by using a scrub brush. Seek medical attention. Always wash hands after removing gloves.

  Incompatibilities

  Avoid prolonged contact with any solution of an alkaline pH as it will result in hydrolysis of the drug. Do not mix Epirubicin Hydrochloride Injection with heparin or fluorouracil due to chemical incompatibility that may lead to precipitation.

  Epirubicin Hydrochloride Injection can be used in combination with other antitumor agents, but do not mix with other drugs in the same syringe.

  Preparation of Infusion Solution

  Administer Epirubicin Hydrochloride Injection into the tubing of a freely flowing intravenous infusion (0.9% sodium chloride or 5% glucose solution). Patients receiving initial therapy at the recommended starting doses of 100-120 mg/m2 should generally have Epirubicin Hydrochloride Injection infused over 15-20 minutes. For patients who require lower Epirubicin Hydrochloride Injection starting doses due to organ dysfunction or who require modification of Epirubicin Hydrochloride Injection doses during therapy, the Epirubicin Hydrochloride Injection infusion time may be proportionally decreased, but should not be less than 3 minutes. This technique is intended to minimize the risk of thrombosis or perivenous extravasation, which could lead to severe cellulitis, vesication, or tissue necrosis. A direct push injection is not recommended due to the risk of extravasation, which may occur even in the presence of adequate blood return upon needle aspiration. Venous sclerosis may result from injection into small vessels or repeated injections into the same vein [see Warnings and Precautions (5.9)]. Use Epirubicin Hydrochloride Injection within 24 hours of first penetration of the rubber stopper. Discard any unused solution.

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• Bleomycin
  

  ×

  Bleomycin

  

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  Because of the possibility of an anaphylactoid reaction, lymphoma patients should be treated with 2 units or less for the first 2 doses. If no acute reaction occurs, then the regular dosage schedule may be followed.

  The following dose schedule is recommended:

  Squamous cell carcinoma, non-Hodgkin’s lymphoma, testicular carcinoma - 0.25 to 0.50 units/kg (10 to 20 units/m2) given intravenously, intramuscularly, or subcutaneously weekly or twice weekly.

  Hodgkin’s Disease - 0.25 to 0.50 units/kg (10 to 20 units/m2) given intravenously, intramuscularly, or subcutaneously weekly or twice weekly. After a 50% response, a maintenance dose of 1 unit daily or 5 units weekly intravenously or intramuscularly should be given.

  Pulmonary toxicity of bleomycin appears to be dose-related with a striking increase when the total dose is over 400 units. Total doses over 400 units should be given with great caution.

  Note: When Bleomycin for Injection is used in combination with other antineoplastic agents, pulmonary toxicities may occur at lower doses.

  Improvement of Hodgkin’s disease and testicular tumors is prompt and noted within 2 weeks. If no improvement is seen by this time, improvement is unlikely. Squamous cell cancers respond more slowly, sometimes requiring as long as 3 weeks before any improvement is noted.

  Malignant Pleural Effusion—60 units administered as a single dose bolus intrapleural injection (see Administration: Intrapleural).

  Use in Patients with Renal Insufficiency

  The following dosing reductions are proposed for patients with creatinine clearance (CrCL) values of less than 50 mL/min:

  Patient CrCL(mL/min) Bleomycin for Injection, USPDose (%) 50 and above 100 40 to 50 70 30 to 40 60 20 to 30

  55

  10 to 20

  45

  5 to 10 40 CrCL can be estimated from the individual patient’s measured serum creatinine (Scr) values using the Cockcroft and Gault formula:

  Males CrCL = [weight x (140 - Age)]/(72 x Scr)

  Females CrCL = 0.85 x [weight x (140 - Age)]/(72 x Scr)

  Where CrCL in mL/min/1.73m2, weight in kg, age in years, and Scr in mg/dL.

  Administration

  Bleomycin for Injection may be given by the intramuscular, intravenous, subcutaneous or intrapleural routes.

  Administration Precautions

  Caution should be exercised when handling Bleomycin for injection. Procedures for proper handling and disposal of anticancer drugs should be utilized. Several guidelines on this subject have been published.1-4 To minimize the risk of dermal exposure, always wear impervious gloves when handling vials containing Bleomycin for injection. If Bleomycin for injection contacts the skin, immediately wash the skin thoroughly with soap and water. If contact with mucous membranes occurs, the membranes should be flushed immediately and thoroughly with water. More information is available in the references listed below.

  Intramuscular or Subcutaneous

  The Bleomycin for Injection, USP 15 units vial should be reconstituted with 1 to 5 mL of Sterile Water for Injection, USP, Sodium Chloride for Injection, 0.9%, USP, or Sterile Bacteriostatic Water for Injection, USP. The Bleomycin for Injection, USP 30 units vial should be reconstituted with 2 to 10 mL of the above diluents.

  Intravenous

  The contents of the 15 units or 30 units vial should be dissolved in 5 mL or 10 mL, respectively of Sodium Chloride for Injection, 0.9%, USP, and administered slowly over a period of 10 minutes.

  Intrapleural

  Sixty units of Bleomycin are dissolved in 50 to 100 mL Sodium Chloride for Injection, 0.9%, USP, and administered through a thoracostomy tube following drainage of excess pleural fluid and confirmation of complete lung expansion. The literature suggests that successful pleurodesis is, in part, dependent upon complete drainage of the pleural fluid and reestablishment of negative intrapleural pressure prior to instillation of a sclerosing agent. Therefore, the amount of drainage from the chest tube should be as minimal as possible prior to instillation of Bleomycin. Although there is no conclusive evidence to support this contention, it is generally accepted that chest tube drainage should be less than 100 mL in a 24-hour period prior to sclerosis. However, Bleomycin instillation may be appropriate when drainage is between 100 to 300 mL under clinical conditions that necessitate sclerosis therapy. The thoracostomy tube is clamped after Bleomcyin instillation. The patient is moved from the supine to the left and right lateral positions several times during the next four hours. The clamp is thenremoved and suction reestablished. The amount of time the chest tube remains in place following sclerosis is dictated by the clinical situation.

  The intrapleural injection of topical anesthetics or systemic narcotic analgesia is generally not required.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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• Paclitaxel
  

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  Paclitaxel

  

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  NOTE: Contact of the undiluted concentrate with plasticized PVC equipment or devices used to prepare solutions for infusion is not recommended. In order to minimize patient exposure to the plasticizer DEHP [di-(2-ethylhexyl)phthalate], which may be leached from PVC infusion bags or sets, diluted paclitaxel solutions should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets.

  All patients should be premedicated prior to paclitaxel administration in order to prevent severe hypersensitivity reactions. Such premedication may consist of dexamethasone 20 mg PO administered approximately 12 and 6 hours before paclitaxel, diphenhydramine (or its equivalent) 50 mg I.V. 30 to 60 minutes prior to paclitaxel, and cimetidine (300 mg) or ranitidine (50 mg) I.V. 30 to 60 minutes before paclitaxel.

  For patients with carcinoma of the ovary the following regimen is recommended: (see CLINICAL STUDIES: Ovarian Carcinoma):

  1)   For previously untreated patients with carcinoma of the ovary, one of the following recommended regimens may be given every 3 weeks. In selecting the appropriate regimen, differences in toxicities should be considered (see Table 11 in ADVERSE REACTIONS: Disease-Specific Adverse Event Experiences).

  a.   Paclitaxel administered intravenously over 3 hours at a dose of 175 mg/m2 followed by cisplatin at a dose of 75 mg/m2; or

  b.   Paclitaxel administered intravenously over 24 hours at a dose of 135 mg/m2 followed by cisplatin at a dose of 75 mg/m2.

  2)   In patients previously treated with chemotherapy for carcinoma of the ovary, paclitaxel has been used at several doses and schedules; however, the optimal regimen is not yet clear. (See CLINICAL STUDIES: Ovarian Carcinoma section). The recommended regimen is paclitaxel 135 mg/m2 or 175 mg/m2 administered intravenously over 3 hours every 3 weeks.

  For patients with carcinoma of the breast, the following is recommended (see CLINICAL STUDIES: Breast Carcinoma section):

  1)   For the adjuvant treatment of node-positive breast cancer, the recommended regimen is paclitaxel, at a dose of 175 mg/m2 intravenously over 3 hours every 3 weeks for 4 courses administered sequentially to doxorubicin-containing combination chemotherapy. The clinical trial used 4 courses of doxorubicin and cyclophosphamide (see CLINICAL STUDIES: Breast Carcinoma).

  2)   After failure of initial chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy, paclitaxel at a dose of 175 mg/m2 administered intravenously over 3 hours every 3 weeks has been shown to be effective.

  For patients with non-small cell lung carcinoma, the recommended regimen, given every 3 weeks, is paclitaxel administered intravenously over 24 hours at a dose of 135 mg/m2 followed by cisplatin, 75 mg/m2.

  For patients with AIDS-related Kaposi’s sarcoma, paclitaxel administered at a dose of 135 mg/m2 given intravenously over 3 hours every 3 weeks or at a dose of 100 mg/m2 given intravenously over 3 hours every 2 weeks is recommended (dose intensity 45–50 mg/m2/week). In the 2 clinical trials evaluating these schedules (see CLINICAL STUDIES: AIDS-Related Kaposi’s Sarcoma), the former schedule (135 mg/m2 every 3 weeks) was more toxic than the latter. In addition, all patients with low performance status were treated with the latter schedule (100 mg/m2 every 2 weeks).

  Based upon the immunosuppression in patients with advanced HIV disease, the following modifications are recommended in these patients:

  1)   Reduce the dose of dexamethasone as 1 of the 3 premedication drugs to 10 mg PO (instead of 20 mg PO);

  2)   Initiate or repeat treatment with paclitaxel only if the neutrophil count is at least 1,000 cells/mm3;

  3)   Reduce the dose of subsequent courses of paclitaxel by 20% for patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer); and

  4)   Initiate concomitant hematopoietic growth factor (G-CSF) as clinically indicated.

  For the therapy of patients with solid tumors (ovary, breast and NSCLC), courses of paclitaxel should not be repeated until the neutrophil count is at least 1,500 cells/mm3 and the platelet count is at least 100,000 cells/mm3. Paclitaxel should not be given to patients with AIDS-related Kaposi’s sarcoma if the baseline or subsequent neutrophil count is less than 1,000 cells/mm3. Patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer) or severe peripheral neuropathy during Paclitaxel Injection, USP therapy should have dosage reduced by 20% for subsequent courses of paclitaxel. The incidence of neurotoxicity and the severity of neutropenia increase with dose.

  Hepatic Impairment: Patients with hepatic impairment may be at increased risk of toxicity, particularly grade III–IV myelosuppression (see CLINICAL PHARMACOLOGY and PRECAUTIONS: Hepatic). Recommendations for dosage adjustment for the first course of therapy are shown in Table 17 for both 3- and 24-hour infusions. Further dose reduction in subsequent courses should be based on individual tolerance. Patients should be monitored closely for the development of profound myelosuppression.

  Table 17. Recommendations for Dosing in Patients with Hepatic Impairment Based on Clinical Trial Dataa

  Degree of Hepatic Impairment

  Recommended Paclitaxel Dosec

  Transaminase

  Levels

  Bilirubin Levelsb

  24-Hour Infusion

  <2 x ULN

  and

  ≤1.5 mg/dL

  135 mg/m2

  2 to <10 x ULN

  and

  ≤1.5 mg/dL

  100 mg/m2

  <10 x ULN

  and

  1.6-7.5 mg/dL

  50 mg/m2

  ≥10 x ULN

  or

  >7.5 mg/dL

  Not recommended

  3-Hour Infusion

  <10 x ULN

  and

  ≤1.25 x ULN

  175 mg/m2

  <10 x ULN

  and

  1.26-2.0 x ULN

  135 mg/m2

  <10 x ULN

  and

  2.01-5.0 x ULN

  90 mg/m2

  ≥10 x ULN

  or

  >5.0 x ULN

  Not recommended

  a   These recommendations are based on dosages for patients without hepatic imairement of 135 mg/m2 over 24 hours or 175 mg/m2 over 3 hours; data are not available to make dose adjustment recommendations for other regimens (eg, for AIDS-related Kaposi’s sarcoma).

  b   Differences in criteria for bilirubin levels between the 3- and 24-hour infusion are due to differences in clinical trial design.

  c   Dosage recommendations are for the first course of therapy; further dose reduction in subsequent courses should be based on individual tolerance.

  Preparation and Administration Precautions: Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1–4 To minimize the risk of dermal exposure, always wear impervious gloves when handling vials containing paclitaxel Injection. If paclitaxel solution contacts the skin, wash the skin immediately and thoroughly with soap and water. Following topical exposure, events have included tingling, burning, and redness. If paclitaxel contacts mucous membranes, the membranes should be flushed thoroughly with water. Upon inhalation, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported.

  Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration. (See PRECAUTIONS: Injection Site Reaction section.)

  Preparation for Intravenous Administration: Paclitaxel must be diluted prior to infusion. Paclitaxel should be diluted in 0.9% Sodium Chloride Injection, USP; 5% Dextrose Injection, USP; 5% Dextrose and 0.9% Sodium Chloride Injection, USP or 5% Dextrose in Ringer’s Injection to a final concentration of 0.3 to 1.2 mg/mL. The solutions are physically and chemically stable for up to 27 hours at ambient temperature (approximately 25°C) and room lighting conditions. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

  Upon preparation, solutions may show haziness, which is attributed to the formulation vehicle. No significant losses in potency have been noted following simulated delivery of the solution through I.V. tubing containing an in-line (0.22 micron) filter.

  Data collected for the presence of the extractable plasticizer DEHP [di-(2-ethylhexyl) phthalate] show that levels increase with time and concentration when dilutions are prepared in PVC containers. Consequently, the use of plasticized PVC containers and administration sets is not recommended.

  Paclitaxel solutions should be prepared and stored in glass, polypropylene, or polyolefin containers. Non-PVC containing administration sets, such as those which are polyethylene-lined, should be used.

  Paclitaxel should be administered through an in-line filter with a microporous membrane not greater than 0.22 microns. Use of filter devices such as IVEX-2® filters which incorporate short inlet and outlet PVC-coated tubing has not resulted in significant leaching of DEHP.

  The Chemo Dispensing Pin™ device or similar devices with spikes should not be used with vials of paclitaxel since they can cause the stopper to collapse resulting in loss of sterile integrity of the paclitaxel solution.

  Stability: Unopened vials of Paclitaxel Injection, USP are stable until the date indicated on the package when stored between 20° to 25°C (68° to 77°F), in the original package. Neither freezing nor refrigeration adversely affects the stability of the product. Upon refrigeration components in the paclitaxel vial may precipitate, but will redissolve upon reaching room temperature with little or no agitation. There is no impact on product quality under these circumstances. If the solution remains cloudy or if an insoluble precipitate is noted, the vial should be discarded. Solutions for infusion prepared as recommended are stable at ambient temperature (approximately 25°C) and lighting conditions for up to 27 hours.

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• Vincristine Sulfate
  

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  Vincristine Sulfate

  

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  This preparation is for intravenous use only (see WARNINGS).

  Neurotoxicity appears to be dose related. Extreme care must be used in calculating and administering the dose of Vincristine Sulfate Injection, USP since overdosage may have a very serious or fatal outcome.

  The usual dose of Vincristine Sulfate Injection, USP for pediatric patients is 1.5–2 mg/m2. For pediatric patients weighing 10 kg or less, the starting dose should be 0.05 mg/kg, administered once a week. The usual dose of Vincristine Sulfate Injection, USP for adults is 1.4 mg/m2. A 50% reduction in the dose of Vincristine Sulfate Injection, USP is recommended for patients having a direct serum bilirubin value above 3 mg/100 mL.

  The drug is administered intravenously at weekly intervals.

  TO REDUCE THE POTENTIAL FOR FATAL MEDICATION ERRORS DUE TO INCORRECT ROUTE OF ADMINISTRATION, VINCRISTINE SULFATE INJECTION SHOULD BE DILUTED IN A FLEXIBLE PLASTIC CONTAINER AND PROMINENTLY LABELED FOR INTRAVENOUS USE ONLY (See WARNINGS).

  The concentration of Vincristine Sulfate Injection, USP is 1 mg/mL. Do not add extra fluid to the vial prior to removal of the dose. Withdraw the solution of Vincristine Sulfate Injection, USP into an accurate dry syringe, measuring the dose carefully. Do not add extra fluid to the vial in an attempt to empty it completely.

  Preparation for flexible plastic container

  Vincristine Sulfate Injection, USP when diluted with 0.9% Sodium Chloride Injection in concentrations from 0.0015 mg/mL to 0.08 mg/mL is stable for up to 24 hours when protected from light or 8 hours under normal light at 25°C.

  Preparation for syringe

  Special Dispensing Information: when dispensing Vincristine Sulfate Injection, USP in a syringe, it is imperative that it be packaged in the provided overwrap which bears the following statement: “DO NOT REMOVE COVERING UNTIL MOMENT OF INJECTION. FOR INTRAVENOUS USE ONLY – FATAL IF GIVEN BY OTHER ROUTES” (see WARNINGS). A syringe containing a specific dose must be labeled, using the auxiliary sticker provided, to state: “FOR INTRAVENOUS USE ONLY – FATAL IF GIVEN  BY OTHER ROUTES.”

  Caution: It is extremely important that the intravenous needle or catheter be properly positioned before any vincristine is injected. Leakage into surrounding tissue during intravenous administration of Vincristine Sulfate Injection, USP may cause considerable irritation. If extravasation occurs, the injection should be discontinued immediately and any remaining portion of the dose should then be introduced into another vein. Local injection of hyaluronidase and the application of moderate heat to the area of leakage will help disperse the drug and may minimize discomfort and the possibility of cellulitis.

  Vincristine Sulfate Injection, USP must be administered via an intact, free–flowing intravenous needle or catheter. Care should be taken that there is no leakage or swelling occurring during administration (see boxed WARNINGS).

  The solution may be injected either directly into a vein or into the tubing of a running intravenous infusion (see Drug Interactions below). Injection of Vincristine Sulfate Injection, USP should be accomplished within 1 minute.

  Patients Receiving Radiation Therapy - Vincristine Sulfate Injection, USP should not be given to patients while they are receiving radiation therapy through ports that include the liver. When Vincristine Sulfate Injection, USP is used in combination with L–asparaginase, Vincristine Sulfate Injection, USP should be given 12 to 24 hours before administration of the enzyme in order to minimize toxicity; administering L–asparaginase before Vincristine Sulfate Injection, USP may reduce hepatic clearance of vincristine.

  Drug Interactions – Vincristine Sulfate Injection, USP should not be diluted in solutions that raise or lower the pH outside the range of 3.5 to 5.5. It should not be mixed with anything other than normal saline or glucose in water.

  Whenever solution and container permit, parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

  Handling and Disposal – Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1  There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

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• Methotrexate
  

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  Methotrexate

  

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  Neoplastic Diseases

  Oral administration in tablet form is often preferred when low doses are being administered since absorption is rapid and effective serum levels are obtained. Methotrexate injection may be given by the intramuscular, intravenous or intra-arterial route. However, the preserved formulation contains Benzyl Alcohol and must not be used for intrathecal or high dose therapy. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  Choriocarcinoma and similar trophoblastic diseases: Methotrexate is administered orally or intramuscularly in doses of 15 to 30 mg daily for a five-day course. Such courses are usually repeated for 3 to 5 times as required, with rest periods of one or more weeks interposed between courses, until any manifesting toxic symptoms subside. The effectiveness of therapy is ordinarily evaluated by 24 hour quantitative analysis of urinary chorionic gonadotropin (hCG), which should return to normal or less than 50 IU/24 hr usually after the third or fourth course and usually be followed by a complete resolution of measurable lesions in 4 to 6 weeks. One to two courses of methotrexate after normalization of hCG is usually recommended. Before each course of the drug careful clinical assessment is essential. Cyclic combination therapy of methotrexate with other antitumor drugs has been reported as being useful.

  Since hydatidiform mole may precede choriocarcinoma, prophylactic chemotherapy with methotrexate has been recommended.

  Chorioadenoma destruens is considered to be an invasive form of hydatidiform mole.

  Methotrexate is administered in these disease states in doses similar to those recommended for choriocarcinoma.

  Leukemia: Acute lymphoblastic leukemia in pediatric patients and young adolescents is the most responsive to present day chemotherapy. In young adults and older patients, clinical remission is more difficult to obtain and early relapse is more common.

  Methotrexate alone or in combination with steroids was used initially for induction of remission in acute lymphoblastic leukemias. More recently corticosteroid therapy, in combination with other antileukemic drugs or in cyclic combinations with methotrexate included, has appeared to produce rapid and effective remissions. When used for induction, methotrexate in doses of 3.3 mg/m2 in combination with 60 mg/m2 of prednisone, given daily, produced remissions in 50% of patients treated, usually within a period of 4 to 6 weeks. Methotrexate in combination with other agents appears to be the drug of choice for securing maintenance of drug-induced remissions. When remission is achieved and supportive care has produced general clinical improvement, maintenance therapy is initiated, as follows: Methotrexate is administered 2 times weekly either by mouth or intramuscularly in total weekly doses of 30 mg/m2. It has also been given in doses of 2.5 mg/kg intravenously every 14 days. If and when relapse does occur, reinduction of remission can again usually be obtained by repeating the initial induction regimen.

  A variety of combination chemotherapy regimens have been used for both induction and maintenance therapy in acute lymphoblastic leukemia. The physician should be familiar with the new advances in antileukemic therapy.

  Meningeal Leukemia: In the treatment of prophylaxis of meningeal leukemia, methotrexate must be administered intrathecally. Preservative free methotrexate is diluted to a concentration of 1 mg/mL in an appropriate sterile, preservative free medium such as 0.9% Sodium Chloride Injection, USP.

  The cerebrospinal fluid volume is dependent on age and not on body surface area. The CSF is at 40% of the adult volume at birth and reaches the adult volume in several years.

  Intrathecal methotrexate administration at a dose of 12 mg/m2 (maximum 15 mg) has been reported to result in low CSF methotrexate concentrations and reduced efficacy in pediatric patients and high concentrations and neurotoxicity in adults. The following dosage regimen is based on age instead of body surface area:

  AGE (years)

  DOSE (mg)

  <1

  6

  1

  8

  2

  10

  3 or older

  12

  In one study in patients under the age of 40, this dosage regimen appeared to result in more consistent CSF methotrexate concentrations and less neurotoxicity. Another study in pediatric patients with acute lymphocytic leukemia compared this regimen to a dose of 12 mg/m2 (maximum 15 mg), a significant reduction in the rate of CNS relapse was observed in the group whose dose was based on age.

  Because the CSF volume and turnover may decrease with age, a dose reduction may be indicated in elderly patients.

  For treatment of meningeal leukemia, intrathecal methotrexate may be given at intervals of 2 to 5 days. However, administration at intervals of less than 1 week may result in increased subacute toxicity. Methotrexate is administered until the cell count of the cerebrospinal fluid returns to normal. At this point one additional dose is advisable.

  For prophylaxis against meningeal leukemia, the dosage is the same as for treatment except for the intervals of administration. On this subject, it is advisable for the physician to consult the medical literature.

  Untoward side effects may occur with any given intrathecal injection and are commonly neurological in character. Large doses may cause convulsions. Methotrexate given by the intrathecal route appears significantly in the systemic circulation and may cause systemic methotrexate toxicity. Therefore, systemic antileukemic therapy with the drug should be appropriately adjusted, reduced or discontinued. Focal leukemic involvement of the central nervous system may not respond to intrathecal chemotherapy and is best treated with radiotherapy.

  Lymphomas: In Burkitt’s tumor, Stages I-II, methotrexate has produced prolonged remissions in some cases. Recommended dosage is 10 to 25 mg/day orally for 4 to 8 days. In Stage III, methotrexate is commonly given concomitantly with other antitumor agents. Treatment in all stages usually consists of several courses of the drug interposed with 7 to 10 day rest periods. Lymphosarcomas in Stage III may respond to combined drug therapy with methotrexate given in doses of 0.625 to 2.5 mg/kg daily.

  Mycosis fungoides (cutaneous T cell lymphoma): Therapy with methotrexate as a single agent appears to produce clinical responses in up to 50% of patients treated. Dosage in early stages is usually 5 to 50 mg once weekly. Dose reduction or cessation is guided by patient response and hematologic monitoring. Methotrexate has also been administered twice weekly in doses ranging from 15 to 37.5 mg in patients who have responded poorly to weekly therapy. Combination chemotherapy regimens that include intravenous methotrexate administered at higher doses with leucovorin rescue have been utilized in advanced stages of the disease.

  Osteosarcoma: An effective adjuvant chemotherapy regimen requires the administration of several cytotoxic chemotherapeutic agents. In addition to high-dose methotrexate with leucovorin rescue, these agents may include doxorubicin, cisplatin, and the combination of bleomycin, cyclophosphamide and dactinomycin (BCD) in the doses and schedule shown in the table below. The starting dose for high-dose methotrexate treatment is 12 grams/m2. If this dose is not sufficient to produce a peak serum methotrexate concentration of 1,000 micromolar (10-3 mol/L) at the end of the methotrexate infusion, the dose may be escalated to 15 grams/m2 in subsequent treatments. If the patient is vomiting or is unable to tolerate oral medication, leucovorin is given IV or IM at the same dose and schedule.

  Drug*

  Dose*

  Treatment Week After Surgery

  Methotrexate

  12 g/m2 IV as 4 hour infusion (starting dose)

  4,5,6,7,11,12,15,16,29,30,44,45

  Leucovorin

  15 mg orally every six hours for 10 doses starting at 24 hours after start of methotrexate infusion

  - - -

  Doxorubicin† as a single drug

  30 mg/m2 day IV x 3 days

  8,17

  Doxorubicin†

  50 mg/m2 IV

  20,23,33,36

  Cisplatin†

  100 mg/m2 IV

  20,23,33,36

  Bleomycin †

  15 units/m2 IV x 2 days

  2,13,26,39,42

  Cyclophosphamide†

  600 mg/m2 IV x 2 days

  2,13,26,39,42

  Dactinomycin†

  0.6 mg/m2 IV x 2 days

  2,13,26,39,42

  * Link MP, Goorin AM, Miser AW, et al: The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J of Med 1986; 314 (No.25): 1600-1606. † See each respective package insert for full prescribing information. Dosage modifications may be necessary because of drug-induced toxicity.

  When these higher doses of methotrexate are to be administered, the following safety guidelines should be closely observed.

  GUIDELINES FOR METHOTREXATE THERAPY WITH LEUCOVORIN RESCUE

  1.   Administration of methotrexate should be delayed until recovery if:

  the WBC count is less than 1500/microliter the neutrophil count is less than 200/microliter the platelet count is less than 75,000/microliter the serum bilirubin level is greater than 1.2 mg/dL the SGPT level is greater than 450 U mucositis is present, until there is evidence of healing persistent pleural effusion is present; this should be drained dry prior to infusion.

  2.   Adequate renal function must be documented.

          a.   Serum creatinine must be normal, and creatinine clearance must be greater than 60 mL/min, before initiation of therapy.         b.   Serum creatinine must be measured prior to each subsequent course of therapy. If serum creatinine has increased by 50% or more compared to a prior value, the creatinine clearance must be measured and documented to be greater than 60 mL/min (even if the serum creatinine is still within the normal range).

  3.   Patients must be well hydrated, and must be treated with sodium bicarbonate for urinary alkalinization.

          a.   Administer 1,000 mL/m2 of intravenous fluid over 6 hours prior to initiation of the methotrexate infusion. Continue hydration at 125 mL/m2/hr (3 liters/m2/day) during the methotrexate infusion, and for 2 days after the infusion has been completed.         b.   Alkalinize urine to maintain pH above 7.0 during methotrexate infusion and leucovorin calcium therapy. This can be accomplished by the administration of sodium bicarbonate orally or by incorporation into a separate intravenous solution.

  4.   Repeat serum creatinine and serum methotrexate 24 hours after starting methotrexate and at least once daily until the methotrexate level is below 5 x 10-8 mol/L (0.05 micromolar).

  5.   The table below provides guidelines for leucovorin calcium dosage based upon serum methotrexate levels. (See table below.‡)

  Patients who experience delayed early methotrexate elimination are likely to develop nonreversible oliguric renal failure. In addition to appropriate leucovorin therapy, these patients require continuing hydration and urinary alkalinization, and close monitoring of fluid and electrolyte status, until the serum methotrexate level has fallen to below 0.05 micromolar and the renal failure has resolved. If necessary, acute, intermittent hemodialysis with a high-flux dialyzer may also be beneficial in these patients.

  6.    Some patients will have abnormalities in methotrexate elimination, or abnormalities in renal function following methotrexate administration, which are significant but less severe than the abnormalities described in the table below. These abnormalities may or may not be associated with significant clinical toxicity. If significant toxicity is observed, leucovorin rescue should be extended for an additional 24 hours (total 14 doses over 84 hours) in subsequent courses of therapy. The possibility that the patient is taking other medications which interact with methotrexate (e.g., medications which may interfere with methotrexate binding to serum albumin, or elimination) should always be reconsidered when laboratory abnormalities or clinical toxicities are observed.

  CAUTION: DO NOT ADMINISTER LEUCOVORIN INTRATHECALLY.

  Psoriasis, Rheumatoid Arthritis, and Juvenile Rheumatoid Arthritis Adult Rheumatoid Arthritis: Recommended Starting Dosage Schedules

  Single oral doses of 7.5 mg once weekly.† Divided oral dosages of 2.5 mg at 12 hour intervals for 3 doses given as a course once weekly.† † Methotrexate Sodium Tablets for oral administration are available.

  Polyarticular-Course Juvenile Rheumatoid Arthritis: The recommended starting dose is 10 mg/m2 given once weekly.

  For either adult RA or polyarticular-course JRA, dosages may be adjusted gradually to achieve an optimal response. Limited experience shows a significant increase in the incidence and severity of serious toxic reactions, especially bone marrow suppression, at doses greater than 20 mg/wk in adults. Although there is experience with doses up to 30 mg/m2/wk in children, there are too few published data to assess how doses over 20 mg/m2/wk might affect the risk of serious toxicity in children. Experience does suggest, however, that children receiving 20 to 30 mg/m2/wk (0.65 to 1.0 mg/kg/wk) may have better absorption and fewer gastrointestinal side effects if methotrexate is administered either intramuscularly or subcutaneously.

  Therapeutic response usually begins within 3 to 6 weeks and the patient may continue to improve for another 12 weeks or more.

  The optimal duration of therapy is unknown. Limited data available from long-term studies in adults indicate that the initial clinical improvement is maintained for at least two years with continued therapy. When methotrexate is discontinued, the arthritis usually worsens within 3 to 6 weeks.

  The patient should be fully informed of the risks involved and should be under constant supervision of the physician. (See Information for Patients under PRECAUTIONS). Assessment of hematologic, hepatic, renal, and pulmonary function should be made by history, physical examination, and laboratory tests before beginning, periodically during, and before reinstituting methotrexate therapy. (See PRECAUTIONS). Appropriate steps should be taken to avoid conception during methotrexate therapy. (See PRECAUTIONS and CONTRAINDICATIONS).

  All schedules should be continually tailored to the individual patient. An initial test dose may be given prior to the regular dosing schedule to detect any extreme sensitivity to adverse effects (See ADVERSE REACTIONS). Maximal myelosuppression usually occurs in seven to ten days.

  Psoriasis: Recommended Starting Dose Schedule:

  Weekly single oral, IM or IV dosage schedule: 10 to 25 mg per week until adequate response is achieved.† Divided oral dose schedule 2.5 mg at 12 hour intervals for three doses.††Methotrexate Sodium Tablets for oral administration are available.

  Dosages in each schedule may be gradually adjusted to achieve optimal clinical response; 30 mg/week should not ordinarily be exceeded.

  Once optimal clinical response has been achieved, each dosage schedule should be reduced to the lowest possible amount of drug and to the longest possible rest period. The use of methotrexate may permit the return to conventional topical therapy, which should be encouraged.

  HANDLING AND DISPOSAL

  Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

  DILUTION INSTRUCTIONS FOR LIQUID METHOTREXATE INJECTION PRODUCT

  Methotrexate Injection, USP, Isotonic Liquid, Contains Preservative

  If desired, the solution may be further diluted with a compatible medium such as Sodium Chloride Injection, USP. Storage for 24 hours at a temperature of 21°C to 25°C results in a product which is within 90% of label potency.

  Methotrexate Injection, USP, Isotonic Liquid, Preservative Free, for Single Use Only

  If desired, the solution may be further diluted immediately prior to use with an appropriate sterile, preservative free medium such as 5% Dextrose Solution, USP or Sodium Chloride Injection, USP.

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• Pamidronate Disodium
  

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  Pamidronate Disodium

  

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  Hypercalcemia of Malignancy

  Consideration should be given to the severity of as well as the symptoms of hypercalcemia. Vigorous saline hydration alone may be sufficient for treating mild, asymptomatic hypercalcemia.

  Overhydration should be avoided in patients who have potential for cardiac failure. In hypercalcemia associated with hematologic malignancies, the use of glucocorticoid therapy may be helpful.

  Moderate Hypercalcemia

  The recommended dose of pamidronate disodium in moderate hypercalcemia (corrected serum calcium* of approximately 12 to 13.5 mg/dL) is 60 to 90 mg given as a SINGLE-DOSE, intravenous infusion over 2 to 24 hours. Longer infusions (i.e., >2 hours) may reduce the risk for renal toxicity, particularly in patients with preexisting renal insufficiency.

  Severe Hypercalcemia

  The recommended dose of pamidronate disodium in severe hypercalcemia (corrected serum calcium* >13.5 mg/dL) is 90 mg given as a SINGLE-DOSE, intravenous infusion over 2 to 24 hours. Longer infusions (i.e., >2 hours) may reduce the risk for renal toxicity, particularly in patients with preexisting renal insufficiency.

  * Albumin-corrected serum calcium (CCa, mg/dL) = serum calcium, mg/dL + 0.8 (4.0-serum albumin, g/dL).

  Retreatment

  A limited number of patients have received more than one treatment with pamidronate disodium for hypercalcemia. Retreatment with pamidronate disodium, in patients who show complete or partial response initially, may be carried out if serum calcium does not return to normal or remain normal after initial treatment. It is recommended that a minimum of 7 days elapse before retreatment, to allow for full response to the initial dose. The dose and manner of retreatment is identical to that of the initial therapy.

  Paget’s Disease

  The recommended dose of pamidronate disodium in patients with moderate to severe Paget’s disease of bone is 30 mg daily, administered as a 4-hour infusion on 3 consecutive days for a total dose of 90 mg.

  Retreatment

  A limited number of patients with Paget’s disease have received more than one treatment of pamidronate disodium in clinical trials. When clinically indicated, patients should be retreated at the dose of initial therapy.

  Osteolytic Bone Lesions of Multiple Myeloma

  The recommended dose of pamidronate disodium in patients with osteolytic bone lesions of multiple myeloma is 90 mg administered as a 4-hour infusion given on a monthly basis.

  Patients with marked Bence-Jones proteinuria and dehydration should receive adequate hydration prior to pamidronate disodium infusion.

  Limited information is available on the use of pamidronate disodium in multiple myeloma patients with a serum creatinine ≥ 3.0 mg/dL.

  Patients who receive pamidronate disodium should have serum creatinine assessed prior to each treatment. Treatment should be withheld for renal deterioration. In a clinical study, renal deterioration was defined as follows:

  For patients with normal baseline creatinine, increase of 0.5 mg/dL.

  For patients with abnormal baseline creatinine, increase of 1.0 mg/dL.

  In this clinical study, pamidronate disodium treatment was resumed only when the creatinine returned to within 10% of the baseline value.

  The optimal duration of therapy is not yet known, however, in a study of patients with myeloma, final analysis after 21 months demonstrated overall benefits (see Clinical Trials section).

  Osteolytic Bone Metastases of Breast Cancer

  The recommended dose of pamidronate disodium in patients with osteolytic bone metastases is 90 mg administered over a 2-hour infusion given every 3 to 4 weeks.

  Pamidronate disodium has been frequently used with doxorubicin, fluorouracil, cyclophosphamide, methotrexate, mitoxantrone, vinblastine, dexamethasone, prednisone, melphalan, vincristine, megesterol, and tamoxifen. It has been given less frequently with etoposide, cisplatin, cytarabine, paclitaxel, and aminoglutethimide.

  Patients who receive pamidronate disodium should have serum creatinine assessed prior to each treatment. Treatment should be withheld for renal deterioration. In a clinical study, renal deterioration was defined as follows:

  For patients with normal baseline creatinine, increase of 0.5 mg/dL.

  For patients with abnormal baseline creatinine, increase of 1.0 mg/dL.

  In this clinical study, pamidronate disodium treatment was resumed only when the creatinine returned to within 10% of the baseline value.

  The optimal duration of therapy is not known, however, in two breast cancer studies, final analyses performed after 24 months of therapy demonstrated overall benefits (see Clinical Trials section).

  Calcium and Vitamin D Supplementation

  In the absence of hypercalcemia, patients with predominantly lytic bone metastases or multiple myeloma, who are at risk of calcium or vitamin D deficiency, and patients with Paget’s disease of the bone, should be given oral calcium and vitamin D supplementation in order to minimize the risk of hypocalcemia.

  Method of Administration

  DUE TO THE RISK OF CLINICALLY SIGNIFICANT DETERIORATION IN RENAL FUNCTION, WHICH MAY PROGRESS TO RENAL FAILURE, SINGLE DOSES OF PAMIDRONATE DISODIUM SHOULD NOT EXCEED 90 MG. (SEE WARNINGS.)

  There must be strict adherence to the intravenous administration recommendations for pamidronate disodium in order to decrease the risk of deterioration in renal function.

  Hypercalcemia of Malignancy

  The daily dose must be administered as an intravenous infusion over at least 2 to 24 hours for the 60-mg and 90-mg doses. The recommended dose should be diluted in 1000 mL of sterile 0.45% or 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP. This infusion solution is stable for up to 24 hours at room temperature.

  Paget’s Disease

  The recommended daily dose of 30 mg should be diluted in 500 mL of sterile 0.45% or 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP, and administered over a 4-hour period for 3 consecutive days.

  Osteolytic Bone Metastases of Breast Cancer

  The recommended dose of 90 mg should be diluted in 250 mL of sterile 0.45% or 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP, and administered over a 2-hour period every 3 to 4 weeks.

  Osteolytic Bone Lesions of Multiple Myeloma

  The recommended dose of 90 mg should be diluted in 500 mL of sterile 0.45% or 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP, and administered over a 4-hour period on a monthly basis.

  Pamidronate disodium must not be mixed with calcium-containing infusion solutions, such as Ringer’s solution, and should be given in a single intravenous solution and line separate from all other drugs. Note: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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• Aquasol A
  

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  Aquasol A

  

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  For intramuscular use.

  I. Adults 100,000 Units daily for three days followed by 50,000 Units daily for two weeks. II. Pediatric patients 1 to 8 years old 17,500 to 35,000 Units daily for 10 days. III. Infants 7,500 to 15,000 Units daily for 10 days.

  Follow-up therapy with an oral therapeutic multivitamin preparation, containing 10,000 to 20,000 Units vitamin A for adults and for pediatric patients over 8 years old, and 5,000 to 10,000 Units for infants and other pediatric patients under 8 years old, is recommended daily for two months. Low birth-weight infants may require additional vitamin A though the exact dosing in these pediatric patients has not been established. In malabsorption, the parenteral route must be used for an equivalent preparation.

  Poor dietary habits should be corrected and an abundant and well-balanced dietary intake should be prescribed.

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• Mitoxantrone
  

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  Mitoxantrone

  

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  (See also WARNINGS)

  Multiple Sclerosis: The recommended dosage of mitoxantrone is 12 mg/m2 given as a short (approximately 5 to 15 minutes) intravenous infusion every 3 months. Left ventricular ejection fraction (LVEF) should be evaluated by echocardiogram or MUGA prior to administration of the initial dose of mitoxantrone and all subsequent doses. In addition, LVEF evaluations are recommended if signs or symptoms of congestive heart failure develop at any time during treatment with mitoxantrone. Mitoxantrone should not be administered to multiple sclerosis patients with an LVEF <50%, with a clinically significant reduction in LVEF, or to those who have received a cumulative lifetime dose of ≥ 140 mg/m2. Complete blood counts, including platelets, should be monitored prior to each course of mitoxantrone and in the event that signs or symptoms of infection develop. Mitoxantrone generally should not be administered to multiple sclerosis patients with neutrophil counts less than 1500 cells/mm3. Liver function tests should also be monitored prior to each course. Mitoxantrone therapy in multiple sclerosis patients with abnormal liver function tests is not recommended because mitoxantrone clearance is reduced by hepatic impairment and no laboratory measurement can predict drug clearance and dose adjustments.

  Women with multiple sclerosis who are biologically capable of becoming pregnant, even if they are using birth control, should have a pregnancy test, and the results should be known, before receiving each dose of mitoxantrone (see WARNINGS, Pregnancy).

  Hormone-Refractory Prostate Cancer: Based on data from two Phase 3 comparative trials of mitoxantrone plus corticosteroids versus corticosteroids alone, the recommended dosage of mitoxantrone is 12 to 14 mg/m2 given as a short intravenous infusion every 21 days.

  Combination Initial Therapy for ANLL in Adults: For induction, the recommended dosage is 12 mg/m2 of mitoxantrone daily on Days 1 to 3 given as an intravenous infusion, and 100 mg/m2 of cytarabine for 7 days given as a continuous 24-hour infusion on Days 1 to 7.

  Most complete remissions will occur following the initial course of induction therapy. In the event of an incomplete antileukemic response, a second induction course may be given. Mitoxantrone should be given for 2 days and cytarabine for 5 days using the same daily dosage levels.

  If severe or life-threatening nonhematologic toxicity is observed during the first induction course, the second induction course should be withheld until toxicity resolves.

  Consolidation therapy which was used in two large randomized multicenter trials consisted of mitoxantrone, 12 mg/m2 given by intravenous infusion daily on Days 1 and 2 and cytarabine, 100 mg/m2 for 5 days given as a continuous 24-hour infusion on Days 1 to 5. The first course was given approximately 6 weeks after the final induction course; the second was generally administered 4 weeks after the first. Severe myelosuppression occurred. (See CLINICAL PHARMACOLOGY)

  Hepatic Impairment: For patients with hepatic impairment, there is at present no laboratory measurement that allows for dose adjustment recommendations. (See CLINICAL PHARMACOLOGY, Special Populations, Hepatic Impairment)

  Preparation and Administration Precautions

  MITOXANTRONE INJECTION, USP (CONCENTRATE) MUST BE DILUTED PRIOR TO USE.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. The dose of mitoxantrone should be diluted to at least 50 mL with either 0.9% Sodium Chloride Injection (USP) or 5% Dextrose Injection (USP). Mitoxantrone Injection, USP (concentrate) may be further diluted into Dextrose 5% in Water, Normal Saline or Dextrose 5% with Normal Saline and used immediately. DO NOT FREEZE.

  Mitoxantrone should not be mixed in the same infusion as heparin since a precipitate may form. Because specific compatibility data are not available, it is recommended that mitoxantrone not be mixed in the same infusion with other drugs. The diluted solution should be introduced slowly into the tubing as a freely running intravenous infusion of 0.9% Sodium Chloride Injection (USP) or 5% Dextrose Injection (USP) over a period of not less than 3 minutes. Unused infusion solutions should be discarded immediately in an appropriate fashion. In the case of multidose use, after penetration of the stopper, the remaining portion of the undiluted Mitoxantrone Injection, USP concentrate should be stored not longer than 7 days between 15° to 25°C (59° to 77°F) or 14 days under refrigeration. DO NOT FREEZE. CONTAINS NO PRESERVATIVE.

  Care in the administration of mitoxantrone will reduce the chance of extravasation. Mitoxantrone should be administered into the tubing of a freely running intravenous infusion of 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. The tubing should be attached to a Butterfly needle or other suitable device and inserted preferably into a large vein. If possible, avoid veins over joints or in extremities with compromised venous or lymphatic drainage. Care should be taken to avoid extravasation at the infusion site and to avoid contact of mitoxantrone with the skin, mucous membranes, or eyes. MITOXANTRONE SHOULD NOT BE ADMINISTERED SUBCUTANEOUSLY. If any signs or symptoms of extravasation have occurred, including burning, pain, pruritis, erythema, swelling, blue discoloration, or ulceration, the injection or infusion should be immediately terminated and restarted in another vein. During intravenous administration of mitoxantrone extravasation may occur with or without an accompanying stinging or burning sensation even if blood returns well on aspiration of the infusion needle. If it is known or suspected that subcutaneous extravasation has occurred, it is recommended that intermittent ice packs be placed over the area of extravasation and that the affected extremity be elevated. Because of the progressive nature of extravasation reactions, the area of injection should be frequently examined and surgery consultation obtained early if there is any sign of a local reaction.

  Skin accidentally exposed to mitoxantrone should be rinsed copiously with warm water and if the eyes are involved, standard irrigation techniques should be used immediately. The use of goggles, gloves, and protective gowns is recommended during preparation and administration of the drug.

  Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-4 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

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• Levofloxacin
  

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  Levofloxacin

  

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  Oxaliplatin should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of therapy and complications is possible only when adequate diagnostic and treatment facilities are readily available.

  2.1 Dosage

  Administer Oxaliplatin in combination with 5-fluorouracil/leucovorin every 2 weeks. For advanced disease, treatment is recommended until disease progression or unacceptable toxicity. For adjuvant use, treatment is recommended for a total of 6 months (12 cycles):

  Day 1: Oxaliplatin 85 mg/m2 intravenous infusion in 250-500 mL 5% Dextrose injection, USP and leucovorin 200 mg/m2 intravenous infusion in 5% Dextrose Injection, USP both given over 120 minutes at the same time in separate bags using a Y-line, followed by 5-fluorouracil 400 mg/m2 intravenous bolus given over 2 to 4 minutes, followed by 5-fluorouracil 600 mg/m2 intravenous infusion in 500 mL 5% Dextrose Injection, USP (recommended) as a 22-hour continuous infusion.

  Day 2: Leucovorin 200 mg/m2 intravenous infusion over 120 minutes, followed by 5-fluorouracil 400 mg/m2 intravenous bolus given over 2 to 4 minutes, followed by 5-fluorouracil 600 mg/m2 intravenous infusion in 500 mL 5% Dextrose Injection, USP (recommended) as a 22-hour continuous infusion.

  The administration of Oxaliplatin does not require prehydration. Premedication with antiemetics, including 5-HT3 blockers with or without dexamethasone, is recommended.

  For information on 5-fluorouracil and leucovorin, see the respective package inserts.

  2.2 Dose Modification Recommendations

  Prior to subsequent therapy cycles, patients should be evaluated for clinical toxicities and recommended laboratory tests [see Warnings and Precautions (5.6)]. Prolongation of infusion time for Oxaliplatin from 2 hours to 6 hours may mitigate acute toxicities. The infusion times for 5-fluorouracil and leucovorin do not need to be changed.

  Adjuvant Therapy in Patients with Stage III Colon Cancer

  Neuropathy and other toxicities were graded using the NCI CTC scale version 1 [see Warnings and Precautions (5.2)].

  For patients who experience persistent Grade 2 neurosensory events that do not resolve, a dose reduction of Oxaliplatin to 75 mg/m2 should be considered. For patients with persistent Grade 3 neurosensory events, discontinuing therapy should be considered. The infusional 5-fluorouracil/leucovorin regimen need not be altered.

  A dose reduction of Oxaliplatin to 75 mg/m2 and infusional 5-fluorouracil to 300 mg/m2 bolus and 500 mg/m2 22 hour infusion is recommended for patients after recovery from grade 3/4 gastrointestinal (despite prophylactic treatment) or grade 4 neutropenia or grade 3/4 thrombocytopenia. The next dose should be delayed until: neutrophils ≥ 1.5 x 109/L and platelets ≥ 75 x 109/L.

  Dose Modifications in Therapy in Previously Untreated and Previously Treated Patients with Advanced Colorectal Cancer

  Neuropathy was graded using a study-specific neurotoxicity scale [see Warnings and Precautions (5.2)]. Other toxicities were graded by the NCI CTC, Version 2.0.

  For patients who experience persistent Grade 2 neurosensory events that do not resolve, a dose reduction of Oxaliplatin to 65 mg/m2 should be considered. For patients with persistent Grade 3 neurosensory events, discontinuing therapy should be considered. The 5-fluorouracil/leucovorin regimen need not be altered.

  A dose reduction of Oxaliplatin to 65 mg/m2 and 5-fluorouracil by 20% (300 mg/m2 bolus and 500 mg/m2 22-hour infusion) is recommended for patients after recovery from grade 3/4 gastrointestinal (despite prophylactic treatment) or grade 4 neutropenia or grade 3/4 thrombocytopenia. The next dose should be delayed until: neutrophils ≥ 1.5 x 109/L and platelets ≥ 75 x 109/L.

  Dose Modifications in Therapy for Patients with Renal Impairment

  In patients with normal renal function or mild to moderate renal impairment, the recommended dose of Oxaliplatin is 85 mg/m2. In patients with severe renal impairment, the initial recommended Oxaliplatin dose should be reduced to 65 mg/m2 [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

   

  2.3 Preparation of Infusion Solution

  Reconstitution or final dilution must never be performed with a sodium chloride solution or other chloride containing solutions.

  The lyophilized powder is reconstituted by adding 10 mL (for the 50 mg vial) or 20 mL (for the 100 mg vial) of Water for Injection, USP or 5% Dextrose Injection, USP. Do not administer the reconstituted solution without further dilution. The reconstituted solution must be further diluted in an infusion solution of 250-500 mL of 5% Dextrose Injection, USP.

  After reconstitution in the original vial, the solution may be stored up to 24 hours under refrigeration [2-8°C (36-46°F)]. After final dilution with 250-500 mL of 5% Dextrose Injection, USP, the shelf life is 6 hours at room temperature [20-25°C (68-77°F)] or up to 24 hours under refrigeration [2-8°C (36-46°F)].

  Oxaliplatin for Injection, USP is not light sensitive.

  Oxaliplatin Injection, USP is incompatible in solution with alkaline medications or media (such as basic solutions of 5-fluorouracil) and must not be mixed with these or administered simultaneously through the same infusion line. The infusion line should be flushed with 5% Dextrose Injection, USP prior to administration of any concomitant medication.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration and discarded if present.

  Needles or intravenous administration sets containing aluminum parts that may come in contact with Oxaliplatin Injection, USP should not be used for the preparation or mixing of the drug. Aluminum has been reported to cause degradation of platinum compounds.

  2.2 Dose Modification Recommendations

  Prior to subsequent therapy cycles, patients should be evaluated for clinical toxicities and recommended laboratory tests [see Warnings and Precautions (5.6)]. Prolongation of infusion time for Oxaliplatin from 2 hours to 6 hours may mitigate acute toxicities. The infusion times for 5-fluorouracil and leucovorin do not need to be changed.

  Adjuvant Therapy in Patients with Stage III Colon Cancer

  Neuropathy and other toxicities were graded using the NCI CTC scale version 1 [see Warnings and Precautions (5.2)].

  For patients who experience persistent Grade 2 neurosensory events that do not resolve, a dose reduction of Oxaliplatin to 75 mg/m2 should be considered. For patients with persistent Grade 3 neurosensory events, discontinuing therapy should be considered. The infusional 5-fluorouracil/leucovorin regimen need not be altered.

  A dose reduction of Oxaliplatin to 75 mg/m2 and infusional 5-fluorouracil to 300 mg/m2 bolus and 500 mg/m2 22 hour infusion is recommended for patients after recovery from grade 3/4 gastrointestinal (despite prophylactic treatment) or grade 4 neutropenia or grade 3/4 thrombocytopenia. The next dose should be delayed until: neutrophils ≥ 1.5 x 109/L and platelets ≥ 75 x 109/L.

  Dose Modifications in Therapy in Previously Untreated and Previously Treated Patients with Advanced Colorectal Cancer

  Neuropathy was graded using a study-specific neurotoxicity scale [see Warnings and Precautions (5.2)]. Other toxicities were graded by the NCI CTC, Version 2.0.

  For patients who experience persistent Grade 2 neurosensory events that do not resolve, a dose reduction of Oxaliplatin to 65 mg/m2 should be considered. For patients with persistent Grade 3 neurosensory events, discontinuing therapy should be considered. The 5-fluorouracil/leucovorin regimen need not be altered.

  A dose reduction of Oxaliplatin to 65 mg/m2 and 5-fluorouracil by 20% (300 mg/m2 bolus and 500 mg/m2 22-hour infusion) is recommended for patients after recovery from grade 3/4 gastrointestinal (despite prophylactic treatment) or grade 4 neutropenia or grade 3/4 thrombocytopenia. The next dose should be delayed until: neutrophils ≥ 1.5 x 109/L and platelets ≥ 75 x 109/L.

  Dose Modifications in Therapy for Patients with Renal Impairment

  In patients with normal renal function or mild to moderate renal impairment, the recommended dose of Oxaliplatin is 85 mg/m2. In patients with severe renal impairment, the initial recommended Oxaliplatin dose should be reduced to 65 mg/m2 [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

   

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