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2.1 Testing Prior to ESBRIET Administration
Conduct liver function tests prior to initiating treatment with ESBRIET [see Warnings and Precautions (5.1)].
2.2 Recommended Dosage
The recommended daily maintenance dosage of ESBRIET is 801 mg (three 267 mg capsules) three times a day with food for a total of 2403 mg/day. Doses should be taken at the same time each day.
Upon initiation of treatment, titrate to the full dosage of nine capsules per day over a 14-day period as follows:Table 1. Dosage Titration for ESBRIET in Patients with IPF Treatment days Dosage Days 1 through 7 1 capsule three times a day with food Days 8 through 14 2 capsules three times a day with food Days 15 onward 3 capsules three times a day with food
Dosages above 2403 mg/day (9 capsules per day) are not recommended for any patient.
2.3 Dosage Modifications due to Adverse Reactions
Patients who miss 14 or more days of ESBRIET should re-initiate treatment by undergoing the initial 2-week titration regimen up to the full maintenance dosage [see Dosage and Administration (2.2)]. For treatment interruption of less than 14 days, the dosage prior to the interruption can be resumed.
If patients experience significant adverse reactions (i.e., gastrointestinal, photosensitivity reaction or rash), consider temporary dosage reductions or interruptions of ESBRIET to allow for resolution of symptoms [see Warnings and Precautions (5.1, 5.2, 5.3)].
Dosage Modification due to Elevated Liver Enzymes Dosage modifications or interruptions may also be necessary when liver enzyme and bilirubin elevations are exhibited. For liver enzyme elevations, modify the dosage as follows:
If a patient exhibits >3 but ≤5 × the upper limit of normal (ULN) ALT and/or AST without symptoms or hyperbilirubinemia after starting ESBRIET therapy:Discontinue confounding medications, exclude other causes, and monitor the patient closely. Repeat liver chemistry tests as clinically indicated. The full daily dosage may be maintained, if clinically appropriate, or reduced or interrupted (e.g., until liver chemistry tests are within normal limits) with subsequent re-titration to the full dosage as tolerated.
If a patient exhibits >3 but ≤5 × ULN ALT and/or AST accompanied by symptoms or hyperbilirubinemia:Permanently discontinue ESBRIET. Do not rechallenge patient with ESBRIET.
If a patient exhibits >5 × ULN ALT and/or AST:Permanently discontinue ESBRIET. Do not rechallenge patient with ESBRIET.
2.4 Dosage Modification due to Drug Interactions
Strong CYP1A2 Inhibitors (e.g., fluvoxamine, enoxacin) Reduce ESBRIET to one capsule three times a day.
Moderate CYP1A2 Inhibitors (e.g., ciprofloxacin) With use of ciprofloxacin at a dosage of 750 mg twice daily, reduce ESBRIET to two capsules three times a day.
2.1 Evaluation of Iron Stores and Nutritional Factors
2.2 Patients with Chronic Kidney Disease
For all patients with CKD:
When initiating or adjusting therapy, monitor hemoglobin levels at least weekly until stable, then monitor at least monthly. When adjusting therapy consider hemoglobin rate of rise, rate of decline, ESA responsiveness and hemoglobin variability. A single hemoglobin excursion may not require a dosing change.Do not increase the dose more frequently than once every 4 weeks. Decreases in dose can occur more frequently. Avoid frequent dose adjustments. If the hemoglobin rises rapidly (e.g., more than 1 g/dL in any 2-week period), reduce the dose of Mircera by 25% or more as needed to reduce rapid responses. For patients who do not respond adequately, if the hemoglobin has not increased by more than 1 g/dL after 4 weeks of therapy, increase the dose by 25%. For patients who do not respond adequately over a 12-week escalation period, increasing the Mircera dose further is unlikely to improve response and may increase risks. Use the lowest dose that will maintain a hemoglobin level sufficient to reduce the need for RBC transfusions. Evaluate other causes of anemia. Discontinue Mircera if responsiveness does not improve.
Mircera is administered either intravenously (IV) or subcutaneously (SC). When administered SC, Mircera should be injected in the abdomen, arm or thigh.
For Patients with CKD on dialysis:Initiate Mircera treatment when the hemoglobin level is less than 10 g/dL. If the hemoglobin level approaches or exceeds 11 g/dL, reduce or interrupt the dose of Mircera. The recommended starting dose of Mircera for the treatment of anemia in adult CKD patients who are not currently treated with an ESA is 0.6 mcg/kg body weight administered as a single IV or SC injection once every two weeks. The IV route is recommended for patients receiving hemodialysis because the IV route may be less immunogenic [see Adverse Reactions (6.2)]. Once the hemoglobin has been stabilized, Mircera may be administered once monthly using a dose that is twice that of the every-two-week dose and subsequently titrated as necessary.
For Patients with CKD not on dialysis:Consider initiating Mircera treatment only when the hemoglobin level is less than 10 g/dL and the following considerations apply: The rate of hemoglobin decline indicates the likelihood of requiring a RBC transfusion and, Reducing the risk of alloimmunization and/or other RBC transfusion-related risks is a goal If the hemoglobin level exceeds 10 g/dL, reduce or interrupt the dose of Mircera, and use the lowest dose of Mircera sufficient to reduce the need for RBC transfusions. The recommended starting dose of Mircera for the treatment of anemia in adult CKD patients who are not currently treated with an ESA is 0.6 mcg/kg body weight administered as a single IV or SC injection once every two weeks. Once the hemoglobin has been stabilized, Mircera may be administered once monthly using a dose that is twice that of the every-two-week dose and subsequently titrated as necessary.
Refer patients who self-administer Mircera to the Instructions for Use [see Patient Counseling Information (17)].
Conversion from Epoetin alfa or Darbepoetin alfa to Mircera in Patients with CKD
Mircera can be administered once every two weeks or once monthly to patients whose hemoglobin has been stabilized by treatment with an ESA (see Table 1). The dose of Mircera, given as a single IV or SC injection, should be based on the total weekly ESA dose at the time of conversion.Table 1 Mircera Starting Doses for Patients Currently Receiving an ESA Previous Weekly Epoetin alfa Dose (units/week) Previous Weekly Darbepoetin alfa Dose (mcg/week) Mircera Dose Once Monthly (mcg/month) Once Every Two Weeks (mcg/every two weeks) < 8000 < 40 120 60 8000 - 16000 40 - 80 200 100 > 16000 > 80 360 180
2.3 Preparation and Administration of Mircera
Mircera is packaged as single-use prefilled syringes. Mircera contains no preservatives. Discard any unused portion. Do not pool unused portions from the prefilled syringes. Do not use the prefilled syringe more than one time.
Always store Mircera prefilled syringes in their original cartons. Vigorous shaking or prolonged exposure to light should be avoided.
Do not mix Mircera with any parenteral solution.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use any prefilled syringes exhibiting particulate matter or a coloration other than colorless to slightly yellowish.
For administration using the prefilled syringe, the plunger must be fully depressed during injection in order for the needle guard to activate. Following administration, remove the needle from the injection site and then release the plunger to allow the needle guard to move up until the entire needle is covered.
See "Instructions for Use" for complete instructions on the preparation and administration of Mircera. Examine each prefilled syringe for the expiration date. Do not use Mircera after the expiration date.
Administer only as an Intravenous Infusion [see Dosage and Administration (2.7)].
Do not administer as an intravenous push or bolus.
Premedicate before each infusion [see Dosage and Administration (2.7)].
Rituxan should only be administered by a healthcare professional with appropriate medical support to manage severe infusion reactions that can be fatal if they occur [see Warnings and Precautions (5.1)].First Infusion: Initiate infusion at a rate of 50 mg/hr. In the absence of infusion toxicity, increase infusion rate by 50 mg/hr increments every 30 minutes, to a maximum of 400 mg/hr. Subsequent Infusions:Standard Infusion: Initiate infusion at a rate of 100 mg/hr. In the absence of infusion toxicity, increase rate by 100 mg/hr increments at 30-minute intervals, to a maximum of 400 mg/hr.For previously untreated follicular NHL and DLBCL patients: If patients did not experience a Grade 3 or 4 infusion related adverse event during Cycle 1, a 90-minute infusion can be administered in Cycle 2 with a glucocorticoid-containing chemotherapy regimen. Initiate at a rate of 20% of the total dose given in the first 30 minutes and the remaining 80% of the total dose given over the next 60 minutes. If the 90-minute infusion is tolerated in Cycle 2, the same rate can be used when administering the remainder of the treatment regimen (through Cycle 6 or 8). Patients who have clinically significant cardiovascular disease or who have a circulating lymphocyte count ≥5000/mm3 before Cycle 2 should not be administered the 90-minute infusion [see Clinical Studies (14.4)]. Interrupt the infusion or slow the infusion rate for infusion reactions [see Boxed Warning, Warnings and Precautions (5.1)]. Continue the infusion at one-half the previous rate upon improvement of symptoms.
2.2 Recommended Dose for Non-Hodgkin's Lymphoma (NHL)
The recommended dose is 375 mg/m2 as an intravenous infusion according to the following schedules:Relapsed or Refractory, Low-Grade or Follicular, CD20-Positive, B-Cell NHL Administer once weekly for 4 or 8 doses. Retreatment for Relapsed or Refractory, Low-Grade or Follicular, CD20-Positive, B-Cell NHL Administer once weekly for 4 doses. Previously Untreated, Follicular, CD20-Positive, B-Cell NHL Administer on Day 1 of each cycle of chemotherapy, for up to 8 doses. In patients with complete or partial response, initiate Rituxan maintenance eight weeks following completion of Rituxan in combination with chemotherapy. Administer Rituxan as a single-agent every 8 weeks for 12 doses. Non-progressing, Low-Grade, CD20-Positive, B-cell NHL, after first-line CVP chemotherapy Following completion of 6–8 cycles of CVP chemotherapy, administer once weekly for 4 doses at 6-month intervals to a maximum of 16 doses. Diffuse Large B-Cell NHL Administer on Day 1 of each cycle of chemotherapy for up to 8 infusions.
2.3 Recommended Dose for Chronic Lymphocytic Leukemia (CLL)
The recommended dose is:375 mg/m2 the day prior to the initiation of FC chemotherapy, then 500 mg/m2 on Day 1 of cycles 2–6 (every 28 days).
2.4 Recommended Dose as a Component of Zevalin® for treatment of NHLInfuse rituximab 250 mg/m2 within 4 hours prior to the administration of Indium-111-(In-111-) Zevalin and within 4 hours prior to the administration of Yttrium-90- (Y-90-) Zevalin. Administer Rituxan and In-111-Zevalin 7–9 days prior to Rituxan and Y-90- Zevalin. Refer to the Zevalin package insert for full prescribing information regarding the Zevalin therapeutic regimen.
2.5 Recommended Dose for Rheumatoid Arthritis (RA)Administer Rituxan as two-1000 mg intravenous infusions separated by 2 weeks. Glucocorticoids administered as methylprednisolone 100 mg intravenous or its equivalent 30 minutes prior to each infusion are recommended to reduce the incidence and severity of infusion reactions. Subsequent courses should be administered every 24 weeks or based on clinical evaluation, but not sooner than every 16 weeks. Rituxan is given in combination with methotrexate.
2.6 Recommended Dose for Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA)Administer Rituxan as a 375 mg/m2 intravenous infusion once weekly for 4 weeks. Glucocorticoids administered as methylprednisolone 1000 mg intravenously per day for 1 to 3 days followed by oral prednisone 1 mg/kg/day (not to exceed 80 mg/day and tapered per clinical need) are recommended to treat severe vasculitis symptoms. This regimen should begin within 14 days prior to or with the initiation of Rituxan and may continue during and after the 4 week course of Rituximab treatment. Safety and efficacy of treatment with subsequent courses of Rituxan have not been established [see Warnings and Precautions (5.14)].
2.7 Recommended Concomitant Medications
Premedicate before each infusion with acetaminophen and an antihistamine. For patients administered Rituxan according to the 90-minute infusion rate, the glucocorticoid component of their chemotherapy regimen should be administered prior to infusion [see Clinical Studies (14.4)].
For RA patients, methylprednisolone 100 mg intravenously or its equivalent is recommended 30 minutes prior to each infusion.
For GPA and MPA patients, glucocorticoids are given in combination with Rituxan [see Dosage and Administration (2.6)].
Pneumocystis jiroveci pneumonia (PCP) and anti-herpetic viral prophylaxis is recommended for patients with CLL during treatment and for up to 12 months following treatment as appropriate.
PCP prophylaxis is also recommended for patients with GPA and MPA during treatment and for at least 6 months following the last Rituxan infusion.
2.8 Preparation for Administration
Use appropriate aseptic technique. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use vial if particulates or discoloration is present. Withdraw the necessary amount of Rituxan and dilute to a final concentration of 1 mg/mL to 4 mg/mL in an infusion bag containing either 0.9% Sodium Chloride, USP, or 5% Dextrose in Water, USP. Gently invert the bag to mix the solution. Do not mix or dilute with other drugs. Discard any unused portion left in the vial.
Rituxan solutions for infusion may be stored at 2°C–8°C (36°F–46°F) for 24 hours. Rituxan solutions for infusion have been shown to be stable for an additional 24 hours at room temperature. However, since Rituxan solutions do not contain a preservative, diluted solutions should be stored refrigerated (2°C–8°C). No incompatibilities between Rituxan and polyvinylchloride or polyethylene bags have been observed.
2.1 Patient Selection
Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with ZELBORAF [see Warnings and Precautions (5.2)]. Information on FDA approved tests for the detection of BRAF V600 mutations in melanoma is available at http://www.fda.gov/CompanionDiagnostics.
2.2 Recommended Dose
The recommended dose of ZELBORAF is 960 mg (four 240 mg tablets) orally every 12 hours with or without a meal. A missed dose can be taken up to 4 hours prior to the next dose.
Treat patients with ZELBORAF until disease progression or unacceptable toxicity occurs.
Do not take an additional dose if vomiting occurs after ZELBORAF administration, but continue with the next scheduled dose.
Do not crush or chew the tablets.
2.3 Dose Modifications
For New Primary Cutaneous Malignancies: No dose modifications are recommended.
For Other Adverse Reactions:
Permanently discontinue ZELBORAF for any of the following:Grade 4 adverse reaction, first appearance (if clinically appropriate) or second appearance QTc prolongation > 500 ms and increased by > 60 ms from pre-treatment values [see Warnings and Precautions (5.5)]
Withhold ZELBORAF for NCI CTCAE (v4.0) intolerable Grade 2 or greater adverse reactions.Upon recovery to Grade 0–1, restart ZELBORAF at a reduced dose as follows: 720 mg twice daily for first appearance of intolerable Grade 2 or Grade 3 adverse reactions 480 mg twice daily for second appearance of Grade 2 (if intolerable) or Grade 3 adverse reactions or for first appearance of Grade 4 adverse reaction (if clinically appropriate)
Do not dose reduce to below 480 mg twice daily.
2.1 Recommended Dosage
The recommended dosage for use in most cystic fibrosis patients is one 2.5 mg single-use ampule inhaled once daily using a recommended jet nebulizer/compressor system or eRapid™ Nebulizer System.
Some patients may benefit from twice daily administration [see Clinical Studies (14)]
2.2 Directions for UseTable 1 Recommended Jet Nebulizers/Compressors and Nebulizer Systems * Patients who are unable to inhale or exhale orally throughout the entire nebulization period may use the PARI BABY™ nebulizer. † Consisting of the eRapid™ Nebulizer Handset with eBase™ Controller. Jet Nebulizer Compressor Hudson T Up-draft II® with Pulmo-Aide® Marquest Acorn II® with Pulmo-Aide® PARI LC® Plus with PARI PRONEB® *PARI BABY™ with PARI PRONEB® Durable Sidestream® with MOBILAIRE™ Durable Sidestream® with Porta-Neb® Nebulizer System eRapid™ Nebulizer System†
2.3 Storage and Handling
Store PULMOZYME ampules in their protective foil pouch under refrigeration and protected from light. Refrigerate ampules during transport and do not expose to room temperatures for a total time of 24 hours.
Each PULMOZYME ampule should be squeezed prior to use in order to check for leaks. Discard ampules if the solution is cloudy or discolored. Once opened, the entire contents of the ampule must be used or discarded.
CAUTION - DO NOT ADMINISTER CYTOVENE-IV SOLUTION BY RAPID OR BOLUS INTRAVENOUS INJECTION. THE TOXICITY OF CYTOVENE-IV MAY BE INCREASED AS A RESULT OF EXCESSIVE PLASMA LEVELS.
CAUTION - INTRAMUSCULAR OR SUBCUTANEOUS INJECTION OF RECONSTITUTED CYTOVENE-IV SOLUTION MAY RESULT IN SEVERE TISSUE IRRITATION DUE TO HIGH pH (11).
THE RECOMMENDED DOSE FOR CYTOVENE-IV SOLUTION SHOULD NOT BE EXCEEDED. THE RECOMMENDED INFUSION RATE FOR CYTOVENE-IV SOLUTION SHOULD NOT BE EXCEEDED.
For Treatment of CMV Retinitis in Patients With Normal Renal Function
The recommended initial dosage for patients with normal renal function is 5 mg/kg (given intravenously at a constant rate over 1 hour) every 12 hours for 14 to 21 days.
Following induction treatment, the recommended maintenance dosage of CYTOVENE-IV solution is 5 mg/kg given as a constant-rate intravenous infusion over 1 hour once daily, 7 days per week, or 6 mg/kg once daily, 5 days per week.
For patients who experience progression of CMV retinitis while receiving maintenance treatment with CYTOVENE-IV, reinduction treatment is recommended.
For the Prevention of CMV Disease in Transplant Recipients With Normal Renal Function
The recommended initial dosage of CYTOVENE-IV solution for patients with normal renal function is 5 mg/kg (given intravenously at a constant rate over 1 hour) every 12 hours for 7 to 14 days, followed by 5 mg/kg once daily, 7 days per week or 6 mg/kg once daily, 5 days per week.
The duration of treatment with CYTOVENE-IV solution in transplant recipients is dependent upon the duration and degree of immunosuppression. In controlled clinical trials in bone marrow allograft recipients, treatment with CYTOVENE-IV was continued until day 100 to 120 posttransplantation. CMV disease occurred in several patients who discontinued treatment with CYTOVENE-IV solution prematurely. In heart allograft recipients, the onset of newly diagnosed CMV disease occurred after treatment with CYTOVENE-IV was stopped at day 28 posttransplant, suggesting that continued dosing may be necessary to prevent late occurrence of CMV disease in this patient population (see INDICATIONS AND USAGE section for a more detailed discussion).
For patients with impairment of renal function, refer to Table 8 for recommended doses of CYTOVENE-IV solution and adjust the dosing interval as indicated:Table 8 Dosing for Patients with Renal Impairment Creatinine Clearance* (mL/min) CYTOVENE-IV Induction Dose (mg/kg) Dosing Interval (hours) CYTOVENE-IV Maintenance Dose (mg/kg) Dosing Interval (hours) * Creatinine clearance can be related to serum creatinine by the formulas given below. ≥70 5.0 12 5.0 24 50–69 2.5 12 2.5 24 25–49 2.5 24 1.25 24 10–24 1.25 24 0.625 24 <10 1.25 3 times per week, following hemodialysis 0.625 3 times per week, following hemodialysis Creatinine clearance for males = (140 - age [yrs]) (body wt [kg]) (72) (serum creatinine [mg/dL]) Creatinine clearance for females = 0.85 × male value
Dosing for patients undergoing hemodialysis should not exceed 1.25 mg/kg 3 times per week, following each hemodialysis session. CYTOVENE-IV should be given shortly after completion of the hemodialysis session, since hemodialysis has been shown to reduce plasma levels by approximately 50%.
Due to the frequency of granulocytopenia, anemia and thrombocytopenia in patients receiving ganciclovir (see ADVERSE EVENTS), it is recommended that complete blood counts and platelet counts be performed frequently, especially in patients in whom ganciclovir or other nucleoside analogues have previously resulted in cytopenia, or in whom neutrophil counts are less than 1000 cells/µL at the beginning of treatment. Patients should have serum creatinine or creatinine clearance values followed carefully to allow for dosage adjustments in renally impaired patients (see DOSAGE AND ADMINISTRATION).
Reduction of Dose
Dosage reductions in renally impaired patients are required for CYTOVENE-IV (see Renal Impairment). Dosage reductions should also be considered for those with neutropenia, anemia and/or thrombocytopenia (see ADVERSE EVENTS). Ganciclovir should not be administered in patients with severe neutropenia (ANC less than 500/µL) or severe thrombocytopenia (platelets less than 25,000/µL).
Method of Preparation of CYTOVENE-IV Solution
Each 10 mL clear glass vial contains ganciclovir sodium equivalent to 500 mg of ganciclovir and 46 mg of sodium. The contents of the vial should be prepared for administration in the following manner:Reconstituted Solution: Reconstitute lyophilized CYTOVENE-IV by injecting 10 mL of Sterile Water for Injection, USP, into the vial.DO NOT USE BACTERIOSTATIC WATER FOR INJECTION CONTAINING PARABENS. IT IS INCOMPATIBLE WITH CYTOVENE-IV AND MAY CAUSE PRECIPITATION. Shake the vial to dissolve the drug. Visually inspect the reconstituted solution for particulate matter and discoloration prior to proceeding with infusion solution. Discard the vial if particulate matter or discoloration is observed. Reconstituted solution in the vial is stable at room temperature for 12 hours. It should not be refrigerated. Infusion Solution:Based on patient weight, the appropriate volume of the reconstituted solution (ganciclovir concentration 50 mg/mL) should be removed from the vial and added to an acceptable infusion fluid (typically 100 mL) for delivery over the course of 1 hour. Infusion concentrations greater than 10 mg/mL are not recommended. The following infusion fluids have been determined to be chemically and physically compatible with CYTOVENE-IV solution: 0.9% Sodium Chloride, 5% Dextrose, Ringer's Injection and Lactated Ringer's Injection, USP.CYTOVENE-IV, when reconstituted with sterile water for injection, further diluted with 0.9% sodium chloride injection, and stored refrigerated at 5°C in polyvinyl chloride (PVC) bags, remains physically and chemically stable for 14 days.However, because CYTOVENE-IV is reconstituted with nonbacteriostatic sterile water, it is recommended that the infusion solution be used within 24 hours of dilution to reduce the risk of bacterial contamination. The infusion should be refrigerated. Freezing is not recommended.
Handling and Disposal
Caution should be exercised in the handling and preparation of solutions of CYTOVENE-IV. Solutions of CYTOVENE-IV are alkaline (pH 11). Avoid direct contact of the skin or mucous membranes with CYTOVENE-IV solutions. If such contact occurs, wash thoroughly with soap and water; rinse eyes thoroughly with plain water.
Because ganciclovir shares some of the properties of antitumor agents (ie, carcinogenicity and mutagenicity), consideration should be given to handling and disposal according to guidelines issued for antineoplastic drugs. Several guidelines on this subject have been published.7-9
There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
TNKase® (Tenecteplase) is for intravenous administration only. The recommended total dose should not exceed 50 mg and is based upon patient weight.
A single bolus dose should be administered over 5 seconds based on patient weight. Treatment should be initiated as soon as possible after the onset of AMI symptoms (see CLINICAL STUDIES).Dose Information Table Patient Weight(kg) TNKase(mg) Volume TNKase* to be administered (mL) * From one vial of TNKase reconstituted with 10 mL SWFI. <60 30 6 ≥60 to <70 35 7 ≥70 to <80 40 8 ≥80 to <90 45 9 ≥90 50 10
The safety and efficacy of TNKase have only been investigated with concomitant administration of heparin and aspirin as described in CLINICAL STUDIES.
THE ® 10 mL SYRINGE WITH TWINPAK™ DUAL CANNULA DEVICE
NOTE: Read all instructions completely before beginning reconstitution and administration.
Remove the shield assembly from the supplied B-D® 10 mL syringe with TwinPak™ Dual Cannula Device (see figure) and aseptically withdraw 10 mL of Sterile Water for Injection (SWFI), USP, from the supplied diluent vial using the red hub cannula syringe filling device. Do not use Bacteriostatic Water for Injection, USP.
Note: Do not discard the shield assembly.Inject the entire contents of the syringe (10 mL) into the TNKase vial directing the diluent stream into the powder. Slight foaming upon reconstitution is not unusual; any large bubbles will dissipate if the product is allowed to stand undisturbed for several minutes. Gently swirl until contents are completely dissolved. DO NOT SHAKE. The reconstituted preparation results in a colorless to pale yellow transparent solution containing TNKase at 5 mg/mL at a pH of approximately 7.3. The osmolality of this solution is approximately 290 mOsm/kg. Determine the appropriate dose of TNKase (see Dose Information Table) and withdraw this volume (in milliliters) from the reconstituted vial with the syringe. Any unused solution should be discarded. Once the appropriate dose of TNKase is drawn into the syringe, stand the shield vertically on a flat surface (with green side down) and passively recap the red hub cannula. Remove the entire shield assembly, including the red hub cannula, by twisting counterclockwise. Note: The shield assembly also contains the clear-ended blunt plastic cannula; retain for split septum IV access.
Administration1. The product should be visually inspected prior to administration for particulate matter and discoloration. TNKase may be administered as reconstituted at 5 mg/mL. 2. Precipitation may occur when TNKase is administered in an IV line containing dextrose. Dextrose-containing lines should be flushed with a saline-containing solution prior to and following single bolus administration of TNKase. 3. Reconstituted TNKase should be administered as a single IV bolus over 5 seconds. 4. Because TNKase contains no antibacterial preservatives, it should be reconstituted immediately before use. If the reconstituted TNKase is not used immediately, refrigerate the TNKase vial at 2–8°C (36–46°F) and use within 8 hours. 5. Although the supplied syringe is compatible with a conventional needle, this syringe is designed to be used with needleless IV systems. From the information below, follow the instructions applicable to the IV system in use. Split septum IV system: Remove the green cap. Attach the clear-ended blunt plastic cannula to the syringe. Remove the shield and use the blunt plastic cannula to access the split septum injection port. Because the blunt plastic cannula has two side ports, air or fluid expelled through the cannula will exit in two sideways directions; direct away from face or mucous membranes. Luer-Lok® system: Connect syringe directly to IV port. Conventional needle (not supplied in this kit): Attach a large bore needle, e.g., 18 gauge, to the syringe's universal Luer‑Lok®. 6. Dispose of the syringe, cannula and shield per established procedures.
Rocephin may be administered intravenously or intramuscularly.
Do not use diluents containing calcium, such as Ringer's solution or Hartmann's solution, to reconstitute Rocephin vials or to further dilute a reconstituted vial for IV administration because a precipitate can form. Precipitation of ceftriaxone-calcium can also occur when Rocephin is mixed with calcium-containing solutions in the same IV administration line. Rocephin must not be administered simultaneously with calcium-containing IV solutions, including continuous calcium-containing infusions such as parenteral nutrition via a Y-site. However, in patients other than neonates, Rocephin and calcium-containing solutions may be administered sequentially of one another if the infusion lines are thoroughly flushed between infusions with a compatible fluid (see WARNINGS).
There have been no reports of an interaction between ceftriaxone and oral calcium-containing products or interaction between intramuscular ceftriaxone and calcium-containing products (IV or oral).
Hyperbilirubinemic neonates, especially prematures, should not be treated with Rocephin. Rocephin is contraindicated in premature neonates (see CONTRAINDICATIONS).
Rocephin is contraindicated in neonates (≤ 28 days) if they require (or are expected to require) treatment with calcium-containing IV solutions, including continuous calcium-containing infusions such as parenteral nutrition because of the risk of precipitation of ceftriaxone-calcium (see CONTRAINDICATIONS).
Intravenous doses should be given over 60 minutes in neonates to reduce the risk of bilirubin encephalopathy.
For the treatment of skin and skin structure infections, the recommended total daily dose is 50 to 75 mg/kg given once a day (or in equally divided doses twice a day). The total daily dose should not exceed 2 grams.
For the treatment of acute bacterial otitis media, a single intramuscular dose of 50 mg/kg (not to exceed 1 gram) is recommended (see INDICATIONS AND USAGE).
For the treatment of serious miscellaneous infections other than meningitis, the recommended total daily dose is 50 to 75 mg/kg, given in divided doses every 12 hours. The total daily dose should not exceed 2 grams.
In the treatment of meningitis, it is recommended that the initial therapeutic dose be 100 mg/kg (not to exceed 4 grams). Thereafter, a total daily dose of 100 mg/kg/day (not to exceed 4 grams daily) is recommended. The daily dose may be administered once a day (or in equally divided doses every 12 hours). The usual duration of therapy is 7 to 14 days.
The usual adult daily dose is 1 to 2 grams given once a day (or in equally divided doses twice a day) depending on the type and severity of infection. The total daily dose should not exceed 4 grams.
If Chlamydia trachomatis is a suspected pathogen, appropriate antichlamydial coverage should be added, because ceftriaxone sodium has no activity against this organism.
For the treatment of uncomplicated gonococcal infections, a single intramuscular dose of 250 mg is recommended.
For preoperative use (surgical prophylaxis), a single dose of 1 gram administered intravenously 1/2 to 2 hours before surgery is recommended.
Generally, Rocephin therapy should be continued for at least 2 days after the signs and symptoms of infection have disappeared. The usual duration of therapy is 4 to 14 days; in complicated infections, longer therapy may be required.
When treating infections caused by Streptococcus pyogenes, therapy should be continued for at least 10 days.
No dosage adjustment is necessary for patients with impairment of renal or hepatic function (see PRECAUTIONS).
The dosages recommended for adults require no modification in elderly patients up to 2 gm per day provided there is no severe renal and hepatic impairment (see PRECAUTIONS).
Directions For Use
Reconstitute Rocephin powder with the appropriate diluent (see COMPATIBILITY AND STABILITY).
Inject diluent into vial, shake vial thoroughly to form solution. Withdraw entire contents of vial into syringe to equal total labeled dose.
After reconstitution, each 1 mL of solution contains approximately 250 mg or 350 mg equivalent of ceftriaxone according to the amount of diluent indicated below. If required, more dilute solutions could be utilized.
As with all intramuscular preparations, Rocephin should be injected well within the body of a relatively large muscle; aspiration helps to avoid unintentional injection into a blood vessel.Vial Dosage Size Amount of Diluent to be Added 250 mg/mL 350 mg/mL 500 mg 1.8 mL 1.0 mL 1 gm 3.6 mL 2.1 mL
Rocephin should be administered intravenously by infusion over a period of 30 minutes, except in neonates where administration over 60 minutes is recommended to reduce the risk of bilirubin encephalopathy. Concentrations between 10 mg/mL and 40 mg/mL are recommended; however, lower concentrations may be used if desired. Reconstitute vials with an appropriate IV diluent (see COMPATIBILITY AND STABILITY).Vial Dosage Size Amount of Diluent to be Added 500 mg 4.8 mL 1 gm 9.6 mL
After reconstitution, each 1 mL of solution contains approximately 100 mg equivalent of ceftriaxone. Withdraw entire contents and dilute to the desired concentration with the appropriate IV diluent.
Compatibility and Stability
Do not use diluents containing calcium, such as Ringer's solution or Hartmann's solution, to reconstitute Rocephin vials or to further dilute a reconstituted vial for IV administration. Particulate formation can result.
Ceftriaxone has been shown to be compatible with Flagyl® IV (metronidazole hydrochloride). The concentration should not exceed 5 to 7.5 mg/mL metronidazole hydrochloride with ceftriaxone 10 mg/mL as an admixture. The admixture is stable for 24 hours at room temperature only in 0.9% sodium chloride injection or 5% dextrose in water (D5W). No compatibility studies have been conducted with the Flagyl® IV RTU® (metronidazole) formulation or using other diluents. Metronidazole at concentrations greater than 8 mg/mL will precipitate. Do not refrigerate the admixture as precipitation will occur.
Vancomycin, amsacrine, aminoglycosides, and fluconazole are incompatible with ceftriaxone in admixtures. When any of these drugs are to be administered concomitantly with ceftriaxone by intermittent intravenous infusion, it is recommended that they be given sequentially, with thorough flushing of the intravenous lines (with one of the compatible fluids) between the administrations.
Rocephin solutions should not be physically mixed with or piggybacked into solutions containing other antimicrobial drugs or into diluent solutions other than those listed above, due to possible incompatibility (see WARNINGS).
Rocephin sterile powder should be stored at room temperature—77°F (25°C)—or below and protected from light. After reconstitution, protection from normal light is not necessary. The color of solutions ranges from light yellow to amber, depending on the length of storage, concentration and diluent used.
Rocephin intramuscular solutions remain stable (loss of potency less than 10%) for the following time periods:Storage Diluent Concentrationmg/ml Room Temp. (25°C) Refrigerated (4°C) Sterile Water for Injection 100250, 350 2 days24 hours 10 days3 days 0.9% Sodium Chloride Solution 100250, 350 2 days24 hours 10 days3 days 5% Dextrose Solution 100250, 350 2 days24 hours 10 days3 days Bacteriostatic Water + 0.9% Benzyl Alcohol 100250, 350 24 hours24 hours 10 days3 days 1% Lidocaine Solution (without epinephrine) 100250, 350 24 hours24 hours 10 days3 days
Rocephin intravenous solutions, at concentrations of 10, 20 and 40 mg/mL, remain stable (loss of potency less than 10%) for the following time periods stored in glass or PVC containers:Storage Diluent Room Temp. (25°C) Refrigerated (4°C) * Data available for 10 to 40 mg/mL concentrations in this diluent in PVC containers only. Sterile Water 2 days 10 days 0.9% Sodium Chloride Solution 2 days 10 days 5% Dextrose Solution 2 days 10 days 10% Dextrose Solution 2 days 10 days 5% Dextrose + 0.9% Sodium Chloride Solution* 2 days Incompatible 5% Dextrose + 0.45% Sodium Chloride Solution 2 days Incompatible
The following intravenous Rocephin solutions are stable at room temperature (25°C) for 24 hours, at concentrations between 10 mg/mL and 40 mg/mL: Sodium Lactate (PVC container), 10% Invert Sugar (glass container), 5% Sodium Bicarbonate (glass container), Freamine III (glass container), Normosol-M in 5% Dextrose (glass and PVC containers), Ionosol-B in 5% Dextrose (glass container), 5% Mannitol (glass container), 10% Mannitol (glass container).
After the indicated stability time periods, unused portions of solutions should be discarded.
NOTE: Parenteral drug products should be inspected visually for particulate matter before administration.
Rocephin reconstituted with 5% Dextrose or 0.9% Sodium Chloride solution at concentrations between 10 mg/mL and 40 mg/mL, and then stored in frozen state (-20°C) in PVC or polyolefin containers, remains stable for 26 weeks.
Frozen solutions of Rocephin should be thawed at room temperature before use. After thawing, unused portions should be discarded. DO NOT REFREEZE.
The Nutropin® [somatropin (rDNA origin) for injection] dosage and administration schedule should be individualized for each patient. Response to growth hormone therapy in pediatric patients tends to decrease with time. However, in pediatric patients failure to increase growth rate, particularly during the first year of therapy, suggests the need for close assessment of compliance and evaluation of other causes of growth failure, such as hypothyroidism, under‑nutrition, and advanced bone age.
Pediatric Growth Hormone Deficiency (GHD)
A weekly dosage of up to 0.3 mg/kg of body weight divided into daily subcutaneous injection is recommended. In pubertal patients, a weekly dosage of up to 0.7 mg/kg divided daily may be used.
Adult Growth Hormone Deficiency (GHD)
Based on the weight-based dosing utilized in the original pivotal studies described herein, the recommended dosage at the start of therapy is not more than 0.006 mg/kg given as a daily subcutaneous injection. The dose may be increased according to individual patient requirements to a maximum of 0.025 mg/kg daily in patients under 35 years old and to a maximum of 0.0125 mg/kg daily in patients over 35 years old. Clinical response, side effects, and determination of age- and gender-adjusted serum IGF-I levels may be used as guidance in dose titration.
Alternatively, taking into account more recent literature, a starting dose of approximately 0.2 mg/day (range, 0.15‑0.30 mg/day) may be used without consideration of body weight. This dose can be increased gradually every 1-2 months by increments of approximately 0.1-0.2 mg/day, according to individual patient requirements based on the clinical response and serum IGF-I concentrations. During therapy, the dose should be decreased if required by the occurrence of adverse events and/or serum IGF-I levels above the age- and gender-specific normal range. Maintenance dosages vary considerably from person to person.
A lower starting dose and smaller dose increments should be considered for older patients, who are more prone to the adverse effects of somatropin than younger individuals. In addition, obese individuals are more likely to manifest adverse effects when treated with a weight-based regimen. In order to reach the defined treatment goal, estrogen-replete women may need higher doses than men. Oral estrogen administration may increase the dose requirements in women.
Chronic Renal Insufficiency (CRI)
A weekly dosage of up to 0.35 mg/kg of body weight divided into daily subcutaneous injection is recommended.
Nutropin therapy may be continued up to the time of renal transplantation.
In order to optimize therapy for patients who require dialysis, the following guidelines for injection schedule are recommended:Hemodialysis patients should receive their injection at night just prior to going to sleep or at least 3–4 hours after their hemodialysis to prevent hematoma formation due to the heparin. Chronic Cycling Peritoneal Dialysis (CCPD) patients should receive their injection in the morning after they have completed dialysis. Chronic Ambulatory Peritoneal Dialysis (CAPD) patients should receive their injection in the evening at the time of the overnight exchange.
A weekly dosage of up to 0.375 mg/kg of body weight divided into equal doses 3 to 7 times per week by subcutaneous injection is recommended.
Idiopathic Short Stature (ISS)
A weekly dosage of up to 0.3 mg/kg of body weight divided into daily subcutaneous injection has been shown to be safe and efficacious, and is recommended.
After the dose has been determined, reconstitute as follows: each 5 mg vial should be reconstituted with 1–5 mL of Bacteriostatic Water for Injection, USP (benzyl alcohol preserved); or each 10 mg vial should be reconstituted with 1–10 mL of Bacteriostatic Water for Injection, USP (benzyl alcohol preserved), only. For use in newborns, see WARNINGS. The pH of Nutropin after reconstitution with Bacteriostatic Water for Injection, USP (benzyl alcohol preserved), is approximately 7.4.
To prepare the Nutropin solution, inject the Bacteriostatic Water for Injection, USP (benzyl alcohol preserved) into the Nutropin vial, aiming the stream of liquid against the glass wall. Then swirl the product vial with a GENTLE rotary motion until the contents are completely dissolved. DO NOT SHAKE . Because Nutropin is a protein, shaking can result in a cloudy solution. The Nutropin solution should be clear immediately after reconstitution. Occasionally, after refrigeration, you may notice that small colorless particles of protein are present in the Nutropin solution. This is not unusual for solutions containing proteins. If the solution is cloudy immediately after reconstitution or refrigeration, the contents MUST NOT be injected.
Before needle insertion, wipe the septum of both the Nutropin and diluent vials with rubbing alcohol or an antiseptic solution to prevent contamination of the contents by microorganisms that may be introduced by repeated needle insertions. It is recommended that Nutropin be administered using sterile, disposable syringes and needles. The syringes should be of small enough volume that the prescribed dose can be drawn from the vial with reasonable accuracy.
2.1 Acute Ischemic Stroke
Administer Activase as soon as possible but within 3 hours after onset of symptoms.
The recommended dose is 0.9 mg/kg (not to exceed 90 mg total dose), with 10% of the total dose administered as an initial intravenous bolus over 1 minute and the remainder infused over 60 minutes.
During and following Activase administration for the treatment of acute ischemic stroke, frequently monitor and control blood pressure.
In patients without recent use of oral anticoagulants or heparin, Activase treatment can be initiated prior to the availability of coagulation study results. Discontinue Activase if the pretreatment International Normalized Ratio (INR) is greater than 1.7 or the activated partial thromboplastin time (aPTT) is elevated [see Contraindications (4.1)].
2.2 Acute Myocardial Infarction
Administer Activase as soon as possible after the onset of symptoms.
The recommended total doses for acute myocardial infarction (AMI) is based on patient weight, not to exceed 100 mg, regardless of the selected administration regimen (accelerated or 3 hour, described below).
There are two Activase dose regimens (accelerated and 3-hour) for use in the management of AMI; there are no controlled studies to compare clinical outcomes with these regimens [see Clinical Studies (14.2)].
The recommended accelerated infusion dose consists of an IV bolus [see Dosage and Administration (2.5)] followed by an IV infusion as set forth in Table 1.Table 1 Accelerated Infusion Weight-Based Doses for Patients with AMI Patient weight Intravenous Bolus First 30 min Next 60 min > 67 kg 15 mg 50 mg 35 mg ≤ 67 kg 15 mg 0.75 mg/kg 0.50 mg/kg
The safety and efficacy of accelerated infusion of Activase have only been investigated with concomitant administration of heparin and aspirin [see Clinical Studies (14.2)].
For patients weighing ≥ 65 kg, the recommended dose is 100 mg administered as 60 mg in the first hour (6-10 mg administered as a bolus), 20 mg over the second hour, and 20 mg over the third hour. For smaller patients (< 65 kg), a dose of 1.25 mg/kg administered over 3 hours may be used. Weight-based doses are shown in Table 2.Table 2 3-hour Infusion Weight-Based Doses for Patients with AMI Patient weight Bolus Rest of 1st hour 2nd hour 3rd hour ≥ 65 kg 6-10 mg 50-54 mg 20 mg 20 mg < 65 kg 0.075 mg/kg 0.675 mg/kg 0.25 mg/kg 0.25 mg/kg
2.3 Pulmonary Embolism (PE)
The recommended dose is 100 mg administered by IV infusion over 2 hours.
Institute parenteral anticoagulation near the end of or immediately following the Activase infusion when the partial thromboplastin time or thrombin time returns to twice normal or less.
2.4 Preparation for Administration
Use only the accompanying Sterile Water for Injection (SWFI), USP without preservatives. Do not use Bacteriostatic Water for Injection, USP.
Reconstitute using aseptic technique. Do not add other medication to solutions containing Activase. Reconstitute Activase no more than 8 hours before use, as it contains no antibacterial preservatives [see How Supplied/Storage and Handling (16.2)].
Slight foaming is not unusual; let stand undisturbed for several minutes to allow large bubbles to dissipate. Inspect parenteral drug products for particulate matter and discoloration prior to administration whenever solution and container permit.
Activase may be administered as reconstituted at 1 mg/mL or further diluted immediately before administration in an equal volume of 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP, to yield a concentration of 0.5 mg/mL, using either polyvinyl chloride bags or glass vials.
Avoid excessive agitation during dilution; mix by gently swirling and/or slow inversion.
50 mg VialsDO NOT USE IF VACUUM IS NOT PRESENT. Using a large bore needle (e.g., 18 gauge) and a syringe, reconstitute by adding the contents of the accompanying 50 mL vial of SWFI to the 50 mg vial of Activase, directing the SWFI stream into the lyophilized cake.
100 mg VialsTHE 100 mg VIALS DO NOT CONTAIN VACUUM. Using the transfer device provided, reconstitute by adding the contents of the accompanying 100 mL vial of SWFI to the 100 mg vial of Activase. Use aseptic technique. Remove the protective flip-caps from one vial of Activase and one vial of SWFI. Open the package containing the transfer device by peeling the paper label off the package. Remove the protective cap from one end of the transfer device and keeping the vial of SWFI upright, insert the piercing pin vertically into the center of the stopper of the vial of SWFI. Remove the protective cap from the other end of the transfer device. DO NOT INVERT THE VIAL OF SWFI. Hold the vial of Activase upside down, position it so that the center of the stopper is directly over the exposed piercing pin of the transfer device, and push the vial of Activase down so that the piercing pin is inserted through the center of the Activase vial stopper. Invert the two vials so that the vial of Activase is on the bottom (upright) and the vial of SWFI is upside-down, allowing the SWFI to flow down through the transfer device. Allow the entire contents of the vial of SWFI to flow into the Activase vial (approximately 0.5 cc of SWFI will remain in the diluent vial). Remove the transfer device and the empty SWFI vial from the Activase vial and discard. Swirl gently to dissolve the Activase powder. DO NOT SHAKE.
Preparation of Bolus DosePrepare the bolus dose in one of the following ways: Remove the appropriate volume from the vial of reconstituted (1 mg/mL) Activase using a syringe and needle. If this method is used with the 50 mg vials, the syringe should not be primed with air and the needle should be inserted into the Activase vial stopper. If the 100 mg vial is used, the needle should be inserted away from the puncture mark made by the transfer device. Remove the appropriate volume from a port (second injection site) on the infusion line after the infusion set is primed. Program an infusion pump to deliver the appropriate volume as a bolus at the initiation of the infusion
Following bolus dose, if indicated [see Dosage and Administration (2.1, 2.2)]:50 mg vials - administer using either a polyvinyl chloride bag or glass vial and infusion set. 100 mg vials - remove from the vial any quantity of drug in excess of that specified for patient treatment [see Dosage and Administration (2.1, 2.2)]. Insert the spike end of an infusion set through the same puncture site created by the transfer device in the stopper of the vial of reconstituted Activase. Peel the clear plastic hanger from the vial label. Hang the Activase vial from the resulting loop.
Activase is for intravenous administration only. Extravasation of Activase infusion can cause ecchymosis or inflammation. If extravasation occurs, terminate the infusion at that IV site and apply local therapy.
Do not add any other medication to infusion solutions containing Activase.
INVIRASE must be used in combination with ritonavir because ritonavir significantly inhibits saquinavir's metabolism to provide increased plasma saquinavir levels.
2.1 Recommended DoseINVIRASE 1000-mg twice daily (5 × 200-mg capsules or 2 × 500-mg tablets) in combination with ritonavir 100-mg twice daily. Ritonavir should be taken at the same time as INVIRASE. INVIRASE and ritonavir should be taken within 2 hours after a meal. No additional ritonavir is recommended when INVIRASE is administered with lopinavir/ritonavir 400/100 mg twice daily. Pediatric dose recommendations that are both reliably effective and below thresholds of concern for QT and PR interval prolongation could not be determined.
2.2 Administration for Patients Unable to Swallow Capsules
Open the INVIRASE capsules and place the contents into an empty container. Add 15 mL of either sugar syrup or sorbitol syrup (for patients with Type 1 diabetes or glucose intolerance) OR 3 teaspoons of jam to the contents of INVIRASE capsules that are in the container. Stir with a spoon for 30 to 60 seconds. Administer the full amount prepared for each dose. Suspensions should be at room temperature before administering.
Carefully consider the potential benefits and risks of NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension and other treatment options before deciding to use NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).
After observing the response to initial therapy with NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension, the dose and frequency should be adjusted to suit an individual patient's needs.
Different dose strengths and formulations (ie, tablets, suspension) of the drug are not necessarily bioequivalent. This difference should be taken into consideration when changing formulation.
Although NAPROSYN, NAPROSYN Suspension, EC-NAPROSYN, ANAPROX and ANAPROX DS all circulate in the plasma as naproxen, they have pharmacokinetic differences that may affect onset of action. Onset of pain relief can begin within 30 minutes in patients taking naproxen sodium and within 1 hour in patients taking naproxen. Because EC-NAPROSYN dissolves in the small intestine rather than in the stomach, the absorption of the drug is delayed compared to the other naproxen formulations (see CLINICAL PHARMACOLOGY).
The recommended strategy for initiating therapy is to choose a formulation and a starting dose likely to be effective for the patient and then adjust the dosage based on observation of benefit and/or adverse events. A lower dose should be considered in patients with renal or hepatic impairment or in elderly patients (see WARNINGS and PRECAUTIONS).
Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. Caution is advised when high doses are required and some adjustment of dosage may be required in elderly patients. As with other drugs used in the elderly, it is prudent to use the lowest effective dose.
Patients With Moderate to Severe Renal Impairment
Naproxen-containing products are not recommended for use in patients with moderate to severe and severe renal impairment (creatinine clearance <30 mL/min) (see WARNINGS: Renal Effects).
Rheumatoid Arthritis, Osteoarthritis and Ankylosing SpondylitisNAPROSYN 250 mgor 375 mgor 500 mg twice dailytwice dailytwice daily ANAPROX 275 mg (naproxen 250 mg with 25 mg sodium) twice daily ANAPROX DS 550 mg (naproxen 500 mg with 50 mg sodium) twice daily NAPROSYN Suspension 250 mg (10 mL/2 tsp)or 375 mg (15 mL/3 tsp)or 500 mg (20 mL/4 tsp) twice dailytwice dailytwice daily EC-NAPROSYN 375 mgor 500 mg twice dailytwice daily
To maintain the integrity of the enteric coating, the EC-NAPROSYN tablet should not be broken, crushed or chewed during ingestion. NAPROSYN Suspension should be shaken gently before use.
During long-term administration, the dose of naproxen may be adjusted up or down depending on the clinical response of the patient. A lower daily dose may suffice for long-term administration. The morning and evening doses do not have to be equal in size and the administration of the drug more frequently than twice daily is not necessary.
In patients who tolerate lower doses well, the dose may be increased to naproxen 1500 mg/day for limited periods of up to 6 months when a higher level of anti-inflammatory/analgesic activity is required. When treating such patients with naproxen 1500 mg/day, the physician should observe sufficient increased clinical benefits to offset the potential increased risk. The morning and evening doses do not have to be equal in size and administration of the drug more frequently than twice daily does not generally make a difference in response (see CLINICAL PHARMACOLOGY).
The use of NAPROSYN Suspension is recommended for juvenile arthritis in children 2 years or older because it allows for more flexible dose titration based on the child's weight. In pediatric patients, doses of 5 mg/kg/day produced plasma levels of naproxen similar to those seen in adults taking 500 mg of naproxen (see CLINICAL PHARMACOLOGY).
The recommended total daily dose of naproxen is approximately 10 mg/kg given in 2 divided doses (ie, 5 mg/kg given twice a day). A measuring cup marked in 1/2 teaspoon and 2.5 milliliter increments is provided with the NAPROSYN Suspension. The following table may be used as a guide for dosing of NAPROSYN Suspension:Patient's Weight Dose Administered as 13 kg (29 lb) 62.5 mg bid 2.5 mL (1/2 tsp) twice daily 25 kg (55 lb) 125 mg bid 5.0 mL (1 tsp) twice daily 38 kg (84 lb) 187.5 mg bid 7.5 mL (1 1/2 tsp) twice daily
Management of Pain, Primary Dysmenorrhea, and Acute Tendonitis and Bursitis
The recommended starting dose is 550 mg of naproxen sodium as ANAPROX/ANAPROX DS followed by 550 mg every 12 hours or 275 mg every 6 to 8 hours as required. The initial total daily dose should not exceed 1375 mg of naproxen sodium. Thereafter, the total daily dose should not exceed 1100 mg of naproxen sodium. Because the sodium salt of naproxen is more rapidly absorbed, ANAPROX/ANAPROX DS is recommended for the management of acute painful conditions when prompt onset of pain relief is desired. NAPROSYN may also be used but EC-NAPROSYN is not recommended for initial treatment of acute pain because absorption of naproxen is delayed compared to other naproxen-containing products (see CLINICAL PHARMACOLOGY, INDICATIONS AND USAGE).
The recommended starting dose is 750 mg of NAPROSYN followed by 250 mg every 8 hours until the attack has subsided. ANAPROX may also be used at a starting dose of 825 mg followed by 275 mg every 8 hours. EC-NAPROSYN is not recommended because of the delay in absorption (see CLINICAL PHARMACOLOGY).
2.1 Dosage Information
The dose of BONIVA is one 150 mg tablet taken once monthly on the same date each month.
2.2 Important Administration Instructions
Instruct Patients to do the following:Take BONIVA at least 60 minutes before the first food or drink (other than water) of the day or before taking any oral medication or supplementation, including calcium, antacids, or vitamins to maximize absorption and clinical benefit, (see DRUG INTERACTIONS [7.1]). Avoid the use of water with supplements including mineral water because they may have a higher concentration of calcium. Swallow BONIVA tablets whole with a full glass of plain water (6 to 8 oz) while standing or sitting in an upright position to reduce the potential for esophageal irritation. Avoid lying down for 60 minutes after taking BONIVA (see WARNINGS AND PRECAUTIONS [5.1]). Do not chew or suck the tablet because of a potential for oropharyngeal ulceration. Do not eat, drink anything except plain water, or take other medications for at least 60 minutes after taking BONIVA.
2.3 Recommendations for Calcium and Vitamin D Supplementation
Instruct patients to take supplemental calcium and vitamin D if their dietary intake is inadequate. Avoid the use of calcium supplements within 60 minutes of BONVIA administration because co-administration of BONIVA and calcium may interfere with the absorption of ibandronate sodium (see DRUG INTERACTIONS [7.1]).
2.4 Administration Instructions for Missed Once-Monthly Doses
If the once-monthly dose is missed, instruct patients to do the following:If the next scheduled BONIVA day is more than 7 days away, take one BONIVA 150 mg tablet in the morning following the date that it is remembered. If the next scheduled BONIVA day is only 1 to 7 days away, wait until the subsequent month's scheduled BONIVA day to take their tablet.
For subsequent monthly doses for both of the above scenarios, instruct patients to return to their original schedule by taking one BONIVA 150 mg tablet every month on their previous chosen day.
2.1 Important Administration Instructions
BONIVA Injection must be administered intravenously only by a health care professional. Care must be taken not to administer intra-arterially or paravenously as this could lead to tissue damage [see Warnings and Precautions (5.4)].Appropriate medical support and monitoring measures should be readily available when BONIVA Injection is administered. If anaphylactic or other severe hypersensitivity/allergic reactions occur, immediately discontinue the injection and initiate appropriate treatment [see Warnings and Precautions (5.2)]. Visually inspect the liquid in the prefilled syringe for particulate matter and discoloration before administration. Do not use prefilled syringes with particulate matter or discoloration. Administer only with the enclosed needle. Discard any unused portion. Do not mix with calcium-containing solutions or other intravenously administered drugs. Prefilled syringes are for single use only.
2.2 Dosage Information
The recommended dose of BONIVA Injection for the treatment of postmenopausal osteoporosis is 3 mg every 3 months administered intravenously over a period of 15 to 30 seconds. Do not administer more frequently than once every 3 months.
2.3 Laboratory Testing and Oral Examination Prior to Administration
Prior to administration of each dose obtain a serum creatinine [see Warnings and Precautions (5.3)]. Given that bisphosphonates have been associated with osteonecrosis of the jaw (ONJ), perform a routine oral examination prior to administration of BONIVA Injection.
2.4 Calcium and Vitamin D Supplementation
Instruct patients to take supplemental calcium and vitamin D if their dietary intake is inadequate. [see Warnings and Precautions (5.1)].
2.5 Dosing After Missed Dose
If the dose is missed, administer as soon as it can be re-scheduled. Thereafter, BONIVA Injection should be scheduled every 3 months from the date of the last injection.
2.6 Dosage Modifications in Patients with Renal Impairment
Do not administer to patients with severe renal impairment (creatinine clearance less than 30 mL/minute) [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)]. No dose adjustment is necessary for patients with mild or moderate renal impairment (creatinine clearance greater than or equal to 30 mL/min) [see Clinical Pharmacology (12.3)].
COPEGUS should be taken with food. COPEGUS should be given in combination with PEGASYS; it is important to note that COPEGUS should never be given as monotherapy. See PEGASYS Package Insert for all instructions regarding PEGASYS dosing and administration.
2.1 Chronic Hepatitis C Monoinfection
The recommended dose of COPEGUS tablets is provided in Table 1. The recommended duration of treatment for patients previously untreated with ribavirin and interferon is 24 to 48 weeks.
The daily dose of COPEGUS is 800 mg to 1200 mg administered orally in two divided doses. The dose should be individualized to the patient depending on baseline disease characteristics (e.g., genotype), response to therapy, and tolerability of the regimen (see Table 1).Table 1 PEGASYS and COPEGUS Dosing Recommendations Hepatitis C Virus (HCV) Genotype PEGASYS Dose* (once weekly) COPEGUS Dose (daily) Duration Genotypes 2 and 3 showed no increased response to treatment beyond 24 weeks (see Table 10). Data on genotypes 5 and 6 are insufficient for dosing recommendations. * See PEGASYS Package Insert for further details on PEGASYS dosing and administration, including dose modification in patients with renal impairment. Genotypes 1, 4 180 mcg <75 kg = 1000 mg≥75 kg = 1200 mg 48 weeks48 weeks Genotypes 2, 3 180 mcg 800 mg 24 weeks
PEGASYS is administered as 180 mcg/1.73m2 × BSA once weekly subcutaneously, to a maximum dose of 180 mcg, and should be given in combination with ribavirin. The recommended treatment duration for patients with genotype 2 or 3 is 24 weeks and for other genotypes is 48 weeks.
COPEGUS should be given in combination with PEGASYS. COPEGUS is available only as a 200 mg tablet and therefore the healthcare provider should determine if this sized tablet can be swallowed by the pediatric patient. The recommended doses for COPEGUS are provided in Table 2. Patients who initiate treatment prior to their 18th birthday should maintain pediatric dosing through the completion of therapy.Table 2 COPEGUS Dosing Recommendations for Pediatric Patients Body Weight in kilograms (kg) COPEGUS Daily Dose* COPEGUS Number of Tablets * approximately 15 mg/kg/day 23 – 33 400 mg/day 1 × 200 mg tablet A.M.1 × 200 mg tablet P.M. 34 – 46 600 mg/day 1 × 200 mg tablet A.M.2 × 200 mg tablets P.M. 47 – 59 800 mg/day 2 × 200 mg tablets A.M.2 × 200 mg tablets P.M. 60 – 74 1000 mg/day 2 × 200 mg tablets A.M.3 × 200 mg tablets P.M. ≥75 1200 mg/day 3 × 200 mg tablets A.M.3 × 200 mg tablets P.M.
2.2 Chronic Hepatitis C with HIV Coinfection
The recommended dose for treatment of chronic hepatitis C in patients coinfected with HIV is PEGASYS 180 mcg subcutaneous once weekly and COPEGUS 800 mg by mouth daily for a total duration of 48 weeks, regardless of HCV genotype.
2.3 Dose Modifications
Adult and Pediatric Patients
If severe adverse reactions or laboratory abnormalities develop during combination COPEGUS/PEGASYS therapy, the dose should be modified or discontinued, if appropriate, until the adverse reactions abate or decrease in severity. If intolerance persists after dose adjustment, COPEGUS/PEGASYS therapy should be discontinued. Table 3 provides guidelines for dose modifications and discontinuation based on the patient's hemoglobin concentration and cardiac status.
COPEGUS should be administered with caution to patients with pre-existing cardiac disease. Patients should be assessed before commencement of therapy and should be appropriately monitored during therapy. If there is any deterioration of cardiovascular status, therapy should be stopped [see Warnings and Precautions (5.2)].Table 3 COPEGUS Dose Modification Guidelines in Adults and Pediatrics Body weight in kilograms (kg) Laboratory Values Hemoglobin <10 g/dL in patients with no cardiac disease, orDecrease in hemoglobin of ≥2 g/dL during any 4 week period in patients with history of stable cardiac disease Hemoglobin <8.5 g/dL in patients with no cardiac disease, orHemoglobin <12 g/dL despite 4 weeks at reduced dose in patients with history of stable cardiac disease Adult Patients older than 18 years of age Any weight 1 × 200 mg tablet A.M.2 × 200 mg tablets P.M. Discontinue COPEGUS Pediatric Patients 5 to 18 years of age 23 – 33 kg 1 × 200 mg tablet A.M. Discontinue COPEGUS 34 – 46 kg 1 × 200 mg tablet A.M.1 × 200 mg tablet P.M. 47 – 59 kg 1 × 200 mg tablet A.M.1 × 200 mg tablet P.M. 60 – 74 kg 1 × 200 mg tablet A.M.2 × 200 mg tablets P.M. ≥75 kg 1 × 200 mg tablet A.M.2 × 200 mg tablets P.M.
The guidelines for COPEGUS dose modifications outlined in this table also apply to laboratory abnormalities or adverse reactions other than decreases in hemoglobin values.
Once COPEGUS has been withheld due to either a laboratory abnormality or clinical adverse reaction, an attempt may be made to restart COPEGUS at 600 mg daily and further increase the dose to 800 mg daily. However, it is not recommended that COPEGUS be increased to the original assigned dose (1000 mg to 1200 mg).
Upon resolution of a laboratory abnormality or clinical adverse reaction, an increase in COPEGUS dose to the original dose may be attempted depending upon the physician's judgment. If COPEGUS has been withheld due to a laboratory abnormality or clinical adverse reaction, an attempt may be made to restart COPEGUS at one-half the full dose.
2.4 Renal Impairment
The total daily dose of COPEGUS should be reduced for patients with creatinine clearance less than or equal to 50 mL/min; and the weekly dose of PEGASYS should be reduced for creatinine clearance less than 30 mL/min as follows in Table 4 [see Use in Specific Populations (8.7), Pharmacokinetics (12.3), and PEGASYS Package Insert].Table 4 Dosage Modification for Renal Impairment Creatinine Clearance PEGASYS Dose(once weekly) COPEGUS Dose(daily) 30 to 50 mL/min 180 mcg Alternating doses, 200 mg and 400 mg every other day Less than 30 mL/min 135 mcg 200 mg daily Hemodialysis 135 mcg 200 mg daily
The dose of COPEGUS should not be further modified in patients with renal impairment. If severe adverse reactions or laboratory abnormalities develop, COPEGUS should be discontinued, if appropriate, until the adverse reactions abate or decrease in severity. If intolerance persists after restarting COPEGUS, COPEGUS/PEGASYS therapy should be discontinued.
No data are available for pediatric subjects with renal impairment.
2.5 Discontinuation of Dosing
Discontinuation of PEGASYS/COPEGUS therapy should be considered if the patient has failed to demonstrate at least a 2 log10 reduction from baseline in HCV RNA by 12 weeks of therapy, or undetectable HCV RNA levels after 24 weeks of therapy.
PEGASYS/COPEGUS therapy should be discontinued in patients who develop hepatic decompensation during treatment [see Warnings and Precautions (5.3)].
A dose of 1 g administered orally or intravenously (over NO LESS THAN 2 HOURS) twice a day (daily dose of 2 g) is recommended for use in renal transplant patients. Although a dose of 1.5 g administered twice daily (daily dose of 3 g) was used in clinical trials and was shown to be safe and effective, no efficacy advantage could be established for renal transplant patients. Patients receiving 2 g/day of CellCept demonstrated an overall better safety profile than did patients receiving 3 g/day of CellCept.
Pediatrics (3 months to 18 years of age)
The recommended dose of CellCept oral suspension is 600 mg/m2 administered twice daily (up to a maximum daily dose of 2 g/10 mL oral suspension). Patients with a body surface area of 1.25 m2 to 1.5 m2 may be dosed with CellCept capsules at a dose of 750 mg twice daily (1.5 g daily dose). Patients with a body surface area >1.5 m2 may be dosed with CellCept capsules or tablets at a dose of 1 g twice daily (2 g daily dose).
A dose of 1.5 g bid administered intravenously (over NO LESS THAN 2 HOURS) or 1.5 g bid oral (daily dose of 3 g) is recommended for use in adult cardiac transplant patients.
A dose of 1 g bid administered intravenously (over NO LESS THAN 2 HOURS) or 1.5 g bid oral (daily dose of 3 g) is recommended for use in adult hepatic transplant patients.
CellCept Capsules, Tablets, and Oral Suspension
The initial oral dose of CellCept should be given as soon as possible following renal, cardiac or hepatic transplantation. Food had no effect on MPA AUC, but has been shown to decrease MPA Cmax by 40%. Therefore, it is recommended that CellCept be administered on an empty stomach. However, in stable renal transplant patients, CellCept may be administered with food if necessary.
Patients should be instructed to take a missed dose as soon as they remember, except if it is near the next scheduled dose, and then continue to take CellCept at the usual times.
Note: If required, CellCept Oral Suspension can be administered via a nasogastric tube with a minimum size of 8 French (minimum 1.7 mm interior diameter).
Patients With Hepatic Impairment
No dose adjustments are recommended for renal patients with severe hepatic parenchymal disease. However, it is not known whether dose adjustments are needed for hepatic disease with other etiologies (see CLINICAL PHARMACOLOGY: Pharmacokinetics).
No data are available for cardiac transplant patients with severe hepatic parenchymal disease.
The recommended oral dose of 1 g bid for renal transplant patients, 1.5 g bid for cardiac transplant patients, and 1 g bid administered intravenously or 1.5 g bid administered orally in hepatic transplant patients is appropriate for elderly patients (see PRECAUTIONS: Geriatric Use).
Preparation of Oral Suspension
It is recommended that CellCept Oral Suspension be constituted by the pharmacist prior to dispensing to the patient.
CellCept Oral Suspension should not be mixed with any other medication.
Mycophenolate mofetil has demonstrated teratogenic effects in humans. There are no adequate and well-controlled studies in pregnant women (see WARNINGS, PRECAUTIONS, ADVERSE REACTIONS, and HANDLING AND DISPOSAL). Care should be taken to avoid inhalation or direct contact with skin or mucous membranes of the dry powder or the constituted suspension. If such contact occurs, wash thoroughly with soap and water; rinse eyes with water.Tap the closed bottle several times to loosen the powder. Measure 94 mL of water in a graduated cylinder. Add approximately half the total amount of water for constitution to the bottle and shake the closed bottle well for about 1 minute. Add the remainder of water and shake the closed bottle well for about 1 minute. Remove the child-resistant cap and push bottle adapter into neck of bottle. Close bottle with child-resistant cap tightly. This will assure the proper seating of the bottle adapter in the bottle and child-resistant status of the cap.
Dispense with patient instruction sheet and oral dispensers. It is recommended to write the date of expiration of the constituted suspension on the bottle label. (The shelf-life of the constituted suspension is 60 days.)
After constitution the oral suspension contains 200 mg/mL mycophenolate mofetil. Store constituted suspension at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). Storage in a refrigerator at 2° to 8°C (36° to 46°F) is acceptable. Do not freeze. Discard any unused portion 60 days after constitution.
CellCept Intravenous is an alternative dosage form to CellCept capsules, tablets and oral suspension recommended for patients unable to take oral CellCept. CellCept Intravenous should be administered within 24 hours following transplantation. CellCept Intravenous can be administered for up to 14 days; patients should be switched to oral CellCept as soon as they can tolerate oral medication.
CellCept Intravenous must be reconstituted and diluted to a concentration of 6 mg/mL using 5% Dextrose Injection USP. CellCept Intravenous is incompatible with other intravenous infusion solutions. Following reconstitution, CellCept Intravenous must be administered by slow intravenous infusion over a period of NO LESS THAN 2 HOURS by either peripheral or central vein.
CAUTION: CELLCEPT INTRAVENOUS SOLUTION MUST NOT BE ADMINISTERED BY RAPID OR BOLUS INTRAVENOUS INJECTION (see WARNINGS).
Preparation of Infusion Solution (6 mg/mL)
Caution should be exercised in the handling and preparation of solutions of CellCept Intravenous. Avoid direct contact of the prepared solution of CellCept Intravenous with skin or mucous membranes. If such contact occurs, wash thoroughly with soap and water; rinse eyes with plain water (see WARNINGS, PRECAUTIONS, ADVERSE REACTIONS, and HANDLING AND DISPOSAL).
CellCept Intravenous does not contain an antibacterial preservative; therefore, reconstitution and dilution of the product must be performed under aseptic conditions. Additionally, this product is sealed under vacuum and should retain a vacuum throughout its shelf life. If a lack of vacuum in the vial is noted while adding diluent, the vial should not be used.
CellCept Intravenous infusion solution must be prepared in two steps: the first step is a reconstitution step with 5% Dextrose Injection USP, and the second step is a dilution step with 5% Dextrose Injection USP. A detailed description of the preparation is given below:
Step 1a) Two (2) vials of CellCept Intravenous are used for preparing each 1 g dose, whereas three (3) vials are needed for each 1.5 g dose. Reconstitute the contents of each vial by injecting 14 mL of 5% Dextrose Injection USP. b) Gently shake the vial to dissolve the drug. c) Inspect the resulting slightly yellow solution for particulate matter and discoloration prior to further dilution. Discard the vials if particulate matter or discoloration is observed.
Step 2a) To prepare a 1 g dose, further dilute the contents of the two reconstituted vials (approx. 2 × 15 mL) into 140 mL of 5% Dextrose Injection USP. To prepare a 1.5 g dose, further dilute the contents of the three reconstituted vials (approx. 3 × 15 mL) into 210 mL of 5% Dextrose Injection USP. The final concentration of both solutions is 6 mg mycophenolate mofetil per mL. b) Inspect the infusion solution for particulate matter or discoloration. Discard the infusion solution if particulate matter or discoloration is observed.
If the infusion solution is not prepared immediately prior to administration, the commencement of administration of the infusion solution should be within 4 hours from reconstitution and dilution of the drug product. Keep solutions at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).
CellCept Intravenous should not be mixed or administered concurrently via the same infusion catheter with other intravenous drugs or infusion admixtures.
In renal transplant patients with severe chronic renal impairment (GFR <25 mL/min/1.73 m2) outside the immediate posttransplant period, doses of CellCept greater than 1 g administered twice a day should be avoided. These patients should also be carefully observed. No dose adjustments are needed in renal transplant patients experiencing delayed graft function postoperatively (see CLINICAL PHARMACOLOGY: Pharmacokinetics and PRECAUTIONS: Patients with Renal Impairment).
No data are available for cardiac or hepatic transplant patients with severe chronic renal impairment. CellCept may be used for cardiac or hepatic transplant patients with severe chronic renal impairment if the potential benefits outweigh the potential risks.
If neutropenia develops (ANC <1.3 × 103/µL), dosing with CellCept should be interrupted or the dose reduced, appropriate diagnostic tests performed, and the patient managed appropriately (see WARNINGS: Neutropenia, ADVERSE REACTIONS, and PRECAUTIONS: Laboratory Tests).
Cathflo® Activase® (Alteplase) is for instillation into the dysfunctional catheter at a concentration of 1 mg/mL.
• Patients weighing ≥30 kg:2 mg in 2 mL
• Patients weighing <30 kg:110% of the internal lumen volume of the catheter, not to exceed 2 mg in 2 mL
If catheter function is not restored at 120 minutes after 1 dose of Cathflo Activase, a second dose may be instilled (see Instructions for Administration). There is no efficacy or safety information on dosing in excess of 2 mg per dose for this indication. Studies have not been performed with administration of total doses greater than 4 mg (two 2‑mg doses).
Instructions for Administration
Preparation of Solution
Reconstitute Cathflo Activase to a final concentration of 1 mg/mL:Aseptically withdraw 2.2 mL of Sterile Water for Injection, USP (diluent is not provided). Do not use Bacteriostatic Water for Injection. Inject the 2.2 mL of Sterile Water for Injection, USP, into the Cathflo Activase vial, directing the diluent stream into the powder. Slight foaming is not unusual; let the vial stand undisturbed to allow large bubbles to dissipate. Mix by gently swirling until the contents are completely dissolved. Complete dissolution should occur within 3 minutes. DO NOT SHAKE. The reconstituted preparation results in a colorless to pale yellow transparent solution containing 1 mg/mL Cathflo Activase at a pH of approximately 7.3. Cathflo Activase contains no antibacterial preservatives and should be reconstituted immediately before use. The solution may be used for intracatheter instillation within 8 hours following reconstitution when stored at 2–30°C (36–86°F).
No other medication should be added to solutions containing Cathflo Activase.
Instillation of Solution into the CatheterInspect the product prior to administration for foreign matter and discoloration. Withdraw 2 mL (2 mg) of solution from the reconstituted vial. Instill the appropriate dose of Cathflo Activase (see DOSAGE AND ADMINISTRATION) into the occluded catheter. After 30 minutes of dwell time, assess catheter function by attempting to aspirate blood. If the catheter is functional, go to Step 7. If the catheter is not functional, go to Step 5. After 120 minutes of dwell time, assess catheter function by attempting to aspirate blood and catheter contents. If the catheter is functional, go to Step 7. If the catheter is not functional, go to Step 6. If catheter function is not restored after one dose of Cathflo Activase, a second dose of equal amount may be instilled. Repeat the procedure beginning with Step 1 under Preparation of Solution. If catheter function has been restored, aspirate 4–5 mL of blood in patients ≥10 kg or 3 mL in patients <10 kg to remove Cathflo Activase and residual clot, and gently irrigate the catheter with 0.9% Sodium Chloride, USP.
Any unused solution should be discarded.
Stability and Storage
Store lyophilized Cathflo Activase at refrigerated temperature (2–8°C/36–46°F). Do not use beyond the expiration date on the vial. Protect the lyophilized material during extended storage from excessive exposure to light.
2.1 Recommended Doses and Schedules
The initial dose of PERJETA is 840 mg administered as a 60-minute intravenous infusion, followed every 3 weeks by a dose of 420 mg administered as an intravenous infusion over 30 to 60 minutes.
When administered with PERJETA, the recommended initial dose of trastuzumab is 8 mg/kg administered as a 90-minute intravenous infusion, followed every 3 weeks by a dose of 6 mg/kg administered as an intravenous infusion over 30 to 90 minutes.
PERJETA, trastuzumab, and docetaxel should be administered sequentially. PERJETA and trastuzumab can be given in any order. Docetaxel should be administered after PERJETA and trastuzumab. An observation period of 30 to 60 minutes is recommended after each PERJETA infusion and before commencement of any subsequent infusion of trastuzumab or docetaxel [see Warnings and Precautions (5.3)].
Metastatic Breast Cancer (MBC)
When administered with PERJETA, the recommended initial dose of docetaxel is 75 mg/m2 administered as an intravenous infusion. The dose may be escalated to 100 mg/m2 administered every 3 weeks if the initial dose is well tolerated.
Neoadjuvant Treatment of Breast Cancer
PERJETA should be administered every 3 weeks for 3 to 6 cycles as part of one of the following treatment regimens for early breast cancer [see Clinical Studies (14.2)]:Four preoperative cycles of PERJETA in combination with trastuzumab and docetaxel followed by 3 postoperative cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC) as given in Study 2 Three preoperative cycles of FEC alone followed by 3 preoperative cycles of PERJETA in combination with docetaxel and trastuzumab as given in Study 3 Six preoperative cycles of PERJETA in combination with docetaxel, carboplatin, and trastuzumab (TCH) (escalation of docetaxel above 75 mg/m2 is not recommended) as given in Study 3
Following surgery, patients should continue to receive trastuzumab to complete 1 year of treatment. There is insufficient evidence to recommend continued use of PERJETA for greater than 6 cycles for early breast cancer. There is insufficient evidence to recommend concomitant administration of an anthracycline with PERJETA, and there are no safety data to support sequential use of doxorubicin with PERJETA.
2.2 Dose Modification
For delayed or missed doses, if the time between two sequential infusions is less than 6 weeks, the 420 mg dose of PERJETA should be administered. Do not wait until the next planned dose. If the time between two sequential infusions is 6 weeks or more, the initial dose of 840 mg PERJETA should be re-administered as a 60-minute intravenous infusion followed every 3 weeks thereafter by a dose of 420 mg administered as an intravenous infusion over 30 to 60 minutes.
PERJETA should be discontinued if trastuzumab treatment is discontinued.
Dose reductions are not recommended for PERJETA.
For docetaxel dose modifications, see relevant prescribing information.
Left Ventricular Ejection Fraction (LVEF):
Withhold PERJETA and trastuzumab dosing for at least 3 weeks for either:a drop in LVEF to less than 45% or LVEF of 45% to 49% with a 10% or greater absolute decrease below pretreatment values [see Warnings and Precautions (5.1)]
PERJETA may be resumed if the LVEF has recovered to greater than 49% or to 45% to 49% associated with less than a 10% absolute decrease below pretreatment values.
If after a repeat assessment within approximately 3 weeks, the LVEF has not improved, or has declined further, PERJETA and trastuzumab should be discontinued, unless the benefits for the individual patient are deemed to outweigh the risks [see Warnings and Precautions (5.1)].
The infusion rate of PERJETA may be slowed or interrupted if the patient develops an infusion-related reaction [see Warnings and Precautions (5.3)].
The infusion should be discontinued immediately if the patient experiences a serious hypersensitivity reaction [see Warnings and Precautions (5.4)].
2.3 Preparation for Administration
Administer as an intravenous infusion only. Do not administer as an intravenous push or bolus. Do not mix PERJETA with other drugs.
Prepare the solution for infusion, using aseptic technique, as follows:Parenteral drug products should be inspected visually for particulates and discoloration prior to administration. Withdraw the appropriate volume of PERJETA solution from the vial(s). Dilute into a 250 mL 0.9% sodium chloride PVC or non-PVC polyolefin infusion bag. Mix diluted solution by gentle inversion. Do not shake. Administer immediately once prepared. If the diluted infusion solution is not used immediately, it can be stored at 2°C to 8°C for up to 24 hours. Dilute with 0.9% Sodium Chloride injection only. Do not use dextrose (5%) solution.
2.1 Rheumatoid Arthritis
The recommended dosage of ACTEMRA for adult patients given as a 60-minute single intravenous drip infusion is 4 mg per kg every 4 weeks followed by an increase to 8 mg per kg every 4 weeks based on clinical response.Reduction of dose from 8 mg per kg to 4 mg per kg is recommended for management of certain dose-related laboratory changes including elevated liver enzymes, neutropenia, and thrombocytopenia [see Dosage and Administration (2.7), Warnings and Precautions (5.3), and Adverse Reactions (6.1)]. Doses exceeding 800 mg per infusion are not recommended in RA patients [see Clinical Pharmacology (12.3)]. Patients less than 100 kg weight 162 mg administered subcutaneously every other week, followed by an increase to every week based on clinical response Patients at or above 100 kg weight 162 mg administered subcutaneously every week
2.2 Polyarticular Juvenile Idiopathic ArthritisRecommended Intravenous PJIA Dosage Every 4 Weeks Patients less than 30 kg weight 10 mg per kg Patients at or above 30 kg weight 8 mg per kg Do not change dose based solely on a single visit body weight measurement, as weight may fluctuate. Interruption of dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia [see Dosage and Administration (2.7)]. Subcutaneous administration is not approved for PJIA.
2.3 Systemic Juvenile Idiopathic ArthritisRecommended Intravenous SJIA Dosage Every 2 Weeks Patients less than 30 kg weight 12 mg per kg Patients at or above 30 kg weight 8 mg per kg Do not change a dose based solely on a single visit body weight measurement, as weight may fluctuate. Interruption of dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia [see Dosage and Administration (2.7)]. Subcutaneous administration is not approved for SJIA.
2.4 General Considerations for AdministrationACTEMRA has not been studied in combination with biological DMARDs such as TNF antagonists, IL-1R antagonists, anti-CD20 monoclonal antibodies and selective co-stimulation modulators because of the possibility of increased immunosuppression and increased risk of infection. Avoid using ACTEMRA with biological DMARDs. It is recommended that ACTEMRA not be initiated in patients with an absolute neutrophil count (ANC) below 2000 per mm3, platelet count below 100,000 per mm3, or who have ALT or AST above 1.5 times the upper limit of normal (ULN).
2.5 Preparation and Administration Instructions for Intravenous Infusion
ACTEMRA for intravenous infusion should be diluted by a healthcare professional using aseptic technique as follows:PJIA and SJIA patients less than 30 kg: use a 50 mL infusion bag or bottle of 0.9% Sodium Chloride, and then follow steps 1 and 2 below. Adult RA, PJIA and SJIA patients at or above 30 kg weight: use a 100 mL infusion bag or bottle, and then follow steps 1 and 2 below. – Step 1. Withdraw a volume of 0.9% Sodium Chloride injection, equal to the volume of the ACTEMRA injection required for the patient's dose from the infusion bag or bottle [see Dosage and Administration (2.1, 2.2, 2.3)]. For Intravenous Use: Volume of ACTEMRA Injection per kg of Body Weight Dosage Indication Volume of ACTEMRA injection per kg of body weight 4 mg/kg Adult RA 0.2mL/kg 8 mg/kg Adult RASJIA and PJIA (≥30 kg of body weight) 0.4mL/kg 10 mg/kg PJIA (< 30 kg of body weight) 0.5 mL/kg 12 mg/kg SJIA (< 30 kg of body weight) 0.6mL/kg – Step 2. Withdraw the amount of ACTEMRA for intravenous infusion from the vial(s) and add slowly into the Sodium Chloride infusion bag or bottle. To mix the solution, gently invert the bag to avoid foaming. The fully diluted ACTEMRA solutions for infusion may be stored at 2° to 8°C (36° to 46°F) or room temperature for up to 24 hours and should be protected from light. ACTEMRA solutions do not contain preservatives; therefore, unused product remaining in the vials should not be used. Allow the fully diluted ACTEMRA solution to reach room temperature prior to infusion. The infusion should be administered over 60 minutes, and must be administered with an infusion set. Do not administer as an intravenous push or bolus. ACTEMRA should not be infused concomitantly in the same intravenous line with other drugs. No physical or biochemical compatibility studies have been conducted to evaluate the co-administration of ACTEMRA with other drugs. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If particulates and discolorations are noted, the product should not be used. Fully diluted ACTEMRA solutions are compatible with polypropylene, polyethylene and polyvinyl chloride infusion bags and polypropylene, polyethylene and glass infusion bottles.
2.6 Preparation and Administration Instructions for Subcutaneous Injection for RAACTEMRA subcutaneous injection is intended for use under the guidance of a healthcare practitioner. After proper training in subcutaneous injection technique, a patient may self-inject ACTEMRA or the patient's caregiver may administer ACTEMRA if a healthcare practitioner determines that it is appropriate. Patients, or patient caregivers, should be instructed to follow the directions provided in the Instructions for Use (IFU) for additional details on medication administration. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use ACTEMRA prefilled syringes (PFS) exhibiting particulate matter, cloudiness, or discoloration. ACTEMRA for subcutaneous administration should be clear and colorless to pale yellow. Do not use if any part of the PFS appears to be damaged. Patients using ACTEMRA for subcutaneous administration should be instructed to inject the full amount in the syringe (0.9 mL), which provides 162 mg of ACTEMRA, according to the directions provided in the IFU. Injection sites should be rotated with each injection and should never be given into moles, scars, or areas where the skin is tender, bruised, red, hard, or not intact.
2.7 Dosage Modifications due to Serious Infections or Laboratory Abnormalities
Rheumatoid ArthritisLiver Enzyme Abnormalities [see Warnings and Precautions (5.3)]: Lab Value Recommendation Greater than 1 to 3× ULN Dose modify concomitant DMARDs if appropriate For persistent increases in this range: For patients receiving intravenous ACTEMRA, reduce dose to 4 mg per kg or hold ACTEMRA until ALT or AST have normalized For patients receiving subcutaneous ACTEMRA, reduce injection frequency to every other week or hold dosing until ALT or AST have normalized. Resume ACTEMRA at every other week and increase frequency to every week as clinically appropriate. Greater than 3 to 5× ULN Hold ACTEMRA dosing until less than 3× ULN and follow recommendations above for greater than 1 to 3× ULN (confirmed by repeat testing) For persistent increases greater than 3× ULN, discontinue ACTEMRA Greater than 5× ULN Discontinue ACTEMRA Low Absolute Neutrophil Count (ANC) [see Warnings and Precautions (5.3)]: Lab Value(cells per mm3) Recommendation ANC greater than 1000 Maintain dose ANC 500 to 1000 Hold ACTEMRA dosing When ANC greater than 1000 cells per mm3: For patients receiving intravenous ACTEMRA, resume ACTEMRA at 4 mg per kg and increase to 8 mg per kg as clinically appropriate For patients receiving subcutaneous ACTEMRA, resume ACTEMRA at every other week and increase frequency to every week as clinically appropriate ANC less than 500 Discontinue ACTEMRA Low Platelet Count [see Warnings and Precautions (5.3)]: Lab Value(cells per mm3) Recommendation 50,000 to 100,000 Hold ACTEMRA dosing When platelet count is greater than 100,000 cells per mm3: For patients receiving intravenous ACTEMRA, resume ACTEMRA at 4 mg per kg and increase to 8 mg per kg as clinically appropriate For patients receiving subcutaneous ACTEMRA, resume ACTEMRA at every other week and increase frequency to every week as clinically appropriate Less than 50,000 Discontinue ACTEMRA
Polyarticular and Systemic Juvenile Idiopathic Arthritis:
Dose reduction of ACTEMRA has not been studied in the PJIA and SJIA populations. Dose interruptions of ACTEMRA are recommended for liver enzyme abnormalities, low neutrophil counts, and low platelet counts in patients with PJIA and SJIA at levels similar to what is outlined above for patients with RA. If appropriate, dose modify or stop concomitant methotrexate and/or other medications and hold ACTEMRA dosing until the clinical situation has been evaluated. In PJIA and SJIA the decision to discontinue ACTEMRA for a laboratory abnormality should be based upon the medical assessment of the individual patient.
Dosage should be individualized for maximum beneficial effect. While the usual daily dosages given below will meet the needs of most patients, there will be some who may require higher doses. In such cases dosage should be increased cautiously to avoid adverse effects.ADULTS: USUAL DAILY DOSE: Management of Anxiety Disorders and Relief of Symptoms of Anxiety. Depending upon severity of symptoms—2 mg to 10 mg, 2 to 4 times daily Symptomatic Relief in Acute Alcohol Withdrawal. 10 mg, 3 or 4 times during the first 24 hours, reducing to 5 mg, 3 or 4 times daily as needed Adjunctively for Relief of Skeletal Muscle Spasm. 2 mg to 10 mg, 3 or 4 times daily Adjunctively in Convulsive Disorders. 2 mg to 10 mg, 2 to 4 times daily Geriatric Patients,or in the presence of debilitating disease. 2 mg to 2.5 mg, 1 or 2 times daily initially; increase gradually as needed and tolerated PEDIATRIC PATIENTS: Because of varied responses to CNS-acting drugs, initiate therapy with lowest dose and increase as required. Not for use in pediatric patients under 6 months. 1 mg to 2.5 mg, 3 or 4 times daily initially; increase gradually as needed and tolerated
The recommended dose of ERIVEDGE is 150 mg taken orally once daily until disease progression or until unacceptable toxicity [see Clinical Studies (14)].
ERIVEDGE may be taken with or without food. Swallow capsules whole. Do not open or crush capsules.
If a dose of ERIVEDGE is missed, do not make up that dose; resume dosing with the next scheduled dose.
Clonazepam is available as a tablet. The tablets should be administered with water by swallowing the tablet whole.
The initial dose for adults with seizure disorders should not exceed 1.5 mg/day divided into three doses. Dosage may be increased in increments of 0.5 to 1 mg every 3 days until seizures are adequately controlled or until side effects preclude any further increase. Maintenance dosage must be individualized for each patient depending upon response. Maximum recommended daily dose is 20 mg.
The use of multiple anticonvulsants may result in an increase of depressant adverse effects. This should be considered before adding Klonopin to an existing anticonvulsant regimen.
Klonopin is administered orally. In order to minimize drowsiness, the initial dose for infants and children (up to 10 years of age or 30 kg of body weight) should be between 0.01 and 0.03 mg/kg/day but not to exceed 0.05 mg/kg/day given in two or three divided doses. Dosage should be increased by no more than 0.25 to 0.5 mg every third day until a daily maintenance dose of 0.1 to 0.2 mg/kg of body weight has been reached, unless seizures are controlled or side effects preclude further increase. Whenever possible, the daily dose should be divided into three equal doses. If doses are not equally divided, the largest dose should be given before retiring.
There is no clinical trial experience with Klonopin in seizure disorder patients 65 years of age and older. In general, elderly patients should be started on low doses of Klonopin and observed closely (see PRECAUTIONS: Geriatric Use).
The initial dose for adults with panic disorder is 0.25 mg bid. An increase to the target dose for most patients of 1 mg/day may be made after 3 days. The recommended dose of 1 mg/day is based on the results from a fixed dose study in which the optimal effect was seen at 1 mg/day. Higher doses of 2, 3 and 4 mg/day in that study were less effective than the 1 mg/day dose and were associated with more adverse effects. Nevertheless, it is possible that some individual patients may benefit from doses of up to a maximum dose of 4 mg/day, and in those instances, the dose may be increased in increments of 0.125 to 0.25 mg bid every 3 days until panic disorder is controlled or until side effects make further increases undesired. To reduce the inconvenience of somnolence, administration of one dose at bedtime may be desirable.
Treatment should be discontinued gradually, with a decrease of 0.125 mg bid every 3 days, until the drug is completely withdrawn.
There is no body of evidence available to answer the question of how long the patient treated with clonazepam should remain on it. Therefore, the physician who elects to use Klonopin for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.
There is no clinical trial experience with Klonopin in panic disorder patients under 18 years of age.
There is no clinical trial experience with Klonopin in panic disorder patients 65 years of age and older. In general, elderly patients should be started on low doses of Klonopin and observed closely (see PRECAUTIONS: Geriatric Use).
2.1 Standard Starting Dose
Monotherapy (Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer, Metastatic Breast Cancer)
The recommended dose of XELODA is 1250 mg/m2 administered orally twice daily (morning and evening; equivalent to 2500 mg/m2 total daily dose) for 2 weeks followed by a 1-week rest period given as 3-week cycles (see Table 1).
Adjuvant treatment in patients with Dukes' C colon cancer is recommended for a total of 6 months [ie, XELODA 1250 mg/m2 orally twice daily for 2 weeks followed by a 1-week rest period, given as 3-week cycles for a total of 8 cycles (24 weeks)].Table 1 XELODA Dose Calculation According to Body Surface Area Dose Level 1250 mg/m2 Twice a Day Number of Tablets to be Taken at Each Dose (Morning and Evening) Surface Area (m2) Total Daily Dose* (mg) 150 mg 500 mg * Total Daily Dose divided by 2 to allow equal morning and evening doses ≤ 1.25 3000 0 3 1.26-1.37 3300 1 3 1.38-1.51 3600 2 3 1.52-1.65 4000 0 4 1.66-1.77 4300 1 4 1.78-1.91 4600 2 4 1.92-2.05 5000 0 5 2.06-2.17 5300 1 5 ≥ 2.18 5600 2 5
In Combination With Docetaxel (Metastatic Breast Cancer)
In combination with docetaxel, the recommended dose of XELODA is 1250 mg/m2 twice daily for 2 weeks followed by a 1-week rest period, combined with docetaxel at 75 mg/m2 as a 1-hour intravenous infusion every 3 weeks. Pre-medication, according to the docetaxel labeling, should be started prior to docetaxel administration for patients receiving the XELODA plus docetaxel combination. Table 1 displays the total daily dose of XELODA by body surface area and the number of tablets to be taken at each dose.
2.2 Dose Management Guidelines
XELODA dosage may need to be individualized to optimize patient management. Patients should be carefully monitored for toxicity and doses of XELODA should be modified as necessary to accommodate individual patient tolerance to treatment [see Clinical Studies (14)]. Toxicity due to XELODA administration may be managed by symptomatic treatment, dose interruptions and adjustment of XELODA dose. Once the dose has been reduced, it should not be increased at a later time. Doses of XELODA omitted for toxicity are not replaced or restored; instead the patient should resume the planned treatment cycles.
The dose of phenytoin and the dose of coumarin-derivative anticoagulants may need to be reduced when either drug is administered concomitantly with XELODA [see Drug Interactions (7.1)].
Monotherapy (Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer, Metastatic Breast Cancer)
XELODA dose modification scheme as described below (see Table 2) is recommended for the management of adverse reactions.Table 2 Recommended Dose Modifications of XELODA Toxicity NCIC Grades* During a Course of Therapy Dose Adjustment for Next Treatment (% of starting dose) * National Cancer Institute of Canada Common Toxicity Criteria were used except for the hand-and-foot syndrome [see Warnings and Precautions (5)]. Grade 1 Maintain dose level Maintain dose level Grade 2 -1st appearance Interrupt until resolved to grade 0-1 100% -2nd appearance 75% -3rd appearance 50% -4th appearance Discontinue treatment permanently - Grade 3 -1st appearance Interrupt until resolved to grade 0-1 75% -2nd appearance 50% -3rd appearance Discontinue treatment permanently - Grade 4 -1st appearance Discontinue permanentlyORIf physician deems it to be in the patient's best interest to continue, interrupt until resolved to grade 0-1 50%
In Combination With Docetaxel (Metastatic Breast Cancer)
Dose modifications of XELODA for toxicity should be made according to Table 2 above for XELODA. At the beginning of a treatment cycle, if a treatment delay is indicated for either XELODA or docetaxel, then administration of both agents should be delayed until the requirements for restarting both drugs are met.
The dose reduction schedule for docetaxel when used in combination with XELODA for the treatment of metastatic breast cancer is shown in Table 3.Table 3 Docetaxel Dose Reduction Schedule in Combination with XELODA Toxicity NCIC Grades* Grade 2 Grade 3 Grade 4 * National Cancer Institute of Canada Common Toxicity Criteria were used except for hand-and-foot syndrome [see Warnings and Precautions (5)]. 1st appearance Delay treatment until resolved to grade 0-1; Resume treatment with original dose of 75 mg/m2 docetaxel Delay treatment until resolved to grade 0-1; Resume treatment at 55 mg/m2 of docetaxel. Discontinue treatment with docetaxel 2nd appearance Delay treatment until resolved to grade 0-1; Resume treatment at 55 mg/m2 of docetaxel. Discontinue treatment with docetaxel - 3rd appearance Discontinue treatment with docetaxel - -
2.3 Adjustment of Starting Dose in Special Populations
No adjustment to the starting dose of XELODA is recommended in patients with mild renal impairment (creatinine clearance = 51 to 80 mL/min [Cockroft and Gault, as shown below]). In patients with moderate renal impairment (baseline creatinine clearance = 30 to 50 mL/min), a dose reduction to 75% of the XELODA starting dose when used as monotherapy or in combination with docetaxel (from 1250 mg/m2 to 950 mg/m2 twice daily) is recommended [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)]. Subsequent dose adjustment is recommended as outlined in Table 2 and Table 3 (depending on the regimen) if a patient develops a grade 2 to 4 adverse event [see Warnings and Precautions (5.5)]. The starting dose adjustment recommendations for patients with moderate renal impairment apply to both XELODA monotherapy and XELODA in combination use with docetaxel.
Cockroft and Gault Equation:
(140 - age [yrs]) (body wt [kg])
Creatinine clearance for males = ——————————————
(72) (serum creatinine [mg/dL])
Creatinine clearance for females = 0.85 × male value
Physicians should exercise caution in monitoring the effects of XELODA in the elderly. Insufficient data are available to provide a dosage recommendation.
Do not administer as an intravenous push or bolus. Administer only as an intravenous (IV) infusion.Do not initiate Avastin until at least 28 days following major surgery. Administer Avastin after the surgical incision has fully healed. First infusion: Administer infusion over 90 minutes. Subsequent infusions: Administer second infusion over 60 minutes if first infusion is tolerated; administer all subsequent infusions over 30 minutes if infusion over 60 minutes is tolerated.
2.2 Recommended Doses and Schedules
Patients should continue treatment until disease progression or unacceptable toxicity.
Metastatic Colorectal Cancer (mCRC)
The recommended doses are 5 mg/kg or 10 mg/kg every 2 weeks when used in combination with intravenous 5-FU-based chemotherapy.Administer 5 mg/kg when used in combination with bolus-IFL. Administer 10 mg/kg when used in combination with FOLFOX4. Administer 5 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks when used in combination with a fluoropyrimidine-irinotecan or fluoropyrimidine-oxaliplatin based chemotherapy regimen in patients who have progressed on a first-line Avastin-containing regimen.
Non-Squamous Non-Small Cell Lung Cancer (NSCLC)
The recommended dose is 15 mg/kg every 3 weeks in combination with carboplatin and paclitaxel.
The recommended dose is 10 mg/kg every 2 weeks.
Metastatic Renal Cell Carcinoma (mRCC)
The recommended dose is 10 mg/kg every 2 weeks in combination with interferon alfa.
2.3 Preparation for Administration
Use appropriate aseptic technique. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Withdraw necessary amount of Avastin and dilute in a total volume of 100 mL of 0.9% Sodium Chloride Injection, USP. Discard any unused portion left in a vial, as the product contains no preservatives.
DO NOT ADMINISTER OR MIX WITH DEXTROSE SOLUTION.
2.4 Dose Modifications
There are no recommended dose reductions.
Discontinue Avastin for:Gastrointestinal perforations (gastrointestinal perforations, fistula formation in the gastrointestinal tract, intra-abdominal abscess), fistula formation involving an internal organ [See Boxed Warning, Warnings and Precautions (5.1, 5.2).] Wound dehiscence and wound healing complications requiring medical intervention [See Warnings and Precautions (5.3).] Serious hemorrhage (i.e., requiring medical intervention) [See Boxed Warning, Warnings and Precautions (5.4).] Severe arterial thromboembolic events [See Warnings and Precautions (5.5).] Life-threatening (Grade 4) venous thromboembolic events, including pulmonary embolism [See Warnings and Precautions (5.6).] Hypertensive crisis or hypertensive encephalopathy [See Warnings and Precautions (5.7).] Posterior Reversible Encephalopathy Syndrome (PRES) [See Warnings and Precautions (5.8).] Nephrotic syndrome [See Warnings and Precautions (5.9).]
Temporarily suspend Avastin for:At least 4 weeks prior to elective surgery [See Warnings and Precautions (5.3).] Severe hypertension not controlled with medical management [See Warnings and Precautions (5.7).] Moderate to severe proteinuria [See Warnings and Precautions (5.9).] Severe infusion reactions [See Warnings and Precautions (5.10).]
2.1 General Dosing Information
FOR OPHTHALMIC INTRAVITREAL INJECTION ONLY.
2.2 Neovascular (Wet) Age-Related Macular Degeneration (AMD)
LUCENTIS 0.5 mg (0.05 mL of 10 mg/mL LUCENTIS solution) is recommended to be administered by intravitreal injection once a month (approximately 28 days).
Although not as effective, patients may be treated with 3 monthly doses followed by less frequent dosing with regular assessment. In the nine months after 3 initial monthly doses, less frequent dosing with 4-5 doses on average is expected to maintain visual acuity while monthly dosing may be expected to result in an additional average 1-2 letter gain. Patients should be assessed regularly [see Clinical Studies (14.1)].
Although not as effective, patients may also be treated with one dose every 3 months after 4 monthly doses. Compared with continued monthly dosing, dosing every 3 months over the next 9 months will lead to an approximate 5-letter (1-line) loss of visual acuity benefit, on average. Patients should be assessed regularly [see Clinical Studies (14.1)].
2.3 Macular Edema Following Retinal Vein Occlusion (RVO)
LUCENTIS 0.5 mg (0.05 mL of 10 mg/mL LUCENTIS solution) is recommended to be administered by intravitreal injection once a month (approximately 28 days).
In Studies RVO-1 and RVO-2, patients received monthly injections of LUCENTIS for 6 months. In spite of being guided by optical coherence tomography and visual acuity re-treatment criteria, patients who were then not treated at Month 6 experienced on average, a loss of visual acuity at Month 7, whereas patients who were treated at Month 6 did not. Patients should be treated monthly [see Clinical Studies (14.2)].
2.4 Diabetic Macular Edema (DME)
LUCENTIS 0.3 mg (0.05 mL of 6 mg/mL LUCENTIS solution) is recommended to be administered by intravitreal injection once a month (approximately 28 days).
2.5 Diabetic Retinopathy in patients with Diabetic Macular Edema
2.6 Preparation for Administration
Using aseptic technique, all of the LUCENTIS vial contents are withdrawn through a 5-micron, 19-gauge filter needle attached to a 1-cc tuberculin syringe. The filter needle should be discarded after withdrawal of the vial contents and should not be used for intravitreal injection. The filter needle should be replaced with a sterile 30-gauge × 1/2-inch needle for the intravitreal injection. The contents should be expelled until the plunger tip is aligned with the line that marks 0.05 mL on the syringe.
The intravitreal injection procedure should be carried out under controlled aseptic conditions, which include the use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent). Adequate anesthesia and a broad-spectrum microbicide should be given prior to the injection.
Prior to and 30 minutes following the intravitreal injection, patients should be monitored for elevation in intraocular pressure using tonometry. Monitoring may also consist of a check for perfusion of the optic nerve head immediately after the injection [see Warnings and Precautions (5.2)]. Patients should also be monitored for and instructed to report any symptoms suggestive of endophthalmitis without delay following the injection [see Warnings and Precautions (5.1)].
Each vial should only be used for the treatment of a single eye. If the contralateral eye requires treatment, a new vial should be used and the sterile field, syringe, gloves, drapes, eyelid speculum, filter, and injection needles should be changed before LUCENTIS is administered to the other eye.
No special dosage modification is required for any of the populations that have been studied (e.g., gender, elderly).
2.1 Patient Selection
Select patients for the first-line treatment of metastatic NSCLC with TARCEVA based on the presence of EGFR exon 19 deletions or exon 21 (L858R) substitution mutations in tumor specimens [See Clinical Studies (14.1)]. Information on FDA-approved tests for the detection of EGFR mutations in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics
2.2 Recommended Dose – NSCLC
The recommended daily dose of TARCEVA for NSCLC is 150 mg taken on an empty stomach, i.e., at least one hour before or two hours after the ingestion of food. Treatment should continue until disease progression or unacceptable toxicity occurs.
2.3 Recommended Dose – Pancreatic Cancer
The recommended daily dose of TARCEVA for pancreatic cancer is 100 mg taken once daily in combination with gemcitabine. Take TARCEVA on an empty stomach, i.e., at least one hour before or two hours after the ingestion of food. Treatment should continue until disease progression or unacceptable toxicity occurs [see Clinical Studies (14.5)].
2.4 Dose Modifications
Discontinue TARCEVA for:• Interstitial Lung Disease (ILD) [see Warnings and Precautions (5.1)]. • Severe hepatic toxicity that does not improve significantly or resolve within three weeks [see Warnings and Precautions (5.3)]. • Gastrointestinal perforation [see Warnings and Precautions (5.4)]. • Severe bullous, blistering or exfoliating skin conditions [see Warnings and Precautions (5.5)]. • Corneal perforation or severe ulceration [see Warnings and Precautions (5.9)].
Withhold TARCEVA:• During diagnostic evaluation for possible ILD. • For severe (CTCAE grade 3 to 4) renal toxicity, and consider discontinuation of TARCEVA [see Warnings and Precautions (5.2)]. • In patients without pre-existing hepatic impairment for total bilirubin levels greater than 3 times the upper limit of normal or transaminases greater than 5 times the upper limit of normal, and consider discontinuation of TARCEVA [see Warnings and Precautions (5.3)]. • In patients with pre-existing hepatic impairment or biliary obstruction for doubling of bilirubin or tripling of transaminases values over baseline and consider discontinuation of TARCEVA [see Warnings and Precautions (5.3)]. • For persistent severe diarrhea not responsive to medical management (e.g., loperamide). • For severe rash not responsive to medical management. • For keratitis of (NCI-CTC version 4.0) grade 3-4 or for grade 2 lasting more than 2 weeks [see Warnings and Precautions (5.9)]. • For acute/worsening ocular disorders such as eye pain, and consider discontinuation of TARCEVA [see Warnings and Precautions (5.9)].
Reduce TARCEVA by 50 mg decrements:• If severe reactions occur with concomitant use of strong CYP3A4 inhibitors [such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin (TAO), voriconazole, or grapefruit or grapefruit juice] or when using concomitantly with an inhibitor of both CYP3A4 and CYP1A2 (e.g., ciprofloxacin). Avoid concomitant use if possible [see Drug Interactions (7)]. • When restarting therapy following withholding treatment for a dose-limiting toxicity that has resolved to baseline or grade ≤ 1.
Increase TARCEVA by 50 mg increments as tolerated for:• Concomitant use with CYP3A4 inducers, such as rifampin, rifabutin, rifapentine, phenytoin, carbamazepine, phenobarbital, or St. John’s Wort. Increase doses by 50 mg increments at 2 week intervals to a maximum of 450 mg. Avoid concomitant use, if possible [see Drug Interactions (7)]. • Concurrent cigarette smoking. Increase by 50 mg increments at 2 week intervals to a maximum of 300 mg. Immediately reduce the dose of TARCEVA to the recommended dose (150 mg or 100 mg daily) upon cessation of smoking [see Drug Interactions (7) and Clinical Pharmacology (12.3)].
Drugs Affecting Gastric pH• Avoid concomitant use of TARCEVA with proton pump inhibitors if possible. Separation of doses may not eliminate the interaction since proton pump inhibitors affect the pH of the upper GI tract for an extended period. • If treatment with an H 2-receptor antagonist such as ranitidine is required, TARCEVA must be taken 10 hours after the H 2-receptor antagonist dosing and at least 2 hours before the next dose of the H 2-receptor antagonist. • Although the effect of antacids on erlotinib pharmacokinetics has not been evaluated, the antacid dose and the TARCEVA dose should be separated by several hours, if an antacid is necessary.
2.1 Dosing for Treatment and Prophylaxis of Influenza
Treatment with TAMIFLU should begin within 2 days of onset of symptoms of influenza or following close contact with an infected individual.
TAMIFLU may be taken with or without food [see Clinical Pharmacology (12.3)]. However, when taken with food, tolerability may be enhanced in some patients.
For patients who cannot swallow capsules, TAMIFLU for oral suspension is the preferred formulation. If the oral suspension product is not available, TAMIFLU capsules may be opened and mixed with sweetened liquids such as regular or sugar-free chocolate syrup, corn syrup, caramel topping, or light brown sugar (dissolved in water). If the appropriate strengths of TAMIFLU capsules are not available to mix with sweetened liquids and the oral suspension product is not available, then a pharmacist may compound an emergency supply of oral suspension from TAMIFLU 75 mg capsules [see Dosage and Administration (2.8)].
2.2 Treatment of Influenza
Adults and Adolescents (13 years of age and older)
The recommended oral dose of TAMIFLU for treatment of influenza in adults and adolescents 13 years and older is 75 mg twice daily for 5 days. TAMIFLU for oral suspension may be used by patients who cannot swallow a capsule (12.5 mL of TAMIFLU for oral suspension [6 mg/mL] delivers 75 mg) [see Dosage and Administration (2.1)].
Pediatric Patients (2 weeks to 12 years of age)
The recommended oral dose of TAMIFLU for treatment of influenza in pediatric patients 1 year to 12 years of age is shown in Table 1.
The recommended oral dose of TAMIFLU for treatment of influenza in pediatric patients 2 weeks to less than 1 year of age is 3 mg/kg twice daily for 5 days (shown in Table 1).
2.3 Prophylaxis of Influenza
Adults and Adolescents (13 years of age and older)
The recommended oral dose of TAMIFLU for prophylaxis of influenza in adults and adolescents 13 years and older following close contact with an infected individual is 75 mg once daily for at least 10 days. The recommended dose for prophylaxis during a community outbreak of influenza is 75 mg once daily. Safety and efficacy have been demonstrated for up to 6 weeks in immunocompetent patients. The duration of protection lasts for as long as dosing is continued. Safety has been demonstrated for up to 12 weeks in immunocompromised patients. TAMIFLU for oral suspension may also be used by patients who cannot swallow a capsule (12.5 mL of TAMIFLU for oral suspension [6 mg/mL] delivers 75 mg).
Pediatric Patients (2 weeks to 12 years of age)
The recommended oral dose of TAMIFLU for prophylaxis of influenza in pediatric patients 1 to 12 years of age based on body weight is shown in Table 1. Prophylaxis in pediatric patients following close contact with an infected individual is recommended for 10 days. For prophylaxis in pediatric patients during a community outbreak of influenza, dosing may be continued for up to 6 weeks.
The safety and efficacy of TAMIFLU for prophylaxis of influenza have not been established in infants less than 1 year of age.Table 1 Treatment (twice daily dosing for 5 days) and Prophylaxis (once daily dosing for 10 days) Dosing of Oral TAMIFLU for Influenza in Pediatric Patients Weight(kg) Treatment Dosing for 5 days Prophylaxis Dosing for 10 days Volume of Oral Suspension (6 mg/mL) for each Dose* Number of Bottles of Oral Suspension to Dispense Number of Capsules and Strength to Dispense† * An oral dosing dispensing device that measures the appropriate volume in mL should be utilized with the oral suspension. † Oral Suspension is the preferred formulation for patients who cannot swallow capsules. ‡ TAMIFLU is not approved for prophylaxis of patients less than 1 year of age § For patients less than 1 year of age, provide an appropriate dosing device that can accurately measure and administer small volumes. Patients from 2 Weeks to less than 1 Year of Age Any weight 3 mg/kg twice daily Not applicable‡ 0.5 mL/kg§ 1 bottle Not applicable Patients 1 to 12 Years of Age Based on Body Weight 15 kg or less 30 mg twice daily 30 mg once daily 5 mL 1 bottle 10 Capsules30 mg 15.1 kg thru 23 kg 45 mg twice daily 45 mg once daily 7.5 mL 2 bottles 10 Capsules45 mg 23.1 kg thru 40 kg 60 mg twice daily 60 mg once daily 10 mL 2 bottles 20 Capsules30 mg 40.1 kg or more 75 mg twice daily 75 mg once daily 12.5 mL 3 bottles 10 Capsules75 mg
2.4 Renal Impairment
Data are available on plasma concentrations of oseltamivir carboxylate following various dosing schedules in patients with renal impairment [see Clinical Pharmacology (12.3)].
Treatment of InfluenzaTable 2 Recommended Dose Adjustments for Treatment of Influenza in Adult Patients with Renal Impairment or End Stage Renal Disease (ESRD) on Dialysis Renal Impairment/Creatinine Clearance Recommended Treatment Regimen* * Capsules or suspension can be used for 30 mg dosing. † Assuming three hemodialysis sessions are performed in the 5-day period. Treatment can be initiated immediately if influenza symptoms develop during the 48 hours between hemodialysis sessions; however, the post-hemodialysis dose should still be administered independently of time of administration of the initial dose. ‡ Data derived from studies in continuous ambulatory peritoneal dialysis (CAPD) patients. Mild Creatinine Clearance >60-90 mL/min 75 mg twice daily for 5 days Moderate Creatinine Clearance >30-60 mL/min 30 mg twice daily for 5 days Severe Creatinine Clearance >10-30 mL/min 30 mg once daily for 5 days ESRD Patients on Hemodialysis Creatinine Clearance ≤10 mL/min 30 mg after every hemodialysis cycle. Treatment duration not to exceed 5 days† ESRD Patients on Continuous Ambulatory Peritoneal Dialysis‡ Creatinine Clearance ≤10 mL/min A single 30 mg dose administered immediately after a dialysis exchange
Prophylaxis of InfluenzaTable 3 Recommended Dose Adjustments for Prophylaxis of Influenza in Adult Patients with Renal Impairment or End Stage Renal Disease (ESRD) on Dialysis Renal Impairment/Creatinine Clearance Recommended Prophylaxis Regimen* * Capsules or suspension can be used for 30 mg dosing. † An initial dose can be administered prior to the start of dialysis. ‡ Data derived from studies in continuous ambulatory peritoneal dialysis (CAPD) patients. Mild Creatinine Clearance >60-90 mL/min 75 mg once daily Moderate Creatinine Clearance >30-60 mL/min 30 mg once daily Severe Creatinine Clearance >10-30 mL/min 30 mg every other day ESRD Patients on Hemodialysis Creatinine Clearance ≤10 mL/min 30 mg after alternate hemodialysis cycles† ESRD Patients on Continuous Ambulatory Peritoneal Dialysis‡ Creatinine Clearance ≤10 mL/min 30 mg once weekly immediately after dialysis exchange
2.5 Hepatic Impairment
No dose adjustment is recommended for patients with mild or moderate hepatic impairment (Child-Pugh score ≤9) [see Clinical Pharmacology (12.3)].
2.6 Geriatric Patients
No dose adjustment is required for geriatric patients [see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)].
2.7 Preparation of TAMIFLU for Oral Suspension
It is recommended that TAMIFLU for oral suspension be constituted by the pharmacist prior to dispensing to the patient:a) Tap the closed bottle several times to loosen the powder. b) Measure 55 mL of water in a graduated cylinder. c) Add the total amount of water for constitution to the bottle. d) Close bottle with child-resistant cap tightly and shake the closed bottle well for 15 seconds.
Label the bottle with instructions to Shake Well before each use.
The constituted TAMIFLU for oral suspension (6 mg/mL) should be used within 17 days of preparation when stored under refrigeration or within 10 days if stored at controlled room temperature; the pharmacist should write the date of expiration of the constituted suspension on a pharmacy label. The patient package insert should be dispensed to the patient. Pharmacists should ensure patients have an oral dosing dispenser that measures the appropriate volume in milliliters. Pharmacists should counsel patients on how to utilize an oral dosing dispenser and correctly measure the oral suspension as prescribed (see Table 1).
2.8 Emergency Compounding of an Oral Suspension from 75 mg TAMIFLU Capsules (Final Concentration 6 mg/mL)
The following directions are provided for use only during emergency situations. These directions are not intended to be used if the FDA-approved, commercially manufactured TAMIFLU for oral suspension is readily available from wholesalers or the manufacturer.
Compounding an oral suspension with this procedure will provide one patient with enough medication for a 5-day course of treatment or a 10-day course of prophylaxis.
Commercially manufactured TAMIFLU for oral suspension (6 mg/mL) is the preferred product for pediatric and adult patients who have difficulty swallowing capsules or where lower doses are needed. In the event that TAMIFLU for oral suspension is not available, the pharmacist may compound a suspension (6 mg/mL) from TAMIFLU capsules 75 mg using one of these vehicles: Cherry Syrup (Humco®), Ora-Sweet® SF (sugar-free) (Paddock Laboratories), or simple syrup. Other vehicles have not been studied. This compounded suspension should not be used for convenience or when the FDA-approved TAMIFLU for oral suspension is commercially available.
First, determine the dose of TAMIFLU for the patients [see Dosage and Administration (2)] then determine total volume of an oral suspension needed to be compounded based on Table 4.Table 4 Volume of an Oral Suspension (6 mg/mL) Needed to be Compounded Based Upon the Patient's TAMIFLU Dose TAMIFLU Dose* Total Volume to Compound per Patient (mL) * If the TAMIFLU dose is between the doses listed, the total volume of oral suspension to compound should default to the next greater dose listed. 15 mg or less 37.5 mL 30 mg 75 mL 45 mg 100 mL 60 mg 125 mL 75 mg 150 mL
Second, determine the number of capsules and the amount of water and vehicle (Cherry Syrup, Ora-Sweet® SF, or simple syrup) that are needed to prepare the total volume (determined from Table 4: 37.5 mL, 75 mL, 100 mL, 125 mL, or 150 mL) of compounded oral suspension (6 mg/mL) (see Table 5).Table 5 Number of TAMIFLU 75 mg Capsules and Amount of Vehicle (Cherry Syrup, Ora-Sweet® SF, or Simple Syrup) Needed to Prepare the Total Volume of a Compounded Oral Suspension (6 mg/mL) Total Volume of Compounded Oral Suspension to be Prepared 37.5 mL 75 mL 100 mL 125 mL 150 mL * Includes overage to ensure all doses can be delivered Number of TAMIFLU 75 mg Capsules* 3 capsules (225 mg oseltamivir) 6 capsules (450 mg oseltamivir) 8 capsules (600 mg oseltamivir) 10 capsules (750 mg oseltamivir) 12 capsules (900 mg oseltamivir) Amount of Water 2.5 mL 5 mL 7 mL 8 mL 10 mL Volume of VehicleCherry Syrup (Humco®) OROra-Sweet® SF (Paddock Laboratories) OR simple syrup 34.5 mL 69 mL 91 mL 115 mL 137 mL
Third, follow the procedure below for compounding the oral suspension (6 mg/mL) from TAMIFLU capsules 75 mg:Place the specified amount of water into a polyethyleneterephthalate (PET) or glass bottle (see Table 5). Carefully separate the capsule body and cap and pour the contents of the required number of TAMIFLU 75 mg capsules into the PET or glass bottle. Gently swirl the suspension to ensure adequate wetting of the TAMIFLU powder for at least 2 minutes. Slowly add the specified amount of vehicle to the bottle. Close the bottle using a child-resistant cap and shake well for 30 seconds to completely dissolve the active drug and to ensure homogeneous distribution of the dissolved drug in the resulting suspension. (Note: The active drug, oseltamivir phosphate, readily dissolves in the specified vehicles. The suspension is caused by inert ingredients of TAMIFLU capsules which are insoluble in these vehicles.) Put an ancillary label on the bottle indicating "Shake Well Before Use." Instruct the parent or caregiver that any unused suspension remaining in the bottle following completion of therapy must be discarded by either affixing an ancillary label to the bottle or adding a statement to the pharmacy label instructions. Place an appropriate expiration date on the label according to storage conditions below.
Storage of the Emergency Compounded SuspensionRefrigeration: Stable for 5 weeks (35 days) when stored in a refrigerator at 2° to 8°C (36° to 46°F). Room Temperature: Stable for five days (5 days) when stored at room temperature, 25°C (77°F).
Note: The storage conditions are based on stability studies of compounded oral suspensions, using the above mentioned vehicles, which were placed in glass and polyethyleneterephthalate (PET) bottles. Stability studies have not been conducted with other vehicles or bottle types.
Place a pharmacy label on the bottle that includes the patient's name, dosing instructions, and drug name and any other required information to be in compliance with all State and Federal Pharmacy Regulations.
Dosing of the Compounded Suspension (6 mg/mL)
Refer to Dosage and Administration sections 2.2, 2.3, 2.4 and Table 1 for the proper dosing instructions for the pharmacy label.
2.1 Recommended Dosing
The recommended dose of XENICAL is one 120-mg capsule three times a day with each main meal containing fat (during or up to 1 hour after the meal).
The patient should be on a nutritionally balanced, reduced-calorie diet that contains approximately 30% of calories from fat. The daily intake of fat, carbohydrate, and protein should be distributed over three main meals. If a meal is occasionally missed or contains no fat, the dose of XENICAL can be omitted.
Because XENICAL has been shown to reduce the absorption of some fat-soluble vitamins and beta-carotene, patients should be counseled to take a multivitamin containing fat-soluble vitamins to ensure adequate nutrition [see Warnings and Precautions (5.1)]. The vitamin supplement should be taken at least 2 hours before or after the administration of XENICAL, such as at bedtime.
For patients receiving both XENICAL and cyclosporine therapy, administer cyclosporine 3 hours after XENICAL.
For patients receiving both XENICAL and levothyroxine therapy, administer levothyroxine and XENICAL at least 4 hours apart. Patients treated concomitantly with XENICAL and levothyroxine should be monitored for changes in thyroid function.
Doses above 120 mg three times a day have not been shown to provide additional benefit.
Based on fecal fat measurements, the effect of XENICAL is seen as soon as 24 to 48 hours after dosing. Upon discontinuation of therapy, fecal fat content usually returns to pretreatment levels within 48 to 72 hours.
Nutropin Aq Pen 10
For subcutaneous injection.
Therapy with Nutropin AQ should be supervised by a physician who is experienced in the diagnosis and management of pediatric patients with short stature associated with growth hormone deficiency (GHD), chronic kidney disease, Turner syndrome, idiopathic short stature, or adult patients with either childhood-onset or adult-onset GHD.
2.1 Dosing for Pediatric Patients
Nutropin AQ dosage and administration schedule should be individualized for each patient. Response to growth hormone (GH) therapy in pediatric patients tends to decrease with time. However, in pediatric patients failure to increase growth rate, particularly during the first year of therapy, suggests the need for close assessment of compliance and evaluation of other causes of growth failure, such as hypothyroidism, under-nutrition, advanced bone age and antibodies to recombinant human GH (rhGH).
Treatment with Nutropin AQ for short stature should be discontinued when the epiphyses are fused.
Pediatric Growth Hormone Deficiency (GHD)
A weekly dosage of up to 0.3 mg/kg of body weight divided into daily subcutaneous injection is recommended.
In pubertal patients, a weekly dosage of up to 0.7 mg/kg divided daily may be used.
Growth Failure Secondary to Chronic Kidney Disease (CKD)
A weekly dosage of up to 0.35 mg/kg of body weight divided into daily subcutaneous injection is recommended.
Nutropin AQ therapy may be continued up to the time of renal transplantation.
In order to optimize therapy for patients who require dialysis, the following guidelines for injection schedule are recommended:Hemodialysis patients should receive their injection at night just prior to going to sleep or at least 3 to 4 hours after their hemodialysis to prevent hematoma formation due to the heparin. Chronic Cycling Peritoneal Dialysis (CCPD) patients should receive their injection in the morning after they have completed dialysis. Chronic Ambulatory Peritoneal Dialysis (CAPD) patients should receive their injection in the evening at the time of the overnight exchange.
Idiopathic Short Stature (ISS)
A weekly dosage of up to 0.3 mg/kg of body weight divided into daily subcutaneous injections is recommended.
Short Stature Associated with Turner Syndrome (TS)
A weekly dosage of up to 0.375 mg/kg of body weight divided into equal doses 3 to 7 times per week by subcutaneous injection is recommended.
2.2 Dosing for Adult Patients
Adult Growth Hormone Deficiency (GHD)
Either of two approaches to Nutropin AQ dosing may be followed: a weight-based regimen or a non-weight-based regimen.
Weight based – Based on the dosing regimen used in the original adult GHD registration trials, the recommended dosage at the start of treatment is not more than 0.006 mg/kg daily. The dose may be increased according to individual patient requirements to a maximum of 0.025 mg/kg daily in patients ≤ 35 years and to a maximum of 0.0125 mg/kg daily in patients over 35 years old. Clinical response, side effects, and determination of age- and gender-adjusted serum insulin-like growth factor (IGF-1) concentrations should be used as guidance in dose titration.
Non-weight based – Alternatively, taking into account the published literature, a starting dose of approximately 0.2 mg/day (range, 0.15 to 0.30 mg/day) may be used without consideration of body weight. This dose can be increased gradually every 1 to 2 months by increments of approximately 0.1 to 0.2 mg/day, according to individual patient requirements based on the clinical response and serum IGF-1 concentrations. The dose should be decreased as necessary on the basis of adverse events and/or serum IGF-1 concentrations above the age- and gender-specific normal range.
Maintenance dosages vary considerably from person to person, and between male and female patients.
A lower starting dose and smaller dose increments should be considered for older patients, who are more prone to the adverse effects of somatropin than younger individuals. In addition, obese individuals are more likely to manifest adverse effects, when treated with a weight-based regimen. In order to reach the defined treatment goal, estrogen-replete women may need higher doses than men. Oral estrogen administration may increase the dose requirements in women.
2.3 Preparation and Administration
The solution should be clear immediately after removal from the refrigerator. Occasionally, after refrigeration, you may notice that small colorless particles of protein are present in the solution. This is not unusual for solutions containing proteins. Allow the pen cartridge or NuSpin® to come to room temperature and gently swirl. If the solution is cloudy, the contents MUST NOT be injected.
Parenteral drug products should always be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Injection sites, which may be located on the thigh, upper arm, abdomen or buttock, should always be rotated to avoid lipoatrophy.
Nutropin AQ Pen Cartridge
The Nutropin AQ Pen 10 and 20 mg Cartridges are color-banded to help ensure appropriate use with the Nutropin AQ Pen delivery device. Each cartridge must be used with its corresponding color-coded Nutropin AQ Pen [See Dosage Forms and Strengths (3)].
Wipe the septum of the Nutropin AQ Pen Cartridge with rubbing alcohol or an antiseptic solution to prevent contamination of the contents by microorganisms that may be introduced by repeated needle insertions. It is recommended that Nutropin AQ be administered using sterile, disposable needles. Follow the directions provided in the Nutropin AQ Pen Instructions for Use.
The Nutropin AQ Pen 10 allows for administration of a minimum dose of 0.1 mg to a maximum dose of 4.0 mg, in 0.1 mg increments.
The Nutropin AQ Pen 20 allows for administration of a minimum dose of 0.2 mg to a maximum dose of 8.0 mg, in 0.2 mg increments.
Nutropin AQ NuSpin
The Nutropin AQ NuSpin 5, 10 and 20 are multi-dose, dial-a-dose injection devices prefilled with Nutropin AQ in a 5 mg/2 mL, 10 mg/2 mL or 20 mg/ 2 mL cartridge, respectively, for subcutaneous use. It is recommended that Nutropin AQ be administered using sterile, disposable needles. Follow the directions provided in the Nutropin AQ NuSpin 5, 10 or 20 Instructions for Use.
The Nutropin AQ NuSpin 5 allows for administration of a minimum dose of 0.05 mg to a maximum dose of 1.75 mg, in increments of 0.05 mg.
The Nutropin AQ NuSpin 10 allows for administration of a minimum dose of 0.1 mg to a maximum dose of 3.5 mg, in increments of 0.1 mg.
The Nutropin AQ NuSpin 20 allows for administration of a minimum dose of 0.2 mg to a maximum dose of 7.0 mg, in increments of 0.2 mg.
2.1 Recommended Doses and SchedulesDo not administer as an intravenous push or bolus. Do not mix Herceptin with other drugs. Do not substitute Herceptin (trastuzumab) for or with ado-trastuzumab emtansine.
Adjuvant Treatment, Breast Cancer:
Administer according to one of the following doses and schedules for a total of 52 weeks of Herceptin therapy:
During and following paclitaxel, docetaxel, or docetaxel/carboplatin:Initial dose of 4 mg/kg as an intravenous infusion over 90 minutes then at 2 mg/kg as an intravenous infusion over 30 minutes weekly during chemotherapy for the first 12 weeks (paclitaxel or docetaxel) or 18 weeks (docetaxel/carboplatin). One week following the last weekly dose of Herceptin, administer Herceptin at 6 mg/kg as an intravenous infusion over 30–90 minutes every three weeks.
As a single agent within three weeks following completion of multi-modality, anthracycline-based chemotherapy regimens:Initial dose at 8 mg/kg as an intravenous infusion over 90 minutes Subsequent doses at 6 mg/kg as an intravenous infusion over 30–90 minutes every three weeks.
[see Dosage and Administration (2.2)]Extending adjuvant treatment beyond one year is not recommended [see Adverse Reactions (6.1)].
Metastatic Treatment, Breast Cancer:Administer Herceptin, alone or in combination with paclitaxel, at an initial dose of 4 mg/kg as a 90 minute intravenous infusion followed by subsequent once weekly doses of 2 mg/kg as 30 minute intravenous infusions until disease progression.
Metastatic Gastric Cancer:Administer Herceptin at an initial dose of 8 mg/kg as a 90 minute intravenous infusion followed by subsequent doses of 6 mg/kg as an intravenous infusion over 30-90 minutes every three weeks until disease progression [see Dosage and Administration (2.2)].
2.2 Important Dosing Considerations
[see Boxed Warning, Warnings and Precautions (5.2)]Decrease the rate of infusion for mild or moderate infusion reactions Interrupt the infusion in patients with dyspnea or clinically significant hypotension Discontinue Herceptin for severe or life-threatening infusion reactions.
[see Boxed Warning, Warnings and Precautions (5.1)]
Assess left ventricular ejection fraction (LVEF) prior to initiation of Herceptin and at regular intervals during treatment. Withhold Herceptin dosing for at least 4 weeks for either of the following:≥ 16% absolute decrease in LVEF from pre-treatment values LVEF below institutional limits of normal and ≥ 10% absolute decrease in LVEF from pretreatment values.
Herceptin may be resumed if, within 4–8 weeks, the LVEF returns to normal limits and the absolute decrease from baseline is ≤ 15%.
Permanently discontinue Herceptin for a persistent (> 8 weeks) LVEF decline or for suspension of Herceptin dosing on more than 3 occasions for cardiomyopathy.
2.3 Preparation for Administration
To prevent medication errors, it is important to check the vial labels to ensure that the drug being prepared and administered is Herceptin (trastuzumab) and not ado-trastuzumab emtansine.
Reconstitute each 440 mg vial of Herceptin with 20 mL of Bacteriostatic Water for Injection (BWFI), USP, containing 1.1% benzyl alcohol as a preservative to yield a multi-dose solution containing 21 mg/mL trastuzumab. In patients with known hypersensitivity to benzyl alcohol, reconstitute with 20 mL of Sterile Water for Injection (SWFI) without preservative to yield a single use solution.
Use appropriate aseptic technique when performing the following reconstitution steps:Using a sterile syringe, slowly inject the 20 mL of diluent into the vial containing the lyophilized cake of Herceptin. The stream of diluent should be directed into the lyophilized cake. Swirl the vial gently to aid reconstitution. DO NOT SHAKE. Slight foaming of the product may be present upon reconstitution. Allow the vial to stand undisturbed for approximately 5 minutes. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Inspect visually for particulates and discoloration. The solution should be free of visible particulates, clear to slightly opalescent and colorless to pale yellow. Store reconstituted Herceptin at 2–8° C; discard unused Herceptin after 28 days. If Herceptin is reconstituted with SWFI without preservative, use immediately and discard any unused portion.
DilutionDetermine the dose (mg) of Herceptin [see Dosage and Administration (2.1)]. Calculate the volume of the 21 mg/mL reconstituted Herceptin solution needed, withdraw this amount from the vial and add it to an infusion bag containing 250 mL of 0.9% Sodium Chloride Injection, USP.DO NOT USE DEXTROSE (5%) SOLUTION. Gently invert the bag to mix the solution.
The recommended dose of FUZEON is 90 mg (1 mL) twice daily injected subcutaneously into the upper arm, anterior thigh or abdomen. Each injection should be given at a site different from the preceding injection site, and only where there is no current injection site reaction from an earlier dose. FUZEON should not be injected near any anatomical areas where large nerves course close to the skin, such as near the elbow, knee, groin or the inferior or medial section of the buttocks, skin abnormalities, including directly over a blood vessel, into moles, scar tissue, bruises, or near the navel, surgical scars, tattoos or burn sites. Additional detailed information regarding the administration of FUZEON is described in the FUZEON Injection Instructions.
2.2 Pediatric Patients
Insufficient data are available to establish a dose recommendation of FUZEON in pediatric patients below the age of 6 years. In pediatric patients 6 years through 16 years of age, the recommended dosage of FUZEON is 2 mg/kg twice daily up to a maximum dose of 90 mg twice daily injected subcutaneously into the upper arm, anterior thigh or abdomen. Each injection should be given at a site different from the preceding injection site and only where there is no current injection site reaction from an earlier dose. FUZEON should not be injected into moles, scar tissue, bruises or the navel. Table 1 contains dosing guidelines for FUZEON based on body weight. Weight should be monitored periodically and the FUZEON dose adjusted accordingly.Table 1 Pediatric Dosing Guidelines Weight Dose per bid Injection (mg/dose) Injection Volume (90 mg enfuvirtide per mL) Kilograms (kg) Pounds (lbs) 11.0 to 15.5 24 to 34 27 0.3 mL 15.6 to 20.0 >34 to 44 36 0.4 mL 20.1 to 24.5 >44 to 54 45 0.5 mL 24.6 to 29.0 >54 to 64 54 0.6 mL 29.1 to 33.5 >64 to 74 63 0.7 mL 33.6 to 38.0 >74 to 84 72 0.8 mL 38.1 to 42.5 >84 to 94 81 0.9 mL ≥42.6 >94 90 1.0 mL
2.3 Directions for Use
For more detailed instructions, see FUZEON Injection Instructions.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.
FUZEON must only be reconstituted with 1 mL of Sterile Water for Injection provided in the Convenience Kit. After adding sterile water, the vial should be gently tapped for 10 seconds and then gently rolled between the hands to avoid foaming and to ensure all particles of drug are in contact with the liquid and no drug remains on the vial wall. The vial should then be allowed to stand until the powder goes completely into solution, which could take up to 45 minutes. Reconstitution time can be reduced by gently rolling the vial between the hands until the product is completely dissolved. Before the solution is withdrawn for administration, the vial should be inspected visually to ensure that the contents are fully dissolved in solution, and that the solution is clear, colorless and without bubbles or particulate matter. If the FUZEON is foamy or jelled, allow more time for it to dissolve. If there is evidence of particulate matter, the vial must not be used and should be returned to the pharmacy.
FUZEON contains no preservatives. Once reconstituted, FUZEON should be injected immediately or kept refrigerated in the original vial until use. Reconstituted FUZEON must be used within 24 hours. The subsequent dose of FUZEON can be reconstituted in advance and must be stored in the refrigerator in the original vial and used within 24 hours. Refrigerated reconstituted solution should be brought to room temperature before injection and the vial should be inspected visually again to ensure that the contents are fully dissolved in solution and that the solution is clear, colorless, and without bubbles or particulate matter.
A vial is suitable for single use only; unused portions must be discarded (see FUZEON Injection Instructions).
Patients should contact their healthcare provider for any questions regarding the administration of FUZEON. Information about the self-administration of FUZEON may also be obtained by calling the toll-free number 1-877-4-FUZEON (1-877-438-9366) or at the FUZEON website, www.FUZEON.com. Patients should be taught to recognize the signs and symptoms of injection site reactions and instructed when to contact their healthcare provider about these reactions.
2.1 Dosage for Asthma
Administer Xolair 150 to 375 mg by subcutaneous injection every 2 or 4 weeks. Determine doses (mg) and dosing frequency by serum total IgE level (IU/mL), measured before the start of treatment, and body weight (kg) (see Table 1 and 2).
Adjust doses for significant changes in body weight (see Table 1 and 2).
Total IgE levels are elevated during treatment and remain elevated for up to one year after the discontinuation of treatment. Therefore, re-testing of IgE levels during Xolair treatment cannot be used as a guide for dose determination.Interruptions lasting less than one year: Dose based on serum IgE levels obtained at the initial dose determination. Interruptions lasting one year or more: Re-test total serum IgE levels for dose determination.
Periodically reassess the need for continued therapy based upon the patient's disease severity and level of asthma control.Table 1. Subcutaneous Xolair Doses Every 4 Weeks for Patients 12 Years of Age and Older with Asthma Pre-treatment Serum IgE Body Weight 30–60 kg > 60–70 kg > 70–90 kg > 90–150 kg ≥ 30–100 IU/mL 150 mg 150 mg 150 mg 300 mg > 100–200 IU/mL 300 mg 300 mg 300 mg > 200–300 IU/mL 300 mg > 300–400 IU/mL SEE TABLE 2 > 400–500 IU/mL > 500–600 IU/mL Table 2. Subcutaneous Xolair Doses Every 2 Weeks for Patients 12 Years of Age and Older with Asthma Pre-treatment Serum IgE Body Weight 30–60 kg > 60–70 kg > 70–90 kg > 90–150 kg ≥ 30–100 IU/mL SEE TABLE 1 > 100–200 IU/mL 225 mg > 200–300 IU/mL 225 mg 225 mg 300 mg > 300–400 IU/mL 225 mg 225 mg 300 mg > 400–500 IU/mL 300 mg 300 mg 375mg > 500–600 IU/mL 300 mg 375 mg DO NOT DOSE > 600–700 IU/mL 375 mg
2.2 Dosage for Chronic Idiopathic Urticaria
Dosing of Xolair in CIU patients is not dependent on serum IgE (free or total) level or body weight.
The appropriate duration of therapy for CIU has not been evaluated. Periodically reassess the need for continued therapy.
The supplied Xolair lyophilized powder must be reconstituted with Sterile Water for Injection (SWFI) USP, using the following instructions:1) Before reconstitution, determine the number of vials that will need to be reconstituted (each vial delivers 150 mg of Xolair) [see Dosage and Administration (2.1, 2.2)]. 2) Draw 1.4 mL of SWFI, USP, into a 3 mL syringe equipped with a 1 inch, 18-gauge needle. 3) Place the vial upright on a flat surface and using standard aseptic technique, insert the needle and inject the SWFI, USP, directly onto the product. 4) Keeping the vial upright, gently swirl the upright vial for approximately 1 minute to evenly wet the powder. Do not shake. 5) Gently swirl the vial for 5 to 10 seconds approximately every 5 minutes in order to dissolve any remaining solids. The lyophilized product takes 15 to 20 minutes to dissolve. If it takes longer than 20 minutes to dissolve completely, gently swirl the vial for 5 to 10 seconds approximately every 5 minutes until there are no visible gel-like particles in the solution. Do not use if the contents of the vial do not dissolve completely by 40 minutes. 6) After reconstitution, Xolair solution is somewhat viscous and will appear clear or slightly opalescent. It is acceptable if there are a few small bubbles or foam around the edge of the vial; there should be no visible gel-like particles in the reconstituted solution. Do not use if foreign particles are present. 7) Invert the vial for 15 seconds in order to allow the solution to drain toward the stopper. 8) Use the Xolair solution within 8 hours following reconstitution when stored in the vial at 2 to 8ºC (36 to 46ºF), or within 4 hours of reconstitution when stored at room temperature. Reconstituted Xolair vials should be protected from sunlight. 9) Using a new 3 mL syringe equipped with a 1-inch, 18-gauge needle, insert the needle into the inverted vial. Position the needle tip at the very bottom of the solution in the vial stopper when drawing the solution into the syringe. The reconstituted product is somewhat viscous; in order to obtain the full 1.2 mL dose, all of the product must be withdrawn from the vial before expelling any air or excess solution from the syringe. Before removing the needle from the vial, pull the plunger all the way back to the end of the syringe barrel in order to remove all of the solution from the inverted vial. 10) Replace the 18-gauge needle with a 25-gauge needle for subcutaneous injection. 11) Expel air, large bubbles, and any excess solution in order to obtain the required 1.2 mL dose. A thin layer of small bubbles may remain at the top of the solution in the syringe.
Administer Xolair by subcutaneous injection. The injection may take 5-10 seconds to administer because the solution is slightly viscous. Do not administer more than 150 mg (contents of one vial) per injection site. Divide doses of more than 150 mg among two or more injection sites (Table 3).Table 3. Number of Injections and Total Injection Volumes Xolair Dose* Number of Injections Total Volume Injected * All doses in the table are approved for use in asthma patients. The 150 mg and 300 mg Xolair doses are intended for use in CIU patients. 150 mg 1 1.2 mL 225 mg 2 1.8 mL 300 mg 2 2.4 mL 375mg 3 3.0 mL
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