Kadmon Pharmaceuticals, Llc

Kadmon Pharmaceuticals, Llc Drugs

• Amphotec
  

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  Amphotec

  

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  The recommended dose for adults and pediatric patients is 3 - 4 mg/kg as required, once a day.

  AMPHOTEC, reconstituted in Sterile Water for Injection, is administered diluted in 5% Dextrose for Injection by intravenous infusion at a rate of 1 mg/kg/hour. A test dose immediately preceding the first dose is advisable when commencing all new courses of treatment. A small amount of drug (e.g., 10 mL of the final preparation containing between 1.6 to 8.3 mg) should be infused over 15 to 30 minutes and the patient carefully observed for the next 30 minutes.

  The infusion time may be shortened to a minimum of 2 hours for patients who show no evidence of intolerance or infusion-related reactions. If the patient experiences acute reactions or cannot tolerate the infusion volume, the infusion time may be extended.

  Directions for reconstitution and preparation of infusion admixture

  AMPHOTEC must be reconstituted by addition of Sterile Water for Injection. Using sterile syringe and a 20-gauge needle, rapidly add the following volumes to the vial to provide a liquid containing 5 mg of amphotericin B per mL. Shake gently by hand, rotating the vial until all solids have dissolved. Note that the fluid may be opalescent or clear.

  50 mg/vial add 10 mL Sterile Water for Injection 100 mg/vial add 20 mL Sterile Water for Injection

  For infusion, further dilute the reconstituted liquid to a final concentration of approximately 0.6 mg/mL (range 0.16 mg/mL to 0.83 mg/mL). The following table provides dilution recommendations:

  Dose ofAMPHOTEC Volume of ReconstitutedAMPHOTEC Infusion Bag Size for5% Dextrose for Injection 10 – 35 mg 2 – 7 mL 50 mL 35 – 70 mg 7 – 14 mL 100 mL 70 – 175 mg 14 – 35 mL 250 mL 175 – 350 mg 35 – 70 mL 500 mL 350 – 1000 mg 70 – 200 mL 1000 mL

  Do not reconstitute the lyophilized powder with saline or dextrose solutions, or admix the reconstituted liquid with saline or electrolytes.

  The use of any solution other than those recommended, or the presence of a bacteriostatic agent (e.g., benzyl alcohol) in the solution may cause precipitation of AMPHOTEC. Do not filter or use an in-line filter with AMPHOTEC.

  Do not mix the infusion admixture with other drugs. If administered through an existing intravenous line, flush with 5% Dextrose for Injection prior to, and following, infusion of AMPHOTEC, otherwise administer via a separate line.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use if a precipitate or foreign matter is present, or if the seal is not intact. Strict aseptic technique always should be observed during reconstitution and dilution since no preservatives are present in the lyophilized drug or in the solutions used for reconstitution and dilution.

  After reconstitution, the drug should be refrigerated at 2-8°C (36-46°F) and used within 24 hours. Do not freeze. After further dilution with 5% Dextrose for Injection, the infusion should be stored in a refrigerator (2-8°C) and used within 24 hours. Partially used vials should be discarded.

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• Infergen
  

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  Infergen

  

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  2.1 INFERGEN Monotherapy Dosing

  The recommended dose of INFERGEN monotherapy for the initial treatment of chronic HCV infection is 9 mcg administered three times a week as a single subcutaneous injection for 24 weeks [see Clinical Studies (14.1), Medication Guide for instructions].

  The recommended dose of INFERGEN monotherapy for patients who tolerated previous interferon therapy and did not respond or relapsed following its discontinuation is 15 mcg administered three times a week as a single subcutaneous injection for up to 48 weeks [see Clinical Studies (14.2), Medication Guide for instructions]. Patients who do not tolerate initial standard interferon therapy should not be treated with INFERGEN therapy 15 mcg three times a week.

  2.2 Combination Treatment with INFERGEN/Ribavirin Dosing

  The recommended dose of INFERGEN is 15 mcg daily administered as a single subcutaneous injection in combination with weight-based ribavirin at 1,000 mg - 1,200 mg (< 75 kg and ≥75 kg) orally in two divided doses for up to 48 weeks. [see Clinical Studies (14.3), Medication Guide for instructions].

  Ribavirin should be taken with food. INFERGEN/ribavirin should not be used in patients with creatinine clearance < 50 mL/min [see CONTRAINDICATIONS (4)].

  2.3 Dose Modifications

  If a serious adverse reaction develops during the course of treatment [see WARNINGS AND PRECAUTIONS (5)] discontinue or modify the dosage of INFERGEN and/or ribavirin until the adverse event abates or decreases in severity. If persistent or recurrent serious adverse events develop despite adequate dosage adjustment, discontinue treatment. Upon resolution or improvement of the adverse reaction, resuming INFERGEN and/or ribavirin may be considered.

  INFERGEN Monotherapy Dose Modifications

  Dose reduction to 7.5 mcg may be necessary following a serious adverse reaction. If serious adverse events continue to occur, dosing should be interrupted or discontinued as the efficacy of lower doses has not been established.

  INFERGEN/Ribavirin Combination Therapy Dose Modifications

  Stepwise dose reduction from 15 mcg to 9 mcg and from 9 mcg to 6 mcg may be necessary for serious adverse reactions.

  Guidelines for INFERGEN/Ribavirin Dose Modifications

  Tables 1, 2, and 3 provide guidelines for dose modifications and discontinuation of INFERGEN and/or ribavirin based on depression or laboratory parameters.

  Table 1. Guidelines for Dose Modification or Discontinuation of INFERGEN and for Scheduling Visits for Patients with Depression * See DSM-IV for definitions.

  Depression Severity*   

  Initial Management

  (4–8 Weeks)

  Depression

   

  Dose Modification   

  Visit Schedule   

  Remains Stable   

  Improves   

  Worsens   

  Mild

  No change to INFERGEN dose or ribavirin dose.

  Evaluate once weekly by visit and/or phone.

  Continue weekly visit schedule.

  Resume normal visit schedule.

  (See moderate or severe depression)

  Moderate

  Decrease INFERGEN dose from 15 mcg to 9 mcg; or from 9 mcg to 6 mcg, no change to ribavirin dose.

  Evaluate once weekly (office visit at least every other week).

  Consider psychiatric consultation. Continue reduced dosing.

  If symptoms improve and are stable for 4 weeks, may resume normal visit schedule. Continue reduced INFERGEN dosing or return to normal INFERGEN dose.

  (See severe depression)

  Severe

  Discontinue INFERGEN and ribavirin permanently.

  Not applicable.

  Psychiatric therapy necessary.

  Not applicable.

  Not applicable.

  Table 2. Guidelines for Dose Modification or Discontinuation of INFERGEN for Hematologic Toxicities

  Laboratory Values

  Action

  ANC < 0.75 × 109/L

  Reduce INFERGEN dose from 15 mcg to 9 mcg, or from 9 mcg to 6 mcg; maintain ribavirin dose at 1200 mg or 1000 mg.

  ANC < 0.50 × 109/L

  INFERGEN and ribavirin treatment should be suspended until ANC values return to more than 1000/mm3.

  Platelet Count < 50 × 109/L   

  Reduce INFERGEN dose from 15 mcg to 9 mcg or from 9 mcg to 6 mcg; maintain ribavirin dose at 1200 mg or 1000 mg.

  Platelet Count < 25 × 109/L   

  INFERGEN and ribavirin treatment should be discontinued.

  Table 3. Guidelines for Dose Modification or Discontinuation of INFERGEN/Ribavirin for the Management of Anemia* * For adult patients with a history of stable cardiac disease receiving INFERGEN in combination with ribavirin, the INFERGEN dose should be reduced from 15 mcg to 9 mcg or 9 mcg to 6 mcg and the ribavirin dose by 200 mg/day if a >2 g/dL decrease in hemoglobin is observed during any 4-week period. Both INFERGEN and ribavirin should be permanently discontinued if patients have hemoglobin levels <12 g/dL after this ribavirin dose reduction.** 1st dose reduction of ribavirin is by 200 mg/day. 2nd dose reduction of ribavirin (if needed) is by an additional 200 mg/day.

  Condition

  INFERGEN

  Ribavirin

  Hgb <10 g/dL

  History of Cardiac or Cerebrovascular Disease, reduce dose of INFERGEN

  Adjust dose**

  Hgb <8.5 g/dL

  Permanently discontinue

  Permanently discontinue

  Renal Function: INFERGEN/ribavirin should not be used in patients with creatinine clearance <50 mL/min. [See CONTRAINDICATIONS (4), WARNINGS AND PRECAUTIONS (5) and Ribavirin Labeling].

  2.4 Discontinuation of Treatment

  Patients who fail to achieve at least a 2 log10 drop at 12 weeks or undetectable HCV-RNA at week 24 are highly unlikely to achieve SVR and discontinuation of therapy should be considered [See Clinical Studies (14)].

  Ribavirin should be discontinued in any patient who temporarily or permanently discontinues INFERGEN.

  2.5 Preparation and Administration

  Just prior to injection, INFERGEN may be allowed to reach room temperature.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration; if particulates or discoloration are observed, the vial should not be used.

  If home use is determined to be desirable by the physician, instructions on appropriate use should be given by a healthcare professional. After administration of INFERGEN, it is essential to follow the procedure for proper disposal of syringes and needles. [see Medication Guide for detailed instructions].

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• Anastrozole
  

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  Anastrozole

  

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  2.1 Recommended Dose

  The dose of anastrozole tablets is one 1 mg tablet taken once a day. For patients with advanced breast cancer, anastrozole tablets should be continued until tumor progression. Anastrozole tablets can be taken with or without food.

  For adjuvant treatment of early breast cancer in postmenopausal women, the optimal duration of therapy is unknown. In the ATAC trial anastrozole tablets was administered for five years [see Clinical Studies (14.1)].

  No dosage adjustment is necessary for patients with renal impairment or for elderly patients [see Use in Specific Populations (8.6)].

  2.2 Patients with Hepatic Impairment

  No changes in dose are recommended for patients with mild-to-moderate hepatic impairment. Anastrozole tablets has not been studied in patients with severe hepatic impairment [see Use in Specific Populations (8.7)].

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• Amlodipine Besylate And...
  

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  Amlodipine Besylate And Benazepril Hydrochloride

  

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  Ribasphere (ribavirin, USP) should be taken with food. Ribasphere should be given in combination with peginterferon alfa-2a; it is important to note that Ribasphere should never be given as monotherapy. See Peginterferon alfa-2a Package Insert for all instructions regarding peginterferon alfa-2a dosing and administration.

  2.1 Chronic Hepatitis C Monoinfection

  Adult Patients

  The recommended dose of Ribasphere 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 Ribasphere 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  Peginterferon alfa-2a and Ribasphere Dosing Recommendations Hepatitis C Virus (HCV) Genotype Peginterferon alfa-2a Dose*(once weekly) Ribasphere 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 Peginterferon alfa-2a Package Insert for further details on peginterferon alfa-2a 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

  Pediatric Patients

  Peginterferon alfa-2a is administered as 180 mcg/1.73m2 x 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.

  Ribasphere should be given in combination with peginterferon alfa-2a. Ribasphere is available as a 200 mg, 400 mg and 600 mg tablet and therefore the healthcare provider should determine if this sized tablet can be swallowed by the pediatric patient. The recommended doses for Ribasphere 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  Ribasphere Dosing Recommendations for Pediatric Patients *approximately 15 mg/kg/day**or 1 x 400 mg tablet***or 1 x 600 mg tablet

  Body Weight in kilograms (kg)

  Ribasphere Daily Dose*

  RibasphereNumber of Tablets

  23 – 33

  400 mg/day

  1 x 200 mg tablet A.M.1 x 200 mg tablet P.M.

  34 – 46

  600 mg/day

  1 x 200 mg tablet A.M.2 x 200 mg tablets P.M.**

  47 – 59

  800 mg/day

  2 x 200 mg tablets A.M.** 2 x 200 mg tablets P.M.**

  60 – 74

  1000 mg/day

  2 x 200 mg tablets A.M.** 3 x 200 mg tablets P.M.***

  ≥75

  1200 mg/day

  3 x 200 mg tablets A.M.*** 3 x 200 mg tablets P.M.***

  2.2 Chronic Hepatitis C with HIV Coinfection

  Adult Patients

  The recommended dose for treatment of chronic hepatitis C in patients coinfected with HIV is peginterferon alfa-2a 180 mcg subcutaneous once weekly and Ribasphere 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 Ribasphere/peginterferon alfa-2a 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, Ribasphere/peginterferon alfa-2a therapy should be discontinued. Table 3 provides guidelines for dose modifications and discontinuation based on the patient’s hemoglobin concentration and cardiac status.

  Ribasphere 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  Ribasphere Dose Modification Guidelines in Adults and Pediatrics

  Body weight in kilograms (kg)

  Laboratory Values

  Hemoglobin <10 g/dL in patients with no cardiac disease, or

  Decrease 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, or

  Hemoglobin <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 x 200 mg tablet A.M.2 x 200 mg tablets or 1 x 400 mg tablet P.M.

  Discontinue Ribasphere

  Pediatric Patients 5 to 18 years of age

  23 – 33 kg

  1 x 200 mg tablet A.M.

  Discontinue Ribasphere

  34 – 46 kg

  1 x 200 mg tablet A.M.1 x 200 mg tablet P.M.

  47 – 59 kg

  1 x 200 mg tablet A.M.1 x 200 mg tablet P.M.

  60 – 74 kg

  1 x 200 mg tablet A.M.2 x 200 mg tablets P.M. or 1 x 400 mg tablet P.M.

  ≥75 kg

  1 x 200 mg tablet A.M.2 x 200 mg tablets P.M. or 1 x 400 mg tablet P.M.

  The guidelines for Ribasphere dose modifications outlined in this table also apply to laboratory abnormalities or adverse reactions other than decreases in hemoglobin values.

  Adult Patients

  Once Ribasphere has been withheld due to either a laboratory abnormality or clinical adverse reaction, an attempt may be made to restart Ribasphere at 600 mg daily and further increase the dose to 800 mg daily. However, it is not recommended that Ribasphere be increased to the original assigned dose (1000 mg to 1200 mg).

  Pediatric Patients

  Upon resolution of a laboratory abnormality or clinical adverse reaction, an increase in Ribasphere dose to the original dose may be attempted depending upon the physician’s judgment. If Ribasphere has been withheld due to a laboratory abnormality or clinical adverse reaction, an attempt may be made to restart Ribasphere at one-half the full dose.

  2.4 Renal Impairment

  The total daily dose of Ribasphere should be reduced for patients with creatinine clearance less than or equal to 50 mL/min; and the weekly dose of peginterferon alfa-2a 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 Peginterferon alfa-2a Package Insert].

  Table 4  Dosage Modification for Renal Impairment

  Creatinine Clearance

  Peginterferon alfa-2a Dose (once weekly)

  Ribasphere 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 Ribasphere should not be further modified in patients with renal impairment. If severe adverse reactions or laboratory abnormalities develop, Ribasphere should be discontinued, if appropriate, until the adverse reactions abate or decrease in severity. If intolerance persists after restarting Ribasphere, Ribasphere/peginterferon alfa-2a therapy should be discontinued.

  No data are available for pediatric subjects with renal impairment.

  2.5 Discontinuation of Dosing

  Discontinuation of peginterferon alfa-2a/Ribasphere 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.

  Peginterferon alfa-2a/Ribasphere therapy should be discontinued in patients who develop hepatic decompensation during treatment [see Warnings and Precautions (5.3)].

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• Amlodipine Besylate
  

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  Amlodipine Besylate

  

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  Under no circumstances should RIBASPHERE capsules be opened, crushed, or broken. RIBASPHERE should be taken with food [see Clinical Pharmacology (12.3)]. RIBASPHERE should not be used in patients with creatinine clearance less than 50 mL/min.

  2.1 RIBASPHERE/Peginterferon alfa-2b Combination Therapy

  Adult Patients

  The recommended dose of peginterferon alfa-2b is 1.5 mcg/kg/week subcutaneously in combination with 800 to 1400 mg RIBASPHERE capsules orally based on patient body weight (see Table 1). The volume of peginterferon alfa-2b to be injected depends on the strength of peginterferon alfa-2b and patient’s body weight, refer to labeling for peginterferon alfa-2b for additional dosing information.

  Duration of Treatment – Interferon Alpha-naïve Patients

  The treatment duration for patients with genotype 1 is 48 weeks. Discontinuation of therapy should be considered in patients who do not achieve at least a 2 log10 drop or loss of HCV-RNA at 12 weeks, or if HCV-RNA remains detectable after 24 weeks of therapy. Patients with genotype 2 and 3 should be treated for 24 weeks.

  Duration of Treatment – Re-treatment with Peginterferon alfa-2b/Ribavirin of Prior Treatment Failures

  The treatment duration for patients who previously failed therapy is 48 weeks, regardless of HCV genotype. Re-treated patients who fail to achieve undetectable HCV-RNA at week 12 of therapy, or whose HCV-RNA remains detectable after 24 weeks of therapy, are highly unlikely to achieve SVR and discontinuation of therapy should be considered [see Clinical Studies (14.1)].

  Table 1: Recommended Dosing for RIBASPHERE in Combination Therapy with Peginterferon alfa-2b (Adults)

  Body Weight kg (lbs)

  RIBASPHERE

  Daily Dose

  RIBASPHERE Number of Capsules

  <66

  (<144)

  800 mg/day

  2 x 200-mg capsules A.M.

  2 x 200-mg capsules P.M.

  66-80

  (145-177)

  1000 mg/day

  2 x 200-mg capsules A.M.

  3 x 200-mg capsules P.M.

  81-105

  (178-231)

  1200 mg/day

  3 x 200-mg capsules A.M.

  3 x 200-mg capsules P.M.

  >105

  (231)

  1400 mg/day

  3 x 200-mg capsules A.M.

  4 x 200-mg capsules P.M.

  Pediatric Patients

  Dosing for pediatric patients is determined by body surface area for peginterferon alfa-2b and by body weight for RIBASPHERE. The recommended dose of peginterferon alfa-2b is 60 mcg/m2/week subcutaneously in combination with 15 mg/kg/day of RIBASPHERE orally in two divided doses (see Table 2) for pediatric patients ages 3-17 years. Patients who reach their 18th birthday while receiving peginterferon alfa-2b/RIBASPHERE should remain on the pediatric dosing regimen. The treatment duration for patients with genotype 1 is 48 weeks. Patients with genotype 2 and 3 should be treated for 24 weeks.

  Table 2: Recommended RIBASPHERE* Dosing in Combination Therapy (Pediatrics) * RIBASPHERE to be used in combination with peginterferon alfa-2b 60 mcg/m 2 weekly.

  Body Weight    kg (lbs)

  RIBASPHERE    Daily Dose

  RIBASPHERE Number of Capsules

  47–59 (103–131)

  800 mg/day

  2 x 200-mg capsules A.M.   2 x 200-mg capsules P.M.

  60–73 (132–162)

  1000 mg/day

  2 x 200-mg capsules A.M. 3 x 200-mg capsules P.M.

  >73 (>162)

  1200 mg/day

  3 x 200-mg capsules A.M. 3 x 200-mg capsules P.M.

  2.2 RIBASPHERE/Interferon alfa-2b Combination Therapy

  Adults

  Duration of Treatment – Interferon Alpha-naïve Patients

  The recommended dose of interferon alfa-2b is 3 million IU three times weekly subcutaneously. The recommended dose of RIBASPHERE capsules depends on the patient’s body weight (refer to Table 3). The recommended duration of treatment for patients previously untreated with interferon is 24 to 48 weeks. The duration of treatment should be individualized to the patient depending on baseline disease characteristics, response to therapy, and tolerability of the regimen [see Indications and Usage (1.1), Adverse Reactions (6.1), and Clinical Studies (14)]. After 24 weeks of treatment, virologic response should be assessed. Treatment discontinuation should be considered in any patient who has not achieved an HCV-RNA below the limit of detection of the assay by 24 weeks. There are no safety and efficacy data on treatment for longer than 48 weeks in the previously untreated patient population.

  Duration of Treatment – Re-treatment with Interferon alfa-2b/RIBASPHERE in Relapse Patients

  In patients who relapse following nonpegylated interferon monotherapy, the recommended duration of treatment is 24 weeks.

  Table 3: Recommended Dosing

  Body Weight    

  RIBASPHERE® (ribavirin capsules)

  ≤75 kg

  2 × 200-mg capsules AM3 × 200-mg capsules PM daily orally

  >75 kg

  3 × 200-mg capsules AM3 × 200-mg capsules PMdaily orally

  Pediatrics

  The recommended dose of RIBASPHERE is 15 mg/kg per day orally (divided dose AM and PM). Refer to Table 2 for Pediatric Dosing of RIBASPHERE in combination with interferon alfa-2b. Interferon alfa-2b for Injection by body weight of 25 kg to 61 kg is 3 million IU/m2 three times weekly subcutaneously. Refer to adult dosing table for greater than 61 kg body weight.

  The recommended duration of treatment is 48 weeks for pediatric patients with genotype 1. After 24 weeks of treatment, virologic response should be assessed. Treatment discontinuation should be considered in any patient who has not achieved an HCV-RNA below the limit of detection of the assay by this time. The recommended duration of treatment for pediatric patients with genotype 2/3 is 24 weeks.

  2.3 Laboratory Tests

  The following laboratory tests are recommended for all patients treated with RIBASPHERE, prior to beginning treatment and then periodically thereafter.

  • Standard hematologic tests - including hemoglobin (pretreatment, Week 2 and Week 4 of therapy, and as clinically appropriate [see Warnings and Precautions (5.2, 5.7)]), complete and differential white blood cell counts, and platelet count. • Blood chemistries - liver function tests and TSH. • Pregnancy - including monthly monitoring for women of childbearing potential. • ECG [see Warnings and Precautions (5.2)].

  2.4 Dose Modifications

  If severe adverse reactions or laboratory abnormalities develop during combination RIBASPHERE/interferon alfa-2b therapy or RIBASPHERE/peginterferon alfa-2b therapy, modify, or discontinue the dose until the adverse reaction abates or decreases in severity [see Warnings and Precautions (5)]. If intolerance persists after dose adjustment, combination therapy should be discontinued. Dose reduction of peginterferon alfa-2b in adult patients on RIBASPHERE/peginterferon alfa-2b combination therapy is accomplished in a two-step process from the original starting dose of 1.5 mcg/kg/week, to 1 mcg/kg/week, then to 0.5 mcg/kg/week, if needed.

  Refer to labeling for peginterferon alfa-2b for additional information regarding dose reduction of peginterferon alfa-2b.

  In the adult combination therapy Study 2, dose reductions occurred in 42% of subjects receiving peginterferon alfa-2b 1.5 mcg/kg and RIBASPHERE 800 mg daily, including 57% of those subjects weighing 60 kg or less. In Study 4, 16% of subjects had a dose reduction of peginterferon alfa-2b to 1 mcg/kg in combination with RIBASPHERE, with an additional 4% requiring the second dose reduction of peginterferon alfa-2b to 0.5 mcg/kg due to adverse events [see Adverse Reactions (6.1)].

  Dose reduction in pediatric patients is accomplished by modifying the recommended peginterferon alfa-2b dose in a two-step process from the original starting dose of 60 mcg/m2/week, to 40 mcg/m2/week, then to 20 mcg/m2/week, if needed (see Table 4). In the pediatric combination therapy trial, dose reductions occurred in 25% of subjects receiving peginterferon alfa-2b 60 mcg/m2 weekly and RIBASPHERE 15 mg/kg daily. Dose reduction in pediatric patients is accomplished by modifying the recommended RIBASPHERE dose from the original starting dose of 15 mg/kg daily in a two-step process to 12 mg/kg/day, then to 8 mg/kg/day, if needed (see Table 4).

  RIBASPHERE should not be used in patients with creatinine clearance less than 50 mL/min. Patients with impaired renal function and those over the age of 50 should be carefully monitored with respect to development of anemia [see Warnings and Precautions (5.2), Use in Specific Populations (8.5), and Clinical Pharmacology (12.3)].

  RIBASPHERE 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)].

  For patients with a history of stable cardiovascular disease, a permanent dose reduction is required if the hemoglobin decreases by greater than or equal to 2 g/dL during any 4-week period. In addition, for these cardiac history patients, if the hemoglobin remains less than 12 g/dL after 4 weeks on a reduced dose, the patient should discontinue combination therapy.

  It is recommended that a patient whose hemoglobin level falls below 10 g/dL have his/her RIBASPHERE dose modified or discontinued per Table 4 [see Warnings and Precautions (5.2)].

  Table 4: Guidelines for Dose Modification and Discontinuation of Ribavirin in combination with Peginterferon alfa-2b or Interferon alfa-2b Based on Laboratory Parameters in Adults and Pediatrics Laboratory Parameters Reduce RIBASPHERE Daily Dose (see note 1) if: Reduce Peginterferon alfa‑2b or Interferon alfa‑2b Dose (see note 2) if: Discontinue Therapy if: Note 1: Adult patients: 1st dose reduction of ribavirin is by 200 mg/day (except in patients receiving the 1,400 mg, dose reduction should be by 400 mg/day). If needed, 2nd dose reduction of ribavirin is by an additional 200 mg/day. Patients whose dose of ribavirin is reduced to 600 mg daily receive one 200 mg capsule in the morning and two 200 mg capsules in the evening.Pediatric patients: 1st dose reduction of ribavirin is to 12 mg/kg/day, 2nd dose reduction of ribavirin is to 8 mg/kg/day. Note 2: Adult patients treated with RIBASPHERE and Peginterferon alfa-2b: 1st dose reduction of Peginterferon alfa-2b is to 1 mcg/kg/week. If needed, 2nd dose reduction of Peginterferon alfa-2b is to 0.5 mcg/kg/week. Pediatric patients treated with RIBASPHERE and Peginterferon alfa-2b: 1st dose reduction of Peginterferon alfa-2b is to 40 mcg/m2/week, 2nd dose reduction of Peginterferon alfa-2b is to 20 mcg/m2/week. For patients on Ribavirin/Interferon alfa-2b combination therapy: reduce Interferon alfa-2b dose by 50%. * Pediatric patients who have pre-existing cardiac conditions and experience a hemoglobin decrease greater than or equal to 2 g/dL during any 4-week period during treatment should have weekly evaluations and hematology testing. † These guidelines are for patients with stable cardiac disease. Patients with a history of significant or unstable cardiac disease should not be treated with Peginterferon alfa-2b /Ribavirin combination therapy [see Warnings and Precautions (5.2)].

  WBC

  N/A

  1.0 to <1.5 x 109/L

  <1.0 x 109/L

  Neutrophils

  N/A

  0.5 to <0.75 x 109/L

  <0.5 x 109/L

  Platelets

  N/A

  25 to <50 x 109/L (adults)

  <25 x 109/L (adults)

  N/A

  50 to <70 x 109/L (pediatrics)

  <50 x 109/L (pediatrics)

  Creatinine

  N/A

  N/A

  >2 mg/dL (pediatrics)

  Hemoglobin in patients without history of cardiac disease

  8.5 to <10 g/dL

  N/A

  <8.5 g/dL

  Reduce RIBASPHERE Dose by 200 mg/day and Peginterferon alfa-2b or Interferon alfa-2b Dose by Half if:

  Hemoglobin in patients with history of stable cardiac disease*†

  ≥2 g/dL decrease in hemoglobin during any

  four week period during treatment

  <8.5 g/dL or

  <12 g/dL after four weeks of

  dose reduction

  Refer to labeling for interferon alfa-2b or peginterferon alfa-2b for additional information about how to reduce an interferon alfa-2b or peginterferon alfa-2b dose.

  2.5 Discontinuation of Dosing

  Adults

  In HCV genotype 1, interferon-alfa-naïve patients receiving peginterferon alfa-2b in combination with ribavirin, discontinuation of therapy is recommended if there is not at least a 2 log10 drop or loss of HCV-RNA at 12 weeks of therapy, or if HCV-RNA levels remain detectable after 24 weeks of therapy. Regardless of genotype, previously treated patients who have detectable HCV-RNA at Week 12 or 24 are highly unlikely to achieve SVR and discontinuation of therapy should be considered.

  Pediatrics (3-17 years of age)

  It is recommended that patients receiving peginterferon alfa-2b/RIBASPHERE combination (excluding HCV Genotype 2 and 3) be discontinued from therapy at 12 weeks if their treatment Week 12 HCV-RNA dropped less than 2 log10 compared to a pretreatment or at 24 weeks if they have detectable HCV-RNA at treatment Week 24.

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