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Questions & Answers
Side Effects & Adverse Reactions
Myopathy/Rhabdomyolysis
Lovastatin, like other inhibitors of HMG-CoA reductase, occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above ten times the upper limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities have occurred. The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma.
The risk of myopathy/rhabdomyolysis is dose related. In a clinical study (EXCEL) in which patients were carefully monitored and some interacting drugs were excluded, there was one case of myopathy among 4933 patients randomized to lovastatin 20 to 40 mg daily for 48 weeks, and 4 among 1649 patients randomized to 80 mg daily.
There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents.
All patients starting therapy with lovastatin, or whose dose of lovastatin is being increased, should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing lovastatin. Lovastatin therapy should be discontinued immediately if myopathy is diagnosed or suspected. In most cases, muscle symptoms and CK increases resolved when treatment was promptly discontinued. Periodic CK determinations may be considered in patients starting therapy with lovastatin or whose dose is being increased, but there is no assurance that such monitoring will prevent myopathy.
Many of the patients who have developed rhabdomyolysis on therapy with lovastatin have had complicated medical histories, including renal insufficiency usually as a consequence of long-standing diabetes mellitus. Such patients merit closer monitoring. Lovastatin therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. Lovastatin therapy should also be temporarily withheld in any patient experiencing an acute or serious condition predisposing to the development of renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy.
The risk of myopathy/rhabdomyolysis is increased by concomitant use of lovastatin with the following:
Strong inhibitors of CYP3A4: Lovastatin, like several other inhibitors of HMG-CoA reductase, is a substrate of cytochrome P450 3A4 (CYP3A4). Certain drugs which inhibit this metabolic pathway can raise the plasma levels of lovastatin and may increase the risk of myopathy. These include itraconazole, ketoconazole, posaconazole, voriconazole, the macrolide antibiotics erythromycin and clarithromycin, the ketolide antibiotic telithromycin, HIV protease inhibitors, boceprevir, telaprevir, the antidepressant nefazodone, or cobicistat-containing products. Combination of these drugs with lovastatin is contraindicated. If short-term treatment with strong CYP3A4 inhibitors is unavoidable, therapy with lovastatin should be suspended during the course of treatment (see CONTRAINDICATIONS; PRECAUTIONS, Drug Interactions).
Gemfibrozil:The combined use of lovastatin with gemfibrozil should be avoided.
Other lipid-lowering drugs (other fibrates or ≥ 1 g/day of niacin): Caution should be used when prescribing other fibrates or lipid-lowering doses (≥ 1 g/day) of niacin with lovastatin, as these agents can cause myopathy when given alone. The benefit of further alterations in lipid levels by the combined use of lovastatin with other fibrates or niacin should be carefully weighed against the potential risks of these combinations.
Cyclosporine:The use of lovastatin with cyclosporine should be avoided.
Danazol, diltiazem, dronedarone, or verapamil with higher doses of lovastatin: The dose of lovastatin should not exceed 20 mg daily in patients receiving concomitant medication with danazol, diltiazem, dronedarone, or verapamil. The benefits of the use of lovastatin in patients receiving danazol, diltiazem, dronedarone, or verapamil should be carefully weighed against the risks of these combinations.
Amiodarone: The dose of lovastatin should not exceed 40 mg daily in patients receiving concomitant medication with amiodarone. The combined use of lovastatin at doses higher than 40 mg daily with amiodarone should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy. The risk of myopathy/rhabdomyolysis is increased when amiodarone is used concomitantly with higher doses of a closely related member of the HMG-CoA reductase inhibitor class.
Colchicine: Cases of myopathy, including rhabdomyolysis, have been reported with lovastatin coadministered with colchicine, and caution should be exercised when prescribing lovastatin with colchicine (see PRECAUTIONS, Drug Interactions).
Ranolazine: The risk of myopathy, including rhabdomyolysis, may be increased by concomitant administration of ranolazine. Dose adjustment of lovastatin may be considered during coadministration with ranolazine.
Prescribing recommendations for interacting agents are summarized in Table VII (see also CLINICAL PHARMACOLOGY, Pharmacokinetics; PRECAUTIONS, Drug Interactions; DOSAGE AND ADMINISTRATION).
Table VII: Drug Interactions Associated With Increased Risk of Myopathy/Rhabdomyolysis
| Interacting Agents |
Prescribing Recommendations |
| Strong CYP3A4 inhibitors, e.g.: |
Contraindicated with lovastatin |
| Ketoconazole |
|
| Itraconazole |
|
| Posaconazole |
|
| Voriconazole |
|
| Erythromycin |
|
| Clarithromycin |
|
| Telithromycin |
|
| HIV protease inhibitors |
|
| Boceprevir |
|
| Telaprevir |
|
| Nefazodone |
|
| Cobicistat-containing products | |
| Gemfibrozil |
Avoid with lovastatin |
| Cyclosporine |
|
| Danazol |
Do not exceed 20 mg lovastatin daily |
| Diltiazem |
|
| Dronedarone |
|
| Verapamil |
|
| Amiodarone |
Do not exceed 40 mg lovastatin daily |
| Grapefruit juice |
Avoid grapefruit juice |
Liver Dysfunction
Persistent increases (to more than 3 times the upper limit of normal) in serum transaminases occurred in 1.9% of adult patients who received lovastatin for at least one year in early clinical trials (see ADVERSE REACTIONS). When the drug was interrupted or discontinued in these patients, the transaminase levels usually fell slowly to pretreatment levels. The increases usually appeared 3 to 12 months after the start of therapy with lovastatin, and were not associated with jaundice or other clinical signs or symptoms. There was no evidence of hypersensitivity. In the EXCEL study (see CLINICAL PHARMACOLOGY, Clinical Studies in Adults), the incidence of persistent increases in serum transaminases over 48 weeks was 0.1% for placebo, 0.1% at 20 mg/day, 0.9% at 40 mg/day, and 1.5% at 80 mg/day in patients on lovastatin. However, in postmarketing experience with lovastatin, symptomatic liver disease has been reported rarely at all dosages (see ADVERSE REACTIONS).
In AFCAPS/TexCAPS, the number of participants with consecutive elevations of either alanine aminotransferase (ALT) or aspartate aminotransferase (AST) (> 3 times the upper limit of normal), over a median of 5.1 years of follow-up, was not significantly different between the lovastatin and placebo groups (18 [0.6%] vs. 11 [0.3%]). The starting dose of lovastatin was 20 mg/day; 50% of the lovastatin treated participants were titrated to 40 mg/day at Week 18. Of the 18 participants on lovastatin with consecutive elevations of either ALT or AST, 11 (0.7%) elevations occurred in participants taking 20 mg/day, while 7 (0.4%) elevations occurred in participants titrated to 40 mg/day. Elevated transaminases resulted in discontinuation of 6 (0.2%) participants from therapy in the lovastatin group (n = 3,304) and 4 (0.1%) in the placebo group (n = 3,301).
It is recommended that liver enzyme tests be obtained prior to initiating therapy with lovastatin and repeated as clinically indicated.
There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including lovastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with lovastatin, promptly interrupt therapy. If an alternate etiology is not found do not restart lovastatin.
The drug should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Active liver disease or unexplained transaminase elevations are contraindications to the use of lovastatin.
Moderate (less than three times the upper limit of normal) elevations of serum transaminases have been reported following therapy with lovastatin (see ADVERSE REACTIONS). These changes appeared soon after initiation of therapy with lovastatin, were often transient, were not accompanied by any symptoms and interruption of treatment was not required.
Legal Issues
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Manufacturer Warnings
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FDA Labeling Changes
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Uses
Therapy with Lovastatin Tablets USP should be a component of multiple risk factor intervention in those individuals with dyslipidemia at risk for atherosclerotic vascular disease. Lovastatin Tablets USP should be used in addition to a diet restricted in saturated fat and cholesterol as part of a treatment strategy to lower total-C and LDL-C to target levels when the response to diet and other nonpharmacological measures alone has been inadequate to reduce risk.
Primary Prevention of Coronary Heart Disease
In individuals without symptomatic cardiovascular disease, average to moderately elevated total-C and LDL-C, and below average HDL-C, Lovastatin Tablets USP are indicated to reduce the risk of:
- Myocardial infarction
- Unstable angina
- Coronary revascularization procedures
(See CLINICAL PHARMACOLOGY, Clinical Studies in Adults.)
Coronary Heart Disease
Lovastatin Tablets USP are indicated to slow the progression of coronary atherosclerosis in patients with coronary heart disease as part of a treatment strategy to lower total-C and LDL-C to target levels.
Hypercholesterolemia
Therapy with lipid-altering agents should be a component of multiple risk factor intervention in those individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Lovastatin Tablets USP are indicated as an adjunct to diet for the reduction of elevated total-C and LDL-C levels in patients with primary hypercholesterolemia (Types IIa and IIb2), when the response to diet restricted in saturated fat and cholesterol and to other nonpharmacological measures alone has been inadequate.
2Classification of Hyperlipoproteinemias
| Lipid Elevations | |||
| Type |
Lipoproteins elevated |
major |
minor |
| I |
chylomicrons |
TG |
↑→C |
| IIa |
LDL |
C |
— |
| IIb |
LDL, VLDL |
C |
TG |
| III (rare) |
IDL |
C/TG |
— |
| IV |
VLDL |
TG |
↑→C |
| V (rare) |
chylomicrons, VLDL |
TG |
↑→C |
| IDL = intermediate-density lipoprotein. |
|||
Adolescent Patients With Heterozygous Familial Hypercholesterolemia
Lovastatin Tablets USP are indicated as an adjunct to diet to reduce total-C, LDL-C and apolipoprotein B levels in adolescent boys and girls who are at least one year post-menarche, 10 to 17 years of age, with heFH if after an adequate trial of diet therapy the following findings are present:
1. LDL-C remains > 189 mg/dL or
2. LDL-C remains > 160 mg/dL and:
- there is a positive family history of premature cardiovascular disease or
- two or more other CVD risk factors are present in the adolescent patient
General Recommendations
Prior to initiating therapy with lovastatin, secondary causes for hypercholesterolemia (e.g., poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemias, obstructive liver disease, other drug therapy, alcoholism) should be excluded, and a lipid profile performed to measure total-C, HDL-C, and TG. For patients with TG less than 400 mg/dL (< 4.5 mmol/L), LDL-C can be estimated using the following equation:
LDL-C = total-C - [0.2 x (TG) + HDL-C]
For TG levels > 400 mg/dL (> 4.5 mmol/L), this equation is less accurate and LDL-C concentrations should be determined by ultracentrifugation. In hypertriglyceridemic patients, LDL-C may be low or normal despite elevated total-C. In such cases, Lovastatin Tablets USP are not indicated.
The National Cholesterol Education Program (NCEP) Treatment Guidelines are summarized below:
NCEP Treatment Guidelines: LDL-C Goals and Cutpoints for Therapeutic Lifestyle Changes and Drug Therapy in Different Risk Categories
| Risk Category |
LDL Goal (mg/dL) |
LDL Level at Which to Initiate Therapeutic Lifestyle Changes (mg/dL) |
LDL Level at Which to Consider Drug Therapy (mg/dL) |
| CHD* or CHD risk equivalents (10 year risk > 20%) |
< 100 |
≥ 100 |
≥ 130 (100 to 129: drug optional)† |
| 2+ Risk factors (10 year risk ≤ 20%) |
< 130 |
≥ 130 |
10 year risk 10 to 20%: ≥ 130 |
| 10 year risk < 10%: ≥ 160 |
|||
| 0 to 1 Risk factor‡ |
< 160 |
≥ 160 |
≥ 190 (160 to 189: LDL-lowering drug optional) |
| * CHD, coronary heart disease † Some authorities recommend use of LDL-lowering drugs in this category if an LDL-C level of < 100 mg/dL cannot be achieved by therapeutic lifestyle changes. Others prefer use of drugs that primarily modify triglycerides and HDL-C, e.g., nicotinic acid or fibrate. Clinical judgment also may call for deferring drug therapy in this subcategory. ‡ Almost all people with 0 to 1 risk factor have a 10 year risk < 10%; thus, 10 year risk assessment in people with 0 to 1 risk factor is not necessary. |
|||
After the LDL-C goal has been achieved, if the TG is still ≥ 200 mg/dL, non-HDL-C (total-C minus HDL-C) becomes a secondary target of therapy. Non-HDL-C goals are set 30 mg/dL higher than LDL-C goals for each risk category.
At the time of hospitalization for an acute coronary event, consideration can be given to initiating drug therapy at discharge if the LDL-C is ≥ 130 mg/dL (see NCEP Treatment Guidelines above).
Since the goal of treatment is to lower LDL-C, the NCEP recommends that LDL-C levels be used to initiate and assess treatment response. Only if LDL-C levels are not available, should the total-C be used to monitor therapy.
Although Lovastatin Tablets USP may be useful to reduce elevated LDL-C levels in patients with combined hypercholesterolemia and hypertriglyceridemia where hypercholesterolemia is the major abnormality (Type IIb hyperlipoproteinemia), it has not been studied in conditions where the major abnormality is elevation of chylomicrons, VLDL or IDL (i.e., hyperlipoproteinemia types I, III, IV, or V).***
The NCEP classification of cholesterol levels in pediatric patients with a familial history of hypercholesterolemia or premature cardiovascular disease is summarized below:
| Category |
Total-C (mg/dL) |
LDL-C (mg/dL) |
| Acceptable |
< 170 |
< 110 |
| Borderline |
170 to 199 |
110 to 129 |
| High |
≥ 200 |
≥ 130 |
Children treated with lovastatin in adolescence should be re-evaluated in adulthood and appropriate changes made to their cholesterol-lowering regimen to achieve adult goals for LDL-C.
History
There is currently no drug history available for this drug.
Other Information
Lovastatin, USP is a cholesterol lowering agent isolated from a strain of Aspergillus terreus. After oral ingestion, lovastatin, USP, which is an inactive lactone, is hydrolyzed to the corresponding β-hydroxyacid form. This is a principal metabolite and an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, which is an early and rate limiting step in the biosynthesis of cholesterol.
Lovastatin, USP is [1S-[1α(R*),3α,7β,8β(2S*,4S*),8aβ]]-1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1-naphthalenyl 2-methylbutanoate. Its structural formula is:
Structure Formula
C24H36O5 M.W. 404.55
Lovastatin, USP is a white, nonhygroscopic crystalline powder that is insoluble in water and sparingly soluble in ethanol, methanol, and acetonitrile.
Lovastatin Tablets USP are supplied as 10 mg, 20 mg and 40 mg tablets for oral administration. In addition to the active ingredient lovastatin, USP, each tablet contains the following inactive ingredients: lactose monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinized corn starch. Butylated hydroxyanisole (BHA) is added as a preservative. Lovastatin Tablets USP, 10 mg also contain FD&C Yellow #6 Aluminum Lake. Lovastatin Tablets USP, 20 mg also contain FD&C Blue #1 Aluminum Lake. Lovastatin Tablets USP, 40 mg also contain D&C Yellow #10 Aluminum Lake, FD&C Blue #1 Aluminum Lake, and FD&C Yellow #6 Aluminum Lake.
Sources
Pegintron Manufacturers
-
Merck Sharp & Dohme Corp.
![Pegintron (Peginterferon Alfa-2b) Kit [Merck Sharp & Dohme Corp.]](/wp-content/themes/bootstrap/assets/img/loading2.gif)
Pegintron | International Labs, Inc.
The patient should be placed on a standard cholesterol-lowering diet before receiving lovastatin tablets and should continue on this diet during treatment with lovastatin tablets (see NCEP Treatment Guidelines for details on dietary therapy). Lovastatin tablets should be given with meals.
Adult Patients
The usual recommended starting dose is 20 mg once a day given with the evening meal. The recommended dosing range of lovastatin is 10 to 80 mg/day in single or two divided doses; the maximum recommended dose is 80 mg/day. Doses should be individualized according to the recommended goal of therapy (see NCEP Treatment Guidelines and CLINICAL PHARMACOLOGY). Patients requiring reductions in LDL-C of 20% or more to achieve their goal (see INDICATIONS AND USAGE) should be started on 20 mg/day of lovastatin tablets. A starting dose of 10 mg of lovastatin may be considered for patients requiring smaller reductions. Adjustments should be made at intervals of 4 weeks or more.
Cholesterol levels should be monitored periodically and consideration should be given to reducing the dosage of lovastatin tablets if cholesterol levels fall significantly below the targeted range.
Dosage in Patients Taking Danazol, Diltiazem, Dronedarone or Verapamil
In patients taking danazol, diltiazem, dronedarone or verapamil concomitantly with lovastatin, therapy should begin with 10 mg of lovastatin and should not exceed 20 mg/day (see CLINICAL PHARMACOLOGY, Pharmacokinetics, WARNINGS, Myopathy/Rhabdomyolysis, PRECAUTIONS, Drug Interactions, Other Drug Interactions).
Dosage in Patients Taking Amiodarone
In patients taking amiodarone concomitantly with lovastatin tablets, the dose should not exceed 40 mg/day (see WARNINGS, Myopathy/Rhabdomyolysis and PRECAUTIONS, Drug Interactions, Other Drug Interactions).
Adolescent Patients (10 to 17 Years of Age) With Heterozygous Familial Hypercholesterolemia
The recommended dosing range of lovastatin is 10 to 40 mg/day; the maximum recommended dose is 40 mg/day. Doses should be individualized according to the recommended goal of therapy (see NCEP Pediatric Panel Guidelines4, CLINICAL PHARMACOLOGY, and INDICATIONS AND USAGE). Patients requiring reductions in LDL-C of 20% or more to achieve their goal should be started on 20 mg/day of lovastatin tablets. A starting dose of 10 mg of lovastatin may be considered for patients requiring smaller reductions. Adjustments should be made at intervals of 4 weeks or more.
4 National Cholesterol Education Program (NCEP): Highlights of the Report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents. Pediatrics. 89(3):495-501. 1992.
Concomitant Lipid-Lowering Therapy
Lovastatin tablets are effective alone or when used concomitantly with bile-acid sequestrants (see WARNINGS, Myopathy/Rhabdomyolysis and PRECAUTIONS, Drug Interactions).
Dosage in Patients With Renal Insufficiency
In patients with severe renal insufficiency (creatinine clearance < 30 mL/min), dosage increases above 20 mg/day should be carefully considered and, if deemed necessary, implemented cautiously (see CLINICAL PHARMACOLOGY and WARNINGS, Myopathy/Rhabdomyolysis).
-
Merck Sharp & Dohme Corp.
Pegintron | Merck Sharp & Dohme Corp.
2.1 PegIntron Combination TherapyAdults
The recommended dose of PegIntron is 1.5 mcg/kg/week. The volume of PegIntron to be injected depends on the strength of PegIntron and patient's body weight (see Table 1).
The recommended dose of REBETOL for use with PegIntron is 800 to 1400 mg orally based on patient body weight. REBETOL should be taken with food. REBETOL should not be used in patients with creatinine clearance less than 50 mL/min.
See labeling of the specific HCV NS3/4A protease inhibitor for information regarding dosing regimen and administration of the protease inhibitor in combination with PegIntron and ribavirin.
Duration of Treatment – Treatment with PegIntron/REBETOL of 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 PegIntron/REBETOL of Prior Treatment Failures
For patients with genotype 1 infection, PegIntron and REBETOL without an HCV NS3/4A protease inhibitor should only be used if there are contraindications, significant intolerance or other clinical factors that would not warrant use of an HCV NS3/4A protease inhibitor. 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 PegIntron Combination Therapy Dosing (Adults) Body Weight
kg (lbs) PegIntron REDIPEN Pre-filled pen or Vial Strength to Use Amount of PegIntron to Administer
(mcg) Volume* of PegIntron to Administer
(mL) REBETOL Daily Dose REBETOL Number of Capsules * When reconstituted as directed. † For patients weighing greater than 105 kg (greater than 231 pounds), the PegIntron dose of 1.5 mcg/kg/week should be calculated based on the individual patient weight. This may require combinations of various PegIntron dose strengths and volumes. <40
(<88) 50 mcg per 0.5 mL 50 0.5 800 mg/day 2 × 200 mg capsules A.M.
2 × 200 mg capsules P.M. 40-50
(88-111) 80 mcg per 0.5 mL 64 0.4 800 mg/day 2 × 200 mg capsules A.M.
2 × 200 mg capsules P.M. 51-60
(112-133) 80 0.5 800 mg/day 2 × 200 mg capsules A.M.
2 × 200 mg capsules P.M. 61-65
(134-144) 120 mcg per 0.5 mL 96 0.4 800 mg/day 2 × 200 mg capsules A.M.
2 × 200 mg capsules P.M. 66-75
(145-166) 96 0.4 1000 mg/day 2 × 200 mg capsules A.M.
3 × 200 mg capsules P.M. 76-80
(167-177) 120 0.5 1000 mg/day 2 × 200 mg capsules A.M.
3 × 200 mg capsules P.M. 81-85
(178-187) 1200 mg/day 3 × 200 mg capsules A.M.
3 × 200 mg capsules P.M. 86-105
(188-231) 150 mcg per 0.5 mL 150 0.5 1200 mg/day 3 × 200 mg capsules A.M.
3 × 200 mg capsules P.M. >105
(>231) † † † 1400 mg/day 3 × 200 mg capsules A.M.
4 × 200 mg capsules P.M.Pediatric Patients
Dosing for pediatric patients is determined by body surface area for PegIntron and by body weight for REBETOL. The recommended dose of PegIntron is 60 mcg/m2/week subcutaneously in combination with 15 mg/kg/day of REBETOL orally in 2 divided doses (see Table 2) for pediatric patients ages 3 to 17 years. Patients who reach their 18th birthday while receiving PegIntron/REBETOL 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 REBETOL* Dosing in Combination Therapy (Pediatrics) Body Weight
kg (lbs) REBETOL Daily Dose REBETOL Number of Capsules * REBETOL to be used in combination with PegIntron 60 mcg/m 2 weekly. † REBETOL oral solution may be used for any patient regardless of body weight. <47
(<103) 15 mg/kg/day Use REBETOL oral solution† 47-59
(103-131) 800 mg/day 2 × 200 mg capsules A.M.
2 × 200 mg capsules P.M. 60-73
(132-162) 1000 mg/day 2 × 200 mg capsules A.M.
3 × 200 mg capsules P.M. >73
(>162) 1200 mg/day 3 × 200 mg capsules A.M.
3 × 200 mg capsules P.M. 2.2 PegIntron MonotherapyThe recommended dose of PegIntron regimen is 1 mcg/kg/week subcutaneously for 1 year administered on the same day of the week. 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 of therapy, or whose HCV-RNA levels remain detectable after 24 weeks of therapy. The volume of PegIntron to be injected depends on patient weight (see Table 3).
Table 3: Recommended PegIntron Monotherapy Dosing Body Weight
kg (lbs) PegIntron REDIPEN Pre-filled pen or Vial Strength to Use Amount of PegIntron to Administer
(mcg) Volume of PegIntron to Administer
(mL)* * When reconstituted as directed. ≤45
(≤100) 50 mcg per 0.5 mL 40 0.4 46-56
(101-124) 50 0.5 57-72
(125-159) 80 mcg per 0.5 mL 64 0.4 73-88
(160-195) 80 0.5 89-106
(196-234) 120 mcg per 0.5 mL 96 0.4 107-136
(235-300) 120 0.5 137-160
(301-353) 150 mcg per 0.5 mL 150 0.5 2.3 Dose ReductionIf a serious adverse reaction develops during the course of treatment discontinue or modify the dosage of PegIntron and REBETOL until the adverse event abates or decreases in severity [see Warnings and Precautions (5)]. If persistent or recurrent serious adverse events develop despite adequate dosage adjustment, discontinue treatment. For guidelines for dose modifications and discontinuation based on depression or laboratory parameters see Tables 4 and 5. Dose reduction of PegIntron in adult patients on PegIntron/REBETOL 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. Dose reduction in patients on PegIntron monotherapy is accomplished by reducing the original starting dose of 1 mcg/kg/week to 0.5 mcg/kg/week. Instructions for dose reductions in adults are outlined in Tables 6 (Monotherapy: REDIPEN/Vial) and 7 (Combination therapy: REDIPEN/Vial).
In the adult combination therapy Study 2, dose reductions occurred in 42% of subjects receiving PegIntron 1.5 mcg/kg plus REBETOL 800 mg daily, including 57% of those subjects weighing 60 kg or less. In Study 4, 16% of subjects had a dose reduction of PegIntron to 1 mcg/kg in combination with REBETOL, with an additional 4% requiring the second dose reduction of PegIntron 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 dose in a 2-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 Tables 4 and 5). In the pediatric combination therapy trial, dose reductions occurred in 25% of subjects receiving PegIntron 60 mcg/m2 weekly plus REBETOL 15 mg/kg daily.
Table 4: Guidelines for Modification or Discontinuation of PegIntron or PegIntron/REBETOL and for Scheduling Visits for Patients with Depression Depression Severity* Initial Management (4-8 weeks) Depression Status Dose Modification Visit Schedule Remains Stable Improves Worsens * See DSM-IV for definitions. For patients on PegIntron/REBETOL combination therapy: 1 st dose reduction of PegIntron is to 1 mcg/kg/week, 2 nd dose reduction (if needed) of PegIntron is to 0.5 mcg/kg/week. For patients on PegIntron monotherapy: decrease PegIntron dose to 0.5 mcg/kg/week. Mild No change Evaluate once weekly by visit or phone Continue weekly visit schedule Resume normal visit schedule See moderate or severe depression Moderate Adults: Adjust Dose*
Pediatrics: Decrease dose to 40 mcg/m2/week, then to 20 mcg/m2/week, if needed 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 dosing or return to normal dose See severe depression Severe Discontinue PegIntron/REBETOL permanently Obtain immediate psychiatric consultation Psychiatric therapy as necessary Table 5: Guidelines for Dose Modification and Discontinuation of PegIntron or PegIntron/REBETOL Based on Laboratory Parameters in Adults and Pediatrics Laboratory Parameters Reduce PegIntron Dose (see note 1) if: Reduce ribavirin Daily Dose (see note 2) if: Discontinue Therapy if: Note 1: Adult patients on combination therapy: 1st dose reduction of PegIntron is to 1 mcg/kg/week. If needed, 2nd dose reduction of PegIntron is to 0.5 mcg/kg/week.
Adult patients on PegIntron monotherapy: decrease PegIntron dose to 0.5 mcg/kg/week.
Pediatric patients: 1st dose reduction of PegIntron is to 40 mcg/m2/week, 2nd dose reduction of PegIntron is to 20 mcg/m2/week. Note 2: Adult patients: 1st dose reduction of ribavirin is by 200 mg/day (except in patients receiving the 1400 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. * 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 PegIntron /REBETOL combination therapy [see Warnings and Precautions (5.3)]. WBC 1.0 to <1.5 × 109/L N/A <1.0 × 109/L Neutrophils 0.5 to <0.75 × 109/L N/A <0.5 × 109/L Platelets 25 to <50 × 109/L (adults) N/A <25 × 109/L (adults) 50 to <70 × 109/L (pediatrics) N/A <50 × 109/L (pediatrics) Creatinine N/A N/A >2 mg/dL (pediatrics) Hemoglobin in patients without history of cardiac disease N/A 8.5 to <10 g/dL <8.5 g/dL Reduce PegIntron Dose by Half and the Ribavirin Dose by 200 mg/day if: Hemoglobin in patients with history of 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 Table 6: Reduced PegIntron Dose (0.5 mcg/kg) for (1 mcg/kg) Monotherapy in Adults Body Weight
kg (lbs) PegIntron
REDIPEN/Vial Strength to Use Amount to Administer
(mcg) Volume* to Administer
(mL) * When reconstituted as directed. † Must use vial. Minimum delivery for REDIPEN 0.3 mL. ≤45
(≤100) 50 mcg per 0.5 mL† 20 0.2 46-56
(101-124) 50 mcg per 0.5 mL† 25 0.25 57-72
(125-159) 50 mcg per 0.5 mL 30 0.3 73-88
(160-195) 50 mcg per 0.5 mL 40 0.4 89-106
(196-234) 50 mcg per 0.5 mL 50 0.5 107-136
(235-300) 80 mcg per 0.5 mL 64 0.4 ≥137
(≥301) 80 mcg per 0.5 mL 80 0.5 Table 7: Two-Step Dose Reduction of PegIntron REDIPEN/Vial in Combination Therapy in Adults First Dose Reduction to PegIntron 1 mcg/kg Second Dose Reduction to PegIntron 0.5 mcg/kg Body weight
kg (lbs) PegIntron REDIPEN/Vial Strength to Use Amount of PegIntron (mcg) to Administer Volume (mL) * of PegIntron to Administer Body weight
kg (lbs) PegIntron REDIPEN/ Vial Strength to Use Amount of PegIntron (mcg) to Administer Volume (mL) * of PegIntron to Administer * When reconstituted as directed. † Must use vial. Minimum delivery for REDIPEN 0.3 mL. <40
(<88) 50 mcg per 0.5 mL 35 0.35 <40
(<88) 50 mcg per 0.5 mL† 20 0.2 40-50
(88-111) 45 0.45 40-50
(88-111) 25 0.25 51-60
(112-133) 50 0.5 51-60
(112-133) 50 mcg per 0.5 mL 30 0.3 61-75
(134-166) 80 mcg per 0.5 mL 64 0.4 61-75
(134-166) 35 0.35 76-85
(167-187) 80 0.5 76-85
(167-187) 45 0.45 86-104
(188-230)
120 mcg per 0.5 mL 96 0.4 86-104
(188-230) 50 0.5 105-125
(231-275) 108 0.45 105-125
(231-275) 80 mcg per 0.5 mL 64 0.4 >125
(>275) 150 mcg per 0.5 mL 135 0.45 >125
(>275) 72 0.45 2.4 Discontinuation of DosingAdults
See labeling of the specific HCV NS3/4A protease inhibitor for information regarding discontinuation of dosing based on treatment futility.
In HCV genotype 1, interferon-alfa-naïve patients receiving PegIntron, alone or in combination with REBETOL, 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 is recommended.
Pediatrics (3-17 years of age)
It is recommended that patients receiving PegIntron/REBETOL combination (excluding those with 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 pretreatment or at 24 weeks if they have detectable HCV-RNA at treatment Week 24.
2.5 Renal FunctionIn patients with moderate renal dysfunction (creatinine clearance 30-50 mL/min), the PegIntron dose should be reduced by 25%. Patients with severe renal dysfunction (creatinine clearance 10-29 mL/min), including those on hemodialysis, should have the PegIntron dose reduced by 50%. If renal function decreases during treatment, PegIntron therapy should be discontinued. When PegIntron is administered in combination with REBETOL, subjects with impaired renal function or those over the age of 50 should be more carefully monitored with respect to the development of anemia. PegIntron/REBETOL should not be used in patients with creatinine clearance less than 50 mL/min.
2.6 Preparation and AdministrationA patient should self-inject PegIntron only if the physician determines that it is appropriate and the patient agrees to medical follow-up as necessary and has been trained in proper injection technique [see illustrated FDA-approved Medication Guide and Instructions for Use for directions on injection site preparation and injection instructions].
Reconstitute PegIntron Powder for Solution with 0.7 mL of Sterile Water for Injection, USP. The Sterile Water for Injection supplied contains 5 mL and is intended for single use only. Discard the unused portion. The reconstituted solution should be visually inspected for discoloration and particulate matter prior to administration. Do not use the solution if it is discolored or not clear, or if particulates are present.
DO NOT REUSE THE VIAL OR PRE-FILLED PEN; DISCARD THE UNUSED PORTION. Pooling of unused portions of some medications has been linked to bacterial contamination and morbidity.
![Pegintron (Peginterferon Alfa-2b) Injection, Powder, Lyophilized, For Solution Pegintron (Peginterferon Alfa-2b) Kit [Merck Sharp & Dohme Corp.]](http://dailymed.nlm.nih.gov/dailymed/image.cfm?setid=b70816bb-913a-467f-acb8-67ef62cf8dac&name=pegintron-5mL-37.jpg)
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