Peginterferon Alfa 2b

Peginterferon alfa-2b is made from human proteins that help the body fight viral infections.

Peginterferon alfa-2b is used to treat chronic hepatitis C in adults. Peginterferon alfa-2b is often used in combination with another medicine called ribavirin (Rebetol, Ribasphere).

Peginterferon alfa-2b may be used in combination with boceprevir (Victrelis) or telaprevir (Incivek) to treat hepatitis C. The Sylatron brand of peginterferon alfa-2b is used to treat melanoma (skin cancer) after surgery.

Peginterferon alfa-2b may also be used for purposes not listed in this medication guide.

You should not use this medicine if you have liver failure or autoimmune hepatitis. You should not use peginterferon alfa-2b with ribavirin if you have severe kidney disease, or a hemoglobin blood cell disorder (sickle-cell anemia, thalassemia).

Do not use peginterferon alfa-2b and ribavirin if you are pregnant, or if you are a man and your sexual partner is pregnant. Prevent pregnancy while using this medicine, and for at least 6 months after you stop using it.

Peginterferon alfa-2b can cause life-threatening infections, autoimmune disorders, serious mood or behavior problems, or a stroke. Stop using this medicine and call your doctor at once if you have any unusual changes in mood or behavior, such as: depression, irritability, aggression, or thoughts about suicide or hurting yourself.

You should not use this medicine if you are allergic to peginterferon alfa-2b or other alfa interferons, or if you have:

• liver failure; or
• autoimmune hepatitis.

You should not use peginterferon alfa-2b with ribavirin if you have:

• severe kidney disease;
• a hemoglobin blood cell disorder such as sickle-cell anemia or thalassemia; or
• if you are pregnant, or if you are a man and your sexual partner is pregnant.

To make sure peginterferon alfa-2b is safe for you, tell your doctor if you have:

• cirrhosis, hepatitis B, or liver problems other than hepatitis C;
• a history of depression, mental illness, suicidal thoughts, alcoholism, or drug addiction;
• heart disease, high blood pressure, or a history of heart attack, stroke, or blood clot;
• lung disease;
• an autoimmune disorder such as rheumatoid arthritis, lupus, or psoriasis;
• any blood cell disorder causing bleeding episodes, infections, or fever-related illness;
• HIV or AIDS;
• diabetes;
• high triglycerides (a type of fat in the blood);
• a thyroid disorder;
• kidney disease (or if you are on dialysis);
• a weak immune system caused by cancer or other conditions;
• ulcerative colitis; or
• a history of organ transplant.

Peginterferon alfa-2b may be harmful to an unborn baby. Tell your doctor if you are pregnant.

Peginterferon alfa-2b is often used together with ribavirin. Ribavirin is known to cause birth defects or death in an unborn baby. You may need to have a negative pregnancy test before taking these two medications together, and every month during your treatment.

• If you are a woman, do not use peginterferon alfa-2b and ribavirin if you are pregnant.
• If you are a man, do not use peginterferon alfa-2b and ribavirin if your sexual partner is pregnant. An unborn baby could also be harmed if a man fathers the child while he is taking ribavirin.
• Use at least 2 effective forms of birth control while either sexual partner is using peginterferon alfa-2b with ribavirin. Keep using 2 forms of birth control for at least 6 months after treatment ends.
• Tell your doctor right away if a pregnancy occurs while either the mother or the father is using peginterferon alfa-2b with ribavirin.

It is not known whether peginterferon alfa-2b passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are using this medicine.

Peginterferon alfa-2b can affect growth in children. Talk with your doctor if you think your child is not growing at a normal rate while using this medication.

PegIntron should not be used in a child younger than 3 years old. Sylatron is not approved for use by anyone younger than 18 years old.

Mechanism Of Action

Pegylated recombinant human interferon alfa-2b is an inducer of the innate antiviral immune response [see Microbiology].

Pharmacodynamics

The pharmacodynamic effects of peginterferon alfa-2b include inhibition of viral replication in virus-infected cells, the suppression of cell cycle progression/cell proliferation, induction of apoptosis, anti-angiogenic activities, and numerous immunomodulating activities, such as enhancement of the phagocytic activity of macrophages, activation of NK cells, stimulation of cytotoxic T-lymphocytes, and the upregulation of the Th1 T-helper cell subset.

PegIntron raises concentrations of effector proteins such as serum neopterin and 2'5' oligoadenylate synthetase, raises body temperature, and causes reversible decreases in leukocyte and platelet counts. The correlation between the in vitro and in vivo pharmacologic and pharmacodynamic and clinical effects is unknown.

Pharmacokinetics

Following a single subcutaneous dose of PegIntron, the mean absorption half-life (t ½ ka) was 4.6 hours. Maximal serum concentrations (Cmax) occur between 15 and 44 hours postdose, and are sustained for up to 48 to 72 hours. The Cmax and AUC measurements of PegIntron increase in a dose-related manner. After multiple dosing, there is an increase in bioavailability of PegIntron. Week 48 mean trough concentrations (320 pg/mL; range 0, 2960) are approximately 3-fold higher than Week 4 mean trough concentrations (94 pg/mL; range 0, 416). The mean PegIntron elimination half-life is approximately 40 hours (range 22-60 hours) in patients with HCV infection. The apparent clearance of PegIntron is estimated to be approximately 22 mL/hr·kg. Renal elimination accounts for 30% of the clearance.

Pegylation of interferon alfa-2b produces a product (PegIntron) whose clearance is lower than that of nonpegylated interferon alfa-2b. When compared to INTRON A, PegIntron (1 mcg/kg) has approximately a 7-fold lower mean apparent clearance and a 5-fold greater mean half-life, permitting a reduced dosing frequency. At effective therapeutic doses, PegIntron has approximately 10-fold greater Cmax and 50-fold greater AUC than interferon alfa-2b.

Following multiple dosing of PegIntron (1 mcg/kg subcutaneously given every week for 4 weeks) the clearance of PegIntron is reduced by a mean of 17% in subjects with moderate renal impairment (creatinine clearance 30-49 mL/min) and by a mean of 44% in subjects with severe renal impairment (creatinine clearance 10-29 mL/min) compared to subjects with normal renal function. Clearance was similar in subjects with severe renal impairment not on dialysis and subjects who are receiving hemodialysis. The dose of PegIntron for monotherapy should be reduced in patients with moderate or severe renal impairment [see DOSAGE AND ADMINISTRATION and REBETOL labeling]. REBETOL should not be used in patients with creatinine clearance less than 50 mL/min [see REBETOL labeling, WARNINGS].

During the 48-week treatment period with PegIntron, no differences in the pharmacokinetic profiles were observed between male and female subjects with chronic hepatitis C infection.

The pharmacokinetics of geriatric subjects (65 years of age and older) treated with a single subcutaneous dose of 1 mcg/kg of PegIntron were similar in Cmax, AUC, clearance, or elimination half-life as compared to younger subjects (28-44 years of age).

Population pharmacokinetics for PegIntron and REBETOL (capsules and oral solution) were evaluated in pediatric subjects with chronic hepatitis C between 3 and 17 years of age. In pediatric patients receiving PegIntron 60 mcg/m² /week subcutaneously, exposure may be approximately 50% higher than observed in adults receiving 1.5 mcg/kg/week subcutaneously. The pharmacokinetics of REBETOL (dose-normalized) in this trial were similar to those reported in a prior trial of REBETOL in combination with INTRON A in pediatric subjects and in adults.

Both AUCtf and Cmax increased by 70% when REBETOL capsules were administered with a high-fat meal (841 kcal, 53.8 g fat, 31.6 g protein, and 57.4 g carbohydrate) in a single-dose pharmacokinetic trial [see DOSAGE AND ADMINISTRATION].

Drug Interactions

Table 13: Effect of PegIntron on Coadministered Drugs

The pharmacokinetics of concomitant administration of methadone and PegIntron were evaluated in 18 PegIntron-naïve chronic hepatitis C subjects receiving 1.5 mcg/kg PegIntron subcutaneously weekly. All subjects were on stable methadone maintenance therapy receiving greater than or equal to 40 mg/day prior to initiating PegIntron. Mean methadone AUC was approximately 16% higher after 4 weeks of PegIntron treatment as compared to baseline. In 2 subjects, methadone AUC was approximately double after 4 weeks of PegIntron treatment as compared to baseline [see DRUG INTERACTIONS].

Zidovudine, Lamivudine, and Stavudine

Ribavirin has been shown in vitro to inhibit phosphorylation of zidovudine, lamivudine, and stavudine. However, in a trial with another pegylated interferon in combination with ribavirin, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n=18), stavudine (n=10), or zidovudine (n=6) were co-administered as part of a multi-drug regimen to HIV/HCV co-infected subjects [see DRUG INTERACTIONS].

Didanosine

Exposure to didanosine or its active metabolite (dideoxyadenosine 5'-triphosphate) is increased when didanosine is co-administered with ribavirin, which could cause or worsen clinical toxicities [see DRUG INTERACTIONS].

Microbiology

The biological activity of PegIntron is derived from its interferon alfa-2b moiety. Peginterferon alfa-2b binds to and activates the human type 1 interferon receptor. Upon binding, the receptor subunits dimerize, and activate multiple intracellular signal transduction pathways. Signal transduction is initially mediated by the JAK/STAT activation, which may occur in a wide variety of cells. Interferon receptor activation also activates NFκB in many cell types. Given the diversity of cell types that respond to interferon alfa-2b, and the multiplicity of potential intracellular responses to interferon receptor activation, peginterferon alfa-2b is expected to have pleiotropic biological effects in the body.

The mechanism by which ribavirin contributes to its antiviral efficacy in the clinic is not fully understood. Ribavirin has direct antiviral activity in tissue culture against many RNA viruses. Ribavirin increases the mutation frequency in the genomes of several viruses and ribavirin triphosphate inhibits HCV polymerase in a biochemical reaction.

The anti-HCV activity of interferon was demonstrated in cell culture using self-replicating HCV-RNA (HCV replicon cells) or HCV infection and resulted in an effective concentration (EC50) value of 1 to 10 IU/mL.

The antiviral activity of ribavirin in the HCV-replicon is not well understood and has not been defined because of the cellular toxicity of ribavirin.

HCV genotypes show wide variability in their response to pegylated recombinant human interferon/ribavirin therapy. Genetic changes associated with the variable response have not been identified.

There is no reported cross-resistance between pegylated/nonpegylated interferons and ribavirin.

Pharmacogenomics

A retrospective genome-wide association analysis1,2 of 1671 subjects (1604 subjects from Study 4 [see Clinical Studies] and 67 subjects from another clinical trial) was performed to identify human genetic contributions to anti-HCV treatment response in previously untreated HCV genotype 1 subjects. A single nucleotide polymorphism near the gene encoding interferon-lambda-3 (IL28B rs12979860) was associated with variable SVR rates. The rs12979860 genotype was categorized as CC, CT and TT. In the pooled analysis of Caucasian, African-American, and Hispanic subjects from these trials (n=1587), SVR rates by rs12979860 genotype were as follows: CC 66% vs. CT 30% vs. TT 22%. The genotype frequencies differed depending on racial/ethnic background, but the relationship of SVR to IL28B genotype was consistent across various racial/ethnic groups (see Table 14). Other variants near the IL28B gene (e.g., rs8099917 and rs8103142) have been identified; however, they have not been shown to independently influence SVR rates during treatment with pegylated interferon alpha therapies combined with ribavirin.1

Table 14: SVR Rates by IL28B Genotype*

Animal Toxicology And/Or Pharmacology

Cariprazine caused bilateral cataract and cystic degeneration of the retina in the dog following oral daily administration for 13 weeks and/or 1 year and retinal degeneration/atrophy in the rat following oral daily administration for 2 years. Cataract in the dog was observed at 4 mg/kg/day which is 7.1 (male) and 7.7 (female) times the MRHD of 6 mg/day based on AUC of total cariprazine. The NOEL for cataract and retinal toxicity in the dog is 2 mg/kg/day which is 5 (males) to 3.6 (females) times the MRHD of 6 mg/day based on AUC of total cariprazine. Increased incidence and severity of retinal degeneration/atrophy in the rat occurred at all doses tested, including the low dose of 0.75 mg/kg/day, at total cariprazine plasma levels less than clinical exposure (AUC) at the MRHD of 6 mg/day. Cataract was not observed in other repeat dose studies in pigmented mice or albino rats.

Phospholipidosis was observed in the lungs of rats, dogs, and mice (with or without inflammation) and in the adrenal gland cortex of dogs at clinically relevant exposures (AUC) of total cariprazine. Phospholipidosis was not reversible at the end of the 1-2 month drug-free periods. Inflammation was observed in the lungs of dogs dosed daily for 1 year with a NOEL of 1 mg/kg/day which is 2.7 (males) and 1.7 (females) times the MRHD of 6 mg/day based on AUC of total cariprazine. No inflammation was observed at the end of 2-month drug free period following administration of 2 mg/kg/day which is 5 (males) and 3.6 (females) times the MRHD of 6 mg/day based on AUC of total cariprazine; however, inflammation was still present at higher doses.

Hypertrophy of the adrenal gland cortex was observed at clinically relevant total cariprazine plasma concentrations in rats (females only) and mice following daily oral administration of cariprazine for 2 years and 6 months, respectively. Reversible hypertrophy/hyperplasia and vacuolation/vesiculation of the adrenal gland cortex were observed following daily oral administration of cariprazine to dogs for 1 year. The NOEL was 2 mg/kg/day which is 5 (males) and 3.6 (females) times the MRHD of 6 mg/day based on AUC of total cariprazine. The relevance of these findings to human risk is unknown.

Clinical Studies

Chronic Hepatitis C In Adults

A randomized trial compared treatment with PegIntron (0.5, 1, or 1.5 mcg/kg once weekly subcutaneously) to treatment with INTRON A (3 million units 3 times weekly subcutaneously) in 1219 adults with chronic hepatitis from HCV infection. The subjects were not previously treated with interferon alpha, had compensated liver disease, detectable HCV-RNA, elevated ALT, and liver histopathology consistent with chronic hepatitis. Subjects were treated for 48 weeks and were followed for 24 weeks post-treatment.

Seventy percent of all subjects were infected with HCV genotype 1, and 74 percent of all subjects had high baseline levels of HCV-RNA (more than 2 million copies per mL of serum), two factors known to predict poor response to treatment.

Response to treatment was defined as undetectable HCV-RNA and normalization of ALT at 24 weeks post-treatment. The response rates to the 1 and 1.5 mcg/kg PegIntron doses were similar (approximately 24%) to each other and were both higher than the response rate to INTRON A (12%) (see Table 15).

Table 15: Rates of Response to Treatment – Study 1

Subjects with both viral genotype 1 and high serum levels of HCV-RNA at baseline were less likely to respond to treatment with PegIntron. Among subjects with the two unfavorable prognostic variables, 8% (12/157) responded to PegIntron treatment and 2% (4/169) responded to INTRON A. Doses of PegIntron higher than the recommended dose did not result in higher response rates in these subjects. Subjects receiving PegIntron with viral genotype 1 had a response rate of 14% (28/199) while subjects with other viral genotypes had a 45% (43/96) response rate.

Ninety-six percent of the responders in the PegIntron groups and 100% of responders in the INTRON A group first cleared their viral RNA by Week 24 of treatment [see DOSAGE AND ADMINISTRATION].

The treatment response rates were similar in men and women. Response rates were lower in African-American and Hispanic subjects and higher in Asians compared to Caucasians. Although African Americans had a higher proportion of poor prognostic factors compared to Caucasians, the number of non-Caucasians studied (9% of the total) was insufficient to allow meaningful conclusions about differences in response rates after adjusting for prognostic factors.

Liver biopsies were obtained before and after treatment in 60% of subjects. A modest reduction in inflammation compared to baseline that was similar in all 4 treatment groups was observed.

A randomized trial compared treatment with two PegIntron/REBETOL regimens [PegIntron 1.5 mcg/kg subcutaneously once weekly/REBETOL 800 mg orally daily (in divided doses); PegIntron 1.5 mcg/kg subcutaneously once weekly for 4 weeks then 0.5 mcg/kg subcutaneously once weekly for 44 weeks/REBETOL 1000 or 1200 mg orally daily (in divided doses)] with INTRON A [3 MIU subcutaneously thrice weekly/REBETOL 1000 or 1200 mg orally daily (in divided doses)] in 1530 adults with chronic hepatitis C. Interferon-naïve subjects were treated for 48 weeks and followed for 24 weeks post-treatment. Eligible subjects had compensated liver disease, detectable HCV-RNA, elevated ALT, and liver histopathology consistent with chronic hepatitis.

Response to treatment was defined as undetectable HCV-RNA at 24 weeks post-treatment. The response rate to the PegIntron 1.5 mcg/kg plus REBETOL 800 mg dose was higher than the response rate to INTRON A/REBETOL (see Table 16). The response rate to PegIntron 1.5→0.5 mcg/kg/REBETOL was essentially the same as the response to INTRON A/REBETOL (data not shown).

Table 16: Rates of Response to Treatment – Study 2

Subjects with viral genotype 1, regardless of viral load, had a lower response rate to PegIntron (1.5 mcg/kg)/REBETOL (800 mg) compared to subjects with other viral genotypes. Subjects with both poor prognostic factors (genotype 1 and high viral load) had a response rate of 30% (78/256) compared to a response rate of 29% (71/247) with INTRON A/REBETOL.

Subjects with lower body weight tended to have higher adverse reaction rates [see ADVERSE REACTIONS] and higher response rates than subjects with higher body weights. Differences in response rates between treatment arms did not substantially vary with body weight.

Treatment response rates with PegIntron/REBETOL were 49% in men and 56% in women. Response rates were lower in African American and Hispanic subjects and higher in Asians compared to Caucasians. Although African Americans had a higher proportion of poor prognostic factors compared to Caucasians, the number of non-Caucasians studied (11% of the total) was insufficient to allow meaningful conclusions about differences in response rates after adjusting for prognostic factors in this trial.

Liver biopsies were obtained before and after treatment in 68% of subjects. Compared to baseline, approximately two-thirds of subjects in all treatment groups were observed to have a modest reduction in inflammation.

In a large United States community-based trial, 4913 subjects with chronic hepatitis C were randomized to receive PegIntron 1.5 mcg/kg subcutaneously once weekly in combination with a REBETOL dose of 800 to 1400 mg (weight-based dosing [WBD]) or 800 mg (flat) orally daily (in divided doses) for 24 or 48 weeks based on genotype. Response to treatment was defined as undetectable HCV-RNA (based on an assay with a lower limit of detection of 125 IU/mL) at 24 weeks post-treatment.

Treatment with PegIntron 1.5 mcg/kg and REBETOL 800 to 1400 mg resulted in a higher sustained virologic response compared to PegIntron in combination with a flat 800 mg daily dose of REBETOL. Subjects weighing greater than 105 kg obtained the greatest benefit with WBD, although a modest benefit was also observed in subjects weighing greater than 85 to 105 kg (see Table 17). The benefit of WBD in subjects weighing greater than 85 kg was observed with HCV genotypes 1-3. Insufficient data were available to reach conclusions regarding other genotypes. Use of WBD resulted in an increased incidence of anemia [see ADVERSE REACTIONS].

Table 17: SVR Rates by Treatment and Baseline Weight – Study 3

A total of 1552 subjects weighing greater than 65 kg in Study 3 had genotype 2 or 3 and were randomized to 24 or 48 weeks of therapy. No additional benefit was observed with the longer treatment duration.

A large randomized trial compared the safety and efficacy of treatment for 48 weeks with two PegIntron/REBETOL regimens [PegIntron 1.5 mcg/kg and 1 mcg/kg subcutaneously once weekly both in combination with REBETOL 800 to 1400 mg PO daily (in two divided doses)] and Pegasys 180 mcg subcutaneously once weekly in combination with Copegus 1000 to 1200 mg PO daily (in two divided doses) in 3070 treatment-naïve adults with chronic hepatitis C genotype 1. In this trial, lack of early virologic response (undetectable HCV-RNA or greater than or equal to 2 log10 reduction from baseline) by treatment Week 12 was the criterion for discontinuation of treatment. SVR was defined as undetectable HCV-RNA (Roche COBAS TaqMan assay, a lower limit of quantitation of 27 IU/mL) at 24 weeks post-treatment (see Table 18).

Table 18: SVR Rates by Treatment – Study 4

Overall SVR rates were similar among the three treatment groups. Regardless of treatment group, SVR rates were lower in subjects with poor prognostic factors. Subjects with poor prognostic factors randomized to PegIntron (1.5 mcg/kg)/REBETOL or Pegasys/Copegus, however, achieved higher SVR rates compared to similar subjects randomized to PegIntron 1 mcg/kg/REBETOL. For the PegIntron 1.5 mcg/kg plus REBETOL dose, SVR rates for subjects with and without the following prognostic factors were as follows: cirrhosis (10% vs. 42%), normal ALT levels (32% vs. 42%), baseline viral load greater than 600,000 IU/mL (35% vs. 61%), 40 years of age and older (38% vs. 50%), and African American race (23% vs. 44%). In subjects with undetectable HCV-RNA at Week 12 who received PegIntron (1.5 mcg/kg)/REBETOL, the SVR rate was 81% (328/407).

In a noncomparative trial, 2293 subjects with moderate to severe fibrosis who failed previous treatment with combination alpha interferon/ribavirin were re-treated with PegIntron, 1.5 mcg/kg subcutaneously, once weekly, in combination with weight adjusted ribavirin. Eligible subjects included prior nonresponders (subjects who were HCV-RNA positive at the end of a minimum 12 weeks of treatment) and prior relapsers (subjects who were HCVRNA negative at the end of a minimum 12 weeks of treatment and subsequently relapsed after post-treatment follow-up). Subjects who were negative at Week 12 were treated for 48 weeks and followed for 24 weeks post-treatment. Response to treatment was defined as undetectable HCV-RNA at 24 weeks post-treatment (measured using a research-based test, limit of detection 125 IU/mL). The overall response rate was 22% (497/2293) (99% CI: 19.5, 23.9). Subjects with the following characteristics were less likely to benefit from re-treatment: previous nonresponse, previous pegylated interferon treatment, significant bridging fibrosis or cirrhosis, and genotype 1 infection.

The re-treatment sustained virologic response rates by baseline characteristics are summarized in Table 19.

Table 19: SVR Rates by Baseline Characteristics of Prior Treatment Failures

Achievement of an undetectable HCV-RNA at treatment Week 12 was a strong predictor of SVR. In this trial, 1470 (64%) subjects did not achieve an undetectable HCV-RNA at treatment Week 12, and were offered enrollment into long-term treatment trials, due to an inadequate treatment response. Of the 823 (36%) subjects who were HCV-RNA undetectable at treatment Week 12, those infected with genotype 1 had an SVR of 48% (245/507), with a range of responses by fibrosis scores (F4-F2) of 39-55%. Subjects infected with genotype 2/3 who were HCV-RNA undetectable at treatment Week 12 had an overall SVR of 70% (196/281), with a range of responses by fibrosis scores (F4-F2) of 60-83%. For all genotypes, higher fibrosis scores were associated with a decreased likelihood of achieving SVR.

Chronic Hepatitis C In Pediatrics

Previously untreated pediatric subjects 3 to 17 years of age with compensated chronic hepatitis C and detectable HCV-RNA were treated with REBETOL 15 mg/kg/day plus PegIntron 60 mcg/m² once weekly for 24 or 48 weeks based on HCV genotype and baseline viral load. All subjects were to be followed for 24 weeks post-treatment. A total of 107 subjects received treatment, of which 52% were female, 89% were Caucasian, and 67% were infected with HCV genotype 1. Subjects infected with genotype 1, 4 or genotype 3 with HCV-RNA greater than or equal to 600,000 IU/mL received 48 weeks of therapy while those infected with genotype 2 or genotype 3 with HCV-RNA less than 600,000 IU/mL received 24 weeks of therapy. The trial results are summarized in Table 20.

Table 20: SVR Rates by Genotype and Treatment Duration – Pediatric Trial

REFERENCES

1. Ge, D., Fellay, J., Thompson, A.J., Simon, J.S., Shianna, K.V., Urban, T.J., Heinzen, E.L., Qiu, P., Bertelsen, A.H., Muir, A.J., Sulkowski, M., McHutchison, J.G., Goldstein, D.B., Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance, Nature 2009;461(7262):399-401.

2. Thompson, A.J., Muir, A.J., Sulkowski, M.S., Ge, D., Fellay, J., Shianna, K.V., Urban, T., Afdhal, N.H., Jacobson, I.M., Esteban, R., Poordad, F., Lawitz, E.J., McCone, J., Shiffman, M.L., Galler, G.W., Lee, W.M., Reindollar, R., King, J.W., Kwo, P.Y., Ghalib, R.H., Freilich, B., Nyberg, L.M., Zeuzem, S., Poynard, T., Vock, D.M., Pieper, K.S., Patel, K., Tillmann, H.L., Noviello, S., Koury, K., Pedicone, L.D., Brass, C.A., Albrecht, J.K., Goldstein, D.B., McHutchison, J.G., Interlukin-28B polymorphism improves viral kinetics and is the strongest pretreatment predictor of sustained virologic response in genotype 1 hepatitis C virus, Gastroenterology 2010;139:120-129.

Peginterferon alfa-2b is made from human proteins that help the body fight viral infections.

Peginterferon alfa-2b is used to treat chronic hepatitis C in adults. Peginterferon alfa-2b is often used in combination with another medication called ribavirin (Rebetol, Ribasphere) to treat hepatitis C in adults and children who are at least 3 years old.

Peginterferon alfa-2b may be used in combination with boceprevir (Victrelis) or telaprevir (Incivek) to treat hepatitis C in adults. The Sylatron brand of peginterferon alfa-2b is used to treat melanoma (skin cancer) after surgery.

Peginterferon alfa-2b may also be used for purposes not listed in this medication guide.

In children receiving PegIntron 60 mcg/m2/week, exposure may be ~50% higher than that observed in adults receiving 1.5 mcg/kg/week.

Chronic hepatitis C (CHC): Peg-Intron: Treatment of chronic hepatitis C (CHC) in compensated liver disease:

Combination therapy with ribavirin and an approved hepatitis C virus [HCV] NS3/4A protease inhibitor in adult patients with HCV genotype 1 infection. Note: Regimen is not recommended for hepatitis C virus (HCV) genotype 1 in HCV treatment guidelines (treatment-naive or treatment-experienced) (AASLD/IDSA 2015).

Combination therapy with ribavirin in adult patients with HCV genotypes other than 1, in pediatric patients (3 to 17 years), or in patients with HCV genotype 1 with contraindications or intolerance to HCV NS3/4A protease inhibitor use. Note: Combination therapy with ribavirin (without the addition of another preferred HCV antiviral agent) is not recommended for HCV genotypes other than 1 (ie, genotypes 2, 3, 4, 5, or 6) in HCV adult treatment guidelines (treatment-naive or treatment-experienced) (AASLD/IDSA 2015).

Monotherapy in adult patients with contraindications or significant intolerance to ribavirin if previously untreated. Note: Monotherapy with peginterferon is not recommended in HCV treatment guidelines (treatment-naive or treatment-experienced) (AASLD/IDSA 2015).

Limitations of use: Manufacturer’s labeling: Combination therapy with ribavirin provides substantially better response rates than monotherapy.

Guideline recommendations: Current AASLD/IDSA recommendations do not specify a particular peginterferon (eg, 2a or 2b); however, guideline recommendations are based on clinical trials that used peginterferon alfa-2a (AASLD/IDSA 2015). Hepatitis C treatment guidelines are constantly changing with the advent of new treatment therapies and information; consult current clinical practice guidelines for the most recent treatment recommendations.

Melanoma: Sylatron: Adjuvant treatment of melanoma (with microscopic or gross nodal involvement within 84 days of definitive surgical resection, including complete lymphadenectomy)

Chronic hepatitis C (CHC):

Manufacturer labeling: Children 3 to 17 years: SubQ: Combination therapy with ribavirin: 60 mcg/m2 once weekly; Note: Children who reach their 18th birthday during treatment should remain on the pediatric regimen. Treatment duration is 48 weeks for genotype 1, 24 weeks for genotypes 2 and 3. Discontinue combination therapy in patients with HCV (genotype 1) at 12 weeks if HCV-RNA does not decrease by at least 2 log (compared to pretreatment) or if detectable HCV-RNA present at 24 weeks.

Decompensated liver disease or autoimmune hepatitis: Use is contraindicated.

Hepatic decompensation or severe hepatic injury during treatment (Child-Pugh score >6 [class B or C]): Discontinue immediately.

Melanoma:

Discontinue for any of the following: Persistent or worsening severe neuropsychiatric disorders (depression, psychosis, encephalopathy), grade 4 nonhematologic toxicity, new or worsening retinopathy, new-onset ventricular arrhythmia or cardiovascular decompensation, evidence of hepatic injury (severe) or hepatic decompensation (Child-Pugh score >6 [Class B or C]), development of hyper- or hypothyroidism or diabetes that cannot be effectively managed with medication, or inability to tolerate a dose of 1 mcg/kg/week

Temporarily withhold for any of the following: ANC <500/mm3, platelets <50,000/mm3, ECOG performance status (PS) ≥2, nonhematologic toxicity ≥ grade 3

May reinitiate at a reduced dose once ANC ≥500/mm3, platelets ≥50,000/mm3, ECOG PS at 0 to 1, and nonhematologic toxicity completely resolved or improved to grade 1.

Reduced dose schedule, Weeks 1 to 8:

First dose reduction (if prior dose 6 mcg/kg/week): 3 mcg/kg/week

Second dose reduction (if prior dose 3 mcg/kg/week): 2 mcg/kg/week

Third dose reduction (if prior dose 2 mcg/kg/week): 1 mcg/kg/week

Discontinue permanently if unable to tolerate 1 mcg/kg/week

Reduced dose schedule, Weeks 9 to 260:

First dose reduction (if prior dose 3 mcg/kg/week): 2 mcg/kg/week

Second dose reduction (if prior dose 2 mcg/kg/week): 1 mcg/kg/week

Discontinue permanently if unable to tolerate 1 mcg/kg/week

Chronic hepatitis C: Dosage adjustment for depression (severity based upon DSM-IV criteria):

Mild depression: No dosage adjustment required; evaluate once weekly by visit/phone call. If depression remains stable, continue weekly visits. If depression improves, resume normal visit schedule. For worsening depression, see “Moderate depression” or “Severe depression” below.

Moderate depression: Note: Evaluate once weekly (visit or phone) with an office visit at least every other week. If depression remains stable, consider psychiatric evaluation and continue with reduced dosing. If symptoms improve and remain stable for 4 weeks, resume normal visit schedule; continue reduced dosing or return to normal dose. For worsening depression, see “Severe depression” below.

Children: Decrease peginterferon alfa-2b dose to 40 mcg/m2/week, may further decrease to 20 mcg/m2/week if needed

Adults:

Peginterferon alfa-2b combination therapy: Refer to adult weight-based dosage reduction with combination therapy for depression below

Peginterferon alfa-2b monotherapy: Refer to adult weight-based dosage reduction with monotherapy for depression below

Severe depression: Discontinue peginterferon alfa-2b and ribavirin permanently. Obtain immediate psychiatric consultation. Utilize followup psychiatric therapy as needed.

Chronic hepatitis C: Dosage adjustment in hematologic toxicity:

Children:

Hemoglobin decrease ≥2 g/dL in any 4-week period and stable cardiac disease: Decrease peginterferon alfa-2b dose by 50%; decrease ribavirin dose by 200 mg daily (regardless of the patient’s initial dose); monitor and evaluate weekly. If hemoglobin <8.5 g/dL any time after dose reduction or <12 g/dL after 4 weeks of dose reduction, permanently discontinue both peginterferon alfa-2b and ribavirin.

Hemoglobin 8.5 to <10 g/dL and no history of cardiac disease: Decrease ribavirin dose to 12 mg/kg/day; may further reduce to 8 mg/kg/day; no dosage adjustment necessary for peginterferon alfa-2b.

WBC 1000 to <1500/mm3, neutrophils 500 to <750/mm3, or platelets 50,000 to <70,000/mm3: Reduce peginterferon alfa-2b dose to 40 mcg/m2/week; may further reduce to 20 mcg/m2/week

Hemoglobin <8.5 g/dL, WBC <1000/mm3, neutrophils <500/mm3, or platelets <50,000/mm3: Permanently discontinue peginterferon alfa-2b and ribavirin

Adults:

Hemoglobin decrease ≥2 g/dL in any 4-week period and stable cardiac disease: Decrease peginterferon alfa-2b dose by 50%; decrease ribavirin dose by 200 mg daily. If hemoglobin <8.5 g/dL any time after dose reduction or <12 g/dL after 4 weeks of dose reduction, permanently discontinue both peginterferon alfa-2b and ribavirin.

Hemoglobin 8.5 to <10 g/dL and no history of cardiac disease: Decrease ribavirin dose by 200 mg daily (patients receiving 1400 mg daily should decrease dose by 400 mg daily [ie, first dose reduction to 1000 mg daily]); may further reduce ribavirin dose by additional 200 mg daily if needed. No dosage adjustment necessary for peginterferon alfa-2b.

WBC 1000 to <1500/mm3, neutrophils 500 to <750/mm3, or platelets 25,000 to <50,000/mm3:

Peginterferon alfa-2b combination therapy: Refer to adult weight-based dosage reduction with combination therapy for hematologic toxicity below.

Peginterferon alfa-2b monotherapy: Refer to adult weight-based dosage reduction monotherapy for hematologic toxicity below.

Hemoglobin <8.5 g/dL, WBC <1000/mm3, neutrophils <500/mm3, or platelets <25,000/mm3: Permanently discontinue peginterferon alfa-2b and ribavirin.

Chronic hepatitis C: Adult weight-based dosage reduction for depression or hematologic toxicity:

Peginterferon alfa-2b combination therapy: Initially reduce to average weekly dose of 1 mcg/kg; may further reduce to average weekly dose of 0.5 mcg/kg if needed as follows:

<40 kg: 35 mcg once weekly; may further reduce to 20 mcg once weekly if needed

40 to 50 kg: 45 mcg once weekly; may further reduce to 25 mcg once weekly if needed

51 to 60 kg: 50 mcg once weekly; may further reduce to 30 mcg once weekly if needed

61 to 75 kg: 64 mcg once weekly; may further reduce to 35 mcg once weekly if needed

76 to 85 kg: 80 mcg once weekly; may further reduce to 45 mcg once weekly if needed

86 to 104 kg: 96 mcg once weekly; may further reduce to 50 mcg once weekly if needed

105 to 125 kg: 108 mcg once weekly; may further reduce to 64 mcg once weekly if needed

>125 kg: 135 mcg once weekly; may further reduce to 72 mcg once weekly if needed

Peginterferon alfa-2b monotherapy: Reduce to average weekly dose of 0.5 mcg/kg as follows:

≤45 kg: 20 mcg once weekly

46 to 56 kg: 25 mcg once weekly

57 to 72 kg: 30 mcg once weekly

73 to 88 kg: 40 mcg once weekly

89 to 106 kg: 50 mcg once weekly

107 to 136 kg: 64 mcg once weekly

≥137 kg: 80 mcg once weekly

Manufacturer’s labeling:

Baseline and periodic TSH (for patients being treated for melanoma, obtain baseline within 4 weeks prior to treatment initiation, and then at 3 and 6 months, and every 6 months thereafter during treatment); CBC with differential and platelets; serum chemistries, liver function tests (for patients with melanoma, monitor serum bilirubin, ALT, AST, alkaline phosphatase, and LDH at 2 and 8 weeks, and 2 and 3 months following initiation, then every 6 months during therapy), renal function, triglycerides; serum glucose or HbA1c (for patients with diabetes mellitus). Clinical studies (for combination therapy) tested as follows: CBC (including hemoglobin, WBC, and platelets) and chemistries (including liver function tests and uric acid) measured at weeks 2, 4, 8, and 12, and then every 6 weeks; TSH measured every 12 weeks during treatment. ECG at baseline for patients with pre-existing cardiac abnormalities (for combination therapy with ribavirin).

Evaluate for depression and other psychiatric symptoms before and after initiation of therapy; patients being treated for melanoma should be monitored for depression and psychiatric symptoms every 3 weeks during the first eight weeks of treatment and every 6 months thereafter, and continued monitoring for 6 months after the last dose; baseline ophthalmic eye examination; periodic ophthalmic exam in patients with diabetic or hypertensive retinopathy; baseline ECG in patients with cardiac disease; serum glucose or HbA1c (for patients with diabetes mellitus). In combination therapy with ribavirin, pregnancy tests (for women of childbearing age who are receiving treatment or who have male partners who are receiving treatment), continue monthly up to 6 months after discontinuation of therapy. In pediatric patients, growth velocity and weight should also be monitored during and periodically after treatment discontinuation.

Hepatitic C: Serum HCV RNA levels (pretreatment, 12 and 24 weeks after therapy initiation, 24 weeks after completion of therapy).

Alternate recommendations (AASLD/IDSA 2015): Chronic Hepatitis C:

Baseline (within 12 weeks prior to starting antiviral therapy): CBC, INR, hepatic function panel (albumin, total and direct bilirubin, ALT, AST, and alkaline phosphatase), calculated GFR.

Baseline (at any time prior to starting antiviral therapy): HCV genotype and subtype, quantitative HCV viral load.

During therapy: CBC, serum creatinine, calculated GFR, hepatic function panel (after 4 weeks of therapy and as clinically indicated); quantitative HCV viral load testing (after 4 weeks of therapy and at 12 weeks after completion of therapy). If quantitative HCV viral load is detectable at treatment week 4, repeat testing is recommended after 2 additional weeks of treatment (treatment week 6).

Use with ribavirin is contraindicated in pregnant women and males whose female partners are pregnant.

[US Boxed Warning]: Combination therapy with ribavirin may cause birth defects and/or fetal mortality; avoid pregnancy in females and female partners of male patients. Two forms of contraception should be used along with monthly pregnancy tests during combination therapy and for 6 months after therapy has been discontinued. If used in combination with ribavirin, all warnings related to the use of ribavirin and pregnancy and/or contraception should be followed.

Reproduction studies with pegylated interferon alfa have not been conducted. Animal reproduction studies with nonpegylated interferon alfa-2b have demonstrated abortifacient effects. Disruption of the normal menstrual cycle was also observed in animal studies; therefore, the manufacturer recommends that reliable contraception is used in women of childbearing potential. Alfa interferon is endogenous to normal amniotic fluid (Lebon 1982). In vitro administration studies have reported that when administered to the mother, it does not cross the placenta (Waysbort 1993). Case reports of use in pregnant women are limited.

The HHS Perinatal HIV Guidelines do not recommend that peginterferon alfa be used during pregnancy (HHS [perinatal] 2016). Mother-to-child transmission of HCV does not occur if the woman is not viremic, therefore, HCV-infected women of childbearing potential should postpone pregnancy until therapy is complete. Treatment of HCV is not recommended for women who are already pregnant (AASLD/IDSA 2015).

A pregnancy registry has been established for women inadvertently exposed to ribavirin while pregnant (800-593-2214).

Applies to peginterferon alfa-2b: subcutaneous kit, subcutaneous powder for injection

General

Nearly all study patients experienced at least 1 side effect. The most common side effects associated with the product used for the treatment of chronic hepatitis C (CHC), with or without ribavirin, have included headache, myalgia, fatigue/asthenia, injection site inflammation/reaction, emotional lability/irritability, nausea, rigors, and fevers. Chills, insomnia, anemia, alopecia, anorexia, weight loss, and rash were also reported very commonly with peginterferon alfa-2b/ribavirin. Serious side effects associated with this drug (with or without ribavirin) have been reported in about 12% of subjects during clinical trials. The most common serious side effects associated with peginterferon alfa-2b/ribavirin were depression and suicidal ideation in less than 1% of subjects. The most common fatal side effects associated with this combination were cardiac arrest, suicidal ideation, and suicide attempt in less than 1% of subjects. In most cases, side effects resolved upon discontinuation of therapy. During clinical trials, 10% to 15% of CHC patients discontinued therapy due to side effects.

The most common side effects associated with the product used for adjuvant treatment of melanoma have included fatigue, increased ALT, increased AST, pyrexia, headache, anorexia, myalgia, nausea, chills, and injection site reaction. The most common serious side effects were fatigue, increased ALT, increased AST, and pyrexia. During a clinical trial, 33% of melanoma patients discontinued therapy due to side effects.[Ref]

Hematologic

Decreased neutrophil counts (alone: 70%; with ribavirin: 85%), anemia (with ribavirin: up to 35%), neutropenia (alone: 6%; with ribavirin: up to 31%), thrombocytopenia (alone: 7%; with ribavirin: 5%), and leukopenia (alone: less than 1%; with ribavirin: up to 10%) have been reported in CHC patients.

WHO grade 3 (21%) and WHO grade 4 (7%) neutropenia and hemoglobin levels below 100 g/L (up to 14%) were reported with peginterferon alfa-2b/ribavirin.

Granulocytopenia (less than 0.75 x 10[9]/L) was reported in 4% and 7% of patients using 0.5 and 1 mcg/kg of peginterferon alfa-2b, respectively. Thrombocytopenia (less than 70 x 10[9]/L) was reported in 1% and 3% of patients using 0.5 and 1 mcg/kg of peginterferon alfa-2b, respectively.

Neutropenia, thrombocytopenia, and anemia occurred more often in hepatitis C virus (HCV)/HIV-coinfected patients. Neutropenia (26%), decreased absolute neutrophil count levels (less than 500 cells/mm3: 4%), decreased platelets (less than 50,000/mm3: 4%), anemia (hemoglobin less than 9.4 g/dL: 12%), and decreased CD4 lymphocytes (8%) were reported in HCV/HIV-coinfected patients receiving peginterferon alfa-2b/ribavirin.

Anemia (all grades: 6%; grade 3/4: less than 1%) has been reported in melanoma patients.

A 48-year-old patient with multiple myeloma experienced severe bone marrow hypoplasia coincident with peginterferon alfa-2b therapy. The patient was taking oral thalidomide for several months prior to adding peginterferon alfa-2b to her regimen; she developed a severe bone marrow hypoplasia while using both drugs. Since she used thalidomide previously and this agent was never stopped, it would appear the peginterferon alfa-2b was responsible for the myelosuppression; however, a possible interaction between thalidomide and interferon alfa-2b cannot be ruled out.[Ref]

CHC Patients:
-Very common (10% or more): Decreased neutrophil counts (up to 85%), decreased hemoglobin levels (up to 47%), decreased platelet counts (20%), anemia (up to 35%), neutropenia (up to 31%)
-Common (1% to 10%): Granulocytopenia, thrombocytopenia, leukopenia, hemolytic anemia, lymphadenopathy, decreased CD4 lymphocytes
-Uncommon (0.1% to 1%): Autoimmune thrombocytopenia with or without purpura, severe potentially life-threatening neutropenia
-Very rare (less than 0.01%): Aplastic anemia
-Frequency not reported: Hemolysis
-Postmarketing reports: Pure red cell aplasia, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura

Melanoma Patients:
-Common (1% to 10%): Anemia
-Frequency not reported: Severe bone marrow hypoplasia[Ref]

Nervous system

Headache (alone: 56%; with ribavirin: up to 62%), dizziness (alone: 12%; with ribavirin: up to 21%), and taste perversion (alone: less than 1%; with ribavirin: 9%) have been reported in CHC patients.

Paresthesia was reported in 5% of HCV/HIV-coinfected patients receiving peginterferon alfa-2b/ribavirin.

Vertigo, migraine headache, paresthesia, hearing impairment, hearing loss, encephalopathy, and peripheral neuropathy have also been reported during postmarketing experience.

Headache (all grades: 70%; grade 3/4: 4%), dysgeusia (all grades: 38%), dizziness (all grades: 35%; grade 3/4: 2%), olfactory nerve disorder (all grades: 23%), and paresthesia (all grades: 21%; grade 3/4: less than 1%) have been reported in melanoma patients.[Ref]

CHC Patients:
-Very common (10% or more): Headache (up to 64%), dizziness (up to 21%)
-Common (1% to 10%): Hypertonia, taste perversion, amnesia, memory impairment, syncope, migraine, ataxia, confusion, neuralgia, paresthesia, hypoesthesia, hyperesthesia, somnolence, disturbance in attention, tremor, dysgeusia, hearing impairment/loss, tinnitus, vertigo
-Uncommon (0.1% to 1%): Nerve palsy (facial, oculomotor), transient ischemic attack, loss of consciousness, neuropathy, peripheral neuropathy
-Rare (0.01% to 0.1%): Convulsion
-Very rare (less than 0.01%): Cerebrovascular hemorrhage, cerebrovascular ischemia, encephalopathy
-Frequency not reported: Mononeuropathies, hearing/vestibular disorders
-Postmarketing reports: Seizures, memory loss

Melanoma Patients:
-Very common (10% or more): Headache (up to 70%), dysgeusia (up to 38%), dizziness (up to 35%), olfactory nerve disorder (up to 23%), paresthesia (up to 21%)[Ref]

Psychiatric

CHC Patients:
-Very common (10% or more): Anxiety/emotional lability/irritability (up to 47%), insomnia (up to 41%), depression (up to 31%), impaired concentration (up to 17%)
-Common (1% to 10%): Nervousness, agitation, aggression, anger, altered mood, abnormal behavior, sleep disorder, decreased libido, apathy, abnormal dreams, crying
-Uncommon (0.1% to 1%): Life-threatening or fatal neuropsychiatric events (including suicide, suicide attempt, suicidal and homicidal ideation, severe depression, psychosis, aggressive reaction, relapse of drug addiction/overdose), hallucinations, panic attack
-Rare (0.01% to 0.1%): Bipolar disorders
-Postmarketing reports: Homicidal ideation, aggressive behavior (sometimes directed towards others), mania

Melanoma Patients:
-Very common (10% or more): Depression (up to 59%)[Ref]

Anxiety/emotional lability/irritability (alone: 28%; with ribavirin: up to 47%), insomnia (alone: 23%; with ribavirin: up to 41%), depression (alone: 29%; with ribavirin: up to 31%), impaired concentration (alone: 10%; with ribavirin: 17%), agitation (alone: 2%; with ribavirin: 8%), and nervousness (alone: 4%; with ribavirin: 6%) have been reported in CHC patients.

Life-threatening or fatal neuropsychiatric events have been reported in CHC patients with and without a previous psychiatric disorder.

Psychosis and hallucinations have been reported in patients treated with alpha interferons.

Psychoses, hallucinations, and bipolar disorders have also been reported during postmarketing experience.

Depression (all grades: 59%; grade 3/4: 7%) has been reported in melanoma patients.[Ref]

Other

Fatigue/asthenia (alone: 52%; with ribavirin: up to 68%), rigors (alone: 23%; with ribavirin: 48%), fever (alone: 22%; with ribavirin: up to 46%), chills (with ribavirin: up to 39%), weight decrease (alone: 11%; with ribavirin: up to 29%), unspecified pain (with ribavirin: up to 13%), right upper quadrant pain (alone: 8%; with ribavirin: 12%), viral infections (alone: 11%; with ribavirin: 12%), malaise (alone: 7%; with ribavirin: 4%), chest pain (alone: 6%; with ribavirin: 8%), flushing (alone: 6%; with ribavirin: 4%), and fungal infections (alone: less than 1%; with ribavirin: 6%) have been reported in CHC patients.

Influenza-like symptoms may decrease in severity as treatment continues.

Bacterial infection (including sepsis) has also been reported during postmarketing experience.

Fatigue (all grades: 94%; grade 3/4: 16%), pyrexia (all grades: 75%; grade 3/4: 4%), chills (all grades: 63%; grade 3/4: 1%), and decreased weight (all grades: 11%; grade 3/4: less than 1%) have been reported in melanoma patients.[Ref]

CHC Patients:
-Very common (10% or more): Fatigue/asthenia (up to 68%), rigors (up to 48%), influenza-like symptoms/illness (up to 46%), fever/pyrexia (up to 46%), chills (up to 39%), weight decrease (up to 29%), unspecified pain (up to 13%), right upper quadrant pain (up to 12%), viral infections (up to 12%)
-Common (1% to 10%): Chest pain, malaise, flushing, bacterial infection (including sepsis), fungal infections, otitis media, breast pain, chest discomfort, face edema, peripheral edema, feeling abnormal, thirst
-Uncommon (0.1% to 1%): Infection (sepsis, pneumonia, abscess, cellulitis), ear pain
-Postmarketing reports: Asthenic conditions (including asthenia, malaise, fatigue)

Melanoma Patients:
-Very common (10% or more): Fatigue (up to 94%), pyrexia (up to 75%), chills (up to 63%), decreased weight (up to 11%)[Ref]

Musculoskeletal

CHC Patients:
-Very common (10% or more): Myalgia (up to 56%), arthralgia (up to 34%), musculoskeletal pain (up to 28%)
-Common (1% to 10%): Arthritis, back pain, muscle spasms, pain in extremity, pain in limb
-Uncommon (0.1% to 1%): Gout, rheumatoid arthritis, bone pain, muscle weakness
-Rare (0.01% to 0.1%): Rhabdomyolysis, myositis

Melanoma Patients:
-Very common (10% or more): Myalgia (up to 68%), arthralgia (up to 51%)[Ref]

Myalgia (alone: 54%; with ribavirin: up to 56%), arthralgia (alone: 23%; with ribavirin: up to 34%), and musculoskeletal pain (alone: 28%; with ribavirin: 21%) have been reported in CHC patients.

Pain in limb (6%) and back pain (5%) were reported in HCV/HIV-coinfected patients receiving peginterferon alfa-2b/ribavirin.

A small number of patients developed mild to moderate gout.

Rhabdomyolysis, myositis, and rheumatoid arthritis have also been reported during postmarketing experience.

Myalgia (all grades: 68%; grade 3/4: 4%) and arthralgia (all grades: 51%; grade 3/4: 3%) have been reported in melanoma patients.[Ref]

Local

CHC Patients:
-Very common (10% or more): Injection site inflammation/reaction (including bruise, itchiness, irritation; up to 75%)
-Common (1% to 10%): Injection site pain
-Uncommon (0.1% to 1%): Injection site necrosis, injection site infection
-Frequency not reported: Localized skin ulcerations (after subcutaneous and IM injection)

Melanoma Patients:
-Very common (10% or more): Injection site reaction (up to 62%)[Ref]

Injection site inflammation/reaction (including bruise, itchiness, irritation; alone: 47%; with ribavirin: up to 75%) has been reported in CHC patients.

Injection site reaction (all grades: 62%; grade 3/4: 1.8%) has been reported in melanoma patients.[Ref]

Gastrointestinal

CHC Patients:
-Very common (10% or more): Nausea (up to 43%), diarrhea (up to 22%), abdominal pain (up to 15%), vomiting (up to 14%), oral candidiasis (14%), dry mouth (up to 12%)
-Common (1% to 10%): Dyspepsia, constipation, gastroesophageal reflux disease, stomatitis, mouth ulceration, glossodynia, gingival bleeding, flatulence, hemorrhoids, cheilitis, abdominal distension, gingivitis, glossitis, tooth disorder, increased blood amylase, increased lipase, loose stools, ulcerative stomatitis
-Uncommon (0.1% to 1%): Gastroenteritis, pancreatitis, oral pain
-Rare (0.01% to 0.1%): Ischemic colitis
-Very rare (less than 0.01%): Ulcerative colitis
-Frequency not reported: Hemorrhagic colitis, tongue pigmentation, tooth disorder, tooth fracture
-Postmarketing reports: Aphthous stomatitis, colitis

Melanoma Patients:
-Very common (10% or more): Nausea (up to 64%), diarrhea (up to 37%), vomiting (up to 26%)[Ref]

Nausea (alone: 26%; with ribavirin: up to 43%), diarrhea (alone: 18%; with ribavirin: up to 22%), abdominal pain (alone: 15%; with ribavirin: up to 13%), vomiting (alone: 7%; with ribavirin: up to 14%), dry mouth (alone: 6%; with ribavirin: 12%), dyspepsia (alone: 6%; with ribavirin: 9%), and constipation (alone: 1%; with ribavirin: 5%) have been reported in CHC patients.

Oral candidiasis (14%), increased blood amylase (6%), and increased lipase (6%) were reported in HCV/HIV-coinfected patients receiving peginterferon alfa-2b/ribavirin.

Both fatal and nonfatal ulcerative or hemorrhagic/ischemic colitis have been reported within the first 3 months of alpha interferon therapy. Pancreatitis, fatal and nonfatal, has also been reported with the use of alpha interferon therapy.

Pancreatitis has also been reported during postmarketing experience.

Nausea (all grades: 64%; grade 3/4: 3%), diarrhea (all grades: 37%; grade 3/4: 1%), and vomiting (all grades: 26%; grade 3/4: 1%) have been reported in melanoma patients.[Ref]

Metabolic

Hyperbilirubinemia (10% to 14%) and hyperuricemia (33% to 38%), in association with hemolysis, have been reported during combination therapy trials using peginterferon alfa-2b/ribavirin.

Anorexia (alone: 20%; with ribavirin: up to 32%) has been reported in CHC patients.

Decreased appetite (8%) and increased blood lactic acid (5%) were reported in HCV/HIV-coinfected patients receiving peginterferon alfa-2b/ribavirin.

A 48-year-old man experienced sudden onset of diabetic ketoacidosis 7 months after the start of treatment for hepatitis C.

Elevated triglyceride levels have been associated with interferon alphas.

Dehydration, hypertriglyceridemia, and diabetic ketoacidosis have also been reported during postmarketing experience.

Anorexia (all grades: 69%; grade 3/4: 3%) and increased blood alkaline phosphatase (all grades: 23%) have been reported in melanoma patients.[Ref]

CHC Patients:
-Very common (10% or more): Hyperuricemia (up to 38%), anorexia (up to 32%)
-Common (1% to 10%): Hypocalcemia, dehydration, increased appetite, decreased appetite, increased blood lactic acid
-Uncommon (0.1% to 1%): Hyperglycemia, diabetes mellitus (new onset or worsening), hypertriglyceridemia
-Rare (0.01% to 0.1%): Diabetic ketoacidosis
-Frequency not reported: Elevated triglyceride levels
-Postmarketing reports: Diabetes

Melanoma Patients:
-Very common (10% or more): Anorexia (up to 69%), increased blood alkaline phosphatase (23%)[Ref]

Dermatologic

CHC Patients:
-Very common (10% or more): Alopecia (up to 36%), rash (up to 34%), pruritus (up to 29%), dry skin (up to 24%), acquired lipodystrophy (13%), increased sweating (up to 11%)
-Common (1% to 10%): Herpes simplex, psoriasis, photosensitivity reaction, maculopapular rash, dermatitis, erythematous rash, eczema, night sweats, hyperhidrosis, acne, furuncle, erythema, urticaria, abnormal hair texture, nail disorder
-Uncommon (0.1% to 1%): Aggravated psoriasis, phototoxicity
-Rare (0.01% to 0.1%): Cutaneous sarcoidosis
-Very rare (less than 0.01%): Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme
-Frequency not reported: Generalized exfoliative dermatitis, cutaneous desquamation, seborrhea, pigmentation disorder

Melanoma Patients:
-Very common (10% or more): Exfoliative rash (up to 36%), alopecia (34%)[Ref]

Alopecia (alone: 22%; with ribavirin: up to 36%), rash (alone: 6%; with ribavirin: up to 34%), pruritus (alone: 12%; with ribavirin: up to 29%), dry skin (alone: 11%; with ribavirin: up to 24%), and increased sweating (alone: 6%; with ribavirin: 11%) have been reported in CHC patients.

Acquired lipodystrophy was reported in 13% of HCV/HIV-coinfected patients receiving peginterferon alfa-2b/ribavirin.

Urticaria and cutaneous desquamation of all of the patient's body except his face have been reported in a 41-year-old man with chronic hepatitis C infection after 3 months of combination antiviral therapy with peginterferon alfa-2b/ribavirin. Initially, ribavirin was stopped and topical corticosteroid therapy started without significant improvement. Two weeks later peginterferon alfa-2b was discontinued and significant improvement (decrease in cutaneous lesions) was observed during the following week. Rechallenge with interferon alfa-2b confirmed the development of systemic cutaneous lesions and pruritus.

Erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, urticaria, and psoriasis have also been reported during postmarketing experience.

Exfoliative rash (all grades: 36%; grade 3/4: 1%) and alopecia (all grades: 34%) have been reported in melanoma patients.[Ref]

Respiratory

CHC Patients:
-Very common (10% or more): Dyspnea (up to 26%), cough (up to 23%), pharyngitis (up to 12%)
-Common (1% to 10%): Sinusitis, rhinitis, influenza, upper respiratory tract infection, bronchitis, dysphonia, epistaxis, respiratory disorder, respiratory tract congestion, sinus congestion, nasal congestion, rhinorrhea, increased upper airway secretion, pharyngolaryngeal pain, nonproductive cough
-Uncommon (0.1% to 1%): Emphysema, bronchiolitis obliterans, pleural effusion, lower respiratory tract infection
-Frequency not reported: Pulmonary infiltrates, pneumonitis, pneumonia (sometimes fatal)
-Postmarketing reports: Interstitial pneumonitis, pulmonary hypertension

Melanoma Patients:
-Common (1% to 10%): Dyspnea, cough[Ref]

Dyspnea (alone: 4%; with ribavirin: up to 26%), coughing (alone: 8%; with ribavirin: up to 23%), pharyngitis (alone: 10%; with ribavirin: 12%), sinusitis (alone: 7%; with ribavirin: 6%), and rhinitis (alone: 2%; with ribavirin: 8%) have been reported in CHC patients.

Rhinitis was reported in 5% of HCV/HIV-coinfected patients receiving peginterferon alfa-2b/ribavirin.

Pulmonary infiltrates, pneumonitis, and pneumonia (sometimes fatal) have been reported with the use of peginterferon alfa-2b or alpha interferon therapy in general.

Dyspnea, pulmonary infiltrates, pneumonia, and bronchiolitis obliterans have also been reported during postmarketing experience.

Dyspnea (all grades: 6%; grade 3/4: 1%) and cough (all grades: 5%; grade 3/4: less than 1%) have been reported in melanoma patients.[Ref]

Hepatic

CHC Patients:
-Very common (10% or more): Hyperbilirubinemia (up to 14%)
-Common (1% to 10%): Hepatomegaly, increased GGT
-Frequency not reported: Increased risk of hepatic decompensation and death, hepatic decompensation (including fatalities), cirrhosis

Melanoma Patients:
-Very common (10% or more): Increased ALT or AST (up to 77%)
-Common (1% to 10%): Increased GGT[Ref]

Hyperbilirubinemia (10% to 14%) and hyperuricemia (33% to 38%), in association with hemolysis, have been reported during combination therapy trials using peginterferon alfa-2b/ribavirin.

Hepatomegaly (alone: 6%; with ribavirin: 4%) has been reported in CHC patients.

Increased GGT (9%) and cytolytic hepatitis (6%) were reported in HCV/HIV-coinfected patients receiving peginterferon alfa-2b/ribavirin. Hepatic decompensation (including fatalities) and cirrhosis were reported in a study in HCV/HIV coinfection.

Increased risks of hepatic decompensation and death have been reported in patients with cirrhosis.

Increased ALT or AST (all grades: 77%; grade 3/4: 11%) and increased GGT (all grades: 8%; grade 3/4: 4%) have been reported in melanoma patients.[Ref]

Cardiovascular

Palpitations, cardiomyopathy, hypertension, and hypotension have also been reported during postmarketing experience.[Ref]

CHC Patients:
-Common (1% to 10%): Palpitations, tachycardia, hypertension, hypotension
-Uncommon (0.1% to 1%): Cardiomyopathy, angina pectoris, pericardial effusion, supraventricular arrhythmias, vasculitis, myocardial infarction
-Rare (0.01% to 0.1%): Congestive heart failure, arrhythmia, pericarditis
-Very rare (less than 0.01%): Cardiac ischemia
-Postmarketing reports: Stroke, angina pectoris

Melanoma Patients:
-Common (1% to 10%): Myocardial infarction, bundle-branch block, ventricular tachycardia, supraventricular arrhythmia[Ref]

Endocrine

CHC Patients:
-Common (1% to 10%): Hypothyroidism (new onset or worsening), hyperthyroidism (new onset or worsening)
-Frequency not reported: Thyroid-stimulating hormone (TSH) abnormalities, thyroid disorders
-Postmarketing reports: Thyroiditis

Melanoma Patients:
-Common (1% to 10%): Endocrine disorders, hypothyroidism[Ref]

Hypothyroidism (with or without ribavirin: 5%) and hyperthyroidism (with or without ribavirin: 3%) have been reported in CHC patients.

TSH abnormalities, with and without clinical manifestations, have been associated with interferon therapies.[Ref]

Ocular

Conjunctivitis (alone: 4%; with ribavirin: 4%) and blurred vision (alone: 2%; with ribavirin: 5%) have been reported in CHC patients.

Retinal and ocular changes induced or aggravated by treatment with this or other alpha interferons have included decreased or loss of vision, retinopathy including macular edema, retinal hemorrhages and cotton wool spots, retinal artery or vein thrombosis, optic neuritis, papilledema, and serous retinal detachment.[Ref]

CHC Patients:
-Common (1% to 10%): Conjunctivitis, blurred vision, visual disturbance, photophobia, eye irritation, lacrimal gland disorder, eye pain, dry eye, abnormal vision
-Uncommon (0.1% to 1%): Retinal ischemia, retinal artery or vein thrombosis/occlusion, blindness, decreased visual acuity, optic neuritis, retinal exudates
-Rare (0.01% to 0.1%): Loss of visual acuity or visual fields, retinal hemorrhages, retinopathy, papilledema, macular edema
-Frequency not reported: Retinal and ocular changes, decreased or loss of vision, cotton wool spots, serous retinal detachment

Melanoma Patients:
-Uncommon (0.1% to 1%): Serious retinal disorders, visual disturbances, blurred vision, reduction in visual acuity
-Frequency not reported: Partial loss of vision due to retinal thrombosis or retinopathy[Ref]

Genitourinary

CHC Patients:
-Common (1% to 10%): Menstrual disorder, frequent micturition, polyuria, urine abnormality, amenorrhea, menorrhagia, ovarian disorder, vaginal disorder, sexual dysfunction, prostatitis, erectile dysfunction/impotence

Melanoma Patients:
-Common (1% to 10%): Proteinuria

Menstrual disorder (alone: 4%; with ribavirin: 7%) has been reported in CHC patients.

Proteinuria (all grades: 7%) has been reported in melanoma patients.

Immunologic

Autoimmune thrombocytopenia has been reported 4 weeks after the start of treatment for hepatitis C.

A case report of Hashimoto encephalopathy has been associated with the use of peginterferon alfa-2b/ribavirin for chronic hepatitis C infection in a 36-year-old woman with a 10-year history of autoimmune thyroiditis. After discontinuation of the drugs, corticosteroid therapy was started and the patient experienced full recovery.

Sarcoidosis has also been reported during postmarketing experience.[Ref]

CHC Patients:
-Uncommon (0.1% to 1%): Lupus-like syndrome, sarcoidosis
-Very rare (less than 0.01%): Exacerbation of sarcoidosis
-Frequency not reported: Exacerbation of autoimmune disorders, autoimmune hepatitis, development of binding antibodies (including neutralizing antibodies) to peginterferon alfa-2b, autoimmune thrombocytopenia, Hashimoto encephalopathy
-Postmarketing reports: Systemic lupus erythematosus, Vogt-Koyanagi-Harada syndrome[Ref]

Hypersensitivity

Serious acute hypersensitivity reactions have been reported rarely with the use of alpha interferon therapy.[Ref]

CHC Patients:
-Uncommon (0.1% to 1%): Drug hypersensitivity
-Rare (0.01% to 0.1%): Serious acute hypersensitivity reactions
-Postmarketing reports: Acute hypersensitivity reactions (including anaphylaxis, angioedema, bronchoconstriction, urticaria), anaphylactic reactions (including anaphylactic shock)[Ref]

Renal

Renal insufficiency, renal failure, and interstitial nephritis have also been reported during postmarketing experience.[Ref]

CHC Patients:
-Uncommon (0.1% to 1%): Interstitial nephritis
-Rare (0.01% to 0.1%): Renal insufficiency, renal failure[Ref]

Some side effects of peginterferon alfa-2b may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

CHRONIC HEPATITIS C PATIENTS:
If a serious side effect develops during therapy, the dose of peginterferon alfa-2b and ribavirin should be modified or discontinued until the side effect abates or decreases in severity. If persistent or recurrent serious side effects develop despite adequate dose adjustment, therapy should be discontinued.

Adults:
Combination Therapy: Dose reduction is accomplished in a 2-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.

Monotherapy: Dose reduction is accomplished by reducing the original starting dose of 1 mcg/kg/week to 0.5 mcg/kg/week.

Based on Depression Severity (DSM-IV):
-Mild: No adjustment recommended.
-Moderate: Initial management (4 to 8 weeks) includes reducing the original starting dose to 1 mcg/kg/week, then to 0.5 mcg/kg/week, if needed, for patients on combination therapy or to 0.5 mcg/kg/week for patients on monotherapy. If symptoms improve and are stable for 4 weeks, recommendations are to continue reduced dosing or return to normal dose.
-Severe: Peginterferon alfa-2b/ribavirin should be permanently discontinued.

Based on Laboratory Parameters:
The original starting dose should be reduced (to 1 mcg/kg/week, then to 0.5 mcg/kg/week, if needed, for patients on combination therapy or to 0.5 mcg/kg/week for patients on monotherapy) if:
-WBC 1 x 10(9)/L to less than 1.5 x 10(9)/L
-Neutrophils 0.5 x 10(9)/L to less than 0.75 x 10(9)/L
-Platelets 25 x 10(9)/L to less than 50 x 10(9)/L

In patients without history of cardiac disease, ribavirin daily dose should be reduced (first dose reduction - by 200 mg/day [or by 400 mg/day if original dose 1400 mg/day]; second dose reduction [if needed] - by an additional 200 mg/day) if:
-Hemoglobin (Hgb) 8.5 to less than 10 g/dL

In patients with history of cardiac disease, peginterferon alfa-2b dose should be reduced by 50% and ribavirin dose should be reduced by 200 mg/day if:
-At least 2 g/dL decrease in Hgb during any 4 week period during therapy

Peginterferon alfa-2b/ribavirin should be discontinued if:
-WBC less than 1 x 10(9)/L
-Neutrophils less than 0.5 x 10(9)/L
-Platelets less than 25 x 10(9)/L
-Hgb less than 8.5 g/dL
-Hgb less than 12 g/dL after 4 weeks of dose reduction (in patients with history of cardiac disease)

Discontinuation of Therapy:
-In HCV genotype 1, interferon alfa-naive patients receiving this drug (alone or with ribavirin) should discontinue therapy 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 sustained virologic response and discontinuation of therapy is recommended.
-The manufacturer product information for the specific HCV NS3/4A protease inhibitor should be consulted for information regarding discontinuation based on treatment futility.

Pediatrics:
Dose reduction is accomplished 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.

Based on Depression Severity:
-Mild: No adjustment recommended.
-Moderate: Initial management (4 to 8 weeks) includes reducing the original starting dose to 40 mcg/m2/week, then to 20 mcg/m2/week, if needed. If symptoms improve and are stable for 4 weeks, recommendations are to continue reduced dosing or return to normal dose.
-Severe: Peginterferon alfa-2b/ribavirin should be permanently discontinued.

Based on Laboratory Parameters:
The original starting dose should be reduced (to 40 mcg/m2/week, then to 20 mcg/m2/week, if needed) if:
-WBC 1 x 10(9)/L to less than 1.5 x 10(9)/L
-Neutrophils 0.5 x 10(9)/L to less than 0.75 x 10(9)/L
-Platelets 50 x 10(9)/L to less than 70 x 10(9)/L

In patients without history of cardiac disease, ribavirin daily dose should be reduced (first dose reduction - to 12 mg/kg/day; second dose reduction - to 8 mg/kg/day) if:
-Hgb 8.5 to less than 10 g/dL

Pediatric patients who have preexisting cardiac conditions should have weekly evaluations and hematology testing if:
-At least 2 g/dL decrease in Hgb during any 4 week period during therapy

Peginterferon alfa-2b/ribavirin should be discontinued if:
-WBC less than 1 x 10(9)/L
-Neutrophils less than 0.5 x 10(9)/L
-Platelets less than 50 x 10(9)/L
-Creatinine greater than 2 mg/dL
-Hgb less than 8.5 g/dL
-Hgb less than 12 g/dL after 4 weeks of dose reduction (in patients with history of cardiac disease)

Discontinuation of Therapy:
-Pediatric patients receiving peginterferon alfa-2b/ribavirin (excluding those with HCV genotype 2 and 3) should discontinue therapy at 12 weeks if their HCV-RNA dropped less than 2 log10 at 12 weeks of therapy compared to pretreatment or at 24 weeks if they have detectable HCV-RNA at 24 weeks of therapy.

MELANOMA PATIENTS:
This drug should be permanently discontinued for:
-Persistent or worsening severe neuropsychiatric disorders
-Grade 4 nonhematologic toxicity
-Inability to tolerate dose of 1 mcg/kg/week
-New or worsening retinopathy

This drug should be withheld if any of the following occurs:
-Absolute neutrophil count (ANC) less than 0.5 x 10(9)/L
-Platelet count less than 50 x 10(9)/L
-ECOG performance status (PS) 2 or greater
-Nonhematologic toxicity grade 3 or greater

This drug may be resumed at a reduced dose when all of the following are present:
-ANC at least 0.5 x 10(9)/L
-Platelet count at least 50 x 10(9)/L
-ECOG PS 0 to 1
-Nonhematologic toxicity has completely resolved or improved to grade 1

Dose modifications when starting dose is 6 mcg/kg/week (Doses 1 to 8):
-First dose reduction: 3 mcg/kg/week
-Second dose reduction: 2 mcg/kg/week
-Third dose reduction: 1 mcg/kg/week
-If unable to tolerate 1 mcg/kg/week: Permanently discontinue.

Dose modifications when starting dose is 3 mcg/kg/week (Doses 9 to 260):
-First dose reduction: 2 mcg/kg/week
-Second dose reduction: 1 mcg/kg/week
-If unable to tolerate 1 mcg/kg/week: Permanently discontinue.