Peginterferon beta-1a

Interferons have been reported to reduce the activity of hepatic cytochrome P450-dependent enzymes in humans and animals. Caution should be exercised when peginterferon beta-1a is administered in combination with medicinal products that have a narrow therapeutic index and are largely dependent on the hepatic cytochrome P450 system for clearance, e.g. some classes of antiepileptics and antidepressants.

Peginterferon beta-1a has not been studied in patients with hepatic impairment.

Caution should be used and close monitoring considered when administering peginterferon beta-1a to patients with severe hepatic impairment. Patients should be monitored for signs of hepatic injury and caution exercised when interferons are used concomitantly with other medicinal products associated with hepatic injury.

Caution should be used when administering peginterferon beta-1a to patients with severe renal impairment.

Peginterferon beta-1a should be administered with caution to patients with previous depressive disorders. Depression occurs with increased frequency in the multiple sclerosis population and in association with interferon use. Patients should be advised to immediately report any symptoms of depression and/or suicidal ideation to their prescribing physician.

Patients exhibiting depression should be monitored closely during therapy and treated appropriately. Cessation of therapy with peginterferon beta-1a should be considered.

Peginterferon beta-1a should be administered with caution to patients with a history of seizures, to those receiving treatment with anti-epileptics, particularly if their epilepsy is not adequately controlled with anti-epileptics.

Worsening of cardiac disease has been reported in patients receiving interferon beta. The incidence of cardiovascular events was similar between peginterferon beta-1a (125 micrograms every 2 weeks) and placebo treatment groups (7% in each group). No serious cardiovascular events were reported in patients who received peginterferon beta-1a in the ADVANCE study. Nevertheless, patients with preexisting- significant cardiac disease, such as congestive heart failure, coronary artery disease or arrhythmia should be monitored for worsening of their cardiac condition, particularly during initiation of treatment.

A large amount of data (more than 1,000 pregnancy outcomes) from registries and post-marketing experience indicates no increased risk of major congenital anomalies after pre-conception exposure to interferon beta or such exposure during the first trimester of pregnancy. However, the duration of exposure during the first trimester is uncertain, because data were collected when interferon beta use was contraindicated during pregnancy, and treatment likely interrupted when pregnancy was detected and/or confirmed. Experience with exposure during the second and third trimester is very limited.

Based on animal data, there is a possibly increased risk for spontaneous abortion. The risk of spontaneous abortions in pregnant women exposed to interferon beta cannot adequately be evaluated based on the currently available data, but the data do not suggest an increased risk so far.

If clinically needed, the use of peginterferon beta-1a may be considered during pregnancy.

It is not known whether peginferferon beta-1a is secreted in human milk. Limited information available on the transfer of interferon beta-1a into breast milk, together with the chemical/physiological characteristics of interferon beta, suggests that levels of interferon beta-1a excreted in human milk are negligible. No harmful effects on the breastfed newborn/infant are anticipated.

Peginterferon beta-1a can be used during breast-feeding.

Fertility

There are no data on the effects of peginferferon beta-1a on human fertility. In animals, anovulatory effects were observed at very high doses. No information is available on the effects of peginterferon beta-1a on male fertility in animals.

Peginterferon beta-1a has no or negligible influence on the ability to drive and use machines.

Summary of safety profile

The most common adverse drug reactions (ADR) (at a higher incidence than placebo) for peginterferon beta-1a 125 micrograms subcutaneously every 2 weeks were injection site erythema, influenza like illness, pyrexia, headache, myalgia, chills, injection site pain, asthenia, injection site pruritus, and arthralgia.

The most commonly reported adverse reaction leading to discontinuation in patients treated with peginterferon beta-1a 125 micrograms subcutaneously every 2 weeks was influenza-like illness (<1%).

List of adverse reactions

In clinical studies, a total of 1468 patients received peginterferon beta-1a for up to 278 weeks with an overall exposure equivalent of 4217 person-years. 1285 patients received at least 1 year, 1124 patients have received at least 2 years, 947 patients received at least 3 years, and 658 patients received at least 4 years of treatment with peginterferon beta-1a. The experience in the randomised, uncontrolled phase (year 2) of the ADVANCE study and in the extension study ATTAIN (treatment received for up to 4 years) was consistent with the experience in the 1 year placebo-controlled phase of the ADVANCE study.

The list summarizes ADRs (incidence above placebo and with a reasonable possibility of causality) from 512 patients treated with peginterferon beta-1a 125 micrograms subcutaneously every 2 weeks and 500 patients who received placebo for up to 48 weeks and post-marketing data.

The ADRs are presented as MedDRA preferred terms under the MedDRA System Organ Class. The incidence of the adverse reactions below are expressed according to the following categories:

Very common (≥1/10)
Common (≥1/100 to <1/10)
Uncommon (≥1/1, 000 to <1/100)
Rare (≥1/10, 000 to <1/1,000)
Very rare (<1/10,000)
Not known (cannot be estimated from the available data)

Tabulated summary of adverse drug reactions:

* Class label for interferon beta products.
^┼ Class label for interferon products, see below Pulmonary arterial hypertension
^$ Class label for interferon products
¹ Adverse reactions derived only during post marketing experience

Description of selected adverse reactions

Flu-like symptoms

Influenza-like illness was experienced by 47% of patients receiving peginterferon beta-1a 125 micrograms every 2 weeks and 13% of patients receiving placebo. The incidence of flu-like symptoms (e.g. influenza-like illness, chills, hyperpyrexia, musculoskeletal pain, myalgia, pain, pyrexia) was highest at the initiation of treatment and generally decreased over the first 6 months. Of the patients who reported flu-like symptoms 90% reported them as mild or moderate in severity. None were considered serious in nature. Less than 1% of patients who received peginterferon beta-1a during the placebo controlled phase of the ADVANCE study discontinued treatment due to flu-like symptoms. An open-label study in patients switching from interferon beta therapy to peginterferon beta-1a evaluated the onset and duration of prophylactically treated flu-like symptoms. In patients experiencing flu-like symptoms, the median time to onset was 10 hours (interquartile range, 7 to 16 hours) after injection, and the median duration was 17 hours (interquartile range, 12 to 22 hours).

Injection site reactions

Injection site reactions (e.g. injection site erythema, pain, pruritus, or oedema) were reported by 66% of patients who received peginterferon beta-1a 125 micrograms every 2 weeks compared to 11% of patients receiving placebo. Injection site erythema was the most commonly reported injection site reaction. Of the patients who experienced injection site reactions 95% reported them as mild or moderate in severity. One patient out of 1468 patients who received peginterferon beta-1a in clinical studies experienced an injection site necrosis which resolved with standard medical treatment.

Hepatic transaminase abnormalities

The incidence of hepatic transaminase increases was greater in patients receiving peginterferon beta-1a compared to placebo. The majority of enzyme elevations were <3 times the upper limit of normal (ULN). Elevations of alanine aminotransferase and aspartate aminotransferase (>5 times ULN), were reported in 1% and <1% of placebo-treated patients and 2% and <1% of patients treated with peginterferon beta-1a respectively. Elevations of serum hepatic transaminases combined with elevated bilirubin were observed in two patients who had pre-existing liver test abnormalities prior to receiving peginterferon beta-1a in the clinical trials. Both cases resolved following discontinuation of peginterferon beta-1a.

Haematological disorders

Decreases in white blood cell counts of <3.0 × 10⁹/L were observed in 7% of patients receiving peginterferon beta-1a and in 1% receiving placebo. Mean white blood cell counts remained within normal limits in patients treated with peginterferon beta-1a. Decreases in white blood cell counts were not associated with an increased risk of infections or serious infections. The incidence of potentially clinically significant decreases in lymphocyte counts (<0.5 × 10⁹/L) (<1%), neutrophil counts (≤1.0 × 10⁹/L) (<1%) and platelet counts (≤100 × 10⁹/L) (≤1%) was similar in peginterferon beta-1a-treated patients compared to placebotreated patients. Two serious cases were reported in patients treated with peginterferon beta-1a: one patient (<1%) experienced severe thrombocytopenia (platelet count <10 × 10⁹/L), another patient (<1%) experienced severe neutropenia (neutrophil count <0.5 × 10⁹/L). In both patients, cell counts recovered after discontinuation of peginterferon beta-1a. Slight decreases in mean red blood cell (RBC) counts were observed in peginterferon beta-1a treated patients. The incidence of potentially clinically significant decreases in RBC counts (<3.3 × 10¹²/L) was similar in peginterferon beta-1a-treated patients compared to placebo-treated patients.

Hypersensitivity reactions

Hypersensitivity events were reported in 16% of patients treated with peginterferon beta-1a 125 micrograms every 2 weeks and 14% of patients who received placebo. Less than 1% of peginterferon beta-1a treated patients experienced a serious hypersensitivity event (e.g. angioedema, urticaria) and they recovered promptly after treatment with anti-histamines and/or corticosteroids. In post marketing experience, serious hypersensitivity events including cases of anaphylaxis (frequency not known) have been reported following peginterferon beta-1a administration.

Pulmonary arterial hypertension

Cases of pulmonary arterial hypertension (PAH) have been reported with interferon beta products. Events were reported at various time points including up to several years after starting treatment with interferon beta.

Intramuscular route of administration

An open-label, crossover study enrolled 136 subjects to assess the bioequivalence of single doses of 125 micrograms of peginterferon beta-1a administered SC and IM injection in healthy volunteers. The most commonly reported AEs (with >10% incidence in either arm) across both treatment periods were chills (35.6% in IM vs 26.9% in SC ), pain (22.0% in IM vs 14.2% in SC), injection site pain (11.4% in IM vs 14.9% in SC), injection site erythema (2.3% in IM vs 25.4% in SC ), and headache (35.6% in IM vs 41.0% in SC). Injection site reactions were reported with a lower frequency in IM (14.4%) compared to SC (32.1%).

Abnormal urine protein was reported in 1/130 (0.8%) for the SC arm and 4/131 (3.1%) in the IM group without any associated adverse drug reactions.