Plegridy Drug Information

PLEGRIDY is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.

Dosing Information PLEGRIDY may only be administered subcutaneously (SC) or intramuscularly (IM). For subcutaneous injection: Patients may rotate injection sites between the abdomen, back of the upper arm, or thigh. For intramuscular injection: Patients may rotate injection sites between the left and right thighs.

Treatment Initiation Dose titration at the initiation of treatment may help to ameliorate flu-like symptoms that can occur at treatment initiation with interferons. Prophylactic and concurrent use of analgesics and/or antipyretics may prevent or ameliorate flu-like symptoms sometimes experienced during treatment with PLEGRIDY. Switching between the subcutaneous and intramuscular routes of administration and vice versa has not been studied.

It is not expected that dose titration should be repeated to ameliorate flu-like symptoms if switching between subcutaneous and intramuscular routes of administration, or vice versa based upon bioequivalence demonstrated between the two routes of administration. Subcutaneous Administration of PLEGRIDY Patients using PLEGRIDY for the first time should start treatment with 63 micrograms on day 1. Patients continue with the full dose (125 micrograms) every 14 days thereafter (see Table 1 ).

Table 1: Schedule for Subcutaneous Intramuscular Administration of PLEGRIDY For patients using PLEGRIDY injected intramuscularly for the first time, PLEGRIDY should be titrated using the PLEGRIDY Titration Kit designed for use with the prefilled syringe. The PLEGRIDY Titration Kit is supplied separately and contains two titration devices to be used only with PLEGRIDY prefilled syringes for intramuscular use. Patients should start treatment with 63 micrograms (yellow clip) on day 1.

Table 2: Schedule for Intramuscular

Important Administration Instructions (All Dosage Forms)

Healthcare professionals should train patients in the proper technique for self-administering subcutaneous injections using the prefilled pen or syringe or intramuscular injections using the prefilled syringe. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Advise patients and caregivers to rotate injection sites with each administration to minimize the likelihood of severe injection site reactions, including necrosis or localized infection.

Once removed from the refrigerator, PLEGRIDY should be allowed to warm to room temperature (about 30 minutes) prior to injection. Do not use external heat sources such as hot water to warm PLEGRIDY. Each PLEGRIDY pen and syringe for subcutaneous injection is provided with the needle pre-attached.

PLEGRIDY prefilled syringe for intramuscular injection is supplied as a prefilled syringe with a separate needle. Both intramuscular and subcutaneous prefilled syringes and subcutaneously administered prefilled pens are for one-time use in one patient only and should be discarded after use.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of PLEGRIDY cannot be directly compared to rates in clinical trials of other drugs and may not reflect the rates observed in practice. In the placebo-controlled phase of Study 1, the most common adverse drug reactions for PLEGRIDY 125 micrograms subcutaneously every 14 days were injection site erythema, influenza-like illness, pyrexia, headache, myalgia, chills, injection site pain, asthenia, injection site pruritus, and arthralgia (all had incidence more than 10% and at least 2% more than placebo). The most commonly reported adverse event leading to discontinuation in patients treated with PLEGRIDY 125 micrograms subcutaneously every 14 days was influenza-like illness (in less than 1% of patients).

Fewer than 1% of PLEGRIDY-treated patients in Study 1 discontinued treatment due to flu-like symptoms. Comparison Between Subcutaneous and Intramuscular Administration An open-label, crossover study analyzed findings from 130 healthy volunteers to assess the bioequivalence of single doses of 125 micrograms of PLEGRIDY administered as a subcutaneous and intramuscular injection (Study 3). Overall, injection site reactions were reported in 14% via IM route as compared to 32% via SC route.

Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease.

For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other interferon beta-1a products may be misleading. Approximately 7% of PLEGRIDY SC-treated patients developed antibodies to the polyethylene glycol moiety. No formal studies have been conducted with regards to immunogenicity of the intramuscular route of administration of PLEGRIDY.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of PLEGRIDY. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Anaphylactic reactions In post marketing experience, serious hypersensitivity reactions, including cases of anaphylaxis, have been reported following PLEGRIDY administration.

Hepatic injury In post marketing experience, noninfectious hepatitis (including serious hepatitis) cases have been reported following PLEGRIDY administration. Pulmonary Arterial Hypertension In postmarketing experience, pulmonary arterial hypertension has been reported following PLEGRIDY administration.

Pregnancy Risk Summary Data from a large population-based cohort study, as well as other published studies over several decades, have not identified a drug-associated risk of major birth defects with the use of interferon beta products during early pregnancy. Findings regarding a potential risk for low birth weight or miscarriage with the use of interferon beta products in pregnancy have been inconsistent (see Data ). In a study in pregnant monkeys, administration of interferon beta during pregnancy resulted in an increased rate of abortion ( see Data ).

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Human Data The majority of observational studies reporting on pregnancies exposed to interferon beta products did not identify an association between the use of interferon beta products during early pregnancy and an increased risk of major birth defects.

In a population-based cohort study conducted in Finland and Sweden, data were collected from 1996--2014 in Finland and 2005--2014 in Sweden on 2,831 pregnancy outcomes from women with MS. 797 pregnancies were in women exposed to interferon beta only. No evidence was found of an increased risk of major birth defects among women with MS exposed to interferon beta products compared to women with MS that were unexposed to any non-steroid therapy for MS (n=1,647) within the study. No increased risks were observed for miscarriages and ectopic pregnancies, though there were limitations in obtaining complete data capture for these outcomes, making the interpretation of the findings more difficult.

Two small cohort studies that examined pregnancies exposed to interferon beta products (without differentiating between subtypes of interferon beta products) suggested that a decrease in mean birth weight may be associated with interferon beta exposure during pregnancy, but this finding was not confirmed in larger observational studies. Two small studies observed an increased prevalence of miscarriage, although the finding was only statistically significant in one study. Most studies enrolled patients later in pregnancy, which made it difficult to ascertain the true percentage of miscarriages.

In one small cohort study, a significantly increased risk of preterm birth following interferon beta exposure during pregnancy was observed. Animal Data PLEGRIDY has not been tested for developmental toxicity in pregnant animals. In monkeys given interferon beta by subcutaneous injection every other day during early pregnancy, no adverse effects on embryofetal development were observed.

Abortifacient activity was evident following 3 to 5 doses.

Pediatric Use Safety and effectiveness in pediatric patients have not been established.

PLEGRIDY is contraindicated in patients with a history of hypersensitivity to natural or recombinant interferon beta or peginterferon, or any other component of PLEGRIDY.