orted with interferon beta products. discontinue plegridy if clinical symptoms and laboratory findings consistent with tma occur ( 5.7 ) autoimmune disorders: consider discontinuation of plegridy if a new autoimmune disorder occurs ( 5.8 ) 5.1 hepatic injury severe hepatic injury, including hepatitis, autoimmune hepatitis, and rare cases of severe hepatic failure, have been reported with interferon beta. asymptomatic elevation of hepatic transaminases has also been reported, and in some patients has recurred upon rechallenge with interferon beta. elevations in hepatic enzymes and hepatic injury have been observed with the use of plegridy in clinical studies. the incidence of increases in hepatic transaminases was greater in patients taking plegridy than in those taking placebo. the incidence of elevations of alanine aminotransferase above 5 times the upper limit of normal was 1% in placebo-treated patients and 2% in plegridy-treated patients. the incidence of elevations of aspartate aminotransferase above 5 times the upper limit of normal was less than 1% in placebo-treated patients and less than 1% in plegridy-treated patients. elevations of serum hepatic transaminases combined with elevated bilirubin occurred in 2 patients. both cases resolved following discontinuation of plegridy. cases of noninfectious hepatitis have been reported in the postmarketing setting with use of plegridy. monitor patients for signs and symptoms of hepatic injury. 5.2 depression and suicide depression, suicidal ideation, and suicide occur more frequently in patients receiving interferon beta than in patients receiving placebo. in clinical studies, the overall incidence of adverse events related to depression and suicidal ideation in multiple sclerosis patients was 8% in both the plegridy and placebo groups. the incidence of serious events related to depression and suicidal ideation was similar and less than 1% in both groups. advise patients to report immediately any symptom of depression or suicidal ideation to their healthcare provider. if a patient develops depression or other severe psychiatric symptoms, consider stopping treatment with plegridy. 5.3 anaphylaxis and other allergic reactions serious allergic reactions are rare complications of treatment with interferon beta; anaphylaxis has been reported with use of plegridy in the postmarketing setting. less than 1% of plegridy-treated patients experienced a serious allergic reaction such as angioedema or urticaria. those who did have serious allergic reactions recovered promptly after treatment with antihistamines or corticosteroids. discontinue plegridy if a serious allergic reaction occurs. the protective rubber cover of the plegridy prefilled syringe for intramuscular administration contains natural rubber latex which may cause allergic reactions and should not be handled by latex-sensitive individuals. the safe use of plegridy prefilled syringe in latex-sensitive individuals has not been studied. 5.4 injection site reactions including necrosis injection site reactions, including injection site necrosis, can occur with the use of interferon beta, including plegridy. in clinical studies of subcutaneous plegridy, the incidence of injection site reactions (e.g., injection site erythema, pain, pruritus, or edema) was 66% in the plegridy group and 11% in the placebo group; the incidence of severe injection site reactions was 3% in the plegridy group and 0% in the placebo group. one patient out of 1468 patients who received plegridy in clinical studies experienced injection site necrosis. the injury resolved with standard medical treatment. in study 3, which compared single doses of intramuscular and subcutaneous plegridy [see adverse reactions ( 6.1 )] , the incidence of injection site reactions (e.g., injection site erythema, pain, pruritus, or edema) was 14% in the intramuscular plegridy group and 32% in the subcutaneous plegridy group. injection site abscesses and cellulitis have been reported in the postmarketing setting with use of interferon beta. some cases required treatment with hospitalization for surgical drainage and intravenous antibiotics. periodically evaluate patient understanding and use of aseptic self-injection techniques and procedures, particularly if injection site necrosis has occurred. decisions to discontinue therapy following necrosis at a single injection site should be based on the extent of the necrosis. for patients who continue therapy with plegridy after injection site necrosis has occurred, avoid administration of plegridy near the affected area until it is fully healed. if multiple lesions occur, change injection site or discontinue plegridy until healing occurs. 5.5 congestive heart failure congestive heart failure, cardiomyopathy, and cardiomyopathy with congestive heart failure occur in patients receiving interferon beta. in clinical studies, the incidence of cardiovascular events was 7% in both plegridy and placebo treatment groups. no serious cardiovascular events were reported in the plegridy group. monitor patients with significant cardiac disease for worsening of their cardiac condition during initiation and continuation of treatment with plegridy. 5.6 decreased peripheral blood counts interferon beta can cause decreased peripheral blood counts in all cell lines, including rare instances of pancytopenia and severe thrombocytopenia. in clinical studies, decreases in white blood cell counts below 3.0 x 10 9 /l occurred in 7% of patients receiving plegridy and in 1% receiving placebo. there is no apparent association between decreases in white blood cell counts and an increased risk of infections or serious infections. the incidence of clinically significant decreases in lymphocyte counts (below 0.5 x 10 9 /l), neutrophil counts (below 1.0 x 10 9 /l), and platelet counts (below 100 x 10 9 /l) were all less than 1% and similar in both placebo and plegridy groups. two serious cases were reported in patients treated with plegridy: one patient (less than 1%) experienced severe thrombocytopenia (defined as a platelet count less than or equal to 10 x 10 9 /l), and another patient (less than 1%) experienced severe neutropenia (defined as a neutrophil count less than or equal to 0.5 x 10 9 /l). in both patients, cell counts recovered after discontinuation of plegridy. compared to placebo, there were no significant differences in red blood cell counts in patients treated with plegridy. monitor patients for infections, bleeding, and symptoms of anemia. monitor complete blood cell counts, differential white blood cell counts, and platelet counts during treatment with plegridy. patients with myelosuppression may require more intensive monitoring of blood cell counts. 5.7 thrombotic microangiopathy cases of thrombotic microangiopathy (tma), including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, some fatal, have been reported with interferon beta products. cases have been reported several weeks to years after starting interferon beta products. discontinue plegridy if clinical symptoms and laboratory findings consistent with tma occur, and manage as clinically indicated. 5.8 autoimmune disorders autoimmune disorders of multiple target organs including idiopathic thrombocytopenia, hyper- and hypothyroidism, and autoimmune hepatitis have been reported with interferon beta. in clinical studies, the incidence of autoimmune disorders was less than 1% in both plegridy and placebo treatment groups. if patients develop a new autoimmune disorder, consider stopping plegridy. 5.9 seizures seizures are associated with the use of interferon beta. the incidence of seizures in multiple sclerosis clinical studies was less than 1% in patients receiving plegridy and placebo. exercise caution when administering plegridy to patients with a seizure disorder.

: 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. on day 15 (14 days later), the dose is increased to 94 micrograms, reaching the full dose of 125 micrograms on day 29 (after another 14 days). patients continue with the full dose (125 micrograms) every 14 days thereafter (see table 1 ). a plegridy starter pack is available containing two prefilled pens or syringes: 63 micrograms (dose 1) and 94 micrograms (dose 2). table 1: schedule for subcutaneous dose titration dose time a amount (micrograms) color of pen or syringe label a dosed every 14 days dose 1 on day 1 63 orange dose 2 on day 15 94 blue dose 3 on day 29 and every 14 days thereafter 125 (full dose) grey 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. on day 15 (14 days later), the dose is increased to 94 micrograms (purple clip), reaching the full dose of 125 micrograms on day 29 (after another 14 days). patients continue with the full dose (125 micrograms) every 14 days thereafter (see table 2 ). table 2: schedule for intramuscular dose titration dose time a amount (micrograms) titration clip a dosed every 14 days dose 1 on day 1 63 yellow dose 2 on day 15 94 purple dose 3 on day 29 and every 14 days thereafter 125 (full dose) no clips needed 2.2 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 [see warnings and precautions ( 5.4 ) ]. 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. 2.3 premedication for flu-like symptoms prophylactic and concurrent use of analgesics and/or antipyretics may prevent or ameliorate flu-like symptoms sometimes experienced during treatment with plegridy.

ction site pruritus, and arthralgia ( 6.1 ) to report suspected adverse reactions, contact biogen at 1-800-456-2255 or fda at 1-800-fda-1088 or http://www.fda.gov/medwatch. 6.1 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. plegridy via subcutaneous administration in clinical studies (study 1 and study 2), a total of 1468 patients with relapsing multiple sclerosis received plegridy by subcutaneous injection for up to 177 weeks (41 months), with an overall exposure equivalent to 1932 person-years. a total of 1093 patients received at least 1 year, and 415 patients at least 2 years of treatment with plegridy. a total of 512 and 500 patients, respectively, received plegridy 125 micrograms every 14 days or every 28 days during the placebo-controlled phase of study 1 (year 1). the experience in year 2 of study 1 and in the 2-year safety extension study (study 2) was consistent with the experience in the 1-year placebo-controlled phase of study 1. 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). table 3 summarizes adverse reactions reported over 48 weeks from patients treated in the placebo-controlled phase of study 1 who received subcutaneous plegridy 125 micrograms (n=512), or placebo (n=500), every 14 days. table 3: adverse reactions in the 48-week placebo-controlled phase of study 1 with an incidence 2% higher for plegridy than for placebo plegridy (n=512) % placebo (n=500) % nervous system disorders headache 44 33 gastrointestinal disorders nausea 9 6 vomiting 5 2 musculoskeletal and connective tissue disorders myalgia 19 6 arthralgia 11 7 general disorders and administration site conditions injection site erythema 62 7 influenza like illness 47 13 pyrexia 45 15 chills 17 5 injection site pain 15 3 asthenia 13 8 injection site pruritus 13 1 hyperthermia 4 1 pain 5 3 injection site edema 3 0 injection site warmth 3 0 injection site hematoma 3 1 injection site rash 2 0 investigations body temperature increased 6 3 alanine aminotransferase increased 6 3 aspartate aminotransferase increased 4 2 gamma-glutamyl-transferase increased 3 1 skin and subcutaneous tissue disorder pruritus 4 1 flu-like symptoms influenza-like illness was experienced by 47% of patients receiving plegridy 125 micrograms every 14 days and 13% of patients receiving placebo. 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). the most commonly reported adverse reactions (with >10% incidence in either arm) across both treatment periods were chills (36% in im vs 27% in sc), pain (22% in im vs 14% in sc), headache (36% in im vs 41% in sc), injection site pain (11% in im vs 15% in sc), and injection site erythema (2% in im vs 25% in sc). overall, injection site reactions were reported in 14% via im route as compared to 32% via sc route. 6.2 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. in study 1, fewer than 1% of patients treated with plegridy sc every 14 days for 1 year developed neutralizing antibodies. 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. 6.3 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 [see warnings and precautions ( 5.3 )]. hepatic injury in post marketing experience, noninfectious hepatitis (including serious hepatitis) cases have been reported following plegridy administration [see warnings and precautions ( 5.1 )] .

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. 8.2 lactation risk summary limited published literature has described the presence of interferon beta-1a products in human milk at low levels. there are no data on the effects of interferon beta-1a on milk production. therefore, the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for plegridy and any potential adverse effects on the breastfed infant from plegridy or from the underlying maternal condition. 8.4 pediatric use safety and effectiveness in pediatric patients have not been established. 8.5 geriatric use clinical studies of plegridy did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. other reported clinical experience has not identified differences in responses between the elderly and younger patients. 8.6 renal impairment monitor for adverse reactions due to increased drug exposure in patients with severe renal impairment [ see clinical pharmacology ( 12.3 ) ].

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.

45% to 93%, respectively). absorption after 125 microgram subcutaneous doses of plegridy in multiple sclerosis patients, the maximum concentration occurred between 1 and 1.5 days, the mean c max was 280 pg/ml, and the auc over the 14 day dosing interval was 34.8 ng.hr/ml. distribution in multiple sclerosis patients taking 125 microgram subcutaneous doses of plegridy every 14 days, the estimated volume of distribution was 481 liters. metabolism and elimination clearance mechanisms for plegridy include catabolism and excretion. the major pathway of elimination is renal. the half-life is approximately 78 hours in multiple sclerosis patients. the mean steady state clearance of plegridy is approximately 4.1 l/hr. plegridy is not extensively metabolized in the liver. the pharmacokinetics of 125 μg single dose of plegridy administered subcutaneously and intramuscularly were similar. specific populations body weight, gender, and age do not require dosage adjustment. renal impairment can increase the c max and auc for plegridy. results of a pharmacokinetic study in patients with mild, moderate, and severe renal impairment (creatinine clearance 50 to 80, 30 to 50, and less than 30 ml/minute, respectively) showed increases above normal for c max of 27%, 26%, and 42%, and for auc, increases of 30%, 40%, and 53%. the half-life was 53, 49, and 82 hours in patients with mild, moderate, and severe renal impairment, respectively, compared to 54 hours in normal subjects. in the same study, subjects with end stage renal disease requiring hemodialysis two or three times weekly had auc and c max of plegridy values that were similar to those of normal controls. each hemodialysis session removed approximately 24% of circulating plegridy from the systemic circulation [see use in specific populations ( 8.6 )] .

ribution in multiple sclerosis patients taking 125 microgram subcutaneous doses of plegridy every 14 days, the estimated volume of distribution was 481 liters. metabolism and elimination clearance mechanisms for plegridy include catabolism and excretion. the major pathway of elimination is renal. the half-life is approximately 78 hours in multiple sclerosis patients. the mean steady state clearance of plegridy is approximately 4.1 l/hr. plegridy is not extensively metabolized in the liver. the pharmacokinetics of 125 μg single dose of plegridy administered subcutaneously and intramuscularly were similar. specific populations body weight, gender, and age do not require dosage adjustment. renal impairment can increase the c max and auc for plegridy. results of a pharmacokinetic study in patients with mild, moderate, and severe renal impairment (creatinine clearance 50 to 80, 30 to 50, and less than 30 ml/minute, respectively) showed increases above normal for c max of 27%, 26%, and 42%, and for auc, increases of 30%, 40%, and 53%. the half-life was 53, 49, and 82 hours in patients with mild, moderate, and severe renal impairment, respectively, compared to 54 hours in normal subjects. in the same study, subjects with end stage renal disease requiring hemodialysis two or three times weekly had auc and c max of plegridy values that were similar to those of normal controls. each hemodialysis session removed approximately 24% of circulating plegridy from the systemic circulation [see use in specific populations ( 8.6 )] .

eek 48. the primary outcome was the annualized relapse rate over 1 year. secondary outcomes included the proportion of patients relapsing, number of new or newly enlarging t2 hyperintense lesions, and time to confirmed disability progression. confirmed disability progression was defined as follows: if the baseline edss score was 0, a sustained 12-week increase in edss score of 1.5 points was required; if the baseline edss score was greater than 0, a sustained 12-week increase in edss score of 1 point was required. table 4 and figure 1 show the results of study 1. table 4: clinical and mri results of study 1 endpoint plegridy 125 micrograms every 14 days placebo p-value clinical outcomes at 48 weeks n=512 n=500 annualized relapse rate 0.26 0.40 0.0007 relative reduction 36% proportion of patients with relapses 0.19 0.29 0.0003 relative risk reduction 39% proportion of patients with disability progression 0.07 0.11 0.0383 relative risk reduction 38% mri outcomes at 48 weeks n=457 n=476 mean number of new or newly enlarging t2 hyperintense lesions 3.6 10.9 <0.0001 relative reduction 67% mean number of gd enhancing lesions 0.2 1.4 <0.0001 relative reduction 86% figure 1: time to first relapse figure

dose prefilled syringes; dose 1 provides 63 mcg/0.5 ml of plegridy, and dose 2 provides 94 mcg/0.5 ml of plegridy (ndc 64406-016-01). intramuscular administration plegridy (peginterferon beta-1a) injection for intramuscular use is supplied as a single-dose prefilled syringe with a rubber stopper and a 23-gauge, 1.25-inch staked needle provided separately with the syringe in the following packaging configurations: carton containing two-125 mcg/0.5 ml single-dose prefilled syringes of plegridy (ndc 64406-017-01). the plegridy titration kit must be prescribed and dispensed separately for treatment initiation. the titration kit contains two titration clips: the yellow clip (for dose 1) allows a delivered dose of 63 mcg of plegridy, and the purple clip (for dose 2) allows a delivered dose of 94 mcg of plegridy. 16.2 storage and handling store plegridy prefilled pens and prefilled syringes in a refrigerator between 2°c to 8°c (36°f to 46°f) in the closed original carton to protect from light until ready for injection. do not freeze. discard if frozen. if refrigeration is unavailable, plegridy may be stored at room temperature up to 25°c (77°f) for a period up to 30 days, protected from light. plegridy can be removed from, and returned to, a refrigerator if necessary. the total combined time out of refrigeration should not exceed 30 days. plegridy prefilled syringe for intramuscular administration contains natural rubber latex which may cause allergic reactions. dispose in a sharps-bin container or other hard plastic or metal sealable container. always follow local regulations for disposal.

neous administration, the usual injection sites are the abdomen, back of the upper arm, and thigh. for intramuscular administration, alternate injections between the left and right thigh. not to inject into an area of the body where the skin is irritated, reddened, bruised, infected, or scarred in any way to check the injection site after 2 hours for redness, swelling, and tenderness to contact their healthcare professional if they have a skin reaction and it does not clear up in a few days pregnancy advise patients to notify their healthcare provider if they become pregnant during treatment or plan to become pregnant [see use in specific populations ( 8.1 )]. liver disease advise patients that severe hepatic injury, including rare cases of hepatic failure, has been reported during the use of interferon beta. advise patients of symptoms of hepatic dysfunction, and instruct patients to report them immediately to their physician [see warnings and precautions ( 5.1 )] . depression and suicide advise patients that depression, suicidal ideation, and suicide have been reported with the use of interferon beta. instruct patients to report symptoms of depression or thoughts of suicide to their physician immediately [see warnings and precautions ( 5.2 )] . anaphylaxis and other allergic reactions advise patients of the symptoms of allergic reactions and anaphylaxis, and instruct patients to seek immediate medical attention if these symptoms occur. inform latex-sensitive patients that the plegridy prefilled syringe for intramuscular administration contains natural rubber latex [see warnings and precautions ( 5.3 )] . injection site reactions including necrosis advise patients that injection site reactions can occur and that the reactions can include injection site necrosis. instruct patients to report promptly any break in the skin that is associated with blue-black discoloration, swelling, or drainage of fluid from the injection site [see warnings and precautions ( 5.4 )] . cardiac disease advise patients that worsening of significant cardiac disease has been reported in patients using interferon beta. advise patients of symptoms of worsening cardiac condition, and instruct patients to report them immediately to their physician [see warnings and precautions ( 5.5 )] . seizure advise patients that seizures have been reported in patients using plegridy. instruct patients to report seizures immediately to their physician [see warnings and precautions ( 5.9 )] . flu-like symptoms inform patients that flu-like symptoms are common following initiation of therapy with plegridy. prophylactic and concurrent use of analgesics and/or antipyretics may prevent or ameliorate flu-like symptoms sometimes experienced during interferon treatment [see dosage and administration ( 2.3 ) and adverse reactions ( 6.1 )] . 43643-08 manufactured by: biogen inc. cambridge, ma 02142 u.s. license # 1697 1-800-456-2255 plegridy is a registered trademark of biogen. ©2013-2022 biogen