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PLEGRIDY (peginterferon beta-1a) is an interferon beta-1a to which a single, linear 20,000 dalton (Da) methoxy poly(ethyleneglycol)-O-2-methylpropionaldehyde molecule is covalently attached to the alpha amino group of the N-terminal amino acid residue.
The interferon beta-1a portion of PLEGRIDY is produced as a glycosylated protein using genetically-engineered Chinese hamster ovary cells into which the human interferon beta gene has been introduced. The amino acid sequence of the recombinant interferon beta-1a is identical to that of the human interferon beta counterpart. The molecular mass of PLEGRIDY is approximately 44,000 Da, consistent with the mass of the protein (approximately 20,000 Da), the carbohydrate moieties (approximately 2,500 Da), and the attached poly(ethylene glycol). However, because of the extended and flexible nature of the attached poly(ethylene glycol) chain, the apparent mass of PLEGRIDY in solution is greater than 300,000 Da. The more than 10-fold increase in apparent mass of PLEGRIDY compared to interferon beta-1a has been shown to contribute to the reduced clearance in vivo.
PLEGRIDY 125 micrograms contains 125 micrograms of interferon beta-1a plus 125 micrograms of poly(ethylene glycol). Using the World Health Organization International Standard for interferon beta, PLEGRIDY has a specific antiviral activity of approximately 100 million International Units (MIU) per mg of protein as determined using an in vitro cytopathic effect assay. PLEGRIDY 125 micrograms contains approximately 12 MIU of antiviral activity. PLEGRIDY contains no preservative.
PLEGRIDY PEN is composed of an autoinjector that surrounds a prefilled glass syringe containing 0.5 mL of a sterile solution in water for injection of 63, 94, or 125 micrograms of peginterferon beta-1a, 15.8 mg of L-arginine HCl, 0.79 mg of sodium acetate trihydrate, 0.25 mg of glacial acetic acid, and 0.025 mg of polysorbate 20. The pH is approximately 4.8.
A prefilled syringe of PLEGRIDY for subcutaneous injection contains 0.5 mL of a sterile solution in water for injection of 63, 94, or 125 micrograms of peginterferon beta-1a, 15.8 mg of L-arginine HCl, 0.79 mg of sodium acetate trihydrate, 0.25 mg of glacial acetic acid, and 0.025 mg of polysorbate 20. The pH is approximately 4.8.
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.
PLEGRIDY may only be administered subcutaneously (SC) or intramuscularly (IM). Recommended Maintenance Dosage After initial titration (see Table 1 and Table 2), the recommended dosage of PLEGRIDY is 125 Â micrograms injected every 14 days.
Patients may rotate injection sites between the abdomen, back of the upper arm, or thigh.
Patients may rotate injection sites between the left and right thighs.
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.
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 | Timea | Amount (micrograms) | Color of Pen or Syringe Label |
| 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 |
| a Dosed every 14 days | |||
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 | Timea | Amount (micrograms) | Titration Clip |
| 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 |
| a Dosed every 14 days | |||
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].
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 preÂattached. 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.
Prophylactic and concurrent use of analgesics and/or antipyretics may prevent or ameliorate flu-like symptoms sometimes experienced during treatment with PLEGRIDY.
PLEGRIDY is a clear to slightly opalescent and colorless to slightly yellow solution.
PLEGRIDY (peginterferon beta-1a) injection is a sterile, preservative-free, clear to slightly opalescent and colorless to slightly yellow solution supplied as a 0.5 mL single-dose prefilled pen or a 0.5 mL single-dose prefilled syringe.
PLEGRIDY (peginterferon beta-1a) injection for subcutaneous use is supplied as a single-dose prefilled pen or single-dose prefilled syringe with a rubber stopper and a 29-gauge, 0.5-inch staked needle with a rigid needle shield in the following packaging configurations:
Carton containing two-125 mcg/0.5 mL single-dose prefilled pens of PLEGRIDY (NDC 64406-011-01).
Starter Pack carton containing two single-dose prefilled pens; dose 1 provides 63 mcg/0.5 mL of PLEGRIDY and dose 2 provides 94 mcg/0.5 mL of PLEGRIDY (NDC 64406-012-01).
Carton containing two-125 mcg/0.5 mL single-dose prefilled syringes of PLEGRIDY (NDC 64406-015-01).
Starter Pack carton containing two single-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).
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.
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.
Manufactured by: Biogen Inc. Cambridge, MA 02142. Revised: Jul 2023
The following serious adverse reactions are discussed in more detail in other sections of labeling:
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 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 |
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.
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 IMvs 25% in SC). Overall, injection site reactions were reported in 14% via IM route as compared to 32% via SC route.
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.
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.
In post marketing experience, serious hypersensitivity reactions, including cases of anaphylaxis, have been reported following PLEGRIDY administration [see WARNINGS AND PRECAUTIONS].
In post marketing experience, noninfectious hepatitis (including serious hepatitis) cases have been reported following PLEGRIDY administration [see WARNINGS AND PRECAUTIONS].
In postmarketing experience, pulmonary arterial hypertension has been reported following PLEGRIDY administration [see WARNINGS AND PRECAUTIONS].
No Information provided
Included as part of the PRECAUTIONS section.
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.
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.
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.
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], 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.
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.
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 109/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 109/L), neutrophil counts (below 1.0 x 109/L), and platelet counts (below 100 x 109/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 109/L), and another patient (less than 1%) experienced severe neutropenia (defined as a neutrophil count less than or equal to 0.5 x 109/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.
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.
Cases of pulmonary arterial hypertension (PAH) have been reported in patients treated with interferon beta products, including PLEGRIDY. PAH has occurred in patients treated with interferon beta products in the absence of other contributory factors. Many of the reported cases required hospitalization, including one case with interferon beta in which the patient underwent a lung transplant. PAH has developed at various time points after initiating therapy with interferon beta products and may occur several years after starting treatment.
Patients who develop unexplained symptoms (e.g., dyspnea, new or increasing fatigue) should be assessed for PAH. If alternative etiologies have been ruled out and a diagnosis of PAH is confirmed, discontinue treatment and manage as clinically indicated.
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.
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.
Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).
Provide appropriate instruction for methods of self-injection, including careful review of the PLEGRIDY Medication Guide and Instructions for Use. Instruct patients in the use of aseptic technique when administering PLEGRIDY.
Inform patients that a healthcare provider should show them or their caregiver how to prepare to inject PLEGRIDY before administering the first dose. Tell patients not to re-use needles or syringes, and instruct patients on safe disposal procedures. Inform patients to dispose of used needles and syringes in a puncture-resistant container, and instruct patients regarding safe disposal of full containers.
Advise patients to notify their healthcare provider if they become pregnant during treatment or plan to become pregnant [see Use In Specific Populations].
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].
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].
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].
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].
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].
Inform patients that PAH has occurred in patients treated with interferon beta products, including PLEGRIDY. Instruct patients to promptly report any new symptoms such as new or increasing fatigue or shortness of breath to their healthcare provider [see WARNINGS AND PRECAUTIONS].
Advise patients that seizures have been reported in patients using PLEGRIDY. Instruct patients to report seizures immediately to their physician [see WARNINGS AND PRECAUTIONS].
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 and ADVERSE REACTIONS].
The carcinogenic potential of PLEGRIDY has not been tested in animals.
PLEGRIDY was not mutagenic when tested in an in vitro bacterial reverse mutation (Ames) test and was not clastogenic in an in vitro assay in human lymphocytes.
In monkeys administered interferon beta by subcutaneous injection over the course of one menstrual cycle, menstrual irregularities, anovulation, and decreased serum progesterone levels were observed. These effects were reversible after discontinuation of drug.
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.
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.
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.
Safety and effectiveness in pediatric patients have not been established.
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.
Monitor for adverse reactions due to increased drug exposure in patients with severe renal impairment [see CLINICAL PHARMACOLOGY].
No Information provided
PLEGRIDY is contraindicated in patients with a history of hypersensitivity to natural or recombinant interferon beta or peginterferon, or any other component of PLEGRIDY [see WARNINGS AND PRECAUTIONS].
The mechanism by which PLEGRIDY exerts its effects in patients with multiple sclerosis is unknown.
There is no biochemical or physiologic effect known to relate directly to the clinical effect of PLEGRIDY.
After single-dose or multiple-dose subcutaneous administration of PLEGRIDY to healthy subjects, serum PLEGRIDY peak concentration (Cmax) and total exposure over time (area under the curve, or AUC) increased in proportion to doses from 63 to 188 micrograms. PLEGRIDY did not accumulate in the serum after multiple doses of 125 micrograms every 14 days. Pharmacokinetic parameters for PLEGRIDY, including Cmax and AUC, did not differ significantly between healthy volunteers and multiple sclerosis patients or between single-dose and multiple-dose administrations. However, the coefficient of variation between individual patients for AUC, Cmax, and half-life was high (41% to 68%, 74% to 89%, and 45% to 93%, respectively).
After 125 microgram subcutaneous doses of PLEGRIDY in multiple sclerosis patients, the maximum concentration occurred between 1 and 1.5 days, the mean Cmax was 280 pg/mL, and the AUC over the 14 day dosing interval was 34.8 ng.hr/mL.
In multiple sclerosis patients taking 125 microgram subcutaneous doses of PLEGRIDY every 14 days, the estimated volume of distribution was 481 liters.
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.
Body weight, gender, and age do not require dosage adjustment.
Renal impairment can increase the Cmax 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 Cmax 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 Cmax 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].
The efficacy of PLEGRIDY was demonstrated in the randomized, double-blind, and placebo-controlled phase (year 1) of Study 1. The trial compared clinical and MRI outcomes at 48 weeks in patients who received PLEGRIDY 125 micrograms (n=512) or placebo (n=500) by the subcutaneous route, once every 14 days.
Study 1 enrolled patients who had a baseline Expanded Disability Status Scale (EDSS) score from 0 to 5, who had experienced at least 2 relapses within the previous three years, and had experienced at least 1 relapse in the previous year. The trial excluded patients with progressive forms of multiple sclerosis. The mean age of the study population was 37 years, the mean disease duration was 3.6 years, and the mean EDSS score at baseline was 2.46. The majority of the patients were women (71%).
The trial scheduled neurological evaluations at baseline, every 12 weeks, and at the time of a suspected relapse. Brain MRI evaluations were scheduled at baseline, week 24, and week 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
 |
PLEGRIDY®
(PLEGG-rih-dee)
(peginterferon beta-1a) injection, for subcutaneous or intramuscular use
Read this Medication Guide before you start using PLEGRIDY, and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment.
What is the most important information I should know about PLEGRIDY?
PLEGRIDY can cause serious side effects, including:
Call your healthcare provider right away if you have any of the symptoms listed above.
What is PLEGRIDY?
Do not take PLEGRIDY if you:
Before using PLEGRIDY, tell your healthcare provider about all of your medical conditions, including if you:
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
How should I use PLEGRIDY?
What are the possible side effects of PLEGRIDY?
See “What is the most important information I should know about PLEGRIDY?”
PLEGRIDY may cause serious side effects, including:
The most common side effects of PLEGRIDY include:
Flu-like symptoms or other common side effects of PLEGRIDY may include: headache, muscle and joint aches, fever, chills, or tiredness.
These are not all the possible side effects of PLEGRIDY.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
General Information about the safe and effective use of PLEGRIDY.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use PLEGRIDY for a condition for which it was not prescribed. Do not give PLEGRIDY to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about PLEGRIDY that is written for health professionals.
What are the ingredients in PLEGRIDY?
Active ingredient: peginterferon beta-1a.
Inactive ingredients:
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Instructions for Use
PLEGRIDY®
(PLEGG-rih-dee)
(peginterferon beta-1a) injection for Subcutaneous Use
Single-Dose Prefilled Syringe
Starter Pack
How to Inject your Plegridy Prefilled Syringe
Read this Instructions for Use before you start using Plegridy and each time you get a refill of your prescription. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.
Note:
How should I store Plegridy?
Supplies needed for your Starter Pack for Plegridy Prefilled Syringe injection (See Figure A):
Figure A
 |
Additional supplies which are not included in the pack (See Figure B):
Figure B
 |
Dose Schedule
 |
Ask your healthcare provider which Plegridy Prefilled Syringe you should use for your correct dose if you are not sure.
Parts of your Plegridy Prefilled Syringe (See Figure E):
Figure E
 |
Preparing for your injection:
Step 1: Take your Plegridy Prefilled Syringe out of the refrigerator and let it come to roomtemperature for at least 30 minutes.
Step 2: Collect your supplies and wash your hands
Step 3: Check your Plegridy Prefilled Syringe
Figure G
 |
Step 4: Choose and clean your injection site
Figure H
 |
Giving Your Injection:
Step 5: Remove the Plegridy Prefilled Syringe needle cover
Figure I
 |
Step 6: Gently pinch the injection site
Figure J
 |
Step 7: Give your Plegridy Prefilled Syringe injection
Figure K
 |
Figure L
 |
Figure M
 |
After Your Injection:
Step 8: Disposing of your used Plegridy Prefilled Syringes
Step 9: Check your injection site
Questions?
For product or service-related questions, call 1-800-456-2255 or go to www.plegridy.com.
Instructions for Use
PLEGRIDY®
(PLEGG-rih-dee)
(peginterferon beta-1a) injection, for Subcutaneous Use
Single-Dose Prefilled Pen 125 mcg
Important: Do not remove the Plegridy Pen cap until you are ready to inject.
How to Inject your Plegridy Pen
Read this Instructions for Use before you start using Plegridy and each time you get a refill of your prescription. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.
Note:
How should I store Plegridy?
Supplies needed for your Plegridy Pen injection:
Before Use – Parts of your Plegridy Pen (Figure A)
Figure A
 |
Important: Do not remove the Plegridy Pen cap until you are ready to inject. If you remove the cap before you are ready to inject, do not re-cap the pen. Re-capping could cause the pen to lock.
Additional supplies which are not included in the pack (See Figure B):
Figure B
 |
Preparing for your injection:
Step 1: Take your Plegridy Pen out of the refrigerator and let it come to room temperaturefor at least 30 minutes.
Step 2: Collect your supplies and wash your hands
Step 3: Check your Plegridy Pen (see Figure C)
Figure C
 |
Step 4: Choose and clean your injection site
Figure D
 |
Giving your injection:
Step 5: Remove the Plegridy Pen cap
Figure E
 |
Step 6: Give your injection
Figure F
 |
Note: Be ready to inject before you start pressing your Plegridy Pen down on your injection site. After you start pressing, the needle cover will lock when it is lifted from the site.
Figure G
 |
Figure H
 |
If you do not hear clicking sounds or you do not see green checkmarks in the injection status window after trying to give your injection, your Plegridy Pen may have locked and you should call 1-800-456-2255.
Step 7: Remove your Plegridy Pen from your injection site
Figure I
 |
Step 8: Check and make sure you received your full dose of Plegridy (see Figure J)
Figure J
 |
After your injection:
After Use – Parts of your Plegridy Pen (Figure K)
Figure K
 |
Important: Do not touch the needle cover in any way. You could get a needle stick injury.
Note: After the pen has been removed from the injection site, the needle cover will lock to protect against needle stick injury. Do not recap your Plegridy Pen.
Step 9: Disposing of your used Plegridy Pens
Step 10: Check your injection site
Questions?
For product or service-related questions, call 1-800-456-2255 or go to www.plegridy.com.
Instructions for Use
PLEGRIDY®
(PLEGG-rih-dee)
(peginterferon beta-1a) injection, for Subcutaneous Use
Single-Dose Prefilled Pen
Starter Pack
Important: Do not remove the Plegridy Pen cap until you are ready to inject. How to Inject your Plegridy Pen
Read this Instructions for Use before you start using Plegridy and each time you get a refill of your prescription. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.
Note:
How should I store Plegridy?
Supplies needed for your Starter Pack for Plegridy Pen injection (See Figure A):
Figure A
 |
Additional supplies which are not included in the pack (See Figure B):
Figure B
 |
Dose Schedule
 |
Ask your healthcare provider which Plegridy Pen you should use for your correct dose if you are not sure.
Before Use – Parts of your Plegridy Pen before use (See Figure E):
Figure E
 |
Important: Do not remove the Plegridy Pen cap until you are ready to inject. If you remove the cap before you are ready to inject, do not re-cap the pen. Re-capping could cause the pen to lock.
Preparing for your injection:
Step 1: Take your Plegridy Pen out of the refrigerator and let it come to room temperature for at least 30 minutes.
Step 2: Collect your supplies and wash your hands
Step 3: Check your Plegridy Pen (see Figure F)
Figure F
 |
Step 4: Choose and clean your injection site
Figure G
 |
Giving your injection:
Step 5: Remove the Plegridy Pen cap
Figure H
 |
Step 6: Give your injection
Figure I
 |
Note: Be ready to inject before you start pressing your Plegridy Pen down on your injection site. After you start pressing, the needle cover will lock when it is lifted from the site.
Figure J
 |
Figure K
 |
If you do not hear clicking sounds, or you do not see green checkmarks in the injection status window after trying to give your injection, your Plegridy Pen may have locked and you should call 1-800-456-2255 for help.
Step 7: Remove your Plegridy Pen from your injection site
Figure L
 |
Step 8: Check to make sure you have received your full dose of Plegridy (see Figure M)
Figure M
 |
After your injection:
After Use – Parts of your Plegridy Pen (Figure N)
Figure N
 |
Important: Do not touch the needle cover in any way. You could get a needle stick injury.
Note: After the pen has been removed from the injection site, the needle cover will lock to protect against needle stick injury. Do not recap your Plegridy Pen.
Step 9: Disposing of your used Plegridy Pens
Step 10: Check your injection site
PLEGRIDY®
(PLEGG-rih-dee)
 (peginterferon beta-1a)  injection for intramuscular use
Single-Dose Prefilled Syringe
Read this Instructions for Use before you start using Plegridy and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.
Important information:
Note:
How should I store Plegridy?
Keep the Plegridy prefilled syringe and all medicines out of the reach of children.
Supplies you will need for the Plegridy injection:
 |
Additional supplies not included in your Plegridy Administration Dose pack:
 |
Preparing the dose of Plegridy:
Identifying parts of the Plegridy prefilled syringe (See Figure A).
Preparing the Plegridy injection:
Step 1: Check the Plegridy prefilled syringe (See Figure A):
Do not use the Plegridy prefilled syringe if:
If you cannot use that syringe, you will need to get a new syringe. Contact Biogen at 1-800-456-2255.
Figure A
 |
Step 2: With 1 hand, hold the Plegridy prefilled syringe right under the cap and with the cap pointing up (See Figure B).
Figure B
 |
Step 3: With the other hand, grasp the cap and bend it at a 90° angle until the cap snaps off (See Figure C and Figure D).
Figure C
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Figure D
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Step 4: Open the sterile needle package and take out the covered needle. Hold the Plegridy prefilled syringe with the glass syringe tip pointing up. Press the needle on the Plegridy prefilled syringe glass tip (See Figure E).
Figure E
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Step 5: Gently turn the needle to the right (clockwise) until it is tight and firmly attached (See Figure F).
Figure F
 |
Giving the Plegridy injection:
Step 6: Choose your left or right thigh and wipe the skin with an alcohol wipe (See Figure G). Let the injection site dry before injecting the dose.
Figure G
 |
Step 7: Pull the protective cover straight off the needle (See Figure H). Do not twist the cover off.
Figure H
 |
Step 8: With 1 hand, stretch the skin out around the injection site. With the other hand, hold the syringe like a pencil. Use a quick dart-like motion and insert the needle at a 90° angle, through the skin and into the muscle (See Figure I). After the needle is in, let go of the skin.
Figure I
 |
Step 9: Slowly push the plunger down until the syringe is empty (See Figure J).
Figure J
 |
Step 10: Pull the needle out of the skin (See Figure K). Press down on the injection site with the gauze pad for a few seconds or rub gently in a circular motion.
Figure K
 |
After the Plegridy injection:
Check your injection site:
General information about the safe and effective use of Plegridy
Instructions for Use
PLEGRIDY®
(PLEGG-rih-dee)
(peginterferon beta-1a) injection for intramuscular use
Titration Kit for use with the PLEGRIDY intramuscular
Single-Dose Prefilled Syringe Only
Read this Instructions for Use before you start using Plegridy and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.
Important information: The tip of the cap of the Plegridy prefilled syringe is made of natural rubber latex. Tell your healthcare provider if you are allergic to rubber or latex.
Note:
How should I store Plegridy?
Keep the Plegridy Titration Kit, the Plegridy prefilled syringe, and all medicines out of the reach of children.
Supplies you will need for the Plegridy injection:
 |
Additional supplies not included in your Plegridy Titration Kit and Plegridy Administration Dose Pack:
 |
Preparing the Plegridy Prefilled Syringe:
Identifying parts of the Plegridy prefilled syringe (See Figure A).
Preparing the Plegridy injection:
Step 1: Check the Plegridy prefilled syringe (Figure A):
Do not use the Plegridy prefilled syringe if:
If you cannot use that syringe, you will need to get a new syringe. Contact Biogen at 1-800-4562255.
Figure A
 |
Step 2: With 1 hand, hold the Plegridy prefilled syringe right under the cap and with the cap pointing up (See Figure B).
Figure B
 |
Step 3: With the other hand, grasp the cap and bend it at a 90° angle until the cap snaps off (See Figure C and Figure D).
Figure C
 |
Figure D
 |
Step 4: Open the sterile needle package and take out the covered needle. Hold the Plegridy prefilled syringe with the glass syringe tip pointing up. Press the needle on the Plegridy prefilled syringe glass tip (See Figure E).
Figure E
 |
Step 5: Gently turn the needle to the right (clockwise) until it is tight and firmly attached (See Figure F).
Figure F
 |
Using the Plegridy prefilled syringe with the Plegridy Titration Kit:
Identifying the parts of Plegridy Titration Kit (See Figure G):
Figure G
 |
Figure H
 |
Attaching the Plegridy titration clip:
Step 6: Choose the right titration clip for your dose.
Figure I
 |
Figure J
 |
Step 7: Put the correct titration clip on a flat surface with the door open (See Figure K).
Figure K
 |
Step 8: Line up the Plegridy prefilled syringe over the titration clip with the plunger pointing to the left and the needle pointing to the right (See Figure L).
Figure L
 |
Step 9: Push the Plegridy prefilled syringe down into the titration clip until both ends “snap” into place (See Figure M).
Figure M
 |
Step 10: Using 2 fingers, push the door down until it closes over the Plegridy prefilled syringe (See Figure N).
Figure N
 |
Step 11: Check to make sure that the Plegridy prefilled syringe is in the titration clip the right way and that the door is tightly closed.
Figure O
 |
Giving the Plegridy injection:
Step 12: Choose your left or right thigh and wipe the skin with an alcohol wipe (See Figure P). Let the injection site dry before injecting the dose.
Figure P
 |
Step 13: Pull the protective cover straight off the needle (See Figure Q). Do not twist the cover off.
Figure Q
 |
Step 14: With 1 hand, stretch the skin out around the injection site. With the other hand, hold the syringe like a pencil. Use a quick dart-like motion and insert the needle at a 90° angle, through the skin and into the muscle (See Figure R). After the needle is in, let go of the skin.
Figure R
 |
Step 15: Slowly push the plunger all the way down until it touches the collar (See Figure S).
Figure S
 |
Step 16: Pull the needle out of the skin (See Figure T). Press down on the injection site with the gauze pad for a few seconds or rub gently in a circular motion.
Figure T
 |
After the Plegridy injection:
Check the injection site:
General information about the safe and effective use of Plegridy
 |
Instructions for Use
PLEGRIDY®
(PLEGG-rih-dee)
(peginterferon beta-1a) injection, for Subcutaneous Use
Single-Dose Prefilled Syringe 125 mcg
How to Inject your Plegridy Prefilled Syringe
Read this Instructions for Use before you start using Plegridy and each time you get a refill of your prescription. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.
Important Information
Follow this Instructions for Use for the Plegridy prefilled syringe for subcutaneous use (under the skin). There is a different Instructions for Use for the Plegridy prefilled syringe for intramuscular use (into the muscle).
Note:
How should I store Plegridy?
Supplies needed for your Plegridy Prefilled Syringe injection:
Figure A
 |
Additional supplies which are not included in the pack (See Figure B):
Figure B
 |
Preparing for your injection:
Step 1: Take your Plegridy Prefilled Syringe out of the refrigerator and let it come to roomtemperature for at least 30 minutes.
Step 2: Collect your supplies and wash your hands
Step 3: Check your Plegridy Prefilled Syringe
Figure D and Figure E
 |
Step 4: Choose and clean your injection site
Figure E
 |
Giving Your Injection:
Step 5: Remove the Plegridy Prefilled Syringe needle cover
Figure F
 |
Step 6: Gently pinch the injection site
Figure G
 |
Step 7: Give your Plegridy Prefilled Syringe injection
Figure H
 |
Figure I
 |
Figure J
 |
After Your Injection:
Step 8: Disposing of your used Plegridy Prefilled Syringes
Step 9: Check your injection site
Questions?
For product or service-related questions, call 1-800-456-2255 or go to www.plegridy.com.
