Plegridy

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.

• For subcutaneous or intramuscular use only (
  2.1 Dosing Information

  PLEGRIDY may only be administered subcutaneously (SC) or intramuscularly (IM).

  Recommended Maintenance Dosage

  After initial titration (see Table 1and Table 2), the recommended dosage of PLEGRIDY is 125 micrograms injected every 14 days.

  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. 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
  aDosed 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
  aDosed 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
  )
• Recommended dose: 125 micrograms every 14 days (
  2.1 Dosing Information

  PLEGRIDY may only be administered subcutaneously (SC) or intramuscularly (IM).

  Recommended Maintenance Dosage

  After initial titration (see Table 1and Table 2), the recommended dosage of PLEGRIDY is 125 micrograms injected every 14 days.

  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. 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
  aDosed 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
  aDosed 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
  )
• PLEGRIDY dose should be titrated, starting with 63 micrograms on day 1, 94 micrograms on day 15, and 125 micrograms (full dose) on day 29 (
  2.1 Dosing Information

  PLEGRIDY may only be administered subcutaneously (SC) or intramuscularly (IM).

  Recommended Maintenance Dosage

  After initial titration (see Table 1and Table 2), the recommended dosage of PLEGRIDY is 125 micrograms injected every 14 days.

  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. 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
  aDosed 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
  aDosed 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
  )
• A healthcare professional 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 (
  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

  ].

  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.
  )
• Analgesics and/or antipyretics on treatment days may help ameliorate flu-like symptoms (
  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.
  )

PLEGRIDY is a clear to slightly opalescent and colorless to slightly yellow solution.

• Pregnancy: Epidemiological data do not suggest a clear relationship between interferon beta use and major congenital malformations, but interferon beta may cause fetal harm based on animal data (
  8.1 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.
  )
• Severe Renal Impairment: monitor for adverse reactions (
  8.6 Renal Impairment

  Monitor for adverse reactions due to increased drug exposure in patients with severe renal impairment [

  see Clinical Pharmacology (

  12.3

  )

  ].
  )