PLEGRIDY

Sclerosis (MS) is a chronic and inflammatory autoimmune disease of the central nervous system, disrupting communication between the brain and other parts of the body.

Most patients diagnosed with this illness experience their initial disease symptoms between the age of 20-40, often the most productive years of life.

Symptoms may include but are not limited to fatigue, gait changes, bowel or bladder dysfunction, abnormal muscle twitching, vision disturbance, and depressing or mood swings.

MS is one of the most common causes of neurological disability in young adults and is found to occur more frequently in women than in men. 3, 12 Peginterferon beta-1a is an interferon therapy used for the management of relapsing forms of MS.

It was originally approved by the

FDA in for subcutaneous use, and was approved for intramuscular use in January 2021.

Currently, it is the only approved pegylated interferon for the management of MS with an proven ability to reduce relapses and delay the progression of disability resulting from MS.

Peginterferon beta-1a is indicated for the treatment of adult patients with relapsing forms of MS, including relapsing-remitting disease, clinically isolated syndrome, and active progressive secondary disease.

Peginterferon beta-1a likely reduces MS relapses and the progression of disability and brain lesions associated with MS by reducing inflammation. 8, 4 Specifically, IFN-beta decreases antigen presentation and T-cell proliferation.

In addition, it modifies cytokine and matrix metalloproteinase (MMP) expression while restoring suppressor function.

The mechanism by which peginterferon beta-1a exerts its effects in patients with multiple sclerosis is unknown 13, however, it likely exerts its therapeutic actions by reducing inflammation.

Through the binding of

IFN-beta to its receptor 9, a cascade of transcriptional events occur, decreasing the inflammation that normally results in the progression of MS.

Immune cells are the most likely target of therapeutic effects exerted by IFN-beta.

Interferon alpha/beta receptor 1 activator downregulator Humans.

Peginterferon beta-1a is almost completely absorbed after subcutaneous administration.

After 125 microgram subcutaneous doses of peginterferon beta-1a to patient with MS, a Cmax of 280 pg/mL was reached between and 1.5 days 4, and the AUC over a 14 day dosing interval was 34.8 ng.hr/mL.

AUC ranges from 23.5-29.5 ng ml −1 h, according to one pharmacokinetic study of patients with MS.

Impairment of renal function may alter the Cmax and AUC of interferon beta-1a.

The volume of distribution of peginterferon beta-1a is about 481 L.

One pharmacokinetic study of patients administered interferon beta-1a revealed a volume of distribution in the range of 248-726 L, depending on the week of treatment.

Peginterferon beta-1a is not extensively metabolized in the liver.

Peginterferon beta-1a is mainly cleared through the kidneys. 4, 13.

The mean half life of peginterferon beta-1a is approximately 78 h in patients with MS 15, however, the half-life is highly variable and depends on duration of treatment and other factors.

The average steady state clearance of peginterferon beta-1a is about 4.1 L/h.

One pharmacokinetic study revealed a clearance within the range of 3.68-7.89 L/h, depending on the week of treatment.

Improve decision support & research outcomes With structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates.

View sample adverse effects data in our new Data Library! See the data Improve decision support & research outcomes with our structured adverse effects data.

LD50 information for peginterferon beta-1a is not readily available in the literature.

In clinical trials, no cases of overdoses occurred with the administration of interferon beta-1a at a dose of 75 μg administered Subcutaneous 3 times a week.

In a case report, a 38-year-old patient attempted suicide with about 6 or 7 pre-filled syringes containing 44 mug (12 MIU) of subcutaneous interferon beta-1a; symptoms were limited to malaise and skin erythema, which resolved within 24 hours with no intervention.

Laboratory test results were unremarkable.

In the case of an overdose with interferon-beta 1a, prescribing information suggests to contact the local poison control centre.

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

History of hypersensitivity to natural or recombinant interferon beta or peginterferon, or any other component of PLEGRIDY.

For subcutaneous or intramuscular use only

Recommended dose: 125 micrograms every 14 days 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 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 Analgesics and/or antipyretics on treatment days may help ameliorate flu-like symptoms 2.1 Dosing Information PLEGRIDY may only be administered subcutaneously (SC) or intramuscularly (IM).

After initial titration, 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.

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.

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 On day 1 63 Orange Dose On day 15 94 Blue Dose On day 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.

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).

Table 2: Schedule for Intramuscular Dose Titration Dose Time a Amount (micrograms) Titration Clip a Dosed every 14 days Dose On day 1 63 Yellow Dose On day 15 94 Purple Dose On day 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.

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.

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.

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).

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).

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).

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.

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.

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.

In a study in pregnant monkeys, administration of interferon beta during pregnancy resulted in an increased rate of abortion.

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.

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.

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 to 5 doses.

Safety and effectiveness in pediatric patients have not been established.

Clinical studies of

PLEGRIDY did not include sufficient numbers of subjects aged 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.