Plegridy
(peginterferon beta-1a)Dosage & Administration
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Plegridy Prescribing Information
PLEGRIDY is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.
Dosing Information
PLEGRIDY may only be administered subcutaneously (SC) or intramuscularly (IM).
Recommended Maintenance Dosage
After initial titration (see Table 1 and 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).
| Dose | Timea | 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).
| Dose | Timea | 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 |
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.
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.
Subcutaneous Administration:
- Injection: 125 mcg/0.5 mL in a single-dose prefilled pen or single-dose prefilled syringe
- Injection: 63 mcg/0.5 mL in a single-dose prefilled pen or a single-dose prefilled syringe
- Injection: 94 mcg/0.5 mL in a single-dose prefilled pen or a single-dose prefilled syringe
Intramuscular Administration:
- Injection: 125 mcg/0.5 mL in a single-dose prefilled syringe
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.
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.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
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.
Renal Impairment
Monitor for adverse reactions due to increased drug exposure in patients with severe renal impairment [see Clinical Pharmacology ( 12.3)].
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 ( 5.3)].
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.
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.
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.
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 ], 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
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.
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 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.
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.
Pulmonary Arterial Hypertension
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
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
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.