INTERFERON BETA-1A: 67,471 Adverse Event Reports & Safety Profile

REBIF (interferon beta-1a) is a purified 166 amino acid glycoprotein with a molecular weight of approximately 22,500 daltons. It is produced by recombinant DNA technology using genetically engineered Chinese Hamster Ovary cells into which the human interferon beta gene has been introduced. The amino acid sequence of REBIF is identical to that of natural fibroblast derived human interferon beta. Natural interferon beta and interferon beta-1a (REBIF) are glycosylated with each containing a single N-linked complex carbohydrate moiety. Using a reference standard calibrated against the World Health Organization natural interferon beta standard (Second International Standard for Interferon, Human Fibroblast GB 23 902 531), REBIF has a specific activity of approximately 270 million international units (MIU) of antiviral activity per mg of interferon beta-1a determined specifically by an in vitro cytopathic effect bioassay using WISH cells and Vesicular Stomatitis virus. REBIF 8.8 mcg, 22 mcg and 44 mcg contains approximately 2.4 million international units, 6 million international units or 12 million international units, respectively, of antiviral activity using this method. REBIF (interferon beta-1a) is formulated as a sterile solution in a prefilled syringe or REBIF Rebidose autoinjector intended for subcutaneous (sc) injection.

Each

0.5 mL (0.5 cc) of REBIF contains either 22 mcg or 44 mcg of interferon beta-1a, 2 mg or 4 mg albumin (human), 27.3 mg mannitol, 0.4 mg sodium acetate, and water for injection.

Each

0.2 mL (0.2 cc) of REBIF contains 8.8 mcg of interferon beta-1a, 0.8 mg albumin (human), 10.9 mg mannitol, 0.16 mg sodium acetate, and water for injection.

AND USAGE REBIF 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. Rebif is an interferon beta 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. ( 1 )

AND ADMINISTRATION For subcutaneous injection only ( 2.1 ) The recommended dose is either 22 mcg or 44 mcg injected subcutaneously three times per week ( 2.1 ) Titration: Generally, the starting dose should be 20% of the prescribed dose three times per week, and increased over a 4 week period to the targeted recommended dose of either 22 mcg or 44 mcg injected subcutaneously three times per week ( 2.1 ) Analgesics and/or antipyretics on treatment days may help ameliorate flu-like symptoms ( 2.3 )

2.1 Dosing Information The recommended dose of REBIF is either 22 mcg or 44 mcg injected subcutaneously three times per week. REBIF should be administered, if possible, at the same time (preferably in the late afternoon or evening) on the same three days (e.g., Monday, Wednesday, and Friday) at least 48 hours apart each week. Generally, patients should be started at 20% of the prescribed dose three times per week and increased over a 4-week period to the targeted dose, either 22 mcg three times per week (see Table 1 ) or 44 mcg three times per week (see Table 2 ). Patients prescribed a targeted dose of 22 mcg three times per week should use the prefilled syringes for titration. A Titration Pack containing 6 doses of 8.8 mcg (0.2 mL) and 6 doses of 22 mcg (0.5 mL) is available for use during the titration period in both REBIF prefilled syringes and REBIF Rebidose autoinjectors.

Table

1: Titration Schedule for a 22 mcg Prescribed Dose Use only prefilled syringes, not autoinjectors, to titrate to the 22 mcg Prescribed Dose Week of Use Dose Syringe to Use Amount of syringe Week 1 Titration 4.4 mcg 8.8 mcg syringe Use half of syringe Week 2 Titration 4.4 mcg 8.8 mcg syringe Use half of syringe Week 3 Titration 11 mcg 22 mcg syringe Use half of syringe Week 4 Titration 11 mcg 22 mcg syringe Use half of syringe Week 5 and after 22 mcg 22 mcg syringe or autoinjector Use full syringe or autoinjector Table 2: Titration Schedule for a 44 mcg Prescribed Dose Prefilled syringes or autoinjectors can be used to titrate to the 44 mcg Prescribed Dose Week of Use Dose Syringe or Autoinjector to Use Amount of syringe or autoinjector Week 1 Titration 8.8 mcg 8.8 mcg syringe or autoinjector Use full syringe or autoinjector Week 2 Titration 8.8 mcg 8.8 mcg syringe or autoinjector Use full syringe or autoinjector Week 3 Titration 22 mcg 22 mcg syringe or autoinjector Use full syringe or autoinjector Week 4 Titration 22 mcg 22 mcg syringe or autoinjector Use full syringe or autoinjector Week 5 and after 44 mcg 44 mcg syringe or autoinjector Use full syringe or autoinjector Decreased peripheral blood counts or elevated liver function tests may necessitate dose reduction or discontinuation of REBIF administration until toxicity is resolved [see Warnings and Precautions (5.2 , 5.5) and Adverse Reactions (6) ].

2.2 Important Administration Instructions REBIF is intended for use under the guidance and supervision of a physician. It is recommended that physicians or qualified medical personnel train patients in the proper technique for self-administering subcutaneous injections using the prefilled syringe or injection device approved for use with REBIF. Injection depth of the REBIF Rebidose autoinjector is fixed at 8 mm; the healthcare provider should determine the injection technique. The initial injection should be performed under the supervision of an appropriately qualified healthcare provider. Appropriate instruction for self-injection or injection by another person should be provided to the patient or their caregiver, including careful review of the REBIF Medication Guide and the REBIF Rebidose autoinjector Instructions for Use that accompanies the product. Users should demonstrate competency in all aspects of the injection prior to independent use. If a patient is to self-administer REBIF, the physical and cognitive ability of that patient to self-administer and properly dispose of prefilled syringes or the REBIF Rebidose autoinjectors should be assessed. Patients with severe neurological deficits should not self-administer injections without assistance from a trained caregiver. Advise patients and caregivers to: visually inspect REBIF for particulate matter and discoloration prior to administration use aseptic technique when administering REBIF rotate site of injection with each dose to minimize the likelihood of severe injection site reactions, including necrosis or localized infection <span class="opacity-50 text-xs">[see Warnings and Precautions (5.4) ]</span> use a puncture-resistant container for safe disposal of used needles, prefilled syringes and REBIF Rebidose autoinjectors do not re-use needles, syringes or REBIF Rebidose autoinjectors

2.3 Premedication for Flu-like Symptoms Concurrent use of analgesics and/or antipyretics may help ameliorate flu-like symptoms associated with REBIF use on treatment days.

AVONEX is contraindicated in patients with a history of hypersensitivity to natural or recombinant interferon beta, or any other component of the formulation [see Warnings and Precautions ( 5.3 )] . The formerly available lyophilized vial formulation of AVONEX is contraindicated in patients with a history of hypersensitivity to albumin (human). History of hypersensitivity to natural or recombinant interferon beta, albumin or any other component of the formulation ( 4 )

REACTIONS The following adverse reactions are discussed in more detail in the Warnings and Precautions section of the label: Depression and Suicide [see Warnings and Precautions (5.1) ]

Hepatic

Injury [see Warnings and Precautions (5.2) ] Anaphylaxis and Other Allergic Reactions [see Warnings and Precautions (5.3) ]

Injection Site

Reactions including Necrosis [see Warnings and Precautions (5.4) ]

Decreased Peripheral Blood

Counts [see Warnings and Precautions (5.5) ]

Thrombotic

Microangiopathy [see Warnings and Precautions (5.6) ]

Pulmonary Arterial

Hypertension [ see Warnings and Precautions (5.7) ] Seizures [see Warnings and Precautions (5.8) ]

Laboratory

Tests [see Warnings and Precautions (5.9) ] The most common adverse reactions in controlled clinical trials were injection site disorders, influenza-like symptoms, abdominal pain, depression, elevation of liver enzymes and hematologic abnormalities ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact EMD Serono at 1-800-283-8088 ext. 5563 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of REBIF cannot be directly compared to rates in the clinical trials of other drugs and may not reflect the rates observed in practice. A total of 712 patients with relapsing-remitting multiple sclerosis (RRMS) in two controlled clinical trials took REBIF (22 mcg or 44 mcg given three times per week) [ see Clinical Studies (14) ]. Ages ranged from 18 to 55 years. Nearly three-fourths of the patients were female, and more than 90% were Caucasian, largely reflecting the general demographics of the population of patients with multiple sclerosis. The most commonly reported adverse reactions were injection site disorders, influenza-like symptoms (headache, fatigue, fever, rigors, chest pain, back pain, myalgia), abdominal pain, depression, elevation of liver enzymes and hematologic abnormalities. The most frequently reported adverse reactions resulting in clinical intervention (e.g., discontinuation of REBIF, adjustment in dosage, or the need for concomitant medication to treat an adverse reaction were injection site disorders, influenza-like symptoms, depression, and elevation of liver enzymes <span class="opacity-50 text-xs">[see Warnings and Precautions (5) ]</span> .

Study

1 was a 2-year placebo-controlled study in RRMS patients treated with REBIF 22 mcg (n=189), 44 mcg (n=184), or placebo (n=187).

Table

3 enumerates adverse reactions and laboratory abnormalities that occurred at an incidence that was at least 2% more in either REBIF-treated group than was observed in the placebo group.

Table

3.

Adverse

Reactions and Laboratory Abnormalities in Study 1 Body System Placebo tiw (n=187) REBIF 22 mcg tiw (n=189) REBIF 44 mcg tiw (n=184)

Preferred

Term % % % BODY AS A WHOLE Influenza-like symptoms 51 56 59 Headache 63 65 70 Fatigue 36 33 41 Fever 16 25 28 Rigors 5 6 13 Chest pain 5 6 8 Malaise 1 4 5 INJECTION SITE DISORDERS Injection Site Reaction 39 89 92 Injection Site Necrosis 0 1 3 NERVOUS SYSTEM DISORDERS Hypertonia 5 7 6 Coordination Abnormal 2 5 4 Convulsions 2 5 4 Somnolence 1 4 5 ENDOCRINE DISORDERS Thyroid Disorder 3 4 6 GASTROINTESTINAL SYSTEM DISORDERS Abdominal Pain 17 22 20 Dry Mouth 1 1 5 LIVER AND BILIARY SYSTEM DISORDERS SGPT Increased 4 20 27 SGOT Increased 4 10 17 Bilirubinemia 1 3 2 MUSCULO-SKELETAL SYSTEM DISORDERS Myalgia 20 25 25 Back Pain 20 23 25 Skeletal Pain 10 15 10 HEMATOLOGIC DISORDERS Leukopenia 14 28 36 Lymphadenopathy 8 11 12 Thrombocytopenia 2 2 8 Anemia 3 3 5 SKIN DISORDERS Rash Erythematous 3 7 5 Rash Maculo-Papular 2 5 4 Hyperhidrosis 2 4 4 URINARY SYSTEM DISORDERS Micturition Frequency 4 2 7 Urinary Incontinence 2 4 2 VISION DISORDERS Vision Abnormal 7 7 13 Xerophthalmia 0 3 1 Adverse reactions in Study 2, a 1-year active-controlled (vs. interferon beta-1a, 30 mcg once weekly intramuscular injection, n=338) study including 339 patients with MS treated with REBIF were generally similar to those in Study 1, taking into account the disparity in study durations.

6.2 Immunogenicity Anaphylaxis and other allergic reactions have been observed with the use of REBIF <span class="opacity-50 text-xs">[see Warnings and Precautions (5.3) ]</span> . As with all therapeutic proteins, there is a potential for immunogenicity.

In Study

1, the presence of neutralizing antibodies (NAb) to REBIF was determined by collecting and analyzing serum pre-study and at 6 month time intervals during the 2 years of the clinical trial. Serum NAb were detected in 59/189 (31%) and 45/184 (24%) of REBIF-treated patients at the 22 mcg and 44 mcg three times per week doses, respectively, at one or more times during the study. The data reflect the percentage of patients whose test results were considered positive for antibodies to REBIF using an antiviral cytopathic effect assay, and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of NAb positivity in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of the incidence of antibodies to REBIF with the incidence of antibodies to other products may be misleading.

6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of REBIF. 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.

Autoimmune

Disorders: Drug-induced lupus erythematosus , autoimmune hepatitis Eye Disorders: Retinal vascular disorders (i.e. retinopathy, cotton wool spots or obstruction of retinal artery or vein) Respiratory, Thoracic and mediastinal disorders: Pulmonary Arterial Hypertension Skin and Subcutaneous Tissue Disorders: Erythema multiforme, Stevens-Johnson syndrome Blood and Lymphatic System Disorders: Hemolytic anemia

AND PRECAUTIONS Depression and Suicide: Advise patients to immediately report any symptoms of depression and/or suicidal ideation; consider discontinuation of REBIF if depression occurs ( 5.1 )

Hepatic

Injury: Monitor liver function tests; monitor patients for signs and symptoms of hepatic injury; consider discontinuing REBIF if hepatic injury occurs ( 5.2 ) Anaphylaxis and Other Allergic Reactions: Discontinue REBIF if anaphylaxis occurs ( 5.3 )

Injection Site Reactions Including

Necrosis: Do not administer REBIF into affected area until fully healed; if multiple lesions occur, change injections sites or discontinue REBIF until healing of skin lesions ( 5.4 )

Decreased Peripheral Blood

Counts: Monitor complete blood counts ( 5.5 )

Thrombotic

Microangiopathy: Cases of thrombotic microangiopathy have been reported. Discontinue REBIF if clinical symptoms and laboratory findings consistent with TMA occur ( 5.6 ).

Pulmonary Arterial

Hypertension: Cases of pulmonary arterial hypertension (PAH) have been reported in patients treated with interferon beta products, including REBIF. Discontinue REBIF if PAH is diagnosed ( 5.7 ) Seizures: Monitor for seizures when administering REBIF to patients, particularly those with pre-existing seizure disorders ( 5.8 )

5.1 Depression and Suicide REBIF (interferon beta-1a) should be used with caution in patients with depression, a condition that is common in people with multiple sclerosis. Depression, suicidal ideation, and suicide attempts have been reported to occur with increased frequency in patients receiving interferon compounds, including REBIF. In addition, there have been postmarketing reports of suicide in patients treated with REBIF. Patients should be advised to report immediately any symptoms of depression and/or suicidal ideation to the prescribing physician. If a patient develops depression, cessation of treatment with REBIF should be considered.

5.2 Hepatic Injury Severe liver injury, including some cases of hepatic failure requiring liver transplantation, has been reported rarely in patients taking REBIF. Symptoms of liver dysfunction began from one to six months following the initiation of REBIF. If jaundice or other symptoms of liver dysfunction appear, treatment with REBIF should be discontinued immediately due to the potential for rapid progression to liver failure. Asymptomatic elevation of hepatic transaminases (particularly SGPT) is common with interferon therapy <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . REBIF should be initiated with caution in patients with active liver disease, alcohol abuse, increased serum SGPT (&gt; 2.5 times ULN), or a history of significant liver disease. Also, the potential risk of REBIF used in combination with known hepatotoxic products should be considered prior to REBIF administration, or when adding new agents to the regimen of patients already on REBIF. Reduction of REBIF dose should be considered if SGPT rises above 5 times the upper limit of normal. The dose may be gradually re-escalated when enzyme levels have normalized <span class="opacity-50 text-xs">[see Warnings and Precautions (5.9) and Dosage and Administration (2.1) ]</span>.

5.3 Anaphylaxis and Other Allergic Reactions Anaphylaxis has been reported as a rare complication of REBIF use. Other allergic reactions have included skin rash and urticaria, and have ranged from mild to severe without a clear relationship to dose or duration of exposure. Several allergic reactions, some severe, have occurred after prolonged use. Discontinue REBIF if anaphylaxis occurs.

5.4 Injection Site Reactions Including Necrosis Injection site reactions, including injection site necrosis, can occur with the use of interferon beta products, including REBIF. In controlled clinical trials, injection site reactions occurred more frequently in REBIF-treated patients (92% in the 44 mcg group and 89% in the 22 mcg group) than in placebo-treated patients (39%) and at a higher frequency in REBIF treated patients (83%) than in AVONEX-treated patients (28%). Injection site necrosis also occurred more frequently in REBIF-treated patients (3% in the 44 mcg group and 1% in the 22 mcg group) than in placebo- treated patients (0) during the two years of therapy. Injection site reactions including injection site pain, erythema, edema, cellulitis, abscess, and necrosis have been reported in the postmarketing setting. Some occurred more than 2 years after initiation of REBIF. Necrosis occurred at single and at multiple injection sites. Some cases of injection site necrosis required treatment with intravenous antibiotics and surgical intervention (debridement and skin grafting). Some cases of injection site abscesses and cellulitis required treatment with hospitalization for surgical drainage and intravenous antibiotics. Patient understanding and use of aseptic self-injection techniques and procedures should be periodically evaluated, particularly if injection site necrosis has occurred. Patients should be advised of the importance of rotating sites of injection with each dose and not reusing syringes. Patients should be advised against injecting an area which is inflamed, edematous, erythematous, ecchymotic, or has any other signs of infection. These signs should be reported to a healthcare professional immediately. If multiple lesions occur, change injection site or discontinue therapy until healing occurs.

5.5 Decreased Peripheral Blood Counts Decreased peripheral blood counts in all cell lines, including pancytopenia, have been reported in REBIF-treated patients. In controlled clinical trials, leukopenia occurred at a higher frequency in REBIF-treated patients (36% in 44 mcg group and 28% in 22 mcg group) than in placebo-treated patients (14%) and at a higher frequency in REBIF-treated patients (6%) compared to the AVONEX-treated patients (&lt;1%). Thrombocytopenia and anemia occurred more frequently in 44 mcg REBIF-treated patients (8% and 5%, respectively) than in placebo-treated patients (2% and 3%, respectively). In a pooled analysis of 7 placebo controlled trials with REBIF doses of 22 mcg or 44 mcg, the rate of pancytopenia (in subjects with normal baseline values who developed laboratory values less than the lower limit of normal for all 3 hematology parameters simultaneously) was higher in the total REBIF group (5.5 per 1000 subject-year) than in the placebo group (1.2 per 1000 subject-year). Patients should be monitored for symptoms or signs of decreased blood counts. Monitoring of complete blood and differential white blood cell counts is also recommended <span class="opacity-50 text-xs">[see Dosage and Administration (2.1) and Warnings and Precautions (5.9) ]</span>.

5.6 Thrombotic Microangiopathy Cases of thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, some fatal, have been reported with interferon beta products, including REBIF. Cases have been reported several weeks to years after starting interferon beta products. Discontinue REBIF if clinical symptoms and laboratory findings consistent with TMA occur, and manage as clinically indicated.

5.7 Pulmonary Arterial Hypertension Cases of pulmonary arterial hypertension (PAH) have been reported with interferon beta products, including REBIF. 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.

5.8 Seizures Caution should be exercised when administering REBIF to patients with pre-existing seizure disorders. Seizures have been temporally associated with the use of beta interferons, including REBIF, in clinical trials and in postmarketing reports.

5.9 Laboratory Tests In addition to those laboratory tests normally required for monitoring patients with multiple sclerosis, blood cell counts and liver function tests are recommended at regular intervals (1, 3, and 6 months) following introduction of REBIF therapy and then periodically thereafter in the absence of clinical symptoms. Patients with myelosuppression may require more intensive monitoring of complete blood cell counts, with differential and platelet counts <span class="opacity-50 text-xs">[see Dosage and Administration (2.1) and Warnings and Precautions (5.5) ]</span> . New or worsening thyroid abnormalities have developed in some patients treated with REBIF. Thyroid function tests are recommended every 6 months in patients with a history of thyroid dysfunction or as clinically indicated.