Interferon beta-1a

12.1 Mechanism of Action The mechanism(s) by which REBIF (interferon beta-1a) exerts its therapeutic effects in patients with multiple sclerosis is unknown.

1 INDICATIONS 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 )

2 DOSAGE 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 [see Warnings and Precautions (5.4) ] 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.

6 ADVERSE 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 [see Warnings and Precautions (5) ] . 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 [see Warnings and Precautions (5.3) ] . 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