Rebif Side Effects

Generic Name: interferon beta-1a

Please note - some side effects for Rebif may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Rebif - for the Consumer

Rebif

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Rebif:

Drowsiness; flu-like symptoms (eg, headache, tiredness, fever, chills, back pain, muscle aches, weakness); pain, redness, or swelling at the injection site; stomach pain.

Seek medical attention right away if any of these SEVERE side effects occur when using Rebif:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); change in vision; chest pain; dark urine; depression; easy bruising or bleeding; extreme tiredness or weakness; fast or irregular heartbeat; feeling cold or hot all the time; infection at the injection site; seizures; suicidal thoughts or behaviors; unexplained change in weight; yellowing of the eyes or skin.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

Top

Rebif Side Effects - for the Professional

Rebif

The most frequently reported serious adverse reactions with Rebif® were psychiatric disorders including depression and suicidal ideation or attempt.  The incidence of depression of any severity in the Rebif®-treated groups and placebo-treated group was approximately 25%. 

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 symptom) were injection site disorders, influenza-like symptoms, depression and elevation of liver enzymes.

In Study 1, 6 patients randomized to Rebif® 44 mcg tiw (3%), and 2 patients who received Rebif® 22 mcg tiw (1%) developed injection site necrosis during two years of therapy.    Rebif® was continued in 7 patients and interrupted briefly in one patient. There was one report of injection site necrosis in Study 2 during 48 weeks of Rebif® treatment.  All events resolved with conservative management.

The rates of adverse reactions and association with Rebif® in patients with relapsing-remitting multiple sclerosis are drawn from the placebo-controlled study (n = 560) and the active comparator-controlled study (n = 339).

The population encompassed an age range 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.

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.

Table 3 enumerates adverse events 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	Rebif® 22 mcg tiw	Rebif® 44 mcg tiw
			Preferred Term	(n=187)	(n=189)	(n=184)
The adverse reactions were generally similar in Studies 1 and 2, taking into account the disparity in study durations.
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%
CENTRAL & PERIPH NERVOUS SYSTEM DISORDERS
	Hypertonia			5%	7%	6%
	Coordination Abnormal			2%	5%	4%
	Convulsions			2%	5%	4%
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%
	Hepatic Function Abnormal			2%	4%	9%
	Bilirubinaemia			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%
PSYCHIATRIC DISORDERS
	Somnolence			1%	4%	5%
SKIN DISORDERS
	Rash Erythematous			3%	7%	5%
	Rash Maculo-Papular			2%	5%	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%

Postmarketing Experience

In addition to adverse events reported from clinical trials, the following events have been reported during postmarketing use of Rebif®.  Because these reactions were reported voluntarily from a population of uncertain size, the frequency or a causal relationship to Rebif can not be reliably determined.

Blood and Lymphatic System Disorders: Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS).

Eye Disorders:  Retinal vascular disorders (i.e. retinopathy, cotton wool spots or obstruction of retinal artery or vein).

Hepatobiliary Disorders:  Rare cases of severe liver dysfunction, including hepatic failure requiring liver transplantation.

Nervous System:  Seizures.  Transient neurological symptoms (i.e., hypoesthesia, muscle spasm, paresthesia, difficulty walking, musculoskeletal stiffness) that mimic MS exacerbations of limited duration, temporally related to the injections and most prominent at the initiation of therapy. In some cases, these symptoms were associated with flu-like syndrome.

  

Psychiatric Disorders:  suicide.

Skin and Subcutaneous Tissue Disorders: Injection site abscesses, injecton site infections, including cellulitis and necrosis requiring debridement, systemic antibiotic treatment and/or grafting; erythema multiforme, and Stevens-Johnson syndrome.

Immunogenicity

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 tiw doses, respectively, at one or more times during the study.  The clinical significance of the presence of NAb to Rebif® is unknown.

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.

Anaphylaxis and other allergic reactions have been observed with the use of Rebif®.

Top

Side Effects by Body System - for Healthcare Professionals

General

In general, the use of interferon beta-1a in patients with multiple sclerosis is limited. It is probable that rarely occurring adverse effects may not have been reported to date.

The most commonly reported adverse effects associated with Avonex (R) have included influenza-like and other symptoms occurring within hours to days after an injection. Symptoms have included muscle aches, fever, chills, fatigue, headache, nausea, and vomiting. The most common side effects resulting in clinical intervention (e.g., treatment discontinuation or need for treatment due to adverse effects) were influenza-like symptoms and depression.

The most commonly reported serious side effects associated with Rebif (R) have included psychiatric disorders including depression and suicidal ideation or attempt. The most common side effects have included injection site disorders, influenza-like symptoms (headache, fatigue, fever, rigors, chest pain, back pain, myalgia), abdominal pain, depression, elevated liver enzymes, and hematologic abnormalities. The most common side effects resulting in clinical intervention (e.g., treatment discontinuation or need for treatment due to adverse effects) were injection site disorders, influenza-like symptoms, depression, and elevated liver enzymes.

Nervous system

Nervous system side effects have included headache (up to 70%), dizziness (up to 15%), hypertonia (up to 7%), seizures (up to 5%), abnormal coordination (up to 5%), migraine (up to 5%), sleep difficulty, muscle spasm, paresthesia, myasthenia, and extrapyramidal symptoms. Sudden hearing loss and tinnitus have been associated with interferon beta (the specific interferon beta was not identified in the case report). Ototoxic effects resolved 7 to 14 days after discontinuation of the drug. Transient neurological symptoms that may mimic multiple sclerosis exacerbations (i.e., hypoesthesia, muscle spasm, paresthesia, musculoskeletal stiffness, difficulty in walking) have been reported during postmarketing experience with Rebif (R).

In a placebo-controlled study, four patients receiving interferon beta-1a experienced a seizure, while none receiving placebo experienced a seizure. Three of four patients had no prior seizure history. However, a causal relationship with interferon beta-1a has not been confirmed.

Seizures and extrapyramidal symptoms were reported in a 21-year-old man with a history of Tourette's syndrome and Asperger's syndrome, who was recently diagnosed with multiple sclerosis. Generalized tonic-clonic seizures occurred on days 14 and 34 following the start of therapy with interferon beta-1a 30 mcg per week. Given this patient's other neurologic conditions require a drug regimen with multiple pharmacodynamic properties, it was difficult to establish causality. A new drug regimen without interferon beta-1a has prevented seizure activity and controlled his symptoms of Tourette's syndrome.

Other

A register nurse reported to the manufacturer that a 48-year-old female patient with stage 4 non-small cell lung cancer with metastases discontinued Avonex (R) due to chills, shaking, and difficulty breathing following injection. The registered nurse reported the lung cancer was not related to Avonex (R); however, causality for the other events was not assessed. Avonex (R) was discontinued prior to the patient's death due to lung cancer.

Other side effects have included influenza-like symptoms (up to 59%), fatigue (up to 41%), fever (up to 28%), asthenia (up to 24%), pain (up to 23%), chills/rigors (up to 19%), chest pain (up to 8%), abdominal pain (up to 8%), infection (up to 7%), malaise (up to 5%), and toothache (up to 3%). Chills and shaking following injection have been associated with Avonex (R).

Psychiatric

Psychiatric side effects have included depression (up to 25%), somnolence (up to 5%), suicidal ideation, new or worsening other psychiatric disorders (including psychosis), attempted suicide, and suicide.

Data from the SPECTRIMS (Secondary Progressive Efficacy Trial of Interferon beta-1a in MS) study suggest that depression is not a side effect of interferon beta-1a.

A case reported to the manufacturer pertained to a 62-year-old female patient on Avonex (R) for multiple sclerosis who was hospitalized for 2 to 3 days due to attempting suicide by overdosing on alprazolam. Treatment is unknown and the patient recovered. Avonex (R) therapy was not discontinued. Upon follow-up, the patient's neurologist confirmed hospitalization due to suicide attempt, but indicated she had overdosed on Valium (R). No further information was provided and the neurologist did not assess causality.

Local

Injection site reactions were reported more frequently by patients receiving Rebif (R) than in patients receiving Avonex (R) (83% vs. 28%, p less than 0.001) during the EVIDENCE Trial (EVidence of Interferon Dose-response: European North American Comparative Efficacy) where efficacy and safety of interferon beta-1a (Rebif (R)) 44 mcg subcutaneously three times weekly was compared against interferon beta-1a (Avonex (R)) 30 mcg intramuscularly once weekly in patients with relapsing-remitting multiple sclerosis (n=667).

Local side effects have included injection site reaction (up to 92%), inflammation at site of subcutaneous injection (up to 52%), injection site pain (up to 8%), injection site inflammation (up to 6%), and injection site necrosis (up to 4%). Subcutaneous injection sites were also associated with injection site necrosis, injection site atrophy, injection site edema, and injection site hemorrhage. Injection site abscesses and injection site infections (including severe cellulitis and necrosis requiring debridement, systemic antibiotic treatment, and/or grafting) have been reported during postmarketing experience.

Hepatic

Hepatic side effects have included elevated SGPT (up to 27%) and SGOT (up to 17%), abnormal hepatic function (up to 9%), autoimmune hepatitis, bilirubinemia (up to 3%), and jaundice. Severe liver injury, including some cases of hepatic failure requiring liver transplantation, has been reported rarely in patients receiving Rebif (R). Symptoms of liver dysfunction appeared from one to six months following the initiation of therapy. Hepatic injury, including cases of hepatic failure and elevated serum hepatic enzyme levels, has been reported during postmarketing experience with Avonex (R).

Fulminant liver failure occurring 7 weeks after the start of Rebif (R) therapy that required a liver transplantation has been reported in a patient who was also receiving nefazodone.

Asymptomatic elevation of hepatic transaminases has been reported, and in some patients has occurred upon rechallenge with Avonex (R).

Asymptomatic abnormalities of liver enzymes have been reported more frequently in patients receiving Rebif (R) compared with the patients receiving Avonex (R) (18% vs. 10%, p=0.002) during the EVIDENCE Trial (EVidence of Interferon Dose-response: European North American Comparative Efficacy) where efficacy and safety of interferon beta-1a (Rebif (R)) 44 mcg subcutaneously three times weekly was compared against interferon beta-1a (Avonex (R)) 30 mcg intramuscularly once weekly in patients with relapsing-remitting multiple sclerosis (n=667).

Hematologic

Hematologic side effects have included leukopenia (up to 36%), lymphadenopathy (up to 12%), thrombocytopenia (up to 8%), injection site ecchymosis (up to 6%), and anemia (up to 5%). Other hematologic side effects reported during the postmarketing of Avonex (R) have included decreased peripheral blood counts in all cell lines, including pancytopenia and thrombocytopenia.

Altered leukocyte counts were reported more frequently by patients receiving Rebif (R) than in patients receiving Avonex (R) (11% vs. 5%, p=0.003) during the EVIDENCE Trial (EVidence of Interferon Dose-response: European North American Comparative Efficacy) where efficacy and safety of interferon beta-1a (Rebif (R)) 44 mcg subcutaneously three times weekly was compared against interferon beta-1a (Avonex (R)) 30 mcg intramuscularly once weekly in patients with relapsing-remitting multiple sclerosis (n=667).

Gastrointestinal

Gastrointestinal side effects have included nausea (up to 23%), abdominal pain (up to 22%), dry mouth (up to 5%), and gastrointestinal upset (i.e., nausea, diarrhea, dyspepsia).

Cardiovascular

Cardiovascular side effects have included vasodilation (up to 2%). Congestive heart failure, cardiomyopathy, and cardiomyopathy with congestive heart failure have been reported, during postmarketing experience with Avonex (R), in patients without prior known history to these events. In some cases recurrence was observed upon rechallenge.

Musculoskeletal

Musculoskeletal side effects have included myalgia (up to 29%), back pain (up to 25%), skeletal pain (up to 15%), and arthralgia (up to 9%).

Hypersensitivity

Hypersensitivity side effects have included anaphylaxis and other allergic reactions (including dyspnea, orolingual edema, skin rash, and urticaria).

Respiratory

Respiratory side effects have included upper respiratory tract infection (up to 14%), sinusitis (up to 14%), and bronchitis (up to 8%). Difficulty breathing following injection has been associated with Avonex (R).

A register nurse reported to the manufacturer that a 48-year-old female patient with stage 4 non-small cell lung cancer with metastases discontinued Avonex (R) due to chills, shaking, and difficulty breathing following injection. The registered nurse reported the lung cancer was not related to Avonex (R); however, causality for the other events was not assessed. Avonex (R) was discontinued prior to the patient's death due to lung cancer.

Genitourinary

Genitourinary side effects have included urinary tract infection (up to 17%), micturition frequency (up to 7%), abnormal urine constituents (up to 3%), and urinary incontinence (up to 4%). Menorrhagia and metrorrhagia have been reported during postmarketing experience with Avonex (R).

Ocular

Ocular side effects have included eye disorder in 4% of patients treated with Avonex (R). Abnormal vision (up to 13%) and xerophthalmia (up to 3%) have been reported with Rebif (R). At least one case of retinopathy has been reported.

A 48-year-old female with relapsing-remitting multiple sclerosis experienced retinopathy coincident with interferon beta-1a therapy. Five months prior to presenting with blurry vision in the inferonasal quadrant of her right eye, the patient began interferon beta-1a 44 mcg subcutaneously three times per week. Dilated fundus examination showed cotton wool spots in the maculae of each eye. Therapy with interferon beta-1a was discontinued. Six weeks later a follow-up fundoscopic examination showed complete resolution of her cotton wool spots. Four years later, she remained without any symptoms and without recurrence of retinal findings.

Dermatologic

A 30-year-old woman developed severe widespread urticaria within 30 minutes of her second dose of interferon beta-1a. The patient had suspended therapy with interferon beta-1a due to pregnancy, and reinitiated her treatment 18 months later. Patient underwent prick and intradermal tests with 0.03 mL of the drug diluted in normal saline, starting with a concentration of 1:1000. She had a positive response to the most diluted concentration of the drug.

A 24-year-old female with multiple sclerosis experienced a 12-month history of subcutaneous nodules coincident with Rebif (R) therapy. These lesions became apparent during the early stages of pregnancy at which time she was taking a break from therapy. Prior to pregnancy, she had received 3 years of subcutaneous treatment, requiring injections of Rebif (R) 44 mcg three times weekly. The site of injection had included the thighs, abdomen, upper arms, and buttocks, although her preferred site of injection was the abdomen. The examination showed multiple 5 to 10 mm diameter firm subcutaneous nodules in a bandlike distribution across the lower abdomen, below the umbilicus. The subcutaneous nodules stayed palpable after 18 months. No further cutaneous adverse events developed once the site of injection was rotated without preference.

Dermatologic side effects have included erythematous rash (up to 7%), maculopapular rash (up to 5%), and alopecia (up to 4%). Rare reports of rash (including vesicular rash) have been reported during postmarketing experience. At least one case each of severe urticaria, calcified subcutaneous nodules, psoriasis, and periungual and nail alterations have been reported.

Immunologic

Immunologic side effects have included reports of autoimmune disorders of multiple target organs (including idiopathic thrombocytopenia, hyperthyroidism, hypothyroidism, seizures, and autoimmune hepatitis) during postmarketing experience. Serum neutralizing antibodies (NAb) have been detected in up to 31% of patients treated with Rebif (R) and up to 5% of patients treated with Avonex (R). The clinical significance of the presence of NAb is unknown. A small preliminary study suggests that switching these patients to alternate interferon beta preparations may not be clinically beneficial. At least one case of subacute cutaneous lupus erythematosus has been reported.

Subacute cutaneous lupus erythematosus was confirmed in a 43-year-old white man with a long history of multiple sclerosis. He had received interferon beta-1a 3 million international units weekly for 5 months and listed no family history of autoimmune diseases.

Autoimmune hepatitis in a 38-year-old female treated with Avonex (R) has been reported to occur after 24 months of treatment.

Neutralizing antibodies developed in up to 31% receiving Rebif (R) and up to 5% of patients receiving Avonex (R) during the EVIDENCE Trial (EVidence of Interferon Dose-response: European North American Comparative Efficacy) where efficacy and safety of interferon beta-1a (Rebif (R)) 44 mcg subcutaneously three times weekly was compared against interferon beta-1a (Avonex (R)) 30 mcg intramuscularly once weekly in patients with relapsing-remitting multiple sclerosis (n=667).

Endocrine

Endocrine side effects have included thyroid disorder (up to 6%).

Top

Disclaimer: Every effort has been made to ensure that the information provided is accurate, up-to-date, and complete, but no guarantee is made to that effect. In addition, the drug information contained herein may be time sensitive and should not be utilized as a reference resource beyond the date hereof. This information does not endorse drugs, diagnose patients, or recommend therapy. This drug information is a reference resource designed as supplement to, and not a substitute for, the expertise, skill , knowledge, and judgement of healthcare practitioners in patient care. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug of drug combination is safe, effective, or appropriate for any given patient. Drugs.com does not assume any responsibility for any aspect of healthcare administered with the aid of information provided. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse, or pharmacist.