Ribasphere Side Effects

Generic Name: ribavirin

Please note - some side effects for Ribasphere may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA at http://www.fda.gov/medwatch/ or 1-800-FDA-1088 (1-800-332-1088).

Side Effects of Ribasphere - for the Consumer

Ribasphere

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 Ribasphere:

Blurred vision; cough; diarrhea; dizziness; dry mouth; dry skin; hair loss; joint pain; loss of appetite; mild headache, nausea, or vomiting; tiredness; trouble sleeping; upset stomach; weakness or fatigue.

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); black, tarry stools; changes in vision or speech; chest pain; confusion; dark urine; decrease in the amount of urine; depression; fever, chills, or sore throat; irregular heartbeat; memory problems; muscle pain or weakness; numbness or tingling of arms or legs; one-sided weakness; prolonged nausea and vomiting; rapid breathing; severe headache, dizziness, or vomiting; severe stomach or back pain; shortness of breath; sinus problems; thoughts of suicide; unusual bruising or bleeding; unusual mental or mood changes; unusual or severe tiredness and fatigue; vomit that looks like coffee grounds; weight loss; yellowing of eyes or skin.

Ribasphere Capsules

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 Ribasphere Capsules:

Cough; diarrhea; dizziness; dry mouth; dry skin; loss of appetite; mild headache, nausea, or vomiting; mild pain, redness, or swelling at the injection site; tiredness; upset stomach; weakness or fatigue.

Severe allergic reactions (rash; hives; itching; difficulty breathing; itching; tightness in the chest; swelling of the mouth, face, lips, or tongue); black, tarry stools; changes in hearing, taste, or vision; chest pain; dark urine; decrease in the amount of urine; fever, chills, or sore throat; hair loss; irregular heartbeat; joint pain; muscle pain or weakness; numbness or tingling of arms or legs; prolonged nausea and vomiting; rapid breathing; severe headache; severe stomach or back pain; shortness of breath; sinus problems; thoughts of suicide; trouble sleeping; unusual bruising or bleeding; unusual mental or mood changes; unusual or severe tiredness and fatigue; vomit that looks like coffee grounds; weight loss; yellowing of eyes or skin.

Ribasphere Side Effects - for the Professional

Ribasphere

The primary toxicity of ribavirin is hemolytic anemia. Reductions in hemoglobin levels occurred within the first 1 to 2 weeks of oral therapy. Cardiac and pulmonary events associated with anemia occurred in approximately 10% of patients.

Ribavirin/INTRON A Combination Therapy

In clinical trials, 19% and 6% of previously untreated and relapse patients, respectively, discontinued therapy due to adverse events in the combination arms compared to 13% and 3% in the interferon arms. Selected treatment-emergent adverse events that occurred in the US studies with >5% incidence are provided in TABLE 5 by treatment group. In general, the selected treatment-emergent adverse events reported with lower incidence in the international studies as compared to the US studies with the exception of asthenia, influenza-like symptoms, nervousness, and pruritus.

In addition, the following spontaneous adverse events have been reported during the marketing surveillance of ribavirin/INTRON A therapy: hearing disorder and vertigo.

Ribavirin/PEG-INTRON (peginterferon alfa-2b, recombinant) Combination Therapy

Overall, in clinical trials, 14% of patients receiving ribavirin in combination with PEG-INTRON, discontinued therapy compared with 13% treated with ribavirin in combination with INTRON A (interferon alfa-2b, recombinant). The most common reasons for discontinuation of therapy were related to psychiatric, systemic (e.g., fatigue, headache), or gastrointestinal adverse events. Adverse events that occurred in clinical trial at >5% incidence are provided in TABLE 6 by treatment group. Safety and effectiveness of Ribavirin capsules in combination with PEG-INTRON has not been established in pediatric patients.

Laboratory Values

Changes in selected hematologic values (hemoglobin, white blood cells, neutrophils, and platelets) during therapy are described below.

Hemoglobin

Hemoglobin decreases among patients receiving ribavirin therapy began at Week 1, with stabilization by Week 4. In previously untreated patients treated for 48 weeks the mean maximum decrease from baseline was 3.1 g/dL in the US study and 2.9 g/dL in the International study. In relapse patients the mean maximum decrease from baseline was 2.8 g/dL in the US study and 2.6 g/dL in the International study. Hemoglobin values returned to pretreatment levels within 4 to 8 weeks of cessation of therapy in most patients.

Bilirubin and Uric Acid

Increases in both bilirubin and uric acid, associated with hemolysis, were noted in clinical trials. Most were moderate biochemical changes and were reversed within 4 weeks after treatment discontinuation. This observation occurs most frequently in patients with a previous diagnosis of Gilbert’s syndrome. This has not been associated with hepatic dysfunction or clinical morbidity.

Changes in selected hematologic values (hemoglobin, white blood cells, neutrophils, and platelets) during therapy are described below.

Hemoglobin

Ribavirin induced a decrease in hemoglobin levels in approximately two thirds of patients. Hemoglobin levels decreased to <11 g/dL in about 30% of patients. Severe anemia (<8 g/dL) occurred in <1% of patients. Dose modification was required in 9 and 13% of patients in the PEG-INTRON/ribavirin and INTRON A Injection/ribavirin groups.

Bilirubin and Uric Acid

In the ribavirin/PEG-INTRON combination trial 10 to 14% of patients developed hyperbilirubenemia and 33 to 38% developed hyperuricemia in association with hemolysis. Six patients developed mild to moderate gout.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of ribavirin in combination with INTRON A or PEG-INTRON therapy: hearing disorder, vertigo, aplastic anemia and pure red cell aplasia. Because these reactions are reported voluntarily from a population of an uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Side Effects by Body System

General

The most common life-threatening or fatal side effects associated with ribavirin-peginterferon therapy have included depression, suicide, relapse of drug abuse/overdose, bacterial infections, and hepatic decompensation.

The most common serious side effects in CHC monoinfected and CHC-HIV coinfected patients have included bacterial infections.

Common side effects reported in CHC-HIV coinfected patients receiving ribavirin-peginterferon have included neutropenia, anemia, thrombocytopenia, weight, decrease, and mood alteration.

Side effects with aerosolized ribavirin are rare.

Respiratory

Patients with chronic obstructive pulmonary disease or asthma receiving aerosolized ribavirin have been reported to experience deterioration of pulmonary functions, dyspnea, and chest soreness. Mechanically ventilated patients may also be predisposed to respiratory deterioration. Minor changes in pulmonary function tests have been reported in healthy volunteers receiving aerosolized ribavirin.

Health experts recommend the use of aerosol containment systems with all types of ribavirin administration units except mechanical ventilators.

Severe hypoxia was described in a case report of a previously healthy infant who experienced a dramatic drop in transcutaneous oxygen within 1 minute of receiving ribavirin. Oxygen levels returned to normal promptly following discontinuation of therapy. However, the infant later died, and postmortem examination revealed a high pulmonary arterial pressure and a patent ductus arteriosus. A definitive causal relationship was not established, and equipment failure was not specifically ruled out by the authors.

Respiratory side effects have included worsening of respiratory status, hypoventilation, cyanosis, dyspnea, and bronchoconstriction in patients receiving aerosolized ribavirin therapy and are more common in patients with underlying respiratory or cardiopulmonary diseases. Bronchoconstriction is generally transient and may easily be reversed with bronchodilator therapy. Bacterial pneumonia, cough, pneumothorax, pulmonary edema, apnea, atelectasis and ventilator dependence has also been reported.

Hypersensitivity

Hypersensitivity side effects have included reactions such as urticaria, angioedema, bronchoconstriction, and anaphylaxis in patients treated with alfa interferon and ribavirin and have been reported rarely. Severe skin reactions (including vesiculobullous eruptions, Stevens-Johnson syndrome, erythema multiforme, and exfoliative dermatitis/erythroderma) have been rarely reported in patients treated with peginterferon alfa-2a alone and with ribavirin. Serious skin reactions have been reported during postmarketing experience in patients treated with peginterferon alfa-2a.

Dermatologic

Dermatologic side effects have included rash and skin irritation from prolonged drug contact. Alopecia, pruritus, dermatitis, and dry skin have been reported with higher frequency. Grover's disease has been reported in a 55-year-old man two weeks after the start of ribavirin therapy. A photoallergic skin reaction was reported to occur 4 months after initiation of ribavirin treatment, and recurred approximately 24 hours after reexposure to ribavirin. Increased sweating, rash, and eczema have been reported. Skin disorders associated with oral ribavirin and peginterferon alfa-2a combination therapy have included lichenoid eruptions and maculopapular rashes.

Grover's disease (suprabasal transient acantholytic dermatosis) secondary to ribavirin use was confirmed upon drug rechallenge in a 55-year-old man with chronic active hepatitis C.

Cardiovascular

Cardiovascular side effects have been reported rarely with aerosolized ribavirin. These have included cardiac arrest, hypotension, hypertension (usually slight increases in blood pressure), and digitalis toxicity. Bigeminy, bradycardia, and tachycardia have been reported in patients with underlying congenital heart disease. Angina, arrhythmia, and pulmonary embolism have been reported in patients treated with peginterferon alfa-2a alone or with ribavirin.

Hematologic

Hematologic side effects have been reported the most frequently with the use of oral and intravenous ribavirin. These have included hemolytic anemia, anemia, lymphopenia, neutropenia, thrombocytopenia, and thrombotic thrombocytopenic purpura. Aplastic anemia and pure red cell aplasia have been reported during postmarketing experience of oral ribavirin in combination with recombinant interferon alfa-2b or recombinant peginterferon alfa-2b. Postmarketing adverse events associated with aerosolized ribavirin have included cases of anemia (unspecified), reticulocytosis, and hemolytic anemia.

Hemolytic anemia is the primary toxicity of ribavirin therapy. Hemoglobin levels generally declined within the first one to two weeks of oral therapy. Cardiac and pulmonary adverse effects associated with anemia have been reported in 10% of patients.

Ocular

The eye and conjunctival irritation resolved spontaneously when the care givers left the hospital. In five of six cases, the care givers were wearing contact lenses. After the staff stopped wearing the lenses while caring for these patients, the reactions did not occur.

Ocular side effects associated with aerosolized ribavirin have included eye irritation and conjunctivitis in patients and their caregivers. Blurred vision has been reported with the use of oral ribavirin (in combination with peginterferon alfa). Corneal ulcer has been reported in patients treated with peginterferon alfa-2a alone or with ribavirin. Serious retinal detachment has been reported during postmarketing experience in patients treated with peginterferon alfa-2a.

Gastrointestinal

Gastrointestinal side effects have been reported frequently with the use of oral ribavirin (in combination with peginterferon alfa). These have included nausea and vomiting, diarrhea, abdominal pain, dry mouth, and dyspepsia. Peptic ulcer, gastrointestinal bleeding, pancreatitis, and colitis have been reported in patients treated with peginterferon alfa-2a alone or with ribavirin.

Musculoskeletal

Musculoskeletal side effects have been reported frequently with the use of oral ribavirin (in combination with peginterferon alfa). These have included myalgia, arthralgia, and back pain. Myositis has been reported in patients treated with peginterferon alfa-2a alone or with ribavirin.

Nervous system

Nervous system side effects have been reported frequently with the use of oral ribavirin (in combination with peginterferon alfa). These have included headache, dizziness (excluding vertigo), and memory impairment. Vertigo and hearing disorder have been reported during postmarketing experience of oral ribavirin in combination with recombinant interferon alfa-2b or recombinant peginterferon alfa-2b. Peripheral neuropathy and cerebral hemorrhage have been reported in patients treated with peginterferon alfa-2a alone or with ribavirin. Hearing impairment and hearing loss have been reported during postmarketing experience in patients treated with peginterferon alfa-2a.

Metabolic

Metabolic side effects have been reported frequently with the use of oral ribavirin (in combination with peginterferon alfa). These have included anorexia and weight decrease. Diabetes mellitus has been reported in patients treated with peginterferon alfa-2a alone or with ribavirin. Falsely low hemoglobin A1c levels have been reported. Dehydration has been reported during postmarketing experience in patients treated with peginterferon alfa-2a.

Psychiatric

Psychiatric side effects have been reported frequently with the use of oral ribavirin (in combination with peginterferon alfa). These have included irritability, anxiety, nervousness, insomnia, depression, concentration impairment, and mood alteration. Suicide, suicidal ideation, psychosis, aggression, psychotic disorder, and hallucination have been reported in patients treated with peginterferon alfa-2a alone or with ribavirin.

Endocrine

Endocrine side effects have included hypothyroidism.

Other

Other side effects have included fatigue, asthenia, pyrexia, rigors, influenza-like symptoms, and pain. Coma has been reported in patients treated with peginterferon alfa-2a alone or with ribavirin.

Immunologic

Immunologic side effects have included autoimmune phenomena such as hyperthyroidism, hypothyroidism, sarcoidosis, systemic lupus erythematosus, and rheumatoid arthritis in patients treated with peginterferon alfa-2a alone or with ribavirin.

Local

Local side effects have included injection site reactions in patients treated with oral ribavirin in combination with interferon alfa-2b or peginterferon alfa-2a. Skin disorders associated with oral ribavirin and peginterferon alfa-2a combination therapy have included cutaneous necrosis at peginterferon alfa-2a injection sites. Hyperpigmentation around/over peginterferon alfa-2a injection sites has been reported.

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