Drug Information

Rebetol Side Effects

Generic Name: ribavirin

Please note - some side effects for Rebetol 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 Rebetol - for the Consumer

Rebetol

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 Rebetol:

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.

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

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.

Rebetol Solution

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 Rebetol Solution:

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

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

Severe allergic reactions (rash; hives; 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; loss of appetite; 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.

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Rebetol Side Effects - for the Professional

Rebetol

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

Rebetol®/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 7 by treatment group. In general, the selected treatment-emergent adverse events were 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.

Pediatric Patients

In clinical trials of 118 pediatric patients 3 to 16 years of age, 6% discontinued therapy due to adverse events. Dose modifications were required in 30% of patients, most commonly for anemia and neutropenia. In general, the adverse event profile in the pediatric population was similar to that observed in adults. Injection site disorders, fever, anorexia, vomiting, and emotional lability occurred more frequently in pediatric patients compared to adult patients. Conversely, pediatric patients experienced less fatigue, dyspepsia, arthralgia, insomnia, irritability, impaired concentration, dyspnea, and pruritus compared to adult patients. Selected treatment-emergent adverse events that occurred with ≥5% incidence among all pediatric patients who received the recommended dose of Rebetol/INTRON A combination therapy are provided in TABLE 7.

TABLE 7. Selected Treatment-Emergent Adverse Events: Previously Untreated and Relapse Adult Patients and Previously Untreated Pediatric Patients
Percentage of Patients
	US Previously Untreated Study				US Relapse Study		Pediatric Patients
24 weeks of treatment			48 weeks of treatment		24 weeks of treatment		48 weeks of treatment
Patients Reporting Adverse Events*	INTRON A plus Rebetol (N=228)	INTRON A plus Placebo (N=231)	INTRON A plus Rebetol (N=228)	INTRON A plus Placebo (N=225)	INTRON A plus Rebetol (N=77)	INTRON A plus Placebo (N=76)	INTRON A Plus Rebetol (N=118)
* Patients reporting one or more adverse events. A patient may have reported more than one adverse event within a body system/organ class category.
Application Site Disorders
Injection site inflammation	13	10	12	14	6	8	14
Injection site reaction	7	9	8	9	5	3	19
Body as a Whole - General Disorders
Headache	63	63	66	67	66	68	69
Fatigue	68	62	70	72	60	53	58
Rigors	40	32	42	39	43	37	25
Fever	37	35	41	40	32	36	61
Influenza-like symptoms	14	18	18	20	13	13	31
Asthenia	9	4	9	9	10	4	5
Chest pain	5	4	9	8	6	7	5
Central & Peripheral Nervous System Disorders
Dizziness	17	15	23	19	26	21	20
Gastrointestinal System Disorders
Nausea	38	35	46	33	47	33	33
Anorexia	27	16	25	19	21	14	51
Dyspepsia	14	6	16	9	16	9	<1
Vomiting	11	10	9	13	12	8	42
Musculoskeletal System Disorders
Myalgia	61	57	64	63	61	58	32
Arthralgia	30	27	33	36	29	29	15
Musculoskeletal pain	20	26	28	32	22	28	21
Psychiatric Disorders
Insomnia	39	27	39	30	26	25	14
Irritability	23	19	32	27	25	20	10
Depression	32	25	36	37	23	14	13
Emotional lability	7	6	11	8	12	8	16
Concentration impaired	11	14	14	14	10	12	5
Nervousness	4	2	4	4	5	4	3
Respiratory System Disorders
Dyspnea	19	9	18	10	17	12	5
Sinusitis	9	7	10	14	12	7	<1
Skin and Appendages Disorders
Alopecia	28	27	32	28	27	26	23
Rash	20	9	28	8	21	5	17
Pruritus	21	9	19	8	13	4	12
Special Senses, Other Disorders
Taste perversion	7	4	8	4	6	5	<1

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

Rebetol/PegIntron Combination Therapy

Overall, in clinical trials, 14% of patients receiving Rebetol in combination with PegIntron™, discontinued therapy compared with 13% treated with Rebetol in combination with INTRON A. 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 8 by treatment group. Safety and effectiveness of Rebetol in combination with PegIntron has not been established in pediatric patients.

TABLE 8. Adverse Events Occurring in > 5% of Patients
	Percentage of Patients Reporting Adverse Events*			Percentage of Patients Reporting Adverse Events*
Adverse Events	PegIntron 1.5µg/kg/ Rebetol (N=511)	INTRON A/ Rebetol (N=505)	Adverse Events	PegIntron 1.5µg/kg/ Rebetol (N=511)	INTRON A/ Rebetol (N=505)
* Patients reporting one or more adverse events. A patient may have reported more than one adverse event within a body system/organ class category.
Application Site			Musculoskeletal
Injection site Inflammation	25	18	Myalgia	56	50
Injection Site Reaction	58	36	Arthralgia	34	28
Autonomic Nervous Sys.			Musculoskeletal Pain	21	19
Mouth Dry	12	8	Psychiatric
Sweating Increased	11	7	Insomnia	40	41
Flushing	4	3	Depression	31	34
Body as a Whole			Anxiety/Emotional Lability/Irritability	47	47
Fatigue/Asthenia	66	63	Concentration Impaired	17	21
Headache	62	58	Agitation	8	5
Rigors	48	41	Nervousness	6	6
Fever	46	33	Reproductive, Female
Weight Decrease	29	20	Menstrual Disorder	7	6
RUQ Pain	12	6	Resistance Mechanism
Chest Pain	8	7	Infection Viral	12	12
Malaise	4	6	Infection Fungal	6	1
Central/Peripheral Nervous System			Respiratory System
Dizziness	21	17	Dyspnea	26	24
Endocrine			Coughing	23	16
Hypothyroidism	5	4	Pharyngitis	12	13
Gastrointestinal			Rhinitis	8	6
Nausea	43	33	Sinusitis	6	5
Anorexia	32	27	Skin and Appendages
Diarrhea	22	17	Alopecia	36	32
Vomiting	14	12	Pruritus	29	28
Abdominal Pain	13	13	Rash	24	23
Dyspepsia	9	8	Skin Dry	24	23
Constipation	5	5	Special Senses, Other
Hematologic Disorders			Taste Perversion	9	4
Neutropenia	26	14	Vision Disorders
Anemia	12	17	Vision blurred	5	6
Leukopenia	6	5	Conjunctivitis	4	5
Thrombocytopenia	5	2
Liver and Biliary System
Hepatomegaly	4	4

Laboratory Values

Rebetol/INTRON A Combination Therapy

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

Hemoglobin

Hemoglobin decreases among patients receiving Rebetol 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 – 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.

TABLE 9. Selected Hematologic Values During Treatment with Rebetol plus INTRON A: Previously Untreated and Relapse Adult Patients and Previously Untreated Pediatric Patients
Percentage of Patients
	US Previously Untreated Study				US Relapse Study		Pediatric Patients
	24 weeks of treatment		48 weeks of treatment		24 weeks of treatment		48 weeks of treatment
	INTRON A plus Rebetol (N=228)	INTRON A plus Placebo (N=231)	INTRON A plus Rebetol (N=228)	INTRON A plus Placebo (N=225)	INTRON A plus Rebetol (N=77)	INTRON A plus Placebo (N=76)	INTRON A Plus Rebetol (N=118)
Hemoglobin (g/dL)
9.5–10.9	24	1	32	1	21	3	24
8.0–9.4	5	0	4	0	4	0	3
6.5–7.9	0	0	0	0.4	0	0	0
<6.5	0	0	0	0	0	0	0
Leukocytes (×109/L)
2.0–2.9	40	20	38	23	45	26	35
1.5–1.9	4	1	9	2	5	3	8
1.0–1.4	0.9	0	2	0	0	0	0
<1.0	0	0	0	0	0	0	0
Neutrophils (×109/L)
1.0–1.49	30	32	31	44	42	34	37
0.75–0.99	14	15	14	11	16	18	15
0.5–0.74	9	9	14	7	8	4	16
<0.5	11	8	11	5	5	8	3
Platelets (×109/L)
70–99	9	11	11	14	6	12	0.8
50–69	2	3	2	3	0	5	2
30–49	0	0.4	0	0.4	0	0	0
<30	0.9	0	1	0.9	0	0	0
Total Bilirubin (mg/dL)
1.5 –3.0	27	13	32	13	21	7	2
3.1–6.0	0.9	0.4	2	0	3	0	0
6.1–12.0	0	0	0.4	0	0	0	0
>12.0	0	0	0	0	0	0	0

Rebetol/PegIntron Combination Therapy

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

Hemoglobin

Rebetol induced a decrease in hemoglobin levels in approximately two thirds of patients. Hemoglobin levels decreased to < 11g/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 PegIntron/Rebetol and INTRON A/Rebetol groups.

Bilirubin and Uric Acid

In the Rebetol/PegIntron combination trial 10–14% of patients developed hyperbilirubinemia and 33–38% developed hyperuricemia in association with hemolysis. Six patients developed mild to moderate gout.

TABLE 10. Selected Hematologic Values During Treatment with Rebetol plus PegIntron
Number (%) of Subjects
	PegIntron plus Rebetol (N=511)	INTRON A plus Rebetol (N=505)		PegIntron plus Rebetol (N=511)	INTRON A plus Rebetol (N=505)
Hemoglobin (g/dL)			Platelets (×109/L)
9.5–10.9	26	27	70–99	15	5
8.0–9.4	3	3	50–69	3	0.8
6.5–7.9	0.2	0.2	30–49	0.2	0.2
<6.5	0	0	<30	0	0
Leukocytes (×109/L)			Total Bilirubin (mg/dL)
2.0–2.9	46	41	1.5 –3.0	10	13
1.5–1.9	24	8	3.1–6.0	0.6	0.2
1.0–1.4	5	1	6.1–12.0	0	0.2
<1.0	0	0	>12.0	0	0
Neutrophils (×109/L)			ALT (SGPT)
1.0–1.49	33	37	2 × Baseline	0.6	0.2
0.75–0.99	25	13	2.1–5 × Baseline	3	1
0.5–0.74	18	7	5.1–10 × Baseline	0	0
<0.5	4	2	>10 × Baseline	0	0

Postmarketing Experiences

The following adverse reactions have been identified during post-approval use of Rebetol in combination with INTRON A or PegIntron therapy: hearing disorder, vertigo, aplastic anemia, pure red cell aplasia. 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.

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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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