Ribavirin (Ribavirin) - Side Effects and Adverse Reactions

ADVERSE REACTIONS

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

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 4 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.

TABLE 4. Selected Treatment-Emergent Adverse Events: Previously Untreated and Relapse Adult Patients

	Percentage of Patients
	US Previously Untreated Study				US Relapse Study
	24 weeks of treatment		48 weeks of treatment		24 weeks of treatment
Patients Reporting Adverse Events 1	INTRON A plus Ribavirin (N=228)	INTRON A plus Placebo (N=231)	INTRON A plus Ribavirin (N=228)	INTRON A plus Placebo (N=225)	INTRON A plus Ribavirin (N=77)	INTRON A plus Placebo (N=76)
Application Site Disorders
Injection site inflammation	13	10	12	14	6	8
Injection site reaction	7	9	8	9	5	3
Body as a Whole – General Disorders
Headache	63	63	66	67	66	68
Fatigue	68	62	70	72	60	53
Rigors	40	32	42	39	43	37
Fever	37	35	41	40	32	36
Influenza-like symptoms	14	18	18	20	13	13
Asthenia	9	4	9	9	10	4
Chest pain	5	4	9	8	6	7
Central & Peripheral Nervous System Disorders
Dizziness	17	15	23	19	26	21
Gastrointestinal System Disorders
Nausea	38	35	46	33	47	33
Anorexia	27	16	25	19	21	14
Dyspepsia	14	6	16	9	16	9
Vomiting	11	10	9	13	12	8

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

Laboratory Values

Ribavirin/INTRON A Combination Therapy

Changes in selected hematologic values (hemoglobin, white blood cells, neutrophils, and platelets)during therapy are described below. (See TABLE 5).

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.

TABLE 5. Selected Hematologic Values During Treatment with Ribavirin Capsules plus INTRON A: Previously Untreated and Relapse Adult Patients

	Percentage of Patients
	US Previously Untreated Study				US Relapse Study
	24 weeks of treatment		48 weeks of treatment		24 weeks of treatment
	INTRON A plus Ribavirin (N=228)	INTRON A plus Placebo (N=231)	INTRON A plus Ribavirin (N=228)	INTRON A plus Placebo (N=225)	INTRON A plus Ribavirin (N=77)	INTRON A plus Placebo (N=76)
Hemoglobin (g/dL)
9.5-10.9	24	1	32	1	21	3
8.0-9.4	5	0	4	0	4	0
6.5-7.9	0	0	0	0.4	0	0
<6.5	0	0	0	0	0	0
Leukocytes (x109/L)
2.0-2.9	40	20	38	23	45	26
1.5-1.9	4	1	9	2	5	3
1.0-1.4	0.9	0	2	0	0	0
<1.0	0	0	0	0	0	0
Neutrophils (x109/L)
1.0-1.49	30	32	31	44	42	34
0.75-0.99	14	15	14	11	16	18
0.5-0.74	9	9	14	7	8	4
<0.5	11	8	11	5	5	8
Platelets (x109/L)
70-99	9	11	11	14	6	12
50-69	2	3	2	3	0	5
30-49	0	0.4	0	0.4	0	0
<30	0.9	0	1	0.9	0	0
Total Bilirubin (mg/dL)
1.5-3.0	27	13	32	13	21	7
3.1-6.0	0.9	0.4	2	0	3	0
6.1-12.0	0	0	0.4	0	0	0
>12.0	0	0	0	0	0	0

Postmarketing Experiences

The following adverse reactions have been identified during the post approval use of ribavirin capsules in combination with INTRON A: hearing disorder, vertigo, aplastic anemia and 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.

ADVERSE REACTIONS

The safety of combination ribavirin capsules/INTRON A therapy was evaluated in controlled trials of 1010 HCV-infected adults who were previously untreated with interferon therapy and were subsequently treated for 24 or 48 weeks with combination ribavirin capsules/INTRON A therapy and in 173 HCV-infected patients who had relapsed after interferon therapy and were subsequently treated for 24 weeks with combination ribavirin capsules/INTRON A therapy. (See Description of Clinical Studies.) Overall, 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.

The primary toxicity of ribavirin is hemolytic anemia. Reductions in hemoglobin levels occurred within the first 1 to 2 weeks of therapy (see WARNINGS). Cardiac and pulmonary events associated with anemia occurred in approximately 10% of patients treated with ribavirin capsules/INTRON A therapy. (See WARNINGS.)

The most common psychiatric events occurring in US studies of previously untreated and relapse patients treated with ribavirin capsules/INTRON A therapy, respectively, were insomnia (39%, 26%), depression (34%, 23%), and irritability (27%, 25%). Suicidal behavior (ideation, attempts, and suicides) occurred in 1% of patients. (See WARNINGS.) In addition, the following spontaneous adverse events have been reported during the marketing surveillance of ribavirin capsules/INTRON A therapy: hearing disorder and vertigo. Very rarely, combination ribavirin capsules/INTRON A therapy may be associated with aplastic anemia.

Selected treatment-emergent adverse events that occurred in the US studies with ≥5% incidence are provided in TABLE 4 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.

TABLE 4. Selected Treatment-Emergent Adverse Events: Previously Untreated and Relapse Patients

	Percentage of Patients
	US Previously Untreated Study				US Relapse Study
	24 weeks of treatment		48 weeks of treatment		24 weeks of treatment
Patients Reporting Adverse Events 1	INTRON A plus Ribavirin capsules (N=228)	INTRON A plus Placebo (N=231)	INTRON A plus Ribavirin capsules (N=228)	INTRON A plus Placebo (N=225)	INTRON A plus Ribavirin capsules (N=77)	INTRON A plus Placebo (N=76)
Application Site Disorders
Injection site inflammation	13	10	12	14	6	8
Injection site reaction	7	9	8	9	5	3
Body as a Whole – General Disorders
Headache	63	63	66	67	66	68
Fatigue	68	62	70	72	60	53
Rigors	40	32	42	39	43	37
Fever	37	35	41	40	32	36
Influenza-like symptoms	14	18	18	20	13	13
Asthenia	9	4	9	9	10	4
Chest pain	5	4	9	8	6	7
Central & Peripheral Nervous System Disorders
Dizziness	17	15	23	19	26	21
Gastrointestinal System Disorders
Nausea	38	35	46	33	47	33
Anorexia	27	16	25	19	21	14
Dyspepsia	14	6	16	9	16	9
Vomiting	11	10	9	13	12	8

REPORTS OF SUSPECTED RIBAVIRIN SIDE EFFECTS / ADVERSE REACTIONS

Possible Ribavirin side effects / adverse reactions in 56 year old male

Reported by a health professional (non-physician/pharmacist) from United States on 2011-10-04

Patient: 56 year old male weighing 88.0 kg (193.6 pounds)

Reactions: Drug Interaction, DRY Skin, Sinus Bradycardia, Cardiac Disorder, Long QT Syndrome, Palpitations, International Normalised Ratio Decreased, Chest Pain, Hypertension, Skin Warm, Oxygen Saturation Decreased, Influenza Like Illness

Adverse event resulted in: hospitalization

Suspect drug(s):
PEG-Intron
    Dosage: 150 mg;qw
    Indication: Product Used FOR Unknown Indication
    Start date: 2011-08-10

Amitriptyline HCL
    Indication: Product Used FOR Unknown Indication
    End date: 2011-08-10

Ribavirin
    Dosage: 600 mg;bid;po
    Administration route: Oral
    Indication: Product Used FOR Unknown Indication
    Start date: 2011-08-09

PEG-Intron
    Indication: Product Used FOR Unknown Indication
    Start date: 2011-08-09
    End date: 2011-08-09

Trazodone Hydrochloride
    Indication: Product Used FOR Unknown Indication
    End date: 2011-08-10

Other drugs received by patient: Colace; Metoprolol Tartrate; Lovenox; Oxycontin; Nexium

Possible Ribavirin side effects / adverse reactions in 65 year old male

Reported by a physician from Japan on 2011-10-04

Patient: 65 year old male

Reactions: Glomerulonephritis Membranous, Ascites

Adverse event resulted in: hospitalization

Suspect drug(s):
Ribavirin
    Dosage: po
    Administration route: Oral
    Indication: Hepatitis C
    Start date: 2009-03-01
    End date: 2010-07-01

PEG-Intron
    Dosage: sc
    Indication: Hepatitis C
    Start date: 2009-03-01
    End date: 2010-07-01

Possible Ribavirin side effects / adverse reactions in 65 year old female

Reported by a health professional (non-physician/pharmacist) from United States on 2011-10-04

Patient: 65 year old female

Reactions: Weight Decreased, White Blood Cell Count Decreased, Dyspnoea, Fatigue, Cystitis, Fall

Adverse event resulted in: hospitalization

Suspect drug(s):
Ribavirin
    Indication: Hepatitis C
    Start date: 2011-08-01

PEG-Intron
    Indication: Hepatitis C
    Start date: 2011-08-01