ADVERSE REACTIONS
The primary toxicity of ribavirin is hemolytic anemia. Reductions in hemoglobin levels occurred within the first 1–2 weeks of oral therapy (see WARNINGS). Cardiac and pulmonary events associated with anemia occurred in approximately 10% of patients (see WARNINGS).
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
EventsPatients reporting one or more adverse events. A patient may have reported more than one adverse event within a body system/organ class category. | 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) |
|---|
| 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) |
|---|
| 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 (see TABLE 9).
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 (see TABLE 10).
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.
|
REPORTS OF SIDE EFFECTS / ADVERSE REACTIONS RELATED TO REBETOL
Below is a sample of reports where side effects / adverse reactions may be related to Rebetol. The information is not vetted and should not be cosidered as verified clinical evidence.
Possible Rebetol side effects / adverse reactions in 59 year old female
Reported by a consumer/non-health professional from United States on 2007-01-10
Patient: 59 year old female
Reactions: Haemorrhage, Rectal Haemorrhage, Pain, Chills, Disorientation, Headache, Pyrexia, Hyperhidrosis, Faeces Discoloured, Fatigue, Palpitations, Feeling Hot, Dizziness, Depression, Cold Sweat, Blood Glucose Increased, Decreased Appetite, Crying, Muscle Spasms, Nervousness, Blood Pressure Increased, Vomiting, Dyspnoea, Tremor, Anxiety, Blood Glucose Decreased, Incoherent, Heart Rate Decreased, Arthralgia, Feeling Jittery, Memory Impairment, Asthenia
Adverse event resulted in: hospitalization
Suspect drug(s):
PEG-Intron
Dosage: sc
Indication: Hepatitis C
Start date: 2006-10-02
End date: 2006-11-15
Rebetol
Dosage: po
Administration route: Oral
Indication: Hepatitis C
Start date: 2006-10-02
End date: 2006-11-15
Other drugs received by patient: Cardura /00639301/; Norvasc
Possible Rebetol side effects / adverse reactions in 53 year old female
Reported by a consumer/non-health professional from United States on 2007-01-10
Patient: 53 year old female
Reactions: Vomiting, Dysphagia, Glossodynia, Nausea, Food Poisoning, Tongue Ulceration, Throat Tightness, Tongue Disorder, Dehydration, Psychiatric Symptom, Alopecia, Injection Site Reaction, Injection Site Rash, Depression, Influenza Like Illness
Suspect drug(s):
PEG-Intron
Dosage: 150 mcg; qw; sc
Indication: Hepatitis C
Start date: 2006-10-06
Rebetol
Dosage: 1400 mg; qd; po
Administration route: Oral
Indication: Hepatitis C
Start date: 2006-10-06
End date: 2006-12-01
Ribasphere
Dosage: 1400 mg; qd; po
Administration route: Oral
Indication: Hepatitis C
Start date: 2006-12-01
Other drugs received by patient: Phenergan; Synthroid; Lorcet-HD; Motrin
Possible Rebetol side effects / adverse reactions in 47 year old female
Reported by a consumer/non-health professional from United States on 2007-01-16
Patient: 47 year old female weighing 89.4 kg (196.6 pounds)
Reactions: Weight Decreased, Pyrexia, Loss of Consciousness, Myalgia, Haematocrit Decreased, Fatigue, RED Blood Cell Count Decreased, DRY Mouth, Anger, Decreased Appetite, White Blood Cell Count Decreased, Blood Pressure Increased, Vomiting, Chest Discomfort, Dysphagia, Dyspnoea, Nausea, Haemoglobin Decreased, Arthralgia, Alopecia, Heart Rate Increased
Adverse event resulted in: hospitalization
Suspect drug(s):
PEG-Intron
Dosage: sc
Indication: Hepatitis C
Start date: 2006-10-06
Rebetol
Dosage: po
Administration route: Oral
Indication: Hepatitis C
Start date: 2006-10-06
|
