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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.

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:

Constipation; cough; diarrhea; dizziness; dry mouth; dry skin; loss of appetite; mild headache, nausea, or vomiting; sinus problems; 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); changes in hearing, taste, or vision; chest pain; dark, tarry, or bloody stools; dark urine; decrease in the amount of urine; fainting; fever, chills, or sore throat; hair loss; joint pain; menstrual problems; mood or mental problems (eg, agitation, aggression, anger, anxiety, decreased concentration, depression, irritability, nervousness); muscle pain or weakness; numbness of an arm or leg; pale stools; prolonged nausea and vomiting; rapid breathing; red, swollen, blistered, or peeling skin; severe headache; severe or persistent diarrhea; severe stomach or back pain; shortness of breath; suicidal thoughts or actions; trouble sleeping; unusual bruising or bleeding; unusual or severe tiredness, weakness, or fatigue; weight loss; 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.

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:

Constipation; cough; diarrhea; dizziness; dry mouth; dry skin; loss of appetite; mild headache, nausea, or vomiting; sinus problems; 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; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); changes in hearing, taste, or vision; chest pain; dark, tarry, or bloody stools; dark urine; decrease in the amount of urine; fainting; fever, chills, or sore throat; hair loss; joint pain; mood or mental problems (eg, agitation, aggression, anger, anxiety, decreased concentration, depression, irritability, nervousness); menstrual problems; muscle pain or weakness; numbness of an arm or leg; pale stools; prolonged nausea and vomiting; rapid breathing; red, swollen, blistered, or peeling skin; severe headache; severe or persistent diarrhea; severe stomach or back pain; shortness of breath; suicidal thoughts or actions; trouble sleeping; unusual bruising or bleeding; unusual or severe tiredness, weakness, or fatigue; weight loss; 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.

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Rebetol Side Effects - for the Professional

Rebetol

Clinical trials with Rebetol in combination with PegIntron or INTRON A have been conducted in over 7800 subjects from 3 to 76 years of age.

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 reactions associated with anemia occurred in approximately 10% of patients [see Warnings and Precautions (5.2)].

Greater than 96% of all subjects in clinical trials experienced one or more adverse reactions. The most commonly reported adverse reactions in adult subjects receiving PegIntron or INTRON A in combination with Rebetol were injection site inflammation/reaction, fatigue/asthenia, headache, rigors, fevers, nausea, myalgia and anxiety/emotional lability/irritability. The most common adverse reactions in pediatric subjects, ages 3 and older, receiving Rebetol in combination with PegIntron or INTRON A were pyrexia, headache, neutropenia, fatigue, anorexia, injection site erythema, and vomiting.

The Adverse Reactions section references the following clinical studies:

  • Rebetol/PegIntron Combination therapy studies:
    • Clinical Study 1 - evaluated PegIntron monotherapy (not further described in this label; see PegIntron Powder for Injection Package Insert for information about this study).
    • Study 2 - evaluated Rebetol 800 mg/day flat dose in combination with 1.5 mcg/kg/week PegIntron or with INTRON A.
    • Study 3 - evaluated PegIntron/weight-based Rebetol in combination with PegIntron/flat dose Rebetol regimen.
    • Study 4- compared two PegIntron (1.5 mcg/kg/week and 1 mcg/kg/week) doses in combination with Rebetol and a third treatment group receiving Pegasys® (180 mcg/week)/Copegus® (1000–1200 mg/day).
    • Study 5 – evaluated PegIntron (1.5 mcg/kg/week) in combination with weight-based Rebetol in prior treatment failure subjects.
  • PegIntron/Rebetol Combination Therapy in Pediatric Patients
  • Rebetol/INTRON A Combination Therapy studies for adults and pediatrics

Serious adverse reactions have occurred in approximately 12% of subjects in clinical trials with PegIntron with or without Rebetol [see BOXED WARNING, Warnings and Precautions (5)]. The most common serious events occurring in subjects treated with PegIntron and Rebetol were depression and suicidal ideation [see Warnings and Precautions (5.2)], each occurring at a frequency of less than 1%. Suicidal ideation or attempts occurred more frequently among pediatric patients, primarily adolescents, compared to adult patients (2.4% versus 1%) during treatment and off-therapy follow-up [see Warnings and Precautions (5.10)]. The most common fatal reaction occurring in subjects treated with PegIntron and Rebetol was cardiac arrest, suicide ideation, and suicide attempt [see Warnings and Precautions (5.10)], all occurring in less than 1% of subjects.

Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rated in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Clinical Studies Experience – Rebetol/PegIntron Combination Therapy

Adult Subjects

Adverse reactions that occurred in the clinical trial at > 5% incidence are provided by treatment group from the Rebetol/PegIntron Combination Therapy (Study 2) in Table 6.

Table 6: Adverse Reactions Occurring in > 5% of Adult Subjects
Adverse reactions Percentage of Subjects Reporting Adverse Reactions* Adverse Reactions Percentage of Subjects Reporting Adverse Reactions*
PegIntron
1.5 mcg/kg/ Rebetol
(N=511)
INTRON A/
Rebetol
 
(N=505)
PegIntron
1.5 mcg/kg/ Rebetol
(N=511)
INTRON A/
Rebetol
 
(N=505)
*
A subject may have reported more than one adverse reaction 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 System   Musculoskeletal Pain 21 19
  Dry Mouth 12 8 Psychiatric
  Increased Sweating 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 Loss 29 20   Menstrual Disorder 7 6
  Right Upper Quadrant Pain 12 6 Resistance Mechanism
  Chest Pain 8 7   Viral Infection 12 12
  Malaise 4 6   Fungal Infection 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

Table 7 summarizes the treatment related adverse reactions in Study 4 that occurred at a ≥10% incidence.

Table 7: Summary of Treatment-Related Adverse Reactions (≥10% Incidence) By Descending Frequency
Study 4
Percentage of Patients Reporting Treatment-Related Adverse Reactions
Adverse Reactions PegIntron 1.5 mcg/kg with Rebetol PegIntron 1 mcg/kg with Rebetol Pegasys 180 mcg with Copegus
(n=1019) (n=1016) (n=1035)
Fatigue 67 68 64
Headache 50 47 41
Nausea 40 35 34
Chills 39 36 23
Insomnia 38 37 41
Anemia 35 30 34
Pyrexia 35 32 21
Injection Site Reactions 34 35 23
Anorexia 29 25 21
Rash 29 25 34
Myalgia 27 26 22
Neutropenia 26 19 31
Irritability 25 25 25
Depression 25 19 20
Alopecia 23 20 17
Dyspnea 21 20 22
Arthralgia 21 22 22
Pruritus 18 15 19
Influenza-like Illness 16 15 15
Dizziness 16 14 13
Diarrhea 15 16 14
Cough 15 16 17
Weight Decreased 13 10 10
Vomiting 12 10 9
Unspecified Pain 12 13 9
Dry Skin 11 11 12
Anxiety 11 11 10
Abdominal Pain 10 10 10
Leukopenia 9 7 10

The incidence of serious adverse reactions was comparable in all studies. In Study 3, there was a similar incidence of serious adverse reactions reported for the weight-based Rebetol group (12%) and with the flat-dose Rebetol regimen. In Study 2, the incidence of serious adverse reactions was 17% in the PegIntron/Rebetol groups compared to 14% in the INTRON A/Rebetol group.

In many but not all cases, adverse reactions resolved after dose reduction or discontinuation of therapy. Some subjects experienced ongoing or new serious adverse reactions during the 6-month follow-up period. In Study 2, many subjects continued to experience adverse reactions several months after discontinuation of therapy. By the end of the 6-month follow-up period, the incidence of ongoing adverse reactions by body class in the PegIntron 1.5/Rebetol group was 33% (psychiatric), 20% (musculoskeletal), and 10% (for endocrine and for GI). In approximately 10 to 15% of subjects' weight loss, fatigue, and headache had not resolved.

There have been 31 subject deaths which occurred during treatment or during follow-up in these clinical trials. In Study 1, there was 1 suicide in a subject receiving PegIntron monotherapy and 2 deaths among subjects receiving INTRON A monotherapy (1 murder/suicide and 1 sudden death). In Study 2, there was 1 suicide in a subject receiving PegIntron/Rebetol combination therapy; and 1 subject death in the INTRON A/Rebetol group (motor vehicle accident). There have been 31 subject deaths which occurred during treatment or during follow-up in the three clinical trials. In Study 3, there were 14 deaths, 2 of which were probable suicides and 1 was an unexplained death in a person with a relevant medical history of depression. In Study 4, there were 12 deaths, 6 of which occurred in subjects who received PegIntron/Rebetol combination therapy, 5 in the PegIntron 1.5 mcg/Rebetol arm (N=1019) and 1 in the PegIntron 1 mcg/Rebetol arm (N=1016), and 6 of which occurred in subjects receiving Pegasys/Copegus (N=1035). There were 3 suicides which occurred during the off treatment follow-up period in subjects who received PegIntron (1.5 mcg/kg)/Rebetol combination therapy.

In studies 1 and 2, 10 to 14% of subjects receiving PegIntron, alone or in combination with Rebetol, discontinued therapy compared with 6% treated with INTRON A alone and 13% treated with INTRON A in combination with Rebetol. Similarly in Study 3, 15% of subjects receiving PegIntron in combination with weight-based Rebetol and 14% of subjects receiving PegIntron and flat dose Rebetol discontinued therapy due to an adverse reaction. The most common reasons for discontinuation of therapy were related to known interferon effects of psychiatric, systemic (e.g., fatigue, headache), or gastrointestinal adverse reactions. In study 4, 13% of subjects in the PegIntron 1.5 mcg/Rebetol arm, 10% in the PegIntron 1 mcg/Rebetol arm and 13% in the Pegasys 180 mcg/Copegus arm discontinued due to adverse events.

In Study 2, dose reductions due to adverse reactions occurred in 42% of subjects receiving PegIntron (1.5 mcg/kg)/Rebetol and in 34% of those receiving INTRON A/Rebetol. The majority of subjects (57%) weighing 60 kg or less receiving PegIntron (1.5 mcg/kg)/Rebetol required dose reduction. Reduction of interferon was dose related (PegIntron 1.5 mcg/kg > PegIntron 0.5 mcg/kg or INTRON A), 40%, 27%, 28%, respectively. Dose reduction for Rebetol was similar across all three groups, 33 to 35%. The most common reasons for dose modifications were neutropenia (18%), or anemia (9%). Other common reasons included depression, fatigue, nausea, and thrombocytopenia. In Study 3, dose modifications due to adverse reactions occurred more frequently with WBD compared to flat dosing (29% and 23%, respectively). In Study 4, 16% of subjects had a dose reduction of PegIntron to 1 mcg/kg in combination with Rebetol, with an additional 4% requiring the second dose reduction of PegIntron to 0.5 mcg/kg due to adverse events compared to 15% of subjects in the Pegasys/Copegus arm, who required a dose reduction to 135 mcg/week with Pegasys, with an additional 7% in the Pegasys/Copegus arm requiring second dose reduction to 90 mcg/week with Pegasys.

In the PegIntron/Rebetol combination trials the most common adverse reactions were psychiatric which occurred among 77% of subjects in Study 2 and 68% to 69% of subjects in Study 3. These psychiatric adverse reactions included most commonly depression, irritability, and insomnia, each reported by approximately 30% to 40% of subjects in all treatment groups. Suicidal behavior (ideation, attempts, and suicides) occurred in 2% of all subjects during treatment or during follow-up after treatment cessation [see Warnings and Precautions (5)]. In study 4 psychiatric adverse reactions occurred in 58 % of subjects in the PegIntron 1.5 mcg/Rebetol arm, 55% of subjects in the PegIntron 1 mcg/Rebetol arm, 57% of subjects in the Pegasys 180 mcg/Copegus arm.

PegIntron induced fatigue or headache in approximately two-thirds of subjects, with fever or rigors in approximately half of the subjects. The severity of some of these systemic symptoms (e.g., fever and headache) tends to decrease as treatment continues. In Studies 1 and 2, application site inflammation and reaction (e.g., bruise, itchiness, and irritation) occurred at approximately twice the incidence with PegIntron therapies (in up to 75% of subjects) compared with INTRON A. However, injection site pain was infrequent (2 to 3%) in all groups. In Study 3 there was a 23 to 24% incidence overall for injection site reactions or inflammation.

Subjects receiving Rebetol/PegIntron as retreatment after failing a previous interferon combination regimen reported adverse reactions similar to those previously associated with this regimen during clinical trials of treatment-naïve subjects.

Pediatric Subjects

In general, the adverse-reaction profile in the pediatric population was similar to that observed in adults. In the pediatric study, the most prevalent adverse reactions in all subjects were pyrexia (80%), headache (62%), neutropenia (33%), fatigue (30%), anorexia (29%), injection-site erythema (29%) and vomiting (27%). The majority of adverse reactions reported in the study were mild or moderate in severity. Severe adverse reactions were reported in 7% (8/107) of all subjects and included injection site pain (1%), pain in extremity (1%), headache (1%), neutropenia (1%), and pyrexia (4%). Important adverse reactions that occurred in this subject population were nervousness (7%; 7/107), aggression (3%; 3/107), anger (2%; 2/107), and depression (1%; 1/107). Five subjects received levothyroxine treatment, 3 with clinical hypothyroidism and 2 with asymptomatic TSH elevations.

Dose modifications of PegIntron and/or ribavirin were required in 25% of subjects due to treatment-related adverse reactions, most commonly for anemia, neutropenia and weight loss. Two subjects (2%; 2/107) discontinued therapy as the result of an adverse reaction.

Adverse reactions that occurred with a ≥ 10% incidence in the pediatric trial subjects are provided in Table 8.

Table 8: Percentage (%) of Pediatric Subjects With Treatment-Related Adverse Reactions (in at Least 10% of All Subjects)
System Organ Class
     Preferred Term
All subjects
(N=107)
Blood and Lymphatic System Disorders
     Neutropenia 33%
     Anemia 11%
     Leukopenia 10%
Gastrointestinal Disorders
     Abdominal Pain 21%
     Abdominal Pain Upper 12%
     Vomiting 27%
     Nausea 18%
General Disorders and Administration Site Conditions
     Pyrexia 80%
     Fatigue 30%
     Injection Site Erythema 29%
     Chills 21%
     Asthenia 15%
     Irritability 14%
Investigations
     Weight Loss 19%
Metabolism and Nutrition Disorders
     Anorexia 29%
     Decreased Appetite 22%
Musculoskeletal and Connective Tissue Disorders
     Arthralgia 17%
     Myalgia 17%
Nervous System Disorders
     Headache 62%
     Dizziness 14%
Skin and Subcutaneous Tissue Disorders
     Alopecia 17%

Laboratory Values

Adult and Pediatric Subjects

The adverse reaction profile in Study 3, which compared PegIntron/weight-based Rebetol combination to a PegIntron/flat dose Rebetol regimen, revealed an increased rate of anemia with weight-based dosing (29% vs. 19% for weight-based vs. flat dose regimens, respectively). However, the majority of cases of anemia were mild and responded to dose reductions.

Changes in selected laboratory values during treatment in combination with Rebetol treatment are described below. Decreases in hemoglobin, leukocytes, neutrophils, and platelets may require dose reduction or permanent discontinuation from therapy [see Dosage and Administration (2.4)]. Changes in selected laboratory values during therapy are described in Table 9. Most of the changes in laboratory values in the PegIntron/Rebetol study with pediatric were mild or moderate.

Table 9: Selected Laboratory Values During Treatment With Rebetol Plus PegIntron or Rebetol Plus INTRON A in Previously Untreated Subjects
Laboratory Parameters* Percent of Subjects
Adults (Study 2) Pediatrics
PegIntron plus Rebetol
(N=511)
INTRON A plus Rebetol
(N=505)
PegIntron
plus
Rebetol
(N=107)*
*
The table summarizes the worst category observed within the period per subject per laboratory test. Only subjects with at least one treatment value for a given laboratory test are included.
N=Upper limit of normal
Hemoglobin (g/dL)
     9.5–<11.0 26 27 30
     8.0–<9.5 3 3 2
     6.5–7.9 0.2 0.2 -
Leukocytes (×109/L)
     2.0–2.9 46 41 39
     1.5–<2.0 24 8 3
     1.0–1.4 5 1 -
Neutrophils (×109/L)
     1.0–1.5 33 37 35
     0.75–<1.0 25 13 26
     0.5–<0.75 18 7 13
     <0.5 4 2 3
Platelets (×109/L)
     70–100 15 5 1
     50–<70 3 0.8 -
     30–49 0.2 0.2 --
     25–<50 -- -- 1
Total Bilirubin (mg/dL) (µmole/L)
     1.5 –3.0 10 13 --
     1.26–2.59 × N -- -- 7
     3.1–6.0 0.6 0.2 --
     2.6–5 × N -- -- -
     6.1–12.0 0 0.2 --
ALT (U/L)
     2 × Baseline 0.6 0.2 1
     2.1–5 × Baseline 3 1 5
     5.1–10 × Baseline 0 0 3

Hemoglobin. Hemoglobin levels decreased to < 11 g/dL in about 30% of subjects in Study 2. In Study 3, 47% of subjects receiving WBD Rebetol and 33% on flat dose Rebetol had decreases in hemoglobin levels <11 g/dl. Reductions in hemoglobin to < 9 g/dL occurred more frequently in subjects receiving WBD compared to flat dosing (4% and 2%, respectively). In Study 2, dose modification was required in 9% and 13% of subjects in the PegIntron/Rebetol and INTRON A /Rebetol groups. In Study 4, patients receiving PegIntron (1.5 mcg/kg)/Rebetol had decreases in hemoglobin levels to between 8.5 to <10 g/dL (28%) and to <8.5 g/dL (3%), whereas in patients receiving Pegasys 180 mcg/Copegus these decreases occurred in 26% and 4% of subjects respectively. Hemoglobin levels become stable by treatment Weeks 4–6 on average. The typical pattern observed was a decrease in hemoglobin levels by treatment Week 4 followed by stabilization and a plateau, which was maintained to the end of treatment. In the PegIntron monotherapy trial, hemoglobin decreases were generally mild and dose modifications were rarely necessary [see Dosage and Administration (2.4)].

Neutrophils. Decreases in neutrophil counts were observed in a majority of adult subjects treated with combination therapy with Rebetol in Study 2 (85%) and INTRON A/Rebetol (60%). Severe potentially life-threatening neutropenia (<0.5 × 109/L) occurred in 2% of subjects treated with INTRON A/Rebetol and in approximately 4% of subjects treated with PegIntron/Rebetol in Study 2. Eighteen percent of subjects receiving PegIntron/Rebetol in Study 2 required modification of interferon dosage. Few subjects (< 1%) required permanent discontinuation of treatment. Neutrophil counts generally return to pre-treatment levels 4 weeks after cessation of therapy [see Dosage and Administration (2.4)].

Platelets. Platelet counts decreased to < 100,000/mm3 in approximately 20% of subjects treated with PegIntron alone or with Rebetol and in 6% of adult subjects treated with INTRON A/Rebetol. Severe decreases in platelet counts (< 50,000/mm3) occur in < 4% of adult subjects. Subjects may require discontinuation or dose modification as a result of platelet decreases [see Dosage and Administration (2.4)]. In Study 2, 1% or 3% of subjects required dose modification of INTRON A or PegIntron, respectively. Platelet counts generally returned to pretreatment levels 4 weeks after the cessation of therapy.

Thyroid Function. Development of TSH abnormalities, with and without clinical manifestations, are associated with interferon therapies. In Study 2, clinically apparent thyroid disorders occur among subjects treated with either INTRON A or PegIntron (with or without Rebetol) at a similar incidence (5% for hypothyroidism and 3% for hyperthyroidism). Subjects developed new onset TSH abnormalities while on treatment and during the follow-up period. At the end of the follow-up period 7% of subjects still had abnormal TSH values.

Bilirubin and uric acid. In Study 2, 10 to 14% of subjects developed hyperbilirubinemia and 33 to 38% developed hyperuricemia in association with hemolysis. Six subjects developed mild to moderate gout.

Clinical Studies Experience – Rebetol/INTRON A Combination Therapy

Adult Subjects

In clinical trials, 19% and 6% of previously untreated and relapse subjects, respectively, discontinued therapy due to adverse reactions in the combination arms compared to 13% and 3% in the interferon arms. Selected treatment-related adverse reactions that occurred in the US studies with ≥ 5% incidence are provided by treatment group. In general, the selected treatment-related adverse reactions 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 Subjects

In clinical trials of 118 pediatric subjects 3 to 16 years of age, 6% discontinued therapy due to adverse reactions. Dose modifications were required in 30% of subjects, most commonly for anemia and neutropenia. In general, the adverse-reaction 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 subjects compared to adult subjects. Conversely, pediatric subjects experienced less fatigue, dyspepsia, arthralgia, insomnia, irritability, impaired concentration, dyspnea, and pruritus compared to adult subjects. Selected treatment-related adverse reactions that occurred with ≥ 5% incidence among all pediatric subjects who received the recommended dose of Rebetol/INTRON A combination therapy are provided in Table 10.

Table 10: Selected Treatment-Related Adverse Reactions: Previously Untreated and Relapse Adult Subjects and Previously Untreated Pediatric Subjects
Patients Reporting Adverse reactions* Percentage of Subjects
US Previously Untreated Study US Relapse Study Pediatric Subjects
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)
*
Subjects reporting one or more adverse reactions. A patient may have reported more than one adverse reaction 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

Laboratory Values

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

Hemoglobin. Hemoglobin decreases among subjects receiving Rebetol therapy began at Week 1, with stabilization by Week 4. In previously untreated subjects 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 subjects 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 subjects.

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 subjects with a previous diagnosis of Gilbert's syndrome. This has not been associated with hepatic dysfunction or clinical morbidity.

Table 11: Selected Hematologic Abnormalities During Treatment With Rebetol Plus INTRON A: Previously Untreated and Relapse Adult Subjects and Previously Untreated Pediatric Subjects
Percentage of Subjects
US Previously Untreated Study US Relapse Study Pediatric Subjects
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 to 10.9 24 1 32 1 21 3 24
  8.0 to 9.4 5 0 4 0 4 0 3
  6.5 to 7.9 0 0 0 0.4 0 0 0
  < 6.5 0 0 0 0 0 0 0
Leukocytes (x109/L)
  2.0 to 2.9 40 20 38 23 45 26 35
  1.5 to 1.9 4 1 9 2 5 3 8
  1.0 to 1.4 0.9 0 2 0 0 0 0
  < 1.0 0 0 0 0 0 0 0
Neutrophils (x109/L)
  1.0 to 1.49 30 32 31 44 42 34 37
  0.75 to 0.99 14 15 14 11 16 18 15
  0.5 to 0.74 9 9 14 7 8 4 16
  < 0.5 11 8 11 5 5 8 3
Platelets (x109/L)
  70 to 99 9 11 11 14 6 12 0.8
  50 to 69 2 3 2 3 0 5 2
  30 to 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 to 3.0 27 13 32 13 21 7 2
  3.1 to 6.0 0.9 0.4 2 0 3 0 0
  6.1 to 12.0 0 0 0.4 0 0 0 0
  > 12.0 0 0 0 0 0 0 0

Postmarketing Experiences

The following adverse reactions have been identified and reported during post approval use of Rebetol in combination with INTRON A or PegIntron. 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.

Blood and Lymphatic System disorders

 
Pure red cell aplasia, aplastic anemia

Ear and Labyrinth disorders

 
Hearing disorder, vertigo

Respiratory, Thoracic and mediastinal disorders

 
Pulmonary hypertension

Eye disorders

 
Serous retinal detachment

Endocrine disorders

 
Diabetes
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Side Effects by Body System - for Healthcare Professionals

General

The most common serious or life-threatening side effects induced or aggravated by ribavirin tablets in combination with peginterferon alfa-2a have included depression, suicide, relapse of drug abuse/overdose, and bacterial infections in less than 1% of patients and hepatic decompensation in 2% of chronic hepatitis C (CHC)-HIV coinfected patients. The most common serious side effect in CHC monoinfected (3%) and CHC-HIV coinfected (5%) patients receiving peginterferon alfa-2a alone or in combination with ribavirin tablets was bacterial infection (e.g., sepsis, osteomyelitis, endocarditis, pyelonephritis, pneumonia). Common side effects reported in CHC-HIV coinfected patients receiving ribavirin tablets in combination with peginterferon alfa-2a have included neutropenia, anemia, thrombocytopenia, weight decrease, and mood alteration.

The most common side effects reported in patients receiving ribavirin capsules/oral solution in combination with peginterferon alfa-2b or interferon alfa-2b were injection site inflammation/reaction, fatigue/asthenia, headache, rigors, fevers, nausea, myalgia, and anxiety/emotional lability/irritability. The most common serious side effects associated with peginterferon alfa-2b in combination with ribavirin capsules/oral solution were depression and suicidal ideation in less than 1% of patients. The most common fatal side effects reported in patients receiving peginterferon alfa-2b in combination with ribavirin capsules/oral solution were cardiac arrest, suicidal ideation, and suicide attempt in less than 1% of patients.

Respiratory

Mechanically ventilated patients may be predisposed to respiratory deterioration.

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.

Most signs and symptoms reported in exposed health care workers resolved within minutes to hours of stopping close exposure to aerosolized ribavirin.

Respiratory side effects associated with oral ribavirin in combination with peginterferon alfa-2a, peginterferon alfa-2b, or interferon alfa-2b have included dyspnea (up to 26%), cough (up to 23%), and exertional dyspnea (up to 7%). Pharyngitis (up to 13%), rhinitis (up to 8%), and sinusitis (up to 12%) have been reported with ribavirin capsules/oral solution in combination with peginterferon alfa-2b or interferon alfa-2b. Pulmonary symptoms (including dyspnea, pulmonary infiltrates, pneumonitis, pulmonary hypertension, pneumonia, and fatal pneumonia), sarcoidosis, and exacerbation of sarcoidosis have been reported with oral ribavirin in combination with alpha interferon. Pulmonary hypertension has been reported during postmarketing experience with ribavirin capsules/oral solution in combination with interferon alfa-2b or peginterferon alfa-2b. Significant deterioration of pulmonary function in patients with chronic obstructive pulmonary disease or asthma and minor pulmonary function abnormalities in healthy volunteers have been reported with aerosolized ribavirin. Asthmatic patients have also reported dyspnea and chest soreness with aerosolized ribavirin. Worsening of respiratory status, bronchospasm, hypoventilation, cyanosis, dyspnea, bronchoconstriction, bacterial pneumonia, cough, pneumothorax, pulmonary edema, apnea, atelectasis, hypoxia, and ventilator dependence have been reported with aerosolized ribavirin. Rhinitis and pharyngitis, as well as several cases of bronchospasm and/or chest pain (usually in individuals with underlying reactive airway disease), have been reported in health care workers exposed to aerosolized ribavirin.

Hypersensitivity

Hypersensitivity side effects have included reactions such as urticaria, angioedema, bronchoconstriction, and anaphylaxis in patients treated with alfa interferon and ribavirin. Severe skin reactions (including vesiculobullous eruptions, Stevens-Johnson syndrome, erythema multiforme, and exfoliative dermatitis/erythroderma) have been reported in patients treated with peginterferon alfa-2a alone or in combination with ribavirin tablets. 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 (up to 36%), pruritus (up to 29%), dermatitis (up to 16%), dry skin (up to 24%), increased sweating (up to 11%), rash (up to 34%), and eczema (up to 5%) have been associated with oral ribavirin in combination with peginterferon alfa-2a, peginterferon alfa-2b, or interferon alfa-2b. Grover's disease has been reported in a 55-year-old man 2 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. Skin disorders associated with ribavirin tablets in combination with peginterferon alfa-2a have included lichenoid eruptions and maculopapular rashes. Rash has been reported in patients treated with and health care workers exposed to aerosolized ribavirin. Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported during postmarketing experience with ribavirin tablets in combination with peginterferon alfa-2a.

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.

Rash associated with aerosolized ribavirin usually resolved within hours of stopping treatment in patients and within minutes to hours of stopping close exposure in health care workers.

Cardiovascular

Cardiovascular side effects have included angina, arrhythmia, and pulmonary embolism in less than 1% of patients treated with peginterferon alfa-2a alone or in combination with ribavirin tablets. Fatal and nonfatal myocardial infarctions have been reported in patients with anemia due to ribavirin capsules/oral solution. Cardiac arrest, hypotension, bradycardia, bigeminy, tachycardia, hypertension (usually slight increases in blood pressure), and digitalis toxicity have been reported with aerosolized ribavirin.

Bigeminy, bradycardia, and tachycardia have been reported in patients with underlying congenital heart disease.

Hematologic

Hemolytic anemia is the primary toxicity of ribavirin therapy. Hemoglobin levels generally declined within the first 1 to 2 weeks of oral therapy. Cardiac and pulmonary adverse effects associated with anemia have been reported in 10% of patients.

Hemoglobin less than 10 g/dL was reported in 13% of patients receiving ribavirin tablets in combination with peginterferon alfa-2a. Additional laboratory abnormalities during treatment with ribavirin tablets in combination with peginterferon alfa-2a or interferon alfa-2b have included decreased neutrophils (1000 to less than 1500 cells/mm3: up to 38%; 500 to less than 1000 cells/mm3: up to 49%; less than 500 cells/mm3: up to 5%), platelets (50,000 to less than 75,000 cells/mm3: up to 11%; 20,000 to less than 50,000 cells/mm3: up to 5%), and hemoglobin (8.5 to 9.9 g/dL: 11%; less than 8.5 g/dL: up to 2%).

Changes in laboratory values during treatment with ribavirin capsules/oral solution in combination with peginterferon alfa-2b or interferon alfa-2b have included decreased hemoglobin (9.5 to 10.9 g/dL: up to 32%; 8 to 9.4 g/dL: up to 5%; 6.5 to 7.9 g/dL: up to 0.2%), leukocytes [2 to 2.9 x 10(9)/L: up to 46%; 1.5 to 1.9 x 10(9)/L: up to 24%; 1 to 1.4 x 10(9)/L: up to 5%], neutrophils [1 to 1.49 x 10(9)/L: up to 42%; 0.75 to 0.99 x 10(9)/L: up to 25%; 0.5 to 0.74 x 10(9)/L: up to 18%; less than 0.5 x 10(9)/L: up to 11%], and platelets [70 to 99 x 10(9)/L: up to 15%; 50 to 69 x 10(9)/L: up to 3%; 30 to 49 x 10(9)/L: up to 0.2%; less than 30 x 10(9)/L: up to 1%].

Hematologic side effects associated with oral ribavirin in combination with peginterferon alfa-2a, peginterferon alfa-2b, or interferon alfa-2b have included anemia (up to 35%), lymphopenia (up to 14%), neutropenia (up to 40%), thrombocytopenia (up to 8%), and leukopenia (up to 10%). Hemolytic anemia is the most significant toxicity of ribavirin. Aplastic anemia and thrombotic thrombocytopenic purpura have been reported in less than 1% of patients treated with peginterferon alfa-2a alone or in combination with ribavirin tablets. Pancytopenia (marked decreases in red blood cells, neutrophils, and platelets) and bone marrow suppression have been reported following concomitant administration of pegylated interferon plus oral ribavirin and azathioprine. Aplastic anemia has been reported during postmarketing experience with ribavirin capsules/oral solution in combination with interferon alfa-2b or peginterferon alfa-2b. Pure red cell aplasia has been reported during postmarketing experience with oral ribavirin in combination with peginterferon alfa-2a, peginterferon alfa-2b, or interferon alfa-2b. Cases of anemia (type unspecified), reticulocytosis, and hemolytic anemia associated with aerosolized ribavirin have been reported during postmarketing experience and have been reversible with drug discontinuation.

Ocular

Ocular side effects associated with oral ribavirin in combination with peginterferon alfa-2a, peginterferon alfa-2b, or interferon alfa-2b have included blurred vision (up to 6%). Corneal ulcer has been reported in less than 1% of patients treated with peginterferon alfa-2a alone or in combination with ribavirin tablets. Conjunctivitis (up to 5%) has been reported with ribavirin capsules/oral solution in combination with peginterferon alfa-2b or interferon alfa-2b. Serous retinal detachment has been reported during postmarketing experience with oral ribavirin in combination with peginterferon alfa-2a, interferon alfa-2b, or peginterferon alfa-2b. Eye irritation and conjunctivitis have been reported in patients treated with and health care workers exposed to aerosolized ribavirin. Lacrimation has been reported in health care workers exposed to aerosolized ribavirin. Damage to contact lenses after prolonged close exposure to aerosolized ribavirin has also been reported.

Conjunctivitis associated with aerosolized ribavirin usually resolved within hours of stopping treatment in patients. Most signs and symptoms reported in exposed health care workers resolved within minutes to hours of stopping close exposure to aerosolized ribavirin.

Eye and conjunctival irritation resolved spontaneously when the caregivers left the hospital. In five of six cases, the caregivers were wearing contact lenses. After the staff stopped wearing contact lenses while caring for patients receiving aerosolized ribavirin, the reactions did not occur.

Gastrointestinal

Most signs and symptoms reported in exposed health care workers resolved within minutes to hours of stopping close exposure to aerosolized ribavirin.

Gastrointestinal side effects associated with oral ribavirin in combination with peginterferon alfa-2a, peginterferon alfa-2b, or interferon alfa-2b have included nausea (up to 47%), nausea and vomiting (up to 29%), diarrhea (up to 22%), vomiting (up to 14%), abdominal pain (up to 13%), dry mouth (up to 12%), dyspepsia (up to 16%), and constipation (5%). Peptic ulcer, gastrointestinal bleeding, pancreatitis, and colitis have been reported in less than 1% of patients treated with peginterferon alfa-2a alone or in combination with ribavirin tablets. Nausea has been reported in health care workers exposed to aerosolized ribavirin.

Musculoskeletal

Musculoskeletal side effects associated with oral ribavirin in combination with peginterferon alfa-2a, peginterferon alfa-2b, or interferon alfa-2b have included myalgia (up to 64%), arthralgia (up to 34%), musculoskeletal pain (up to 28%), and back pain (5%). Myositis has been reported in less than 1% of patients treated with peginterferon alfa-2a alone or in combination with ribavirin tablets. At least 6 cases of mild to moderate gout have been reported with ribavirin capsules/oral solution in combination with peginterferon alfa-2b or interferon alfa-2b.

Nervous system

Nervous system side effects associated with oral ribavirin in combination with peginterferon alfa-2a, peginterferon alfa-2b, or interferon alfa-2b have included headache (up to 66%), dizziness (excluding vertigo; 26%), and memory impairment (up to 6%). Peripheral neuropathy, coma, and cerebral hemorrhage have been reported in less than 1% of patients treated with peginterferon alfa-2a alone or in combination with ribavirin tablets. Taste perversion (up to 9%) has been reported with ribavirin capsules/oral solution in combination with peginterferon alfa-2b or interferon alfa-2b. Hearing impairment and hearing loss have been reported during postmarketing experience with ribavirin tablets in combination with peginterferon alfa-2a. Vertigo and hearing disorder have been reported during postmarketing experience with ribavirin capsules/oral solution in combination with interferon alfa-2b or peginterferon alfa-2b. Headache and dizziness have been reported in health care workers exposed to aerosolized ribavirin. Seizures have been reported with experimental intravenous ribavirin.

Most signs and symptoms reported in exposed health care workers resolved within minutes to hours of stopping close exposure to aerosolized ribavirin.

Metabolic

Metabolic side effects associated with oral ribavirin in combination with peginterferon alfa-2a, peginterferon alfa-2b, or interferon alfa-2b have included anorexia (up to 32%) and weight decrease (up to 29%). Diabetes mellitus has been reported in less than 1% of patients treated with peginterferon alfa-2a alone or in combination with ribavirin tablets. Falsely low hemoglobin A1c levels have been reported. Dehydration has been reported during postmarketing experience with ribavirin tablets in combination with peginterferon alfa-2a. Diabetes has been reported during postmarketing experience with ribavirin capsules/oral solution in combination with interferon alfa-2b or peginterferon alfa-2b.

Falsely low hemoglobin A1c levels may be due to ribavirin-induced hemolysis decreasing the number of circulating glycosylated hemoglobin molecules.

Psychiatric

Psychiatric side effects associated with oral ribavirin in combination with peginterferon alfa-2a, peginterferon alfa-2b, or interferon alfa-2b have included irritability/anxiety/nervousness/emotional lability (up to 47%), insomnia (up to 41%), depression (up to 36%), concentration impairment (up to 21%), mood alteration (up to 9%), and agitation (up to 8%). Suicide, suicidal ideation, psychosis, aggression, anxiety, drug abuse/overdose, psychotic disorder, and hallucination have been reported in less than 1% of patients treated with peginterferon alfa-2a alone or in combination with ribavirin tablets. Impairment of desire and the potential to affect sexual satisfaction have been reported with ribavirin tablets in combination with peginterferon alfa-2a in male patients.

Endocrine

Endocrine side effects associated with oral ribavirin in combination with peginterferon alfa-2a, peginterferon alfa-2b, or interferon alfa-2b have included hypothyroidism (up to 5%).

Other

Other side effects frequently associated with ribavirin tablets in combination with peginterferon alfa-2a have included influenza-like symptoms (such as fatigue, pyrexia, myalgia, headache, and rigors). Fatigue/asthenia (up to 70%), pyrexia (up to 55%), rigors (up to 48%), chills (up to 39%), influenza-like illness (up to 18%), unspecified pain (up to 13%), right upper quadrant pain (up to 12%), pain (up to 10%), chest pain (up to 9%), and malaise (up to 6%) have been associated with oral ribavirin in combination with peginterferon alfa-2a, peginterferon alfa-2b, or interferon alfa-2b. Hyperuricemia (in association with hemolysis; up to 38%) and flushing (up to 4%) have been reported with ribavirin capsules/oral solution in combination with peginterferon alfa-2b or interferon alfa-2b. Asthenia has been reported with experimental intravenous ribavirin.

Hepatic

Hepatic side effects have included hepatic dysfunction, fatty liver, and cholangitis in less than 1% of patients treated with peginterferon alfa-2a alone or in combination with ribavirin tablets. Hepatic decompensation has been reported in 2% of CHC-HIV coinfected patients receiving peginterferon alfa-2a in combination with ribavirin tablets. Hyperbilirubinemia (in association with hemolysis; up to 14%), hepatomegaly (4%), and increased ALT have been reported with ribavirin capsules/oral solution in combination with peginterferon alfa-2b or interferon alfa-2b.

Changes in laboratory values during treatment with ribavirin capsules/oral solution in combination with peginterferon alfa-2b or interferon alfa-2b have included increased total bilirubin (1.5 to 3 mg/dL: up to 32%; 3.1 to 6 mg/dL: up to 3%; 6.1 to 12 mg/dL: up to 0.4%) and ALT (2 x baseline: up to 0.6%; 2.1 to 5 x baseline: up to 3%).

Immunologic

Immunologic side effects associated with peginterferon alfa-2a alone or in combination with ribavirin tablets have included bacterial infection (e.g., sepsis, osteomyelitis, endocarditis, pyelonephritis, pneumonia) in 3% of CHC and 5% of CHC-HIV patients and autoimmune phenomena (such as hyperthyroidism, hypothyroidism, sarcoidosis, systemic lupus erythematosus, rheumatoid arthritis) in less than 1% of patients. Resistance mechanism disorders (overall: up to 12%), including viral infection (12%) and fungal infection (up to 6%), have been associated with oral ribavirin in combination with peginterferon alfa-2a, peginterferon alfa-2b, or interferon alfa-2b. Liver and renal graft rejections have been reported during postmarketing experience with ribavirin tablets in combination with peginterferon alfa-2a.

Genitourinary

Genitourinary side effects associated with ribavirin tablets in combination with peginterferon alfa-2a have included sexual dysfunction in male patients. Menstrual disorder has been reported with ribavirin capsules/oral solution in combination with peginterferon alfa-2b or interferon alfa-2b.

Local

Local side effects have included injection site reactions (up to 58%) in patients treated with oral ribavirin in combination with interferon alfa-2b, peginterferon alfa-2b, or peginterferon alfa-2a. Injection site inflammation (up to 25%) has been reported with ribavirin capsules/oral solution in combination with peginterferon alfa-2b or interferon alfa-2b. Skin disorders associated with ribavirin tablets in combination with peginterferon alfa-2a 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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