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Intron A Rebetol

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Intron A - Rebetol

Intron A Rebetol Side Effects Center

Medical Editor: John P. Cunha, DO, FACOEP

Rebetol (ribavirin) is an antiviral drug used in combination with Intron A (interferon alfa-2b, recombinant) Injection for the treatment of chronic hepatitis C in patients with compensated liver disease previously untreated with alpha interferon or who have relapsed following alpha interferon therapy. Common side effects include injection site inflammation/reaction, fatigue/weakness, headache, rigors, fevers, nausea, muscle pain, and anxiety/emotional instability/irritability.

The recommended dose of Rebetol Capsules depends on the patient's body weight. Rebetol may interact with didanosine, nucleoside reverse transcriptase inhibitors (NRTIs), lamivudine, stavudine, zidovudine, and azathioprine. Tell your doctor all medications and supplements you use. Rebetol is not recommended for use during pregnancy. It can cause birth defects or death in an unborn baby. You may need to have a negative pregnancy test before using this medication and every month during your treatment. If you are a man, do not use this drug if your female sexual partner is pregnant. Use at least 2 forms of birth control while either sexual partner is using this drug, and keep using 2 forms of birth control for at least 6 months after treatment ends. Tell your doctor right away if a pregnancy occurs while either the mother or the father is using Rebetol. It is unknown if this drug passes into breast milk. Consult your doctor before breastfeeding.

Our Rebetol (ribavirin) Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What is Prescribing information?

The FDA package insert formatted in easy-to-find categories for health professionals and clinicians.

Intron A Rebetol FDA Prescribing Information: Side Effects
(Adverse Reactions)

SIDE EFFECTS

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].

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 trials:

  • REBETOL/PegIntron Combination therapy trials:
    • Clinical Study 1 - evaluated PegIntron monotherapy (not further described in this label; see labeling for PegIntron for information about this trial).
    • 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 trials 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]. The most common serious events occurring in subjects treated with PegIntron and REBETOL were depression and suicidal ideation [see WARNINGS AND PRECAUTIONS], 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]. 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], 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 rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Clinical Trials Experience - REBETOL/PegIntron Combination Therapy

Adult Subjects

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

Table 5: Adverse Reactions Occurring in Greater Than 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)
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      
* A subject may have reported more than one adverse reaction within a body system/organ class category.

Table 6 summarizes the treatment-related adverse reactions in Study 4 that occurred at a greater than or equal to 10% incidence.

Table 6: Treatment-Related Adverse Reactions (Greater Than or Equal to 10% Incidence) By Descending Frequency

Adverse Reactions Study 4 Percentage of Subjects Reporting Treatment-Related Adverse Reactions
PegIntron 1.5 mcg/kgwith REBETOL
(N=1019)
PegIntron 1 mcg/kgwith REBETOL
(N=1016)
Pegasys 180 mcg withCopegus
(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 trials. In Study 3, there was a similar incidence of serious adverse reactions reported for the weight-based REBETOL group (12%) and for 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 that 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). 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 that 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 greater than 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%) (see Laboratory Values). Other common reasons included depression, fatigue, nausea, and thrombocytopenia. In Study 3, dose modifications due to adverse reactions occurred more frequently with weight-based dosing (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]. 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, and 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) tended to decrease as treatment continued. 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 re-treatment after failing a previous interferon combination regimen reported adverse reactions similar to those previously associated with this regimen during clinical trials of treatment-na´ve subjects.

Pediatric Subjects

In general, the adverse-reaction profile in the pediatric population was similar to that observed in adults. In the pediatric trial, 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 trial 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, three with clinical hypothyroidism and two with asymptomatic TSH elevations. Weight and height gain of pediatric subjects treated with PegIntron plus REBETOL lagged behind that predicted by normative population data for the entire length of treatment. Severely inhibited growth velocity (less than 3rd percentile) was observed in 70% of the subjects while on treatment.

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 greater than or equal to 10% incidence in the pediatric trial subjects are provided in Table 7.

Table 7: 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%

Ninety-four of 107 subjects enrolled in a 5 year long-term follow-up trial. The long-term effects on growth were less in those subjects treated for 24 weeks than those treated for 48 weeks. Twenty-four percent of subjects (11/46) treated for 24 weeks and 40% of subjects (19/48) treated for 48 weeks had a > 15 percentile height-for-age decrease from pre-treatment to the end of 5 year long-term follow-up compared to pre-treatment baseline percentiles. Eleven percent of subjects (5/46) treated for 24 weeks and 13% of subjects (6/48) treated for 48 weeks were observed to have a decrease from pre-treatment baseline of > 30 height-for-age percentiles to the end of the 5 year long-term follow-up. While observed across all age groups, the highest risk for reduced height at the end of long-term follow-up appeared to correlate with initiation of combination therapy during the years of expected peak growth velocity. [See WARNINGS AND PRECAUTIONS]

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 ]. Changes in selected laboratory values during therapy are described in Table 8. Most of the changes in laboratory values in the PegIntron/REBETOL trial with pediatrics were mild or moderate.

Table 8: Selected Laboratory Abnormalities During Treatment with REBETOL and PegIntron or REBETOL and INTRON A in Previously Untreated Subjects

Laboratory Parameters* Percentage of Subjects
Adults (Study 2) Pediatrics
PegIntron/ REBETOL
(N=511)
INTRON A/ REBETOL
(N=505)
PegIntron/ REBETOL
(N=107)*
Hemoglobin (g/dL)
  9.5 to < 11.0 26 27 30
  8.0 to < 9.5 3 3 2
  6.5-7.9 0.2 0.2 -
Leukocytes (x 109/L)
  2.0-2.9 46 41 39
  1.5 to < 2.0 24 8 3
  1.0-1.4 5 1 -
Neutrophils (x 109/L)
  1.0-1.5 33 37 35
  0.75 to < 1.0 25 13 26
  0.5 to < 0.75 18 7 13
   < 0.5 4 2 3
Platelets (x 109/L)
  70-100 15 5 1
  50 to < 70 3 0.8 -
  30-49 0.2 0.2 -
  25 to < 50 - - 1
Total Bilirubin (mg/dL) (μmole/L)
  1.5-3.0 10 13 -
  1.26-2.59 x ULN† - - 7
  3.1-6.0 0.6 0.2 -
  2.6-5 x ULN† - - -
  6.1-12.0 0 0.2 -
ALT (U/L)
  2 x Baseline 0.6 0.2 1
  2.1-5 x Baseline 3 1 5
  5.1-10 x Baseline 0 0 3
* 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.
† ULN=Upper limit of normal.

Hemoglobin

Hemoglobin levels decreased to less than 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 less than 11 g/dl. Reductions in hemoglobin to less than 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, subjects receiving PegIntron (1.5 mcg/kg)/REBETOL had decreases in hemoglobin levels to between 8.5 to less than 10 g/dL (28%) and to less than 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 became 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].

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 (less than 0.5 x 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 (less than 1%) required permanent discontinuation of treatment. Neutrophil counts generally returned to pre-treatment levels 4 weeks after cessation of therapy [see DOSAGE AND ADMINISTRATION].

Platelets

Platelet counts decreased to less than 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 (less than 50,000/mm³) occur in less than 4% of adult subjects. Patients may require discontinuation or dose modification as a result of platelet decreases [see DOSAGE AND ADMINISTRATION]. 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 or without clinical manifestations, is associated with interferon therapies. In Study 2, clinically apparent thyroid disorders occurred 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 Trials 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 trials with greater than or equal to 5% incidence are provided by treatment group (see Table 9). In general, the selected treatment-related adverse reactions were reported with lower incidence in the international trials as compared to the US trials, 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 greater than or equal to 5% incidence among all pediatric subjects who received the recommended dose of REBETOL/INTRON A combination therapy are provided in Table 9.

Table 9: Selected Treatment-Related Adverse Reactions: 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/ REBETOL
(N=228)
INTRON A/ Placebo
(N=231)
INTRON A/ REBETOL
(N=228)
INTRON A/ Placebo
(N=225)
INTRON A/ REBETOL
(N=77)
INTRON A/ Placebo
(N=76)
INTRON A/ 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

* Subjects reporting one or more adverse reactions. A subject may have reported more than one adverse reaction within a body system/organ class category.

During a 48-week course of therapy there was a decrease in the rate of linear growth (mean percentile assignment decrease of 7%) and a decrease in the rate of weight gain (mean percentile assignment decrease of 9%). A general reversal of these trends was noted during the 24-week post-treatment period. Long-term data in a limited number of patients, however, suggests that combination therapy may induce a growth inhibition that results in reduced final adult height in some patients [see WARNINGS AND PRECAUTIONS].

Laboratory Values

Changes in selected hematologic values (hemoglobin, white blood cells, neutrophils, and platelets) during therapy are described below (see Table 10).

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 trial and 2.9 g/dL in the international trial. In relapse subjects, the mean maximum decrease from baseline was 2.8 g/dL in the US trial and 2.6 g/dL in the international trial. 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 occurred most frequently in subjects with a previous diagnosis of Gilbert’s syndrome. This has not been associated with hepatic dysfunction or clinical morbidity.

Table 10: Selected Laboratory Abnormalities During Treatment With REBETOL and 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/ REBETOL
(N=228)
INTRON A/ Placebo
(N=231)
INTRON A/ REBETOL
(N=228)
INTRON A/ Placebo
(N=225)
INTRON A/ REBETOL
(N=77)
INTRON A/ Placebo
(N=76)
INTRON A/ 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 (x 109/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 (x 109/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 (x 109/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

Read the entire FDA prescribing information for Intron A Rebetol (Ribavirin, Interferon Alfa-2b, Recombinant) »

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Report Problems to the Food and Drug Administration

 

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


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