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Ribavirin (Ribavirin) - Warnings and Precautions

 
 



BOX WARNING

CONTRAINDICATIONS AND WARNINGS

Combination ribavirin capsules/INTRON A therapy is contraindicated in females who are pregnant and in the male partners of females who are pregnant. Extreme care must be taken to avoid pregnancy during therapy and for 6 months after completion of treatment in female patients, and in female partners of male patients who are taking combination ribavirin capsules/INTRON A therapy. Females of childbearing potential and males must use two reliable forms of effective contraception during treatment and during the 6-month posttreatment follow-up period. Significant teratogenic and/or embryocidal effects have been demonstrated for ribavirin in all animal species studied. See CONTRAINDICATIONS and WARNINGS.

Ribavirin capsules monotherapy is not effective for the treatment of chronic hepatitis C and should not be used for this indication. See WARNINGS.

Alpha interferons, including INTRON A, cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Patients with persistently severe or worsening signs or symptoms of these conditions should be withdrawn from therapy. In many but not all cases these disorders resolve after stopping INTRON A therapy. See WARNINGS and ADVERSE REACTIONS.

 

WARNINGS

Based on results of clinical trials ribavirin monotherapy is not effective for the treatment of chronic hepatitis C virus infection; therefore, ribavirin capsules must not be used alone. The safety and efficacy of ribavirin capsules with non-pegylated interferons other than INTRON A product have not been established.

There are significant adverse events caused by ribavirin/INTRON A therapy, including severe depression and suicidal ideation, hemolytic anemia, suppression of bone marrow function, autoimmune and infectious disorders, pulmonary dysfunction, pancreatitis, and diabetes. 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. The Appendix to this package insert should be reviewed in its entirety prior to initiation of therapy of ribavirin capsules taken together with INTRON A for additional safety information.

Pregnancy

Ribavirin capsules may cause birth defects and/or death of the exposed fetus. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Ribavirin capsules have demonstrated significant teratogenic and/or embryocidal effects in all animal species in which adequate studies have been conducted. These effects occurred at doses as low as one twentieth of the recommended human dose of ribavirin. RIBAVIRIN THERAPY SHOULD NOT BE STARTED UNTIL A REPORT OF A NEGATIVE PREGNANCY TEST HAS BEEN OBTAINED IMMEDIATELY PRIOR TO PLANNED INITIATION OF THERAPY. Patients should be instructed to use at least two forms of effective contraception during treatment and during the six month period after treatment has been stopped based on multiple dose half-life of ribavirin of 12 days. Pregnancy testing should occur monthly during ribavirin therapy and for six months after therapy has stopped (see CONTRAINDICATIONS and PRECAUTIONS: Information for Patients and Pregnancy Category X).

Anemia

The primary toxicity of ribavirin is hemolytic anemia, which was observed in approximately 10% of ribavirin/INTRON A-treated patients in clinical trials (see ADVERSE REACTIONS: Laboratory Values: Hemoglobin ). The anemia associated with ribavirin capsules occurs within 1 to 2 weeks of initiation of therapy. BECAUSE THE INITIAL DROP IN HEMOGLOBIN MAY BE SIGNIFICANT, IT IS ADVISED THAT HEMOGLOBIN OR HEMATOCRIT BE OBTAINED PRETREATMENT AND AT WEEK 2 AND WEEK 4 OF THERAPY, OR MORE FREQUENTLY IF CLINICALLY INDICATED. Patients should then be followed as clinically appropriate.

Fatal and nonfatal myocardial infarctions have been reported in patients with anemia caused by ribavirin. Patients should be assessed for underlying cardiac disease before initiation of ribavirin therapy. Patients with pre-existing cardiac disease should have electrocardiograms administered before treatment, and should be appropriately monitored during therapy. If there is any deterioration of cardiovascular status, therapy should be suspended or discontinued. (See DOSAGE AND ADMINISTRATION: Guidelines for Dose Modification). Because cardiac disease may be worsened by drug induced anemia, patients with a history of significant or unstable cardiac disease should not use ribavirin. (See ADVERSE REACTIONS).

Ribavirin and INTRON A therapy should be suspended in patients with signs and symptoms of pancreatitis and discontinued in patients with confirmed pancreatitis.

Ribavirin should not be used in patients with creatinine clearance <50 mL/min. (See CLINICAL PHARMACOLOGY: Special Populations).

Pulmonary

Pulmonary symptoms, including dyspnea, pulmonary infiltrates, pneumonitis and pneumonia, have been reported during therapy with ribavirin/INTRON A; occasional cases of fatal pneumonia have occurred. In addition, sarcoidosis or the exacerbation of sarcoidosis has been reported. If there is evidence of pulmonary infiltrates or pulmonary function impairment, the patient should be closely monitored, and if appropriate, combination ribavirin/INTRON A treatment should be discontinued.

Dental and Periodontal Disorders

Dental and periodontal disorders have been reported in patients receiving ribavirin and interferon combination therapy. In addition, dry mouth could have a damaging effect on teeth and mucous membranes of the mouth during long-term treatment with the combination of ribavirin capsules and interferon alfa-2b. Patients should brush their teeth thoroughly twice daily and have regular dental examinations. In addition, some patients may experience vomiting. If this reaction occurs, they should be advised to rinse out their mouth thoroughly afterwards.


PRECAUTIONS

The safety and efficacy of ribavirin/INTRON A therapy for the treatment of HIV infection, adenovirus, RSV, parainfluenza, or influenza infections have not been established. Ribavirin capsules should not be used for these indications. Ribavirin for inhalation has a separate package insert, which should be consulted if ribavirin inhalation therapy is being considered.

The safety and efficacy of ribavirin/INTRON A therapy has not been established in liver or other organ transplant patients, patients with decompensated liver disease due to hepatitis C infection, patients who are nonresponders to interferon therapy, or patients coinfected with HBV or HIV.

Information for Patients

Patients must be informed that ribavirin capsules may cause birth defects and/or death of the exposed fetus. Ribavirin must not be used by women who are pregnant or by men whose female partners are pregnant. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients taking ribavirin. Ribavirin should not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Patients must perform a pregnancy test monthly during therapy and for 6 months posttherapy. Women of childbearing potential must be counseled about use of effective contraception (two reliable forms) prior to initiating therapy. Patients (male and female) must be advised of the teratogenic/embryocidal risks and must be instructed to practice effective contraception during ribavirin and for 6 months posttherapy. Patients (male and female) should be advised to notify the physician immediately in the event of a pregnancy. (See CONTRAINDICATIONS and WARNINGS).

If pregnancy does occur during treatment or during 6 months posttherapy, the patient must be advised of the teratogenic risk of ribavirin therapy to the fetus. Patients, or partners of patients, should immediately report any pregnancy that occurs during treatment or within 6 months after treatment cessation to their physician. Physicians should report such cases by calling the Ribavirin Pregnancy Registry at 1-800-593-2214.

Patients receiving ribavirin capsules should be informed of the benefits and risks associated with treatment, directed in its appropriate use, and referred to the patient MEDICATION GUIDE for ribavirin capsules. Patients should be informed that the effect of treatment of hepatitis C infection on transmission is not known, and that appropriate precautions to prevent transmission of the hepatitis C virus should be taken.

The most common adverse experience occurring with ribavirin capsules is anemia, which may be severe. (See ADVERSE REACTIONS). Patients should be advised that laboratory evaluations are required prior to starting therapy and periodically thereafter. (See Laboratory Tests). It is advised that patients be well hydrated, especially during the initial stages of treatment.

Laboratory Tests

The following laboratory tests are recommended for all patients treated with ribavirin capsules, prior to beginning treatment and then periodically thereafter.

  • Standard hematologic tests – including hemoglobin (pretreatment, week 2 and week 4 of therapy, and as clinically appropriate [see WARNINGS ]), complete and differential white blood cell counts, and platelet count.
  • Blood chemistries – liver function tests and TSH.
  • Pregnancy – including monthly monitoring for women of childbearing potential.
  • ECG (See WARNINGS)

Carcinogenesis and Mutagenesis

Ribavirin did not cause an increase in any tumor type when administered for 6 months in the transgenic p53 deficient mouse model at doses up to 300 mg/kg (estimated human equivalent of 25 mg/kg based on body surface area adjustment for a 60 kg adult; approximately 1.9 times the maximum recommended human daily dose). Ribavirin was non-carcinogenic when administered for 2 years to rats at doses up to 40 mg/kg (estimated human equivalent of 5.71 mg/kg based on body surface area adjustment for a 60 kg adult). However, this dose was less than the maximum tolerated dose, and therefore the study was not adequate to fully characterize the carcinogenic potential of ribavirin.

Ribavirin demonstrated increased incidences of mutation and cell transformation in multiple genotoxicity assays. Ribavirin was active in the Balb/3T3 In Vitro Cell Transformation Assay. Mutagenic activity was observed in the mouse lymphoma assay, and at doses of 20 to 200 mg/kg (estimated human equivalent of 1.67 to 16.7 mg/kg, based on body surface area adjustment for a 60 kg adult; 0.1 to 1 times the maximum recommended human 24-hour dose of ribavirin) in a mouse micronucleus assay. A dominant lethal assay in rats was negative, indicating that if mutations occurred in rats they were not transmitted through male gametes.

Impairment of Fertility

Ribavirin demonstrated significant embryocidal and/or teratogenic effects at doses well below the recommended human dose in all animal species in which adequate studies have been conducted.

Fertile women and partners of fertile women should not receive ribavirin unless the patient and his/her partner are using effective contraception (two reliable forms). Based on a multiple dose half-life(t1/2) of ribavirin of 12 days, effective contraception must be utilized for 6 months posttherapy (e.g., 15 half-lives of clearance for ribavirin).

Ribavirin should be used with caution in fertile men. In studies in mice to evaluate the time course and reversibility of ribavirin-induced testicular degeneration at doses of 15 to 150 mg/kg/day (estimated human equivalent of 1.25 to 12.5 mg/kg/day, based on body surface area adjustment for a 60 kg adult; 0.1 to 0.8 times the maximum human 24-hour dose of ribavirin) administered for 3 or 6 months, abnormalities in sperm occurred. Upon cessation of treatment, essentially total recovery from ribavirin-induced testicular toxicity was apparent within 1 or 2 spermatogenesis cycles.

Animal Toxicology

Long-term studies in the mouse and rat (18 to 24 months; doses of 20 to 75 and 10 to 40 mg/kg/day, respectively {estimated human equivalent doses of 1.67 to 6.25 and 1.43 to 5.71 mg/kg/day, respectively, based on body surface area adjustment for a 60 kg adult; approximately 0.1 to 0.4 times the maximum human 24-hour dose of ribavirin}) have demonstrated a relationship between chronic ribavirin exposure and increased incidences of vascular lesions (microscopic hemorrhages) in mice. In rats, retinal degeneration occurred in controls, but the incidence was increased in ribavirin-treated rats.


Pregnancy Category X

(See CONTRAINDICATIONS.)

Ribavirin produced significant embryocidal and/or teratogenic effects in all animal species in which adequate studies have been conducted. Malformations of the skull, palate, eye, jaw, limbs, skeleton, and gastrointestinal tract were noted. The incidence and severity of teratogenic effects increased with escalation of the drug dose. Survival of fetuses and offspring was reduced. In conventional embryotoxicity/teratogenicity studies in rats and rabbits, observed no effect dose levels were well below those for proposed clinical use (0.3 mg/kg/day for both the rat and rabbit; approximately 0.06 times the recommended human 24-hour dose of ribavirin). No maternal toxicity or effects on offspring were observed in a peri/postnatal toxicity study in rats dosed orally at up to 1 mg/kg/day (estimated human equivalent dose of 0.17 mg/kg based on body surface area adjustment for a 60 kg adult; approximately 0.01 times the maximum recommended human 24-hour dose of ribavirin).

Treatment and Posttreatment

Potential Risk to the Fetus

Ribavirin is known to accumulate in intracellular components from where it is cleared very slowly. It is not known whether ribavirin contained in sperm will exert a potential teratogenic effect upon fertilization of the ova. In a study in rats, it was concluded that dominant lethality was not induced by ribavirin at doses up to 200 mg/kg for 5 days (estimated human equivalent doses of 7.14 to 28.6 mg/kg, based on body surface area adjustment for a 60 kg adult; up to 1.7 times the maximum recommended human dose of ribavirin). However, because of the potential human teratogenic effects of ribavirin, male patients should be advised to take every precaution to avoid risk of pregnancy for their female partners.

Women of childbearing potential should not receive ribavirin unless they are using effective contraception (two reliable forms) during the therapy period. In addition, effective contraception should be utilized for 6 months post-therapy based on a multiple-dose half-life (t1/2) of ribavirin of 12 days.

Male patients and their female partners must practice effective contraception (two reliable forms) during treatment with ribavirin and for the 6-month post-therapy period (e.g., 15 half-lives for ribavirin clearance from the body).

Ribavirin Pregnancy Registry

A Ribavirin Pregnancy Registry has been established to monitor maternal-fetal outcomes of pregnancies in female patients and female partners of male patients exposed to ribavirin during treatment and for six months following cessation of treatment. Physicians and patients are encouraged to report such cases by calling the Ribavirin Pregnancy Registry at 1-800-593-2214.

Nursing Mothers

It is not known whether the ribavirin product is excreted in human milk. Because of the potential for serious adverse reactions from the drug in nursing infants, a decision should be made whether to discontinue nursing or to delay or discontinue ribavirin capsules.

Geriatric Use

Clinical studies of ribavirin/INTRON A therapy did not include sufficient numbers of subjects aged 65 and over to determine if they respond differently from younger subjects.

Ribavirin is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients often have decreased renal function, care should be taken in dose selection. Renal function should be monitored and dosage adjustments should be made accordingly. Ribavirin should not be used in patients with creatinine clearance <50 mL/min. (See WARNINGS).

In general, ribavirin capsules should be administered to elderly patients cautiously, starting at the lower end of the dosing range, reflecting the greater frequency of decreased hepatic and/or cardiac function, and of concomitant disease or other drug therapy. In clinical trials, elderly subjects had a higher frequency of anemia (67%) than did younger patients (28%) (See WARNINGS).

Pediatric Use

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). As in adult patients, pediatric patients experienced other psychiatric adverse events (eg, depression, emotional lability, somnolence), anemia, and neutropenia (see WARNINGS). During a 48-week course of therapy there was a decrease in the rate of linear growth (mean percentile assignment decrease of 9%) and a decrease in the rate of weight gain (mean percentile assignment decrease of 13%). A general reversal of these trends was noted during the 24-week post-treatment period.

Drug Interactions

Didanosine

Co-administration of ribavirin capsules and didanosine is not recommended. Reports of fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactactemia/lactic acidosis have been reported in clinical trials (see CLINICAL PHARMACOLOGY: Drug Interactions).

Stavudine and Zidovudine

Ribavirin may antagonize the in vitro antiviral activity of stavudine and zidovudine against HIV. Therefore, concomitant use of ribavirin with either of these drugs should be used with caution (see CLINICAL PHARMACOLOGY: Drug Interactions).

WARNINGS

Pregnancy

Category X, may cause birth defects. See boxed CONTRAINDICATIONS AND WARNINGS. See CONTRAINDICATIONS.

Anemia

HEMOLYTIC ANEMIA (HEMOGLOBIN <10 G/DL) WAS OBSERVED IN APPROXIMATELY 10% OF RIBAVIRIN CAPSULES/INTRON A-TREATED PATIENTS IN CLINICAL TRIALS (See ADVERSE REACTIONS: Laboratory Values: Hemoglobin ). ANEMIA OCCURRED WITHIN 1 TO 2 WEEKS OF INITIATION OF RIBAVIRIN THERAPY. BECAUSE OF THIS INITIAL ACUTE DROP IN HEMOGLOBIN, IT IS ADVISED THAT COMPLETE BLOOD COUNTS (CBC) SHOULD BE OBTAINED PRETREATMENT AND AT WEEK 2 AND WEEK 4 OF THERAPY OR MORE FREQUENTLY IF CLINICALLY INDICATED. PATIENTS SHOULD THEN BE FOLLOWED AS CLINICALLY APPROPRIATE.

The anemia associated with ribavirin capsules/INTRON A therapy may result in deterioration of cardiac function and/or exacerbation of the symptoms of coronary disease. Patients should be assessed before initiation of therapy and should be appropriately monitored during therapy. If there is any deterioration of cardiovascular status, therapy should be suspended or discontinued. (See DOSAGE AND ADMINISTRATION.) Because cardiac disease may be worsened by drug induced anemia, patients with a history of significant or unstable cardiac disease should not use combination ribavirin capsules/INTRON A therapy. (See ADVERSE REACTIONS.)

Similarly, patients with hemoglobinopathies (e.g., thalassemia, sickle-cell anemia) should not be treated with combination ribavirin capsules/INTRON A therapy.

Psychiatric

Severe psychiatric adverse events, including depression, psychoses, aggressive behavior, hallucinations, violent behavior (suicidal ideation, suicidal attempts, suicides) and rare instances of homicidal ideation have occurred during combination ribavirin capsules/Intron A therapy, both in patients with and without a previous psychiatric disorder. Ribavirin capsules/Intron A therapy should be used with extreme caution in patients with a history of pre-existing psychiatric disorders, and all patients should be carefully monitored for evidence of depression and other psychiatric symptoms.

Suspension of ribavirin capsules/Intron A therapy should be considered if psychiatric intervention and/or dose reduction is unsuccessful in controlling psychiatric symptoms. In severe cases, therapy should be stopped immediately and psychiatric intervention sought. (See ADVERSE REACTIONS.)


Bone Marrow Toxicity

INTRON A therapy suppresses bone marrow function and may result in severe cytopenias including very rare events of aplastic anemia. It is advised that complete blood counts (CBC) be obtained pretreatment and monitored routinely during therapy (see PRECAUTIONS: Laboratory Tests). INTRON A therapy should be discontinued in patients who develop severe decreases in neutrophil (<0.5 x 109/L) or platelet counts (<25 x 109/L) (see DOSAGE AND ADMINISTRATION: Guidelines for Dose Modifications).

Pulmonary

Pulmonary symptoms, including dyspnea, pulmonary infiltrates, pneumonitis and pneumonia, have been reported during therapy with ribavirin capsules/INTRON A; occasional cases of fatal pneumonia have occurred. In addition, sarcoidosis or the exacerbation of sarcoidosis has been reported. If there is evidence of pulmonary infiltrates or pulmonary function impairment, the patient should be closely monitored, and if appropriate, combination ribavirin capsules/INTRON A treatment should be discontinued.

Other

  • Ribavirin capsules monotherapy is not effective for the treatment of chronic hepatitis C and should not be used for this indication.
  • Fatal and nonfatal pancreatitis has been observed in patients treated with ribavirin capsules/INTRON A therapy. Ribavirin capsules/INTRON A therapy should be suspended in patients with signs and symptoms of pancreatitis and discontinued in patients with confirmed pancreatitis.
  • Combination ribavirin capsules/INTRON A therapy should not be used in patients with creatinine clearance <50 mL/min.
  • Diabetes mellitus and hyperglycemia have been observed in patients treated with INTRON A.
  • Ophthalmologic disorders have been reported with treatment with alpha interferons (including INTRON A therapy). Investigators using alpha interferons have reported the occurrence of retinal hemorrhages, cotton wool spots, and retinal artery or vein obstruction in rare instances. Any patient complaining of loss of visual acuity or visual field should have an eye examination. Because these ocular events may occur in conjunction with other disease states, a visual exam prior to initiation of combination ribavirin capsules/INTRON A therapy is recommended in patients with diabetes mellitus or hypertension.
  • Acute serious hypersensitivity reactions (eg, urticaria, angioedema, bronchoconstriction, anaphylaxis) have been observed in INTRON A-treated patients; if such an acute reaction develops, combination ribavirin capsules/INTRON A therapy should be discontinued immediately and appropriate medical therapy instituted.
  • Combination ribavirin capsules/INTRON A therapy should be discontinued for patients developing thyroid abnormalities during treatment whose thyroid function cannot be controlled by medication.

PRECAUTIONS

Exacerbation of autoimmune disease has been reported in patients receiving alpha interferon therapy (including INTRON A therapy). Ribavirin capsules/INTRON A therapy should be used with caution in patients with other autoimmune disorders.

There have been reports of interferon, including INTRON A (interferon alfa-2b, recombinant) exacerbating pre-existing psoriasis; therefore, combination ribavirin capsules/INTRON A therapy should be used in these patients only if the potential benefit justifies the potential risk.

The safety and efficacy of ribavirin capsules/INTRON A therapy has not been established in liver or other organ transplant patients, decompensated hepatitis C patients, patients who are nonresponders to interferon therapy, or patients coinfected with HBV or HIV.

The safety and efficacy of ribavirin capsules monotherapy for the treatment of HIV infection, adenovirus, early RSV infection, parainfluenza, or influenza have not been established and ribavirin capsules should not be used for these indications.

There is no information regarding the use of ribavirin capsules with other interferons.

Triglycerides

Elevated triglyceride levels have been observed in patients treated with interferon including ribavirin capsules/INTRON A therapy. Elevated triglyceride levels should be managed as clinically appropriate. Severe hypertriglyceridemia (triglycerides >1000 mg/dL) may result in pancreatitis. Discontinuation of ribavirin capsules/INTRON A therapy should be considered for patients with persistently elevated triglycerides (triglycerides >1000 mg/dL) associated with symptoms of potential pancreatitis, such as abdominal pain, nausea, or vomiting (see WARNINGS: Other).

Drug Interactions

Nucleoside Analogs

Administration of nucleoside analogues has resulted in fatal and nonfatal lactic acidosis. Coadministration of ribavirin and nucleoside analogues should be undertaken with caution and only if the potential benefit outweighs the potential risks.

Information for Patients

Combination ribavirin capsules/INTRON A therapy must not be used by females who are pregnant or by males whose female partners are pregnant. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients taking combination ribavirin capsules/INTRON A therapy. Combination ribavirin capsules/INTRON A therapy should not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Patients must perform a pregnancy test monthly during therapy and for 6 months posttherapy. Females of childbearing potential must be counseled about use of effective contraception (two reliable forms) prior to initiating therapy. Patients (male and female) must be advised of the teratogenic/embryocidal risks and must be instructed to practice effective contraception during combination ribavirin capsules/INTRON A therapy and for 6 months posttherapy. Patients (male and female) should be advised to notify the physician immediately in the event of a pregnancy. (See CONTRAINDICATIONS).

If pregnancy does occur during treatment or during 6 months posttherapy, the patient must be advised of the significant teratogenic risk of ribavirin capsules therapy to the fetus. Patients, or partners of patients, should immediately report any pregnancy that occurs during treatment or within 6 months after treatment cessation to their physician. Physicians are encouraged to report such cases by calling the Ribavirin Pregnancy Registry at 1-800-593-2214.

Patients receiving combination ribavirin capsules/INTRON A treatment should be directed in its appropriate use, informed of the benefits and risks associated with treatment, and referred to the Appendix of the Medication Guide on ribavirin capsules. There are no data evaluating whether ribavirin capsules/INTRON A therapy will prevent transmission of infection to others. Also, it is not known if treatment with ribavirin capsules/INTRON A therapy will cure hepatitis C or prevent cirrhosis, liver failure, or liver cancer that may be the result of infection with the hepatitis C virus.

If home use is prescribed, a puncture-resistant container for the disposal of used syringes and needles should be supplied to the patient. Patients should be thoroughly instructed in the importance of proper disposal and cautioned against any reuse of needles and syringes. The full container should be disposed of according to the directions provided by the physician. [see Appendix to the Medication Guide on ribavirin capsules.] To avoid possible transmission of disease, do not share your multidose pen with anyone; it is for you and you alone.

The most common adverse experiences occurring with combination ribavirin capsules/INTRON A therapy are “flu-like” symptoms, such as headache, fatigue, myalgia, and fever (see ADVERSE REACTIONS) and appear to decrease in severity as treatment continues. Some of these “flu-like” symptoms may be minimized by bedtime administration of INTRON A therapy. Antipyretics should be considered to prevent or partially alleviate the fever and headache. Another common adverse experience associated with INTRON A therapy is thinning of the hair.

Patients should be advised that laboratory evaluations are required prior to starting therapy and periodically thereafter (see Laboratory Tests). It is advised that patients be well hydrated, especially during the initial stages of treatment.

Laboratory Tests

The following laboratory tests are recommended for all patients on combination ribavirin capsules/INTRON A therapy, prior to beginning treatment and then periodically thereafter.

  • Standard hematologic tests – including hemoglobin (pretreatment, week 2 and week 4 of therapy, and as clinically appropriate [see WARNINGS ]), complete and differential white blood cell counts, and platelet count.
  • Blood chemistries – liver function tests and TSH.
  • Pregnancy – including monthly monitoring for females of child bearing potential.

Carcinogenesis and Mutagenesis

Carcinogenicity studies with interferon alfa-2b, recombinant have not been performed because neutralizing activity appears in the serum after multiple dosing in all of the animal species tested.

Ribavirin did not cause an increase in any tumor type when administered for 6 months in the transgenic p53 deficient mouse model at doses up to 300 mg/kg (estimated human equivalent of 25 mg/kg based on body surface area adjustment for a 60 kg adult; approximately 1.9 times the maximum recommended human daily dose). Ribavirin was non-carcinogenic when administered for 2 years to rats at doses up to 40 mg/kg (estimated human equivalent of 5.71 mg/kg based on body surface area adjustment for a 60 kg adult). However, this dose was less than the maximum tolerated dose, and therefore the study was not adequate to fully characterize the carcinogenic potential of ribavirin.

Mutagenicity studies have demonstrated that interferon alfa-2b, recombinant is not mutagenic. Ribavirin demonstrated increased incidences of mutation and cell transformation in multiple genotoxicity assays. Ribavirin was active in the Balb/3T3 In Vitro Cell Transformation Assay. Mutagenic activity was observed in the mouse lymphoma assay, and at doses of 20 to 200 mg/kg (estimated human equivalent of 1.67 to 16.7 mg/kg, based on body surface area adjustment for a 60 kg adult; 0.1 to 1 times the maximum recommended human 24-hour dose of ribavirin) in a mouse micronucleus assay. A dominant lethal assay in rats was negative, indicating that if mutations occurred in rats they were not transmitted through male gametes.

Impairment of Fertility

No reproductive toxicology studies have been performed using interferon alfa-2b, recombinant in combination with ribavirin. However, evidence provided below for interferon alfa-2b, recombinant and ribavirin when administered alone indicate that both agents have adverse effects on reproduction. It should be assumed that the effects produced by either agent alone will also be caused by the combination of the two agents. Interferons may impair human fertility. In studies of interferon alfa-2b recombinant administration in nonhuman primates, menstrual cycle abnormalities have been observed. Decreases in serum estradiol and progesterone concentrations have been reported in females treated with human leukocyte interferon. In addition, ribavirin demonstrated significant embryocidal and/or teratogenic effects at doses well below the recommended human dose in all animal species in which adequate studies have been conducted.

Fertile females and partners of fertile females should not receive combination ribavirin capsules/INTRON A therapy unless the patient and his/her partner are using effective contraception (two reliable forms). Based on a multiple dose half-life (t1/2 ) of ribavirin of 12 days, effective contraception must be utilized for 6 months posttherapy (e.g., 15 half-lives of clearance for ribavirin).

Combination ribavirin capsules/INTRON A therapy should be used with caution in fertile males. In studies in mice to evaluate the time course and reversibility of ribavirin-induced testicular degeneration at doses of 15 to 150 mg/kg/day (estimated human equivalent of 1.25 to 12.5 mg/kg/day, based on body surface area adjustment for a 60 kg adult; 0.1 to 0.8 times the maximum human 24-hour dose of ribavirin) administered for 3 or 6 months, abnormalities in sperm occurred. Upon cessation of treatment, essentially total recovery from ribavirin-induced testicular toxicity was apparent within 1 or 2 spermatogenesis cycles.

Animal Toxicology

Long-term studies in the mouse and rat (18 to 24 months; doses of 20 to 75 and 10 to 40 mg/kg/day, respectively [estimated human equivalent doses of 1.67 to 6.25 and 1.43 to 5.71 mg/kg/day, respectively, based on body surface area adjustment for a 60 kg adult; approximately 0.1 to 0.4 times the maximum human 24-hour dose of ribavirin]) have demonstrated a relationship between chronic ribavirin exposure and increased incidences of vascular lesions (microscopic hemorrhages) in mice. In rats, retinal degeneration occurred in controls, but the incidence was increased in ribavirin-treated rats.

Pregnancy Category X:

(See CONTRAINDICATIONS.)

Interferon alfa-2b, recombinant has been shown to have abortifacient effects in Macaca mulatta (rhesus monkeys) at 15 and 30 million IU/kg (estimated human equivalent of 5 and 10 million IU/kg, based on body surface area adjustment for a 60 kg adult). There are no adequate and well-controlled studies in pregnant females.

Ribavirin produced significant embryocidal and/or teratogenic effects in all animal species in which adequate studies have been conducted. Malformations of the skull, palate, eye, jaw, limbs, skeleton, and gastrointestinal tract were noted. The incidence and severity of teratogenic effects increased with escalation of the drug dose. Survival of fetuses and offspring was reduced. In conventional embryotoxicity/teratogenicity studies in rats and rabbits, observed no effect dose levels were well below those for proposed clinical use (0.3 mg/kg/day for both the rat and rabbit; approximately 0.06 times the recommended human 24-hour dose of ribavirin). No maternal toxicity or effects on offspring were observed in a peri/postnatal toxicity study in rats dosed orally at up to 1 mg/kg/day (estimated human equivalent dose of 0.17 mg/kg based on body surface area adjustment for a 60 kg adult; approximately 0.01 times the maximum recommended human 24-hour dose of ribavirin).

Treatment and Posttreatment

Potential Risk to the Fetus

Ribavirin is known to accumulate in intracellular components from where it is cleared very slowly. It is not known whether ribavirin contained in sperm will exert a potential teratogenic effect upon fertilization of the ova. In a study in rats, it was concluded that dominant lethality was not induced by ribavirin at doses up to 200 mg/kg for 5 days (estimated human equivalent doses of 7.14 to 28.6 mg/kg, based on body surface area adjustment for a 60 kg adult; up to 1.7 times the maximum recommended human dose of ribavirin). However, because of the potential human teratogenic effects of ribavirin, male patients should be advised to take every precaution to avoid risk of pregnancy for their female partners.

Females of childbearing potential should not receive combination ribavirin capsules/INTRON A therapy unless they are using effective contraception (two reliable forms) during the therapy period. In addition, effective contraception should be utilized for 6 months posttherapy based on a multiple dose half-life (t1/2) of ribavirin of 12 days.

Male patients and their female partners must practice effective contraception (two reliable forms) during treatment with combination ribavirin capsules/INTRON A therapy and for the 6-month posttherapy period (e.g., 15 half-lives for ribavirin clearance from the body).

If pregnancy occurs in a patient or partner of a patient during treatment or during the 6 months after treatment cessation, physicians are encouraged to report such cases by calling the Ribavirin Pregnancy Registry at (800) 593-2214.

Ribavirin Pregnancy Registry

A Ribavirin Pregnancy Registry has been established to monitor maternal-fetal outcomes of pregnancies in female patients and female partners of male patients exposed to ribavirin during treatment and for six months following cessation of treatment. Physicians and patients are encouraged to report such cases by calling the Ribavirin Pregnancy Registry at 1-800-593-2214.

Nursing Mothers

It is not known whether ribavirin capsules and INTRON A are excreted in human milk. However, studies in mice have shown that mouse interferons are excreted into the milk. Because of the potential for serious adverse reactions from the drugs in nursing infants, a decision should be made whether to discontinue nursing or to discontinue combination ribavirin capsules/INTRON A therapy, taking into account the importance of the therapy to the mother.

Pediatric Use

Suicidal ideation or attempts occurred more frequently among pediatric patients compared to adult patients (2.4% versus 1%) during treatment and off therapy follow-up (see WARNINGS). As in adult patients, pediatric patients experienced other psychiatric adverse events (e.g., depression, emotional lability, somnolence), anemia, and neutropenia (see WARNINGS). 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.

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 pruritis compared to adult patients.

Geriatric Use

Clinical studies of combination therapy of ribavirin capsules taken together with INTRON A did not include sufficient numbers of subjects aged 65 and over to determine if they respond differently from younger subjects. In clinical trials, elderly subjects had a higher frequency of anemia (67%) than did younger patients (28%) (see WARNINGS).

In general, ribavirin capsules should be administered to elderly patients cautiously, starting at the lower end of the dosing range, reflecting the greater frequency of decreased renal, hepatic and/or cardiac function, and of concomitant disease or other drug therapy.

Ribavirin capsules are known to be substantially excreted by the kidney, and the risk of adverse reactions to ribavirin may be greater in patients with impaired renal function. Because elderly patients often have decreased renal function, care should be taken in dose selection. Renal function should be monitored and dosage adjustments of ribavirin should be made accordingly (see DOSAGE AND ADMINISTRATION: Guidelines for Dose Modification). Ribavirin capsules should not be used in elderly patients with creatinine clearance <50 mL/min (see WARNINGS).

Ribavirin capsules taken together with INTRON A should be used very cautiously in elderly patients with a history of psychiatric disorders (see WARNINGS).


Page last updated: 2008-01-17

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