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Ribavirin (Ribavirin) - Indications and Dosage

 
 



INDICATIONS AND USAGE

Ribavirin capsules are indicated in combination with INTRON A (interferon alfa-2b, recombinant) Injection for the treatment of chronic hepatitis C in patients 18 years of age and older with compensated liver disease previously untreated with alpha interferon or in patients 18 years of age and older who have relapsed following alpha interferon therapy.

The safety and efficacy of ribavirin capsules with non-pegylated interferons other than the INTRON A product have not been established.


Description of Clinical Studies

Ribavirin/INTRON A Combination Therapy

Adult Patients

Previously Untreated Patients

Adults with compensated chronic hepatitis C and detectable HCV RNA (assessed by a central laboratory using a research-based RT-PCR assay) who were previously untreated with alpha interferon therapy were enrolled into two multi-center, double-blind trials (US and International) and randomized to receive ribavirin capsules 1200 mg/day (1000 mg/day for patients weighing ≤75 kg) plus INTRON A Injection 3 MIU TIW or INTRON A Injection plus placebo for 24 or 48 weeks followed by 24 weeks of off-therapy follow-up. The International study did not contain a 24-week INTRON A plus placebo treatment arm. The US study enrolled 912 patients who, at baseline, were 67% male, 89% Caucasian with a mean Knodell HAI score (I+II+III) of 7.5, and 72% genotype 1. The International study, conducted in Europe, Israel, Canada, and Australia, enrolled 799 patients (65% male, 95% Caucasian, mean Knodell score 6.8, and 58% genotype 1).

Study results are summarized in TABLE 2.


TABLE 2. Virologic and Histologic Responses: Previously Untreated Patients 1
US Study International Study
24 weeks of treatment 48 weeks of treatment

24 weeks of

treatment

48 weeks of treatment

INTRON A

plus

Ribavirin

(N=228)

INTRON A

plus

Placebo

(N=231)

INTRON A

plus

Ribavirin

(N=228)

INTRON A

plus

Placebo

(N=225)

INTRON A

plus

Ribavirin

(N=265)

INTRON A

plus

Ribavirin

(N=268)

INTRON A

plus

Placebo

(N=266)

Virologic

Response

Responder 2 65 (29) 13 (6) 85 (37) 27 (12) 86 (32)113 (42) 46 (17)
Nonresponder147 (64)194 (84)110 (48)168 (75)158 (60)120 (45)196 (74)
Missing Data 16 (7) 24 (10) 33 (14) 30 (13) 21 (8) 35 (13) 24 (9)

Histologic

Response

Improvement 3 102 (45) 77 (33) 96 (42) 65 (29)103 (39)102 (38) 69 (26)
No improvement 77 (34) 99 (43) 61 (27) 93 (41) 85 (32) 58 (22)111 (41)
Missing Data 49 (21) 55 (24) 71 (31) 67 (30) 77 (29)108 (40) 86 (32)

1 Number (%) of patients.
2 Defined as HCV RNA below limit of detection using a research based RT-PCR assay at end of treatment and during follow-up period.
3 Defined as posttreatment (end of follow-up) minus pretreatment liver biopsy Knodell HAI score (I+II+III) improvement of ≥2 points.


Of patients who had not achieved HCV RNA below the limit of detection of the research based assay by week 24 of ribavirin/INTRON A treatment, less than 5% responded to an additional 24 weeks of combination treatment.

Among patients with HCV Genotype 1 treated with ribavirin/INTRON A therapy who achieved HCV RNA below the detection limit of the research-based assay by 24 weeks, those randomized to 48 weeks of treatment had higher virologic responses compared to those in the 24 week treatment group. There was no observed increase in response rates for patients with HCV nongenotype 1 randomized to ribavirin/INTRON A therapy for 48 weeks compared to 24 weeks.

Relapse Patients

Patients with compensated chronic hepatitis C and detectable HCV RNA (assessed by a central laboratory using a research-based RT-PCR assay) who had relapsed following one or two courses of interferon therapy (defined as abnormal serum ALT levels) were enrolled into two multicenter, double-blind trials (US and International) and randomized to receive ribavirin 1200 mg/day (1000 mg/day for patients weighing ≤75 kg) plus INTRON A 3 MIU TIW or INTRON A plus placebo for 24 weeks followed by 24 weeks of off-therapy follow-up. The US study enrolled 153 patients who, at baseline, were 67% male, 92% Caucasian with a mean Knodell HAI score (I+II+III) of 6.8, and 58% genotype 1. The International study, conducted in Europe, Israel, Canada, and Australia, enrolled 192 patients (64% male, 95% Caucasian, mean Knodell score 6.6, and 56% genotype 1).

Study results are summarized in TABLE 3.

TABLE 3. Virologic and Histologic Responses: Relapse Patients 1
US Study International Study

INTRON A

plus

Ribavirin

(N=77)

INTRON A

plus

Placebo

(N=76)

INTRON A

plus

Ribavirin

(N=96)

INTRON A

plus

Placebo

(N=96)

Virologic

Response

Responder 2 33 (43)3 (4)46 (48)5 (5)
Nonresponder36 (47)66 (87)45 (47)91 (95)
Missing Data8 (10)7 (9)5 (5)0 (0)

Histologic

Response

Improvement 3 38 (49)27 (36)49 (51)30 (31)
No improvement23 (30)37 (49)29 (30)44 (46)
Missing Data16 (21)12 (16)18 (19)22 (23)

1 Number (%) of patients.
2 Defined as HCV RNA below limit of detection using a research based RT-PCR assay at end of treatment and during follow-up period.
3 Defined as posttreatment (end of follow-up) minus pretreatment liver biopsy Knodell HAI score (I+II+III) improvement of ≥2 points.

Virologic and histologic responses were similar among male and female patients in both the previously untreated and relapse studies.

INDICATIONS AND USAGE

Ribavirin capsules are indicated in combination with INTRON A (interferon alfa-2b, recombinant) Injection for the treatment of chronic hepatitis C in patients 18 years of age and older with compensated liver disease previously untreated with alpha interferon or in patients 18 years of age and older who have relapsed following alpha interferon therapy.

The safety and efficacy of ribavirin capsules with non-pegylated interferons other than the INTRON A product have not been established.


Description of Clinical Studies

Previously Untreated Patients

Adults with compensated chronic hepatitis C and detectable HCV RNA (assessed by a central laboratory using a research-based RT-PCR assay) who were previously untreated with alpha interferon therapy were enrolled into two multicenter, double-blind trials (US and International) and randomized to receive ribavirin capsules 1200 mg/day (1000 mg/day for patients weighing ≤75 kg) plus INTRON A Injection 3 MIU TIW or INTRON A Injection plus placebo for 24 or 48 weeks followed by 24 weeks of off-therapy follow-up. The International study did not contain a 24-week INTRON A plus placebo treatment arm. The US study enrolled 912 patients who, at baseline, were 67% male, 89% caucasian with a mean Knodell HAI score (I+II+III) of 7.5, and 72% genotype 1. The International study, conducted in Europe, Israel, Canada, and Australia, enrolled 799 patients (65% male, 95% caucasian, mean Knodell score 6.8, and 58% genotype 1).

Study results are summarized in TABLE 2.


TABLE 2. Virologic and Histologic Responses: Previously Untreated Patients 1
US Study International Study
24 weeks of treatment 48 weeks of treatment

24 weeks of

treatment

48 weeks of treatment

INTRON A

plus

Ribavirin

capsules

(N=228)

INTRON A

plus

Placebo

(N=231)

INTRON A

plus

Ribavirin

capsules

(N=228)

INTRON A

plus

Placebo

(N=225)

INTRON A

plus

Ribavirin

capsules

(N=265)

INTRON A

plus

Ribavirin

capsules

(N=268)

INTRON A

plus

Placebo

(N=266)

Virologic

Response

Responder 2 65 (29) 13 (6) 85 (37) 27 (12) 86 (32)113 (42) 46 (17)
Nonresponder147 (64)194 (84)110 (48)168 (75)158 (60)120 (45)196 (74)
Missing Data 16 (7) 24 (10) 33 (14) 30 (13) 21 (8) 35 (13) 24 (9)

Histologic

Response

Improvement 3 102 (45) 77 (33) 96 (42) 65 (29)103 (39)102 (38) 69 (26)
No improvement 77 (34) 99 (43) 61 (27) 93 (41) 85 (32) 58 (22)111 (41)
Missing Data 49 (21) 55 (24) 71 (31) 67 (30) 77 (29)108 (40) 86 (32)

1 Number (%) of patients.
2 Defined as HCV RNA below limit of detection using a research based RT-PCR assay at end of treatment and during follow-up period.
3 Defined as posttreatment (end of follow-up) minus pretreatment liver biopsy Knodell HAI score (I+II+III) improvement of ≥2 points.


Of patients who had not achieved HCV RNA below the limit of detection of the research based assay by week 24 of ribavirin capsules/INTRON A treatment, less than 5% responded to an additional 24 weeks of combination treatment.

Among patients with HCV genotype 1 treated with ribavirin capsules/INTRON A therapy who achieved HCV RNA below the detection limit of the research-based assay by 24 weeks, those randomized to 48 weeks of treatment had higher virologic responses compared to those in the 24-week treatment group. There was no observed increase in response rates for patients with HCV nongenotype 1 randomized to ribavirin capsules/INTRON A therapy for 48 weeks compared to 24 weeks.

Relapse Patients

Patients with compensated chronic hepatitis C and detectable HCV RNA (assessed by a central laboratory using a research based RT-PCR assay) who had relapsed following one or two courses of interferon therapy (defined as abnormal serum ALT levels) were enrolled into two multicenter, double-blind trials (US and International) and randomized to receive ribavirin capsules 1200 mg/day (1000 mg/day for patients weighing ≤75 kg) plus INTRON A 3 MIU TIW or INTRON A plus placebo for 24 weeks followed by 24 weeks of off-therapy follow-up. The US study enrolled 153 patients who, at baseline, were 67% male, 92% caucasian with a mean Knodell HAI score (I+II+III) of 6.8, and 58% genotype 1. The International study, conducted in Europe, Israel, Canada, and Australia, enrolled 192 patients (64% male, 95% caucasian, mean Knodell score 6.6, and 56% genotype 1).

Study results are summarized in TABLE 3.


TABLE 3. Virologic and Histologic Responses: Relapse Patients 1
US Study International Study

INTRON A

plus

Ribavirin

capsules

(N=77)

INTRON A

plus

Placebo

(N=76)

INTRON A

plus

Ribavirin

capsules

(N=96)

INTRON A

plus

Placebo

(N=96)

Virologic

Response

Responder 2 33 (43)3 (4)46 (48)5 (5)
Nonresponder36 (47)66 (87)45 (47)91 (95)
Missing Data8 (10)7 (9)5 (5)0 (0)

Histologic

Response

Improvement 3 38 (49)27 (36)49 (51)30 (31)
No improvement23 (30)37 (49)29 (30)44 (46)
Missing Data16 (21)12 (16)18 (19)22 (23)

1 Number (%) of patients.
2 Defined as HCV RNA below limit of detection using a research based RT-PCR assay at end of treatment and during follow-up period.
3 Defined as posttreatment (end of follow-up) minus pretreatment liver biopsy Knodell HAI score (I+II+III) improvement of ≥2 points.

Virologic and histologic responses were similar among male and female patients in both the previously untreated and relapse studies.

DOSAGE AND ADMINISTRATION

(See CLINICAL PHARMACOLOGY: Special Populations; see WARNINGS.)

Ribavirin/INTRON A Combination Therapy

Adults

The recommended dose of ribavirin capsules in patients 18 years of age and older depends on the patient’s body weight. The recommended dose of ribavirin is provided in TABLE 6.

The recommended duration of treatment for patients previously untreated with interferon is 24 to 48 weeks. The duration of treatment should be individualized to the patient depending on baseline disease characteristics, response to therapy, and tolerability of the regimen. (See Description of Clinical Studies and ADVERSE REACTIONS). After 24 weeks of treatment, virologic response should be assessed. Treatment discontinuation should be considered in any patient who has not achieved an HCV RNA below the limit of detection of the assay by 24 weeks. There are no safety and efficacy data on treatment for longer than 48 weeks in the previously untreated patient population.

In patients who relapse following non-pegylated interferon mono-therapy, the recommended duration of treatment is 24 weeks. There are no safety and efficacy data on treatment for longer than 24 weeks in the relapse patient population.


TABLE 6. Recommended Dosing for Patients 18 years of age and older
Body Weight Ribavirin Capsules

≤75 kg

2 x 200 mg capsules AM,

3 x 200 mg capsules PM

daily p.o.

>75 kg

3 x 200 mg capsules AM,

3 x 200 mg capsules PM

daily p.o.

Ribavirin may be administered without regard to food, but should be administered in a consistent manner with respect to food intake. (See CLINICAL PHARMACOLOGY).

Dose Modifications

(See TABLE 7.)

If severe adverse reactions or laboratory abnormalities develop during combination ribavirin/INTRON A therapy the dose should be modified, or discontinued if appropriate, until the adverse reactions abate. If intolerance persists after dose adjustment, ribavirin/INTRON A therapy should be discontinued.

Ribavirin should not be used in patients with creatinine clearance <50 mL/min. Subjects with impaired renal function and/or those over the age of 50 should be carefully monitored with respect to development of anemia. (See WARNINGS and CLINICAL PHARMACOLOGY: Special Populations).

Ribavirin should be administered with caution to patients with pre-existing cardiac disease. Patients should be assessed before commencement of therapy and should be appropriately monitored during therapy. If there is any deterioration of cardiovascular status, therapy should be stopped. (See WARNINGS).

For patients with a history of stable cardiovascular disease, a permanent dose reduction is required if the hemoglobin decreases by ≥2 g/dL during any 4-week period. In addition, for these cardiac history patients, if the hemoglobin remains <12 g/dL after 4 weeks on a reduced dose, the patient should discontinue combination ribavirin/INTRON A therapy.

It is recommended that a patient whose hemoglobin level falls below 10 g/dL have his/her ribavirin dose reduced to 600 mg daily (1 x 200 mg capsule AM, 2 x 200 mg capsules PM) for adults. A patient whose hemoglobin level falls below 8.5 g/dL should be permanently discontinued from ribavirin therapy. (See WARNINGS).


TABLE 7. Guidelines for Dose Modifications and Discontinuation for Anemia

Dose Reduction

Ribavirin –

600 mg daily adults

Permanent

Discontinuation of

Ribavirin Treatment

Hemoglobin
No Cardiac History < 10 g/dL < 8.5 g/dL

Cardiac History Patients

≥2 g/dL decrease

during any 4-week

period during treatment

< 12 g/dL after

4 weeks dose

reduction

DOSAGE AND ADMINISTRATION

INTRON A Injection should be administered subcutaneously and ribavirin capsules should be administered orally. Ribavirin capsules may be administered without regard to food, but should be administered in a consistent manner. (See CLINICAL PHARMACOLOGY.)

Adults

The recommended dose of ribavirin capsules in patients 18 years of age and older depends on the patient’s body weight. The recommended doses of ribavirin capsules and INTRON A for adults are given in TABLE 6.

The recommended duration of treatment for patients previously untreated with interferon is 24 to 48 weeks. The duration of treatment should be individualized to the patient depending on baseline disease characteristics, response to therapy, and tolerability of the regimen (see Description of Clinical Studies and ADVERSE REACTIONS). After 24 weeks of treatment virologic response should be assessed. Treatment discontinuation should be considered in any patient who has not achieved an HCV-RNA below the limit of detection of the assay by 24 weeks. There are no safety and efficacy data on treatment for longer than 48 weeks in the previously untreated patient population.

In patients who relapse following interferon therapy, the recommended duration of treatment is 24 weeks. There are no safety and efficacy data on treatment for longer than 24 weeks in the relapse patient population.

TABLE 6. Recommended Adult Dosing
Body Weight Ribavirin Capsules INTRON A Injection

≤75 kg

2 x 200 mg capsules AM,

3 x 200 mg capsules PM

daily p.o.

3 million

IU 3 times weekly s.c.

>75 kg

3 x 200 mg capsules AM,

3 x 200 mg capsules PM

daily p.o.

3 million

IU 3 times weekly s.c.

Under no circumstances should ribavirin capsules be opened, crushed or broken (see CONTRAINDICATIONS and WARNINGS).

Dose Modifications

(See TABLE 7.)

In clinical trials, approximately 26% of patients required modification of their dose of ribavirin capsules, INTRON A Injection, or both agents. If severe adverse reactions or laboratory abnormalities develop during combination ribavirin capsules/INTRON A therapy the dose should be modified, or discontinued if appropriate, until the adverse reactions abate. If intolerance persists after dose adjustment, ribavirin capsules/INTRON A therapy should be discontinued.

Ribavirin capsules/INTRON A therapy should be administered with caution to patients with preexisting cardiac disease. Patients should be assessed before commencement of therapy and should be appropriately monitored during therapy. If there is any deterioration of cardiovascular status, therapy should be stopped. (See WARNINGS.)

For patients with a history of stable cardiovascular disease, a permanent dose reduction is required if the hemoglobin decreases by ≥2 g/dL during any 4-week period. In addition, for these cardiac history patients, if the hemoglobin remains <12 g/dL after 4 weeks on a reduced dose, the patient should discontinue combination ribavirin capsules/INTRON A therapy.

It is recommended that a patient whose hemoglobin level falls below 10 g/dL have his/her ribavirin capsules dose reduced to 600 mg daily (1 x 200 mg capsule AM, 2 x 200 mg capsules PM). A patient whose hemoglobin level falls below 8.5 g/dL should be permanently discontinued from ribavirin capsules/INTRON A therapy. (See WARNINGS.)

It is recommended that a patient who experiences moderate depression (persistent low mood, loss of interest, poor self image, and/or hopelessness) have his/her INTRON A dose temporarily reduced and/or be considered for medical therapy. A patient experiencing severe depression or suicidal ideation/attempt should be discontinued from ribavirin capsules/INTRON A therapy and followed closely with appropriate medical management. (See WARNINGS.)


TABLE 7. Guidelines for Dose Modifications

Dose Reduction 1

Ribavirin capsules –

Adults 600 mg daily

INTRON A Adults

1.5 million IU TIW

Permanent

Discontinuation

of Treatment

Ribavirin capsules

and INTRON A

Hemoglobin

<10 g/dL

(Ribavirin capsules)

<8.5 g/dL

Cardiac History

Patients Only

≥2 g/dL decrease

during any 4-week

period during treatment

(Ribavirin capsules/

INTRON A)

< 12 g/dL after

4 weeks of dose

reduction

White blood count<1.5 x 109/L (INTRON A)<1.0 X 109/L
Neutrophil count<0.75 x 109/L (INTRON A)<0.5 X 109/L

Platelet count

Adults: <50 x 109/L

(INTRON A)

Adults: <25 x 109/L

1 Study medication to be dose reduced is shown in parenthesis.

Administration of INTRON A Injection

At the discretion of the physician, the patient may self-administer the INTRON A. [See illustrated Appendix to Medication Guide on ribavirin capsules for instructions.]

The Intron A Injection is supplied as a clear and colorless solution. The appropriate INTRON A dose should be withdrawn from the vial or set on the multidose pen and injected subcutaneously. The INTRON A Injection supplied with the B-D Safety Lok™ syringes contain a plastic sleeve to be pulled over the needle after use. The syringe locks with an audible click when the green stripe on the safety sleeve covers the red stripe on the needle. After administration of INTRON A Injection, it is essential to follow the procedure for proper disposal of syringes and needles. [See Appendix to Medication Guide on ribavirin capsules for detailed instructions.]

Vial/Pen Label Strength Fill Volume Concentration
3 million IU vial0.5 mL3 million IU/0.5 mL
18 million IU multidose vial 1 3.8 mL3 million IU/0.5 mL
18 million IU multidose pen 2 1.5 mL3 million IU/0.2 mL

1 This is a multidose vial which contains a total of 22.8 million IU of interferon alfa-2b, recombinant per 3.8 mL in order to provide the delivery of six 0.5-mL doses, each containing 3 million IU of interferon alfa-2b, recombinant (for a label strength of 18 million IU).
2 This is a multidose pen which contains a total of 22.5 million IU of interferon alfa-2b, recombinant per 1.5 mL in order to provide the delivery of six 0.2-mL doses, each containing 3 million IU of interferon alfa-2b, recombinant (for a label strength of 18 million IU).

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. INTRON A Injection may be administered using either sterilized glass or plastic disposable syringes.

Stability

INTRON A Injection provided in vials is stable at 35°C (95°F) for up to 7 days and at 30°C (86°F) for up to 14 days. INTRON A Injection provided in a multidose pen is stable at 30°C (86°F) for up to 2 days. The solution is clear and colorless.

HOW SUPPLIED

Ribavirin capsules, 200 mg are white, opaque, hard gelatin capsules imprinted (in blue) RIBAVIRIN over 200 mg on cap and GG 608 on body, and are supplied as follows:

NDC 0781-2043-42 in bottles of 42 capsules

NDC 0781-2043-16 in bottles of 56 capsules

NDC 0781-2043-67 in bottles of 70 capsules

NDC 0781-2043-04 in bottles of 84 capsules

NDC 0781-2043-01 in bottles of 100 capsules

NDC 0781-2043-28 in bottles of 168 capsules

NDC 0781-2043-10 in bottles of 1000 capsules

NDC 0781-2043-13 in unit dose packages of 100 capsules

Dispense in a tight container as defined in the USP.

Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].

HOW SUPPLIED

Ribavirin capsules, 200 mg are white, opaque, hard gelatin capsules imprinted (in blue) RIBAVIRIN over 200 mg on cap and GG 608 on body, and are supplied as follows:

NDC 0781-2043-42 in bottles of 42 capsules

NDC 0781-2043-16 in bottles of 56 capsules

NDC 0781-2043-67 in bottles of 70 capsules

NDC 0781-2043-04 in bottles of 84 capsules

NDC 0781-2043-01 in bottles of 100 capsules

NDC 0781-2043-28 in bottles of 168 capsules

NDC 0781-2043-10 in bottles of 1000 capsules

NDC 0781-2043-13 in unit dose package of 100 capsules

Dispense in a tight container as defined in the USP.

Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].

INTRON A Injection is a clear, colorless solution packaged in single dose and multidose vials, and a multidose pen.

INTRON A Injection and the INTRON A Multidose Pen should be stored refrigerated between 2° and 8°C (36° and 46°F).

INTRON® A is a registered trademark of Schering Corporation.

Mylanta® is a registered trademark of Johnson & Johnson-Merck Consumer Pharmaceuticals Co.

REBETOL® is a registered trademark of Schering Corporation.

REBETRON® is a registered trademark of Schering Corporation.

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