Ribavirin (Page 6 of 9)

8.6 Organ Transplant Recipients

The safety and efficacy of INTRON A alone or in combination with ribavirin for the treatment of hepatitis C in liver or other organ transplant recipients have not been established. In a small (n = 16) single-center, uncontrolled case experience, renal failure in renal allograft recipients receiving interferon alpha and ribavirin combination therapy was more frequent than expected from the center’s previous experience with renal allograft recipients not receiving combination therapy. The relationship of the renal failure to renal allograft rejection is not clear.

8.7 HIV or HBV Co-infection

The safety and efficacy of INTRON A/ribavirin for the treatment of patients with HCV co-infected with HIV or HBV have not been established.

10 OVERDOSAGE

There is limited experience with overdosage. Acute ingestion of up to 20 g of ribavirin capsules, INTRON A ingestion of up to 120 million units, and subcutaneous doses of INTRON A up to 10 times the recommended doses have been reported. Primary effects that have been observed are increased incidence and severity of the adverse reactions related to the therapeutic use of INTRON A and ribavirin. However, hepatic enzyme abnormalities, renal failure, hemorrhage, and myocardial infarction have been reported with administration of single subcutaneous doses of INTRON A that exceed dosing recommendations.

There is no specific antidote for INTRON A or ribavirin overdose, and hemodialysis and peritoneal dialysis are not effective for treatment of overdose of these agents.

11 DESCRIPTION

Ribavirin, USP is a synthetic nucleoside analogue (purine analogue). The chemical name of ribavirin, USP is 1-β-D-ribofuranosyl-1H -1,2,4-triazole-3-carboxamide and has the following structural formula:

ribavirin structural formula

C8 H12 N4 O5 M.W. 244.21

Ribavirin, USP is a white, crystalline powder. It is freely soluble in water and slightly soluble in anhydrous alcohol.

Ribavirin capsules consist of a white to off-white powder in an opaque white, hard gelatin capsule. Each capsule, for oral administration, contains 200 mg ribavirin, USP. In addition, each capsule contains the following inactive ingredients: calcium phosphate dibasic, croscarmellose sodium, FD&C blue # 2 aluminum lake, magnesium stearate, povidone, shellac and titanium dioxide. The gelatin capsule contains gelatin and titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Ribavirin is an antiviral agent [see Microbiology (12.4) ].

12.3 Pharmacokinetics

Single- and multiple-dose pharmacokinetic properties in adults are summarized in Table 11. Ribavirin was rapidly and extensively absorbed following oral administration. However, due to first-pass metabolism, the absolute bioavailability averaged 64% (44%). There was a linear relationship between dose and AUCtf (AUC from time zero to last measurable concentration) following single doses of 200 to 1200 mg ribavirin. The relationship between dose and Cmax was curvilinear, tending to asymptote above single doses of 400 to 600 mg.

Upon multiple oral dosing, based on AUC12hr , a 6 fold accumulation of ribavirin was observed in plasma. Following oral dosing with 600 mg twice daily, steady-state was reached by approximately 4 weeks, with mean steady-state plasma concentrations of 2200 ng/mL (37%). Upon discontinuation of dosing, the mean half-life was 298 (30%) hours, which probably reflects slow elimination from nonplasma compartments.

Effect of Antacid on Absorption of Ribavirin

Coadministration of ribavirin capsules with an antacid containing magnesium, aluminum, and simethicone resulted in a 14% decrease in mean ribavirin AUCtf . The clinical relevance of results from this single-dose study is unknown.

Table 11: Mean (% CV) Pharmacokinetic Parameters for Ribavirin When Administered Individually to Adults
*
N = 11.
Data obtained from a single-dose pharmacokinetic study using 14 C labeled ribavirin; N = 5.
N = 6.

Parameter

Ribavirin Capsules

Single-Dose 600 mg Capsules (N = 12)

Multiple-Dose 600 mg Capsules twice daily

(N = 12)

Tmax (hr)

1.7 (46)*

3 (60)

Cmax (ng/mL)

782 (37)

3680 (85)

AUCtf (ng•hr/mL)

13,400 (48)

228,000 (25)

T½ (hr)

43.6 (47)

298 (30)

Apparent Volume of Distribution (L)

2825 (9)

Apparent Clearance (L/hr)

38.2 (40)

Absolute Bioavailability

64% (44)

Tissue Distribution

Ribavirin transport into nonplasma compartments has been most extensively studied in red blood cells, and has been identified to be primarily via an es -type equilibrative nucleoside transporter. This type of transporter is present on virtually all cell types and may account for the extensive volume of distribution. Ribavirin does not bind to plasma proteins.

Metabolism and Excretion

Ribavirin has two pathways of metabolism: (i) a reversible phosphorylation pathway in nucleated cells; and (ii) a degradative pathway involving deribosylation and amide hydrolysis to yield a triazole carboxylic acid metabolite. Ribavirin and its triazole carboxamide and triazole carboxylic acid metabolites are excreted renally. After oral administration of 600 mg of 14 C-ribavirin, approximately 61% and 12% of the radioactivity was eliminated in the urine and feces, respectively, in 336 hours. Unchanged ribavirin accounted for 17% of the administered dose.

Special Populations

Renal Dysfunction

The pharmacokinetics of ribavirin were assessed after administration of a single oral dose (400 mg) of ribavirin to non HCV-infected subjects with varying degrees of renal dysfunction. The mean AUCtf value was threefold greater in subjects with creatinine clearance values between 10 to 30 mL/min when compared to control subjects (creatinine clearance greater than 90 mL/min). In subjects with creatinine clearance values between 30 to 60 mL/min, AUCtf was twofold greater when compared to control subjects. The increased AUCtf appears to be due to reduction of renal and nonrenal clearance in these subjects. Phase 3 efficacy trials included subjects with creatinine clearance values greater than 50 mL/min. The multiple-dose pharmacokinetics of ribavirin cannot be accurately predicted in patients with renal dysfunction. Ribavirin is not effectively removed by hemodialysis. Patients with creatinine clearance less than 50 mL/min should not be treated with ribavirin [see Contraindications (4) ].

Hepatic Dysfunction

The effect of hepatic dysfunction was assessed after a single oral dose of ribavirin (600 mg). The mean AUCtf values were not significantly different in subjects with mild, moderate, or severe hepatic dysfunction (Child-Pugh Classification A, B, or C) when compared to control subjects. However, the mean Cmax values increased with severity of hepatic dysfunction and was twofold greater in subjects with severe hepatic dysfunction when compared to control subjects.

Elderly Patients

Pharmacokinetic evaluations in elderly subjects have not been performed.

Gender

There were no clinically significant pharmacokinetic differences noted in a single-dose trial of 18 male and 18 female subjects.

Pediatric Patients

Multiple-dose pharmacokinetic properties for ribavirin capsules and INTRON A in pediatric subjects with chronic hepatitis C between 5 and 16 years of age are summarized in Table 12. The pharmacokinetics of ribavirin and INTRON A (dose-normalized) are similar in adults and pediatric subjects.

Complete pharmacokinetic characteristics of ribavirin oral solution have not been determined in pediatric subjects. Ribavirin Cmin values were similar following administration of ribavirin oral solution or ribavirin capsules during 48 weeks of therapy in pediatric subjects (3 to 16 years of age).

Table 12: Mean (% CV) Multiple-Dose Pharmacokinetic Parameters for INTRON A and Ribavirin Capsules When Administered to Pediatric Subjects With Chronic Hepatitis C
*
AUC12 (ng•hr/mL) for ribavirin; AUC0-24 (IU•hr/mL) for INTRON A.
ND = not done.

Parameter

Ribavirin

15 mg/kg/day as 2 divided doses

(N = 17)

INTRON A

3 MIU/m2 three times weekly

(N = 54)

Tmax (hr)

1.9 (83)

5.9 (36)

Cmax (ng/mL)

3275 (25)

51 (48)

AUC *

29,774 (26)

622 (48)

Apparent Clearance L/hr/kg

0.27 (27)

ND

Note: numbers in parentheses indicate % coefficient of variation.

Effect of Food on Absorption of Ribavirin

Both AUCtf and Cmax increased by 70% when ribavirin capsules were administered with a high-fat meal (841 kcal, 53.8 g fat, 31.6 g protein, and 57.4 g carbohydrate) in a single-dose pharmacokinetic study [see Dosage and Administration (2) ].

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