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Ribavirin (Ribavirin) - Description and Clinical Pharmacology

 
 



DESCRIPTION

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

Ribavirin is a white, crystalline powder. It is freely soluble in water and slightly soluble in anhydrous alcohol. The empirical formula is C8H12N4O5 and the molecular weight is 244.21.

Ribavirin capsules consist of white powder in a white, opaque, gelatin capsule. Each capsule, for oral administration, contains 200 mg ribavirin. In addition, each capsule contains the following inactive ingredients: croscarmellose sodium, hypromellose, magnesium stearate, mannitol and povidone. The capsule shell consists of gelatin and titanium dioxide. The capsule is printed with edible blue pharmaceutical ink which is made of FD&C Blue #2 aluminum lake, propylene glycol, shellac and titanium dioxide.

Mechanism of Action

The mechanism of inhibition of hepatitis C virus (HCV) RNA by combination therapy with ribavirin and interferon products has not been established.

DESCRIPTION

Ribavirin Capsules

Ribavirin is a nucleoside analog with antiviral activity. The chemical name of ribavirin is 1-β-D-ribofuranosyl-1 H -1,2,4-triazole-3-carboxamide and has the following structural formula:

Ribavirin is a white, crystalline powder. It is freely soluble in water and slightly soluble in anhydrous alcohol. The molecular formula is C8H12N4O5 and the molecular weight is 244.21.

Ribavirin capsules consist of white powder in a white, opaque, gelatin capsule. Each capsule, for oral administration, contains 200 mg ribavirin. In addition, each capsule contains the following inactive ingredients: croscarmellose sodium, hypromellose, magnesium stearate, mannitol and povidone. The capsule shell consists of gelatin and titanium dioxide. The capsule is printed with edible blue pharmaceutical ink which is made of FD&C Blue #2 aluminum lake, propylene glycol, shellac and titanium dioxide.

INTRON A

INTRON A is Schering Corporation’s brand name for interferon alfa-2b, recombinant, a purified, sterile, recombinant interferon product.

Interferon alfa-2b, recombinant has been classified as an alpha interferon and is a water-soluble protein composed of 165 amino acids with a molecular weight of 19,271 daltons produced by recombinant DNA techniques. It is obtained from the bacterial fermentation of a strain of Escherichia coli bearing a genetically engineered plasmid containing an interferon alfa-2b gene from human leukocytes. The fermentation is carried out in a defined nutrient medium containing the antibiotic tetracycline hydrochloride at a concentration of 5 to 10 mg/L; the presence of this antibiotic is not detectable in the final product.

INTRON A Injection is a clear, colorless solution. The 3 million IU vial of INTRON A Injection contains 3 million IU of interferon alfa-2b, recombinant per 0.5 mL. The 18 million IU multidose vial of INTRON A Injection contains a total of 22.8 million IU of interferon alfa-2b, recombinant per 3.8 mL (3 million IU/0.5 mL) in order to provide the delivery of six 0.5 mL doses, each containing 3 million IU of INTRON A (for a label strength of 18 million IU). The 18 million IU INTRON A Injection multidose pen contains a total of 22.5 million IU of interferon alfa-2b, recombinant per 1.5 mL (3 million IU/0.2 mL) in order to provide the delivery of six 0.2-mL doses, each containing 3 million IU of INTRON A (for a label strength of 18 million IU). Each mL also contains 7.5 mg sodium chloride, 1.8 mg sodium phosphate dibasic, 1.3 mg sodium phosphate monobasic, 0.1 mg edetate disodium, 0.1 mg polysorbate 80, and 1.5 mg m-cresol as a preservative.

Based on the specific activity of approximately 2.6 x 108 IU/mg protein as measured by HPLC assay, the corresponding quantities of interferon alfa-2b, recombinant in the vials and pen described above are approximately 0.012 mg, 0.088 mg, and 0.087 mg protein, respectively.

Mechanism of Action

Ribavirin/Interferon alfa-2b, recombinant

The mechanism of inhibition of hepatitis C virus (HCV) RNA by combination therapy with ribavirin capsules and INTRON A has not been established.

CLINICAL PHARMACOLOGY

Pharmacokinetics

Ribavirin

Single- and multiple-dose pharmacokinetic properties in adults are summarized in TABLE 1. Ribavirin was rapidly and extensively absorbed following oral administration. However, due to first-pass metabolism, the absolute bioavailability averaged 64% (44%) [In this section of the label, numbers in parenthesis indicate % coefficient of variation.] . 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 sixfold accumulation of ribavirin was observed in plasma. Following oral dosing with 600 mg BID, steady-state was reached by approximately 4 weeks, with mean steady-state plasma concentrations of 2200 (37%) ng/mL. Upon discontinuation of dosing, the mean half-life was 298 (30%) hours, which probably reflects slow elimination from nonplasma compartments.

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. There are insufficient data to address the clinical relevance of these results. Clinical efficacy studies with ribavirin/INTRON® A (interferon alfa-2b, recombinant) were conducted without instructions with respect to food consumption. During clinical studies with ribavirin/INTRON A, all subjects were instructed to take ribavirin capsules with food. (See DOSAGE AND ADMINISTRATION).

Effect of Antacid on Absorption of Ribavirin

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


TABLE 1. Mean (% CV) Pharmacokinetic Parameters for Ribavirin Capsules when Administered Individually to Adults
Ribavirin Capsules
Parameter

Single Dose

600 mg

Capsules

(N=12)

Multiple Dose

600 mg BID

Capsules

(N=12)

Tmax (hr) 1.7 (46) 1 3 (60)
Cmax 2 782 (37) 3680 (85)
AUCtf 3 13400 (48)228000 (25)
T1/2 (hr) 43.6 (47) 298 (30)
Apparent Volume of Distribution (L) 2825 (9) 4
Apparent Clearance (L/hr) 38.2 (40)
Absolute Bioavailability 64% (44) 5

1 N=11
2 ng/mL
3 ng•hr/mL
4 data obtained from a single-dose pharmacokinetic study using 14C labeled ribavirin; N=5
5 N=6

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.

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 14C-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.

Results of in vitro studies using both human and rat liver microsome preparations indicated little or no cytochrome P450 enzyme-mediated metabolism of ribavirin, with minimal potential for P450 enzyme-based drug interactions.

No pharmacokinetic interactions were noted between INTRON A injection and ribavirin capsules in a multiple-dose pharmacokinetic study.

Drug Interactions

Ribavirin has been shown in vitro to inhibit phosphorylation of zidovudine and stavudine which could lead to decreased antiretroviral activity. Exposure to didanosine or its active metabolite (dideoxyadenosine 5’-triphosphate) is increased when didanosine is coadministered with ribavirin, which could cause or worsen clinical toxicities (see PRECAUTIONS: Drug Interactions).

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 >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 non-renal clearance in these patients. Phase III efficacy trials included subjects with creatinine clearance values >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 <50 mL/min should not be treated with ribavirin (See WARNINGS).

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 study of eighteen male and eighteen female subjects.

CLINICAL PHARMACOLOGY

Pharmacokinetics

Interferon alfa-2b, recombinant

Single- and multiple-dose pharmacokinetic properties of INTRON A (interferon alfa-2b, recombinant) are summarized in TABLE 1. Following a single 3 million IU (MIU) subcutaneous dose in 12 patients with chronic hepatitis C, mean (% CV 6) serum concentrations peaked at 7 (44%) hours. Following 4 weeks of subcutaneous dosing with 3 MIU three times a week (TIW), interferon serum concentrations were undetectable predose. However, a twofold increase in bioavailability was noted upon multiple dosing of interferon; the reason for this is unknown. Mean half-life values following single- and multiple-dose administrations were 6.8 (24%) hours and 6.5 (29%) hours, respectively.

Ribavirin

Single- and multiple-dose pharmacokinetic properties in adults with chronic hepatitis C are summarized in TABLE 1. 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 sixfold accumulation of ribavirin was observed in plasma. Following oral dosing with 600 mg BID, steady-state was reached by approximately 4 weeks, with mean steady-state plasma concentrations of 2200 (37%) ng/mL. Upon discontinuation of dosing, the mean half-life was 298 (30%) hours, which probably reflects slow elimination from nonplasma compartments.

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. There are insufficient data to address the clinical relevance of these results. Clinical efficacy studies were conducted without instructions with respect to food consumption. (See DOSAGE AND ADMINISTRATION.)

Effect of Antacid on Absorption of Ribavirin

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


TABLE 1. Mean (% CV) Pharmacokinetic Parameters for INTRON A and RIBAVIRIN CAPSULES When Administered Individually to Adults with Chronic Hepatitis C
INTRON A (N=12)

Ribavirin Capsules

(N=12)

Parameter

Single

Dose

3 MIU

Multiple

Dose

3 MIU

TIW

Single

Dose

600 mg

Multiple

Dose

600 mg BID

Tmax (hr) 7 (44) 5 (37) 1.7 (46) 1 3 (60)
Cmax 2 13.9 (32)29.7 (33) 782 (37) 3680 (85)
AUCtf 3 142 (43) 333 (39)13400 (48)228000 (25)
T1/2 (hr) 6.8 (24) 6.5 (29) 43.6 (47) 298 (30)
Apparent
Volume of
Distribution (L) 2825 (9) 4

Apparent

Clearance (L/hr)

14.3 (17) 38.2 (40)

Absolute

Bioavailability

64% (44) 5

1 N=11
2 IU/mL for INTRON A and ng/mL for RIBAVIRIN CAPSULES
3 IU•hr/mL for INTRON A and ng•hr/mL for RIBAVIRIN CAPSULES
4 data obtained from a single-dose pharmacokinetic study using 14C labeled ribavirin; N=5
5 N=6
6

In this section of the label, numbers in parenthesis indicate % coefficient of variation.


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.

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 14C-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.

Results of in vitro studies using both human and rat liver microsome preparations indicated little or no cytochrome P450 enzyme-mediated metabolism of ribavirin, with minimal potential for P450 enzyme-based drug interactions.

No pharmacokinetic interactions were noted between INTRON A Injection and ribavirin capsules in a multiple-dose pharmacokinetic study.


Special Populations

Renal Dysfunction

The pharmacokinetics of ribavirin were assessed after administration of a single oral dose (400 mg) of ribavirin to 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 >90 mL/min). This appears to be due to reduction of apparent clearance in these patients. Ribavirin was not removed by hemodialysis. Patients with creatinine clearance < 50 mL/min should not be treated with ribavirin capsules (see WARNINGS).

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 for elderly subjects have not been performed.

Gender

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

Drug Interactions

Ribavirin has been shown in vitro to inhibit phosphorylation of zidovudine and stavudine which could lead to decreased antiretroviral activity. Exposure to didanosine or its active metabolite (dideoxyadenosine 5’-triphosphate) is increased when didanosine is coadministered with ribavirin, which could cause or worsen clinical toxicities (see PRECAUTIONS: Drug Interactions).

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