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Virazole

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Virazole uses


WARNING: RISK OF SERIOUS DISORDERS AND RIBAVIRIN-ASSOCIATED EFFECTS

WARNING: RISK OF SERIOUS DISORDERS AND RIBAVIRINASSOCIATED EFFECTS

See full prescribing information for complete boxed warning.

Virazole monotherapy is not effective for the treatment of chronic hepatitis C virus infection and should not be used alone for this indication.

The primary clinical toxicity of Virazole is hemolytic anemia. The anemia associated with Virazole therapy may result in worsening of cardiac disease and lead to fatal and nonfatal myocardial infarctions. Patients with a history of significant or unstable cardiac disease should not be treated with Virazole.

Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to Virazole. In addition, Virazole has a multiple dose half-life of 12 days, and it may persist in non-plasma compartments for as long as 6 months. Therefore, Virazole, including Virazole, is contraindicated in women who are pregnant and in the male partners of women who are pregnant. Extreme care must be taken to avoid pregnancy during therapy and for 6 months after completion of therapy in both female patients and in female partners of male patients who are taking Virazole therapy. At least two reliable forms of effective contraception must be utilized during treatment and during the 6month post treatment follow-up period.

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RECENT MAJOR CHANGES

Warnings and Precautions (5.8) 08/2015

1 INDICATIONS AND USAGE

Virazole is a nucleoside analogue indicated for the treatment of chronic hepatitis C (CHC) virus infection in combination with peginterferon alfa-2a in patients 5 years of age and older with compensated liver disease not previously treated with interferon alpha, and in adult CHC patients coinfected with HIV (1)

Virazole tablets in combination with peginterferon alfa-2a are indicated for the treatment of patients 5 years of age and older with chronic hepatitis C (CHC) virus infection who have compensated liver disease and have not been previously treated with interferon alpha.

The following points should be considered when initiating Virazole tablets combination therapy with peginterferon alfa-2a:

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2 DOSAGE AND ADMINISTRATION

Virazole should be taken with food. Virazole should be given in combination with peginterferon alfa-2a; it is important to note that Virazole should never be given as monotherapy. See peginterferon alfa-2a Package Insert for all instructions regarding peginterferon alfa-2a dosing and administration.

2.1 Chronic Hepatitis C Monoinfection

Adult Patients

The recommended dose of Virazole tablets is provided in Table 1. The recommended duration of treatment for patients previously untreated with Virazole and interferon is 24 to 48 weeks.

The daily dose of Virazole is 800 mg to 1200 mg administered orally in two divided doses. The dose should be individualized to the patient depending on baseline disease characteristics (e.g., genotype), response to therapy, and tolerability of the regimen (see Table 1).

Hepatitis C Virus ( HCV ) Genotype

Peginterferon Alfa - 2a Dose *

( once weekly )

Ribavirin Dose

( daily )

Duration

Genotypes 2 and 3 showed no increased response to treatment beyond 24 weeks (see Table 10).

Data on genotypes 5 and 6 are insufficient for dosing recommendations.
*See Peginterferon alfa-2a Package Insert for further details on peginterferon alfa-2a dosing and administration, including dose modification in patients with renal impairment.
Genotypes 1, 4

180 mcg

 < 75 kg = 1000 mg

≥ 75 kg = 1200 mg

 48 weeks

48 weeks
Genotypes 2, 3

180 mcg

 800 mg

 24 weeks
Pediatric Patients

Peginterferon alfa-2a is administered as 180 mcg/1.73m2 x BSA once weekly subcutaneously, to a maximum dose of 180 mcg, and should be given in combination with Virazole. The recommended treatment duration for patients with genotype 2 or 3 is 24 weeks and for other genotypes is 48 weeks.

Virazole should be given in combination with peginterferon alfa-2a. Virazole is available only as a 200 mg tablet and therefore the healthcare provider should determine if this sized tablet can be swallowed by the pediatric patient. The recommended doses for Virazole are provided in Table 2. Patients who initiate treatment prior to their 18th birthday should maintain pediatric dosing through the completion of therapy

*approximately 15 mg/kg/day

Body Weight in kilograms ( kg )

Ribavirin Daily Dose *

Ribavirin Number of Tablets

23 to 33

400 mg/day

1 x 200 mg tablet A.M.

1 x 200 mg tablet P.M.

34 to 46

600 mg/day

1 x 200 mg tablet A.M.

2 x 200 mg tablets P.M.

47 to 59

800 mg/day

2 x 200 mg tablets A.M.

2 x 200 mg tablets P.M.

60 to 74

1000 mg/day

2 x 200 mg tablets A.M.

3 x 200 mg tablets P.M.

≥ 75

1200 mg/day

3 x 200 mg tablets A.M.

3 x 200 mg tablets P.M.

2.2 Chronic Hepatitis C with HIV Coinfection

Adult Patients

The recommended dose for treatment of chronic hepatitis C in patients coinfected with HIV is peginterferon alfa-2a 180 mcg subcutaneous once weekly and Virazole 800 mg by mouth daily for a total duration of 48 weeks, regardless of HCV genotype.

2.3 Dose Modifications

Adult and Pediatric Patients

If severe adverse reactions or laboratory abnormalities develop during combination ribavirin/peginterferon alfa-2a therapy, the dose should be modified or discontinued, if appropriate, until the adverse reactions abate or decrease in severity. If intolerance persists after dose adjustment, ribavirin/peginterferon alfa-2a therapy should be discontinued. Table 3 provides guidelines for dose modifications and discontinuation based on the patient's hemoglobin concentration and cardiac status.

Virazole 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 AND PRECAUTIONS ].

Body weight in kilograms ( kg )

Laboratory Values



Hemoglobin <10 g/dL in patients with no cardiac disease, or Decrease in hemoglobin of ≥2 g/dL during any 4 week period in patients with history of stable cardiac disease

Hemoglobin <8.5 g/dL in patients with no cardiac disease, or Hemoglobin <12 g/dL despite 4 weeks at reduced dose in patients with history of stable cardiac disease
Adult Patients older than 18 years of age



Any weight

1 x 200 mg tablet A.M.

2 x 200 mg tablets P.M.

 Discontinue Ribavirin
Pediatric Patients 5 to 18 years of age



23 to 33 kg

1 x 200 mg tablet A.M.


34 to 46 kg

1 x 200 mg tablet A.M.

1 x 200 mg tablet P.M.

47 to 59 kg

1 x 200 mg tablet A.M.

1 x 200 mg tablet P.M.

 Discontinue Ribavirin

60 to 74 kg

1 x 200 mg tablet A.M.

2 x 200 mg tablets P.M.

≥ 75kg

1 x 200 mg tablet A.M.

2 x 200 mg tablets P.M.

The guidelines for Virazole dose modifications outlined in this table also apply to laboratory abnormalities or adverse reactions other than decreases in hemoglobin values.

Adult Patients

Once Virazole has been withheld due to either a laboratory abnormality or clinical adverse reaction, an attempt may be made to restart Virazole at 600 mg daily and further increase the dose to 800 mg daily. However, it is not recommended that Virazole be increased to the original assigned dose (1000 mg to 1200 mg).

Pediatric Patients

Upon resolution of a laboratory abnormality or clinical adverse reaction, an increase in Virazole dose to the original dose may be attempted depending upon the physician's judgment. If Virazole has been withheld due to a laboratory abnormality or clinical adverse reaction, an attempt may be made to restart Virazole at one-half the full dose.

2.4 Renal Impairment

The total daily dose of Virazole should be reduced for patients with creatinine clearance less than or equal to 50 mL/min; and the weekly dose of peginterferon alfa-2a should be reduced for creatinine clearance less than 30 mL/min as follows in Table 4 [see USE IN SPECIFIC POPULATIONS (8.7), PHARMACOKINETICS (12.3), and Peginterferon Alfa-2a PACKAGE INSERT].

Creatinine Clearance

Peginterferon Alfa - 2a Dose ( once weekly )

Ribavirin Dose

( daily )

30 to 50 mL/min

180 mcg

 Alternating doses, 200 mg and 400 mg every other day
Less than 30 mL/min

135 mcg

 200 mg daily
Hemodialysis

135 mcg

 200 mg daily
The dose of Virazole should not be further modified in patients with renal impairment. If severe adverse reactions or laboratory abnormalities develop, Virazole should be discontinued, if appropriate, until the adverse reactions abate or decrease in severity. If intolerance persists after restarting Virazole, Virazole /peginterferon alfa-2a therapy should be discontinued.

No data are available for pediatric subjects with renal impairment.

2.5 Discontinuation of Dosing

Discontinuation of peginterferon alfa-2a /ribavirin therapy should be considered if the patient has failed to demonstrate at least a 2 log10 reduction from baseline in HCV RNA by 12 weeks of therapy, or undetectable HCV RNA levels after 24 weeks of therapy.

Peginterferon alfa-2a/ribavirin therapy should be discontinued in patients who develop hepatic decompensation during treatment [see WARNINGS AND PRECAUTIONS (5.3)].

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3 DOSAGE FORMS AND STRENGTHS

Virazole tablets for oral administration are available as:

200 mg - light pink to pink, round, biconvex, beveled, film-coated tablets;

400 mg - light pink to pink, capsule shaped, biconvex, film-coated tablets;

500 mg - light pink to pink, modified capsule shaped, biconvex, film-coated tablets;

600 mg - light pink to pink, modified capsule shaped, biconvex, film-coated tablets

4 CONTRAINDICATIONS

Virazole in combination with peginterferon alfa-2a is contraindicated in patients with:

Virazole is contraindicated in:

Virazole and peginterferon alfa-2a combination therapy is contraindicated in patients with:

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5 WARNINGS AND PRECAUTIONS

Peginterferon alfa-2a/Ribavirin: Patients exhibiting the following conditions should be closely monitored and may require dose reduction or discontinuation of therapy:

Significant adverse reactions associated with ribavirin/peginterferon alfa-2a combination therapy include severe depression and suicidal ideation, hemolytic anemia, suppression of bone marrow function, autoimmune and infectious disorders, ophthalmologic disorders, cerebrovascular disorders, pulmonary dysfunction, colitis, pancreatitis, and diabetes.

The Peginterferon alfa-2a Package Insert should be reviewed in its entirety for additional safety information prior to initiation of combination treatment.

5.1 Pregnancy

Virazole may cause birth defects and/or death of the exposed fetus. Virazole has 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 Virazole.

Virazole therapy should not be started unless a report of a negative pregnancy test has been obtained immediately prior to planned initiation of therapy. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Patients should be instructed to use at least two forms of effective contraception during treatment and for 6 months after treatment has been stopped. Pregnancy testing should occur monthly during Virazole therapy and for 6 months after therapy has stopped [see BOXED WARNING, CONTRAINDICATIONS (4), USE IN SPECIFIC POPULATIONS (8.1), and PATIENT COUNSELING INFORMATION (17)].

5.2 Anemia

The primary toxicity of Virazole is hemolytic anemia, which was observed in approximately 13% of all ribavirin/peginterferon alfa-2a- treated subjects in clinical trials. Anemia associated with Virazole 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. Caution should be exercised in initiating treatment in any patient with baseline risk of severe anemia [see DOSAGE AND ADMINISTRATION (2.3)].

Fatal and nonfatal myocardial infarctions have been reported in patients with anemia caused by Virazole. Patients should be assessed for underlying cardiac disease before initiation of Virazole 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 (2.3)]. Because cardiac disease may be worsened by drug-induced anemia, patients with a history of significant or unstable cardiac disease should not use Virazole [see BOXED WARNING, and DOSAGE AND ADMINISTRATION (2.3)].

5.3 Hepatic Failure

Chronic hepatitis C (CHC) patients with cirrhosis may be at risk of hepatic decompensation and death when treated with alpha interferons, including peginterferon alfa-2a. Cirrhotic CHC patients coinfected with HIV receiving highly active antiretroviral therapy (HAART) and interferon alfa-2a with or without Virazole appear to be at increased risk for the development of hepatic decompensation compared to patients not receiving HAART. In Study NR15961 [see CLINICAL STUDIES (14.3)], among 129 CHC/HIV cirrhotic patients receiving HAART, 14 (11%) of these patients across all treatment arms developed hepatic decompensation resulting in 6 deaths. All 14 patients were on NRTIs, including stavudine, didanosine, abacavir, zidovudine, and lamivudine. These small numbers of patients do not permit discrimination between specific NRTIs or the associated risk. During treatment, patients’ clinical status and hepatic function should be closely monitored for signs and symptoms of hepatic decompensation. Treatment with peginterferon alfa-2a/ Virazole should be discontinued immediately in patients with hepatic decompensation [see CONTRAINDICATIONS (4)]

5.4 Hypersensitivity

Severe acute hypersensitivity reactions have been observed during alpha interferon and Virazole therapy. If such a reaction occurs, therapy with peginterferon alfa-2a and Virazole should be discontinued immediately and appropriate medical therapy instituted. Serious skin reactions including vesiculobullous eruptions, reactions in the spectrum of Stevens-Johnson Syndrome (erythema multiforme major) with varying degrees of skin and mucosal involvement and exfoliative dermatitis (erythroderma) have been reported in patients receiving peginterferon alfa-2a with and without Virazole. Patients developing signs or symptoms of severe skin reactions must discontinue therapy [see ADVERSE REACTIONS (6.2)].

5.5 Pulmonary Disorders

Dyspnea, pulmonary infiltrates, pneumonitis, pulmonary hypertension, and pneumonia have been reported during therapy with Virazole and interferon. 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, patients should be closely monitored and, if appropriate, combination ribavirin/peginterferon alfa-2a treatment should be discontinued.

5.6 Bone Marrow Suppression

Pancytopenia and bone marrow suppression have been reported in the literature to occur within 3 to 7 weeks after the concomitant administration of pegylated interferon/ribavirin and azathioprine. In this limited number of patients (n=8), myelotoxicity was reversible within 4 to 6 weeks upon withdrawal of both HCV antiviral therapy and concomitant azathioprine and did not recur upon reintroduction of either treatment alone. peginterferon alfa-2a, Virazole, and azathioprine should be discontinued for pancytopenia, and pegylated interferon/ribavirin should not be re-introduced with concomitant azathioprine [see Drug Interactions (7.3)].

5.7 Pancreatitis

Virazole and peginterferon alfa-2a therapy should be suspended in patients with signs and symptoms of pancreatitis, and discontinued in patients with confirmed pancreatitis.

5.8 Impact on Growth in Pediatric Patients

During combination therapy for up to 48 weeks with peginterferon alfa-2a plus Virazole, growth inhibition was observed in pediatric subjects 5 to 17 years of age. Decreases in weight for age z-score and height for age z-score up to 48 weeks of therapy compared with baseline were observed. At 2 years post-treatment, 16% of pediatric subjects were more than 15 percentiles below their baseline weight curve and 11% were more than 15 percentiles below their baseline height curve.

The available longer term data on subjects who were followed up to 6 years post-treatment are too limited to determine the risk of reduced adult height in some patients .

5.9 Laboratory Tests

Before beginning ribavirin/peginterferon alfa-2a combination therapy, standard hematological and biochemical laboratory tests are recommended for all patients. Pregnancy screening for women of childbearing potential must be performed. Patients who have pre-existing cardiac abnormalities should have electrocardiograms administered before treatment with ribavirin/peginterferon alfa-2a.


After initiation of therapy, hematological tests should be performed at 2 weeks and 4 weeks and biochemical tests should be performed at 4 weeks. Additional testing should be performed periodically during therapy. In adult clinical studies, the CBC (including hemoglobin level and white blood cell and platelet counts) and chemistries (including liver function tests and uric acid) were measured at 1, 2, 4, 6, and 8 weeks, and then every 4 to 6 weeks or more frequently if abnormalities were found. In the pediatric clinical trial, hematological and chemistry assessments were at 1, 3, 5, and 8 weeks, then every 4 weeks. Thyroid stimulating hormone (TSH) was measured every 12 weeks. Monthly pregnancy testing should be performed during combination therapy and for 6 months after discontinuing therapy.

The entrance criteria used for the clinical studies of Virazole and peginterferon alfa-2a may be considered as a guideline to acceptable baseline values for initiation of treatment:

6 ADVERSE REACTIONS

The most common adverse reactions in adults receiving combination therapy are fatigue/asthenia, pyrexia, myalgia, and headache. (6.1)

The most common adverse reactions in pediatric subjects were similar to those seen in adults. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals USA Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

Peginterferon alfa-2a in combination with Virazole causes a broad variety of serious adverse reactions [see BOXED WARNING and WARNINGS AND PRECAUTIONS (5)]. The most common serious or life-threatening adverse reactions induced or aggravated by ribavirin/peginterferon alfa-2a include depression, suicide, relapse of drug abuse/overdose, and bacterial infections each occurring at a frequency of less than 1%. Hepatic decompensation occurred in 2% (10/574) CHC/HIV patients [see WARNINGS AND PRECAUTIONS (5.3)].

6.1 Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction 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.

Adult Patients

In the pivotal registration trials NV15801 and NV15942, 886 patients received Virazole for 48 weeks at doses of 1000/1200 mg based on body weight. In these trials, one or more serious adverse reactions occurred in 10% of CHC monoinfected subjects and in 19% of CHC/HIV subjects receiving peginterferon alfa-2a alone or in combination with Virazole. The most common serious adverse event (3% in CHC and 5% in CHC/HIV) was bacterial infection (e.g., sepsis, osteomyelitis, endocarditis, pyelonephritis, pneumonia).

Other serious adverse reactions occurred at a frequency of less than 1% and included: suicide, suicidal ideation, psychosis, aggression, anxiety, drug abuse and drug overdose, angina, hepatic dysfunction, fatty liver, cholangitis, arrhythmia, diabetes mellitus, autoimmune phenomena (e.g., hyperthyroidism, hypothyroidism, sarcoidosis, systemic lupus erythematosus, rheumatoid arthritis), peripheral neuropathy, aplastic anemia, peptic ulcer, gastrointestinal bleeding, pancreatitis, colitis, corneal ulcer, pulmonary embolism, coma, myositis, cerebral hemorrhage, thrombotic thrombocytopenic purpura, psychotic disorder, and hallucination.

The percentage of patients in clinical trials who experienced one or more adverse events was 98%. The most commonly reported adverse reactions were psychiatric reactions, including depression, insomnia, irritability, anxiety, and flu-like symptoms such as fatigue, pyrexia, myalgia, headache and rigors. Other common reactions were anorexia, nausea and vomiting, diarrhea, arthralgias, injection site reactions, alopecia, and pruritus. Table 5 shows rates of adverse events occurring in greater than or equal to 5% of subjects receiving pegylated interferon and Virazole combination therapy in the CHC Clinical Trial, NV15801.

Ten percent of CHC monoinfected patients receiving 48 weeks of therapy with peginterferon alfa-2a in combination with Virazole discontinued therapy; 16% of CHC/HIV coinfected patients discontinued therapy. The most common reasons for discontinuation of therapy were psychiatric, flu-like syndrome (e.g., lethargy, fatigue, headache), dermatologic and gastrointestinal disorders, and laboratory abnormalities (thrombocytopenia, neutropenia, and anemia).

Overall 39% of patients with CHC or CHC/HIV required modification of peginterferon alfa-2a and/or Virazole therapy. The most common reason for dose modification of peginterferon alfa-2a in CHC and CHC/HIV patients was for laboratory abnormalities; neutropenia (20% and 27%, respectively) and thrombocytopenia (4% and 6%, respectively). The most common reason for dose modification of Virazole in CHC and CHC/HIV patients was anemia (22% and 16%, respectively).

Peginterferon alfa-2a dose was reduced in 12% of patients receiving 1000 mg to 1200 mg Virazole for 48 weeks and in 7% of patients receiving 800 mg Virazole for 24 weeks. Virazole dose was reduced in 21% of patients receiving 1000 mg to 1200 mg Virazole for 48 weeks and in 12% of patients receiving 800 mg Virazole for 24 weeks.

Chronic hepatitis C monoinfected patients treated for 24 weeks with peginterferon alfa-2a and 800 mg Virazole were observed to have lower incidence of serious adverse events (3% vs. 10%), hemoglobin less than 10g/dL (3% vs. 15%), dose modification of peginterferon alfa-2a (30% vs. 36%) and Virazole (19% vs. 38%), and of withdrawal from treatment (5% vs. 15%) compared to patients treated for 48 weeks with peginterferon alfa-2a and 1000 mg or 1200 mg Virazole. On the other hand, the overall incidence of adverse events appeared to be similar in the two treatment groups.


 CHC Combination Therapy Study NV15801


*Severe hematologic abnormalities (lymphocyte less than 500 cells/mm3; hemoglobin less than 10 g/dL; neutrophil less than 750 cells/mm3; platelet less than 50,000 cells/mm3).
Body System

Peginterferon Alfa - 2a 180 mcg + 1000 mg or 1200 mg Ribavirin Tablets

48 weeks

Interferon alfa - 2b + 1000 mg or 1200 mg Ribavirin Capsules

48 weeks


N = 451

N = 443


%

%

Application Site Disorders



Injection site reaction

23

 16
Endocrine Disorders



Hypothyroidism

4

 5
Flu - like Symptoms and Signs



Fatigue/Asthenia

65

 68
Pyrexia

41

 55
Rigors

 25

 37
Pain

 10

 9
Gastrointestinal



Nausea/Vomiting

25

 29
Diarrhea

 11

 10
Abdominal pain

 8

 9
Dry mouth

 4

 7
Dyspepsia

6

 5
Hematologic *



Lymphopenia

14

 12
Anemia

 11

 11
Neutropenia

 27

 8
Thrombocytopenia

5

 < 1
Metabolic and Nutritional



Anorexia

24

 26
Weight decrease

10

 10
Musculoskeletal , Connective Tissue and Bone



Myalgia

40

 49
Arthralgia

22

 23
Back pain

5

 5
Neurological



Headache

43

 49
Dizziness (excluding vertigo)

14

 14
Memory impairment

6

 5
Psychiatric



Irritability/Anxiety/Nervousness

33

 38
Insomnia

30

 37
Depression

20

 28
Concentration impairment

10

 13
Mood alteration

5

 6
Resistance Mechanism Disorders



Overall

12

 10
Respiratory , Thoracic and Mediastinal



Dyspnea

13

 14
Cough

10

 7
Dyspnea exertional

4

 7
Skin and Subcutaneous Tissue



Alopecia

28

 33
Pruritus

19

 18
Dermatitis

16

 13
Dry skin

10

 13
Rash

8

 5
Sweating increased

6

 5
Eczema

5

 4
Visual Disorders



Vision blurred

5

 2
Pediatric Patients

In a clinical trial with 114 pediatric subjects (5 to 17 years of age) treated with peginterferon alfa-2a alone or in combination with Virazole, dose modifications were required in approximately one-third of subjects, most commonly for neutropenia and anemia. In general, the safety profile observed in pediatric subjects was similar to that seen in adults. In the pediatric study, the most common adverse events in subjects treated with combination therapy peginterferon alfa-2a and Virazole for up to 48 weeks were influenza-like illness (91%), upper respiratory tract infection (60%), headache (64%), gastrointestinal disorder (56%), skin disorder (47%), and injection-site reaction (45%). Seven subjects receiving combination peginterferon alfa-2a and Virazole treatment for 48 weeks discontinued therapy for safety reasons (depression, psychiatric evaluation abnormal, transient blindness, retinal exudates, hyperglycemia, type 1 diabetes mellitus, and anemia). Severe adverse events were reported in 2 subjects in the peginterferon alfa-2a plus Virazole combination therapy group (hyperglycemia and cholecystectomy).

* Displayed adverse drug reactions include all grades of reported adverse clinical events considered possibly, probably, or definitely related to study drug.

**Subjects in the peginterferon alfa-2a plus placebo arm who did not achieve undetectable viral load at week 24 switched to combination treatment thereafter. Therefore, only the first 24 weeks are presented for the comparison of combination therapy with monotherapy.


Study NV17424




System Organ Class

Peginterferon Alfa - 2a

180 mcg / 1 . 73 m ² x BSA + Virazole

15 mg / kg

( N = 55 )

Peginterferon Alfa - 2a

180 mcg / 1 . 73 m ² x BSA + Placebo **

( N = 59 )


%

 %
General disorders and administration site conditions



Influenza like illness

 91

 81
Injection site reaction

 44

 42
Fatigue

 25

 20
Irritability

 24

 14
Gastrointestinal disorders



Gastrointestinal disorder

 49

 44
Nervous system disorders



Headache

 51

 39
Skin and subcutaneous tissue disorders



Rash

 15

 10
Pruritus

 11

 12
Musculoskeletal , connective tissue and bone disorders



Musculoskeletal pain

 35

 29
Psychiatric disorders



Insomnia

 9

 12
Metabolism and nutrition disorders



Decreased appetite

 11

 14
In pediatric subjects randomized to combination therapy, the incidence of most adverse reactions was similar for the entire treatment period (up to 48 weeks plus 24 weeks follow-up) in comparison to the first 24 weeks, and increased only slightly for headache, gastrointestinal disorder, irritability and rash. The majority of adverse reactions occurred in the first 24 weeks of treatment.

Growth Inhibition in Pediatric Subjects .

Pediatric subjects treated with PEGASYS plus Virazole combination therapy showed a delay in weight and height increases with up to 48 weeks of therapy compared with baseline. Both weight for age and height for age z-scores as well as the percentiles of the normative population for subject weight and height decreased during treatment. At the end of 2 years follow-up after treatment, most subjects had returned to baseline normative curve percentiles for weight (64th mean percentile at baseline, 60th mean percentile at 2 years post-treatment) and height (54th mean percentile at baseline, 56th mean percentile at 2 years post-treatment). At the end of treatment, 43% (23 of 53) of subjects experienced a weight percentile decrease of more than 15 percentiles, and 25% (13 of 53) experienced a height percentile decrease of more than 15 percentiles on the normative growth curves. At 2 years post-treatment, 16% (6 of 38) of subjects were more than 15 percentiles below their baseline weight curve and 11% (4 of 38) were more than 15 percentiles below their baseline height curve.

Thirty-eight of the 114 subjects enrolled in the long-term follow-up study, extending up to 6 years posttreatment. For most subjects, post-treatment recovery in growth at 2 years post-treatment was maintained to 6 years post-treatment.

Common Adverse Reactions in CHC with HIV Coinfection (Adults)

The adverse event profile of coinfected patients treated with peginterferon alfa-2a/ribavirin in Study NR15961 was generally similar to that shown for monoinfected patients in Study NV15801 (Table 5). Events occurring more frequently in coinfected patients were neutropenia (40%), anemia (14%), thrombocytopenia (8%), weight decrease (16%), and mood alteration (9%).

Laboratory Test Abnormalities

Adult Patients

Anemia due to hemolysis is the most significant toxicity of Virazole therapy. Anemia (hemoglobin less than 10 g/dL) was observed in 13% of all Virazole and peginterferon alfa-2a combination-treated patients in clinical trials. The maximum drop in hemoglobin occurred during the first 8 weeks of initiation of Virazole therapy [see DOSAGE AND ADMINISTRATION (2.3)].

Laboratory Parameter

Peginterferon Alfa - 2a +

Ribavirin

1000 / 1200 mg

48 wks

Interferon alfa - 2b

+

Ribavirin

1000 / 1200 mg

48 wks


( N = 887 )

( N = 443 )

Neutrophils ( cells / mm3 )



1,000 <1,500

 34%

 38%
500 <1,000

 49%

 21%
<500

 5%

 1%
Platelets ( cells / mm3 )



50,000 - <75,000

 11%

 4%
20,000 - <50,000

 5%

 < 1%
<20,000

 0

 0
Hemoglobin ( g / dL )



8.5 - 9.9

 11%

 11%
<8.5

 2%

 < 1%
Pediatric Patients

Decreases in hemoglobin, neutrophils and platelets may require dose reduction or permanent discontinuation from treatment [see DOSAGE AND ADMINISTRATION (2.4)]. Most laboratory abnormalities noted during the clinical trial returned to baseline levels shortly after discontinuation of treatment.

* Subjects in the peginterferon alfa-2a plus placebo arm who did not achieve undetectable viral load at week 24 switched to combination treatment thereafter. Therefore, only the first 24 weeks are presented for the comparison of combination therapy with monotherapy.

Laboratory Parameter

Peginterferon Alfa - 2a 180 mcg / 1 . 73 m ² x BSA + Ribavirin 15 mg / kg

( N = 55 )

Peginterferon Alfa - 2a 180 mcg / 1 . 73 m ² x BSA + Placebo *

( N = 59 )

Neutrophils ( cells / mm3 )



1,000 to < 1,500

31%

 39%
750 to < 1,000

27%

 17%
500 to < 750

25%

 15%
< 500

7%

 5%
Platelets ( cells / mm3 )



75,000 to < 100,000

4%

 2%
50,000 to < 75,000

0%

 2%
< 50,000

0%

 0%
Hemoglobin ( g / dL )



8.5 to < 10

7%

 3%
< 8.5

0%

 0%
In patients randomized to combination therapy, the incidence of abnormalities during the entire treatment phase (up to 48 weeks plus 24 weeks follow-up) in comparison to the first 24 weeks increased slightly for neutrophils between 500 and 1,000 cells/mm and hemoglobin values between 8.5 and 10 g/dL. The majority of hematologic abnormalities occurred in the first 24 weeks of treatment.

6.2 Postmarketing Experience

The following adverse reactions have been identified and reported during post-approval use of peginterferon alfa-2a/ribavirin combination therapy. 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

Ear and Labyrinth disorders

Hearing impairment, hearing loss

Eye disorders

Serous retinal detachment

Immune disorders

Liver and renal graft rejection

Metabolism and Nutrition disorders

Dehydration

Skin and Subcutaneous Tissue disorders

Stevens-Johnson Syndrome (SJS)

Toxic epidermal necrolysis (TEN)

7 DRUG INTERACTIONS

Results from a pharmacokinetic sub-study demonstrated no pharmacokinetic interaction between peginterferon alfa-2a and Virazole.

7.1 Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

In vitro data indicate Virazole reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV/HCV virologic suppression) interaction was observed when Virazole and lamivudine (n=18), stavudine (n=10), or zidovudine (n=6) were co-administered as part of a multi-drug regimen to HCV/HIV coinfected patients.

In Study NR15961 among the CHC/HIV coinfected cirrhotic patients receiving NRTIs, cases of hepatic decompensation (some fatal) were observed [see WARNINGS AND PRECAUTIONS (5.3)].

Patients receiving peginterferon alfa-2a/ribavirin and NRTIs should be closely monitored for treatment-associated toxicities. Physicians should refer to prescribing information for the respective NRTIs for guidance regarding toxicity management. In addition, dose reduction or discontinuation of peginterferon alfa-2a, Virazole or both should also be considered if worsening toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than or equal to 6) [see WARNINGS AND PRECAUTIONS (5.3) and DOSAGE AND ADMINISTRATION (2.3)].

Didanosine

Co-administration of Virazole and didanosine is contraindicated. Didanosine or its active metabolite (dideoxyadenosine 5'-triphosphate) concentrations are increased when didanosine is co-administered with Virazole, which could cause or worsen clinical toxicities. Reports of fatal hepatic failure as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in clinical trials [see CONTRAINDICATIONS (4)].

Zidovudine

In Study NR15961, patients who were administered zidovudine in combination with peginterferon alfa-2a/ribavirin developed severe neutropenia (ANC less than 500) and severe anemia (hemoglobin less than 8 g/dL) more frequently than similar patients not receiving zidovudine (neutropenia 15% vs. 9%) (anemia 5% vs. 1%). Discontinuation of zidovudine should be considered as medically appropriate.

7.2 Drugs Metabolized by Cytochrome P450

In vitro studies indicate that Virazole does not inhibit CYP 2C9, CYP 2C19, CYP 2D6 or CYP 3A4.

7.3 Azathioprine

The use of Virazole to treat chronic hepatitis C in patients receiving azathioprine has been reported to induce severe pancytopenia and may increase the risk of azathioprine-related myelotoxicity. Inosine monophosphate dehydrogenase (IMDH) is required for one of the metabolic pathways of azathioprine. Virazole is known to inhibit IMDH, thereby leading to accumulation of an azathioprine metabolite, 6-methylthioinosine monophosphate (6-MTITP), which is associated with myelotoxicity (neutropenia, thrombocytopenia, and anemia). Patients receiving azathioprine with Virazole should have complete blood counts, including platelet counts, monitored weekly for the first month, twice monthly for the second and third months of treatment, then monthly or more frequently if dosage or other therapy changes are necessary [see WARNINGS AND PRECAUTIONS (5.6)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic Effects

Pregnancy: Category X.

Virazole 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 [see CONTRAINDICATIONS (4) and WARNINGS AND PRECAUTIONS (5.1)].

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 daily human dose of Virazole). 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 (approximately 0.01 times the maximum recommended daily human dose of Virazole).

Treatment and Post-treatment: Potential Risk to the Fetus

Virazole is known to accumulate in intracellular components from where it is cleared very slowly. It is not known whether Virazole is contained in sperm, and if so, will exert a potential teratogenic effect upon fertilization of the ova. However, because of the potential human teratogenic effects of Virazole, male patients should be advised to take every precaution to avoid risk of pregnancy for their female partners.

Virazole should not be used by pregnant women or by men whose female partners are pregnant. Female patients of childbearing potential and male patients with female partners of childbearing potential should not receive Virazole unless the patient and his/her partner are using effective contraception (two reliable forms) during therapy and for 6 months post therapy [see CONTRAINDICATIONS (4)].

Virazole Pregnancy Registry

A Virazole Pregnancy Registry has been established to monitor maternal-fetal outcomes of pregnancies of female patients and female partners of male patients exposed to Virazole during treatment and for 6 months following cessation of treatment. Healthcare providers and patients are encouraged to report such cases by calling 1-800-593-2214.

8.3 Nursing Mothers

It is not known whether Virazole is excreted in human milk. Because many drugs are excreted in human milk and to avoid any potential for serious adverse reactions in nursing infants from Virazole, a decision should be made either to discontinue nursing or therapy with Virazole, based on the importance of the therapy to the mother.

8.4 Pediatric Use

Pharmacokinetic evaluations in pediatric patients have not been performed.

Safety and effectiveness of Virazole have not been established in patients below the age of 5 years.

8.5 Geriatric Use

Clinical studies of Virazole and peginterferon alfa-2a did not include sufficient numbers of subjects aged 65 or over to determine whether they respond differently from younger subjects. Specific pharmacokinetic evaluations for Virazole in the elderly have not been performed. The risk of toxic reactions to this drug may be greater in patients with impaired renal function. The dose of Virazole should be reduced in patients with creatinine clearance less than or equal to 50 mL/min; and the dose of peginterferon alfa-2a should be reduced in patients with creatinine clearance less than 30 mL/min [see DOSAGE AND ADMINISTRATION ; USE IN SPECIFIC POPULATIONS (8.7)].

8.6 Race

A pharmacokinetic study in 42 subjects demonstrated there is no clinically significant difference in Virazole pharmacokinetics among Black (n=14), Hispanic (n=13) and Caucasian (n=15) subjects.

8.7 Renal Impairment

Renal function should be evaluated in all patients prior to initiation of Virazole by estimating the patient's creatinine clearance.

A clinical trial evaluated treatment with Virazole and peginterferon alfa-2a in 50 CHC subjects with moderate or severe (creatinine clearance less than 30 mL/min) renal impairment or end stage renal disease (ESRD) requiring chronic hemodialysis (HD). In 18 subjects with ESRD receiving chronic HD, Virazole was administered at a dose of 200 mg daily with no apparent difference in the adverse event profile in comparison to subjects with normal renal function. Dose reductions and temporary interruptions of Virazole (due to ribavirin-related adverse reactions, mainly anemia) were observed in up to one-third ESRD/HD subjects during treatment; and only one-third of these subjects received Virazole for 48 weeks. Virazole plasma exposures were approximately 20% lower in subjects with ESRD on HD compared to subjects with normal renal function receiving the standard 1000/1200 mg Virazole daily dose.

Subjects with moderate (n=17) or severe (n=14) renal impairment did not tolerate 600 mg or 400 mg daily doses of Virazole, respectively, due to ribavirin-related adverse reactions, mainly anemia, and exhibited 20% to 30% higher Virazole plasma exposures (despite frequent dose modifications) compared to subjects with normal renal function (creatinine clearance greater than 80 mL/min) receiving the standard dose of Virazole. Discontinuation rates were higher in subjects with severe renal impairment compared to that observed in subjects with moderate renal impairment or normal renal function. Pharmacokinetic modeling and simulation indicate that a dose of 200 mg daily in patients with severe renal impairment and a dose of 200 mg daily alternating with 400 mg the following day in patients with moderate renal impairment will provide plasma Virazole exposure similar to patients with normal renal function receiving the approved regimen of Virazole. These doses have not been studied in patients [see DOSAGE AND ADMINISTRATION (2.4), and CLINICAL PHARMACOLOGY (12.3)].

Based on the pharmacokinetic and safety results from this trial, patients with creatinine clearance less than or equal to 50 mL/min should receive a reduced dose of Virazole; and patients with creatinine clearance less than 30 mL/min should receive a reduced dose of peginterferon alfa-2a. The clinical and hematologic status of patients with creatinine clearance less than or equal to 50 mL/min receiving Virazole should be carefully monitored. Patients with clinically significant laboratory abnormalities or adverse reactions which are persistently severe or worsening should have therapy withdrawn [see DOSAGE AND ADMINISTRATION (2.4), CLINICAL PHARMACOLOGY (12.3), and PEGINTERFERON ALFA-2A PACKAGE INSERT].

8.8 Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of Virazole following administration of Virazole has not been evaluated. The clinical trials of Virazole were restricted to patients with Child-Pugh class A disease.

8.9 Gender

No clinically significant differences in the pharmacokinetics of Virazole were observed between male and female subjects.

Virazole pharmacokinetics, when corrected for weight, are similar in male and female patients.

8.10 Organ Transplant Recipients

The safety and efficacy of peginterferon alfa-2a and Virazole treatment have not been established in patients with liver and other transplantations. As with other alpha interferons, liver and renal graft rejections have been reported on peginterferon alfa-2a, alone or in combination with Virazole [see ADVERSE REACTIONS (6.2)].

10 OVERDOSAGE

No cases of overdose with Virazole have been reported in clinical trials. Hypocalcemia and hypomagnesemia have been observed in persons administered greater than the recommended dosage of Virazole. In most of these cases, Virazole was administered intravenously at dosages up to and in some cases exceeding four times the recommended maximum oral daily dose.

11 DESCRIPTION

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

The molecular formula of Virazole is C8H12N4O5 and the molecular weight is 244.2.

Virazole, USP is white, crystalline powder. It is freely soluble in water and slightly soluble in dehydrated alcohol.

Each film-coated Virazole tablet intended for oral administration contains 200 mg or 400 mg or 500 mg or 600 mg of Virazole. In addition, each tablet contains the following inactive ingredients: crospovidone, hypromellose, iron oxide red, iron oxide yellow, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, silicon dioxide, talc and titanium dioxide.

Organic test number pending in the USP.

structured formula for Virazole

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Virazole is an antiviral drug [see MICROBIOLOGY ].

12.3 Pharmacokinetics

Multiple dose Virazole pharmacokinetic data are available for HCV patients who received Virazole in combination with peginterferon alfa-2a. Following administration of 1200 mg/day with food for 12 weeks mean±SD (n=39; body weight greater than 75 kg) AUC0-12hr was 25,361±7110 ng·hr/mL and Cmax was 2748±818 ng/mL. The average time to reach Cmax was 2 hours. Trough Virazole plasma concentrations following 12 weeks of dosing with food were 1662±545 ng/mL in HCV infected patients who received 800 mg/day (n=89), and 2112±810 ng/mL in patients who received 1200 mg/day (n=75; body weight greater than 75 kg).

The terminal half-life of Virazole following administration of a single oral dose of Virazole is about 120 to 170 hours. The total apparent clearance following administration of a single oral dose of Virazole is about 26 L/h. There is extensive accumulation of Virazole after multiple dosing (twice daily) such that the Cmax at steady state was four-fold higher than that of a single dose.

Effect of Food on Absorption of Virazole

Bioavailability of a single oral dose of Virazole was increased by co-administration with a high-fat meal. The absorption was slowed (Tmax was doubled) and the AUC0-192h and Cmax increased by 42% and 66%, respectively, when Virazole was taken with a high-fat meal compared with fasting conditions [see DOSAGE AND ADMINISTRATION (2) and PATIENT COUNSELING INFORMATION (17)].

Elimination and Metabolism

The contribution of renal and hepatic pathways to Virazole elimination after administration of Virazole is not known. In vitro studies indicate that Virazole is not a substrate of CYP450 enzymes.

Renal Impairment

A clinical trial evaluated 50 CHC subjects with either moderate (creatinine clearance 30 to 50 mL/min) or severe (creatinine clearance less than 30 mL/min) renal impairment or end stage renal disease (ESRD) requiring chronic hemodialysis (HD). The apparent clearance of Virazole was reduced in subjects with creatinine clearance less than or equal to 50 mL/min, including subjects with ESRD on HD, exhibiting approximately 30% of the value found in subjects with normal renal function. Pharmacokinetic modeling and simulation indicates that a dose of 200 mg daily in patients with severe renal impairment and a dose of 200 mg daily alternating with 400 mg the following day in patients with moderate renal impairment will provide plasma Virazole exposures similar to that observed in patients with normal renal function receiving the standard 1000/1200 mg Virazole daily dose. These doses have not been studied in patients.

In 18 subjects with ESRD receiving chronic HD, Virazole was administered at a dose of 200 mg daily. Virazole plasma exposures in these subjects were approximately 20% lower compared to subjects with normal renal function receiving the standard 1000/1200 mg Virazole daily dose [see DOSAGE AND ADMINISTRATION (2.4), USE IN SPECIFIC POPULATIONS (8.7)].

Plasma Virazole is removed by hemodialysis with an extraction ratio of approximately 50%; however, due to the large volume of distribution of Virazole, plasma exposure is not expected to change with hemodialysis.

12.4 Microbiology

Mechanism of Action

The mechanism by which Virazole contributes to its antiviral efficacy in the clinic is not fully understood. Virazole has direct antiviral activity in tissue culture against many RNA viruses. Virazole increases the mutation frequency in the genomes of several RNA viruses and Virazole triphosphate inhibits HCV polymerase in a biochemical reaction.

Antiviral Activity in Cell Culture

In the stable HCV cell culture model system (HCV replicon), Virazole inhibited autonomous HCV RNA replication with a 50% effective concentration (EC50) value of 11 to 21 mcM. In the same model, PEG-IFN α-2a also inhibited HCV RNA replication, with an EC50 value of 0.1 to 3 ng/mL. The combination of PEG-IFN α-2a and Virazole was more effective at inhibiting HCV RNA replication than either agent alone.

Resistance

Different HCV genotypes display considerable clinical variability in their response to PEG-IFN-α and Virazole therapy. Viral genetic determinants associated with the variable response have not been definitively identified.

Cross-resistance

Cross-resistance between IFN α and Virazole has not been observed.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

In a p53 mouse carcinogenicity study up to the maximum tolerated dose of 100 mg/kg/day, Virazole was not oncogenic. Virazole was also not oncogenic in a rat 2 year carcinogenicity study at doses up to the maximum tolerated dose of 60 mg/kg/day. On a body surface area basis, these doses are approximately 0.5 and 0.6 times the maximum recommended daily human dose of Virazole, respectively.


Mutagenesis

Virazole demonstrated mutagenic activity in the in vitro mouse lymphoma assay. No clastogenic activity was observed in an in vivo mouse micronucleus assay at doses up to 2000 mg/kg. However, results from studies published in the literature show clastogenic activity in the in vivo mouse micronucleus assay at oral doses up to 2000 mg/kg. 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

In a fertility study in rats, Virazole showed a marginal reduction in sperm counts at the dose of 100 mg/kg/day with no effect on fertility. Upon cessation of treatment, total recovery occurred after 1 spermatogenesis cycle. Abnormalities in sperm were observed in studies in mice designed to evaluate the time course and reversibility of ribavirin-induced testicular degeneration at doses of 15 to 150 mg/kg/day (approximately 0.1 to 0.8 times the maximum recommended daily human dose of Virazole) administered for 3 to 6 months. Upon cessation of treatment, essentially total recovery from ribavirin-induced testicular toxicity was apparent within 1 or 2 spermatogenic cycles.

Female patients of childbearing potential and male patients with female partners of childbearing potential should not receive Virazole unless the patient and his/her partner are using effective contraception (two reliable forms). Based on a multiple dose half-life (t1/2) of Virazole of 12 days, effective contraception must be utilized for 6 months post therapy (i.e., 15 half-lives of clearance for Virazole).


No reproductive toxicology studies have been performed using peginterferon alfa-2a in combination with Virazole. However, peginterferon alfa-2a and Virazole when administered separately, each has adverse effects on reproduction. It should be assumed that the effects produced by either agent alone would also be caused by the combination of the two agents.

13.2 ANIMAL PHARMACOLOGY AND OR TOXICOLOGY

In a study in rats, it was concluded that dominant lethality was not induced by Virazole at doses up to 200 mg/kg for 5 days (up to 1.7 times the maximum recommended human dose of Virazole).

Long-term studies in the mouse and rat (18 to 24 months; dose 20 to 75, and 10 to 40 mg/kg/day, respectively, approximately 0.1 to 0.4 times the maximum daily human dose of Virazole) have demonstrated a relationship between chronic Virazole exposure and an increased incidence of vascular lesions (microscopic hemorrhages) in mice. In rats, retinal degeneration occurred in controls, but the incidence was increased in ribavirin-treated rats.

14 CLINICAL STUDIES

14.1 Chronic Hepatitis C Patients

Adult Patients

The safety and effectiveness of peginterferon alfa-2a in combination with Virazole for the treatment of hepatitis C virus infection were assessed in two randomized controlled clinical trials. All patients were adults, had compensated liver disease, detectable hepatitis C virus, liver biopsy diagnosis of chronic hepatitis, and were previously untreated with interferon. Approximately 20% of patients in both studies had compensated cirrhosis. Patients coinfected with HIV were excluded from these studies.

In Study NV15801, patients were randomized to receive either peginterferon alfa-2a 180 mcg subcutaneous once weekly with an oral placebo, peginterferon alfa-2a 180 mcg once weekly with Virazole 1000 mg by mouth (body weight less than 75 kg) or 1200 mg by mouth (body weight greater than or equal to 75 kg) or interferon alfa-2b 3 MIU subcutaneous three times a week plus Virazole 1000 mg or 1200 mg by mouth. All patients received 48 weeks of therapy followed by 24 weeks of treatment-free follow-up. Virazole or placebo treatment assignment was blinded. Sustained virological response was defined as undetectable (less than 50 IU/mL) HCV RNA on or after study week 68. Peginterferon alfa-2a in combination with Virazole resulted in a higher SVR compared to peginterferon alfa-2a alone or interferon alfa-2b and Virazole (Table 9). In all treatment arms, patients with viral genotype 1, regardless of viral load, had a lower response rate to peginterferon alfa-2a in combination with Virazole compared to patients with other viral genotypes.


 Interferon alfa - 2b + Ribavirin 1000 mg or 1200 mg

Peginterferon Alfa - 2a + Placebo

Peginterferon Alfa - 2a + Ribavirin 1000 mg or 1200 mg

All patients

197/444 (44%)

 65/224 (29%)

 241/453 (53%)
Genotype 1

103/285 (36%)

 29/145 (20%)

 132/298 (44%)
Genotypes 2 to 6

94/159 (59%)

 36/79 (46%)

 109/155 (70%)
Difference in overall treatment response (Peginterferon alfa-2a/ribavirin – Interferon alfa-2b/ribavirin) was 9% (95% CI 2.3, 15.3).

In Study NV15942, all patients received peginterferon alfa-2a 180 mcg subcutaneous once weekly and were randomized to treatment for either 24 or 48 weeks and to a Virazole dose of either 800 mg or 1000 mg/1200 mg (for body weight less than 75 kg/ greater than or equal to 75 kg). Assignment to the four treatment arms was stratified by viral genotype and baseline HCV viral titer. Patients with genotype 1 and high viral titer (defined as greater than 2 x 106HCV RNA copies/mL serum) were preferentially assigned to treatment for 48 weeks.

Sustained Virologic Response (SVR) and HCV Genotype

HCV 1 and 4–Irrespective of baseline viral titer, treatment for 48 weeks with peginterferon alfa-2a and 1000 mg or 1200 mg of Virazole resulted in higher SVR (defined as undetectable HCV RNA at the end of the 24 week treatment-free follow-up period) compared to shorter treatment (24 weeks) and/or 800 mg Virazole.

HCV 2 and 3– Irrespective of baseline viral titer, treatment for 24 weeks with peginterferon alfa-2a and 800 mg of Virazole resulted in a similar SVR compared to longer treatment (48 weeks) and/or 1000 mg or 1200 mg of Virazole (see Table 10).

The numbers of patients with genotype 5 and 6 were too few to allow for meaningful assessment.


 24 Weeks Treatment


48 Weeks Treatment


*1000 mg for body weight less than 75 kg; 1200 mg for body weight greater than or equal to 75 kg.


Peginterferon Alfa - 2a + Ribavirin 800 mg

( N = 207 )

Peginterferon Alfa - 2a + Ribavirin 1000 mg or 1200 mg *

( N = 280 )

Peginterferon Alfa - 2a + Ribavirin 800 mg

( N = 361 )

Peginterferon Alfa - 2a + Ribavirin 1000 mg or 1200 mg *

( N = 436 )

Genotype 1

29/101 (29%)

 48/118 (41%)

 99/250 (40%)

 138/271 (51%)
Genotypes 2, 3

79/96 (82%)

 116/144 (81%)

 75/99 (76%)

 117/153 (76%)
Genotype 4

0/5 (0%)

 7/12 (58%)

 5/8 (63%)

 9/11 (82%)
Pediatric Patients

Previously untreated pediatric subjects 5 through 17 years of age (55% less than 12 years old) with chronic hepatitis C, compensated liver disease and detectable HCV RNA were treated with Virazole approximately 15 mg/kg/day plus peginterferon alfa-2a 180 mcg/1.73 m2 x body surface area once weekly for 48 weeks. All subjects were followed for 24 weeks post-treatment. Sustained virological response (SVR) was defined as undetectable (less than 50 IU/mL) HCV RNA on or after study week 68. A total of 114 subjects were randomized to receive either combination treatment of Virazole plus peginterferon alfa-2a or peginterferon alfa-2a monotherapy; subjects failing peginterferon alfa-2a monotherapy at 24 weeks or later could receive open-label Virazole plus peginterferon alfa-2a. The initial randomized arms were balanced for demographic factors; 55 subjects received initial combination treatment of Virazole plus peginterferon alfa-2a and 59 received peginterferon alfa-2a plus placebo; in the overall intent-to-treat population, 45% were female, 80% were Caucasian, and 81% were infected with HCV genotype 1. The SVR results are summarized in Table 11.

*Results indicate undetectable HCV RNA defined as HCV RNA less than 50 IU/mL at 24 weeks post-treatment using the AMPLICOR HCV test v2

**Scheduled treatment duration was 48 weeks regardless of the genotype

***Includes HCV genotypes 2,3 and others


Peginterferon alfa - 2a 180 mcg / 1 . 73 m ² x BSA + Ribavirin 15 mg / kg *

( N = 55 )

Peginterferon alfa - 2a 180 mcg / 1 . 73 m ² x BSA + Placebo *

( N = 59 )

All HCV genotypes **

29 (53%)

 12 (20%)
HCV genotype 1

21/45 (47%)

 8/47 (17%)
HCV non - genotype 1 ***

8/10 (80%)

 4/12 (33%)

14.2 Other Treatment Response Predictors

Treatment response rates are lower in patients with poor prognostic factors receiving pegylated interferon alpha therapy. In studies NV15801 and NV15942, treatment response rates were lower in patients older than 40 years (50% vs. 66%), in patients with cirrhosis (47% vs. 59%), in patients weighing over 85 kg (49% vs. 60%), and in patients with genotype 1 with high vs. low viral load (43% vs. 56%). African-American patients had lower response rates compared to Caucasians.

In studies NV15801 and NV15942, lack of early virologic response by 12 weeks (defined as HCV RNA undetectable or greater than 2 log10 lower than baseline) was grounds for discontinuation of treatment. Of patients who lacked an early viral response by 12 weeks and completed a recommended course of therapy despite a protocol-defined option to discontinue therapy, 5/39 (13%) achieved an SVR. Of patients who lacked an early viral response by 24 weeks, 19 completed a full course of therapy and none achieved an SVR.

14.3 Chronic Hepatitis C/HIV Coinfected Patients

In Study NR15961, patients with CHC/HIV were randomized to receive either peginterferon alfa-2a 180 mcg subcutaneous once weekly plus an oral placebo, peginterferon alfa-2a 180 mcg once weekly plus Virazole 800 mg by mouth daily or interferon alfa-2a, 3 MIU subcutaneous three times a week plus Virazole 800 mg by mouth daily. All patients received 48 weeks of therapy and sustained virologic response (SVR) was assessed at 24 weeks of treatment-free follow-up. Virazole or placebo treatment assignment was blinded in the peginterferon alfa-2a treatment arms. All patients were adults, had compensated liver disease, detectable hepatitis C virus, liver biopsy diagnosis of chronic hepatitis C, and were previously untreated with interferon. Patients also had CD4+ cell count greater than or equal to 200 cells/mm3 or CD4+ cell count greater than or equal to 100 cells/mm3 but less than 200 cells/mm3 and HIV-1 RNA less than 5000 copies/mL, and stable status of HIV. Approximately 15% of patients in the study had cirrhosis. Results are shown in Table 12.


Interferon Alfa - 2a + Ribavirin 800 mg

( N = 289 )

Peginterferon Alfa - 2a + Placebo

( N = 289 )

Peginterferon Alfa - 2a + Ribavirin 800 mg

( N = 290 )

All patients

33 (11%)

 58 (20%)

 116 (40%)
Genotype 1

12/171 (7%)

 24/175 (14%)

 51/176 (29%)
Genotypes 2, 3

18/89 (20%)

 32/90 (36%)

 59/95 (62%)
Treatment response rates were lower in CHC/HIV patients with poor prognostic factors (including HCV genotype 1, HCV RNA greater than 800,000 IU/mL, and cirrhosis) receiving pegylated interferon alpha therapy.

Of the patients who did not demonstrate either undetectable HCV RNA or at least a 2 log10 reduction from baseline in HCV RNA titer by 12 weeks of peginterferon alfa-2a and Virazole combination therapy, 2% (2/85) achieved an SVR.

In CHC patients with HIV coinfection who received 48 weeks of peginterferon alfa-2a alone or in combination with Virazole treatment, mean and median HIV RNA titers did not increase above baseline during treatment or 24 weeks post-treatment.

16 HOW SUPPLIED/STORAGE AND HANDLING

Virazole Tablets, 200 mg are light pink to pink, round, biconvex, beveled, film-coated tablets debossed with the logo of 'ZC19' on one side, other side plain and supplied as follows:

NDC 68382-046-03 in bottle of 168 tablets

NDC 68382-046-28 in bottle of 180 tablets

NDC 68382-046-10 in bottle of 1000 tablets

NDC 68382-046-77 in unit-dose blister cartons of 100 (10 x 10) unit-dose tablets

Virazole Tablets, 400 mg are light pink to pink, capsule shaped, biconvex, film-coated tablets debossed with 'ZD' and '07' on one side and plain on other side and supplied as follows:

NDC 68382-127-17 in bottle of 28 tablets

NDC 68382-127-07 in bottle of 56 tablets

NDC 68382-127-14 in bottle of 60 tablets

Virazole Tablets, 500 mg are light pink to pink, modified capsule shaped, biconvex, film-coated tablets debossed with 'ZC56' on one side and plain on the other side and supplied as follows:

NDC 68382-128-17 in bottle of 28 tablets

NDC 68382-128-07 in bottle of 56 tablets

NDC 68382-128-14 in bottle of 60 tablets

Virazole Tablets, 600 mg are light pink to pink, modified capsule shaped, biconvex, film-coated tablets debossed with 'ZD' and '08' on one side and plain on other side and supplied as follows:

NDC 68382-129-17 in bottle of 28 tablets

NDC 68382-129-07 in bottle of 56 tablets

NDC 68382-129-14 in bottle of 60 tablets

Storage and Handling

Store at 20° to 25°C (68° to 77°F).

Keep bottle tightly closed.

17 PATIENT COUNSELING INFORMATION

Pregnancy

Patients must be informed that Virazole may cause birth defects and/or death of the exposed fetus. Virazole therapy 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 Virazole therapy and for 6 months post therapy. Patients should use two reliable methods of birth control while taking Virazole therapy and for 6 months post therapy. Virazole 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 post therapy.

Female patients of childbearing potential and male patients with female partners of childbearing potential must be advised of the teratogenic/embryocidal risks and must be instructed to practice effective contraception during Virazole therapy and for 6 months post therapy. Patients should be advised to notify the healthcare provider immediately in the event of a pregnancy [see CONTRAINDICATIONS (4) and WARNINGS AND PRECAUTIONS (5.1)].

Anemia

The most common adverse event associated with Virazole is anemia, which may be severe [see BOXED WARNING, WARNINGS AND PRECAUTIONS (5.2) and ADVERSE REACTIONS (6.1)]. Patients should be advised that laboratory evaluations are required prior to starting Virazole therapy and periodically thereafter [see WARNINGS AND PRECAUTIONS (5.9)]. It is advised that patients be well hydrated, especially during the initial stages of treatment.

Patients who develop dizziness, confusion, somnolence, and fatigue should be cautioned to avoid driving or operating machinery.

Patients should be advised to take Virazole with food.

Patients should be questioned about prior history of drug abuse before initiating ribavirin/peginterferon alfa-2a, as relapse of drug addiction and drug overdoses have been reported in patients treated with interferons.

Patients should be advised not to drink alcohol, as alcohol may exacerbate chronic hepatitis C infection.

Patients should be informed about what to do in the event they miss a dose of Virazole. The missed doses should be taken as soon as possible during the same day. Patients should not double the next dose. Patients should be advised to call their healthcare provider if they have questions.

Patients should be informed that the effect of peginterferon alfa-2a/ribavirin treatment of hepatitis C infection on transmission is not known, and that appropriate precautions to prevent transmission of hepatitis C virus during treatment or in the event of treatment failure should be taken.

Patients should be informed regarding the potential benefits and risks attendant to the use of Virazole. Instructions on appropriate use should be given, including review of the contents of the enclosed MEDICATION GUIDE, which is not a disclosure of all or possible adverse effects.

Manufactured by:

Cadila Healthcare Ltd.

Ahmedabad, India

Distributed by:

Zydus Pharmaceuticals USA Inc.

Pennington, NJ 08534

Rev.: 10/15

MEDICATION GUIDE

Virazole

(rye-ba-VYE-rin)

Tablets

Read this Medication Guide carefully before you start taking Virazole and read the Medication Guide each time you get more Virazole. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.

Also read the Medication Guide for peginterferon alfa-2a.

What is the most important information I should know about Virazole?

What is R ibavirin?

Virazole is a prescription medicine used with another medicine called peginterferon alfa-2a to treat chronic (lasting a long time) hepatitis C infection in people 5 years and older whose liver still works normally, and who have not been treated before with a medicine called an interferon alpha. It is not known if Virazole is safe and will work in children under 5 years of age.

Who should not take Virazole?

See "What is the most important information I should know about Virazole?"

Do not take Virazole if you:

Talk to your healthcare provider before starting treatment with Virazole if you have any of these medical conditions.

What should I tell my healthcare provider before taking Virazole?

Before you take Virazole, tell your healthcare provider if you have or have had:

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Some medicines can cause serious side effects if taken while you also take Virazole. Some medicines may affect how Virazole works or Virazole may affect how your other medicines work.

Especially tell your healthcare provider if you take any medicines to treat HIV, including didanosine (Videx or Videx EC), or if you take azathioprine (Imuran or Azasan).

Know the medicines you take. Keep a list of them to show your healthcare provider or pharmacist when you get a new medicine.

How should I take Virazole?

What should I avoid while taking Virazole?

What are the possible side effects of Virazole?

Virazole may cause serious side effects including:

See "What is the most important information I should know about Virazole?"

Call your healthcare provider or get medical help right away if you have any of the symptoms listed above. These may be signs of a serious side effect of Virazole treatment.

Common side effects of Virazole taken with peginterferon alfa-2a include:

Tell your healthcare provider about any side effect that bothers you or that does not go away.

These are not all the possible side effects of Virazole treatment. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Please address medical inquiries to, (MedicalAffairsVirazolezydususa.com) Tel.: 1-877-993-8779.

How should I store Virazole?

Keep Virazole and all medicines out of the reach of children.

General information about the safe and effective use of Virazole

It is not known if treatment with Virazole in combination with peginterferon alfa-2a will prevent an infected person from spreading the hepatitis C virus to another person while on treatment.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Virazole for a condition for which it was not prescribed. Do not give Virazole to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about Virazole. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Virazole that is written for healthcare professionals.

What are the ingredients in Virazole Tablets?

Active Ingredient: Virazole, USP

Inactive Ingredients: crospovidone, hypromellose, iron oxide red, iron oxide yellow, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, silicon dioxide, talc and titanium dioxide.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

This product's label may have been updated. For current full prescribing information, please visit www.zydususa.com.

Manufactured by:

Cadila Healthcare Ltd.

Ahmedabad, India

Distributed by:

Zydus Pharmaceuticals USA Inc.

Pennington, NJ 08534

Rev.: 02/15

NDC 68382-046-03 in bottle of 168 tablets

Virazole Tablets, 200 mg

Rx only

168 tablets

ZYDUS

NDC 68382-127-07 in bottle of 56 tablets

Virazole Tablets, 400 mg

Rx only

56 tablets

ZYDUS

NDC 68382-128-07 in bottle of 56 tablets

Virazole Tablets, 500 mg

Rx only

56 tablets

ZYDUS

NDC 68382-129-07 in bottle of 56 tablets

Virazole Tablets, 600 mg

Rx only

56 tablets

ZYDUS

Virazole tablets, 200 mg Virazole tablet,400 mg Virazole Tablet 500 mg Virazole tablet 600 mg

Virazole pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Virazole available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Virazole destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Virazole Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Virazole pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."RIBAVIRIN TABLET, FILM COATED [ZYDUS PHARMACEUTICALS (USA) INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."RIBAVIRIN: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. "ribavirin". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Virazole?

Depending on the reaction of the Virazole after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Virazole not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Virazole addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Virazole, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Virazole consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology


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