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AVIGAN is contraindicated in the following patients.
Note: Use only as directed by a physician.
Since early embryonic deaths and teratogenicity have been observed in animal studies for AVIGAN, do not administer the drug to women known or suspected to be pregnant.
When administering AVIGAN to women of child-bearing potential, confirm a negative pregnancy test result before starting the treatment. Explain fully the risks and instruct thoroughly to use most effective contraceptive methods with her partner during and for 7 days after the end of the treatment. If pregnancy is suspected during the treatment, instruct to discontinue the treatment immediately and to consult a doctor.
AVIGAN is distributed in n sperm. When administering the drug to male patients, explain fully the risks and instruct thoroughly to use most effective contraceptive methods in sexual intercourse during and for 7 days after the end of the treatment (men must wear a condom). In addition, instruct not to have sexual intercourse with pregnant women.
Prior to the treatment, explain thoroughly the efficacy and risks (including the risk of exposure to fetus) in writing to patients or their family members and obtain their written consent.
Examine carefully the necessity of AVIGAN before use.
Careful Administration (AVIGAN should be administered with care in the following patients.): Patients with gout or a history of gout, and patients with hyperuricaemia (Blood uric acid level may increase, and symptoms may be aggravated.
No clinical study has been conducted to examine the efficacy and safety of AVIGAN with the approved dosage. The approved dosage was estimated based on the results of a placebo-controlled phase I/II clinical study in patients with influenza virus infection and the pharmacokinetic data from Japanese and overseas studies. Increase of plasma level of favipiravir has been reported in patients with liver function impairment in pharmacokinetic study conducted outside of Japan 2.
Although the causal relationship is unknown, psychoneurotic symptoms such as abnormal behavior after administration of anti-influenza virus agents including AVIGAN have been reported. For the treatment of children and minors, as a preventive approach in case of an accident due to abnormal behavior such as fall, patients/their family should be instructed that, after the start of treatment with anti-influenza virus agents, (i) abnormal behavior may be developed, and (ii) guardians and others should make an arrangement so that children/minors are not left alone for at least 2 days when they are treated at home. Since similar symptoms associated with influenza encephalopathy have been reported, the same instruction as above should be given.
Influenza virus infection may be complicated with bacterial infections or may be confused with influenza-like symptoms. In case of bacterial infection or suspected to be bacterial infection, appropriate measures should be taken, such as administration of anti-bacterial agents.
In animal studies, histopathological changes of testis in rats (12 weeks old) and young dogs (7 to 8 months old), and abnormal findings of sperm in mice (11 weeks old) have been reported. Recovery or tendency of recovery has been observed in those studies after the administration was suspended.
AVIGAN is not metabolized by cytochrome P-450 (CYP), mostly metabolized by aldehyde oxidase (AO), and partly metabolized by xanthine oxidase (XO). The drug inhibits AO and CYP2C8, but does not induce CYP.
AVIGAN should be administered with care when co-administered with the following drugs:
| Drugs | Signs, Symptoms, and Treatment | Mechanism and Risk Factors |
|---|---|---|
| Pyrazinamide | Blood uric acid level increases. When pyrazinamide 1.5g once daily and AVIGAN 1200 mg /400 mg BID were administered, the blood uric acid level was 11.6 mg/dL when pyrazinamide was administered alone, and 13.9 mg/dL in combination with AVIGAN. | Reabsorption of uric acid in the renal tubule is additively enhanced. |
| Repaglinide | Blood level of repaglinide may increase, and adverse reactions to repaglinide may occur. | Inhibition of CYP2C8 increases blood level of repaglinide. |
| Theophylline | Blood level of AVIGAN may increase, and adverse reactions to AVIGAN may occur. | Interaction with XO may increase blood level of AVIGAN. |
| Famciclovir | Efficacy of these drugs may be reduced. | Inhibition of AO by AVIGAN may decrease blood level of active forms of these drugs. |
| Sulindac |
AVIGAN has never been administered with the approved dosage. In Japanese clinical studies and the global phase III study (studies conducted with dose levels lower than the approved dosage), adverse reactions were observed in 100 of 501 subjects (19.96%) evaluated for the safety (including abnormal laboratory test values). Major adverse reactions included increase of blood uric acid level in 24 subjects (4.79%), diarrhoea in 24 subjects (4.79%), decrease of neutrophil count in 9 subjects (1.80%), increase of AST (GOT) in 9 subjects (1.80%), increase of ALT (GPT) in 8 subjects (1.60%).
The following clinically significant adverse reactions have been reported with other anti-influenza virus agents. Patients should be carefully monitored, and if any abnormality is observed, the treatment should be discontinued and appropriate measures should be taken.
If the following adverse reactions occur, appropriate measures should be taken according to the symptoms.
| ≥1% | 0.5 - <1% | <0.5% | |
|---|---|---|---|
| Hypersensitivity | Rash | Eczema, pruritus | |
| Hepatic | AST (GOT) increased, ALT (GPT) increased, γ-GTP increased | Blood ALP increased, blood bilirubin increased | |
| Gastrointestinal | Diarrhoea (4.79%) | Nausea, vomiting, abdominal pain | Abdominal discomfort, duodenal ulcer, haematochezia, gastritis |
| Hematologic | Neutrophil count decreased, white blood cell count decreased | White blood cell count increased, reticulocyte count decreased, monocyte increased | |
| Metabolic disorders | Blood uric acid increased (4.79%), blood triglycerides increased | Glucose urine present | Blood potassium decreased |
| Respiratory | Asthma, oropharyngeal pain, rhinitis, nasopharyngitis | ||
| Others | Blood CK (CPK) increased, blood urine present, tonsil polyp, pigmentation, dysgeusia, bruise, vision blurred, eye pain, vertigo, supraventricular extrasystoles |
Note 1: Adverse reactions observed in Japanese clinical studies and the global phase III clinical study (studies conducted with dose levels lower than the approval dosage).
Do not administer favipiravir to women known or suspected to be pregnant.
Early embryonic deaths (rats) and teratogenicity (monkeys, mice, rats and rabbits) have been observed in animal studies with exposure levels similar to or lower than the clinical exposure.
When administering favipiravir to lactating women, instruct to stop lactating.
The major metabolite of favipiravir, a hydroxylated form, was found to be distributed in breast milk.
AVIGAN has never been administered with the approved dosage. In Japanese clinical studies and the global phase III study (studies conducted with dose levels lower than the approved dosage), adverse reactions were observed in 100 of 501 subjects (19.96%) evaluated for the safety (including abnormal laboratory test values). Major adverse reactions included increase of blood uric acid level in 24 subjects (4.79%), diarrhoea in 24 subjects (4.79%), decrease of neutrophil count in 9 subjects (1.80%), increase of AST (GOT) in 9 subjects (1.80%), increase of ALT (GPT) in 8 subjects (1.60%) (See “CLINICAL STUDIES”).
The following clinically significant adverse reactions have been reported with other anti-influenza virus agents. Patients should be carefully monitored, and if any abnormality is observed, the treatment should be discontinued and appropriate measures should be taken.
If the following adverse reactions occur, appropriate measures should be taken according to the symptoms.
| ≥1% | 0.5 - <1% | <0.5% | |
|---|---|---|---|
| Hypersensitivity | Rash | Eczema, pruritus | |
| Hepatic | AST (GOT) increased, ALT (GPT) increased, γ-GTP increased | Blood ALP increased, blood bilirubin increased | |
| Gastrointestinal | Diarrhoea (4.79%) | Nausea, vomiting, abdominal pain | Abdominal discomfort, duodenal ulcer, haematochezia, gastritis |
| Hematologic | Neutrophil count decreased, white blood cell count decreased | White blood cell count increased, reticulocyte count decreased, monocyte increased | |
| Metabolic disorders | Blood uric acid increased (4.79%), blood triglycerides increased | Glucose urine present | Blood potassium decreased |
| Respiratory | Asthma, oropharyngeal pain, rhinitis, nasopharyngitis | ||
| Others | Blood CK (CPK) increased, blood urine present, tonsil polyp, pigmentation, dysgeusia, bruise, vision blurred, eye pain, vertigo, supraventricular extrasystoles |
Note 1: Adverse reactions observed in Japanese clinical studies and the global phase III clinical study (studies conducted with dose levels lower than the approval dosage).
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