Flumivir®: Each capsule contains Oseltamivir Phosphate eq. to Oseltamivir: 75 mg.
Excipients: Starch, croscarmellose sodium, povidone, talc, sodium stearyl fumarate, gelatin, sunset yellow, titanium dioxide, allura red, brilliant blue.
TREATMENT OF INFLUENZA:
In patients one year of age or older who present with symptoms typical of influenza, when influenza virus is circulating in the community.
Efficacy has been demonstrated when treatment is initiated within two days of first onset of symptoms. This indication is based on clinical studies of naturally occurring influenza in which the predominant infection was influenza A.
Prevention of influenza: Post-exposure prevention in individuals one year of age or older following contact with a clinically diagnosed influenza case when influenza virus is circulating in the community.
The appropriate use of Flumivir® for prevention of influenza should be determined on a case by case basis by the circumstances and the population requiring protection. In exceptional situations (e.g., in case of a mismatch between the circulating and vaccine virus strains, and a pandemic situation) seasonal prevention could be considered in individuals one year of age or older.
Flumivir® is not a substitute for influenza vaccination.
The use of antivirals for the treatment and prevention of influenza should be determined on the basis of official recommendations, taking into consideration variability of epidemiology and the impact of the disease in different geographical areas and patient populations.
CONTRAINDICATIONS
Hypersensitivity to the active substance or to any of the excipients.
Oseltamivir phosphate is effective only against illness caused by influenza viruses. There is no evidence for efficacy of Oseltamivir phosphate in any illness caused by agents other than influenza viruses.
The safety and efficacy of Oseltamivir phosphate for the treatment and prevention of influenza in children of less than one year of age have not been established.
No information is available regarding the safety and efficacy of Oseltamivir phosphate in patients with any medical condition sufficiently severe or unstable to be considered at imminent risk of requiring hospitalisation.
The safety and efficacy of Oseltamivir phosphate in either treatment or prevention of influenza in immunocompromised patients have not been established.
Efficacy of Oseltamivir phosphate in the treatment of subjects with chronic cardiac disease and/or respiratory disease has not been established. No difference in the incidence of complications was observed between the treatment and placebo groups in this population.
Oseltamivir phosphate is not a substitute for influenza vaccination. Use of Oseltamivir phosphate must not affect the evaluation of individuals for annual influenza vaccination. The protection against influenza lasts only as long as Oseltamivir phosphate is administered. Oseltamivir phosphate should be used for the treatment and prevention of influenza only when reliable epidemiological data indicate that influenza virus is circulating in the community.
Severe renal impairment: Dose adjustment is recommended for both treatment and prevention in adults with severe renal insufficiency. There is insufficient clinical data available in children with renal impairment to be able to make any dosing recommendation.
Ability to drive and use machine: Oseltamivir phosphate has no influence on the ability to drive and use machines.
PREGNANCY AND LACTATION
There are no adequate data from the use of Oseltamivir phosphate in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal or postnatal development. Oseltamivir phosphate should not be used during pregnancy unless the potential benefit to the mother justifies the potential risk to the foetus. In lactating rats, Oseltamivir phosphate and the active metabolite are excreted in the milk. It is not known whether Oseltamivir phosphate or the active metabolite are excreted in human milk. Oseltamivir phosphate should be used during breast-feeding only if the potential benefit for the mother justifies the potential risk for the breast-fed infant.
DRUG INTERACTIONS
Pharmacokinetic properties of Oseltamivir phosphate, such as low protein binding and metabolism independent of the CYP450 and glucuronidase systems, suggest that clinically significant drug interactions via these mechanisms are unlikely.
No dose adjustment is required when co-administering with probenecid in patients with normal renal function. Co-administration of probenecid, a potent inhibitor of the anionic pathway of renal tubular secretion, results in an approximate 2-fold increase in exposure to the active metabolite of Oseltamivir phosphate. Oseltamivir phosphate has no kinetic interaction with amoxicillin, which is eliminated via the same pathway, suggesting that Oseltamivir phosphate interaction with this pathway is weak.
Clinically important drug interactions involving competition for renal tubular secretion are unlikely, due to the known safety margin for most of these substances, the elimination characteristics of the active metabolite (glomerular filtration and anionic tubular secretion) and the excretion capacity of these pathways. However, care should be taken when prescribing Oseltamivir phosphate in subjects when taking co-excreted agents with a narrow therapeutic margin (e.g., chlorpropamide, methotrexate, phenylbutazone).
No pharmacokinetic interactions between Oseltamivir phosphate or its major metabolite have been observed when co-administering Oseltamivir phosphate with paracetamol, acetyl-salicylic acid, cimetidine or with antacids (magnesium and aluminum hydroxides and calcium carbonates).
Treatment of influenza in adults and adolescents: A total of 2107 patients participated in phase III studies in the treatment of influenza. The most frequently reported undesirable effects were nausea, vomiting and abdominal pain. The majority of these events were reported on a single occasion on either the first or second treatment day and resolved spontaneously within 1-2 days. All events that were reported commonly (i.e., at an incidence of at least 1% irrespective of causality) in subjects receiving Oseltamivir 75 mg twice daily are included in the table below.
Treatment of influenza in elderly: In general, the safety profile in the elderly patients was similar to adults aged up to 65 years: the incidence of nausea was lower in oseltamivir treated elderly persons (6.7 %) than in those taking placebo (7.8 %) whereas the incidence of vomiting was higher in those who received oseltamivir (4.7 %) than among placebo recipients (3.1 %).
The adverse event profile in adolescents and in patients with chronic cardiac and/or respiratory disease was qualitatively similar to that of healthy young adults.
Prevention of influenza: In prevention studies, where the dosage of Oseltamivir was 75 mg once daily for up to 6 weeks, adverse events reported more commonly in subjects receiving Oseltamivir phosphate compared to subjects receiving placebo (in addition to the events listed in the table below) were: aches and pains, rhinorrhea, dyspepsia and upper respiratory tract infection. There were no phosphate or placebo compared with the younger population.
Most frequent Adverse Events in Studies in Naturally Acquired Influenza. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness under treatment with Oseltamivir 75 mg twice daily.
| System Organ Class | Adverse Event | Treatment | Prevention | ||
| Placebo
(N=1050) |
Oseltamivir 75 mg twice daily
(N=1057) |
Placebo
(N=1434) |
Oseltamivir 75 mg once daily
(N=1480) |
||
| Gastrointestinal Disorders | Vomiting2 | 3.0% | 8.0% | 1.0% | 2.1% |
| Nausea1,2 | 5.7% | 7.9% | 3.9% | 7.0% | |
| Diarrhea | 8.0% | 5.5% | 2.6% | 3.2% | |
| Abdominal Pain | 2.0% | 2.2% | 1.6% | 2.0% | |
| Infections and Infestations | Bronchitis | 5.0% | 3.7% | 1.2% | 0.7% |
| Bronchitis acute | 1.0% | 1.0% | – | – | |
| Cough | 1.1% | 0.9% | 6.0% | 5.6% | |
| General Disorders | Dizziness | 3.0% | 1.9% | 1.5% | 1.6% |
| Fatigue | 0.7% | 0.8% | 7.5% | 7.9% | |
| Neurological Disorders | Headache | 1.5% | 1.6% | 17.5% | 20.1% |
| Insomnia | 1.0% | 1.0% | 1.0% | 1.2% | |
| Vertigo | 0.6% | 0.9% | 0.2% | 0.3% | |
1 Subjects who experienced nausea alone; exclude subjects who experienced nausea in association with vomiting.
2 The difference between the placebo and Oseltamivir phosphate groups was statistically significant.
Treatment of influenza in children: A total of 1032 children aged 1 to 12 years (including 695 otherwise healthy children aged 1 to 12 years and 334 asthmatic children aged 6 to 12 years) participated in phase II studies of Oseltamivir phosphate given for the treatment of influenza.
Adverse events occurring in greater than 1% of children receiving Oseltamivir phosphate are listed in the table below. The most frequently reported adverse event was vomiting. Other events reported more frequently by Oseltamivir phosphate treated children included abdominal pain, epistaxis, ear disorder and conjunctivitis. These events generally ocurred once, resolved despite continued dosing and did not cause discontinuation of treatment in the vast majority of cases.
Most Frequent Adverse Events in Studies in Naturally Acquired Influenza in Children (Adverse Events Occurring on Treatment in > 1% of Pediatric Patients).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness under treatment with Oseltamivir 2 mg/kg bid.
| Treatment1 | Treatment2 | Prevention2 | ||
| Adverse Event | Placebo
N=517 |
Oseltamivir 2mg/kg bid
N=515 |
Oseltamivir 30 to 75 mg3
N=158 |
Oseltamivir 30 to 75 mg3
N=99 |
| Vomiting | 48 (9.3%) | 77 (15.0%) | 31 (19.6%) | 10 (10.1%) |
| Diarrhea | 55 (10.6%) | 49 (9.5%) | 5 (3.2%) | 1 (1.0%) |
| Otitis media | 58 (11.2%) | 45 (8.7%) | 2 (1.3%) | 2 (2.0%) |
| Abdominal pain | 20 (3.9%) | 24 (4.7%) | 3 (1.9%) | 3 (3.0%) |
| Asthma (including aggravated) | 19 (3.7%) | 18 (3.5%) | – | 1 (1.0%) |
| Nausea | 22 (4.3%) | 17 (3.3%) | 10 (6.3%) | 4 (4.0%) |
| Epistaxis | 13 (2.5%) | 16 (3.1%) | 2 (1.3%) | 1 (1.0%) |
| Pneumonia | 17 (3.3%) | 10 (1.9%) | – | – |
| Ear disorder | 6 (1.2%) | 9 (1.7%) | – | – |
| Sinusitis | 13 (2.5%) | 9 (1.7%) | – | – |
| Bronchitis | 11 (2.1%) | 8 (1.6%) | 3 (1.9%) | – |
| Conjunctivitis | 2 (0.4%) | 5 (1.0%) | – | – |
| Dermatitis | 10 (1.9%) | 5 (1.0%) | 1 (0.6%) | – |
| Lymphadenopathy | 8 (1.5%) | 5 (1.0%) | 1 (0.6%) | – |
| Tympanic membrane disorder | 6 (1.2%) | 5 (1.0%) | – | – |
1 Pooled data from Phase III trials of Oseltamivir phosphate treatment of naturally acquired influenza.
2 Uncontrolled study comparing treatment (twice-daily dosing for 5 days) with prevention (once-daily dosing for 10 days).
3 30 to 75 mg = age-based dosing.
Adverse events included are: all events reported in the treatment studies with a frequency ≥ 1% in the Oseltamivir 2 mg/kg bid group.
In general, the adverse event profile in the children with asthma was qualitatively similar to that of otherwise healthy children.
Prevention of influenza in children: Pediatric patients aged 1 to 12 years participated in a postexposure prevention study in households, both as index cases (n=134) and as contacts (n=222).
Gastrointestinal events, particularly vomiting, were the most frequently reported. The adverse events were consistent with those previously observed (see table above).
Observed during clinical practice: The following adverse reactions have been reported during post marketing use of Oseltamivir phosphate: dermatitis, rash, eczema, angioneurotic oedema, hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, as well as very rare reports of severe skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme. Additionally, there are very rare reports of hepato-biliary system disorders, including hepatitis and elevated liver enzymes in patients with influenza-like illness.
These cases include fatal fulminant hepatitis/hepatic failure.
Convulsions and psychiatric events such as depressed level of consciousness, abnormal behavior, hallucinations and delirium have been reported during Oseltamivir phosphate administration. In rare cases, the delirium resulted in accidental injury. The symptoms were mainly reported in children adolescents. Convulsions and psychiatric symptoms have also been reported in patients with influenza not taking Oseltamivir phosphate.
In rare cases gastro-intestinal bleedings and hemorrhagic colitis were observed after the use of Oseltamivir phosphate.
Flumivir® is not recommended for use in children less than one year of age due to insufficient data on safety and efficacy.
TREATMENT OF INFLUENZA:
Treatment should be initiated as soon as possible within the first two days of onset of symptoms of influenza.
Adolescents 13-17 years and adults: The recommended oral dose is 75 mg Flumivir® twice daily for 5 days.
Children 2-12 years: Children weighing > 40 kg and who are able to swallow capsules may receive treatment with the adult dosage of 75 mg capsules twice daily for 5 days.
Elderly: No dose adjustment is required, unless there is evidence of severe renal impairment.
Renal impairment: Dose adjustment is recommended for adults with severe renal impairment.
Recommended doses are detailed in the table below.
| Clcr | Recommended dose for treatment |
| > 30 (ml/min) | 75 mg twice daily |
| > 10 to ≤ 30 (ml/min) | 75 mg once daily, or 30 mg capsules twice daily |
| ≤ 10 (ml/min) | Not recommended |
| Dialysis patients | Not recommended |
PREVENTION OF INFLUENZA: Post-exposure prevention:
Adolescents 13-17 years and adults: The recommended dose for prevention of influenza following close contact with an infected individual is Flumivir® 75 mg once daily for 10 days. Therapy should begin as soon as possible within two days of exposure to an infected individual.
Children 2-12 years: Children weighing > 40 kg and who are able to swallow capsules may receive prevention with a 75 mg capsule once daily for 10 days.
Elderly: No dose adjustment is required, unless there is evidence of severe renal impairment.
Renal impairment: Dose adjustment is recommended for adults with severe renal impairment as detailed in the table below.
| Clcr | Recommended dose for treatment |
| > 30 (ml/min) | 75 mg once daily |
| > 10 to ≤ 30 (ml/min) | 75 mg second day, or 30 mg capsules once daily |
| ≤ 10 (ml/min) | Not recommended |
| Dialysis patients | Not recommended |
Hepatic impairment: No dose adjustment is required either for treatment or for prevention in patients with hepatic dysfunction. No studies have been carried out in paediatric patients with hepatic disorder.
PREVENTION DURING AN INFLUENZA EPIDEMIC IN THE COMMUNITY:
The recommended dose for prevention of influenza during a community outbreak is Flumivir® 75 mg once daily for up to 6 weeks.
OVERDOSAGE
There is no experience with overdose. However, the anticipated manifestations of acute overdose would be nausea, with or without accompanying vomiting, and dizziness. Patients should discontinue the treatment in the event of overdose. No specific antidote is known.
STORAGE CONDITIONS
Store below 30°C.
Keep in original pack in intact conditions.
