Source: Health Sciences Authority (SG) Publisher: Manufactured by: Natco Pharma Limited, Kothur – 509 228, Rangareddy District, Telangana, India Marketed by: Natco Pharma Asia Pte Ltd., 111, North Bridge Road, # 23-05 Peninsula Plaza, Singapore 179098 ...
Oseltamivir phosphate capsules are contraindicated in patients with known hypersensitivity to Oseltamivir phosphate or to any component of the product.
Oseltamivir is effective only against illness caused by influenza viruses. There is no evidence for efficacy of oseltamivir in any illness caused by agents other than influenza viruses.
No information is available regarding the safety and efficacy of oseltamivir 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 in either treatment or prevention of influenza in immunocompromised patients have not been established.
Efficacy of oseltamivir 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 (see section 4.1).
Frequency not known: influenza can be associated with a variety of neurologic and behavioural symptoms which can include events such as hallucinations, delirium, and abnormal behaviour, in some cases resulting in fatal outcomes. These events may occur in the setting of encephalitis or encephalopathy but can occur without obvious severe disease.
In patients with influenza who were receiving oseltamivir phosphate capsules, there have been postmarketing reports of convulsions and delirium (including symptoms such as altered level of consciousness, confusion, abnormal behaviour, delusions, hallucinations, agitation, anxiety, nightmares), in a very few cases resulting in accidental injury or fatal outcomes. These events were reported primarily among pediatric and adolescent patients and often had an abrupt onset and rapid resolution. The contribution of oseltamivir phosphate capsules to those events is unknown. Such neuropsychiatric events have also been reported in patients with influenza who were not taking oseltamivir phosphate capsules. Three separate large epidemiological studies confirmed that influenza infected patients receiving oseltamivir phosphate capsules are at no higher risk to develop neuropsychiatric events in comparison to influenza infected patients not receiving antivirals.
Patients with influenza should be closely monitored for signs of abnormal behaviour. If neuropsychiatric symptoms occur, the risks and benefits of continuing treatment should be evaluated for each patient.
Oseltamivir phosphate capsules are not a substitute for influenza vaccination. Use of oseltamivir phosphate capsules must not affect the evaluation of individuals for annual influenza vaccination. The protection against influenza lasts only as long as oseltamivir phosphate capsules are administered. Oseltamivir phosphate capsules should be used for the treatment and prevention of influenza only when reliable epidemiological data indicate that influenza virus is circulating in the community.
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. (see sections 3.2 and 4.2).
Fertility studies have been conducted in rats. There was no evidence of an effect on male or female fertility at any dose of oseltamivir studied.
Pharmacokinetic properties of oseltamivir, such as low protein binding and metabolism independent of the CYP450 and glucuronidase systems (see section 4.2), 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.
Oseltamivir has no kinetic interaction with amoxicillin, which is eliminated via the same pathway, suggesting that oseltamivir 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 in subjects when taking co-excreted agents with a narrow therapeutic margin (e.g., chlorpropamide, methotrexate, phenylbutazone).
No pharmacokinetic interactions between oseltamivir or its major metabolite have been observed when co-administering oseltamivir with paracetamol, acetyl-salicylic acid, cimetidine or with antacids (magnesium and aluminium hydroxides and calcium carbonates), warfarin, rimantadine or amantadine.
In animal reproductive studies in rats and rabbits, no teratogenic effect was observed. Foetal exposure in rats and rabbits was approximately 15-20% of that of the mother.
No controlled clinical trials have been conducted on the use of oseltamivir in pregnant women; however there is evidence from post-marketing and observational studies showing benefit of the current dosing regimen in this patient population. Results from pharmacokinetic analyses indicate a lower exposure to the active metabolite, however dose adjustments are not recommended for pregnant women in the treatment or prophylaxis of influenza. A large amount of data from pregnant women exposed to Oseltamivir (more than 1000 exposed outcomes during the first trimester) from post-marketing reports and observational studies in conjunction with animal studies indicate no direct or indirect harmful effects with respect to pregnancy, embryonal/foetal or postnatal development (see section 4.3 Preclinical safety data). Pregnant women may receive oseltamivir phosphate capsules, after considering the available safety and benefit information, the pathogenicity of the circulating influenza virus strain and the underlying condition of the pregnant woman.
In lactating rats, oseltamivir and the active metabolite are excreted in milk. Very limited information is available on children breast-fed by mothers taking oseltamivir and on excretion of oseltamivir in breast milk. Limited data demonstrated that oseltamivir and the active metabolite were detected in breast milk, however the levels were low, which would result in a subtherapeutic dose to the infant. Based on this information, the pathogenicity of the circulating influenza virus strain and the underlying condition of the lactating woman, administration of oseltamivir may be considered, where there are clear potential benefits to lactating mothers
The safe use of oseltamivir during labor and delivery has not been established.
No or negligible influence on the ability to drive and use machines.
The overall safety profile of oseltamivir phosphate capsules is based on data from 2646 adult/adolescent and 859 paediatric patients with influenza, and on data from 1943 adult/adolescent and 148 paediatric patients receiving oseltamivir phosphate capsules for the prophylaxis of influenza in clinical trials.
In adults/adolescent, the most commonly reported adverse drug reactions (ADRs) were vomiting, nausea and headache in the treatment studies. The majority of these ADRs were reported on a single occasion on either the first or second treatment day and resolved spontaneously within 1-2 days. In adult/adolescent prophylaxis studies, the most frequently reported ADRs were nausea, vomiting, headache and pain. In children, the most commonly reported ADR was vomiting. In the majority of patients, these events did not lead to discontinuation of oseltamivir phosphate capsules.
Adverse drug reactions from clinical trials are listed according to the MedDRA system organ class. The corresponding frequency category for each adverse drug reaction listed in the tables below is based on the following convention: Very Common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100), Rare (≥1/10,000 to <1/1,000), Very rare (<1/10,000).
In adult/adolescent treatment and prophylaxis studies, ADRs that occurred the most frequently (≥1%) at the recommended dose (75 mg b.i.d. for 5 days for treatment and 75 mg o.d. for up to 6 weeks for prophylaxis), and whose incidence is at least 1% higher on oseltamivir phosphate capsules compared to placebo are presented in the table below.
The population included in the influenza treatment studies comprised of otherwise healthy adults/adolescents and patients “at risk” (patients at higher risk of developing complications associated with influenza, e.g. elderly patients and patients with chronic cardiac or respiratory disease). In general, the safety profile in the patients “at risk” was qualitatively similar to that in otherwise healthy adults/adolescents.
The safety profile reported in the subjects that received the recommended dose of oseltamivir phosphate capsules for prophylaxis (75 mg once daily for up to 6 weeks) was qualitatively similar to that seen in the treatment studies, despite a longer duration of dosing in the prophylaxis studies.
Summary of Adverse Drug Reactions in ≥1% of adult and adolescent patients that received oseltamivir for treatment or prophylaxis of influenza, in clinical studies (difference to placebo ≥1%):
| System Organ Class (SOC) Adverse Drug Reaction | Treatment studies | Prophylaxis | Frequency Categorya |
|---|---|---|---|
| Oseltamivir 75 mg bid (n=2646) | Oseltamivir 75 mg od (n=1943) | ||
| Nervous system disorders | |||
| Headache | 2% | 17% | very common |
| Gastrointestinal disorders | |||
| Nausea Vomiting | 10% 8% | 8% 2% | very common common |
| General disorders | |||
| Pain | <1% | 4% | common |
a Frequency category is reported only for the oseltamivir group.
A total of 1481 children (including otherwise healthy children aged 1–12 and asthmatic children aged 6–12) participated in clinical studies of oseltamivir given for the treatment of influenza. A total of 859 children received treatment with oseltamivir suspension.
The ADR that occurred in ≥ 1% of children aged 1 to 12 years receiving oseltamivir in the clinical trials for treatment of naturally acquired influenza (n=859), and whose incidence is at least 1% higher on oseltamivir phosphate capsules compared to placebo (n=622), is vomiting (16% on oseltamivir vs. 8% on placebo). Amongst the 148 children who received the recommended dose of oseltamivir phosphate capsules once daily in a post-exposure prophylaxis study in households (n=99), and in a separate 6–week paediatric prophylaxis study (n=49), vomiting was the most frequent ADR (8% on oseltamivir vs. 2% in the no prophylaxis group). Oseltamivir phosphate capsules was well tolerated in these studies and the adverse events noted were consistent with those previously observed in paediatric treatment studies.
Frequency not known: hypersensitivity reactions, including anaphylactic/anaphylactoid reactions.
Frequency not known: visual disturbance.
Frequency not known: cardiac arrhythmia.
Frequency not known: gastrointestinal bleedings and hemorrhagic colitis.
Frequency not known: Hepatobiliary disorders, including hepatitis and elevated liver enzymes in patients with influenza-like illness. These cases include fatal fulminant hepatitis/hepatic failure.
Frequency not known: severe skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme and angioneurotic oedema.
Frequency not known: Hallucinations and convulsions
There were no clinically relevant differences in the safety profile of the 942 subjects, 65 years of age and older, who received oseltamivir phosphate capsules or placebo, compared with the younger population (aged up to 65 years).
The adverse event profile in adolescents and patients with chronic cardiac and/or respiratory disease was qualitatively similar to those of healthy young adults.
Not applicable.
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