Tamiflu®: composition and pharmaceutical form
Tamiflu® comes as hard capsules; one capsule contains oseltamivir phosphate in an amount corresponding to 30 mg, 45 mg or 75 mg of oseltamivir.
There is also a powder for oral suspension at a concentration of 6 mg/ml. That form is preferable for children and adolescents, and also for adults who find capsules hard to swallow or who need smaller doses. Both forms are bioequivalent, so the 75 mg dose can be made up from capsules of different strengths or from the suspension.
How Tamiflu® works
Oseltamivir phosphate is the precursor of the active metabolite, oseltamivir carboxylate. That metabolite selectively inhibits the neuraminidase enzymes of the influenza virus — glycoproteins on the surface of the virion. The activity of viral neuraminidase matters both for the entry of the viral particle into uninfected cells and for the release of newly formed particles from infected cells, that is, for the further spread of the infection through the body.
In vitro, oseltamivir carboxylate inhibits the neuraminidase of influenza viruses of types A and B, and oseltamivir phosphate itself holds back infection and viral multiplication. In animal models, at an exposure comparable to that reached in humans taking 75 mg twice a day, oseltamivir inhibited the replication and pathogenicity of influenza A and B viruses. The IC50 value for the neuraminidase of clinical influenza A isolates is 0.1 to 1.3 nM and for influenza B 2.6 nM, although published work for influenza B describes higher values, on average up to 8.5 nM.
Indications
The medicine is used in adults and children, including full-term newborns, with typical influenza symptoms when the influenza virus is circulating in that environment. The efficacy of treatment has been shown if it is started within 2 days of the first symptoms appearing.
The second indication is post-exposure prophylaxis in people from 1 year of age after contact with a case of clinically diagnosed influenza and, during a pandemic, also in children under one year. In exceptional situations, for example when circulating strains do not match the vaccine strains or during a pandemic, seasonal prophylaxis in people from 1 year is considered. The medicine does not replace influenza vaccination, and the decision to use it rests on official recommendations, the characteristics of the circulating viruses and data on their sensitivity in the current season.
Method of use and dosage
For treatment the medicine is started as early as possible — within the first 2 days of symptoms appearing — and for post-exposure prophylaxis, within the first 2 days after contact with someone who is ill. In children the dose is calculated by body weight.
| Situation | Dose |
|---|---|
| Adults and adolescents from 13 years weighing over 40 kg, treatment | 75 mg twice a day for 5 days |
| The same, post-exposure prophylaxis | 75 mg once a day for 10 days |
| The same, prophylaxis during an epidemic in the surroundings | 75 mg once a day for up to 6 weeks |
| Children from 1 year, 5-day treatment | 10–15 kg — 30 mg; over 15–23 kg — 45 mg; over 23–40 kg — 60 mg; over 40 kg — 75 mg, all twice a day |
| Children from 1 year, 10-day prophylaxis | the same doses by body weight, but once a day |
| Children under 12 months, 5-day treatment | 3 mg per kg of body weight twice a day |
In severe renal impairment, in adolescents aged 13–17 and in adults, both the treatment and the prophylactic dose are reduced. For children from one year with renal impairment the clinical data are insufficient to give dosing recommendations, and for premature infants under 36 weeks post-conceptional age such data do not exist at all. Prophylaxis during an epidemic in children under 12 has not been studied.
Contraindications
The list consists of a single point.
- hypersensitivity to oseltamivir or to any excipient of the medicine.
Special warnings and precautions
Oseltamivir works only in illness caused by influenza viruses; there is no evidence of its efficacy in diseases of another nature. It should be used for treatment and prophylaxis only when reliable epidemiological data confirm that the virus is circulating. The sensitivity of circulating strains to oseltamivir varies appreciably, so before prescribing it the doctor takes recent sensitivity data into account. Protection lasts only for as long as the medicine is being taken, and the prescription itself does not remove the need for annual vaccination.
Where the data are insufficient
- there is no information on safety and efficacy in people whose condition is so severe or unstable that it requires immediate hospitalisation;
- efficacy in immunocompromised patients has not been reliably established — neither for treatment nor for prophylaxis;
- efficacy in chronic heart and respiratory disease has not been established: in those groups the frequency of complications on oseltamivir and on placebo did not differ;
- there are no data to give dosing recommendations in premature infants under 36 weeks post-conceptional age;
- in children from one year with renal impairment the clinical data are insufficient for recommendations;
- in patients with influenza, especially children and adolescents, neuropsychiatric events were observed — they also occur in those not taking the medicine, but changes in behaviour must be watched closely;
- the risks and the benefit of continuing treatment in such events are assessed individually;
- the medicine has no influence on the ability to drive and operate machinery.
Drug interactions
The pharmacokinetics of oseltamivir — weak protein binding and a metabolism independent of the cytochrome P450 and glucuronidase systems — indicates that clinically significant interactions through those mechanisms are unlikely. No interactions have been noted with paracetamol, acetylsalicylic acid, cimetidine, antacids based on magnesium and aluminium hydroxides and calcium carbonate, rimantadine or warfarin in stable patients without influenza.
Tubular secretion deserves separate attention. Probenecid, a strong inhibitor of the anionic secretion pathway in the renal tubules, roughly doubles the exposure to the active metabolite, though with normal kidney function no dose change is needed. With amoxicillin, which is eliminated by the same route, there are no kinetic interactions, which speaks to the weakness of that mechanism. Even so, caution is needed if the patient is at the same time taking substances eliminated by that route with a narrow therapeutic window — chlorpropamide, methotrexate, phenylbutazone.
Pregnancy and breastfeeding
No controlled clinical studies have been carried out in pregnant women, but the data gathered after the medicine reached the market and in observational studies, together with the results of animal studies, do not indicate a direct or indirect harmful effect on the course of pregnancy, embryonic and foetal development or postnatal development. A pregnant woman may take the medicine after an assessment of the available safety data, the pathogenicity of the circulating strain and the underlying illness.
In lactating rats oseltamivir and the active metabolite are excreted in the milk. Data on children breastfed by mothers taking the medicine are very scarce: limited observations show that oseltamivir and the metabolite were detected in breast milk, but at concentrations so low that the dose in the child would be subtherapeutic. With that in mind, along with the pathogenicity of the circulating virus and the woman's own condition, use during breastfeeding is possible if the expected benefit is substantial. Preclinical data do not indicate an influence of the medicine on fertility in men and women.
Adverse effects
In adults and adolescents nausea and vomiting during treatment and nausea during prophylaxis were reported most often; in children, vomiting. Most of these reactions occurred once on the first or second day of use and passed on their own within 1–2 days, without requiring treatment to be stopped.
- very common: headache;
- common: insomnia, bronchitis, herpes simplex, nasopharyngitis, upper respiratory tract infections, sinusitis;
- uncommon: hypersensitivity reactions, altered level of consciousness, seizures, heart rhythm disturbances;
- rare: thrombocytopenia, anaphylactic and anaphylactoid reactions, visual disturbances;
- rare in the psychic sphere: agitation, unusual behaviour, restlessness, confusion, delusions, delirium, hallucinations, nightmares, self-harm;
- rare serious reactions noted after the medicine reached the market: liver damage, including fulminant hepatitis, impaired liver function and jaundice;
- rare serious skin reactions: angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis;
- other rare serious reactions: gastrointestinal bleeding and neuropsychiatric disturbances.
The safety profile with prophylactic use — 75 mg once a day for up to 6 weeks — did not differ qualitatively from that seen with treatment, despite the longer duration of use.
Overdose
Reports of overdose have come both from clinical trials and from practice after the medicine reached the market. In most cases no adverse events were recorded, and those that were recorded resembled, in nature and frequency, the reactions seen at ordinary therapeutic doses.
There is no specific antidote. Overdose occurred more often in children than in adults and adolescents, so particular care is needed when preparing the oral suspension and when dosing it to a child — that is precisely the step where a mistake is easiest.
How to get a prescription for Tamiflu® online
Tamiflu® is a prescription-only medicine, and time is decisive here: treatment is effective if started within the first 2 days of symptoms appearing, and prophylaxis within the first 2 days after contact. During the online consultation the doctor will assess the symptoms, clarify whether there was contact with someone ill with influenza and take the epidemiological situation into account.
If the medicine is indicated, the doctor will issue an electronic prescription, choose the dose and the form — capsules or suspension — and explain the length of the course, as well as which changes in behaviour call for contacting a doctor.
