Oseltamivir 12mg/ml Powder for Oral Suspension Taj Pharma

Oseltamivir 12mg/ml powder for oral suspension

  1. Name of the medicinal product

Oseltamivir 12mg/ml powder for oral suspension Taj Pharma

  1. Qualitative and quantitative composition

Each ml of reconstituted suspension contains oseltamivir phosphate equivalent to 12mg of oseltamivir.

One bottle of reconstituted suspension (65 ml) contains 780mg of oseltamivir.

Excipients with known effect:

For the full list of excipients, see section 6.1.

  1. Pharmaceutical form

Powder for oral suspension

  1. Clinical particulars

4.1 Therapeutic indications

Treatment of influenza

Oseltamivir is indicated in adults and children including full term neonates 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.

Prevention of influenza

– Post-exposure prevention in individuals 1 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 Oseltamivir 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.

– Oseltamivir is indicated for post-exposure prevention of influenza in infants less than 1 year of age during a pandemic influenza outbreak (see section 5.2).

Oseltamivir 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. Decisions regarding the use of oseltamivir for treatment and prophylaxis should take into consideration what is known about the characteristics of the circulating influenza viruses, available information on influenza drug susceptibility patterns for each season and the impact of the disease in different geographical areas and patient populations (see section 5.1).

4.2 Posology and method of administration

Posology

Oseltamivir suspension and Oseltamivir hard capsules are bioequivalent formulations. 75mg doses can be administered as either

– one 75mg capsule or

– one 30mg capsule plus one 45mg capsule or

– by administering one 30mg dose plus one 45mg dose of suspension.

Adults, adolescents or children (> 40 kg) who are able to swallow capsules may receive appropriate doses of Oseltamivir capsules.

Treatment

Treatment should be initiated as soon as possible within the first two days of onset of symptoms of influenza.

For adolescents (13 to 17 years of age) and adults: The recommended oral dose is 75mg oseltamivir twice daily for 5 days.

Paediatric population

For infants and children1 year of age or older: The recommended dose of Oseltamivir 12mg/ml oral suspension is indicated in the table below. Oseltamivir 30mg and 45mg capsules are available as an alternative to the recommended dose of Oseltamivir 12mg/ml suspension.

The following weight-adjusted dosing regimens are recommended for infants and children 1 year of age or older:

Body weight Recommended dose for 5 days Amount of oral suspension to withdraw
10 kg to 15 kg 30mg twice daily 5 ml twice daily
> 15 kg to 23 kg 45mg twice daily 7.5 ml twice daily
> 23 kg to 40 kg 60mg twice daily 10 ml twice daily
> 40 kg 75mg twice daily 12.5 ml twice daily

Children weighing > 40 kg and who are able to swallow capsules may receive treatment with the adult dosage of 75mg capsules twice daily for 5 days as an alternative to the recommended dose of Oseltamivir suspension.

For infants less than 1 year of age: The recommended treatment dose for infants 0 – 12 months of age is 3mg/kg twice daily. This is based upon pharmacokinetic and safety data indicating that this dose in infants 0 – 12 months provides plasma concentrations of the pro-drug and active metabolite that are anticipated to be clinically efficacious with a safety profile comparable to that seen in older children and adults (see section 5.2).

A 3 ml oral dispenser (graduated in 0.1 ml steps) should be used for dosing children 0 – 12 months of age requiring 1 ml to 3 ml of Oseltamivir 12mg/ml oral suspension. For higher doses the 10 ml syringe should be used. The following dosing regimen is recommended for treatment of infants below 1 year of age:

Dosing table of oseltamivir for children less than 1 year of age: 3mg/kg twice daily

Body Weight* Recommended dose for 5 days Amount of oral suspension to withdraw Dispenser size to use
3 kg 9mg twice daily 1.5 ml twice daily 3 ml
3.5 kg 10.5mg twice daily 1.8 ml twice daily 3 ml
4 kg 12mg twice daily 2.0 ml twice daily 3 ml
4.5 kg 13.5mg twice daily 2.3 ml twice daily 3 ml
5 kg 15mg twice daily 2.5 ml twice daily 3 ml
5.5 kg 16.5mg twice daily 2.8 ml twice daily 3 ml
6 kg 18mg twice daily 3.0 ml twice daily 3 ml
> 6 – 7 kg 21mg twice daily 3.5 ml twice daily 10 ml
> 7 – 8 kg 24mg twice daily 4.0 ml twice daily 10 ml
> 8 – 9 kg 27mg twice daily 4.5 ml twice daily 10 ml
> 9 – 10 kg 30mg twice daily 5.0 ml twice daily 10 ml

* This table is not intended to contain all possible weights for this population.

This dosing recommendation is not intended for premature infants, i.e. those with a post-conceptual age less than 36 weeks. Insufficient data are available for these patients, in whom different dosing may be required due to the immaturity of physiological functions.

Prevention

Post-exposure prevention

For adolescents (13 to 17 years of age) and adults: The recommended dose for prevention of influenza following close contact with an infected individual is 75mg oseltamivir once daily for 10 days. Therapy should begin as soon as possible within two days of exposure to an infected individual.

For infants and children 1 year of age or older: Oseltamivir 30mg and 45mg capsules are available as an alternative to the recommended dose of Oseltamivir 12mg/ml suspension.

The recommended post-exposure prevention dose of Oseltamivir is:

Body weight Recommended dose for 10 days Amount of oral suspension to withdraw
10 kg to 15 kg 30mg once daily 5 ml once daily
> 15 kg to 23 kg 45mg once daily 7.5 ml once daily
> 23 kg to 40 kg 60mg once daily 10 ml once daily
> 40 kg 75mg once daily 12.5 ml once daily

Children weighing > 40 kg and who are able to swallow capsules may receive prophylaxis with a 75mg capsule once daily for 10 days as an alternative to the recommended dose of Oseltamivir suspension.

For infants less than 1 year of age: The recommended prophylaxis dose for infants less than 12 months during a pandemic influenza outbreak is half of the daily treatment dose. This is based upon clinical data in children > 1 year of age and adults showing that a prophylaxis dose equivalent to half the daily treatment dose is clinically efficacious for the prevention of influenza (see Section 5.2 for exposure simulation).

In case of a pandemic, a 3 ml oral dispenser (graduated in 0.1 ml steps) should be used for dosing children below 1 year of age requiring 1 ml to 3 ml of Oseltamivir 12mg/ml oral suspension. For higher doses the 10 ml syringe should be used.

The following dosing regimen is recommended for infants less than 1 year of age:

Dosing table of oseltamivir for children below one year of age: 3mg/kg once daily

Body Weight* Recommended dose for 10 days Amount of oral suspension to withdraw Dispenser size to use
3 kg 9mg once daily 1.5 ml once daily 3 ml
3.5 kg 10.5mg once daily 1.8 ml once daily 3 ml
4 kg 12mg once daily 2.0 ml once daily 3 ml
4.5 kg 13.5mg once daily 2.3 ml once daily 3 ml
5 kg 15mg once daily 2.5 ml once daily 3 ml
5.5 kg 16.5mg once daily 2.8 ml once daily 3 ml
6 kg 18mg once daily 3.0 ml once daily 3 ml
> 6 – 7 kg 21mg once daily 3.5 ml once daily 10 ml
> 7 – 8 kg 24mg once daily 4.0 ml once daily 10 ml
> 8 – 9 kg 27mg once daily 4.5 ml once daily 10 ml
> 9 – 10 kg 30mg once daily 5.0 ml once daily 10 ml

* This table is not intended to contain all possible weights for this population.

This dosing recommendation is not intended for premature infants, i.e. those with a post-conceptual age less than 36 weeks. Insufficient data are available for these patients, in whom different dosing may be required due to the immaturity of physiological functions.

Prevention during an influenza epidemic in the community

Prevention during an influenza epidemic has not been studied in children below 12 years of age. The recommended dose for adults and adolescents for prevention of influenza during a community outbreak is 75mg oseltamivir once daily for up to 6 weeks.

Special populations

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.

Renal impairment

Treatment of influenza: Dose adjustment is recommended for adults and adolescents (13 to 17 years of age) with moderate or severe renal impairment. Recommended doses are detailed in the table below.

Creatinine clearance Recommended dose for treatment
> 60 (ml/min) 75mg twice daily
> 30 to 60 (ml/min) 30mg (suspension or capsules) twice daily
> 10 to 30 (ml/min) 30mg (suspension or capsules) once daily
≤ 10 (ml/min) Not recommended (no data available)
Haemodialysis patients 30mg after each haemodialysis session
Peritoneal dialysis patients* 30mg (suspension or capsules) single dose

* Data derived from studies in continuous ambulatory peritoneal dialysis (CAPD) patients; the clearance of oseltamivir carboxylate is expected to be higher when automated peritoneal dialysis (APD) mode is used. Treatment mode can be switched from APD to CAPD if considered necessary by a nephrologist.

Prevention of influenza: Dose adjustment is recommended for adults and adolescents (13 to 17 years of age) with moderate or severe renal impairment as detailed in the table below.

Creatinine clearance Recommended dose for prevention
> 60 (ml/min) 75mg once daily
> 30 to 60 (ml/min) 30mg (suspension or capsules) once daily
> 10 to 30 (ml/min) 30mg (suspension or capsules) every second day
≤ 10 (ml/min) Not recommended (no data available)
Haemodialysis patients 30mg after every second haemodialysis session
Peritoneal dialysis patients* 30mg (suspension or capsules) once weekly

* Data derived from studies in continuous ambulatory peritoneal dialysis (CAPD) patients; the clearance of oseltamivir carboxylate is expected to be higher when automated peritoneal dialysis (APD) mode is used. Treatment mode can be switched from APD to CAPD if considered necessary by a nephrologist.

There is insufficient clinical data available in infants and children (12 years of age and younger) with renal impairment to be able to make any dosing recommendation.

Elderly

No dose adjustment is required, unless there is evidence of moderate or severe renal impairment.

Immunocompromised patients

Treatment: The recommended oral dose is 75mg oseltamivir twice daily for 10 days for adults (see sections 4.4, 4.8 and 5.1). Treatment should be initiated as soon as possible within the first two days of onset of symptoms of influenza.

Seasonal prophylaxis: Longer duration of seasonal prophylaxis up to 12 weeks has been evaluated in immunocompromised patients (see sections 4.4, 4.8 and 5.1).

Method of administration

For dosing, a 3 ml and 10 ml oral dispenser is provided in the box.

It is recommended that Oseltamivir powder for oral suspension be constituted by a pharmacist prior to dispensing to the patient (see section 6.6).

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

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 (see section 5.1).

Oseltamivir is not a substitute for influenza vaccination. Use of Oseltamivir must not affect the evaluation of individuals for annual influenza vaccination. The protection against influenza lasts only as long as Oseltamivir is administered. Oseltamivir should be used for the treatment and prevention of influenza only when reliable epidemiological data indicate that influenza virus is circulating in the community.

Susceptibility of circulating influenza virus strains to oseltamivir has been shown to be highly variable (see section 5.1). Therefore, prescribers should take into account the most recent information available on oseltamivir susceptibility patterns of the currently circulating viruses when deciding whether to use Oseltamivir.

Severe concomitant condition

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.

Immunocompromised patients

The efficacy of oseltamivir in either treatment or prophylaxis of influenza in immunocompromised patients has not been firmly established. However, the duration of treatment of influenza in immunocompromised adult patients should be 10 days, as there are no studies of a shorter course of oseltamivir in this patient group (see section 5.1).

Cardiac / respiratory disease

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 5.1).

Paediatric population

No data allowing a dose recommendation for premature children (<36 weeks post-conceptual age) are currently available.

Severe renal impairment

Dose adjustment is recommended for both treatment and prevention in adolescents (13 to 17 years of age) and adults with severe renal impairment. There is insufficient clinical data available in infants and children (1 year of age or older) with renal impairment to be able to make any dosing recommendation (see sections 4.2 and 5.2).

Neuropsychiatric events

Neuropsychiatric events have been reported during administration of Oseltamivir in patients with influenza, especially in children and adolescents. These events are also experienced by patients with influenza without oseltamivir administration. Patients should be closely monitored for behavioural changes, and the benefits and risks of continuing treatment should be carefully evaluated for each patient (see section 4.8).

This medicinal product contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.

Sorbitol can have a mild laxative effect.

4.5 Interaction with other medicinal products and other forms of interaction

Pharmacokinetic properties of oseltamivir, such as low protein binding and metabolism independent of the CYP450 and glucuronidase systems (see section 5.2), suggest that clinically significant drug interactions via these mechanisms are unlikely.

Probenecid

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.

Amoxicillin

Oseltamivir has no kinetic interaction with amoxicillin, which is eliminated via the same pathway, suggesting that oseltamivir interaction with this pathway is weak.

Renal elimination

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).

Additional information

No pharmacokinetic interactions between oseltamivir or its major metabolite have been observed when co-administering oseltamivir with paracetamol, acetylsalicylic acid, cimetidine, antacids (magnesium and aluminium hydroxides and calcium carbonates), rimantadine or warfarin (in subjects stable on warfarin and without influenza).

4.6 Fertility, pregnancy and lactation

Pregnancy

Influenza is associated with adverse pregnancy and foetal outcomes, with a risk of major congenital malformations, including congenital heart defects. A large amount of data on oseltamivir exposure of pregnant women from post-marketing reports and observational studies (more than 1000 exposed outcomes during the first trimester) indicate no malformative nor feto/neonatal toxicity by oseltamivir.

However, in one observational study, while the overall malformation risk was not increased, the results for major congenital heart defects diagnosed within 12 months of birth were not conclusive. In this study, the rate of major congenital heart defects following oseltamivir exposure during the first trimester was 1.76% (7 infants out of 397 pregnancies) compared to 1.01% in unexposed pregnancies from the general population (Odds Ratio 1.75, 95% Confidence Interval 0.51 to 5.98). The clinical significance of this finding is not clear, as the study had limited power. Additionally, this study was too small to reliably assess individual types of major malformations; moreover women exposed to oseltamivir and women unexposed could not be made fully comparable, in particular whether or not they had influenza.

Animal studies do not indicate reproductive toxicity (see section 5.3).

The use of Oseltamivir may be considered during pregnancy if necessary and after considering the available safety and benefit information (for data on benefit in pregnant women please refer to section 5.1 “Treatment of influenza in pregnant women”), and the pathogenicity of the circulating influenza virus strain.

Breastfeeding

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. Considering this information, the pathogenicity of the circulating influenza virus strain and the underlying condition of the breastfeeding woman, administration of oseltamivir may be considered, where there are clear potential benefits to breastfeeding mothers.

Fertility

Based on preclinical data, there is no evidence that Oseltamivir has an effect on male or female fertility (see section 5.3).

4.7 Effects on ability to drive and use machines

Oseltamivir has no influence on the ability to drive and use machines.

4.8 Undesirable effects

Summary of the safety profile

The overall safety profile of Oseltamivir is based on data from 6049 adult/adolescent and 1473 paediatric patients treated with Oseltamivir or placebo for influenza, and on data from 3990 adult/adolescent and 253 paediatric patients receiving Oseltamivir or placebo/no treatment for the prophylaxis of influenza in clinical trials. In addition, 199 immunocompromised adult patients received Oseltamivir for the treatment of influenza and 475 immunocompromised patients (including 18 children, of these 10 Oseltamivir and 8 placebo) received Oseltamivir or placebo for the prophylaxis of influenza.

In adults/adolescents, the most commonly reported adverse reactions (ARs) were nausea and vomiting in the treatment studies, and nausea in the prevention studies. The majority of these ARs were reported on a single occasion on either the first or second treatment day and resolved spontaneously within 1-2 days. In children, the most commonly reported adverse reaction was vomiting. In the majority of patients, these ARs did not lead to discontinuation of Oseltamivir.

The following serious adverse reactions have been rarely reported since oseltamivir has been marketed: Anaphylactic and anaphylactoid reactions, hepatic disorders (fulminant hepatitis, hepatic function disorder and jaundice), angioneurotic oedema, Stevens-Johnson syndrome and toxic epidermal necrolysis, gastrointestinal bleeding and neuropsychiatric disorders.

(Regarding neuropsychiatric disorders, see section 4.4.)

Tabulated list of adverse reactions

The ARs listed in the tables below fall into the following categories: 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), and very rare (< 1/10,000). ARs are added to the appropriate category in the tables according to the pooled analysis from clinical studies.

Treatment and prevention of influenza in adults and adolescents:

In adult/adolescent treatment and prevention studies, ARs that occurred the most frequently at the recommended dose (75mg bid for 5 days for treatment and 75mg od for up to 6 weeks for prophylaxis) are shown in Table 1.

The safety profile reported in subjects who received the recommended dose of Oseltamivir for prophylaxis (75mg 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.

Table 1 Adverse reactions in studies investigating Oseltamivir for treatment and prevention of influenza in adults and adolescents or through post-marketing surveillance

System Organ Class (SOC) Adverse reactions according to frequency
Very common Common Uncommon Rare
Infections and infestations Bronchitis, Herpes simplex, Nasopharyngitis, Upper respiratory tract infections, Sinusitis
Blood and lymphatic system disorders Thrombocytopenia
Immune system disorders Hypersensitivity reaction Anaphylactic reactions, Anaphylactoid reactions
Psychiatric disorders Agitation, Abnormal behaviour, Anxiety, Confusion, Delusions, Delirium, Hallucination, Nightmares, Self-injury
Nervous system disorders Headache Insomnia Altered level of consciousness, Convulsion
Eye disorders Visual disturbance
Cardiac disorders Cardiac arrhythmia
Respiratory, thoracic and mediastinal disorders Cough, Sore throat, Rhinorrhea
Gastrointestinal disorders Nausea Vomiting

Abdominal pain (incl. upper abdominal pain), Dyspepsia

Gastrointestinal bleedings, Haemorrhagic colitis
Hepatobiliary disorders Elevated liver enzymes Fulminant hepatitis, Hepatic failure, Hepatitis
Skin and subcutaneous tissue disorders Eczema, Dermatitis, Rash, Urticaria Angioneurotic oedema, Erythema multiforme, Stevens-Johnson syndrome, Toxic epidermal necrolysis
General disorders and administration site conditions Pain

Dizziness (incl. vertigo), Fatigue, Pyrexia, Pain in limb

Treatment and prevention of influenza in children:

A total of 1473 children (including otherwise healthy children aged 1-12 years old and asthmatic children aged 6-12 years old) participated in clinical studies of oseltamivir given for the treatment of influenza. Of those, 851 children received treatment with oseltamivir suspension. A total of 158 children received the recommended dose of Oseltamivir once daily in a post-exposure prophylaxis study in households (n = 99), a 6-week paediatric seasonal prophylaxis study (n = 49) and a 12-week paediatric seasonal prophylaxis study in immunocompromised subjects (n = 10).

Table 2 shows the most frequently reported ARs from paediatric clinical trials.

Table 2 Adverse reactions in studies investigating Oseltamivir for treatment and prevention of influenza in children (age/weight-based dosing [30mg to 75mg o.d.])

System Organ Class (SOC) Adverse reactions according to frequency
Very common Common Uncommon Rare
Infections and infestations Otitis media,
Nervous system disorders Headache
Eye disorders: Conjunctivitis (including red eyes, eye discharge and eye pain)
Ear and labyrinth disorders: Earache Tympanic membrane disorder
Respiratory, thoracic and mediastinal disorders Cough, Nasal congestion Rhinorrhoea
Gastrointestinal disorders Vomiting Abdominal pain (incl. upper abdominal pain), Dyspepsia, Nausea
Skin and subcutaneous tissue disorders Dermatitis (including allergic and atopic dermatitis)

Description of selected adverse reactions

Psychiatric disorders and nervous system disorders

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, 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 self-injury or fatal outcomes. These events were reported primarily among paediatric and adolescent patients and often had an abrupt onset and rapid resolution. The contribution of Oseltamivir to those events is unknown. Such neuropsychiatric events have also been reported in patients with influenza who were not taking Oseltamivir.

Hepato-biliary disorders

Hepato-biliary system disorders, including hepatitis and elevated liver enzymes in patients with influenza-like illness. These cases include fatal fulminant hepatitis/hepatic failure.

Other special populations

Paediatric population (infants less than one year of age)

In two studies to characterise the pharmacokinetics, pharmacodynamics and safety profile of oseltamivir therapy in 135 influenza infected children less than one year of age, the safety profile was similar among age cohorts with vomiting, diarrohea and diaper rash being the most frequently reported adverse events (see section 5.2). Insufficient data are available for infants who have a post-conceptual age of less than 36 weeks.

Safety information available on oseltamivir administered for treatment of influenza in infants less than one year of age from prospective and retrospective observational studies (comprising together more than 2,400 infants of that age class), epidemiological databases research and postmarketing reports suggest that the safety profile in infants less than one year of age is similar to the established safety profile of children aged one year and older.

Older people and patients with chronic cardiac and/or respiratory disease

The population included in the influenza treatment studies is comprised of otherwise healthy adults/adolescents and patients “at risk” (patients at higher risk of developing complications associated with influenza, e.g. older people 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.

Immunocompromised patients

In a double blind study for the treatment of influenza, a total of 199 adult immunocompromised patients (evaluable for safety) were randomized to receive Oseltamivir for 10 days: 98 patients received the standard dose (75mg twice daily) and 101 patients received the double dose (150mg twice daily). The safety profile of Oseltamivir observed in this study was consistent with that observed in previous clinical trials where Oseltamivir was administered for treatment of influenza in non-immunocompromised patients (otherwise healthy patients or “at risk” patients [i.e., those with respiratory and/or cardiac co-morbidities]). The percentage of patients reporting adverse events was lower in the standard dose group compared to the double dose group (49.0% vs 59.4 %, respectively) (See section 5.1).

In a 12-week prophylaxis study in 475 immunocompromised patients, including 18 children 1 to 12 years of age and older, the safety profile in the 238 patients who received oseltamivir was consistent with that previously observed in Oseltamivir prophylaxis clinical studies.

Children with pre-existing bronchial asthma

In general, the adverse reaction profile in children with pre-existing bronchial asthma was qualitatively similar to that of otherwise healthy children.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

4.9 Overdose

Reports of overdoses with Oseltamivir have been received from clinical trials and during post-marketing experience. In the majority of cases reporting overdose, no adverse events were reported.

Adverse events reported following overdose were similar in nature and distribution to those observed with therapeutic doses of Oseltamivir, described in section 4.8 Undesirable effects.

No specific antidote is known.

Paediatric population

Overdose has been reported more frequently for children than adults and adolescents. Caution should be exercised when preparing Oseltamivir oral suspension and when administering Oseltamivir products to children.

  1. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antivirals for systemic use, neuraminidase inhibitors

Oseltamivir phosphate is a pro-drug of the active metabolite (oseltamivir carboxylate). The active metabolite is a selective inhibitor of influenza virus neuraminidase enzymes, which are glycoproteins found on the virion surface. Viral neuraminidase enzyme activity is important both for viral entry into uninfected cells and for the release of recently formed virus particles from infected cells, and for the further spread of infectious virus in the body.

Oseltamivir carboxylate inhibits influenza A and B neuraminidases in vitro. Oseltamivir phosphate inhibits influenza virus infection and replication in vitro. Oseltamivir given orally inhibits influenza A and B virus replication and pathogenicity in vivo in animal models of influenza infection at antiviral exposures similar to that achieved in man with 75mg twice daily.

Antiviral activity of oseltamivir was supported for influenza A and B by experimental challenge studies in healthy volunteers.

Neuraminidase enzyme IC50 values for oseltamivir for clinically isolated influenza A ranged from 0.1 nM to 1.3 nM, and for influenza B was 2.6 nM. Higher IC50 values for influenza B, up to a median of 8.5 nM, have been observed in published studies.

Clinical studies

Treatment of influenza infection

The indication is based on clinical studies of naturally occurring influenza in which the predominant infection was influenza A. Oseltamivir is effective only against illnesses caused by influenza virus. Statistical analyses are therefore presented only for influenza-infected subjects. In the pooled treatment study population, which included both influenza-positive and -negative subjects (ITT), primary efficacy was reduced proportionally to the number of influenza-negative individuals. In the overall treatment population, influenza infection was confirmed in 67 % (range 46 % to 74 %) of the recruited patients. Of the older subjects, 64 % were influenza-positive and of those with chronic cardiac and/or respiratory disease 62 % were influenza-positive. In all phase III treatment studies, patients were recruited only during the period in which influenza was circulating in the local community.

Adults and adolescents 13 years of age and older: Patients were eligible if they reported within 36 hours of onset of symptoms, had fever ≥ 37.8 °C, accompanied by at least one respiratory symptom (cough, nasal symptoms or sore throat) and at least one systemic symptom (myalgia, chills/sweats, malaise, fatigue or headache). In a pooled analysis of all influenza-positive adults and adolescents (N = 2,413) enrolled into treatment studies, oseltamivir 75mg twice daily for 5 days reduced the median duration of influenza illness by approximately one day from 5.2 days (95 % CI 4.9 – 5.5 days) in the placebo group to 4.2 days (95 % CI 4.0 – 4.4 days; p ≤ 0.0001).

The proportion of subjects who developed specified lower respiratory tract complications (mainly bronchitis) treated with antibiotics was reduced from 12.7 % (135/1,063) in the placebo group to 8.6 % (116/1,350) in the oseltamivir treated population (p = 0.0012).

Treatment of influenza in high risk populations: The median duration of influenza illness in older subjects (≥ 65 years) and in subjects with chronic cardiac and/or respiratory disease receiving oseltamivir 75mg twice daily for 5 days was not reduced significantly. The total duration of fever was reduced by one day in the groups treated with oseltamivir. In influenza-positive older people, oseltamivir significantly reduced the incidence of specified lower respiratory tract complications (mainly bronchitis) treated with antibiotics from 19 % (52/268) in the placebo group to 12 % (29/250) in the oseltamivir treated population (p = 0.0156).

In influenza-positive patients with chronic cardiac and/or respiratory disease, the combined incidence of lower respiratory tract complications (mainly bronchitis) treated with antibiotics was 17 % (22/133) in the placebo group and 14 % (16/118) in the oseltamivir treated population (p = 0.5976).

Treatment of influenza in pregnant women: No controlled clinical studies have been conducted on the use of oseltamivir in pregnant women, however, there is evidence from post-marketing and retrospective observational studies showing benefit of the current dosing regimen in this patient population in terms of lower morbidity/mortality. 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 (see section 5.2, Pharmacokinetics, Special Population).

Treatment of influenza in children: In a study of otherwise healthy children (65 % influenza-positive) aged 1 to 12 years (mean age 5.3 years) who had fever (≥ 37.8 °C) plus either cough or coryza, 67 % of influenza-positive patients were infected with influenza A and 33 % with influenza B. Oseltamivir treatment, started within 48 hours of onset of symptoms, significantly reduced the time to freedom from illness (defined as the simultaneous return to normal health and activity and alleviation of fever, cough and coryza) by 1.5 days (95 % CI 0.6 – 2.2 days; p < 0.0001) compared to placebo. Oseltamivir reduced the incidence of acute otitis media from 26.5 % (53/200) in the placebo group to 16 % (29/183) in the oseltamivir treated children (p = 0.013).

A second study was completed in 334 asthmatic children aged 6 to 12 years old of which 53.6 % were influenza-positive. In the oseltamivir treated group, the median duration of illness was not reduced significantly. By day 6 (the last day of treatment) FEV1 had increased by 10.8 % in the oseltamivir treated group compared to 4.7 % on placebo (p = 0.0148) in this population.

The European Medicines Agency has deferred the obligation to submit the results of studies with Oseltamivir in one or more subsets of the paediatric population in influenza. See section 4.2 for information on paediatric use.

The indication in infants below the age of 1 is based upon extrapolation of efficacy data from older children and the recommended posology is based upon pharmacokinetic modelling data (see Section 5.2).

Treatment of influenza B infection: Overall, 15 % of the influenza-positive population were infected by influenza B, proportions ranging from 1 to 33 % in individual studies. The median duration of illness in influenza B infected subjects did not differ significantly between the treatment groups in individual studies. Data from 504 influenza B infected subjects were pooled across all studies for analysis. Oseltamivir reduced the time to alleviation of all symptoms by 0.7 days (95 % CI 0.1 – 1.6 days; p = 0.022) and the duration of fever (≥ 37.8 °C), cough and coryza by one day (95 % CI 0.4 – 1.7 days; p < 0.001) compared to placebo.

Treatment of influenza in immunocompromised adults: A randomized, double blind study, to evaluate safety and characterize the effects of oseltamivir on the development of resistant influenza virus (primary analysis) in influenza-infected adult immunocompromised patients, included 151 patients evaluable for efficacy of oseltamivir (secondary analysis, not powered). The study included solid organ transplant [SOT] patients, haematopoietic stem cell transplant [HSCT] patients, HIV positive patients with a CD4+ cell count <500 cells/mm3, patients on systemic immunosuppressive therapy, and those with haematological malignancy. These patients were randomized to be treated, within 96 hours of symptoms onset, with standard dose (73 patients) or double dose (78 patients) of oseltamivir, for a duration of 10 days.

The median time to resolution of symptoms (TTRS) was similar between the standard dose group (103 hours [90% CI 75.4-110.0]) and double dose group (104 hours [90% CI 65.8-131.0]). The proportion of patients with secondary infections in the standard dose group and double dose group was comparable (8.2% vs 5.1%).

Prevention of influenza

The efficacy of oseltamivir in preventing naturally occurring influenza illness has been demonstrated in a post-exposure prevention study in households and two seasonal prevention studies. The primary efficacy parameter for all of these studies was the incidence of laboratory-confirmed influenza. The virulence of influenza epidemics is not predictable and varies within a region and from season to season, therefore the number needed to treat (NNT) in order to prevent one case of influenza illness varies.

Post-exposure prevention: In a study in contacts (12.6 % vaccinated against influenza) of an index case of influenza, oseltamivir 75mg once daily was started within 2 days of onset of symptoms in the index case and continued for seven days. Influenza was confirmed in 163 out of 377 index cases. Oseltamivir significantly reduced the incidence of clinical influenza illness occurring in the contacts of confirmed influenza cases from 24/200 (12 %) in the placebo group to 2/205 (1 %) in the oseltamivir group (92 % reduction [95 % CI 6 – 16; p ≤ 0.0001]). The number needed to treat (NNT) in contacts of true influenza cases was 10 (95 % CI 9 – 12) and was 16 (95 % CI 15 – 19) in the whole population (ITT) regardless of infection status in the index case.

The efficacy of oseltamivir in preventing naturally occurring influenza illness has been demonstrated in a post-exposure prevention study in households that included adults, adolescents, and children aged 1 to 12 years, both as index cases and as family contacts. The primary efficacy parameter for this study was the incidence of laboratory-confirmed clinical influenza in the households. Oseltamivir prophylaxis lasted for 10 days. In the total population, there was a reduction in the incidence of laboratory-confirmed clinical influenza in households from 20 % (27/136) in the group not receiving prevention to 7 % (10/135) in the group receiving prevention (62.7 % reduction [95 % CI 26.0 – 81.2; p = 0.0042]). In households of influenza-infected index cases, there was a reduction in the incidence of influenza from 26 % (23/89) in the group not receiving prevention to 11 % (9/84) in the group receiving prevention (58.5 % reduction [95 % CI 15.6 – 79.6; p = 0.0114]).

According to subgroup analysis in children at 1 to 12 years of age, the incidence of laboratory-confirmed clinical influenza among children was significantly reduced from 19 % (21/111) in the group not receiving prevention to 7 % (7/104) in the group receiving prevention (64.4 % reduction [95 % CI 15.8 – 85.0; p = 0.0188]). Among children who were not already shedding virus at baseline, the incidence of laboratory-confirmed clinical influenza was reduced from 21 % (15/70) in the group not receiving prevention to 4 % (2/47) in the group receiving prevention (80.1 % reduction [95 % CI 22.0 – 94.9; p = 0.0206]). The NNT for the total paediatric population was 9 (95 % CI 7 – 24) and 8 (95 % CI 6, upper limit not estimable) in the whole population (ITT) and in paediatric contacts of infected index cases (ITTII), respectively.

Post-exposure prevention of influenza in infants less than 1 year of age during a pandemic:

Prevention during an influenza pandemic has not been studied in controlled clinical studies in children 0-12 months of age. See Section 5.2 for exposure simulation details.

Prevention during an influenza epidemic in the community: In a pooled analysis of two other studies conducted in unvaccinated otherwise healthy adults, oseltamivir 75mg once daily given for 6 weeks significantly reduced the incidence of clinical influenza illness from 25/519 (4.8 %) in the placebo group to 6/520 (1.2 %) in the oseltamivir group (76 % reduction [95 % CI 1.6 – 5.7; p = 0.0006]) during a community outbreak of influenza. The NNT in this study was 28 (95 % CI 24 – 50).

A study in older people in nursing homes, where 80 % of participants received vaccine in the season of the study, oseltamivir 75mg once daily given for 6 weeks significantly reduced the incidence of clinical influenza illness from 12/272 (4.4 %) in the placebo group to 1/276 (0.4 %) in the oseltamivir group (92 % reduction [95 % CI 1.5 – 6.6; p = 0.0015]). The NNT in this study was 25 (95 % CI 23 – 62).

Prophylaxis of influenza in immunocompromised patients: A double-blind, placebo-controlled, randomised study was conducted for seasonal prophylaxis of influenza in 475 immunocompromised patients (388 patients with solid organ transplantation [195 placebo; 193 oseltamivir], 87 patients with haemopoetic stem cell transplantation [43 placebo; 44 oseltamivir], no patient with other immunosuppressant conditions), including 18 children 1 to 12 years of age. The primary endpoint in this study was the incidence of laboratory-confirmed clinical influenza as determined by viral culture and/or a four-fold rise in HAI antibodies. The incidence of laboratory-confirmed clinical influenza was 2.9 % (7/238) in the placebo group and 2.1 % (5/237) in the oseltamivir group (95 % CI -2.3 % – 4.1 %; p = 0.772).

Specific studies have not been conducted to assess the reduction in the risk of complications.

Oseltamivir resistance

Clinical studies: The risk of emergence of influenza viruses with reduced susceptibility or frank resistance to oseltamivir has been examined during Roche-sponsored clinical studies. Developing oseltamivir-resistant virus during treatment was more frequent in children than adults, ranging from less than 1% in adults to 18% in infants aged below 1 year. Children who were found to carry oseltamivir-resistant virus in general shed the virus for a prolonged period compared with subjects with susceptible virus. However treatment-emergent resistance to oseltamivir did not affect treatment response and caused no prolongation of influenza symptoms.

An overall higher incidence of oseltamivir-resistance was observed in adult immunocompromised patients treated with standard dose or double dose of oseltamivir for a duration of 10 days [14.9% (10/67) in standard dose group and 2.8% (2/71) in double dose group], compared to data from studies with oseltamivir-treated otherwise healthy adult patients. The majority of patients that developed resistance were transplant recipients (8/10 patients in the standard dose group and 2/2 patients in the double dose group). Most of the patients with oseltamivir-resistant virus were infected with influenza type A and had prolonged viral shedding.

Incidence of Oseltamivir Resistance in Clinical Studies

Patient Population Patients with Resistance Mutations (%)
Phenotyping* Geno- and Phenotyping*
Adults and adolescents 0.88% (21/2377) 1.12% (27/2391)
Children (1-12 years) 3.89% (66/1698) 4.24% (72/1698)
Infant (<1 year) 18.31% (13/71) 18.31 (13/71)

* Full genotyping was not performed in all studies.

Prophylaxis of Influenza

There has been no evidence for emergence of drug resistance associated with the use of Oseltamivir in clinical studies conducted to date in post-exposure (7 days), post-exposure within household groups (10 days) and seasonal (42 days) prevention of influenza in immunocompetent patients. There was no resistance observed during a 12-week prophylaxis study in immunocompromised patients.

Clinical and surveillance data: Natural mutations associated with reduced susceptibility to oseltamivir in vitro have been detected in influenza A and B viruses isolated from patients without exposure to oseltamivir. Resistant strains selected during oseltamivir treatment have been isolated from both immunocompetent and immunocompromised patients. Immunocompromised patients and young children are at a higher risk of developing oseltamivir-resistant virus during treatment.

Oseltamivir-resistant viruses isolated from oseltamivir-treated patients and oseltamivir-resistant laboratory strains of influenza viruses have been found to contain mutations in N1 and N2 neuraminidases. Resistance mutations tend to be viral sub-type specific. Since 2007 naturally occurring resistance associated with the H275Y mutation in seasonal H1N1 strains has been sporadically detected. The susceptibility to oseltamivir and the prevalence of such viruses appear to vary seasonally and geographically. In 2008, H275Y was found in > 99 % of circulating H1N1 influenza isolates in Europe. The 2009 H1N1 influenza (“swine flu”) was almost uniformly susceptible to oseltamivir, with only sporadic reports of resistance in connection with both therapeutic and prophylactic regimens.

5.2 Pharmacokinetic properties

General Information

Absorption

Oseltamivir is readily absorbed from the gastrointestinal tract after oral administration of oseltamivir phosphate (pro-drug) and is extensively converted by predominantly hepatic esterases to the active metabolite (oseltamivir carboxylate). At least 75 % of an oral dose reaches the systemic circulation as the active metabolite. Exposure to the pro-drug is less than 5 % relative to the active metabolite. Plasma concentrations of both pro-drug and active metabolite are proportional to dose and are unaffected by co-administration with food.

Distribution

The mean volume of distribution at steady state of the oseltamivir carboxylate is approximately 23 litres in humans, a volume equivalent to extracellular body fluid. Since neuraminidase activity is extracellular, oseltamivir carboxylate distributes to all sites of influenza virus spread.

The binding of the oseltamivir carboxylate to human plasma protein is negligible (approximately 3 %).

Biotransformation

Oseltamivir is extensively converted to oseltamivir carboxylate by esterases located predominantly in the liver. In vitro studies demonstrated that neither oseltamivir nor the active metabolite is a substrate for, or an inhibitor of, the major cytochrome P450 isoforms. No phase 2 conjugates of either compound have been identified in vivo.

Elimination

Absorbed oseltamivir is primarily (> 90 %) eliminated by conversion to oseltamivir carboxylate. It is not further metabolised and is eliminated in the urine. Peak plasma concentrations of oseltamivir carboxylate decline with a half-life of 6 to 10 hours in most subjects. The active metabolite is eliminated entirely by renal excretion. Renal clearance (18.8 l/h) exceeds glomerular filtration rate (7.5 l/h) indicating that tubular secretion occurs in addition to glomerular filtration. Less than 20 % of an oral radiolabelled dose is eliminated in faeces.

Other special populations

Paediatric population

Infants less than 1 year of age: The pharmacokinetics, pharmacodynamics and safety of Oseltamivir have been evaluated in two uncontrolled open-label studies including influenza infected children less than one year of age (n=135). The rate of clearance of the active metabolite, corrected for body-weight, decreases with ages below one year. Metabolite exposures are also more variable in the youngest infants. The available data indicates that the exposure following a 3mg/kg dose in infants 0-12 months of age provides pro-drug and metabolite exposures anticipated to be efficacious with a safety profile comparable to that seen in older children and adults using the approved dose (see sections 4.1 and 4.2). The reported adverse events were consistent with the established safety profile in older children.

There are no data available for infants below 1 year of age for post exposure prevention of influenza. Prevention during an influenza epidemic in the community has not been studied in children below 12 years of age.

Post-exposure prevention of influenza in infants less than 1 year of age during a pandemic: Simulation of once daily dosing of 3mg/kg in infants <1 year shows an exposure in the same range or higher than for once daily dosing of 75mg in adults. Exposure does not exceed that for treatment of infants < 1 year (3mg/kg twice daily) and is anticipated to result in a comparable safety profile (see Section 4.8). No clinical studies of prophylaxis in infants aged <1 have been performed.

Infants and children 1 year of age or older: The pharmacokinetics of oseltamivir have been evaluated in single-dose pharmacokinetic studies in infants, children and adolescents 1 to 16 years of age. Multiple-dose pharmacokinetics were studied in a small number of children enrolled in a clinical efficacy study. Younger children cleared both the pro-drug and its active metabolite faster than adults, resulting in a lower exposure for a givenmg/kg dose. Doses of 2mg/kg give oseltamivir carboxylate exposures comparable to those achieved in adults receiving a single 75mg dose (approximately 1mg/kg). The pharmacokinetics of oseltamivir in children and adolescents 12 years of age or older are similar to those in adults.

Elderly

Exposure to the active metabolite at steady state was 25 to 35 % higher in older people (age 65 to 78 years) compared to adults less than 65 years of age given comparable doses of oseltamivir. Half-lives observed in older people were similar to those seen in young adults. On the basis of drug exposure and tolerability, dosage adjustments are not required for older people unless there is evidence of moderate or severe renal impairment (creatinine clearance below 60 ml /min) (see section 4.2).

Renal impairment

Administration of 100mg oseltamivir phosphate twice daily for 5 days to patients with various degrees of renal impairment showed that exposure to oseltamivir carboxylate is inversely proportional to declining renal function. For dosing, see section 4.2.

Hepatic impairment

In vitro studies have concluded that exposure to oseltamivir is not expected to be increased significantly nor is exposure to the active metabolite expected to be significantly decreased in patients with hepatic impairment (see section 4.2).

Pregnant Women

A pooled population pharmacokinetic analysis indicates that the Oseltamivir dosage regimen described in Section 4.2 Posology and method of administration results in lower exposure (30% on average across all trimesters) to the active metabolite in pregnant women compared to non-pregnant women. The lower predicted exposure however, remains above inhibitoy concentrations (IC95 values) and at a therapeutic level for a range of influenza virus strains. In addition, there is evidence from observational studies showing benefit of the current dosing regimen in this patient population. Therefore, dose adjustments are not recommended for pregnant women in the treatment or prophylaxis of influenza (see section 4.6 Fertility, pregnancy and lactation).

Immunocompromised Patients

Population pharmacokinetic analysis indicates that treatment of adult immunocompromised patients with oseltamivir (as described in Section 4.2. Posology and method of administration) results in an increased exposure (of up to 50%) to the active metabolite when compared to adult non-immunocompromised patients with comparable creatinine clearance. Due to the wide safety margin of the active metabolite, no dose adjustments are required in adults due to their immunocompromised status. However, for adult immunocompromised patients with renal impairment, doses should be adjusted as outlined in section 4.2. Posology and method of administration.

5.3 Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated-dose toxicity and genotoxicity. Results of the conventional rodent carcinogenicity studies showed a trend towards a dose-dependent increase in the incidence of some tumours that are typical for the rodent strains used. Considering the margins of exposure in relation to the expected exposure in the human use, these findings do not change the benefit-risk of Oseltamivir in its adopted therapeutic indications.

Teratology studies have been conducted in rats and rabbits at doses of up to 1,500mg/kg/day and 500mg/kg/day, respectively. No effects on foetal development were observed. A rat fertility study up to a dose of 1,500mg/kg/day demonstrated no adverse reactions on either sex. In pre- and post-natal rat studies, prolonged parturition was noted at 1,500mg/kg/day: the safety margin between human exposure and the highest no-effect dose (500mg/kg/day) in rats is 480-fold for oseltamivir and 44-fold for the active metabolite, respectively. Foetal exposure in the rats and rabbits was approximately 15 to 20 % of that of the mother.

In lactating rats, oseltamivir and the active metabolite are excreted in the milk. Limited data indicate that oseltamivir and the active metabolite are excreted in human milk. Extrapolation of the animal data provides estimates of 0.01mg/day and 0.3mg/day for the respective compounds.

A potential for skin sensitisation to oseltamivir was observed in a “maximisation” test in guinea pigs. Approximately 50 % of the animals treated with the unformulated active substance showed erythema after challenging the induced animals. Reversible irritancy of rabbits’ eyes was detected.

Whereas very high oral single doses of oseltamivir phosphate salt, up to the highest dose tested (1,310mg/kg), had no adverse reactions in adult rats, such doses resulted in toxicity in juvenile 7-day-old rat pups, including death. These reactions were seen at doses of 657mg/kg and higher. At 500mg/kg, no adverse reactions were seen, including upon chronic treatment (500mg/kg/day administered from 7 to 21 days post partum).

  1. Pharmaceutical particulars

6.1 List of excipients

Sorbitol, Sodium dihydrogen citrate, Xanthan gum, Sodium benzoate, Saccharin sodium, Titanium dioxide

Tutti frutti flavour (including maltodextrins [maize], propylene glycol, arabic gum and natural identical flavouring substances [mainly consisting of banana, pineapple and peach flavour]).

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

4 years

After reconstitution, store below 25 °C for 10 days.

6.4 Special precautions for storage

Do not store above 30°C.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

100 ml amber glass bottle (with child-resistant polypropylene screw cap, outer part: polyethylene; inner part: polypropylene; liner: polyethylene) with 13 g of powder for oral suspension, a plastic adapter (low density polyethylene), plastic 3 ml oral dispenser (0.1 ml graduation) and 10 ml oral dispenser (0.5 ml graduation) (barrel and plunger: polypropylene, silicon based seal ring) and a plastic measuring cup (polypropylene).

Pack-size of one bottle.

6.6 Special precautions for disposal and other handling

It is recommended that Oseltamivir oral suspension should be reconstituted by the pharmacist prior to being dispensed to the patient.

After reconstitution with 55 ml of water, the usable volume of oral suspension allows for the retrieval of a total of 10 doses of 30mg oseltamivir.

Preparation of oral suspension

  1. Tap the closed bottle gently several times to loosen the powder.
  2. Measure 55 ml of water by filling the measuring cup to the indicated level (measuring cup included in the box).
  3. Add all 55 ml of water into the bottle, recap the bottle and shake the closed bottle well for 15 seconds.
  4. Remove the cap and push the bottle adapter into the neck of the bottle.
  5. Close the bottle tightly with the cap (on the top of the bottle adapter). This will make sure that the bottle adapter fits in the bottle in the right position.

Oseltamivir powder for suspension will appear as an opaque and white to light yellow suspension after reconstitution.

Any unused product or waste material should be disposed of in accordance with local requirements.

 

  1. Manufactured By:
    Taj Pharmaceuticals Ltd.
    at: Plot. No. 220, Mahagujarat
    Industrial Estate, At & Post-Moraiya,
    Tal-Sanand, Dist- Ahmedabad Gujarat (India)

 

Oseltamivir 12mg/ml powder for oral suspension

Package Leaflet: Information for the user

Oseltamivir 12mg/ml powder for oral suspension

oseltamivir

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

  • Keep this leaflet. You may need to read it again.
  • If you have further questions, ask your doctor or pharmacist.
  • This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
  • If you get any of the side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

  1. What Oseltamivir is and what it is used for
    2. What you need to know before you take Oseltamivir
    3. How to take Oseltamivir
    4. Possible side effects
    5. How to store Oseltamivir
    6. Contents of the pack and other information
  2. What Oseltamivir is and what it is used for
  • Oseltamivir is used for adults, adolescents, children and infants (including full-term newborn babies) for treating flu (influenza). It can be used when you have flu symptoms, and the flu virus is known to be going round in your community.
  • Oseltamivir can also be prescribed for adults, adolescents, children and infants above 1 year of age for preventing flu, on a case-by-case basis – for instance, if you have been in contact with someone who has flu.
  • Oseltamivir may be prescribed for adults, adolescents, children and infants (including full-term newborn babies) as preventive treatment in exceptional circumstances – for example, if there is a global epidemic of flu (a flu pandemic) and the seasonal flu vaccine may not provide sufficient protection.

Oseltamivir contains oseltamivir, which belongs to a group of medicines named neuraminidase inhibitors. These medicines prevent the flu virus from spreading inside the body. They help to ease or prevent the symptoms of the flu virus infection.

Influenza, usually called flu, is an infection caused by a virus. The signs of flu often include a sudden fever (more than 37.8 °C), cough, runny or stuffy nose, headaches, muscle aches and extreme tiredness. These symptoms can also be caused by other infections. True influenza infection only occurs during annual outbreaks (epidemics) when flu viruses are spreading in the local community. Outside epidemic periods, flu-like symptoms are usually caused by a different type of illness.

  1. What you need to know before you take Oseltamivir

Do not take Oseltamivir:

  • if you are allergic (hypersensitive) to oseltamivir or any of the other ingredients of Oseltamivir listed in section 6.

Talk to your doctor if this applies to you. Do not take Oseltamivir.

Warnings and precautions:

Before you take Oseltamivir, make sure the prescribing doctor knows

  • if you are allergic to other medicines
  • if you have problems with your kidneys. If so, your dose may need adjustment
  • if you have a severe medical condition, which may require immediate hospitalisation
  • if your immune system is not working
  • if you have chronic heart disease or respiratory disease.

During treatment with Oseltamivir, tell a doctor immediately:

  • if you notice changes in behaviour or mood (neuropsychiatric events), especially in children and adolescents). These may be signs of rare but serious side effects.

Oseltamivir is not a flu vaccine

Oseltamivir is not a vaccine: it treats infection, or prevents the flu virus spreading. A vaccine gives you antibodies against the virus. Oseltamivir will not change the effectiveness of a flu vaccine, and you might be prescribed both by your doctor.

Other medicines and Oseltamivir

Tell your doctor or pharmacist if you are taking any other medicines, or have recently taken any. This includes medicines obtained without a prescription. The following medicines are particularly important:

  • chlorpropamide (used to treat diabetes)
  • methotrexate (used to treat e.g. rheumatoid arthritis)
  • phenylbutazone (used to treat pain and inflammation)
  • probenecid (used to treat gout)

Pregnancy and breast-feeding

You must tell your doctor if you are pregnant, if you think you are pregnant or if you are trying to get pregnant so that your doctor can decide if Oseltamivir is right for you.

The effects on breast-fed infants are unknown. You must tell your doctor if you are breast-feeding so that your doctor can decide if Oseltamivir is right for you.

Ask your doctor or pharmacist for advice before taking this medicine.

Driving and using machines

Oseltamivir has no effect on your ability to drive or use machines.

Oseltamivir contains fructose

Before you take Oseltamivir, make sure your prescribing doctor knows if you have hereditary fructose intolerance. This medicine contains sorbitol, which is a form of fructose.

Sorbitol can have a mild laxative effect.

  1. How to take Oseltamivir

Take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure.

Always use the oral dispenser that is provided in the box and has markings indicating the dose in millilitres (ml).

Take Oseltamivir as soon as possible, ideally within two days of the flu symptoms starting.

The recommended doses

For treating flu, take two doses daily. It is usually convenient to take one dose in the morning and one in the evening. It is important to complete the whole 5-day course, even if you start to feel better quickly.

For adult patients with a weak immune system, treatment will continue for 10 days.

For preventing flu or after being exposed to an infected person, take one dose daily for 10 days. It is best to take this in the mornings with breakfast.

In special situations, such as widespread flu, or for patients with a weak immune system, treatment will continue for up to 6 or 12 weeks.

The recommended dose is based on the patient’s body weight. You must use the amount of Oseltamivir prescribed by the doctor. The oral suspension can be used by people who find it hard to take capsules. See the instructions overleaf to make up and give a dose.

Adults, and adolescents 13 years and over

For adults and adolescents 13 years and over and weighing 40 kg or more, the recommended dose for treating flu is 12.5 ml twice daily for 5 days.

For adults and adolescents 13 years and over and weighing 40 kg or more, the recommended dose for preventing flu is 12.5 ml once daily for 10 days.

A 12.5 ml dose can be made up of a 5 ml dose plus a 7.5 ml dose.

Children 1 to 12 years

For children aged 1 to 12 years and weighing 10 kg to 15 kg, the recommended dose for treating flu is 5.0 ml twice daily for 5 days.

For children aged 1 to 12 years and weighing 10 kg to 15 kg, the recommended dose for preventing flu is 5.0 ml once daily for 10 days.

For children aged 1 to 12 years and weighing more than 15 kg and up to 23 kg, the recommended dose for treating flu is 7.5 ml twice daily for 5 days.

For children aged 1 to 12 years and weighing more than 15 kg and up to 23 kg, the recommended dose for preventing flu is 7.5 ml once daily for 10 days.

For children aged 1 to 12 years and weighing more than 23 kg and up to 40 kg, the recommended dose for treating flu is 10.0 ml twice daily for 5 days.

For children aged 1 to 12 years and weighing more than 23 kg and up to 40 kg, the recommended dose for preventing flu is 10.0 ml once daily for 10 days.

For children aged 1 to 12 years and weighing more than 40 kg, the recommended dose for treating flu is 12.5 ml twice daily for 5 days.

For children aged 1 to 12 years and weighing more than 40 kg, the recommended dose for treating flu is 12.5 ml once daily for 10 days.

Infants less than 1 year (0 to 12 months)

Giving Oseltamivir to infants less than 1 year old for preventing flu during flu pandemic should be based upon the judgment of a doctor after considering the potential benefit versus any potential risk to the infant.

A 3 ml oral dispenser (graduated in 0.1 ml steps) should be used for dosing infants less than 1 year old requiring 1 to 3 ml of Oseltamivir oral suspension.

For infants aged between 0 and 12 months, weighing around 3 kg, the recommended dose for treating flu is 1.5 ml twice daily for 5 days using a dispenser size of 3 ml.

For infants aged between 0 and 12 months, weighing around 3 kg, the recommended dose for preventing flu is 1.5 ml once daily for 10 days using a dispenser size of 3 ml.

For infants aged between 0 and 12 months, weighing around 3.5 kg, the recommended dose for treating flu is 1.8 ml twice daily for 5 days using a dispenser size of 3 ml.

For infants aged between 0 and 12 months, weighing around 3.5 kg, the recommended dose for preventing flu is 1.8 ml once daily for 10 days using a dispenser size of 3 ml.

For infants aged between 0 and 12 months, weighing around 4 kg, the recommended dose for treating flu is 2.0 ml twice daily for 5 days using a dispenser size of 3 ml.

For infants aged between 0 and 12 months, weighing around 4 kg, the recommended dose for preventing flu is 2.0 ml once daily for 10 days using a dispenser size of 3 ml.

For infants aged between 0 and 12 months, weighing around 4.5 kg, the recommended dose for treating flu is 2.3 ml twice daily for 5 days using a dispenser size of 3 ml.

For infants aged between 0 and 12 months, weighing around 4.5 kg, the recommended dose for preventing flu is 2.3 ml once daily for 10 days using a dispenser size of 3 ml.

For infants aged between 0 and 12 months, weighing around 5 kg, the recommended dose for treating flu is 2.5 ml twice daily for 5 days using a dispenser size of 3 ml.

For infants aged between 0 and 12 months, weighing around 5 kg, the recommended dose for preventing flu is 2.5 ml once daily for 10 days using a dispenser size of 3 ml.

For infants aged between 0 and 12 months, weighing around 5.5 kg, the recommended dose for treating flu is 2.8 ml twice daily for 5 days using a dispenser size of 3 ml.

For infants aged between 0 and 12 months, weighing around 5.5 kg, the recommended dose for preventing flu is 2.8 ml once daily for 10 days using a dispenser size of 3 ml.

For infants aged between 0 and 12 months, weighing around 6 kg, the recommended dose for treating flu is 3.0 ml twice daily for 5 days using a dispenser size of 3 ml.

For infants aged between 0 and 12 months, weighing around 6 kg, the recommended dose for preventing flu is 3.0 ml once daily for 10 days using a dispenser size of 3 ml.

For infants aged between 0 and 12 months, weighing more than 6 kg and up to 7 kg, the recommended dose for treating flu is 3.5 ml twice daily for 5 days using a dispenser size of 10 ml.

For infants aged between 0 and 12 months, weighing more than 6 kg and up to 7 kg, the recommended dose for preventing flu is 3.5 ml once daily for 10 days using a dispenser size of 10 ml.

For infants aged between 0 and 12 months, weighing more than 7 kg and up to 8 kg, the recommended dose for treating flu is 4.0 ml twice daily for 5 days using a dispenser size of 10 ml.

For infants aged between 0 and 12 months, weighing more than 7 kg and up to 8 kg, the recommended dose for preventing flu is 4.0 ml once daily for 10 days using a dispenser size of 10 ml.

For infants aged between 0 and 12 months, weighing more than 8 kg and up to 9 kg, the recommended dose for treating flu is 4.5 ml twice daily for 5 days using a dispenser size of 10 ml.

For infants aged between 0 and 12 months, weighing more than 8 kg and up to 9 kg, the recommended dose for preventing flu is 4.5 ml once daily for 10 days using a dispenser size of 10 ml.

For infants aged between 0 and 12 months, weighing more than 9 kg and up to 10 kg, the recommended dose for treating flu is 5.0 ml twice daily for 5 days using a dispenser size of 10 ml.

For infants aged between 0 and 12 months, weighing more than 9 kg and up to 10 kg, the recommended dose for preventing flu is 5.0 ml once daily for 10 days using a dispenser size of 10 ml.

If you take more Oseltamivir than you should

Stop taking Oseltamivir and contact a doctor or pharmacist immediately.

In most cases of overdose, people have not reported any side effects. When side effects were reported, they were similar to those from normal doses, as listed in section 4.

Overdose has been reported to have occurred more frequently when Oseltamivir was given to children than to adults and adolescents. Caution should be exercised when preparing liquid Oseltamivir for children and when administering Oseltamivir capsules or liquid Oseltamivir to children.

If you forget to take Oseltamivir

Do not take a double dose to make up for a forgotten dose.

If you stop taking Oseltamivir

There are no side effects when you stop Oseltamivir. But if Oseltamivir is stopped earlier than your doctor told you, the symptoms of flu may come back. Always complete the course that your doctor prescribed.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

  1. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. Many of the side effects listed below may also be caused by influenza.

The following serious side effects have been rarely reported since oseltamivir has been marketed:

  • Anaphylactic and anaphylactoid reactions: severe allergic reactions, with face and skin swelling, itchy rashes, low blood pressure and breathing difficulties
  • Hepatic disorders (fulminant hepatitis, hepatic function disorder and jaundice): yellowing of the skin and white of the eyes, change in stool color, changes in behaviour
  • Angioneuroticoedema: sudden onset of severe swelling of the skin mainly around the head and neck area, including eyes and tongue, with difficulties breathing
  • Stevens-Johnson syndrome and toxic epidermal necrolysis: complicated, possibly life-threatening allergic reaction, severe inflammation of the outer and possibly inner skin, initially with fever, sore throat, and fatigue, skin rashes, leading to blisters, peeling, shedding of larger areas of skin, possible breathing difficulties and low blood pressure
  • Gastrointestinal bleeding: prolonged bleeding from the large bowel or spitting up blood
  • Neuropsychiatric disorders, as described below.

If you notice any of these symptoms, get medical help immediately.

The most frequently (very common and common) reported side effects of Oseltamivir are feeling or being sick (nausea, vomiting), stomach ache, stomach upset, headache and pain. These side effects mostly occur after the first dose of the medicine and will usually stop as treatment continues. The frequency of these effects is reduced if the medicinal product is taken with food.

Rare but serious effects: get medical help at once

(These may affect up to 1 in 1,000 people)

During Oseltamivir treatment, rare events have been reported that include

  • Convulsions and delirium, including altered level of consciousness
  • Confusion, abnormal behaviour
  • Delusions, hallucinations, agitation, anxiety, nightmares

These are reported primarily among children and adolescents and often started suddenly and resolved rapidly. A few cases resulted in self-injury, some with fatal outcome. Such neuropsychiatric events have also been reported in patients with influenza who were not taking Oseltamivir.

  • Patients, especially children and adolescents, should be closely monitored for the behavioural changes described above.

If you notice any of these symptoms, especially in younger people, get medical help immediately.

Adults and adolescents 13 and over

Very common side effects

(may affect more than 1 in 10 people)

  • Headache
  • Nausea.

Common side effects

(may affect up to 1 in 10 people)

  • Bronchitis
  • Cold sore virus
  • Cough
  • Dizziness
  • Fever
  • Pain
  • Pain in limb
  • Runny nose
  • Sleeping difficulties
  • Sore throat
  • Stomach ache
  • Tiredness
  • Upper abdominal fullness
  • Upper respiratory tract infections (inflammation of the nose, throat and sinuses)
  • Upset stomach
  • Vomiting.

Uncommon side effects

(may affect up to 1 in 100 people)

  • Allergic reactions
  • Altered level of consciousness
  • Convulsion
  • Heart rhythm abnormalities
  • Mild to severe liver function disorders
  • Skin reactions (inflammation of the skin, red and itchy rash, scaling skin).

Rare side effects

(may affect up to 1 in 1,000 people)

  • Thrombocytopenia (low platelet count)
  • Visual disturbances.

Children 1 to 12 years

Very common side effects

(may affect more than 1 in 10 people)

  • Cough
  • Nasal congestion
  • Vomiting.

Common side effects

(may affect up to 1 in 10 people)

  • Conjunctivitis (red eyes and discharge or pain in the eye)
  • Ear inflammation and other ear disorders
  • Headache
  • Nausea
  • Runny nose
  • Stomach ache
  • Upper abdominal fullness
  • Upset stomach.

Uncommon side effects

(may affect up to 1 in 100 people)

  • Inflammation of the skin
  • Tympanic membrane (eardrum) disorder.

Infants less than 1 year

The reported side effects in infants 0 to 12 months old are mostly similar to the side effects reported for older children (1 year old or older). Additionally, diarrhoea and diaper rash have been reported.

If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, tell your doctor or pharmacist. However,

  • if you or your child are repeatedly sick, or
  • if the influenza symptoms get worse or the fever continues

Tell your doctor as soon as possible.

Reporting of side effects

If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet.

  1. How to store Oseltamivir

Keep out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and bottle after EXP. The expiry date refers to the last day of that month.

Powder: Do not store above 30°C.

After reconstitution, store below 25 °C for 10 days.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

  1. Contents of the pack and other information

What Oseltamivir contains

  • The active substance is oseltamivir (12mg/ml oseltamivir after reconstitution).
  • The other ingredients are sorbitol , sodium dihydrogen citrate , xanthan gum , sodium benzoate , saccharin sodium , titanium dioxide and tuttifruttiflavour (including maltodextrins [maize], propylene glycol, arabic gum and natural identical flavouring substances [mainly consisting of banana, pineapple and peach flavour]).

What Oseltamivir looks like and contents of the pack

Powder for oral suspension

 

Instructions for the user

There are two stages to taking Oseltamivir oral suspension.

Stage 1 Prepare a new bottle of the medicine

Your pharmacist may have prepared the medicine for you when you collected your prescription. If not, you can do it easily yourself. See the first set of instructions. You only need to do this once, at the beginning of your course.

Stage 2 Measure and give the correct dose

Shake the suspension well and draw the appropriate recommended dose into the dispenser. See the second set of instructions. You will need to do this every time you need a dose.

Stage 1: Prepare a new bottle of the medicine

You will need:

  • The bottle, containing Oseltamivir powder (in the medicine pack)
  • The bottle cap (in the medicine pack)
  • A plastic measuring jug (in the medicine pack)
  • The plastic bottle adapter (in the medicine pack)
  • Water
  • Tap the bottle to loosen the powder
    Tap the closed bottle gently several times to loosen the powder.
  • Use the jug to measure 55 ml of water
    The measuring jug in the pack has a line marked to show you an exact amount.
    Fill it with water to the indicated level.
  • Add all the water, close and shake
    Pour all of the water from the jug into the bottle, onto the powder.
    Always use 55 ml of water, whatever the dose you need.
    Put the cap back on the bottle. Shake the bottle well for 15 seconds.
  • Press in the adapter
    Open the bottle and press the bottle adapter hard into the neck of the bottle.
  • Close the bottle again
    Screw the cap tightly onto the top of the bottle, which now includes the adapter.
    This will make sure that the bottle adapter fits in the bottle in the right position.

You now have a bottle of Oseltamivir oral suspension ready to measure out a dose. You will not need to prepare it again unless you start a new bottle.

Stage 2: Measure and give the correct dose

You will need:

  • A bottle of prepared Oseltamivir oral suspension
  • Depending on the required dose you will need the 3 ml oral dispenser (yellow plunger, 0.1 ml graduation) or the 10 ml oral dispenser (white plunger 0.5 ml graduation) from the medicine pack.
  • For doses from 1.0 ml to 3.0 ml, the 3 ml oral dispenser should be used. For doses above 3.0 ml to 10 ml, 10 ml oral dispenser should be used.

Always use the oral dispenser provided with your medicine to measure a correct dose.

  • Shake the bottle
    Check the cap is secure, and then shake the bottle of Oseltamivir oral suspension.
    Always shake well before use.
  • Prepare the oral dispenser
    Depending on the required dose, use the 3 ml dispenser (yellow plunger) or the 10 ml oral dispenser (white plunger) provided in the pack.
    Push the plunger completely down toward the tip of the dispenser.
  • Fill the dispenser with the correct dose
    Unscrew the cap from the bottle.
    Push the tip of the dispenser into the bottle adapter.
    Then turn the whole unit upside down (bottle and dispenser together).
    Slowly pull out the plunger to draw medicine into the dispenser.
    Stop at the mark that shows the dose you need.
    Turn the whole unit upright.
    Remove the dispenser from the bottle.
  • Give the medicine into the mouth
    Deliver the suspension directly into the mouth by pushing down the plunger of the dispenser.
    Make sure the medicine is swallowed.
    You may drink and eat something after taking the medicine.
  • Close the bottle, keep it safe
    Put the cap back on the bottle. Keep it out of sight and reach of children.
    Store the medicine below 25 ° C for up to 10 days. See 5 How to store Oseltamivir, overleaf.

 

  1. Manufactured By:
    Taj Pharmaceuticals Ltd.
    at: Plot. No. 220, Mahagujarat
    Industrial Estate, At & Post-Moraiya,
    Tal-Sanand, Dist- Ahmedabad Gujarat (India)