Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd.  
Product proprietary name: OZETIR 6 mg/mL powder for oral suspension  
Dosage form and strength:6 mg/mL powder for oral suspension  
APPROVED PROFESSIONAL INFORMATION FOR OZETIR  
SCHEDULING STATUS  
S4  
1. NAME OF THE MEDICINE  
OZETIR 6 mg/mL powder for oral suspension  
2. QUALITATIVE AND QUANTITATIVE COMPOSITION  
Each mL contains 6 mg oseltamivir equivalent to 7,882 mg of oseltamivir.  
phosphate after constitution.  
Contains sugar “sorbitol and saccharin sodium”.  
OZETIR: contains 173,128 mg sorbitol.  
OZETIR: contains 0,640 mg Saccharin sodium.  
For full list of excipients, see section 6.1  
3. PHARMACEUTICAL FORM  
Powder for oral suspension  
White to pale yellow, tutti-frutti flavored granular or clumped granular powder.  
4. CLINICAL PARTICULARS  
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Product proprietary name: OZETIR 6 mg/mL powder for oral suspension  
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4.1 Therapeutic indications  
Treatment:  
OZETIR is indicated for the treatment of influenza in adults and children ≥ 1 year of age (see section  
4.4 and section 4.2).  
PANDEMIC USE:  
OZETIR is indicated for the treatment of infants 6-12 months of age during a pandemic influenza  
outbreak only, and not for endemic (seasonal) influenza use, (see section 4.4 and  
section 5.2)  
PROPHYLAXIS:  
OZETIR is indicated for the prophylaxis of influenza in adults and children ≥ 1 year of age.  
4.2 Posology and method of administration  
Posology  
Standard Dosage  
Treatment of influenza  
Treatment should begin within the first or second day of onset of symptoms of influenza.  
Adults and adolescents ≥ 13 years of age who are unable to swallow capsules may receive a dose of  
75 mg OZETIR powder for oral suspension twice daily, for 5 days.  
Children:  
The recommended oral dose of OZETIR powder for oral suspension for children ≥ 1 year of age is:  
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Product proprietary name: OZETIR 6 mg/mL powder for oral suspension  
Dosage form and strength:6 mg/mL powder for oral suspension  
Body weight  
Recommended treatment dose for 5 days  
6 mg/mL oral suspension  
5,0 mL twice daily  
≤15 kg  
> 15 kg to 23 kg  
> 23 kg to 40 kg  
> 40 kg  
7,5 mL twice daily  
10,0 mL twice daily  
12,5 mL twice daily  
A 10 mL oral dosing syringe is provided for the 6 mg/mL oral suspension for  
children ≥ 1 year of age.  
It is recommended that OZETIR powder for oral suspension be constituted by  
a pharmacist prior to dispensing to the patient.  
The recommended oral dose of OZETIR for children 6 – 12 months of age:  
Based on limited pharmacokinetic data currently available, a dosage of 3 mg/kg twice daily  
in children 6 - 12 months of age provides plasma exposure to the active metabolite in the majority  
of patients similar to that shown to be clinically efficacious in older children and adults.  
Recommended volumes of reconstituted oral suspension to be drawn up into an oral syringe  
(3 mg/kg body weight) are shown in the table below:  
Body weight (kg)  
OZETIR (mg)  
Rounded volume of 6 mg/mL  
suspension  
6
18  
3 mL  
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Product proprietary name: OZETIR 6 mg/mL powder for oral suspension  
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7
8
21  
24  
27  
30  
3,5 mL  
4 mL  
9
4,5 mL  
5 mL  
≥ 10  
Use the smallest graduated oral syringe that will accurately deliver the  
appropriate volume.  
The recommended treatment dose for infants 6 - 12 months is3 mg/kg twice daily  
for 5 days, during a pandemic influenza outbreak only, and not for endemic  
(seasonal) influenza use (see section 5.2)  
Children ≥ 1 year of age  
The recommended prophylactic oral dose of OZETIR for children ≥ 1 year of age is:  
Body weight  
Recommended treatment dose for 10 days  
6 mg/mL oral suspension  
5,0 mL once daily  
≥15 kg  
> 15 kg to 23 kg  
> 23 kg to 40 kg  
> 40 kg  
7,5 mL once daily  
10,0 mL once daily  
12,5 mL once daily  
A 10 mL oral dosing syringe is provided for the 6 mg/mL oral suspension.  
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Product proprietary name: OZETIR 6 mg/mL powder for oral suspension  
Dosage form and strength:6 mg/mL powder for oral suspension  
It is recommended that OZETIR powder for oral suspension be constituted by a pharmacist prior to  
dispensing to the patient (see section 6.6)  
Special Dosage Instructions  
Patients with renal impairment  
Treatment of influenza: No dose adjustment is necessary for patients with creatinine  
clearance above 60 mL/min. In patients a with creatinine of > 30 – 60 mL/min, it is  
recommended that the treatment dose be reduced to 30 mg of OZETIR twice daily  
for 5 days. In patients with a creatinine clearance of 10 - 30 mL/min, it is recommended that  
the dose be reduced to 30 mg of OZETIR once daily for 5 days. In patients  
undergoing routine haemodialysis an initial dose of 30 mg OZETIR can be  
administered prior to the start of dialysis if influenza symptoms develop during the 48 hours  
between dialysis sessions. To maintain plasma concentrations at a therapeutic level, a dose  
of 30 mg should be administered after every haemodialysis session.  
For peritoneal dialysis an initial dose of 30 mg of OZETIR administered prior to the  
start of dialysis followed by further 30 mg doses administered every 5 day s is recommended  
for treatment(see section 5.2 and 4.4). The pharmacokinetics of OZETIR have not  
been studied in patients with “endstage renal disease” (i.e. creatinine clearance < 10 mL/min) not  
undergoing dialysis. Hence, dosing recommendation cannot be provided for this group.  
Prophylaxis of influenza: No dose adjustment is necessary for patients with creatinine clearance  
above 60 mL/min. In patients with a creatinine clearance of > 30 - 60 mL/min, it is recommended  
that the dose be reduced to 30 mg of OZETIR once daily. In patients with a creatinine clearance  
between 10 and 30 mL/min receiving OZETIR, it is recommended that the  
dose be reduced to 30 mg of OZETIR every other day. In patients undergoing routine haemodialysis  
an initial dose of 30 mg of OZETIR can be administered prior to the start of dialysis.  
To maintain plasma concentrations at a therapeutic level, a dose of 30 mg should be administered  
after every alternate haemodialysis session. For peritoneal dialysis an initial dose of 30 mg of  
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Product proprietary name: OZETIR 6 mg/mL powder for oral suspension  
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OZETIR administered prior to the start of dialysis followed by further 30 mg doses administered  
every 7 days is recommended for prophylaxis (see section 5.2 and 4.24). The pharmacokinetics of  
OZETIR have not been studied in patients with“end-stage renal disease” (i.e.,creatinine clearance <  
10 mL/min) not undergoing dialysis Hence, dosing  
recommendation cannot be provided for this group.  
Patients with hepatic impairment  
No dose adjustment is required for patients with mild or moderate hepatic dysfunction in the  
treatment or prophylaxis of influenza(see 5.2). The safety and pharmacokinetics in patients with  
severe hepatic impairment have not been studied.  
Immuno-compromised patients  
Seasonal prophylaxis in immuno-compromised patients 1 year of age and older is recommended  
for 12 weeks. No dose adjustment is necessary.  
Elderly  
No dose adjustment is required for elderly patients in the treatment or prophylaxis of influenza (see  
section 5.2).  
Children  
The safety and efficacy of OZETIR in children under1 year has not been established  
(see section 5.2). OZETIR should not be used in children under 1 year of age, other  
than during a pandemic influenza outbreak.  
Method of administration  
For oral use  
OZETIR may be taken with or without food. (see section 5.2).  
However, OZETIR taken with food may enhance tolerability in some patients.  
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4.3 Contraindications  
Hypersensitivity to any of the ingredients of OZETIR, including the excipients listed in section 6.1.  
4.4 Special warnings and precautions for use  
Neuropsychiatric events such as convulsions, abnormal and inappropriate behaviour,disturbances  
in consciousness, hallucinations and delirium have been reported during oseltamivir administration  
in patients with influenza. In some cases, the delirium resulted in accidental self-injury and death.  
These events occurred mostly within the first few days of taking oseltamivir.  
Patients, and especially paediatric and adolescent patients, taking oseltamivir should be carefully  
monitored for signs of abnormal behaviour, and the benefits and risks of continuing treatment should  
be carefully evaluated for each patient (see section 4.8).  
OZETIR is effective only against illness caused by influenza viruses.  
There is no evidence for efficacy of OZETIR in any illness caused by medicines other than influenza  
viruses types A and B (see section 5.1).  
OZETIR is not a substitute for influenza vaccination.  
Resistance of influenza viruses to oseltamivir have been reported. The prevalence of virus  
resistance and virus strains on subtypes differs between countries and seasons. In South Africa  
where H1N1 viruses predominated among circulating strains, 100 % [225/225] of H1N1 viruses  
tested in 2008 were resistant to oseltamivir. The resistance of the predominant virus to  
oseltamivir generally changes from season to season. Updated local surveillance data from the  
National Institute for Communicable Diseases (NICD) should be consulted for information on  
seasonal prevalence of medicine resistant viruses.  
Based on limited pharmacokinetic and safety data, OZETIR may only be used in infants 6 – 12  
months of age for treatment during a pandemic influenza outbreak. The treating doctor should take  
into account the pathogenicity of the circulating strain and the underlying condition of the patient to  
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Product proprietary name: OZETIR 6 mg/mL powder for oral suspension  
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ensure that there is a potential benefit to the child.  
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 (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).  
Severe renal impairment  
Dose adjustment is recommended for both treatment and prevention in adolescents (13-17 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 section 4.2 and 5.2).  
Dose adjustment is recommended for patients with creatinine clearance of 10 - 60 mL/min for the  
treatment of influenza and the prophylaxis of influenza.  
No dosing recommendation is available for patients undergoing routine haemodialysis and  
continuous peritoneal dialysis with end stage renal disease and for patients with creatinine clearance  
of ≤ 10 mL/min (see section 4.2).  
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Product proprietary name: OZETIR 6 mg/mL powder for oral suspension  
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OZETIR should not be used in children under 1 year of age, other than during a pandemic influenza  
outbreak.  
Excipients  
OZETIR contains sorbitol. Patients with hereditary fructose intolerance  
(HFI) should not take OZETIR.  
Sorbitol may cause gastrointestinal discomfort and mild laxative effect.  
This medicine contains sodium benzoate. Sodium benzoate may increase jaundice in newborn  
babies (up to 4 weeks old).  
Paediatric population  
No data allowing a dose recommendation for premature children (<36 weeks post-conceptual age)  
are currently available.  
4.5 Interaction with other medicines and other forms of interaction  
Pharmacokinetic properties of oseltamivir, such as low protein binding and metabolism independent  
of the CYP450 and glucuronidase systems suggest that clinically significant medicine interactions  
are unlikely.  
Oseltamivir is extensively converted to the active compound by esterases, located predominantly in  
the liver. Interactions involving competition for esterases have not been extensively reported in the  
literature.  
In vitro studies demonstrated that neither oseltamivir nor the active metabolite is a good substrate  
for P450 mixed-function oxidases or for glucuronyl transferases, see section 5.2 There is no  
mechanistic basis for an interaction with oral contraceptives.  
Probenecid  
No dose adjustment is required when co-administering with probenecid in patients with normal renal  
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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 medicine interactions involving competition for renal tubular secretion are  
unlikely, due to the known safety margin for most of these medicines, 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 OZETIR in patients  
when taking co- excreted medicines with a narrow therapeutic margin (e.g. chlorpropamide,  
methothrexate, phenylbutazone).  
Additional information  
No pharmacokinetic interactions between oseltamivir or its major metabolite have been observed  
when co-administering OZETIR with paracetamol, acetyl-salicylic acid, cimetidine or with antacids  
(magnesium and aluminium hydroxides and calcium carbonates),rimantadine or warfarin (in patients  
stable on warfarin and without influenza).  
4.6 Fertility, pregnancy and lactation  
Pregnancy  
Safety in pregnancy has not been established.  
No teratogenic effect was not observed in animal reproductive studies. No studies have been  
conducted with the use of OZETIR in pregnant women.  
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Breastfeeding  
Safety in lactation has not been established.  
In lactating rats, oseltamivir and the active metabolite are excreted in the milk.  
Limited information is available on infants breastfed by mothers taking  
oseltamivir and on excretion of oseltamivir in breast milk.  
Limited data demonstrated that low levels of oseltamivir and the active metabolite were detected in  
breast milk.  
Safety in humans has not been demonstrated in children of breastfeeding women using OZETIR.  
Mothers on treatment with OZETIR should not breastfeed their infants.  
Fertility  
No fertility data are available.  
4.7 Effects on ability to drive and use machines  
It is not known whether OZETIR could affect the ability to drive a car or operate machinery.  
However, if symptoms such as delirium or fever are experienced while taking OZETIR, patients  
should be advised not drive or use machines until the symptoms disappear.  
4.8 Undesirable effects  
a) Summary of the safety profiles  
In adults/ adolescents, treatment studies the most frequently reported adverse reactions (ARs) were  
nausea and vomiting and headache. 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 adult/adolescent prophylaxis studies, the most frequently reported adverse reaction were vomiting  
nausea headache and pain. In children the most frequently reported ADR was vomiting.  
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The following serious adverse reactions have been reported anaphylactic and anaphylactoid  
reactions, hepatic disorders (fulminant hepatitis, hepatic function disorder and jaundice)  
angioneutotic oedema, stevens-johnson syndrome and toxic epidermal necrolysis, gastrointestinal  
bleeding and neuropsychiatric disorders. (Regarding neuropsychiatric disorders, see section 4.4).  
b. Tabulated summary of adverse reactions  
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 (75 mg twice a day for 5 days for treatment and 75 mg once  
daily for up to 6 weeks for prophylaxis) are shown in Table 1.  
The safety profile reported in subjects who received the recommended dose of OZETIR 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.  
Table 1 Adverse reactions in studies investigating Tamiflu for treatment  
and prevention of influenza in adults and adolescents or through post- marketing  
surveillance  
Infections and infestations  
Frequency unknown:  
Bronchitis, Herpes simplex,  
Nasopharyngitis, Upper respiratory tract  
infections, Sinusitis, Influenza  
Blood and lymphatic system disorders  
Less frequent:  
Thrombocytopenia  
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Immune system disorders  
Less frequent:  
Hypersensitivity reaction, anaphylactic  
reactions, anaphylactoid reactions  
Psychiatric disorders  
Less frequent:  
Agitation, abnormal behaviour, anxiety,  
confusion, delusions, delirium,  
hallucination, nightmares, self-injury  
Nervous system disorders  
Frequent:  
Headache,  
Less frequent:  
Altered level of consciousness, convulsion  
Insomnia  
Frequency unknown  
Eye disorders  
Less frequent  
Visual disturbance  
Cardiac disorders  
Less frequent:  
Cardiac dysrhythmia  
Respiratory, thoracic and mediastinal disorders  
Frequent:  
sore throat,  
Frequency unknown  
Gastrointestinal disorders  
Cough, nasal congestion, rhinorrhea  
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Frequent:  
Nausea, vomiting,  
Less frequent:  
Gastrointestinal bleedings, haemorrhagic  
colitis  
Frequency unknown  
abdominal pain (including upper abdominal  
pain), diarrhoea, dyspepsia  
Hepato-biliary disorders  
Less frequent:  
Elevated liver enzymes, fulminant hepatitis,  
hepatic failure, hepatitis  
Skin and subcutaneous tissue disorders  
Less frequent:  
Eczema, dermatitis, rash, urticaria,  
angioneurotic oedema, erythema  
multiforme, Stevens-Johnson syndrome,  
toxic epidermal necrolysis  
Musculoskeletal and connective tissue disorders  
Frequency unknown:  
Back pain, arthralgia, myalgia  
Reproductive system and breast disorders  
Frequency unknown:  
dysmenorrhoea  
General disorders and administration site conditions  
Frequent:  
Pain  
Frequency unknown  
dizziness (including vertigo), fatigue,  
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pyrexia, pain in limb, influenza-like illness  
Treatment and prevention of influenza in children:  
Table 2 Adverse reactions of OZETIR for treatment and prevention of influenza in children  
Infections and infestations  
Frequency unknown:  
Otitis media, pneumonia, sinusitis,  
bronchitis,  
Blood and lymphatic system disorders  
Frequency unknown:  
Nervous system disorders  
Frequent:  
Lymphadenopathy  
Headache  
Eye disorders  
Frequency unknown:  
Conjunctivitis (including red eyes, eye  
discharge and eye pain)  
Ear and labyrinth disorders  
Frequency unknown:  
Earache, Tympanic membrane disorder  
Respiratory, thoracic and mediastinal disorders  
Frequency unknown:  
Cough, nasal congestion, rhinorrhoea,  
asthma (including aggravated asthma),  
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epistaxis  
Gastrointestinal disorders  
Frequent:  
Vomiting, dyspepsia  
Frequency unknown:  
diarrhoea, abdominal pain (including  
upper abdominal pain), nausea  
Skin and subcutaneous tissue disorders  
Frequency unknown:  
Dermatitis (including allergic and atopic  
dermatitis)  
c. 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 OZETIR, there have been post marketing 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.  
Immune system disorders: allergy, anaphylactic/anaphylactoid reactions and face  
oedema have been reported.  
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Skin and subcutaneous tissue disorders: Cases of hypersensitivity reactions such as allergic skin  
reactions including dermatitis, rash, eczema, urticaria, erythema multiforme, Stevens-Johnson  
Syndrome, and toxic epidermal necrolysis have been reported.  
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.  
Gastrointestinal disorders: Gastrointestinal bleedings, in particular, haemorrhagic colitis was  
reported that subsided when the course of influenza abated or treatment with oseltamivir was  
interrupted.  
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 influenza infected children less than one year of age, the safety profile was  
similar among age cohorts with vomiting, diarrhoea 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, epidemiological  
databases research and post marketing 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  
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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  
The treatment of influenza in immunocompromised patients were evaluated in two studies receiving  
standard dose or high dose regimens (double dose or triple dose) of oseltamivir (see section 5.1).  
The safety profile of oseltamivir observed in these studies was consistent with that observed in  
previous clinical trials where oseltamivir was administered for treatment of influenza in non-  
immunocompromised patients across all age groups (otherwise healthy patients or “at risk” patients  
[i.e., those with respiratory and/or cardiac co-morbidities]). The most frequent adverse reaction  
reported in immunocompromised children was vomiting (28%). In a 12-week prophylaxis study in  
immunocompromised patients, including 18 children 1 to 12 years of age and older, the safety profile  
in 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 medicine is important. It allows  
continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to  
report any suspected adverse to report any suspected adverse reactions to SAHPRA via the “6.04  
Adverse Drug Reactions Reporting Form”, found online under SAHPRA’s publications:  
https://www.sahpra.org.za/publications/Index/8  
4.9 Overdose  
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In overdose symptoms may be the exacerbation or exaggeration of side effects  
Treatment is supportive and symptomatic  
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 OZETIR oral suspension and when administering OZETIR to  
children.  
5 PHARMACOLOGICAL PROPERTIES  
5.1 Pharmacodynamic properties  
Pharmacotherapeutic group: Antivirals for systemic use,  
neuraminidase inhibitors ATC code: J05AH02  
CATEGORY AND CLASS  
A 20.2.8 Antiviral agents  
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 is essential for both 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 75 mg  
twice daily.  
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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.  
Oseltamivir resistance  
Clinical studies: The risk of emergence of influenza viruses with reduced susceptibility or frank  
resistance to oseltamivir has been examined in 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.  
5.2 Pharmacokinetic properties  
Absorption  
Oseltamivir is readily absorbed from the gastrointestinal tract after oral administration of oseltamivir  
phosphate (pro-drug) and is extensively converted predominantly by hepatic esterases to the active  
metabolite (oseltamivir carboxylate). Plasma concentrations of the active metabolite are measurable  
within 30 minutes, reach exceed near maximal levels in 2 to 3 hours post dose, and substantially (>  
20-fold) those of the pro-drug.  
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 (see section 4.2)  
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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd.  
Product proprietary name: OZETIR 6 mg/mL powder for oral suspension  
Dosage form and strength:6 mg/mL powder for oral suspension  
Distribution  
The mean volume of distribution (Vss) of the active metabolite is approximately 23 litres in humans,  
a volume equivalent to extracellular body fluid. The active moiety reaches all key sites of influenza  
infection as shown by studies in the ferret, rat and rabbit.  
In these studies, antiviral concentrations of the active metabolite were seen in the lung,  
bronchoalveolar lavage, nasal mucosa, middle ear and trachea following oral administration of  
doses of oseltamivir phosphate. The binding of the active metabolite to human plasma protein is  
negligible (approximately 3 %).  
The binding of the pro-drug to human plasma protein is 42 %. These levels are insufficient to cause  
significant medicine interactions.  
Biotransformation  
Oseltamivir phosphate is extensively converted to the active metabolite by esterases located  
predominantly in the liver. Neither oseltamivir nor the active metabolite is substrates for or inhibitors  
of cytochrome P450 isoforms, (see section 4.5)  
Elimination  
Absorbed oseltamivir is primarily (> 90 %) eliminated by conversion to the active metabolite. The  
active metabolite is not further metabolised and is eliminated in the urine. Peak plasma  
concentrations of the active metabolite decline, with a half-life of 6-10 hours in most subjects. The  
active drug is eliminated entirely (>99 %) by renal excretion. Renal clearance (18,8 L/h) exceeds  
glomerular filtration rate (7,5 L/h) indicating that tubular secretion in addition to glomerular  
filtration occurs. Less than 20 % of an oral radio-labelled dose is eliminated in faeces.  
Pharmacokinetics in special population  
Patients with renal impairment:  
Administration of 100 mg of oseltamivir twice daily for five days to patients with various degrees of  
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Product proprietary name: OZETIR 6 mg/mL powder for oral suspension  
Dosage form and strength:6 mg/mL powder for oral suspension  
renal impairment showed that exposure to the active metabolite is inversely proportional to declining  
renal function.  
Treatment of influenza:  
No dose adjustment is necessary for patients with creatinine clearance above 60 mL/min. In patients  
with a creatinine clearance of 30-60 mL/min, it is recommended that the dose be reduced to 30 mg  
of oseltamivir once daily for 5 days.  
In patients undergoing routine haemodialysis an initial dose of 30 mg of oseltamivir can be  
administered prior to the start of dialysis in patients with influenza symptoms during the 48 hours  
between dialysis sessions.  
To maintain plasma concentrations at a therapeutic level, a dose of 30 mg should be  
administered after every haemodialysis session. For peritoneal dialysis an initial dose of 30 mg of  
oseltamivir administered prior to the start of dialysis followed by further 30 mg doses administered  
every 5 days is recommended for treatment (see section 4.2 and 4.4). The pharmacokinetics of  
oseltamivir have not been studied in patients with “end-stage renal disease” (i.e., creatinine  
clearance of < 10 mL/min) not undergoing dialysis. Hence, dosing recommendation cannot be  
provided for this group.  
Prophylaxis of influenza:  
No dose adjustment is necessary for patients with creatinine clearance above 60 mL/min. In patients  
with a creatinine clearance of > 30 - 60 mL/min, it is recommended that the dose be reduced to 30  
mg of oseltamivir once daily.  
In patients with creatinine clearance between 10 and 30 mL/min receiving oseltamivir it is  
recommended that the dose be reduced to 30 mg of oseltamivir every other day. In patients  
undergoing routine haemodialysis an initial dose of 30 mg of oseltamivir can be administered prior to  
the start of dialysis. To maintain plasma concentrations at a therapeutic level, a dose of 30  
mg should be administered after every alternate haemodialysis session. For peritoneal dialysis an  
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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd.  
Product proprietary name: OZETIR 6 mg/mL powder for oral suspension  
Dosage form and strength:6 mg/mL powder for oral suspension  
initial dose of 30 mg of oseltamivir administered prior to the start of dialysis followed by further 30  
mg doses administered every 7 days is oseltamivir have not been studied in patients with “end-stage  
renal disease” (i.e., creatinine clearance of < 10 mL/min) not undergoing dialysis. Hence, dosing  
recommendation cannot be provided for this group.  
Patients with hepatic impairment  
In-vitro studies have shown 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)  
The safety and pharmacokinetics in patients with severe hepatic impairment have not been studied.  
Elderly  
Exposure to the active metabolite at steady state was 25-35 % higher in elderly (age range 65-78)  
compared to young adults who were given comparable doses observed in the elderly were similar to  
those seen in young of medicine exposure and tolerability, dosage adjustments are not required for  
elderly patients for either the treatment or prophylaxis of influenza unless there is evidence of  
moderate or severe renal Impairment (creatinine clearance below 60 mL/min) (see section 4.2).  
Immunocompromised Patients  
Population pharmacokinetic analyses indicate that treatment of adult and paediatric (< 18 years old)  
immunocompromised patients with oseltamivir (as described in section 4.2 results in an increased  
predicted exposure (from approximately 5 % up to 50 %) to the active metabolite when compared to  
non-immunocompromised patients with comparable creatinine clearance.  
Due to the wide safe margin of the active metabolite, no dose adjustments are required in patients  
due to their immunocompromised status. However, for immunocompromised patients with renal  
impairment, doses should be adjusted as outlined in section 4.2.  
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Product proprietary name: OZETIR 6 mg/mL powder for oral suspension  
Dosage form and strength:6 mg/mL powder for oral suspension  
Pharmacokinetic and pharmacodynamic analyses from two studies in immunocompromised patients  
indicated that there was no meaningful additional benefit in exposures higher than those achieved  
after the administration of the standard dose.  
Paediatric population  
Children ≥ 1 year of age  
The pharmacokinetics of oseltamivir has been evaluated in single dose pharmacokinetic studies in  
children aged 1 to 16 years. Multiple dose pharmacokinetics was studied in a small number of  
children aged 3-12 years enrolled in a clinical trial. The rate of clearance of the active metabolite,  
corrected for bodyweight, was faster in children than in adults, resulting in lower exposure  
in these children for a given mg/kg dose. The rate of clearance of the active metabolite increased  
with decreasing age over the age 16 years. Doses of 2 mg/kg yield oseltamivir carboxylate  
exposures comparable to those achieved in adults receiving a single 75 mg capsule dose  
(approximately 1 mg/kg). The pharmacokinetics of oseltamivir in children over 12 years of age are  
similar to those in adults.  
Infants 6 to 12 months of age  
Limited pharmacokinetic and safety data are available for infants less than 2 years of age.  
Pharmacokinetic modelling was undertaken using these data in addition to data from studies in  
adults and children older than 1 year of age.  
The results demonstrate that doses of 3 mg/kg twice daily for infants aged 6 to 12 months provide  
exposures similar to those shown to be clinically efficacious in adults and children > 1 year of age  
(see section 4.1)  
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  
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Product proprietary name: OZETIR 6 mg/mL powder for oral suspension  
Dosage form and strength:6 mg/mL powder for oral suspension  
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  
given mg/kg dose. Doses of 2 mg/kg give oseltamivir carboxylate exposures comparable to those  
achieved in adults receiving a single 75 mg dose (approximately 1 mg/kg). The pharmacokinetics of  
oseltamivir in children and adolescents 12 years of age or older are similar to those in adults.  
6. Pharmaceutical particulars  
6.1 List of excipients  
Oseltamivir phosphate  
Sorbitol  
Saccharin sodium  
Monosodium citrate anhydrous  
Dehydrated alcohol  
Sodium benzoate  
Titanium dioxide  
Tutti-frutti Flavor  
6.2 Incompatibilities  
Not applicable  
6.3 Shelf life  
24 months  
6.4 Special precautions for storage  
Store at or below 25 °C. Protect from light and moisture.  
Keep the bottle tightly closed  
KEEP OUT OF REACH OF CHILDREN.  
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Product proprietary name: OZETIR 6 mg/mL powder for oral suspension  
Dosage form and strength:6 mg/mL powder for oral suspension  
6.5 Nature and contents of container  
100 ml Amber glass bottle (type-III (SGD)) with a child- resistant plastic caps with Expended PE  
wad, 28 mm  
6.6 Special precautions for disposal and other handling  
It is recommended that Powder for Oral Suspension should be reconstituted by the pharmacist prior  
to its dispensing to the patient.  
After reconstitution with 55 ml of water, this usable volume of oral Suspension allows for the retrieval  
of a total doses of 30 mg Oseltamivir.  
Preparation of 6 mg/ml Oral Suspension  
To obtain 64,7 ml (60 ml retrievable) of suspension  
1.Tap the closed bottle gently several times to loosen the powder.  
2. Measure 55 ml of water. Use the measuring cup (where  
provided) and fill it to the indicated level.  
3. Add all 55 ml of water for constitution to the bottle and shake  
the closed bottle well for 15 seconds.  
4. Remove the child-resistant cap and push bottle adapter into  
neck of bottle.  
5. Close bottle with the child-resistant cap tightly. This will assure  
the proper seating of the bottle adapter in the bottle and child-  
resistant status of the cap.  
When OZETIR Powder for Oral Suspension is not Available.  
During situations when commercially manufactured OZETIR powder for oral suspension is not  
readily available, adults, adolescents or children who are unable to swallow  
capsules may receive appropriate doses of OZETIR by opening capsules and pouring the contents  
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Product proprietary name: OZETIR 6 mg/mL powder for oral suspension  
Dosage form and strength:6 mg/mL powder for oral suspension  
of capsules into a suitable, small amount (1 teaspoon (5 ml) maximum) of  
sweetened food product such as regular or sugar-free chocolate syrup, honey (only for children two  
years or older), light brown or table sugar dissolved in water, dessert toppings, sweetened  
condensed milk, apple sauce or yoghurt to mask the bitter taste.  
The mixture should be stirred and the entire contents given to the patient. The mixture must be  
swallowed immediately after its preparation.  
When using the 30 mg and 45 mg capsules: follow these instructions to ensure proper dosing:  
1. Determine the number of capsules that are needed to prepare a mixture with this procedure:  
Body Weight*  
Recommended number of  
Required number of  
capsule(s) needed to  
capsule(s) needed to  
obtain the recommended  
obtain the  
recommended  
doses for 5 days  
treatment  
doses for prevention (10  
days)  
Less than or equal to  
15 kg  
1 capsule of 30 mg twice  
daily  
1 capsule of 30 mg once  
daily  
More than 15 kg and  
up to 23 kg  
1 capsule of 45 mg twice  
daily  
1 capsule of 45 mg once  
daily  
More than 23 kg and  
up to 40 kg  
2 capsules of 30 mg twice  
daily  
2 capsules of 30 mg once  
daily  
2. Check that the correct dose according to the table above is used. The capsule(s) must be held  
over a small bowl, carefully pulled open and the powder poured into the bowl.  
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Product proprietary name: OZETIR 6 mg/mL powder for oral suspension  
Dosage form and strength:6 mg/mL powder for oral suspension  
3. A suitable, small amount (1 teaspoon (5 ml) maximum) of sweetened food product must be added  
to the bowl (to mask the bitter taste) and the contents well mixed.  
4. The mixture must be stirred and the entire contents of the bowl given to the patient.  
This mixture must be swallowed by the patient immediately after some mixture left inside the bowl,  
the bowl must be rinsed with a small amount of water and the patient must drink this remaining  
mixture.  
For patients requiring 30 - 60 mg doses, follow these instructions:  
1. One OZETIR 75 mg capsule must be held over a the capsule must be carefully pulled open and  
the powder poured into the small bowl.  
2. 5 ml water must be added to the powder using a graduated syringe and the mixture stirred for  
approximately two minutes.  
3. The correct amount of mixture must be drawn up into the syringe from the bowl. See the table  
below to determine the correct amount of mixture, based on the patient’s weight.  
It is not necessary to draw up any undissolved white powder as this is inert material.  
The plunger of the syringe must be pushed down to empty its entire contents into a second bowl  
and any unused mixture discarded.  
Body weight  
Recommended t  
dose  
Required amount of {PRODUCT  
NAME} mixture for one dose  
Less than or equal  
to 5 kg  
40 mg  
45 mg  
60 mg  
2 ml  
3 ml  
4 ml  
More than 23 kg  
and up to 40 kg  
More than 23 kg  
and up to 40 kg  
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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd.  
Product proprietary name: OZETIR 6 mg/mL powder for oral suspension  
Dosage form and strength:6 mg/mL powder for oral suspension  
4. The recommended dose is 30 mg, 45 mg or 60 mg twice daily for 5 days for treatment, and once  
daily for prevention for 10 days.  
5. In the second bowl, a suitable, small amount (1 teaspoon (5 ml) maximum) of sweetened food  
product must be added to the mixture (to mask the bitter taste) and well mixed.  
6. This mixture must be stirred and the entire contents of the second bowl given to the patient. This  
mixture must be swallowed immediately after its preparation. If there is some mixture left inside the  
bowl, the bowl must be rinsed with a small amount of water and the patient must drink this remaining  
mixture.  
For patients requiring 75 mg dose, follow these instructions:  
1. One 75 mg capsule must be held over a small bowl, the capsule must be carefully pulled open  
and the powder poured into the bowl.  
2. A suitable, small amount (1 teaspoon (5 ml) maximum) of sweetened food product must be added  
to the mixture (to mask the bitter taste) and well mixed.  
3. The mixture must be stirred and the entire contents of the bowl given to the patient. This mixture  
must be swallowed immediately after its preparation. If there is some mixture left inside the bowl,  
it must be rinsed with a small amount of water and the patient must drink this remaining mixture.  
Repeat this procedure every time this medicine is taken.  
7 HOLDER OF CERTIFICATE OF REGISTRATION  
Hetero Drugs South Africa (Pty) Ltd  
Waterfall Corporate Campus  
Building No. 2, First floor  
74 Waterfall Drive  
Midrand, 2066  
Telephone: 012 644 1220  
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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd.  
Product proprietary name: OZETIR 6 mg/mL powder for oral suspension  
Dosage form and strength:6 mg/mL powder for oral suspension  
Fax number: 012 644 1564  
e-mail address: nokuthula.n@heterodrugs.com  
8 REGISTRATION NUMBER (S)  
OZELET 6 mg/mL:56/20.8/1086  
9 DATE OF FIRST AUTHORISATION  
10 October 2023  
10 DATE OF REVISION OF THE NEXT  
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