Antiviral
Composition
Active ingredient: oseltamivir phosphate.
Capsules containing 98.5 mg oseltamivir phosphate equivalent to 75 mg of oseltamivir
Oseltamivir is presented as hard capsule with Red cap and White body
Properties and effects
Mechanism of action
Oseltamivir phosphate is a pro-drug of a potent and selective inhibitor of influenza virus neuraminidase enzymes. Viral neuraminidase is essential for the release of recently formed virus particles from infected cells, and the further spread of infectious virus.
The active metabolite of oseltamivir inhibits neuraminidases of influenza viruses of both types A and B. Concentrations of the active metabolite required to inhibit the enzyme activity by 50% (IC50) are in the low nanomolar range. The active metabolite also inhibit influenza virus growth in-vitro and inhibits influenza virus replication and pathogenicity in-vivo.
The active metabolite reduces shedding of both influenza A and B virus by inhibiting the release of infectious virus from infected cells
Efficacy
Clinical efficacy of oseltamivir has been demonstrated in human experimental infection studies and phase III studies in naturally occurring influenza.
In studies in naturally acquired and experimental influenza, treatment with oseltamivir did not impair normal humoral antibody response to infection, Antibody response to inactivated vaccine is not expected to be affected by treatment with oseltamivir.
In phase III clinical trials, patients were treated with oseltamivir for up to 40 hours after reported onset of symptoms. In these studies, 97% of patients were infected with influenza A and 3% with influenza B. Oseltamivir treatment significantly reduced the duration of clinically relevant signs and symptoms of influenza by 32 hours. Disease severity in patients with confirmed influenza taking oseltamivir was also reduced by 38% compared to placebo. Moreover oseltamivir reduced the incidence of complications associated with influenza treated with antibiotic therapy in otherwise healthy young adults by approximately 50%. These complications include bronchitis, pneumonia, sinusitis and otitis media. In phase III clinical trials there was clear evidence of efficacy in the secondary endpoints related to antiviral activity in terms of both reduction of duration of virus shedding and reduction in the AUC of viral titres. Data from a partially recruited study in the elderly population have shown that oseltamivir 75 mg twice a day for five days was associated with a reduction in median duration of illness that was clinically relevant and similar to that seen in the adult treatment studies. In a separate partially recruited study, patients aged › 13 years with influenza and co-existing chronic cardiac and/or respiratory disease received the same regimen of either oseltamivir or placebo. No difference in the median time to alleviation of all symptoms was seen between patients taking oseltamivir or placebo however, the duration of febrile illness was reduced by approximately one day by receipt of oseltamivir. The proportion of patients shedding virus on days 2 and 4 was also markedly reduced by active treatment. There was no difference in the safety profile of oseltamivir in the at-risk populations compared to the general adult population.
Viral Resistance
The risk of emergence of drug resistance in clinical use has been extensively examined. The incidence of resistance to the active metabolite in viral isolates from clinical studies is up to 1.5% in influenza A. Patients with Viruses displaying reduced sensitivity, cleared virus normally and showed no clinical deterioration. All resistant genotypes are disadvantaged compared to the corresponding wild-type isolate and are likely to be less contagious in man There IS no evidence for resistance in influenza B in vitro or in clinical isolates.
Pharmacokinetics
Absorption
Oseltamivir is readily absorbed from the gastrointestinal tract after oral administration of oseltamivir phosphate and is extensively converted predominantly by hepatic esterases to the active metabolite. Plasma concentrations of the active metabolite, are measurable within 30 minutes. reach near maximal levels in 2 to 3 hours post dose, and substantially exceed (› 20 fold) those of the prodrug. At least 75% of an oral dose reaches the systemic circulation as the active metabolite. Plasma concentrations of active metabolite are proportional to dose and are unaffected by co-administration with food (see Dosage and Administration).
Distribution
The mean volume of distribution (Vss) of the active metabolite is approximately 23 liters in humans. The active moiety reaches all key sites of influenza infection as shown by studies in the ferret, rat and rabbit. In these studies, anti-viral 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 prodrug to human plasma protein is 42%. These levels are insufficient to cause significant drug interactions.
Metabolism
Oseltamivir phosphate is extensively converted to the active metabolite by esterases located predominantly in the liver. Neither oseltamivir nor the active metabolite are substrates for or inhibitors of cytochrome P450 isoforms (see interactions).
Elimination
Absorbed oseltamivir is primarily (›90%) eliminated by conversion to the active metabolite. The active metabolite is not further metabolized and is eliminated in the urine. Peak plasma concentrations of the active metabolite decline with a half-life of 6 to 10 hours in most subjects. The active drug is eliminated entirely (›99%) by renal excretion. Renal clearance (18.8 1/h) exceeds glomerular filtration rate (7.5 1/h) indicating that tubular secretion in addition to glomerular filtration occurs. Less than 20% of an oral radio-labeled dose is eliminated in feces. Pharmacokinetics in special populations
Patients with renal impairment
Administration of 100 mg of oseltamivir twice daily for five days to patients with various degrees of renal impairment showed that exposure to the active metabolite is inversely proportional to declining renal function. No dose adjustment is necessary for patients with creatinine clearance above 30 ml/min. In patients with a creatinine clearance of 10-30 ml/min, it is recommended that the dose is reduced to 75 mg of oseltamivir once daily for 5 days (see Special dosage instructions and Precautions).
In patients with end stage renal disease (creatinine clearance ‹10 ml/min) undergoing routine hemodialysis or peritoneal dialysis treatment. predicted plasma concentrations indicate that a single dose of 75 mg oseltamivir will deliver antiviral levels for up to 5 days (see Precautions) 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 Special dosage instructions).
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 of oseltamivir. Half-lives observed in the elderly were similar to those seen in young adults. On the basis of drug exposure and tolerability, dosage adjustments are not required for elderly patients (see Special dosage instructions)
Children
The pharmacokinetics of oseltamivir have been evaluated in a small group of children 5 to 18 years of age after administration of a single 2 mg/kg oral dose given as an oral powder for reconstitution. The pharmacokinetic data showed that younger children cleared both the prodrug and the active metabolite faster than older children resulting in lower exposure for a given mg/kg dose. In children 5-8 years old, 2 mg/kg gives comparable exposure to that achieved in adults receiving a single 75 mg capsule dose (approximately 1 mg/kg). With advancing age, the difference in exposure between children and adults (per mg/kg dose) became less, such that exposure in children over 12 years of age was similar to that in adults.
Indications
Treatment of influenza in adults and children one year of age or older who present with symptoms typical of influenza, when influenza virus is circulating in the community. Efficacy has been demonstrated when treatment is initiated within two days of first onset of symptoms. This Indication is based on clinical studies of naturally occurring influenza in which the predominant infection was influenza A.
Prevention of influenza
- Post exposure prevention in adults and adolescents 13 years 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 adults and adolescents 13 years of age or older
The use of antivirals for the treatment and prevention of influenza should be determined on the basis of official recommendations taking into consideration variability of epidemiology and the impact of the disease in different geographical areas and patient populations.
Dosage and administration
Oseltamivir may be taken with or without food. However, taking with food may enhance tolerability in some patients.
Treatment of influenza
Treatment should be initiated as soon as possible within the first two of days of onset of symptoms of influenza.
For adults and adolescents 13 years or older the recommended oral dose is 75 mg oseltamivir twice daily, for 5 days.
For children one year or older, oseltamivir oral suspension is available. For children with body weight above 40 kg, capsules may be prescribed at the adult dosage of 75 mg twice daily for 5 days. The safety and efficacy of oseltamivir in children less than one year of age have not been established.
Prevention of influenza
Post exposure prevention in adults and adolescents 13 years or older: The recommended dose for prevention of influenza following close contact with an infected individual is 75 mg oseltamivir once daily for at least 7 days. Therapy should begin as soon as possible within two days of exposure to an infected individual.
Prevention during an influenza epidemic in the community: The recommended dose for prevention of influenza during a community outbreak is 75 mg oseltamivir once daily for up to six weeks.
The safety and efficacy of oseltamivir for the prevention of influenza in children 12 years of younger have not been established
Special dosage instructions
Patients with renal impairment
Treatment of influenza: Dose adjustment is recommended for adults with severe renal impairment. Recommended doses are detailed in the table below.
| Creatinine clearance | Recommended dose for treatment |
| › 30 (ml/min) | 75 mg twice daily |
| › 10 to ‹ 30 (ml/min) | 75 mg once daily or 30 mg suspension twice daily |
| ‹ 10 (ml/min) | Not recommended |
| dialysis patients | Not recommended |
Prevention of influenza: Dose adjustment is recommended for adults with severe renal impairment as detailed in the table below
| Creatinine clearance | Recommended dose for treatment |
| › 30 (ml/min) | 75 mg once daily |
| › 10 to ‹30 (ml/min) | 75 mg every second day or 30 mg suspension once daily |
| ‹ 10 (ml/min) | Not recommended |
| dialysis patients | Not recommended |
Elderly
No dose adjustment is required, unless there is evidence of severe renal impairment.
Patients with hepatic impairment.
No dose adjustment is required for patients with hepatic dysfunction.
No dose adjustment is required for elderly patients.
Children
The safety and efficacy of oseltamivir in children under 12 years has not been established.
Limited pediatric pharmacokinetic information is available.
Contraindications
Hypersensitivity to oseltamivir phosphate or to any component of the product.
Precautions
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.
The safety and efficacy of oseltamivir treatment of children of less than one year of age have not been established.
The safety and efficacy of oseltamivir for the prevention of influenza in children 12 years or younger have not been established.
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 hospitalization.
The safety and efficacy of oseltamivir in either treatment or prevention of influenza in immunocompromised patiens have not been established.
Efficacy of oseltamivir in the treatment of subjects with chronic cardiac disease and/or respiratory disease has not been established, No difference in the incidence of complications was observed between the treatment and placebo groups in this population.
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.
Severe renal impairment
Dose adjustment is recommended for both treatment and prevention in adults with severe renal
insufficiency. There are no data concerning the safety and efficacy of oseltamivir in children with
renal impairment.
Pregnancy and lactation
There are no adequate data from the use of oseltamivir in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal or postnatal development. Oseltamivir should not be used during pregnancy unless the potential benefit to the mother justifies the potential risk to the foetus.
In lactating rats, oseltamivir and the active metabolite are excreted in the milk. It is not known whether oseltamivir or the active metabolite are excreted in human milk, Oseltamivir should be used during lactation only if the potential benefit for the mother Justifies the potential risk for the nursing infant.
Undesirable effects
Treatment of influenza in adults and adolescents: A total of 2107 patients participated in phase III studies in the treatment of influenza. The most frequently reported undesirable effects were nausea, vomiting and abdominal pain. The majority of these events were reported on a single occasion on either the first or second treatment day and resolved spontaneously within 1-2 days. All events that were reported commonly, (i.e. at an incidence of at least 1 %, irrespective of causality) in subjects receiving oseltamivir 75 mg twice daily, are included in the table below.
Treatment of influenza in elderly: In general, the safety profile in the elderly patients was similar to adults aged up to 65 years: incidence of nausea was lower in oseltamivir treated elderly persons (6.7 %) than in those taking placebo (7.8 %) whereas the incidence of vomiting was higher in those who received oseltamivir (4.7 %) than among placebo recipients (3.1 %).
The adverse event profile in adolescents and in the patients with chronic cardiac and/or respiratory disease was qualitatively similar to that of healthy young adults.
Prevention of influenza In prevention studies, where the dosage of oseltamivir was 75 mg once daily for up to 6 weeks, adverse events reported more commonly in subjects receiving oseltamivir compared to subjects receiving placebo (in addition to the events listed in the table below) were: Aches and pains, rhinorrhoea, dyspepsia and upper respiratory tract infection. There were no clinically relevant differences in the safety profile of the elderly subjects, who received oseltamivir or placebo, compared with the younger population.
Most Frequent Adverse Events in Studies in Naturally Acquired Influenza
System Organ
Class
|
Adverse Event
|
Treatment
|
Prevention
| ||
Placebo (N=1050)
|
Oseltamivir
75 mg twice
daily (N=1057)
|
Placebo (N=1434)
|
Oseltamivir
75 mg once
daily (N=1480)
| ||
Gastrointestinal
Disorders | Vomitting1 Nausea1, 2 Diarrhoea Abdominal Pain |
3.0 %
5.7 %
8.0 %
2.0 %
|
8.0 %
7.9 %
5.5 %
2.2 %
|
1.0 %
3.9 %
2.6 %
1.6 %
|
2.1 %
7.0 %
3.2 %
2.0 %
|
| Infections and Infestations | Bronchitis Bronchitis acute |
5.0 %
1.0 %
|
3.7 %
1.0 %
|
1.2 %
-
|
0.7 %
-
|
| General Disorders | Dizziness Fatigue |
3.0 %
0.7 %
|
1.9 %
0.8 %
|
1.5 %
7.5 %
|
1.6 %
7.9 %
|
| Neurological Disorders | Headache Insomnia |
1.5 %
1.0 %
|
1.6 %
1.0 %
|
17.5 %
1.0 %
|
20.1 %
1.2 %
|
| 1 | Subjects who experienced nausea alone: excludes subjects who experienced nausea in association with vomiting |
| 2 | The difference between the placebo and oseltamivir groups was statistically significant |
Treatment of influenza in children: A total of 1032 children aged 1 to 12 years (including 695 otherwise healthy children aged 1 to 12 years and 334 asthmatic children aged 6 to 12 years) participated in phase III studies of oseltamivir given for the treatment of influenza. A total of 515 children received treatment with oseltamivir suspension. Adverse events occurring in greater than 1% of children receiving oseltamivir are listed In the table below. The most frequently reported adverse event was vomiting, Other events reported more frequently by oseltamivir treated children included abdominal pain, epistaxis, ear disorder and conjunctivitis.
These events generally occurred once, resolved despite continued dosing and did not cause discontinuation of treatment in the vast majority of cases.
Adverse Events occurring in greater than 1 % of children enrolled in Phase III studies of oseltamivir treatment of naturally acquired influenza.
System Organ Class
|
Adverse Event
|
Treatment
| |
Placebo (N=517)
|
Oseltamivir
2 mg/kg (N=515)
| ||
| Gastrointestinal Disorders | Vomiting Diarrhoea Abdominal pain Nausea |
9.3 %
10.6 %
3.9 %
4.3 %
|
15.0 %
9.5 %
4.7 %
3.3 %
|
| Infections and Infestations | Otitis media Pneumonia Sinusitis Bronchitis |
11.2 %
3.3 %
2.5 %
2.1 %
|
8.7 %
1.9 %
1.7 %
1.6 %
|
| Respiratory Disorders | Asthma (incl. Aggravated) Epistaxis |
3.7 %
2.5 %
|
3.5 %
3.1 %
|
| Disorders of the Ear and Labyrinth | Ear disorder Tympanic membrane Disorder |
1.2 %
1.2 %
|
1.7 %
1.0 %
|
| Skin and Subcutaneous Disorders | Dermatitis |
1.9 %
|
1.0 %
|
| Disorders of the Blood and Lymphatic System | Lymphadenopathy |
1.5 %
|
1.0 %
|
| Vision disorders | Conjunctivitis |
0.4 %
|
1.0 %
|
In general, the adverse event profile in the children with asthma was qualitatively similar to that of otherwise healthy children.
Observed during clinical practice: The following adverse reactions have been reporterted during post marketing use of oseltamivir: dermatitis, rash, eczema, urticaria hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, as well as very rare reports of severe skin reactions, including Stevens-Johnson Syndrome and erythema multiforme Additionally, there are very rare reports of hepatic function disorders, including hepatitis and elevated liver enzymes in patients with influenza-like illness.
Interactions
Information derived from pharmacology and pharmacokinetic studies of oseltamivir phosphate suggest that clinically significant drug interactions are unlikely, Oseltamivir phosphate is extensively converted to the active compound by esterases, located predominantly in the liver. Drug interactions involving competition for esterases have not been extensively reported in the literature. Low protein binding of oseltamivir and the active metabolite do not suggest the probability of drug displacement interactions In-vitro studies demonstrated that neither oseltamivir phosphate nor the active metabolite is a good substrate for P450 mixed-function oxidases or for glucuronyl transferases (see Pharmacokinetics). There is no mechanistic basis for an interaction with oral contraceptives
Cimetidine, a non-specific inhibitor of cytochrome P450 isoforms and competitor for renal tubular secretion of basic or cationic drugs has no effect on plasma levels of oseltamivir or its active metabolite.
Clinically important drug interactions involving competition for renal tubular secretion are unlikely due to the known safety margin for most of these drugs. the elimination characteristics of the active metabolite (glomerular filtration and anionic tubular secretion) and the excretion capacity of these pathways. Co-administration of probenecid results in twofold increase in exposure to the active metabolite due to a decrease active tubular secretion in the kidney. However, due to the wide safety margin of the active metabolite, no dose adjustments are required when co-administering with probenecid.
Co-administration with amoxicillin does not alter plasma levels of either compound, indicating that competition for the anionic secretion pathway is weak.
Co-administration with paracetamol does not alter plasma levels of oseltamivir, its active metabolite, or paracetamol. In phase III clinical studies, oseltamivir has been administered with commonly used drugs such as ACE inhibitors (enalapril, captopril), thiazide diuretics (bendrofluazide) antibiotics (penicillin, cephalosporin. azithromycin, erythromycin and doxycycline), H2 receptor blockers (ranitidine, cimetidine), beta-blockers (propranolol) xanthines (theophylline), sympathomimetics (pseudoephidrine), opoids (codeine) corticosteroids, inhaled bronchodilators. and analgesic agents (aspirin, ibuprofen and paracetamol). No change in adverse event profile or frequency has been observed as a result of co-administration of oseltamivir with these compounds.
Overdose
There is no experience with overdose. However, the anticipated manifestations of acute overdose would be nausea. with or without accompanying vomiting, and dizziness. Patients should discontinue the treatment in the event of overdose. No specific antidote is known Special remarks
Stability
See outer pack for storage remark
This medicine should not be used after the expiry date (EXP) shown on the pack
Packs
Blister pack of 10's
Medicine: Keep out of reach of children
Manufactured by
HETERO DRUGS LIMITED
22-110, I.D.A., Jeedimetia, Hyderabad - 500 055, INDIA.
Imported and Distributed by
PT INDOFARMA
Bekasi Indonesia
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