Oseltamivir HEC Pharm 30 mg Hartkapseln - Beipackzettel, Nebenwirkungen, Wirkung, Anwendungsgebiete

ADMINISTRATIVE INFORMATION

Proposed name of the medicinal product in the RMS	Oseltamivir HEC Pharm 30 mg Hartkapseln Oseltamivir HEC Pharm 45 mg Hartkapseln Oseltamivir HEC Pharm 75 mg Hartkapseln
Name of the drug substance (INN name):	Oseltamivir
Pharmaco-therapeutic group (ATC Code):	J05AH02
Pharmaceutical form(s) and strength(s):	Capsule, hard; 75 mg, 45 mg, 30 mg
Reference Number(s) for the Decentralised Procedure	DE/H/5970/001–003/DC
Reference Member State:	DE
Concerned Member States:	ES, FR, IT, UK
Legal basis of application:	Generic application Art 10.1 Dir 2001/83/EC
Applicant (name and address)	HEC Pharm GmbH Gabriele-Tergit-Promenade 17 10963 Berlin Germany
Names and addresses of all proposed manufacturer(s) responsible for batch release in the EEA	Formula Pharmazeutische und chemische Entwicklungs GmbH Goerzallee 305 b 14167 Berlin Germany

• I. INTRODUCTION

Based on the review of the data on quality, safety and efficacy, the application for Oseltamivir HEC Pharm 30 / 45 / 75 mg Hartkapseln , indicated for the treatment and prevention of influenza, is approved.

• II. EXECUTIVE SUMMARY

  • II.1 Problem statement

N/A

• II.2 About the product

Influenza is an acute viral infection that spreads easily from person to person and can affect anybody in any age group. Influenza circulates worldwide and causes annual epidemics that peak during winter in temperate regions. Influenza is thus a serious public health problem that causes severe illnesses and deaths for higher risk populations.

There are three types of seasonal influenza – A, B and C. Type A influenza viruses are further typed into subtypes according to different kinds and combinations of virus surface proteins. Among many subtypes of influenza A viruses, currently influenza A(H1N1) and A(H3N2) subtypes are circulating among humans.

Seasonal influenza is characterized by a sudden onset of high fever, cough (usually dry), headache, muscle and joint pain, severe malaise, sore throat and runny nose. The incubation period is about two days.

The most effective way to prevent the disease or severe outcomes from the illness is vaccination. In addition, antiviral drugs for treatment and prevention of influenza are available. There are two classes of such medicines, 1) adamantanes (amantadine and remantadine), and 2) inhibitors of influenza neuraminidase (oseltamivir and zanamivir).

Oseltamivir HEC, a neuraminidase inhibitor, claims to be a generic of the originator product Tamiflu. Claimed indications are as follows:

Treatment of influenza

Oseltamivir HEC 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 HEC 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 HEC 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).

Claimed posology is as follows:

Oseltamivir 75 mg doses can be administered as either

• – one 75 mg capsule or

• – one 30 mg capsule plus one 45 mg capsule

Commercially manufactured oseltamivir powder for oral suspension (6 mg/ml) may be available and is the preferred product for paediatric and adult patients who have difficulties swallowing capsules or where lower doses are needed.

Adults, and adolescents 13 years and over

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

Body Weight	Recommended dose for 5 days
> 40 kg	75 mg twice daily

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

Post-exposure prevention : The recommended dose for prevention of influenza following close contact with an infected individual is 75 mg oseltamivir once daily for 10 days for adolescents (13 to 17 years of age) and adults.

Body Weight	Recommended dose for 10 days
> 40 kg	75 mg once daily

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 6 weeks.

Paediatric population

Children 1 to 12 years of age

Oseltamivir HEC 30 mg, 45 mg and 75 mg capsules are available for infants and children 1 year of age or older.

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

Body Weight	Recommended dose for 5 days
10 kg to 15 kg	30 mg twice daily
> 15 kg to 23 kg	45 mg twice daily
> 23 kg to 40 kg	60 mg twice daily
> 40 kg	75 mg twice daily

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

Post-exposure prevention : The recommended post-exposure prevention dose of oseltamivir is

Body Weight	Recommended dose for 10 days
10 kg to 15 kg	30 mg once daily
> 15 kg to 23 kg	45 mg once daily
> 23 kg to 40 kg	60 mg once daily
> 40 kg	75 mg once daily

Prevention during an influenza epidemic in the community : Prevention during an influenza epidemic has not been studied in children below 12 years of age.

Infants 0 – 12 months of age

Treatment : The recommended treatment dose for infants 0 – 12 months of age is 3 mg/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).

The following dosing regimen is recommended for treatment of infants 0 – 12 months of age:

Body weight*	Recommended dose for 5 days
3 kg	9 mg twice daily
4 kg	12 mg twice daily
5 kg	15 mg twice daily
6 kg	18 mg twice daily
7 kg	21 mg twice daily
8 kg	24 mg twice daily
9 kg	27 mg twice daily
10 kg	30 mg twice daily

* This table is not intended to contain all possible weights for this population. For all patients under the age of 1 year, 3 mg/kg should be used to determine dose regardless of the weight of the patient.

Solid formulations (capsules) are not suitable for use in this patient population. Commercially manufactured oseltamivir for oral suspension (6 mg/ml) may be available and is the preferred product for paediatric and adult patients who have difficulties swallowing capsules or where lower doses are needed. In the event that commercially manufactured oseltamivir powder for oral suspension is not available, the pharmacist may compound a suspension (6 mg/ml) from Oseltamivir HEC capsules or patients can prepare the suspension from capsules at home (see section 6.6 for further instructions).

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

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.

Post-exposure prevention : The recommended prophylaxis dose for infants less than 1 year of age during a pandemic influenza outbreak is half of the daily treatment dose. This is based upon clinical data in infants and children 1 year of age or older and adults showing that a prophylaxis dose equivalent to half the daily treatment dose is clinically efficacious for the prevention of influenza. The following age-adjusted dosing prophylaxis regimen is recommended for infants 0 – 12 months of age (see section 5.2 for exposure simulation):

Age	Recommended dose for 10 days
0 – 12 months	3 mg/kg once daily

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 0–12 months of age.

For instructions on preparing the extemporaneous formulation, see section 6.6.

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)	75 mg twice daily
> 30 to 60 (ml/min)	30 mg twice daily
> 10 to 30 (ml/min)	30 mg once daily
≤ 10 (ml/min)	Not recommended (no data available)
Haemodialysis patients	30 mg after each haemodialysis session
Peritoneal dialysis patients*	30 mg 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)	75 mg once daily
> 30 to 60 (ml/min)	30 mg once daily
> 10 to 30 (ml/min)	30 mg every second day
≤ 10 (ml/min)	Not recommended (no data available)
Haemodialysis patients	30 mg after every second haemodialysis session
Peritoneal dialysis patients*	30 mg 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 75 mg 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

Oral use.

Patients who are unable to swallow capsules may receive commercially manufactured oseltamivir powder for oral suspension (6 mg/ml) or appropriate extemporaneous formulation, see section 6.6 for preparation.

• II.3 General comments on the submitted dossier

This is an application for oseltamivir 30 mg, 45 mg and 75 mg hard capsules referring to Directive 2001/83/EC, Article 10(1), so-called “generic application”. As a reference medicinal product Tamiflu 30 mg, 45 mg, 75 mg hard capsules were used. Tamiflu from Roche Registration GmbH, has been authorised for more than 10 years in the EU under the marketing authorization number EU/1/02/222/001, 003–004. The marketing authorisation of this reference product was granted on 20.06.2002 in the EU.

The reference product used in the bioequivalence study is Tamiflu 75 mg hard capsules, marketing authorization number EU/1/02/222/001.

With DE as the Reference Member State in this Decentralized Procedure, HEC Pharm GmbH is applying for the Marketing Authorisations for oseltamivir 30 mg, 45 mg and 75 mg hard capsules in ES, FR, IT, and UK as CMS.

The active substance is not considered a new active substance.

• II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles

GMP:

The RMS has been assured that acceptable standards of GMP are in place for these product types at all sites responsible for the manufacture and assembly of this product.

For manufacturing sites within the Community, the RMS has accepted copies of current manufacturer authorisations issued by inspection services of the competent authorities as certification that acceptable standards of GMP are in place at those sites.

For manufacturing sites outside the Community, the RMS has accepted copies of current GMP Certificates of satisfactory inspection summary reports, ‘close-out letters’ or ‘exchange of information’ issued by the inspection services of the competent authorities (or those countries with which the EEA has a Mutual Recognition Agreement for their own territories) as certification that acceptable standards of GMP are in place at those non-Community sites.

GMP active substance

Regarding the statement on GMP for the active substance a statement/decla­ration is provided from the manufacturers responsible for manufacture of the finished product and batch release situated in the EU.

GCP:

Statements on GCP compliance as well as a tabular listing of previous inspections of NRAs of the clinical, bioanalytical and statistical sites have been provided. The trial sites have been inspected by MS/EU/EEA inspectors in 2007, 2010, 2012, 2013, 2016, no critical findings. The agreed ethical principles have been followed.

• III. SCIENTIFIC OVERVIEW AND DISCUSSION

  • III.1 Quality aspects

Drug substance

The drug substance is a compendia substance. The CEP is valid according to the CEP database.

Drug substance specification and batch analysis data for the drug substance tested by the drug product manufacturer are provided.

The CEP states a re-test period of 36 months, if stored below 25°C, in double polyethylene bag (outer black) in a triple laminated bag placed in polyethylene container.

Drug product

The products are hard capsules containing 30, 45 and 75 mg Oseltamivir. There are packaged in PVC and PVDC films and push-through blister foils.

A bioequivalence study comparing the 75 mg strength of drug product and the originator product Tamiflu 75 mg was performed (see clinical assessment). Adequate comparative dissolution profiles between the test and reference products used in bioequivalence study are provided.

The strength biowaiver for the 30 and 45 mg formulations was sufficiently justified.

The manufacturing process including in-process controls and critical steps is described in detail. Satisfactorily process validation data for each of the strengths are given.

The proposed release and shelf life specifications contain the quality relevant characteristics required for this pharmaceutical form. The acceptance criteria in the release and shelf life specifications are sufficiently justified.

The descriptions of the test procedures are adequate. Validation data for analytical methods are in accordance with the ICH validation guideline.

Satisfactorily batch analysis data for each of the strengths are provided showing compliance with specifications.

The conditions used in the stability studies are according to the ICH stability guideline. 6 months stability data for accelerated conditions were within specification. Based on 24 months respectively 18 months stability data for long-term conditions the proposed shelf-life of 24 months without storage precaution for the drug product can be accepted.

• III.2 Non-clinical aspects

There are no objections to approval of Oseltamivir HEC Pharm 30 / 45 / 75 mg Hartkapseln from a non-clinical point of view.

Environmental Risk Assessment (ERA)

Since Oseltamivir HEC is intended for generic substitution, this will not lead to an increased exposure to the environment. An environmental risk assessment is therefore not deemed necessary.

• III.3 Clinical aspects

A clinical overview on human pharmacology, efficacy and safety has been provided by the applicant. Human pharmacology, efficacy and safety of oseltamivir are well known. The clinical overview is based on appropriate scientific literature.

Pharmacokinetics

To support this application, the applicant has submitted as report one bioequivalence stu­dy:

An open label, balanced, randomized, two-treatment, two-sequence, two-period, single oral dose, crossover, BE study of test product (Oseltamivir HEC 75 mg hard capsules of Sunshine Lake Pharma Co., Ltd, China) with reference product (Tamiflu® 75 mg Hartkapseln of Roche Registration Limited, UK) in normal, healthy, adult, human subjects under fasting conditions.

The bioequivalence study was conducted with the 75 mg strength, a biowaiver was requested for Oseltamivir HEC 30 mg and Oseltamivir HEC 45 mg. General biowaiver criteria according to the Guideline on the Investigation of Bioequivalence CPMP/EWPQWP/1401/98 Rev. 1/Corr ** are fulfilled. In vitro dissolution tests were conducted with test products (30 mg, 45 mg and 75 mg strength) and the reference product Tamiflu 75 mg capsules.

More than 85% of the drug is dissolved within 15 minutes for all batches at all conditions.

The study design and the statistical analysis are scientifically sou­nd.

A total of 17 blood samples of 7.0 mL each were collected from each subject in each period at pre-dose (0.00 hour) and at 0.25, 0.50, 0.75, 01.00, 01.50, 02.00, 03.00, 04.00, 05.00, 06.00, 08.00, 10.00, 12.00, 24.00, 36.00 and 48.00 hours post-dose following drug administration.

Population(s) studied

A total of sixty, non-smoker, normal, healthy, adult, male human subjects, aged between 18 – 45 years (both inclusive) and within the BMI range of 18.50 to 30.00 kg/m2 weighing at least 45 kg were enrolled in the study. 60 subjects were dosed in Period-I of the trial. 54 subjects completed both periods of the study. 6 subjects were withdrawn due to adverse events. Plasma samples of 60 subjects were analysed. Pharmacokinetic and statistical analyses were performed over 54 subjects. All 60 subjects were considered in the safety analysis.

Analytical methods

Method validation of Oseltamivir in human plasma was carried out by using bioanalytical method developed at Veeda clinical research Pvt. Ltd. This bio-analytical method was validated for the sensitivity, specificity, matrix effect, linearity, ruggedness, accuracy and precision (repeatability and reproducibility), percent recovery and stability of samples (freeze-thaw stability, bench-top stability, auto sampler stability, short-term and long-term stability of stock solution and internal standard).

Pharmacokinetic Variables

The pharmacokinetic parameters included Cmax, AUC0-t, AUC0-∞, Tmax, t½, λz, and AUC_%Extrap_obs. In order to assess the relative bioavailability, 90% confidence intervals of the geometric least square mean ratio of test to reference formulations were calculated for the pharmacokinetic parameters Cmax, AUC0-t and AUC0-∞ for oseltamivir.

Primary pharmacokinetic parameters: Cmax and AUC0-t

Secondary pharmacokinetic parameters: AUC0-¥, Tmax, t½, λz, and AUC_%Extrap_obs

The primary endpoints are defined as AUC0-t and Cmax.

Statistical methods

The pharmacokinetic parameters were calculated from the drug concentration-time profile by noncompartmental model using Phoenix WinNonlin® Version 7.0 (Pharsight Corporation, USA) for oseltamivir. Analysis of variance was carried out by employing PROC GLM of SAS® Version 9.4 (SAS Institute Inc., USA) for ln-transformed pharmacokinetic parameters Cmax, AUC0-t and AUC0-∞ for oseltamivir. ANOVA model included Sequence, Formulation, Period and Subject (Sequence) as fixed effects. The bioequivalence acceptance range of the 90% CI was defined as 80% to 125% for Cmax and AUC0-t.

Statistical tests like ANOVA, least square means for test and reference formulations, difference between test and reference formulations, intrasubject variability and power were calculated for ln-transformed pharmacokinetic parameters Cmax, AUC0-t and AUC0-∞ of Oseltamivir.

Geometric least square means of test and reference formulations, its ratio, 90% confidence interval for geometric least square mean ratio and Two One-Sided Tests for 90% confidence interval limits were calculated for pharmacokinetic parameters Cmax, AUC0-t and AUC0-∞ of Oseltamivir.

Results:

Pharmacokinetic Conclusion

The Test Product (Oseltamivir HEC 75 mg hard capsules) when compared with the Reference Product (Tamiflu® 75 mg hard capsules) meets the predefined bioequivalence criteria in terms of rate and extent of absorption after administration of single dose as set in the protocol.

Pharmacodynamics

No such studies are required for this application.

Clinical efficacy

See assessment of bioequivalence study under “Pharmacokinetics”.

Clinical safety

The two products had similar safety profiles. There are no new safety concerns arising from the study. No significant or serious adverse events or deaths were reported during the study.

Legal Status

The medicinal product is subject to medical prescription.

User Testing

The methodology of the user testing is considered appropriate in terms of conduct, evaluation and data documentation. The conclusions match the results of the testing; they are clear, concise and well organised. The patient information leaflets for Oseltamivir HEC Pharm 30 / 45 / 75 mg Hartkapseln have been user tested and achieved satisfactory results, as at least 90 % of all participants were able to find the information. The user testing is acceptable.

Summary Pharmacovigilance system

The Applicant has submitted a signed Summary of the Applicant's and/or Proposed Future MAH's Pharmaco­vigilance System. Provided that the Pharmacovigilance System Master File fully complies

with the new legal requirements as set out in the Commission Implementing Regulation and as detailed in the GVP module, the RMS considers the Summary acceptable.

Risk Management Plan

The MAA has submitted a risk management plan, in accordance with the requirements of Directive 2001/83/EC as amended, describing the pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to the medicinal product(s) applied for authorisation.

Safety specification

According to the Applicant the safety specification is in full accordance with the current safety specification agreed and published for a similar product/similar products which is acceptable.

Pharmacovigilance Plan

Routine pharmacovigilance is suggested and no additional pharmacovigilance activities are proposed by the applicant, which is endorsed.

Risk minimisation measures

Routine risk minimisation is suggested and no additional risk minimisation activities are proposed by the applicant, which is endorsed.

Summary of the RMP

The submitted Risk Management Plan is considered acceptable.

After approval the MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMP.

An updated RMP should be submitted:

• – At the request of the RMS;

• – Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached.

If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the same time, but via different procedures.

Periodic Safety Update Report (PSUR)

With regard to PSUR submission, the MAH should take the following into account:

• PSURs shall be submitted in accordance with the requirements set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal. Marketing authorisation holders shall continuously check the European medicines web-portal for the DLP and frequency of submission of the next PSUR.
• For medicinal products authorized under the legal basis of Article 10(1) or Article 10a of Directive 2001/83/EC, no routine PSURs need to be submitted, unless otherwise specified in the EURD list.
• In case the active substance will be removed in the future from the EURD list because the MAs have been withdrawn in all but one MS, the MAH shall contact that MS and propose DLP and frequency for further PSUR submissions together with a justification.

• IV. BENEFIT RISK ASSESSMENT