2004.11.02 Dr. Pogány - WHO, Geneva 1/34 IMPROVING ACCESS TO APPROPRIATE PAEDIATRIC ART...

2004.11.02 Dr. Pogány - WHO, Geneva 1/34

IMPROVING ACCESS TO APPROPRIATE PAEDIATRIC ART FORMULATIONS

János Pogány, pharmacist, Ph.D.,

UNICEF/MSF/WHO, Geneva, 02 November 2004

E-mail: [email protected]

Development pharmaceutics– formulations for paediatric ARVs

FIFTH INVITATION FOR EXPRESSION OF INTEREST

(EOI)

HIV and related diseases

Rev. 27/10/04


NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS

Abacavir Didanosine Lamivudine Stavudine Tenofovir Zidovudine


NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS

Efavirenz Nevirapine


PROTEASE INHIBITORS

Indinavir Lopinavir + Ritonavir Nelfinavir Saquinavir Ritonavir


FIXED DOSE COMBINATIONS

Lamivudine + Stavudine Lamivudine + Stavudine + Efavirenz Lamivudine + Stavudine + Nevirapine Lamivudine + Zidovudine Lamivudine + Zidovudine + Efavirenz Lamivudine + Zidovudine + Nevirapine


BASIC REQUIREMENTS

SAFETY (no innovator for FDC-FPPs)

EFFICACY (no innovator for FDC-FPPs)

QUALITY (once safe and effective doses are

established, FDC-FPPs can be developed and bioequivalence demonstrated)

POTENTIAL PAEDIATRIC APPLICATIONS

Innovator Antiretroviral Finished Pharmaceutical

Products


Videx EC 125mg, 200mg, 250mg and 400mg Gastro-resistant Capsules Each gastro-resistant capsule, hard contains 125 mg, 200 mg, 250 mg

or 400 mg of didanosine. Sodium carmellose, diethyl phthalate, 30% methacrylic acid copolymer

dispersion (EUDRAGIT L30D-55), sodium starch glycolate and talc. Capsule shell - gelatin, sodium laurilsulfate, colloidal anhydrous silica

and titanium dioxide (E171). Capsule shell imprints (edible ink) shellac, ammonium hydroxide,

propylene glycol, simethicone and red iron oxide 2 years Do not store above 25°C. Polyvinyl Chloride/Polyethylene/ACLAR/Aluminium foil blisters


Videx EC 125mg, 200mg, 250mg and 400mg Gastro-resistant Capsules

Children: Safety data for children were generally similar to those seen in adults. A higher haematotoxicity has been reported with the combination with zidovudine compared to didanosine monotherapy. Retinal or optic nerve changes have been reported in a small number of children usually at doses above those recommended. It is recommended that children on didanosine treatment undergo dilated retinal examination every 6 months or if a change in vision occurs.

There are no specific pharmacokinetic data from children treated with Videx gastro-resistant capsules.


SUSTIVA 30 mg/ml oral solution Each millilitre contains 30 mg efavirenz Medium chain triglycerides, benzoic acid (E210) and

strawberry/mint flavour. 3 years. The oral solution should be used within one month of first

opening the bottle. No special precautions for storage. HDPE bottles with a child-resistant polypropylene closure

containing 180 ml of oral solution. An oral syringe with a push-in bottle-neck adapter is included in the carton.


Epivir 10 mg/ml oral solution Oral solution containing 10 mg/ml of lamivudine Sucrose 20 %(3 g/15 ml) Methyl parahydroxybenzoate Propyl parahydroxybenzoate Citric acid Anhydrous Propylene glycol Sodium citrate Artificial strawberry flavour Artificial banana flavour Purified water


Epivir 10 mg/ml oral solution 2 years Discard the oral solution one month after first opening. Do not store above 25°C. 240 ml oral solution in a white high density polyethylene

(HDPE) bottle, with a child resistant closure. A 10 ml polypropylene oral dosing syringe and a polyethylene adapter are also included in the pack.

Zeffix oral solution contains 5 mg/ml lamivudine


Epivir 10 mg/ml oral solution Children Three months to 12 years of age: the recommended dose

is 4 mg/kg twice daily up to a maximum of 300 mg daily. Less than three months of age the limited data available

are insufficient to propose specific dosage recommendations (see section 5.2)


VIRAMUNE 50 mg/5 ml oral suspension

Oral suspension containing 10 mg/ml of nevirapine (active substance) as 10.35 mg/ml nevirapine hemihydrate.

VIRAMUNE 50 mg/5 ml oral suspension is a white to off-white homogenous suspension.

Carbomer, methyl parahydroxybenzoate, propyl parahydroxybenzoate, sorbitol, sucrose, polysorbate 80, sodium hydroxide and purified water.

2 years. The product should be used within 2 months of opening. No special precautions for storage.



White high density polyethylene (HDPE) bottle with two piece child-resistant closure (outer shell white high density polyethylene, inner shell natural polypropylene) with a low density polyethylene (LDPE) foam liner. Each bottle contains 240 ml of oral suspension.

Clear polypropylene 5 ml dispensing syringe with silicone rubber piston seal.

Clear low density polyethylene bottle-syringe adapter.



Infants under the age of 3 months: safety data is available from clinical trials up to 6 weeks of treatment in 179 newborns and infants < 3 months of age (see section 4.6).



Patients aged 2 months up to 8 years The recommended dose for patients 2 months up to 8

years is 4 mg/kg once daily for two weeks followed by 7 mg/kg twice daily thereafter. The total daily dose should not exceed 400 mg for any patient.

Patients aged 8 years up to 16 years The recommended dose for patients 8 years up to 16 years

is 4 mg/kg once daily for two weeks followed by 4 mg/kg twice daily thereafter. The total daily dose should not exceed 400 mg for any patient.


Zerit® 200 mg powder for oral solution The reconstituted solution contains 1 mg of stavudine per ml. Cherry flavour Methylparaben Propylparaben Silicon dioxide Simethicone Sodium

carmellose Sorbic acid Stearate emulsifiers Sucrose 2 years. After reconstitution with water, store the solution in tightly

closed bottles at 2°C to 8°C. HDPE bottle with child resistant screw cap, fill mark (200 ml

of solution after constitution) and measuring cup.


Retrovir® 100 mg/10 ml, oral solution 10 ml of solution contains: Zidovudine 100 mg Retrovir 100mg/10ml oral solution/syrup: A clear, pale yellow, strawberry-flavoured, sugar-free oral solution. The pack contains an oral-dosing syringe which should be fitted to the bottle

before use. Maltitol solution Glycerol Citric Acid E211 Sodium Benzoate Saccharin Sodium Flavour Strawberry Flavour White Sugar Purified Water 2 years. Discard oral solution 1 month after first opening bottle. Do not store above 30°C. Store the bottle in the original outer carton.


Retrovir® 100 mg/10 ml, oral solution Retrovir Oral Solution/Syrup: 200ml amber glass bottle with a plastic cap and polyethylene

wad. A 10ml oral-dosing syringe is included in the pack, with an adaptor, which should be fitted to the bottle before use.

Retrovir Oral Solution/Syrup (Neonate Pack): 200ml amber glass bottle with a plastic cap and polyethylene

wad. A 1 ml oral-dosing syringe is included in the pack, with an adaptor, which should be fitted to the bottle before use.


Combivir film-coated tablets Each film-coated tablet contains 150 mg lamivudine and 300 mg

zidovudine. Tablet core: Microcrystalline cellulose (E460), sodium starch

glycollate, colloidal silicon dioxide, magnesium stearate Tablet film coat: Hypromellose (E464), titanium dioxide (E171),

macrogol 400, polysorbate 80 2 years Do not store above 30°C Tamper-evident cartons containing opaque polyvinyl

chloride/foil blister packs or white high density polyethylene (HDPE) bottle with a child-resistant closure. Each pack type contains 60 film-coated tablets.


TRIZIVIR film-coated tablets TRIZIVIR (300mg of abacavir as abacavir sulfate, 150mg

lamivudine and 300mg zidovudine) film-coated tablets. Core: microcrystalline cellulose, sodium starch glycollate

(type A), magnesium stearate. Coating: Opadry Green 03B11434 containing:

hypromellose, titanium dioxide, polyethylene glycol, indigo carmine aluminium lake, iron oxide yellow.

2 years Do not store above 30°C opaque PVC/Aclar blister packs HDPE bottles


INNOVATOR PAEDIATRIC FPPs

Efavirenz 30mg/ml oral solution

Lamivudine 10mg/ml oral solution

Nevirapine 50mg/5ml oral suspension

Stavudine 200mg powder for oral solution

Zidovudine 100mg/10ml, oral solution

POTENTIAL PAEDIATRIC APPLICATIONS

Generic Antiretroviral Finished Pharmaceutical

Products


Potential paediatric dosage forms for FDC-FPPs

Powder for oral suspension (priority from pharmaceutical development and stability points of view)

Film-coated tablets (priority from economic, pharmaceutical development and stability points of view)

Powder for oral solution Chocolate pastilles (expensive and

storage/bioavailability may be a problem in tropical climates and hot seasons)


ILLUSTRATIVE R+D ISSUES Key physicochemical characteristics (e.g., water

content, solubility, particle size, etc.) of the APIs that can influence the performance of the FPP should be optimized and supported by experimental data.

The compatibility of APIs with each other should be studied and the results documented.

The compatibility of the APIs with excipients should be documented.


ILLUSTRATIVE R+D ISSUES

A discriminating dissolution method should be developed for the final composition of the FPP. Limits should be set for each API in fixed-dose FPPs. The dissolution method should be incorporated into the stability and quality control programmes. Multipoint dissolution profiles of both the test and the reference FPPs should be compared.


HYPOTHETICAL DISSOLUTION PROFILE OF A 2-FDC FPP

020406080

100120

0 15 30 45 60

minutes

% d

isso

lved Series1

Series2

Series3

Series4

EXISTING FDC-FPPsBracketing and Matrixing

Multiple strengths of identical

or closely related formulations


BRACKETING

Examples include but are not limited to 1. tablets of different strengths manufactured by

compressing varying amounts of the same granulation, and

2. oral solutions/suspensions of different strengths with formulations that differ only in minor excipients (e.g., colourants, flavourings).


MATRIXING

Examples include but are not limited to 1. tablets of different strengths manufactured

by compressing varying amounts of the same granulation, and

2. oral solutions/suspensions of different strengths with formulations that differ only in minor excipients (e.g., colourants or flavourings).


SmPC and PIL

The results from pharmacokinetic investigations must be described briefly in the SmPC of the FPP.

The SmPC and package insert should be specific with regard to the HIVinfections which can be reasonably treated with the FPP.


CONCLUSIONS Safe and effective paediatric doses for FDC-FPPs,

SmPCs and PILs should come from (literature survey of) clinical studies.

Film-coated tablets and oral solutions or suspensions can be developed in about 18 months, if pre-formulation is started soon.

Development can be accelerated if paediatric FDC-FPPs have the same ratio of APIs and compositions are essentially similar to those already registered in the ICH region or prequalified by WHO.

2004.11.02 Dr. Pogány - WHO, Geneva 1/34 IMPROVING ACCESS TO APPROPRIATE PAEDIATRIC ART...

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