1. 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: pogany@axelero.hupogany@axelero.hu Development pharmaceutics – formulations for paediatric ARVs

2. FIFTH INVITATION FOR EXPRESSION OF INTEREST (EOI) HIV and related diseases Rev. 27/10/04

3. 2004.11.02 Dr. Pogány - WHO, Geneva 3/34 NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS Abacavir Didanosine Lamivudine Stavudine Tenofovir Zidovudine

4. 2004.11.02 Dr. Pogány - WHO, Geneva 4/34 NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS Efavirenz Nevirapine

5. 2004.11.02 Dr. Pogány - WHO, Geneva 5/34 PROTEASE INHIBITORS Indinavir Lopinavir + Ritonavir Nelfinavir Saquinavir Ritonavir

6. 2004.11.02 Dr. Pogány - WHO, Geneva 6/34 FIXED DOSE COMBINATIONS Lamivudine + Stavudine Lamivudine + Stavudine + Efavirenz Lamivudine + Stavudine + Nevirapine Lamivudine + Zidovudine Lamivudine + Zidovudine + Efavirenz Lamivudine + Zidovudine + Nevirapine

7. 2004.11.02 Dr. Pogány - WHO, Geneva 7/34 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)

8. POTENTIAL PAEDIATRIC APPLICATIONS Innovator Antiretroviral Finished Pharmaceutical Products

9. 2004.11.02 Dr. Pogány - WHO, Geneva 9/34 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

10. 2004.11.02 Dr. Pogány - WHO, Geneva 10/34 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.

11. 2004.11.02 Dr. Pogány - WHO, Geneva 11/34 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.

12. 2004.11.02 Dr. Pogány - WHO, Geneva 12/34 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

13. 2004.11.02 Dr. Pogány - WHO, Geneva 13/34 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

14. 2004.11.02 Dr. Pogány - WHO, Geneva 14/34 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)

15. 2004.11.02 Dr. Pogány - WHO, Geneva 15/34 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.

16. 2004.11.02 Dr. Pogány - WHO, Geneva 16/34 VIRAMUNE 50 mg/5 ml oral suspension 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.

17. 2004.11.02 Dr. Pogány - WHO, Geneva 17/34 VIRAMUNE 50 mg/5 ml oral suspension 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).

18. 2004.11.02 Dr. Pogány - WHO, Geneva 18/34 VIRAMUNE 50 mg/5 ml oral suspension 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.

19. 2004.11.02 Dr. Pogány - WHO, Geneva 19/34 Zerit ® 200 mg powder for oral solution The reconstituted solution contains 1 mg of stavudine per ml. Cherry flavour Methylparaben Propylparaben Silicon dioxide SimethiconeSodium 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.

20. 2004.11.02 Dr. Pogány - WHO, Geneva 20/34 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.

21. 2004.11.02 Dr. Pogány - WHO, Geneva 21/34 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.

22. 2004.11.02 Dr. Pogány - WHO, Geneva 22/34 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.

23. 2004.11.02 Dr. Pogány - WHO, Geneva 23/34 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

24. 2004.11.02 Dr. Pogány - WHO, Geneva 24/34 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

25. POTENTIAL PAEDIATRIC APPLICATIONS Generic Antiretroviral Finished Pharmaceutical Products

26. 2004.11.02 Dr. Pogány - WHO, Geneva 26/34 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)

27. 2004.11.02 Dr. Pogány - WHO, Geneva 27/34 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.

28. 2004.11.02 Dr. Pogány - WHO, Geneva 28/34 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.

29. 2004.11.02 Dr. Pogány - WHO, Geneva 29/34 HYPOTHETICAL DISSOLUTION PROFILE OF A 2-FDC FPP

30. EXISTING FDC-FPPs Bracketing and Matrixing Multiple strengths of identical or closely related formulations

31. 2004.11.02 Dr. Pogány - WHO, Geneva 31/34 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).

32. 2004.11.02 Dr. Pogány - WHO, Geneva 32/34 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).

33. 2004.11.02 Dr. Pogány - WHO, Geneva 33/34 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.

34. 2004.11.02 Dr. Pogány - WHO, Geneva 34/34 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.