Fixed Dose Combination – a Simplified Approach to Pediatric Antiretroviral

Treatment

Dr. David Pugatch Clinton Foundation

Phnom Penh, Cambodia February, 2007

Lecture Goals

• To introduce and define fixed dose combination medications (FDCs)

• To review the advantages of FDCs for children

• To discuss FDCs currently available for children

Background

• There is an urgent need for affordable, safe, quality ARV formulations appropriate for children

• Ideally these should be solid fixed dose combination (FDC) formulations

• For adult treatment, FDCs have improved program planning, adherence and scale up

• Pediatric FDCs promise the same benefits for children• The first pediatric FDC formulations are available for

use in children• Clinical trials of FDCs in children are underway

Too many different pills!

Syrup Formulations are Problematic

Syrups• First available pediatric

formulations• Allow for precise dosing• Difficult for pharmacists to

dispense• Difficult and messy for

caregivers to administer• Difficult for children to

swallow- bitter taste• Poor adherence

FDCs – Introduction

• FDCs = Fixed Dose Combination pills• Adults FDCs widely used and facilitated rapid

scale-up in many countries• Use of adult FDCs in children can result in

inaccurate dosing of some drug components (e.g. Nevirapine)

• FDCs made specifically for HIV infected children is high priority

Compare an Adult FDC to an Adult Single Dose Formulation

Fixed Dose Combination: (NVP 200 mg, 3TC 150 mg, D4T 30 mg)

Single dose formulations of:NVP 200 mg3TC 150 mgD4T 30 mg

# of different tablets

1 3

Dosing frequency

2X per day 2X per day

Total # of tablets per day

2 6

Why FDCs, and Which FDCs?

• FDCs were critical to scale up of adult ART because they greatly simplify dosing

• FDCs are easier to procure, easier to ship, easier to store

• FDCs are easier to prescribe, easier to give and easier to take!

• There are TWO types of adult first line FDCs which contain NVP – D4T based and AZT based

Pediatric FDCs

• Currently, four manufacturers of Pediatric FDCs

• Contain D4T, 3TC, NVP

• Tablets are:– Scored– Dispersible– Easily broken, crushed or dissolved in water– Good for children who cannot swallow tablets

FDC Formulations

Stavudine(mg)

Lamivudine(mg)

Nevirapine(mg)

DualFDC Available

CIPLA Triomune Baby FDC 6 6 30 50 Yes

Triomune Junior FDC 12 12 60 100 Yes

Ranbaxy Triviro Kids FDC 5 5 20 35 Soon

Triviro Kids DS FDC 10 10 40 70 Soon

Emcure FDC 10 10 40 70 Yes

GPO FDC 7 7 30 50 No

Simplified ART with Pediatric FDCs

Adult Junior Baby

• All tablets are dispersible in water and breakable if needed

• Higher proportion of NVP than adult formulation, so better suited for children who metabolize NVP faster than adults

• Simplified dosing by weight band

CIPLA

D4T 30/40 mg 12 mg 6 mg

3TC 150 mg 60 mg 30 mg

NVP 200 mg 100 mg 50 mg

Ratio 1:5:6.6 1:5:8.3

RANBAXY

Pediatric FDCs

• CIPLA and Ranbaxy use different ratios of NVP than the adult FDCs in their respective formulations

• Both pediatric products have a greater proportion of NVP than the adult FDCs

• Pediatric FDCs are better suited for the dosing children since the metabolism of NVP is faster in children than adults.

Advantages of Pediatric FDCs

• More Accurate Dosing

• Easier for caregivers to provide

• Increased Adherence

• Simplified supply chain

• Cost Effective

Dosing of FDCs

• FDCs contain fixed amounts of each of the ARV components

• Dosed by weight band

• WHO criteria for dosing– www.who.int/hiv/events/paediatricmeetingreport.pdf

Suggested WHO dosing of FDCs that contain NVP, D4T and 3TC

Weight range (kg) Formulation DOSE (tablets)

AM PM 3 3.9 50/6/30 mg tablets 1 1 4 4.9 50/6/30 mg tablets 1 1 5 5.9 50/6/30 mg tablets 1 1 6 6.9 50/6/30 mg tablets 1.5 1.5 7 7.9 50/6/30 mg tablets 1.5 1.5 8 8.9 50/6/30 mg tablets 1.5 1.5 9 9.9 50/6/30 mg tablets 1.5 1.5 10 10.9 50/6/30 mg tablets 2 2 11 11.9 50/6/30 mg tablets 2 2 12 13.9 50/6/30 mg tablets 2 2 14 16.9 100/12/60 mg tablets 1.5 1 17 19.9 100/12/60 mg tablets 1.5 1 20 24.9 100/12/60 mg tablets 1.5 1.5 25 29.9 200/30/150 mg tablets 1 1 30 34.9 200/30/150 mg tablets 1 1

Weight range (kg) Formulation DOSE (tablets)

AM PM 3 3.9 35/5/20 mg tablets not recommended 4 4.9 35/5/20 mg tablets not recommended 5 5.9 35/5/20 mg tablets not recommended 6 6.9 35/5/20 mg tablets not recommended 7 7.9 35/5/20 mg tablets 2 2 8 8.9 35/5/20 mg tablets 2 2 9 9.9 35/5/20 mg tablets 2 2 10 10.9 35/5/20 mg tablets 2.5 2.5 11 11.9 35/5/20 mg tablets 2.5 2.5 12 13.9 35/5/20 mg tablets 3 3 14 16.9 70/10/40 mg tablets 2 2 17 19.9 70/10/40 mg tablets 2 2 20 24.9 70/10/40 mg tablets 2.5 2.5 25 29.9 200/30/150 mg tablets 1 1 30 34.9 200/30/150 mg tablets 1 1

Cipla drugs Ranbaxy drugs

Use of Dual FDCs When Initiating NVP – based HAART

• Initiation of any NVP-based ART regimen requires a “lead-in period” of 2 weeks when the NVP is dosed once per day

• Dual FDCs containing, for example, D4T and 3TC are available for pediatrics

• Can use dual FDC during the “lead-in” period:– Morning dose: NVP, 3TC, D4T as FDC– Evening dose: 3TC, D4T as FDC

Experience with FDCs from other countries

• India has been using the CIPLA pediatric FDC for several months as part of its national scale up program – rapid scale up to >2500 children on ART

• FDCs have been registered and introduced in Cameroon, Burkina Faso, Mozambique, DRC

• FDCs made by both CIPLA and Ranbaxy have been submitted to WHO, and satisfy Global Fund quality assurance criteria, based on equivalence of the “API” and the fact that they are being made in “GMP-compliant” facilities

• Under UNITAID, Cambodia will be able to procure the four triple FDCs produced by Ranbaxy and CIPLA

D4T therapy in adults

• There is increasing evidence suggesting that D4T based regimens in adults cause significant toxicity by affecting mitochondrial function.

• Although all NRTIs cause mitochondrial toxicity, D4T > DDI > AZT > ABC

• Long-term toxicities of D4T: lipoatrophy, lactic acidosis, peripheral neuropathy

• As a result, WHO adult guidelines for first line therapy have changed

• Preference for AZT over D4T in the first-line regimen

D4T therapy in children

There is less data available for d4T in children

• Child programs are less mature, so toxicity not yet been reported as widely

• Children tolerate ART better than adults in general• D4T suspension needs cold storage, so ZDV suspension

used more widely• But on the other hand, many programs use divided Adult

D4T based FDCs for children• And anemia is much more common in children than adults,

so ZDV toxicity is worse in children

Use of D4T in Children – MSF Data

•MSF recently published data on a large cohort using adult D4T based FDCs with excellent outcomes and minimal side effects [AIDS 2006:20:1955-60]

• 1184 children• At baseline, 85% had CD4 < 15%. By 12 m only 11% had

CD4 < 15% • 46 children had side effects, but only 26 children had to

switch• Most of the side effects were related to NVP, not d4T

What does WHO propose for Ped ART

Both D4T and AZT are considered appropriate first line therapy

How should this be interpreted

WHO expert working group on new formulations has made recent recommendations

Urgent production of several NEW pediatric FDCs including AZT based and ABC based triple combination is needed

However, these will take a minimum of 18m to 24m to produce, test and approve, even if manufacturers start immediately

WHO recommends using currently available FDCs for rapid scale up - with the possibility of switching to ZDV based or ABC based FDCs once these are available

Summary

• Pediatric FDCs offer important and unique advantages over syrups and single dose formulations

• The first pediatric D4T-based triple combination FDCs are available

• Production of new pediatric FDCs including AZT and ABC- based triple formulations are urgently needed

• National treatment programs should incorporate the use of Pediatric FDCs into their ARV guidelines for children

Acknowledgements

•Dr. Shaffiq Essajee – Clinton Foundation•Dr. Kenneth Mayer – Brown University

Thank you