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 mg 3TC 150 mg D4T 30 mg # of different tablets Dosing frequency Total # of tablets per day 1 3 2X per day 2X 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 Lamivudine Nevirapine Dual (mg) (mg) (mg) FDC 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 CIPLA RANBAXY Adult Junior Baby 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 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
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 ABCbased 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