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Home , Abacavir, Lamivudine

WHO MODEL LIST OF ESSENTIAL MEDICINES APPLICATION

Information to be included with an application for inclusion, change or deletion of a medicine in the WHO Model List of Essential Medicines: 1. Name of the focal point in WHO submitting or supporting the application: ...... 3 2. Name of the organization(s) consulted and/or supporting the application: ...... 3 3. International Nonproprietary Name (INN, generic name) of the medicine: ...... 3 4. Dosage form or strength proposed for inclusion: ...... 3 5. International availability - sources, if possible manufacturers:...... 3 6. Whether listing is requested as an individual medicine or as an example of a therapeutic group:...... 3 7. Information supporting the public health relevance ...... 3 7.1. Epidemiological information on disease burden: ...... 3 7.2. Assessment of current use: ...... 4 7.3. Target population:...... 5 8. Treatment details ...... 5 8.1. Reference to existing WHO and other clinical guidelines: ...... 5 8.2. Dosage regimen, duration: ...... 5 9. Summary of comparative effectiveness in a variety of clinical settings: ...... 6 9.1. Fixed-dose Combinations ...... 7 9.2. Dispersibility ...... 7 9.3. Scored tablets ...... 7 10. Summary of comparative evidence on safety: ...... 7 10.1. Estimate of total patient exposure to date ...... 7 10.2. Description of adverse effects/reactions ...... 8 10.3. Identification of variation in safety due to health systems and patient factors ...... 9 10.4. Special Populations ...... 9 10.5. Drug Interactions ...... 10 11. Summary of available data on comparative cost1 and cost-effectiveness within the pharmacological class or therapeutic group: ...... 11 11.1. Range of costs of the proposed medicine...... 11 11.2. Comparative cost-effectiveness presented as range of cost per routine outcome ...... 11 12. Summary of regulatory status of the medicine ...... 11 13. Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia, United States Pharmacopoeia) ...... 11 14. Proposed (new/adapted) text for the WHO Model Formulary ...... 11

1 WHO MODEL LIST OF ESSENTIAL MEDICINES APPLICATION

Summary statement of the proposal for inclusion, change or deletion: This document proposes the inclusion of the dispersible, scored tablet formulation of (as sulfate)/ (ABC/3TC) 120mg/60mg for treatment of HIV-1 infection among children living with HIV/AIDS in the WHO Essential Medicines List for Children (EMLc). Both the adult formulation of ABC/3TC 600mg/300mg and a lower strength pediatric formulation ABC/3TC 60mg/30mg are already listed in the EML. The principal reasons for requesting this inclusion are as follows:  Children living with HIV infection in resource-limited settings presently have limited treatment options for their infection.  Since 2013 WHO Guidelines have recommended Abacavir/Lamivudine (ABC/3TC) as the preferred NRTI backbone in first-line ART in children ages 3-10years and as one of two preferred NRTI backbones for first line in infants and children ages 0-3 years.  The WHO’s Interagency Task Team on Prevention and Treatment (IATT) Pediatric Working Group includes the dispersible, scored formulation of ABC+3TC 120mg/60mg as “Optimal” for pediatric treatment of HIV on its Optimized Pediatric ARV list.  In comparison to syrups, dispersible solid formulations offer many advantages:  More convenient for active pharmaceutical ingredients with insufficient stability in water;  More easily transportable and they generate less handling and transportation costs for the same amount of active ingredient (less volume, less weight);  Easier to produce and the production costs are less, which makes them more affordable than standard liquid formulations;  Can still be used in very young children (0 – 6 months) and can be dispersed in breast milk;  Are easy to dispense and they require minimal manipulation by health professionals and parents prior to use which minimizes the risk of errors; and  Dispersible with only a small amount of water for administration.  Antiretroviral therapy generally requires the use of three or more drugs. This often requires taking a large number of tablets/capsules each day. Fixed-dose combinations (FDCs) of ARV drugs may:  Allow for once- or twice-daily dosing using one or two pills, reducing the pill-burden;  Increase patient adherence to treatment;  Delay the development of resistance;  Lower the total cost, including production, storage, transport, dispensing and other health system costs; and  Reduce the risk of errors by prescribers, dispensers or patients themselves.

2 WHO MODEL LIST OF ESSENTIAL MEDICINES APPLICATION

1. Name of the focal point in WHO submitting or supporting the application: Martina Penazzato, MD, DTMH, MSC, PHD, Paediatric Focal Point for the HIV Department of WHO 2. Name of the organization(s) consulted and/or supporting the application: Clinton Health Access Initiative, Inc. (CHAI) 3. International Nonproprietary Name (INN, generic name) of the medicine: Abacavir (as sulfate)/Lamivudine, ATC code : J05AR02 4. Dosage form or strength proposed for inclusion: Each dispersible, scored tablet contains abacavir (as sulfate) 120mg and lamivudine 60mg (WHO supported). 5. International availability - sources, if possible manufacturers: Abacavir (as sulfate)/Lamivudine 120mg/60mg dispersible, scored tablets are manufactured at: Mylan Laboratories Limited (formerly Matrix Laboratories Limited) H-12 & H-13, MIDC, Waluj, Aurangabad, 431136, Maharashtra India 6. Whether listing is requested as an individual medicine or as an example of a therapeutic group: Since ABC and 3TC are nucleoside inhibitor, in this case as a combined product, inclusion within ‘FIXED-DOSE COMBINATIONS’ (6.4.2) is requested. 7. Information supporting the public health relevance 7.1. Epidemiological information on disease burden: Despite an impressive reduction in mother to child transmission of HIV in recent years, 150,000 new pediatric infections occurred in 2015. There are now 1.8 million children living with HIV, the vast majority in sub-Saharan Africa. Evidence shows that in the absence of antiretroviral treatment (ART), over 50% of HIV-infected infant’s progress to AIDS and death by the age of 2 years1, but the introduction of pediatric ART has changed HIV infection in children from a life-threatening illness to a chronic but manageable infection. Despite recognition of the advantages of early treatment, pediatric treatment coverage still only reaches 49% of children eligible for treatment and in 2015 an estimated 110,000 HIV/AIDS related deaths occurred in children <15 years of age2. However, with increasing evidence about the beneficial effects of earlier ART initiation and the release of the 2016 WHO Consolidated Guidelines, new recommendations stress the need for early testing and treatment for all infants and children living with HIV. The global community, led by UNAIDS, now has a target to end the AIDS epidemic by 2030 but the particular vulnerabilities of pediatric patients necessitate the even more ambitious goal of ending

3 WHO MODEL LIST OF ESSENTIAL MEDICINES APPLICATION pediatric AIDS by 20203. These super fast-track targets aim to reach 1.6 million children with ART by 2018. In order to successfully scale-up treatment of pediatric HIV infection, it is critical that ARV dosage forms appropriate for use in infant and young children are accessible, particularly in resource limiting settings. The availability of dispersible solid dosage forms has proven to be an advantage over liquid dosage forms in that they are more easily stored, ease administration, and support adherence in infants and young children. The WHO now recommends that for pediatric treatment, liquid dosage forms should be avoided when possible in favor of dispersible, fixed-dose combination tablets. Recent years has seen the development of a variety of dosage forms for pediatric ARVs but, compared to the demand for adult ARVs, children account for just 5% of patients on ART, thereby rendering the global pediatric market smaller and more vulnerable to supply disruption. The IATT Optimal Pediatric ARV Formulary and Limited-use list was first developed in 2011 to address this challenge and now provides guidance to streamline the selection of pediatric ARV dosage forms to those that conform to a list of criteria, including dosing flexibility, user-friendliness, optimization of supply chain management, and availability of quality assured products in resource limited settings.4 The IATT Optimal Formulary is also revised on a regular basis to reflect current WHO recommended regimens. 7.2. Assessment of current use: According to the WHO TUAPR in 2010, in combination with NNRTIs or PIs nearly 51,000 children (~13.7%) were treated with ABC+3TC in first-line treatment across 45 low- and middle-income countries (excludes the Region of the Americas). As noted above, pediatric treatment rates have increased substantially since 2010, with worldwide treatment of over 870,000 HIV-infected children by the end of 2015, marking a 49 percent coverage rate. By 2015, ABC (combined with 3TC) comprised 46% of the pediatric market of LMICs with access to generic ARVs according to a CHAI market analysis, with some countries prescribing it to over 60% of their pediatric patients. The proportion of pediatric patients receiving ABC/3TC is expected to continue to increase over the next several years as noted in the graph below. 5 Graph: Pediatric NRTI Market in LMICs with Access to Generic ARVs5

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7.3. Target population: ABC/3TC is one of two NRTI backbone regimens preferred in pediatric patients. In 2015, WHO recommended ART should be initiated in all children living with HIV, regardless of WHO clinical stage or at any CD4 cell count. The Guidelines note that as a priority, ART should be initiated in all children ≤2 years of age or children younger than 5 years of age with WHO clinical stage 3 or 4 or CD4 count ≤750 cells/mm³ or CD4 percentage <25%, and children 5 years of age and older with WHO HIV clinical stage 3 or 4 disease or CD4 count ≤350 cells/mm³. 8. Treatment details 8.1. Reference to existing WHO and other clinical guidelines: As of 2015, WHO guidelines recommend ART should be initiated in all children living with HIV, regardless of WHO clinical stage or at any CD4 cell count. The WHO 2016 Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection make the following recommendations for first-line regimens6: Infants (<3 years of age): 1. For infants and children younger than 3 years, the NRTI backbone for an ART regimen should be ABC or AZT + 3TC (strong recommendation, moderate-quality evidence). 2. An LPV/r-based regimen should be used as first-line ART for all children infected with HIV younger than 3 years (36 months) of age, regardless of NNRTI exposure. If LPV/r is not feasible, treatment should be initiated with an NVP-based regimen (strong recommendation, moderate- quality evidence). 3. Where viral load monitoring is available, consideration can be given to substituting LPV/r with EFV at 3 years of age after viral suppression is sustained (conditional recommendation, moderate-quality evidence). 4. For infants and children infected with HIV younger than 3 years, ABC + 3TC + AZT is recommended as an option for children who develop TB while on an ART regimen containing NVP or LPV/r. Once TB therapy has been completed, this regimen should be stopped and the initial regimen should be restarted (strong recommendation, moderate-quality evidence). Children (3-10 years of age): 1. For children 3 to less than 10 years of age, the NRTI backbone should be one of the following, in preferential order (conditional recommendation, moderate quality evidence): • ABC + 3TC • AZT or TDF + 3TC (or FTC). 2. For children 3 years and older, EFV is the preferred NNRTI for first-line treatment and NVP is the preferred alternative (strong recommendation, low-quality evidence). 8.2. Dosage regimen, duration: Dosing ABC/3TC 120mg/60mg tablets: Depending on the regimen with which it is being administered, ABC/3TC may be given either once or twice daily as shown in the two tables below.

5 WHO MODEL LIST OF ESSENTIAL MEDICINES APPLICATION

Number of ABC/3TC 120mg/60mg dispersible tablets by weight band to be taken twice daily (approximately 12 hours apart).

Weight range (kg) Dose (tablets) Bottom Top am pm 3.0 5.9 0.5 0.5 6.0 9.9 0.5 1 10.0 13.9 1 1 14.0 19.9 1 1.5 20.0 24.9 1.5 1.5

Number of ABC/3TC 120mg/60mg dispersible tablets by weight band to be taken once daily:

Weight range (kg) Dose (tablets) Bottom Top daily 3.0 5.9 1 6.0 9.9 1.5 10.0 13.9 2 14.0 19.9 2.5 20.0 24.9 3

For children who cannot swallow the tablets whole: 1. Take 2 teaspoons (10 ml) of water in a small and clean container and add the required dose. 2. Swirl the container until tablet disperses, and administer the entire mixture immediately. Rinse the container with an additional 10 ml of water and get the child drink this water. Children weighing 25 kg or more, adolescents and adults: For these patient groups, other formulations with higher amounts of the active substances are available. Abacavir (as sulfate)/Lamivudine 120mg/60mg Tablets can be taken with or without food. Duration of use: Treatment of HIV infection is expected to be lifelong. Need for special diagnostic or treatment facilities and skills: Not needed. 9. Summary of comparative effectiveness in a variety of clinical settings: In compiling the evidence of effectiveness, it is recognized that ABC and 3TC have both been individually included in the WHO EML since 2002 and at that time evidence had been satisfactorily summarized and submitted for review. This ABC/3TC 120mg/60mg dispersible, scored tablet represents a dosage form for children who are not able to swallow intact tablets and also provides improved dosing flexibility and further decreases pill burden for children.

6 WHO MODEL LIST OF ESSENTIAL MEDICINES APPLICATION

9.1. Fixed-dose Combinations Antiretroviral therapy generally requires the use of three or more drugs. This often requires taking a large number of tablets/capsules each day. Fixed-dose combinations (FDCs) of ARV drugs may:  Allow for once- or twice-daily dosing using one or two pills, reducing the pill-burden;  Increase patient adherence to treatment;  Delay the development of resistance;  Lower the total cost, including production, storage, transport, dispensing and other health system costs; and  Reduce the risk of medication errors by prescribers, dispensers or patients themselves Co-formulation of abacavir and lamivudine into an FDC has similar virologic and immunologic efficacy to the products dosed separately. Simplification of cART regimens from twice-daily NRTIs to once- daily FDC has also proven to be effective at maintaining virologic suppression and immunologic recovery. In one of these studies, a larger proportion of subjects in the once-daily ABC/3TC group (67%) achieved greater than 95% adherence compared to those on twice-daily abacavir and lamivudine (53%).7 As expected, overall patient satisfaction and adherence with the once-daily FDC is excellent and comparable to or better than twice- daily dosing.8 9.2. Dispersibility In comparison to syrups, dispersible formulations offer many advantages9:  More convenient for active pharmaceutical ingredients with insufficient stability in water;  More easily transportable and they generate less handling and transportation costs for the same amount of active ingredient (less volume, less weight);  Easier to produce and the production costs are less, which makes them more affordable than standard liquid formulations;  Can still be used in very young children (0 – 6 months) and can be dispersed in breast milk;  Are easy to dispense and they require minimal manipulation by health professionals and parents prior to use which minimizes the risk of errors; and  Dispersible with only a small amount of water for administration. 9.3. Scored tablets In addition to dispersibility, scoring pediatric tablets also provide advantages in pediatric formulations. Scoring allows for increased flexibility of dosing across a wider age/weight range and decreased pill burden. A properly scored tablet can be counted on to provide a reliable half-dose with little wastage from crumbled or poorly divided tablets. 10. Summary of comparative evidence on safety: 10.1. Estimate of total patient exposure to date ABC and 3TC have been used extensively as an NRTI backbone, in both first-line and second-line pediatric treatment regimens. Please see Section 8.2 and Section 10.

7 WHO MODEL LIST OF ESSENTIAL MEDICINES APPLICATION

10.2. Description of adverse effects/reactions The safety profile of ABC/3TC has also been previously reviewed and determined to be acceptable. The following information summarizes key safety information that applies to children. Adverse reactions from pediatric clinical trials: and , , , , rashes, . Laboratory abnormalities (Grade 3 or 4): anaemia, neutropenia; elevations in function tests, creatine kinase. Hypersensitivity reactions: Fatal hypersensitivity reactions have been associated with therapy with abacavir. Patients developing signs or symptoms of hypersensitivity (which include fever; skin rash; ; gastrointestinal symptoms such as nausea, vomiting, diarrhea, or ; and respiratory symptoms such as pharyngitis, dyspnoea, or ) should discontinue abacavir as soon as a hypersensitivity reaction is suspected. To avoid a delay in diagnosis and minimize the risk of a life- threatening hypersensitivity reaction, abacavir should be permanently discontinued if hypersensitivity cannot be ruled out, even when other diagnoses are possible (e.g., acute onset respiratory diseases, gastroenteritis, or reactions to other ). Abacavir must not be restarted following a hypersensitivity reaction because more severe symptoms will recur within hours and may include life- threatening hypotension and death. Severe or fatal hypersensitivity reactions can occur within hours after reintroduction of abacavir in patients who have no identified history or unrecognised symptoms of hypersensitivity to abacavir therapy. In clinical studies, approximately 5% of adult and paediatric patients receiving abacavir developed a hypersensitivity reaction. This reaction is characterized by the appearance of symptoms indicating multi- organ/body system involvement. Symptoms usually appear within the first 6 weeks of treatment with abacavir, although these reactions may occur at any time during therapy. Frequently observed include fever; skin rash; fatigue; and gastrointestinal symptoms such as nausea, vomiting, diarrhea, or abdominal pain. Other signs and symptoms include , lethargy, , myolysis, arthralgia, oedema, pharyngitis, cough, dyspnoea, headache, and paraesthesia. Some patients who experienced a hypersensitivity reaction were initially thought to have acute onset or worsening respiratory disease. The diagnosis of hypersensitivity reaction should be carefully considered for patients presenting with symptoms of acute onset respiratory diseases, even if alternative respiratory diagnoses (pneumonia, bronchitis, pharyngitis, or flu-like illness) are possible. Physical findings include lymphadenopathy, mucous membrane lesions (conjunctivitis and mouth ulcerations), and rash. The rash usually appears maculopapular or urticarial but may be variable in appearance. Hypersensitivity reactions have occurred without rash. As noted in the U.S. product label for Epzicom® (ABC/3TC, ViiV Healthcare), adult patients who carry the HLA-B*5701 allele are at a higher risk of abacavir hypersensitivity reactions; although, patients who do not carry the HLA-B*5701 allele have developed hypersensitivity reactions.9 In a meta-analysis of pediatric patients receiving ABC treatment, the estimated incidence of hypersensitivity reactions among children exposed to ABC was low (2.2%), as were reported deaths (3.3%), with none of the deaths reported as being associated with ABC toxicity.10 In addition, the HLA-B*5701 allele is more commonly found in Caucasian populations (5%) than in black African populations (2%). Therefore, WHO guidelines recommend that where screening is not feasible, appropriately trained clinical staff should manage patients clinically, with education provided to caregivers and older children. : Patients with chronic B or C and treated with antiretroviral agents are at increased risk for severe and potentially fatal liver adverse events and may require blood tests to monitor liver

8 WHO MODEL LIST OF ESSENTIAL MEDICINES APPLICATION function. : Females, particularly if very overweight, and patients with liver disease may be more at risk of getting a rare, but serious side effect called lactic acidosis, a buildup of lactic acid in the body. If lactic acidosis occurs, it usually develops after a few months of treatment. Deep rapid breathing, drowsiness and non- specific symptoms such as nausea, vomiting and stomach pain, might indicate the development of this condition. Fat redistribution: Redistribution, accumulation or loss of body fat may occur in patients receiving combination antiretroviral therapy. Immune reactivation syndrome: In some patients with advanced HIV infection (AIDS) and a history of opportunistic infections, signs and symptoms of from previous infections may occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an improvement in the body’s immune response, enabling the body to fight infections that may have been present previously with no symptoms. Bone problems: Some patients taking combination antiretroviral therapy may develop a bone disease called osteonecrosis (death of bone tissue). The risk of developing this disease may be higher, e.g. when the immune system is severely compromised or when drinking alcohol regularly. So far, this disease has been reported mainly in adults. However, if a child notices has joint stiffness, aches and pains (especially of the hip, knee and shoulder) and difficulty in movement, osteonecrosis should be considered. Heart attack: Based on data in adults, it cannot be excluded that abacavir might be associated with an increased risk of heart attack. Important information about some of the other ingredients of Abacavir 60: This medicine contains 3.3.mg aspartame per tablet, which is a source of phenlyalanine. Abacavir 60 should not be taken by patients that have phenylketonuria. 10.3. Identification of variation in safety due to health systems and patient factors Antiretroviral therapy cannot be successfully introduced in a healthcare system vacuum. However, facilities and personnel infrastructure can be expanded in parallel with the implementation of antiretroviral agent delivery programs. Health care provider and patient education, an essential health care package, and the ability to do at least limited clinical and laboratory monitoring are all necessary to try to insure programmatic success. Abacavir use carries the risk of a hypersensitivity reaction in a small percentage of patients which is strongly associated with one specific haplotype at the HLA complex type I (HLA-B*5701). As heterogeneity in the prevalence of HLA-B*5701 exists across distinct ethnicities there are differences in the risk of abacavir hypersensitivity reactions in distinct populations. Approximately 5-8% of Caucasian patients may develop hypersensitivity to ABC however similar reactions may be found more or less frequently in other ethnic groups. See Section 11.2. 10.4. Special Populations Use in : Treatment recommendations globally endorse treatment of all HIV-infected pregnant women. The U.S. FDA recently reviewed available safety data related to ABC and 3TC use in pregnant women and included a summary in the U.S. product label for Epzicom®. Available data from the Antiretroviral Pregnancy Registry (APR) show no difference in the risk of overall major birth defects for ABC or 3TC compared with the background rate for major birth defects of 2.7% in the U.S. reference

9 WHO MODEL LIST OF ESSENTIAL MEDICINES APPLICATION population (the Metropolitan Atlanta Congenital Defects Program). Based on prospective reports from the APR of over 2,000 exposures to ABC during pregnancy resulting in live births (including over 900 exposed in the first trimester), the prevalence of defects in the first trimester was 3.0% (95% CI: 2.0% to 4.4%). Based on prospective reports from the APR of over 11,000 exposures to 3TC during pregnancy resulting in live births (including over 4,300 exposed in the first trimester), the prevalence of defects in the first trimester was 3.1% (95% CI: 2.6% to 3.7%).9 3TC have been studied in pregnant women during 2 clinical trials conducted in South Africa. The trials assessed pharmacokinetics in 16 women at 36 weeks gestation using 150 mg 3TC twice daily with AZT, 10 women at 38 weeks gestation using 150 mg 3TC twice daily with AZT, and 10 women at 38 weeks gestation using 3TC 300 mg twice daily without other ARVs. These trials were not designed or powered to provide efficacy information. 3TC pharmacokinetics in pregnant women were similar to those seen in non-pregnant adults and in postpartum women. 3TC concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples.9 disease: For children with renal disease the dose of 3TC may need to be reduced. In such cases, other formulations of ABC and 3TC than ABC/3TC 120mg/60mg tablets should be used. Coinfection with or C: Patients with chronic hepatitis B or C and treated with antiretroviral agents are at increased risk for severe and potentially fatal liver adverse events and may require blood tests to monitor liver function. If a child has chronic hepatitis B infection, the child should not abruptly stop treatment as there may be a recurrence of hepatitis. This recurrence may be more severe if there is serious liver disease. 10.5. Drug Interactions Co-administration of abacavir and is not recommended due to a possible lower response rate to ribavirin-containing hepatitis treatment. An increased dose may be required in a small number of patients receiving abacavir. Since abacavir increases the metabolism of methadone. Patients taking methadone should be checked for withdrawal symptoms and may need dose adjustment of methadone. Serum levels of Abacavir may be altered by the concomitant use with:  alcohol  oral vitamin A related medicines, e.g. isotretinoin   phenobarbital and phenytoin  with , with ritonavir  high dose cotrimoxazole (No change in dose of either drug is recommended) Lamivudine should not be used in combination with:  (another antiretroviral medicine)

10 WHO MODEL LIST OF ESSENTIAL MEDICINES APPLICATION

11. Summary of available data on comparative cost1 and cost-effectiveness within the pharmacological class or therapeutic group: 11.1. Range of costs of the proposed medicine As illustrated in the following table, various sources indicate an average price per patient per year (PPPY) for the ABC/3TC dispersible/scored tablet (120/60mg) of USD ~$85.

ABC/3TC ABC Oral Solution ABC/3TC Disp/Scored Disp/Scored FDC (20mg/ml) + 3TC Oral FDC Tablet (60/30mg) Tablet (120/60mg) Solution (50mg/ml) Price/Unit Price/Unit Price/Unit Source PPPY* PPPY* PPPY* (USD) (USD) (USD) Médecins Sans Frontières n/a n/a $0.075 $110 $0.034 $146 (MSF) Price, July 2016 Global Fund Pricing, July $0.117 $85 $0.071 $103 $0.045 $199 2016 CHAI Reference Price, $0.117 $85 $0.058 $85 n/a n/a 2016 Average of reported $0.117 $85 $0.068 $100 $0.040 $172 prices *PPPY in USD is based on WHO dosing guidelines for the 10 – 13.9 kg weight bands; 365 days a year 11.2. Comparative cost-effectiveness presented as range of cost per routine outcome As the table in section 12.1 indicates, the dispersible formulation of Abacavir/Lamivudine 120/60 offers a significant price advantage over the oral solution, costing approximately 50% less in PPPY terms. Furthermore, due to the reduced pill burden, the cost (PPPY) of the ABC/3TC 120/60mg is 14% lower than the low-dose ABC/3TC 60/30mg. In addition to the cost of the product itself, there are also cost savings related to the shipment and storage of the tablets relative to the oral solution. Due to the oral solution's cold-chain requirements, storage of the tablets is relatively easier. There are also significant freight savings associated with using tablets over oral solutions, which have a significantly greater weight and bulk. Moreover, wastage at the patient level is typically presumed to be significantly higher with oral solutions than tablets. Compared to existing ABC tablet formulations, the 120/60mg can also help reduce the pill burden for children by at least 50%, which can potentially simplify country supply chains. 12. Summary of regulatory status of the medicine The FDA granted ABC/3TC 120mg/60mg dispersible tablets tentative approval on 23 October, 2014 for purchase and use only as part of the President's Emergency Plan for AIDS Relief (PEPFAR) in resource-limited countries. 13. Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia, United States Pharmacopoeia) Abacavir (as sulfate) and Lamivudine are both included in the International Pharmocopoeia, Fifth Edition (2015). 14. Proposed (new/adapted) text for the WHO Model Formulary Add Dosage form: ABC/3TC Tablet (dispersible, scored): 120mg/60mg

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12 WHO MODEL LIST OF ESSENTIAL MEDICINES APPLICATION

References: 1. Newell ML, Coovadia H, Cortina-Borja M, et.al. “Mortality of infected and uninfected infants born to HIV-infected mothers in Africa: a pooled analysis.” Lancet. 2004 Oct 2-8;364(9441):1236-43. 2. Fact Sheet: Children and HIV. UNAIDS. July 2016, http://www.aidsdatahub.org/fact-sheet-children- and-hiv-unaids-2016. 3. Start free, stay free, AIDS free: A super-fast-track framework for ending aids in children, adolescents and young women by 2020. UNAIDS, 2016, https://free.unaids.org. 4. Meeting Report: Update to the optimal list of paediatric ARV formulations. Inter-Agency Task Team. September, 2013. http://apps.who.int/medicinedocs/documents/s21435en/s21435en.pdf. 5. ARV Market Report: The State of the Antiretroviral Drug Market in Low- and Middle-Income Countries, 2015-2020. Clinton Health Access Initiative, Inc. Issue 7, October, 2016. 6. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach. World Health Organization. June, 2016, http://www.who.int/hiv/pub/arv/arv-2016/en/. 7. Musiime V, Kasirye P, et. al. “Randomised comparison of once versus twice daily abacavir and lamivudine among 669 HIV-infected children in the ARROW trial.” Conference on Retroviruses and Opportunistic Infections. 2013. Atlanta, GA 8. Achenbach, C et al. “Abacavir/lamivudine fixed-dose combination antiretroviral therapy for the treatment of HIV.” Advances in Therapy 27:1-16, 2010. 9. Supplies and Logistics: Dispersible Tablets. UNICEF, http://www.unicef.org/supply/index_53571.html. 10. Epzicom® U.S. package insert. U.S. Food and Drug Administration. http://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=021652. 11. Jesson J, Dahourou DL, Renaud F, Penazzato M, Leroy V. “Adverse events associated with abacavir use in HIV-infected children and adolescents: a systematic review and meta-analysis.” Lancet HIV. 2016;3(2): e64– e75.

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