Application for Inclusion of Lopinavir /Ritonavir Oral Granules (LPV/R) Formulation on WHO Model List of Essential Medicines for Children

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Application for Inclusion of Lopinavir /Ritonavir Oral Granules (LPV/r) Formulation on WHO Model List of Essential Medicines for Children

Table of Contents 1. Summary statement of proposal for inclusion ...... 2 2. Antiretroviral therapy is recommended for all HIV-infected children, adolescents, and adults...... 2 3. Name of the focal point in WHO submitting the application: ...... 2 4. Name of the organization(s) consulted and/or supporting the application: ...... 2 5. International Non-proprietary Name: ...... 2 6. Formulation and strength proposed for inclusion:...... 2 7. International availability ...... 2 8. Whether listing is requested as an individual medicine or as an example of a therapeutic group: ...... 2 9. Information supporting public health relevance ...... 3 9.1 Epidemiological information on disease burden 3 9.2 Assessment of current use 3 9.3 Target population 4 10. Treatment details ...... 4 10.1 Reference to existing WHO guidelines 4 10.2 Dosage regimen, duration 4 Table 1: Recommended dosing of LPV/r oral granules by weight band to be taken twice daily ...... 5 11. Summary of comparative effectiveness in a variety of clinical settings ...... 6 12. Comparative evidence on safety: ...... 7 12.1 Estimate of total patient exposure to date 7 12.2 Description of adverse effects/reactions 7 12.3 Identification of variation in safety due to health systems and patient factors 7 12.4 Drug interactions requiring dose adjustment 7 13. Summary of available data on comparative cost and cost-effectiveness within the pharmacological class or therapeutic group: ...... 7 Table 2: Price per Unit and Price per Patient per Year for TDF/3TC/DTG and other First-Line Products ...... 8 14. Summary of regulatory status of the medicine (in country of origin and preferably in other countries as well): ...... 8 15. Availability of pharmacopoieal standards: ...... 8 16. Proposed (new/adapted) text for the WHO Model Formulary ...... 9 Table 3: Recommended dosing of LPV/r granules by weight band to be taken twice daily ...... 9 17. References: Comprehensive reference list and in-text citations...... 9 1

1. Summary statement of proposal for inclusion This document proposes the inclusion of lopinavir/ritonavir oral granules formulation (LPV/r, 40mg/10mg) as part of a combination treatment of HIV infection among children living with HIV/AIDS in the WHO Essential Medicines List for Children (EMLc). Low dose ritonavir is included in this product, not for its intrinsic anti-retroviral activity, but because it inhibits the metabolic clearance of lopinavir. LPV/r in the dosage forms of tablets (400mg/100mg and 100mg/25mg), oral solution (80mg/20mg/mL), and oral pellets (40mg/10mg) are currently included in the EML and EMLc.

2. Antiretroviral therapy is recommended for all HIV-infected children, adolescents, and adults.

3. Name of the focal point in WHO submitting the application: Martina Penazzato, WHO/HTM/HIV/ATC

4. Name of the organization(s) consulted and/or supporting the application: Clinton Health Access Initiative, Inc (CHAI)

5. International Non-proprietary Name: Co-formulated lopinavir + ritonavir, ATC code: J05AR10

6. Formulation and strength proposed for inclusion: Each sachet contains 40mg of lopinavir and 10mg of ritonavir as oral granules.

7. International availability LPV/r oral granules are manufactured by Mylan Laboratories, Limited: Mylan Laboratories, Limited Robert J. Coury Global Center 1000 Mylan Blvd. Canonsburg, PA 15317

8. Whether listing is requested as an individual medicine or as an example of a therapeutic group: Listing is requested on the Model List of Essential Medicines for Children as a new formulation for LPV/r intended for pediatric use; it is an example of the therapeutic class of HIV protease inhibitors. Other members of this class of drugs may serve as alternatives, depending on quality, price and local availability.

9. Information supporting public health relevance 9.1 Epidemiological information on disease burden Despite an impressive reduction in mother to child transmission of HIV in recent years, 180,000 new pediatric infections occurred in 2017. There are now 1.8 million children living with HIV, the vast majority in sub-Saharan Africa. Evidence shows that in the absence of ART, over 50% of HIV- infected infants 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 52% of children eligible for treatment2 and in 2017 an estimated 110,000 HIV/AIDS related deaths occurred in children <15 years of age3. 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.4 Scaling up early infant testing (including testing at birth) to identify perinatal transmission will allow many more infants to receive life-saving ARVs within the first few weeks of life. Since 2014 and as led by UNAIDS, the global community has set a target to end the AIDS epidemic by 2030, but the particular vulnerabilities of pediatric patients necessitate an even more ambitious goal - ending pediatric AIDS by 2020.5 This super fast-track target 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 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 solid dosage forms, ideally dispersible, fixed-dose combination tablets if available. 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 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. This Optimal Formulary/LUL is revised on a regular basis to reflect current WHO recommended regimens. LPV/r oral pellets and oral granules are currently listed as optimal formulations and are listed collectively as a “solid oral dosage form 40mg/10mg..”6 These two formulations are listed to be used with 2 NRTIs for alternative first-line or second-line treatment for infants and children below 10 kg or unable to swallow 100mg/25mg tablets whole.

9.2 Assessment of current use Estimates of current usage of LPV/r oral granules are not available as the formulation was only recently approved and added to the Optimal Formulary list. According to CHAI ARV market analysis, use of LPV/r in pediatric patients will remain at about 25% of the treated population for the next several years. The report notes that since late 2016, global demand for the LPV/r pellets has 3

outpaced supply, which has limited uptake in LMICs. However, increased production of LPV/r pellets and introduction of LPV/r oral granules should ease global supply constraints in the future.7

9.3 Target population Like the oral pellets, LPV/r oral granules are intended as alternate first-line treatment of HIV infection in pediatric patients younger than 3 years of age. LPV/r oral granules should not be administered to premature neonates (born one month or more before expected date of delivery) until 14 days after their due date.

10. Treatment details 10.1 Reference to existing WHO guidelines Based on evidence from randomized controlled trials showing the superiority of LPV/r-based regimens over NVP-based regimens for treating young children, the WHO 2013 guidelines first recommended the use of LPV/r-based treatment in children younger than 3 years (36 months) of age where feasible, regardless of NNRTI exposure. In the WHO 2016 Consolidated Guidelines on the use of antiretroviral drugs for treating and preventing HIV infection, LPV/r in combination with 2 NRTIs was the preferred regimen in infants and children younger than 3 years.4 The recommended NRTI backbone in this age group is either abacavir (ABC) or zidovudine (ZDV) plus lamivudine (3TC). In their updated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of HIV published in 2018, WHO elevated the integrase inhibitors dolutegravir (DTG) and raltegravir (RAL) in combination with 2 NRTIs to first-line treatment for infants and children.8 However, LPV/r formulations remain alternate first-line treatment in patients younger than 3 years and as second-line therapy in older children who have received an integrase inhibitor. Lack of dosing recommendations for young infants (for DTG) and lack of availability (for RAL) of integrase inhibitors will likely mean continued use of LPV/r in young patients for several years.

10.2 Dosage regimen, duration ART treatment is recommended for all patients determined to have HIV infection regardless of age or stage of disease. LPV/r must be given in combination with other antiretroviral medications. WHO guidelines recommend combination with ABC (or ZDV) plus 3TC in children younger than 3 years of age. Treatment is intended to be life-long, however, patients should be monitored for treatment failure according to applicable national guidelines. Dosing in children: LPV/r oral granules are dosed as shown in Table 1 below. Sachets containing granules must be opened and the granules are then mixed with liquid or semi-solid food for administration to infants and young children.

Table 1: Recommended dosing of LPV/r oral granules by weight band to be taken twice daily

How to Administer Lopinavir/Ritonavir Oral Granules: Lopinavir / Ritonavir Oral Granules 40 mg / 10 mg must be taken with a meal twice daily. Lopinavir / Ritonavir Oral Granules 40 mg / 10 mg should be sprinkled/mixed with soft food such as applesauce or porridge, or mixed with liquid such as water, as described below. Lopinavir / Ritonavir Oral Granules 40 mg / 10 mg should not be chewed or crushed.

Instructions for Mixing Lopinavir / Ritonavir Oral Granules 40 mg / 10 mg 1. Determine the number of sachets needed to prepare a dose. 2. Prior to mixing, tap the sachet(s) to move all the granules to the bottom of the sachet(s). 3. Completely tear or cut off the top of the sachet(s) and make sure the sachet(s) are fully open. 4. Mixing with soft food such as applesauce or porridge: Using a spoon, mix the entire contents of the Lopinavir / Ritonavir Oral Granules 40 mg / 10 mg sachet(s) with soft food (approximately 1 teaspoon of soft food for 1 sachet; 2 teaspoons for 2 sachets, etc.) in a small cup or bowl. Make sure no granules/powder are left inside the sachet(s). Give or take all of the mixture. If any granules are left in the small cup/bowl or spoon, add more soft food to the granules and mix. Then give or take the mixture along with adequate drinking water, to ensure that no granules are left behind in the mouth. 5. Mixing with liquid such as drinking water: Mix the entire contents of the Lopinavir / Ritonavir Oral Granules 40 mg /10 mg sachet(s) with approximately 5 - 15 ml of drinking water in a teaspoon/ tablespoon (1 teaspoon of water for 2 sachets; 2 teaspoons of water for 3 to 8 sachets; 3 teaspoons or 1 tablespoon for 10 sachets). Make sure no granules/powder are left inside the sachet(s). Give or take all of the mixture. If any granules are left in the spoon, add more liquid (water) and mix. Then give or take the mixture.

6. Administer the drug/food mixture within 2 hours of preparation. If not administered within 2 hours of preparation, throw away the mixture and prepare a new dose. 7. Repeat above steps for next dose.

For infants not yet taking solid food, i.e. less than 6 months of age: There is currently no experience administering granules to infants less than 3 months. In the youngest infants (3-6 months of age), oral pellets were added to a small volume of expressed breastmilk in a spoon and given to the infant or administered directly on the infant’s tongue prior to breastfeeding. Since oral granules should not be chewed or crushed prior to administration, it is important to ensure that infants are developmentally able to swallow them. 1. Determine the number of sachets needed to prepare a dose. 2. Prior to mixing, tap the sachet(s) to move all the granules to the bottom of the sachet(s). 3. Completely tear or cut off the top of the sachet(s) and make sure the sachet(s) are fully open. 4. Granules can be added to a small volume of expressed breast milk or formula in a spoon and given to the infant or put directly on the infant’s tongue before breastfeeding. 5. Administer the entire dose of granules to the infant immediately. 6. It is important to make sure the infant has taken the entire dose of granules by limiting the breastmilk (or formula) used to an amount the infant is able to easily consume in few swallows (e.g. two or three teaspoons), which may be followed by additional breastmilk (or formula) to ensure the full dose is ingested. In children who require concomitant ART and treatment for TB, WHO has recommended the approach of “super-boosting” LPV/r with additional ritonavir (RTV) (1:1 instead of 4:1 LPV/r ratio, i.e. equal doses of LPV and RTV) for the duration of rifampicin treatment.

Need for special diagnostic or treatment facilities and skills: No special testing or facilities are needed beyond that required for any pediatric HIV care and treatment.

11. Summary of comparative effectiveness in a variety of clinical settings The effectiveness of LPV/r in HIV-infected adult and pediatric patients has been demonstrated in a variety of clinical settings and populations and has been previously reviewed. The data supporting use of the oral pellets (also LPV/r 40mg/10mg) was summarized in the dossier submitted in 2016 requesting addition of the pellets to the EMLc. LPV/r oral granules are expected to be used in the same settings and for the same patient population as the LPV/r pellets. Since the previous EML application for LPV/r pellets was submitted, additional data on this dosage form has been reported. The LIVING Study conducted in Kenya and Uganda evaluated use and acceptability of LPV/r pellets in 723 infants and young children from 3kg to <25kg. As of the July 2018 report, 303 patients had reached week 48 of treatment; 266 had HIV RNA data available for the week 48 visit. At 48 weeks, 49-60% of patients across 4 age groups had HIV RNA < 50 copies/mL.9 These data suggest that the oral granules will also be an acceptable formulation in young infants.

12. Comparative evidence on safety: 12.1 Estimate of total patient exposure to date LPV/r has been widely used in the pediatric population since its approval in 2000, however, there has not been significant use of LPV/r oral granules up to this time.

12.2 Description of adverse effects/reactions In general, the safety profile of LPV/r is similar in adults and across the pediatric age range and has been described in detail in earlier dossiers for other formulations. The LPV/r oral granules formulation is expected to have the same safety and tolerability profile as other LPV/r formulations.

12.3 Identification of variation in safety due to health systems and patient factors There is no evidence of variations in safety or risk of toxicity in any specific population or region with the use of LPV/r oral granules or any differences in safety and tolerability due to differences in health systems.

12.4 Drug interactions requiring dose adjustment LPV/r is a potent CYP3A4 inhibitor and has significant drug-drug interaction with other drugs metabolized by this isoenzyme. These interactions have been reviewed in past dossiers. In general, infants and young children receiving LPV/r oral granules are less likely to require other medications that might interact compared to adult patients. One key interaction has resulted in a different management strategy in children compared to adults. Lopinavir concentrations are substantially reduced when LPV/r is given concomitantly with rifampicin. HIV/TB co-infection occurs in many children in countries where both infections are endemic. Since 2010, WHO has recommended the approach of “super-boosting” LPV/r with additional ritonavir (RTV) (1:1 instead of 4:1 LPV/r ratio, i.e. equal doses of LPV and RTV) to manage rifampicin-based TB co-treatment in children on an LPV/r-based regimen. Alternative regimens are also recommended in the guidelines for children who cannot tolerate the additional RTV. These recommendations are reiterated in the 2016 consolidated guidelines.4

13. Summary of available data on comparative cost and cost-effectiveness within the pharmacological class or therapeutic group: As illustrated in Table 2 below, the Médecins Sans Frontières (MSF) price per patient per year (PPPY) for LPV/r (40/10 mg) oral granules is US$281.

Table 2: Price per Unit and Price per Patient per Year for TDF/3TC/DTG and other First-Line Products LPV/r (40/10 mg) LPV/r (40/10 mg) LPV/r (80/20 AZT/3TC/NVP Oral Granules Oral Pellets mg/ml) Oral (60/30/50 mg) Solution Dispersible Tablet Reference Price/Unit PPPY* Price/Unit PPPY* Price/Unit PPPY* Price/Unit PPPY* Price Source Global Fund PPM, July - - $.160 $292 $.103 $94 $.050 $45.63 2018 GHSC-PSM, - - $.160 $292 $.103 $94 $.048 $43.80 August 2018 MSF, July $.154 $281 $.160 $292 $.103 $94 $.050 $45.63 2018 Average $.154 $281 $.160 $292 $.103 $94 $.049 $45.02 All prices in USD. Please note that the GHSC-PSM prices are not reference prices but represent the latest blended average pricing of actual procurement. *Price per patient per year based on WHO dosing guidelines for the 3.0 - 9.9kg weight band (recommended weight band for LPV/r (40/10 mg) solid oral dosage forms), 365 days a year.

In the WHO’s 2018 updated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of HIV, LPV/r-based regimens are recommended as alternatives for children unable to tolerate DTG-based regimens or when DTG dosing recommendations are not available (in this case, children weighing less than 15kg). In the WHO’s 2018 optimal formulary and limited-use list for paediatric ARVs, LPV/r (40/10 mg) solid oral dosage forms (pellets or granules) are considered optimal and indicated for use in children below 10kg or those unable to swallow LPV/r (100/25 mg) tablets whole. LPV/r (40/10 mg) solid oral dosage forms are more expensive than LPV/r (80/20 mg/ml) oral solution (as seen above), but the pellets (and granules, once introduced) do not require cold chain and are more palatable than the oral solution, thus resulting in a higher likelihood of children taking their medicine. At the time of submission, no known special pricing arrangements or cost-effectiveness studies have been conducted for LPV/r (40/10 mg) solid oral dosage forms.

14. Summary of regulatory status of the medicine (in country of origin and preferably in other countries as well): The FDA granted Mylan’s Lopinavir/Ritonavir 40mg/10mg oral granules tentative approval in August 2018.

15. Availability of pharmacopoieal standards: Lopinavir and Ritonavir are included in the International Pharmacopoeia, Eighth Edition (2018).

16. Proposed (new/adapted) text for the WHO Model Formulary Add formulation: Lopinavir and Ritonavir oral granules 40mg/10mg per sachet

Add pediatric dosing for granules: LPV/r granules are dosed as shown in Table 3 below. Sachets containing granules must be opened and the granules mixed with liquid or semi-solid food for administering to infants and young children. Table 3: Recommended dosing of LPV/r granules by weight band to be taken twice daily

17. References: Comprehensive reference list and in-text citations. Comprehensive reference list and in-text citations. 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. Global AIDS Update 2018 – Miles to Go, Breaking Barriers, Righting Injustices. UNAIDS. August 2018, http://www.unaids.org/sites/default/files/media_asset/miles-to-go_en.pdf 3. UNAIDS Core Epidemiology Slides. UNAIDS. July 2018, http://www.unaids.org/en/resources/documents/2018/core-epidemiology-slides 4. 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/. 5. “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/ 6. The 2018 Optimal Formulary and Limited-Use List for paediatric ARVs. Geneva, Switzerland: World Health Organization; 2018. Licence: CC BY-NC-SA 3.0 IGO. http://apps.who.int/iris/bitstream/handle/10665/273153/WHO-CDS-HIV-18.15-eng.pdf?ua=1

7. HIV Market Report: The state of the HIV treatment, testing, and prevention markets in low- and middle-income countries, 2017-2022. Clinton Health Access Initiative, Inc. Issue 9, September 2018. https://clintonhealthaccess.org/content/uploads/2018/09/2018-HIV-Market-Report_FINAL.pdf 8. Updated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of HIV: interim guidance. Geneva: World Health Organization; 2018 (WHO/CDS/HIV/18.18). Licence: CC BY-NC-SA 3.0 IGO. http://apps.who.int/iris/bitstream/handle/10665/273632/WHO-CDS-HIV-18.18-eng.pdf?ua=1 9. Andrieux-Meyer I, Salami O, Omollo R, et al. Oral Abstract WEAB0204 “Pellets formulation of lopinavir/ritonavir in children: 48-week evolution of viral suppression across age categories in the LIVING study. Presented at AIDS2018 Conference, Amsterdam, Netherlands, July 23-27, 2018.