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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: Table of Contents 1. Summary statement of the proposal for inclusion, change or deletion: ...... 2 2. Name of the focal point in WHO submitting or supporting the application: ...... 2 3. International Nonproprietary Name (INN, generic name) of the medicine: ...... 2 4. Dosage form or strength proposed for inclusion: ...... 2 5. International availability - sources, if possible manufacturers: ...... 2 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: ...... 3 7.3. Target population: ...... 4 8. Treatment details ...... 4 8.1. Reference to existing WHO and other clinical guidelines: ...... 4 8.2. Need for special diagnostic or treatment facilities and skills: ...... 5 9. Summary of comparative effectiveness in a variety of clinical settings: ...... 5 Fixed-dose combination ...... 5 10. Summary of comparative evidence on safety: ...... 6 10.1. Estimate of total patient exposure to date ...... 6 10.2. Description of adverse effects/reactions ...... 6 10.3. Drug Interactions: (See also Section 11.2) ...... 8 10.4. Special Populations ...... 9 11. Summary of available data on comparative cost and cost-effectiveness within the pharmacological class or therapeutic group: ...... 10 11.1. Range of costs of the proposed medicine ...... 10 11.2. Comparative cost-effectiveness presented as range of cost per routine outcome ...... 10 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

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1. Summary statement of the proposal for inclusion, change or deletion: This document proposes the inclusion of the tablet formulation of boosted atazanavir 300mg/100mg (ATV/r) for treatment of HIV infection among adults and adolescents living with HIV/AIDS in the WHO Essential Medicines List (EML). In this case, low dose ritonavir is included in this product, not for its intrinsic anti-retroviral activity, but because it inhibits the metabolism of atazanavir. The principal reasons for requesting this inclusion are as follows:  Anti-retroviral therapy (ART) requires lifelong adherence to regimens of three or more drugs which can require a high daily pill burden.  According to the WHO 2016 Treatment Guidelines ATV/r is one of the two preferred PI for use in second-line ART regimens in adolescents and adults.  As a fixed-dose combination with once-daily dosing, this formulation versus single drug formulations, may:  Increase patient adherence to treatment;  Delay the development of resistance;  Lower the total cost, including production, storage, transport, dispensing and other health system costs;  Reduce the risk of medication errors by prescribers, dispensers or patients themselves; and  Simplify and increase security of supply systems

2. Name of the focal point in WHO submitting or supporting the application: Marco Vitoria, WHO/HTM/HIV/ATC 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: Atazanavir/ritonavir, ATC code : not found

4. Dosage form or strength proposed for inclusion: Each tablet contains atazanavir 300mg and ritonavir 100mg (WHO supported dosing).

5. International availability - sources, if possible manufacturers: Atazanavir/ritonavir 300mg/100mg tablets are manufactured at: Mylan Pharmaceuticals Private Limited Commercial Operations Prestige Tech Park,Platina-3, 7th to 12th floor, Prestige Tech Park,

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Kadubesanahalli, Bangalore -560103 Emcure Pharma Limited Emcure House T 184, M.I.D.C., Bhosari, Pune 411 026

6. Whether listing is requested as an individual medicine or as an example of a therapeutic group: Since atazanavir and ritonavir are both protease inhibitors to be used in this fixed dose combination, inclusion as an example of the therapeutic group is requested within ‘Protease Inhibitors’ (6.4.2.3).

7. Information supporting the public health relevance 7.1. Epidemiological information on disease burden: As of 2015, UNAIDS reported there were 36.7 million people were living with HIV/AIDS globally, 2.1 million new HIV-1 infections, and 1.1 million HIV-related deaths. Over 95% of infected people live in low and middle income countries with inadequate resources to effectively combat the epidemic. While some countries have achieved declines in new HIV infections among adults of 50% or more, global data show that many others have not made measurable progress and others have experienced worrying increases in new HIV infections. Overall, approximately 17 million people were receiving antiretroviral therapy (ART) in 2015 but this still represents less than half of infected people1. Early and effective ART not only significantly improves the health of those living with HIV, but also reduces transmission of the disease as shown in the recently reported START study. For this reason, the World Health Organization released new guidelines in 2015 calling for treatment for all people with HIV. Easy to administer, highly effective, safe treatment options are desperately needed in many areas of the world in order to meet the UNAIDS 90-90-90 targets, which call for 90 percent of people living with HIV to know their status, 90 percent of those with known status to be on ART, and 90 percent of those on ART to be virally suppressed (i.e., on successful therapy) by the year 2020. The scale-up of ART in resource limited settings has thus far relied on the use of convenient, inexpensive NNRTI-based first-line regimens which have a low genetic barrier to resistance. Increasing number of patients in resource limited settings will require new second- and third-line regimens as they fail their current treatment. Guidelines place a high value on using simpler second-line regimens, ideally in heat-stable formulations fixed dose combination (FDC) solid dosage forms. In all cases, the drugs used in first-line therapy should determine the choice of NRTI backbone in second-line regimens and following failure on an NNRTI based regimen, PI based regimens are the preferred second-line. ATV/r fits into this second-line treatment armamentarium by virtue of its effectiveness in this setting and the acceptability of its safety profile. ATV/r 300mg/100mg, in combination with other antiretrovirals, is indicated as second-line treatment of HIV infection in adolescents and adults weighing over 30kg. 7.2. Assessment of current use: Atazanavir boosted with ritonavir (ATV/r) is currently used as an alternate to combined with ritonavir (LPV/r) which is the dominant PI in low and middle income countries. As of 2010, 2.9% of patients in LMIC (excluding the Americas) were on a second-line regimen and the majority of them are using LPV/r. However, given that the switching rate from first to second line regimens is expected to

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increase, the use of ATV/r is expected to increase with its wider availability in low and middle income countries. According to CHAI ARV market analyses, in 2015, 22% of adult second-line patients were estimated to be on ATV/r. India, Malawi, and Zimbabwe continued to have the highest individual market shares for ATV/r with more than 80 percent of their second-line adult patients at the end of 2015. As shown in the graph below, ATV/r use for second-line patients is expected to grow and ultimately surpass LPV/r use by 2020.2 Graph: Patient Growth and Share of Second-Line PI Market in LMICs with Generic Access2

7.3. Target population: HIV-1 infected adults and adolescents who require a protease inhibitor-containing second-line regimen.

8. Treatment details 8.1. Reference to existing WHO and other clinical guidelines: In the 2016 WHO Consolidated Guidelines on the use of antiretroviral drugs for treating and preventing HIV infection, ATV/r is recommended as one of two preferred PIs for use in adults and adolescents requiring second-line regimens, in combination with an appropriate NRTI backbone.3 Adolescents and Adults 35kg and above: The recommended oral dose of ATV/r 300mg/100mg tablets for adolescents and adults is one tablet daily, in combination with other antiretroviral agents, usually a dual NRTI combination. ATV/r 300mg/100mg tablets should be taken with food. Dose Adjustment: Because it is a fixed-dose tablet, ATV/r 300mg/100mg tablets should not be prescribed for patients requiring dosage adjustment unless the separate components necessary for appropriate dose adjustment are also available. The dose of ATV/r remains the same for adults if combined with an H2-receptor antagonist. If combined with tenofovir and an H2-receptor antagonist, the recommended dose is ATV 400mg with ritonavir 100mg. It is recommended that proton pump inhibitors should not be used in treatment- experienced patients receiving atazanavir.

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8.2. 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, it is recognized that ATV has been individually included in the WHO EML since 2009 and at that time evidence had been satisfactorily summarized and submitted for review. Likewise, ritonavir has been included as a protease-inhibitor booster in the EML since 2002 and in 2008 the 17th edition of the EML was updated to include the heat stable formulation of ritonavir. In addition, the WHO 2016 Consolidated Guidelines state that heat-stable fixed-dose combinations of ATV/r and LPV/r are the preferred boosted PI options for second-line ART. A recently published retrospective study reported the experience of investigators in Nigeria with their patients receiving second-line ART.4 The study hypothesized that switching patients from LPV/r to ATV/r might improve tolerability of treatment and adherence as ATV/r was once daily and was expected to have fewer GI adverse drug reactions. At a large teaching hospital HIV program, 400 patients were switched to ATV/r-based second-line ART and immunologic and virologic outcomes were recorded. A comparison group of 576 patients were maintained on LPV/r-based second line regimens. Of 99 patients evaluated 12 months after ATV/r switch, 2 (2%) had detectable viral load and none of the 26 (0%) evaluated at 24 months had detectable viral load. Of the LPV/r patients, 359 (62.3%) had undetectable viral loads after 12 months and 25/318 (7.9%) patients with data after 24 months had detectable VL. The investigators concluded that among patients switched to ATV/r-containing regimens improvements in immunological responses were observed and no increase in risk of virologic failure was identified. It must be noted that the number of evaluable patients switched to ATV/r was much lower than those remaining of LPV/r but these data generally support the similarity of treatment outcomes with ATV/r and LPV/r. Fixed-dose combination 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:  Reduce pill-burden;  Support 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 Co-formulation of atazanavir and ritonavir into the FDC has similar virologic and immunologic efficacy to the products dosed separately. Overall patient satisfaction and adherence with the once-daily FDC is excellent and comparable to or better than twice- daily dosing.

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10. Summary of comparative evidence on safety: 10.1. Estimate of total patient exposure to date Estimates of total patient exposure to date are not available. As stated in Section 8.1, ATV/r is currently used as an alternate to LPV/r which is the currently the dominant PI in low and middle income countries and accounts for about 22% of patients on second-line therapy in these countries. 10.2. Description of adverse effects/reactions Hyperbilirubinaemia has been observed to be associated with ATV. The most common event observed is an indirect (unconjugated) elevation of , related to inhibition of UDP-glucuronosyl transferase. While the occurrence of hyperbilirubinaemia has no clinical consequences, <2% of patients receiving ATV discontinue treatment for cosmetic reasons (intolerance of ). Adverse effects/reactions: , , , jaundice, scleral icterus, , lipodystrophy, rash, , asthenia, malaise, anorexia, dyspepsia, paresthesia, dizziness, taste perversion

Laboratory abnormalities (Grade 3 or 4): Total bilirubin elevation, unconjugated bilirubin elevation, neutropenia, thrombocytopenia, ALT/AST elevation

Warnings and Precautions described in product labeling5: Contraindications: ATV/r 300 mg /100 mg tablets are contraindicated in patients with known hypersensitivity to atazanavir, ritonavir, or any of the excipients. ATV/r is contraindicated when coadministered with drugs that are highly dependent on CYP3A or UGT1A1 for clearance, and for which elevated plasma concentrations of the interacting drugs are associated with serious and/or life-threatening events or when coadministered with drugs that strongly induce CYP3A and may lead to lower exposure and loss of efficacy of ATV/r. Severe Skin Reactions: Rash (all grades, regardless of causality) occurred in approximately 20% of patients receiving ATV/r in clinical trials. The discontinuation rate for rash in clinical trials was <1%. Cases of Stevens-Johnson syndrome, erythema multiform, and toxic skin eruptions, including drug rash, eosinophilia, and systemic symptoms (DRESS) syndrome, have been reported. Hepatotoxicity: ATV/r is primarily hepatically metabolized and increased plasma concentrations were observed in patients with hepatic impairment. Patients with pre-existing dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice. The safety and efficacy of ATV/r has not been established in patients with significant underlying liver disorders. Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions. Ritonavir should not be given to patients with decompensated liver disease. For patients with stable severe hepatic impairment (Child Pugh Grade C) without decompensation. Cardiac Conduction Abnormalities: Dose related asymptomatic prolongations in PR interval with atazanavir have been observed in clinical studies. Caution should be used with medicinal products known to induce PR prolongations. In patients with pre-existing conduction problems (second degree or higher atrioventricular or complex bundle-branch block), atazanavir should be used with caution and only if the benefits exceed the risk. Particular caution should be used when prescribing atazanavir in association

6 WHO MODEL LIST OF ESSENTIAL MEDICINES APPLICATION with medicinal products which have the potential to increase the QT interval and/or in patients with pre-existing risk factors (bradycardia, long congenital QT, electrolyte imbalances). Ritonavir has been shown to cause modest asymptomatic prolongation of the PR interval in some healthy adult subjects. Rare reports of 2nd or 3rd degree atrioventricular block in patients with underlying structural heart disease and pre-existing conduction system abnormalities or in patients receiving drugs known to prolong the PR interval (such as verapamil or atazanavir) have been reported in patients receiving ritonavir. Risk of Serious Adverse Reactions Due to Drug Interactions: Initiation of ATV/r, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving ATV/r, may increase plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of ATV/r, respectively. These interactions may lead to: • Clinically significant adverse reactions potentially leading to severe, life threatening, or fatal events from greater exposures of concomitant medications. • Clinically significant adverse reactions from greater exposures of atazanavir with ritonavir. • Loss of therapeutic effect of atazanavir with ritonavir and possible development of resistance. (See Section 11.3) Hemophilia: There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthroses, in type A and B haemophiliac patients treated with protease inhibitors. In some patients, additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced if treatment had been discontinued. A causal relationship has been suggested, although the mechanism of action has not been elucidated. Haemophiliac patients should therefore be made aware of the possibility of increased bleeding. Hyperlipidaemia: In clinical studies, atazanavir (with or without ritonavir) has been shown to induce dyslipidaemia to a lesser extent than comparators. The clinical impact of such findings has not been demonstrated in the absence of specific studies on cardiovascular risk. The selection of antiretroviral therapy must be guided principally by antiviral efficacy. Consultation with standard guidelines for management of dyslipidaemia is recommended. Diabetes Mellitus/: New onset diabetes mellitus, hyperglycaemia, and exacerbation of existing diabetes mellitus have been reported in patients receiving protease inhibitors. In some of these, the hyperglycaemia was severe and in some cases also associated with ketoacidosis. Many patients had confounding medical conditions, some of which required therapy with medicinal products that have been associated with development of diabetes or hyperglycaemia. Hyperbilirubinemia: Reversible elevations in indirect (unconjugated) bilirubin related to inhibition of UDP- glucuronosyl transferase (UGT) occur in most patients receiving atazanavir. Hepatic transaminase elevations that occur with elevated bilirubin in patients receiving atazanavir should be evaluated for alternative etiologies. Alternative antiretroviral therapy to atazanavir may be considered if jaundice or scleral icterus is unacceptable to a patient. Nephrolithiasis and Cholelithiasis: Cases of nephrolithiasis and/or cholelithiasis have been reported during postmarketing surveillance in HIV-infected patients receiving ATV/r therapy. Some patients required hospitalization for additional management and some had complications. Because these events were

7 WHO MODEL LIST OF ESSENTIAL MEDICINES APPLICATION reported voluntarily during clinical practice, estimates of frequency cannot be made. If signs or symptoms of nephrolithiasis and/or cholelithiasis occur, temporary interruption or discontinuation of therapy may be considered Diarrhea: The relatively high frequency of diarrhea during treatment with ritonavir may compromise the absorption and efficacy (due to decreased compliance) of ritonavir or other concurrent medications. Serious persistent and/or diarrhea associated with ritonavir use might also compromise renal function. It is advisable to monitor renal function in patients with renal function impairment. Pancreatitis: Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal pain) or abnormalities in laboratory values (such as increased serum lipase or amylase values) suggestive of pancreatitis should occur. Patients who exhibit these signs or symptoms should be evaluated and ritonavir therapy should be discontinued if a diagnosis of pancreatitis is made. Fat Redistribution: Combination antiretroviral therapy has been associated with the redistribution of body fat (lipodystrophy) in HIV patients. The long-term consequences of these events are currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and protease inhibitors and lipoatrophy and nucleoside reverse transcriptase inhibitors has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older age, and with drug related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include evaluation for physical signs of fat redistribution. Combination antiretroviral therapy (CART), including atazanavir (with or without ritonavir)-based CART, is associated with dyslipidaemia. Consideration should be given to the measurement of fasting serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate. 10.3. Drug Interactions: (See also Section 11.2) Atazanavir: Atazanavir is metabolised principally by CYP3A4. Co-administration of atazanavir with ritonavir and medicinal products that induce CYP3A4 is not recommended Co-administration of atazanavir with or is not recommended. If the co-administration of atazanavir with an NNRTI is required, an increase in the dose of both atazanavir and ritonavir to 400 mg and 200 mg, respectively, in combination with could be considered with close clinical monitoring. There is limited data on the concomitant use of ritonavir- boosted atazanavir hormonal contraception and alternative forms of contraception may need to be considered. Co-administration of voriconazole and atazanavir with ritonavir is not recommended unless an assessment of the benefit/risk justifies the use of voriconazole. Concomitant use of atazanavir/ritonavir and fluticasone or other glucocorticoids that are metabolized by CYP3A4 is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression. Co-administration of atazanavir with proton pump inhibitors is not recommended as the absorption of atazanavir may be reduced in situations where gastric pH is increased irrespective of cause. If the combination of atazanavir with a proton pump inhibitor is judged unavoidable, close clinical monitoring is recommended in combination with an increase in the dose of atazanavir to 400 mg with 100 mg of ritonavir; doses of proton pump inhibitors comparable to 20 mg should not be exceeded.

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Ritonavir: Ritonavir has a high affinity for several cytochrome P450 (CYP) isoforms and may inhibit oxidation with the following ranked order: CYP3A4 > CYP2D6. Co-administration of ritonavir Tablets and medicinal products primarily metabolised by CYP3A may result in increased plasma concentrations of the other medicinal product, which could increase or prolong its therapeutic and adverse effects. For select medicinal products (for example, alprazolam) the inhibitory effects of ritonavir on CYP3A4 may decrease over time. Ritonavir also has a high affinity for P-glycoprotein and may inhibit this transporter. The inhibitory effect of ritonavir (with or without other protease inhibitors) on P-gp activity may decrease over time (eg digoxin and fexofenadine). Ritonavir may induce glucuronidation and oxidation by CYP1A2, CYP2C8, CYP2C9 and CYP2C19 thereby increasing the biotransformation of some medicinal products metabolised by these pathways, and may result in decreased systemic exposure to such medicinal products, which could decease or shorten their therapeutic effect. 10.4. Special Populations and Lactation: Atazanavir : The following information was abstracted from the U.S. product label for Reyataz® (ATV, Bristol-Myers Squibb)5 As noted in the U.S. product label, atazanavir has been evaluated in a limited number of women during pregnancy. Available human and animal data suggest that ATV does not increase the risk of major birth defects. Based on prospective reports from the Antiretroviral Pregnancy Registry of approximately 1600 live births following exposure to atazanavir-containing regimens (including 1037 live births in infants exposed in the first trimester and 569 exposed in second/third trimesters), there was no difference between atazanavir and overall birth defects compared with the background birth defect rate. For pregnant patients, no dosage adjustment is required for ATV with the following exceptions: For treatment-experienced pregnant women during the second or third trimester, when ATV is coadministered with either an H2-receptor antagonist or tenofovir ATV 400 mg with ritonavir 100 mg once daily is recommended. In a of 41 pregnant women receiving ATV/r (300mg/100mg or 400mg/100mg), ATV drug concentrations in fetal umbilical cord blood were approximately 12% to 19% of maternal concentrations. Among the 40 infants born to 40 HIV-infected pregnant women, all had test results that were negative for HIV-1 DNA at the time of delivery and/or during the first 6 months postpartum. All 40 infants received antiretroviral prophylactic treatment containing . No evidence of severe hyperbilirubinemia (total bilirubin levels greater than 20 mg/dL) or acute or chronic bilirubin encephalopathy was observed among neonates in this study. However, 10/36 (28%) infants (6 greater than or equal to 38 weeks gestation and 4 less than 38 weeks gestation) had bilirubin levels of 4 mg/dL or greater within the first day of life. Ritonavir: The following information was abstracted from the U.S. product label for Norvir® (RTV, Abbvie)6 As noted in the Norvir product label, as of January 2012, the Antiretroviral Pregnancy Registry (APR) has received prospective reports of 3860 exposures to ritonavir containing regimens (1567 exposed in the first trimester and 2293 exposed in the second and third trimester). Birth defects occurred in 35 of the 1567 (2.2%) live births (first trimester exposure) and 59 of the 2293 (2.6%) live

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births (second/third trimester exposure). Among pregnant women in the U.S. reference population, the background rate of birth defects is 2.7%. There was no association between ritonavir and overall birth defects observed in the APR. There are no adequate and well-controlled studies in pregnant women. RTV should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Hepatic impairment: Atazanavir with ritonavir has not been studied in patients with hepatic impairment. Atazanavir with ritonavir should be used with caution in patients with mild hepatic impairment. Atazanavir should not be used in patients with moderate to severe hepatic impairment. Ritonavir should not be given as a pharmacokinetic enhancer to patients with decompensated liver disease. In the absence of pharmacokinetic studies in patients with stable severe hepatic impairment (Child Pugh Grade C) without decompensation, caution should be exercised when ritonavir is used as a pharmacokinetic enhancer as increased levels of the co-administered PI may occur.

11. Summary of available data on comparative cost 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 ATV/r (300/100mg) tablet of USD ~$203.

ATV/r FDC Tablet ATV Tablet (300mg) Capsule

(300/100mg) + RTV Tablet (100mg) Price/Unit PPPY Price/Unit PPPY Source (USD) (USD)* (USD) (USD)* Médecins Sans Frontières $0.583 $213 $0.581 $253 (MSF) Price, July 2016 Global Fund Pricing, July $0.550 $201 $0.681 $249 2016 CHAI Reference Price, $0.533 $195 n/a n/a 2016 Average of reported $0.555 $203 $0.631 $251 prices *Price per patient per year based on WHO dosing guidelines; 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, this formulation offers a significant price advantage over the combined cost of the individual formulations, costing approximately 19% less in PPPY terms. In addition to the cost of the product itself, there are also potential freight savings associated with procuring fewer packs. Moreover, consolidation around a single product facilitates simpler management of country supply chains.

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12. Summary of regulatory status of the medicine The FDA first granted tentative approval to ATV/r 300mg/100mg on 18 November, 2011 for purchase and use only as part of the President's Emergency Plan for AIDS Relief (PEPFAR) in resource-limited countries. A second supplier was granted tentative approval on March 17, 2014. The WHO granted pre-qualified status on 28 November, 2011 and ERP reviewed the product on 31 October, 2015.

13. Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia, United States Pharmacopoeia) Atazanavir (as a sulfate) and ritonavir are included in the International Pharmocopoeia, Fifth Edition (2015).

14. Proposed (new/adapted) text for the WHO Model Formulary Add dosage forms: tablet, 300mg/100mg

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References 1. “AIDS by the numbers — AIDS is not over, but it can be.” UNAIDS. November, 2016, http://www.unaids.org/en/resources/documents/2016/AIDS-by-the-numbers. 2. 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. 3. 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/. 4. Akanmu AS, Adeyemo T, Lesi F, et. al. “Immunological and virological outcomes of patients switched from LPV/r to ATV/r-containing second- line regimens.” Curr HIV Res. 2015;13(3):176-83. 5. Reyataz U.S. package insert. U.S. Food and Drug Administration. September, 2016, http://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=021567. 6. Norvir U.S. package insert. U.S. Food and Drug Administration. September, 2016, http://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=022417.

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