WHO MODEL LIST OF ESSENTIAL MEDICINES APPLICATION

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1 WHO MODEL LIST OF ESSENTIAL MEDICINES APPLICATION 1. Summary statement of the proposal for inclusion, change or deletion: Inclusion of the tablet formulations of etravirine (ETR) 100mg is proposed for treatment of multi-drug resistant HIV among adults living with HIV/AIDS. The principal reasons for requesting this inclusion are as follows: 1. Adults living with multi-drug resistant HIV in resource-limited settings presently have limited options for their infection. 2. WHO Guidelines recommend etravirine for third-line antiretroviral therapy (ART). 3. Treatment of HIV will be improved with wider availability of this tablet. 2. Name of the focal point in WHO submitting or supporting the application: Marco Vitoria and Amitabh Suthar, WHO/HTM/HIV/ATC 3. Name of the organization(s) consulted and/or supporting the application: Tibotec BVBA Turnhoutseweg 30, Beerse, 2340 Belgium Contact: Mercè Caturla, Global Regulatory Affairs 4. International Nonproprietary Name (INN, generic name) of the medicine: Etravirine 5. Dosage form or strength proposed for inclusion: In order to make HIV treatment regimens as patient and programme friendly as possible ATC proposes to manufacture scored tablets whenever possible. Etravirine 200mg tablets (Supported by WHO) Etravirine 100mg tablets (Supported by WHO and Tibotec) Etravirine 25mg tablets (Supported by WHO) 6. International availability sources, if possible manufacturers. Janssen-Cilag S.p.A via C.Janssen Borgo S Michele 04010, Latina, Italy 7. Whether listing is requested as an individual medicine or as an example of a therapeutic group: Since ETR is a non-nucleoside reverse transcriptase inhibitor, inclusion within Nonnucleoside reverse transcriptase inhibitors ( ) is requested. 8. Information supporting the public health relevance 8.1 Epidemiological information on disease burden

2 UNAIDS reported that as of December 2008, 95% of the world s 33.4 million people living with HIV/AIDS (PLHIV) were in low and middle income countries. In 2008 there were 2.7 million new HIV infections and two million AIDS-related deaths. The 2010 WHO Progress Report for HIV/AIDS indicated that at the end of 2009 there were approximately 5.25 million people in low and middle income countries on antiretroviral therapy (36% of those in need of therapy). Resistance to ART may emerge due to inappropriate prescribing of ART (monotherapy or dual therapy), treatment interruptions due to suboptimal patient adherence, poor patient retention on ART, or ART supply shortages or stock-outs at unacceptably high levels. Etravirine, in combination with other antiretrovirals, is indicated for the treatment of HIV in antiretroviral experienced adults, including those with non nucleoside reverse transcriptase inhibitor (NNRTI) resistance. The target population is patients who are resistant to other antiretrovirals. These patients would usually be on the 3rd line therapy. Data to support the number of patients who may require 3rd line treatment in resource limited settings is very limited due to poor monitoring of virological failures. Guidelines recommend clinical and/or immunological markers to detect ART failure but it is well documented that once this occurs, virological failure has been present for a prolonged period of time. Under such circumstances development of mutations to ARVs will be considerable, and will impact future treatment options. In case virologic failure occurs, patients will present detectable viral load which might harbour drug resistance virus. This situation can lead to the transmission of drug-resistant HIV viruses. Such new infections will require more 2nd or 3rd line ART for initial treatment. These types of treatments will be more expensive than widely available 1 st line regimens. Therefore, increasing access to third line regimens is critical to suppressing HIV in persons with multi-drug resistant HIV. The Swiss Federal Commission for HIV/AIDS has stated that if patients are on HAART then the likelihood of transmission is significantly reduced. Mathematical modelling has shown that if all HIV infected patients are treated with ARVs, new infections are likely to fall to very low levels. Hence the need for continued treatment and virological suppression is paramount in controlling the epidemic. ARVs like etravirine are important in managing treatment-experienced patients. 8.2 Assessment of current use Statistics on the number of persons on etravirine are not collected, although cumulative exposure is estimated for pharmacovigilance (see Section 11). 8.3 Target population HIV-infected adults who have failed WHO-recommended first and second line regimens. 9. Treatment details 9.1 Reference to existing WHO and other clinical guidelines Etravirine is a second generation NNRTI recommended in the 2010 WHO adult antiretroviral therapy guidelines for third-line regimens:

3 1. National programmes should develop policies for third-line therapy that consider funding, sustainability, and the provision of equitable access to ART. (Conditional recommendation, low quality of evidence) 2. Third-line regimens should include new drugs likely to have anti-hiv activity, such as integrase inhibitors and second-generation NNRTIs and PIs. (Conditional recommendation, low quality of evidence) 3. Patients on a failing second-line regimen with no new ARV options should continue with a tolerated regimen. (Conditional recommendation, very low quality of evidence) 9.2 Dosage regimen Etravirine must always be given in combination with other antiretroviral medicinal products. ART-experienced adults: ETR 200 mg twice daily following a meal. Hepatic impairment: No dose adjustment is required in patients with mild or moderate hepatic impairment (Child-Pugh score A or B). The pharmacokinetics of etravirine have not been studied in patients with severe hepatic impairment (Child-Pugh score C). Renal impairment: Dosage adjustment is not needed in patients with renal impairment. ART-experienced children: Use of ETR is under investigation in this population. A recent presentation indicated that ETR 25mg is safe and acceptable Need for special diagnostic or treatment facilities and skills Not needed 10. Summary of comparative effectiveness in a variety of clinical settings The analyses of 48-week data from two, randomised, double-blinded, placebo-controlled, Phase III trials (DUET-1 and DUET-2) 2 were used to evaluate the efficacy of ETR 200mg b.i.d. in ART-experienced patients. 3 Treatment-experienced HIV-1 patients with a plasma HIV-1 RNA > 5000 copies/ml, one reverse transcriptase resistance mutation, three protease resistance mutations, and on a stable antiretroviral regimen for at least 8 weeks were eligible. Randomisation was stratified by the intended use of enfuvirtide (ENF) in the background regimen (BR), previous use of darunavir/ritonavir, and screening viral load. This analysis included 612 patients in DUET-1 and 591 patients in DUET-2 who had completed 48 weeks of treatment or discontinued earlier. DUET-1 and DUET-2 were identical in design. Similar ETR efficacy was seen in each trial. The results presented are pooled data from the two trials. At 48 weeks, the virologic response rate was evaluated in patients receiving etravirine (200 mg b.i.d.) in addition to an optimised background versus patients receiving placebo in addition to an optimised background. The optimised background consisted of darunavir/ritonavir 600/100 mg b.i.d.

4 and at least two other investigator-selected antiretroviral agents. Virologic response was defined as achieving a confirmed undetectable viral load (<50 HIV-1 RNA copies/ml). The table below shows the efficacy results at 48 weeks for patients in the etravirine arm and patients in the placebo arm from the pooled DUET-1 and DUET-2 trials. At baseline the median plasma HIV-1 RNA was 4.8 log copies/ml while the median CD4 count was 105 cells/µl. Outcome Etravirine + BR, N=599 Placebo + BR, N=604 Treatment difference (95% CI) Viral Load < 50 copies/ml 1, n(%) 363 (60.6%) 240 (39.7%) 20.9% (15.3%; 26.4%) 4 Viral load < 400 copies/ml 1, n(%) 428 (71.5%) 286 (47.4%) 24.1% (18.7%; 29.5%) 4 HIV-1 RNA log 10 mean change from baseline (log 10 copies/ml) (-0.82; -0.46) 3 CD4 cell count mean change from baseline (x 10 6 /l) (10.4; 38.5) 3 AIDS defining illness and/or -3.9% (-6.9; -0.9) 5 35 (5.8%) 59 (9.8%) death, n (%) 1 Imputations according to the TLOVR algorithm 0. 2 Non-completer is failure (NC = F) imputation: patients who discontinued prematurely are imputed with a change equal to 0 at all timepoints after discontinuation. 3 Treatment differences are based on Least Square means from an ANCOVA model including the stratification factors. P-value < for mean decrease in HIV-1 RNA; P-value= for mean change in CD4 cell count. 4 Confidence interval around observed difference of response rates; P-value < Confidence interval around observed difference of incidence rates; P-value= At week 48, significantly fewer patients in the etravirine arm (35 patients, 5.8%) reached a clinical endpoint (AIDS-defining illness and/or death) as compared to the placebo arm (59 patients, 9.8%) (p=0.0408). 11. Summary of comparative evidence on safety: 11.1 Estimate of total patient exposure to date In the clinical trials, cumulatively, up to the cut-off date of 27 September 2010, a total of 13,935 subjects were exposed to etravirine in either Company-sponsored trials, EAPs, Named Patient Programs, or Compassionate Use programs. Post-marketing estimated exposure is 732,398 person-months Description of adverse effects/reactions Adverse events reported in the DUET trials at week 48, myocardial infarction, anaemia, thrombocytopaenia, peripheral neuropathy, headache, diarrhoea, nausea, abdominal pain, vomiting, gastroesophageal reflux disease, flatulence, gastritis, renal failure, rash,

5 lipohypertrophy, night sweats, hypertriglyceridaemia, hypercholesterolaemia, hyperlipidaemia, diabetes mellitus, hypertension, fatigue, insomnia, anxiety, angina pectoris, atrial fibrillation, paraesthesia, somnolence, convulsion, hypoaesthesia, amnesia, syncope, disturbance in attention, hypersomnia, tremor, blurred vision, vertigo, exertional dyspnoea, bronchospasm, abdominal distension, pancreatitis, constipation, dry mouth, haematemesis, retching, stomatitis, prurigo, hyperhidrosis, dry skin, swelling face, disorders: anorexia, dyslipidaemia, sluggishness, drug hypersensitivity, immune reconstitution syndrome, hepatomegaly, cytolytic hepatitis, hepatic steatosis, hepatitis, gynaecomastia, sleep disorders, abnormal dreams, confusional state, disorientation, nervousness, nightmareserror! Reference source not found. Additional ADRs of at least moderate intensity observed in other trials were acquired lipodystrophy, angioneurotic edema, erythema multiforme and haemorrhagic stroke, each reported in no more than 0.5% of patients. Stevens Johnson Syndrome (rare; < 0.1%) and toxic epidermal necrolysis (very rare; < 0.01%) have been reported during clinical development with etravirine. Adverse Drug Reactions identified during postmarketing experience with etravirine: hypersensitivity reactions have been reported and were characterized by rash, constitutional findings, and infrequently organ dysfunction, including hepatic failure; rhabdomyolysis. The following laboratory abnormalities were considered ADRs:pancreatic amylase, creatinine, lipase, white blood cell count, neutrophils, total cholesterol, low density lipoprotein, triglycerides, elevated glucose levels, alanine amino transferase and aspartate amino transferase Identification of variation in safety due to health systems and patient factors No clinically significant differences in safety have been identified due to differences in health systems and patient factors Summary of comparative safety against comparators Please see appendix two for a table describing the adverse events seen after 48 weeks of follow up in patients on placebo and ETR. 12. Summary of available data on comparative cost and cost-effectiveness within the pharmacological class or therapeutic group: 12.1 Range of costs of the proposed medicine The company has signed a royalty-free voluntary license and partnership agreement with the generic manufacturer Aspen to provide access to ETR in sub-saharan Africa. As a result of the agreement there will be a single co-branded product in sub-saharan Africa, under the brand name INTELENCE, distributed by Aspen and sold at a an ex-factory price that should not exceed US$2.5 a day. The product is offered on an FOB basis incoterm Additional costs may include the logistics fee in South Africa, or the freight, insurance, customs handling, taxes and duties, and other costs levied at the discretion of national authorities and other respective entities in the other sub-saharan countries and least

6 developed countries, which are beyond the control of Aspen and Tibotec. Local retail prices may therefore be higher. In middle income countries, the company works with local health authorities to enable prompt regulatory approval and inclusion in the National AIDS program and/or HIV/AIDS treatment guidelines. Middle-income country prices for ETR reflect a substantial reduction from those in the US and Western Europe and reflect health authorities assessments of patient need for ETR in these countries based on the local label indication. In view of the initial indication for treatment of highly treatment experienced patients, demand in developing countries as well as funding by Global Fund and /or PEPFAR has been low. The information in the International Drug Price Indicator Guide as well as the Global Price Reporting Mechanism is thus based on a limited number of transactions, and does not provide an appropriate average price in Middle Income Countries. MSF lists the price of ETR therapy as 913 USD / year Comparative cost-effectiveness (presented as range of cost per routine outcome) The cost-effectiveness studies reported in this section focus on evidence from the developed world, and are available from multiple countries perspectives, including US, and several European countries, based on the pooled 48-week data from the DUET trials. The results may not necessarily be applicable to resource-poor countries, due to different health care settings and unit costs for antiretroviral drugs and other health care resources. There are no analyses that specifically assess the cost-effectiveness of ETR for the treatment of experienced patients in these settings. An overview of several different economic analyses, including cost analyses, costeffectiveness and cost-utility models, has reported that the addition of ETR to a background antiretroviral regimen in treatment-experienced patients has not only been shown to improve outcomes but also to be cost-effective 5. In summary, the economic evaluations showed that the addition of ETR to a regimen was associated with lower costs per person with an undetectable viral load and lower hospital-related costs compared with placebo. Thus, an ARV regimen containing ETR increased the number of patients reaching the treatment goal of undetectable virus for the same initial expenditure. Finally, a lifetime costutility Markov model based on DUET data estimated ETR to be cost-effective in treatmentexperienced people living with HIV/AIDS, compared with an optimized control regimen. 13. Summary of regulatory status of the medicine (in country of origin, and preferably in other countries as well). Etravirine 100 mg tablets Marketing Authorization was first granted by the Food and Drug Administration (FDA) on 18 January The European Medicines Agency (EMA) granted Marketing Authorization to etravirine 100 mg tablets on 28 August Besides these registrations, more than 30 countries in other regions have then granted local Marketing Authorisation. 14. Availability of pharmacopoeial standards (British Pharmacaopoeia, International Pharmacopoeia, United States Pharmacopeia) International Pharmacopoeia

7 15. Proposed (new/adapted) text for the WHO Model Formulary *Note the AHFS Drug Information book was used as a reference for this section. Dosage forms: 100mg tablet Description: Etravirine is a second-generation non-nucleoside reverse transcriptase inhibitor Uses: Treatment of HIV in combination with at least two other antiretrovirals in third-line therapy. Contraindications: Hypersensitivity to etravirine or to any of the excipients. Precautions: Severe, potentially life threatening, and fatal skin reactions have been reported with etravirine; Stevens Johnson Syndrome and toxic epidermal necrolysis have been rarely reported (< 0.1%). Hypersensitivity reactions have also been reported and were characterized by rash, constitutional findings, and infrequently organ dysfunction, including hepatic failure. Most frequently, rash was mild to moderate, occurred in the second week of therapy and was infrequent after week 4. Rash was mostly self limiting and generally resolved after 1 to 2 weeks on continued therapy. In Phase 3 studies, 2.2% of patients on etravirine discontinued therapy because of rash. Discontinue etravirine immediately if signs or symptoms of severe skin reactions or hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis, or eosinophilia). Clinical status including liver transaminases should be monitored and appropriate therapy initiated. Delay in stopping etravirine treatment after the onset of severe rash may result in a life threatening reaction. Doses: ETR 100mg b.i.d. in combination with other antiretrovirals and food. Adverse effects: Adverse events reported in the DUET trials at week 48, myocardial infarction, anaemia, thrombocytopaenia, peripheral neuropathy, headache, diarrhoea, nausea, abdominal pain, vomiting, gastroesophageal reflux disease, flatulence, gastritis, renal failure, rash, lipohypertrophy, night sweats, hypertriglyceridaemia, hypercholesterolaemia, hyperlipidaemia, diabetes mellitus, hypertension, fatigue, insomnia, anxiety, angina pectoris, atrial fibrillation, paraesthesia, somnolence, convulsion, hypoaesthesia, amnesia, syncope, disturbance in attention, hypersomnia, tremor, blurred vision, vertigo, exertional dyspnoea, bronchospasm, abdominal distension, pancreatitis, constipation, dry mouth, haematemesis, retching, stomatitis, prurigo, hyperhidrosis, dry skin, swelling face, disorders: anorexia, dyslipidaemia, sluggishness, drug hypersensitivity, immune reconstitution syndrome, hepatomegaly, cytolytic hepatitis, hepatic steatosis, hepatitis, gynaecomastia, sleep disorders, abnormal dreams, confusional state, disorientation, nervousness, nightmareserror! Reference source not found. Additional ADRs of at least moderate intensity observed in other trials were acquired lipodystrophy, angioneurotic edema, erythema multiforme and haemorrhagic stroke, each

8 reported in no more than 0.5% of patients. Stevens Johnson Syndrome (rare; < 0.1%) and toxic epidermal necrolysis (very rare; < 0.01%) have been reported during clinical development with etravirine. Adverse Drug Reactions identified during postmarketing experience with etravirine: hypersensitivity reactions have been reported and were characterized by rash, constitutional findings, and infrequently organ dysfunction, including hepatic failure; rhabdomyolysis. The following laboratory abnormalities were considered ADRs: pancreatic amylase, creatinine, lipase, white blood cell count, neutrophils, total cholesterol, low density lipoprotein, triglycerides, elevated glucose levels, alanine amino transferase and aspartate amino transferase. Pregnancy: The US FDA has classified ETR as a class B drug (Animal reproduction studies have failed to demonstrate a risk to the foetus and there are no adequate and well-controlled studies in pregnant women). Drug interactions: Etravirine is a weak inducer of CYP3A. Co-administration of etravirine with medicinal products primarily metabolised by CYP3A may result in decreased plasma concentrations of such medicinal products, which could decrease or shorten their therapeutic effects. Etravirine is a weak inhibitor of CYP2C9 and CYP2C19. Etravirine is also a weak inhibitor of P-glycoprotein but not a substrate. Co-administration with medicinal products primarily metabolised by CYP2C9 or CYP2C19 or transported by P-glycoprotein may result in increased plasma concentrations of such medicinal products, which could increase or prolong their therapeutic effect or adverse events profile. Detailed information in Appendix 1.

9 Appendix 1. Drug interactions *amiodarone Plasma concentration of amiodarone decreased *atazanavir atazanavir/ritonavir atorvastatin *bepridil *carbamazepine clarithromycin *clopidrogel *cyclosporine darunavir/ritonavir *dexamethasone (systemic) diazepam digoxin *disopyramide *efavirenz ethinylestradiol *flecainide fluconazole fluvastatin fosamprenavir fosamprenavir/ritonavir *indinavir Plasma concentration of atazanavir decreased; plasma concentration of etravirine increased Plasma concentration of atazanavir decreased; plasma concentration of etravirine increased Plasma concentration of atorvastatin decreased Plasma concentration of bepridil decreased Plasma concentration of clarithromycin decreased; plasma concentration of etravirine increased Activation of clopidrogel to its active metabolite decreased Plasma concentration of cyclosporine affected Plasma concentration of diazepam increased Plasma concentration of digoxin increased Plasma concentration of disopyramide decreased Plasma concentration of ethinylestradiol increased Plasma concentration of flecainide decreased Plasma concentration of etravirine increased Plasma concentration of fluvastatin increased Plasma concentration of amprenavir increased Plasma concentration of amprenavir increased Plasma concentration of indinavir decreased

10 itraconazole ketoconazole *lidocaine (systemic) lopinavir/ritonavir lovastatin maraviroc *mexiletine nelfinavir *nevirapine omeprazole *phenobarbital *phenytoin pitavastatin posaconazole *propafenone *quinidine raltegravir ranitidine rifabutin *rifampicin *rifapentine *ritonavir (600 mg b.i.d.) rosuvastatin *saquinavir Plasma concentration of itraconazole decreased; plasma concentration of etravirine increased Plasma concentration of ketoconazole decreased; plasma concentration of etravirine increased Plasma concentration of lidocaine decreased Plasma concentration of lovastatin decreased Plasma concentration of maraviroc decreased Plasma concentration of mexiletine decreased Plasma concentration of nelfinavir increased Plasma concentration of etravirine increased Plasma concentration of pitavastatin increased Plasma concentration of etravirine increased Plasma concentration of propafenone decreased Plasma concentration of quinidine decreased Plasma concentration of raltegravir decreased Plasma concentration of rifabutin decreased; plasma concentration of etravirine decreased Plasma concentration of rosuvastatin affected Plasma concentration of saquinavir decreased

11 saquinavir/ritonavir sildenafil simvastatin *sirolimus *St John s wort *tacrolimus tadalafil Plasma concentration of sildenafil decreased Plasma concentration of simvastatin decreased Plasma concentration of sirolimus affected Plasma concentration of tacrolimus affected Plasma concentration of tadalafil decreased tenofovir disoproxil fumarate *tipranavir/ritonavir vardenafil voriconazole warfarin Plasma concentration of tipranavir increased; plasma concentration of etravirine decreased Plasma concentration of vardenafil decreased Plasma concentration of voriconazole increased; plasma concentration of etravirine increased Plasma concentration of warfarin affected * indicates a potentially hazardous interaction and the combined administration of the drugs involved should be avoided, or only be taken with caution and appropriate monitoring. Interactions with no symbol do not usually have serious consequences but dose adjustments may be needed. In case of no interaction, drugs are not listed. Medicinal products that affect etravirine exposure Etravirine is metabolised by cytochrome P450 (CYP) 3A, CYP2C9 and CYP2C19 followed by glucuronidation of the metabolites by uridine diphosphate glucuronosyl transferase (UDPGT). Medicinal products that induce CYP3A, CYP2C9, or CYP2C19 may increase the clearance of etravirine resulting in lowered plasma concentrations of etravirine. Coadministration of etravirine and medicinal products that inhibit CYP3A, CYP2C9, or CYP2C19 may decrease the clearance of etravirine and may result in increased plasma concentrations of etravirine. Medicinal products that are affected by the use of etravirine Etravirine is a weak inducer of CYP3A. Co-administration of etravirine with medicinal products primarily metabolised by CYP3A may result in decreased plasma concentrations of such medicinal products, which could decrease or shorten their therapeutic effects. Etravirine is a weak inhibitor of CYP2C9 and CYP2C19. Etravirine is also a weak inhibitor of P-glycoprotein but not a substrate. Co-administration with medicinal products primarily metabolised by CYP2C9 or CYP2C19 or transported by P-glycoprotein may result in

12 increased plasma concentrations of such medicinal products, which could increase or prolong their therapeutic effect or adverse events profile. Known and theoretical interactions with selected antiretrovirals and non-antiretroviral medicinal products are listed in the tables below. Increase is indicated as, decrease as, no change as, not done as ND, once daily as q.d., once daily in the morning as q.a.m. and twice daily as b.i.d. Drug Interactions Etravirine co-administered with antiretroviral medicinal products Co-administered Medicinal Product Dose of Co-administered Medicinal Product (mg) Medicinal Product Assessed AUC C min Nucleoside or Nucleotide Reverse Transcriptase Inhibitors (NRTIs/N[t]RTIs) Didanosine 400 q.d. didanosine ND The combination of etravirine and didanosine can be used without dose adjustments. As didanosine is administered on an empty stomach, didanosine should be administered one hour before or two hours after etravirine (which should be administered following a meal). Tenofovir disoproxil fumarate Other NRTIs 300 q.d. tenofovir 19% etravirine 19% 18% The combination of etravirine and tenofovir disoproxil fumarate can be used without dose adjustments. Based on the primarily renal elimination route for other NRTIs (e.g., abacavir, emtricitabine, lamivudine, stavudine and zidovudine), no drug interactions are expected between these medicinal products and etravirine. Protease Inhibitors (PIs) - Boosted (with low dose ritonavir) Fosamprenavir/ ritonavir 700/100 b.i.d. amprenavir 69% 77% Amprenavir and fosamprenavir/ritonavir may require dose adjustment when co-administered with etravirine. Atazanavir/ritonavir 300/100 q.d. atazanavir 14% 38% etravirine 30% 26% The combination of etravirine and atazanavir/ritonavir can be used without dose adjustments. Darunavir/ritonavir 600/100 b.i.d. darunavir etravirine 37% 49% The combination of etravirine and darunavir/ritonavir can be used without dose adjustments. Lopinavir/ritonavir (soft-gel capsule) Lopinavir/ritonavir (melt extrusion tablet) 400/100 b.i.d. lopinavir 20% 8% etravirine 17% 23% The combination of etravirine and lopinavir/ritonavir (soft-gel capsule) can be used without dose adjustments. 400/100 b.i.d. lopinavir 20% etravirine 35% 45%

13 The combination of etravirine and lopinavir/ritonavir (melt extrusion tablet) can be used without dose adjustments. Saquinavir/ritonavir 1000/100 b.i.d. saquinavir 20% (soft-gel capsule) etravirine 33% 29% The combination of etravirine and saquinavir/ritonavir can be used without dose adjustments. CCR5 Antagonists Maraviroc 300 b.i.d. maraviroc 53% 39% Concomitant use of etravirine with maraviroc may cause a significant decrease in the plasma concentration of maraviroc. When etravirine is co-administered with maraviroc in the absence of a potent CYP3A inhibitor (e.g., a boosted PI), the recommended dose of maraviroc is 600 mg b.i.d. No dose adjustment for etravirine is needed. Maraviroc/darunavir/ ritonavir 150/600/100 b.i.d. maraviroc 3.1-fold* 5.3-fold* When etravirine is co-administered with maraviroc in the presence of a potent CYP3A inhibitor (e.g., a boosted PI), refer to the applicable prescribing information of maraviroc for the recommended dose, treating etravirine as a CYP3A inducer (such as efavirenz). No dose adjustment for etravirine is needed. * compared to maraviroc 150 mg b.i.d. Fusion Inhibitors Enfuvirtide 90 b.i.d. enfuvirtide ND ND etravirine* No interaction is expected for either etravirine or enfuvirtide when co-administered. * based on population pharmacokinetic analysis Integrase Strand Transfer Inhibitors Elvitegravir/ritonavir 150/100 q.d. elvitegravir ND ritonavir ND etravirine ND The combination of etravirine and elvitegravir/ritonavir can be used without dose adjustments. Raltegravir 400 b.i.d. raltegravir 10% 34% The combination of etravirine and raltegravir can be used without dose adjustments. Drug Interactions Etravirine co-administered with non-antiretroviral medicinal products Co-administered Medicinal Product Medicinal Product Assessed AUC Dose of Co-administered Medicinal Product (mg) Antiarrhythmics Digoxin 0.5 mg single dose digoxin 18% ND C min

14 Amiodarone Bepridil Disopyramide Flecainide Lidocaine (systemic) Mexiletine Propafenone Quinidine Anticoagulants Warfarin Anticonvulsants Carbamazepine Phenobarbital Phenytoin The combination of etravirine and digoxin can be used without dose adjustments. It is recommended that digoxin levels be monitored when digoxin is combined with etravirine. Concentrations of these antiarrhythmics may be decreased when co-administered with etravirine. Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when co-administered with etravirine. Warfarin concentrations may be affected when co-administered with etravirine. It is recommended that the international normalised ratio (INR) be monitored when warfarin is combined with etravirine. Carbamazepine, phenobarbital and phenytoin are inducers of CYP450 enzymes. etravirine should not be used in combination with carbamazepine, phenobarbital, or phenytoin as co-administration may cause significant decreases in etravirine plasma concentrations. This may result in loss of therapeutic effect of etravirine. Antifungals Fluconazole 200 q.a.m. fluconazole etravirine 86% 109% The incidence of adverse events was similar in patients coadministering fluconazole and etravirine or placebo in the Phase III trials. The combination of etravirine and fluconazole can be used without dose adjustments. Voriconazole 200 b.i.d. voriconazole 14% 23% etravirine 36% 52% The combination of etravirine and voriconazole can be used without dose adjustments. Itraconazole Ketoconazole Posaconazole Antiinfectives Azithromycin Posaconazole, a potent inhibitor of CYP3A, may increase plasma concentrations of etravirine. Itraconazole and ketoconazole are potent inhibitors as well as substrates of CYP3A. Concomitant systemic use of itraconazole or ketoconazole and etravirine may increase plasma concentrations of etravirine. Simultaneously, plasma concentrations of itraconazole or ketoconazole may be decreased by etravirine. The combination of etravirine and these antifungals can be used without dose adjustments. Based on the renal elimination pathway of azithromycin, no drug interactions are expected between azithromycin and etravirine. Clarithromycin 500 b.i.d. clarithromycin 39% 53% 14-hydroxy- 21% clarithromycin etravirine 42% 46%

15 Antimycobacterials Rifampicin/Rifampin Rifapentine Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-hydroxy-clarithromycin, were increased. Because 14-hydroxy-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore, alternatives to clarithromycin, such as azithromycin, should be considered for the treatment of MAC. Rifampicin and rifapentine are potent inducers of CYP450 enzymes. etravirine should not be used in combination with rifampicin or rifapentine as co-administration may cause significant decreases in etravirine plasma concentrations. This may result in loss of therapeutic effect of etravirine. Rifabutin 300 q.d. rifabutin 17% 24% Antivirals Ribavirin Benzodiazepines Diazepam Corticosteroids Dexamethasone (systemic) 25-O- 17% 22% desacetylrifabutin etravirine 37% 35% If etravirine is not co-administered with a boosted protease inhibitor, then etravirine and rifabutin can be used without dose adjustments. If etravirine is co-administered with boosted darunavir, lopinavir or saquinavir, then the combination with rifabutin should be used with caution due to the potential for significant reductions in etravirine exposure. When etravirine is co-administered with rifabutin and a boosted protease inhibitor, the recommended dose of rifabutin is determined by the prescribing information for the boosted protease inhibitor component of the regimen. Based on the renal elimination pathway of ribavirin, no drug interactions are expected between ribavirin and etravirine. Concomitant use of etravirine with diazepam may increase plasma concentrations of diazepam. Systemic dexamethasone induces CYP3A and can decrease etravirine plasma concentrations. This may result in loss of therapeutic effect of etravirine. Systemic dexamethasone should be used with caution or alternatives should be considered, particularly for long-term use. Estrogen-based Contraceptives Ethinylestradiol q.d. ethinylestradiol 22% Norethindrone 1 q.d. norethindrone 22% The combination of estrogen- and/or progesterone-based contraceptives and etravirine can be used without dose adjustment. Herbal Products St John's wort (Hypericum perforatum) Etravirine should not be used concomitantly with products containing St John s wort because co-administration may cause significant decreases in etravirine plasma concentrations. This may result in loss of therapeutic effect of etravirine. HMG Co-A Reductase Inhibitors Atorvastatin 40 q.d. atorvastatin 37% ND 2-hydroxyatorvastatin 27% ND

16 Fluvastatin Lovastatin Pitavastatin Pravastatin Rosuvastatin Simvastatin Dose adjustment of atorvastatin may be necessary to tailor the clinical response when combined with etravirine. No interaction between pravastatin and etravirine is expected. Lovastatin, rosuvastatin and simvastatin are CYP3A substrates and co-administration with etravirine may result in lower plasma concentrations of the HMG Co-A reductase inhibitor. Fluvastatin, rosuvastatin and, to a lesser extent, pitavastatin are metabolised by CYP2C9 and co-administration with etravirine may result in higher plasma concentrations of the HMG Co-A reductase inhibitor. Dose adjustments for these HMG Co-A reductase inhibitors may be necessary. H 2 -Receptor Antagonists Ranitidine 150 b.i.d. etravirine 14% ND Etravirine can be co-administered with H 2 -receptor antagonists without dose adjustments. Immunosuppressants Cyclosporine Sirolimus Tacrolimus Narcotic Analgesics Methadone Co-administration with systemic immunosuppressants should be done with caution because plasma concentrations of cyclosporine, sirolimus, or tacrolimus may be affected when co-administered with etravirine. individual dose ranging R(-) methadone from 60 to 130 mg/day S(+) methadone No changes in methadone dosage were required based on clinical status during or after the period of etravirine co-administration. Phosphodiesterase, type 5 (PDE-5) inhibitors Sildenafil 50 mg single dose sildenafil 57% ND Vardenafil N-desmethyl- 41% ND Tadalafil sildenafil Concomitant use of PDE-5 inhibitors with etravirine may require dose adjustment of the PDE-5 inhibitor to attain the desired clinical effect. Platelet Aggregation Inhibitors Clopidogrel Activation of clopidogrel to its active metabolite may be decreased when clopidogrel is co-administered with etravirine. Alternatives to clopidogrel should be considered. Proton Pump Inhibitors Omeprazole 40 q.d. etravirine 41% ND Etravirine can be co-administered with proton pump inhibitors without dose adjustments. Selective Serotonin Reuptake Inhibitors (SSRIs) Paroxetine 20 q.d. paroxetine 13% Etravirine can be co-administered with paroxetine without dose adjustments. * In drug-drug interaction studies, different formulations and/or doses of etravirine were used which led to similar exposures and, therefore, interactions relevant for one formulation are relevant for the other.

17 Appendix 2: Overview of adverse events from pooled analysis of DUET studies Etravirine +background regimen (n =599) Placebo +background regimen (n = 604) Incidence and severity of adverse events, n (%) Any adverse event 575 (96) 580 (96) Grade 3 or 4 adverse event 199 (33) 211 (35) Serious adverse events 118 (20) 141 (23) Adverse events leading to discontinuation 43 (7) 34 (6) Deaths 12 (2) 20 (3) Most common adverse events of all intensities and regardless of causality occurring in >10% of etravirine patients, n (%) Rash (any type) 115 (19) 66 (11) Diarrhoea 108 (18) 142 (24) Nausea 89 (15) 77 (13) Nasopharyngitis 66 (11) 63 (10) Headache 65 (11) 77 (13) Injection-site reaction 63 (11) 75 (12) Treatment-emergent adverse events of at least moderate intensity (grades 2 4) in at least 2% of etravirine patients, n (%) Rash 60 (10) 21 (4) Diarrhoea 42 (7) 68 (11) Nausea 31 (5) 29 (5) Anaemia 24 (4) 23 (4) Peripheral neuropathy 23 (4) 12 (2) Abdominal pain 21 (4) 19 (3) Fatigue 21 (4) 28 (5) Hypertension 19 (3) 15 (3) Headache 18 (3) 27 (5) Vomiting 17 (3) 17 (3) Insomnia 16 (3) 17 (3) Renal failure 16 (3) 12 (2) Adverse events of specific interest (grouped terms), n (%) Nervous system 103 (17) 119 (20) Psychiatric 100 (17) 118 (20) Hepatic 39 (7) 37 (6)

18 Appendix 3. List of Abbreviations ADR Adverse Drug Reaction AHFS American Hospital Formulary Service AIDS acquired immunodeficiency syndrome ANCOVA analysis of covariance ART antiretroviral therapy ARV antiretroviral ATC Anatomical Therapeutic Chemical AUC area under curve b.i.d. bis in die ; twice daily BR background regimen CART combination antiretroviral therapy CCR5 CC chemokine receptor type 5 CD4 cluster of differentiation 4 C min minimum plasma concentration CI confidence interval CYP cytochrome P450 EAP Expanded Access Program EMA European Medicines Agency ENF enfuvirtide ETR etravirine FDA Food and Drug Administration FOB free on board HAART highly active antiretroviral therapy HMG Co-A 3-hydroxy-3-methylglutaryl coenzyme-a HTM HIV/AIDS, Tuberculosis, and Malaria INN international non-proprietary name INR international normalised ratio MAC Mycobacterium avium complex MSF Médecins Sans Frontières NC=F non-completer equals failure ND not done NNRTI non-nucleoside reverse transcriptase inhibitor NRTI nucleoside reverse transcriptase inhibitor N[t]RTI Nucleoside [nucleotide] reverse transcriptase inhibitor PDE-5 phosphodiesterase type 5 PEPFAR President s Emergency Plan for AIDS Relief PI protease inhibitor PLHIV people living with HIV/AIDS q.a.m. once daily in the morning q.d. quaque die ; once daily RNA ribonucleic acid SSRI selective serotonin reuptake inhibitor TLOVR time to loss of virologic response UNAIDS Joint United Nations Programme on HIV and AIDS US United States USD United States Dollar WHO World Health Organization

19 References 1 Schöller-Gyüre M, Kakuda TN, Van Solingen-Ristea RM et al. Bioavailability of the 100mg etravirine tablet dispersed in water and of the 25mg pediatric tablet formulation. 17th IAS, Mexico City, Abstract MOPE Katlama C, Haubrich R, Lalezari J, et al. Efficacy and safety of etravirine in treatment-experienced, HIV-1 patients: pooled 48 week analysis of two randomized, controlled trials. AIDS Nov 13;23(17): U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Clinical Medical, October Guidance for Industry, Antiretroviral Drugs Using Pl HIV RNA Measurements Clinical Considerations for Accelerated and Traditional Approval. (Appendix B). 4 Untangling the Web of Antiretroviral Price Reduction [Internet]. [cited 2010 Nov 24]; Available from 5 Fullerton DS, Watson MJ, Anderson D, Witek J, Martin SC, Mrus JM. Pharmacoeconomics of etravirine. Expert Rev Pharmacoecon Outcomes Res Oct;10(5);