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An application to include blood pressure lowering drug fixed dose combinations to the model list of essential medicines lists for the treatment of essential hypertension in adults

Author Organization Abdul Salam The George Institute for Global Health India Raju Kanukula The George Institute for Global Health India Hariprasad Esam The George Institute for Global Health India Ehete Bahiru Northwestern University Feinberg School of Medicine Abhishek Sharma Boston University School of Public Health, and Precision Health Economics David Heller Arnhold Institute for Global Health Mark Huffman Northwestern University Feinberg School of Medicine Rajesh Vedanthan Icahn School of Medicine at Mount Sinai Anubha Agarwal Duke University and NIH Fogarty Global Health Fellow Marc G. Jaffe Resolve to Save Lives, Vital Strategies, and Kaiser Permanente Northern California Tom Frieden Resolve to Save Lives, Vital Strategies Sandeep P. Kishore Arnhold Institute for Global Health & Young Professionals Chronic Disease Network Anthony Rodgers The George Institute for Global Health

Coordinated and Submitted by: Sandeep P. Kishore, Arnhold Institute for Global Health & Young Professionals Chronic Disease Network Anthony Rodgers, The George Institute for Global Health

Marc G. Jaffe, Resolve to Save Lives, Vital Strategies, and Kaiser Permanente Northern California Tom Frieden, Resolve to Save Lives, Vital Strategies

Contact: Cherian Varghese, Coordinator, Management of NCDs, WHO Department for Management of Noncommunicable Diseases, Disability, Violence and Injury Prevention

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Table of Contents

General items ...... 5 1. Summary statement of the proposal for inclusion, change or deletion...... 5 Rationale for inclusion ...... 5 Hypertension guidelines recommendations for use of two BP lowering drugs and FDCs . 5 2. Name of the WHO technical department and focal point supporting the application (where relevant) ...... 7 3. Name of organization(s) consulted and/or supporting the application...... 7 4. International Nonproprietary Name (INN) and Anatomical Therapeutic Chemical (ATC) code of the medicine...... 7 5. Formulation(s) and strength(s) proposed for inclusion; including adult and pediatric (if appropriate)...... 7 6. Whether listing is requested as an individual medicine or as representative of a pharmacological class...... 8 7. Treatment details (requirements for diagnosis, treatment and monitoring)...... 10 Diagnosis and monitoring of hypertension ...... 10 Treatment strategy with dual BP combinations ...... 11 8. Information supporting the public health relevance...... 12 Epidemiological information on disease burden and treatment gaps ...... 12 Comparing Fixed-dose combinations vs. separate pills...... 13 Target population(s) ...... 14 Likely impact of treatment on the disease ...... 14 9. Review of benefits: summary of comparative effectiveness in a variety of clinical settings...... 14 Review of BP lowering efficacy of dual vs mono therapy ...... 14 Review of BP lowering efficacy of initial therapy with dual combination vs mono therapy ...... 14 Review of effects of combination therapy vs. placebo/no treatment on cardiovascular events ...... 15 Review of clinical trials assessing BP lowering efficacy of FDC combinations ...... 16 Review of clinical trials assessing BP lowering efficacy of lisinopril/HCTZ ...... 17 Lisinopril/HCTZ vs. placebo ...... 17 Lisinopril/HCTZ vs. monotherapy ...... 17 Lisinopril/HCTZ vs. other dual combination therapies ...... 17 Review of clinical trials assessing BP lowering efficacy of telmisartan/amlodipine combination ...... 18 Telmisartan/amlodipine vs. placebo ...... 18 Page 3 of 71

Telmisartan-amlodipine vs. monotherapy ...... 18 Telmisartan-amlodipine vs. other dual therapies ...... 19 Telmisartan/amlodipine as initial therapy ...... 19 Review of clinical trials assessing BP lowering efficacy of telmisartan/HCTZ combinations ...... 19 Telmisartan/HCTZ vs. placebo ...... 19 Telmisartan/HCTZ vs. monotherapy ...... 19 Telmisartan/HCTZ vs. dual therapy ...... 20 Review of clinical trials assessing BP lowering efficacy of lisinopril/amlodipine combination ...... 20 10. Review of harms and toxicity: summary of evidence on safety...... 21 Review of safety of dual vs mono therapy ...... 21 Review of safety of initial therapy with dual combination vs mono therapy ...... 21 Safety data for Lisinopril/HCTZ ...... 21 Safety data for Telmisartan/Amlodipine ...... 24 Safety data for lisinopril/amlodipine ...... 26 Safety data for Telmisartan/HCTZ ...... 27 11. Summary of available data on comparative price of medicines within the pharmacological class or therapeutic group...... 28 Current price insights with respect to global use ...... 28 Procurement prices of proposed FDCs versus single pills: case study from India ...... 29 Retail prices of proposed FDCs versus single pills: case study from India ...... 30 Evergreening strategies and FDC price points...... 31 Implications on cost of FDC for hypertension if added to WHO EML ...... 31 12. Summary of regulatory status of the medicine ...... 32 13. Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia, United States Pharmacopoeia, European Pharmacopeia)...... 33 14. References ...... 34 Appendix 1: Gender-specific hypertension awareness, treatment, and control in 2010 in countries with data by world region1 ...... 40 Appendix 2: Initial dual combination PRISMA flow chart reporting identification and inclusion of studies and search strategy ...... 43 Appendix 3: Summary of characteristics of trials included in Initial dual combination therapy systematic review ...... 48 Appendix 4: Summary of characteristics of RCTs that assessed the effects of combination therapy of BP lowering drugs compared to placebo/no treatment on CV outcomes ...... 51 Appendix 5: Lisinopril + HCTZ search strategy ...... 53 Appendix 6: Lisinopril + HCTZ PRISMA flow chart ...... 54 Page 4 of 71

Appendix 7: Summary of characteristics of included trials for assessing lisinopril + HCTZ ...... 55 Appendix 8: Telmisartan + Amlodipine search strategy ...... 56 Appendix 9: Telmisartan + Amlodipine PRISMA flow chart ...... 57 Appendix 10: Summary of characteristics of included trials for assessing telmisartan + amlodipine ...... 58 Appendix 11: Telmisartan + Hydrochlorothiazide search strategy ...... 60 Appendix 12: Telmisartan + HCTZ PRISMA flow chart ...... 61 Appendix 13: Summary of characteristics of included trials for assessing telmisartan + HCTZ ...... 62 Appendix 14: Lisinopril + Amlodipine search strategy ...... 64 Appendix 15: Lisinopril + amlodipine PRISMA flow chart...... 65 Appendix 16: Summary of characteristics of included trials for assessing lisinopril + amlodipine ...... 66 Appendix 17: Manufacturers of proposed combinations in EU, USA and India ...... 67 Appendix 18: Standard doses of component drugs of the proposed combinations .... 70

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General items

1. Summary statement of the proposal for inclusion, change or deletion.

Rationale for inclusion Cardiovascular disease (CVD) is the world’s leading cause of death, driving 18 million deaths annually.1 High blood pressure (BP) – hypertension – is the leading cause of CVD and the greatest cause of preventable morbidity and mortality globally, driving 10 million deaths.1 Worldwide, 1.4 billion people have hypertension, defined as SBP >140 mmHg or DBP >90 mmHg, but less than 15% have BP controlled to less than 140/90.2 Hypertension can be most effectively treated with low-cost, generic, safe, once daily regimens. However, most patients currently receive a single BP lowering drug (monotherapy), with the largest global survey indicating monotherapy was used for 60% of regimens3; while the evidence suggests that the vast majority of patients require two or more drugs to achieve optimal and sustained BP control.4,5 In low- and middle- income countries, more than 70% of people treated for hypertension have uncontrolled BP, with one major reason for low levels of control being that most only receive monotherapy.1 Major international clinical practice guidelines recommend addition of a second BP lowering drug when desired BP control is not achieved with monotherapy. These guidelines also recommend treatment initiation with two drugs for at least selected patients, such as those with markedly elevated BP.4–8 Among patients requiring treatment with more than one BP lowering drug, use of a fixed dose combination (FDC, also known as single-pill combination) is recommended instead of separate drugs (Table 1). For example, the 2017 ACC/AHA guidelines recommend prescribers to “utilize fixed-dose combination agents when available and simplify drug regimens” and the 2013 ESH/ESC Guidelines “favour the use of combinations of two antihypertensive drugs at fixed doses in a single tablet, because reducing the number of pills to be taken daily improves adherence, which is unfortunately low in hypertension, and increases the rate of BP control”. A systematic review of dual combination vs. monotherapy as initial therapy in hypertension is reported for this application, including 33 trials with more than 10,000 participants in total. The results showed a clear improvement in efficacy with similar tolerability. The size of benefit was clinically important: an overall 27% increase in the rate of achieving BP control among patients receiving dual combination therapy.

FDCs have substantial advantages for patients and healthcare programs, including improved adherence, simpler dose schedules, decreased pill burden, simplified logistics leading to fewer drug stock-outs, greater ease of task sharing, training, and supervision. This proposal therefore recommends the inclusion of four dual combinations which would collectively support the implementation of the recommended WHO HEARTS hypertension treatment protocols. Globally, approximately 320 million (37%) of the 510 million people treated for hypertension are not controlled.1 Improving control rates by 25% would therefore increase by 80 million the number of people with successfully controlled hypertension, which would in turn avert many hundreds of thousands of fatal or disabling cardiovascular events annually.

Hypertension guidelines recommendations for use of two BP lowering drugs and FDCs Guidelines from Europe, India, China, the United States as well as the WHO HEARTS program endorse the use of combination therapy for BP reduction. The 2017 guidelines from the American College of Cardiology and American Heart Association recommend combination therapy for BP above 140/90 with ACE inhibitors (ACEI) or Angiotensin Page 6 of 71

Receptor Blockers (ARB), calcium channel blockers (CCB) and thiazide /thiazide like diuretics.8

The latest European hypertension guidelines (2018 ESC/ESH9) recommend single-pill combinations (also known as FDCs) as usual therapy for hypertension as they improve adherence and BP control. In particular, these guidelines recognize and recommend dual combination therapy are initial therapy in most patients.

Table 1: Selected hypertension guideline recommendations on dual combination and FDCs

ACC/AHA ESC/ESH India China Thailand WHO 20178 20189 201310 201011 201512 HEARTS13

Recommendations when to use two BP lowering drugs

Not controlled on Yes Yes Yes Yes Yes Yes monotherapy

Initial treatment for all No Yes* No No No No Individuals Initial treatment for selected patients e.g. Yes Yes Yes Yes Yes Yes >20/10mmHg from goal** and/or high CV risk Recommendations when to use single pill combinations Recommended to substitute for separate pills to improve Yes Yes Yes Yes NR NR adherence * Consider monotherapy in low risk grade 1 hypertension (systolic BP <150 mmHg), or in very old (80 years) or frailer patients ** Some referred to this as stage II HTN or marked BP elevation, NR=Not reported

Addressing concerns raised by 2017 application for a dual BP lowering combination In 2017, the WHO Expert Panel reviewed a petition requesting the addition of an FDC for high BP (lisinopril and hydrochlorothiazide). The petition received favorable, publicly available, peer reviews; one reviewer suggested an amendment to the dose of diuretic; and another suggested a different combination to be included in the petition (in specific: amlodopine + benazepril). The previous petition, in part, prompted the WHO Expert Committee to formally recognize the benefits of cardiovascular FDC in the 2017 WHO EML:

“Fixed-dose combinations for non-communicable diseases may have advantages over the single medicines given concomitantly, including increased adherence and reduced pill burden. The potential value of fixed-dose combinations of currently listed essential medicines, with regulatory approval and demonstrated bioavailability for the management of chronic non-communicable diseases, is recognized.”

We note that a wide range of dual FDCs are available, and there is clinical and public health utility in having a selection available to guide national approaches, since some patients may have contraindications to one class of BP lowering drugs. For example, a significant number of patients, especially from in Asia and Africa, are susceptible to cough and other adverse effects from ACEI and so there is value in having an ARB combination. In this petition, we review possible FDCs to guide the WHO Expert Committee regarding formal inclusion on the EML. Given national and international scale-up opportunities for hypertension control, and substantial benefits of lowering BP well below 140 mmHg systolic14,15; and evidence that dual combination therapy reduces BP and cardiovascular events substantially more than monotherapy16,17 we recommend four two-drug FDC Page 7 of 71

each qualified with a square box additions to the WHO EML to improve competition over available alternative options. The recommendation for multiple dose options and four different combinations will directly address the issues raised in 2017 with the proposal for a single FDC: “that listing a single FDC of cardiovascular medicines would limit choice from the variety of combinations, components and dosages available.” These recommendations are based on worldwide availability and affordability and best available evidence:

Class Drug combinations (as representative) ACEI/Diuretic lisinopril/hydrochlorothiazide (HCTZ) ARB/CCB telmisartan/amlodipine ACEI/CCB lisinopril/amlodipine ARB/Diuretic telmisartan/HCTZ

The square box indication ensures that the pharmacological class therapeutic equivalence is endorsed to provide choice to nations. The approach herein addresses the key bases of rational, practical, affordable, generic, once daily combinations of the four classes of medication currently considered first line in leading national and international guidelines.

2. Name of the WHO technical department and focal point supporting the application (where relevant)

Cherian Varghese, Coordinator, Management of NCDs, WHO Department for Management of Noncommunicable Diseases, Disability, Violence and Injury Prevention

3. Name of organization(s) consulted and/or supporting the application.

Please see supporting letters.

4. International Nonproprietary Name (INN) and Anatomical Therapeutic Chemical (ATC) code of the medicine.

INN ATC code lisinopril/HCTZ C09BA03 telmisartan/amlodipine C09DB04 lisinopril/amlodipine C09BB03 telmisartan/HCTZ C09DA07

5. Formulation(s) and strength(s) proposed for inclusion; including adult and pediatric (if appropriate).

These are summarized in the Table below.

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Combinations Strength(s) Formulation lisinopril/HCTZ 10/12.5 Tablet 20/12.5 Tablet 20/25 Tablet

telmisartan/amlodipine 40/5 Tablet 80/5 Tablet 80/10 Tablet

lisinopril/amlodipine 10/5 Tablet 20/5 Tablet 20/10 Tablet

telmisartan/HCTZ 40/12.5 Tablet 80/12.5 Tablet 80/25 Tablet

The provision of a selection of FDCs and of doses within each FDC addresses the WHO EML 2017 Committee concern about providing choice and flexibility. At the same time, not all possible dose combinations are recommended, in order to reduce complexity of purchase and supply for countries. Also of relevance of the FDA statement that “Over the last decade, the Agency has actively discouraged antihypertensive monotherapy and combination doses with effects that were very close together, considering them a nuisance to physicians seeking to get patients to goal.”18

All of the recommended hypertension algorithms in the WHO HEARTS package would be supported by the provision of these FDCs, which would be utilised in the 1st and/or 2nd step of each protocol (with the exception of the CCB+diuretic as first line protocol – this is not included in this submission given the lack of widely available CCB-diuretic FDCs).

The safety and efficacy of the proposed FDCs have not been established in paediatrics, and the prevalence of hypertension is far lower than in adults; hence, their use in children is not recommended.19–23

6. Whether listing is requested as an individual medicine or as representative of a pharmacological class.

This application requests four ‘square box’ inclusions, taken as representative of the classes. Specifically of:

• FDC of lisinopril/HCTZ as a square box representing two-drug FDC BP lowering therapy of the pharmacological class ACEI/thiazide diuretic. The combination of lisinopril/HCTZ was chosen as it is one of the most commonly used, widely available and affordable BP combinations globally. Given the fact that all or almost all of the benefits of BP lowering drugs are due to the amount of BP lowering per se15,17,24, much the same clinical benefits can be expected from other ACEI-diuretic combinations (and indeed from other dual BP lowering combinations). An additional benefit of this combination is the balancing of the effects on serum potassium of ACEIs, which increase serum potassium, and diuretics, most of which decrease serum potassium. Although this Page 9 of 71

does not preclude the desirability of laboratory monitoring, it is likely to increase the safety of diuretics, particularly in environments where management of serum potassium may be difficult.

Alternatives include:

Benazepril/HCTZ enalapril/HCTZ fosinopril/HCTZ moexipril/HCTZ quinapril/HCTZ perindopril/indapamide

• FDC of telmisartan/amlodipine as a square box representing two-drug FDC BP lowering therapy of the pharmacological class of ARB/CCB. Telmisartan is a long-acting ARB with longer duration of action compared to losartan; and is now available as a generic. Amlodopine is widely used in low and middle-income countries and is widely available in the class of CCB. Other daily long-acting DHP CCB could be considered. Amlodopine is effective for all races, and reduces need for laboratory testing for electrolytes and renal function. The concommitant use of ARB or ACEI with amlodipine, as in the proposed FDCs in this application, reduces the incidence of pedal oedema, which is the most common adverse effect encountered with use of amlodipine.13

Alternatives include:

Valsartan/amlodipine olmesartan medoxomil/amlodipine irbesartan/amlodipine losartan/amlodipine candesartan/amlodipine valsartan/lercanidipine telmisartan/nifedipine SR

• FDC of telmisartan/HCTZ as a square box representing two-drug BP lowering therapy of the pharmacological class of ARB + thiazide diuretic.

Alternatives include: azilsartan medoxomil/chlorthalidone* candesartan/HCTZ eprosartan/HCTZ fimasartan/HCTZ irbesartan/HCTZ losartan/HCTZ olmesartan medoxomil/ HCTZ valsartan/HCTZ

*This formulation is the only widely marketed chlorthalidone combination with ACEI or ARB. Chlorthalidone is more potent25, has longer duration of action26, and has superior cardioprotective effects compared to hydrochlorothiazide27,28, therefore, experts may prefer a combination that includes chlorthalidone as the diuretic8,29–31. However, Page 10 of 71

because chlorthalidone is not widely accessible in many parts of the world, HCTZ has been listed as the example diuretic in these combinations.

• FDC of lisinopril/amlodipine as a square box representing two-drug BP lowering therapy of the pharmacological class of ACEI/CCB.

Alternatives include:

delapril/manidipine enalapril/lercanidipine enalapril/amlodipine perindopril/amlodipine ramipril/felodipine ramipril/amlodipine trandolapril/verapamil

In general, for currently available and future FDCs, substitutions between the components of the proposed FDCs is advised based on national preference. Acceptable alternatives: • switch telmisartan to other once daily generic ARB, such as valsartan • switch lisinopril to other once daily generic ACEi, such as ramipril • switch amlodipine to other once-daily CCB such as felodipine • switch HCTZ to other once daily generic thiazide or thiazide-like diuretic such as chlorthalidone, indapamide, indapamide SR.

Treatment details, public health relevance and evidence appraisal and synthesis

7. Treatment details (requirements for diagnosis, treatment and monitoring)

Diagnosis and monitoring of hypertension We reference the WHO HEARTS approach for diagnosis, treatment and monitoring of hypertension for the purposes of this application:

Measuring BP is the only way to diagnose hypertension, as most people with raised BP have no symptoms. Accurate BP measurements should be conducted on adults during routine visits to primary health care facilities, including all adults at first presentation to the facility, and, if normal, periodically thereafter (e.g., every 1 to 5 years). The diagnosis of hypertension should be based on an average of two or more blood pressure readings obtained on two or more occasions or current treatment with antihypertensive drug therapy. Every patient with elevated BP readings requires immediate follow-up, according to the following protocol.

Effective treatment algorithms for hypertension are dependent on accurate BP measurement. The following advice should be followed for measuring BP (1): Use the appropriate cuff size, noting the lines on the cuff to ensure that it is positioned correctly on the arm. (If the arm circumference is >32 cm, use large cuff.) Page 11 of 71

• Although at the initial evaluation it is preferable to measure BP in both arms and use the arm with the higher reading thereafter, this may not be practical in a busy health care environment. • The patient should be sitting with back supported, legs uncrossed, empty bladder, relaxed for 5 minutes and not talking. • For persons who are getting their BP measured for the first time, it is preferable to take at least two readings and to use the second reading, or three readings and take an average of the last two readings. • BP can be measured either by a conventional sphygmomanometer, using a stethoscope, or by an automated electronic device. The electronic device, if available, is preferred because it provides more reproducible results and is not influenced by variations in technique or by the bias of the observers. • If the health care facility has electricity or regular access to batteries, then consider an automated validated BP device with a digital reading. If the health care facility has no electricity or batteries, then a manual BP cuff will have to be used with a stethoscope.

The diagnosis of hypertension should be confirmed at an additional patient visit, usually 1 to 4 weeks after the first measurement. In general, hypertension is diagnosed if, on two visits on different days: systolic BP on both days is ≥140 mmHg and/or diastolic BP on both days is ≥90 mmHg. Patients with an initial reading of ≥160 mmHg systolic and/or diastolic BP ≥100 mmHg are often recommended to be initiated on treatment the same day.

Treatment strategy with dual BP combinations Several major international guidelines now recommend initial combination therapy for selected patients, as noted in Table 1.

For example, the ESH/ESC 2013 guidelines32 note that this strategy will achieve “a prompter response in a larger number of patients (potentially beneficial in high-risk patients), a greater probability of achieving the target BP in patients with higher BP values and a lower probability of discouraging patient adherence with many treatment changes.” The AHA/ACC guidelines8 indicate FDC for stage II hypertension (>140/90mmHg) and a BP 20/10mmHg above target. Per guidelines in Table 1, an FDC may be used for initial therapy where local guidelines recommend such treatment, such as for people who are >20/10mmHg from goal.

The FDCs are not indicated for the treatment of renovascular hypertension. Treatment with an FDC requires considerations of recent BP lowering drug treatment and the magnitude of baseline BP elevation. Adjustment of the existing BP lowering treatment may be needed. The FDC should be taken at about the same time every day as advised by the treating physician.

In patients receiving diuretic therapy electrolyte abnormalities, orthostatic hypotension or dizziness may occur following the initial dose of an FDC, particularly due to volume/salt depletion with diuretic therapy. In the elderly, although reported BP responses were similar to that in younger patients, it is recommended that the proposed FDC should be used after considering BP response and renal function. Dose should be selected cautiously, preferably starting with the low dose of FDC. Any dose versions of the proposed FDC are not recommended in patients with severe renal impairment. In patients with mild-to- moderate renal impairment the FDC can be used after titration of the component drugs. Page 12 of 71

8. Information supporting the public health relevance.

Epidemiological information on disease burden and treatment gaps Figure 1: Worldwide levels of raised blood pressure1

Mills KT, Bundy JD, Kelly TN, et al. Global disparities of hypertension prevalence and control: a systematic analysis of population-based studies from 90 countries. Circulation 2016;134: 441–50.

The benefits of BP lowering in reducing cardiovascular (CV) events are well established,24 and there is clear evidence that greater BP reduction confers larger reduction in CV events.15,17,33 However, control of high BP is poor with only one in three on treatment achieving BP targets of under 140/90 mmHg.3 Overall, control is reported at 13.% globally and as low as 7.7% in low and middle income countries.1

While 88% of people who are aware of hypertension received some pharmacological treatment, only 34% of those treated were controlled.3 There are substantial disparities: high-income countries had almost double the proportions of awareness (67.0% versus 37.9%) and treatment (55.6% versus 29.0%) and 4 times the proportion of control among patients with hypertension (28.4% versus 7.7%) in comparison with low- and middle income countries in 2010.1 Gender-specific hypertension awareness, treatment and control by income level in 2000 and 2010 is reported in Table 2, and Gender-specific hypertension awareness, treatment, and control in 2010 in countries with data by world region is reported in Appendix 1.

This is in large part due to the fact that most treated patients only receive monotherapy,3 despite guidelines recognizing that the large majority of patients require combination therapy for BP control. The recommended use of dual BP lowering in major hypertension management guidelines recommend is outlined in Table 1. Guidelines also recommend one or more of the proposed combinations among the preferred combinations.4–7,10,34,35 Finally, guidelines recommend use of FDC as a means of simplifying treatment regimen Page 13 of 71

which could potentially improve adherence to prescribed drugs and be cost- effective.4,5,10,34

Table 2: Gender-specific hypertension awareness, treatment and control by income level in 2000 and 2010 (Also see Appendix 1) Awareness Treatment Control* Control† 2000 2010 2000 2010 2000 2010 2000 2010 Global Overall 41.4 46.5 31.8 36.9 33.9 37.1 11.7 13.8 (34.3– (41.9– (25.6– (33.8– (26.5– (33.6– (7.1– (11.4– 48.5) 51.1) 37.9) 40.0) 41.3) 40.5) 16.2) 16.3) Men 36.1 40.2 26.8 30.3 34.2 35.8 10.0 10.9 (25.9– (34.0– (18.4– (26.1– (24.1– (30.8– (4.0– (7.7– 46.2) 46.5) 35.2) 34.5) 44.2) 40.7) 15.9) 14.2) Women 46.6 52.9 36.7 43.6 33.7 38.0 13.4 16.8 (36.7– (46.1– (27.7– (39.1– (23.2– (33.2– (6.5– (13.1– 56.5) 59.6) 45.7) 48.1) 44.2) 42.8) 20.2) 20.5) High-income countries Overall 58.2 67.0 44.5 55.6 38.6 50.4 17.9 28.4 (42.2– (58.1– (31.1– (49.8– (25.5– (44.4– (7.7– (22.3– 74.3) 75.9) 58.0) 61.4) 51.6) 56.4) 28.0) 34.5) Men 52.4 61.8 38.3 49.4 38.6 49.1 15.5 24.6 (29.0– (48.0– (19.7– (40.8– (21.1– (40.7– (2.3– (16.0– 75.8) 75.7) 56.9) 58.1) 56.0) 57.4) 28.7) 33.2) Women 64.1 72.2 50.9 61.7 38.6 51.5 20.3 32.2 (42.1– (60.9– (31.6– (54.1– (19.8– (43.1– (4.8– (23.6– 86.0) 83.4) 70.3) 69.3) 57.4) 59.9) 35.8) 40.8) Low- and middle-income countries Overall 32.3 37.9 24.9 29.0 29.4 26.3 8.4 7.7 (25.7– (32.5– (18.7– (25.4– (22.1– (22.3– (4.0– (5.3– 38.9) 43.2) 31.0) 32.7) 36.7) 30.3) 12.7) 10.1) Men 27.0 31.2 20.4 22.3 29.5 23.4 6.9 5.2 (18.0– (24.5– (12.4– (17.6– (19.9– (17.9– (1.3– (2.3– 36.0) 38.0) 28.4) 27.0) 39.2) 28.9) 12.6) 8.1) Women 37.4 44.7 29.2 35.9 29.2 28.1 9.7 10.2 (27.8– (36.3– (20.0– (30.3– (18.9– (22.6– (3.2– (6.4– 47.1) 53.0) 38.4) 41.5) 39.6) 33.7) 16.3) 14.0) From Kelley et al 20161. Values are percentages and 95% confidence intervals. Awareness is defined as self-reported previous diagnosis of hypertension among those with hypertension. Treatment is defined as self-reported antihypertensive medication use among those with hypertension. Control is defined as systolic blood pressure <140 mmHg and diastolic blood pressure <90 mmHg. *Among those self-reporting treatment. †Among all participants with hypertension.

Comparing Fixed-dose combinations vs. separate pills Previous reviews of the 2017 FDC petition summarized trials that compared FDC vs the monocomponents taken as separate pills over short periods, often 4-12 weeks.36 However, these trials were conducted in tightly controlled settings in which adherence has been optimized in order to assess pharmacological equivalence and hence support a Page 14 of 71

“substitution” indication. Such trials are not informative regarding the role of FDCs in overcoming treatment inertia and long-term adherence in real clinical practice. FDC therapy improves adherence to prescribed drugs and reduces treatment inertia.37

Target population(s) • Patients with uncontrolled BP despite treatment with one of the component drug in the proposed FDC. • Initial treatment where indicated by local guidelines. • Patients currently receiving treatment with the both component drugs separately at the dose as in FDC.

Likely impact of treatment on the disease The proposed FDC has the potential to significantly improve BP control in a large number of hypertensives. The impact is expected to be substantially higher in low- and middle- income countries where the majority of the patients receive monotherapy and have uncontrolled BP.

Per numbers needed to treat calculations,38 with current projections, it is estimated that 1 in 125 would have prevented death, 1 in 67 would have prevented stroke and 1 in 100 prevented heart attack (fatal and non-fatal myocardial infarction and sudden/rapid cardiac death).

9. Review of benefits: summary of comparative effectiveness in a variety of clinical settings.

In support of the application, an overview of all dual BP combinations, in terms of efficacy in lowering BP and reducing cardiovascular events, was undertaken.

Review of BP lowering efficacy of dual vs mono therapy Wald et al39 performed meta-analysis of 42 factorial trials (10,968 participants) and showed that combining drugs from the four classes, ACEIs, Beta-blockers, thiazide and calcium channel blockers, produced additive BP lowering effects, also the effect was approximately five times greater compared to doubling the dose of monotherapy.

Review of BP lowering efficacy of initial therapy with dual combination vs mono therapy

A systematic review of dual vs monotherapy as initial treatment (among patients who were untreated or had washout of previous BP lowering therapy for ≥4 weeks) is reported (literature search strategy – Appendix 2). The review included 33 randomised, double- blind trials with more than 10,000 participants in total (Appendix 3). Antihypertensive therapy in each randomised treatment group were defined in terms of “standard-dose” of the drug(s). Standard-dose of a drug is the most common daily maintenance dose reported in Martindale, British National Formulary, Medical Information Management System Australia. If there was no consensus in these sources the World Health Organization’s defined daily dose is taken as the standard dose. In a dual combination, if both drugs were at less than standard-dose, the regimen would be classified and labelled as “<1+<1” (dual low dose); if one drug at standard-dose and other drug at less than standard-does as “1+<1” (dual standard and low dose); and if both drugs are at standard- Page 15 of 71

dose the regimen is classified as “1+1” (dual standard dose). These three dual combinations were collectively referred to as dual low-to-standard dose,

The results showed a clear improvement in efficacy with no increases in withdrawals due to adverse events. The size of benefits was clinically important, with a 27% increase in average improvement, with three dual combination of low-to-standard dose, in the rate of achieving BP control among patients receiving dual combination therapy.

Figure 2: Dual therapy vs standard-dose monotherapy – effects on mean BP reduction and hypertension control rates

<1+<1=dual low dose; 1+<1= dual standard and low dose; 1+1= dual standard dose. WDAE= withdrawal due to adverse event

Two other trials40,41 have compared strategies for initial treatment of hypertension of dual- combination therapy vs monotherapy based care, each showing improved efficacy in patients receiving combination therapy. In the Simplified Treatment Intervention to Control Hypertension (STITCH) trial conducted in primary care practices in Canada, a simplified algorithm starting with ACE inhibitor-diuretic combination gave better BP control than a stepped care titration schedule at 6 months (65% vs 53%, p=0.03).40 In the STRATHE trial among patients with uncomplicated hypertension in France, a low dose combination ACE inhibitor-thiazide gave superior BP control without side effects compared to both sequential monotherapy and a stepped care regimen.41 Finally, the PATHWAYS-142 trial recently demonstrated the superiority of dual combination therapy vs monotherapy, without an increase in clinically important side effects and with no subgroup identified in whom dual therapy was not superior to monotherapy.

Review of effects of combination therapy vs. placebo/no treatment on cardiovascular events A systematic review of RCTs was conducted to assess the effects of combination therapy of BP lowering drugs compared to no treatment on coronary heart disease (CHD), stroke, heart failure and death, based on previously published systematic reviews.15,17 One additional recently published trial43 was included. Eleven trials involving 35208 patients were included in the analysis. Mean age across patient groups was 64 years, and baseline BP was 148/84 mmHg (Appendix 4).

The effects on cardiovascular events are shown in Table 3. Given the pivotal role of the extent of BP reduction, the trials are divided into those which achieved a BP separation of more than or less than 6 mmHg SBP. In short-term trials, for which adherence will have been high, among people with hypertension dual combination BP lowering therapy has been shown to reduce BP by around 15/9 mmHg.16 The trials achieving a large BP separation were mostly conducted among patients with hypertension and did not have background treatment. Among these trials, there was a 25% reduction in CHD, a 39% reduction in stroke, a 52% reduction in heart failure and a 19% reduction in mortality (all p<0.001). The two trials with <6 mmHg SBP reduction were conducted among patients with a wide range of BP levels, a relatively low mean starting BP level, and a high number Page 16 of 71

of patients already receiving background treatment. In these two trials there were lesser and non-significant reductions in major cardiovascular events. However, there was still a reduction in total mortality (p=0.05).

Table 3: Effects of combination therapy vs. placebo on CHD, stroke, heart failure and death Studies Intervention Control RR (95% CI) events/participants events/participants Studies with >6 mm Hg reduction in SBP CHD 11 175/5585 240/5694 0.75 (0.62-0.91) Stroke 11 310/5669 518/5694 0.61 (0.53-0.69) Heart failure 8 66/3172 157/3879 0.48 (0.36-0.63) Death 11 499/5596 627/5694 0.81 (0.72-0.90) Studies with ≤6 mm Hg reduction in SBP CHD 2 317/11925 356/11920 0.90 (0.77-1.03) Stroke 2 290/11925 312/11920 0.93 (0.80-1.10) Heart failure 1 21/6356 29 / 6349 0.72 (0.41-1.27) Death 2 750/11925 820/11920 0.91 (0.83-1.00) All studies CHD 13 492/17510 596/17614 0.84 (0.74-0.94) Stroke 13 600/17594 830/17614 0.73 (0.66-0.80) Heart failure 9 87/9528 186/10228 0.52 (0.40-0.67) Death 13 1249/17521 1447/17614 0.87 (0.80-0.93)

Effects of combination therapy of BP lowering drugs compared to placebo on CHD, stroke and death in major patient groups are reported in Figure 2.

Figure 3: Effects of combination therapy of BP lowering drugs compared to placebo on coronary heart disease, stroke and death in major patient groups.

Review of clinical trials assessing BP lowering efficacy of FDC combinations MEDLINE, Embase, and Cochrane Register of Controlled Trials, were searched, until March 2018, for RCTs of dual combinations compared to placebo, monotherapy or other dual combinations, published in English language. Included RCTs were double-blind that enrolled patients with hypertension, and had treatment with fixed-doses of drugs for at least four weeks. Trial of secondary hypertension were excluded. Detailed literature search strategy, PRISMA flow chart and summary of characteristics of included trials are reported in Appendices. Page 17 of 71

Review of clinical trials assessing BP lowering efficacy of lisinopril/HCTZ Lisinopril/HCTZ vs. placebo Two RCTs 44,45 reported data for this comparison (Figure 4).

Figure 4: Change from baseline BP with lisinopril/HCTZ compared to placebo

L = Lisinopril, H = Hydrochlorothiazide

Lisinopril/HCTZ vs. monotherapy One RCT44 compared two strengths of dual combination to respective monotherpies of component drugs (Figure 5).

Figure 5: Change from baseline DBP with lisinopril/HCTZ compared to monotherapy components

L = Lisinopril, H = Hydrochlorothiazide

Lisinopril/HCTZ vs. other dual combination therapies Two RCTs45,46 reported data for this comparison (Figure 6).

Figure 6: Change from baseline BP with lisinopril/HCTZ compared to other dual combinations

A = Amlodipine, C = Chlorthalidone, C = Candesartan, L = Lisinopril, H = Hydrochlorothiazide, V = Verapamil

Appendix 5-7 details search strategies used and summary characteristics of trials. Page 18 of 71

Review of clinical trials assessing BP lowering efficacy of telmisartan/amlodipine combination Telmisartan/amlodipine vs. placebo One RCT47 reported data for BP lowering efficacy of various dual combinations of telmisartan/amlodipine compared to placebo (Figure 7).

Figure 7: Change from baseline BP with telmisartan/amlodipine compared to placebo.

T= Telmisartan; A = Amlodipine

Telmisartan-amlodipine vs. monotherapy

Six RCTs48,48–53 reported data for BP lowering efficacy of dual combinations compared to one of the component drug (monotherapy) (Figure 8).

Figure 8: Change from baseline BP with telmisartan/amlodipine compared to one of the components, at same or higher dose

T= Telmisartan; A = Amlodipine

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Telmisartan-amlodipine vs. other dual therapies One RCT54 (n=481) assessed the effects of telmisartan 80mg/amlodipine 5mg compared to olmesartan 40 mg/hydrochlorothiazide 12.5 mg in 481 hypertensive patients. Both the dual combinations were equally efficacious (BP reduction 12.7/9.1 vs. 12.8/10).

Telmisartan/amlodipine as initial therapy Neldam et. al55 analysed patient-level data for three double-blind RCTs, conducted by Boehringer Ingelheim, to assess BP lowering efficacy of telmisartan/amlodipine combination therapy with respective monotherapies at week(s) 1, 2 and 4. Among patients initiated on combination therapy, greater reduction in BP and improvement in BP control was achieved with combination compared to monotherapies at these earlier time-points during the treatment period. The BP lowering effect of telmisartan and amlodipine combination does not differ substantially between blacks and whites (Table 4).

Table 4: Telmisartan (T) and amlodipine (A) reduction in DBP (mmHg), by race56

T80+A10 T40+A10 T80+A5 T40+A5

Black 17.2 20.9 16.7 13.7

Caucasian 20.6 20.3 15.6 17.0

Appendix 8-10 details search strategies used and summary characteristics of trials.

Review of clinical trials assessing BP lowering efficacy of telmisartan/HCTZ combinations

Telmisartan/HCTZ vs. placebo Three RCTs57–59 reported data for this comparison (Figure 9).

Figure 9: Change from baseline in SBP & DBP with telmisartan/hydrochlorothiazide compared to placebo

T= Telmisartan; H = hydrochlorothiazide

Telmisartan/HCTZ vs. monotherapy Three RCTs60–62 reported data for this comparison (Figure 10).

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Figure 10: Change from baseline in SBP & DBP with telmisartan/hydrochlorothiazide compared to monotherapy

T= Telmisartan; H = hydrochlorothiazide

Telmisartan/HCTZ vs. dual therapy Four trials58,59,63,64 reported data for this comparison.

Figure 11: Change from baseline in SBP & DBP with telmisartan/hydrochlorothiazide compared to same dual combination at different dose or different dual combinations

T= Telmisartan; H = hydrochlorothiazide

Appendix 11-13 details search strategies used and summary characteristics of trials.

Review of clinical trials assessing BP lowering efficacy of lisinopril/amlodipine combination

Only one small crossover RCT65 (n=15) assessed efficacy of lisinopril 10mg/amlodipine 5mg was compared with lisinopril 10mg, and amlodipine 5mg, for 1 month. SBP reduction with combination therapy was significantly higher with combination compared to respective monotherapies (13.3 [95% CI 9.9-17.2] vs. 5.5 [-1.1-12.0] vs. 8.6 [3.7-13.4], mmHg). Similar pattern was seen with DBP.

Appendix 14-16 details search strategies used and summary characteristics of trials.

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10. Review of harms and toxicity: summary of evidence on safety.

Based on the systematic reviews described above (see section 9), an examination of harms and toxicity was completed.

Review of safety of dual vs mono therapy In an analysis of 33 placebo controlled factorial trials of dual combination therapy (i.e. placebo vs drug A vs drug B vs drugs A+B together) reported by Law et al66, the incidence of symptoms/adverse events was 5.2% (3.6% to 6.6%) in monotherapy groups and 7.5% (5.8% to 9.3%) in dual combination groups (p=0.03).

Review of safety of initial therapy with dual combination vs mono therapy Initiation of therapy with dual combinations of low-to-standard doses did not differ when compared to standard-dose monotherapy (Figure 12) for the safety outcomes of withdrawals due to adverse events (WDAEs) and dizziness.

Figure 12: Incidence of WDAEs and dizziness with initial dual combination vs. standard-dose monotherapy

<1+<1=dual low dose; 1+<1= dual standard and low dose; 1+1= dual standard dose. WDAE= withdrawal due to adverse event

Safety data for Lisinopril/HCTZ Lisinopril/HCTZ vs. placebo In Chrysant et al.44, there was insignificantly higher incidence of pharyngitis and cough with lisinopril/HCTZ compared with placebo. In Leeuw et al45, incidence of adverse events did not differ significantly between treatments.

Lisinopril/HCTZ vs. monotherapy In Chrysant et al.44, there was insignificantly higher incidence of pharyngitis and cough with lisinopril/HCTZ compared with monotherapy.

Lisinopril/HCTZ vs. other dual combinations Of the two studies in this comparison, Leeuw et al.45 reported no difference in tolerability between the treatments that were compared. In McInnes et al.46 both the FDCs were well tolerated; however, significantly more patients in lisinopril/HCTZ group experienced adverse events, predominantly cough.

Safety data from the marked products monographs/labels of the lisinopril/HCTZ FDC. Page 22 of 71

Table 5: Adverse experiences occurring in >1% of patients treated with lisinopril/HCTZ in controlled clinical trials67 lisinopril/HCTZ Placebo (n=930) (n=207) Incidence (discontinuation) Incidence Dizziness 7.5 1.9 Headache 5.2 1.9 Cough 3.9 1.0 Fatigue 3.7 1.0 Orthostatic Effects 3.2 1.0 Diarrhea 2.5 2.4 Nausea 2.2 2.4 Upper Respiratory 2.2 0.0 Infection Muscle Cramps 2.0 0.5 Asthenia 1.8 1.0 Paresthesia 1.5 0.0 Hypotension 1.4 0.5 Vomiting 1.4 0.5 Dyspepsia 1.3 0.0 Rash 1.2 0.5 Impotence 1.2 0.0

Table 6: Incidence of adverse reactions in patients receiving lisinopril/HCTZ in controlled trials.19 lisinopril/HCTZ lisinopril (n = 930) % (n = 2633) % Body as a whole Fatigue 3.7 - Asthenia 1.8 2.7 Impotence 1.2 0.7 Decreased libido 1.0 0.2 Fever 0.5 0.3 Gout 0.2 0.2 Cardiovascular Orthostatic effects 3.2 0.9 Hypotension 1.9 0.8 Chest pain 1.0 1.1 Palpitation 0.9 0.8 Syncope 0.8 0.2 Chest discomfort 0.6 - Edema 0.1 0.6 Rhythm disturbances 0.1 0.5 Angina 0.1 0.3 Digestive Page 23 of 71

Diarrhea 2.5 1.8 Nausea 2.2 1.9 Vomiting 1.4 1.1 Dyspepsia 1.3 0.5 Abdominal pain 0.9 1.4 Constipation 0.3 0.2 Dry mouth 0.2 0.5 Anorexia 0.2 0.4 Flatulence 0.2 0.3 Dermatologic Rash 1.2 1.0 Flushing 0.8 0.3 Pruritis 0.4 0.5 Angioedema -* 0.1 Musculoskeletal Muscle cramps 2.0 0.5 Back pain 0.8 0.5 Shoulder pain 0.5 0.2 Nervous/Psychiatric Dizziness 7.5 4.4 Headache 5.2 5.6 Paresthesia 1.5 0.5 Vertigo 0.9 0.2 Depression 0.5 0.7 Somnolence 0.4 0.8 Insomnia 0.2 0.3 Respiratory Cough 3.9 3.0 Upper respiratory infection 2.2 2.1 Dyspnea 0.4 0.4 * Marketing Experience Only

Safety profile in elderly patients (age >65 years)67 Clinical studies did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Evaluation of the hypertensive patient should always include assessment of renal function.

The FDC is contraindicated in selected clinical situations and so safety issues may arise in health system, and patient factors affect the ability to detect such situations.19,20,67

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• In patients with history of previous hypersensitivity to the ingredients, ACEI, sulfonamide-derived drugs. • Women who are pregnant, intend to become pregnant, or of child bearing potential who are not using adequate contraception. • Nursing women. • In patients with anuria or sever hepatic impairment or severe renal impairment. • In patients with a history of hereditary and/or idiopathic angioedema or angioedema associated with previous ACEI treatment. Black patients reported higher incidence of angioedema with ACEIs compared to non-blacks. • Contraindicated in combination with a neprilysin inhibitor (e.g., sacubitril). • Do not administer within 36 hours of switching to or from sacubitril/valsartan, a neprilysin inhibitor. • Do not co-administer with aliskiren or ARB in patients with diabetes or renal impairment or hyperkalemia or congestive heart failure who are hypotensive.

Safety data for Telmisartan/Amlodipine

Figure 13: Withdrawals due to AEs with telmisartan/amlodipine compared to one of the component, and compared to higher dose of one of the component.

T= Telmisartan; H = hydrochlorothiazide

The FDA labelling for telmisartan/amlodipine21 reported that the concomitant use of these drugs has been evaluated for safety in more than 3700 patients with hypertension; approximately 1900 of these patients were exposed for at least 6 months and over 160 of these patients were exposed for at least one year. Adverse reactions have generally been mild and transient in nature and have only infrequently required discontinuation of therapy.

In the placebo-controlled factorial design study47 the population treated with a telmisartan and amlodipine combination had a mean age of 53 years and included approximately 50% Page 25 of 71

males, 79% were Caucasian, 17% Blacks, and 4% Asians. Patients received doses ranging from 20/2.5 mg to 80/10 mg orally, once daily.

The frequency of adverse reactions was not related to gender, age, or race.

The adverse reactions that occurred in the placebo-controlled factorial design trial in ≥2% of patients treated with TWYNSTA and at a higher incidence in TWYNSTA-treated patients (n=789) than placebo-treated patients (n=46) were peripheral edema (4.8% vs 0%), dizziness (3.0% vs 2.2%), and back pain (2.2% vs 0%). Edema (other than peripheral edema), hypotension, and syncope were reported in <2% of patients treated with TWYNSTA tablets.

In the placebo-controlled factorial design trial, discontinuation due to adverse events occurred in 2.2% of all treatment cells of patients in the telmisartan/amlodipine treated patients and in 4.3% in the placebo-treated group. The most common reasons for discontinuation of therapy with TWYNSTA tablets were peripheral edema, dizziness, and hypotension (each ≤0.5%).

Peripheral edema is a known, dose-dependent adverse reaction of amlodipine, but not of telmisartan. In the factorial design study, the incidence of peripheral edema during the 8 week, randomized, double-blind treatment period was highest with amlodipine 10 mg monotherapy. The incidence was notably lower when telmisartan was used in combination with amlodipine 10 mg.

Table 7: Incidence of peripheral edema during the 8-week treatment period21 Telmisartan Placebo 40 mg 80 mg Placebo 0% 0.80% 0.70% 5 mg 0.70% 1.40% 2.10% 10 mg 17.80% 6.20% 11.30% Amlodipine

Safety profile in elderly patients (age >65 years)21 Of the total number of 3282 hypertensive patients receiving a telmisartan/amlodipine combination in clinical studies, 605 (18%) patients were 65 years of age or older and of these, 88 (3%) patients were 75 years and older. No overall differences in efficacy or safety were observed in this patient population. Since patients age 75 and older have decreased clearance of amlodipine, start amlodipine or add amlodipine 2.5 mg to telmisartan. The lowest dose of 40/5 mg; therefore, initial therapy is not recommended in patients 75 years of age and older. Since patients with hepatic impairment have decreased clearance of amlodipine, start amlodipine or add amlodipine 2.5 mg to telmisartan. The lowest dose of is 40/5 mg; therefore, initial therapy is not recommended in hepatically impaired patients

The FDC is contraindicated in selected clinical situations and so safety issues may arise in health system, and patient factors affect the ability to detect such situations:21,68

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• Known hypersensitivity (e.g., anaphylaxis or angioedema) to ingredients or ARBs or dihydropyridine derivatives. • Patients with biliary obstructive disorders or sever hepatic impairment or cardiogenic shock. • During pregnancy or breastfeeding. • Do not use with other ACEI or aliskiren in patients with diabetes or renal impairment or hyperkalemia. • Patients with the rare hereditary condition of fructose intolerance (e.g. products containing sorbitol).

Safety data for lisinopril/amlodipine

Table 8: Adverse reactions reported in ≥ 1% of patients among patients treated with amlodipine plus lisinopril, amlodipine and lisinopril.23 System Organ Adverse Lisonorm Amlodipine Lisinopril Class reaction (Amlodipine/ (n=64) (n=68) lisinopril) (n=64) Nervous system Dizziness 3% 1.5% 4.4% disorders Headache 8% 6% 8.8% Cardiac Palpitation 1.5% 4.6% disorders Respiratory, Cough 5% 3% thoracic and mediastinal disorders Gastrointestinal Nausea 1.5% disorders Skin and Pruritus 1.5% subcutaneous tissue disorders

Safety profile in elderly patients (> 65 years)23 In clinical studies, there was no age-related change in the efficacy or safety profile of amlodipine or lisinopril. To find the optimal maintenance dose for elderly patients they should be individually titrated using the free combination of lisinopril and amlodipine. Combination is indicated only for patients in whom the optimal maintenance dose of lisinopril and amlodipine has been titrated to 10 mg and 5 mg, respectively.

The FDC is contraindicated in selected clinical situations and so safety issues may arise in health system, and patient factors affect the ability to detect such situations.23

• Hypersensitivity to lisinopril or to any other angiotensin converting enzyme (ACE) inhibitor. Page 27 of 71

• Hypersensitivity to amlodipine or to any other dihydropyridine derivatives. • Hypersensitivity to any of the excipients. • Severe hypotension. • A history of angioedema relating to previous ACEI therapy. • Hereditary or idiopathic angioedema. • Haemodynamically significant obstruction in the outflow tract of the left ventricle (aortic stenosis, hypertrophic cardiomyopathy), mitral stenosis or cardiogenic shock. • Heart failure after acute myocardial infarction (during the first 28 days). • Unstable angina pectoris (excluding Prinzmetal’s angina). • Pregnancy and lactation.

Safety data for Telmisartan/HCTZ Two trials61,62 assess withdrawals due to AEs for the FDC compared to telmisartan alone, demonstrating no clear increase.

Figure 14: Withdrawals due to AEs with telmisartan/HCTZ compared to one of the component drug

Table 9: Adverse Reactions Occurring at an Incidence of ≥2% in Patients Treated with Telmisartan/Hydrochlorothiazide and at a Greater Rate Than in Patients Treated with Placebo*22 Telmisartan Placebo Telmisartan HCTZ /HCTZ(n=4 (n=74) (n=209) (n=121) 14) Body as a whole Fatigue 3% 1% 3% 3% Influenza-like symptoms 2% 1% 2% 3% Central/Peripheral nervous system Dizziness 5% 1% 4% 6% Gastrointestinal system Diarrhea 3% 0% 5% 2% Nausea 2% 0% 1% 2% Respiratory system disorder Sinusitis 4% 3% 3% 6% Upper respiratory tract 8% 7% 7% 10% infection

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The FDC is contraindicated in selected clinical situations and so safety issues may arise in health system, and patient factors affect the ability to detect such situations:22,69,70 • In patients with hypersensitivity to any of ingredients of the product or ARBs or sulfonamide-derived drugs. • In patients with anuria. • Pregnant or nursing women. • Do not co-administer with aliskiren or ACEI in patients with diabetes or renal impairment. • Patients with biliary obstructive disorders or sever hepatic impairment or sever hepatic impairment or cardiogenic shock. • Patients with the rare hereditary condition of fructose or galactose intolerance (e.g. products containing sorbitol or Lactose).

11. Summary of available data on comparative price of medicines within the pharmacological class or therapeutic group.

Current price insights with respect to global use

We utilized Quintiles IMS (http://www.imshealth.com/) data on 2015-16 medicine sales – by volume and value - in 73 countries globally (North America, 12 countries in South and Central America, 25 countries from Europe and 29 elsewhere). During these years, Lisinopril-HCTZ was the most commonly prescribed ACE-diuretic combination and had the lowest unit price. See table 10.

Table 10: Quintiles IMS sales of ACE-diuretic combinations in 2015 and 2016 2015 2016*

Stock units sold Average price Stock units sold Average price (Millions) per pill (Euro) (Millions) per pill (Euro) Lisinopril + HCTZ 7,153 0.08 7,162 0.07 Perindopril + indapamide 5,528 0.24 6,022 0.23 Ramipril + HCTZ 5,089 0.11 5,048 0.11 Enalapril + HCTZ 4,670 0.11 4,553 0.11 Quinapril + HCTZ 825 0.20 747 0.19 Captopril + HCTZ 766 0.12 702 0.11 Zofenopril + HCTZ 504 0.31 518 0.27 Benazepril + HCTZ 485 0.62 467 0.43 Fosinopril + HCTZ 456 0.20 444 0.18 Cilazapril + HCTZ 328 0.16 305 0.16 * Projections made based on Q2 sales

In 11 countries, we utilized Quintles IMS data on 2013-2014 sales of CCB + ARB combinations. See Table 11 for number of medicine units (pills) sold and the average unit price (i.e. price per pill) during these years. Across studied countries, the median of price per pill was 0.19 and 0.17 Euros in years 2013 and 2014, respectively. The USA had the highest unit price, about 170 times the lowest unit price that was from India.

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Table 11: CCB+ARB sales in 11 countries 2013 2014 Medicine units Average Medicine units Average (pills) sold (in Median price (pills) sold (in Median price Millions) per pill (Euro) Millions) per pill (Euro) Australia 1,245,306 0.12 1,557,842 0.11 Brazil 4,214,477 0.16 4,570,294 0.15 China 6,413,435 0.06 9,577,657 0.06 France 3,730,504 0.26 3,844,684 0.27 Germany 2,339,436 0.52 2,484,979 0.51 India 61,204,872 0.01 69,116,835 0.01 Italy 1,820,286 0.19 2,311,639 0.17 Mexico 908,476 0.29 1,029,660 0.31 Turkey 2,853,299 0.04 3,244,745 0.04 UK 77,594 0.26 79,040 0.26 USA 4,540,755 1.50 4,169,954 1.73 Median of average price per pill 0.19 0.17

Procurement prices of proposed FDCs versus single pills: case study from India

To understand how the public-sector procurement prices of FDCs compare to that of monotherapy single pills, we conducted online searches to obtain publicly available data from India. Comparison was performed for a sample of FDCs proposed in this petition, for which procurement price data were available for both FDCs and constituent monotherapy pills.

We found that procurement prices of combination therapies were similar to the sum of procurement prices of constituting monotherapies. For instance, median procurement price of single pill of FDC Telmisartan 40 mg + Amlodipine 5 mg was Euro 0.0084 (INR 0.673) compared to Euro 0.007 (INR 0.557) for two monotherapy pills. FDC Telmisartan 40 mg + Hydrochlorothiazide 12.5 mg was procured at Euro 0.011 (INR 0.8550) that was comparable to sum of price for two monotherapy pills (Euro 00.009/INR 0.694). See Exhibit A Tab ‘Price compare-procurement’ for detailed procurement price comparisons.

Table 12: Procurement prices of fixed dose combinations versus single pills in India Procurement prices (FDC) Price per tablet (Euros)

• Telmisartan/HCTZ Telmisartan 40mg/ HCTZ 12.5mg 0.007-0.015 Source: Jan-Aushadi/BPPI (India)

• Lisinopril/Amlodopine Lisinopril 5mg / Amlodopine 5mg 0.004-0.023 Source: Rajasthan/J &K state (India)

• Telmisartan/Amlodopine Telmisartan 40mg / Amlodopine 5mg 0.008–0.014 Source: Central government/ESIC (India)

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In addition, we obtained procurement prices of various classes of monotherapies from several procurement agencies globally such as UNWRA, Organization of Eastern Caribbean States, Telangana Health and Family Welfare Department, and Thailand Ministry of Public Health. See Table 13 for mean procurement prices for classes of monotherapies.

Table 13: Mean procurement prices of various medicine classes from 15 international procurement agencies Medicine class Procurement price (Euro) Mean Min Max CCB 0.011 0.0003 0.27 ARB 0.036 0.026 0.043 ACEi 0.036 0.0032 0.11 HCTZ 0.038 0.0042 0089

Retail prices of proposed FDCs versus single pills: case study from India

We conducted systematic searches in MedInd and MIMS-India databases to obtain private- sector retail prices of various FDC brands marketed in India. We also obtained prices of the respective constituent single pills/monotherapies. Table 14 summarizes the unit prices comparisons for various combination medicines and respective constituent monotherapy. We found that retail prices of FDCs were similar if not lower compared to the price of constituent monotherapies. For detailed calculations, see tab ‘Price compare-Retail’ in Exhibit A.

Table 14: Private-sector retail unit price (in INR) in India: FDC versus monotherapy Median (range) unit price Fixed dose combination per pill (2018, Euros) Lisinopril 5 mg + Hydrochlorothiazide 12.5 mg 0.060 (0.013 – 0.087) Constituent monotherapy pills Lisinopril 5 mg 0.045 (0.031-0.130) Hydrochlorothiazide 12.5 mg 0.013 (0.008-0.026) Sum of median prices of two monotherapy pills 0.059 Fixed dose combination Telmisartan 40mg + Amlodipine 5 mg 0.090 (0.004-0.120) Constituent monotherapy pills Telmisartan 40mg 0.079 (0.038-0.100) Amlodipine 5 mg 0.026 (0.013-0.053) Sum of median prices of two monotherapy pills 0.11 Fixed dose combination Telmisartan 40 mg + Hydrochlorothiazide 12.5 mg 0.09 (0.004-0.190) Constituent monotherapy pills Telmisartan 40 mg 0.088 (0.038-0.100) Hydrochlorothiazide 12.5 mg 0.013 (0.008-0.026) Sum of median prices of two monotherapy pills 0.093 Note: A full listing of retail and procurement prices is provided (Exhibit A) and manufacturers (Exhibit B) for one country (India)

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Evergreening strategies and FDC price points

FDCs have in numerous instances been used as ‘evergreening’ strategies, in efforts by originator companies to reduce price erosion once a molecule comes off patent. However, now monotherapy constituents of different dual combination drugs are now off-patent; one reason that various GDCs are available at low cost. Furthermore, we note that dual combination drugs can be more affordable than the same medications as separate pills (see table 14: example of Lisinopril-HCTZ 5-12.5 mg that has a large share in India’s pharmaceutical market).71

Once established on the market, there is often a cost saving from use of dual combination therapy compared to the cost of both the separate products, both from direct medication costs and reduced script fees from a dual combination. However, when combinations first come to a market or are scarce, they attract a price premium.

The retail drug prices need to be contextualized within the potential cost-savings from improved hypertension control due to improved compliance,36,37,72 reduced need for repeat visits to achieve BP control and with the use of FDC in settings where individuals requiring more than one BP lowering drug may have limited access to multiple drug classes.73,74

In a meta-analysis75 published in 2011, the annual total health care costs from 44,336 patients in all included observational studies (n = 7) were lower for patients treated with FDC compared to individual monotherapy for hypertension (mean pooled difference - 1357.01 USD; 95% CI -1935.49 USD, -778.53 USD). An analysis using data from the 2004 Medical Expenditure Panel Survey in the United States demonstrated that total monthly prescription expenditures were lower for 23 of 27 FDC medications examined compared to the separate individual drugs76 (mean decrease in monthly total costs $20.89, 95% CI $20.10, $21.68). Using pharmacy claims data in Japan, a study demonstrated transitioning to FDC therapy from separate drugs was associated with an annual saving of $112 for patients.77 The cost savings of FDC therapy for patients also translate to the larger health system. In Canada, 60-100% of patients receiving two separate drugs transitioning to FDC therapy would lead to an estimated yearly cost-saving of $27 to $45 million.78

Implications on cost of FDC for hypertension if added to WHO EML

Given the large and growing global burden of hypertension and the increasing and political attention to non-communicable diseases, addition of FDCs for hypertension as a WHO essential medicines prompt other nations to follow, thereby reducing overall healthcare and societal costs for patients and governments – while allowing more people to be treated.

In discussing implications of EML listing, Magrini et al79 indicated that:

“Previous expert committees have recognized the message that comes with identifying a medicine as essential. In some cases, medicines have been included in the core list to underscore their importance, for example, antiretrovirals in 2002.80 In other cases, the model list has been used to stimulate the entry of new manufacturers for products that are not widely available, such as with zinc sulfate in 2005 and rectal artesunate in 2009. Page 32 of 71

Inclusion of effective but expensive medicines in the model list may also focus the attention of all stakeholders on the need to increase affordability and access to essential medicines.”

The addition of FDC for hypertension to the WHO EML is an example, in our view, where reduced costs will be a consequence, not a precondition, to listing. Listing of FDC for hypertension could stimulate new manufacturers of products and sharpen attention on FDC costs, as seen for FDC for tuberculosis and HIV/AIDS.71

12. Summary of regulatory status of the medicine

Availability of the proposed FDCs is outlined in the Table below, indicating widespread availability. However, numerous countries do not have all four options, which supports the rationale for a square box listing for each FDC, since alternative acceptable options are widely available.

Table 15: Availability of various formulations of proposed FDCs in the United States, Europe, Canada and other countries. Lisinopril Telmisartan- Lisinopril Telmisartan Country /HCTZ /amlodipine /amlodipine /HCTZ 40mg/5mg 10mg/12.5mg 40mg/10mg 20 mg/12.5mg 80mg/5mg 80mg/12.5mg Canada 20mg/25mg 80mg/10mg n/a 80mg/25mg 40mg/5mg 40mg/10mg 40mg/12.5mg 80mg/5mg 80mg/12.5 mg Australia n/a 80mg/10mg n/a 80mg/25 mg 80mg/12.5mg China n/a n/a n/a 40mg/12.5mg Ethiopia 10mg/12.5mg n/a n/a 40mg/5mg 10mg/12.5mg 40mg/10mg 10mg/5mg 40mg/12.5mg 20mg/12.5mg 80mg/5mg 20mg/5mg 80mg/12.5mg Europe 20mg/25mg 80mg/10mg 20mg/10mg 80mg/25mg 2.5mg/12.5mg 5mg/12.5mg 5mg/25mg 40mg/5mg 2.5mg/2.5mg 40mg/12.5mg India 10mg/12.5mg 80mg/5mg 5mg/5mg 80mg/12.5mg 40mg/5mg 40mg/10mg 10mg/12.5mg 80mg/5mg 10mg/5mg 40mg/12.5mg Russia 20mg/12.5mg 80mg/10mg 20mg/10mg 80mg/12.5mg 40mg/5mg 40mg/10mg 40mg/12.5mg Thailand n/a 80mg/5mg n/a 80mg/12.5mg Page 33 of 71

80mg/10mg 12.5mg/10mg 12.5mg/20mg Turkey 20mg/12.5mg 80mg/5mg 80mg/12.5m 20mg/25mg 80mg/10mg n/a 80mg/25mg 10mg/5mg 40mg/12.5mg 10mg/12.5mg 20mg/5mg 80mg/12.5mg United Kingdom 20mg/12.5mg NA 20mg/10mg 80mg/25mg 40mg/5mg 10mg/12.5mg 40mg/10mg 40mg/12.5mg 20mg/12.5mg 80mg/5mg 80mg/12.5ng Unites States 20mg/25mg 80m/10mg n/a 80mg/25mg n/a=Not available. A listing of manufacturers for selected regions is provided in Appendix .

Note: A full list of manufacturers and date of approvals in the United States (FDA) and Europe (European Medicine Association) is provided in Exhibit C; and Appendix 17.

13. Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia, United States Pharmacopoeia, European Pharmacopeia).

These are summarised in the following table: Pharmacopoeia Lisinopril Telmisartan- Lisinopril Telmisartan /HCTZ /amlodipine /amlodipine /HCTZ

British Both drugs are Both drugs are Both drugs are Both drugs Pharmacopoeia available as available as available as available as separate separate separate separate substances substances substances substances The International Only HCTZ is neither of the neither of the Only HCTZ is Pharmacopoeia available two drugs are two drugs are available available available The United States Both drugs are Both drugs are Both drugs are Available Pharmacopoeia available as available as available as separate separate separate substances substances substances The European Both drugs are Both drugs are Both drugs are Both drugs are Pharmacopoeia available as available as available as available as separate separate separate separate substances substances substances substances

Appendix 18 reviews standard doses of key components.

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14. References

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Appendix 1: Gender-specific hypertension awareness, treatment, and control in 2010 in countries with data by world region1

Control (among Awareness Treatment Control (among treated) Country hypertension) Men Women Men Women Men Women Men Women High Income Economies Australia -- -- 52.5 59.1 58.7 55.8 30.8 33.0 Chile 55.2 75.6 25.8 49.5 33.8 50.1 8.7 24.8 Czech Republic 68.4 71.4 58.2 58.9 41.9 42.2 24.4 24.9 Finland 63.3 72.7 31.3 39.9 33.8 39.9 10.6 15.9 France 46.9 58.8 41.0 62.0 41.7 58.4 17.1 36.2 Germany 77.9 86.6 ------Ireland -- -- 30.4 45.2 27.8 40.7 8.5 18.4 Japan -- -- 47.1 51.4 32.5 41.6 36.9 49.4 Korea, Rep. 58.5 76.1 51.7 71.3 70.5 68.4 15.3 21.4 Luxembourg 38.5 42.4 ------Puerto Rico 82.9 80.7 71.4 76.5 ------Russian 53.3 64.9 42.4 54.2 14.3 22.5 6.1 12.2 Federation Saudi Arabia 35.6 52.0 33.1 42.7 32.0 41.1 7.5 13.6 Singapore 70.8 77.2 ------Spain 50.9 64.6 ------Sweden -- -- 45.6 55.7 50.3 46.2 22.9 25.7 Switzerland 60.0 65.0 46.0 52.0 45.0 50.0 21.0 26.0 United Kingdom 61.0 66.0 52.4 58.2 61.8 59.8 32.4 34.8 United States 78.1 84.4 69.3 79.2 69.6 68.1 48.3 54.1 Uruguay 54.8 82.0 43.3 68.3 36.8 52.9 15.9 36.1 East Asia and Pacific China 30.4 36.7 20.6 27.7 17.0 15.5 3.5 4.3 Mongolia 25.7 51.3 28.1 54.1 26.7 39.6 7.5 21.4 Thailand 39.5 59.4 30.3 51.3 ------Page 41 of 71

Control (among Awareness Treatment Control (among treated) Country hypertension) Men Women Men Women Men Women Men Women Vietnam 37.9 53.2 22.1 36.7 28.0 40.3 3.8 9.9 Europe and Central Asia Albania 14.4 29.9 6.1 16.7 19.7 17.9 1.2 3.0 Armenia 25.8 25.7 10.3 19.1 23.1 36.6 2.4 7.0 Azerbaijan 17.6 53.0 12.0 46.2 36.2 47.6 4.4 22.0 Bosnia 40.2 57.2 35.5 54.2 25.4 41.0 9.0 22.2 Romania 62.2 75.6 49.7 66.9 27.4 23.6 13.6 15.8 Serbia 48.6 66.5 56.2 63.2 18.8 22.1 10.6 14.0 Turkey 36.9 55.7 23.6 38.9 ------Ukraine 31.9 64.6 16.8 57.4 21.9 20.9 3.7 12.0 Latin America and the Caribbean Argentina 46.7 64.6 32.6 52.1 31.6 37.4 10.3 19.5 Brazil -- -- 44.0 73.0 30.3 47.7 13.3 34.9 Cuba 54.8 76.0 44.1 67.9 46.2 49.4 20.3 33.5 Jamaica 30.6 69.6 21.0 57.8 31.2 44.9 6.6 26.0 Mexico 24.8 41.0 17.4 33.8 17.4 24.9 3.0 8.4 Panama 53.1 73.6 51.9 71.9 35.3 50.9 17.9 34.6 Peru 45.4 50.5 35.7 43.4 34.7 36.2 12.4 15.7 Middle East and North Africa Algeria -- -- 22.2 39.6 20.5 24.3 4.5 9.6 Egypt 55.7 79.7 33.9 48.5 50.7 55.7 17.2 27.0 Iran, Islamic 22.5 44.7 16.1 33.1 25.7 23.5 4.1 7.7 Rep. Jordan 54.7 56.7 36.7 35.1 42.9 38.2 15.6 13.5 Tunisia 28.8 44.8 24.6 37.9 27.5 22.8 6.5 8.6 Yemen 40.7 47.6 36.5 43.6 17.2 28.8 6.3 12.5 South Asia India 20.4 36.7 14.2 19.2 51.4 40.8 7.3 7.8 Page 42 of 71

Control (among Awareness Treatment Control (among treated) Country hypertension) Men Women Men Women Men Women Men Women Sub-Saharan Africa Angola 15.3 27.5 ------Ghana 12.8 17.7 9.6 10.6 20.6 12.8 2.0 1.4 Kenya 26.5 57.6 16.2 39.4 9.1 26.9 1.5 10.6 Mozambique 10.6 18.4 3.5 11.2 28.7 42.9 1.0 4.8 Senegal 21.2 50.3 14.3 36.5 17.9 27.7 2.6 10.1 South Africa 12.1 25.1 10.1 22.3 20.1 19.3 2.0 4.3

Page 43 of 71

Appendix 2: Initial dual combination PRISMA flow chart reporting identification and inclusion of studies and search strategy

Ovid MEDLINE Search Strategy Search date: Week 2, August 2017 1 exp Calcium Channel Blockers/ 2 (calcium adj2 (antagonist? or block$ or inhibit$)).tw. 3 (amlodipine or aranidipine or barnidipine or bencyclane or benidipine or bepridil or cilnidipine or cinnarizine or clentiazem or darodipine or diltiazem or efonidipine or elgodipine or etafenone or fantofarone or felodipine or fendiline or flunarizine or gallopamil or isradipine or lacidipine or lercanidipine or lidoflazine or lomerizine or manidipine or mibefradil or nicardipine or nifedipine or niguldipine or nilvadipine or nimodipine or nisoldipine or nitrendipine or perhexiline or prenylamine or semotiadil or terodiline or tiapamil or verapamil or cardizem or dilacor or tiazac or cardizem or calan or isoptin or calan or isoptin or verelan).mp. 4 Ccb?.tw. 5 1 or 2 or 3 or 4 6 exp Thiazides/ Page 44 of 71

7 exp Sodium Chloride Symporter Inhibitors/ 8 (sodium chloride adj (symporter? or cotransporter? or co-transporter?)).tw. 9 (potassium depleting adj2 diuretic?).tw. 10 (Hydrochlorothiazide or chlorthalidone or benzothiadiazine or bendrofluazide or buthiazide or bendroflumethiazide or benzhydroflumethiazide or bezthiazide or chlorothiazide or cyclopenthiazide or cyclothiazide or diucardin or diuril or enduron or esidrix or ezna or hydroflumethiazide or methyclothiazide or microzide or polythiazide or mykrox or naqua or naturetin or renese or trichlormethiazide or metolazone or thiazide?).mp. 11 (chlorthalidone or chlortalidone or phthalamudine or chlorphthalidolone or clopamide or clopamine or clorexolone or diapamide or fenquizone or hydromox or oxodoline or thalitone or hygroton or indapamide or isodapamide or lozol or mefruside or metindamide or oxodoline or quinethazone or zaroxolyn or s-1520 or s1520 or se-1520 or se1520 or xipamide).mp. 12 6 or 7 or 8 or 9 or 10 or 11 13 ((loop or ceiling) adj diuretic?).tw. 14 exp sodium potassium chloride symporter inhibitors/ 15 (sodium potassium chloride adj2 (cotransporter? or co-transporter? or symporter?)).tw. 16 (azosemide or furosemide or frusemide or fursemide indacrinone or ozolinone or phenoxybenzoic acid or muzolimine or bumetanide or burinex or cicletanine or etozolonie or torsemide or ethacrynic acid or veratide or piretanide or ticrynafen or tienilic acid or tizolemid).mp. 17 13 or 14 or 15 or 16 18 exp aldosterone antagonists/ 19 ((K or potassium) adj sparing adj diuretic$).tw. 20 (amiloride or triamterene or canrenoate potassium or canrenone$ or spironolactone$ or aldosterone antagonist$ or aldactone$ or practon$ or sc-9420$ or spiractin$ or sc-14266$ or soldactone$ or soludactone$ or aldadiene$ or phanurane$ or sc-9376 or eplerenone$).mp. 21 18 or 19 or 20 22 exp Angiotensin-Converting Enzyme Inhibitors/ 23 ((angiotensin$ or dipeptidyl$ or kininase) adj3 (convert$ or enzyme or inhibit$ or recept$ or block$)).tw. 24 (ace adj2 inhibit$).tw. 25 Acei.tw. 26 (alacepril or altiopril or ancovenin or benazepril or captopril or ceranapril or ceronapril or cilazapril or deacetylalacepril or delapril or derapril or enalapril or epicaptopril or fasidotril or fosinopril or foroxymithine or gemopatrilat or idapril or imidapril or indolapril or libenzapril or lisinopril or moexipril or moveltipril or omapatrilat or pentopril$ or perindopril$ Page 45 of 71

or pivopril or quinapril$ or ramipril$ or rentiapril or saralasin or s nitrosocaptopril or spirapril$ or temocapril$ or teprotide or trandolapril$ or utibapril$ or zabicipril$ or zofenopril$).mp. 27 22 or 23 or 24 or 25 or 26 28 exp Angiotensin Receptor Antagonists/ 29 (angiotensin adj3 (receptor antagon$ or receptor block$)).tw. 30 arb?.tw. 31 (abitesartan or azilsartan or candesartan or elisartan or embusartan or eprosartan or forasartan or irbesartan or losartan or milfasartan or olmesartan or saprisartan or tasosartan or telmisartan or valsartan or zolasartan or fimasartan).mp. 32 28 or 29 or 30 or 31 33 exp Adrenergic beta-Antagonists/ 34 (beta adj2 (adrenergic? or antagonist? or block$ or receptor?)).tw. 35 (acebutolol or adimolol or afurolol or alprenolol or amosulalol or arotinolol or atenolol or befunolol or betaxolol or bevantolol or bisoprolol or bopindolol or bornaprolol or brefonalol or bucindolol or bucumolol or bufetolol or bufuralol or bunitrolol or bunolol or bupranolol or butofilolol or butoxamine or carazolol or carteolol or carvedilol or celiprolol or cetamolol or chlortalidone cloranolol or cyanoiodopindolol or cyanopindolol or deacetylmetipranolol or diacetolol or dihydroalprenolol or dilevalol or epanolol or esmolol or exaprolol or falintolol or flestolol or flusoxolol or hydroxybenzylpinodolol or hydroxycarteolol or hydroxymetoprolol or indenolol or iodocyanopindolol or iodopindolol or iprocrolol or isoxaprolol or labetalol or landiolol or levobunolol or levomoprolol or medroxalol or mepindolol or methylthiopropranolol or metipranolol or metoprolol or moprolol or nadolol or oxprenolol or penbutolol or pindolol or nadolol or nebivolol or nifenalol or nipradilol or oxprenolol or pafenolol or pamatolol or penbutolol or pindolol or practolol or primidolol or prizidilol or procinolol or pronetalol or propranolol or proxodolol or ridazolol or salcardolol or soquinolol or sotalol or spirendolol or talinolol or tertatolol or tienoxolol or tilisolol or timolol or tolamolol or toliprolol or tribendilol or xibenolol).mp. 36 33 or 34 or 35 37 exp adrenergic alpha antagonists/ 38 (adrenergic adj2 (alpha or antagonist?)).tw. 39 ((adrenergic or alpha or receptor?) adj2 block$).tw. 40 ((adrenergic or alpha or receptor?) adj2 block$).tw. 41 (alfuzosin or bunazosin or doxazosin or metazosin or neldazosin or prazosin or silodosin or tamsulosin or terazosin or tiodazosin or trimazosin).mp. 42 37 or 38 or 39 or 40 or 41 43 (renin inhibi$ or renin blocker).tw. Page 46 of 71

44 (aliskiren or ciprokiren or ditekiren or enalkiren or remikiren or rasilez or tekturna or terlakiren or zankiren).mp. 45 43 or 44 46 (Centra$ adj2 antihypertensive$).tw. 47 (reserpine or serpasil or rauwolfia or clonidine or catapres or methyldopa or guanfacine or guanabenz or guanadrel or guanethidine).mp. 48 46 or 47 49 (hydralazine or diazoxide or minoxidil or nitroprusside sodium).mp. 50 5 and (12 or 17 or 21 or 27 or 32 or 36 or 42 or 45 or 48 or 49) 51 12 and (17 or 21 or 27 or 32 or 36 or 42 or 45 or 48 or 49) 52 17 and (21 or 27 or 32 or 36 or 42 or 45 or 48 or 49) 53 21 and (27 or 32 or 36 or 42 or 45 or 48 or 49) 54 27 and (32 or 36 or 42 or 45 or 48 or 49) 55 32 and (36 or 42 or 45 or 48 or 49) 56 36 and (42 or 45 or 48 or 49) 57 42 and (45 or 48 or 49) 58 45 and (48 or 49) 59 48 and 49 60 50 or 51 or 52 or 53 or 54 or 55 or 56 or 57 or 58 or 59 61 Drug Therapy, Combination/ 62 (Fixed adj2 combination$).tw. 63 (combin$ fixed dose or triple or dual or double or single pill or multi$).tw. 64 61 or 62 or 63 65 Antihypertensive Agents/ 66 64 and 65 67 60 or 66 68 randomized controlled trial.pt. 69 controlled clinical trial.pt. 70 randomized.ab. 71 placebo.ab. 72 clinical trials as topic.sh. 73 randomly.ab. 74 trial.ti. 75 68 or 69 or 70 or 71 or 72 or 73 or 74 76 ((first line or firstline or earl$ or initia$ or start$ or upfront) adj2 combin$).tw. 77 ((first line or firstline or earl$ or initia$ or start$ or upfront) adj2 fixed dose).tw. 78 ((drug or treatment or therapy or medic$ or antihyperten$) adj2 na?v$).tw. Page 47 of 71

79 (Untreated or never treated).tw. 80 (Never adj2 treat$).tw. 81 76 or 77 or 78 or 79 or 80 82 67 and 75 and 81 83 animals/ not (humans/ and animals/) 84 Pregnancy/ or Hypertension, Pregnancy-Induced/ or Pregnancy Complications, Cardiovascular/ or exp Ocular Hypertension/ 85 (pregnancy-induced or ocular hypertens$ or preeclampsia or pre-eclampsia).ti. 86 82 not (83 or 84 or 85)

Page 48 of 71

Appendix 3: Summary of characteristics of trials included in Initial dual combination therapy systematic review

Study BP Eligibility Sample Female Previously Mean BP measure Baseline Baseli BP Treatment mmHg size (%) untreated Age, SBP ne lowering duration (%) years mmHg DBP drug weeks mmHg class Applegate 1996 seDBP 95–115 336 35 NR 55 seated, 155 101 ACEI + CCB 6 trough Benz 1998 seDBP 95–115 871 40 NR (26) 52 seated, 153 101 ARB + TZD 8 trough Burris 1990 suDBP 95-100 300 38 NR 52 supine, trough 152 99 CCB + TZD 6

Chan 1997 seDBP 95-114 156 40 NR 72 seated, 168 105 ACEI + CCB 12 trough Chrysant 1994 seDBP 100-114 505 38 NR 53 seated, 154 104 ACEI + TZD 8 trough Cushman 1998 seDBP 95-115 867 32 NR 54 seated, NR 102 ACEI + CCB 12 trough DeQuattro 1997 suDBP 95-114 726 37 NR 55 supine, trough 150 100 ACEI + CCB 6

Farsang 2001 seDBP 95-114 341 32 99 (29) 53 seated, 164 103 ARB + CCB 8 trough Fernandez 1994 seDBP 95-110 67 66 1 (1) 53 seated, 149 101 ACEI + TZD 8 trough Frishman 1995 (A) seDBP 100-115 332 37 NR 54 seated, 157 105 ACEI + CCB 10 trough Frishman 1995 (B) se stage I/II 547 28 NR NR seated, 151 101 BB + TZD 4 HTN trough Giles 2014 seDBP 95-110 4161 24 NR 51 seated, 155 100 ARB + BB 8 trough Gradman 1997 seDBP 95 -115 707 35 NR 54 seated, 156 102 ACEI + CCB 8 trough Group 1997 seDBP 100-110 272 37 NR 49 seated, 155 102 ACEI + CCB 8 trough Kochar 1999 seDBP 95-110 683 35 NR 55 seated, 151 100 ARB + TZD 8 trough Page 49 of 71

Heesen 1998 ISH, 51 76 51 (100) 68 supine, NR 179 90 TZD + KSD 26 suSBP>=160, suDBP<95 Kuschnir 1996 seDBP 100-120 308 55 NR 57 seated, 167 107 ACEI + CCB 8 trough levine 1995 seDBP 95-114 186 56 NR 53 seated, 150 101 ACEI + CCB 4 trough Messerli 1998 seDBP 95-114 631 36 NR 55 seated, 152 101 ACEI + CCB 6 trough MacKay 1996 seSBP 95-115 703 40 NR 53 seated, 152 101 ARB + TZD 12 trough Mallion 2000 seDBP 95–114 446 52 134 (30) 56 supine, trough 163 101 ACEI + TZD 12

Myers 2000 suDBP 95-114 438 43 101 (23) 55 supine, trough 162 104 ACEI + TZD 8

Neutel 2005 seSBP 160-200, 443 53 NR 68 seated, NR 169 88 ACEI + CCB 8 seDBP<=100, daytime ambulatory SBP 150–200, DBP 60–100 Philipp 2007 seDBP 95-109 1911 47 NR 54 seated, 153 99 ARB + CCB 8 trough Pool 2001 seSBP 100-115 454 37 NR 54 seated, 155 104 ACEI + CCB 8 trough Pool 1997 seDBP 95-109 551 39 NR 52 seated, 150 100 ACEI + TZD 8 trough Pordy 1994 seDBP 95-115 1138 40 NR 54 seated, NR 100 ACEI + TZD 4 trough Poisson 1996 seDBP 95-115 642 44 208 (32) 58 supine, trough 165 102 ACEI + CCB 12

Scholze 1998 seDBP 100-115 424 NR 222 (52) NR seated, NR NR ACEI + CCB 6 trough Weinberger 2010 seDBP 95-109 1346 45 511 (38) 53 seated, 152 99 ARB + TZD 8 trough Weir 1992 suDBP 95-110 303 32 NR 54 supine, trough 152 100 CCB + TZD 12 Page 50 of 71

Saruta 2007 seDBP 95-115 942 40 395 (41) 55 seated, 155 101 ARB + TZD 8 trough Veratran 1997 seDBP 100-110 234 40 NR 49 seated, 155 101 ACEI + CCB 8 trough ACEI=angiotensin converting enzyme inhibitor, ARB=angiotensin receptor blocker, CCB=calcium channel blocker, DBP=diastolic blood pressure, NR=not reported, SBP=systolic blood pressure, se=seated, Su=supine, TZD=thiazide diuretic

Page 51 of 71

Appendix 4: Summary of characteristics of RCTs that assessed the effects of combination therapy of BP lowering drugs compared to placebo/no treatment on CV outcomes

Follow Achieved BP Mean age, Baseline Study Design participants Sample size Females (%) Interventions up red. in Eligibility years SBP/DBP years SBP/DBP DB, PC, PB, DM2, High No BP perindopril + ADVANCE81 11140 4735 (43) 66 4.3 145/81 -5.6/-2.2 MC Risk for CVD criteria indapamide DB, PC, PG, Stroke / TIA No BP perindopril + PROGRESS82 3544 1852 (30) 64 3.9 147/86 -9/-4 MC ± HTN criteria indapamide SBP 140- Methyclothiazide DB, PC, PG, HTN, 187 HSCSG83 220, DBP 452 59 + 3 164/100 -25/-12 MC Stroke/TIA (41) 90-116 deserpidine methyldopa + SBP <160 or 43 Carter84 OL, PG, SC Stroke, HTN 99 64 bethanidine/debr 4 >160/>110 -17/-9 DBP>110 (44) isoquine HCTZ/ amiloride/ SBP 160- DB, PC, PG, atenolol/metopro STOP85 HTN 219, DBP< 1627 1019 (63) 76 2.1 170/77 -19.5/-8.1 MC lol/pindolol ± 90 beta- blocker/diuretic SBP 170- OL, PC, PG, 611 atenolol ± HEP86 Elderly, HTN 280, DBP 884 69 4.4 196/99 -18/-11 MC (69) bendrofluazide 105-120 DB, PC, PB, Elderly (≥80 indapamide ± HYVET87 SBP160-199 3845 2326 (60) 84 2.1 173/90.8 -15/-6.1 MC yrs), HTN perindopril 78 chlorthalidone + USPHS88 PG, MC HTN DBP 90-115 389 44 7 147/99 -15.9/-10 (20) rauwolfia HCTZ + DB, PC, PG, 0 VA-289 HTN DBP 90-114 380 51 reserpine + 18 164/104 -31.4/-18.4 MC (0) hydralazine Page 52 of 71

HCTZ + DB, PC, PG, DBP 115- 0 VA-190 HTN 143 51 reserpine + 1.5 186/121 -39.4/-26.8 MC 129 (0) hydralazine Intermediat DB, PC, PG, No BP HOPE 343 e CV risk, no 12705 5874 (46) 66 candesartan + 5.6 138/82 -6/-3 MC criteria CVD HCTZ

DB=Double Blind, PC=Placebo Controlled, PG=Parallel Group, MC=Multicenter, HTN=Hypertension, CVD=Cardiovascular

Page 53 of 71

Appendix 5: Lisinopril + HCTZ search strategy Literature databases searched: MEDLINE, Embase, and Cochrane CENTRAL Search Date: March 26th, 2018 Search strategy:

1 Lisinopril/ 2 Lisinopril.mp. 3 1 or 2 4 Hydrochlorothiazide/ 5 Hydrocholorthiazide.mp. 6 4 or 5 7 randomized controlled trial.pt. 8 controlled clinical trial.pt. 9 randomized.ab. 10 placebo.ab. 11 clinical trials as topic/ 12 randomly.ab. 13 trial.ti. 14 or/7-13 15 3 and 6 and 14 16 Pregnancy/ or Hypertension, Pregnancy-Induced/ or Pregnancy Complications, Cardiovascular/ or exp Ocular Hypertension/ 17 (pregnancy-induced or ocular hypertens$ or preeclampsia or pre-eclampsia).ti. 18 animals/ not (humans/ and animals/) 19 15 not (16 or 17 or 18) Page 54 of 71

Appendix 6: Lisinopril + HCTZ PRISMA flow chart

Page 55 of 71

Appendix 7: Summary of characteristics of included trials for assessing lisinopril + HCTZ

Author/Study Year Design Eligibility Sample BP Males, Mean SBP, DBP, Interventions, dose in mg/day Treatment size measure for % age, mmHg mmHg duration, outcome years weeks assessment

Chrysant44 1994 DB, PC, seDBP 100 to 505 seated 62 53 154.0 104 lisinopril 10 + HCTZ 25 vs. lisinopril 12 PG, MC 114 10 + HCTZ 12.5 vs. lisinopril 10 vs. HCTZ 25 vs. HCTZ 12.5 vs. placebo Leeuw45 1996 DB, PC, suDBP 101-114 215 seated 53.2 55 169.8 106.8 lisinopril 20 + HCTZ 12.5 vs. atenolol 8 PG, MC after 4 weeks 100 + chlorthalidone 25 vs. on Placebo verapamil 180 + trandolapril 2 washout vs. placebo

Mcinnes46 2000 DB, PG, seDBP 95–114 353 seated 55 57 166.3 102.4 lisinopril 10 + HCTZ 12.5 vs. 26 MC after 2 weeks candesartan 8 + HCTZ 12.5 on any monotherapy

DB=double blind, MC=multicentre, AC=active controlled, PG=parallel group, se=seated, su=supine, HCTZ=hydrochlorothiazide, NR=not reported Page 56 of 71

Appendix 8: Telmisartan + Amlodipine search strategy Literature databases searched: MEDLINE, Embase, and Cochrane CENTRAL rd Search Date: April 3 , 2018 Search strategy:

1 Telmisartan.tw. 2 Telmisartan.mp. 3 1 or 2 4 Amlodipine/ 5 Amlodipine.mp. 6 4 or 5 7 randomized controlled trial.pt. 8 controlled clinical trial.pt. 9 randomized.ab. 10 placebo.ab. 11 clinical trials as topic/ 12 randomly.ab. 13 trial.ti. 14 or/7-13 15 3 and 6 and 14 16 Pregnancy/ or Hypertension, Pregnancy-Induced/ or Pregnancy Complications, Cardiovascular/ or exp Ocular Hypertension/ 17 (pregnancy-induced or ocular hypertens$ or preeclampsia or pre- eclampsia).ti. 18 animals/ not (humans/ and animals/) 19 15 not (16 or 17 or 18)

Page 57 of 71

Appendix 9: Telmisartan + Amlodipine PRISMA flow chart

Page 58 of 71

Appendix 10: Summary of characteristics of included trials for assessing telmisartan + amlodipine

Mean SBP, DBP, Treatment Male, Interventions, Author Design Eligibility N age, mmHg mmHg duration, % dose in mg/day years * * weeks DB, DD, Placebo vs T20 to Littlejohn Stage 1 or 2 HTN (DBP: ≥95 and PC, PG, 1461 52 53 155 104 T80 vs A2.5 to 10 vs 8 2009 ≤ 119) factoria T20-80/A2.5 to A10 l Neldam 2011 DB, HTN (DBP: ≥95 on AHT; ≥ 100 1098 62 54 148 97 T40/A5 vs T80/A5 8 TEAMSTA- PG, MC treatment naïve)* 5 Treated controlled or uncontrolled HTN and treatment naïve with 3 Jagodzins T80/A5 vs DB,SC ≥ CV risk factors (such as 577 69 61 135 85 26 ki 2017 O40/H12.5 metabolic syndrome and/or DM, and/or end-organ damage) DB, HTN (DBP: ≥95 on AHT; ≥ 100 Zhu 2014 324 53 52 155 103 T80/A5 vs A5 8 DD, MC treatment naïve)* Sharma DB, T2DM and stage 1 or 2 HTN (SBP: 706 52 61 161 91 T80/A10 vs A10 8 2012 PG, MC > 150)* Sharma Stage II HTN (SBP: 160 – 179; DB, MC 210 68 51 174 100 T40/A5 vs A5 12 2007 DBP: 100 - 109) Neutel DB, T80/A10 vs T80 vs SBP ≥180 and DBP ≥95 1315 52 58 185 103 8 2012 PG, MC A10 Neldam HTN, uncontrolled after 6 weeks 2011 DB, run-in treatment with A10 (DBP: T40/A10 vs T80/A10 949 56 56 148 96 8 TEAMSTA- PG, MC ≥95 on AHT; ≥ 100 treatment vs A10 10 naïve)* Page 59 of 71

* = Blood pressure measured at seated position, A = Amlodipine, AHT = anti-hypertensives, BP = Blood pressure, DB = Double blind, DBP = Diastolic blood pressure, DD = Double dummy, H = Hydrochlorthiazide, HTN = Hypertension, MC = Multi centre, N = Sample Size, O = Olmesartan, PG = Parallel group, SBP = Systolic blood pressure, SC = Single centre, T = Telmisartan; all BP values in mmHg

Page 60 of 71

Appendix 11: Telmisartan + Hydrochlorothiazide search strategy Literature databases searched: MEDLINE, Embase, and Cochrane CENTRAL Search Date: April 5th, 2018 Search strategy: 1 Telmisartan.tw. 2 Telmisartan.mp. 3 1 or 2 4 hydrochlorothiazide/ 5 hydrochlorothiazide.mp. 6 4 or 5 7 randomized controlled trial.pt. 8 controlled clinical trial.pt. 9 randomized.ab. 10 placebo.ab. 11 clinical trials as topic/ 12 randomly.ab. 13 trial.ti. 14 or/7-13 15 3 and 6 and 14 16 Pregnancy/ or Hypertension, Pregnancy-Induced/ or Pregnancy Complications, Cardiovascular/ or exp Ocular Hypertension/ 17 (pregnancy-induced or ocular hypertens$ or preeclampsia or pre- eclampsia).ti. 18 animals/ not (humans/ and animals/) 19 15 not (16 or 17 or 18)

Page 61 of 71

Appendix 12: Telmisartan + HCTZ PRISMA flow chart

Page 62 of 71

Appendix 13: Summary of characteristics of included trials for assessing telmisartan + HCTZ

Position of Mean SBP, Interventio Treatment BP Males, age, mmH DBP, ns, dose in duration, Author Design Eligibility N measure % years g mmHg mg/day weeks Lacourcier DD, PG, DBP >90 after 8 weeks of Seated, T80/H12.5 vs e 2001 MC telmisartan 491 standing 63 55 149 97 T80 8 Lacourcier DBP >90 after 4 weeks of T40/H12.5 e 2002 DB, PG 40 mg telmisartan 327 Seated 54 58 147 96 vs T40 8 DBP: ≥95 on 1 current Neldam AHT or DBP ≥90 on 2 or 3 Seated, T80/H12.5 2008 DB, DD current AHT 713 standing 57 57 148 95 vs T80/H25 8 T20-160 vs H6.25-25 vs suDBP: 95 to 114 at 2 T20- weeks of the 4-week, 160/H6.25- McGill DB, PC, single-blind, placebo run- Supine, 25 vs 2001 PG, MC in period 818 standing 60 53 154 101 Placebo 8 T20-160 vs H6.25-25 vs T20- 160/H6.25- McGill b DB, DD, Black, suDBP: 95 to 114, 25 vs 2001 PC, PG suSBP: 140 to 200 222 Supine 51 48 155 104 Placebo 8 SBP≥140 ≤180 DBP≥90); Derosa controlled T2DM (HbA1c B10/L100 vs 2015 DB, MC ≤7.5%) 148 Seated 50 60 152 97 T80/H12.5 26 DB, AC, seated, T80/H25 vs Zhu 2012 PG, MC SBP≥160, DBP≥100 894 trough 54 57 172.3 104.3 T80 7 Page 63 of 71

White DB, PC, 110 seated, T80/H25 vs 2006 PG, MC DBP≥95 after 4 w placebo 9 trough 58 53.5 155 102 V160/H25 8 White DB, PC, DBP 95-119 after 2-3 118 seated, T80/H25 vs 2008 PG, MC week placebo 5 trough 55 53 155 102 V160/H25 8

AHT = Antihypertensive therapy, B = Barnidipine, BP = Blood pressure, DB = Double blind, DBP = Diastolic blood pressure, DD = Double dummy, HbA1c = Glycated haemoglobin, H = Hydrochlorthiazide, L = Lisinopril, MC = Multi centre, N = Sample Size, O = Olmesartan, PG = Parallel group, SBP = Systolic blood pressure, su = supine, T = Telmisartan, T2DM = Type 2 diabetes mellitus, V = Valsartan

Page 64 of 71

Appendix 14: Lisinopril + Amlodipine search strategy Literature databases searched: MEDLINE, Embase, and Cochrane CENTRAL Search Date: April 6th, 2018 Search Strategy: 1 Lisinopril/ 2 Lisinopril.mp. 3 1 or 2 4 Amlodipine/ 5 Amlodipine.mp. 6 4 or 5 7 randomized controlled trial.pt. 8 controlled clinical trial.pt. 9 randomized.ab. 10 placebo.ab. 11 clinical trials as topic/ 12 randomly.ab. 13 trial.ti. 14 or/7-13 15 3 and 6 and 14 16 Pregnancy/ or Hypertension, Pregnancy-Induced/ or Pregnancy Complications, Cardiovascular/ or exp Ocular Hypertension/ 17 (pregnancy-induced or ocular hypertens$ or preeclampsia or pre- eclampsia).ti. 18 animals/ not (humans/ and animals/) 19 15 not (16 or 17 or 18)

Page 65 of 71

Appendix 15: Lisinopril + amlodipine PRISMA flow chart

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Appendix 16: Summary of characteristics of included trials for assessing lisinopril + amlodipine Mean Interventions, Treatment Male, SBP, DBP, Author Design Eligibility N age, dose in duration, % mmHg mmHg years mg/day weeks Cappuccio Supine DBP ≥95 after 4 L10+A5 vs A5 DB, CO 15 53 53 165 99 4 1993 weeks on placebo vs L10 A=Amlodipine, CO=Crossover, DB = Double blind, DBP = Diastolic blood pressure, L=Losartan Page 67 of 71

Appendix 17: Manufacturers of proposed combinations in EU, USA and India Page 68 of 71

Combinations India USA EU lisinopril/HCTZ Registered (Aug 7, 2016) Apotex Teva *ramipril registered Aurobindo Gedeon Richter Hikma Jenson Pharmaceutical Invagen Services Limited Ivax Heumann Pharma GmbH & Co Lupin Generica KG Mylan Hexal Prinston DOC Generici Sandoz Sun Watson labs telmisartan/amlodipine Registered (Jul 7, 2015) Alembic Zentiva Lupin KRKA Mylan BOEHRINGER INGELHEIM Torrent Boehringer ingelheim Page 69 of 71

telmisartan/HCTZ Registered (July 16, 2015) Boehringer ingelheim DOC Generici Alembic Gedeon Richter Aurobindo EGIS Pharmaceuticals Lupin Teva Macleods Adamed Mylan Billev Pharma Prinston Sandoz Torrent HEXAL Zydus Zentiva Laboratorios LICONSA Chemo Ibérica axunio Pharma Apotex Europe Alvogen Ferrer Internacional, S.A. Stada Arzneimittel AG Sigillata Ltd. Mylan S.p.A. Glenmark Generics (Europe) Limited PharmaSwiss Medana Pharma Accord Healthcare Micro Labs GmbH lisinopril/amlodipine Registered (July 7, 2015) Gedeon Richter

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Appendix 18: Standard doses of component drugs of the proposed combinations

Medication WHO BNF Martindale MIMS online DECISION ON STANDARD DOSE

Amlodipine 5 5 -10 5-10 2.5-10 5 Hydrochlorothiazide 25 - 25-50 - 25 Lisinopril 10 20 20 10-20 20 Telmisartan 40 40 20-80 40 40 Page 71 of 71