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Table of Contents

1. Summary statement of the proposal for inclusion ......................................................................... 2 2. Name of the focal point in WHO submitting or supporting the application ................................ 2 3. Name of the organization(s) consulted and/or supporting the application ................................. 2 4. International Non-proprietary Name (INN, generic name) of the medicine ............................... 2 5. Formulation proposed for inclusion; including adult and pediatric (if appropriate) .................... 2 6. International availability - sources, if possible manufacturers: ..................................................... 3 7. Whether listing is requested as an individual medicine or as representative of a pharmacological

class ................................................................................................................................................ 3 8. Information supporting public health relevance ............................................................................ 3

8.1. Epidemiological information on disease burden ....................................................................................... 3 8.2. Assessment of current use ............................................................................................................................. 4 8.3. Target populations: ......................................................................................................................................... 4

9. Treatment details ........................................................................................................................... 5 9.1. Reference to existing WHO and other clinical guidelines: ....................................................................... 5 9.2. Dosage regimen and duration: ...................................................................................................................... 6 9.3. Need for special diagnostic or treatment facilities and skills: .................................................................. 6

10. Summary of comparative effectiveness in a variety of clinical settings ......................................... 7 10.1. Clinical Effectiveness: .................................................................................................................................... 7 10.2. Advantages of Fixed-dose combination ...................................................................................................... 9 10.3. Scored tablets ................................................................................................................................................... 9

11. Review of harms and toxicity: summary of the evidence on safety ............................................... 9 11.1. Estimate of total patient exposure to date .................................................................................................. 9 11.2. Description of adverse effects/reactions .................................................................................................... 9 11.3. Drug Interactions: ......................................................................................................................................... 10 11.4. Identification of variation in safety due to health systems and patient factors ................................... 10

12. Summary of available data on comparative cost and cost-effectiveness within the

pharmacological class or therapeutic group. ................................................................................ 11 12.1. Range of costs of the proposed medicine ................................................................................................. 11 12.2. Comparative cost-effectiveness .................................................................................................................. 11

13. Summary of the regulatory status of the medicine ........................................................................ 11 14. Availability of pharmacopoeial standards ..................................................................................... 12 15. Proposed text for WHO model formulary ..................................................................................... 12

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WHO MODEL LIST OF ESSENTIAL MEDICINES APPLICATION

1. Summary statement of the proposal for inclusion

The fixed-dose combination of sulfamethoxazole 800mg and trimethoprim 160mg (co-trimoxazole, CTX), isoniazid (INH) 300mg, and pyridoxine (Vitamin B6) 25 mg, is proposed. It will prevent tuberculosis, toxoplasmosis, pneumocystosis, bacterial pneumonia, malaria, and isosporiasis; and reduce mortality and hospitalizations among adults and children living with HIV/AIDS (PLHIV). The individual products INH and pyridoxine and the combination product CTX (sulfamethoxazole and trimethoprim fixed dose combination) are listed as Essential Medicines.

WHO has listed this fixed-dose combination of isoniazid, pyridoxine, sulfamethoxazole, and trimethoprim in the 10th Invitation for Expression of Interest for HIV medicinal products, and we therefore now propose its consideration for inclusion on the Essential Medicines List and the Essential Medicines List for Children. The principal reasons for requesting inclusion of a FDC (in adults and children) in the WHO Model List of Essential Medicines are as follows:

Current WHO Consolidated Guidelines recommend both co-trimoxazole preventive therapy (CPT) and isoniazid preventive therapy (IPT) as part of the standard package of care available to PLHIV, on the condition that active TB has been excluded. In most settings CPT is recommended indefinitely while IPT is recommended for at least 6 months and for a longer duration for specific groups populations, settings or where evidence results in changing the balance of risk-benefit.[1]

Co-trimoxazole (Sulfamethoxazole 800mg and trimethoprim160mg) preventive therapy (CPT) prevents Pneumocystis jirovecii pneumonia (PCP), cerebral toxoplasmosis, bacterial pneumonia, isosporiasis, malaria, and other co-infections in persons living with HIV (PLHIV). This has led to a significant morbidity and mortality benefit in clinical trials in low and high income countries.

Isoniazid (300mg daily) preventive therapy (IPT) prevents active tuberculosis in HIV- infected persons, which decreases community cases of tuberculosis. Maximizing IPT coverage and adherence will enhance these individual and population benefits.

Pyridoxine is recommended in all HIV-infected persons on INH to mitigate toxicity. It may be difficult for countries to procure and distribute pyridoxine with INH. Including it in the FDC ensures all patients on IPT are on concomitant pyridoxine, thereby preventing INH-induced toxicity.

Several large trials have found fixed dose combinations improve compliance, particularly in individuals with chronic conditions.[2, 3]

2. Name of the focal point in WHO submitting or supporting the application

Marco Vitoria, WHO/HTM/HIV/ATC

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

Clinton Health Access Initiative, Inc. (CHAI)

4. International Non-proprietary Name (INN, generic name) of the medicine

Sulfamethoxazole/trimethoprim/isoniazid/pyridoxine

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

Combination tablet comprised of sulfamethoxazole 800 mg, trimethoprim 160 mg, isoniazid 300 mg, and pyridoxine 25 mg (CTX/INH/B6 FDC) for adult and adolescent patients (over 25 kg). The oval/capsule-shaped tablet is scored, enabling children between 14 kg and 25 kg to receive ½ tablet.

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6. International availability - sources, if possible manufacturers:

The fixed-dose combination of sulfamethoxazole 800mg and trimethoprim 160mg (co-trimoxazole, CTX), isoniazid (INH) 300mg, pyridoxine (Vitamin B6) 25 mg is manufactured by Cipla.

Cipla Ltd. Cipla House, Peninsula Business Park, Ganpatrao Kadam Marg, Lower Parel, Mumbai-400013

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

This FDC is proposed for the ‘Other Antibacterials’ category (6.2.2)

8. Information supporting public health relevance

8.1. Epidemiological information on disease burden

Past surveys indicated that HIV infection increases the risk of TB 20-37-fold, depending on the severity of the HIV epidemic,[4] and in some countries in Sub-Saharan Africa up to 77% of new patients with TB have HIV [5]. In 2015, 6.4 million people with TB were notified to national TB programs (NTPs) and reported to WHO. Of these, just over 6.1 million had an incident episode of TB. The number of new and relapse TB cases notified and the notification rate per 100 000 population increased globally in 2013–2015, mostly explained by a 34% increase in notifications in India.[6] WHO estimated overall 10.4 million people developed TB in 2015, including 1.2 million PLHIV. TB was one of the top 10 causes of death worldwide in 2015, and was responsible for more deaths than HIV and malaria. In 2015, 1.8 million people died from TB, including 0.4 million among PLHIV.[7]

The World Health Assembly, convened annually by WHO in Geneva, passed a resolution in May 2014 approving with full support new post-2015 Global TB Strategy with ambitious targets. While the overall goal of the WHO is to end the global tuberculosis epidemic, the Assembly endorsed the following milestone goals for 2025:

75% reduction in tuberculosis deaths (compared with 2015)

50% reduction in tuberculosis incidence rate (less than 55 tuberculosis cases per 100 000 population)

No affected families facing catastrophic costs due to tuberculosis[7]

Similarly, one of the goals of the Global Plan to End TB 2016-2020[8] was to achieve three targets called the 90-(90)-90 targets: reach 90% of all people who need TB treatment, including 90% of people in key populations, and achieve at least 90% treatment success. These goals mirror the UNAIDS 90-90-90 goals for HIV diagnosis and treatment.

In 2015 there were 36.7 million people living with HIV/AIDS (PLHIV).[9] Globally:

2.1 million were new infections

95% of the 36.7 million were in low and middle income countries

70% of new infections occur in sub-Saharan Africa, a region heavily affected by TB.

18.2 million PLHIV were treated with ARVs

3.44 million (about 10%) were screened for TB.

1.1 million people with active TB were HIV positive, of these 1.1 million cases 390,000 resulted in death. This makes TB the most common cause of death in PLHIV, even among those on antiretroviral therapy.

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Estimated 0.45 million people were prescribed IPT in 2011[5]

79% of HIV positive TB patients were on CPT[3]

Before antiretroviral therapy and Pneumocystis jirovecii pneumonia (PCP) prophylaxis were given to PLHIV, PCP occurred in 70-80% of patients with AIDS.[10] Among those with significant immunosuppression, approximately 20-40% died. Most PCP cases occur in patients who are unaware of their HIV infection or not receiving HIV care regularly.[11] For patients with advanced immunosuppression who were seropositive for T. gondii and not receiving prophylaxis with drugs active against T. gondii, the 12-month incidence of toxoplasmosis was 33%. In resource limited settings where exposures to bacteria and other pathogens are different than in industrialized settings, deaths due to malaria, isosporiasis, mycobacterium tuberculosis, and bacterial pneumonia are common in HIV infected persons.[12, 13] Furthermore, current evidence shows that HIV infection increases the risk of malaria and worsens malaria outcomes while malaria infection increases viremia in HIV-infected individuals. While antiretroviral therapy has reduced mortality due to HIV, additional simple, safe, and effective interventions are needed to prevent PCP, malaria, tuberculosis, bacterial infections, and improve survival among HIV-infected persons.

8.2. Assessment of current use

The CTX/INH/B6 FDC has been used as part of a clinical trial (the REALITY study, see Section 10 below) conducted in 1805 African patients, including 72 pediatric patients (5 through 17 years). Other use of the product has not been documented as the FDC is only now becoming commercially available. However, previous estimations of usage of its components are as follows:

The WHO does not routinely collect statistics on the PLHIV without active TB who are also taking co-trimoxazole but most of the 18 million people on ART are eligible for co-trimoxazole. According to a previously published Global TB Report, 79% (410,000) of patients with TB and HIV received CPT in 2011.[5] As these patients were persons with TB disease, they would not take IPT but rather a TB treatment regimen which contains isoniazid. In 2011 there were an estimated 2.3 million people living with HIV who did not have TB and who might be eligible for CPT and IPT or the FDC if it were available.

In 2008, the WHO sent out a survey on CPT and IPT policy and implementation to 69 countries with a high burden of TB-HIV. Forty-one countries responded to the survey, representing 82% of the global HIV burden and 85% of the global HIV/TB burden. Of the responding countries, 93% had a national CPT policy, and 66% had nationwide implementation; 51% of responding countries had a national IPT policy, with 28% indicating nationwide implementation.[14].

8.3. Target populations:

In general, the target population for this FDC is PLHIV in whom active TB has been excluded.

Co-trimoxazole, isoniazid, and pyridoxine remain on the EML as separate components and should be given in instances where these drugs are not required at the same time. The inadvertent administration of the combined formulation where only one component is primarily recommended would not however be harmful, since both IPT and CPT are conditionally recommended as lifelong medications for PLHIV in high burden settings. In fact, recent studies have found that in high burden settings, the protective effect of IPT against TB disease stops soon after prophylaxis is stopped.[15, 16] In addition although some countries recommend stopping CPT when PLHIV commence ART and have a CD4 count of > 200 cells/mm3, Campbell et al found that continuing CPT while on ART and CD4 count >200 cells/mm3was associated with reduced incidences of malaria and diarrhea.[17]. A systematic review found that CPT given while taking ART significantly improved mortality and morbidity in PLHIV on ART[18]

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9. Treatment details

9.1. Reference to existing WHO and other clinical guidelines:

The WHO 2016 Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection contain recommendations for the use of drugs for prevention and treatment of opportunistic infections such as PCP and serious bacterial infections.[1] The Guidelines offer the following recommendations:

Co-trimoxazole preventive therapy (CPT) for adults:

CPT is recommended for adults (including pregnant women) with severe or advanced HIV clinical disease (WHO stage 3 or 4) and/or with a CD4 count ≤350 cells/mm3 (strong recommendation, moderate-quality evidence).

In settings where malaria and/or severe bacterial infections (SBIs) are highly prevalent, CPT should be initiated regardless of CD4 cell count or WHO stage (conditional recommendation, moderate-quality evidence).

CPT may be discontinued in adults (including pregnant women) with HIV who are clinically stable on ART, with evidence of immune recovery and viral suppression (conditional recommendation, low-quality evidence).

In settings where malaria and/or severe bacterial infections are highly prevalent, CPT should be continued regardless of CD4 cell count or WHO clinical stage (conditional recommendation, moderate-quality evidence).

Routine CPT should be given to all HIV-infected patients with active TB disease regardless of CD4 cell count (strong recommendation, high-quality evidence).

CPT for HIV-infected infants, children and adolescents:

CPT is recommended for infants, children and adolescents with HIV, irrespective of clinical and immune conditions. Priority should be given to all children younger than 5 years old regardless of CD4 cell count or clinical stage, and children with severe or advanced HIV clinical disease (WHO clinical stage 3 or 4) and/or those with a CD4 count ≤350 cells/mm3 (strong recommendation, high-quality evidence).

In settings where malaria and/or severe bacterial infections are highly prevalent, CPT should be continued until adulthood, irrespective of whether ART is provided (conditional recommendation, moderate-quality evidence).

In settings with low prevalence for both malaria and bacterial infections, CPT may be discontinued for children five years of age and older who are clinically stable and/or virally suppressed on ART for at least six months and with a CD4 count >350 cells/mm3 (strong recommendation, very low quality evidence).

CPT is recommended for HIV-exposed infants 4 to 6 weeks of age and should be continued until HIV infection has been excluded by an age-appropriate HIV test to establish final diagnosis after complete cessation of breastfeeding (strong recommendation, very low-quality evidence).

The guidelines also provide recommendations on preventing TB disease in patients at high risk. They note that all HIV-infected adults, adolescents, and children should be screened clinically for TB to identify people who should either be expedited for TB diagnosis or given preventive TB therapy. In the absence of a clinical suspicion of active TB, HIV-infected patients should be offered IPT as follows:

Adults and adolescents living with HIV should be screened with a clinical algorithm; those who do not report any one of the symptoms of current cough, fever, weight loss or night sweats are unlikely to have active TB and should be offered IPT (strong recommendation, moderate-quality evidence).

Adults and adolescents living with HIV who have an unknown or positive tuberculin skin test (TST) status and are unlikely to have active TB should receive at least six months of IPT as part of a comprehensive package of HIV care. IPT should be given to such individuals regardless of the

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degree of immunosuppression, and to those on ART, those who have previously been treated for TB and pregnant women (strong recommendation, high-quality evidence).

Adults and adolescents living with HIV who have an unknown or positive tuberculin skin test status and among whom active TB disease has been safely ruled out should receive at least 36 months of IPT. IPT should be given to such individuals regardless of whether they are receiving ART. IPT should also be given irrespective of the degree of immunosuppression, history of previous TB treatment and pregnancy (conditional recommendation, moderate-quality evidence).

Children living with HIV who do not have poor weight gain, fever or current cough are unlikely to have active TB. Children living with HIV who have poor weight gain, fever or current cough or contact history with a TB case may have TB and should be evaluated for TB and other conditions. If the evaluation shows no TB, they should be offered IPT regardless of their age (strong recommendation, low-quality evidence).

Children living with HIV who are more than 12 months of age and who are unlikely to have active TB on symptom-based screening and have no contact with a TB case should receive six months of IPT (10 mg/kg/day) as part of a comprehensive package of HIV prevention and care (strong recommendation, moderate-quality evidence).

In children living with HIV who are less than 12 months of age, only those who have contact with a TB case and who are evaluated for TB (using investigations) should receive six months of IPT if the evaluation shows no TB disease (strong recommendation, low-quality evidence).

All children living with HIV, after successful completion of treatment for TB, should receive IPT for an additional six months (conditional recommendation, low-quality evidence).

The WHO’s Consolidated Guidelines recommend that countries’ HIV programs provide IPT as part of the package of care for PLHIV when active tuberculosis is safely excluded.[1] This recommendation also states that use of antiretroviral drugs does not preclude the use of IPT. Pyridoxine (B6) is recommended in patients on isoniazid as it is a benign intervention which prevents peripheral neuropathy and other isoniazid toxicities. CPT is also recommended as part of the package of care provided by countries for PLHIV.

9.2. Dosage regimen and duration:

For adults and adolescents (25 kg and above), the recommended dose of the FDC component drugs is co-trimoxazole 800mg/160 mg, INH 300mg, and pyridoxine 25 mg, all given once daily. Therefore, the dosage regimen is one CTX/INH/B6 FDC tablet daily for the duration all drugs are required (see duration recommendations in Section 9.1).

For children, the dosing of isoniazid is weight based (10mg/kg, range 7-15mg/kg) while that of co-trimoxazole is age-based (6 months-5 years 240mg, 5-14 years 480mg, ≥ 14 years 960mg). Supplemental pyridoxine (5– 10 mg/day) is recommended in children treated for TB that are HIV-infected or severely malnourished.[19] Use of the scored FDC was investigated for this population in the REALITY trial. The ½-tablet dose given daily was evaluated in children 5 to < 12 years of age and is recommended for children 14 kg to 25 kg (see duration recommendations in Section 9.1).

INH should not be administered with food.

9.3. Need for special diagnostic or treatment facilities and skills:

None needed beyond those required for adequate diagnosis and evaluation of active TB.

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10. Summary of comparative effectiveness in a variety of clinical settings

10.1. Clinical Effectiveness:

Both CTX for prevention of PCP and other opportunistic infections and INH plus B6 supplementation for TB have been evaluated and used in clinical practice over a period of many years.

INH Preventive Therapy: A Cochrane review on IPT in HIV-infected individuals published in January 2010 was reviewed as the primary summary of IPT-related data.[33] The randomized studies included in the Cochrane review indicate that IPT decreases the incidence of active tuberculosis by one third. It is also well tolerated with a pooled risk difference of 0.01 (95% CI 0.0007, 0.0193) in the 7 randomized studies. Clinically, this means that 1 out of every 100 patients treated with INH will experience a treatment limiting adverse event due to INH.

One systematic review of INH plus B6 supplementation[19] explored impact of antiretroviral treatment and TB-HIV co-infection. From cross-sectional reports, 2–12% of patients treated with low or standard dosages of 3–5 mg/kg/day develop peripheral neuropathy (PN) symptom, this figure has been found to increase fourfold in PLHIV. Although no recent trials (post 1980) were found which specifically examined the effects of pyridoxine in HIV patients, recent trials evaluating IPT and which have used pyridoxine prophylaxis have reported low incidences of PN.[20,21] Recommendations for IPT in HIV-infected adults include a recommendation for pyridoxine ranging from 10-50mg daily.

Co-trimoxazole Preventive Therapy (sulfamethoxazole/trimethoprim 800mg/160mg daily): The critical outcomes of interest were efficacies of CPT on improving survival, decreasing hospitalizations, preventing malaria, preventing isosporiasis, adverse events, and preventing bacterial pneumonia. These are summarized in a Cochrane review published in 2003.[34]

In a review and commentary published in 2015, Harries and colleagues summarized the need for a fixed dose combination product that would include all the components of IPT and CPT in a single tablet.[22] These authors concluded that IPT is a useful adjunct to ART in preventing tuberculosis in settings of high tuberculosis transmission, but long-term treatment is needed to maintain ongoing benefits. They found no evidence to suggest IPT increased the risk of INH-resistant TB. In addition, they noted CPT reduced death

by 60% if started with ART at CD4 counts at 350 cells/μL or lower regardless of geographic region. Among

patients in Africa, CPT started without ART at CD4 counts greater than 350 cells per μL reduced death and

malaria infection and the continuation of CPT after recovery of CD4 cell counts > 350 cells/μl was

associated with reduced hospital admissions and reduced prevalence of malaria, pneumonia, and diarrhea. They note the benefits of continuing CPT were further supported by a randomized trial in Uganda and Zimbabwe of children infected with HIV, showing that those who continued CPT after 2 years of ART had reduced admissions to hospitals from malaria, pneumonia, sepsis, and meningitis. Finally, the authors of this review note that while there have been substantial advances in developing and accessing single tablet, once daily regimens for ARVs, HIV-associated opportunistic infection prophylaxis has not been a focus of treatment simplification, and as a result IPT and CPT are still taken separately.[22]

The desired CTX/INH/B6 FDC is now manufactured by Cipla Ltd and was evaluated in a recently reported clinical trial conducted in Kenya, Malawi, Uganda, and Zimbabwe.[23] The open-label REALITY trial (Reduction of EArly mortaLITY in HIV-infected adults and children starting antiretroviral therapy), which randomized ART-naïve HIV-infected adults and children >5 years with CD4< 100 cells/mm3, was conducted to evaluate whether an enhanced package of infection prophylaxis at time of ART initiation would reduce mortality in an African population. The randomization compared initiating ART with enhanced prophylaxis (continuous co-trimoxazole plus 12 weeks isoniazid/pyridoxine (anti-tuberculosis) and fluconazole (anti-cryptococcal/candida), 5 days azithromycin (anti-bacterial/protozoal) and single-dose albendazole (anti-helminth)), versus standard-of-care co-trimoxazole. CTX/INH/B6 was formulated as a scored FDC tablet. Two other randomizations investigated 12-week adjunctive raltegravir or supplementary food. The primary endpoint was 24-week mortality. A total of 1805 eligible adults (n=1733; 96.0%) and children/adolescents (n=72; 4.0%) were randomized to enhanced (n=906) or standard prophylaxis (n=899)

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and followed for 48 weeks; 3.8% were lost-to-follow-up. Approximately 90% of participants were receiving EFV-based ART. Median baseline CD4 was 36 cells/mm3 (IQR 16-62) but 47.3% were WHO stage 1/2. By 24 weeks of the study, 80 (8.9%) in the enhanced prophylaxis group compared to 108 (12.2%) in the standard prophylaxis group had died and 98 (11.0%) versus 12 7(14.4%), respectively, had died before 48 weeks (see Figure below).[23] There was no evidence of interaction with the two other randomizations. Enhanced prophylaxis significantly reduced incidence of tuberculosis (p=0.02), cryptococcal disease (p=0.01), oral/esophageal candidiasis (p=0.02), deaths of unknown cause (p=0.02), and (marginally) hospitalizations (p=0.06) but not presumed severe bacterial infections (p=0.38). Serious and grade 4 adverse events were marginally less common with enhanced prophylaxis (p=0.06). CD4 increases and VL suppression were similar between groups (p>0.2).

The REALITY study investigators concluded:

In HIV-infected adults and children (> 5 years of age) with CD4<100 cells/mm3 enhanced prophylaxis at ART initiation:

– Reduced early mortality from 14.4% to 11.0% over 96-week study period (25% relative reduction)

– Reduced adverse events and hospitalizations

The additional pill burden did not adversely affect VL suppression and was decreased by a well-accepted FDC of CTX/INH/B6

Policy-makers should consider adopting and implementing this low-cost broad infection prevention package which could save 3.3 lives for every 100 individuals treated.[23]

The results of the REALITY study are highly supportive of the use of CTX/INH/B6 FDC in HIV-infected adults. The small number of pediatric patients enrolled in the study makes it difficult to interpret efficacy results in patients 5 to 17 years of age but the available data support use of the ½-dose in patients < 12 years of age and at least 14 kg and use of the full dose in patients 12 to 17 years of age.

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10.2. Advantages of Fixed-dose combination

Opportunistic infection prophylaxis generally requires the use of multiple drugs. This often requires taking many tablets/capsules each day. An FDC containing prophylaxis for both TB and other opportunistic infections is expected to:

Reduce pill-burden;

Support patient adherence to treatment;

Delay the development of resistance;

Lower the total cost, including production, storage, transport, dispensing and other health system costs; and

Reduce the risk of medication errors by prescribers, dispensers or patients

This FDC tablet has been shown to be bioequivalent for the INH, sulfamethoxazole, and trimethoprim components compared to the individual reference products. The pyridoxine component was not reported as part of the bioequivalence testing. In addition, the FDC was shown to be similarly acceptable to patients and had similar adherence reporting.[24]

10.3. Scored tablets

Scoring tablets also provides advantages in pediatric formulations. Scoring allows for increased flexibility of dosing across a wider age/weight range and decreased pill burden. A properly scored tablet can be counted on to provide a reliable half-dose with little wastage from crumbled or poorly divided tablets.

11. Review of harms and toxicity: summary of the evidence on safety

11.1. Estimate of total patient exposure to date

There are no sources which indicate total patient exposure to INH, B6, and CTX. However, concomitant use of these products (as well as other TB drugs and ART) is recommended in the WHO Consolidated Guidelines and consequently has had wide usage in the relevant patient populations over many years.

11.2. Description of adverse effects/reactions

All the component drugs of the CTX/INH/B6 FDC have well-characterized toxicity and tolerability profiles. The combination of these drugs into the bioequivalent FDC does not alter the toxicity profile but is expected to improve tolerability by decreasing pill burden.

Isoniazid:

Neurological effects of chronic INH treatment include dysarthria, irritability, dysphoria, inability to concentrate, seizures, hallucinations, psychosis, memory loss, confusion and altered mental status, ototoxicity, optic neuropathy, and other cranial neuropathies. A more common neurological toxicity related to GABA deficiency is peripheral neuropathy. Peripheral neuropathy appears to be dose related and is seen in 0.2-1.2% of patients not receiving B6 supplementation. The symptoms are reversible after withdrawal of INH. B6 given at 25-50mg daily can prevent occurrence of neuropathy and is recommended in high risk groups (i.e. HIV, increased age, slow acetylator status, malnutrition, diabetes, renal failure, heavy alcohol intake, pregnancy, and breastfeeding) and in patients taking INH for extended periods of time (greater than six months). With routine monitoring, asymptomatic elevation in liver enzymes was seen in 10 – 20% of patients on INH during the first 4-6 months of therapy.[25] These elevated liver enzymes usually resolve, despite drug continuation, although around one fifth of these patients may persistently have elevated transaminases, which return to normal only after stopping the medication.

Severe and sometimes fatal hepatitis has been reported in association with INH therapy and may occur even after many months of treatment. The risk of developing hepatitis increases with increasing age (2.3% in those older than 50 years) and with daily consumption of alcohol. Recommendations in the U.S. product label include that preventive treatment should be deferred in persons with acute hepatic diseases.[25]

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Co-trimoxazole:

The most frequent adverse effects of CTX are adverse GI effects (nausea, vomiting, anorexia) and sensitivity skin reactions (e.g., rash, urticaria).[26] Indeed, Walker et al. reported that 3% of participants experienced an adverse event; all were hematological, rash, or hypersensitivity.[27] Watera et al. reported 29 adverse events in 602 participants exposed to CPT (17 were dermatological (itching or rash), 6 were constitutional, 4 were gastrointestinal, 1 had recurrent oral sores, and 1 bruised easily)[28] The incidence and severity of adverse reactions are generally dose related, and adverse reactions may occasionally be obviated by a reduction in dosage. Hypersensitivity and hematologic reactions are the most serious adverse effects of CTX, reportedly occurring in less than 0.5% of patients.

Pyridoxine:

Pyridoxine (B6) is usually well tolerated. Doses of more than 2 grams daily for 2-40 months have been associated with sensory neuropathy.[29] However, since 2 grams is nearly 100 times the dose of 25mg daily provided in this fixed dose combination, sensory neuropathy is not expected with use of this FDC.

11.3. Drug Interactions:

According to the U.S. product label for Bactrim DS (sulfamethoxazole/trimethoprim, Sun Pharmaceuticals), trimethoprim is an inhibitor of CYP2C8 as well as OCT2 transporter. Sulfamethoxazole is an inhibitor of CYP2C9. Caution is recommended when CTX is co-administered with drugs that are substrates of CYP2C8 and 2C9 or OCT2.[26]

Co-trimoxazole: CTX may prolong the prothrombin time in patients who are receiving the anticoagulant warfarin (a CYP2C9 substrate). This interaction should be kept in mind when CTX is given to patients already on anticoagulant therapy, and the coagulation time should be reassessed. CTX may inhibit the hepatic metabolism of phenytoin (a CYP2C9 substrate). Sulfonamides can also displace methotrexate from plasma protein binding sites and can compete with the renal transport of methotrexate, thus increasing free methotrexate concentrations. Administration of CTX and digoxin may also result in increased digoxin levels, which has been reported in geriatric patients. Therefore, patients on this fixed dose combination and digoxin should be monitored closely.

Isoniazid: INH is an inducer of cytochrome P450 (CYP) 2E1. It inhibits CYPs 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4. Since carbamazepine is a CYP 3A4 substrate its concentrations may increase with isoniazid administration, resulting in ataxia, headache, vomiting, blurred vision, drowsiness, and confusion. These symptoms will subside after discontinuation of INH or dose reduction of carbamazepine. Since phenytoin is a 2C19 substrate its concentrations may increase with isoniazid administration, resulting in phenytoin toxicity. Phenytoin toxicity may also arise in slow INH inactivators. Because INH might have some MAO inhibiting activity, when it is used with selective serotonin reuptake inhibitors patients should be monitored for serotonin syndrome. INH should be administered at least one hour before aluminum hydroxide because this antacid decreases GI absorption of INH. As a result of probable alterations in dopamine metabolism, patients receiving INH and disulfiram have experienced coordination difficulties and psychotic episodes.[25]

Pyridoxine: No known drug interactions.

11.4. Identification of variation in safety due to health systems and patient factors

No specific safety issues associated with CTX/INH/B6 FDC that would preclude its use are expected to pose a differential risk in the international health setting.

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12. Summary of available data on comparative cost and cost-effectiveness within the pharmacological class or therapeutic group.

12.1. Range of costs of the proposed medicine

Pricing for this FDC is currently unavailable. Recent prices of the individual component drugs purchased/imported from Indian generic suppliers are shown in the table below. Based on these prices, use of the CTX/INH/B6 FDC might be expected to cost about USD $15 per adult patient per year.

Given the low cost of the component drugs already available, it is not known whether the FDC will result in substantial cost savings over the individual drugs.

12.2. Comparative cost-effectiveness

Health economists suggest that a life-saving intervention that costs between two to three times the gross national product (GNP) per year-of-life saved represents a reasonable expenditure. Yazdanpanah et al. reported that using CPT would cost USD 200/life-year gained[30]. This analysis was performed in Cote d’Ivoire, where the per capita GDP is USD 1700, making this a cost-effective intervention. Given the vast majority of African countries have a GDP above USD 200 this cost-effectiveness research can also be generalized to other countries.

When treating patients with isoniazid for nine months, regardless of PPD status, Shrestha et al. used a Markov model to estimate a cost-utility of USD 106/quality adjusted life-year gained in Uganda and found that this treatment approach would produce 30 QALY/100 ALHIV. Since USD 1300 is the per capita income in Uganda this is a cost-effective intervention.[31] Bell et al. used a Markov model to estimate that six months of isoniazid preventive therapy will save USD 24 per primary or secondary case prevented with IPT (considering medical care and societal costs), will increase life expectancy and quality adjusted life expectancy, and will reduce TB incidence.[32]

In addition, there may also be cost savings related to the shipment and storage of the FDC tablets resulting from significant freight savings associated with using FDC tablets over multiple individual tablets, which may have a significantly greater weight and bulk. Compared to multiple individual tablet formulations, the CTX/INH/B6 FDC can also help reduce the pill burden for adult and pediatric patients, which can potentially simplify country supply chains.

13. Summary of the regulatory status of the medicine

This FDC is currently being manufactured by Cipla Ltd. for use in a clinical trial involving adults and children. The REALITY Trial, sponsored by MRC, has completed enrollment and recruited over 1800 adults, adolescents and children in Uganda, Zimbabwe, Malawi, and Kenya to look at strategies to reduce early mortality. Better prevention of opportunistic infections is one strategy investigated. The product is now ready for marketing, pending completion of WHO Pre-qualification evaluation.

All the component drugs of CTX/INH/B6 are off patent and available from multiple generic suppliers.

The CTX/INH/B6 FDC is currently under review by the WHO Pre-qualification Program and some national regulatory agencies. It has not been reviewed by either the U.S. FDA or EMA.

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14. Availability of pharmacopoeial standards

Isoniazid, sulfamethoxazole, trimethoprim, and pyridoxine are available in the United States Pharmacopoeia and the International Pharmacopoeia 5th edition (2015).

15. Proposed text for WHO model formulary

Dosage forms: Scored tablet containing sulfamethoxazole 800mg/trimethoprim 160mg/isoniazid 300mg/pyridoxine 25mg.

Description: CTX/INH/B6 FDC is a fixed dose combination product for prevention of opportunistic infections. Sulfamethoxazole and trimethoprim (CTX) are synthetic folate-antagonist antibiotics. INH is an antibiotic used for treatment of mycobacterial infections. Pyridoxine, vitamin B6, is a water-soluble vitamin.

Uses: Prevention of opportunistic infections (TB, PCP, toxoplasmosis, isosporiasis, malaria, and serious bacterial infections) in HIV-infected patients and prevention of adverse effects related to INH therapy.

Contraindications: CTX/INH/B6 FDC is contraindicated in persons who have developed severe hypersensitivity reactions to any of the component drugs. Isoniazid is contraindicated in patients with acute liver disease or a history of previous isoniazid associated hepatic injury.

Warnings and Precautions:

Caution should be exercised when giving co-trimoxazole to patients with G6PD deficiency.

Gastrointestinal intolerance, rash (which can progress to Stephens-Johnson syndrome), thrombocytopenia, leucopenia, hepatitis, and hyperkalemia can occur with administration of co-trimoxazole.

The US Food and Drug Administration has given isoniazid a black box warning for the possibility of severe and sometimes fatal hepatitis. This typically occurs within the first three months of treatment, but can develop later.

Caution should be exercised when administering isoniazid to patients with hepatic and/or renal impairment, in daily users of alcohol, and in individuals who inject illicit drugs.

Hepatotoxicity and peripheral neuropathy (due to pyridoxine deficiency) can occur with administration of isoniazid

Doses: CTX/INH/B6 FDC is given as one tablet daily to adults and adolescents (25 kg and above). For children 14 kg to 25 kg, the dose is ½-tablet given daily.

Adverse effects: The most common adverse events reported were insomnia, headache, nausea, asthenia, and fatigue.

Pregnancy: Although there are no adequate and controlled studies to date in humans, studies in pregnant women suggest that the incidence of congenital abnormalities in those who received co-trimoxazole was similar to the incidence in pregnant women who received placebo; there were no abnormalities in 10 children whose mothers had received the drug during the first trimester. In one report, there were no congenital abnormalities in 35 children whose mothers had received co-trimoxazole at the time of conception or shortly thereafter. Reproduction studies in rats using oral trimethoprim (as co-trimoxazole) dosages up to 70 mg/kg daily have not revealed evidence of impaired fertility.

Isoniazid has been reported to induce pulmonary tumors in animals; however, there is no evidence to date to support carcinogenic effects in humans. The American Thoracic Society (ATS), US Centers for Disease Control and Prevention (CDC), and Infectious Diseases Society of America (IDSA) state that isoniazid is considered safe for use in pregnant women, but the risk of hepatitis may be increased in the peripartum period.

Effects of pyridoxine on pregnancy outcomes have not been explored.

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Drug Interactions: Both INH and CTX have important drug interactions.

Co-trimoxazole: CTX may prolong the prothrombin time in patients who are receiving the anticoagulant warfarin (a CYP2C9 substrate). This interaction should be kept in mind when CTX is given to patients already on anticoagulant therapy, and the coagulation time should be reassessed. CTX may inhibit the hepatic metabolism of phenytoin (a CYP2C9 substrate). Sulfonamides can also displace methotrexate from plasma protein binding sites and can compete with the renal transport of methotrexate, thus increasing free methotrexate concentrations. Administration of CTX and digoxin may also result in increased digoxin levels, which has been reported in geriatric patients. Therefore, patients on this fixed dose combination and digoxin should be monitored closely.

Isoniazid: Carbamazepine concentrations may increase with INH administration, resulting in ataxia, headache, vomiting, blurred vision, drowsiness, and confusion. These symptoms will subside after discontinuation of INH or dose reduction of carbamazepine. Phenytoin concentrations may also increase with INH administration, resulting in phenytoin toxicity. Phenytoin toxicity may also arise in slow INH inactivators. Because INH might have some MAO inhibiting activity, when it is used with selective serotonin reuptake inhibitors patients should be monitored for serotonin syndrome. INH should be administered at least one hour before aluminum hydroxide because this antacid decreases GI absorption of INH. As a result of probable alterations in dopamine metabolism, patients receiving INH and disulfiram have experienced coordination difficulties and psychotic episodes.

Pyridoxine: No known drug interactions.

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