Application for Inclusion of Diazoxide in the WHO Model List of Essential Medicines for Children (March 2019)

Application for inclusion of Diazoxide in the WHO Model List of Essential Medicines for Children (March 2019)

Submitted by: Global Pediatric Endocrinology and Diabetes (GPED), Vancouver, Canada Caring & Living As Neighbours (CLAN), Sydney, Australia Congenital Hyperinsulinism International (CHI), Glen Ridge, New Jersey, US

To: 21st WHO Expert Committee on the Selection and Use of Essential Medicines World Health Organization, Geneva

Authors: Dr Jean-Pierre Chanoine (GPED and British Columbia Children’s Hospital, Vancouver, Canada) Dr Julia von Oettingen (GPED and McGill University, Montreal, Canada) Dr Jennifer Kendrick (Department of Pharmacy, British Columbia Children’s Hospital, Vancouver, Canada) Dr Kate Armstrong (CLAN, Sydney, Australia) Dr Jamal Raza (NICH, APPES, Karachi, Pakistan) Julie Raskin (Executive Director, CHI, Glen Ridge, NJ, US) Margaret Zacharin (GPED and Royal Children’s Hospital, Melbourne, Australia)

Contact: Jean-Pierre Chanoine, MD, FRCPC (Academic) Clinical Professor and Head Endocrinology and Diabetes Unit K4-212 British Columbia Children’s Hospital 4480 Oak Street Vancouver BC V6H 3V4 Canada

Email: [email protected]; Phone: 1-604-8752624; Fax: 1-604-8753231

1. Summary statement of the proposal for inclusion, change or deletion This proposal requests inclusion of diazoxide for the management of hypoglycemia secondary to prolonged hyperinsulinism (HI) to the EMLc. Context - Non communicable diseases Pediatric Endocrinology is a subspecialty of Pediatrics that focuses on the diagnosis and treatment of children with diseases of the endocrine system. These conditions are part of the non-communicable diseases (NCD) group group. In 2011 CLAN founded NCD Child (www.ncdchild.org), an international coalition committed to integrating children and adolescents within the global NCD, health and development agenda. In 2015, the UN convened to prepare a post- Millennium Declaration (MD) development agenda that contains 17 Sustainable Development Goals (SDG). Importantly, while MD Goals did not focus specifically on NCDs, NCDs are now a SDG target (1). - Capacity in Pediatric Endocrinology Over the last 10 years, thanks to training programs developed by several regional societies for Pediatric Endocrinology, capacity in Pediatric Endocrinology has increased markedly worldwide. We are now in a situation where many endocrine conditions, previously unrecognized by health professionals in Low and Middle Income Countries (LMICs), are diagnosed in a timely fashion. However, in many cases, access to medicines that can save lives or prevent irreversible complications and that have been available in High Income Countries (HICs) for decades remains poor. - Relevant organizations involved in addressing inequities of care for children with HI Global Pediatric Endocrinology and Diabetes (GPED) GPED is a non-profit organisation founded in 2010 and incorporated in Canada. It is endorsed by all regional pediatric endocrine societies (see www.globalpedendo.org) and is a founding member of the International Consortium of Pediatric Endocrine and Diabetes Societies (ICPE, see 3. and letter of support #1). The mission of GPED is “to improve the care of children living in developing countries and presenting with endocrine disorders or with diabetes”. One of the specific objectives of GPED is to improve access to essential medicines for Pediatric Endocrine diseases in LMICs. Caring and Living as Neighbours (CLAN CLAN is an Australian-based, not-for-profit, non-governmental organisation (www.clanchildhealth.org), approved by AusAID for Overseas Aid Gift Deductibility Status (OAGDS) and the Australian Taxation Office for Tax Deductibility Status. In 2010 CLAN was formally approved for association by the United Nations Department of Public Information (UNDPI) as an NGO. CLAN was proud to serve as the inaugural Secretariat of NCD Child. CLAN is dedicated to the dream that all children living with chronic health conditions in resource-poor countries of the world will enjoy a quality of life on par with that of their neighbours' children in wealthier countries.

Congenital Hyperinsulinism International Congenital Hyperinsulinism International (CHI), a US-based 501(c)3 nonprofit organization, was founded in 2005 by an international group of concerned parents of children with HI. CHI’s mission is to improve the lives of people born with HI. CHI is supported in its work by a Scientific Advisory Group comprised of leading HI experts in the field of pediatric endocrinology from around the world. CHI supports research for better treatments and cures and is the sponsor of the HI Global Registry, a patient-powered research study. CHI is the foremost advocate for increased awareness and better medical protocols for HI to reduce preventable brain damage and death from prolonged hypoglycemia. CHI is dedicated to improving access to genetic testing, lifesaving medication, and treatment for those with HI all over the world. CHI is an important information source and networking hub for HI families, schools, medical professionals, researchers, and biotechs.

Congenital hyperinsulinism disorders (HI) Congenital hyperinsulinism comprises a group of disorders, including a number of identified genetic disorders, with the common finding of recurrent episodes of hyperinsulinemic hypoglycemias due to an inappropriate secretion of insulin by the pancreatic β-cells. As a result, the infant and, in long-term cases, the child, has unpredictable, rapid onset, severe episodes of low blood glucose, causing confusion, seizures and collapse. Immediate treatment is required, with intravenous administration of glucose. Early management of hyperinsulinism is paramount for successful prevention of neurological damage occurring as a direct result and consequence of neonatal and later hypoglycemia. If appropriately treated, congenital hyperinsulinism is associated with a normal life. Babies born with HI typically stay in the hospital connected to intravenous administration of very high doses of glucose (and often needing other adjunctive treatments of glucagon and octreotide where these are available), to try to maintain normal glucose levels, until a long-term strategy for managing hypoglycemia in the home setting has been established. Short-term management strategies include dietary measures (early feeding, corn starch) and intravenous administration of glucose and of glucagon. Both glucose and glucagon are already included in the 6th List WHO Model List of Essential Medicines for Children (March 2017): injectable solution of 10% glucose (section 26.2) and glucagon (section 18.5). Long term management strategies include diazoxide (the mainstay in treatment for congenital hyperinsulinism since 1964 and partially or completely effective in 75% of all cases of HI (2), parenteral somatostatin analogues (rarely available) or near-total pancreatectomy (a difficult surgery that leads to diabetes). There is presently no PO medical alternative to diazoxide in the EMLc. Diazoxide is notoriously difficult to access in many settings. Diazoxide inhibits the secretion of insulin and is the first-line drug for controlling hypoglycemia secondary to prolonged transient HI or to permanent HI. By doing so, it prevents hypoglycemia and the permanent neurological sequelae associated with hypoglycemia. Even relatively few episodes of hypoglycaemia cause organic changes in the brain, easily demonstrated and well recognized occipital flaring on MRI imaging. Longer

3 term damage with scarring and demyelination result in severe learning difficulties and long- term epilepsy in patients where glucose control cannot be obtained and maintained (3). Although some genetic forms of HI are non-responsive to diazoxide, the majority of all cases do respond immediately, with resolution of hypoglycaemia within hours if administration. For those infants who eventually require pancreatectomy to control the problem, this is an extremely difficult and potentially dangerous procedure that needs weeks of careful planning prior to execution, to try to ensure success. Even after a near total pancreatectomy there is no guarantee of resolution and diazoxide may still be required for assistance in keeping glucose normal. However, in most cases, hypoglycaemia is transient, resolving naturally over 3-24 months and is totally treatable with diazoxide. Diazoxide is rapidly effective and provides enormous protection against the adverse effects of hypoglycaemia on the brain.

2. Name of the WHO technical department and focal point supporting the application This application was discussed with the following members at the Department of Essential Medicines and Health Products in WHO

Dr Suzanne Hill, B. Med (Hons), Grad Dip Epi, PhD, FAFPHM Director Email: [email protected]

Dr Nicola Magrini, MD Scientist Secretary of the Expert Committee on the Selection and Use of Essential Medicines Policy, Access and Use Team (Office M527), Email: [email protected]

World Health Organization 20, Avenue Appia - 1211 Geneva 27 - Switzerland website: www.who.int

3. Name of organization(s) consulted and/or supporting the application. This application is supported by several key organisations and stakeholders (see letters of support).

a. The International Consortium of Paediatric Endocrinology & Diabetes Societies. This consortium regroups all major regional Pediatric Endocrine Societies in the world (see letter of support # 1): - African Society for Paediatric and Adolescent Endocrinology (ASPAE, www.aspae.co.za/home.html) - Arab Society for Paediatric Endocrinology and Diabetes (ASPED, www.asped.org) - Asian-Pacific Pediatric Endocrine Society (APPES, www.appes.org) - Australasian Paediatric Endocrine Group (APEG, https://apeg.org.au/) - Chinese Society for Pediatric Endocrinology and Metabolism (CSPEM) - European Society for Paediatric Endocrinology (ESPE, www.eurospe.org) - Indian Society for Pediatric and Adolescent Endocrinology (ISPAE, www.ispae.org.in) - Japanese Society of Pediatric Endocrinology (JSPE, jspe.umin.jp/eng/) - Pediatric Endocrine Society (PES, www.pedsendo.org/) - Latin American Society for Pediatric Endocrinology (SLEP, www.slep.com.br) - Russian Paediatric Endocrinology Group b. In addition the non-profit, non-government organisation Global Pediatric Endocrinology & Diabetes (GPED, www.globalpedendo.org) and the International Society for Pediatric and Adolescent Diabetes (ISPAD, www.ispad.org) have joined the ICPE. c. The leading experts of the two most important centers of excellence for the management of HI (Dr Stanley, CHOP, Philadelphia, USA and Dr Hussain, UK) (see letter of support # 2 and 3)

4. International Nonproprietary Name (INN) and Anatomical Therapeutic Chemical (ATC) code of the medicine. INN: Diazoxide ATC: C02DA01, V03AH01

5. Formulation(s) and strength(s) proposed for inclusion; including adult and paediatric (if appropriate). Diazoxide is present as a liquid solution and as tablets. For children, it is best used as a liquid preparation as defined in the Report of the 2015 WHO Expert Committee on Selection and Use of Essential Medicines (Annex 1, Table 1.2). The most commonly used commercial preparation (possibly the only one) is distributed as a 50 mg/mL solution (https://www.drugs.com/cons/diazoxide.html). It is also present as Tablets that can be taken as such or made into syrup locally. Tablets are usually easier to access than commercial liquid solutions. We request the addition of diaxoxide liquid solution (50 mg/ml) and tablets (50 mg) to the EMLc.

6. Whether listing is requested as an individual medicine or as representative of a pharmacological class. This application concerns diazoxide as an individual medicine. There is no other medicine of this pharmacological class that is used in this indication (hypoglycemia secondary to hyperinsulinism).

7. Treatment details (requirements for diagnosis, treatment and monitoring). Diagnosis Neonatal and infantile hypoglycemia is an emergency and needs to be treated as soon as it is recognized in order to prevent permanent sequelae. Hypoglycemia is easily recognized at the bedside using point-of-care meters for measuring plasma glucose. In high income settings, the diagnosis of HI in children, as in adults, relies heavily on markers of inappropriate insulin effects (eg, suppressed ketogenesis). Diagnosis is most reliably based on a closely monitored provocative fasting test that includes: 1) frequent sampling of plasma concentrations of glucose, insulin, -hydroxybutyrate, and free fatty acids; and 2) terminating the test when glucose concentrations decline toward 50 mg/dL (2.8 mmol/L) with a determination of the glycemic response to glucagon. This can be accomplished quickly, and preliminary results can be obtained immediately and beta-hydroxybutyrate (tests of urine ketones are of little value). In low income settings, we are not aware of clinical guidelines and it is expected that the above information will not be readily available. The diagnosis will be made based on the clinical history, the clinical presentation, the measurements of blood glucose through a glucometer and a very high glucose requirements (> 10 mg glucose/kg/min). Many infants with HI require 18-20mg/kg/min glucose. At this level, high concentration of glucose required (due to volume restriction in the small baby) has major problems of its own, with loss of venous access due to sclerotic changes in veins and hyperosmolarity, which in turn increases risk for thrombotic events and death. WHO guidelines To our knowledge, although the WHO recognizes the importance of neonatal and infantile hypoglycemia as well as the high risk of permanent sequelae, there are no WHO guidelines for the management of hypoglycemia secondary to hyperinsulinism. WHO defines hypoglycemia as a blood glucose < 2.5 mmol/liter (< 45 mg/dl) or < 3.0 mmol/liter (< 54 mg/dl) in a severely malnourished child (4, 5), while the Pediatric Endocrine Society recently suggested that no single blood glucose concentration can be used to define hypoglycemia, however recommended a threshold of <2.8 for neonates <48 hours of life and <3.3 mmol/L for neonates >48 mmol/L, infants and children (6). We are aware of two documents published by the WHO: 1. A review article published in 1997 that specifically discusses hypoglycemia and its treatment (7). This document briefly mentions diazoxide as playing a role in the management of persistent hypoglycemia but not in the management of “transient

hypoglycemia associated with abnormal metabolic adaptation in preterm and SGA infants”. However, this has been challenged and diazoxide has been shown to be effective in 24/26 neonates with transient, prolonged hyperinsulinism (18-403 days) associated with small for gestational age and Caesarian section (8). 2. The 2013 edition of the WHO “Pocket Book of Hospital Care for Children” emphasizes the importance of hypoglycemia and the need to treat it as an emergency in order to prevent neurological sequelae but focuses on the most common causes of hypoglycemia and does not consider hyperinsulinism or mention diazoxide (5). Current guidelines Although there is variability in the definition of neonatal hypoglycemia, the definition provided by the WHO appropriately serves the purpose of this application. Emergency treatment of hypoglycemia consists in glucose (either PO or IV) as well as, when available, glucagon (2, 6).

When HI is suspected, diazoxide is the first line medicine (9). It was originally used as an antihypertensive antidiuretic benzothiadiazine and was found in 1964 to be effective in decreasing insulin secretion (10). It is now used as a first line agent in HI. Its action on the pancreatic b-cells opens the KATP channel, thereby inhibiting insulin. It is given at the dose of 5 to 20 mg/kg/day, PO, divided in 3 doses. Doses above 20 mg/kg/day are unlikely to be of additional benefit (2). Diazoxide is used until resolution of the prolonged transient hyperinsulinism (transient HI) or as a lifelong medicine in case of permanent HI. Requirements and monitoring Diazoxide can be administered in hospital or at home as a liquid solution or as a tablet. Monitoring consists in regular blood glucose monitoring using a glucometer (in the fasting state) which is easily performed at home. The dose of the medicine is adjusted based on the blood glucose values. In high income countries clinical follow up is performed 2-4 times/year. Core vs complementary list We request inclusion in the complementary list of essential medicines, defined as “priority diseases, for which specialized diagnostic or monitoring facilities, and/or specialist medical care, and/or specialist training are needed”. Diazoxide will be prescribed following evaluation in a health care facility by a pediatrician or a pediatric endocrinologist. In case of prolonged transient HI or permanent HI responsive to diazoxide, it is a medicine that is required to prevent long term, irreversible sequelae of hypoglycemia, including mental retardation and epilepsy. NOTE: Items 8, 9 and 10 are critical elements upon which Expert Committee judgments are made. The available evidence for public health relevance (item 8), clinical benefits (item 9) and harms (item 10) should be presented separately.

8. Information supporting the public health relevance. Congenital hyperinsulinism disorders are a group of disorders characterized by inappropriately persistent secretion of insulin in the context of low blood glucose. This condition can be transient or permanent. It is responsible for permanent neurological damage in the newborn and infant. Neurological damage is present in ⅓ to ½ of the children with early onset HI. Importantly, neurodevelopmental damage is observed in both transient and permanent forms of HI and in both mild and severe forms of HI emphasizing the need to recognize and manage hypoglycemia as early as possible (11-14). There is presently no randomized study comparing the effect of diazoxide on neurodevelopment. This is however not surprising as the adverse long-term effects of hypoglycemia on brain development are well recognized and that every effort is made to initiate hypoglycemia management as early as possible in order to prevent irreversible consequences. However, despite the worldwide increase in capacity in pediatric endocrinology, and in particular in Africa (15), irreversible sequalae of HI cannot successfully be prevented without access to diazoxide. Assessment of current use As the capacity in Pediatric Endocrinology is increasing, so is the recognition of prolonged transient or permanent HI. a. Diazoxide is usually readily available in high income countries. In low -and middle-income countries, a survey of all the national model lists of essential medicines shows that despite the fact that the drug is presently not included in the WHO EMLc, it is included in: - 16% of Latin American countries (16) - 8% of Western Pacific countries (unpublished data) - 11% of South East Asian countries (unpublished data) - 29% of the Eastern Mediterranean countries (unpublished data) - None of the African countries (17) However, whether diazoxide is actually available to the patient in countries that have included it in their national list is unclear. Global Pediatric Endocrinology and Diabetes (GPED), Caring and Living as Neighbours (CLAN) and Congenital Hyperinsulinism International (CHI) regularly receive requests for diazoxide. b. Congenital Hyperinsulinism International (CHI) has recently finalized (Nov 2018) an International Congenital Hyperinsulinism Global Access Survey to assess the availability and needs of diazoxide. The preliminary results are as follows:

• 72 pediatric endocrinologists from around the world have responded to the Congenital Hyperinsulinism Global Access Survey (as of November 27, 2018) • The Congenital Hyperinsulinism Global Access Survey link was first made available on October 29, 2018 and remains open on Survey Monkey. • The respondents work in 41 different countries and represent all continents. Responses come from physicians in the following countries:

o Algeria, Argentina, Australia, Bangladesh, Belgium, Brazil, Bulgaria, Canada, Chile, China, Colombia, Georgia, Germany, Ghana, Haiti, Hong Kong, Hungary, Iceland, India, Iraq, Israel, Japan, Kosovo, Luxembourg, Mexico, Montenegro, Myanmar, the Netherlands, Peru, Romania, Russia, Serbia, Spain, Sudan, Sweden, Switzerland, Tanzania, The United Kingdom, Ukraine, The United States, Venezuela. • 62% is the average response to “Approximately what portion of your HI patients require diazoxide?” • 23% of respondents answer “No,” to “Is diazoxide approved for use in your country?” As reported by respondents to the survey, countries where diazoxide is not approved for use are: Bangladesh, Brazil, Bulgaria, China, Georgia, India, Mexico, Peru, Russia, Tanzania, and Ukraine. • 26% of respondents answer “No,” to “Is diazoxide approved for the treatment of HI in your country? • 63% of respondents answer “Yes,” to “Is accessing diazoxide a problem for HI patients in your country?” As reported by respondents to the survey, the countries are: Algeria, Bangladesh, Brazil, Bulgaria, Canada, Chile, China, Colombia, Georgia, Ghana, Haiti, Hungary, India, Iraq, Kosovo, Mexico, Romania, Russia, Sudan, Tanzania, the United Kingdom, Ukraine, Venezuela. • 61% respondents answer “No,” to “Is there a consistent supply of diazoxide in your country?” As reported by respondents to the survey, the countries are: Algeria, Bangladesh, Brazil, Bulgaria, Canada, Chile, China, Colombia, Georgia, Ghana, India, Iraq, Kosovo, Mexico, Montenegro, Myanmar, Peru, Romania, Russia, Sudan, Tanzania, the United Kingdom, Ukraine, Venezuela. • 53% of respondents answer “Yes,” to “Is cost to the patient an obstacle to accessing diazoxide?” As reported by respondents to the survey, the countries are: Brazil, Bulgaria, Canada, Chile, Colombia, Georgia, Ghana, Haiti, Hungary, India, Kosovo, Mexico, Myanmar, Peru, Romania, Sudan, Tanzania, Ukraine, The United States, Venezuela Target population(s) Diazoxide is indicated for hypoglycemia that is secondary to transient and prolonged inappropriate insulin secretion and as a first line treatment in patients with permanent HI where a dietary approach alone does not appropriately prevent hypoglycemia: - Transient: HI is a well-known transient complication of gestational diabetes. In LMICs, where the prevalence of gestational diabetes is increasing rapidly (18) and where it is often sub optimally managed (19), the median prevalence of neonatal hypoglycemia (which in the case of gestational diabetes is usually secondary to HI) in LMICs is 13.5 (interquartile range 5.1–30.4). Although not all neonates with hypoglycemia caused by gestational diabetes will require diazoxide (because of moderate hypoglycemia or short duration of the transient hyperinsulinism), diazoxide is expected to be effective in ALL patients who need it (8). - Permanent: Estimates of the incidence of congenital HI range from 1 in 50 000 births in Holland to as high as 1 in 2500 in Saudi Arabia (related to high rates of consanguinity) (20). Thus, although it is needed in each country, more patients will

need diazoxide in countries where consanguinity is higher (Figure). Overall diazoxide is completely or partially effective in 75% of the patients (2), depending on the genotype and the population.

Figure: Global prevalence of consanguineous unions, Bittles, 2001 (21)

- The effect of diazoxide depends on the genetic cause of hyperinsulinism. It is not effective in HI caused by defect in the KATP channel of the beta-cell of the pancreas, one of the key regulatory steps of insulin secretion (9). Likely impact of treatment on the disease The use of diazoxide in the indications where it is effective, coupled with a dietary approach (regular meals), effectively prevents hypoglycemia and its permanent neurodevelopmental consequences. In the case of prolonged transient HI, it allows the patient to successfully manage HI during the critical period. In the case of permanent HI, it is a lifelong approach that prevents recurrent hypoglycemia and obviates the need for invasive near-total pancreatectomy. 9. Review of benefits: summary of comparative effectiveness in a variety of clinical settings. There is to our knowledge no randomized trial involving diazoxide. The response to diazoxide reported in various series is described below. Resistance to diazoxide is defined as an absence of response to doses of up to 20 mg/kg/d. However many patients were declared non-responsive at doses well below 20 mg/kg/d and none of the studies below reports the duration of the therapeutic trial:

- In China, 54/73 (74%) Chinese patients (22), likely including 16/29 patients belonging to the Han ethnic group (55%) (23) responded to diazoxide (Dose: ?). - In Germany, 47/114 patients from Germany (91), Turkey (14), Austria (3), The Netherlands (3), Russia (1), Bulgaria (1) and Rumania (1) (41%) (Dose: up to 15 mg/kg/d) (13) - In Turkey, 13/24 patients (59%) were diazoxide-responsive. Diazoxide treatment was stopped between 15 days and 12 years in seven of these patients (53.8%) (Dose in diazoxide-responsive patients 8.8±4 (range 4-15) mg/kg/d and in non-responsive 18.1±3 (range 12-20) mg/kg/d (24) - In a different population in Turkey, 18/35 (51.5%) of the patients were diazoxide- responsive (Dose up to 15 mg/kg/d) (25) - In Thailand, 4/10 (40%) of the patients were diazoxide-responsive (Dose: ?) (26) - In United Kingdom, 64/94 (68%) of the patients were diazoxide-responsive (Dose up to 20 mg/kg/d) (27) 10. Review of harms and toxicity: summary of evidence on safety. Diazoxide is a treatment of choice for congenital hyperinsulinism that is effective for a variety of subtypes and is given orally. Other alternatives such as octreotide and glucagon must be administered via multiple daily subcutaneous injections. These alternatives also carry their own risk of adverse effects. In addition, glucagon is frequently unavailable in many countries and octreotide is financially out of reach for almost all patients in low income and developing countries. The total number of patients who have received diazoxide to date has not been assessed. It is estimated that tens of thousands of patients have received diazoxide since 1964. The medicine is usually well tolerated. Adverse effects include: - Water retention and hyponatremia at onset of therapy. For this reason, the treatment is initiated at the dose of 5 mg/kg/d and increased after 2-3 days depending on the results. Water retention can be readily assessed in low income settings through clinical examination (puffiness), excessive weight gain and when available the measurement of serum sodium after 1-2 treatment. When present, it is reversible when the treatment is discontinued and can be avoided with slow resuming of the treatment. It was observed in 14/44 of Chinese patients (28). In many institutions, addition of low dose thiazide diuretic (Included in EML and EMLc, section 16.) is instituted simultaneous with diazoxide, eliminating this problem. - Hypertrichosis (in particular on back and limbs) that is reversible after the treatment is discontinued. This complication is present in a majority (36/44, 82%) of the patients and is do-dependent. Except for psychological distress, hypertrichosis is well tolerated (28). These and other adverse events have been reported with varying frequency in cohorts of infants and children receiving diazoxide at doses up to 25 mg/kg/d for congenital hyperinsulinism (Table 1). Adverse events may be dose-related and are usually reversible

with dose reduction or discontinuations. Less commonly reported adverse events in children include rash, thrombocytopenia, neutropenia, heart failure, extrapyramidal adverse events, and paradoxical hypoglycemia (Table 1). The US Food and Drug Administration (FDA) identified 11 cases of pulmonary hypertension in neonates and infants treated with diazoxide from their Adverse Event Reporting System (n=7) and the medical literature (n=4) between 1973 and 2015 (https://fis.fda.gov/sense/app/d10be6bb-494e-4cd2-82e4-0135608ddc13/sheet/45beeb74- 30ab-46be-8267-5756582633b4/state/analysis). For the cases in the FDA database, risk factors included meconium ileus, congenital heart disease and streptococcal infection and pulmonary hypertension improved or resolved following discontinuation of diazoxide. The Health Canada Adverse Reaction Online Database includes 3 reports of pulmonary hypertension in infants between 1965 and 2018 (https://www.canada.ca/en/health- canada/services/drugs-health-products/medeffect-canada/adverse-reaction-database.html) No report of diazoxide adverse effects in children were found in the European Database of Suspected Adverse Drug Reactions Reports (http://www.adrreports.eu/en/). Overall, the quality of the safety data is weak as it comes from small series of patients and case reports. No randomized controlled trials are available. Adverse events data was not systematically collected in the cohort studies. The likelihood that adverse events were associated with diazoxide was not assessed in any of the cohort studies or case reports.

Table 1 – Literature Reports of Diazoxide Adverse Events in Children

Trial Patients Intervention Adverse Events

Cohort Studies

Gong et al. (2015) Congenital Diazoxide and -Sodium and water retention (22) hyperinsulinism, octreotide (n=73) 55/73 (n=4 discontinued median age 3.5 mos (0- diazoxide)

24 mos) -GI disturbance in 41/73 (n=8 Prospective cohort F/U 6mos-5yrs discontinued diazoxide) (2006-13) -Polytrichia 25/73- N=95 - Thrombocytopenia 5/73 Yoshida et al. 142/50,895 infants Diazoxide (n=78), (2014) (29) diagnosed with dose range 3-25 hypoglycemic mg/kg/d Complication n=78

hyperinsulinism (HIH); (%) Survey 134 infants included (n=119 transient, n=15 Total 29 (37) congenital) Edema 15 (19) N=103 NICUs Oliguria 4 (5)

PDA reopened 3 (4)

Hypertrichosis 12 (15)

Hyperkalemia 3 (4)

Liver function 1(1) deteriorated

-Younger gestational age and higher max dose independent risk factors for circulatory complications in multivariate analysis (OR 0.76 and 1.2)

Meissner et al. Congenital Diazoxide up to 15 -Sinus tachycardia 1/47 (2003) (13) hyperinsulinism: mg/kg/d (n=47) (discontinued diazoxide) neonatal onset (n=74), infancy (n=32), -Recurrent rash 2/47 (both discontinued diazoxide) Retrospective childhood (n=8) cohort -Transient disturbances in electrolytes or edema “frequent” N=114

Hu et al. (2012) Congenital Diazoxide 5-15 8/44 unresponsive (28) hyperinsulinism mg/kg/d x 7-10d trial, then continue -Facial or leg edema 18/44

if responsive -Transient gastrointestinal Cohort (2002-11) reactions 12/44 N=44 -Hypertrichosis 100%

Touati et al. (1998) Hyperinsulinemic Diazoxide 10-15 42/77 unresponsive (30) hypoglycemia mg/kg/day x 5 d trial, then continue -Hirsutism “almost every case” Retrospective if responsive cohort (10 year -Immunoallergic neutropenia n=2 period) (n=1 discontinued diazoxide) N=77

Abu-Osba (1989) Persistent neonatal Diazoxide 12-24 -Toxicity (defined as HR and RR (31) hyperinsulinism mg/kg/d increase by more than 1 standard deviation and cardiomegaly, murmur or hepatomegaly) in Retrospective 8/11 treatment courses cohort (1983-6) -Toxicity associated with N=7 (N=11 diazoxide dose treatments)

Goode et al. (1986) Insulinoma, age 5 mos- Diazoxide 40-1500 -Hirsutism 56% (32) 73 yrs mg/d x 3wks-11yrs (n=18) -Fluid retention 50% *number of children not reported -Hypersensitivity n=2 Retrospective (discontinued diazoxide) cohort (1967-84) N=24

Case reports

Silvani et al. (2004) 43 day old infant Diazoxide 17 Fluid retention, heart failure, (33) mg/kg/d with respiratory failure after a few octreotide days of therapy. Resolved 5 days after stopping therapy. Case report N=1

Parker et al. (1991) 14 y/o male with Diazoxide 30 -Hypertrophic cardiomyopathy on (34) postneonatal mg/kg/d x 12 yrs echo. Normal contractility within hyperinsulinemic 3 months of stopping diazoxide hypoglycemia -Coarsened facial features, Case report hypertrichosis, grade 3 murmur N=1 noted at age 10 yr

Combs et al. (1967) Case 1 - 5 week old Case 1 - Diazoxide Case 1- Eosinophilia with (35) female with persistent 10 mg/kg/d neutropenia after 3 days. hypoglycemia Resolution 2 months after discontinuing diazoxide

Case report Case 2 - Diazoxide Case 2 - 15 y/o male 300-600 mg daily N=2 Case 2 - Eosinophilia with thrombocytopenia after 8 days Resolution a few weeks after drug discontinuation.

McGraw et al. Case 1 – 18 day infant Case 1 - Diazoxide Case 1 - Cardiac failure (1985) (36) with hyperinsulinemic 22 mg/kg/d unresponsive to digoxin and hyperinsulinism diuretics. Symptoms resolved Case report with diazoxide dose reduction to

N=2 Case 2 - Diazoxide 2 mg/kg/day Case 2 - 12 month old 10 mg/kg/d child with hyperinsulinemic Case 2 – ongoing truncal ataxia, hyperinsulinism diazoxide continued

Ponmani et al. Case 1 – 10 day infant Case 1 and 2 – Cases 1 and 2 – paradoxical (2013) (37) with hyperinsulinemic diazoxide 15 hypoglycemia, improved when hyperinsulinism mg/kg/d discontinued diazoxide

Case report Case 2 – 3 day infant N=2 with hyperinsulinemic hyperinsulinism

Darendeliler et al. Male with Diazoxide 6-8 -No adverse events noted, (1997) (38) hyperinsulinemia mg/kg/d including hypertrichosis treated with diazoxide from age 32d to 5 yrs Case report N=1

Tas et al. (2015) 10 day old male with Diazoxide 9-10 Cardiorespiratory failure after 7 (39) hyperinsulinemic mg/kg/d wks of treatment. Echo suggested hypoglycemia pulmonary hypertension. Case report Improvement following diazoxide N=1 discontinuation

Summary of comparative safety against comparators Diazoxide is the mainstay treatment for HI and there is no other first line therapeutic option. Identification of variation in safety that may relate to health systems and patient factors Heart failure secondary to water retention has been reported in premature babies and associated with the reopening of the ductus arteriosus. Diazoxide should be used with caution in these patients (29)

11. Summary of available data on comparative cost and cost-effectiveness within the pharmacological class or therapeutic group. Not applicable. There is no comparative medicine.

12. Summary of regulatory status of the medicine.

Country Indication

Japan Approved; indication not listed (Aroglycem capsules)

US Hypoglycemia due to hyperinsulinism associated with the following conditions in infants and children: leucine sensitivity, islet cell (Proglycem hyperplasia, nesidioblastosis, extrapancreatic malignancy, islet cell capsules, liquid) adenoma, or adenomatosis; in adults: inoperable islet cell adenoma or carcinoma or extrapancreatic malignancy.

Canada Hypoglycemia due to hyperinsulinism associated with the following conditions in infants and children: leucine sensitivity, islet cell (Proglycem hyperplasia, nesidioblastosis, extrapancreatic malignancy, islet cell capsules) adenoma, or adenomatosis; in adults: inoperable islet cell adenoma or carcinoma or extrapancreatic malignancy.

Australia Malignant hypertension (injection)

Great Britain Intractable hypoglycaemia with severe symptoms from a variety of causes including: idiopathic hypoglycaemia in infancy, leucine- (Eudemine brand sensitive or unclassified; functional islet cell tumours both malignant tablets) and benign if inoperable, extra-pancreatic neoplasms producing hypoglycaemia; glycogen storage disease; hypoglycaemia of unknown origin

13. Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia, United States Pharmacopoeia, European Pharmacopeia). Diazoxide is listed in the British Pharmacopoeia, the United States Pharmacopoeia and the European Pharmacopoeia

14. References 1. Boerma T, Mathers C, AbouZahr C, Somnath C, Hogan D, G. S. WHO | Health in 2015: from MDGs to SDGs. Geneva; 2015. 2. Banerjee I, Salomon-Estebanez M, Shah P, Nicholson J, Cosgrove KE, Dunne MJ. Therapies and outcomes of congenital hyperinsulinism-induced hypoglycaemia. Diabet Med. 2019;36(1):9-21. 3. Helleskov A, Melikyan M, Globa E, Shcherderkina I, Poertner F, Larsen AM, et al. Both Low Blood Glucose and Insufficient Treatment Confer Risk of Neurodevelopmental Impairment in Congenital Hyperinsulinism: A Multinational Cohort Study. Front Endocrinol (Lausanne). 2017;8:156. 4. WHO. Management of Severe Malnutrition: A Manual for Physicians and Other Senior Health Workers. Geneva: World Health Organization; 1999. 5. WHO. Pocket Book of Hospital Care for Children. 2nd ed ed. Organization WH, editor. Malta2013. 6. Thornton PS, Stanley CA, De Leon DD, Harris D, Haymond MW, Hussain K, et al. Recommendations from the Pediatric Endocrine Society for Evaluation and Management of Persistent Hypoglycemia in Neonates, Infants, and Children. J Pediatr. 2015;167(2):238-45. 7. Division of Child Health and Development and maternal and Newborn Health/Safe Motherhood. Hypoglycemia of the Newborn - Review of the Literature. Geneva. 1997. 8. Hoe FM, Thornton PS, Wanner LA, Steinkrauss L, Simmons RA, Stanley CA. Clinical features and insulin regulation in infants with a syndrome of prolonged neonatal hyperinsulinism. J Pediatr. 2006;148(2):207-12. 9. Yorifuji T, Horikawa R, Hasegawa T, Adachi M, Soneda S, Minagawa M, et al. Clinical practice guidelines for congenital hyperinsulinism. Clin Pediatr Endocrinol. 2017;26(3):127- 52. 10. Drash A, Wolff F. Drug Therapy in Leucine-Sensitive Hypoglycemia. Metabolism. 1964;13:487-92. 11. Avatapalle HB, Banerjee I, Shah S, Pryce M, Nicholson J, Rigby L, et al. Abnormal Neurodevelopmental Outcomes are Common in Children with Transient Congenital Hyperinsulinism. Front Endocrinol (Lausanne). 2013;4:60. 12. Ludwig A, Ziegenhorn K, Empting S, Meissner T, Marquard J, Holl R, et al. Glucose metabolism and neurological outcome in congenital hyperinsulinism. Semin Pediatr Surg. 2011;20(1):45-9. 13. Meissner T, Wendel U, Burgard P, Schaetzle S, Mayatepek E. Long-term follow-up of 114 patients with congenital hyperinsulinism. Eur J Endocrinol. 2003;149(1):43-51. 14. Menni F, de Lonlay P, Sevin C, Touati G, Peigne C, Barbier V, et al. Neurologic outcomes of 90 neonates and infants with persistent hyperinsulinemic hypoglycemia. Pediatrics. 2001;107(3):476-9. 15. Odundo GO, Ngwiri T, Otuoma O, Chanzu NM. Developing equity in capacity of paediatric endocrinology subspecialists worldwide. Lancet Diabetes Endocrinol. 2016;4(3):204-5. 16. Rowlands A, Acosta-Gualandri A, Guevara-Aguirre J, Chanoine JP. WHO and national lists of essential medicines in Mexico, Central and South America, and the Caribbean: are they adequate to promote paediatric endocrinology and diabetes care? BMJ Glob Health. 2016;1(3):e000114.

17. Rowlands A, Ameyaw E, Rutagarama F, Dipesalema J, Majaliwa ES, Mbogo J, et al. Insights from the WHO and National Lists of Essential Medicines: Focus on Pediatric Diabetes Care in Africa. Horm Res Paediatr. 2018;90(2):82-92. 18. Guariguata L, Linnenkamp U, Beagley J, Whiting DR, Cho NH. Global estimates of the prevalence of hyperglycaemia in pregnancy. Diabetes Res Clin Pract. 2014;103(2):176-85. 19. Utz B, De Brouwere V. "Why screen if we cannot follow-up and manage?" Challenges for gestational diabetes screening and management in low and lower-middle income countries: results of a cross-sectional survey. BMC Pregnancy Childbirth. 2016;16(1):341. 20. Makov M, Chodick G, Mohnike K, Otonkoski T, Huopio H, Banerjee I, et al. Congenital hyperinsulinism, neonatal diabetes and the risk of malignancies: an international collaborative study. Preliminary communication. Diabet Med. 2015;32(5):701-3. 21. Bittles A. Consanguinity and its relevance to clinical genetics. Clin Genet. 2001;60(2):89-98. 22. Gong C, Huang S, Su C, Qi Z, Liu F, Wu D, et al. Congenital hyperinsulinism in Chinese patients: 5-yr treatment outcome of 95 clinical cases with genetic analysis of 55 cases. Pediatr Diabetes. 2016;17(3):227-34. 23. Sang Y, Xu Z, Liu M, Yan J, Wu Y, Zhu C, et al. Mutational analysis of ABCC8, KCNJ11, GLUD1, HNF4A and GCK genes in 30 Chinese patients with congenital hyperinsulinism. Endocr J. 2014;61(9):901-10. 24. Guven A, Cebeci AN, Ellard S, Flanagan SE. Clinical and Genetic Characteristics, Management and Long-Term Follow-Up of Turkish Patients with Congenital Hyperinsulinism. J Clin Res Pediatr Endocrinol. 2016;8(2):197-204. 25. Demirbilek H, Arya VB, Ozbek MN, Akinci A, Dogan M, Demirel F, et al. Clinical characteristics and phenotype-genotype analysis in Turkish patients with congenital hyperinsulinism; predominance of recessive KATP channel mutations. Eur J Endocrinol. 2014;170(6):885-92. 26. Sawathiparnich P, Likitmaskul S, Angsusingha K, Nimkarn S, Chaichanwatanakul K, Laohapansang M, et al. Persistent hyperinsulinemic hypoglycemia of infancy: experience at Siriraj Hospital. J Med Assoc Thai. 2002;85 Suppl 2:S506-12. 27. Banerjee I, Skae M, Flanagan SE, Rigby L, Patel L, Didi M, et al. The contribution of rapid KATP channel gene mutation analysis to the clinical management of children with congenital hyperinsulinism. Eur J Endocrinol. 2011;164(5):733-40. 28. Hu S, Xu Z, Yan J, Liu M, Sun B, Li W, et al. The treatment effect of diazoxide on 44 patients with congenital hyperinsulinism. J Pediatr Endocrinol Metab. 2012;25(11-12):1119- 22. 29. Yoshida K, Kawai M, Marumo C, Kanazawa H, Matsukura T, Kusuda S, et al. High prevalence of severe circulatory complications with diazoxide in premature infants. Neonatology. 2014;105(3):166-71. 30. Touati G, Poggi-Travert F, Ogier de Baulny H, Rahier J, Brunelle F, Nihoul-Fekete C, et al. Long-term treatment of persistent hyperinsulinaemic hypoglycaemia of infancy with diazoxide: a retrospective review of 77 cases and analysis of efficacy-predicting criteria. Eur J Pediatr. 1998;157(8):628-33. 31. Abu-Osba YK, Manasra KB, Mathew PM. Complications of diazoxide treatment in persistent neonatal hyperinsulinism. Arch Dis Child. 1989;64(10):1496-500. 32. Goode PN, Farndon JR, Anderson J, Johnston ID, Morte JA. Diazoxide in the management of patients with insulinoma. World J Surg. 1986;10(4):586-92.

33. Silvani P, Camporesi A, Mandelli A, Wolfler A, Salvo I. A case of severe diazoxide toxicity. Paediatr Anaesth. 2004;14(7):607-9. 34. Parker JJ, Allen DB. Hypertrophic cardiomyopathy after prolonged diazoxide therapy for hyperinsulinemic hypoglycemia. J Pediatr. 1991;118(6):906-9. 35. Combs JT, Grunt JA, Brandt IK. Hematologic reactions to diazoxide. Pediatrics. 1967;40(1):90-2. 36. McGraw ME, Price DA. Complications of diazoxide in the treatment of nesidioblastosis. Arch Dis Child. 1985;60(1):62-4. 37. Ponmani C, Gannon H, Hussain K, Senniappan S. Paradoxical hypoglycaemia associated with diazoxide therapy for hyperinsulinaemic hypoglycaemia. Horm Res Paediatr. 2013;80(2):129-33. 38. Darendeliler F, Bundak R, Bas F, Saka N, Gunoz H. Long-term diazoxide treatment in persistent hyperinsulinemic hypoglycemia of infancy: a patient report. J Pediatr Endocrinol Metab. 1997;10(1):79-81. 39. Tas E, Mahmood B, Garibaldi L, Sperling M. Liver injury may increase the risk of diazoxide toxicity: a case report. Eur J Pediatr. 2015;174(3):403-6.