The Committee recommended the addition of diazoxide to the complementary list of the EMLc for the management of hypoglycaemia secondary to prolonged hyperinsulinism (HI), based on evidence of favourable efficacy and tolerability, and taking into account the serious consequences of this condition in children not treated.
The Committee noted the variable global availability and reliability of supply of diazoxide and considered inclusion of diazoxide on the EMLc could help to facilitate more reliable access.
The application requested the inclusion of diazoxide on the EMLc for the management of hypoglycaemia secondary to prolonged hyperinsulinism (HI). Diazoxide had not previously been considered for inclusion on the EMLc for this indication.
Public health relevance
Congenital hyperinsulinism (HI) 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. Congenital HI has an estimated incidence ranging from 1 in 50 000 live births, with considerably higher incidence (up to 1 in 2500) seen in populations with high rates of consanguineous unions (1). Recurrent episodes of hypoglycaemia produced by HI increase risk for seizures, brain damage and intellectual disability. Management of hypoglycaemia is critical to prevent and reduce the risk of these serious consequences (2).
Neurological damage is present in up to 50% of children with early onset HI. Neurodevelopmental damage is observed in transient, permanent, mild and severe forms of HI, emphasizing the need for rapid diagnosis and prompt management (3–6).
Diazoxide is indicated for hypoglycaemia 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 hypoglycaemia.
No randomized controlled trials involving diazoxide were identified in the application.
Case series studies from China (7), Germany (5), Turkey (8, 9), Thailand (10) and the United Kingdom (11) have reported the clinical response to diazoxide therapy ranging from 40% to 74% at dose ranges up to 20 mg/kg/day.
The effect of diazoxide depends on the genetic cause of hyperinsulinism. The majority of cases of neonatal onset persistent congenital HI are caused by defects in the KATP channel genes of the beta-cell of the pancreas, and diazoxide is ineffective in these patients (12).
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 application summarized safety findings for diazoxide from cohort studies and case reports (5, 7, 13–24). The medicine is usually well tolerated. Adverse effects include water retention and hyponatraemia at onset of therapy, and hypertrichosis (in particular on back and limbs) that is reversible after the treatment is discontinued. Less commonly reported adverse events include rash, thrombocytopenia, neutropenia, heart failure, extrapyramidal adverse events and paradoxical hypoglycaemia. Adverse events may be dose-related and are usually reversible with dose reduction or discontinuation of therapy. Heart failure secondary to water retention has been reported in premature babies and associated with reopening of the ductus arteriosus. Diazoxide is recommended to be used with caution in these patients (13).
Pulmonary hypertension has been reported to the United States Food and Drug Administration and Health Canada in neonates and infants treated with diazoxide.
The application noted that 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.
A retrospective cohort study of 295 patients investigated the prevalence of adverse events in children with congenital HI treated with diazoxide (25). 2.4% of children developed pulmonary hypertension after initiation of diazoxide (most of them had additional risk factors such as prematurity, structural heart disease and respiratory failure). In addition, 15.6% developed neutropenia, 4.7% thrombocytopenia and 5% hyperuricaemia. The authors concluded that screening for neutropenia, thrombocytopenia and hyperuricaemia in diazoxide-treated patients may be of value given the relatively high prevalence of these events.
Cost / cost effectiveness
No information was provided in the application regarding the cost and cost-effectiveness of diazoxide.
Preliminary results of an international survey of paediatric endocrinologists conducted in 2018 by Congenital Hyperinsulinism International to assess the availability and need for diazoxide reported that 53% of respondents agreed that cost to the patient was an obstacle to accessing diazoxide.
The 2013 WHO Pocket book of Hospital Care for Children (26) recognizes the importance of hypoglycaemia and the need to treat it as an emergency in order to prevent neurological sequelae. It focuses on the most common causes of hypoglycaemia and does not consider HI or make recommendations regarding diazoxide treatment.
Clinical practice guidelines for congenital HI developed by the The Japanese Society for Pediatric Endocrinology and The Japanese Society of Pediatric Surgeons (12) make the following recommendations for first-line treatment of congenital HI:
• Maintain blood glucose above the target range by continuous glucose infusion. [Recommendation level 1, Evidence level A].
• When blood glucose is successfully maintained by continuous glucose infusion, nutritional support by frequent feeding, continuous feeding, cornstarch (after nine months), or formula for glycogen storage diseases should be attempted. [Recommendation level 1, Evidence level A].
• When blood glucose is not maintained by continuous glucose infusion, or when it is difficult to withdraw glucose infusion for an extended period, a 5-day trial of oral diazoxide, in 2–3 divided doses, at 5–15 mg/kg/day should be attempted, unless contraindicated by cardiac failure or pulmonary hypertension. [Recommendation level 1, Evidence level A].
• When diazoxide is effective in stabilizing blood glucose levels, intravenous glucose infusion should be withdrawn and transfer to nutritional support (frequent feeding, continuous feeding, or cornstarch formula for glycogen storage diseases) should be attempted. [Recommendation level 1, Evidence level A].
• While on diazoxide, the patient should be on a glucose self-monitoring regimen to detect episodes of hypoglycaemia. Furthermore, complete blood count (CBC), blood chemistry, and physical examination should be performed to detect frequent adverse events, such as hypertrichosis, tachycardia, or oedema. [Recommendation level 1, Evidence level B].
• When euglycaemia is not achieved by the first line treatment and continuous glucose infusion cannot be withdrawn, the second-line treatment should be initiated. [Recommendation level 1, Evidence level A].
Global availability, although reliable supply and regulatory approval of diazoxide is variable.
Comments on the applications were received from the WHO department of Management of NCDs, Disability, Violence and Injury Prevention. The technical unit advised that it supported the addition of diazoxide to the complementary list of the EMLc, stating that congenital hyperinsulinism is a rare but serious condition requiring specialist assessment and care, and that inclusion of diazoxide on the EMLc could facilitate access to this medicine in countries where it is currently unavailable.
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