Diazoxide

Generic name
Diazoxide
Brand name
ATC Code
V03AH01
Dosages
Side effects in children
Warnings & precautions in children
Contra-indications in children

Interactions
PK
Renal impairment
References

Pharmacokinetics in children

The half-life in children from 4 months to 6 years varies from 9.5 to 24 hours in long-term use of the oral dose. In adults, the half-life is 24-36 hours after oral administration [SmPC Proglicem].
Additionally, a population PK model found a half-life of 15±5.3 h (range 5.9-27.7) after oral administration in children aged 0.1-15.2 years (median 4.3 years) with hyperinsulinemic hypoglycemia [Kizu 2017].

dose recommendation of formulary compared to licensed use (on-label versus off-label)

No information is present at this moment.

Available formulations

No information is present at this moment.

Dosages

Congenital hyperinsulinism
  • Oral
    • < 1 year
      [1] [2] [3] [4] [5] [6] [7]
      • Initial dose: 10 mg/kg/day in 2 doses.
      • Maintenance dose: Thereafter depending on the effect 5 - 15 mg/kg/day in 2 doses. Max: 20 mg/kg/day.

      • In combination with a diuretic (chlorothiazide, furosemide) in fluid retention.
        Only use the maximum dose in exceptional cases; administer in 3 doses

    • 1 year up to 18 years
      [1] [2] [3] [4] [5] [6] [7]
      • Initial dose: 5 mg/kg/day in 2 doses.
      • Maintenance dose: Depending on the effect 3 - 8 mg/kg/day in 2 - 3 doses.

      • In combination with a diuretic (chlorothiazide, furosemide) in fluid retention.
Hyperinsulinism
  • Oral
    • Term neonate
      • Initial dose: 8 mg/kg/day in 2 - 3 doses. Higher or lower starting doses can be used based on blood glucose levels.
      • Maintenance dose: Thereafter depending on the effect 3 - 15 mg/kg/day in 2 - 3 doses. Max: 20 mg/kg/day.

      • Only use the maximum dose in exceptional cases; administer in 3 doses

    • 1 month up to 2 years
      • Initial dose: 8 mg/kg/day in 2 - 3 doses. Higher or lower starting doses can be used based on blood glucose levels.
      • Maintenance dose: Thereafter depending on the effect 3 - 15 mg/kg/day in 2 - 3 doses. Max: 20 mg/kg/day.

      • Only use the maximum dose in exceptional cases; administer in 3 doses

    • 2 years up to 18 years
      • Initial dose: 3 mg/kg/day in 2 - 3 doses. Higher or lower starting doses can be used based on blood glucose levels.
      • Maintenance dose: Thereafter depending on the effect  3 - 8 mg/kg/day in 2 - 3 doses. Max: 15 mg/kg/day. Max. 800 mg/day.

Renal impaiment in children > 3 months

GFR ≥10 ml/min/1.73m2: Dose adjustment not required.

GFR <10 ml/min/1.73m2: A general recommendation on dose adjustment cannot be provided.

Clinical consequences

As half life is prolonged in case of impaired renal function, consider reducing the dose and monitoring serum electrolytes [SmPC Proglicem].

The complete list of all undesirable drug reactions can be found in the national Summary of Product Characteristics (SmPC) – click here

Side effects in children

Fluid retention, hypertrichosis, pulmonary hypertension, cardiac failure and neutropenia; most symptoms disappear after stopping the therapy. Hirsutism of the lanugo type. Gastrointestinal reaction. Trombocytopenia. Voice changes and abnormal faces (on long term therapy). Decreased immunoglobulins (IgG). Necrotizing enterocolitis.
[SmPC Proglicem] [SmPC Eudemine] [Chen 2021] [Duggal 2024]

The complete list of all contra-indications can be found in the national Summary of Product Characteristics (SmPC) – click here

Contra-indications

No information available on specific contra indications in children.

The complete list of all warnings and precautions can be found in the national Summary of Product Characteristics (SmPC) – click here

Warnings & precautions in children

Pulmonary hypertension has been reported in children, infants, and newborns; in most cases, this resolved after discontinuation of treatment. Monitor newborns closely during treatment, especially if there are risk factors such as meconium aspiration syndrome, hyaline membrane disease, neonatal tachypnea, pneumonia, sepsis, congenital diaphragmatic hernia, and congenital heart disease. Discontinue treatment if pulmonary hypertension is diagnosed. Instruct parents/caregivers to contact you immediately if children show signs of respiratory distress.

There have been reports of necrotizing enterocolitis (NEC) in newborns, in some cases with fatal consequences. Closely monitor newborns during treatment for symptoms such as vomiting, abdominal distension, blood in the stool, and lethargy, especially in those at increased risk of NEC (such as premature infants). If NEC is suspected, discontinue treatment.

Caution is recommended when used in neonates with elevated bilirubin levels, as diazoxide can displace bilirubin from its protein binding [SmPC Proglicem]. 

Providers should be aware of the risks and monitor for neutropenia and thrombocytopenia. Complete blood count with differential should be measured at baseline and 5 to 7 days after starting diazoxide and every 3 to 6 months thereafter [Brar 2020].

Patients should be monitored for weight, electrolytes and edema, and cardiopulmonary function, especially when starting or increasing doses [Chen 2021].

Interactions

The complete list of all interactions can be found in the national Summary of Product Characteristics (SmPC) – click here

ALL OTHER THERAPEUTIC PRODUCTS

This pages provides a list of drugs from the same ATC class for comparison. This does not necessarily mean that these drugs are interchangeable.

Antidotes
V03AB27
V03AB16
V03AB24
V03AB25
V03AB33
V03AB17
V03AB15
V03AB13
V03AB19
V03AB14
V03AB06
V03AB35
Iron chelating agents
V03AC03
V03AC02
V03AC01
Drugs for treatment of hyperkalemia and hyperphosphatemia
V03AE07
V03AE01
V03AE02
V03AE01
Detoxifying agents for antineoplastic treatment
V03AF03
V03AF01
V03AF07
Other therapeutic products
V03AX03
DETOXIFYING AGENTS FOR ANTINEOPLASTIC TREATMENT
V03AF03
V03AF01
V03AF07
OTHER THERAPEUTIC PRODUCTS
V03AX03

References

  1. Fafoula O, et al, Prolonged hyperinsulinaemic hypoglycaemia in newborns with intrauterine growth retardation, Arch Dis Child Fetal Neonatal Ed, 2006, Nov;91(6), F467
  2. Hoe FM, et al, Clinical features and insulin regulation in infants with a syndrome of prolonged neonatal hyperinsulinism, J Pediatr, 2006, Feb;148(2), 207-1
  3. Giurgea I, et al, [Congenital hyperinsulinism in newborn and infant] L'hyperinsulinisme congenital du nouveau-ne et du nourrisson. , Arch Pediatr., 2005, Nov;12(11), 1628-3
  4. Tyrrell VJ, et al, Ten years' experience of persistent hyperinsulinaemic hypoglycaemia of infancy, J Paediatr Child Health., 2001, Oct;37(5), 483-8
  5. Ortqvist E, et al, Temporary preservation of beta-cell function by diazoxide treatment in childhood type 1 diabetes, Diabetes Care, 2004, Sep;27(9), 2191-7
  6. Yildizdas D, et al, Pulmonary hypertension, heart failure and neutropenia due to diazoxide therapy, Adv Ther, 2008, May;25(5), 515-9
  7. Nebesio TD, et al, Development of pulmonary hypertension in an infant treated with diazoxide, J Pediatr Endocrinol Metab, 2007, Aug;20(8), 939-44
  8. MSD BV, SPC Proglicem (RVG 06865), www.cbg-meb.nl, 28-01-2024, http://db.cbg-meb.nl/IB-teksten/h06865.pdf
  9. FDA Drug safety communications, FDA warns about a serious lung condition in infants and newborns treated with Proglycem (diazoxide), www.fda.gov, 16-7-2015
  10. MSD Sharp & Dohme GmbH, SmPC PROGLICEM® 25/100 mg Hartkapseln (6426992.01.00), 02/2024
  11. RPH Pharamceuticals AB, SmPC (UK) Eudemine, 12-05-2021
  12. Kizu R, et al., Population Pharmacokinetics of Diazoxide in Children with Hyperinsulinemic Hypoglycemia, Horm Res Paediatr., 2017, 88(5), 316-23
  13. Duggal M, et al., Pulmonary Hypertension and Necrotizing Enterocolitis in Neonates Treated with Diazoxide., Am J Perinatol., 2024, 41(S01)
  14. Brar PC, et al., Management and Appropriate Use of Diazoxide in Infants and Children with Hyperinsulinism., J Clin Endocrinol Metab., 2020, 105(12)
  15. Balachandran B, et al., Randomised controlled trial of diazoxide for small for gestational age neonates with hyperinsulinaemic hypoglycaemia provided early hypoglycaemic control without adverse effects., Acta Paediatr., 2018, 107(6), 990-5
  16. Chandran S, et al., Safety and efficacy of low-dose diazoxide in small-for-gestational-age infants with hyperinsulinaemic hypoglycaemia., Arch Dis Child Fetal Neonatal Ed., 2022, 107(4), 359-63
  17. Yoshida K, et al., High prevalence of severe circulatory complications with diazoxide in premature infants., Neonatology, 2014, 105(3), 166-71
  18. Giurgea I, et al, [Congenital hyperinsulinism in newborn and infant] L'hyperinsulinisme congenital du nouveau-ne et du nourrisson., Arch Pediatr., 2005, Nov;12(11), 1628-3
  19. Chen X, et al., Efficacy and safety of diazoxide for treating hyperinsulinemic hypoglycemia: A systematic review and meta-analysis., PLoS One, 2021, 16(2)
  20. Teva Pharmaceuticals, SmPC (USA) Proglycem, 7/2024

Changes

Therapeutic Drug Monitoring


Overdose