Pharmacokinetics in children

The table below shows the limited information about PK in children with diabetes mellitus type 2 with a mean (± SD) age of 14.1±2.0 years and a body weight of 96.7±23.5 kg.[Laffel 2018]

	Empagliflozine 5 mg (n=9)		Empagliflozine 10 mg (n=8)		Empagliflozine 25 mg (n=10)
	Mean	%CV	Mean	%CV	Mean	%CV
Cmax nmol/l	175	54,2	211	59,1	692	57,3
Tmax h	1,5	0,95-7,92	1,25	0,97-4,17	1,78	0,5-4
T1/2, h	7,03	18,9	7,61	27	8,09	26,8

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

Type 2 diabetes mellitus
Oral ≥ 10 years 10 mg/day in 1 dose Increase if needed to 25 mg/day in 1 dose..

Symptomatic neutrophil dysfunction in glycogen stacking disease type Ib

Oral 6 months up to 18 years Initial dose: 0.3 mg/kg/day in 1 - 2 doses. Max: 10 mg/day. Maintenance dose: If necessary, increase the dosage up to 0.9 mg/kg/day in 1 - 2 doses. Max: 25 mg/day. Increased awareness for the occurrence of hypoglycemia and disruption of metabolic control is advised during treatment, especially during dose titration, times of reduced enteral intake and at (risk of) dehydration. Ensure adequate enteral intake to prevent hypoglycemia and metabolic decompensation. Treatment by or after consultation with a pediatrician-specialist (metabolic diseases) experienced in the use of empagliflozin in GSD patients. Consider clinical initiation of empagliflozin treatment, especially in children < 6 years of age. Note: Children < 6 years have a pre-existing increased risk of hypoglycemia, due in part to relatively higher glucose requirements than older children and adults Note: Children < 1 year of age may have decreased renal clearance and decreased hepatic excretion of empagliflozin. 0 months up to 6 months Initial dose: 0.2 mg/kg/day in 1 - 2 doses. Max: 10 mg/day. Maintenance dose: If necessary, increase the dosage up to 0.9 mg/kg/day in 1 - 2 doses. Max: 25 mg/day. Increased awareness for the occurrence of hypoglycemia and disruption of metabolic control is advised during treatment, especially during dose titration, times of reduced enteral intake and at (risk of) dehydration. Ensure adequate enteral intake to prevent hypoglycemia and metabolic decompensation. Treatment by or after consultation with a pediatrician-specialist (metabolic diseases) experienced in the use of empagliflozin in GSD patients. Start clinical empagliflozin treatment during hospital admission.  Note: Children < 6 years have a pre-existing increased risk of hypoglycemia, due in part to relatively higher glucose requirements than older children and adults Note: Children < 1 year of age may have decreased renal clearance and decreased hepatic excretion of empagliflozin.

Renal impaiment in children > 3 months

Do not initiate treatment with empaliflozin at a creatinine clearance < 30 ml/kg/min.

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

Overall, the safety profile in children is similar to the safety profile in adults with type 2 diabetes mellitus.

Hypoglycemia was the most commonly reported adverse event in children in a placebo-controlled study. None of these events was serious and immediate help was not required [SmPC]

Grünert et al reported on the experiences with empagliflozin use in 112 individuals with GSDIb (median age 10.5 years, range 0-38 years). Most persons (69%) experienced no adverse events. The most common adverse event was level 3 hypoglycemia (< 3 mmol/L with altered mental and or physical status requiring assistance) occurring in 14 (18%) of individuals <18 year and 6 (14%) individuals >18 year. Dosing frequency (once or twice daily) did not impact the incidence of hypoglycemia and it occurred in both adults and children. The most severe adverse event was lactic acidosis and occurred in six persons (five children and one adult). In one adult, two decompensations requiring ICU-admission were reported, both associated with gastroenteritis and dehydration. Importantly, since hypoglycemia and hyperlactatemia are common finding in GSDIb, it was impossible to determine in which cases empagliflozin treatment contributed to these episodes of hypoglycemia.

Recently another study was published that enrolled 158 children aged 10 – 17 years with type 2 diabetes, examining the efficacy safety of empagliflozin (n=52) and linagliptin (n=53) versus placebo (n=53). Adverse events occurred in 40 (77%) participants with empagliflozin and 34 (64%) participants with placebo. The most common adverse events was hypoglycemia, occurring more frequently with empagliflozin 12 (23%) than on placebo 5 (9%). No cases of severe hypoglycemia were reported. Serious adverse events occurred in two (4%) participants with empagliflozin and two (4%) participants with placebo. The serious adverse events in the empagliflozin treated participants were hospitalization because of suicidal ideation (n=1) and skin candida (n=1), and in the placebo group hospitalization for splenic vein thrombosis (n=1) and hyperglycemia (n=1).

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

In GSD Type 1b:

Caution: to prevent hypoglycemia and metabolic decompensation, temporarily discontinue empagliflozin administration in periods when sufficient enteral intake cannot be guaranteed (e.g. vomiting, febrile illnesses, reduced intake, warm weather, prior to major surgical procedures).

As SGLT2 inhibition induces glucosuria, risk mitigation for hypoglycemia requires baseline dietary assessment and metabolic stability, including frequent blood glucose measurements, especially during the initiation of treatment. Combining epidemiologic and physiological data, the risk may be increased in in young, pre-verbal children as they (1) have higher endogenous glucose requirements23,24 (2) cannot express their symptoms clearly, (3) are more prone to intercurrent infections, and (4) may develop higher levels of fever during these intercurrent infections. Clinical or in-hospital initiation of empagliflozin treatment, especially in children < 6 years, may therefore be considered.

Furthermore, since SGLT2 inhibition also has a natriuretic and diuretic effect, the advice to ensure proper fluid intake should be given. Empagliflozin may be temporarily stopped in periods when persons with GSDIb are at risk to develop dehydration, by (combinations of) reduced intake, increased losses (e.g., vomiting and/or diarrhea during intercurrent infections, extremely hot weather conditions), or before major surgery. GSDIb patients have an emergency protocol and an emergency letter, which describes the first treatment during these situations.

Markers for metabolic control which includes (1) capillary glucose concentrations or continuous glucose monitoring metrics, (2) serum levels of transaminases, uric acid and lipids, and (3) kidney function (e.g. eGFR, urea nitrogen) may be tested regularly to assess for any metabolic or renal disturbances, especially during the initiation of treatment.

The risk of urinary tract infections is probably related to inducing glucosuria that facilitates bacterial growth in the urinary tract. Careful monitoring for signs of urinary tract infection in this population is reasonable.

Interactions

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

• ALIMENTARY TRACT AND METABOLISM
• DRUGS USED IN DIABETES

BLOOD GLUCOSE LOWERING DRUGS, EXCL. INSULINS

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

Biguanides
	Metformin Related Medicines Menu">	A10BA02

Sulfonylureas
	Glibenclamid Related Medicines Menu">	A10BB01

Combinations of oral blood glucose lowering drugs
	Empagliflozine + metformine Related Medicines Menu">	A10BD20

Glucagon-like peptide-1 (GLP-1) analogues
	Dulaglutide Related Medicines Menu">	A10BJ05
	Exenatide Related Medicines Menu">	A10BJ01
	Liraglutide Related Medicines Menu">	A10BJ02

Sodium-glucose co-transporter 2 (SGLT2) inhibitors
	Dapagliflozine Related Medicines Menu">	A10BK01

References

1. Halligan RK, et al., Understanding the role of SGLT2 inhibitors in glycogen storage disease type Ib: the experience of one UK centre. , Orphanet J Rare Dis., 2022, 17(1)
2. Weinstein DA, et al., Inborn Errors of Metabolism with Hypoglycemia: Glycogen Storage Diseases and Inherited Disorders of Gluconeogenesis., Pediatr Clin North Am., 2018, 65(2), 247-265
3. Schroten H, et al., Colony-stimulating factors for neutropenia in glycogen storage disease Ib., Lancet., 1991, 337(8743), 736-737
4. Wortmann SB, et al. , Treating neutropenia and neutrophil dysfunction in glycogen storage disease type Ib with an SGLT2 inhibitor. , Blood., 2020, 136(9), 1033-1043
5. Roe TF, et al., Brief report: treatment of chronic inflammatory bowel disease in glycogen storage disease type Ib with colony-stimulating factors., N Engl J Med., 1992, 326(25), 1666-1669
6. Khalaf D, et al., A case of secondary acute myeloid leukemia on a background of glycogen storage disease with chronic neutropenia treated with granulocyte colony stimulating factor., JIMD Rep, 2019, 49(1)
7. Dale DC, et al., Neutropenia in glycogen storage disease Ib: Outcomes for patients treated with granulocyte colony-stimulating factor, Curr Opin Hematol., 2019, 26(1)
8. Bidiuk J, et al., The overall benefits of empagliflozin treatment in adult siblings with glycogen storage disease type Ib: one year experience., Archives of Medical Science, 2022, 18(4)
9. Hexner-Erlichman Z, et al., Favorable outcome of empagliflozin treatment in two pediatric glycogen storage disease type 1b patients., Front Pediatr., 2022, 10
10. Laffel LMB, et al., Pharmacokinetic and pharmacodynamic profile of the sodium-glucose co-transporter-2 inhibitor empagliflozin in young people with Type 2 diabetes: a randomized trial. , Diabet Med, 2018, 35(8), 1096-1104
11. Riggs MM, et al., Exposure-response modelling for empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes. , Br J Clin Pharmacol., 2014, 78(6), 1407-1418
12. OMIM - Johns Hopkins University. . , Glycogen Storage Disease Ib. , https://www.omim.org/entry/232220#7, Published July 2022., MIM Number: 232220, Accessed April 26, 2023
13. Grünert SC, et al., Efficacy and safety of empagliflozin in glycogen storage disease type Ib: Data from an international questionnaire., Genetics in Medicine, 2022, 24(8), 1781-1788
14. Veiga-da-Cunha M, et al., Failure to eliminate a phosphorylated glucose analog leads to neutropenia in patients with G6PT and G6PC3 deficiency., Proc Natl Acad Sci U S A., 2019, 116(4), 1241-1250
15. Visser G, et al., Consensus guidelines for management of glycogen storage disease type 1b - European Study on Glycogen Storage Disease Type 1., Eur J Pediatr, 2002, 161 Suppl 1(0), S120-S123
16. Grünert SC, et al., Improved inflammatory bowel disease, wound healing and normal oxidative burst under treatment with empagliflozin in glycogen storage disease type Ib., Orphanet J Rare Dis, 2020, 15(1)
17. Rossi A, et al., Crohn disease-like enterocolitis remission after empagliflozin treatment in a child with glycogen storage disease type Ib: a case report., Ital J Pediatr., 2021, 47(1)
18. Kishnani PS, et al., Diagnosis and management of glycogen storage disease type I: a practice guideline of the American College of Medical Genetics and Genomics., Genet Med., 2014, 16(11), 1-29
19. Derks T, et al., Zorgpad Glycogeenstapelingsziekte Type I - Behandelarenversie, 2021
20. Tallis E, et al., Untargeted metabolomic profiling in a patient with glycogen storage disease Ib receiving empagliflozin treatment., JIMD Rep, 2022, 63(4)
21. Makrilakis K, et al., Repurposing of Empagliflozin as a Possible Treatment for Neutropenia and Inflammatory Bowel Disease in Glycogen Storage Disease Type Ib: A Case Report., Cureus. Published online, 2022
22. Laffel LM, et al., Efficacy and safety of the SGLT2 inhibitor empagliflozin versus placebo and the DPP-4 inhibitor linagliptin versus placebo in young people with type 2 diabetes (DINAMO): a multicentre, randomised, double-blind, parallel group, phase 3 trial., Lancet Diabetes Endocrinol., 2023, 11(3)
23. Wu Q, et al., Efficacy and safety of empagliflozin at different doses in patients with type 2 diabetes mellitus: A network meta-analysis based on randomized controlled trials. , J Clin Pharm Ther., 2022, 47(3), 270-286
24. Halligan RK, et al., Understanding the role of SGLT2 inhibitors in glycogen storage disease type Ib: the experience of one UK centre., Orphanet J Rare Dis., 2022, 17(1)
25. Wortmann SB, et al., Treating neutropenia and neutrophil dysfunction in glycogen storage disease type Ib with an SGLT2 inhibitor., Blood., 2020, 136(9), 1033-1043
26. Laffel LMB, et al., Pharmacokinetic and pharmacodynamic profile of the sodium-glucose co-transporter-2 inhibitor empagliflozin in young people with Type 2 diabetes: a randomized trial., Diabet Med, 2018, 35(8), 1096-1104
27. Riggs MM, et al., Exposure-response modelling for empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes., Br J Clin Pharmacol., 2014, 78(6), 1407-1418
28. OMIM - Johns Hopkins University. ., Glycogen Storage Disease Ib., https://www.omim.org/entry/232220#7, Published July 2022., MIM Number: 232220, Accessed April 26, 2023
29. Wu Q, et al., Efficacy and safety of empagliflozin at different doses in patients with type 2 diabetes mellitus: A network meta-analysis based on randomized controlled trials., J Clin Pharm Ther., 2022, 47(3), 270-286

Changes

Therapeutic Drug Monitoring

Overdose