Pharmacokinetics in children

Juárez Olguín et al. 2004 found the following pharmacokinetic parameters in children receiving acetylsalicylic acid 25 mg/kg/dose orally:

	JIA (n=17)	Post-streptococcal reactive arthritis (n=17)	Healthy controls (n=15)
Age (years)	13,5 (9,0-15,0)	12,0 (2,70-14,0)	14 (12-16)
Cmax (mmol/L)	5,20 (0,38-10,26)	3,70 (0,26-8,30)	5,32 (0,27-8,60)
tmax (hour)	3,7 (1,8-4,0)	3,6 (1,4-4,1)	3,7 (2,0-4,0)
t½ (hour)	4,44 (0,74-11,74)	1,56 (0,76-2,04	4,5 (0,65-5,77)

Cmax and t½ were statistically significantly different between the JIA and post-streptococcal reactive arthritis group and between the post-streptococcal reactive arthritis group and the healthy controls, but not between the JIA group and the healthy controls.

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

Kawasaki disease

Oral 1 month up to 18 years [2] [3] [4] [26] [27] [28] [29] Initial dose: Acetylsalicylic acid: 30 - 50 mg/kg/day in 3 - 4 doses. Max: 3.000 mg/day. Maintenance dose: After the temperature is normalized and the CRP has fallen: reduce the dose of to 3 - 5 mg/kg/day in 1 dose There is little evidence to support the need for high starting doses. A choice may also be made to start at the maintenance dose of 3-5 mg/kg/day. 1 mg acetylsalicylic acid = 1,25 mg carbasalate calcium   Intravenous 1 month up to 18 years [26] [27] [28] Initial dose: Acetylsalicylic acid: 30 - 50 mg/kg/day in 3 - 4 doses. Max: 3.000 mg/day. Maintenance dose: After the temperature is normalized and the CRP has fallen: reduce the dose of to 3 - 5 mg/kg/day in 1 dose There is little evidence to support the need for high starting doses. A choice may also be made to start at the maintenance dose of 3-5 mg/kg/day.

Prophylaxis and treatment of thrombo-embolic events (cardiac and neurological)
Intravenous 1 month up to 18 years [23] [24] Acetylsalicylic acid: 3 - 5 mg/kg/day in 1 dose. Max: 80 mg/day. Oral 1 month up to 18 years [23] [24] [30] [31] Acetylsalicylic acid: 3 - 5 mg/kg/day in 1 dose. Max: 80 mg/day. 1 mg acetylsalicylic acid = 1,25 mg carbasalate calcium

Renal impaiment in children > 3 months

In cases of impaired renal function, the following applies:

• Consider whether use of an NSAID is warranted.
• If acetylsalicylic acid/carbasalate calcium is prescribed nevertheless and the patient belongs to a risk group: check renal function prior to and within 1 week after starting acetylsalicylic acid/carbasalate calcium in high doses.
• At low doses (platelet aggregation inhibition), no monitoring of renal function is necessary.

Clinical consequences

Risk factors include heart failure, cirrhosis of the liver, nephrotic syndrome, chronic kidney disease, causes leading to dehydration (e.g., also summer heat), use of drugs that may reduce renal function, such as diuretics or RAAS inhibitors.

NSAIDs (including COX-2 inhibitors) can cause acute renal failure due to decreased renal perfusion (due to hypovolemia). Normally, an excessive decrease in renal perfusion is prevented by increased prostaglandin synthesis in the kidneys; NSAIDs interfere with this compensatory mechanism. Reduced renal perfusion also leads to water and salt retention, resulting in exacerbation or development of hypertension and heart failure.

Possibly, acetylsalicylic acid and carbasalate calcium additionally increase the risk of bleeding in renal failure.

Patients on dialysis

Hemodialysis/continuous venovenous hemodialysis/hemo(dia)filtration:

• residual kidney function (urine production) PRESENT: avoid use to spare residual kidney function
• residual renal function (urine production) NOT PRESENT: avoid use is not necessary

Patients on dialysis have a higher bleeding risk, probably related to abnormal platelet function. Bleeding risk may be additionally increased by use of a LMWH at the beginning of hemodialysis to prevent clotting in the extracorporeal circulation.

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

Mild, often transient, transaminase increase; tinnitus (usually reversible).

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

Watch out when prescribing: 500 mg acetylsalicylic acid = 900 mg Aspegic (= lysine-acetylsalicylic acid).
100 mg acetylsalicylic acid is equivalent to 125 mg carbasalate calcium.

Reye’s syndrome has been observed in children with viral infections who have used acetylsalicylic acid. In such a situation, acetylsalicylic acid should only be used as a treatment of last resort; stop the treatment if there is lengthy vomiting, reduced consciousness or behavioural disorders. Prolonged vomiting, loss of consciousness, or behavioral disturbances may indicate Reye's syndrome. Discontinue treatment if these symptoms occur.

The excretion of acetylsalicylic acid is strongly dependent on the pH of the urine. Alkalizing the urine can increase the proportion of unchanged acetylsalicylic acid in the excretion from about 10% to about 80%. 

In obese children, dosing based on total body weight is recommended for short-term loading doses such as Kawasaki disease. For long-term use, because of an increased risk of accumulation, ideal body weight may be used (Ross et al. 2015). This can be calculated as follows: (0.5 x BMI for age) x height in m2.

Interactions

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

• BLOOD AND BLOOD FORMING ORGANS
• ANTITHROMBOTIC AGENTS

ANTITHROMBOTIC AGENTS

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

Heparin group
	Dalteparin Related Medicines Menu">	B01AB04
	Enoxaparin Related Medicines Menu">	B01AB05
	Heparin Related Medicines Menu">	B01AB01
	Nadroparine Related Medicines Menu">	B01AB06

References

1. Rademaker C.M.A. et al, Geneesmiddelen-Formularium voor Kinderen, 2007
2. Kneepkens CMF et al, Werkboek Kinderreumatologie, VU Uitgeverij, 2014, 3e druk
3. AWMF-Leitlinie (S1), Vaskulitiden – Kawasaki-Syndrom (027/063), 01/2013
4. Brogan PA, Kawasaki disease: an evidence based approach to diagnosis, treatment, and proposals for future research, Arch Dis Child, 2002, 4, 286–290
5. Heumann, SmPC ASS 100 mg Heumann®, 1899.98.99, 04/2014, 1899.98.99
6. Bayer, SmPC Aspirin®, 86750.00.00, 09/2016
7. Bayer, SmPC Aspirin® protect 100 mg/- 300 mg, 16854.01.01/30828.01.01/33171.00.00/16854.00.01/30828.00.01/33171.01.00, 03/2017
8. Bayer, SmPC Aspirin® i.v. 500mg, 54243.00.00, 01/2018
9. Bayer, SmPC Aspirin® N 100 mg/- 300 mg (16854.01.00 / 16854.00.00 / 30828.00.00), 03/2017
10. Bayer, SmPC Aspirin® Direkt (51094.00.00, 38117.00.00), 01/2015
11. Bayer, SmPC ASPIRIN® MIGRÄNE (50352.00.00), 01/2015
12. Bayer, SmPC Aspirin® Effect (38118.00.00 / 52012.00.00), 01/2015
13. Pfleger, SmPC Godamed® 50 mg ASS TAH (47324.00.00), 06/2015
14. Pfleger, SmPC Godamed® 100 mg ASS TAH (38675.00.00), 06/2015
15. Pfleger, SmPC Godamed® 300 mg ASS TAH (47324.01.00), 03/2015
16. Pfleger, SmPC Godamed® 500 mg Tabletten (5848.00.00), 11/2013
17. ratiopharm, SmPC ASS-ratiopharm® 100 mg TAH Tabletten (46074.00.00), 08/2017
18. ratiopharm, SmPC ASS-ratiopharm® 300 mg (6367456.01.00), 05/2014
19. ratiopharm, SmPC ASS-ratiopharm® 500 mg (1899.99.99), 03/2017
20. ratiopharm, SmPC ASS-ratiopharm® 100 mg magensaftresistente Tabletten (95662.00.00), 03/2017
21. Wörwag Pharma GmbH & Co.KG, SmPC ASS gamma® 75 mg Tabletten (6553986.00.00), 06/2014
22. Juárez Olguín, H., et al. , Comparative pharmacokinetics of acetyl salicylic acid and its metabolites in children suffering from autoimmune diseases, Biopharm Drug Dispos, 2004, 25 (1), 1-7
23. Giglia, T.M., et al. , Prevention and treatment of thrombosis in pediatric and congenital heart disease: a scientific statement from the American Heart Association, Circulation, 2013, 128 (24), 2622-703
24. Monagle, P., et al. , Antithrombotic therapy in neonates and children: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines, Chest, 2012, 141 (2 Suppl), e737S-e801S
25. Ross, E. L., et al., Development of recommendations for dosing of commonly prescribed medications in critically ill obese children, Am J Health Syst Pharm, 2015, 72 (7), 542-56
26. Zheng, X., et al. , Efficacy between low and high dose aspirin for the initial treatment of Kawasaki disease: Current evidence based on a meta-analysis., PLoS One, 2019, 14 (5), e0217274
27. Jia, X., et al., What dose of aspirin should be used in the initial treatment of Kawasaki disease? A meta-analysis., Rheumatology (Oxford) , 2020, 59(8), 1826-1833
28. Platt, B., et al. , Comparison of Risk of Recrudescent Fever in Children With Kawasaki Disease Treated With Intravenous Immunoglobulin and Low-Dose vs High-Dose Aspirin, JAMA Netw Open, 2020, 3 (1), e1918565
29. De Graeff et al:, European consensus-based recommendations for the diagnosis and treatment of Kawasaki disease the SHARE initiative. , Rheumatology, 2019, April 1; 58(4), 672-682
30. Sträter R, et al., Aspirin versus low-dose low-molecular-weight heparin: antithrombotic therapy in pediatric ischemic stroke patients: a prospective follow-up study., Stroke, 2001, 32(11), 2554-8
31. Bonduel M, et al. , Arterial ischemic stroke and cerebral venous thrombosis in children: a 12-year Argentinean registry. , Acta Haematol, 2006, 115(3-4), 180-5

Changes

Therapeutic Drug Monitoring

Overdose