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Active substances and pharmaceuticals concerned

Name of active substance	Trade name	Affected micronutrients
Carbamazepine	Tegretol®, Neurotop®	Vitamin D Folic acid Biotin Vitamin K Vitamin E
Phenytoin	Epilan- D®
Phenobarbital	In Austria only registered for veterinary application.
Primidone	Mysoline®
Valproic acid	Convulex®, Depakine®
Lamotrigine	Lamictal®

Specially affected active substances and pharmaceuticals

Name of active substance	Trade name	Affected micronutrients
Valproic acid	Convulex^®, Depakine^®	L-Carnitine
Phenobarbital, Primidone	Mysoline^®	Niacin
Phenytoin	Epilan-D^®	Folic acid
Phenytoin, Phenobarbital	Epilan-D^®	Vitamin B₁

Mechanism of interaction

Mechanism of interaction
Vitamin D	Antiepileptics increase vitamin D degradation in the liver and biliary excretion. Furthermore, taking antiepileptic drugs can lead to disorders of calcium metabolism and bone mineralization.
Folic acid	Intestinal folic acid resorption is disturbed and the intestinal deconjugation is inhibited. This leads to an increased catabolism. Folic Acid is less able to be absorbed from food. Primidone hinders the conversion of folic acid to 5-methyltetrahydrofolic Acid, lamotrigine has a weak inhibitory effect on dihydrofolate reductase. With phenytoin, particular attention should be paid to the dosage of the folic acid. On the one hand, the inhibition of deconjugase leads to a folic acid deficiency, on the other hand it can accelerate the oxidative phenytoin degradation with folic acid doses of more than 1 mg per day and thus cause a weakening of the antiepileptic effect. Studies show the same problem at high doses of vitamin B₆ (80–400 mg/d).
Thiamine	Malnutrition and increased degradation and metabolism in the liver lead to thiamine deficiencies. Thiamine deficiency very often manifests with the occurrence of polyneuropathies. These occur in 50% of all antiepileptic drug therapies
Biotin	Resorption in the intestine is prevented by antiepileptic drugs. Carbamazepine and primidone competitively inhibit biotin absorption. This leads to increased biotin catabolism. Biotin is thus excreted in higher quantities in the urine.
Vitamin K	Pregnant women and newborns are particularly affected. The administration of antiepileptic drugs accelerates the breakdown of vitamin K. The largely unexplored mechanism appears closely related to folic acid and biotin metabolism.
Vitamin E	Antioxidative protective mechanisms may be disturbed by antiepileptics.
L-carnitine	The renal excretion of L-carnitine is increased by ester formation (valproic carnitine ester) of valproic acid. Furthermore, binding by coenzyme A blocks the coenzyme-dependent metabolic pathways. Valproic acid also disrupts cellular carnitine uptake by inhibiting carnitine transporters.
Nicotinamide	Nicotinamide reduces conversion of primidone to phenobarbital by inhibiting CYP-P450 enzymes.

Consequences and possible symptoms of the interaction

Negative consequences of the interaction		Possible symptoms
Vitamin D	Decrease in vitamin D levels	Fatigue, weakness, insomnia Susceptibility to infection Decrease in bone density, rickets, osteopenia; in children: Rickets with skeletal deformations, spinal deformations, delay of tooth breakthrough Calcification of the vessels of the cardiovascular system, cardiac insufficiency Increase in alkaline phosphatase in the blood, insufficient absorption of calcium and phosphate ECG changes, tetanic muscle spasms (trousseaus sign of hands and feet); in children: increased nervousness and irritability Reduced insulin secretion and increased risk of type 1 diabetes Fertility problems
Folic acid	Decrease in folic acid levels	Anorexia, pallor, depression, weakness, forgetfulness Risk of neural tube defects during pregnancy Impairment of erythropoiesis and development of pernicious anemia, thrombocytopenia, leukopenia, hyperhomocysteinemia Increased risk of stroke due to increase in blood homocysteine Increased risk of dementia and polyneuropathy Glossitis, stomatitis, mucosal atrophy in the GIT and urogenital tract
Thiamine	Decrease of vitamin B₁levels	Weight loss, loss of appetite, irritability, insomnia Peripheral neuropathy, weakness, fatigue, foot burning Anemia, thrombocytopenia Heart failure, tachycardia, edema (beriberi) Polyneuropathies, angiopathies Wernicke's encephalopathy (paresis of the eye muscle, ataxia, psychosis, cerebellar atrophy)
Biotin	Decrease of biotin level	Loss of appetite, drowsiness, weakness Dry, flaky skin, seborrheic dermatitis Keratoconjunctivitis Hair loss, dry and brittle hair/nails Muscle pain, paresthesia, neuropathy Anemia
Vitamin K	Decrease in vitamin K levels	Synthesis of blood clotting factors is disturbed In newborns with vitamin K deficiency bleeding Disturbance of bone structure, decrease in bone density, osteoarthritis Increased risk of bone fracture
Vitamin E	Decrease in vitamin E levels	Increase in frequency of seizures Increased susceptibility to free-radical-associated diseases Tendency of erythrocytes to hemolysis Premature skin aging, Age spots and lipofuscin deposits, hair loss, neuro- and myopathies
L-carnitine	Decrease of L-carnitine levels	Diminished performance, rapid fatigue Increased susceptibility to infections hyperinsulinemia, hypoglycemia, insulin resistance fat deposits in tissue, elevated blood fat levels, increase in lipid peroxidation Arrhythmias, cardiomyopathies, heart failure Growth disorders in infants

Positive consequences of the interaction		Possible symptoms
Nicotinamide	Enhancement of the anticonvulsant effect	Extension of half-life of Primidone Increase in the therapeutic index of phenobarbital

Recommended Supplementation

Medical substance	Recommended supplementation	Dosage
Antiepileptics	Vitamin D Folic acid Thiamin Benfotiamine Biotin Vitamin K Vitamin E	3000–5000 I.U./d p.o. 0.4–1 mg/d p.o. 10–50 mg/d p.o. 300–600 mg/d p.o. 0.5–5 mg/d p.o. 100–500 µg/d p.o. 500 I.U./d p.o.
Valproic acid	L-carnitin	25–100 mg/kg BW/d p.o.
Phenobarbital, Primidone	Nicotinamide	50–200 mg/d p.o.

Special instructions for use

Instructions for use
Folic acid	A time interval of at least two hours should be observed between phenytoin and folic acid intake. A combination with vitamin B₆ and B₁₂is recommended.
Thiamine	Thiamine in its fat-soluble form, benfotiamine, is recommended for increased bioavailability. It is also advisable to supplement with vitamin B complex.
Biotin	In long-term therapy it is advisable to supplement with vitamin B complex.
Vitamin K	Since vitamin K is also important for bone metabolism, it is advisable to supplement with bone-supporting vitamins and minerals such as vitamin D, calcium and zinc.

References

Apeland T et al. Antiepileptic drugs as independent predictors of plasma total homocysteine levels. Epilepsy Res. 2001 Nov;47(1-2):27-35.
Baylis EM, Crowley JM, Preece JM et al. Influence of folic acid on blood-phenytoin levels. Lancet 1971;1:62-64.
Bohan TP et al. Effect of L-carnitine treatment for valproate-induced hepatotoxicity. Neurology. 2001 May 22;56(10):1405-9.
Botez MI et al. Thiamine and folate treatment of chronic epileptic patients: a controlled study with the Wechsler IQ scale. Epilepsy Res. 1993 Oct;16(2):157-63.
Bourgeois BF et al. Potentiation of the antiepileptic activity of phenobarbital by nicotinamide.Epilepsia. 1983 Apr;24(2):238-44.
De Vivo DC et al. L-carnitine supplementation in childhood epilepsy: current perspectives. Epilepsia. 1998 Nov;39(11):1216-25.
Eller DP et al. Maternal and fetal implications of anticonvulsive therapy during pregnancy. Obstet Gynecol Clin North Am. 1997 Sep;24(3):523-34.
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Gröber U. Arzneimittel und Mikronährstoffe. Medikationsorientierte Supplementierung. 3. Akt. und erw. Auflage, 2014
Lazzari AA et al. Prevention of bone loss and vertebral fractures in patients with chronic epilepsy--antiepileptic drug and osteoporosis prevention trial. Epilepsia. 2013 Nov;54(11):1997-2004. doi: 10.1111/epi.12351. Epub 2013 Sep 6.
Lewis DP et al. Phenytoin-folic acid interaction. Ann Pharmacother. 1995 Jul-Aug;29(7-8):726-35.
Mock DM et al. Disturbances in biotin metabolism in children undergoing long-term anticonvulsant therapy. J Pediatr Gastroenterol Nutr. 1998 Mar;26(3):245-50.
Ogunmekan AO, Hwang PA. A randomized, double-blind, placebo-controlled, clinical trial of D-alpha-tocopheryl acetate (vitamin E), as add-on therapy, for epilepsy in children. Epilepsia. 1989 Jan-Feb;30(1):84-9.
Stargrove Mitchell Bebel, Treasure Jonathan, McKee Dwight L.: Herb, Nutrient, and Drug Interactions: Clinical Implications and Therapeutic Strategies. 2008