A 52 y/o WF., approx. 1 year post hemorrhagic stroke, living at home, with pretty good self care (eating, dressing, etc), generalized seizures controlled with phenytoin. The patient was on tube feeds initially, but feeding tube was pulled in November 2001.  Prior to stroke, she had a diagnosis of HTN, but no meds.

Patient is currently taking phenytoin 200mg QHS, Prempro® [conjugated estrogens / medroxyprogesterone) po QD , fexofenadine [Allegra®] 180mg po QD, fluticasone nasal spray [Flonase®] QD.  Over the last week, her phenytoin levels are climbing and she is ataxic, a definite change over her baseline. She has had a stable serum phenytoin level around 18 or 19 since November. Subsequent serum phenytoin levels were - 2/26/02 level = 24.6, 3/1/02 level = 28.3. No change in nutritional status, renal function, LFTs, or volume status. No other medications confirmed with family, including over the counter meds and herbal/alternative medicine products. Albumin is WNL (4.6). She has been on the same salt and dosage form of phenytoin throughout her course of therapy. Compliance has been assessed and confirmed by the husband. There is no evidence of over dosing or 'double dipping'.

The attending physician asks you why this is happening. Is this a lab error? Is a free phenytoin level indicated?

        ** This is from an actual case. THANKS to CAPT (Dr.) Libby Schindler at Wilford Hall and Lt Col (Dr.) Jeff Snyder at Luke AFB for their help with this Pearl.**

There is a complex interaction of folic acid and phenytoin. Phenyotin reduces folate absorption, which can lead to a macrocytosis and/or a megaloblastic anemia. Folic acid enhances the clearance of phenytoin. Repleacement of folic acid in deficient patients can reduce serum phenytoin concentrations. This may result in loss of efficacy or seizure control. The following additional information and references are from MICROmedex.

§       1. Concurrent use of folic acid and phenytoin has resulted in increased seizure frequency and decreased phenytoin levels in some patients (Berg et al, 1983a; Baylis et al, 1971). Subnormal folate levels frequently develop in patients receiving long-term phenytoin therapy, but progression to megaloblastic anemia occurs in less than 1% of patients (Flexner & Hartmann, 1960; Rivey et al, 1984; MacCosbe & Toomey, 1993).

§       2. Adverse Effect: decreased phenytoin effectiveness.
§       3. Clinical Management: If folic acid is added to phenytoin therapy, monitor patients for decreased seizure control. Phenytoin can reduce folic acid concentrations and therefore should be avoided in pregnancy.

§       4. Severity: moderate
§       5. Onset: delayed
§       6. Documentation: fair
§       7. Probable Mechanism: increased phenytoin metabolism
§       8. Literature Reports:

a.      Subnormal serum folate concentrations occur in 27% to 91% of patients receiving long-term phenytoin (Reynolds, 1972; Rivey et al, 1984). Progression to megaloblastic anemia occurs in less than 1% of patients (Flexner & Hartmann, 1960; Rivey et al, 1984; MacCosbe & Toomey, 1983), although macrocytosis is common (Reynolds et al, 1966; Klipstein, 1964; Ibbotson et al, 1967; Rivey et al, 1984). Reduced folate concentrations in red blood cells (RBCs) and cerebrospinal fluid (CSF) have also been identified in patients receiving chronic phenytoin therapy (Dahike & Mertens-Roesler, 1967; Preece et al, 1971; Wells & Casey, 1967; Reynolds et al, 1969; Reizenstein & Lund, 1973). The development of subnormal folate levels in this patient population does not appear related to dose, duration of therapy, or serum levels.

b.      Additionally, several studies addressed the effect of folic acid supplementation on the serum concentrations of phenytoin. In 5 subjects receiving phenytoin 300 milligrams daily, Glazko (1975) measured blood phenytoin levels for 10 days, then started patients on folic acid 10 milligrams daily for 15 days. Phenytoin blood levels decreased by 15% to 45% within 10 days. A similar study by Furlanut et al (1978) found a mean decrease in serum phenytoin levels of 16%. Two studies reported significant decreases in phenytoin blood levels in a total of 62 epileptic patients receiving folic acid 5 to 15 milligrams daily. One study showed 11 of 12 patients had decreases in serum phenytoin levels up to 20%, with one patient experiencing a drop of 50% (Streiff et al, 1972). The other report described a patient receiving folic acid 5 milligrams daily who had increased frequency and severity of seizures after 10 days of therapy (Baylis et al, 1971). Case studies have also described decreased phenytoin concentrations and subsequent loss of seizure control as a result of folic acid supplementation (Strauss & Bernstein, 1974; Arellano-Isaac & Rivera-Calimlim, 1978). Some uncontrolled studies also report a loss of seizure control (MacCosbe & Toomey, 1983). However, numerous large controlled studies, mostly double-blind, have found no significant difference in mean seizure frequency when a group of folate-deficient epileptic patients treated with folic acid was compared with a similar group receiving placebo (Rivey et al, 1984; Houben et al, 1971; Norris & Pratt, 1971; Ralston et al, 1970; Makki et al, 1980; Mattson et al, 1973).

c.      It may be possible both indirect effects upon phenytoin's pharmacokinetic disposition and direct effects on seizure frequency are involved in folate's interaction with phenytoin. Several studies indicate that folic acid supplementation increases phenytoin liver metabolism; two studies suggest increased phenytoin parahydroxylation (Kutt et al, 1966; Makki et al, 1980), and another suggests increased O-methylation of the catechol metabolite (Glazko, 1975). Andreason et al (1971) concluded folic acid does not stimulate phenytoin metabolism, but that change in the rates of different elimination pathways was responsible. Evidence of a direct effect includes animal data which demonstrates strong seizure-evoking potential of folic acid, especially when injected directly into the third ventricle of the brain (Hommes et al, 1973; Hommes & Obbens, 1972; Noell et al, 1960). Although several controlled studies with folate showed no significant effect on seizure frequency in patients controlled with phenytoin, MacCosbe & Toomey (1983) theorize that the studies may not have been conducted over a sufficient period of time, since CSF folate concentrations may take several months to rise. However, this does not explain why short-term folate therapy can markedly increase seizure frequency in some patients previously stabilized on phenytoin.

A free phenytoin level is probably not indicated since we do not have a strong suspicion of a protein binding interaction.

References

- Baylis EM, Crowley JM, Preece JM et al: Influence of folic acid on blood-phenytoin levels. Lancet 1971; 1:62-64.

- Berg JM, Rivey MP, Vern BA et al: Phenytoin and folic acid: individualized drug-drug interaction. Ther Drug Monit 1983a; 5:395-399.

- Flexner JM & Hartmann RC: Megaloblastic anemia associated with anticonvulsant drugs. Am J Med 1960; 28:386-396.

- Rivey MP, Schottelius DD & Berg MJ: Phenytoin-folic acid: a review. DICP 1984; 18:292-301.

- MacCosbe PE & Toomey K: Interaction of phenytoin and folic acid. Clin Pharm 1983; 2:362-369.

- Reynolds EH, Milner G, Matthew DM et al: Anticonvulsant therapy, megaloblastic haemopoiesis and folic acid metabolism. Q J Med 1966; 35:521-537.

- Ibbotson RN, Dilena BA & Horwood JM: Studies on deficiency and absorption of folates in patients on anticonvulsant drugs. Aust Ann Med 1967; 16:144-150.

- Klipstein FA: Subnormal serum folate and macrocytosis associated with anticonvulsant drug therapy. Blood 1964; 23:68-85.

- Glazko AJ: Antiepileptic drugs: biotransformation, metabolism, and serum half-life. Epilepsia 1975; 16:367-391.

- Glazko AJ: Diphenylhydantoin metabolism. A prospective review. Drug Metab Dispos Biol Fate Chem 1973; 1:711.

- Furlanut M, Benetello P, Avogaro A et al: Effects of folic acid on phenytoin kinetics in healthy subjects. Clin Pharmacol Ther 1978; 24:294-297.

- Streiff RR, Wilder BJ & Hammer RH: Diphenyihydantoin: hematological aspects of toxicity. In: Woodbury DM, Perry JK, Schmidt RP (Eds). Antiepileptic Drugs. Raven Press, New York, NY, 1972; 263-266.

- Makki KA, Perucca E & Richens A: Metabolic effects of folic acid replacement therapy in folate-deficient epileptic patients. In: Johannessen SI, Morselli PI, Pippenger CE (Eds): Antiepileptic therapy: advances in drug monitoring. Raven Press, New York, NY, 1980; 391-396.

- Kutt H, Winters W & McDowell FH: Depression of parahydroxylation of diphenylhydantoin by antituberculosis chemotherapy. Neurology 1966; 16:594-602.

- Hommes OR & Obbens EAMT: The epileptogenic action of Na-folate in the rat. J Neurol Sci 1972; 16:271-281.

- Hommes OR, Obbens EAMT & Wijffels CCB: Epileptogenic activity of sodium-folate and the blood-brain barrier in the rat. J Neurol Sci 1973; 19:63-71.

- Houben PF, Hommes OR & Knaven PJ: Anticonvulsant drugs and folic acid in young mentally retarded epileptic patients. A study of serum folate, fit frequency, and IQ. Epilepsia 1971; 21:235-247.

- Norris JW & Pratt RF: A controlled study of folic acid in epilepsy. Neurology 1971; 21:659-664.

- Mattson RH, Gallagher BB, Reynolds EH et al: Folate therapy in epilepsy. Arch Neurol 1973; 29:78-81.

- Ralston AJ, Snaith RP & Hinley JB: Effects of folic acid on fit-frequency and behavior in epileptics on anticonvulsants. Lancet 1970; 1:867-868.