Phenytoin dosing

Plasma phenytoin concentrations are increased in the presence of chloramphenicol, disulfiram, and isoniazid, since the latter drugs inhibit the hepatic metabolism of phenytoin. A reduction in phenytoin dose can alleviate the consequences of these drug-drug interactions. 

A 45-year-old woman taking phenytoin 300 mg/day had a plasma phenytoin concentration of 66 pmol/1 (29). When she became depressed fluvoxamine 50 mg/day was added. A month later her depressive symptoms had improved, but she was ataxic and the plasma phenytoin concentration was 196 pmol/1. The fluvoxamine was withdrawn and the phenytoin dose reduced to 150 mg/day. Her plasma phenytoin concentration fell to 99 pmol/1, with resolution of the ataxia. 

AMIODARONE ANTIEPILEPTICS-PHENYTOIN Phenytoin levels may be t by amiodarone conversely, amiodarone levels may be 1 by phenytoin Uncertain amiodarone inhibits CYP2C9, which plays a role in phenytoin metabolism while phenytoin is a known hepatic enzyme inducer. Also, amiodarone inhibits intestinal P-gp, which may T the bioavailability of phenytoin 1 phenytoin dose by 25-30% and monitor levels watch for amiodarone toxicity. Note that phenytoin and amiodarone share similar features of toxicity, such as arrhythmias and ataxia... 

PHENYTOIN ANTIPROTOZOALS -LEVAMISOLE Possible t phenytoin levels Uncertain case report of this interaction when levamisole and fluorouracil were co-administered with phenytoin Monitor phenytoin levels and i phenytoin dose as necessary... 

You start a 19-year-old man on phenytoin in a dose of 300 mg/day to control generalized (grand mal) seizures. Ten days later, he is brought to an emergency room following a seizure. His phenytoin level is found to be 5 xg/mL and the phenytoin dose is increased to 600 mg/day. Two weeks later, he returns to your office complaining of drowsiness and ataxia. At that time his phenytoin level is 30 jxg/mL. 

FIGURE 5.2 Comparison of free and total plasma phenytoin levels in a patient with normal renal function and in a functionally anephric patient both are treated with a 300-mg daily phenytoin dose and have identical Although free phenytoin levels are... 

A major problem arises in clinical practice when only total (protein bound + free) phenytoin concentrations are measured and used to guide therapy of patients with severely impaired renal function. The decreases in phenytoin binding that occur in these patients result in commensurate decreases in total plasma levels (Figure 5.2). Even though therapeutic and toxic pharmacologic effects are correlated with unbound rather than total phenytoin concentrations in plasma, the decrease in total concentrations can mislead physicians to increase phenytoin doses inappropriately. Fortunately, rapid ultrafiltration procedures are available that make it possible to measure free phenytoin concentrations in these patients on a routine basis. 

Monitor digoxin levels, signs/symptoms of toxicity decrease digoxin dosing Decrease dose of quinidine by 30-50% Decrease dose of procainamide by 30% when starting amiodarone Monitor phenytoin levels and s/s of toxicity decrease phenytoin dosing if necessary Avoid NSAID use if possible in the elderly... 

Sachdeo R, Wagner ML, Sachdeo S, Shumaker RC, Lyness WH, Rosenberg A, Ward D, Perhach JL. Coadministration of phenytoin and felbamate evidence of additional phenytoin dose-reduction requirements based on pharmacokinetics and tolerabihty with increasing doses of felbamate. Epilepsia 1999 40(8) 1122-8. 

AH of the equations previously described for predicting dose or concentration assume linear kinetic systems they are therefore not adaptable to treatment with drugs that display nonlinear kinetics. Using a linearized Michaelis-Menten equation, methods for predicting phenytoin dose and concentration have been developed and apphed to individual drug dosing regimens. 

Phenytoin doses are very difficult to individualize because the drug follows Michaelis-Menteu kiuetics, and there is a large amount of interpatient variability in Vniax and Km- Initial maintenance doses of phenytoin in adults usually range between 4 and 7 mg/kg per day, yielding starting doses of 300 to 400 mg/day in most individuals. If... 

Privitera MD. Clinical rules for phenytoin dosing. Ann Pharmacother 1993 27 1169-1173. 

Warfarin—(major interaction), results in increased anticoagulant effects, increased risk of bleeding monitor coagulation parameters closely phenytoin—may require phenytoin dose reduction monitor phenytoin levels closely leucovorin increases the activity and toxicity of capecitabine... 

B. Maintenance oral phenytoin dose. Give 5 mg/kg/day as a single oral dose of capsules or twice dally for other dosage fonns and in children. Monitor serum phenytoin levels. 

Phenytoin Cisplatin Carmustine Brain tumours A retrospective study reviewed the effects of 3 or more cycles of 72 hours of carmustine and cispiatin chemotherapy in 19 patients who did not vomit. A phenytoin dose increase was required in three-quarters of patients, which was, on average, 40% of the originai dose (range 20 to 100%). The effect on phenytoin levek persisted after the chemotherapy had finished, with levels returning to normal 2 to 3 weeks later. 1... 

Phenytoin Carboplatin Small cell lung cancer with brain metastases Phenytoin ievei dropped from 9.7 to 4.6 micrograms/mL 10 days into chemotherapy, resuiting in seizures. Phenytoin dose had to be increased by 35% to achieve a level of iO.7 micrograms/mL. 6... 

Oxcarbazepine appears not to affect the pharmacokinetics of car-bamazepine, phenobarbital or valproate to a clinically relevant extent, but may modestly reduce lamotrigine levels. High doses of oxcarbazepine increase phenytoin levels, and a reduction in the phenytoin dose may be required. Phenytoin and phenobarbital can increase the loss of the active metabolite of oxcarbazepine, monohydroxyoxcarbazepine, although this is probably not clinically relevant. Lamotrigine may increase levels of monohydroxyoxcarbazepine, although one study found no pharmacokinetic interaction. 

Information about the concurrent use of oxcarbazepine and other antiepi-lepties is limited, but growing. The overall picture seems to be that, oxcarbazepine is a less potent enzyme inducer than carbamazepine, and therefore it does not markedly affect the serum levels of other antiepilep-ties. If oxearbazepine is substituted for carbamazepine, be aware that drug levels of some other antiepileptics may rise. High oxcarbazepine doses may inerease phenytoin levels, and the manufacturer notes that a decrease in the phenytoin dose may be required. The clinical relevance of the modest reductions in lamotrigine levels is uncertain. For mention of modestly reduced levetiracetam levels, see Levetiracetam + Other antiepileptics , p.543. 

The phenytoin dosage should be redueed as neeessary. A 25 to 30% reduction has been recommended for those taking phenytoin 2 to 4 mg/kg daily, but it should be remembered that small alterations in phenytoin dose may result in a large change in phenytoin levels, as phenytoin kineties are non-linear. Note that the phenytoin levels in some individuals were doubled after only 10 days of concurrent use. Amiodarone has a long half-life so that this interaction will persist for weeks after its withdrawal. Continued monitoring is important. Be aware that ataxia due to phenytoin toxicity (e.g. blurred vision, nystagmus, ataxia or drowsiness) may be confused with amiodarone-induced ataxia. ... 

A pilot study in 4 patients noted that felbamate increased plasma phenytoin levels. Therefore, in a further study the phenytoin dose was automatically reduced by 20% when felbamate was given. Of 5 patients, one needed a slight increase in phenytoin dosage, whereas 2 others needed a further reduction in their phenytoin dosage. In a later full report of this study, it was noted that phenytoin dosage decreases of 10 to 30% were required to maintain stable levels. Another study in epileptic patients found that felbamate 1.2 or 1.8 g daily increased the maximum plasma phenytoin levels by 31% and 69%, respectively. Higher felbamate doses necessitated phenytoin dose reductions of 20 to 40%. ... 

A study in 10 subjects found that famotidine 40 mg daily for 7 days did not alter the pharmacokinetics of a single dose of phenytoin. " However, a single case report describes phenytoin toxicity and an dmost doubled serum level (increase from 18 to 33 micrograms/mL) in a patient given famotidine. This was managed by a reduction in the phenytoin dose. ... 

About one month after starting to take fluvoxamine 50 mg daily, a woman taking phenytoin 300 mg daily experienced ataxia and was found to have a threefold increase in her phenytoin levels (from 16.6 to 49.1 mierograms/mL). Fluvoxamine was subsequently discontinued, and the phenytoin dose reduced, with gradual recovery. Another report describes phenytoin toxicity (serum levels of 48 mg/L) in an 86-year-old woman after she took fluvoxamine 100 to 200 mg daily for 10 days. ... 

Sucralfate 1 g was found to reduce the absorption (measured over a 24-hour period) of a single 300-mg dose of phenytoin in 8 healthy subjects by 20%. Peak serum phenytoin levels were also reduced, but this was not statistically significant. Another single-dose study found a reduction in phenytoin absorption of 7.7 to 9.5%. However, sucralfate 1 g four times daily for 7 days had no effect on the steady-state levels of phenytoin 5 to 7 mg/kg daily in 6 healthy subjects. The fourth daily dose of sucralfate was taken simultaneously with the daily phenytoin dose at bedtime. After 7 days, all phenytoin levels were within I5%ofthe baseline values (range, 6% decrease to 15% increase). ... 

The interaction is established and clinically important, but its incidence is unknown. It would now be prudent to monitor serum phenytoin levels very closely in any patient if ticlopidine is added to established treatment, being alert for the need to reduce the phenytoin dosage. If ticlopidine is discontinued, the phenytoin dose may need to be increased. 

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