Phenytoin dosage

Nonlinear relationship of phenytoin dosage and plasma concentrations. Five patients (identified by different symbols) received increasing dosages of phenytoin by mouth, and the steady-state serum concentration was measured at each dosage. The curves are not linear, since, as the dosage increases, the metabolism is saturable. Note also the marked variation among patients in the serum levels achieved at any dosage. 

Nonlinear effect of phenytoin dosage on plasma concentration of drug. 

Fig. 6 The Bayesian feedback method of phenytoin dosage prediction. The eccentric circles represent the fraction of the sample population whose Em and values are within that orbit. By drawing lines from the measured Css values via the given doses of phenytoin, the most probable values of Em and can be estimated and further used in calculation of new dosing rates corresponding to a target concentration. (From Ref. " " / also discussed in Ref. " l)...

Three patients with severe myoclonic epilepsy in infancy developed choreoathetosis after an increase in phenytoin dosage it resolved when the phenytoin dosage was reduced (17). In one, an ictal SPECT showed reduced perfusion in the basal ganglia contralateral to the unilateral choreoathetosis. Polypharmacy, including carbama-zepine and zonisamide, may have facilitated the onset of choreoathetosis. 

An 18-year-old man with heterozygous point mutation in the defective allele of CYP2C9 and CYP2C19 (two enzymes involved in phenjdoin metabolism) developed gynecomastia about 1 month after phenytoin dosage was increased from 175 to 190 mg/day, resulting in a serum phenytoin concentration of 68 pmol/1 (49). 

Vozeh S, Muir KT, Sheiner LB, Eollath F. Predicting individual phenytoin dosage. J Pharmacokinet Biopharm 1991 9 131-146. 

Ludden TM, Allen JR Valutsky WA, el al. Individualization of phenytoin dosage regimens. CUn Pharmacol Ther 1977 21 287-293. 

Vozeh, S. et ah. Predicting individual phenytoin dosage regimens, J. Pharmacokinet. Biopham., 9 131-146, 1991. 

Yuen, G. J. et al.. Predicting phenytoin dosages using Bayesian feedback a comparison with other methods. Then Drug Monk., 5 437-441, 1983. 

A 13-year-old boy with Lesch-Nyhan syndrome who was taking phenobarbital, elonazepam, valproic acid and phenytoin 200 mg daily became somnolent within 7 days of starting to take allopurinol 150 mg daily. TEs serum phenytoin levels were found to have increased from 7.5 to 20.8 micrograms/mL. In another study, 2 patients had a marked increase in phenytoin levels when given allopurinol (150 mg daily in those less than 20 kg, and 300 mg daily for other patients) for 4 months, which in one case led to withdrawal from the study, and in the other to a phenytoin dosage reduction. However, 16 other patients had no change in phenytoin levels while taking this dose of allopurinol. ... 

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. ... 

Direct information seems to be limited to these reports, but the interactions appear to be of clinical importance. Monitor the serum phen5doin levels and increase the dosage appropriately if rifampicin alone is started. Reduce the dosage if the rifampicin is stopped. If both rifampicin and isoniazid are given, the outcome may depend on the isoniazid acetylator status of the patient. Those who are fast acetylators will probably also need an increased phenytoin dosage. Those who are slow acetylators may need a smaller phenytoin dosage if toxicity is to be avoided. All patients should be monitored very closely as, unless acetylator status is known, the outcome is unpredictable. 

The increase in serum phenytoin levels with fluconazole is established and clinically important. Toxicity can develop within 2 to 7 days unless the phenytoin dosage is reduced. Monitor serum phenytoin levels closely and reduce the dosage appropriately. Also be alert for any evidence of reduced fluconazole effeets. 

A study in 6 epileptic patients taking phenytoin 350 to 600 mg daily found that over a 12-week period the addition of carbamazepine 600 to 800 mg daily increased the phenytoin serum levels by 35%, increased its half-life by 41% and reduced its clearance by 36.5%. Neurotoxicity increased by 204%, with additional symptoms of toxicity (sedation, ataxia, nystagmus, etc.) developing in 5 of the 6 patients. The phenytoin dosage remained unchanged throughout the period of the study. ... 

The rise in serum phenytoin levels with intravenous chloramphenicol in adults is well documented and clinically important. A two to fourfold rise can occur within a few days. Concurrent use should be avoided unless the effects can be closely monitored and appropriate phenytoin dosage reductions made as necessary. The use of a single prophylactic dose of phenytoin or fosphenytoin may be an exception to this. It seems very doubtful if enough chloramphenicol is absorbed from eye drops or ointments for an interaction to occur. 

None of these interaetions has been extensively studied nor are they well established, but what is known suggests that the use of dicoumarol with phenytoin should be avoided or monitored very closely. Serum phenytoin levels and anticoagulant control should be well monitored if acenoeou-marol, phenprocoumon or warfarin is given with phenytoin. Dosage adjustments may be needed to accommodate any interactions. Information about other anticoagulants (apart from phenindione, which had no effect... 

Information is limited to these reports, but the interaction would appear to be established. Monitor the effects of concurrent use, being alert for the need to increase the phenytoin dosage. The clinical importance of the reduced diazoxide effects is uncertain. 

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%. ... 

Established interactions. The phenytoin dosage may need to be reduced (a 20 to 40% reduction seems to be about right / ) if felbamate is added, and to increase it if felbamate is withdrawn. However, note that as phenytoin pharmacokinetics are non-linear any dosage adjustments will need to be assessed in individual patients. The importance of the reduced felbamate levels is uncertain, but is probably less important because felbamate has a wide therapeutic range. ... 

In 9 patients the steady-state half-life of phenytoin was prolonged from 32 to 47 hours by pheneturide. Mean serum levels were raised by about 50% but fell rapidly over the 2 weeks after pheneturide was withdrawn. This study confirms a previous report of this interaction. The reason for this interaction is uncertain, but since the two drugs have a similar structure it is possible that they compete for the same metabolising enzymes in the liver, thereby resulting, at least initially, in a reduction in the metabolism of the phenytoin. If concurrent use is undertaken the outcome should be well monitored. Reduce the phenytoin dosage as necessary. 

A study in 10 epileptic patients taking phenytoin 2.8 to 6.8 mg/kg daily found that while taking phenobarbital 1.1 to 2.5 mg/kg daily their serum phenytoin levels were reduced. Five patients had a mean reduction of about 65%, from 15.7 to 5.7 micrograms/mL. In most cases phenytoin levels rose again when the phenobarbital was withdrawn. In one patient this was so rapid and steep that he developed ataxia and a cerebellar syndrome with phenytoin levels of up to 60 micrograms/mL, despite a reduction in the phenytoin dosage. ... 

Two other patients, taking phenytoin 300 and 400 mg daily, respectively, had marked rises in serum phenytoin levels (from 15 to 35 micrograms/mL and from 11.5 to 47 micrograms/mL), accompanied hy signs of phenytoin toxicity, within 5 to 10 days of starting fluoxetine 20 or 40 mg daily. The problem resolved when the fluoxetine was stopped or the phenytoin dosage reduced. Another patient only developed this interaction after taking fluoxetine for about 9 months. ... 

The interaction between phenytoin and fluoxetine appears to be established but its incidence is not known. Because of the unpredictable nature of this interaction, if fluoxetine is added to treatment with phenytoin in any patient be alert for the need to reduce the phenytoin dosage. Ideally the phenytoin serum levels should be monitored. Similarly, to be on the safe side phenytoin levels should be monitored when fluvoxamine is first added to treatment with phenytoin so that any patient affected can be quickly identified. Although an interaction with sertraline appears less likely, be alert for any evidence of an increase in phenytoin adverse effects (e.g. blurred vision, nystagmus, ataxia or drowsiness) if sertraline is given. More study of these interactions is needed. Note that SSRIs should be avoided in patients with unstable epilepsy, and those with controlled epilepsy should be carefully monitored, because of the potential increased seizure risk. 

Information seems to be limited to these studies, whieh await confirmation. A similar interaction with phenytoin has been reported with phenylbutazone, which has a very close chemical relationship with sulfinpyiazone (see Phenytoin + Aspirin or NSAIDs , p.551). Thus what is known suggests that concuncnt use should be monitored and suitable phenytoin dosage reductions made where necessary. 

The documentation seems to be limited to the reports eited, but the interaction is established. Co-trimoxazole, sulfamethizole, sulfadiazine and trimethoprim can increase serum phenytoin levels. The interaction probably occurs in most patients, but the small number of adverse reaction reports suggests that the risk of toxicity is small. It is clearly most likely in those with serum phenytoin levels at the top end of the range. If concurrent use is thought appropriate, the serum phenytoin levels should be closely monitored and the phenytoin dosage reduced if necessary. Alternatively, if appropriate, use a non-interacting antibacterial (in some circumstances penicillins , (p.562), or macrolides , (p.560), may be appropriate). There seems to be no information about other sulfonamides but it would be prudent to be alert for this interaction with any of them. 

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. 

A 65-year-old man taking phenytoin 200 mg daily and clobazam developed signs of phenytoin toxicity (vertigo, ataxia, somnolence) within a week of starting ticlopidine 250 mg daily. His serum phenytoin levels had risen from 18 mg/L to 34 mg/L. When the phenytoin dosage was reduced to 200 mg daily the toxic symptoms disappeared within a few days and his serum phenytoin levels fell to 18 mg/L. To test whether an interaction had occurred, the ticlopidine was stopped, whereupon the serum phenytoin levels fell, within about 3 weeks, to 8 mg/L, during which time the patient... 

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