Oral and intramuscular phenytoin Twelve epileptic patients, after 1 wk on their previously established oral dose of phenytoin, were given a 50% larger dose intramuscularly for 1 wk after which they were put on an oral phenytoin regimen for 1 wk on a dose one-half the original oral dose. Plasma phenytoin levels did not show a sharp decrease in the intramuscular (im) nor a dangerous increase in the second oral phase. Those receiving drug once a day maintained remarkably stable levels. By the end of the im phase, patients receiving drug in multiple daily doses had some increase in plasma levels proportional to the dose increase. Seizure control was maintained equally well throughout all phases of the study. Except for local irritation at the site of injection, there were no adverse experiences. The data indicate that the dosage regimen described is suitable for patients on oral phenytoin who have to be transferred to im drug for short periods.

B. Joe Wilder, M.D., and R. Eugene Ramsay, M.D. Gainesville, Fla. Neurology Section, Veterans Administration Hospital, and College of Medicine, University of Florida

Phenytoin is one of the drugs of choice for the clinical management of major motor and psychomotor seizure disorders. Since seizure control requires long-term therapy, anticonvulsant medications such as phenytoin are more practical when taken orally. Seizure patients may be unable to receive or retain oral medication for short periods, such as in acute gastrointestinal upsets, elective surgical procedures, or some catastrophic event such as status epilepticus, and in such cases parenteral administration is required. Previous studies by Dam and Olesen,3 Supported by the Veterans Administration (MRIS-9335-02), the Epilepsy Research Foundation of Florida, Inc., and the NIH-CRC No. RR-82, Gainesville, Fla. Received for publication Aug. 11, 1975. Accepted for publication Dec. 15, 1975. Reprint requests to: Dr. B. J. Wilder, Professor of Neurology, College of Medicine, University of Florida. Gainesville. Fla. 32601.

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Serrano and associates,S and Wilensky and Lowden 1o demonstrated that a dose of phenytoin administered intramuscularly produces lower plasma levels than the same dose administered orally (po). In a single-dose crossover study in normal subjects, Kinkel, Smith, and Oppelt4 found that 100 mg of phenytoin po produced higher plasma levels than 100 mg im. Plasma levels from the im dose were more persistent, however, indicating slower absorption. Total urinary excretion of 5-hydroxyphenyl-5-phenyl hydantoin (HPPH) was approximately equal for both routes of administration, indicating that total absorption was equal for the two forms. In a multiple-dose crossover study in seizure patients, Wilder and associates 9 found that when patients were transferred from oral to im phenytoin and the daily dose remained the same, plasma levels of phenytoin fell approxi-

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Phenytoin

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Table I. Daily plasma levels of phenytoin in 8 patients receiving single daily doses during alternate oral and intramuscular Om) administration of phenytoin Dilantin plasma levels by patient (Dilantin dosage in mg/kg patient body weight)

Route of administration (duration of Rx in days) Oral

(1-7)

im

(8-14)

Oral

(15-21)

Daily mean Dilantin conc. ( J.Lg/ml)

Study day

3

(Dosage)

(3.61)

(3.90)

(4.16)

(4.23)

7.8 8.5 8.6 8.7 8.2 8.3 10.6 (5.42)

9.9 10.1 7.5 9.9 11.0 6.4 (5.84)

6.8 8.0 8.3 8.0 9.9 9.8 9.5 (6.25)

8.7 9.0 10.5 9.6 8.0 9.1 10.2 (6.34)

15.0 14.7 13.9 15.0 14.2 15.8 15.0 (7.25)

13.5 15.6 14.0 17.0 16.0 13.9 14.0 (7.32)

3.3 3.3 4.9 2.5 3.2 3.1 3.0 (7.96)

6.6 11.0 5.5 5.8 9.2 4.6 6.2 (8.33)

8.95 10.02 9.39 9.26 9.82 9.45 9.36

5.4 6.4 5.5 5.1 4.7 6.2 5.3 (1.95)

7.9 8.4 8.3 5.6 4.3 5.0 5.3 (2.08)

7.9 8.7 9.3 8.9 10.2 10.5 9.8 (2.11)

14.0 17.0 12.2 13.8 14.7 15.8 16.5 (2.42)

12.0 14.1 14.3 13.0 16.0 15.5 14.9 (2.44)

3.0 3.5 4.3 4.9 5.9 6.9 6.0 (2.65)

6.3 6.6 6.5 7.0 8.3 7.4 6.8 (2.77)

8.00 9.06 8.36 8.1l 8.78 9.10 8.75

(Dosage)

7.5 7.8 6.5 6.6 6.2 5.5 5.4 (1.81)

15 16 17 18 19 20 21

6.5 7.3 7.0 5.8 8.3 6.4 7.2

5.3 4.9 6.3 5.3 12.2 12.5

4.8 4.2 3.9 4.2 5.7 4.5 6.1

10.3 9.4 9.0 8.8 9.1 8.5 9.0

15.0 15.6 14.7 23.1 15.5 13.8 19.0

16.0 14.5 15.1 14.3 14.0 12.5 12.7

3.8 4.1 2.7

8.5 7.6 7.8 7.6 6.0 8.8 4.8

8.77 8.45 8.36 8.87 9.05 8.56 8.61

1 2 3 4 5 6 7 (Dosage)

8 9 10 11 12 13 14

I

7

NS

N.S.

I

4

I

11

I

5

(4.83)

I

10

(4.88)

I

9

(5.31)

1.7

1.9 1.5

1.5

I

2

(5.55)

NS: not specified

mately 60% and seizure control was less effective. When the patients were returned to the same daily dose of oral phenytoin, plasma levels rose to significantly higher levels than those reached with previous oral administration. A preliminary study of dose adjustment was conducted with 4 patients in which the daily dose of phenytoin was increased 50% when patients were transferred to im drug and reduced to 50% of the original oral dose when returned to the oral route. The present study explores this phenomenon further in a larger group of patients. Methods and materials

Nine men and 2 women, all inpatients at the Veterans Administration Hospital in Gaines-

ville, Fla., were selected for the study. Eight patients had psychomotor seizure disorders, 2 had focal motor disorders, and 1 had a diagnosis of grand mal seizures. They ranged from 26 to 64 yr of age (mean: 45 yr); 8 were Caucasian; 3 were Negro. They had all been on a stable oral dose of phenytoin for at least 3 mo at the time of the study. None had any signs of phenytoin toxicity or liver or renal disease that might affect phenytoin metabolism. Seizures in all were at least 90% under control. At the start of the study each patient was continued on the oral phenytoin preparation at his previous dosage for I wk (dose: 200 or 300 mg/day; 1 to 3 doses/day). Each was then given im phenytoin at a 50% increase in daily dosage. After 1 wk on this regimen, each subject was

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Wilder and Ramsay

Clinical Pharmacology and Therapeutics

I M (1.5 xl

7

DAYS

Oral

4

(o.5xl

21

Fig. 1. Mean plasma levels of phenytoin in 4 patients receiving drug in divided daily doses (- - -) and 8 receiving drug once a day (--). X, Original daily dose.

again returned to the oral phenytoin regimen at a daily dose one-half the original oral dose, for a final week of observation. Blood plasma for assay was obtained daily 1 hr before each morning dose to determine whether phenytoin given the previous day still provided therapeutic levels. All of the assays were performed at the Epilepsy Research Laboratory, University of Florida, by a gas-liquid chromatographic method. 7 Seizures and adverse experiences were observed and recorded. Neurologic examinations for ataxia, dysarthria, and mental confusion, symptoms indicative of phenytoin toxicity, were also conducted throughout the study. One patient received phenobarbital concurrently during the study. Phenobarbital may affect phenytoin plasma levels,2 but in this patient the phenobarbital dose remained constant throughout the study so that its effects should have been the same in each phase. Results

Only 2 patients, both with psychomotor disorders, exhibited seizures during the trial. One patient had 2 seizures in the initial oral phase, 2 in the im phase, and 3 in the final (reduceddose) oral phase. The other patient had 3 sei-

zures in the initial oral phase, 2 during the im phase, and 2 in the final oral phase. All eleven patients had normal neurological signs during the entire trial period. The mean daily phenytoin plasma levels remained relatively constant throughout the three phases in the 8 patients who received injections once a day (Table I). The levels in the 4 patients who received drug in divided doses, however, rose during the im phase (the increase approaching 50%) and fell only gradually during the final oral phase (Fig. 1). There was no difference between the main daily plasma levels in the three phases (p < 0.05, 3-way analysis of variance) in the 8 patients on single daily doses. No statistical test was applied to the data from the other 4 patients because the sample was too small. One patient participated in the study twice with about a 3-mo interval between courses. In his first participation he received his daily dose in three parts; in his second participation he received his daily dose at one time. The comparison between the results with the two administration schedules for this one patient parallel those for the whole group, i.e., the same rise occurred during the im phase on a multiple-dose schedule but not on a single-dose schedule.

Phenytoin

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During the final oral phase, however, there was no decrease in plasma level on the multiple dose but there was an increase on the single dose. Adverse experiences. Ten of the 11 patients reported symptoms of local irritation during the im phase which ranged from mild local pain and erythema to moderate induration and hematoma; in no case were the symptoms severe, and all disappeared in the early part of the final oral phase. Discussion

The results of the study indicate that increasing the daily dose of phenytoin by 50% when administration is changed from oral to im prevents the decrease in plasma phenytoin which occurs after this transfer. 3 • 8. 10 Within I wk on im phenytoin, patients receiving drug in divided doses had increases in plasma phenytoin corresponding to the increase in dose. This finding suggests that I wk is as long as the im regimen on the 50% larger dose should be continued. Among the patients who received the im phenytoin in a single daily dose, plasma levels of phenytoin did not generally show an increase; in fact, they were remarkably stable. This finding supports a once-daily im phenytoin regimen. It is also recommended because it avoids the obvious discomfort of multiple injections. Patients receiving multiple daily injections of phenytoin had a significant elevation of plasma phenytoin that may be attributable to an increased area for absorption due to the multiple im pools of phenytoin. There was no sudden increase in mean plasma level in either group when the regimen was changed to oral phenytoin, at 50% of the original dose. The group receiving phenytoin in multiple daily doses maintained the increased plasma levels achieved during the im phase. The level gradually began to decrease in the final oral phase. These findings indicate that the reduced oral dose during the transition from im to oral phenytoin will prevent the increase in plasma phenytoin levels that has been reported when the dose was not reduced. 9 The usual adult therapeutic dose of phenytoin is 300 mg/day, which provides plasma levels

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in the range of 10 to 15 fLg/m!. The plasma samples were taken just before the first morning dose of phenytoin, i.e., approximately 24 hr after the previous dose (or first dose if multiple doses given) and thus represent minimal daily levels. Buchthal, Svensmark, and Schiller1 have reported that serum levels of phenytoin decrease about 25% to 30% in 24 hr. If the values found in the plasma samples in this study were down 25% to 30% from peak values, the peak values were virtually all in the therapeutic range. One patient had lower plasma values than would be expected (1.5 to 6.9 fLg/ml). He may have metabolized phenytoin more rapidly than the other patients; such rapid metabolism may result in low plasma levels. 5 Despite the low plasma levels, the patient's seizures were adequately controlled throughout the study. Another patient had higher plasma values than would be expected (13.5 to 26.3 fLg/ml). This patient was receiving 400 mg/ day in the first oral phase (600 mg/day in the im phase), which might account for the higher plasma levels of drug. Toxic signs may appear at plasma levels in the range of 20 to 25 fLg/ m!. 6 This patient, however, exhibited no signs of toxicity. None of the patients dropped out of the study because of local irritation. There was no evidence of muscle necrosis or sterile abscess formation. The authors thank Dr. Frank T. Hess for this assistance in the preparation of this article.

References I. Buchthal, F., Svensmark, D., and Schiller,

2.

3. 4.

5.

P. J.: Clinical and electroencephalographic correlations with serum levels of diphenylhydantoin, Arch. Neurol. 2:624-630, 1960. Cucinell, S. A., Koster, R., Conney, A. H., and Bums, J. J.: Stimulatory effect of phenobarbital on the metabolism of diphenylhydantoin, J. Pharmacol Exp. Ther. 141:157-160, 1963. Dam, M., and Olesen, V.: Intramuscular administration of phenytoin, Neurology 16:288292,1966. Kinkel, A. W., Smith, T. c., and Oppelt, W. W.: Plasma levels, metabolism and urinary excretion of diphenylhydantoin after single oral or intramuscular doses in normal volunteers. Submitted for presentation at the 1975 fall meeting of the American Society for Pharmacology and Experimental Therapeutics. Kutt, H., Haynes, J., and McDowell, F.: Some

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causes of ineffectiveness of diphenylhydantoin, Arch. Neurol. 14:489-492, 1966. 6. Kutt, H., Winters, W., Kukenge, R., and McDowelI, F.: Diphenylhydantoin metabolism, blood levels, and toxicity, Arch. Neurol. 11: 642-648, 1964. 7. Perchalski, R. J., Scott, K. N., Wilder, B. J., and Hammer, R. H.: Rapid simultaneous GLC determination of phenobarbital, primidone and diphenylhydantoin, J. Pharm. Sci. 62:17351736, 1973. 8. Serrano, E. E., Roye, D. B., Hammer, R. H., and Wilder, B. J.: Plasma diphenylhydantoin

Clinical Pharmacology and Therapeutics

values after oral and intramuscular administration of diphenylhydantoin, Neurology 23:311317, 1973. 9. Wilder, B. J., Serrano, E. E., Ramsey, E., and Buchanan, R. A.: A method for shifting from oral to intramuscular diphenylhydantoin administration, CUN. PHARMACOL. THER. 16: 507-513, 1974. 10. Wilensky, A. J., and Lowden, J. A.: Inadequate serum levels after intramuscular administration of diphenylhydantoin, Neurology 23:318-324, 1973.

Oral and intramuscular phenytoin.

Oral and intramuscular phenytoin Twelve epileptic patients, after 1 wk on their previously established oral dose of phenytoin, were given a 50% larger...
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