PHENYTOIN SODIUM- phenytoin sodium capsule, extended release
RPK Pharmaceuticals, Inc.
1 INDICATIONS AND USAGE
Extended phenytoin sodium capsules, USP are indicated for the treatment of tonic-clonic (grand mal) and psychomotor (temporal lobe) seizures and prevention and treatment of seizures occurring during or following neurosurgery.
2 DOSAGE AND ADMINISTRATION
2.1 Adult Dosage
Divided daily dosage:
The recommended starting dose for adult patients who have received no previous treatment is one 100-mg extended phenytoin sodium capsule, USP by mouth three times daily. Adjust the dosage to suit individual requirements up to a maximum of two capsules three times a day. For most adults, the satisfactory maintenance dosage will be one capsule three to four times a day.
In adults, if seizure control is established with divided doses of three 100-mg extended phenytoin sodium capsules, USP daily, once-a-day dosage with 300 mg of extended phenytoin sodium capsules, USP may be considered. Studies comparing divided doses of 300 mg with a single daily dose of this quantity indicated absorption, peak serum levels, biologic half-life, difference between peak and minimum values, and urinary recovery were equivalent. Once-a-day dosage offers a convenience to the individual patient or to nursing personnel for institutionalized patients and is intended to be used only for patients requiring this amount of drug daily. A major problem in motivating noncompliant patients may also be lessened when the patient can take this drug once a day. However, patients should be cautioned not to miss a dose, inadvertently. Only extended phenytoin sodium capsules, USP are recommended for once-a-day dosing. Inherent differences in dissolution characteristics and resultant absorption rates of phenytoin due to different manufacturing procedures and/or dosage forms preclude such recommendation for other phenytoin products. When a change in the dosage form or brand is prescribed, careful monitoring of phenytoin serum levels should be carried out.
Some authorities have advocated use of an oral loading dose of phenytoin in adults who require rapid steady-state serum levels and where intravenous administration is not desirable. This dosing regimen should be reserved for patients in a clinic or hospital setting where phenytoin serum levels can be closely monitored. Patients with a history of renal or liver disease should not receive the oral loading regimen. Initially, one gram of extended phenytoin sodium capsules, USP is divided into three doses (400 mg, 300 mg, 300 mg) and administered at two-hour intervals. Normal maintenance dosage is then instituted 24 hours after the loading dose, with frequent serum level determinations.
2.2 Pediatric Dosage
The recommended starting dosage for pediatric patients is 5 mg/kg/day by mouth in two or three equally divided doses, with subsequent dosage individualized to a maximum of 300 mg daily in divided doses. A recommended daily maintenance dosage is usually 4 mg/kg/day to 8 mg/kg/day in equally divided doses. Children over 6 years and adolescents may require the minimum adult dosage (300 mg/day).
2.3 Dosage Adjustments
Dosage should be individualized to provide maximum benefit. In some cases, serum blood level determinations may be necessary for optimal dosage adjustments. Trough levels provide information about clinically effective serum level range and confirm patient compliance, and are obtained just prior to the patient’s next scheduled dose. Peak levels indicate an individual’s threshold for emergence of dose-related side effects and are obtained at the time of expected peak concentration. Therapeutic effect without clinical signs of toxicity occurs more often with serum total concentrations between 10 mcg/mL and 20 mcg/mL (unbound phenytoin concentrations between 1 mcg/mL and 2 mcg/mL), although some mild cases of tonic-clonic (grand mal) epilepsy may be controlled with lower serum levels of phenytoin. In patients with renal or hepatic disease, or in those with hypoalbuminemia, the monitoring of unbound phenytoin concentrations may be more relevant [see Dosage and Administration (2.5)].
With recommended dosage, a period of seven to ten days may be required to achieve steady-state blood levels with phenytoin and changes in dosage (increase or decrease) should not be carried out at intervals shorter than seven to ten days.
2.4 Switching Between Phenytoin Formulations
The free acid form of phenytoin is used in phenytoin oral suspension and phenytoin chewable tablets. Extended phenytoin sodium capsules and parenteral phenytoin are formulated with the sodium salt of phenytoin. Because there is approximately an 8% increase in drug content with the free acid form over that of the sodium salt, dosage adjustments and serum level monitoring may be necessary when switching from a product formulated with the free acid to a product formulated with the sodium salt and vice versa.
2.5 Dosing in Patients with Renal or Hepatic Impairment or Hypoalbuminemia
Because the fraction of unbound phenytoin is increased in patients with renal or hepatic disease, or in those with hypoalbuminemia, the monitoring of phenytoin serum levels should be based on the unbound fraction in those patients [see Warnings and Precautions (5.11) and Use in Specific Populations (8.6)].
2.6 Geriatric Dosage
Phenytoin clearance is decreased slightly in elderly patients and lower or less frequent dosing may be required [see Clinical Pharmacology (12.3)].
2.7 Dosing during Pregnancy
Decreased serum concentrations of phenytoin may occur during pregnancy because of altered phenytoin pharmacokinetics. Periodic measurement of serum phenytoin concentrations should be performed during pregnancy, and the extended phenytoin sodium capsule dosage should be adjusted as necessary. Postpartum restoration of the original dosage will probably be indicated [see Use in Specific Populations (8.1)]. Because of potential changes in protein binding during pregnancy, the monitoring of phenytoin serum levels should be based on the unbound fraction.
3 DOSAGE FORMS AND STRENGTHS
Extended phenytoin sodium capsules, USP are available as:
- 100 mg: hard, gelatin capsules No. 3 with an opaque orange cap, opaque orange body with black imprint “SUN808” on both body and cap. Contains white to off-white powder.
Extended phenytoin sodium capsules are contraindicated in patients with:
- A history of hypersensitivity to phenytoin, its inactive ingredients, or other hydantoins [see Warnings and Precautions (5.5)]. Reactions have included angioedema.
- A history of prior acute hepatotoxicity attributable to phenytoin [see Warnings and Precautions (5.8)].
- Coadministration with delavirdine because of the potential for loss of virologic response and possible resistance to delavirdine or to the class of non-nucleoside reverse transcriptase inhibitors.
5 WARNINGS AND PRECAUTIONS
5.1 Withdrawal Precipitated Seizure, Status Epilepticus
Abrupt withdrawal of phenytoin in epileptic patients may precipitate status epilepticus. When, in the judgment of the clinician, the need for dosage reduction, discontinuation, or substitution of alternative anticonvulsant medication arises, this should be done gradually. However, in the event of an allergic or hypersensitivity reaction, more rapid substitution of alternative therapy may be necessary. In this case, alternative therapy should be an anticonvulsant drug not belonging to the hydantoin chemical class.
5.2 Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including extended phenytoin sodium capsules, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 years to 100 years) in the clinical trials analyzed.
Table 1 shows absolute and relative risk by indication for all evaluated AEDs.
|Indication||Placebo Patients with Events Per 1000 Patients||Drug Patients with Events Per 1000 Patients||Relative Risk: |
Incidence of Events in Drug Patients/Incidence in Placebo Patients
|Risk Difference: |
Additional Drug Patients with Events Per 1000 Patients
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
Anyone considering prescribing extended phenytoin sodium capsules or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
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