CYP2C9 activity is decreased in individuals with genetic variants such as the CYP2C9*2 and CYP2C9*3 alleles. Carriers of variant alleles, resulting in intermediate (e.g., *1/*3, *2/*2) or poor metabolism (e.g., *2/*3, *3/*3) have decreased clearance of phenytoin. Other decreased or nonfunctional CYP2C9 alleles may also result in decreased clearance of phenytoin (e.g., *5, *6, *8, *11).
The prevalence of the CYP2C9 poor metabolizer phenotype is approximately 2–3% in the White population, 0.5–4% in the Asian population, and <1% in the African American population. The CYP2C9 intermediate phenotype prevalence is approximately 35% in the White population, 24% in the African American population, and 15–36% in the Asian population [see Warnings and Precautions (5.3) and Use in Specific Populations (8.7)].
Carcinogenesis [see Warnings and Precautions (5.9)]
In carcinogenicity studies, phenytoin was administered in the diet to mice (10, 25, or 45 mg/kg/day) and rats (25, 50, or 100 mg/kg/day) for 2 years. The incidences of hepatocellular tumors were increased in male and female mice at the highest dose. No increases in tumor incidence were observed in rats. The highest doses tested in these studies were associated with peak serum phenytoin levels below human therapeutic concentrations.
In carcinogenicity studies reported in the literature, phenytoin was administered in the diet for 2 years at doses up to 600 ppm (approximately 160 mg/kg/day) to mice and up to 2400 ppm (approximately 120 mg/kg/day) to rats. The incidences of hepatocellular tumors were increased in female mice at all but the lowest dose tested. No increases in tumor incidence were observed in rats.
Phenytoin was negative in the Ames test and in the in vitro clastogenicity assay in Chinese hamster ovary (CHO) cells.
In studies reported in the literature, phenytoin was negative in the in vitro mouse lymphoma assay and the in vivo micronucleus assay in mouse. Phenytoin was clastogenic in the in vitro sister chromatid exchange assay in CHO cells.
Phenytoin has not been adequately assessed for effects on male or female fertility.
DILANTIN (extended phenytoin sodium capsules, USP) is supplied as follows:
|100’s||30 mg||NDC 0071-3740-66|
|100’s||100 mg||NDC 0071-0369-24|
|1000’s||100 mg||NDC 0071-0369-32|
|Unit Dose 100’s||100 mg||NDC 0071-0369-40|
DILANTIN 30 mg extended capsules are available as a size 4 hemispherical Coni-Snap capsule with a white opaque body and pale pink opaque cap containing a white powder. Capsule is imprinted with black rectified radial print, “PD” on cap and “DILANTIN 30 mg” on body.
DILANTIN 100 mg extended capsules are available as hard, filled No. 3 capsules containing a white powder. The medium orange cap having “PD” printed in black ink and the white, opaque body having “DILANTIN” over “100 mg” printed in black ink.
Store at 20 to 25°C (68 to 77°F) [See USP Controlled Room Temperature]. Preserve in tight, light-resistant containers. Protect from moisture.
Advise patients to read the FDA-approved patient labeling (Medication Guide).
Advise patients taking phenytoin of the importance of adhering strictly to the prescribed dosage regimen, and of informing the physician of any clinical condition in which it is not possible to take the drug orally as prescribed, e.g., surgery, etc.
Advise patients not to use capsules which are discolored.
Withdrawal of Antiepileptic Drugs
Advise patients not to discontinue use of DILANTIN without consulting with their healthcare provider. DILANTIN should normally be gradually withdrawn to reduce the potential for increased seizure frequency and status epilepticus [see Warnings and Precautions (5.1)].
Suicidal Ideation and Behavior
Counsel patients, their caregivers, and families that AEDs, including DILANTIN, may increase the risk of suicidal thoughts and behavior and advise them of the need to be alert for the emergence or worsening of 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 [see Warnings and Precautions (5.2)].
Serious Dermatologic Reactions
Advise patients of the early signs and symptoms of severe cutaneous adverse reactions and to report any occurrence immediately to a physician [see Warnings and Precautions (5.3)].
Potential Signs of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) and Other Systemic Reactions
Advise patients of the early toxic signs and symptoms of potential hematologic, dermatologic, hypersensitivity, or hepatic reactions. These symptoms may include, but are not limited to, fever, sore throat, rash, ulcers in the mouth, easy bruising, lymphadenopathy, facial swelling, and petechial or purpuric hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or jaundice. Advise the patient that, because these signs and symptoms may signal a serious reaction, that they must report any occurrence immediately to a physician. In addition, advise the patient that these signs and symptoms should be reported even if mild or when occurring after extended use [see Warnings and Precautions (5.3, 5.4, 5.5, 5.8, 5.9)].
Counsel patients that cases of bradycardia and cardiac arrest have been reported, both at recommended phenytoin doses and levels, and in association with phenytoin toxicity. Patients should report cardiac signs or symptoms to their healthcare provider [see Warnings and Precautions (5.6) and Overdosage (10)].
Advise patients to discontinue DILANTIN and seek immediate medical care if they develop signs or symptoms of angioedema, such as facial, perioral, or upper airway swelling [see Warnings and Precautions (5.7)].
Effects of Alcohol Use and Other Drugs and Over-the-Counter Drug Interactions
Caution patients against the use of other drugs or alcoholic beverages without first seeking their physician’s advice [Drug Interactions (7.1, 7.2)].
Inform patients that certain over-the-counter medications (e.g., antacids, cimetidine, and omeprazole), vitamins (e.g., folic acid), and herbal supplements (e.g., St. John’s wort) can alter their phenytoin levels.
Advise patients that DILANTIN may cause an increase in blood glucose levels [see Warnings and Precautions (5.14)].
Advise patients of the importance of good dental hygiene in order to minimize the development of gingival hyperplasia and its complications.
Counsel patients that DILANTIN may cause dizziness, gait disturbance, decreased coordination and somnolence. Advise patients taking DILANTIN not to drive, operate complex machinery, or engage in other hazardous activities until they have become accustomed to any such effects associated with DILANTIN.
Use in Pregnancy
Inform pregnant women and women of childbearing potential that use of DILANTIN during pregnancy can cause fetal harm, including an increased risk for cleft lip and/or cleft palate (oral clefts), cardiac defects, dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities (including microcephaly), and cognitive deficits. When appropriate, counsel pregnant women and women of childbearing potential about alternative therapeutic options. Advise women of childbearing potential who are not planning a pregnancy to use effective contraception while using DILANTIN, keeping in mind that there is a potential for decreased hormonal contraceptive efficacy [see Drug Interactions (7.2)].
Instruct patients to notify their physician if they become pregnant or intend to become pregnant during therapy, and to notify their physician if they are breastfeeding or intend to breastfeed during therapy [see Use in Specific Populations (8.1, 8.2)].
Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy [see Use in Specific Populations (8.1)].
|This Medication Guide has been approved by the U.S. Food and Drug Administration||Revised: 12/2018|
|MEDICATION GUIDE DILANTIN (Dī lan’ tĭn)(extended phenytoin sodium capsules)|
|What is the most important information I should know about DILANTIN?|
|Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.How can I watch for early symptoms of suicidal thoughts and actions? |
|Call your healthcare provider even if the symptoms are mild or if you have been taking DILANTIN for an extended period of time. These symptoms can be a sign of a serious allergic reaction.|
|What is DILANTIN? DILANTIN is a prescription medicine used to treat certain types of seizures called tonic-clonic (grand mal) and psychomotor (temporal lobe) seizures.|
|Do not take DILANTIN if you: |
|Before taking DILANTIN, tell your healthcare provider about all of your medical conditions, including if you: |
|How should I take DILANTIN? |
|What should I avoid while taking DILANTIN? |
|What are the possible side effects of DILANTIN? See “What is the most important information I should know about DILANTIN?“ DILANTIN may cause other serious side effects including: |
|DILANTIN can cause overgrowth of your gums. Brushing and flossing your teeth and seeing a dentist regularly while taking DILANTIN can help prevent this from happening.These are not all of the possible side effects of DILANTIN.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.|
|How should I store DILANTIN? |
|General information about the safe and effective use of DILANTIN. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use DILANTIN for a condition for which it was not prescribed. Do not give DILANTIN to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about DILANTIN that is written for health professionals.|
|What are the ingredients in DILANTIN Capsules? DILANTIN 30 mg: Active ingredient: 30 mg phenytoin sodium, USPInactive ingredients: lactose monohydrate, confectioner’s sugar, talc, and magnesium stearate. The capsule shell cap and body contain Titanium Dioxide (cap and body); gelatin (cap and body); D&C yellow No. 10 (cap); FD&C red No. 3 (cap).DILANTIN 100 mg: Active ingredient: 100 mg phenytoin sodium, USPInactive ingredients: lactose monohydrate, confectioner’s sugar, talc, and magnesium stearate. The capsule body contains titanium dioxide and gelatin. The capsule cap contains FD&C red No. 28, FD&C yellow No. 6, and gelatin. |
LAB-0586-12.0For more information about DILANTIN, visit http://www.pfizer.com or call 1 800 438 1985.
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