Dilantin (Page 6 of 7)

12.5 Pharmacogenomics

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)].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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.

Mutagenesis

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.

Fertility

Phenytoin has not been adequately assessed for effects on male or female fertility.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

DILANTIN (extended phenytoin sodium capsules, USP) is supplied as follows:

Package Configuration	Strength	NDC
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.

16.2 Storage and Handling

Store at 20 to 25°C (68 to 77°F) [See USP Controlled Room Temperature]. Preserve in tight, light-resistant containers. Protect from moisture.

17 PATIENT COUNSELING INFORMATION

Advise patients to read the FDA-approved patient labeling (Medication Guide).

Administration Information

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)].

Cardiac Effects

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)].

Angioedema

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.

Hyperglycemia

Advise patients that DILANTIN may cause an increase in blood glucose levels [see Warnings and Precautions (5.14)].

Gingival Hyperplasia

Advise patients of the importance of good dental hygiene in order to minimize the development of gingival hyperplasia and its complications.

Neurologic Effects

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)].

LAB-0375-34.0

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? 1. Do not stop taking DILANTIN without first talking to your healthcare provider. Stopping DILANTIN suddenly can cause serious problems. Stopping a seizure medicine suddenly can cause you to have seizures more often or seizures that will not stop (status epilepticus). 2. Like other antiepileptic drugs, DILANTIN may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:
	Thoughts about suicide or dying Attempts to commit suicide New or worse depression	New or worse anxiety Feeling agitated or restless Panic attacks	Trouble sleeping (insomnia) New or worse irritability Acting aggressive, being angry, or violent	Acting on dangerous impulses An extreme increase in activity and talking (mania) Other unusual changes in behavior or mood
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? Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you are worried about symptoms.
3. DILANTIN can cause a type of serious allergic reaction that may affect different parts of the body such as your liver, kidneys, blood, heart, skin or other parts of your body. These can be very serious and cause death. Call your healthcare provider right away if you have any or all of these symptoms:
	Fever Rash Swollen lymph glands Swelling of your face, eye, lips, or tongue Trouble swallowing or breathing	Sore throat Sores in your mouth Bruise easily Purple or red spots on your skin Increase infections		Not wanting to eat (anorexia) Nausea Vomiting Yellowing of the skin and the white part of your eyes (jaundice)
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. 4. DILANTIN can cause problems with your heart, including a slow heartbeat. Let your healthcare provider know right away if you have any of these symptoms: dizziness tiredness feeling like your heart is beating slowly or skipping beats chest pain
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: Are allergic to phenytoin or any of the ingredients in DILANTIN. See the end of this leaflet for a complete list of ingredients in DILANTIN. Have had an allergic reaction to CEREBYX (fosphenytoin), PEGANONE (ethotoin), or MESANTOIN (mephenytoin). Have had liver problems from taking phenytoin. Take delavirdine.
Before taking DILANTIN, tell your healthcare provider about all of your medical conditions, including if you: Have or have had depression, mood problems, or suicidal thoughts or behavior Have had an allergic reaction to a medicine similar to DILANTIN called carboxamides, barbiturates, succinimides, and oxazolidinediones Have or had liver or kidney problems Have or had an enzyme problem called porphyria Have or had high blood sugar (hyperglycemia) Drink alcohol Are pregnant or plan to become pregnant. DILANTIN may harm your unborn baby. If you take DILANTIN during pregnancy, your baby is at risk for serious birth defects. If you become pregnant while taking DILANTIN, the level of DILANTIN in your blood may decrease, causing your seizures to become worse. Your healthcare provider may change your dose of DILANTIN. If you take DILANTIN during pregnancy, your baby is also at risk for bleeding problems right after birth. Your healthcare provider may give you and your baby medicine to prevent this. All women of child-bearing age should talk to their healthcare provider about using other possible treatments instead of DILANTIN. If you are of childbearing age and are not planning on getting pregnant, you should use effective birth control (contraception) while taking DILANTIN. Pregnancy Registry: If you become pregnant while taking DILANTIN, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy. Are breastfeeding or plan to breastfeed. DILANTIN can pass into breast milk. You and your healthcare provider should decide if you will take DILANTIN while you are breastfeeding. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. These medicines can change the levels of DILANTIN in your blood.Taking DILANTIN with certain other medicines can cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider.Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.
How should I take DILANTIN? Take DILANTIN exactly as your healthcare provider tells you. Your healthcare provider will tell you how much DILANTIN to take and when to take it. Your healthcare provider may change your dose if needed. Do not change your dose of DILANTIN without talking to your healthcare provider. If your healthcare provider has prescribed DILANTIN oral suspension, ask your pharmacist for a medicine dropper or medicine cup to help you measure the correct amount of DILANTIN. Do not use a household teaspoon. Ask your pharmacist for instructions on how to use the measuring device the right way. Do not stop taking DILANTIN without first talking to your healthcare provider. Stopping DILANTIN suddenly can cause serious problems.
What should I avoid while taking DILANTIN? Do not drink alcohol while you take DILANTIN without first talking to your healthcare provider. Drinking alcohol while taking DILANTIN may change your blood levels of DILANTIN which can cause serious problems. Do not drive, operate heavy machinery, or do other dangerous activities until you know how DILANTIN affects you. DILANTIN can slow your thinking and motor skills.
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: Liver problems. Low blood count which could increase your chance of getting infections, bruising, bleeding and increased fatigue Softening of your bones (osteopenia, osteoporosis, and osteomalacia) can cause your bones to break (fractures). High blood sugar (hyperglycemia). High levels of DILANTIN in your blood that could cause confusion also known as delirium, psychosis or a more serious condition that affects how your brain works (encephalopathy). Call your healthcare provider right away, if you have any of the symptoms listed above.The most common side effects of DILANTIN include:
Irregular movement of the eye (nystagmus) Problems with movement and balance (ataxia)		Slurred speech Decrease in coordination	Drowsiness (somnolence) Confusion
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? Store DILANTIN Capsules at room temperature between 68°F to 77°F (20°C to 25°C). Store in tight, light-resistant containers. Protect from moisture. Keep DILANTIN and all medicines out of the reach of children.
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.