Drug Safety-related Labeling Changes (SrLC)

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DILANTIN (NDA-010151)

(PHENYTOIN SODIUM)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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10/31/2017 (SUPPL-48)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

Risk Summary

In humans, prenatal exposure to phenytoin (the active metabolite of CEREBYX) may increase the risks for congenital malformations and other adverse developmental outcomes. Prenatal phenytoin exposure is associated with an increased incidence of major malformations, including orofacial clefts and cardiac defects. In addition, the fetal hydantoin syndrome, a pattern of abnormalities including dysmorphic skull and facial features …

The background risk of major birth defects and miscarriage for the indicated population is unknown.

Data

Human Data

Meta-analyses using data from published observational studies and registries have estimated an approximately 2.4-fold increased risk for any major malformation in children with prenatal phenytoin exposure compared to controls. An increased risk of heart defects, facial clefts, and digital hypoplasia has been reported. The fetal hydantoin syndrome is a pattern of congenital anomalies including craniofacial anomalies, nail and digital hypoplasia, prenatal-onset growth deficiency, and neurodevelopmental deficiencies.

Animal Data

08/15/2017 (SUPPL-46)

Approved Drug Label (PDF)

6 Adverse Reactions

Additions and/or revisions underlined:

Laboratory Test Abnormality: Phenytoin may decrease serum concentrations of thyroid hormone (T4 and T3), sometimes with an accompanying increase in thyroid-stimulating hormone (TSH), but usually in the absence of clinical hypothyroidism. Phenytoin may also produce lower than normal values

11/30/2016 (SUPPL-45)

4 Contraindications

(additions and/or revisions are underlined)

  • A history of prior acute hepatotoxicity attributable to phenytoin

5 Warnings and Precautions

5.1 Cardiovascular Risk Associated with Rapid Infusion

(additions and/or revisions are underlined)

Rapid intravenous administration of DILANTIN increases the risk of adverse cardiovascular reactions, including severe hypotension and cardiac arrhythmias.

In pediatric patients, administer the drug at a rate not exceeding 1 to 3 mg/kg/min or 50 mg per minute, whichever is slower.

Although the risk of cardiovascular toxicity increases with infusion rates above the recommended infusion rate, these events have also been reported at or below the recommended infusion rate.

Because adverse cardiovascular reactions have occurred during and after infusions, careful cardiac and respiratory monitoring is needed during and after the administration of intravenous DILANTIN.

5.11 Teratogenicity and Other Harm to the Newborn

(additions and/or revisions are underlined)

DILANTIN may cause fetal harm when administered to a pregnant woman.

5.12 Slow Metabolizers of Phenytoin

(additions and/or revisions are underlined)

If early signs of dose-related CNS toxicity develop, serum levels should be checked immediately.

5.4 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity

(additions and/or revisions are underlined)

Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, in association with other organ system involvement…

5.9 Renal or Hepatic Impairment or Hypoalbuminemia

(additions and/or revisions are underlined)

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.

6 Adverse Reactions

(additions and/or revisions are underlined)

The following adverse reactions associated with the use of DILANTIN were identified in clinical studies or postmarketing reports. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Nervous System:Cerebellar atrophy has been reported, and appears more likely in settings of elevated phenytoin levels and/or long-term phenytoin use.

7 Drug Interactions

(additions and/or revisions are underlined; summary in italics)

Monitoring of phenytoin serum levels is recommended when a drug interaction is suspected.

Table 1: Drugs That Affect Phenytoin Concentrations (New table added; refer to label)

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion)

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as DILANTIN, during pregnancy. Physicians are advised to recommend that pregnant patients taking Dilantin enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/

Risk Summary

An increased incidence of major malformations (such as orofacial clefts and cardiac defects) and abnormalities characteristic of fetal hydantoin syndrome (dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities [including microcephaly], and cognitive deficits) has been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy.

In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal data

Administration of phenytoin to pregnant rats, rabbits, and mice during organogenesis resulted in embryofetal death, fetal malformations, and decreased fetal growth retardation. Malformations (including craniofacial, cardiovascular, neural, limb, and digit abnormalities) were observed in rats, rabbits, and mice at doses as low as 100, 75, and 12.5 mg/kg, respectively.

8.2 Lactation

(PLLR conversion)                      

Risk Summary

Phenytoin is secreted in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for DILANTIN and any potential adverse effects on the breastfed infant from DILANTIN or from the underlying maternal condition.

8.4 Pediatric Use

(additions and/or revisions are underlined)

A loading dose of 15-20 mg/kg of DILANTIN intravenously will usually produce serum concentrations of phenytoin within the generally accepted serum total concentrations between 10 and 20 mcg/mL (unbound phenytoin concentrations of 1 to 2 mcg/mL). Because of the increased risk of adverse cardiovascular reactions associated with rapid administration DILANTIN should be injected slowly intravenously at a rate not exceeding 1-3 mg/kg/min or 50 mg per minute, whichever is slower.

8.6 Renal and/or Hepatic Impairment or Hypoalbuminemia

(additions and/or revisions are underlined)

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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(newly added section)

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.

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.

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.

Inform patients that certain over-the-counter medications (e.g., 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.

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.

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.

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.

Other

PLR conversion

06/16/2016 (SUPPL-42)

Approved Drug Label (PDF)

5 Warnings and Precautions

General

  • Serum levels of phenytoin sustained above the optimal range may produce confusional states referred to as “delirium,” “psychosis,” or “encephalopathy,” or rarely irreversible cerebellar dysfunction and/or cerebellar atrophy. (addition of cerebellar atrophy).

6 Adverse Reactions

  • Nervous System: Cerebellar atrophy has been reported, and appears more likely in settings of elevated phenytoin levels and/or long-term phenytoin use. (addition to first paragraph)

Questions related to the drug data in these files should be directed to the Center for Drug Evaluation and Research, Division of Drug Information
druginfo@fda.hhs.gov.

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