4
Contraindications
(additions and/or revisions are underlined)
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.
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