Approved Drug Label (PDF)
4
Contraindications
Additions
and/or revisions underlined:
5
Warnings and Precautions
5.3 Serious
Dermatologic Reactions
Additions and/or
revisions underlined:
CEREBRYX
can cause severe cutaneous adverse reactions (SCARs), which may be
fatal. Reported reactions in phenytoin (the active metabolite of
CEREBRYX)-treated patients have included toxic epidermal necrolysis (TEN),
Stevens-Johnson syndrome (SJS), acute generalized exanthematous pustulosis
(AGEP), and Drug Reaction with Eosinophilia and Systemic Symptoms
(DRESS). The onset of symptoms is
usually within 28 days but can occur later. CEREBRYX should be discontinued at
the first sign of a rash, unless the rash is clearly not drug-related. If signs
or symptoms suggest a severe cutaneous adverse reaction, use of this
drug should not be resumed and alternative therapy should be considered. If a
rash occurs, the patient should be evaluated for signs and symptoms of SCARs.
Newly added
subsection:
5.7 Angioedema
Angioedema
has been reported in patients treated with CEREBRYX in the post marketing
setting. CEREBRYX should be discontinued immediately if symptoms of angioedema,
such as facial, perioral, or upper airway swelling occur. CEREBRYX should be
discontinued permanently if a clear alternative etiology for the reaction
cannot be established.
Additions and/or
revisions underlined:
5.9
Hematopoietic Complications
…
Lymph node involvement may occur with or without symptoms and signs resembling
DRESS. In all cases of
lymphadenopathy, follow-up observation for an extended period is indicated and
every effort should be made to achieve seizure control using alternative
antiepileptic drugs.
6
Adverse Reactions
Addition of
‘angioedema’ to the bulleted line listing.
6.2
Postmarketing Experience
Additions
underlined:
Body as a Whole:
Anaphylaxis,
angioedema
7
Drug Interactions
Addition of the
following subsection subtitle:
7.3
Drug/Laboratory Test Interactions
Care
should be taken when using immunoanalytical methods …
8
Use in Specific Populations
8.1 Pregnancy
Additions and/or
revisions underlined:
…
as a guide to appropriate adjustment of dosage. There have been several
reported cases of malignancies, including neuroblastoma, in children whose
mothers received phenytoin during pregnancy.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Newly added
information:
Cardiovascular
Risk Associated with Rapid Infusion
Inform
patients that rapid intravenous administration of CEREBYX increases the risk of
adverse cardiovascular reactions, including severe hypotension and cardiac
arrhythmias. Cardiac arrhythmias have included bradycardia, heart block, ventricular
tachycardia, and ventricular fibrillation which have resulted in asystole,
cardiac arrest, and death. Patients should report cardiac signs or symptoms to
their healthcare provider.
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.
Angioedema
Advise
patients to discontinue CEREBYX and seek immediate medical care if they develop
signs or symptoms of angioedema such as facial, perioral, or upper airway
swelling.
Approved Drug Label (PDF)
Boxed Warning
PLR
conversion
Additions
and/or revisions underlined:
WARNING:
CARDIOVASCULAR RISK ASSOCIATED WITH RAPID INFUSION RATES
The
rate of intravenous CEREBYX administration should not exceed 150 mg phenytoin
sodium equivalents (PE) per minute in adults and 2 mg PE/kg/min (or 150 mg
PE/min, whichever is slower) in pediatric patients because of the risk of
severe hypotension and cardiac arrhythmias. Careful cardiac monitoring is needed during and after
administering intravenous CEREBYX …
5
Warnings and Precautions
PLR conversion: subsections listed
below; for more information, please refer to label:
5.1
Dosing Errors
5.2
Cardiovascular Risk Associated with Rapid Infusion
5.3
Withdrawal Precipitated Seizure, Status Epilepticus
5.4
Serious Dermatological Reactions
5.5
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan
Hypersensitivity
5.6
Hypersensitivity
5.7
Hepatic Injury
5.8
Hematopoietic Complications
5.9
Sensory Distrubances
5.10
Local Toxicity (Including Purple Glove Syndrome)
5.11
Phosphate Load
5.12
Renal or Hepatic Disease or Hypoalbuminemia
5.13
Exacerbation of Porphyria
5.14
Teratogenicity and Other Harm to the Newborn
5.15
Slow Metabolizers of Phenytoin
5.16
Hyperglycemia
5.17
Serum Phenytoin Levels above Therapeutic Range
6
Adverse Reactions
PLR
conversion:
The
following serious adverse reactions are described elsewhere in the labeling:
- Cardiovascular Risk Associated with Rapid Infusion
- Withdrawal Precipitated Seizure, Status Epilepticus
Serious Dermatologic Reactions
- Drug Reaction with Eosinophilia and Systemic Symptoms
(DRESS)/Multiorgan Hypersensitivity
- Hypersensitivity
- Hepatic Injury
- Hematopoietic Complications
- Sensory Disturbances
- Local Toxicity (Including Purple Glove Syndrome)
- Exacerbation of Porphyria
- Teratogenicity and Other Harm to the Newborn
- Hyperglycemia
6.1 Clinical Trials Experience
Additions and/or revisions
underlined:
Because
clinical trials are conducted under widely varying conditions, adverse reaction
rates observed in the clinical trials of a drug cannot be directly compared to
rates in the clinical trials of another drug and may not reflect the rates
observed in practice.
… The
adverse reactions most commonly observed with the use of CEREBYX
in clinical trials were nystagmus, dizziness, pruritus,
somnolence, and ataxia. With
one exception, these reactions are commonly
associated with the administration of
IV phenytoin. Pruritus, however, was seen much more often
following CEREBYX administration
…
TABLE
1. Adverse Reaction Incidence Following
IV Administration at the Maximum Dose and Rate to Adult Patients with
Epilepsy or Neurosurgical Patients (Events in at Least 2% of CEREBYX-Treated
Patients)
Adult added to title to table that
was previously labeled as Table 2. Data
in table has been revised somewhat; please refer to label.
TABLE
2. Adverse Reaction Incidence Following
Substitution of IM CEREBYX for Oral Phenytoin in Adult Patients with
Epilepsy (Events in at Least 2% of CEREBYX-Treated Patients)
Adult added to title to table that
was previously labeled as Table 3. Data
in table has been revised somewhat; please refer to label.
Adverse
Events During Clinical Trials in Adult and Pediatric Patients
CEREBYX has been
administered to approximately 900 individuals during
clinical trials ..
…
Laboratory Test Abnormality: Phenytoin (the active metabolite of
CEREBYX) may cause increased serum levels of glucose and alkaline phosphatase.
6.2 Postmarketing Experience
Additions and/or revisions
underlined:
The following
adverse reactions have been identified
during post-approval use
of fosphenytoin … or establish a causal
relationship to drug exposure.
Body
as a Whole: Anaphylaxis
Laboratory
Test Abnormality: Phenytoin
or CEREBYX may decrease serum concentrations of T4. It may also produce lower
than normal values for dexamethasone or metyrapone tests. Phenytoin may also
cause increased serum levels of gamma glutamyl transpeptidase (GGT).
Nervous
System Disorders: Dyskinesia
7
Drug Interactions
PLR conversion:
Fosphenytoin is extensively bound to
human plasma proteins. Drugs
highly bound to albumin could increase the unbound fraction of fosphenytoin. Although, it is unknown whether
this could result in clinically significant effects, caution
is advised when administering CEREBYX with other drugs that significantly bind to serum
albumin. The most significant drug interactions following administration of CEREBYX are expected to occur
with drugs that interact
with phenytoin. Phenytoin is extensively bound to
serum plasma proteins and is prone to
competitive displacement. Phenytoin is metabolized by hepatic cytochrome P450 enzymes CYP2C9 and CYP2C19
and is particularly susceptible to inhibitory drug interactions because it is subject to saturable
metabolism. Inhibition of metabolism may produce
significant increases in circulating phenytoin concentrations
and enhance the risk of drug
toxicity. Monitoring of phenytoin serum levels is recommended when a
drug interaction is suspected.
Phenytoin or CEREBYX is a potent
inducer of hepatic drug-metabolizing enzymes.
7.1
Drugs that Affect Phenytoin or
CEREBYX
Table 3 includes commonly occurring
drug interactions that affect
phenytoin (the active
metabolite of
CEREBYX) concentrations. However, this list is not intended
to be inclusive or comprehensive. Individual prescribing information from relevant
drugs should be consulted.
The addition
or withdrawal of these
agents in patients
on phenytoin therapy may require
an adjustment of the phenytoin dose to achieve optimal clinical
outcome.
Table
3. Drugs That Affect Phenytoin Concentrations Newly
added table; please refer to label.
7.2
Drugs Affected by Phenytoin or CEREBYX
Table
4 includes commonly occurring drug interactions affected by phenytoin (the
active metabolite of CEREBYX). However, this list is not intended to be
inclusive or comprehensive. Individual drug package inserts should be
consulted. The addition or withdrawal of phenytoin during concomitant therapy
with these agents may require adjustment of the dose of these agents to achieve
optimal clinical outcome.
Table
4: Drugs Affected by Phenytoin Newly added table; please refer to
label.
7.3
Drug/Laboratory Test Interactions
Care
should be taken when using immunoanalytical methods to measure serum phenytoin
concentrations following CEREBYX administration.
8
Use in Specific Populations
8.1 Pregnancy
Pregnancy Exposure
Registry
There is a pregnancy exposure registry that monitors
pregnancy outcomes in women exposed
to antiepileptic drugs (AEDs),
such as CEREBYX, during
pregnancy. Physicians are advised to recommend that pregnant patients taking CEREBYX 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
In
humans, prenatal exposure
to phenytoin …
Administration of phenytoin to pregnant animals resulted
in an increased incidence of fetal
malformations and other manifestations of developmental toxicity (including embryofetal death, growth
impairment, and behavioral abnormalities) in multiple species
at clinically relevant
doses.
In
the U.S. general population, the estimated background risk of major birth defects and of miscarriage
in clinically recognized pregnancies is 2 to 4% and
15 to 20%, respectively.
Clinical Considerations
Disease-associated maternal risk
An increase in seizure
frequency may occur
during pregnancy …
Fetal/Neonatal adverse reactions
A potentially life-threatening bleeding disorder …to the mother before delivery and to the neonate
after birth.
Data
Animal data
Administration of phenytoin to pregnant rats, rabbits, and mice during
organogenesis resulted in embryofetal death, fetal malformations,
and decreased fetal growth.
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
Risk Summary
It is not known whether fosphenytoin is secreted
in human milk. Following administration of phenytoin (the
active metabolite of CEREBYX),
phenytoin is secreted
in human milk. The developmental and health
benefits of breastfeeding should be considered along with the mother’s
clinical need for CEREBYX and any potential
adverse effects on the
breastfed infant from CEREBYX or from
the underlying maternal
condition.
8.4 Pediatric Use
Newly added information:
CEREBYX is indicated for the
treatment of generalized tonic-clonic status epilepticus and prevention and treatment of seizures occurring during
neurosurgery in all pediatric age groups. Because rapid intravenous administration of CEREBYX increases the risk
of adverse cardiovascular reactions, the rate of administration should not exceed
2 mg PE/kg/min (or
150 mg PE/min, whichever
is slower) in pediatric
patients.
8.5 Geriatric Use
Additions underlined:
…
Phenytoin clearance tends to decrease with increasing age. Lower or less
frequent dosing may be required.
8.6 Renal and/or Hepatic Impairment, or Hypoalbuminemia
Newly added subsection:
The
liver is the site of biotransformation. Patients with impaired liver function,
elderly patients, or those who are gravely ill may show early toxicity.
Because
the fraction of unbound phenytoin (the active metabolite of CEREBYX) 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.
After
IV administration to patients with renal and/or hepatic disease, or in those
with hypoalbuminemia, fosphenytoin clearance to phenytoin may be increased
without a similar increase in phenytoin clearance. This has the potential to
increase the frequency and severity of adverse events.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Withdrawal of Antiepileptic Drugs
Advise
patients not to discontinue use of CEREBYX without consulting with their healthcare provider. CEREBYX 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.
Hyperglycemia
Advise
patients that CEREBYX may cause an increase in blood glucose levels.
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.
Use
in Pregnancy
Inform
pregnant women and women of childbearing potential that use of CEREBYX 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 CEREBYX, 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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