A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Cerebyx Warnings, Precautions, Pregnancy, Nursing, Abuse - Fosphenytoin
Cerebyx Warnings, Precautions, Pregnancy, Nursing, Abuse - Fosphenytoin
WARNINGS
DOSES OF CEREBYX ARE EXPRESSED AS
THEIR PHENYTOIN SODIUM EQUIVALENTS IN THIS LABELING (PE=phenytoin
sodium equivalent).
DO NOT, THEREFORE, MAKE ANY ADJUSTMENT IN THE RECOMMENDED DOSES
WHEN SUBSTITUTING CEREBYX FOR PHENYTOIN SODIUM OR
VICE VERSA.
The following warnings are based on experience
with Cerebyx or phenytoin.
Status Epilepticus Dosing Regimen
Do not administer Cerebyx at a rate
greater than 150 mg PE/min.
The dose of IV
Cerebyx (15 to 20 mg PE/kg)
that is used to treat status epilepticus is administered at a maximum
rate of 150 mg
PE/min. The typical Cerebyx infusion
administered to a 50 kg patient
would take between 5 and
7 minutes. Note that the delivery
of an identical molar
dose of phenytoin using
parenteral Dilantin
or generic phenytoin
sodium injection
cannot be accomplished in less than 15 to 20 minutes because of
the untoward cardiovascular effects that accompany the direct intravenous
administration
of phenytoin at rates greater than 50 mg/mm.
If rapid phenytoin
loading is a primary
goal, IV administration
of Cerebyx is preferred because the time
to achieve therapeutic
plasma phenytoin
concentrations is greater following IM than that following IV
administration
(see DOSAGE AND ADMINISTRATION).
Withdrawal Precipitated Seizure, Status Epilepticus
Antiepileptic drugs should not be abruptly discontinued because
of the possibility of increased seizure
frequency, including status
epilepticus. When, in the judgement of the clinician, the need
for dosage reduction,
discontinuation, or substitution
of alternative antiepileptic
medication arises, this should be done gradually. However, in the
event of an allergic or hypersensitivity
reaction, rapid substitution
of alternative therapy may be necessary. In
this case, alternative therapy
should be an antiepileptic drug not belonging to the hydantoin
chemical class.
Cardiovascular Depression
Hypotension may occur, especially after IV
administration
at high doses and high rates of administration.
Following administration
of phenytoin, severe cardiovascular
reactions and fatalities have been reported with atrial
and ventricular
conduction depression and ventricular
fibrillation.Severe complications are most commonly encountered
in elderly or gravely ill
patients.
Therefore, careful cardiac
monitoring is needed when administering IV loading doses of Cerebyx.
Reduction in rate of administration
or discontinuation of dosing may be needed. Cerebyx should be used
with caution in patients with hypotension
and severe myocardial
insufficiency.
Rash
Cerebyx should be discontinued if a skin
rash appears. If the rash
is exfoliative, purpuric, or bullous,
or if lupus erythematosus,
Stevens-Johnson syndrome, or toxic
epidermal necrolysis
is suspected, use of this drug should not be resumed and alternative
therapy should be considered.
If the rash is of a milder
type (measles-like or scarlatiniform),
therapy may be resumed after the rash
has completely disappeared. If the rash
recurs upon reinstitution of therapy,
further Cerebyx or phenytoin
administration is contraindicated.
Hepatic Injury
Cases of acute hepatotoxicity,
including infrequent cases of acute
hepatic failure, have been reported with phenytoin. These incidents
have been associated with a hypersensitivity
syndrome characterized
by fever, skin
eruptions, and lymphadenopathy,
and usually occur within the first 2 months of treatment. Other
common manifestations include jaundice,
hepatomegaly, elevated serum transaminase levels, leukocytosis,
and eosinophilia. The clinical
course of acute phenytoin
hepatotoxicity ranges from prompt
recovery to fatal outcomes.
In these patients with acute
hepatotoxicity, Cerebyx should be immediately discontinued and not
readministered.
Hemopoietic System
Hemopoietic complications, some fatal,
have occasionally been reported in association
with administration
of phenytoin. These have included thrombocytopenia, leukopenia,
granulocytopenia, agranulocytosis,
and pancytopenia
with or without bone marrow
suppression.
There have been a number
of reports that have suggested a relationship between phenytoin
and the development
of lymphadenopathy
(local or generalized), including benign
lymph node
hyperplasia, pseudolymphoma,
lymphoma, and Hodgkin’s
disease. Although a cause
and effect relationship
has not been established, the occurrence of lymphadenopathy
indicates the need to differentiate
such a condition from
other types of lymph node
pathology. Lymph node involvement
may occur with or without symptoms and signs resembling serum
sickness, e.g., fever,
rash, and liver
involvement. 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.
Alcohol Use
Acute alcohol intake
may increase plasma phenytoin
concentrations while chronic alcohol
use may decrease plasma
concentrations.
Usage in Pregnancy
Clinical:
A. Risks to Mother An
increase in seizure
frequency may occur during pregnancy
because of altered phenytoin
pharmacokinetics. Periodic measurement of plasma
phenytoin concentrations
may be valuable in the management of pregnant
women as a guide to appropriate
adjustment of dosage
(see PRECAUTIONS: Laboratory Tests). However,
postpartum restoration
of the original dosage
will probably be indicated.
B. Risks to the Fetus. If this drug
is used during pregnancy, or if the patient
becomes pregnant while
taking the drug, the patient
should be apprised of the potential
harm to the fetus.
Prenatal exposure
to phenytoin may increase
the risks for congenital malformations and other adverse developmental
outcomes. Increased frequencies of major malformations (such as
orofacial clefts and
cardiac defects), minor
anomalies (dysmorphic facial
features, nail and digit
hypoplasia), growth abnormalities (including microcephaly), and
mental deficiency
have been reported among children born to epileptic
women who took phenytoin alone or in combination with other antiepileptic
drugs during pregnancy. There have also been several reported cases
of malignancies, including neuroblastoma, in children whose mothers
received phenytoin
during pregnancy. The overall incidence
of malformations for children of epileptic
women treated with antiepileptic
drugs (phenytoin and/or others) during pregnancy is about 10%, or
two-to three- fold that
in the general population. However, the relative contributions of
antiepileptic
drugs and other factors associated with epilepsy
to this increased risk
are uncertain and in most cases it has not been possible to attribute
specific developmental
abnormalities to particular antiepileptic
drugs.
Patients should consult with their physicians to weigh the risks
and benefits of phenytoin
during pregnancy.
C. Postpartum Period. A potentially life-threatening
bleeding disorder related
to decreased levels
of vitamin K-dependent
clotting factors may
occur in newborns exposed to phenytoin in utero. This drug-induced
condition can be prevented
with vitamin K administration
to the mother before
delivery and to the
neonate after birth.
Preclinical: Increased frequencies of malformations
(brain, cardiovascular, digit, and skeletal
anomalies), death, growth
retardation, and functional
impairment (chromodacryorrhea,
hyperactivity, circling) were observed among the offspring of rats
receiving fosphenytoin during pregnancy. Most of the adverse effects
on embryo-fetal development
occurred at doses of 33 mg
PE/kg or higher (approximately 30% of the maximum
human loading dose or higher
on a mg/m2 basis), which produced peak maternal plasma
phenytoin concentrations
of approximately 20 µg/mL or greater. Maternal toxicity
was often associated with these doses and plasma concentrations,
however, there is no evidence
to suggest that the developmental effects were secondary
to the maternal effects.
The single occurrence of a rare brain
malformation at
a non-maternotoxic dose
of 17 mg PE/kg (approximately 10% of the maximum
human loading
dose on a mg/m2
basis) was also considered drug-induced. The developmental
effects of fosphenytoin in rats were similar to those which have
been reported following administration of phenytoin
to pregnant rats.
No effects on embryofetal development
were observed when rabbits were given up to 33 mg
PE/kg of fosphenytoin (approximately 50% of the maximum
human loading dose on a
mg/m2 basis) during pregnancy. Increased resorption and
malformation rates
have been reported following administration
of phenytoin doses of 75 mg/kg or higher (approximately 120% of
the maximum human
loading dose or higher on a mg/m2 basis) to pregnant
rabbits.
PRECAUTIONS
General: (Cerebyx specific)
Sensory Disturbances
Severe burning, itching, and/or paresthesia
were reported by 7 of 16 normal volunteers administered IV
Cerebyx at a dose of 1200
mg PE at the maximum rate
of administration
(150 mg
PE/min). The severe sensory
disturbance lasted
from 3 to 50 minutes in 6 of these subjects and for 14 hours in
the seventh subject. In some
cases, milder sensory
disturbances persisted for as long as 24 hours. The location of
the discomfort varied among subjects with the groin
mentioned most frequently as an area
of discomfort. In a separate
cohort of 16 normal
volunteers (taken from 2 other studies) who were administered IV
Cerebyx at a dose of 1200 mg
PE at the maximum rate
of administration
(150 mg PE/min), none experienced
severe disturbances, but most experienced mild to moderate itching
or tingling.
Patients administered Cerebyx at doses of 20 mg
PE/kg at 150 mg PE/min are
expected to experience
discomfort of some degree. The occurrence and intensity of the discomfort
can be lessened by slowing or temporarily stopping the infusion.
The effect of continuing
infusion unaltered
in the presence of these sensations is unknown. No
permanent sequelae
have been reported thus far. The pharmacologic basis
for these positive
sensory phenomena is
unknown, but other phosphate
ester drugs, which deliver
smaller phosphate loads, have been associated with burning, itching,
and/or tingling predominantly in the groin
area.
Phosphate Load
The phosphate load
provided by Cerebyx (0.0037 mmol phosphate/mg PE Cerebyx) should
be considered when treating patients who require phosphate restriction,
such as those with severe
renal impairment.
IV Loading in Renal and/or Hepatic Disease or in Those With
Hypoalbuminemia
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 (see CLINICAL
PHARMACOLOGY: Special Populations, and DOSAGE
AND ADMINISTRATION: Dosing in Special Populations).
General: (phenytoin associated)
Cerebyx is not indicated for the treatment
of absence seizures.
A small percentage of individuals who have been treated with phenytoin
have been shown to metabolize
the drug slowly. Slow metabolism
may be due to limited enzyme
availability and
lack of induction; it appears to be genetically determined.
Phenytoin and other hydantoins are contraindicated in patients
who have experienced phenytoin
hypersensitivity. Additionally, caution should be exercised if using
structurally similar (e.g., barbiturates, succinimides, oxazolidinediones,
and other related compounds) in these same patients.
Phenytoin has been infrequently associated with the exacerbation
of porphyria. Caution should be exercised when Cerebyx is used in
patients with this disease.
Hyperglycemia, resulting from phenytoin’s inhibitory
effect on insulin release,
has been reported. Phenytoin may also raise the serum glucose concentrations
in diabetic patients.
Plasma concentrations of phenytoin sustained above the optimal range
may produce confusional states referred to as “delirium,” “psychosis,”
or “encephalopathy,” or rarely, irreversible cerebellar dysfunction.
Accordingly, at the first sign
of acute toxicity,
determination
of plasma phenytoin concentrations is recommended (see Laboratory
Tests below). Cerebyx dose
reduction is indicated
if phenytoin concentrations
are excessive; if symptoms persist, administration
of Cerebyx should be discontinued.
The liver is the primary
site of biotransformation
of phenytoin; patients with impaired liver
function, elderly patients, or those who are gravely ill may show
early signs of toxicity.
Phenytoin and other hydantoins are not indicated for seizures due
to hypoglycemic or other metabolic causes. Appropriate diagnostic
procedures should be performed as indicated.
Phenytoin has the potential
to lower serum folate
bevels.
Laboratory Tests
Phenytoin doses are usually selected to attain therapeutic
plasma total phenytoin
concentrations of 10 to 20 µg/mL,(unbound phenytoin
concentrations of ito 2 µg/mL). Following Cerebyx administration,
it is recommended that phenytoin
concentrations not be monitored until conversion
to phenytoin is essentially complete. This occurs within approximately
2 hours after the end of
IV infusion
and 4 hours after lM injection.
Prior to complete conversion, commonly used immunoanalytical techniques,
such as TDx®/TDxFLx™ (fluorescence polarization) and Emit®
2000 (enzyme multiplied), may significantly overestimate plasma
phenytoin concentrations
because of cross-reactivity with fosphenytoin. The error
is dependent on plasma phenytoin
and fosphenytoin concentration
(influenced by Cerebyx dose, route and rate
of administration, and time
of sampling relative
to dosing), and analytical method. Chromatographic assay
methods accurately quantitate phenytoin
concentrations in biological
fluids in the presence of fosphenytoin. Prior to complete conversion,
blood samples for phenytoin
monitoring should be collected in tubes containing EDTA
as an anticoagulant to minimize ex vivo conversion
of fosphenytoin to phenytoin. However, even with specific
assay methods, phenytoin
concentrations measured before conversion of fosphenytoin is complete
will not reflect phenytoin
concentrations ultimately achieved.
Drug Interactions
See DRUG INTERACTIONS section.
Drug/Laboratory Test Interactions
See DRUG INTERACTIONS: Drug/Laboratory
Test Interactions subsection.
Carcinogenesis, Mutagenesis, Impairment of Fertility
The carcinogenic
potential of fosphenytoin
has not been studied. Assessment of the carcinogenic
potential of phenytoin
in mice and rats is ongoing.
Structural chromosome
aberration frequency
in cultured V79 Chinese hamster lung cells was increased by exposure
to fosphenytoin in the presence of metabolic activation. No
evidence of mutagenicity
was observed in bacteria (Ames test) or Chinese hamster
lung cells in vitro,
and no evidence for clastogenic
activity was observed
in an in vivo mouse
bone marrow micrOnucleus
test.
No effects on fertility
were noted in rats of either sex
given fosphenytoin. Maternal toxicity
and altered estrous cycles, delayed mating, prolonged gestation
length, and developmental
toxicity were observed
following administration of fosphenytoin during mating, gestation,
and lactation at doses
of 50 mg PE/kg or higher (approximately 40% of the maximum
human loading
dose or higher on a mg/m2 basis).
Pregnancy - Category D: (see WARNINGS)
Use in Nursing Mothers
It is not known whether fosphenytoin is excreted in human
milk.
Following administration
of Dilantin, phenytoin
appears to be excreted in low concentrations in human
milk. Therefore, breast-feeding is not recommended for women receiving
Cerebyx.
Pediatric Use
The safety of Cerebyx in pediatric
patients has not been established.
Geriatric Use
No systematic studies
in geriatric patients have been conducted. Phenytoin clearance tends
to decrease with increasing age
(see CLINICAL PHARMACOLOGY: Special
Populations).
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