Approved Drug Label (PDF)
5
Warnings and Precautions
Precautions
Additions and revisions underlined:
. . .
Therapy should be prescribed only after critical
benefit-to-risk appraisal in patients with a history
of cardiac conduction disturbance, including second- and third-degree
atrioventricular (AV) block; cardiac, hepatic, or renal damage; adverse
hematologic or hypersensitivity reaction to other drugs including reactions
to other anticonvulsants; or interrupted courses
of therapy with carbamazepine.
AV block, including second- and
third-degree block, has been reported following carbamazepine treatment. This occurred generally, but not solely,
in patients with underlying EKG abnormalities or risk factors for conduction
disturbances.
Hepatic effects, ranging
from slight elevations in liver enzymes
to rare cases of hepatic
failure, have been reported
(see ADVERSE REACTIONS and PRECAUTIONS, Laboratory Tests). In some cases,
hepatic effects may progress despite discontinuation of the drug. In addition,
rare instances of vanishing bile duct syndrome have been reported. This
syndrome consists of a cholestatic process with a variable clinical course
ranging from fulminant to indolent, involving the destruction and disappearance
of the intrahepatic bile ducts. Some, but not all, cases are associated with
features that overlap with other immunoallergenic syndromes such as multiorgan
hypersensitivity/ DRESS and serious dermatologic reactions. As an example,
there has been a report of vanishing bile duct syndrome
associated with Stevens-Johnson syndrome and in another
case an association with fever and eosinophilia.
Laboratory Tests
Carbatrol should be discontinued
based on clinical judgement, if indicated by newly occurring or worsening
clinical or laboratory evidence of liver dysfunction or hepatic damage,
or in the case of active liver disease.
Warnings
Additions and revisions underlined:
Retrospective case-control studies in patients of
European, Korean, and Japanese ancestry have found a moderate association
between the risk of developing hypersensitivity reactions and the presence of
HLA-A*3101, an inherited allelic variant of the HLA-A gene, in patients using
carbamazepine. These hypersensitivity reactions include SJS/TEN,
maculopapular eruptions, and Drug Reaction with Eosinophilia and
Systemic Symptoms (see DRESS/Multiorgan
hypersensitivity below).
HLA-A*3101 is expected
to be carried by more
than 15% of patients of Japanese, Native American,
Southern Indian (e.g., Tamil Nadu) and some Arabic ancestry; up to about
10% in patients of Han Chinese, Korean, European, Latin American and other
Indian ancestry; and up to about 5% in African-Americans and patients of
Thai, Taiwanese, and Chinese (Hong Kong) ancestry.
Drug Reaction with Eosinophilia and Systemic Symptoms
(DRESS)/Multiorgan Hypersensitivity
Drug Reaction with Eosinophilia and Systemic Symptoms
(DRESS), also known as multiorgan hypersensitivity, have occurred with
carbamazepine. 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, such as hepatitis, nephritis, hematologic abnormalities,
myocarditis, or myositis sometimes resembling an acute viral infection.
Anaphylaxis and Angioedema
Newly added subsection:
Rare cases of anaphylaxis and angioedema involving the larynx, glottis,
lips, and eyelids
have been reported in patients
after taking the first or subsequent doses of carbamazepine. Angioedema
associated with laryngeal edema can be fatal. If a patient develops any of
these reactions after treatment with Carbatrol, the drug should be discontinued
and an alternative treatment started.
These patients should not be rechallenged with the drug.
6
Adverse Reactions
Additions and revisions underlined:
Skin: Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome
(SJS) (see BOXED WARNING), Acute
Generalized Exanthematous Pustulosis (AGEP), pruritic and erythematous
rashes, urticaria, photosensitivity reactions, alterations in skin pigmentation, exfoliative dermatitis,
erythema multiforme and nodosum, purpura, aggravation of disseminated lupus
erythematosus, alopecia, diaphoresis, onychomadesis and hirsutism. In
certain cases, discontinuation of therapy may be necessary.
. . .
Genitourinary System:
Urinary frequency, acute urinary retention, oliguria with elevated
blood pressure, azotemia, renal failure, and impotence. Albuminuria,
glycosuria, elevated BUN, and microscopic deposits in the urine
have also been reported. There
have been rare reports of impaired male fertility and/or
abnormal spermatogenesis.
. . .
Metabolism: Fever and chills, decreased levels of plasma
calcium leading to osteoporosis, and hyperammonemia have been reported.
7
Drug Interactions
Additions and revisions underlined:
. . .
Agents that are CYP3A4 inhibitors that have been
found, or are expected, to increase plasma levels of Carbatrol include, for
example, the following:
Acetazolamide, aprepitant, azole antifungals (e.g.,
ketoconazole, itraconazole, fluconazole, voriconazole), cimetidine, ciprofloxacin, clarithromycin, dalfopristin, danazol, dantrolene, delavirdine, diltiazem, erythromycin, fluoxetine, fluvoxamine,
grapefruit juice, ibuprofen, isoniazid, loratadine, macrolides, nefazodone,
niacinamide, nicotinamide, olanzapine, omeprazole, oxybutynin, protease
inhibitors, propoxyphene, quinine, quinupristin, ticlopidine, troleandomycin,
valproate, verapamil, zileuton.
Human microsomal epoxide
hydrolase has been identified as the enzyme responsible for the formation of
the 10,11-transdiol derivative from carbamazepine-10,11 epoxide.
Coadministration of inhibitors of human microsomal epoxide hydrolase may result
in increased carbamazepine-10,11 epoxide plasma concentrations. Accordingly, the dosage
of Carbatrol should
be adjusted and/or
the plasma levels monitored when used concomitantly with loxapine,
quetiapine, or valproic acid.
. . .
Agents with Decreased
Levels in the Presence of Carbamazepine due to Induction
of Cytochrome P450 Enzymes:
Extensive changes; please refer to label
Agents with Increased
Levels in the Presence of Carbamazepine:
Extensive changes; please refer to label
8
Use in Specific Populations
Usage in Pregnancy
Additions and revisions underlined:
Carbamazepine can cause fetal
harm when administered to a pregnant
woman.
Epidemiological data suggest that there may be an
association between the use of carbamazepine during pregnancy and congenital
malformations, including spina bifida. There have also been reports that associate carbamazepine with developmental disorders
and congenital anomalies
(e.g., craniofacial defects, cardiovascular malformations, and anomalies involving various body systems).
Developmental delays have been reported. When treating or counseling women of
childbearing potential, the prescribing physician will wish to weigh
the benefits of therapy against the risks. If
this drug is used during pregnancy, or if the patient becomes
pregnant while taking
this drug, the patient
should be apprised of the potential hazard to the fetus.
Retrospective case reviews suggest that, compared
with monotherapy, there may be a higher prevalence of teratogenic effects
associated with the use of anticonvulsants in combination therapy. Therefore, if therapy is to be
continued, monotherapy may be preferable for pregnant women.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Information for Patients
Newly added information:
. . .
Patients should
be advised that serious skin reactions have been reported in association with
Carbatrol. In the event a skin reaction
should occur while
taking Carbatrol, patients
should consult with their
physician immediately (see WARNINGS).
Patients should be advised that anaphylactic reactions
and angioedema may occur during treatment
with Carbatrol (see WARNINGS). Advise patients to immediately report signs and
symptoms suggesting angioedema (swelling of the face, eyes, lips, or tongue, or
difficulty in swallowing or breathing) and to stop taking the drug until they
have consulted with their healthcare provider.
. . .
Carbatrol may interact
with some drugs.
Therefore, patients should
be advised to report to their
doctors the use of any other prescription or nonprescription medications or
herbal products.
Medication Guide
Additions and revisions underlined:
. . .
Call your healthcare provider right away if you have any of
these
symptoms:
• swelling of your face, eyes, lips, or tongue
• trouble swallowing or breathing
Approved Drug Label (PDF)
7
Drug Interactions
Agents with Decreased Levels in the Presence of Carbamazepine due to Induction of Cytochrome P450 Enzymes:
Additions and/or
revisions underlined:
Carbamazepine
is known to induce CYP1A2 and CYP3A4. Therefore, the potential exists for
interaction between carbamazepine and any agent metabolized by one (or more) of
these enzymes. Agents that have been found, or are expected to have decreased
plasma levels in the presence of Carbatrol® due to induction of CYP enzymes are
the following:
Acetaminophen,
alprazolam, amitriptyline, apixaban(8), bupropion, buspirone,
citalopram, clobazam, clonazepam, clozapine, cyclosporin, dabigatran(8),
delavirdine, desipramine, diazepam, dicumarol, doxycycline, edoxaban(8),
ethosuximide, felbamate, felodipine, glucocorticoids, haloperidol,
itraconazole, lamotrigine, levothyroxine, lorazepam, methadone, midazolam,
mirtazapine, nefazodone(3), nortriptyline, olanzapine, oral and
other hormonal contraceptives(4), oxcarbazepine, phenytoin(5),
praziquantel, protease inhibitors, quetiapine, risperidone, rivaroxaban(8),
theophylline, topiramate, tiagabine, tramadol, triazolam, trazodone(6),
valproate, warfarin(7), ziprasidone, and zonisamide.
(3)Coadministration
of carbamazepine and nefazodone may result in insufficient plasma
concentrations of nefazodone and its active metabolite to achieve a therapeutic
effect. Coadministration of carbamazepine with nefazodone is contraindicated
(see CONTRAINDICATIONS).
(4)Concomitant
use of Carbatrol® with hormonal contraceptive products (e.g., oral and
levonorgestrel subdermal implant contraceptives) may render the contraceptives
less effective because the plasma concentrations of the hormones may be
decreased. Breakthrough bleeding and unintended pregnancies have been reported
with carbamazepine. Alternative or back-up methods of contraception should be
considered.
(5)Phenytoin
has also been reported to increase in the presence of carbamazepine. Careful
monitoring of phenytoin plasma levels following co-medication with
carbamazepine is advised.
(6)Following
co-administration of carbamazepine 400mg/day with trazodone 100mg to 300mg
daily, carbamazepine reduced trough plasma concentrations of trazodone (as well
as meta- chlorophenylpiperazine [mCPP]) by 76 and 60% respectively, compared to
precarbamazepine values.
(7)
Warfarin’s anticoagulant effect can be reduced in the presence of
carbamazepine.
(8)Concomitant
use of carbamazepine with rivaroxaban, apixaban, dabigatran, and edoxaban
(direct acting oral anticoagulants) is expected to result in decreased plasma
concentrations of these anticoagulants that may be insufficient to achieve the
intended therapeutic effect. In general, coadministration of carbamazepine with
rivaroxaban, apixaban, dabigatran, and edoxaban should be avoided.
Thus,
if a patient has been titrated to a stable dosage on one of the agents in this
category, and then begins a course of treatment with Carbatrol®, it is
reasonable to expect that a dose increase for the concomitant agent may be necessary.
…
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