carbamazepine (Rx)

>10%

Ataxia (15%)

Dizziness (44%)

Drowsiness (32%)

Nausea (29%)

Vomiting (18%)

1-10%

Dry mouth (8%)

Rare

MI

Stevens-Johnson syndrome

Hepatic failure

Punctate cortical lens opacities

Syndrome of inappropriate antidiuretic hormone secretion (SIADH)

Frequency Not Defined

Hemopoietic system: Aplastic anemia, agranulocytosis, pancytopenia, bone marrow depression, thrombocytopenia, leukopenia, leukocytosis, eosinophilia, anemia, acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda

Skin: Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) (see Black Box Warnings), 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, generalized exanthematous pustulosis, and onychomadesis

Cardiovascular system: Congestive heart failure, edema, aggravation of hypertension, hypotension, syncope and collapse, aggravation of coronary artery disease, arrhythmias and AV block, thrombophlebitis, thromboembolism, and adenopathy or lymphadenopathy

Liver: Abnormalities in liver function tests, cholestatic and hepatocellular jaundice, hepatitis; very rare cases of hepatic failure

Pancreatic: Pancreatitis

Respiratory System: Pulmonary hypersensitivity characterized by fever, dyspnea, pneumonitis, or pneumonia

Genitourinary System: Urinary frequency, acute urinary retention, oliguria with elevated blood pressure, azotemia, renal failure, and impotence (rare reports of impaired male fertility and/or abnormal spermatogenesis)

Laboratory: Albuminuria, glycosuria, elevated BUN, decreased plasma calcium, and microscopic deposits in the urine, decreased values of thyroid function tests

Nervous system: Dizziness, drowsiness, disturbances of coordination, confusion, headache, fatigue, blurred vision, visual hallucinations, transient diplopia, oculomotor disturbances, nystagmus, speech disturbances, abnormal involuntary movements, peripheral neuritis and paresthesias, depression with agitation, talkativeness, tinnitus, hyperacusis, isolated cases of neuroleptic malignant syndrome

Digestive system: Nausea, vomiting, gastric distress and abdominal pain, diarrhea, constipation, anorexia, and dryness of the mouth and pharynx, including glossitis, and stomatitis, liver damage

Eyes: Scattered punctate cortical lens opacities, increased intraocular pressure as well as conjunctivitis

Musculoskeletal system: Aching joints and muscles, and leg cramps

Metabolism: Fever and chills; SIADH; cases of frank water intoxication, with decreased serum sodium (hyponatremia) and confusion; decreased levels of plasma calcium leading to osteoporosis

Immune system disorders: Hypogammaglobulinemia

Other: Multiorgan hypersensitivity reactions occurring days to weeks or months after initiating treatment have been reported in rare cases, signs or symptoms may include fever, skin rashes, vasculitis, lymphadenopathy, disorders mimicking lymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly and abnormal liver function tests

Contraindications

Documented hypersensitivity

History of bone marrow suppression

Administration of MAO inhibitors within last 14 days

Coadministration with nefazodone; carbamazepine decreases plasma levels of nefazodone and its active metabolite

Coadministration with NNRTIs (eg, delavirdine, efavirenz, etravirine, nevirapine, rilpivirine); carbamazepine induces CYP3A4 and may substantially reduce NNRTI serum concentration

Jaundice, hepatitis

Pregnancy (especially first trimester: risk of fetal carbamazepine syndrome)

Cautions

Monitor for notable changes in behavior that might indicate suicidal thoughts or depression and notify healthcare provider immediately if behavioral changes observed

Discontinue if significant bone marrow depression occurs

Withdraw gradually

Increased risk of agranulocytosis and aplastic anemia

May cause ECG abnormalities; use caution in patients with conduction abnormalities; AV heart block, including second and third degree block, reported following carbamazepine treatment; effect occurred generally, but not solely, in patients with underlying EKG abnormalities or risk factors for conduction disturbances

May exacerbate absence seizures; in the event of allergic or hypersensitivity reaction, more rapid substitution of alternative therapy may be necessary

Bipolar mania: Efficacy inconsistent; APA recommends use after failure of or if there is resistance to lithium and valproate

May cause psychosis/confusion/agitation; elderly patients are at greater risk

May render oral contraceptives ineffective

Higher risk of potentially fatal skin reactions (SJS/TEN) in patients of Asian ancestry (genetic testing recommended); increased risk of developing hypersensitivity reactions with presence of HLAA*3101 or HLA-B*1502, inherited allelic variants of the HLA-A and HLA-B gene (see Pharmacogenomics in the Pharmacology section);

Hyponatremia may occur and appears to be a result of SIADH; may be dose-related and elderly individuals are at greater risk

Associated with hypotension, bradycardia, AV block, and signs and symptoms of HF

Fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), reported

Not a simple analgesic; do not use to relieve minor aches and pains

Suspension formulation contains sorbitol; not for administration to patients with rare hereditary problems of fructose intolerance

AV heart block, including second and third degree block, reported following carbamazepine treatment; effect occurred generally, but not solely, in patients with underlying EKG abnormalities or risk factors for conduction disturbances

Rare cases of anaphylaxis and angioedema involving larynx, glottis, lips, and eyelids reported with first or subsequent doses; angioedema associated with laryngeal edema can be fatal; if a patient develops reactions after treatment discontinue therapy and start alternative treatment; patients should not be rechallenged with drug

Mild anticholinergic activity; use caution in patients with snesitivity to anticholinergic effects

Hepatic effects

• Hepatic effects reported ranging from slight elevations in liver enzymes to rare cases of hepatic failure
• In some cases, hepatic effects may progress despite discontinuation
• Rare instances of vanishing bile duct syndrome reported; consists of a variable clinical course ranging from fulminant to indolent, involving the destruction and disappearance of the intrahepatic bile ducts
• Some cases associated other immunoallergenic syndromes (eg, multiorgan hypersensitivity [DRESS syndrome], 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
• Baseline and periodic evaluations of liver function, particularly in patients with history of liver disease, must be performed during treatment with this drug since liver damage may occur; drug should be discontinued immediately in cases of aggravated liver dysfunction or active liver disease

Caution

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), during pregnancy; encourage women who receive therapy during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry; this can be done by calling the toll-free number 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org, and must be done by the patient herself

Therapy can cause fetal harm when administered to a pregnant woman; an association between use of drug during pregnancy and congenital malformations, including spina bifida and malformations involving other body systems (e.g., craniofacial defects and cardiovascular malformations) shown; developmental delays reported

Women of childbearing potential should be informed of potential risk to fetus

Consideration should be given to discontinuing therapy in women who are pregnant or attempting to become pregnant if benefits of discontinuation outweigh risks of recurrent seizures; women with epilepsy should not discontinue therapy abruptly due to risk of status epilepticus and less severe seizures which may be life-threatening

There have been a few cases of neonatal seizures and/or respiratory depression associated with maternal carbamazepine in combination with other antiepileptic drugs; a few cases of neonatal vomiting, diarrhea, and/or decreased feeding have also been reported in association with maternal carbamazepine use; these symptoms may represent a neonatal withdrawal syndrome

Tests to detect birth defects using currently accepted procedures should be considered a part of routine prenatal care in childbearing women receiving carbamazepine; evidence suggests that folic acid supplementation prior to conception and during first trimester of pregnancy decreases risk for congenital neural tube defects in general population; not known whether risk of neural tube defects in offspring of women receiving therapy is reduced by folic acid supplementation, but dietary folic acid supplementation both prior to conception and during pregnancy should be recommended for patients in therapy

Animal data

• In animal studies, therapy during pregnancy resulted in developmental toxicity, including increased incidences of fetal malformations

Lactation

Drug and its epoxide metabolite are excreted in human milk; there are no data to assess effects of drug or its metabolites on milk production, or on breastfed infant, of mothers taking drug; developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for drug and any potential adverse effects on the breastfed infant from drug or from underlying maternal condition

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Stabilizes inactivated state of sodium channels, thereby making neurons less excitable

May reduce activity of nucleus ventralis of the thalamus or decrease synaptic transmission or summation of temporal stimulation leading to neuronal discharge

Absorption

Bioavailability: 85% (oral suspension)

Peak serum time: 4.5 hr (immediate-release tablets); 3-12 hr (extended-release tablets); 1.5 hr (oral suspension)

Distribution

Protein bound: 75-90%

Vd: 1.5 L/kg (neonates); 1.9 L/kg (children); 0.59-2 L/kg (adults)

Metabolism

Via hepatic CYP3A4

Metabolites: Carbamazepine 10,11-epoxide

Enzymes induced: CYP1A2, CYP2C9, CYP3A4

Elimination

Half-life: 25-65 hr (initial dosing); decreases to 10-20 hr after autoinduction; 35-40 hr (extended release)

Excretion: Urine (72%); feces (28%)

Pharmacogenomics

HLA-B*1502

• It is estimated that 1 in 20 patients with HLA-B*1502 will have a severe dermatologic reaction (eg, TEN, SJS) when taking carbamazepine
• This allele occurs almost exclusively in patients with ancestry across broad areas of Asia, including Han Chinese, Filipinos, Malaysians, South Asian Indians, and Thais

HLA-A*3101

• 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 HLAA*3101, an inherited allelic variant of the HLA-A gene, in patients using carbamazepine; these hypersensitivity reactions include Stevens Johnson syndrome and toxic epidermal necrolysis
• HLA-A*3101 is expected to be carried by more than 15% of patients of Japanese, Native American, Southern Indian (eg, 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

Genetic testing laboratories

• The following companies provide genetic testing for HLA variants
• Kashi Clinical Laboratories (www.kashilab.com)
• LabCorp (http://www.labcorp.com/)
• Specialty Laboratories (http://www.specialtylabs.com)
• Quest (http://www.questdiagnostics.com)

Oral Administration

Take with food

Do not chew, crush, or cut extended-release tablets

IV Preparation

For IV use only

Must be diluted with 100 mL of a compatible diluent before infusion (ie, 0.9% NaCl, lactated Ringer’s solution, or D%W)

Transfer measured dose to 100 mL bag of compatible solution

Inspected visually for particulate matter, cloudiness, or discoloration prior to administration; if any of these are present, discard the solution

IV Administration

Administer IV over 30 minutes

Storage

IV (before dilution)

• Store at 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F)

IV (after dilution)

• Controlled room temperature (20-25°C [68-77°F]): Maximum of 4 hr
• Refrigerated (2-8°C [36-46°F]): Maximum of 24 hr