carbamazepine (Tegretol, Equetro, Epitol, Tegretol XR, Carbamazepine Chewtabs, Carbamazepine CR, Carbatrol, Teril, Carnexiv)

Dosing and uses of Tegretol, Equetro (carbamazepine)

• Adult
• Pediatric

 

Adult dosage forms and strengths

tablet, chewable (Epitol)

• 100mg

tablet, immediate-release (Tegretol)

• 200mg

tablet, extended-release (Tegretol XR)

• 100mg
• 200mg
• 400mg

capsule, extended-release (Equetro, Carbatrol)

• 100mg
• 200mg
• 300mg

oral suspension (Teril)

• 100mg/5mL

IV solution (Carnexiv)

• 10mg/mL (200mg/20mL single-dose vial)

 

Epilepsy

Indicated for the treatment of partial seizures with complex symptomatology (eg, psychomotor, temporal lobe), generalized tonic-clonic seizures (grand mal), and mixed seizure patterns, which include the seizure types listed here or other partial or generalized seizures

Maintenance dose range: 800-1200 mg/day PO in divided doses

Therapeutic range: 4-12 mg/L (16.9-50.8 micromoles/L)

Maximum dose of 1600 mg/day recommended (rarely, some patients have required 1.6-2.4 g/day)

Tablet (immediate-release)

• Initial: 200 mg PO q12hr
• Increase qWeek by 200 mg/day divided PO q6-8hr

Tablet/capsule (extended-release)

• Initial: 200 mg PO q12hr
• Increase qWeek by 200 mg/day PO divided q12hr

Oral suspension

• Initial: 10 mL (200 mg) PO q6hr
• Increase qWeek by up to 200 mg/day PO divided q6-8hr

IV solution

• Indicated as replacement therapy in adults for PO carbamazepine formulations, when PO administration is temporarily not feasible
• Approved as temporary use (ie, ≤7 days) for the following seizure types
  • Partial seizures with complex symptomatology
  • Generalized tonic-clonic seizures
  • Mixed seizure patterns which include the above, or other partial or generalized seizures
• Dose
  • The total daily dose of carbamazepine IV is 70% of the total daily PO dose from which patients are being
  • Equally divide the total daily dose of the IV in four 30-minute infusions, separated by 6 hr
  • Patients should be switched back to oral carbamazepine administration at their previous total daily oral dose and frequency of administration as soon as clinically appropriate
  • IV administration has not been studies for >7 days

Limitations of use

• Not indicated for absence seizures (including atypical absence); carbamazepine has been associated with increased frequency of generalized convulsions in these patients

 

Trigeminal Neuralgia

Indicated for pain associated with trigeminal neuralgia; beneficial results have also been reported in glossopharyngeal neuralgia; carbamazepine is not a simple analgesic and should not be used for the relief of trivial aches or pains

Maintenance dose range: 400-800 mg/day PO in divided doses; attempts to reduce or discontinue the drug should be made at least every 3 months throughout the treatment period

Maximum dose of 1200 mg/day recommended

Tablet (immediate-release)

• Initial: 200 mg/day on day 1 divided q12hr
• Increase by up to 200 mg/day in increments of 100 mg q12hr, to dose range of 400-800 mg/day divided twice daily; not to exceed 1200 mg/day

Tablet/capsule (extended-release)

• Initial (XR tablet): 200 mg/day PO on day 1 divided q12hr
• Initial (XR capsules): 200 mg PO once on the first day; may increase dose by up to 200 mg/day using increments of 100 mg q12hr to reach an effective/tolerated dose; not to exceed 1200 mg/day
• Increase by up to 200 mg/day in increments of 100 mg q12hr, to dose range of 400-800 mg/day divided twice daily; not to exceed 1200 mg/day

Oral suspension

• Initial: 200 mg PO on day 1 divided q6hr
• Increase by up to 200 mg/day in increments of 50 mg q6hr, to dose range of 400-800 mg/day divided twice daily; not to exceed 1200 mg/day

 

Bipolar Mania

Equetro

• Indicated for treatment of patients with acute manic or mixed episodes associated with bipolar I disorder
• Initial: 200 mg PO q12hr
• Increase by increments of 200 mg/day; not to exceed 1600 mg/day

 

Dosage modifications

Renal impairment

• Glomerular filtration rate <10 mL/min: Administer 75% of dose and monitor
• Peritoneal dialysis and hemodialysis: Administer 75% of dose and monitor

Hepatic impairment

• Use caution; drug is metabolized primarily in the liver

 

Restless Legs Syndrome (Off-label)

100-600 mg PO qHS for up to 5 weeks

 

Schizophrenia (Off-label)

200-1300 mg/day for 2.5-8 weeks

 

Postherpatic Neuralgia

100-200 mg PO qDay; may increase slowly to 1200 mg/day

 

Intravenous Carbamazepine (Orphan)

Orphan designation for treatment of epilepsy patients who cannot take anything by mouth

Orphan sponsor

• Lundbeck, LLC; Four Parkway North; Deerfield, IL 60015

 

Pediatric dosage forms and strengths

tablet, chewable (Epitol)

• 100mg

tablet, immediate-release (Tegretol)

• 200mg

tablet, extended-release (Tegretol XR)

• 100mg
• 200mg
• 400mg

capsule, extended-release (Equetro, Carbatrol)

• 100mg
• 200mg
• 300mg

oral suspension (Teril)

• 100mg/5mL

 

Epilepsy

Indicated for the treatment of partial seizures with complex symptomatology (eg, psychomotor, temporal lobe), generalized tonic-clonic seizures (grand mal), and mixed seizure patterns, which include the seizure types listed here or other partial or generalized seizures

<6 Years

• Initial (oral suspension): 10-20 mg/kg/day PO q6hr
• Initial (tablet): 10-20 mg/kg/day PO q8-12hr
• Maintenance: For tablets or suspension may divide frequency into 3-4 times daily not to exceed 35 mg/kg/day

6-12 Years

• Initial (oral suspension): 50 mg PO q6hr
• Initial (tablet, immediate- or extended-release): 100 mg PO q12hr; may increase qWeek by 100 mg/day
• Maintenance: 400-800 mg/day PO q6-8hr (immediate-release); q12hr (extended-release)
• Not to exceed 1000 mg/day

>12 Years

• Initial (oral suspension): 10 mL (200 mg) PO q6hr
• Initial (tablet, immediate- or extended-release tab/cap): 200 mg PO q12hr
• May increase by up to 200 mg/day qWeek; q12hr (extended-release tablet); q6-8hr (other formulations)
• 12-15 years: Dose not to exceed 1000 mg/day
• >15 years: Dose not to exceed 1200 mg/day

 

Dosage modifications

Renal impairment

• Glomerular filtration rate <10 mL/min: Administer 75% of dose and monitor
• Peritoneal dialysis and hemodialysis: Administer 75% of dose and monitor

Hepatic impairment

• Use caution; drug is metabolized primarily in the liver

 

Dosing Considerations

Important to initiate slowly by advancing dose every 5-7 days to minimize GI upset and allow autoinduction of liver enzymes to occur (autoinduction is complete at 3-5 weeks)

Children <12 years who receive >400 mg/day may be converted to Carbatrol ER at the same dose, q12hr PO

Monitor: CBC, LFTs

 

Tegretol, Equetro (carbamazepine) adverse (side) effects

>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, 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

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, neuroleptic malignant syndrome; 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

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

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

 

Warnings

Black box warnings

Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have been reported during treatment with carbamazepine; studies in patients of Chinese ancestry found a strong association between the risk of developing SJS/TEN and the presence of HLA-B*1502, an inherited allelic variant of the HLA-B gene; HLA-B*1502 is found almost exclusively in patients of Asian ancestry, with populations across broad areas of Asia producing such descendants; patients testing positive for the allele should not be treated with carbamazepine unless the benefit clearly outweighs the risk; patients with ancestry in genetically at-risk populations should be screened for the presence of HLA-B*1502 prior to initiation of treatment with carbamazepine

Aplastic anemia and agranulocytosis reported; patients with a previous history of adverse hematologic reaction to any drug may be at increased risk

 

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

May exacerbate absence seizures

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

Tegretol suspension contains sorbitol; not for administration to patients with rare hereditary problems of fructose intolerance

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

 

Pregnancy and lactation

Pregnancy category: d

Lactation: Enters breast milk; not recommended (AAP states compatible with nursing; however, adverse reactions in breastfeeding infant are possible; take into account the importance of the drug to the mother before deciding to discontinue breastfeeding or the drug)

 

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.

 

Pharmacology of Tegretol, Equetro (carbamazepine)

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 (https://www.labcorp.com/)
• Specialty Laboratories (https://www.specialtylabs.com)
• Quest (https://www.questdiagnostics.com)

 

Administration

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