General

The most severe adverse reactions previously observed with carbamazepine were reported in the hemopoietic system and skin (see BOXED WARNING) and in the cardiovascular system.

The most frequently observed adverse reactions, particularly during the initial phases of therapy, are dizziness, drowsiness, unsteadiness, nausea, and vomiting. To minimize the possibility of such reactions, therapy should be initiated at the lowest dosage recommended.

The most commonly observed adverse experiences (5% and at least twice placebo) seen in association with the use of EQUETRO® (400 to 1600 mg/day, dose adjusted in 200 mg daily increments in week 1 in Bipolar I Disorder in the double-blind, placebo-controlled trials of 3 weeks' duration) are included in Table 1 below:

Table 1: Most Common Adverse Events Reported in Double-Blind, Placebo-Controlled Trials (Incidence ≥ 5% and at Least Twice Placebo)

Adverse Events	EQUETRO® (N = 251)	Placebo (N = 248)
DIZZINESS	44%	12%
SOMNOLENCE	32%	13%
NAUSEA	29%	10%
VOMITING	18%	3%
ATAXIA	15%	0%
PRURITUS	8%	2%
DRY MOUTH	8%	3%
AMBLYOPIA*	6%	2%
SPEECH DISORDER	6%	0%
* Reported as blurred vision

EQUETRO® and placebo-treated patients from two of the double-blind, placebo-controlled studies were enrolled in a 6-month open-label study. Table 2 below summarizes the most common adverse events with an incidence of 5% or more.

Table 2: Most Common Adverse Events Reported in Open-Label Trials (Incidence ≥ 5%)

Body as a Whole	% events reported	Nervous System	% events reported
Headache	22%	Dizziness	16%
Infection	12%	Somnolence	12%
Pain	12%	Amnesia^	8%
Asthenia	8%	Anxiety	7%
Accidental Injury	7%	Depression*	7%
Chest Pain	5%	Manic Depressive Reaction	7%
Back Pain	5%	Ataxia	5%
Digestive		Skin Appendages
Diarrhea	10%	Rash	13%
Dyspepsia	10%	Pruritus	5%
Nausea	10%
Constipation	5%
^ Amnesia includes poor memory, forgetful, and memory disturbance. * Depression includes suicidal ideation.

Other significant adverse events seen in less than 5% of patients include: Suicide Attempt, Manic Reaction, Insomnia, Nervousness, Depersonalization and Extrapyramidal Symptoms, Infections (Fungal, Viral, Bacterial), Pharyngitis, Rhinitis, Sinusitis, Bronchitis, Urinary Tract Infection, Leukopenia and Lymphadenopathy, Liver Function Tests Abnormal, Edema, Peripheral Edema, Allergic Reaction, Photosensitivity Reaction, Alopecia, Diplopia, and Ear Pain.

The following additional adverse reactions were previously reported with carbamazepine:

Hemopoietic System: Aplastic anemia, agranulocytosis, pancytopenia, bone marrow depression, thrombocytopenia, leukopenia, leukocytosis, eosinophilia, acute intermittent porphyria.

Skin: Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) (see BOXED WARNING), pruritic and erythematous rashes, urticaria, photosensitivity reactions, alterations in skin pigmentation, exfoliative dermatitis, erythema multiforme and nodosum, purpura, aggravation of disseminated lupus erythematosus, alopecia, and diaphoresis. In certain cases, discontinuation of therapy may be necessary. Isolated cases of hirsutism have been reported, but a causal relationship is not clear.

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. Some of these cardiovascular complications have resulted in fatalities. Myocardial infarction has been associated with other tricyclic compounds.

Liver: Abnormalities in liver function tests, cholestatic and hepatocellular jaundice, hepatitis.

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. Albuminuria, glycosuria, elevated BUN, and microscopic deposits in the urine have also been reported.

Testicular atrophy occurred in rats receiving carbamazepine orally from 4–52 weeks at dosage levels of 50–400 mg/kg/day. Additionally, rats receiving carbamazepine in the diet for 2 years at dosage levels of 25, 75, and 250 mg/kg/day had a dose-related incidence of testicular atrophy and aspermatogenesis. In dogs, it produced a brownish discoloration, presumably a metabolite, in the urinary bladder at dosage levels of 50 mg/kg/day and higher. Relevance of these findings to humans is unknown.

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, and hyperacusis.

There have been reports of associated paralysis and other symptoms of cerebral arterial insufficiency, but the exact relationship of these reactions to the drug has not been established.

Isolated cases of neuroleptic malignant syndrome have been reported with concomitant use of psychotropic drugs.

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, as well as conjunctivitis, have been reported. Although a direct causal relationship has not been established, many phenothiazines and related drugs have been shown to cause eye changes.

Musculoskeletal System: Aching joints and muscles, and leg cramps.

Metabolism: Fever and chills and inappropriate antidiuretic hormone (ADH) secretion syndrome have been reported. Cases of frank water intoxication, with decreased serum sodium (hyponatremia) and confusion, have been reported in association with carbamazepine use (see PRECAUTIONS, Laboratory Tests). Decreased levels of plasma calcium have been reported.

Other: Isolated cases of a lupus erythematosus-like syndrome have been reported. There have been occasional reports of elevated levels of cholesterol, HDL cholesterol, and triglycerides in patients taking anticonvulsants.

A case of aseptic meningitis, accompanied by myoclonus and peripheral eosinophilia, has been reported in a patient taking carbamazepine in combination with other medications. The patient was successfully dechallenged, and the meningitis reappeared upon rechallenge with carbamazepine.

Drug Abuse And Dependence

No evidence of abuse potential has been associated with carbamazepine, nor is there evidence of psychological or physical dependence in humans.

Read the Equetro (carbamazepine xr) Side Effects Center for a complete guide to possible side effects »

Clinically meaningful drug interactions have occurred with concomitant medications and include, but are not limited to, the following:

Agents Highly Bound to Plasma Protein

Carbamazepine is not highly bound to plasma proteins; therefore, administration of EQUETRO® to a patient taking another drug that is highly protein-bound should not cause increased free concentrations of the other drug.

Agents that Inhibit Cytochrome P450 Isoenzymes and/or Epoxide Hydrolase

Carbamazepine is metabolized mainly by cytochrome P450 (CYP) 3A4 to the active carbamazepine-10,11-epoxide, which is further metabolized to the trans-diol by epoxide hydrolase. Therefore, the potential exists for interaction between carbamazepine and any agent that inhibits CYP3A4 and/or epoxide hydrolase. Agents that are CYP3A4 inhibitors that have been found, or are expected, to increase plasma levels of EQUETRO® are the following:

Acetazolamide, azole antifungals, cimetidine, clarithromycin⁽¹⁾, dalfopristin, danazol, delavirdine, diltiazem, erythromycin⁽¹⁾, fluoxetine, fluvoxamine, grapefruit juice, isoniazid, itraconazole, ketoconazole, loratadine, nefazodone, niacinamide, nicotinamide, protease inhibitors, propoxyphene, quinine, quinupristin, troleandomycin, valproate⁽¹⁾, verapamil, zileuton.

Thus, if a patient has been titrated to a stable dosage of EQUETRO® , and then begins a course of treatment with one of these CYP3A4 or epoxide hydrolase inhibitors, it is reasonable to expect that a dose reduction for EQUETRO® may be necessary.

Agents that Induce Cytochrome P450 Isoenzymes

Carbamazepine is metabolized by CYP3A4. Therefore, the potential exists for interaction between carbamazepine and any agent that induces CYP3A4. Agents that are CYP inducers that have been found, or are expected, to decrease plasma levels of EQUETRO® are the following:

Cisplatin, doxorubicin HCl, felbamate, rifampin, phenobarbital, phenytoin⁽²⁾, primidone, methsuximide, and theophylline.

Thus, if a patient has been titrated to a stable dosage on EQUETRO® and then begins a course of treatment with one of these CYP3A4 inducers, it is reasonable to expect that a dose increase for EQUETRO® may be necessary.

Agents with Decreased Levels in the Presence of Carbamazepine Due to Induction of Cytochrome P450 Enzymes

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 EQUETRO® due to induction of CYP enzymes are the following:

Acetaminophen, alprazolam, amitriptyline, bupropion, buspirone, citalopram, clobazam, clonazepam, clozapine, cyclosporin, delavirdine, desipramine, diazepam, dicumarol, doxycycline, ethosuximide, felbamate, felodipine, glucocorticoids, haloperidol, itraconazole, lamotrigine, levothyroxine, lorazepam, methadone, midazolam, mirtazapine, nortriptyline, olanzapine, oral contraceptives⁽³⁾, oxcarbazepine, phenytoin⁽⁴⁾, praziquantel, protease inhibitors, quetiapine, risperidone, theophylline, topiramate, tiagabine, tramadol, triazolam, trazodone⁽⁵⁾, valproate, warfarin⁽⁶⁾ , ziprasidone, and zonisamide.

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 EQUETRO® , it is reasonable to expect that a dose increase for the concomitant agent may be necessary.

Agents with Increased Levels in the Presence of Carbamazepine

EQUETRO® increases the plasma levels of the following agents:

Clomipramine HCl, phenytoin⁽⁷⁾, and primidone.

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 the treatment with EQUETRO® , it is reasonable to expect that a dose decrease for the concomitant agent may be necessary.

Pharmacological/Pharmacodynamic Interactions with Carbamazepine

Concomitant administration of carbamazepine and lithium may increase the risk of neurotoxic side effects.

Given the anticonvulsant properties of carbamazepine, EQUETRO® may reduce the thyroid function, as has been reported with other anticonvulsants. Additionally, anti-malarial drugs, such as chloroquine and mefloquine, may antagonize the activity of carbamazepine.

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 EQUETRO® , it is reasonable to expect that a dose adjustment may be necessary. Because of its primary CNS effect, caution should be used when EQUETRO® is taken with other centrally acting drugs and alcohol.

REFERENCES

⁽¹⁾ Also inhibits epoxide hydrolase, resulting in increased levels of the active metabolite carbamazepine- 10,11-epoxide.
⁽²⁾ Phenytoin plasma levels have also been reported to increase and decrease in the presence of carbamazepine; see below.
⁽³⁾ Breakthrough bleeding has been reported among patients receiving concomitant oral contraceptives, and their reliability may be adversely affected.
⁽⁴⁾ 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.
⁽⁵⁾ Following co-administration of carbamazepine 400 mg/day with trazodone 100 mg to 300 mg daily, carbamazepine reduced the plasma concentration of trazodone (as well as meta-chlorophenylpiperazine [mCPP]) by 76% and 60% respectively, compared to pre-carbamazepine values.
⁽⁶⁾ Warfarin’s anticoagulant effect can be reduced in the presence of carbamazepine.
⁽⁷⁾ Phenytoin has also been reported to decrease in the presence of carbamazepine. Careful monitoring of phenytoin plasma levels following co-medication with carbamazepine is advised.

Last reviewed on RxList: 8/31/2012
This monograph has been modified to include the generic and brand name in many instances.