Side Effects of Tegretol (carbamazepine)

Tegretol (carbamazepine) is an anti-seizure medication (anti-convulsant) used to treat simple and complex seizures and grand mal generalized seizures. 

Recurrent seizures (epilepsy) are divided into two main categories according to how much of the brain is involved, either partial or generalized epilepsy (which includes petit mal, grand mal, and myoclonic epilepsy). Seizures are called "simple" if there is no loss of consciousness and "complex" if there is. 

Tegretol works as an anticonvulsant for partial and grand mal seizures by reducing or blocking certain responses by nerves in the brain. It also is used for treating trigeminal neuralgia. One dosage form, Equetro, has been approved for treating bipolar disorder. 

Common side effects of Tegretol include

• dizziness,
• unsteadiness,
• nausea, and
• vomiting.

Serious side effects of Tegretol include

• dangerously low red and white blood cell counts,
• severe skin reactions,
• serious liver abnormalities (such as hepatitis, resulting in jaundice),
• low sodium levels,
• thyroid abnormalities, and
• an increased risk of suicidal thinking and behavior. 

Drug interactions of Tegretol include phenobarbital, phenytoin, or primidone, because lower levels of Tegretol are seen when administered with these drugs. Warfarin, phenytoin, theophylline, and valproic acid are more rapidly eliminated with Tegretol, while Tegretol levels are elevated when taken with erythromycin, cimetidine, propoxyphene, and calcium channel blockers. 

Tegretol also increases the elimination of the hormones in birth control pills and can reduce the effectiveness of birth control pills. 

Unexpected pregnancies have occurred in patients taking both Tegretol and birth control pills. If possible, Tegretol should not be used in pregnancy or while breastfeeding.

Serious side effects include dangerously low red and white blood cell counts. Severe skin reactions can occur as well as serious liver abnormalities, such as hepatitis, resulting in jaundice. Low sodium levels and thyroid abnormalities have been described.

Minor more common side effects include

• dizziness,
•  unsteadiness,
• nausea, and
• vomiting.

Rarely, patients with Asian ancestry may develop severe skin reactions to carbamazepine (Stevens-Johnson syndrome and toxic epidermal necrolysis). These patients can be identified by genetic testing, and such testing is recommended for all patients who are Asian before starting therapy.

Antiepileptic medications have been associated with an increased risk of suicidal thinking and behavior. Anyone considering the use of antiepileptic drugs must balance this risk of suicide with the clinical need.

Patients who are started on therapy should be closely observed for

• clinical worsening,
• suicidal thoughts, or
• unusual changes in behavior.

If adverse reactions are of such severity that the drug must be discontinued, the physician must be aware that abrupt discontinuation of any anticonvulsant drug in a responsive epileptic patient may lead to seizures or even status epilepticus with its life-threatening hazards.

The most severe adverse reactions have been observed in the hemopoietic system and skin, the liver, and 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 following additional adverse reactions have been reported:

Hemopoietic System

• Aplastic anemia,
• agranulocytosis,
• pancytopenia,
• bone marrow depression,
• thrombocytopenia,
• leukopenia,
• leukocytosis,
• eosinophilia,
• acute intermittent porphyria,
• variegate porphyria,
• porphyria cutanea tarda.

Skin

• Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS),
• 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.

Cardiovascular System

• Congestive heart failure,
• edema,
• aggravation of hypertension,
• hypotension,
• syncope and collapse,
• aggravation of coronary artery disease,
• arrhythmias and AV block,
• thrombophlebitis,
• thromboembolism (e.g., pulmonary embolism), 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,
• 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.

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.

Testicular atrophy occurred in rats receiving Tegretol orally from 4 to 52 weeks at dosage levels of 50 to 400 mg/kg/day. Additionally, rats receiving Tegretol 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 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,
• hyperacusis,
• neuroleptic malignant syndrome.

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 both with and without 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,
• increased intraocular pressure,
• conjunctivitis.

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,
• hyponatremia.

Decreased levels of plasma calcium have been reported. Osteoporosis has been reported.

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

Drug Abuse And Dependence

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

There has been a report of a patient who passed an orange rubbery precipitate in his stool the day after ingesting Tegretol suspension immediately followed by Thorazine solution. Subsequent testing has shown that mixing Tegretol suspension and chlorpromazine solution (both generic and brand name) as well as Tegretol suspension and liquid Mellaril, resulted in the occurrence of this precipitate.

Because the extent to which this occurs with other liquid medications is not known, Tegretol suspension should not be administered simultaneously with other liquid medicinal agents or diluents. Clinically meaningful drug interactions have occurred with concomitant medications and include (but are not limited to) the following:

Agents That May Affect Tegretol Plasma Levels

• When carbamazepine is given with drugs that can increase or decrease carbamazepine levels, close monitoring of carbamazepine levels is indicated and dosage adjustment may be required.

Agents That Increase Carbamazepine Levels

• CYP3A4 inhibitors inhibit Tegretol metabolism and can thus increase plasma carbamazepine levels.
• Drugs that have been shown, or would be expected, to increase plasma carbamazepine levels include aprepitant, cimetidine, ciprofloxacin, danazol, diltiazem, macrolides, erythromycin, troleandomycin, clarithromycin, fluoxetine, fluvoxamine, trazodone, olanzapine, loratadine, terfenadine, omeprazole, oxybutynin, dantrolene, isoniazid, niacinamide, nicotinamide, ibuprofen, propoxyphene, azoles (e.g., ketaconazole, itraconazole, fluconazole, voriconazole), acetazolamide, verapamil, ticlopidine, grapefruit juice, and protease inhibitors.
• 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 Tegretol should be adjusted and/or the plasma levels monitored when used concomitantly with loxapine, quetiapine, or valproic acid.

Agents That Decrease Carbamazepine Levels

• CYP3A4 inducers can increase the rate of Tegretol metabolism. Drugs that have been shown, or that would be expected, to decrease plasma carbamazepine levels include cisplatin, doxorubicin HCl, felbamate, fosphenytoin, rifampin, phenobarbital, phenytoin, primidone, methsuximide, theophylline, aminophylline.

Effect Of Tegretol On Plasma Levels Of Concomitant Agents

Decreased Levels of Concomitant Medications

Tegretol is a potent inducer of hepatic 3A4 and is also known to be an inducer of CYP1A2, 2B6, 2C9/19 and may therefore reduce plasma concentrations of co-medications mainly metabolized by CYP 1A2, 2B6, 2C9/19 and 3A4, through induction of their metabolism.

When used concomitantly with Tegretol, monitoring of concentrations or dosage adjustment of these agents may be necessary:

• When carbamazepine is added to aripiprazole, the aripiprazole dose should be doubled. Additional dose increases should be based on clinical evaluation. If carbamazepine is later withdrawn, the aripiprazole dose should be reduced.
• When carbamazepine is used with tacrolimus, monitoring of tacrolimus blood concentrations and appropriate dosage adjustments are recommended.
• The use of concomitant strong CYP3A4 inducers such as carbamazepine should be avoided with temsirolimus. If patients must be coadministered carbamazepine with temsirolimus, an adjustment of temsirolimus dosage should be considered.
• The use of carbamazepine with lapatinib should generally be avoided. If carbamazepine is started in a patient already taking lapatinib, the dose of lapatinib should be gradually titrated up. If carbamazepine is discontinued, the lapatinib dose should be reduced.
• Concomitant use of carbamazepine with nefazodone results in plasma concentrations of nefazodone and its active metabolite insufficient to achieve a therapeutic effect. Coadministration of carbamazepine with nefazodone is contraindicated.
• Monitor concentrations of valproate when Tegretol is introduced or withdrawn in patients using valproic acid.

In addition, Tegretol causes, or would be expected to cause, decreased levels of the following drugs, for which monitoring of concentrations or dosage adjustment may be necessary:

• acetaminophen,
• albendazole,
• alprazolam,
• aprepitant,
• buprenorphone,
• bupropion,
• citalopram,
• clonazepam,
• clozapine,
• corticosteroids (e.g., prednisolone, dexamethasone),
• cyclosporine,
• dicumarol,
• dihydropyridine calcium channel blockers (e.g., felodipine),
• doxycycline,
• ethosuximide,
• everolimus,
• haloperidol,
• imatinib,
• itraconazole,
• lamotrigine,
• levothyroxine,
•  methadone,
• methsuximide,
• mianserin,
• midazolam,
• olanzapine,
• oral and other hormonal contraceptives,
• oxcarbazepine
• paliperidone,
• phensuximide,
• phenytoin,
• praziquantel,
• protease inhibitors,
• risperidone,
• sertraline,
• sirolimus,
• tadalafil,
• theophylline,
• tiagabine,
• topiramate,
• tramadol,
• trazodone,
• tricyclic antidepressants (e.g., imipramine, amitriptyline, nortriptyline),
• valproate,
• warfarin,
• ziprasidone,
• zonisamide.

Other Drug Interactions

Cyclophosphamide is an inactive prodrug and is converted to its active metabolite in part by CYP3A. The rate of metabolism and the leukopenic activity of cyclophosphamide are reportedly increased by chronic coadministration of CYP3A4 inducers. There is a potential for increased cyclophosphamide toxicity when coadministered with carbamazepine.

• Concomitant administration of carbamazepine and lithium may increase the risk of neurotoxic side effects.
• Concomitant use of carbamazepine and isoniazid has been reported to increase isoniazid-induced hepatotoxicity.
• Alterations of thyroid function have been reported in combination therapy with other anticonvulsant medications.
• Concomitant use of Tegretol 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. Alternative or back-up methods of contraception should be considered.
• Resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents pancuronium, vecuronium, rocuronium and cisatracurium has occurred in patients chronically administered carbamazepine. Whether or not carbamazepine has the same effect on other non- depolarizing agents is unknown. Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher.