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The following serious adverse reactions are discussed in more detail in other sections of the labeling:
- Serious Dermatologic Reactions: Toxic Epidermal Necrolysis and Stevens-Johnson Syndrome [see WARNINGS AND PRECAUTIONS]
- Aplastic anemia/agranulocytosis [see WARNINGS AND PRECAUTIONS]
- Drug Reaction with Eosinophilia and Systemic Symptoms/Multiorgan Hypersensitivity [see WARNINGS AND PRECAUTIONS]
- Suicidal Behavior and Ideation [see WARNINGS AND PRECAUTIONS]
- Embryofetal Toxicity [see WARNINGS AND PRECAUTIONS]
- Abrupt Discontinuation and Seizure Risk [see WARNINGS AND PRECAUTIONS]
- Hyponatremia [see WARNINGS AND PRECAUTIONS]
- Cognitive and Motor Impairment [see WARNINGS AND PRECAUTIONS]
- Drug Interaction with Non-Nucleoside Reverse Transcriptase Inhibitors [see WARNINGS AND PRECAUTIONS]
- Liver Damage [see WARNINGS AND PRECAUTIONS]
- AV Heart Block [see WARNINGS AND PRECAUTIONS]
- Hepatic Porphyria [see WARNINGS AND PRECAUTIONS]
- Increased Intraocular Pressure [see WARNINGS AND PRECAUTIONS]
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
The most commonly reported adverse reactions (>5% in the EQUETRO group and at least twice placebo) in the pooled 3-week placebo-controlled trials in patients with acute mania associated with Bipolar I Disorder (Studies 1 and 2) were dizziness, somnolence, nausea, vomiting, ataxia, constipation, pruritus, dry mouth, asthenia, blurred vision, and speech disorder [see Clinical Studies]. The EQUETRO doses used were 400 to 1600 mg per day.
Table 2. Common Adverse Reactions Reported in Bipolar Disorder Studies 1 and 2 (Incidence > 2% and greater than placebo)
(N = 251)
(N = 248)
The following adverse reactions have been identified during post approval use of EQUETRO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Laboratory Tests: thyroid function tests (T3, T4)- decreased values
Other: lupus erythematosus-like syndrome
One 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.
Additional Adverse Reactions Associated With Carbamazepine
The following is a list of additional adverse reactions identified in clinical trials or postmarketing reports of other forms of carbamazepine and not reported above for EQUETRO. Because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or to establish a causal relationship to drug exposure.
Skin: onychomadesis, acute generalized exanthematous pustulosis (AGEP).
To report SUSPECTED ADVERSE REACTIONS, contact Validus Pharmaceuticals LLC at 1-8669VALIDUS(1-866-982-5438) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
Read the Equetro (carbamazepine xr) Side Effects Center for a complete guide to possible side effects
Pharmacokinetic Effects Of Other Drugs On EQUETRO
Drugs That Inhibit Cytochrome P450 3A4 (CYP3A4)
EQUETRO is metabolized primarily by CYP3A4 to the active carbamazepine-10,11-epoxide, which is further metabolized to the trans-diol by epoxide hydrolase. Inhibitors of CYP 3A4 and/or epoxide hydrolase can increase plasma levels of EQUETRO and its active metabolites, increasing plasma concentrations of EQUETRO and the risk of adverse reactions. It may be necessary to reduce the EQUETRO dose if used concomitantly with inhibitors of CYP3A4 and/or epoxide hydrolase. The following drugs are CYP3A4 inhibitors:
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, nefazodone, niacinamide, nicotinamide, olanzapine, omeprazole, oxybutynin, quinine, quinupristin, ticlopidine, troleandomycin, valproate, verapamil, zileuton.
Drugs That Inhibit Epoxide Hydrolase And CYP3A4
Clarithromycin, erythromycin, loxapine, quetiapine, and valproate also inhibit epoxide hydrolase, resulting in increased levels of the active metabolite carbamazepine-10,11-epoxide [see CLINICAL PHARMACOLOGY].
Drugs That Induce CYP3A4
CYP3A4 inducers can decrease serum concentrations of EQUETRO and decrease its effectiveness. It may be necessary to increase the dose of EQUETRO if used concomitantly with a CYP3A4 inducer. Such drugs include the following:
Aminophylline, cisplatin, doxorubicin, felbamate, phosphenytoin, methsuximide, phenobarbital, phenytoin, primidone, rifampin and theophylline.
Pharmacokinetic Effects Of EQUETRO On Other Drugs
EQUETRO 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 EQUETRO, monitoring of concentrations or dosage adjustment of these agents may be necessary.
EQUETRO Decreases The Concentrations Of The Following Drugs Through Induction Of Their Metabolism:
Oral Contraceptives (CYP3A4 Substrates)
EQUETRO is a strong inducer of CYP3A4. EQUETRO can increase the metabolism of certain oral contraceptives (through CYP3A4 induction), leading to significantly lower concentrations. This can cause contraceptive failure or breakthrough bleeding. Consider alternatives to oral contraceptives that are significantly affected by induction of CYP3A4; or consider alternatives to EQUETRO.
Delavirdine and other Non-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Substrates)
Through induction of CYP3A4, EQUETRO increases the metabolism of delavirdine and certain non-nucleoside reverse transcriptase inhibitors and significantly reduces the plasma concentrations of these drugs. This can cause inadequate antiviral activity, loss of virologic response, and possible resistance to delavirdine or other nonnucleoside reverse transcriptase inhibitors. Therefore, the use of EQUETRO with these non-nucleoside reverse transcriptase inhibitors is contraindicated [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS]
Nefazodone (CYP3A4 Substrate)
The use of EQUETRO is contraindicated with the use of nefazodone because the concomitant use may result in insufficient plasma concentrations of nefazodone and its active metabolite to achieve a therapeutic effect of nefazodone.
Warfarin (CYP1A2 and CYP3A4 Substrate)
Through induction of CYP1A2 and CYP3A4, EQUETRO decreases the concentration of warfarin and decreases its anticoagulant effectiveness.
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.
HIV Protease Inhibitors
Other CYP1A2 And CYP3A4 Substrates
EQUETRO induces CYP1A2 and CYP3A4, leading to decreased concentrations of drugs metabolized by CYP3A4 or CYP1A2. It may be necessary to increase the doses of such drugs when used concomitantly with EQUETRO. Drugs metabolized by CYP3A4 or CYP1A2 include the following:
Acetaminophen, albendazole, alprazolam, aprepitant, buprenorphone, bupropion, buspirone, citalopram, clobazam, clonazepam, clozapine, cyclosporin, delavirdine, desipramine, diazepam, dicumarol, dihydropyridine calcium channel blockers (e.g., felodipine), doxycycline, ethosuximide, everolimus, felbamate, glucocorticoids, haloperidol, imatinib, itraconazole, lamotrigine, levothyroxine, lorazepam, methadone, methsuxamide, mianserin, midazolam, mirtazapine, nefazodone, olanzapine, oral and other hormonal contraceptives, oxcarbazepine, paliperidone, phenytoin, praziquantel, quetiapine, risperidone, sertraline, sirolimus, tadalafil, theophylline, topiramate, tiagabine, tramadol, triazolam, tricyclic antidepressants (e.g., imipramine, amitriptyline, nortriptyline), trazodone, valproate, warfarin , ziprasidone, and zonisamide.
EQUETRO Increases The Plasma Levels Of The Following Drugs By Inhibition Of Their Metabolism:
Clomipramine, Phenytoin, and Primidone
EQUETRO can increase the concentrations of clomipramine, phenytoin, and primidone. If a patient has been titrated to a stable dosage on one of these agents in this category, and then begins treatment with EQUETRO, it may be necessary to decrease the dose of these drugs.
Phenytoin levels have been reported to increase or decrease in the presence of carbamazepine. There are multiple pharmacokinetic mechanisms for changes in phenytoin levels when used concomitantly with EQUETRO. Monitor phenytoin serum levels carefully when used concomitantly with EQUETRO.
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 co-administration of CYP3A4 inducers. There is a potential for increased cyclophosphamide toxicity when coadministered with carbamazepine.
Pharmacodynamic Drug Interactions
Monoamine Oxidase Inhibitors
Concomitant use of carbamazepine and isoniazid has been reported to increase isoniazid-induced hepatotoxicity.
The concomitant use of EQUETRO and other CNS depressants can increase the risk of respiratory depression, profound sedation, hypotension, and syncope. CNS depressants include: alcohol, opioid analgesics, benzodiazepines, tricyclic antidepressants, sedative/hypnotics, anticonvulsants, antipsychotics, antihistamines, anticholinergics, alpha and beta blockers, general anesthetics, muscle relaxants, and illicit CNS depressants. Consider reducing the dose of CNS depressants or EQUETRO when using these drugs concomitantly.
Chloroquine And Mefloquine
The anti-malarial drugs chloroquine and mefloquine can antagonize the activity of EQUETRO.
Neuromuscular Blocking Agents
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 nondepolarizing agents is unknown. Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher.
Read the Equetro Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 11/14/2016
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