Day # 58: Carbamazepine and Oxcarbazepine

Welcome back to our current theme of bipolar disorder. We are continuing our conversation on the medications classified as "mood stabilizers" and today we will discuss carbamazepine and oxcarbazepine.

Today's content level: Beginner; Intermediate

INTRODUCTION AND MECHANISM OF ACTION

•Carbamazepine = Tegretol, Carbatrol

•Oxcarbazepine = Trileptal

•These medications are anti-epileptic drugs (AED) used for seizure disorders, but also can be used for mood stabilization in bipolar disorder as well as other indications we will cover below.

Mechanism of action includes:

• Blocks voltage-dependent sodium channels. It binds the channels in their inactive conformation and stabilizes the inactivated state.

• Inhibits release of glutamate.

• Delayed onset of action (weeks) for all indications.

INDICATIONS

Carbamazepine and Oxcarbazepine

• Bipolar disorder: Carbamazepine has been shown to be an effective treatment of acute manic episodes and mixed features. A 2008 systematic review and a later meta-analysis showed comparable effectiveness to lithium, however was less tolerable from a side effect perspective. It has also been shown to be useful in bipolar maintenance therapy. 1 Oxcarbazepine was thought to be useful in acute mania and has ample low-quality data, however a 2011 meta-analysis failed to establish efficacy over placebo. 2 In spite of this relative lack of strong data for oxcarbazepine it is commonly used prior to carbamazepine since it is closely related and it has superior tolerability.

• Epilepsy: Approved for the treatment of many seizure subtypes including generalized tonic-clonic seizures, partial seizures, and mixed seizure patterns.

• Neuropathic pain: Carbamazepine is specifically approved for the treatment of pain associated with trigeminal neuralgia, but both medications are used off-label for the treatment of neuropathic pain.

• Agitation/Aggression (off-label): Carbamazepine has support for the use of preventing agitation in patients with disinhibition following traumatic brain injury. Oxcarbazepine also demonstrates efficacy in reducing impulsive aggressive episodes over placebo from aggression secondary to "any medical cause". 3

• Schizophrenia (adjunctive): May be useful as an adjunct to atypical antipsychotics in schizophrenia.

SIDE EFFECTS

•Oxcarbazepine is a structural analog of carbamazepine. Oxcarbazepine is rapidly converted to the main active metabolite and this results in significantly less side effects than those seen in carbamazepine. The possible side effects are similar between the two drugs, however typically less common and less severe in oxcarbazepine.

Common side effects include:

• Sedation (oxcarbazepine is less sedating)

• GI upset

• Dizziness and ataxia

• Vertigo, blurred vision

• Weight gain

• Benign rash

• SIADH

Serious side effects include:

• Bone marrow suppression: Can lead to leukopenia, aplastic anemia, thrombocytopenia, and agranulocytosis. There is a black-box warning for aplastic anemia and agranulocytosis.

• Rare serious rash = Stevens Johnson Syndrome (SJS) or Toxic Epidermal Necrolysis (TEN). Severe skin and systemic reaction that exists on a spectrum (TEN is more severe than SJS). Syndrome includes fever + flu-like symptoms -> painful blistering/peeling rash -> mucous membranes (such as the mouth) are often involved -> potential complications include dehydration, sepsis, pneumonia, multiple organ failure, and death. This is urgent and treatment occurs in an ICU setting or burn unit. This potential side effect should obviously be taken very seriously, however it is very rare. Individuals with the HLA-B*1502 allele are at increased risk. The FDA recommends screening for the HLA-B*1502 allele before initiating carbamazepine in patients with Asian ancestry.

• Teratogenicity: When used during pregnancy can cause craniofacial anomalies or neural tube defects such as spina bifida.

• Intraventricular cardiac conduction delay.

• Elevation of liver enzymes, causing hepatitis.

• Increased risk for suicidality.

• Overdose-> GI upset, tremor, arrhythmia, anticholinergic affects, altered mental status (confusion, stupor). May be fatal at doses as small as two times the maximum dose. Oxcarbazepine is significantly less toxic/fatal. Overdose generally benign but characterized by sedation and ataxia.

•Contraindications include bone marrow suppression, HLAB1502 subtype, and allergy to carbamazepine/oxcarbazepine and TCAs.

UNIQUE METABOLISM

•Carbamezapine is a potent inducer of the CYP3A4 enzyme and this results in MANY drug-drug interactions.

•It induces hepatic metabolism of many drugs such as valproate, lamotrigine, clonazepam, and oral contraceptives to name a few.

•Carbamazepine is also an "auto inducer" which means it induces its own metabolism. The initial half-life at start of therapy is 18-55 hours but is significantly reduced to 5-20 hours after successive doses. This requires progressive increases in dosage that are typically required during the initial months of carbamazepine therapy (dose should be increased 2-3 weeks after initiation to maintain blood levels).

LABORATORY TESTING

•The therapeutic range of carbamazepine is from 4 to 12 mcg/mL. Obtain drug levels after 3-4 doses of starting the medication or changing the dose.

Prior to starting carbamazepine:

• CBC with differential & platelets

• Liver FunctionTests (LFTs)

• Basic metabolic panel (looking for sodium levels specifically)

• Thyroid stimulating hormone

• Weight

• Pregnancy test for women of childbearing potential

Serial monitoring should include:

• CBC every month for the first two months.

• Then CBC, LFT's, BMP, and TSH every 6-12 months.

• Drug levels with changes in clinical state and after 3-4 days of a dose change.

CONCLUSIONS

Great job today. Next lesson we will discuss topiramate.

Resources for today's post include the Maudsley Prescribers Guide, Stahl's Essentials for Psychopharmacology, and Pocket Psychiatry.

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