Drug-drug interactions: Avoid serious adverse events with mood stabilizers

Using valproic acid with clonazepam may produce absence status in patients with a history of absence-type seizures.¹⁷ Valproic acid also displaces diazepam from its plasma albumin binding sites and inhibits its metabolism.

Concomitant use of valproic acid can increase serum concentrations of other antiepileptic drugs. For example, lamotrigine levels may double,²⁴ and felbamate’s peak concentration may increase and require dosage reduction. Valproic acid may also interact with nonpsychiatric medications:

• Subtherapeutic valproic acid levels have been reported when co-administered with the antibiotic meropenem.
  
• In patients with HIV infection, valproic acid can decrease clearance of the antiretroviral zidovudine by 38%.
  
• Patients receiving rifampin for tuberculosis may need a dosage adjustment, as oral rifampin’s clearance can increase 40% with concomitant valproic acid.
  

CARBAMAZEPINE: SELF-INDUCER

Metabolized by CYP 3A4, carbamazepine may induce its own metabolism as well as the CYP 3A4 isoenzyme. Therefore inhibitors and inducers of CYP 3A4 may affect carbamazepine plasma levels.

Carbamazepine can increase plasma levels of other psychotropics including clomipramine, phenytoin, and primidone.^17,22 When used with lithium, it may increase the risk of neurotoxic side effects and confusion.²³ It can alter thyroid function when used with other anticonvulsants.

For bipolar patients with diabetes, carbamazepine can cause hyperglycemia by inducing the metabolism of oral sulfonylureas such as glipizide and tolbutamide. In women, carbamazepine decreases the reliability of oral contraceptives¹⁷ and can cause false-negative pregnancy tests.²⁴

For cancer patients, concurrent carbamazepine may induce metabolism of chemotherapy drugs such as docetaxel, estrogens, paclitaxel, progesterone, and cyclophosphamide, decreasing their efficacy.²¹ It can increase metabolism of aprepitant and granisetron—used to treat chemotherapy-related nausea—reducing plasma concentrations and possibly efficacy. Carbamazepine’s additive dopamine blockade can increase the risk of extrapyramidal symptoms when used with docetaxel or the antiemetic/antivertigo agents chlorpromazine, metoclopramide, or prochlorperazine.

Carbamazepine increases elimination of some cardiovascular drugs and may decrease the effect of antiarrhythmics such as lidocaine and quinidine; calcium channel blockers such as amlodipine, nifedipine, felodipine, nisoldipine, diltiazem, and verapamil; the beta blocker propranolol; and the vasodilator bosetan.²¹ Carbamazepine also reduces anticoagulant concentrations, and breakthrough bleeding has been reported.

(See "Out of the Pipeline−extended−release carbamazepine" for a listing of drugs that interact with this agent.)

OTHER ANTICONVULSANTS

Lamotrigine. Some concomitant CNS medications—such as carbamazepine, phenytoin or phenobarbital—reduce lamotrigine serum concentrations by as much as 50%.¹⁷ This substantial reduction may give the impression that the patient is not responding to therapeutic lamotrigine doses.

Patients taking lamotrigine with carbamazepine may be at greater risk for dizziness, diplopia, ataxia, and blurred vision because of increased serum concentration of carbamazepine’s epoxide metabolite. Valproic acid doubles lamotrigine serum concentration and increases the risk of rash, whereas lamotrigine decreases valproic acid concentration by 25%.¹⁷ Lamotrigine’s manufacturer offers special starting kits for patients taking carbamazepine or valproic acid.

Sertraline increases plasma lamotrigine concentration—but to a lesser extent than does valproic acid¹⁷ —and no dosage adjustment is needed.

Topiramate. Concomitant carbamazepine or phenytoin reduces topiramate concentration by 40% to 48%, whereas topiramate increases phenytoin concentration up to 25%. Similarly, valproic acid reduces topiramate’s concentration by 14%, while at the same time valproic acid concentration increases by 11%.¹⁷

Topiramate slightly decreases digoxin’s bioavailability and the efficacy of estrogenic oral contraceptives.^17,22

Related resources

• Cytochrome P-450 interaction checker. www.drug-interaction.com.
  
• FDA-reported drug-drug interactions. https://vm.cfsan.fda.gov/~lrd/fdinter.html.
  
• Psychiatric drug interactions. www.preskorn.com.
  
• FDA definitions Adverse event: https://www.fda.gov/cder/guidance/iche2a.pdf. Serious adverse event: https://www.fda.gov/medwatch/report/DESK/advevnt.htm.
  

• Aprepitant • Emend
  
• Bosentan • Tracleer
  
• Carbamazepine • Tegretol, others
  
• Chlorpromazine • Thorazine
  
• Clomipramine • Anafranil, others
  
• Clonazepam • Klonopin
  
• Cyclophosphamide • Cytoxan, Neosar
  
• Diazepam • Valium
  
• Diltiazem • Cardizem, others
  
• Docetaxel • Taxotere
  
• Felbamate • Felbatol
  
• Felodipine • Plendil
  
• Granisetron • Kytril
  
• Glipizide • Glucotrol
  
• Haloperidol • Haldol
  
• Indomethacin • Indocin
  
• Lamotrigine • Lamictal
  
• Meropenem • Merrem
  
• Metoclopramide • Reglan
  
• Metronidazole • Flagyl
  
• Nifedipine • Adalat, Procardia
  
• Nisoldipine • Sular
  
• Paclitaxel • Taxol, others
  
• Phenobarbital • Solfoton
  
• Phenytoin • Dilantin
  
• Piroxicam • Feldene
  
• Primidone • Mysoline
  
• Prochlorperazine • Compazine
  
• Propranolol • Inderal
  
• Rifampin • Rifadin
  
• Sertraline • Zoloft
  
• Tolbutamide • Orinase
  
• Topiramate • Topamax
  
• Valproic acid • Depakote
  
• Verapamil • Calan, others
  
• Zidovudine • Retrovir
  

Dr. Ramadan and Dr. Werder report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Preskorn has received grants or has been a consultant or speaker for Abbott Laboratories, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb Co., Merck & Co., Eisai Inc., Eli Lilly and Co., GlaxoSmithKline, Janssen Pharmaceutica, Johnson & Johnson, Novartis Pharmaceuticals, Organon, Otsuka America Pharmaceutical Inc., Pfizer Inc., Solvay Pharmaceuticals, Sanofi-Aventis, and Wyeth.