Can venlafaxine (Efexor) be combined with reboxetine (Edronax)?/nWhat concentration of venlafaxine

Fråga: Can venlafaxine (Efexor) be combined with reboxetine (Edronax)?

What concentration of venlafaxine might be toxic?

A 27-year-old man has major depressive disorder with lack of energy and inertia as dominating symptoms. On previous therapy with mirtazapine (Remeron) he put on quite some weight. Prior combination with mirtazapine and SSRI did not have sufficient effect.

While on venlafaxine (Efexor Depot) 225 mg/day he had a plasma concentration of 381 nmol/L of venlafaxine and 385 nmol/L of O-desmethylvenlafaxine (sum 766 nmol/L, therapeutic window for the sum 750-1530 nmol/L). The venlafaxine dose has since been raised to 300 mg daily.

Sammanfattning: There is neither evidence nor pharmacological rationale for the combination of venlafaxine and reboxetine. It seems more plausible to titrate the dose of venlafaxine to achieve adequate plasma concentrations. The range from the upper limit of the therapeutic window to toxicity seems fairly wide (at least 10-fold).

Svar: Venlafaxine inhibits serotonin reuptake, and at higher concentrations also noradrenaline and to some extent dopamine reuptake (1). Reboxetine is a selective noradrenaline reuptake inhibitor (NRI) (2). Thus it is uncertain whether the combination of the two would be superior to a higher dosage of venlafaxine.

Venlafaxine has hypertension as a dose dependant side effect with an incidence of 13% at doses higher than 300 mg/day (3). Reboxetine has, in spite of its mechanism of action, not hypertension as a listed side effect, but rather orthostatic hypotension (2,3).

There is one case report of serotonergic syndrome after combining venlafaxine (300 mg) with the two NRIs reboxetine (8 mg) and maprotiline (150 mg) (4).

Reboxetine is mainly metabolised by CYP3A4 and has a weak inhibitory effect on both CYP2D6 and CYP3A4, but it is uncertain whether this has any relevance at the doses used in clinical practice. Venlafaxine is metabolised to the active metabolite O-desmethylvenlafaxine (ODV) by CYP2D6 and to the inactive metabolites N-desmethylvenlafaxine and O,N-didesmethylvenlafaxine by CYP3A4. Venlafaxine is a weak inhibitor of CYP2D6 (5).

Reboxetine has been used as an adjunct to venlafaxine in an open study. No serious adverse events were noted and all twelve patients completed the six-week study. Increased sweating, dry mouth and tremor were the side effects reported. Six patients had remission of depression and two had a partial response. The doses used were 156 +/- 68 mg of venlafaxine and 2-8 mg of reboxetine, no concentrations reported (6).

The answer to the toxicological question is more difficult, but there are case reports of survivors and non-survivors of venlafaxine overdosing. Casualties have been reported with venlafaxine blood concentrations from 26000 nmol/L or (venlafaxine + O-desmethylvenlafaxine) 45000 nmol/L (7). Forensic whole blood concentrations are, however, not directly comparable to plasma concentrations from living patients.

Survivors who have had plasma concentrations of venlafaxine up to 88000 nmol/L have been reported (8). The lowest concentrations found in a published case of symptomatic venlafaxine intoxication were 9700 nmol/L of venlafaxine and 6000 nmol/L of O-desmethylvenlafaxine (9). Thus there is a ten-fold range between the upper limit of the therapeutic window and the lowest published plasma level in symptomatic intoxication (1530 nmol/L compared to 15700 nmol/L for the sum of venlafaxine and O-desmethylvenlafaxine). Drugline 21639 (year 2004) FASS 2005 Venlafaxin. Drugdex(R) System; Thomson MICROMEDEX, Greenwood Village, Colorado (2005-11-09) Bertolin-Guillen JM, Climent-Diaz B, Navarre-Gimeno A. Serotonin syndrome due to association of venlafaxine, maprotiline and reboxetine. Eur Psychiatry 2004;19(7):456-7. Spina E, Scordo MG, D´arrigo C. Metabolic drug interactions with new psychotropic agents. Fundam Clin Pharmacol 2003;17:517-38. Rubio G, San L, Lopez-Munoz F, Alamo C. Reboxetine adjunct for partial or nonresponders to antidepressant treatment. J Affect Disord 2004;81:67-72. Oliver JJ, Kelly C, Jarvie D, Denieul S, Bateman DN. Venlafaxine poisoning complicated by a late rise in creatine kinase: two case reports. Hum Exp Toxicol 2002;21:463-6. Bond GR, Steele PE, Uges DR. Massive venlafaxine overdose resulted in a false positive Abbott AxSYM(R) urine immunoassay for phencyclidine. J Toxicol Clin Toxicol 2003;41(7):999-1002. Langford NJ, Martin U, Ruprah M, Ferner RE. Alternative venlafaxine kinetics in overdose. J Clin Pharm Ther 2002;27:465-7.