While venlafaxine has not been systematically studied in clinical studies for its potential for abuse, there was no indication of drug-seeking behavior in the clinical studies. However, it is not possible to predict on the basis of premarketing experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of venlafaxine (e.g., development of tolerance, incrementation of dose, drug-seeking behavior).
Venlafaxine was not found to have any significant CNS stimulant activity in rodents. In primate drug discrimination studies, venlafaxine showed no significant stimulant or depressant abuse liability. Discontinuation effects have been reported in patients receiving venlafaxine [see Dosage and Administration (2.8) ].
During the premarketing evaluations of venlafaxine hydrochloride extended-release capsules (for MDD,GAD,SAD, and PD) and venlafaxine hydrochloride tablets (for MDD), there were twenty reports of acute overdosage with venlafaxine hydrochloride tablets(6 and 14 reports in venlafaxine hydrochloride extended-release capsules and venlafaxine hydrochloride tablets patients, respectively), either alone or in combination with other drugs and/or alcohol.
Somnolence was the most commonly reported symptom. Among the other reported symptoms were paresthesia of all four limbs, moderate dizziness, nausea, numb hands and feet, and hot-cold spells 5 days after the overdose. In most cases, no signs or symptoms were associated with overdose. The majority of the reports involved ingestion in which the total dose of venlafaxine taken was estimated to be no more than several-fold higher than the usual therapeutic dose. One patient who ingested 2.75 g of venlafaxine was observed to have two generalized convulsions and a prolongation of QTc to 500 msec, compared with 405 msec at baseline. Mild sinus tachycardia was reported in two of the other patients.
Actions taken to treat the overdose included no treatment, hospitalization and symptomatic treatment, and hospitalization plus treatment with activated charcoal. All patients recovered.
In postmarketing experience, overdose with venlafaxine has occurred predominantly in combination with alcohol and/or other drugs. The most commonly reported events in overdosage include tachycardia, changes in level of consciousness (ranging from somnolence to coma), mydriasis, seizures, and vomiting. Electrocardiogram changes (e.g., prolongation of QT interval, bundle branch block, QRS prolongation), ventricular tachycardia, bradycardia, hypotension, rhabdomyolysis, vertigo, liver necrosis, serotonin syndrome, and death have been reported.
Published retrospective studies report that venlafaxine overdosage may be associated with an increased risk of fatal outcomes compared to that observed with SSRI antidepressant products, but lower than that for tricyclic antidepressants. Epidemiological studies have shown that venlafaxine-treated patients have a higher preexisting burden of suicide risk factors than SSRI-treated patients. The extent to which the finding of an increased risk of fatal outcomes can be attributed to the toxicity of venlafaxine in overdosage, as opposed to some characteristic(s) of venlafaxine-treated patients, is not clear. Prescriptions for venlafaxine hydrochloride extended-release capsules should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose.
Consult a Certified Poison Control Center for up-to-date guidance and advice (1-800-222-1222 or www.poison.org). In case of an overdose, provide supportive care, including close medical supervision and monitoring. Treatment should consist of those general measures employed in the management of overdosage with any drug. Consider the possibility of multiple drug overdose. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Provide supportive and symptomatic measures.
Venlafaxine is designated (R/S)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl] cyclohexanol hydrochloride or (±)-1-[α-[(dimethylamino)methyl]-p-methoxybenzyl] cyclohexanol hydrochloride and has the empirical formula of C17 H27 NO2 HCl. Its molecular weight is 313.86. The structural formula is shown as follows:
Venlafaxine hydrochloride is a white to off-white crystalline solid, with a solubility of 572 mg/mL in water (adjusted to ionic strength of 0.2 M with sodium chloride). Its octanol:water (0.2 M sodium chloride) partition coefficient is 0.43.
Drug release is controlled by diffusion through the coating membrane on the spheroids and is not pH-dependent. Capsules contain venlafaxine hydrochloride equivalent to 37.5 mg, 75 mg, or 150 mg venlafaxine. Inactive ingredients consist of ethylcellulose, hypromellose and sugar spheres. The empty hard gelatin capsule shells contain gelatin and titanium dioxide. The 37.5 mg capsules also contain iron oxide black. The 75 mg capsules also contain FD&C red No. 3 and FD&C yellow No. 6. The 150 mg capsules also contain iron oxide red and iron oxide yellow.
The 37.5 mg, 75 mg and 150 mg capsules are imprinted with black and grey ink which contains iron oxide black, butyl alcohol, dehydrated alcohol, isopropyl alcohol, potassium hydroxide, propylene glycol, purified water, shellac and strong ammonia solution. Grey ink also contains titanium dioxide.
The exact mechanism of the antidepressant action of venlafaxine in humans is unknown, but is thought to be related to the potentiation of serotonin and norepinephrine in the central nervous system, through inhibition of their reuptake. Non-clinical studies have demonstrated that venlafaxine and its active metabolite, ODV, are potent and selective inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake.
Venlafaxine and ODV have no significant affinity for muscarinic-cholinergic, H1 -histaminergic, or α1 adrenergic receptors in vitro. Pharmacologic activity at these receptors is hypothesized to be associated with the various anticholinergic, sedative, and cardiovascular effects seen with other psychotropic drugs. Venlafaxine and ODV do not possess monoamine oxidase (MAO) inhibitory activity.
The effect of venlafaxine on the QT interval was evaluated in a randomized, double-blind, placebo-and positive-controlled three-period crossover thorough QT study in 54 healthy adult subjects. No significant QT prolongation effect of venlafaxine 450 mg was detected.
Steady-state concentrations of venlafaxine and ODV in plasma are attained within 3 days of oral multiple-dose therapy. Venlafaxine and ODV exhibited linear kinetics over the dose range of 75 to 450 mg per day. Mean±SD steady-state plasma clearance of venlafaxine and ODV is 1.3±0.6 and 0.4±0.2 L/h/kg, respectively; apparent elimination half-life is 5±2 and 11±2 hours, respectively; and apparent (steadystate) volume of distribution is 7.5±3.7 and 5.7±1.8 L/kg, respectively. Venlafaxine and ODV are minimally bound at therapeutic concentrations to plasma proteins (27% and 30%, respectively).
Absorption and Distribution
Venlafaxine is well absorbed and extensively metabolized in the liver. ODV is the major active metabolite. On the basis of mass balance studies, at least 92% of a single oral dose of venlafaxine is absorbed. The absolute bioavailability of venlafaxine is approximately 45%.
Administration of venlafaxine hydrochloride extended-release capsules (150 mg once daily) generally resulted in lower Cmax and later Tmax values than for venlafaxine hydrochloride tablets (immediate release) administered twice daily (Table 16). When equal daily doses of venlafaxine were administered as either an immediate-release tablet or the extended-release capsule, the exposure to both venlafaxine and ODV was similar for the two treatments, and the fluctuation in plasma concentrations was slightly lower with the venlafaxine hydrochloride extended-release capsules. Therefore, venlafaxine hydrochloride extended-release capsules, provides a slower rate of absorption, but the same extent of absorption compared with the immediate-release tablet.
|Cm a x||Tm a x||Cm a x||Tm a x|
|( ng / mL )||( h )||( ng / mL )||( h )|
|Venlafaxine HydrochlorideExtended-release Capsules (150 mg once daily)||150||5.5||260||9|
|Venlafaxine HydrochlorideTablets(75 mg twice daily)||225||2||290||3|
Food did not affect the bioavailability of venlafaxine or its active metabolite, ODV. Time of administration (AM versus PM) did not affect the pharmacokinetics of venlafaxine and ODV from the 75 mg venlafaxine hydrochloride extended-release capsules .
Venlafaxine is not highly bound to plasma proteins; therefore, administration of venlafaxine hydrochloride extended-release capsules to a patient taking another drug that is highly protein-bound should not cause increased free concentrations of the other drug.
Metabolism and Elimination
Following absorption, venlafaxine undergoes extensive presystemic metabolism in the liver, primarily to ODV, but also to N-desmethylvenlafaxine, N,O-didesmethylvenlafaxine, and other minor metabolites. In vitro studies indicate that the formation of ODV is catalyzed by CYP2D6; this has been confirmed in a clinical study showing that patients with low CYP2D6 levels (poor metabolizers) had increased levels of venlafaxine and reduced levels of ODV compared to people with normal CYP2D6 levels (extensive metabolizers) [see Use in Specific Populations (8.7) ].
Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%). Renal elimination of venlafaxine and its metabolites is thus the primary route of excretion.
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