Venlafaxine Hydrochloride (Page 9 of 15)

8.2 Labor and Delivery

The effect of venlafaxine on labor and delivery in humans is unknown.

8.3 Nursing Mothers

Venlafaxine and ODV have been reported to be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from venlafaxine hydrochloride extended-release capsules, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

Two placebo-controlled trials in 766 pediatric patients with MDD and two placebo-controlled trials in 793 pediatric patients with GAD have been conducted with venlafaxine hydrochloride extended-release capsules, and the data were not sufficient to support a claim for use in pediatric patients.
Anyone considering the use of venlafaxine hydrochloride extended-release capsules in a child or adolescent must balance the potential risks with the clinical need [see Boxed Warning, Warnings and Precautions (5.1, 5.10, 5.11) and Adverse Reactions (6.4 )] . Although no studies have been designed to primarily assess venlafaxine hydrochloride extended-release capsule’s impact on the growth, development, and maturation of children and adolescents, the studies that have been done suggest that venlafaxine hydrochloride extended-release capsules may adversely affect weight and height [see Warnings and Precautions (5.10)]. Should the decision be made to treat a pediatric patient with venlafaxine hydrochloride extended-release capsules, regular monitoring of weight and height is recommended during treatment, particularly if treatment is to be continued long-term [see Warnings and Precautions (5.10, 5.11)] . The safety of venlafaxine hydrochloride extended-release capsules treatment for pediatric patients has not been systematically assessed for chronic treatment longer than six months in duration. In the studies conducted in pediatric patients (ages 6 to 17), the occurrence of blood pressure and cholesterol increases considered to be clinically relevant in pediatric patients was similar to that observed in adult patients. Consequently, the precautions for adults apply to pediatric patients [see Warnings and Precautions (5.3, 6.3)] .

8.5 Geriatric Use

The percentage of patients in clinical studies for venlafaxine hydrochloride extended-release capsules for MDD, GAD, SAD, and PD who were 65 years of age or older are shown in Table 15.

Table 15: Percentage (and Number of Patients Studied) of Patients 65 Years of Age and Older by Indication a
a In addition, in the premarketing assessment of venlafaxine hydrochloride (immediate release), 12% (357/2,897) of patients were ≥ 65 years of age.
Indication Venlafaxine Hydrochloride Extended-Release Capsules
MDD 4 (14/357)
GAD 6 (77/1,381)
SAD 1 (10/819)
PD 2 (16/1,001)

No overall differences in effectiveness or safety were observed between geriatric patients and younger patients, and other reported clinical experience generally has not identified differences in response between the elderly and younger patients. However, greater sensitivity of some older individuals cannot be ruled out. SSRIs and SNRIs, including venlafaxine hydrochloride extended-release capsules, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event [see Warnings and Precautions (5.9)] .

The pharmacokinetics of venlafaxine and ODV are not substantially altered in the elderly [see Clinical Pharmacology (12.3)] (see Figure 3) . No dose adjustment is recommended for the elderly on the basis of age alone, although other clinical circumstances, some of which may be more common in the elderly, such as renal or hepatic impairment, may warrant a dose reduction [see Dosage and Administration (2.6)] .

8.6 Age and Gender

A population pharmacokinetic analysis of 404 venlafaxine hydrochloride-treated patients from two studies involving both twice daily and three times daily regimens showed that dose-normalized trough plasma levels of either venlafaxine or ODV were unaltered by age or gender differences. Dosage adjustment based on the age or gender of a patient is generally not necessary [see Dosage and Administration (2.6)] (see Table 15).

8.7 Use in Patient Subgroups

Figure 3: Pharmacokinetics of venlafaxine and its metabolite O-desmethylvenlafaxine (ODV) in special populations.

Figure 3: Pharmacokinetics of venlafaxine and its metabolite O-desmethylvenlafaxine (ODV) in special populations.
(click image for full-size original)

Abbreviations: ODV, O-desmethylvenlafaxine; AUC, area under the curve; C max , peak plasma concentrations;
*Similar effect is expected with strong CYP2D6 inhibitors

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

Venlafaxine hydrochloride extended-release capsule is not a controlled substance.

9.2 Abuse

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).

9.3 Dependence

In vitro studies revealed that venlafaxine has virtually no affinity for opiate, benzodiazepine, phencyclidine (PCP), or N-methyl-D-aspartic acid (NMDA) receptors.
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)] .

10 OVERDOSAGE

10.1 Human Experience

During the premarketing evaluations of venlafaxine hydrochloride extended-release capsules (for MDD, GAD, SAD, and PD) and venlafaxine hydrochloride (for MDD), there were twenty reports of acute overdosage with venlafaxine hydrochloride (6 and 14 reports in venlafaxine hydrochloride extended-release capsules and venlafaxine hydrochloride 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.

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