Venlafaxine Hydrochloride (Page 8 of 15)

7.2 Monoamine Oxidase Inhibitors

Adverse reactions, some of which were serious, have been reported in patients who have recently been discontinued from an MAOI and started on antidepressants with pharmacological properties similar to venlafaxine hydrochloride extended-release capsules (SNRIs or SSRIs), or who have recently had SNRI or SSRI therapy discontinued prior to initiation of an MAOI [see Dosage and Administration ( 2.9), Contraindications ( 4.2) and Warnings and Precautions ( 5.2)].

7.3 Serotonergic Drugs

Based on the mechanism of action of venlafaxine hydrochloride extended-release capsules and the potential for serotonin syndrome, caution is advised when venlafaxine hydrochloride extended-release capsules are coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, SSRIs, other SNRIs, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St. John’s wort. If concomitant treatment with venlafaxine hydrochloride extended-release capsules and these drugs is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. The concomitant use of venlafaxine hydrochloride extended-release capsules with tryptophan supplements is not recommended [see Dosage and Administration ( 2.9), Contraindications ( 4.2), and Warnings and Precautions ( 5.2)].

7.4 Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin)

Serotonin release by platelets plays an important role in hemostasis. The use of psychotropic drugs that interfere with serotonin reuptake is associated with the occurrence of upper gastrointestinal bleeding and concurrent use of an NSAID or aspirin may potentiate this risk of bleeding [see Warnings and Precautions ( 5.4)]. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when venlafaxine hydrochloride extended release capsules are initiated or discontinued.

7.5 Weight Loss Agents

The safety and efficacy of venlafaxine therapy in combination with weight loss agents, including phentermine, have not been established. Coadministration of venlafaxine hydrochloride extended-release capsules and weight loss agents is not recommended. Venlafaxine hydrochloride extended-release capsules are not indicated for weight loss alone or in combination with other products.

7.6 Effects of Other Drugs on Venlafaxine Hydrochloride Extended-Release Capsules

Figure 1: Effect of interacting drugs on the pharmacokinetics of venlafaxine and active metabolite O-desmethylvenlafaxine (ODV).

Abbreviations: ODV, O-desmethylvenlafaxine; AUC, area under the curve; C _max , peak plasma concentrations; EM’s, extensive metabolizers; PM’s, poor metabolizers * No dose adjustment on co-administration with CYP2D6 inhibitors (Fig 3 and Metabolism Section 12.3)

7.7 Effects of Venlafaxine Hydrochloride Extended-Release Capsules on Other Drugs

Figure 2: Effect of venlafaxine on the pharmacokinetics interacting drugs and their active metabolites.

Abbreviations: AUC, area under the curve; C _max , peak plasma concentrations; OH, hydroxyl
* Data for 2-OH desipramine were not plotted to enhance clarity; the fold change and 90% CI for C _max and AUC of 2-OH desipramine were 6.6 (5.5, 7.9) and 4.4 (3.8, 5.0), respectively.
Note: *: Administration of venlafaxine in a stable regimen did not exaggerate the psychomotor and psychometric effects induced by ethanol in these same subjects when they were not receiving venlafaxine.

7.8 Drug-Laboratory Test Interactions

False-positive urine immunoassay screening tests for phencyclidine (PCP) and amphetamine have been reported in patients taking venlafaxine. This is due to lack of specificity of the screening tests. False positive test results may be expected for several days following discontinuation of venlafaxine therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish venlafaxine from PCP and amphetamine.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic Effects — Pregnancy Category C
Venlafaxine did not cause malformations in offspring of rats or rabbits given doses up to 2.5 times (rat) or 4 times (rabbit) the maximum recommended human daily dose on a mg/m ² basis. However, in rats, there was a decrease in pup weight, an increase in stillborn pups, and an increase in pup deaths during the first 5 days of lactation, when dosing began during pregnancy and continued until weaning. The cause of these deaths is not known. These effects occurred at 2.5 times (mg/m ²) the maximum human daily dose. The no effect dose for rat pup mortality was 0.25 times the human dose on a mg/m ² basis. In reproductive developmental studies in rats and rabbits with O-desmethylvenlafaxine (ODV), the major human metabolite of venlafaxine, evidence of teratogenicity was not observed at exposure margins of 13 in rats and 0.3 in rabbits. There are no adequate and well-controlled studies in pregnant women. Venlafaxine hydrochloride extended-release capsules should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Non-teratogenic Effects
Neonates exposed to venlafaxine hydrochloride extended-release capsules, other SNRIs, or SSRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs, or possibly a drug discontinuation syndrome. It should be noted, that in some cases the clinical picture is consistent with serotonin syndrome [see Warnings and Precautions ( 5.2) and Drug Interactions ( 7.3)]. When treating a pregnant woman with venlafaxine hydrochloride extended-release capsules during the third trimester, the physician should carefully consider the potential risks and benefits of treatment.

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 capsules 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)].