Venlafaxine Hydrochloride (Page 9 of 13)

CYP3A4

Venlafaxine did not inhibit CYP3A4 in vitro. This finding was confirmed in vivo by clinical drug interaction studies in which venlafaxine did not inhibit the metabolism of several CYP3A4 substrates, including alprazolam, diazepam, and terfenadine.

Indinavir — In a study of 9 healthy volunteers, venlafaxine administered under steady-state conditions at 150 mg/day resulted in a 28% decrease in the AUC of a single 800 mg oral dose of indinavir and a 36% decrease in indinavir C_max . Indinavir did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of this finding is unknown.

CYP1A2

Venlafaxine did not inhibit CYP1A2 in vitro. This finding was confirmed in vivo by a clinical drug interaction study in which venlafaxine did not inhibit the metabolism of caffeine, a CYP1A2 substrate.

CYP2C9

Venlafaxine did not inhibit CYP2C9 in vitro. In vivo, venlafaxine 75 mg by mouth every 12 hours did not alter the pharmacokinetics of a single 500 mg dose of tolbutamide or the CYP2C9 mediated formation of 4-hydroxy-tolbutamide.

CYP2C19

Venlafaxine did not inhibit the metabolism of diazepam, which is partially metabolized by CYP2C19 (see Diazepam above).

7.9 Monoamine Oxidase Inhibitors

See Contraindications (4) and Warnings and Precautions (5.2).

7.10 Other CNS-Active Drugs

The risk of using venlafaxine in combination with other CNS-active drugs has not been systematically evaluated (except in the case of those CNS-active drugs noted above). Consequently, caution is advised if the concomitant administration of venlafaxine and such drugs is required.

Serotonergic Drugs

Based on the mechanism of action of Venlafaxine Extended Release Tablets and the potential for serotonin syndrome, caution is advised when Venlafaxine Extended Release Tablets are co-administered 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 [see Warnings and Precautions (5.3) ]. If concomitant treatment of Venlafaxine Extended Release Tablets with these drugs is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases [see Warnings and Precautions (5.3) ]. The concomitant use of Venlafaxine Extended Release Tablets with tryptophan supplements is not recommended [see Warnings and Precautions (5.3) ].

Triptans

There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of Venlafaxine Extended Release Tablets with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases [see Warnings and Precautions (5.3) ].

7.11 Drugs that Interfere with Hemostasis (e.g., NSAID’s, Aspirin, and Warfarin)

Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. These studies have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRI’s and SNRI’s are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when Venlafaxine Extended-Release Tablets are initiated or discontinued. [See Warnings and Precautions (5.14). ]

7.12 Electroconvulsive Therapy

There are no clinical data establishing the benefit of electroconvulsive therapy combined with Venlafaxine Extended Release Tablets treatment.

7.13 Postmarketing Spontaneous Drug Interaction Reports

There have been reports of elevated clozapine levels that were temporally associated with adverse reactions, including seizures, following the addition of venlafaxine.

There have been reports of increases in prothrombin time, partial thromboplastin time, or INR when venlafaxine was given to patients receiving warfarin therapy.

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/m² 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/m²) the maximum human daily dose. The no effect dose for rat pup mortality was 0.25 times the human dose on a mg/m² basis. There are no adequate and well-controlled studies in pregnant women. 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 (Serotonin and Norepinephrine Reuptake Inhibitors), or SSRIs (Selective Serotonin Reuptake Inhibitors), 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 (5.3) ]. When treating a pregnant woman with Venlafaxine Extended-Release Tablets during the third trimester, the physician should carefully consider the potential risks and benefits of treatment [see Dosage and Administration (2) ].

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 Extended Release Tablets, 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

Safety and effectiveness in the pediatric population have not been established [see BOXED WARNING and Warnings and Precautions (5.1)]. Two placebo-controlled trials in 766 pediatric patients with MDD and two placebo-controlled trials in another disorder in 793 pediatric patients 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 Extended Release Tablets in a child or adolescent must balance the potential risks with the clinical need.

Although no studies have been designed to primarily assess impact of venlafaxine hydrochloride extended-release capsules on the growth, development, and maturation of children and adolescents, the studies that have been done suggest that Venlafaxine Extended Release Tablets may adversely affect weight and height [see Warnings and Precautions (5.8, 5.9, and 5.10)]. Should the decision be made to treat a pediatric patient with Venlafaxine Extended Release Tablets, regular monitoring of weight and height is recommended during treatment, particularly if it is to be continued long term. The safety of Venlafaxine Extended Release Tablets 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 6-17), 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 (5.4 and 5.15)].