Effexor XR (Page 6 of 13)

6.4 Pediatric Patients

In general, the adverse reaction profile of venlafaxine (in placebo-controlled clinical studies) in children and adolescents (ages 6 to 17) was similar to that seen for adults. As with adults, decreased appetite, weight loss, increased blood pressure, and increased serum cholesterol were observed [see Warnings and Precautions (5.3, 5.10, 5.11) and Use in Specific Populations (8.4)].

In pediatric clinical studies, the adverse reaction, suicidal ideation, was observed.

Particularly, the following adverse reactions were observed in pediatric patients: abdominal pain, agitation, dyspepsia, ecchymosis, epistaxis, and myalgia.

6.5 Adverse Reactions Identified During Postapproval Use

The following adverse reactions have been identified during postapproval use of Effexor XR. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:

Body as a whole – Anaphylaxis, angioedema

Cardiovascular system – QT prolongation, ventricular fibrillation, ventricular tachycardia (including torsade de pointes), takotsubo cardiomyopathy

Digestive system – Pancreatitis

Hemic/Lymphatic system – Mucous membrane bleeding [see Warnings and Precautions (5.4)] , blood dyscrasias (including agranulocytosis, aplastic anemia, neutropenia and pancytopenia), prolonged bleeding time, thrombocytopenia

Metabolic/Nutritional – Hyponatremia [see Warnings and Precautions (5.9)] , Syndrome of Inappropriate Antidiuretic Hormone (SIADH) secretion [see Warnings and Precautions (5.9)] , abnormal liver function tests, hepatitis, prolactin increased

Musculoskeletal – Rhabdomyolysis

Nervous system – Neuroleptic Malignant Syndrome (NMS) [see Warnings and Precautions (5.2)] , serotonergic syndrome [see Warnings and Precautions (5.2)] , delirium, extrapyramidal reactions (including dystonia and dyskinesia), impaired coordination and balance, tardive dyskinesia

Respiratory system – Dyspnea, interstitial lung disease, pulmonary eosinophilia [see Warnings and Precautions (5.12)]

Skin and appendages – Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme

Special senses – Angle-closure glaucoma [see Warnings and Precautions (5.5)]

7 DRUG INTERACTIONS

7.1 Central Nervous System (CNS)-Active Drugs

The risk of using venlafaxine in combination with other CNS-active drugs has not been systematically evaluated. Consequently, caution is advised when Effexor XR is taken in combination with other CNS-active drugs.

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 Effexor XR (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 Effexor XR and the potential for serotonin syndrome, caution is advised when Effexor XR is 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 Effexor XR and these drugs is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. The concomitant use of Effexor XR 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 Effexor XR is 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 Effexor XR and weight loss agents is not recommended. Effexor XR is not indicated for weight loss alone or in combination with other products.

7.6 Effects of Other Drugs on Effexor XR

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

Figure 1
(click image for full-size original)

Abbreviations: ODV, O-desmethylvenlafaxine; AUC, area under the curve; Cmax, 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 Effexor XR on Other Drugs

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

Figure 2
(click image for full-size original)

Abbreviations: AUC, area under the curve; Cmax, peak plasma concentrations; OH, hydroxyl

* Data for 2-OH desipramine were not plotted to enhance clarity; the fold change and 90% CI for Cmax 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/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. 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. Effexor XR 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 Effexor XR, 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 Effexor XR during the third trimester, the physician should carefully consider the potential risks and benefits of treatment.

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