Prescription Drug Information: Venlafaxine Hydrochloride (Page 4 of 9)

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of venlafaxine hydrochloride extended-release capsules. 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, Thoracic and Mediastinal Disorders – Anosmia, dyspnea, hyposmia, 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 Drugs Having Clinically Important Interactions with Venlafaxine Hydrochloride Extended-Release Capsules

Table 15: Clinically Important Drug Interactions with Venlafaxine Hydrochloride Extended-Release Capsules

Monoamine Oxidase Inhibitors (MAOI)
Clinical Impact The concomitant use of SNRIs, including venlafaxine hydrochloride extended-release capsules with MAOIs increases the risk of serotonin syndrome.
Intervention Concomitant use of venlafaxine hydrochloride extended-release capsules are contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [see Dosage and Administration (2.11), Contraindications (4) and Warnings and Precautions (5.2)].
Other Serotonergic Drugs
Clinical Impact Concomitant use of venlafaxine hydrochloride extended-release capsules with other serotonergic drugs (including other SNRIs, SSRIs, triptans, tricyclic antidepressants, opioids, lithium, buspirone, amphetamines, tryptophan, and St. John’s Wort) increases the risk of serotonin syndrome.
Intervention Monitor for symptoms of serotonin syndrome when venlafaxine hydrochloride extended-release capsules are used concomitantly with other drugs that may affect the serotonergic neurotransmitter systems. If serotonin syndrome occurs, consider discontinuation of venlafaxine hydrochloride extended-release capsules and/or concomitant serotonergic drugs [see Dosage and Administration (2.11) and Warnings and Precautions (5.2)].
Drugs that Interfere with Hemostasis
Clinical Impact Concomitant use of venlafaxine hydrochloride extended-release capsules with an antiplatelet or anticoagulant drug may potentiate the risk of bleeding. This may be due to the effect of venlafaxine hydrochloride extended-release capsules on the release of serotonin by platelets.
Intervention Closely monitor for bleeding for patients receiving an antiplatelet or anticoagulant drug when venlafaxine hydrochloride extended-release capsules are initiated or discontinued [see Warnings and Precautions (5.4)].
Effect of CYP3A Inhibitors
Clinical Impact Concomitant use of a CYP3A inhibitor increases the Cmax and AUC of venlafaxine and O-desmethylvenlafaxine (ODV) [see Clinical Pharmacology (12.3)] , which may increase the risk of toxicity of venlafaxine hydrochloride extended-release capsules.
Intervention Consider reducing the dose of venlafaxine hydrochloride extended-release capsules.
CYP2D6 Substrates
Clinical Impact Concomitant use of venlafaxine hydrochloride extended-release capsules increases Cmax and AUC of a CYP2D6 substrate, which may increase the risk of toxicity of the CYP2D6 substrate [see Clinical Pharmacology (12.3)].
Intervention Consider reduction in dose of concomitant CYP2D6 substrates.

7.2 Other Drug Interactions with Venlafaxine Hydrochloride Extended-Release Capsules

Central Nervous System (CNS)-Active Drugs
The risk of using venlafaxine concomitantly with other CNS-active drugs (including alcohol) has not been systematically evaluated. Consequently, caution is advised when venlafaxine hydrochloride extended-release capsules are taken concomitantly in combination with other CNS-active drugs.
Weight Loss Agents
Concomitant use of venlafaxine hydrochloride extended-release capsules and weight loss agents is not recommended. The safety and efficacy of venlafaxine therapy in combination with weight loss agents, including phentermine, have not been established. Venlafaxine hydrochloride extended-release capsules are not indicated for weight loss alone or in combination with other products.
Laboratory Test Interference
False-positive urine immunoassay screening tests for phencyclidine (PCP) and amphetamine have been reported in patients taking venlafaxine 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

Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants, including venlafaxine hydrochloride extended-release capsules, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/.
Risk Summary

Based on data from published observational studies, exposure to SNRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Warnings and Precautions (5.4) and Clinical Considerations].

Available data from published epidemiologic studies on venlafaxine use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage or adverse fetal outcomes (see Data). Available data from observational studies with venlafaxine have identified a potential increased risk for preeclampsia when used during mid to late pregnancy; exposure to SNRIs near delivery may increase the risk for postpartum hemorrhage (see Clinical Considerations). There are risks associated with untreated depression in pregnancy and poor neonatal adaptation in newborns with exposure to SNRIs, including venlafaxine hydrochloride extended-release capsules, during pregnancy (see Clinical Considerations).
In animal studies, there was no evidence of malformations or fetotoxicity following administration of venlafaxine during organogenesis at doses up to 2.5 times (rat) or 4 times (rabbit) the maximum recommended human daily dose on a mg/m2 basis. Postnatal mortality and decreased pup weights were observed following venlafaxine administration to pregnant rats during gestation and lactation at 2.5 times (mg/m2) the maximum human daily dose.
The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Clinical Considerations
Disease-Associated Maternal and/or Embryo/Fetal Risk
Women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants. This finding is from a prospective, longitudinal study that followed 201 pregnant women with a history of major depression who were euthymic and taking antidepressants at the beginning of pregnancy. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum.
Maternal Adverse Reactions

Exposure to venlafaxine in mid to late pregnancy may increase the risk for preeclampsia, and exposure to venlafaxine in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see Warnings and Precautions (5.4)].

Fetal/Neonatal Adverse Reactions
Neonates exposed to SNRIs 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, tremors, jitteriness, irritability, and constant crying. These findings are consistent with either a direct toxic effect of 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)]. Monitor neonates who were exposed to venlafaxine hydrochloride extended-release capsules in the third trimester of pregnancy for drug discontinuation syndrome (see Data).
Data
Human Data
Published epidemiological studies of pregnant women exposed to venlafaxine have not established an increased risk of major birth defects, miscarriage or other adverse developmental outcomes. Methodological limitations may both fail to identify true findings and also identify findings that are not true.
Retrospective cohort studies based on claims data have shown an association between venlafaxine use and preeclampsia, compared to depressed women who did not take an antidepressant during pregnancy. One study that assessed venlafaxine exposure in the second trimester or first half of the third trimester and preeclampsia showed an increased risk compared to unexposed depressed women (adjusted [adj] RR 1.57, 95% confidence interval [CI] 1.29-1.91). Preeclampsia was observed at venlafaxine doses equal to or greater than 75 mg per day and a duration of treatment >30 days. Another study that assessed venlafaxine exposure in gestational weeks 10-20 and preeclampsia showed an increased risk at doses equal to or greater than 150 mg per day. Available data are limited by possible outcome misclassification and possible confounding due to depression severity and other confounders.
Retrospective cohort studies based on claims data have suggested an association between venlafaxine use near the time of delivery or through delivery and postpartum hemorrhage. One study showed an increased risk for postpartum hemorrhage when venlafaxine exposure occurred through delivery, compared to unexposed depressed women (adj RR 2.24 [95% CI 1.69-2.97]). There was no increased risk in women who were exposed to venlafaxine earlier in pregnancy. Limitations of this study include possible confounding due to depression severity and other confounders. Another study showed an increased risk for postpartum hemorrhage when SNRI exposure occurred for at least 15 days in the last month of pregnancy or through delivery, compared to unexposed women (adj RR 1.64-1.76). The results of this study may be confounded by the effects of depression.
Animal Data
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.
When desvenlafaxine succinate, the major metabolite of venlafaxine, was administered orally to pregnant rats and rabbits during the period of organogenesis at doses up to 300 mg/kg/day and 75 mg/kg/day, respectively, no fetal malformations were observed. These doses were associated with a plasma exposure (AUC) 19 times (rats) and 0.5 times (rabbits) the AUC exposure at an adult human dose of 100 mg per day. However, fetal weights were decreased and skeletal ossification was delayed in rats in association with maternal toxicity at the highest dose, with an AUC exposure at the no-effect dose that is 4.5-times the AUC exposure at an adult human dose of 100 mg per day.

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