USE IN SPECIFIC POPULATIONS SECTION

Highlight: Pregnancy: Third trimester use may increase risk for symptoms of poor neonatal adaptation (respiratory distress, temperature instability, feeding difficulty, hypotonia, tremor, irritability) in the neonate (8.1).

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

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/m2basis. 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

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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 SNRIs near delivery may increase the risk for postpartum hemorrhage.

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 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/ms) 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.

8.2 Lactation

Risk Summary

Data from published literature report the presence of venlafaxine and its active metabolite in human milk and have not shown adverse reactions in breastfed infants (see Data). There are no data on the effects of venlafaxine on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for venlafaxine hydrochloride extended- release capsules and any potential adverse effects on the breastfed child from venlafaxine hydrochloride extended-release capsules or from the underlying maternal condition.

Data

In a lactation study conducted in 11 breastfeeding women (at a mean of 20.1 months post-partum) who were taking a mean daily dose of 194.3 mg of venlafaxine and in a lactation study conducted in 6 breastfeeding women who were taking a daily dose of 225 mg to 300 mg of venlafaxine (at a mean of 7 months post-partum), the estimated mean relative infant dose was 8.1 % and 6.4% based on the sum of venlafaxine and its major metabolite, desvenlafaxine. No adverse reactions were seen in the infants.

8.4 Pediatric Use

Safety and effectiveness of venlafaxine hydrochloride extended-release capsules in pediatric patients have not been established.

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 use in pediatric patients.

In the studies conducted in pediatric patients ages 6 to17 years, the occurrence of blood pressure and cholesterol increases was considered to be clinically relevant in pediatric patients and was similar to that observed in adult patients [see Warnings and Precautions (5.3), Adverse Reactions (6.1)]. The following adverse reactions were also observed in pediatric patients: abdominal pain, agitation, dyspepsia, ecchymosis, epistaxis, and myalgia.

Although no studies have been designed to primarily assess venlafaxine hydrochloride extended-release capsules'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, 5.11)]. Decreased appetite and weight loss were observed in placebo-controlled studies of pediatric patients 6 to 17 years.

In pediatric clinical studies, the adverse reaction, suicidal ideation, was observed. Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric patients [see Boxed Warning, Warnings and Precautions (5.1)].

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 16.

Table 16 Percentage (and Number of Patients Studied) of Patients 65 Years of Age and Older by Indicationa

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 1). 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 (2.8, 2.9)].

8.6 Renal Impairment

Dosage adjustment is recommended in patients with mild (CLcr= 60-89 mL/min), moderate (CLcr= 30 59 mL/min), or severe (CLcr < 30 mL/min) renal impairment, and in patients undergoing hemodialysis [see Dosage and Administration (2.9) and Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

Dosage adjustment is recommended in patients with mild (Child-Pugh Class A), moderate (Child-Pugh Class B), or severe (Child-Pugh Class C) hepatic impairment or hepatic cirrhosis [see Dosage and Administration (2.8) and Clinical Pharmacology (12.3)].

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ADVERSE REACTIONS SECTION

Highlight: Most common adverse reactions (incidence ≥ 5% and at least twice the rate of placebo): nausea, somnolence, dry mouth, sweating, abnormal ejaculation, anorexia, constipation, impotence (men), and libido decreased (6.1).

**To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-**877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6 ADVERSE REACTIONS

The following adverse reactions are discussed in more detail in other sections of the labeling:

• Hypersensitivity [see Contraindications (4)]
• Suicidal Thoughts and Behaviors in Adolescents and Young Adults [see Warnings andPrecautions (5.1)]
• Serotonin Syndrome [see Warnings and Precautions (5.2)]
• Elevated Blood Pressure [see Warnings and Precautions (5.3)]
• Increased Risk of Bleeding [see Warnings and Precautions (5.4)]
• Angle Closure Glaucoma [see Warnings and Precautions (5.5)]
• Activation of Mania/Hypomania [see Warnings and Precautions (5.6)]
• Discontinuation Syndrome [see Warnings and Precautions (5.7)]
• Seizure [see Warnings and Precautions (5.8)]
• Hyponatremia [see Warnings and Precautions (5.9)]
• Weight and Height changes in Pediatric Patients [see Warnings and Precautions (5.10)]
• Appetite Changes in Pediatric Patients [see Warnings and Precautions (5.11)]
• Interstitial Lung Disease and Eosinophilic Pneumonia [see Warnings and Precautions (5.12)]
• Sexual Dysfunction [see Warnings and Precautions (5.13)]

6.1 Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.

Most Common Adverse Reactions

The most commonly observed adverse reactions in the clinical study database in venlafaxine hydrochloride extended-release capsules treated patients in MDD, GAD, SAD, and PD (incidence ≥ 5% and at least twice the rate of placebo) were: nausea (30.0%), somnolence (15.3%), dry mouth (14.8%), sweating (11.4%), abnormal ejaculation (9.9%), anorexia (9.8%), constipation (9.3%), impotence (5.3%) and decreased libido (5.1%).

Adverse Reactions Reported as Reasons for Discontinuation of Treatment

Combined across short-term, placebo-controlled premarketing studies for all indications, 12% of the 3,558 patients who received venlafaxine hydrochloride extended-release capsules (37.5 to 225 mg) discontinued treatment due to an adverse experience, compared with 4% of the 2,197 placebo-treated patients in those studies.

The most common adverse reactions leading to discontinuation in ≥ 1% of the venlafaxine hydrochloride extended-release capsules treated patients in the short-term studies (up to 12 weeks) across indications are shown in Table 7.

Table 7 Incidence (%) of Patients Reporting Adverse Reactions Leading to Discontinuation inPlacebo-controlled Clinical Studies (up to 12 Weeks Duration)

Common Adverse Reactions in Placebo-controlled Studies

The number of patients receiving multiple doses of venlafaxine hydrochloride extended-release capsules during the premarketing assessment for each approved indication is shown in Table 8. The conditions and duration of exposure to venlafaxine in all development programs varied greatly, and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient (venlafaxine hydrochloride tablets only) and outpatient studies, fixed-dose, and titration studies.

Table 8 Patients Receiving Venlafaxine Hydrochloride Extended-Release Capsules in Premarketing Clinical Studies

The incidences of common adverse reactions (those that occurred in ≥ 2% of venlafaxine hydrochloride extended-release capsules treated patients [357 MDD patients, 1,381 GAD patients, 819 SAD patients, and 1,001 PD patients] and more frequently than placebo) in venlafaxine hydrochloride extended-release capsules treated patients in short-term, placebo-controlled, fixed- and flexible-dose clinical studies (doses 37.5 to 225 mg per day) are shown in Table 9.

The adverse reaction profile did not differ substantially between the different patient populations.

Table 9 Common Adverse Reactions: Percentage of Patients Reporting Adverse Reactions (≥ 2% and > placebo) in Placebo-controlled Studies (up to 12 Weeks Duration) across All Indications

Other Adverse Reactions Observed in Clinical Studies

Body as a whole

Photosensitivity reaction, chills

Cardiovascular system

Postural hypotension, syncope, hypotension, tachycardia

Digestive system

Gastrointestinal hemorrhage [see Warnings and Precautions (5.4)], bruxism

Hemic/Lymphatic system

Ecchymosis [see Warnings and Precautions (5.4)]

Metabolic/Nutritional

Hypercholesterolemia, weight gain [see Warnings and Precautions (5.10)], weight loss [see Warnings and Precautions (5.10)]

Nervous system

Seizures [see Warnings and Precautions (5.8)], manic reaction [see Warnings and Precautions (5.6)], agitation, confusion, akathisia, hallucinations, hypertonia, myoclonus, depersonalization, apathy

Skin and appendages

Urticaria, pruritus, rash, alopecia

Special senses

Mydriasis, abnormality of accommodation, tinnitus, taste perversion

Urogenital system

Urinary retention, urination impaired, urinary incontinence, urinary frequency increased, menstrual disorders associated with increased bleeding or increased irregular bleeding (e.g., menorrhagia, metrorrhagia)

V****ital Sign Changes

In placebo-controlled premarketing studies, there were increases in mean blood pressure (see Table 10). Across most indications, a dose-related increase in mean supine systolic and diastolic blood pressure was evident in patients treated with venlafaxine hydrochloride extended-release capsules. Across all clinical studies in MDD, GAD, SAD and PD, 1.4% of patients in the venlafaxine hydrochloride extended-release capsules groups experienced an increase in SDBP of ≥15 mm Hg along with a blood pressure ≥ 105 mm Hg, compared to 0.9% of patients in the placebo groups. Similarly, 1% of patients in the venlafaxine hydrochloride extended-release capsules groups experienced an increase in SSBP of ≥ 20 mm Hg with a blood pressure ≥ 180 mm Hg, compared to 0.3% of patients in the placebo groups.

Table 10 Final On-therapy Mean Changes From Baseline in Supine Systolic (SSBP) and Diastolic(SDBP) Blood Pressure (mm Hg) in Placebo- controlled Studies

Venlafaxine hydrochloride extended-release capsules treatment was associated with sustained hypertension (defined as Supine Diastolic Blood Pressure [SDBP] ≥ 90 mm Hg and ≥ 10 mm Hg above baseline for three consecutive on- therapy visits (see Table 11). An insufficient number of patients received mean doses of venlafaxine hydrochloride extended-release capsules over 300 mg per day in clinical studies to fully evaluate the incidence of sustained increases in blood pressure at these higher doses.

Table 11 Sustained Elevations in SDBP in Venlafaxine Hydrochloride Extended-Release Capsules Premarketing Studies

Venlafaxine hydrochloride extended-release capsule was associated with mean increases in pulse rate compared with placebo in premarketing placebo- controlled studies (see Table 12) [see Warnings and Precautions (5.3, 5.4)].

Table 12 Approximate Mean Final On-therapy Increase in Pulse Rate (beats/min) in Venlafaxine Hydrochloride Extended-Release Capsules Premarketing Placebo-controlled Studies (up to 12 Weeks Duration)

6.3 Laboratory Changes

Serum Cholesterol

Venlafaxine hydrochloride extended-release capsule was associated with mean final increases in serum cholesterol concentrations compared with mean final decreases for placebo in premarketing MDD, GAD, SAD and PD clinical studies (Table 13).

Table 13 Mean Final On-therapy Changes in Cholesterol Concentrations (mg/dL) in Venlafaxine Hydrochloride Extended-Release Capsules Premarketing Studies

Venlafaxine hydrochloride extended-release capsules treatment for up to 12 weeks in premarketing placebo-controlled trials for major depressive disorder was associated with a mean final on- therapy increase in serum cholesterol concentration of approximately 1.5 mg/dL compared with a mean final decrease of 7.4 mg/dL for placebo. Venlafaxine hydrochloride extended-release capsules treatment for up to 8 weeks and up to 6 months in premarketing placebo- controlled GAD trials was associated with mean final on-therapy increases in serum cholesterol concentration of approximately 1.0 mg/dL and 2.3 mg/dL, respectively while placebo subjects experienced mean final decreases of 4.9 mg/dL and 7.7 mg/dL, respectively. Venlafaxine hydrochloride extended-release capsules treatment for up to 12 weeks and up to 6 months in premarketing placebo-controlled Social Anxiety Disorder trials was associated with mean final on-therapy increases in serum cholesterol concentration of approximately 7.9 mg/dL and 5.6 mg/dL, respectively, compared with mean final decreases of 2.9 and 4.2 mg/dL, respectively, for placebo. Venlafaxine hydrochloride extended-release capsules treatment for up to 12 weeks in premarketing placebo- controlled panic disorder trials was associated with mean final on- therapy increases in serum cholesterol concentration of approximately 5.8 mg/dL compared with a mean final decrease of 3.7 mg/dL for placebo.

Patients treated with venlafaxine hydrochloride tablets for at least 3 months in placebo-controlled 12-month extension trials had a mean final on-therapy increase in total cholesterol of 9.1 mg/dL compared with a decrease of 7.1 mg/dL among placebo-treated patients. This increase was duration dependent over the study period and tended to be greater with higher doses. Clinically relevant increases in serum cholesterol, defined as 1) a final on-therapy increase in serum cholesterol ≥50 mg/dL from baseline and to a value ≥261 mg/dL, or 2) an average on-therapy increase in serum cholesterol ≥50 mg/dL from baseline and to a value ≥261 mg/dL, were recorded in 5.3% of venlafaxine- treated patients and 0.0% of placebo- treated patients.

Serum Triglycerides

Venlafaxine hydrochloride extended-release capsules was associated with mean final on-therapy increases in fasting serum triglycerides compared with placebo in premarketing clinical studies of SAD and PD up to 12 weeks (pooled data) and 6 months duration (Table 14).

Table 14 Mean Final On-therapy Increases in Triglyceride Concentrations (mg/dL) in Venlafaxine Hydrochloride Extended-Release Capsules Premarketing Studies

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval 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 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)]

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