Venlafaxineside effects

The following adverse reactions are discussed in more detail in other sections of the labeling: Hypersensitivity Suicidal Thoughts and Behaviors in Adolescents and Young Adults Serotonin Syndrome Elevated Blood Pressure Increased Risk of Bleeding Angle-Closure Glaucoma Activation of Mania/Hypomania Discontinuation Syndrome Seizures Hyponatremia Weight and Height Changes in Pediatric Patients Appetite Changes in Pediatric Patients Interstitial Lung Disease and Eosinophilic Pneumonia Sexual Dysfunction 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. To report SUSPECTED ADVERSE REACTIONS, contact Almatica Pharma LLC at 1-877-447-7979 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical

Studies Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. The safety of Venlafaxine Extended-Release Tablets for the treatment of MDD and GAD is based on adequate and well controlled studies of venlafaxine extended-release capsules. Below is a display of adverse reactions of venlafaxine extended-release capsules from those adequate and well-controlled studies in MDD, GAD, and other indications. Most Common Adverse Reactions The most commonly observed adverse reactions in the clinical study database in venlafaxine extended-release capsules treated patients in MDD, GAD, and other indications (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 MDD, GAD, and other indications, 12% of the 3,558 patients who received venlafaxine extended-release capsules within a dosage range of 37.5 mg to 225 mg discontinued treatment due to an adverse reaction, compared with 4% of the 2,197 placebo-treated patients in those studies [Venlafaxine Extended-Release Tablets are only available as 112.5 mg dosage strength]. The most common adverse reactions leading to discontinuation in ≥ 1% of the venlafaxine extended-release capsules treated patients in the short-term studies (up to 12 weeks) in MDD, GAD, and other indications are shown in Table 7.

Table 7: Adverse Reactions Leading to Discontinuation in Venlafaxine Extended-Release Capsule Placebo-controlled Clinical Studies (up to 12 Weeks Duration) Body System Adverse Reaction Venlafaxine Extended-Release Capsules n = 3,558 Placebo n = 2,197 Body as a whole Asthenia 1.7 0.5 Headache 1.5

0.8 Digestive system

Nausea 4.3

0.4 Nervous system

Dizziness 2.2 0.8 Insomnia 2.1 0.6 Somnolence 1.7 0.3 Skin and appendages 1.5 0.6 Sweating 1.0

0.2 Common Adverse

Reactions in Placebo-controlled Studies Common adverse reactions (those that occurred in ≥ 2% of venlafaxine extended-release capsules treated patients [357 MDD patients, 1,381 GAD patients, and 1,820 patients for other indications] and more frequently than placebo) in venlafaxine extended-release capsules treated patients in short-term, placebo-controlled, fixed- and flexible-dose clinical studies within a dosage range of doses 37.5 mg to 225 mg per day are shown in Table 8 [Venlafaxine Extended-Release Tablets are only available as 112.5 mg dosage strength]. The adverse reaction profile did not differ substantially between the different patient populations.

Table 8: Percentage of Patients Reporting Adverse Reactions (≥ 2% and > placebo) in Placebo-controlled Studies of Venlafaxine Extended-Release Capsules (up to 12 Weeks Duration) in MDD, GAD, and Other Indications a Percentages based on the number of men (venlafaxine extended-release capsules, n = 1,440; placebo, n = 923) b Percentages based on the number of women (venlafaxine extended-release capsules, n = 2,118; placebo, n = 1,274) Body System Adverse Reaction Venlafaxine Extended-Release Capsules n = 3,558 Placebo n = 2,197 Body as a whole Asthenia 12.6

7.8 Cardiovascular system

Hypertension 3.4 2.6 Palpitation 2.2 2.0 Vasodilatation 3.7

1.9 Digestive system

Anorexia 9.8 2.6 Constipation 9.3 3.4 Diarrhea 7.7 7.2 Dry mouth 14.8 5.3 Nausea 30.0 11.8 Vomiting 4.3

2.7 Nervous system

Abnormal dreams 2.9 1.4 Dizziness 15.8 9.5 Insomnia 17.8 9.5 Libido decreased 5.1 1.6 Nervousness 7.1 5.0 Paresthesia 2.4 1.4 Somnolence 15.3 7.5 Tremor 4.7

1.6 Respiratory system

Yawn 3.7

0.2 Skin and appendages

Sweating (including night sweats) 11.4

2.9 Special senses

Abnormal vision 4.2

1.6 Urogenital system

Abnormal ejaculation/orgasm (men) a 9.9 0.5 Anorgasmia (men) a 3.6 0.1 Anorgasmia (women) b 2.0 0.2 Impotence (men) a 5.3

1.0 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, bruxism Hemic/Lymphatic system – Ecchymosis Metabolic/Nutritional – Hypercholesterolemia, weight gain, weight loss Nervous system – Seizures, manic reaction, 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) Vital Sign Changes In placebo-controlled premarketing studies, there were increases in mean blood pressure (see Table 9). A dose-related increase in mean supine systolic and diastolic blood pressure was evident in patients treated with venlafaxine extended-release capsules. Across all clinical studies in MDD, GAD, and other indications, 1.4% of patients in the venlafaxine 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 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 9: Final On-therapy Mean Changes from Baseline in Supine Systolic (SSBP) and Diastolic (SDBP) Blood Pressure (mm Hg) in Placebo-controlled Studies a Venlafaxine Extended-Release Tablets are only available as 112.5 mg dosage strength. b Maximum recommended dosage for Venlafaxine Extended-Release Tablets is 225 mg once daily. Venlafaxine Extended-Release Capsules Placebo Indication ≤ 75 mg per day a > 75 mg per day a,b (Duration) SSBP SDBP SSBP SDBP SSBP SDBP MDD (8–12 weeks) -0.28 0.37 2.93 3.56 -1.08 -0.10 GAD (8 weeks) -0.28 0.02 2.40 1.68 -1.26 -0.92 (6 months) 1.27 -0.69 2.06 1.28 -1.29 -0.74 Venlafaxine 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 10).

Table 10: Sustained Elevations in SDBP in Venlafaxine Extended-Release Capsules Premarketing Studies a Venlafaxine Extended-Release Tablets are only available as 112.5 mg dosage strength. b Maximum recommended dosage for Venlafaxine Extended-Release Tablets is 225 mg once daily. Indication Dose Range (mg per day) a Incidence (%) MDD 75 a to 375 b 19/705 GAD 37.5 a to 225 5/1011 Venlafaxine extended-release capsules was associated with mean increases in pulse rate compared with placebo in premarketing placebo-controlled studies (see Table 11).

Table 11: Approximate Mean Final On-therapy Increase in Pulse Rate (beats/min) in Venlafaxine Extended-Release Capsules Premarketing Placebo-controlled Studies (up to 12 Weeks Duration) Indication (Duration) Venlafaxine Extended-Release Capsules Placebo MDD (12 weeks) 2 1 GAD (8 weeks) 2 < 1 Laboratory Changes Serum Cholesterol Venlafaxine extended-release capsules was associated with mean final increases in serum cholesterol concentrations compared with mean final decreases for placebo in premarketing MDD and GAD clinical studies (Table 12).

Table 12: Mean Final On-therapy Changes in Cholesterol Concentrations (mg/dL) in Venlafaxine Extended-Release Capsules Premarketing Studies Indication (Duration) Venlafaxine Extended-Release Capsules Placebo MDD (12 weeks) +1.5 -7.4 GAD (8 weeks) +1.0 -4.9 (6 months) +2.3 -7.7 Venlafaxine 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 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.

6.2 Postmarketing

Experience The following adverse reactions have been identified during post approval use of venlafaxine 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, blood dyscrasias (including agranulocytosis, aplastic anemia, neutropenia and pancytopenia), prolonged bleeding time, thrombocytopenia Metabolic/Nutritional – Hyponatremia, Syndrome of Inappropriate Antidiuretic Hormone (SIADH) secretion, abnormal liver function tests, hepatitis, prolactin increased Musculoskeletal – Rhabdomyolysis Nervous system – Neuroleptic Malignant Syndrome (NMS), serotonergic syndrome, 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 Skin and appendages – Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme Special senses – Angle-closure glaucoma