Drug Facts
Composition & Profile
Identifiers & Packaging
16 HOW SUPPLIED/STORAGE AND HANDLING Venlafaxine Extended-Release Tablets are suppled as: 112.5 mg, white, round, biconvex tablet, with “ALM” over “632” printed in black ink on one side, and plain on the other side. NDC 52427-632-30 Bottle of 30 tablets Storage and Handling Store at controlled room temperature 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].; PACKAGE LABEL PRINCIPAL DISPLAY PANEL SECTION NDC 52427- 632 -30 Venlafaxine Extended-Release Tablets 112.5 mg PHARMACIST: Dispense the accompanying Medication Guide to each patient. Rx only 30 Tablets
- 16 HOW SUPPLIED/STORAGE AND HANDLING Venlafaxine Extended-Release Tablets are suppled as: 112.5 mg, white, round, biconvex tablet, with “ALM” over “632” printed in black ink on one side, and plain on the other side. NDC 52427-632-30 Bottle of 30 tablets Storage and Handling Store at controlled room temperature 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].
- PACKAGE LABEL PRINCIPAL DISPLAY PANEL SECTION NDC 52427- 632 -30 Venlafaxine Extended-Release Tablets 112.5 mg PHARMACIST: Dispense the accompanying Medication Guide to each patient. Rx only 30 Tablets
Overview
Venlafaxine Extended-Release Tablets contains venlafaxine, an SNRI, present as venlafaxine besylate monohydrate salt. Venlafaxine besylate monohydrate is designated (R/S)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl] cyclohexanol benzene sulfonate monohydrate or Cyclohexanol, 1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]-, benzenesulfonate, monohydrate and has the molecular formula of C 23 H 33 NO 5 S⸱H 2 O. Its molecular weight is 453.59. The structural formula is shown as follows: Venlafaxine besylate is a white to almost white crystalline powder, with a solubility of about 32 mg/ml in water. Its octanol:water partition coefficient is 0.154. Drug release is controlled by a combination of diffusion through the extended-release coating and erosion of the core tablets. The modified drug release is pH independent. Venlafaxine Extended-Release Tablets are intended for oral administration and contains 183.95 mg of venlafaxine besylate monohydrate equivalent to 112.5 mg of venlafaxine. Inactive ingredients: ammonio methacrylate copolymer, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, silicon dioxide, simethicone, talc, titanium dioxide, and triacetin. The tablet printing ink is composed of ammonium hydroxide, black iron oxide, n-butyl alcohol, isopropyl alcohol, propylene glycol, and shellac.
Indications & Usage
Venlafaxine Extended-Release Tablets are indicated in adults for the treatment of: Major depressive disorder (MDD) Generalized Anxiety Disorder (GAD) Venlafaxine Extended-Release Tablets are a serotonin and norepinephrine reuptake inhibitor (SNRI) indicated in adults for the treatment of: Major Depressive Disorder (MDD) ( 1 ) Generalized Anxiety Disorder (GAD) ( 1 )
Dosage & Administration
Do not initiate treatment with Venlafaxine Extended-Release Tablets. Use another venlafaxine extended-release product for initial dosage, titration, and dosages below 112.5 mg once daily ( 2.1 ). Take once daily with food. Swallow tablets whole with fluid. Do not divide, crush, chew, or place in water ( 2.1 ). Venlafaxine Extended-Release Tablets can be initiated at 112.5 mg once daily in patients who have received at least 75 mg of another venlafaxine extended-release product for at least 4 days ( 2.2 , 2.3 ). Maximum recommended dosage is 225 mg once daily ( 2.2 , 2.3 ). When discontinuing treatment, reduce the dose gradually. Gradual dosage reduction will require the use of another venlafaxine extended-release product ( 2.8 , 5.7 ). Hepatic and Renal impairment: Maximum recommended dosage of Venlafaxine Extended-Release Tablets is 112.5 mg once daily. Switch to another venlafaxine extended-release product if doses lower than 112.5 mg are needed ( 2.6 , 2.7 ). 2.1 Important Dosing and Administration Information Do not initiate venlafaxine treatment, titrate by doses less than 112.5 mg, or taper treatment with Venlafaxine Extended-Release Tablets, as dosing is not possible in these scenarios because Venlafaxine Extended-Release Tablets are only available in a 112.5 mg strength. Use another venlafaxine extended-release product for dosage initiation, titration, administration of dosages below 112.5 mg once daily, and to taper during discontinuation [see Dosage and Administration ( 2.6 , 2.7 , 2.8 )] . Refer to the Prescribing Information of other venlafaxine extended-release products for the recommended dosage of those products in these dosing scenarios. Venlafaxine Extended-Release Tablets can be initiated in patients who have received at least 75 mg per day of another venlafaxine extended-release product for at least 4 days [see Dosage and Administration ( 2.2 , 2.3 )] . Administer Venlafaxine Extended-Release Tablets as once daily with food, either in the morning or in the evening at approximately the same time each day [see Clinical Pharmacology ( 12.3 )] . Swallow tablets whole with fluid. Do not divide, crush, chew, or place in water. 2.2 Recommended Dosage for the Treatment of Major Depressive Disorder Initiate Venlafaxine Extended-Release Tablets at a dosage of 112.5 mg once daily in patients who have received at least 75 mg per day of another venlafaxine extended-release product for at least 4 days [see Dosage and Administration ( 2.1 )] . Patients not responding to their current venlafaxine dosage may benefit from dose increases to a maximum of 225 mg per day. Increase the dosage in increments of up to 75 mg per day, as needed, using another venlafaxine extended-release product at intervals of 4 days or more. 2.3 Recommended Dosage for the Treatment of Generalized Anxiety Disorder Initiate Venlafaxine Extended-Release Tablets at a dosage of 112.5 mg once daily in patients who have received at least 75 mg per day of another venlafaxine extended-release product for at least 4 days [see Dosage and Administration ( 2.1 )] . Patients not responding to their current venlafaxine dosage may benefit from dose increases to a maximum of 225 mg per day. Increase the dosage in increments of up to 75 mg per day, as needed, using another venlafaxine extended-release product at intervals of 4 days or more. 2.4 Screen for Bipolar Disorder Prior to Starting Venlafaxine Extended-Release Tablets Prior to initiating treatment with Venlafaxine Extended-Release Tablets, screen patients for a personal or family history of bipolar disorder, mania, or hypomania [see Warnings and Precautions ( 5.6 )] . 2.5 Switching Patients from Venlafaxine Tablets (Immediate-Release Formulation) Patients who are currently receiving venlafaxine tablets (immediate-release formulation) may be switched to Venlafaxine Extended-Release Tablets at the nearest equivalent dose (mg per day) if the total daily dosage is either 112.5 mg or 225 mg once daily. 2.6 Dosage Recommendations in Patients with Hepatic Impairment Reduce the total daily dose of venlafaxine by 50% in patients with mild (Child-Pugh Class A) to moderate (Child-Pugh Class B) hepatic impairment. In patients with severe hepatic impairment (Child-Pugh Class C) or hepatic cirrhosis, it may be necessary to reduce the dose by 50% or more [see Use in Specific Populations ( 8.6 )] . The maximum recommended dosage of Venlafaxine Extended-Release Tablets in patients with hepatic impairment is 112.5 mg once daily. If the total daily dosage of venlafaxine is less than 112.5 mg per day, use another venlafaxine extended-release product [see Dosage and Administration ( 2.1 )] . 2.7 Dosage Recommendations in Patients with Renal Impairment Reduce the total daily dose of venlafaxine by 25% to 50% in patients with mild (CLcr = 60-89 mL/min) or moderate (CLcr = 30-59 mL/min) renal impairment. In patients undergoing hemodialysis or with severe renal impairment (CLcr < 30 mL/min), the total daily dose should be reduced by 50% or more [see Use in Specific Populations ( 8.7 )] . The maximum recommended dosage of Venlafaxine Extended-Release Tablets in patients with renal impairment is 112.5 mg once daily. If the total daily dosage of venlafaxine is less than 112.5 mg per day, use another venlafaxine extended-release product [see Dosage and Administration ( 2.1 )] . 2.8 Discontinuing Treatment with Venlafaxine Extended-Release Tablets A gradual reduction in the dose, rather than abrupt cessation, is recommended whenever possible when discontinuing Venlafaxine Extended-Release Tablets. In clinical studies with venlafaxine extended-release capsules, tapering was achieved by reducing the daily dosage by 75 mg at one-week intervals. Given that dosage strengths of Venlafaxine Extended-Release Tablets are not available below 112.5 mg, use another venlafaxine extended-release product for discontinuation [see Dosage and Administration ( 2.1 )] . Individualization of tapering may be necessary. In some patients, discontinuation may need to occur over a period of several months [see Warnings and Precautions ( 5.7 )] . 2.9 Switching Patients to or from a Monoamine Oxidase Inhibitor (MAOI) Antidepressant At least 14 days must elapse between discontinuation of an MAOI (intended to treat psychiatric disorders) and initiation of therapy with Venlafaxine Extended-Release Tablets. In addition, at least 7 days should be allowed after stopping Venlafaxine Extended-Release Tablets before starting an MAOI intended to treat psychiatric disorders [see Contraindications ( 4 ), Warnings and Precautions ( 5.2 ), and Drug Interactions ( 7.1 )] .
Warnings & Precautions
Serotonin Syndrome: Increased risk when co-administered with other serotonergic agents, but also when taken alone. If it occurs, discontinue Venlafaxine Extended-Release Tablets and serotonergic agents and initiate supportive treatment ( 4 , 5.2 , 7.1 ). Elevated Blood Pressure: Control hypertension before initiating treatment. Monitor blood pressure regularly during treatment ( 5.3 ). Increased Risk of Bleeding: Concomitant use of aspirin, NSAIDs, other antiplatelet drugs, warfarin, and other anticoagulants may increase risk ( 5.4 ). Angle Closure Glaucoma: Angle closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants ( 5.5 ). Activation of Mania/Hypomania: Screen patients for bipolar disorder ( 2.4 , 5.6 ). Discontinuation Syndrome: Taper dose and monitor for discontinuation symptoms ( 5.7 ). Seizure: Can occur. Use with caution in patients with seizure disorder ( 5.8 ). Hyponatremia: Can occur in association with SIADH ( 5.9 ). Interstitial Lung Disease and Eosinophilic Pneumonia: Can occur ( 5.12 ). Sexual Dysfunction: Venlafaxine Extended-Release Tablets may cause symptoms of sexual dysfunction ( 5.13 ). 5.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1,000 patients treated are provided in Table 1. Table 1: Risk Differences of the Number of Patients of Suicidal Thoughts and Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric* and Adult Patients *Venlafaxine Extended-Release Tablets are not approved for use in pediatric patients. Age Range Drug-Placebo Difference in Number of Patients of Suicidal Thoughts and Behaviors per 1,000 Patients Treated Increases Compared to Placebo < 18 years old 14 additional patients 18–24 years old 5 additional patients Decreases Compared to Placebo 25–64 years old 1 fewer patient ≥ 65 years old 6 fewer patients It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors. Monitor all antidepressant-treated patients for any indication for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing Venlafaxine Extended-Release Tablets, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors. 5.2 Serotonin Syndrome Serotonin-norepinephrine reuptake inhibitors (SNRIs), including Venlafaxine Extended-Release Tablets, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, meperidine, methadone, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs [see Contraindications ( 4 ), Drug Interactions ( 7.1 )] . Serotonin syndrome can also occur when these drugs are used alone. Serotonin syndrome signs and symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The concomitant use of Venlafaxine Extended-Release Tablets with MAOIs is contraindicated. In addition, do not initiate Venlafaxine Extended-Release Tablets in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking Venlafaxine Extended-Release Tablets, discontinue Venlafaxine Extended-Release Tablets before initiating treatment with the MAOI [see Dosage and Administration ( 2.9 ), Contraindications ( 4 ), Drug Interactions ( 7.1 )] . Monitor all patients taking Venlafaxine Extended-Release Tablets for the emergence of serotonin syndrome. Discontinue treatment with Venlafaxine Extended-Release Tablets and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of Venlafaxine Extended-Release Tablets with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms. 5.3 Elevated Blood Pressure In controlled trials, there were dose-related increases in systolic and diastolic blood pressure, as well as cases of sustained hypertension [see Adverse Reactions ( 6.1 )] . Monitor blood pressure before initiating treatment with Venlafaxine Extended-Release Tablets and regularly during treatment. Control pre-existing hypertension before initiating treatment with Venlafaxine Extended-Release Tablets. Use caution in treating patients with pre-existing hypertension or cardiovascular or cerebrovascular conditions that might be compromised by increases in blood pressure. Sustained blood pressure elevation can lead to adverse outcomes. Cases of elevated blood pressure requiring immediate treatment have been reported with venlafaxine extended-release capsules. Consider dose reduction or discontinuation of treatment for patients who experience a sustained increase in blood pressure. Across all clinical studies with venlafaxine, 1.4% of patients in the venlafaxine extended-release capsules treated groups experienced a ≥15 mm Hg increase in supine diastolic blood pressure (SDBP) ≥ 105 mm Hg, compared to 0.9% of patients in the placebo groups. Similarly, 1% of patients in the venlafaxine extended-release capsules treated groups experienced a ≥ 20 mm Hg increase in supine systolic blood pressure (SSBP) with blood pressure ≥ 180 mm Hg, compared to 0.3% of patients in the placebo groups [see Adverse Reactions ( 6.1 )] . Treatment with venlafaxine extended-release capsules was associated with sustained hypertension (defined as SDBP ≥ 90 mm Hg and ≥ 10 mm Hg above baseline for three consecutive on-therapy visits) [see Adverse Reactions (6.1)] . An insufficient number of patients received mean doses of venlafaxine 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. 5.4 Increased Risk of Bleeding Drugs that interfere with serotonin reuptake inhibition, including Venlafaxine Extended-Release Tablets, may increase the risk of bleeding events, ranging from ecchymoses, hematomas, epistaxis, petechiae, and gastrointestinal hemorrhage to life-threatening hemorrhage. Concomitant use of aspirin, Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), warfarin, and other anti-coagulants or other drugs known to affect platelet function may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Based on data from the 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 Use in Specific Populations ( 8.1 )] . Inform patients about the increased risk of bleeding associated with the concomitant use of Venlafaxine Extended-Release Tablets and antiplatelet agents or anticoagulants. For patients taking warfarin, carefully monitor coagulation indices when initiating, titrating, or discontinuing Venlafaxine Extended-Release Tablets. 5.5 Angle-Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs, including Venlafaxine Extended-Release Tablets, may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Avoid use of antidepressants, including Venlafaxine Extended-Release Tablets, in patients with untreated anatomically narrow angles. 5.6 Activation of Mania/Hypomania In patients with bipolar disorder, treating a depressive episode with Venlafaxine Extended-Release Tablets or another antidepressant may precipitate a mixed/manic episode. Mania or hypomania was reported in venlafaxine extended-release capsules treated patients in the premarketing studies in MDD (see Table 2). Prior to initiating treatment with Venlafaxine Extended-Release Tablets, screen for any personal or family history of bipolar, mania, or hypomania. Table 2: Incidence (%) of Mania or Hypomania Reported in Venlafaxine Extended-Release Capsules Treated Patients in the Premarketing Studies Indication Venlafaxine Extended-Release Capsules Placebo MDD 0.3 0.0 GAD 0.0 0.2 5.7 Discontinuation Syndrome Discontinuation symptoms have been systematically evaluated in patients taking venlafaxine, including prospective analyses of clinical studies in GAD and retrospective surveys of studies in MDD. Abrupt discontinuation or dose reduction of venlafaxine at various doses has been found to be associated with the appearance of new symptoms, the frequency of which increased with increased dose level and with longer duration of treatment. Reported symptoms include agitation, anorexia, anxiety, confusion, impaired coordination and balance, diarrhea, dizziness, dry mouth, dysphoric mood, fasciculation, fatigue, flu-like symptoms, headaches, hypomania, insomnia, nausea, nervousness, nightmares, sensory disturbances (including shock-like electrical sensations), somnolence, sweating, tremor, vertigo, and vomiting. There have been postmarketing reports of serious discontinuation symptoms which can be protracted and severe. Completed suicide, suicidal thoughts, aggression and violent behavior have been observed in patients during reduction in venlafaxine extended-release capsules dosage, including during discontinuation. Other postmarketing reports describe visual changes (such as blurred vision or trouble focusing) and increased blood pressure after stopping or reducing the dose of venlafaxine extended-release capsules. During marketing of venlafaxine extended-release capsules, other SNRIs, and SSRIs, there have been reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: irritability, lethargy, emotional lability, tinnitus, and seizures. Patients should be monitored for these symptoms when discontinuing treatment with Venlafaxine Extended-Release Tablets. A gradual reduction in the dose, rather than abrupt cessation, is recommended. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the healthcare provider may continue decreasing the dose, but at a more gradual rate. In some patients, discontinuation may need to occur over a period of several months [see Dosage and Administration ( 2.8 )] . Given that dosage strengths of Venlafaxine Extended-Release Tablets are not available below 112.5 mg, use another venlafaxine extended-release product for discontinuation [see Dosage and Administration ( 2.1 )] . 5.8 Seizures Cases of seizures have been reported with venlafaxine therapy. Venlafaxine Extended-Release Tablets has not been systematically evaluated in patients with seizure disorder. Venlafaxine Extended-Release Tablets should be prescribed with caution in patients with a history of seizures and should be discontinued in any patient who develops seizures. 5.9 Hyponatremia Hyponatremia can occur as a result of treatment with SNRIs, including Venlafaxine Extended-Release Tablets In many cases, the hyponatremia appears to be the result of the Syndrome of Inappropriate Antidiuretic Hormone (SIADH) secretion. Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics, or those who are otherwise volume-depleted, may be at greater risk [see Use in Specific Populations ( 8.5 ) and Clinical Pharmacology ( 12.3 )] . Consider discontinuation of Venlafaxine Extended-Release Tablets in patients with symptomatic hyponatremia, and institute appropriate medical intervention. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. 5.10 Weight and Height Changes in Pediatric Patients Weight Changes The average change in body weight and incidence of weight loss (percentage of patients who lost 3.5% or more) in the placebo-controlled pediatric studies in MDD and GAD with venlafaxine extended-release capsules are shown in Tables 3 and 4. Venlafaxine Extended-Release Tablets are not approved for use in pediatric patients [see Use in Specific Populations ( 8.4 )] . Table 3: Average Change in Body Weight (kg) From Beginning of Treatment in Pediatric Patients a in Double-blind, Placebo-controlled Studies of Venlafaxine Extended-Release Capsules Indication (Study Duration) Venlafaxine Extended-Release Capsules Placebo a Venlafaxine Extended-Release Tablets are not approved for use in pediatric patients. MDD and GAD (4 pooled studies, 8 weeks) -0.45 (n = 333) +0.77 (n = 333) Table 4: Incidence (%) of Pediatric Patients a Experiencing Weight Loss (3.5% or more) in Double-blind, Placebo-controlled Studies of Venlafaxine Extended-Release Capsules Indication (Study Duration) Venlafaxine Extended-Release Capsules Placebo a Venlafaxine Extended-Release Tablets are not approved for use in pediatric patients. b p < 0.001 versus placebo MDD and GAD (4 pooled studies, 8 weeks) 18 b (n = 333) 3.6 (n = 333) Weight loss was not limited to patients with anorexia [see Warnings and Precautions ( 5.11 )] . The risks associated with longer term use of venlafaxine extended-release capsules were assessed in an open-label MDD study of pediatric patients 6 years to 17 years old who received venlafaxine extended-release capsules for up to six months. The pediatric patients 6 years to 17 years old in the study had increases in weight that were less than expected, based on data from age- and sex-matched peers. The difference between observed weight gain and expected weight gain was larger for pediatric patients 6 years to < 12 years old than for pediatric patients ≥ 12 years old. Height Changes Table 5 shows the average height increase in pediatric patients in the short-term, placebo-controlled MDD and GAD studies with venlafaxine extended-release capsules. The differences in height increases in GAD and MDD studies were most notable in patients younger than twelve. Venlafaxine Extended-Release Tablets are not approved for use in pediatric patients [see Use in Specific Populations ( 8.4 )] . Table 5: Average Height Increases (cm) in Pediatric Patients a in Placebo-controlled Studies of Venlafaxine Extended-Release Capsules a Venlafaxine Extended-Release Tablets are not approved for use in pediatric patients. b p = 0.041 Indication (Study Duration) Venlafaxine Extended-Release Capsules Placebo MDD (8 weeks) 0.8 (n = 146) 0.7 (n = 147) GAD (8 weeks) 0.3 b (n = 122) 1.0 (n = 132) In the six-month, open-label MDD study with venlafaxine extended-release capsules, pediatric patients 6 years to 17 years old had height increases that were less than expected, based on data from age- and sex-matched peers. The difference between observed and expected growth rates was larger for pediatric patients 6 years to < 12 years old than for pediatric patients ≥ 12 years old [see Use in Specific Populations ( 8.4 )] . 5.11 Appetite Changes in Pediatric Patients Decreased appetite (reported as anorexia) was more commonly observed in venlafaxine extended-release capsule-treated pediatric patients 6 years to 17 years old versus placebo-treated patients in the premarketing evaluation of venlafaxine extended-release capsules for MDD and GAD (see Table 6). Venlafaxine Extended-Release Tablets are not approved for use in pediatric patients [see Use in Specific Populations ( 8.4 )] . Table 6: Incidence (%) of Decreased Appetite and Associated Discontinuation Rates a (%) in Pediatric Patients b in Placebo-controlled Studies of Venlafaxine Extended-Release Capsules Indication (Study Duration) Venlafaxine Extended-Release Capsules Incidence Discontinuation Placebo Incidence a The discontinuation rates for weight loss were 0.7% for patients receiving either venlafaxine extended-release capsules or placebo. b Venlafaxine Extended-Release Tablets are not approved for use in pediatric patients. MDD and GAD (pooled, 8 weeks) 10 0.0 3 5.12 Interstitial Lung Disease and Eosinophilic Pneumonia Interstitial lung disease and eosinophilic pneumonia associated with venlafaxine therapy have been rarely reported. The possibility of these events should be considered in Venlafaxine Extended-Release Tablets patients who present with progressive dyspnea, cough or chest discomfort. Such patients should undergo a prompt medical evaluation, and discontinuation of Venlafaxine Extended-Release Tablets should be considered. 5.13 Sexual Dysfunction Use of SNRIs, including Venlafaxine Extended-Release Tablets, may cause symptoms of sexual dysfunction [see Adverse Reactions ( 6.1 )] . In male patients, SNRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction. In female patients, SNRI use may result in decreased libido and delayed or absent orgasm. It is important for prescribers to inquire about sexual function prior to initiation of Venlafaxine Extended-Release Tablets and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported. When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder. Discuss potential management strategies to support patients in making informed decisions about treatment.
Boxed Warning
SUICIDAL THOUGHTS AND BEHAVIORS Antidepressants increased the risk of suicidal thoughts and behavior in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and emergence of suicidal thoughts and behaviors [see Warnings and Precautions ( 5.1 )]. Venlafaxine Extended-Release Tablets are not approved for use in pediatric patients [see Use in Specific Populations ( 8.4 )]. WARNING: SUICIDAL THOUGHTS AND BEHAVIORS See full prescribing information for complete boxed warning. Increased risk of suicidal thinking and behavior in pediatric and young adult patients taking antidepressants. Closely monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors ( 5.1 ). Venlafaxine Extended-Release Tablets are not approved for use in pediatric patients ( 8.4 )
Contraindications
Venlafaxine Extended-Release Tablets are contraindicated in patients: with known hypersensitivity to venlafaxine besylate, venlafaxine hydrochloride, desvenlafaxine succinate or to any excipients in Venlafaxine Extended-Release Tablets [see Adverse Reactions ( 6.2 )] . taking, or within 14 days of stopping, MAOIs (including the MAOIs linezolid and intravenous methylene blue) because of increased risk of serotonin syndrome [see Dosage and Administration ( 2.9 ), Warnings and Precautions ( 5.2 ), Drug Interactions ( 7.1 )] . Hypersensitivity to venlafaxine besylate, venlafaxine hydrochloride, desvenlafaxine succinate, or any excipients in Venlafaxine Extended-Release Tablets ( 4 ). Concomitant use of monoamine oxidase inhibitors (MAOIs) or within 14 days of discontinuing an MAOI ( 4 , 5.2 , 7.1 ).
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 and Precautions ( 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 )] Seizures [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 )] 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 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 [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) 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 (3) GAD 37.5 a to 225 5/1011 (0.5) Venlafaxine extended-release capsules was associated with mean increases in pulse rate compared with placebo in premarketing placebo-controlled studies (see Table 11) [see Warnings and Precautions (5.3, 5.4)] . 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 [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 )]
Drug Interactions
Alcohol: Increases the release rate of Venlafaxine Extended-Release Tablets. Avoid concomitant use ( 7.1 ). 7.1 Drugs Having Clinically Important Interactions with Venlafaxine Extended-Release Tablets Table 13: Clinically Significant Drug Interactions with Venlafaxine Extended-Release Tablets Monoamine Oxidase Inhibitors (MAOI) Clinical Impact Concomitant use of SNRIs, including Venlafaxine Extended-Release Tablets, with MAOIs increases the risk of serotonin syndrome. Intervention Concomitant use of Venlafaxine Extended-Release Tablets is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [see Dosage and Administration ( 2.9 ), Contraindications ( 4 ), and Warnings and Precautions ( 5.2 )] . Other Serotonergic Drugs Clinical Impact Concomitant use of Venlafaxine Extended-Release Tablets 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 Extended-Release Tablets is used concomitantly with other drugs that may affect the serotonergic neurotransmitter systems. If serotonin syndrome occurs, consider discontinuation of Venlafaxine Extended-Release Tablets and/or concomitant serotonergic drugs [see Dosage and Administration ( 2.8 ), Warnings and Precautions ( 5.2 )] . Alcohol Clinical Impact Based on an in vitro study, alcohol increases the release rate of Venlafaxine Extended-Release Tablets [see Clinical Pharmacology ( 12.3 )] . Intervention Avoid concomitant use of alcohol during treatment with Venlafaxine Extended-Release Tablets. Drugs that Interfere with Hemostasis Clinical Impact Concomitant use of Venlafaxine Extended-Release Tablets with an antiplatelet or anticoagulant drug may potentiate the risk of bleeding. This may be due to the effect of venlafaxine on the release of serotonin by platelets. Intervention Closely monitor patients receiving an antiplatelet or anticoagulant drug for bleeding when Venlafaxine Extended-Release Tablets is initiated or discontinued [see Warnings and Precautions ( 5.4 )] . CYP3A Inhibitors Clinical Impact Concomitant use of Venlafaxine Extended-Release Tablets with a CYP3A inhibitor increases the C max and AUC of venlafaxine and O-desmethylvenlafaxine (ODV) [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of toxicity of venlafaxine. Intervention Consider reducing the dose of Venlafaxine Extended-Release Tablets. CYP2D6 Substrates Clinical Impact Concomitant use of Venlafaxine Extended-Release Tablets with a CYP2D6 substrate increases C max and AUC of the 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 Extended-Release Tablets Weight Loss Agents The safety and efficacy of venlafaxine therapy in combination with weight loss agents, including phentermine, have not been established. Coadministration of Venlafaxine Extended-Release Tablets and weight loss agents is not recommended. Venlafaxine Extended-Release Tablets 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. 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.
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