Pristiq

Pristiq

desvenlafaxine

Manufacturer:

Pfizer

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Desvenlafaxine succinate.
Description
Pristiq also contains the following inactive ingredients: Hypromellose, microcrystalline cellulose, talc, magnesium stearate. Film-Coating: Sodium carboxymethylcellulose, maltodextrin, dextrose, titanium dioxide, stearic acid and iron oxide(s).
Desvenlafaxine is RS-4-[2-dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenol and has the empirical formula of C16H25NO2 (free base) and C16H25NO2·C4H6O4·H2O (succinate monohydrate). Desvenlafaxine succinate monohydrate has a molecular weight of 399.48.
Desvenlafaxine succinate is a white to off-white powder that is soluble in water. The solubility of desvenlafaxine succinate is pH dependent. Its octanol:aqueous system (at pH 7) partition coefficient is 0.21.
Desvenlafaxine (O-desmethylvenlafaxine), a structurally novel serotonin and norepinephrine reuptake inhibitor (SNRI), is the major active metabolite of the antidepressant venlafaxine.
Action
Pharmacology: Mechanism of Action: Non-clinical studies have shown that desvenlafaxine succinate is a selective SNRI. The efficacy of desvenlafaxine succinate is thought to be related to the potentiation of the neurotransmitters serotonin and norepinephrine in the central nervous system.
Desvenlafaxine lacked significant affinity for numerous receptors, including muscarinic-cholinergic, H1-histaminergic, or α1-adrenergic receptors in vitro. In the same comprehensive binding profile assay, desvenlafaxine also lacked significant affinity for various ion channels, including calcium, chloride, potassium and sodium ion channels and also lacked monoamine oxidase (MAO) inhibitory activity. Desvenlafaxine lacked significant activity in the in vitro cardiac potassium channel (hERG) assay.
In preclinical rodent models, desvenlafaxine demonstrated activity predictive of antidepressant, anxiolytic and thermoregulatory actions, and pain inhibitory properties.
Major Depressive Disorder Studies: Pristiq was studied in a clinical programme involving 3292 patients meeting DSM-IV criteria for major depressive disorder. Overall, doses of 50-400 mg/day were shown to be effective in 4 out of 9 randomised, double-blind, placebo-controlled, short-term studies in adult outpatients with major depressive disorder. Pristiq demonstrated superiority over placebo as measured by improvement in the 17-item Hamilton Depression Rating Scale (HAM-D) total score and the Clinical Global Impressions Scale-Improvement (CGI-I).
In a randomised withdrawal study, patients responding to 12 weeks of acute treatment with open-label Pristiq 200-400 mg once daily were randomised to either desvenlafaxine succinate or placebo for a further 6 months. Pristiq demonstrated significantly longer times to relapse of major depressive disorder than subjects receiving placebo during the double-blind phase of the study (p<0.0001). The incidence of relapse during the 6 months double-blind follow-up period was 24% and 42% for Pristiq and placebo, respectively.
Vasomotor Symptoms Associated with Menopause Studies: The efficacy of desvenlafaxine succinate in the treatment of vasomotor symptoms is thought to be related to the potentiation of the neurotransmitters serotonin and norepinephrine in the central nervous system. Desvenlafaxine succinate alleviated temperature dysfunction in hormone-depleted rodent models. In other preclinical rodent models, desvenlafaxine demonstrated activity predictive of antidepressant, and anxiolytic actions and pain inhibitory properties.
Desvenlafaxine lacked significant affinity for numerous receptors, including muscarinic-cholinergic, H1-histaminergic or α1-adrenergic receptors in vitro. Pristiq also lacked MAO inhibitory activity.
Pharmacokinetics: The single-dose pharmacokinetics of desvenlafaxine are linear and dose-proportional over a dose range of 100-600 mg/day. The mean terminal half-life (t1/2) is approximately 11 hrs. With once-daily dosing, steady-state plasma concentrations are achieved within approximately 4-5 days. At steady state, multiple-dose accumulation of desvenlafaxine is linear and predictable from the single-dose pharmacokinetic profile.
The pharmacokinetics of desvenlafaxine have been thoroughly evaluated in women and men. There are minimal differences based on gender.
Absorption and Distribution: Desvenlafaxine is well absorbed, with an absolute oral bioavailability of 80% [20% coefficient of variation (CV)]. Peak plasma concentrations (Cmax) are observed between 7.5 hrs after oral administration. AUC and peak plasma concentrations of 6747 ng·hr/mL (23% CV) and 376 ng·hr/mL (23% CV), respectively, are predicted with once-daily administration of 100 mg.
Administration with food has minimal impact on drug absorption. Following administration with low, medium and high-fat meals, increases in Cmax of approximately 16% were observed only following a high-fat meal. There was no change in AUC values for any of the meals. The plasma protein-binding of desvenlafaxine is low (30%) and is independent of drug concentration. Desvenlafaxine volume of distribution at steady state following IV administration is 3.4 L/kg, indicating distribution into nonvascular compartments.
Metabolism and Elimination: Approximately 45% of desvenlafaxine is excreted unchanged in urine. Desvenlafaxine is primarily metabolized by conjugation to the O-glucuronide, and to a minor extent through oxidative metabolism. Approximately 19% of the administered dose is excreted as the glucuronide metabolite and <5% as the oxidative metabolite (N,O-didesmethylvenlafaxine) in urine. CYP3A4 is the predominant cytochrome P-450 isozyme mediating the oxidative metabolism (N-demethylation) of desvenlafaxine.
In vitro, desvenlafaxine does not inhibit CYP1A2, 2A6, 2C8, 2C9, 2C19 and 3A4 isozymes and does not induce CYP3A4 and other isozyme expressions. Desvenlafaxine is not a substrate for, or an inhibitor of, the P-glycoprotein transporter based on in vitro data.
Special Populations: Elderly: No dosage adjustment is required solely on the basis of age; however, possible reduced renal clearance of desvenlafaxine should be considered when determining dose (see Dosage & Administration).
Pediatric: Safety and effectiveness in patients <18 years have not been established.
Hepatic: Desvenlafaxine 100 mg was studied kinetically in subjects with mild (Child-Pugh A, n=8), moderate (Child-Pugh B, n=8) and severe (Child-Pugh C, n=8) hepatic impairment and in healthy subjects (n=12).
Average AUC was increased by approximately 31% and 35% in patients with moderate and severe hepatic impairment, respectively, as compared to healthy subjects. Average AUC values were comparable in subjects with mild hepatic impairment and healthy subjects (<5% difference).
Systemic clearance (CL/F) was decreased by approximately 20% and 36% in patients with moderate and severe hepatic impairment, respectively, as compared to healthy subjects. CL/F values were comparable in mild hepatic impairment and healthy subjects (<5% difference).
The average t1/2 changed from approximately 10 hrs in healthy subjects and subjects with mild hepatic impairment to 13 and 14 hrs in moderate and severe hepatic impairment, respectively.
Renal: Desvenlafaxine 100 mg was studied kinetically in subjects with mild (n=9), moderate (n=8), severe (n=7) and end-stage renal disease (ESRD) requiring dialysis (n=9) and in healthy, age-matched control subjects (n=8). Elimination significantly correlated with creatinine clearance. Total body clearance was reduced in subjects with impaired renal function by 29% in mild, 39% in moderate, 51% in severe renal impairment (24-hr CrCl <30 mL/min), and 58% in ESRD, compared to normal subjects. This reduced clearance resulted in increases in AUCs of 42% in mild, 46% in moderate, 108% in severe and 116% in ESRD subjects.
The mean terminal half-life was prolonged from 11.1 hrs in the control subjects to 13.5, 15.5, 17.6 and 22.8 hrs in mild, moderate, severe renal impairment and ESRD subjects, respectively.
For patients with severe renal impairment (24-hr CrCl <30 mL/min) or ESRD, dosage adjustment is recommended (see Dosage & Administration).
Less than 5% of the drug in the body was cleared during a standard 4-hr hemodialysis procedure. Therefore, supplemental doses should not be given to patients after dialysis.
Indications/Uses
Treatment of major depressive disorder.
Treatment of moderate to severe vasomotor symptoms associated with menopause eg, hot flushes.
Dosage/Direction for Use
Major Depressive Disorder: Recommended Usual and Maintenance Dose: 50 mg once daily, with or without food. Based on clinical judgment, if dose increases are indicated for individual patients, they should occur gradually and at intervals of not less than 7 days.
It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacologic therapy. Pristiq has been shown to be effective during long-term (up to 9 months) treatment (see Pharmacology under Actions). Patients should continue on the same dose at which they responded. They should be periodically reassessed to determine the need for continued treatment.
Vasomotor Symptoms Associated with Menopause: Recommended Dose: 100 mg once daily, with or without food. It is recommended to start at 50 mg/day for up to 7 days, to allow patients to adjust to the medicine before increasing to 100 mg/day. Patients should be periodically reassessed to determine the need to continue treatment.
When discontinuing therapy, gradual dose reduction should be considered to minimize discontinuation symptoms (see Precautions).
Hepatic Impairment: No dosage adjustment is necessary for patients with hepatic impairment (see Pharmacokinetics under Actions).
Renal Impairment: Major Depressive Disorder: The recommended starting dose in patients with severe renal impairment (24-hr CrCl <30 mL/min) or ESRD is 50 mg every other day. Because of individual variability in clearance in these patients, individualization of dosage may be desirable. Supplemental doses should not be given to patients after dialysis (see Pharmacokinetics under Actions).
Vasomotor Symptoms Associated with Menopause: The recommended dose in patients with severe renal impairment (24-hr CrCl <30 mL/min) or ESRD is 100 mg every other day. Supplemental doses should not be given to patients after dialysis. It is recommended to titrate from 50 mg every other day for up to 7 days, to 100 mg every other day to allow patients to adjust to the medicine. Because of individual variability in clearance in these patients, individualization of dosage may be desirable (see Pharmacokinetics under Actions).
Elderly: No dosage adjustment is required solely on the basis of age; however, possible reduced renal clearance of desvenlafaxine should be considered when determining dose (see Pharmacokinetics under Actions and Precautions).
Major Depressive Disorder: Of the 3292 patients in pre-marketing clinical trials with desvenlafaxine, 5% of patients were ≥65 years. No overall differences in safety or efficacy were observed between these patients and younger patients, but greater sensitivity of some older patients cannot be ruled out.
Vasomotor Symptoms Associated with Menopause: Of the 1432 patients in pre-marketing vasomotor symptoms clinical trials, 2.5% were ≥65 years and 6.7% were ≥60 years. No overall differences in safety or efficacy were observed between older patients (≥60 years) and younger patients.
Pediatric Patients: Safety and effectiveness in patients <18 years have not been established.
Discontinuation of Pristiq: Symptoms associated with discontinuation of desvenlafaxine, other SNRIs and SSRIs have been reported. Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. 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 physician may continue decreasing the dose, but at a more gradual rate (see Precautions and Adverse Reactions).
Administration: For oral administration.
It is recommended that Pristiq be taken at approximately the same time each day. Tablets must be swallowed whole with fluid and not divided, crushed, chewed or dissolved.
Overdosage
There is limited clinical experience with desvenlafaxine succinate overdosage in humans.
Among the patients included in the premarketing major depressive disorder trials of desvenlafaxine succinate, there were 4 adults who ingested doses >800 mg of desvenlafaxine succinate [4000 mg (desvenlafaxine alone), 900, 1800 and 5200 mg (in combination with other drugs)]; all patients recovered. In addition, 1 patient's 11-month-old child accidentally ingested 600 mg of desvenlafaxine succinate, was treated, and recovered.
No specific antidotes for desvenlafaxine are known. Induction of emesis is not recommended. Because of the moderate volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit.
Treatment should consist of those general measures employed in the management of overdosage with any SSRI/SNRI. Ensure an adequate airway, oxygenation and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients. Activated charcoal should be administered.
Contraindications
Hypersensitivity to desvenlafaxine succinate, venlafaxine HCl or to any excipients in the desvenlafaxine formulation.
Desvenlafaxine is an inhibitor of both norepinephrine and serotonin reuptake. Desvenlafaxine succinate must not be used in combination with a monoamine oxidase inhibitor (MAOI), or within at least 14 days of discontinuing treatment with an MAOI. Based on the half-life of desvenlafaxine succinate, at least 7 days should be allowed after stopping desvenlafaxine succinate before starting an MAOI.
Special Precautions
Clinical Worsening of Depressive Symptoms, Unusual Changes in Behavior, and Suicidality: Desvenlafaxine succinate is an SNRI, a class of medicines that may be used to treat depression. All patients treated with desvenlafaxine should be monitored appropriately and observed closely for clinical worsening and suicidality. Patients, their families and caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression and suicidal ideation, especially when initiating therapy or during any change in dose or dosage regimen. The risk of suicide attempt must be considered, especially in depressed patients, and the smallest quantity of drug, consistent with good patient management, should be provided to reduce the risk of overdose.
Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are strong predictors of suicide. Pooled analyses of short-term placebo-controlled trials of antidepressant medicines (SSRIs and others) showed that these medicines increase the risk of suicidality in children, adolescents and young adults (18-24 years) with major depression and other psychiatric disorders.
Mania/Hypomania: In clinical trials, mania was reported for 0.1% of patients treated with desvenlafaxine. As with all antidepressants, desvenlafaxine should be used cautiously in patients with a history or family history of mania or hypomania (see Adverse Reactions).
Serotonin Syndrome: As with other serotonergic agents, the development of a potentially life-threatening serotonin syndrome may occur with desvenlafaxine treatment, particularly with concomitant use of other serotonergic drugs (including SSRIs, SNRIs and triptans) and with drugs that impair metabolism of serotonin (including MAOIs). Serotonin syndrome symptoms may include mental status changes (eg, agitation, hallucinations and coma), autonomic instability (eg, tachycardia, labile blood pressure and hyperthermia), neuromuscular aberrations (eg, hyperreflexia, incoordination) and/or gastrointestinal symptoms (eg, nausea, vomiting and diarrhea) (see Interactions).
If concomitant treatment with desvenlafaxine and an SSRI, another SNRI or a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.
The concomitant use of desvenlafaxine with serotonin precursors (eg, tryptophan supplements) is not recommended.
Narrow-Angle Glaucoma: Mydriasis has been reported in association with desvenlafaxine; therefore, patients with raised intraocular pressure or those at risk of acute narrow-angle glaucoma (angle-closure glaucoma) should be monitored (see Adverse Reactions).
Co-Administration of Drugs Containing Venlafaxine and/or Desvenlafaxine: Products containing desvenlafaxine succinate should not be used concomitantly with products containing venlafaxine HCl or other products containing desvenlafaxine succinate.
Effects on Blood Pressure: Increases in blood pressure were observed in some patients in clinical trials, particularly with higher doses. Preexisting hypertension should be controlled before treatment with desvenlafaxine. Patients receiving desvenlafaxine should have regular monitoring of blood pressure. Cases of elevated blood pressure requiring immediate treatment have been reported with desvenlafaxine. Sustained blood pressure increases could have adverse consequences. For patients who experience a sustained increase in blood pressure while receiving desvenlafaxine, either dose reduction or discontinuation should be considered.
Caution should be exercised in treating patients with underlying conditions that might be compromised by increases in blood pressure (see Adverse Reactions).
Cardiovascular/Cerebrovascular: Caution is advised in administering desvenlafaxine to patients with cardiovascular, cerebrovascular or lipid metabolism disorders. Increases in blood pressure and heart rate were observed in clinical trials with desvenlafaxine. Desvenlafaxine has not been evaluated systematically in patients with a recent history of myocardial infarction, unstable heart disease, uncontrolled hypertension or cerebrovascular disease. Patients with these diagnoses, except for cerebrovascular disease, were excluded from clinical trials (see Adverse Reactions).
Serum Lipids: Dose-related elevations in fasting serum total cholesterol, low-density lipoprotein (LDL) cholesterol and triglycerides were observed in clinical trials. Measurement of serum lipids should be considered during treatment with desvenlafaxine (see Adverse Reactions).
Seizures: Cases of seizure were reported in pre-marketing clinical trials with desvenlafaxine. Desvenlafaxine has not been systematically evaluated in patients with a seizure disorder. Desvenlafaxine should be prescribed with caution in patients with a seizure disorder (see Adverse Reactions).
Discontinuation Effects: During marketing of SNRIs and SSRIs, there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: Dysphoric mood, irritability, agitation, dizziness, sensory disturbances (paraesthesias eg, electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus and seizures. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms.
Patients should be monitored when discontinuing treatment with desvenlafaxine. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible.
Abnormal Bleeding: Drugs that inhibit serotonin uptake in platelets may lead to abnormalities of platelet aggregation. As with other agents that inhibit serotonin-reuptake, desvenlafaxine should be used cautiously in patients predisposed to bleeding.
Hyponatremia: Cases of hyponatremia and/or the syndrome of inappropriate antidiuretic hormone (SIADH) secretion have been described with SNRIs and SSRIs, usually in volume-depleted or dehydrated patients, including elderly patients and patients taking diuretics (see Adverse Reactions).
Effects on the Ability to Drive or Operate Machinery: Since any CNS-active drug may impair judgment, thinking or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that desvenlafaxine therapy does not adversely affect their ability to engage in such activities.
Use in Pregnancy: The safety of desvenlafaxine in human pregnancy has not been established. Desvenlafaxine must only be administered to pregnant women if the expected benefits outweigh the possible risks. If desvenlafaxine is used until, or shortly before birth, discontinuation effects in the newborn should be considered.
Complications, including the need for respiratory support, tube feeding or prolonged hospitalization, have been reported in neonates exposed to SNRIs or SSRIs, late in the 3rd trimester. Such complications can arise immediately upon delivery.
Use in Lactation: Desvenlafaxine (O-desmethylvenlafaxine) is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from desvenlafaxine, a decision should be made whether or not to discontinue the drug, taking into account the importance of the drug to the mother. Administer desvenlafaxine to lactating women only if the expected benefits outweigh the possible risks.
Use In Pregnancy & Lactation
Use in Pregnancy: The safety of desvenlafaxine in human pregnancy has not been established. Desvenlafaxine must only be administered to pregnant women if the expected benefits outweigh the possible risks. If desvenlafaxine is used until, or shortly before birth, discontinuation effects in the newborn should be considered.
Complications, including the need for respiratory support, tube feeding or prolonged hospitalization, have been reported in neonates exposed to SNRIs or SSRIs, late in the 3rd trimester. Such complications can arise immediately upon delivery.
Use in Lactation: Desvenlafaxine (O-desmethylvenlafaxine) is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from desvenlafaxine, a decision should be made whether or not to discontinue the drug, taking into account the importance of the drug to the mother. Administer desvenlafaxine to lactating women only if the expected benefits outweigh the possible risks.
Adverse Reactions
Expected frequency of adverse reactions is presented in Council for International Organizations of Medical Sciences (CIOMS) frequency categories: Very common: ≥10%; common: ≥1% and <10%; uncommon: ≥0.1% and <1%; rare: ≥0.01% and <0.1%; very rare: <0.01%.
Cardiac Disorders: Common: Palpitations, tachycardia.
Ear and Labyrinth Disorders: Common: Tinnitus.
Eye Disorders: Common: Blurred vision, mydriasis.
Gastrointestinal Disorders: Very Common: Nausea, dry mouth, constipation. Common: Diarrhea, vomiting.
General Disorders: Very Common: Fatigue. Common: Chills, asthenia, feeling jittery, irritability. Uncommon: Drug withdrawal syndrome.
Immune System Disorders: Uncommon: Hypersensitivity.
Investigations: Common: Increased weight, blood pressure, blood cholesterol; decreased weight. Uncommon: Increased blood triglycerides, blood prolactin; abnormal liver function test.
Metabolism and Nutritional Disorders: Common: Decreased appetite.
Musculoskeletal, Connective Tissue and Bone Disorders: Common: Musculoskeletal stiffness.
Nervous System Disorders: Very Common: Dizziness. Common: Somnolence, tremor, paraesthesia, dysgeusia, disturbance in attention. Uncommon: Syncope. Rare: Convulsion, extrapyramidal disorder.
Psychiatric Disorders: Very Common: Insomnia. Common: Anxiety, abnormal dreams, nervousness, decreased libido, anorgasmia, abnormal orgasm. Uncommon: Depersonalization, hypomania.
Renal and Urinary Disorders: Common: Urinary hesitation. Rare: Proteinuria.
Reproductive System and Breast Disorders: Common: Erectile dysfunction, delayed ejaculation.
Respiratory, Thoracic and Mediastinal Disorders: Common: Yawning. Uncommon: Epistaxis.
Skin and Subcutaneous Tissue Disorders: Very Common: Hyperhidrosis. Common: Rash.
Vascular Disorders: Common: Hot flush. Uncommon: Orthostatic hypotension.
Ischemic Cardiac Adverse Events: In clinical trials, there were uncommon reports of ischemic cardiac adverse events, including myocardial ischemia, myocardial infarction and coronary occlusion requiring revascularization; these patients had multiple underlying cardiac risk factors. More patients experienced these events during desvenlafaxine treatment as compared to placebo (see Precautions).
Discontinuation Symptoms: Major Depressive Disorder: Adverse drug reactions reported in association with abrupt discontinuation, dose reduction or tapering of treatment in major depressive disorder clinical trials at a rate of ≥5% include: Dizziness, nausea, headache, irritability, diarrhoea, anxiety, abnormal dreams, fatigue and hyperhidrosis. In general, discontinuation symptoms occurred more frequently with longer duration of therapy (see Dosage & Administration and Precautions).
Vasomotor Symptoms Associated with Menopause: Adverse drug reactions reported in association with abrupt discontinuation, dose reduction or tapering of treatment in vasomotor symptoms clinical trials at a rate of >2% include: Dizziness, nausea, headache, insomnia, hot flush, diarrhoea, tinnitus, vomiting, vertigo, fatigue, abnormal dreams, irritability. In general, discontinuation symptoms occurred more frequently with longer duration of therapy. The majority of symptoms were mild and resolved without treatment (see Dosage & Administration and Precautions).
Adverse Reactions Leading to Discontinuation of Therapy: Major Depressive Disorder: The most common adverse reactions leading to discontinuation in at least 2% of the desvenlafaxine-treated patients in the short-term trials, up to 8 weeks, were: Nausea (4%); dizziness and vomiting (2% each); in the long-term trial, up to 9 months, the most common was vomiting (2%).
Vasomotor Symptoms Associated with Menopause: The most common adverse reactions that led to discontinuation (ie, leading to discontinuation in at least 1% of the 100 mg desvenlafaxine-treated subjects) were: Palpitations, dry mouth, insomnia, vomiting, fatigue, somnolence and anxiety.
Drug Interactions
MAOI: Adverse reactions, some of which were serious, have been reported in patients who have recently been discontinued from an MAOI and started on antidepressants with pharmacological properties similar to desvenlafaxine (SNRIs or SSRIs), or who have recently had SNRI or SSRI therapy discontinued prior to initiation of an MAOI. Concomitant use of desvenlafaxine in patients taking MAOIs is contraindicated (see Precautions).
CNS-Active Agents: The risk of using desvenlafaxine in combination with other CNS-active drugs has not been systematically evaluated. Consequently, caution is advised when desvenlafaxine is taken in combination with other CNS-active drugs.
Serotonin Syndrome: As with other serotonergic agents, serotonin syndrome, a potentially life-threatening condition, may occur with desvenlafaxine treatment, particularly with concomitant use of other agents that may affect the serotonergic neurotransmitter system [including triptans, SSRIs, other SNRIs, lithium, sibutramine, tramadol or St. John's wort (Hypericum perforatum)], with drugs that impair metabolism of serotonin [eg, MAOIs, including linezolid (an antibiotic which is a reversible nonselective MAOI), see Contraindications], or with serotonin precursors (eg, tryptophan supplements). Serotonin syndrome symptoms may include mental status changes, autonomic instability, neuromuscular aberrations and/or gastrointestinal symptoms (see Precautions).
If concomitant treatment of desvenlafaxine with an SSRI, an SNRI or a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. The concomitant use of desvenlafaxine with serotonin precursors (eg, tryptophan supplements) is not recommended (see Precautions).
Ethanol: A clinical trial has shown that desvenlafaxine does not increase the impairment of mental and motor skills caused by ethanol. However, as with all CNS-active drugs, patients should be advised to avoid alcohol consumption while taking desvenlafaxine.
Potential for Other Drugs to Affect Desvenlafaxine: Inhibitors of CYP3A4: CYP3A4 is minimally involved in desvenlafaxine elimination. In a clinical study, ketoconazole (200 mg twice a day) increased the area under the concentration vs time curve (AUC) of desvenlafaxine (400 mg, single dose) by approximately 43%, a weak interaction and Cmax by about 8%. Concomitant use of desvenlafaxine with potent inhibitors of CYP3A4 may result in higher concentrations of desvenlafaxine.
Potential for Desvenlafaxine to Affect Other Drugs: Drugs metabolized by CYP2D6: Clinical trials have shown that desvenlafaxine is a weak inhibitor of CYP2D6 at a dose of 100 mg daily. When desvenlafaxine succinate was administered at a dose of 100 mg daily in conjunction with a single 50-mg dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased approximately 17%. When 400 mg was administered, the AUC of desipramine increased approximately 90%. Concomitant use of desvenlafaxine with a drug metabolized by CYP2D6 may result in higher concentrations of that drug.
Drugs Metabolized by CYP3A4: In vitro, desvenlafaxine does not inhibit, or induce the CYP3A4 isozymes. In a clinical trial, desvenlafaxine (400 mg daily) decreased the AUC of midazolam (single 4-mg dose), a CYP3A4 substrate, by approximately 31%. Concomitant use of desvenlafaxine with a drug metabolized by CYP3A4 may result in lower exposures to that drug.
Storage
Store at 15-30°C.
MIMS Class
ATC Classification
N06AX23 - desvenlafaxine ; Belongs to the class of other antidepressants.
Presentation/Packing
XR tab 50 mg x 2 x 14's.
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