Devert-50/Devert-100

Devert-50: Desvenlafaxine Succinate Monohydrate (Devert-50) 50 mg Controlled-Release Tablet is a light pink colored, round-shaped biconvex film-coated tablet debossed with 'T1' on one side and plain on the other side.
Each controlled release tablet contains: Desvenlafaxine Succinate Monohydrate equivalent to Desvenlafaxine 50 mg.
Devert-100: Desvenlafaxine Succinate Monohydrate (Devert-100) 100 mg Controlled-Release Tablet is a reddish-brown colored, round-shaped biconvex film-coated tablet debossed with 'T7' on one side and plain on the other side.
Each controlled release tablet contains: Desvenlafaxine Succinate Monohydrate equivalent to Desvenlafaxine 100 mg.

Antidepressant.
Pharmacology: Mechanism of Action: While the exact mechanism of the antidepressant action is unknown, the clinical efficacy of desvenlafaxine is related to an increased action of these neurotransmitters in the central nervous system through inhibition of their reuptake. Desvenlafaxine is a potent and selective inhibitor of the reuptake of serotonin and noradrenaline (SNRI).
Pharmacodynamics: Desvenlafaxine has no significant affinity for various receptors, including muscarinic-cholinergic receptors, H₁ histaminergic or α₁-adrenergic receptors in vitro. It also showed no inhibitory activity on monoamine oxidase (MAO).
Pharmacokinetics: The single-dose pharmacokinetics of desvenlafaxine is linearly proportional to the dose in a dose range from 50 to 600 mg/day. With administration once daily, plasma concentrations at steady state are achieved in approximately 4-5 days. At steady-state, the accumulation of multiple doses of desvenlafaxine is linear and predictable from a single-dose pharmacokinetic profile. The mean terminal half-life (t_1/2) is approximately 11 hours.
Absorption and Distribution: Desvenlafaxine succinate monohydrate is well absorbed with an absolute oral bioavailability of 80%. The mean time to peak plasma concentration (T_max) is about 7.5 hours after oral administration. The volume of distribution at steady state after intravenous administration is 3.4 L/kg, indicating distribution into non-vascular compartments. The plasma protein binding of desvenlafaxine is low (30%) and is independent of the drug concentration.
Effects of Food: A study of the effect of the presence of food involving the administration of desvenlafaxine in fasting healthy subjects and in the presence of food (meals with high fat content) indicated that the C_max increased approximately 16% in the presence of food, while the AUCs were similar. This difference is not clinically significant; therefore, desvenlafaxine may be taken without regard to meals.
Metabolism and Elimination: Desvenlafaxine is primarily metabolized by conjugation (mediated by UGT isoforms, including UGT1A1, UGT1A3, UGT2B4, UGT2B15 and UGT2B17) and to a lesser degree, by means of oxidative metabolism. CYP3A4 is the predominant cytochrome P450 isozyme that acts as a mediator of the oxidative metabolism (N-demethylation) of desvenlafaxine. Approximately 45% of desvenlafaxine is excreted unchanged in the urine, 19% of the administered dose is excreted as the glucuronide metabolite and <5% as the oxidative metabolite (N,O-Didesmethylvenlafaxine) in the urine.
In Vitro Studies: Drugs Metabolized by CYP3A4: In vitro, desvenlafaxine does not inhibit or induce the CYP3A4 isoenzymes.
P-glycoprotein transporter: In vitro, desvenlafaxine is not a substrate or inhibitor of the P-glycoprotein transporter.
Inhibitors of other CYP enzymes: Based on in vitro data, it is not expected that drugs that inhibit CYP isozymes 1A1, 1A2, 2A6, 2D6, 2C8, 2C9, 2C19 and 2E1 have significant impact on the pharmacokinetic profile of desvenlafaxine.
Special Populations: Geriatric Use: In clinical studies of MDD treated with desvenlafaxine, no overall differences in safety or effectiveness were observed between these patients and younger patients; However, possible reduced renal clearance of desvenlafaxine should be considered when determining the dose.
Pediatric use: The safety and efficacy in patients under 18 years of age have not been established.
Renal Impairment: Elimination was significantly correlated with creatinine clearance. Dosage adjustment is necessary in patients with significant impairment of renal function. Supplemental doses should not be given to patients after dialysis.

It is indicated for the treatment of major depressive disorder (MDD). It is also used in acute and maintenance treatment of major depressive disorder. Desvenlafaxine succinate monohydrate tablet is not indicated for use in any pediatric population.

The recommended dose of is 50 mg once daily with or without food. The 50 mg dose is both a starting dose and the therapeutic dose. Desvenlafaxine succinate monohydrate tablet must be taken at approximately same time each day. Do not chew, open or crush tablets. In clinical studies, doses of 50-400 mg/day have been shown to be effective, though no other benefit was demonstrated at doses greater than 50 mg/day and adverse reactions and discontinuations were more frequent at higher doses. The maximum dose should not exceed 200 mg/day. Gradual reduction in dose is recommended when discontinuing treatment may minimize discontinuation symptoms. The dose intended for a gradual reduction when discontinuing treatment is 25 mg per day to minimize discontinuation symptoms.
Use in Patients with Renal Insufficiency: The recommended starting dose in patients with severe renal impairment (CrCl 15 to 29 mL/min) or end-stage renal disease (ESRD) is 50 mg every other day, for patients with moderate renal impairment (CrCl 30 to 50 mL/min) is 50 mg every day. Additional doses should not be administered to patients after dialysis.
Use in Patients with Liver Failure: No dosage adjustment is necessary for patients with hepatic impairment. However, the escalation of doses above 100 mg/day is not recommended.
Pediatric Use: The safety and efficacy in patients under 18 years of age have not been established.
Elderly Use: No dose adjustment is necessary based solely on age; however, a possible decrease in renal clearance of Desvenlafaxine should be considered when determining the dose to be used. Greater risk for hyponatremia as adverse event is clinically significant.
Discontinuation of Desvenlafaxine: Symptoms associated with the discontinuation of desvenlafaxine, as well as other SNRIs and SSRIs, have been reported. A gradual reduction in dose rather than abrupt cessation is recommended whenever possible. If the patient experiences intolerable symptoms after a dose reduction or discontinuation of treatment, resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose, but at a more gradual rate.
Substitution of Treatment from Other Antidepressants to Desvenlafaxine: Withdrawal symptoms have been reported when the treatment of patients with other antidepressants, including venlafaxine, is replaced by treatment with desvenlafaxine. The gradual discontinuation of the initial antidepressant may be necessary to minimize discontinuation symptoms.
Substitution to or from MAOI (monoamine oxidase inhibitor) for Treating Psychiatric Disorders: At least 7 days should be allowed after stopping Desvenlafaxine before starting therapy on MAOI for treating psychiatric disorders and at least 14 days should elapse between discontinuing MAOI and initiating therapy of Desvenlafaxine.
Use of desvenlafaxine with Reversible MAOI (Linezolid or Methylene blue): Do not start desvenlafaxine in a patient being treated with a reversible MAOI such as linezolid, or in patients whom intravenous methylene blue was administered because of the increased risk of serotonin syndrome. In a patient who requires a more urgent treatment of a psychiatric condition, nonpharmacological interventions, including hospitalization, should be considered. In some cases, a patient who is already receiving therapy with desvenlafaxine may need urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives for the treatment with linezolid or methylene blue intravenously are not available and the potential benefits of treatment with linezolid or methylene blue intravenous outweigh the risk of serotonin syndrome in a specific patient, desvenlafaxine should be stopped immediately, and linezolid or methylene blue may be administered intravenously. The patient should be monitored for symptoms of the syndrome serotonin for two weeks or until 24 hours after the last dose of linezolid or methylene blue intravenously, whichever comes first. Desvenlafaxine therapy can be resumed 24 hours after the last dose of linezolid or intravenous methylene blue.

There is limited clinical experience with overdose of desvenlafaxine in humans. There is no known specific antidote for desvenlafaxine. Induction of vomiting is not recommended. Due to the moderate volume of distribution of this drug, it is unlikely that forced diuresis, dialysis, hemoperfusion and exchange transfusion are beneficial.
Treatment should consist of those general measures employed in the treatment of overdosage with any SSRI/IRNS. Ensure adequate airway, oxygenation and ventilation. Monitor cardiac rhythm and vital signs. General symptomatic and supportive measures are also recommended. Gastric lavage with a large-bore orogastric tube with appropriate protection of the airways, if necessary, may be indicated if performed soon after ingestion or in symptomatic patients. Activated charcoal should be administered.

Hypersensitivity to desvenlafaxine succinate, venlafaxine hydrochloride or to any of its excipients.
Desvenlafaxine should not be used in combination with a monoamine oxidase inhibitor (MAOI) because of an increased risk of serotonin syndrome. The use of MAOI intended for treating psychiatric disorders 7 days after stopping treatment of Desvenlafaxine is contraindicated as well as the use of Desvenlafaxine within 14 days after stopping MAOI treatment.

Suicidal Thoughts and Behaviors: Antidepressants increase the risk of suicidal thinking and behavior (suicidality) in children and adolescents with major depressive disorder (MDD) and other psychiatric disorders and those considering use of these agents must balance risk with the clinical need.

Suicidal Thoughts and Behaviors: Patients with MDD, both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs.
Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are strong predictors of suicide. There has been long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during early phases of treatment. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. Patients, their families and their 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 behavioral changes, worsening of depression and suicidal ideation, especially when starting therapy or during any change in the dose or dosing schedule. The risk of suicide attempt should be considered, especially in depressed patients, and the least amount of medication, consistent with a good patient management, should be provided to reduce the risk of overdose.
Mania/Hypomania: In clinical studies, mania was reported in 0.02% of patients treated with desvenlafaxine. Activation of mania/ hypomania has also been reported in a small proportion of patients with major affective disorder who were treated with other marketed antidepressants. As with all antidepressants, Desvenlafaxine should be used with caution in patients with a personal history or family history of mania or hypomania.
Serotonin Syndrome or reactions similar to Neuroleptic Malignant Syndrome (NMS): As with other serotonergic agents, the development of a potentially life-threatening serotonin syndrome can occur with treatment with desvenlafaxine, particularly with concomitant use of other serotonergic drugs (including SSRIs, SNRIs and triptans) with drugs which impair the metabolism of serotonin (e.g. MAOIs, including reversible MAOIs such as linezolid and intravenous methylene blue), or with antipsychotics or other dopamine antagonists.
Symptoms of serotonin syndrome may include mental status changes (for e.g. agitation, hallucinations, coma), autonomic instability (e.g. tachycardia, instable blood pressure and hyperthermia), neuromuscular aberrations (e.g. hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g. nausea, vomiting and diarrhea). Serotonin syndrome in its most severe form can resemble NMS, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes. If concomitant treatment with desvenlafaxine and other agents that may affect the serotonergic and/or dopaminergic neurotransmitter system is clinically justified, a careful observation of the patient is recommended, particularly during treatment initiation and dose increases. Concomitant use of desvenlafaxine with serotonin precursors (such as tryptophan supplements) is not recommended.
Angle Closure Glaucoma: Mydriasis has been reported in association with desvenlafaxine; therefore, patients with raised intraocular pressure or those at risk of narrow/closed angle glaucoma should be monitored.
Effects on Blood Pressure: Regular monitoring of blood pressure for patients taking Desvenlafaxine is advised since increases in blood pressure were observed in studies. For patients with pre-existing hypertension, blood pressure should be controlled before installing treatment of Desvenlafaxine. For patients who experience a sustained increase in blood pressure while receiving desvenlafaxine, dose reduction or discontinuation should be considered. Caution should be taken in patients with medical conditions that might be compromised by increases in blood pressure.
Seizures: Cases of seizures have been reported in pre-marketing clinical studies with Desvenlafaxine. Desvenlafaxine has not been systematically evaluated in patients with seizure disorder. Patients with a history of seizures were excluded from clinical studies. Desvenlafaxine should be prescribed with caution in these patients.
Effects of Discontinuation of Treatment with Desvenlafaxine succinate monohydrate Tablets: During marketing of SNRIs and SSRIs, there have been spontaneous reports of adverse events that occurred from the discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g. paresthesias such as feelings of electric shock), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. A gradual reduction in dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or discontinuation of treatment, resumption of the previously prescribed dose should be considered. Patients should be monitored for symptoms on discontinuing treatment with Desvenlafaxine.
Abnormal bleeding: SSRIs and SNRIs, including Desvenlafaxine, can increase the risk of bleeding events. Concomitant use of acetylsalicylic acid, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, and other anti-coagulants may contribute to this risk. Bleeding-related to SSRIs and SNRIs ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with concomitant use of Desvenlafaxine and NSAIDs, acetylsalicylic acid or other substances that affect coagulation or bleeding.
Hyponatremia: Cases of hyponatremia and/or Syndrome of Inappropriate Secretion of Antidiuretic Hormone (SIADH) have been reported with SNRIs (including desvenlafaxine succinate) and SSRIs, including elderly patients and patients taking diuretics (volume depleted). Discontinuation of Desvenlafaxine should be considered in patients with symptomatic hyponatremia (e.g. headache, difficulty of concentrating, memory impairment, confusion, weakness, and unsteadiness - which leads to falls) and appropriate medical intervention should be done. Signs and symptoms associated with more severe/acute cases include hallucination, syncope, seizure, coma, respiratory arrest, and death.
Interstitial Lung Disease and Eosinophilic Pneumonia: Interstitial lung disease and eosinophilic pneumonia associated with venlafaxine therapy (parent drug of Desvenlafaxine) have been reported rarely. The possibility of these adverse effects should be considered in patients treated with Desvenlafaxine who develop progressive dyspnea, cough or chest discomfort. Those patients should undergo a prompt medical evaluation and should consider discontinuation of Desvenlafaxine.
Screening Patients for Bipolar Disorder: Prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history because Desvenlafaxine is not approved for use in treating bipolar depression.
Serum Lipids: Dose-related elevations in fasting serum total cholesterol, LDL (low Density Lipoprotein) cholesterol, and triglycerides were observed. Measurement of serum lipids should be considered during treatment with desvenlafaxine.
Abuse and Dependence: Although desvenlafaxine has not been studied for its potential for abuse, no indication of drug-seeking behavior was reported.
Effects on ability to drive and use machines: Results of a clinical study that evaluated the effects of desvenlafaxine on behavioral performance of healthy subjects revealed no clinically significant impairment of psychomotor, cognitive, or complex behavior performance. However, like 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 therapy with desvenlafaxine does not have adverse effect on their ability to perform these activities.

The safety of desvenlafaxine in pregnancy in humans has not been established. Desvenlafaxine should 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 third-quarter. Such complications can arise immediately upon delivery. Exposure to SNRIs in mid to late pregnancy may increase the risk of preeclampsia, and exposure to SNRIs near delivery may increase the risk for postpartum hemorrhage.
Desvenlafaxine is a drug classified in category C of pregnancy risk. Therefore, this medicine should not be used by pregnant women without medical or dentist surgeon guidance.
Desvenlafaxine (O-desmethylvenlafaxine) is excreted in the human milk. Because of the potential for serious adverse reactions in infants due to exposure to desvenlafaxine, it must decide to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Administer desvenlafaxine to breastfeeding women only if the expected benefits outweigh the possible risks.

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Ischemic Cardiac Adverse Events: In clinical studies, 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 treatment with desvenlafaxine compared with placebo.
Serum Lipids: Increased LDL (low density lipoprotein) cholesterol, fasting serum total cholesterol, and triglycerides were reported in patients taking Desvenlafaxine.
Adverse Reactions Leading to Discontinuation of Treatment: The most common adverse drug reactions leading to discontinuation in at least 2% of the patients treated with Desvenlafaxine were nausea, dizziness, headache & vomiting. At a recommended dose of 50 mg, the discontinuation rate due to adverse drug reactions is 4.1% as for 100 mg the discontinuation rate due to adverse drug reactions is 8.7%.
Discontinuation Symptoms: Adverse drug reactions in association with abrupt discontinuation, dose reduction or gradual discontinuation of treatment in MDD clinical studies at a rate ≥2% include dizziness, withdrawal syndrome, nausea, and headache. In general, the symptoms of discontinuation occurred more frequently at higher doses and longer duration of therapy.
Residual Inert Matrix of the Tablet: Patients taking Desvenlafaxine can find the inert matrix of the tablet in the stool or via colostomy. If this occurs, these patients should be informed that the active ingredient of the drug has already been absorbed.
Adverse Drug Reactions with Other SNRIs: Although gastrointestinal bleeding is not considered an adverse reaction to Desvenlafaxine, it is an adverse reaction to other SNRIs and may also occur with Desvenlafaxine.

Monoamine Oxidase Inhibitors (MAOIs): Adverse reactions, some of which were serious, were recently reported in patients who discontinued monoamine oxidase inhibitor (including reversible MAOIs, such as linezolid and intravenous methylene blue), and began treatment with antidepressants with pharmacologic properties similar to desvenlafaxine (SNRIs or SSRIs), or who have recently discontinued an SSRI or SNRI therapy before starting an MAOI. Concomitant use of desvenlafaxine in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated.
At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with Desvenlafaxine. In addition, there must be an interval of at least 7 days after stopping Desvenlafaxine before starting a MAOI.
Serotonin syndrome: As with other serotonergic agents, serotonin syndrome, a potentially fatal condition, can occur with treatment with desvenlafaxine, particularly with concomitant use of other agents that may affect the serotonergic neurotransmitter system (including triptans, SSRIs, other SNRIs, lithium, sibutramine, fentanyl and its analogues, tramadol, dextromethorphan, tapentadol, meperidine, methadone, pentazocine, or St. John's Wort [Hypericum perforatum]), with drugs which impair the metabolism of serotonin (such as MAOIs, including linezolid [an antibiotic which is areversible nonselective MAOI] and methylene blue) or with serotonin precursors (such as tryptophan supplements).
If a concomitant treatment with desvenlafaxine and an SSRI, an SNRI or an agonist of the 5-hydroxytryptamine [triptan] receptor is clinically justified, a careful observation of the patient is recommended, particularly during treatment initiation and dose increases. Concomitant use of desvenlafaxine with serotonin precursors (such as tryptophan supplements) is not recommended.
Alcohol: A clinical study 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.
Drugs Metabolized by CYP2D6: Concomitant use of Desvenlafaxine with drugs that are metabolized by CYP2D6 (e.g. desipramine, atomoxetine, dextromethorphan, metoprolol, nebivolol, perphenazine, and tolterodine) increases Cmax and AUC of drugs primarily metabolized by CYP2D6 which may result to increased risk of toxicity of CYP2D6 substrate drug. Reduction of the dose by up to one-half if co-administered with 400 mg of Desvenlafaxine, original dose if with 100 mg or lower of Desvenlafaxine.
Drugs with no Clinically Significant Interactions: No Dose adjustment required for drugs that are mainly metabolized in by CYP3A4 (e.g. midazolam), CYP2D6 and CYP3A4 (e.g. tamoxifen, aripiprazole) when administered concomitantly.
Drug-Laboratory Interactions: Patients taking Desvenlafaxine may have false positive result on urine immunoassay screening test for phenycyclidine (PCP) and amphetamine due to the lack of specificity of the tests. Confirmatory tests such as gas chromatography and mass spectrometry will differentiate Desvenlafaxine from phenycyclidine (PCP) and amphetamine. A false positive result can also be expected for several days following discontinuation of Desvenlafaxine therapy.
Concomitant use with other CNS-Active Drugs: The risk of concomitant administration with a CNS-active drug has not been evaluated. Caution is advised when desvenlafaxine is taken in combination with other CNS-active drugs.
P-glycoprotein Transporter: Desvenlafaxine is not a substrate or an inhibitor for the P-glycoprotein transporter.
Electroconvulsive Therapy: There are no clinical data establishing the risks and/or benefits of electroconvulsive therapy combined with desvenlafaxine treatment for MDD.

Store at a temperature not exceeding 30°C. Protect from light.

Antidepressants

N06AX23 - desvenlafaxine ; Belongs to the class of other antidepressants.

Rx