Desvenlafaxine Extended Release Tablets 25mg (Serostiq)

1. NAME OF THE MEDICINAL PRODUCT:

Desvenlafaxine Extended-Release Tablets 25mg (Serostiq)
Desvenlafaxine Extended-Release Tablets 50mg (Serostiq)
Desvenlafaxine Extended-Release Tablets 100mg (Serostiq)

QUALITATIVE AND QUANTITATIVE COMPOSITION:

1. Each uncoated extended-release tablet contains:

Desvenlafaxine Succinate equivalent to

Desvenlafaxine                                   25mg

Excipients                                                  q.s.

• Each film-coated extended-release tablet contains:

Desvenlafaxine Succinate Monohydrate

equivalent to Desvenlafaxine              50mg

Excipients                                                    q.s.

Colours: Red Oxide of Iron &

Titanium Dioxide IP

• Each film-coated extended-release tablet contains:

Desvenlafaxine Succinate Monohydrate

equivalent to Desvenlafaxine            100mg

Excipients                                                    q.s.

Colours: Lake of Quinoline Yellow &

Titanium Dioxide IP

• PHARMACEUTICAL FORM:

Extended-Release Tablet

Description:

Desvenlafaxine (O-desmethylvenlafaxine) the major active metabolite of venlafaxine, is an antidepressant from the serotonin-norepinephrine reuptake inhibitor (SNRI) class. Desvenlafaxine may be used to treat the major depressive disorder. It is formulated as an extended-release tablet.

• CLINICAL PARTICULARS:
  • Therapeutic indications:

SEROSTIQ Tablets?are indicated for the treatment of the major depressive disorder (MDD).

• Dosage and administration:

Initial treatment of MDD

The recommended dose for SEROSTIQ Tablets is 50mg once daily, with or without food.

In clinical studies, doses of 50?400mg/day were shown to be effective, although no additional benefit was demonstrated at doses greater than 50mg/day and adverse events and discontinuations were more frequent at higher doses.

SEROSTIQ Tablets?should be taken at approximately the same time each day. Tablets must be swallowed whole with fluid and not divided, crushed, chewed or dissolved.

Maintenance/Continuation/Extended Treatment

It is generally agreed that acute episodes of??????? MDD require several months or longer of sustained pharmacologic therapy. However, the long-term efficacy of desvenlafaxine at a dose of 50mg/day, which was effective in short-term,?? controlled studies, has not been further studied. Patients should be periodically reassessed to determine the need for continued treatment.

Discontinuing SEROSTIQ Tablets

Symptoms associated with discontinuation of desvenlafaxine 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.

Switching patients from other antidepressants to SEROSTIQ Tablets

Discontinuation symptoms have been reported when switching patients from other antidepressants, including venlafaxine, to desvenlafaxine. Tapering of the initial antidepressant may be necessary to minimize discontinuation symptoms.

Switching patients to or from a Monoamine Oxidase Inhibitor (MAOI)

At least 14 days must elapse between discontinuation of a Monoamine oxidase inhibitor (MAOI) and initiation of therapy with SEROSTIQ Tablets. In addition, at least 7 days must be allowed after stopping SEROSTIQ Tablets before starting an MAOI.

Special populations

Renal Impairment

The maximum recommended dose in patients with moderate renal impairment (24-hr creatinine clearance = 30 to 50mL/min, Cockcroft-Gault) is 50mg per day. The maximum recommended dose in patients with severe renal impairment (24-hr CrCl less than 30mL/min, C-G) or end-stage renal disease (ESRD) is 25mg every day or 50mg every other day. Supplemental doses should not be given to patients after dialysis.

Hepatic Impairment

The recommended dose in patients with moderate to severe hepatic impairment is 50mg per day. Dose escalation above 100mg per day is not recommended.

• Contraindications:
• Contraindicated in case of hypersensitivity to desvenlafaxine succinate, venlafaxine hydrochloride or to any excipients in the?SEROSTIQ Tablets?formulation.
• SEROSTIQ Tablets?must not be used concomitantly in patients taking MAOIs or in patients who have taken MAOIs within the preceding 14 days due to the risk of serious, sometimes fatal, drug interactions with SNRI or SSRI treatment or with other serotonergic drugs. These interactions have been associated with symptoms that include tremor, myoclonus, diaphoresis, nausea,?????? vomiting, flushing, dizziness, hyperthermia with features resembling neuroleptic malignant syndrome, seizures, rigidity, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. Based on the half-life of desvenlafaxine, at least 7?????????? days should be allowed after stopping?SEROSTIQ Tablets?before starting an MAOI.
  • Warnings and Precautions:

Suicidal Thoughts and Behaviors in Children, Adolescents and Young Adults

Patients with MDD, both adult and paediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behaviour (suicidality) or unusual changes in behaviour, 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 the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing the worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term, placebo-controlled studies of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behaviour (suicidality) in children, adolescents, and young adults (ages: 18 to 24 years) with MDD and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants, compared to placebo, in adults beyond the age of 24 years; there was a????????? reduction with antidepressants compared to placebo in adults aged 65 years and older.

It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance studies in adults with depression that the use of antidepressants can delay the recurrence of depression.

All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behaviour, especially during the initial few months of a course of drug therapy or at times of dose changes, either increases or decreases.

The following symptoms ? anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania and mania ? have been reported in adult and paediatric patients being treated with antidepressants for MDD as well as for other indications, both psychiatric and non-psychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset or were not part of the patient?s presenting symptoms.

If the decision has been made to discontinue treatment, the medication should be tapered, as rapidly as is feasible, but with the recognition that abrupt discontinuation can be associated with certain symptoms.

Families and caregivers of patients being treated with antidepressants for MDD or other indications, both psychiatric and non-psychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behaviour and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers.?Prescriptions for desvenlafaxine should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

Screening Patients for Bipolar Disorder

A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled studies) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, 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, including a family history of suicide, bipolar disorder and depression. It should be noted that desvenlafaxine is not approved for use in treating bipolar depression.

Serotonin Syndrome

The development of potentially life-threatening serotonin syndrome or neuroleptic malignant syndrome-like reactions have been reported with SNRIs and SSRIs alone, including desvenlafaxine treatment, but particularly with concomitant use of serotonergic drugs (including triptans) with drugs that impair the metabolism of serotonin (including MAOIs) or with antipsychotics or other dopamine antagonists. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, and diarrhoea). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs and mental status changes. Patients should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like signs and symptoms.

The concomitant use of desvenlafaxine with MAOIs intended to treat depression is contraindicated. If concomitant treatment of desvenlafaxine with 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 (such as tryptophan) is not recommended.

Treatment with desvenlafaxine and any concomitant serotonergic or anti-dopaminergic agents, including antipsychotics, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.

Elevated Blood Pressure

Patients receiving desvenlafaxine should have regular monitoring of blood pressure since increases in blood pressure were observed in clinical studies. Pre-existing hypertension should be controlled before initiating treatment with desvenlafaxine. Caution should be exercised in treating patients with pre-existing hypertension or other underlying conditions that might be compromised by increases in the 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.

Treatment with desvenlafaxine at all doses from 50mg/day to 400mg/day in controlled studies was associated with sustained hypertension, defined as treatment-emergent supine diastolic blood pressure) ?90 mm Hg and ?10 mm Hg above baseline for three consecutive on-therapy visits. Analyses of patients in controlled studies on desvenlafaxine, who met the criteria for sustained hypertension, revealed a consistent increase in the proportion of patients who developed sustained hypertension. This was seen at all doses, with a suggestion of a higher rate at 400 mg/day.

Table 1: Proportion of patients with sustained elevation of supine diastolic blood pressure

Abnormal bleeding

SSRIs and SNRIs, including desvenlafaxine,????? may increase the risk of bleeding events.?????????? Concomitant use of aspirin, NSAIDs, warfarin and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between the use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs have ranged from ecchymosis, haematoma, epistaxis and petechiae to life-threatening haemorrhages.?????? Patients should be cautioned about the risk of bleeding associated with the concomitant use of desvenlafaxine and NSAIDs, aspirin or other drugs that affect coagulation or bleeding.

Angle-Closure Glaucoma

The pupillary dilation that occurs following use of many antidepressant drugs including SEROSTIQ may trigger an angle-closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.

Activation of Mania/Hypomania

During all MDD and vasomotor symptoms??????? (VMS) Phase 2 and Phase 3 studies, mania was reported for approximately 0.1% of patients treated with desvenlafaxine. Activation of mania/hypomania has also been reported in a small proportion of patients with the major affective disorder who were treated with other marketed antidepressants. As with all antidepressants,?????? desvenlafaxine should be used cautiously in patients with a history or family history of mania or hypomania.

Discontinuation of Treatment with Desvenlafaxine

Discontinuation symptoms have been systematically and prospectively evaluated in patients treated with desvenlafaxine during clinical studies in MDD. Abrupt discontinuation or dose reduction has been associated with the appearance of new symptoms that include dizziness, nausea, headache, irritability, insomnia, diarrhoea, anxiety, fatigue, abnormal dreams and hyperhidrosis. In general, discontinuation events occurred more frequently with longer duration of therapy.

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 (e.g., paraesthesia, such as 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 for these symptoms when discontinuing treatment with desvenlafaxine. 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.

Seizure

Cases of seizure have been reported in pre-marketing clinical studies with desvenlafaxine. Desvenlafaxine has not been systematically evaluated in patients with a seizure disorder. Patients with a history of seizures were excluded from pre-marketing clinical studies.???????? Desvenlafaxine should be prescribed with caution in patients with a seizure disorder.

Hyponatremia

Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including desvenlafaxine. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volumes depleted can be at greater risk. Discontinuation of desvenlafaxine should be considered in patients with symptomatic hyponatraemia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which can lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.

Interstitial Lung Disease and Eosinophilic Pneumonia

Interstitial lung disease and eosinophilic pneumonia associated with venlafaxine (the parent drug of desvenlafaxine) therapy have been rarely reported. The possibility of these adverse events should be considered in patients treated with desvenlafaxine who present with progressive dyspnea, cough, or chest discomfort. Such patients should undergo a prompt medical evaluation, and discontinuation of desvenlafaxine should be considered.

• Drug Interactions:

MAOIs

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. Do not use MAOIs intended to treat psychiatric disorders with desvenlafaxine or within 7 days of stopping treatment with desvenlafaxine. Do not use desvenlafaxine within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start desvenlafaxine in a patient who is being treated with linezolid or intravenous methylene blue.

Serotonergic Drugs

Based on the mechanism of action of desvenlafaxine and the potential for serotonin syndrome, caution is advised when desvenlafaxine is co-administered with other drugs that may affect the serotonergic neurotransmitter systems.

Drugs that Interfere with Haemostasis (e.g., NSAIDs, Aspirin and Warfarin)

Serotonin release by platelets plays an important role in haemostasis. Epidemiological studies of case-control and cohort design have demonstrated an association between the use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. These studies have also shown that concurrent use of a non-steroidal anti-inflammatory drug (NSAID) or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when desvenlafaxine is initiated or discontinued.

Ethanol

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.

Potential for Other Drugs to Affect Desvenlafaxine

Inhibitors of CYP3A4 (ketoconazole)

CYP3A4 is a minor pathway for the metabolism of desvenlafaxine. In a clinical study, ketoconazole (200mg b.i.d.) increased the area under the concentration versus time curve (AUC) of desvenlafaxine (400mg single dose) by about 43% and the C_max by about 8%. Concomitant use of desvenlafaxine with potent inhibitors of CYP3A4 may result in higher concentrations of desvenlafaxine.

Inhibitors of other CYP enzymes

Based on?in vitro?data, drugs that inhibit CYP isozymes 1A1, 1A2, 2A6, 2D6, 2C8, 2C9, 2C19 and 2E1 are not expected to have a significant impact on the pharmacokinetic profile of desvenlafaxine.

Potential for Desvenlafaxine to Affect Other Drugs

Drugs metabolized by CYP2D6 (desipramine)

In vitro?studies showed a minimal inhibitory effect of desvenlafaxine on CYP2D6. Clinical studies have shown that desvenlafaxine does not have a clinically relevant effect on CYP2D6 metabolism at the dose of 100mg daily. When desvenlafaxine succinate was administered at a dose of 100mg daily in conjunction with a single 50mg dose of desipramine, a CYP2D6 substrate, the C_max?and AUC of desipramine increased by approximately 25% and 17%, respectively.???? When 400mg (8 times the recommended 50 mg dose) was administered, the C_max?and AUC of desipramine increased approximately by 50% and 90%, respectively. Concomitant use of desvenlafaxine with a drug metabolized by CYP2D6 can result in higher concentrations of that drug.

Drugs metabolized by CYP3A4 (midazolam)

In vitro, desvenlafaxine does not inhibit or induce the CYP3A4 isozyme.

In a clinical study, desvenlafaxine 400mg daily (8 times the recommended 50mg dose) was co-administered with a single 4mg dose of midazolam (a CYP3A4 substrate). The AUC and C_max of midazolam decreased by approximately 31% and 16%, respectively. Concomitant use of desvenlafaxine with a drug metabolized by CYP3A4 can result in lower exposures to that drug.

Drugs metabolized by CYP1A2, 2A6, 2C8, 2C9 and 2C19

In vitro, desvenlafaxine does not inhibit CYP1A2, 2A6, 2C8, 2C9, and 2C19 isozymes and would not be expected to affect the pharmacokinetics of drugs that are metabolized by these CYP isozymes.

P-glycoprotein Transporter

In vitro, desvenlafaxine is not a substrate or an inhibitor for the P-glycoprotein transporter. The pharmacokinetics of desvenlafaxine is unlikely to be affected by drugs that inhibit the P-glycoprotein transporter and desvenlafaxine is not likely to affect the pharmacokinetics of drugs that are substrates of the P-glycoprotein transporter.

Co-administration of Drugs Containing Desvenlafaxine and Venlafaxine

Desvenlafaxine is the major active metabolite of venlafaxine. Products containing desvenlafaxine and products containing venlafaxine should not be used concomitantly with desvenlafaxine.

• Pregnancy, lactation and others:

Renal Impairment

In subjects with renal impairment, the clearance of desvenlafaxine was decreased. In subjects with severe renal impairment (24-hour CrCl <30 mL/min) and ESRD, the elimination half-lives were significantly prolonged, increasing exposures to desvenlafaxine; therefore, dosage adjustment is recommended in these patients.

Hepatic Impairment

The mean t_1/2 changed from approximately 10 hours in healthy subjects and subjects with mild hepatic impairment to 13 and 14 hours in moderate and severe hepatic impairment, respectively. The recommended dose in patients with hepatic impairment is 50 mg/day. Dose escalation above 100 mg/day is not recommended.

Pregnancy

Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy.

Teratogenic Effects ? Pregnancy Category C

There are no adequate and well-controlled studies of desvenlafaxine in pregnant women. Therefore, desvenlafaxine should be used during pregnancy only if the potential benefits justify the potential risks.

Non-Teratogenic Effects

Neonates exposed to SNRIs or SSRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnoea, seizures, temperature instability, feeding difficulty, vomiting,????? hypoglycaemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome. When treating a pregnant woman with desvenlafaxine during the third trimester, the physician should carefully consider the potential risks and benefits of treatment.

Labour and Delivery

The effect of desvenlafaxine on labour and delivery in humans is unknown. Desvenlafaxine should be used during labour and delivery only if the potential benefits justify the potential risks.

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 nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Only administer desvenlafaxine to nursing mothers if the expected benefits outweigh any possible risk.

Paediatric Use

Safety and effectiveness in the paediatric population have not been established. Anyone considering the use of desvenlafaxine in a child or adolescent must balance the potential risks with the clinical need.

Geriatric Use

For elderly patients, possible reduced renal clearance of desvenlafaxine should be considered when determining dose. If desvenlafaxine is poorly tolerated, dosing on every other day can be considered.

SSRIs and SNRIs, including desvenlafaxine,????? have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event.?????? The greater sensitivity of some older individuals cannot be ruled out.

Drug Abuse and Dependence

Controlled Substance

Desvenlafaxine is not a controlled substance.

• Undesirable effects:

The most commonly observed adverse reactions in desvenlafaxine-treated MDD patients in short-term, fixed-dose studies (incidence ?5% and at least twice the rate of placebo in the 50 or 100 mg dose groups) were nausea, dizziness, insomnia, hyperhidrosis, constipation, somnolence, decreased appetite, anxiety, and specific male sexual function disorders.

Combined across 8-week placebo-controlled, pre-marketing studies for MDD, 12% of the 1,834 patients who received desvenlafaxine (range: 50 to 400mg) discontinued treatment due to an adverse event, compared with 3% of the 1,116 placebo-treated patients in those studies. At the recommended dose of 50mg, the discontinuation rate due to an adverse event for desvenlafaxine (4.1%) was similar to the rate for placebo (3.8%). For the 100mg dose of desvenlafaxine tablets, the discontinuation rate due to an adverse event was 8.7%.

Adverse events reported in association with abrupt discontinuation, dose reduction or tapering of treatment in MDD clinical studies at a rate of ?5% included dizziness, nausea,?????? headache, irritability, insomnia, diarrhoea,??????????? anxiety, abnormal dreams, fatigue and hyperhidrosis. In general, discontinuation events occurred more frequently with longer duration of therapy.

Table 2 shows the incidence of common adverse reactions that occurred in ?2% of desvenlafaxine-treated MDD patients at any dose in the 8-week, placebo-controlled, fixed-dose, pre-marketing clinical studies. In general, the adverse reactions were most frequent in the first week of treatment.

Table 2: Common adverse reactions: Percentage of patients (?2% in any fixed-dose group) in MDD 8-week placebo-controlled studies

^a Percentage based on the number of patients (placebo, n = 636; desvenlafaxine 50mg, n = 317; desvenlafaxine 100mg, n = 424; desvenlafaxine 200mg, n = 307; desvenlafaxine 400 mg, n = 317).

Sexual function adverse reactions that occurred in ?2% of desvenlafaxine treated MDD patients in any fixed-dose group (8-week, placebo-controlled, fixed-dose and flexible-dose, pre-marketing clinical studies) were: anorgasmia,??????? decreased libido, abnormal orgasm, delayed ejaculation, erectile dysfunction, ejaculation disorder, ejaculation failure, sexual dysfunction in males and anorgasmia in females.

Other infrequent adverse reactions, occurring at an incidence of <2% in MDD patients treated with desvenlafaxine were: hypersensitivity,?????????? increased weight, abnormal liver function test, increased blood prolactin, convulsion, syncope, extrapyramidal disorder, musculoskeletal stiffness, depersonalization, hypomania, epistaxis, orthostatic hypotension.

In clinical studies, there were uncommon reports of ischaemic 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.

Laboratory, ECG and vital sign changes observed in MDD clinical studies

The following changes were observed in placebo-controlled, short-term, pre-marketing MDD studies with desvenlafaxine:

Lipids   

Elevations in fasting serum total cholesterol, LDL cholesterol and triglycerides occurred in the controlled studies. Some of these abnormalities were considered potentially clinically significant.

Proteinuria

Proteinuria, greater than or equal to trace, was observed in the fixed-dose controlled studies. This proteinuria was not associated with increases in BUN or creatinine and was generally transient.

ECG changes

ECGs (electrocardiograms) were obtained from 1,492 desvenlafaxine-treated patients with MDD and 984 placebo-treated patients in clinical studies lasting up to 8 weeks. No clinically relevant differences were observed between desvenlafaxine-treated patients and placebo-treated patients for QT, QTc, PR and QRS intervals. In a thorough QTc study with prospectively determined criteria,      desvenlafaxine did not cause QT prolongation. No difference was observed between placebo and desvenlafaxine treatments for the QRS interval.

Vital sign changes

Table 3 summarizes the changes that were observed in placebo-controlled, short-term, pre-marketing studies with desvenlafaxine in patients with MDD (doses of 50 to 400mg).

Table 3: Mean changes in vital signs at final on therapy for all short-term, fixed-dose controlled studies

At the final on-therapy assessment in the 6-month, double-blind, placebo-controlled phase of a long-term study in patients who had responded to desvenlafaxine during the initial 12-week, open-label phase, there was no statistical difference in the mean weight change between desvenlafaxine and placebo-treated patients.

Orthostatic hypotension

In the short-term, placebo-controlled clinical studies with doses of 50?400mg, systolic orthostatic hypotension (decrease ?30 mm Hg from supine to standing position) occurred more frequently in patients ?65 years of age receiving desvenlafaxine (8.0%, 7/87) versus placebo (2.5%, 1/40), compared to patients <65 years of age receiving desvenlafaxine (0.9%, 18/1,937) versus placebo (0.7%, 8/1,218).

• Overdosage:

There is limited clinical experience with desvenlafaxine succinate overdosage in humans. In pre-marketing clinical studies, no cases of fatal acute overdose of desvenlafaxine were reported.

Among the patients included in the MDD pre-marketing studies of desvenlafaxine, there were four adults who ingested desvenlafaxine succinate (4000mg, 900, 1800 and 5200mg); all patients recovered. In addition, one patient?s 11-month-old child accidentally ingested 600mg of desvenlafaxine succinate, was treated and recovered. The adverse reactions reported within 5 days of an overdose >600mg that were possibly related to desvenlafaxine included headache, vomiting, agitation, dizziness, nausea, constipation, diarrhoea, dry mouth, paraesthesia and tachycardia.

Desvenlafaxine is a major active metabolite of venlafaxine. Overdose experience reported with venlafaxine (parent drug of desvenlafaxine) is presented below.

In post-marketing experience, overdose with venlafaxine has occurred predominantly in combination with alcohol and/or other drugs.??????? The most commonly reported events in overdosage include tachycardia, changes in the level of consciousness (ranging from somnolence to coma), mydriasis, seizures, and vomiting. ECG changes (e.g., prolongation of QT interval,????? bundle branch block, QRS prolongation), sinus and ventricular tachycardia, bradycardia,???? hypotension, rhabdomyolysis, vertigo, liver necrosis, serotonin syndrome, and death have been reported.

Published retrospective studies report that venlafaxine overdosage may be associated with an increased risk of fatal outcomes compared to that observed with SSRI antidepressant products, but lower than that for tricyclic antidepressants. Epidemiological studies have shown that venlafaxine-treated patients have a higher pre-existing burden of suicide risk factors than SSRI-treated patients. The extent to which the finding of an increased risk of fatal outcomes can be attributed to the toxicity of venlafaxine in overdosage, as opposed to some characteristic(s) of venlafaxine-treated patients, is not clear.

Prescriptions for desvenlafaxine should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

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, maybe indicated if performed soon after ingestion or in symptomatic patients. Activated charcoal should be administered. Induction of emesis is not recommended. Because of the moderate volume of distribution of this drug, forced diuresis,?????? dialysis, haemoperfusion and exchange transfusion are unlikely to be of benefit. No specific antidotes for desvenlafaxine are known.

In managing an overdose, consider the possibility of multiple-drug involvement. The physician should consider contacting a poison control centre for additional information on the treatment of any overdose.

• PHARMACOLOGICAL PROPERTIES:
  • Pharmacodynamic properties:

SEROSTIQ Tablets?are extended-release tablets for oral administration, which contain desvenlafaxine succinate, structurally novel serotonin and norepinephrine reuptake inhibitor (SNRI) for the treatment of MDD.????? Desvenlafaxine (O-desmethylvenlafaxine) is the major active metabolite of the antidepressant, venlafaxine, a medication used to treat the major depressive disorder, generalized anxiety, social anxiety and panic disorders.

The clinical efficacy of desvenlafaxine succinate is thought to be related to the potentiation of these neurotransmitters in the central nervous system (CNS).? Desvenlafaxine lacks significant affinity for numerous receptors, including muscarinic-cholinergic, H₁-histaminergic, or alpha₁-adrenergic receptors?in vitro. Desvenlafaxine also lacks monoamine oxidase (MAO) inhibitory activity.

• Pharmacokinetic properties:

The single-dose pharmacokinetics of desvenlafaxine is linear and dose-proportional in a dose range of 50 to 600mg/day. The mean terminal half-life, t_1/2, is approximately 11 hours. With once-daily dosing, steady-state plasma concentrations are achieved within approximately 4?5 days. At the steady-state, multiple-dose accumulation of desvenlafaxine is linear and predictable from the single-dose pharmacokinetic profile.

Absorption

The absolute oral bioavailability of desvenlafaxine after oral administration is about 80%. A food-effect study involving the administration of desvenlafaxine to healthy subjects under fasting and fed conditions (high-fat meal) indicated that the C_max?was increased by about 16% in the fed state, while the area under the curves (AUCs) was similar. This difference was not clinically significant;?????????? therefore, desvenlafaxine can be taken without regard to meals.

Distribution

The plasma protein binding of desvenlafaxine is low (30%) and is independent of the drug concentration. The desvenlafaxine volume of distribution at the steady-state following intravenous administration is 3.4 L/kg, indicating distribution into nonvascular compartments.

Metabolism

Desvenlafaxine is primarily metabolized by conjugation (mediated by UGT isoforms) and, to a minor extent, through oxidative metabolism. Cytochrome (CY) P3A4 is the CYP450 isozyme mediating the oxidative metabolism (N-demethylation) of desvenlafaxine. The CYP2D6 metabolic pathway is not involved and after administration of 100mg, the pharmacokinetics of desvenlafaxine was similar in subjects with CYP2D6 poor and extensive metabolizer phenotypes.

Elimination

Approximately 45% of desvenlafaxine is excreted unchanged in urine at 72 hours after oral administration. Approximately 19% of the administered dose is excreted as the glucuronide metabolite and <5% as the oxidative metabolite (N, O-di desmethyl venlafaxine) in the urine.

Special Populations

Age

In a study of healthy subjects administered doses of up to 300 mg, there was an approximate 32% increase in the C_max and a 55% increase in the AUC in subjects older than 75 years of age (n = 17), compared with subjects 18 to 45 years of age (n = 16). Subjects, 65 to 75 years of age (n = 15), had no change in the C_max, but an approximately 32% increase in the AUC, compared to subjects who were 18 to 45 years of age.

Gender

In a study of healthy subjects administered doses of up to 300 mg, women had an approximately 25% higher C_max?and an approximately 10% higher AUC than age-matched men. No adjustment of dosage on the basis of gender is needed.

Race

Pharmacokinetic analysis showed that race (White, n = 466; Black, n = 97; Hispanic,n = 39; others, n = 33) had no apparent effect on the pharmacokinetics of desvenlafaxine. No adjustment of dosage on the basis of race is needed.

Hepatic impairment

The disposition of desvenlafaxine succinate after administration of 100 mg was studied 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 similar 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. The CL/F values were comparable in mild hepatic impairment and healthy subjects (<5% difference). The mean t_1/2?changed from approximately 10 hours in healthy subjects and subjects with mild hepatic impairment to 13 and 14 hours in moderate and severe hepatic impairment, respectively. The recommended dose in patients with hepatic impairment is 50mg/day. Dose escalation above 100mg/day is not recommended.

Renal impairment

The disposition of desvenlafaxine after administration of 100 mg was studied in subjects with mild (n = 9), moderate (n = 8), severe (n = 7) and end-stage renal disease (; n = 9) requiring dialysis and in healthy, age-matched control subjects (n = 8). Elimination was significantly correlated with the creatinine clearance (CrCl). Increases in the AUCs of about 42% in mild renal impairment (24-hour CrCl = 50?80 mL/min), about 56% in moderate renal impairment (24-hour CrCl = 30?50 mL/min), about 108% in severe renal impairment (24-hour CrCl ?30 mL/min), and about 116% in ESRD subjects were observed, compared with healthy, age-matched control subjects.

The mean terminal half-life (t_1/2) was prolonged from 11.1 hours in the control subjects to approximately 13.5, 15.5, 17.6, and 22.8 hours in mild, moderate, severe renal impairment and ESRD subjects, respectively. Less than 5% of the drug in the body was cleared during a standard 4-hour haemodialysis procedure. The recommended dose in patients with moderate renal impairment is 50mg per day. Dosage adjustment (50mg every other day) is recommended in patients with severe renal impairment or ESRD. Doses should not be escalated in patients with moderate or severe renal impairment, or ESRD.

•  PHARMACEUTICAL PARTICULARS:

• Incompatibilities:

None stated.

• Shelf life:

2 years

• Storage and handling instructions:

Store in a dry and dark place at a temperature below 25?C.

• Packaging information:

SEROSTIQ 25???????A strip of 10 tablets

SEROSTIQ 50???????A strip of 10 tablets

SEROSTIQ 100??????.A strip of 10 tablets

• Special precautions for disposal and another handling:

N/A

7. Manufactured in India By:
TAJ LIFE SCIENCES PVT. LTD.
Unit No. 214, Old Bake House,
Bake House Lane, Fort,
Mumbai-400001
at: Ahmedabad- Gujarat, INDIA.
Ho.NO. +91 8448 444 095
Toll Free Phone: (1800-222-434 / 1800-222-825)