For the use of Registered Medical Practitioner only

1. GENERIC NAME AND BRAND NAME:
Desvenlafaxine extended release and Clonazepam tablets
MDD^® XR Plus 50

Desvenlafaxine extended release and Clonazepam tablets
MDD^® XR Plus 100

2. QUALITATIVE AND QUANTITATIVE COMPOSITION
MDD^® XR Plus 50:
Each Uncoated Bilayered Tablet Contains:
Desvenlafaxine Succinate USP
Eq. to Desvenlafaxine….50 mg
(In Extended Release Form)
Clonazepam I.P…….…..0.5 mg
Excipients………………q.s.
Colour: Quinoline Yellow Lake

MDD^® XR Plus 100:
Each Uncoated Bilayered Tablet Contains:
Desvenlafaxine Succinate USP
Eq. to Desvenlafaxine….100 mg
(In Extended Release Form)
Clonazepam I.P…….…..0.5 mg
Excipients………………q.s.
Colour: Ponceau 4R Lake

3. DOSAGE FORM & STRENGTH
Refer section 1 & 2

4. CLINICAL PARTICULARS

4.1THERAPEUTIC INDICATION
For the treatment of Major Depressive Disorder (MDD)

4.2 POSOLOGY AND METHOD OF ADMINISTRATION
Posology
The recommended dose is 1 tablet once daily with or without food or as directed by the Physician.
Special Populations:
Renal Impairment: The maximum recommended dose of desvenlafaxine in patients with moderate renal impairment is 50 mg per day. The maximum recommended dose in patients with severe renal impairment or end-stage renal disease (ESRD) is 25 mg every day or 50 mg every other day. Supplemental doses should not be given to patients after dialysis. Based on kinetic criteria no dose adjustment of clonazepam is required in patients with renal impairment
Hepatic Impairment: The recommended dose of desvenlafaxine in patients with moderate to severe hepatic impairment is 50 mg per day. Dose escalation above 100 mg per day is not recommended. Patients with severe hepatic impairment should not be treated with clonazepam. Patients with mild to moderate hepatic impairment should be given the lowest possible dose.
General Instructions for Use:
The recommended dose for desvenlafaxine is 50 mg once daily, with or without food. The 50 mg dose is both a starting dose and the therapeutic dose.
In clinical studies, doses of desvenlafaxine 10 mg to 400 mg per day were studied. In clinical studies, doses of 50 mg to 400 mg per day were shown to be effective, although no additional benefit was demonstrated at doses greater than 50 mg per day and adverse reactions and discontinuations were more frequent at higher doses.
Desvenlafaxine 25 mg per day dose is intended for a gradual reduction in dose when discontinuing treatment. When discontinuing therapy, gradual dose reduction is recommended whenever possible to minimize discontinuation symptoms.
Patients should be periodically reassessed to determine the need for continued treatment.
Method of administration: For oral administration only.
Desvenlafaxine/Clonazepam tablets should be taken at approximately the same time each day. Tablets must be swallowed whole with liquid and not divided, crushed, chewed or dissolved.

4.3 CONTRAINDICATIONS
It is contraindicated in patient with known hypersensitivity to desvenlafaxine succinate, venlafaxine hydrochloride or clonazepam or to any excipients in the Desvenlafaxine formulation. Angioedema has been reported in patients treated with Desvenlafaxine.
– The use of MAOIs intended to treat psychiatric disorders with Desvenlafaxine or within 7 days of stopping treatment with Desvenlafaxine is contraindicated because of an increased risk of serotonin syndrome. The use of Desvenlafaxine within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated.
– Starting Desvenlafaxine in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome.
Clonazepam should not be used in patients with a history of sensitivity to benzodiazepines, nor in patients with clinical or biochemical evidence of significant liver disease. It may be used in patients with open angle glaucoma who are receiving appropriate therapy but is contraindicated in acute narrow angle glaucoma.

4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE

Desvenlafaxine:
Warning: Suicidal Thoughts and Behaviors
Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older.
In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber.
Desvenlafaxine is not approved for use in pediatric patients.
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 or Neuroleptic Malignant Syndrome (NMS)-like Reactions:
Serotonin syndrome or NMS-like reactions have been reported with SSRIs and SNRIs. Discontinue desvenlafaxine and initiate supportive treatment.
Elevated Blood Pressure: Has occurred with desvenlafaxine. Hypertension should be controlled before initiating treatment. Monitor blood pressure regularly during treatment.
Abnormal Bleeding: desvenlafaxine may increase the risk of bleeding events. 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.
Narrow-angle Glaucoma: Mydriasis has occurred with desvenlafaxine. Patients with raised intraocular pressure or those at risk of angle-closure glaucoma should be monitored.
Activation of Mania/Hypomania: Has occurred. Use cautiously in patients with Bipolar Disorder. Caution patients about the risk of activation of mania/hypomania.
Cardiovascular/Cerebrovascular Disease: Use cautiously inpatients with cardiovascular or cerebrovascular disease.
Cholesterol and Triglyceride Elevation: Have occurred. Use cautiously in patients with lipid metabolism disorders. Consider monitoring serum cholesterol and triglyceride.
Discontinuation Symptoms: Have occurred. Taper the dose when possible and monitor for discontinuation symptoms.
Renal Impairment: Reduces the clearance of desvenlafaxine. Dosage adjustment is necessary in severe and ESRD. In moderate renal impairment, the dose should not exceed 50 mg/day.
Seizure: Can occur. Use cautiously in patients with seizure disorder.
Hyponatremia:Can occur in association with SIADH.
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.
Clonazepam
Warning: Risks from concomitant use with Opioids
Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death.

• Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.
• Limit dosages and durations to the minimum required.
• Follow patients for signs and symptoms of respiratory depression and sedation. Withdrawal Symptoms: Withdrawal symptoms of the barbiturate type have occurred after the discontinuation of benzodiazepines.

General:

A paradoxical increase in seizure activity or the appearance of new seizure types has occurred in a very few patients during treatment with clonazepam.

The concomitant use of alcohol and/or CNS depressants should be avoided.

• Medical history of alcohol or drug abuse – clonazepam should be used with extreme caution in patients with a history of alcohol or drug abuse.
• Lactose intolerance- Lactose is a non-medicinal ingredient in clonazepam. Therefore, patients with rare hereditary problems of galactose intolerance &Lapp lactase deficiency or glucose-galactosemal absorption should not take this medicine.
• Hepatic- No safety & efficacy data available.
• Respiratory – Respiratory depression may occur following administration of drug.
• Special Populations Pregnant Women-Studies indicate a correlation between the use of anticonvulsant drugs and an elevated incidence of birth defects in children born to epileptic women taking such medication during pregnancy.
• Nursing Women- The mothers receiving clonazepam should not breast-feed their infants.
• Pediatrics (< 5 years of age): The risk-benefit consideration of the long-term use of clonazepam is important in pediatric patients.
• Geriatrics: There is no clinical trial experience with clonazepam in seizure disorder patients 65 years of age and older.
• Prolonged use of clonazepam may result in dependence and withdrawal symptoms on cessation of treatment.

4.5 DRUG INTERACTION

Desvenlafaxine
Drugs Having Clinically Important Interactions with Desvenlafaxine:

Drugs Having No Clinically Important Interactions with Desvenlafaxine: Based on pharmacokinetic studies, no dosage adjustment is required for drugs that are mainly metabolized by CYP3A4 (e.g., midazolam), or for drugs that are metabolized by both CYP2D6 and CYP3A4 (e.g., tamoxifen, aripiprazole), when administered concomitantly with Desvenlafaxine.
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.
Drug-Laboratory Test Interactions: False-positive urine immunoassay screening tests for phencyclidine (PCP) and amphetamine have been reported in patients taking desvenlafaxine. This is due to lack of specificity of the screening tests. False positive test results may be expected for several days following discontinuation of desvenlafaxine therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish desvenlafaxine from PCP and amphetamine.

Clonazepam
Coadministration clonazepam with the following drugs:
Alcohol: To be totally avoided. Since alcohol can provoke epileptic seizures, irrespective of therapy, patients must under no circumstances drink alcohol while under treatment. In combination with clonazepam, alcohol may modify the effects of the drug, compromise the success of therapy or give rise to unpredictable side-effects.
Anti-epileptic drugs: When clonazepam is used in conjunction with other antiepileptic drugs, side-effects such as sedation and apathy, and toxicity may be more evident, particularly with hydantoins or phenobarbital and combinations including them. This requires extra care in adjusting dosage in the initial stages of treatment.
The combination of clonazepam and sodium valproate has, rarely, been associated with the development of absence status epilepticus. Although some patients tolerate and benefit from this combination of drugs, this potential hazard should be borne in mind when its use is considered.
Inhibitors of hepatic enzymes:
Known inhibitors of hepatic enzymes, e.g. cimetidine, have been shown to reduce the clearance of benzodiazepines and may potentiate their action and known inducers of hepatic enzymes, e.g. rifampicin, may increase the clearance of benzodiazepines.
Phenytoin or primidone: In concurrent treatment with phenytoin or primidone, a change, usually a rise in the serum concentration of these two substances has occasionally been observed.
Centrally Acting Drugs: : Concurrent use of clonazepam and other centrally acting medications, e.g. other anticonvulsant (antiepileptic) agents, anaesthetics, hypnotics, psychoactive drugs and some analgesics as well as muscle-relaxants may result in mutual potentiation of drug effects. This is especially true in the presence of alcohol. In combination therapy with centrally-acting medications, the dosage of each drug must be adjusted to achieve the optimum effect.

4.6 USE IN SPECIAL POPULATIONS (SUCH AS PREGNANT WOMEN, LACTATING WOMEN, PAEDIATRIC PATIENTS, GERIATRIC PATIENTS ETC.)

Desvenlafaxine:
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.
Labor and Delivery The effect of desvenlafaxine on labor and delivery in humans is unknown. Desvenlafaxine should be used during labor 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.
Pediatric 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. Greater sensitivity of some older individuals cannot be ruled out.

Clonazepam:
Pregnancy
During pregnancy, Clonazepam may be administered only if there is a compelling indication. Clonazepam has harmful pharmacological effects on pregnancy and the foetus/newborn child. Administration of high doses in the last trimester of pregnancy or during labour can cause irregularities in the heart beat of the unborn child and hypothermia, hypotonia, mild respiratory depression and poor feeding in the neonate. Infants born to mothers who took benzodiazepines chronically during the later stages of pregnancy may have developed physical dependence and may be at some risk for developing withdrawal symptoms in the post-natal period. It should be borne in mind that both pregnancy itself and abrupt discontinuation of the medication can cause exacerbation of epilepsy. Therefore, clonazepam should not be used in pregnancy unless clearly necessary.
Breast-feeding
Although clonazepam has been found to pass into the maternal milk in small amounts only, mothers undergoing treatment with this drug should not breastfeed. If there is a compelling indication for clonazepam, breastfeeding should be discontinued.
Pediatric Use
Because of the possibility that adverse effects on physical or mental development could become apparent only after many years, a benefit-risk consideration of the long-term use of clonazepam is important in pediatric patients being treated for seizure disorder. Safety and effectiveness in pediatric patients with panic disorder below the age of 18 have not been established.
Geriatric Use
Clinical studies of clonazepam did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Because clonazepam undergoes hepatic metabolism, it is possible that liver disease will impair clonazepam elimination. Metabolites of clonazepam are excreted by the kidneys; to avoid their excess accumulation, caution should be exercised in the administration of the drug to patients with impaired renal function. Because elderly patients are more likely to have decreased hepatic and/or renal function, care should be taken in dose selection, and it may be useful to assess hepatic and/or renal function at the time of dose selection.
Sedating drugs may cause confusion and over-sedation in the elderly; elderly patients generally should be started on low doses of clonazepam and observed closely.

4.7 EFFECTS ON ABILITY TO DRIVE AND USE MACHINES
Caution patients 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.
Clonazepam can slow reactions to such an extent that the ability to drive a vehicle or operate machinery is impaired. This medicine can impair cognitive function and can affect a patient’s ability to drive safely.

4.8 UNDESIRABLE EFFECTS

Desvenlafaxine
The following adverse reactions are discussed in greater detail in other sections of the label: Hypersensitivity; Suicidal Thoughts and Behaviors in Pediatric and Young Adult Patients; Serotonin Syndrome; Elevated Blood Pressure; Increased Risk of Bleeding; Angle Closure Glaucoma; Activation of Mania/Hypomania; Discontinuation Syndrome; Seizure; Hyponatremia; and Interstitial Lung Disease and Eosinophilic Pneumonia.

Clinical Studies Experience:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.
Adverse Reactions Reported as Reasons for Discontinuation of Treatment:
In the pre-marketing pooled 8-week placebo-controlled studies in patients with MDD, 1,834 patients were exposed to Desvenlafaxine (50 to 400 mg). Of the 1,834 patients, 12% discontinued treatment due to an adverse reaction, compared with 3% of the 1,116 placebo-treated patients. At the recommended dose of 50 mg, the discontinuation rate due to an adverse reaction for Desvenlafaxine (4.1%) was similar to the rate for placebo (3.8%). For the 100 mg dose of Desvenlafaxine the discontinuation rate due to an adverse reaction was 8.7%.

The most common adverse reactions leading to discontinuation in at least 2% and at a rate greater than placebo of the Desvenlafaxine treated patients in the short-term studies, up to 8 weeks, were: nausea (4%); dizziness, headache and vomiting (2% each). In a longer-term study, up to 9 months, the most common was vomiting (2%).

Common Adverse Reactions in Placebo-Controlled MDD Studies:
The most commonly observed adverse reactions in Desvenlafaxine treated MDD patients in pre-marketing pooled 8-week, placebo-controlled, 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.

Other Adverse Reactions Observed in Premarketing and Post marketing Clinical Studies:
Other infrequent adverse reactions, not described elsewhere in the label, occurring at an incidence of < 2% in MDD patients treated with Desvenlafaxine were:
Cardiac disorders: Tachycardia.
General disorders and administration site conditions: Asthenia.
Investigations: Weight increased, liver function test abnormal, blood prolactin increased.
Musculoskeletal and connective tissue disorders: Musculoskeletal stiffness.
Nervous system disorders: Syncope, convulsion, dystonia.
Psychiatric disorders: Depersonalization, bruxism.
Renal and urinary disorders: Urinary retention.
Skin and subcutaneous tissue disorders: Rash, alopecia, photosensitivity reaction, angioedema.
In clinical studies, there were uncommon reports of ischemic cardiac adverse reactions, 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 pre-marketing placebo-controlled, short-term MDD studies with Desvenlafaxine.
Lipids: Elevations in fasting serum total cholesterol, LDL (low density lipoproteins) 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 pre-marketing fixed-dose controlled studies. This proteinuria was not associated with increases in BUN or creatinine and was generally transient.
Orthostatic Hypotension: : In the pre-marketing short-term, placebo-controlled clinical studies with doses of 50 to 400 mg, systolic orthostatic hypotension (decrease ≥30 mm Hg from supine to standing position) occurred more frequently in patients ≥65 years of age receiving Desvenlafaxine (8%, 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).
Post marketing Experience:
The following adverse reaction has been identified during post-approval use of Desvenlafaxine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:
Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome.
Gastrointestinal disorders: Pancreatitis acute.
Cardiovascular system: Takotsubo cardiomyopathy.

Clonazepam
The following have been observed:
Immune System Disorders: Allergic reactions and very rare cases of anaphylaxis have been reported to occur with benzodiazepines. Angioedema may occur in rare cases
Endocrine Disorders: Isolated cases of reversible development of premature secondary sex characteristics in children (incomplete precocious puberty) have been reported.
Psychiatric Disorders and Paradoxical Reactions: Impaired concentration, restlessness, confusional state, disorientation have been observed. Depression may occur in patients treated with clonazepam, but it may be also associated with the underlying disease.
The following paradoxical reactions have been observed: excitability, irritability, aggression, agitation, nervousness, hostility, anxiety, sleep disturbances, nightmares, vivid dreams and psychotic disorders and activation of new types of seizures may be precipitated. If these occur, the benefit of continuing the drug should be weighed against the adverse effect. The addition to the regimen of another suitable drug may be necessary or, in some cases, it may be advisable to discontinue clonazepam therapy.
Nervous System Disorders: Somnolence, slowed reaction, muscular hypotonia, dizziness and ataxia. These undesirable effects occur relatively frequently and may disappear gradually in the course of the treatment or on reduction of the dosage. They can be partially prevented by increasing the dose slowly at the start of treatment. Headache was observed in rare cases. Causing of generalized fits was observed very rarely. Particularly in long-term or high-dose treatment, reversible disorders such as dysarthria, reduced coordination of movements and gait disorder (ataxia) and nystagmus may occur.
Anterograde amnesia may occur using benzodiazepines at therapeutic dosages, the risk increasing at higher dosages. Amnestic effects may be associated with inappropriate behavior.
With certain forms of epilepsy, an increase in the frequency of seizures during long-term treatment is possible. Although clonazepam has been given uneventfully to patients with porphyria, rarely it may induce convulsions in these patients.
Eye Disorders: Particularly in long-term or high-dose treatment, reversible disorders of vision (diplopia) may occur. Common side effect is nystagmus.
Cardiac Disorders: Cardiac failure including cardiac arrest has been reported.
Respiratory, Thoracic and Mediastinal System Disorders: Respiratory depression may occur, particularly on IV administration of clonazepam. This effect may be aggravated by pre-existing airways obstruction or brain damage or if other medications which depress respiration have been given. As a rule, this effect can be avoided by careful adjustment of the dose to individual requirements.
Gastrointestinal Disorders: The following effects have been reported in rare cases: nausea, gastrointestinal and epigastric symptoms.
Skin and Subcutaneous Tissue Disorders: The following effects may occur in rare cases: urticaria, pruritus, and rash, transient hair loss and pigmentation changes.
Musculoskeletal and Connective Tissue Disorders: Muscle weakness, this undesirable effect occurs relatively frequently and is usually transient and generally disappears spontaneously in the course of the treatment or on reduction of the dosage. It can be partially prevented by increasing the dose slowly at the start of treatment.
Renal and Urinary Disorders: In rare cases urinary incontinence may occur.
Reproductive System and Breast Disorders: In rare cases erectile dysfunction or loss of libido may occur. Persistent sexual dysfunction after drug withdrawal.
General Disorders and Administration Site Conditions: Fatigue (tiredness, lassitude), this undesirable effect occurs relatively frequently and is usually transient and generally disappears spontaneously in the course of the treatment or on reduction of the dosage. It can be partially prevented by increasing the dose slowly at the start of treatment.
Injury, Poisoning and Procedural Complications: There have been reports of falls and fractures in benzodiazepine users. The risk is increased in those taking concomitant sedatives (including alcoholic beverages) and in the elderly.
Investigations: In rare cases decreased platelet count may occur. As with other benzodiazepines, isolated cases of blood dyscrasias and abnormal liver function tests have been reported.

4.9 OVERDOSAGE
Desvenlafaxine
There is limited clinical trial experience with desvenlafaxine succinate overdosage in humans. However, desvenlafaxine is the major active metabolite of venlafaxine. Overdose experience reported with venlafaxine (the parent drug of desvenlafaxine) is presented below; the identical information can be found in the Overdosage section of the venlafaxine package insert.

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 level of consciousness (ranging from somnolence to coma), mydriasis, seizures, and vomiting. Electrocardiogram 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. No specific antidotes for desvenlafaxine are known.

Clonazepam
As with other benzodiazepine drugs; overdosage should not present undue problems of management or threat to life. Patients have recovered from overdoses in excess of 60mg without special treatment. Severe somnolence with muscle hypotonia will be present.

5.0 PHARMACOLOGICAL PROPERTIES

5.1 MECHANISM OF ACTION
Desvenlafaxine
The exact mechanism of the antidepressant action of desvenlafaxine is unknown but is thought to be related to the potentiation of serotonin and norepinephrine in the central nervous system, through inhibition of their reuptake. Non-clinical studies have shown that desvenlafaxine is a potent and selective serotonin and norepinephrine reuptake inhibitor (SNRI).
Clonazepam
The precise mechanism by which clonazepam exerts its anxiolytic effects is unknown, although it is believed to be related to its ability to enhance the activity of gamma aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system.

5.2 PHARMACODYNAMICS PROPERTIES
Desvenlafaxine
Desvenlafaxine is a selective serotonin and norepinephrine reuptake inhibitor. It lacks significant activity on muscarinic-cholinergic, H1-histaminergic, or α1-adrenergic receptors in vitro. Desvenlafaxine does not appear to exert activity against calcium, chloride, potassium and sodium ion channels and also lacks monoamine oxidase (MAO) inhibitory activity. It was also shown to lack significant activity again the cardiac potassium channel, hERG, in vitro. Compared to other SNRIs, desvenlafaxine undergoes simple metabolism, has a low risk of drug-drug interactions and does not have to be extensively titrated to reach a therapeutic dose.
Clonazepam
Clonazepam is an anticonvulsant which exhibits several pharmacological properties characteristic of the benzodiazepine class of medicines. Benzodiazepines increase the polysynaptic inhibitory processes at all levels of the central nervous system. Clonazepam is more effective in blocking spread of electrical activity in the lesion itself. The exact site and mode of action of the anticonvulsant action of clonazepam is unknown.

5.3 PHARMACOKINETIC PROPERTIES

Desvenlafaxine
The absolute oral bioavailability of Desvenlafaxine after oral administration is about 80%. Ingestion of a high-fat meal (800 to 1000 calories) increased desvenlafaxine Cmax about 16% and had no effect on AUC. Steady-state volume of distribution of desvenlafaxine is 3.4 L/kg. Plasma protein binding of desvenlafaxine is 30% and is independent of drug concentration. Desvenlafaxine is primarily metabolized by conjugation (mediated by UGT isoforms) and, to a minor extent, through oxidative metabolism. CYP3A4 mediates the oxidative metabolism (N-demethylation) of desvenlafaxine. The CYP2D6 metabolic pathway is not involved. The pharmacokinetics of desvenlafaxine was similar in subjects with CYP2D6 poor and extensive metabolizer phenotype. 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-didesmethylvenlafaxine) in urine.

Clonazepam
Clonazepam is rapidly and almost completely absorbed after oral administration. Peak plasma concentrations of clonazepam are reached in 1-4 hours. The absorption half-life is around 25 minutes. The absolute bioavailability is 90%. Clonazepam distributes very rapidly to various organs and body tissues with preferential uptake by brain structures. Clonazepam is extensively metabolized by reduction to 7-amino-clonazepam and by N-acetylation to 7-acetamino-clonazepam. The metabolites are present in urine both as free and conjugated (glucuronide and sulphate) compound. 50-70% of the dose is excreted in the urine and 10-30% in feces as metabolites. The urinary excretion of unchanged clonazepam is usually less than 2% of the administered dose. The mean elimination half-life is 30-40 hours. The clearance is 55 ml/min.

6.0 NONCLINICAL PROPERTIES

6.1 ANIMAL TOXICOLOGY OR PHARMACOLOGY

Desvenlafaxine

Carcinogenesis
Desvenlafaxine succinate administered by oral gavage to mice and rats for 2 years did not increase the incidence of tumors in either study.
Mice received desvenlafaxine succinate at dosages up to 500/300 mg/kg/day (dosage lowered after 45 weeks of dosing). The 300 mg/kg/day dose is 15 times a human dose of 100 mg/day on a mg/m² basis.
Rats received desvenlafaxine succinate at dosages up to 300 mg/kg/day (males) or 500 mg/kg/day (females). The highest dose is 29 (males) or 48 (females) times a human dose of 100 mg/day on a mg/m² basis.

Mutagenesis
Desvenlafaxine was not mutagenic in the in vitro bacterial mutation assay (Ames test) and was not clastogenic in an in vitro chromosome aberration assay in cultured CHO cells, an in vivo mouse micronucleus assay, or an in vivo chromosome aberration assay in rats. Additionally, desvenlafaxine was not genotoxic in the in vitro CHO mammalian cell forward mutation assay and was negative in the in vitro BALB/c-3T3 mouse embryo cell transformation assay.

Impairment of fertility
Reduced fertility was observed in a study in which both male and female rats received desvenlafaxine succinate. This effect was noted at oral doses approximately 10 times a human dose of 100 mg/day on a mg/m² basis. There was no effect on fertility at oral doses approximately 3 times a human dose of 100 mg/day on a mg/m² basis.

Clonazepam:

Carcinogenicity
No 2-year carcinogenicity studies have been conducted with clonazepam. However, in an 18-month chronic study in rats no treatment-related histopathological changes were seen up to the highest tested dose of 300 mg/kg/day.
Mutagenicity
Genotoxicity tests using bacterial systems with in vitro or host mediated metabolic activation did not indicate a genotoxic liability for clonazepam.
Impairment of Fertility
Studies assessing fertility and general reproductive performance in rats showed a reduced pregnancy rate and impaired pup survival at doses of 10 and 100 mg/kg/day.
Teratogenicity
No adverse maternal or embryo-fetal effects were observed in either mice or rats following administration of oral clonazepam during organogenesis, at doses of up to 20 or 40 mg/kg/day, respectively.
In several rabbit studies following doses of clonazepam of up to 20 mg/kg/day, a low, non-dose-related incidence of a similar pattern of malformations (cleft palate, open eyelids, fused stern brae and limb defects) was observed

7.0 DESCRIPTION

MDD^® XR Plus 50:
MDD XR Plus 50 is supplied for oral administration, as an uncoated bilayered tablet of Desvenlafaxine and Clonazepam. Each uncoated bilayered tablet of MDD XR Plus 50 contains Desvenlafaxine Succinate equivalent to Desvenlafaxine 50 mg (In Extended Release Form) & Clonazepam 0.5 mg.

MDD^® XR Plus 100:
MDD XR Plus 50 is supplied for oral administration, as an uncoated bilayered tablet of Desvenlafaxine and Clonazepam. Each uncoated bilayered tablet of MDD XR Plus 50 contains Desvenlafaxine Succinate equivalent to Desvenlafaxine 100 mg (In Extended Release Form) & Clonazepam 0.5 mg.

8.0 PHARMACEUTICAL PARTICULARS

8.1 INCOMPATIBILITIES
Not Applicable

8.2 SHELF-LIFE
Refer Pack

8.3 PACKAGING INFORMATION
Refer Pack

8.4 STORAGE CONDITION AND HANDING INSTRUCTIONS
Refer Pack

9. PATIENT COUNSELLING INFORMATION
Advise patients, their families, and their caregivers about the benefits and risks associated with treatment with desvenlafaxine and counsel them in its appropriate use. Advise patients, their families, and their caregivers to be aware of suicidal risk, Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS) like reactions, Elevated blood pressure, abnormal bleeding, Narrow-angle glaucoma, activation of Mania/hypomania, cardiovascular/cerebrovascular disease, Serum cholesterol and Triglyceride Elevation, Interference with Cognitive and Motor Performance,
drug interactions and allergic reactions caused by desvenlafaxine.

• Keep out of reach of children.
• Patients should be advised to avoid alcohol
• Patients should be cautioned when they undertake any jobs that require mental alertness such as driving, operating machinery.
• Avoid abrupt discontinuation of this drug .Gradual reduction over a period of 1 to 2 weeks is advised due to clonazepam in the formulation

Breast feeding is not recommended when women are taking this drug due to clonazepam.

10. DETAILS OF MANUFACTURER
Refer Pack for manufacturer details.

MARKETED BY
Abbott Healthcare Pvt. Ltd.
Angel Space, Bldg. D-4, Gala No. 1 to 6 &
11 to 16 Ground Floor, 101 to 106 &
111 to 116 First Floor, 201 to 206 & 211 to 216
2^nd Floor, Pimplas, Dist. Thane, Bhiwandi – 421 302, India.

11. DETAILS OF PERMISSION OR LICENCE NUMBER
Refer Pack for Permission/License details

12. DATE OF REVISION
Version 2.0 dated 14^th Sep 2023

For Product Complaints/Adverse events or queries, please write to

webmasterindia@abbott.com