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Desvenlafaxine Extended Release Tablets

TABLE OF CONTENTS

1. DESCRIPTION 8. ADVERSE REACTIONS
2. INDICATIONS AND USAGE 9. OVERDOSAGE
3. DOSAGE AND ADMINISTRATION 10. DRUG INTERACTIONS
4. CONTRAINDICATIONS 11. PHARMACODYNAMICS
5. MECHANISM OF ACTION 12. PHARMACOKINETICS
6. USE IN SPECIFIC POPULATIONS 13. HOW SUPPLIED/STORAGE AND HANDLING
7. WARNINGS AND PRECAUTIONS  

 


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 [see Warnings and Precautions].

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 [see Warnings and Precautions].

Desvenlafaxine is not approved for use in pediatric patients [see Use in Specific Populations].


 

1. DESCRIPTION

Desvenlafaxine is an extended-release tablet for oral administration that contains desvenlafaxine succinate, a structurally novel SNRI for the treatment of MDD. Desvenlafaxine (O-desmethylvenlafaxine) is the major active metabolite of the antidepressant venlafaxine, a medication used to treat major depressive, generalized anxiety, social anxiety and panic disorders.

Desvenlafaxine is designated RS-4-[2-dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenol and has the empirical formula of C16H25NO2 (free base) and C16H25NO2•C4H6O4•H2O (succinate monohydrate). Desvenlafaxine succinate monohydrate has a molecular weight of 399.48. The structural formula is shown below.

Desvenlafaxine succinate is a white to off-white powder that is soluble in water. The solubility of desvenlafaxine succinate is pH dependent. Its octanol:aqueous system (at pH 7.0) partition coefficient is 0.21.

Desvenlafaxine is formulated as an extended-release tablet for once-a-day oral administration. There are two different formulations of extended-release desvenlafaxine tablets:

1) KHEDEZLA brand name:

Each 50 mg or 100 mg extended-release tablet contains 50 or 100 mg of desvenlafaxine, respectively.

Inactive ingredients for the 50 mg tablet consist of citric acid monohydrate, hypromellose, microcrystalline cellulose, talc, magnesium stearate and colloidal silicon dioxide, and film coating, which consist of titanium dioxide, polyethylene glycol, talc, polyvinyl alcohol and iron oxides.

Inactive ingredients for the 100 mg tablet consist of citric acid monohydrate, hypromellose, microcrystalline cellulose, talc, magnesium stearate and colloidal silicon dioxide, and film coating, which consist of titanium dioxide, polyethylene glycol, talc, polyvinyl alcohol, iron oxides, and FD&C yellow #6.

2) PRISTIQ brand name:

Each tablet contains 76 or 152 mg of desvenlafaxine succinate equivalent to 50 or 100 mg of desvenlafaxine, respectively.

Inactive ingredients for the 50 mg tablet consist of hypromellose, microcrystalline cellulose, talc, magnesium stearate and film coating, which consists of polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide, and iron oxides.

Inactive ingredients for the 100 mg tablet consist of hypromellose, microcrystalline cellulose, talc, magnesium stearate and film coating, which consists of polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide, iron oxide and FD&C yellow #6.

2. INDICATIONS AND USAGE

Desvenlafaxine, a serotonin and norepinephrine reuptake inhibitor (SNRI), is indicated for the treatment of major depressive disorder (MDD) [see Dosage and Administration]. The efficacy of desvenlafaxine has been established in four short-term (8-week, placebo-controlled studies) and two maintenance studies in adult outpatients who met DSM-IV criteria for major depressive disorder.

3. DOSAGE AND ADMINISTRATION

3.1 General Instruction for Use

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

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.

When discontinuing therapy, gradual dose reduction is recommended whenever possible to minimize discontinuation symptoms [see Dosage and Administration and Warnings and Precautions].

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

3.2 Special Populations

Patients with renal impairment

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

Patients with hepatic impairment

The recommended dose in patients with hepatic impairment is 50 mg/day. Dose escalation above 100 mg/day is not recommended.

3.3 Maintenance/Continuation/Extended Treatment

It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacologic therapy. Longer-term efficacy of desvenlafaxine (50-400 mg) was established in two maintenance trials. Patients should be periodically reassessed to determine the need for continued treatment.

3.4 Discontinuing Desvenlafaxine

Symptoms associated with discontinuation of desvenlafaxine, other SNRIs and SSRIs have been reported [see Warnings and Precautions]. 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.

3.5 Switching Patients From Other Antidepressants to Desvenlafaxine

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 [see Contraindications].

3.6 Switching Patients To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders

At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with desvenlafaxine. Conversely, at least 7 days should be allowed after stopping desvenlafaxine before starting an MAOI intended to treat psychiatric disorders [see Contraindications].

Use of Desvenlafaxine with other MAOIs such as Linezolid or Methylene Blue

Do not start desvenlafaxine in a patient who is being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered [see Contraindications].

In some cases, a patient already receiving desvenlafaxine therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, desvenlafaxine should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 7 days or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with desvenlafaxine may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue [see Warnings and Precautions].

The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with desvenlafaxine is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use [see Warnings and Precautions].

4. CONTRAINDICATIONS

• Hypersensitivity to desvenlafaxine succinate, venlafaxine hydrochloride or to any excipients in the desvenlafaxine formulation. Angioedema has been reported in patients treated with desvenlafaxine [see Adverse Reactions].

• 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 [see Dosage and Administration and Warnings and Precautions].

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 [see Dosage and Administration and Warnings and Precautions].

5. MECHANISM OF ACTION

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).

6. USE IN SPECIFIC POPULATIONS

6.1 Usage in Pregnancy

Pregnancy Category C

Risk summary

There are no adequate and well-controlled studies of desvenlafaxine in pregnant women. In reproductive developmental studies in rats and rabbits with desvenlafaxine succinate, evidence of teratogenicity was not observed at doses up to 30 times a human dose of 100 mg/day (on a mg/m2 basis) in rats, and up to 15 times a human dose of 100 mg/day (on a mg/m2 basis) in rabbits. An increase in rat pup deaths was seen during the first 4 days of lactation when dosing occurred during gestation and lactation, at doses greater than 10 times a human dose of 100 mg/day (on a mg/m2 basis). Desvenlafaxine should be used during pregnancy only if the potential benefits justify the potential risks to the fetus.

Clinical considerations

A prospective longitudinal study of 201 women with history of major depression who were euthymic at the beginning of pregnancy, showed women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication.

Human data

Neonates exposed to SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), or SSRIs (Selective Serotonin Reuptake Inhibitors), 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, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, 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 [see Warnings and Precautions].

Animal data

When desvenlafaxine succinate was administered orally to pregnant rats and rabbits during the period of organogenesis at doses up to 300 mg/kg/day and 75 mg/kg/day, respectively, no teratogenic effects were observed. These doses are 30 times a human dose of 100 mg/day (on a mg/m2 basis) in rats and 15 times a human dose of 100 mg/day (on a mg/m2 basis) in rabbits. However, fetal weights were decreased and skeletal ossification was delayed in rats in association with maternal toxicity at the highest dose, with a no-effect dose 10 times a human dose of 100 mg/day (on a mg/m2 basis).

When desvenlafaxine succinate was administered orally to pregnant rats throughout gestation and lactation, there was a decrease in pup weights and an increase in pup deaths during the first four days of lactation at the highest dose of 300 mg/kg/day. The cause of these deaths is not known. The no-effect dose for rat pup mortality was 10 times a human dose of 100 mg/day (on a mg/m2 basis). Post-weaning growth and reproductive performance of the progeny were not affected by maternal treatment with desvenlafaxine succinate at a dose 30 times a human dose of 100 mg/day (on a mg/m2 basis).

6.2 Nursing Mothers

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 breastfeeding women if the expected benefits outweigh any possible risk.

6.3 Pediatric Use

Safety and effectiveness in the pediatric population have not been established [see Box Warning and Warnings and Precautions]. Anyone considering the use of desvenlafaxine in a child or adolescent must balance the potential risks with the clinical need.

6.4 Geriatric Use

Of the 4,158 patients in clinical studies with desvenlafaxine, 6% were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients; however, in the short-term placebo-controlled studies, there was a higher incidence of systolic orthostatic hypotension in patients ≥65 years of age compared to patients <65 years of age treated with desvenlafaxine [see Adverse Reactions]. For elderly patients, possible reduced renal clearance of desvenlafaxine should be considered when determining dose [see Dosage and Administration].

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 [see Warnings and Precautions].

6.5 Renal Impairment

In subjects with renal impairment the clearance of desvenlafaxine was decreased. In subjects with severe renal impairment (24-hr CrCl < 30 mL/min) and end-stage renal disease, elimination half-lives were significantly prolonged, increasing exposures to desvenlafaxine; therefore, dosage adjustment is recommended in these patients [see Dosage and Administration].

6.6 Hepatic Impairment

The mean t½ 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.

7. WARNINGS AND PRECAUTIONS

7.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults

Patients with major depressive disorder (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 the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing 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 behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (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 age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.

The pooled analyses of placebo-controlled studies in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term studies of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled studies in adults with MDD or other psychiatric disorders included a total of 295 short-term studies (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications.

No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.

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 trials 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 behavior, 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 pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. 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, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION — Discontinuation of Treatment with Citalopram, for a description of the risks of discontinuation of citalopram).

Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers.

Prescriptions for desvenlafaxine should be written for the smallest quantity 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 trials) 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.

7.2 Serotonin Syndrome

The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including desvenlafaxine, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort), and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.

The concomitant use of desvenlafaxine with MAOIs intended to treat psychiatric disorders is contraindicated. Desvenlafaxine should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking desvenlafaxine. Desvenlafaxine should be discontinued before initiating treatment with the MAOI [see Contraindications and Dosage and Administration].

If concomitant use of desvenlafaxine with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John's Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.

Treatment with desvenlafaxine and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.

7.3 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 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 [see Adverse Reactions].

7.4 Abnormal Bleeding

SSRIs and SNRIs, including desvenlafaxine, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages. 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.

7.5 Narrow-angle Glaucoma

Mydriasis has been reported in association with desvenlafaxine; therefore, patients with raised intraocular pressure or those at risk of acute narrow-angle glaucoma (angle-closure glaucoma) should be monitored.

7.6 Activation of Mania/Hypomania

During all MDD 2 and phase 3 studies, mania was reported for approximately 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 cautiously in patients with a history or family history of mania or hypomania.

7.7 Discontinuation Syndrome

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

During marketing of SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), and SSRIs (Selective Serotonin Reuptake Inhibitors), 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., paresthesia, 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 [see Dosage and Administration and Adverse Reactions].

7.8 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.

7.9 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 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted can be at greater risk [see Use in Specific Populations]. Discontinuation of desvenlafaxine should be considered in patients with symptomatic hyponatremia 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.

7.10 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.

8. ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the label:

• Hypersensitivity [see Contraindications]

• Suicidal Thoughts and Behaviors in Adolescents and Young Adults [see Warnings and Precautions]

• Serotonin Syndrome [see Warnings and Precautions]

• Elevated Blood Pressure [see Warnings and Precautions]

• Abnormal Bleeding [see Warnings and Precautions]

• Narrow-Angle Glaucoma [see Warnings and Precautions]

• Activation of Mania/Hypomania [see Warnings and Precautions]

• Discontinuation Syndrome [see Warnings and Precautions]

• Seizure [see Warnings and Precautions]

• Hyponatremia [see Warnings and Precautions]

• Interstitial Lung Disease and Eosinophilic Pneumonia [see Warnings and Precautions].

8.1 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.

Patient exposure

Desvenlafaxine was evaluated for safety in 4,158 patients diagnosed with major depressive disorder who participated in multiple-dose pre-marketing studies, representing 1,677 patient-years of exposure. Among these 4,158 desvenlafaxine treated patients; 1,834 patients were exposed to desvenlafaxine in 8-week, placebo-controlled studies at doses ranging from 50 to 400 mg/day. Out of the 1,834 patients, 687 desvenlafaxine treated patients continued into a 10-month open-label study. Of the total 4,158 patients exposed to at least one dose of desvenlafaxine; 1,320 were exposed to desvenlafaxine for 6 months, representing 1058 patient-years of exposure, and 274 were exposed for one year, representing 241 patient-years of exposure.

Adverse reactions reported as reasons for discontinuation of treatment

In the pooled 8-week placebo-controlled studies in patients with MDD, 12% of the 1,834 patients who received desvenlafaxine (50 to 400 mg) 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 the longer-term studies, up to 11 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 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.

Table 1 shows the incidence of common adverse reactions that occurred in ≥ 2% of desvenlafaxine treated MDD patients and twice the rate of placebo at any dose in the pooled 8-week, placebo-controlled, fixed dose clinical studies

Table 1: Common Adverse Reactions (≥ 2% in any Fixed-Dose Group and Twice the Rate of Placebo) in Pooled MDD 8-Week Placebo-Controlled Studies

Sexual function adverse reactions

Table 2 shows the incidence of sexual function adverse reactions that occurred in ≥ 2% of desvenlafaxine treated MDD patients in any fixed-dose group (8-week, placebo-controlled, fixed and flexible-dose, pre-marketing clinical studies).

Table 2: Sexual Function Disorders: Adverse Reactions (≥ 2% in Mena or Womenb in any Desvenlafaxine Group) During the On-Therapy Period

a: Percentage based on the number of men (placebo, n = 239; desvenlafaxine 50 mg, n = 108; desvenlafaxine 100 mg, n = 157; desvenlafaxine 200 mg, n = 131; desvenlafaxine 400 mg, n = 154).

b: Percentage based on the number of women (placebo, n = 397; desvenlafaxine 50 mg, n = 209; desvenlafaxine 100 mg, n = 267; desvenlafaxine 200 mg, n = 176; desvenlafaxine 400 mg, n = 163).

Other adverse reactions observed in pre-marketing clinical studies

Other infrequent adverse reactions, not described elsewhere, occurring at an incidence of < 2% in MDD patients treated with desvenlafaxine were:

Immune system disorders – Hypersensitivity.

Investigations – Weight increased, liver function test abnormal, blood prolactin increased.

Nervous system disorders – Convulsion, syncope, extrapyramidal disorder.

Musculoskeletal and connective tissue disorders – Musculoskeletal stiffness.

Psychiatric disorders – Depersonalization, hypomania, bruxism.

Respiratory, thoracic and mediastinal disorders – Epistaxis.

Vascular disorders – Orthostatic hypotension.

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 desvenlafaxine treatment as compared to placebo [see Warnings and Precautions].

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 (low density lipoproteins) cholesterol, and triglycerides occurred in the controlled studies. Some of these abnormalities were considered potentially clinically significant [see Warnings and Precautions].

The percentage of patients who exceeded a predetermined threshold value is shown in Table 3.

Table 3: Incidence (%) of Patients With Lipid Abnormalities of Potential Clinical Significance*

Proteinuria

Proteinuria, greater than or equal to trace, was observed in the fixed-dose controlled studies (see Table 4). This proteinuria was not associated with increases in BUN or creatinine and was generally transient.

Table 4: Incidence (%) of Patients with Proteinuria in the Fixed-dose Clinical Studies

Vital sign changes

Table 5 summarizes the changes that were observed in placebo-controlled, short-term, pre-marketing studies with desvenlafaxine in patients with MDD (doses 50 to 400 mg).

Table 5: Mean Changes in Vital Signs at Final on Therapy for All Short-term, Fixed-dose Controlled Studies

Treatment with desvenlafaxine at all doses from 50 mg/day to 400 mg/day in controlled studies was associated with sustained hypertension, defined as treatment-emergent supine diastolic blood pressure (SDBP) ≥90 mm Hg and ≥10 mm Hg above baseline for 3 consecutive on-therapy visits (see Table 6). Analyses of patients in desvenlafaxine short-term controlled studies who met 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 6: Proportion of Patients with Sustained Elevation of Supine Diastolic Blood Pressure

Orthostatic hypotension

In the short-term, placebo-controlled clinical studies with doses of 50-400 mg, systolic orthostatic hypotension (decrease ≥ 30 mm Hg from supine to standing position) occurred more frequently in patients ≥ 65 years of age receiving desvenlafaxine (8.0%, 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).

8.2 Postmarketing Experience

The following adverse reaction has been identified during post-approval use of desvenlafaxine. Because post-approval 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.

9. OVERDOSAGE

9.1 Human Experience with Overdosage

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 postmarketing experience, overdose with venlafaxine (the parent drug of desvenlafaxine) 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.

9.2 Management of Overdosage

No specific antidotes for desvenlafaxine are known. In managing over dosage, consider the possibility of multiple drug involvement. In case of overdose, call Poison Control Center at 1800-222-1222 for latest recommendations.

10. DRUG INTERACTIONS

10.1 Monoamine Oxidase Inhibitors (MAOI)

[see Dosage and Administration, Contraindications and Warnings and Precautions].

10.2 Serotonergic Drugs

[see Dosage and Administration, Contraindications and Warnings and Precautions].

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

Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of case-control and cohort design that have demonstrated an association between 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 an 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.

10.4 Potential for Desvenlafaxine to Affect Other Drugs

Clinical studies have shown that desvenlafaxine does not have a clinically relevant effect on CYP2D6 metabolism at the dose of 100 mg daily. Substrates primarily metabolized by CYP2D6 (e.g., desipramine , atomoxetine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine) should be dosed at the original level when co-administered with desvenlafaxine 100 mg or lower. Reduce the dose of these substrates by one-half if co-administered with 400 mg of desvenlafaxine. The substrate dose should be increased to the original level when 400 mg of desvenlafaxine is discontinued.

10.5 Other Drugs Containing Desvenlafaxine or Venlafaxine

Avoid use of desvenlafaxine with other desvenlafaxine-containing products or venlafaxine products. The concomitant use of desvenlafaxine with other desvenlafaxine-containing products or venlafaxine will increase desvenlafaxine blood levels and increase dose-related adverse reactions [see Adverse Reactions].

10.6 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.

11. PHARMACODYNAMICS

Desvenlafaxine lacked significant affinity for numerous receptors, including muscarinic-cholinergic, H1-histaminergic, or α1-adrenergic receptors in vitro. Desvenlafaxine also lacked monoamine oxidase (MAO) inhibitory activity.

ECG changes

Electrocardiograms were obtained from 1,492 desvenlafaxine treated patients with major depressive disorder and 984 placebo-treated patients in clinical studies lasting up to 8 weeks. No clinically relevant differences were observed between desvenlafaxine treated 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.

12. PHARMACOKINETICS

The single-dose pharmacokinetics of desvenlafaxine are linear and dose-proportional in a dose range of 100 to 600 mg/day. The mean terminal half-life, t½, is approximately 11 hours. With once-daily dosing, steady-state plasma concentrations are achieved within approximately 4-5 days. At steady-state, multiple-dose accumulation of desvenlafaxine is linear and predictable from the single-dose pharmacokinetic profile.

Absorption and Distribution

The absolute oral bioavailability of desvenlafaxine after oral administration is about 80%. Mean time to peak plasma concentrations (Tmax) is about 7.5 hours after oral administration.

A food-effect study involving administration of desvenlafaxine to healthy subjects under fasting and fed conditions (high-fat meal) indicated that the Cmax was increased about 16% in the fed state, while the AUCs were similar. This difference is not clinically significant; therefore, desvenlafaxine can be taken without regard to meals [see Dosage and Administration].

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

Metabolism and Elimination

Desvenlafaxine is primarily metabolized by conjugation (mediated by UGT isoforms) and, to a minor extent, through oxidative metabolism. CYP3A4 is the cytochrome P450 isozyme mediating the oxidative metabolism (N-demethylation) of desvenlafaxine. The CYP2D6 metabolic pathway is not involved, and after administration of 100 mg, 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.

Special Populations

Age

In a study of healthy subjects administered doses of up to 300 mg, there was an approximate 32% increase in Cmax and a 55% increase in 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 Cmax, but an approximately 32% increase in AUC, compared to subjects 18 to 45 years of age [see Dosage and Administration].

Gender

In a study of healthy subjects administered doses of up to 300 mg, women had an approximately 25% higher Cmax 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; Other, n = 33) had no apparent effect on the pharmacokinetics of desvenlafaxine. No adjustment of dosage on the basis of race is needed.

Hepatic insufficiency

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 to 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. CL/F values were comparable in mild hepatic impairment and healthy subjects (< 5% difference).

The mean t½ 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 [see Use in Specific Populations].

Renal insufficiency

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 [ESRD] (n = 9) requiring dialysis and in healthy, age-matched control subjects (n = 8). Elimination was significantly correlated with creatinine clearance. Increases in AUCs of about 42% in mild renal impairment (24-hr CrCl = 50-80 mL/min), about 56% in moderate renal impairment (24-hr CrCl = 30-50 mL/min), about 108% in severe renal impairment (24-hr CrCl ≤ 30 mL/min), and about 116% in ESRD subjects were observed, compared with healthy, age-matched control subjects.

The mean terminal half-life (t½) 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 hemodialysis procedure.

The recommended dose in patients with moderate renal impairment is 50 mg per day. Dosage adjustment (50 mg 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 [see Dosage and Administration and Use in Specific Populations].

13. HOW SUPPLIED/STORAGE AND HANDLING

1) How Available:

a) Brand names:

KHEDEZLA, by Osmotica Pharm.

PRISTIQ, by Wyeth Pharms Inc.

b) Generic drugs: NONE.

2) How Supplied:

KHEDEZLA® (desvenlafaxine) Extended-release Tablets are available as follows:

50 mg, pink, round tablet debossed with "OS" on one side and "231" on the other

NDC 49884-374-11, bottle of 30 tablets in unit-of-use package

NDC 49884-374-4, bottle of 90 tablets in unit-of-use package

100 mg, brown, round tablet debossed with “OS” on one side and "232" on the other

NDC 49884-375-11, bottle of 30 tablets in unit-of-use package

NDC49884-275-4, bottle of 90 tablets in unit-of-use package

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PRISTIQ® (desvenlafaxine) Extended-Release Tablets are available as follows:

50 mg, light pink, square pyramid tablet debossed with “W” (over) “50” on the flat side

NDC 0008-1211-14, bottle of 14 tablets in unit-of-use package

NDC 0008-1211-30, bottle of 30 tablets in unit-of-use package

NDC 0008-1211-01, bottle of 90 tablets in unit-of-use package

NDC 0008-1211-50, 10 blisters of 10 (HUD)

100 mg, reddish-orange, square pyramid tablet debossed with “W” (over) “100” on the flat side

NDC 0008-1222-14, bottle of 14 tablets in unit-of-use package

NDC 0008-1222-30, bottle of 30 tablets in unit-of-use package

NDC 0008-1222-01, bottle of 90 tablets in unit-of-use package

NDC 0008-1222-50, 10 blisters of 10 (HUD)

3) Storage:

Store at 20º-25ºC (68º-77ºF); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Each tablet contains 76 or 152 mg of desvenlafaxine succinate equivalent to 50 or 100 mg of desvenlafaxine, respectively.

Rx only

Rev 07/13