PRISTIQ® (desvenlafaxine)

PRISTIQ® (desvenlafaxine) Extended-Release Tablets

PRISTIQ® (desvenlafaxine)

PRISTIQ 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 disorder.

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.

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.

PRISTIQ is formulated as an extended-release tablet for once-a-day oral administration.

Each tablet contains 38 mg, 76 mg or 152 mg of desvenlafaxine succinate equivalent to 25 mg, 50 mg or 100 mg of desvenlafaxine, respectively.

Inactive ingredients for the 25 mg tablet consist of hypromellose, microcrystalline cellulose, talc, magnesium stearate, a film coating which consists of polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide, and iron oxides.

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.

INDICATIONS AND USAGE

PRISTIQ is indicated for the treatment of adults with major depressive disorder (MDD)

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 SNRI.

DOSAGE AND ADMINISTRATION

The recommended dose for PRISTIQ is 50 mg once daily, with or without food. The 50 mg dose is both a starting dose and the therapeutic dose. PRISTIQ should be taken at approximately the same time each day. Tablets must be swallowed whole with fluid and not divided, crushed, chewed, or dissolved.

The 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

Dosage Recommendations for Patients with Renal Impairment

The maximum recommended dose in patients with moderate renal impairment (24-hr creatinine clearance [ClCr] = 30 to 50 mL/min, Cockcroft-Gault [C-G]) is 50 mg per day. The maximum recommended dose in patients with severe renal impairment (ClCr 15 to 29 mL/min, C-G) or end-stage renal disease (ESRD, ClCr < 15 mL/min, C-G) is 25 mg every day or 50 mg every other day. Supplemental doses should not be given to patients after dialysis

Dosage Recommendations for Patients with Hepatic Impairment

The recommended dose in patients with moderate to severe hepatic impairment (Child-Pugh score 7 to 15) is 50 mg per day. Dose escalation above 100 mg per day is not recommended

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 PRISTIQ (50-400 mg) was established in two maintenance trials. Patients should be periodically reassessed to determine the need for continued treatment.

Discontinuing PRISTIQ

Adverse reactions may occur upon discontinuation of PRISTIQ. Gradually reduce the dosage rather than stopping PRISTIQ abruptly when discontinuing therapy with PRISTIQ. In some patients, discontinuation may need to occur over a period of several months.

Switching Patients From Other Antidepressants to PRISTIQ

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

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 PRISTIQ. Conversely, at least 7 days should be allowed after stopping PRISTIQ before starting an MAOI intended to treat psychiatric disorders.

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

Do not start PRISTIQ 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.

CONTRAINDICATIONS

  • Hypersensitivity to desvenlafaxine succinate, venlafaxine hydrochloride or to any excipients in the PRISTIQ formulation. Angioedema has been reported in patients treated with PRISTIQ
  • The use of MAOIs intended to treat psychiatric disorders with PRISTIQ or within 7 days of stopping treatment with PRISTIQ is contraindicated because of an increased risk of serotonin syndrome. The use of PRISTIQ within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated

WARNINGS AND PRECAUTIONS

  • Suicidal Thoughts and Behaviors in Pediatric and Young Adult Patients: Patients with MDD, both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.
  • Serotonin Syndrome: Increased risk when co-administered with other serotonergic agents (e.g., SSRI, SNRI, triptans), but also when taken alone. If it occurs, discontinue PRISTIQ and initiate supportive treatment.
  • Elevated Blood Pressure: Control hypertension before initiating treatment. Monitor blood pressure regularly during treatment.
  • Increased Risk of Bleeding: Concomitant use of aspirin, NSAIDs, other antiplatelet drugs, warfarin, and other anticoagulants may increase this risk.
  • Angle Closure Glaucoma: Avoid use of antidepressants, including PRISTIQ, in patients with untreated anatomically narrow angles treated.
  • Activation of Mania/Hypomania: Use cautiously in patients with Bipolar Disorder. Caution patients about risk of activation of mania/hypomania.
  • Discontinuation Syndrome: Taper dose when possible and monitor for discontinuation symptoms.
  • Seizure: Can occur. Use cautiously in patients with seizure disorder.
  • Hyponatremia: Can occur in association with SIADH.
  • Interstitial Lung Disease and Eosinophilic Pneumonia: Can occur.
  • Sexual Dysfunction: PRISTIQ may cause symptoms of sexual dysfunction

USE IN SPECIFIC POPULATIONS

Pregnancy: There are no published studies on PRISTIQ in pregnant women; however published epidemiologic studies of pregnant women exposed to venlafaxine, the parent compound, have not reported a clear association with adverse developmental outcomes. There are risks associated with untreated depression in pregnancy and with exposure to SNRIs and SSRIs, including PRISTIQ, during pregnancy

Disease-Associated Maternal and/or Embryo/Fetal Risk: A prospective longitudinal study of 201 women with a history of major depression who were euthymic at the beginning of pregnancy, showed that women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication.

Maternal Adverse Reactions: Exposure to SNRIs in mid to late pregnancy may increase the risk for preeclampsia, and exposure to SNRIs near delivery may increase the risk for postpartum hemorrhage.

Fetal/Neonatal Adverse Reactions: Exposure to SNRIs or SSRIs in late pregnancy may lead to an increased risk for neonatal complications requiring prolonged hospitalization, respiratory support, and tube feeding. Monitor neonates who were exposed to PRISTIQ in the third trimester of pregnancy for drug discontinuation syndrome

Lactation: Available limited data from published literature show low levels of desvenlafaxine in human milk, and have not shown adverse reactions in breastfed infants. There are no data on the effects of desvenlafaxine on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for PRISTIQ and any potential adverse effects on the breastfed child from PRISTIQ or from the underlying maternal condition.

Pediatric Use: The safety and effectiveness of PRISTIQ have not been established in pediatric patients for the treatment of MDD.

Renal Impairment: Adjust the maximum recommended dosage in patients with moderate or severe renal impairment (CLcr 15 to 50 mL/min, C-G), or end-stage renal disease (CLcr < 15 mL/min, C-G)

Hepatic Impairment: Adjust the maximum recommended dosage in patients with moderate to severe hepatic impairment (Child-Pugh score 7 to 15).

OVERDOSAGE

There is limited clinical trial experience with desvenlafaxine succinate overdosage in humans. However, desvenlafaxine (PRISTIQ) is the major active metabolite of venlafaxine. Overdose experience reported with venlafaxine (the parent drug of PRISTIQ) 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 PRISTIQ) 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.

Management of Overdosage

No specific antidotes for PRISTIQ are known. In managing over dosage, consider the possibility of multiple drug involvement. In case of overdose, call Poison Control Center at 1-800-222-1222 for latest recommendations.