PRISTIQ® (desvenlafaxine) Extended

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 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.

Mechanism of Action
Non-clinical studies have shown that desvenlafaxine succinate is a potent and selective serotonin and norepinephrine reuptake inhibitor (SNRI). The clinical efficacy of desvenlafaxine succinate is thought to be related to the potentiation of these neurotransmitters in the central nervous system.

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

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, t1/2, 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.

USE IN SPECIFIC POPULATIONS
Dosage adjustment is recommended in patients with severe renal impairment and end-stage renal disease. The dose should not be escalated in moderate to severe impairment or in ESRD.

There is an increased incidence of orthostatic hypotension in PRISTIQ treated patients >/= 65 years.

For elderly patients, the possibility of reduced renal clearance of desvenlafaxine should be considered when determining dose.

Only administer PRISTIQ to pregnant or breastfeeding women if the expected benefits outweigh the possible risks.

Do not use with an MAOI or within 14 days of stopping an MAOI. Allow 7 days after stopping PRISTIQ before starting an MAOI

• Clinical Worsening/Suicide Risk: Monitor for clinical worsening and suicide risk
• Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions: Serotonin syndrome or NMS-like reactions have been reported with SSRIs and SNRIs. Discontinue PRISTIQ and initiate supportive treatment
• Elevated Blood Pressure: Has occurred with PRISTIQ. Hypertension should be controlled before initiating treatment. Monitor blood pressure regularly during treatment
• Abnormal Bleeding: PRISTIQ may increase the risk of bleeding events. Patients should be cautioned about the risk of bleeding associated with the concomitant use of PRISTIQ and NSAIDs, aspirin, or other drugs that affect coagulation
• Narrow-angle Glaucoma: Mydriasis has occurred with PRISTIQ. 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 in patients 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 PRISTIQ. 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
• Drugs Containing Desvenlafaxine or Venlafaxine: Should not be used concomitantly with PRISTIQ
• Interstitial Lung Disease and Eosinophilic Pneumonia: Can occur

To report SUSPECTED ADVERSE REACTIONS, contact Wyeth Pharmaceuticals Inc., a subsidiary of Pfizer Inc., at 1-800-934-5556 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

In clinical studies, doses of 50-400 mg/day were shown to be effective, although no additional benefit was demonstrated at doses greater than 50 mg/day and adverse events 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 (2.4) and Warnings and Precautions (5.9)].

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.

2.2 Special Populations

Pregnant women during the third trimester
Neonates exposed to SNRIs or SSRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding [see Use in Specific Populations (8.1)]. When treating pregnant women with PRISTIQ during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering PRISTIQ in the third trimester.

Patients with renal impairment
No dosage adjustment is necessary in patients with mild renal impairment (24-hr CrCl = 50-80 mL/min).

The recommended dose in patients with moderate renal impairment (24-hr CrCl = 30-50 mL/min) is 50 mg per day. The recommended dose in patients with severe renal impairment (24-hr CrCl < 30 mL/min) or end-stage renal disease (ESRD) is 50 mg every other day. Supplemental doses should not be given to patients after dialysis. The doses should not be escalated in patients with moderate or severe renal impairment, or ESRD [see Warnings and Precautions (5.10), Use in Specific Populations (8.6) and Clinical Pharmacology (12.6)].

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 [see Clinical Pharmacology (12.6)].

Elderly patients
No dosage adjustment is required solely on the basis of age; however, the possibility of reduced renal clearance of PRISTIQ should be considered when determining the dose [see Use in Specific Populations (8.5) and Clinical Pharmacology (12.6)].

2.3 Maintenance/Continuation/Extended Treatment
It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacologic therapy. However, the longer-term efficacy of PRISTIQ at a dose of 50 mg/day that was effective in short-term, controlled studies has not been studied. Patients should be periodically reassessed to determine the need for continued treatment.

2.4 Discontinuing PRISTIQ
Symptoms associated with discontinuation of PRISTIQ, other SNRIs and SSRIs have been reported [see Warnings and Precautions (5.9)]. 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.

2.5 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 [see Contraindications (4.2)].

2.6 Switching Patients To or From a Monoamine Oxidase Inhibitor (MAOI)
At least 14 days must elapse between discontinuation of an MAOI and initiation of therapy with PRISTIQ. In addition, at least 7 days must be allowed after stopping PRISTIQ before starting an MAOI [see Contraindications (4.2)].

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