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

• Hypersensitivity [see CONTRAINDICATIONS]
• Effects on blood pressure [see WARNINGS AND PRECAUTIONS]
• Abnormal bleeding [see WARNINGS AND PRECAUTIONS]
• Mydriasis [see WARNINGS AND PRECAUTIONS]
• Hypomania and mania [see WARNINGS AND PRECAUTIONS]
• Serum cholesterol and triglyceride elevation [see WARNINGS AND PRECAUTIONS]
• Seizure [see WARNINGS AND PRECAUTIONS]

Clinical Studies Experience

The most commonly observed adverse reactions in PRISTIQ 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.

Adverse reactions reported as reasons for discontinuation of treatment

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

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

Patient exposure

PRISTIQ was evaluated for safety in 3,292 patients diagnosed with major depressive disorder who participated in multiple-dose pre-marketing studies, representing 1,289 patient-years of exposure. Among these 3,292 PRISTIQ treated patients, 1,834 patients were exposed to PRISTIQ in 8-week, placebo-controlled studies at doses ranging from 50 to 400 mg/day. Out of the 1,834 patients, 687 PRISTIQ treated patients continued into a 10-month open-label study. Of the total 3,292 patients exposed to at least one dose of PRISTIQ, 1,070 were exposed to PRISTIQ for 6 months, representing 842 patient-years of exposure, and 274 were exposed for one year, representing 241 patient-years of exposure.

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Common adverse reactions in placebo-controlled MDD studies

Table 3 shows the incidence of common adverse reactions that occurred in ≥ 2% of PRISTIQ treated MDD patients at any dose in the 8-week, placebo-controlled, fixed dose, pre-marketing clinical studies. In general, the adverse reactions were most frequent in the first week of treatment.

Table 3: Common Adverse Reactions: Percentage of Patients ( ≥ 2% in any Fixed-Dose Group) in MDD 8-Week Placebo-Controlled Studies^a

Sexual function adverse reactions

Table 4 shows the incidence of sexual function adverse reactions that occurred in ≥ 2% of PRISTIQ treated MDD patients in any fixed-dose group (8-week, placebo-controlled, fixed and flexible-dose, pre-marketing clinical studies).

Table 4: Sexual Function Disorders: Adverse Reactions ( ≥ 2% in Men^a or Women^b in any PRISTIQ Group) During the On-Therapy Period

Other adverse reactions observed in pre-marketing clinical studies

Other infrequent adverse reactions, not described elsewhere in section 6.1, occurring at an incidence of < 2% in MDD patients treated with PRISTIQ 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 PRISTIQ treatment as compared to placebo [see WARNINGS AND PRECAUTIONS].

Discontinuation events

Adverse events reported in association with abrupt discontinuation, dose reduction or tapering of treatment in MDD clinical studies at a rate of ≥ 5% include: dizziness, nausea, headache, irritability, insomnia, diarrhea, anxiety, abnormal dreams, fatigue, and hyperhidrosis. In general, discontinuation events occurred more frequently with longer duration of therapy [see DOSAGE AND ADMINISTRATION and 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 PRISTIQ.

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 5.

Table 5: 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 6). This proteinuria was not associated with increases in BUN or creatinine and was generally transient.

Table 6: Incidence (%) of Patients with Proteinuria in the Fixed-dose Clinical Studies

ECG changes

Electrocardiograms were obtained from 1,492 PRISTIQ 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 PRISTIQ 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.

Vital sign changes

Table 7 summarizes the changes that were observed in placebo-controlled, short-term, pre-marketing studies with PRISTIQ in patients with MDD (doses 50 to 400 mg).

Table 7: Mean Changes in Vital Signs at Final on Therapy for All Short-term, Fixed-dose Controlled Studies

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

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 PRISTIQ (8.0%, 7/87) versus placebo (2.5%, 1/40), compared to patients < 65 years of age receiving PRISTIQ (0.9%, 18/1,937) versus placebo (0.7%, 8/1,218).

Adverse Reactions Identified During Post-Approval Use

The following adverse reaction has been identified during post-approval use of PRISTIQ. 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 – Angioedema.

Adverse Reactions Reported With Other SNRIs

Although the following are not considered adverse reactions for PRISTIQ, they are adverse reactions for other SNRIs and may also occur with PRISTIQ: gastrointestinal bleeding, hallucinations, photosensitivity reactions and severe cutaneous reactions (such as Stevens-Johnson Syndrome, toxic epidermal necrolysis, and/or erythema multiforme).

Central Nervous System (CNS)-Active Agents

The risk of using PRISTIQ in combination with other CNS-active drugs has not been systematically evaluated. Consequently, caution is advised when PRISTIQ is taken in combination with other CNS-active drugs [see WARNINGS AND PRECAUTIONS].

Monoamine Oxidase Inhibitors (MAOI)

Adverse reactions, some of which were serious, have been reported in patients who have recently been discontinued from a monoamine oxidase inhibitor (MAOI) and started on antidepressants with pharmacological properties similar to PRISTIQ (SNRIs or SSRIs), or who have recently had SNRI or SSRI therapy discontinued prior to initiation of an MAOI [see CONTRAINDICATIONS].

Serotonergic Drugs

Based on the mechanism of action of PRISTIQ and the potential for serotonin syndrome, caution is advised when PRISTIQ is co-administered with other drugs that may affect the serotonergic neurotransmitter systems [see WARNINGS AND PRECAUTIONS].

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 PRISTIQ is initiated or discontinued.

Ethanol

A clinical study has shown that desvenlafaxine does not increase the impairment of mental and motor skills caused by ethanol. However, as with all CNS-active drugs, patients should be advised to avoid alcohol consumption while taking PRISTIQ.

Potential for Other Drugs to Affect Desvenlafaxine

Inhibitors of CYP3A4 (ketoconazole)

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

Inhibitors of other CYP enzymes

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

Potential for Desvenlafaxine to Affect Other Drugs

Drugs metabolized by CYP2D6 (desipramine)

In vitro studies showed minimal inhibitory effect of desvenlafaxine on CYP2D6.

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

Drugs metabolized by CYP3A4 (midazolam)

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

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

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

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

P-glycoprotein Transporter

In vitro, desvenlafaxine is not a substrate or an inhibitor for the P-glycoprotein transporter.

The pharmacokinetics of PRISTIQ are unlikely to be affected by drugs that inhibit the P-glycoprotein transporter, and desvenlafaxine is not likely to affect the pharmacokinetics of drugs that are substrates of the P-glycoprotein transporter.

Electroconvulsive Therapy

There are no clinical data establishing the risks and/or benefits of electroconvulsive therapy combined with PRISTIQ treatment.

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.

Drug Abuse And Dependence

Controlled Substance

Desvenlafaxine is not a controlled substance.

Abuse and Dependence

Although PRISTIQ has not been systematically studied in preclinical or clinical studies for its potential for abuse, no indication of drug-seeking behavior was seen in the clinical studies. However, it is not possible to predict on the basis of pre-marketing experience, the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of PRISTIQ (e.g., development of tolerance, incrementation of dose, drug-seeking behavior).

Last reviewed on RxList: 3/15/2012
This monograph has been modified to include the generic and brand name in many instances.