Pristiq

The safety of PRISTIQ in major depressive disorder was evaluated in 3292 patients exposed to at least one dose of PRISTIQ.

The most commonly observed adverse reactions (incidence of 5% or greater for the DVS SR pooled 50- to 400-mg doses, and incidence higher than placebo) in DVS SR-treated MDD patients in short-term placebo controlled trials were: nausea, headache, dry mouth, hyperhydrosis, dizziness, insomnia, constipation, decreased appetite, somnolence, fatigue, tremor, and vomiting, and, in men, erectile dysfunction and ejaculation delayed.

Uncommon: hypersensitivity.

PRISTIQ is not indicated for use in children under the age of 18. Safety and effectiveness in the pediatric population have not been established (see Warnings and Precautions, Potential Association with Behavioral and Emotional Changes, Including Self-harm).

PRISTIQ desvenlafaxine Extended-release Tablets is indicated for the symptomatic relief of major depressive disorder.

The short-term efficacy of PRISTIQ desvenlafaxine succinate Extended-release Tablets has been demonstrated in placebo-controlled trials of up to 8 weeks.

There is limited clinical experience with desvenlafaxine succinate overdosage in humans. In pre-marketing clinical trials, no cases of fatal acute overdose of desvenlafaxine succinate were reported.

Among the patients included in the pre-marketing major depressive disorder trials of desvenlafaxine succinate, there were four adults who ingested doses over 800 mg of desvenlafaxine (4000 mg [desvenlafaxine alone], 900, 1800 and 5200 mg [in combination with other drugs]); all patients recovered. In addition, a patient’s 11 month-old child accidentally ingested 600 mg of desvenlafaxine, was treated and recovered.

The adverse reactions reported within 5 days of an overdose >600 mg that were possibly related to desvenlafaxine included: headache, vomiting, agitation, dizziness, nausea, constipation, diarrhea, dry mouth, paresthesia, and tachycardia.

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 was reported predominantly in combination with alcohol and/or other drugs. The most commonly reported events in overdose include tachycardia, changes in level of consciousness (ranging from somnolence to coma), mydriasis, convulsion, and vomiting. Electrocardiographic changes (e.g., prolongation of QT interval, bundle branch block, QRS prolongation), ventricular tachycardia, bradycardia, hypotension, delayed rise in plasma creatine kinase levels, rhabdomyolysis, liver necrosis, serotonin syndrome, vertigo, and death have been reported. Muscle enzymes should be monitored in patients with venlafaxine overdose to detect development of rhabdomyolysis at an early stage and to initiate appropriate treatment. According to post-marketing overdose reports with venlafaxine (where overdose amounts were provided) fatal acute overdoses have been reported with venlafaxine alone at doses as low as approximately 1 gram.

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 burden of suicide risk factors than SSRI 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 characteristics of venlafaxine-treated patients is not clear.

Prescriptions for PRISTIQ should be written for the smallest quantity of drug consistent with good patient management, in order to reduce the risk of overdose.

Treatment should consist of those general measures employed in the management of overdosage with any SSRI/SNRI.

Induction of emesis is not recommended. Because of the moderate volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. No specific antidotes for desvenlafaxine are known.

Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients. Activated charcoal should be administered.

In managing an overdose, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose.

Each extended-release, light pink, square pyramid tablet debossed with “W” over “50” on the flat side, contains: desvenlafaxine succinate 50 mg. Nonmedicinal ingredients: hypromellose, magnesium stearate, microcrystalline cellulose and talc; film coating: dextrose, iron oxides, maltodextrin, sodium carboxymethylcellulose, stearic acid and titanium dioxide. HDPE bottles of 14, 30 and 90. Unit dose blisters of 7, 14 and 28.

Each extended-release, reddish-orange, square pyramid tablet debossed with “W” over “100” on the flat side, contains: desvenlafaxine succinate 100 mg. Nonmedicinal ingredients: hypromellose, magnesium stearate, microcrystalline cellulose and talc; film coating: dextrose, iron oxides, maltodextrin, sodium carboxymethylcellulose, stearic acid and titanium dioxide. HDPE bottles of 14, 30 and 90. Unit dose blisters of 7, 14 and 28.

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 (see Adverse Reactions).

Desvenlafaxine is the major active metabolite of venlafaxine, a medication used to treat major depressive, generalized anxiety, social anxiety and panic disorders. Products containing desvenlafaxine succinate should not be used concomitantly with products containing venlafaxine hydrochloride or other products containing desvenlafaxine.

Interstitial lung disease and eosinophilic pneumonia associated with venlafaxine (the parent drug of PRISTIQ) therapy have been rarely reported. The possibility of these adverse events should be considered in patients treated with PRISTIQ who present with progressive dyspnea, cough, or chest discomfort. Such patients should undergo a prompt medical evaluation, and discontinuation of PRISTIQ should be considered.

As with other serotonergic agents, serotonin syndrome, a potentially life-threatening condition, may occur with desvenlafaxine treatment, particularly with concomitant use of other agents that may affect the serotonergic neurotransmitter systems (such as triptans, serotonin reuptake inhibitors, sibutramine, MAOIs, St. John’s Wort (Hypericum perforatum) and/or lithium) and with drugs that impair metabolism of serotonin (including MAOIs). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, and diarrhea).

If concomitant treatment of desvenlafaxine with an SSRI, a Selective Serotonin and Norepinephrine Reuptake Inhibitor (SNRI) or a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. The concomitant use of desvenlafaxine with serotonin precursors (such as tryptophan supplements) is not recommended (see Drug Interactions, Serotonin Syndrome).

Increases in cholesterol (total and LDL) and triglycerides were observed in some patients treated with desvenlafaxine succinate in placebo-controlled pre-marketing clinical trials, particularly with higher doses. Measurement of serum lipid levels should be considered during treatment.

Drugs that inhibit serotonin uptake in platelets may lead to abnormalities of platelet aggregation. As with other agents that inhibit serotonin-reuptake, desvenlafaxine succinate should be used cautiously in patients predisposed to bleeding.

The safety of desvenlafaxine in human pregnancy has not been established. The extent of exposure to PRISTIQ in pregnancy during clinical trials was very limited. There are no adequate and well-controlled studies in pregnant women. Therefore, desvenlafaxine should be used during pregnancy only if the potential benefits justify the potential risks. If desvenlafaxine succinate is used until or shortly before birth, discontinuation effects in the newborn should be considered.

Post-marketing reports indicate that some neonates exposed to SNRIs, SSRIs, or other newer antidepressants 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, hyper-reflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SNRIs, SSRIs and other newer antidepressants, or, possibly a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see Drug Interactions). When treating a pregnant woman with PRISTIQ during the third trimester, the physician should carefully consider the potential risks and benefits of treatment.

Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy.

Patients should be advised to notify their physician if they develop a rash, hives or a related allergic phenomenon.

Rigorous clinical monitoring for suicidal ideation or other indicators of potential for suicidal behaviour is advised in patients of all ages. Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially when initiating therapy or during any change in dose or dosage regimen. (See Warnings and Precautions, Potential Association with Behavioral and Emotional Changes, Including Self-harm.)

Although desvenlafaxine succinate has not been systematically studied in preclinical or clinical trials for its potential for abuse, no indication of drug-seeking behavior was seen in the clinical trials.

Recent analyses of placebo-controlled clinical trial safety databases from Selective Serotonin Reuptake Inhibitors (SSRIs) and other newer anti-depressants suggest that use of these drugs in patients under the age of 18 may be associated with behavioural and emotional changes, including an increased risk of suicidal ideation and behaviour over that of placebo.

The small denominators in the clinical trial database, as well as the variability in placebo rates, preclude reliable conclusions on the relative safety profiles among the drugs in the class.

Increases in cholesterol (total and LDL) and triglycerides were observed in some patients treated with desvenlafaxine succinate in placebo-controlled pre-marketing clinical trials, particularly with higher doses. Measurement of serum lipid levels should be considered during treatment.

Because the PRISTIQ tablet does not appreciably change in shape in the gastrointestinal tract, PRISTIQ should not be administered to patients with pre-existing gastrointestinal narrowing (pathologic or iatrogenic, such as small bowel inflammatory disease, “short gut” syndrome due to adhesions or decreased transit time, past history of peritonitis, cystic fibrosis, chronic intestinal pseudo-obstruction, or Meckel’s diverticulum). There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of other drugs in nondeformable controlled-release formulations, and very rare reports of obstructive symptoms associated with the use of nondeformable controlled-release formulations in patients without known gastrointestinal stricture. Due to the controlled-release design, PRISTIQ tablets should only be used in patients who are able to swallow the tablets whole. (See Dosage and Administration, Recommended Dose and Dosage Adjustment.)

Mania/hypomania may occur in a small proportion of patients with mood disorders who have received medication to treat depression, including desvenlafaxine succinate. During phase 2 and phase 3 studies, mania was reported for approximately 0.1% of patients treated with PRISTIQ. 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, PRISTIQ should be used cautiously in patients with a history or family history of mania or hypomania.

There are clinical trial and post-marketing reports with SSRIs and other newer antidepressants, in both pediatrics and adults, of severe agitation-type adverse events coupled with self-harm or harm to others. The agitation-type events include: akathisia, agitation, disinhibition, emotional lability, hostility, aggression, depersonalization. In some cases, the events occurred within several weeks of starting treatment.

Rigorous clinical monitoring for suicidal ideation or other indicators of potential for suicidal behaviour is advised in patients of all ages especially when initiating therapy or during any change in dose or dosage regimen. This includes monitoring for agitation-type emotional and behavioural changes.

Patients currently taking PRISTIQ should NOT be discontinued abruptly, due to risk of discontinuation symptoms (see Warnings and Precautions, Discontinuation Symptoms). At the time that a medical decision is made to discontinue an SSRI or other newer antidepressant drug, a gradual reduction in the dose, rather than an abrupt cessation, is recommended (see Dosage and Administration).

Caution is advised in administering PRISTIQ to patients with cardiovascular, cerebrovascular, or lipid metabolism disorders (see Clinical Trial Adverse Drug Reactions). Increases in blood pressure and heart rate were observed in clinical trials with PRISTIQ. PRISTIQ has not been evaluated systematically in patients with a recent history of myocardial infarction, unstable heart disease, uncontrolled hypertension, or cerebrovascular disease. Patients with these diagnoses, except for cerebrovascular disease, were excluded from clinical trials.

At the time that a medical decision is made to discontinue PRISTIQ, a gradual reduction in the dose, rather than an abrupt cessation, is recommended.

During marketing of SNRIs, and SSRIs, 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., paraesthesias, 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 PRISTIQ. 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 Adverse Reactions, Discontinuation Symptoms and Dosage and Administration, Discontinuing PRISTIQ).

The effect of desvenlafaxine on labour and delivery in humans is unknown. PRISTIQ should be used during labour and delivery only if the potential benefits justify the potential risks.

Safety and effectiveness in patients less than 18 years of age have not been established.

Of the 3292 patients in clinical trials with PRISTIQ, 5% were 65 years of age or older. While no overall differences in safety or efficacy were detected between these subjects and younger subjects, greater sensitivity of some older individuals cannot be ruled out. For elderly patients, possible reduced renal clearance of desvenlafaxine should be considered when determining dose (see Dosing Considerations, Geriatrics (≥65 years of age) and Action and Clinical Pharmacology, Special Populations and Conditions, Geriatrics).

Cases of hyponatremia and/or the Syndrome of Inappropriate Antidiuretic Hormone (SIADH) secretion have been described with SNRIs and SSRIs, usually in volume-depleted or dehydrated patients, including elderly patients and patients taking diuretics.

Cases of seizures have been reported in pre-marketing trials with PRISTIQ. Desvenlafaxine succinate should be prescribed with caution in patients with a seizure disorder. Desvenlafaxine has not been systematically evaluated in patients with a seizure disorder.

Increases in heart rate and blood pressure were observed in some patients in clinical trials, particularly with higher doses. Measurement of blood pressure is recommended prior to initiating treatment and regularly during treatment with desvenlafaxine succinate (see Adverse Reactions, Vital Sign Changes).

Desvenlafaxine (O-desmethylvenlafaxine) is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from PRISTIQ, 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 PRISTIQ to breastfeeding women if the expected benefits outweigh any possible risk.

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 t_1/2 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. No dosage adjustment is necessary for patients with hepatic impairment.

In a trial of healthy subjects administered doses of up to 300 mg, there was an approximate 32% increase in C_max and a 55% increase in AUC in subjects older than 75 years of age (n=7), compared with subjects 18 to 45 years of age (n=16). Subjects 65 to 75 years of age (n=5) had no change in C_max but an approximately 32% increase in AUC, compared to subjects 18 to 45 years of age. No dosage adjustment is required solely on the basis of age; however, possible reduced renal clearance of desvenlafaxine should be considered when determining dose.

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, t_1/2, 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.

The pharmacokinetics of desvenlafaxine have been thoroughly evaluated in women and men. There are minimal differences based on gender; data from all subjects are presented below.

Desvenlafaxine is the major active metabolite of venlafaxine which is also approved for treatment of depression. Preclinical studies have shown that desvenlafaxine succinate is a selective serotonin and norepinephrine reuptake inhibitor. The clinical efficacy of desvenlafaxine succinate is thought to be related to the potentiation of these neurotransmitters in the central nervous system.

Pharmacokinetic analysis on the basis of race (White, N=466; Black, N=97; Hispanic, N=39; Other, N=33) did not demonstrate an effect on the pharmacokinetics of PRISTIQ. No adjustment of dosage on the basis of race is needed.

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. 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.

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) requiring dialysis (n=9) 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, about 46% in moderate renal impairment, about 108% in severe renal impairment, and about 116% in ESRD subjects were observed, compared with healthy, age-matched, control subjects.

The mean terminal half-life (t_1/2) 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. Therefore, supplemental doses should not be given to patients after dialysis.

Dosage adjustment is recommended in patients with significant impairment of renal function (see Dosage and Administration, Patients with Severe Renal Impairment and End-stage Renal Disease).

In a trial of healthy subjects administered doses up to of 300 mg, women had an approximately 25% higher C_max and an approximately 10% higher AUC than age-matched men. No adjustment of dosage on the basis of gender is needed.

Desvenlafaxine lacked significant affinity for numerous receptors, including muscarinic-cholinergic, H₁-histaminergic, or α₁-adrenergic receptors in vitro. Desvenlafaxine also lacked significant affinity for various ion channels, including calcium, chloride, potassium and sodium ion channels and also lacked monoamine oxidase (MAO) inhibitory activity. Desvenlafaxine lacked significant activity in the in vitro cardiac potassium channel (hERG) assay.

Patients receiving PRISTIQ may notice an inert matrix tablet passing in the stool or via colostomy. Patients should be informed that the active medication has already been absorbed by the time the patient sees the inert matrix tablet.

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

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

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

PRISTIQ is not indicated for use in children and adolescents.