Clinical studies have shown that desvenlafaxine does not have a clinically relevant effect on CYP2D6 metabolism at the dose of 100 mg daily (Figure 2). 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 extended-release tablets 100 mg or lower or when desvenlafaxine extended-release tablets are discontinued. Reduce the dose of these substrates by up to one-half if co-administered with 400 mg of desvenlafaxine extended-release tablets.
No additional dose adjustment is required for concomitant use of substrates of CYP3A4, 1A2, 2A6, 2C8, 2C9, and 2C19 isozymes, and P-glycoprotein transporter. Clinical studies have demonstrated no clinically significant pharmacokinetic interaction between desvenlafaxine extended-release tablets and CYP3A4 substrates (Figure 2).
Clinical studies have shown that desvenlafaxine (100 mg daily) does not have a clinically relevant effect on tamoxifen and aripiprazole, compounds that are metabolized by a combination of both CYP2D6 and CYP3A4 enzymes (Figure 2).
In vitro studies showed minimal inhibitory effect of desvenlafaxine on the CYP2D6 isoenzyme.
In vitro , desvenlafaxine does not inhibit or induce the CYP3A4 isozyme.
In vitro , desvenlafaxine does not inhibit CYP1A2, 2A6, 2C8, 2C9, and 2C19, isozymes, and P-glycoprotein transporter and would not be expected to affect the pharmacokinetics of drugs that are substrates of these CYP isozymes and transporter.
Figure 2: Impact of Desvenlafaxine on Pharmacokinetics (PK) of Desipramine, Midazolam, Tamoxifen and Aripiprazole
Avoid use of desvenlafaxine extended-release tablets with other desvenlafaxine-containing products or venlafaxine products. The concomitant use of desvenlafaxine extended-release tablets with other desvenlafaxine-containing products or venlafaxine will increase desvenlafaxine blood levels and increase dose-related adverse reactions [see Adverse Reactions (6)].
A clinical study has shown that desvenlafaxine extended-release tablets 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 extended-release tablets.
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.
There are no adequate and well-controlled studies of desvenlafaxine extended-release tablets 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 per day (on a mg/m2 basis) in rats, and up to 15 times a human dose of 100 mg per 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 per day (on a mg/m2 basis). Desvenlafaxine extended-release tablets should be used during pregnancy only if the potential benefits justify the potential risks to the fetus.
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.
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 (5.2)].
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 per day (on a mg/m2 basis) in rats and 15 times a human dose of 100 mg per 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 per 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 per 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 per day (on a mg/m2 basis).
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 to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Safety and effectiveness in pediatric patients have not been established [see Boxed Warning and Warnings and Precautions (5.1)]. Anyone considering the use of desvenlafaxine extended-release tablets in a child or adolescent must balance the potential risks with the clinical need.
Of the 4,158 patients in pre-marketing clinical studies with desvenlafaxine extended-release tablets, 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 extended-release tablets [see Adverse Reactions (6)]. For elderly patients, possible reduced renal clearance of desvenlafaxine should be considered when determining dose [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].
SSRIs and SNRIs, including desvenlafaxine extended-release tablets, 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 (5.9)].
The effect of intrinsic patient factors on the pharmacokinetics of desvenlafaxine extended-release tablets is presented in Figure 3.
Figure 3: Impact of Intrinsic Factors (Renal, Hepatic Impairment and Population Description)
In subjects with renal impairment the clearance of desvenlafaxine was decreased. In subjects with severe renal impairment (24-hr CrCl < 30 mL/min, Cockcroft-Gault) 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 (2.2) and Clinical Pharmacology (12.3)].
The mean terminal half-life (t1/2 ) 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. The recommended dose in patients with moderate to severe hepatic impairment is 50 mg per day. Dose escalation above 100 mg per day is not recommended [see Clinical Pharmacology (12.3)].
Desvenlafaxine extended-release tablets are not a controlled substance.
There is limited clinical trial experience with desvenlafaxine succinate overdosage in humans. However, desvenlafaxine (desvenlafaxine extended-release tablets) is the major active metabolite of venlafaxine. Overdose experience reported with venlafaxine (the parent drug of desvenlafaxine extended-release tablets) 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 extended-release tablets) 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.
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