APTRYXOL™ (desvenlafaxine) extended-release tablets

APTRYXOL™ (desvenlafaxine) extended-release tablets

APTRYXOL™ (desvenlafaxine) extended-release tablets

APTRYXOL (desvenlafaxine extended-release tablets) for oral administration contains desvenlafaxine fumarate, a 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 disorders.

Desvenlafaxine is designated RS-4-[2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenol and has the molecular formula of C16H25NO2 (free base) and C16H25NO2•C4H4O4•H2O (fumarate monohydrate). Desvenlafaxine fumarate monohydrate has a molecular weight of 397.45.

Inactive ingredients for the 50 mg tablet consist of microcrystalline cellulose, hypromellose, magnesium stearate, talc, colloidal silicon dioxide, ferric oxide red and film-coating which contains hypromellose, titanium dioxide, polyethylene glycol, talc, iron oxide red and iron oxide yellow.

Inactive ingredients for the 100 mg tablet consist of microcrystalline cellulose, hypromellose, magnesium stearate, talc, colloidal silicon dioxide and film-coating which contain hypromellose, titanium dioxide, polyethylene glycol, talc, iron oxide red and iron oxide yellow.

Indications and usage

APTRYXOL (desvenlafaxine), is a serotonin and norepinephrine reuptake inhibitor (SNRI), 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 serotonin and norepinephrine reuptake inhibitor (SNRI).

Dosage and administration

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

Discontinuing Desvenlafaxine Extended-Release Tablets: Adverse reactions may occur upon discontinuation of desvenlafaxine extended-release tablets. Gradually reduce the dosage rather than stopping desvenlafaxine extended-release tablets abruptly whenever possible.

Switching Patients From Other Antidepressants to Desvenlafaxine Extended-Release Tablets: Discontinuation symptoms have been reported when switching patients from other antidepressants, including venlafaxine, to desvenlafaxine extended-release tablets. 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 desvenlafaxine extended-release tablets. Conversely, at least 7 days should be allowed after stopping desvenlafaxine extended-release tablets before starting an MAOI intended to treat psychiatric disorders

Contraindications

Hypersensitivity to desvenlafaxine fumarate, venlafaxine hydrochloride or to any excipients in the desvenlafaxine extended-release tablet formulation. Angioedema has been reported in patients treated with desvenlafaxine extended-release tablets.

The use of MAOIs intended to treat psychiatric disorders with desvenlafaxine extended-release tablets or within 7 days of stopping treatment with desvenlafaxine extended-release tablets is contraindicated because of an increased risk of serotonin syndrome. The use of desvenlafaxine extended-release tablets within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated.

Starting desvenlafaxine extended-release tablets in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome.

Warnings and precautions

Suicidal Thoughts and Behaviors in Pediatric and Young Adult Patients: Patients with major depressive disorder (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.

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 desvenlafaxine extended-release tablets 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 desvenlafaxine extended-release tablets, in patients with untreated anatomically narrow angles treated.

Activation of Mania/Hypomania: Use cautiously in patients with Bipolar Disorder. Caution patients about the 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

Adverse reactions

Most common adverse reactions (incidence ≥ 5% and twice the rate of placebo in the 50 mg or 100 mg dose groups) were: nausea, dizziness, insomnia, hyperhidrosis, constipation, somnolence, decreased appetite, anxiety, and specific male sexual function disorders

Drug interactions

Monoamine Oxidase Inhibitors (MAOI): Concomitant use of desvenlafaxine extended-release tablets is contraindicated:

  • With an MAOI intended to treat psychiatric disorders or within 7 days of stopping treatment with desvenlafaxine extended-release tablets.
  • Within 14 days of stopping an MAOI intended to treat psychiatric disorders.
  • In a patient who is being treated with linezolid or intravenous methylene blue

Examples: selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue

Other Serotonergic Drugs: Monitor for symptoms of serotonin syndrome when desvenlafaxine extendedrelease tablets is used concomitantly with other drugs that may affect the serotonergic neurotransmitter systems. If serotonin syndrome occurs, consider discontinuation of desvenlafaxine extended-release tablets and/or concomitant serotonergic drugs.

Examples: other SNRIs, SSRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, amphetamines, tryptophan, and St. John’s Wort

Drugs that Interfere with Hemostasis: Closely monitor for bleeding for patients receiving an antiplatelet or anticoagulant drug when desvenlafaxine extended-release tablets is initiated or discontinued.

Examples: NSAIDs, aspirin, and warfarin

Alcohol: A clinical study has shown that desvenlafaxine extended-release tablets do 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.

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.

Use in specific populations

Pregnancy: There are no published studies on desvenlafaxine extended-release tablets 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 desvenlafaxine extended-release tablets, during pregnancy.

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.

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.

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 desvenlafaxine extended-release tablets 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 (see Data). 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 desvenlafaxine extended-release tablets and any potential adverse effects on the breastfed child from desvenlafaxine extended-release tablets or from the underlying maternal condition.

Pediatric Use: The safety and effectiveness of desvenlafaxine extended-release tablets have not been established in pediatric patients for the treatment of MDD. Antidepressants, such as desvenlafaxine, increase the risk of suicidal thoughts and behaviors in pediatric patients

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 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 postmarketing experience, overdose with venlafaxine (the parent drug of desvenlafaxine) 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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