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NOTE: Use of saquinavir or saquinavir-ritonavir with trazodone is contraindicated. Do NOT coadminister. Strong inducers of CYP3A4 including efavirenz (variable effects), etravirine (variable effects) and nevirapine may DECREASE trazodone levels. Trazodone may alter concentrations of Pgp substrates including fosamprenavir, indinavir, lopinavir, nelfinavir, and ritonavir. 200 to 600 mg each bedtime for depression Vilazodone 10 mg once daily 7 days; then 20 mg once daily 20 to 40 mg once daily Maximum 20 mg per day with strong or moderate CYP 3A4 inhibitors Low risk of sexual dysfunction. May improve quality of sleep. More frequent diarrhea, nausea and insomnia. Vilazodone is metabolized by CYP3A4 (major), 2C19 (minor) and 2D6 (minor) Strong and moderate inhibitors of CYP 3A4 including atazanavir, cobicistat containing coformulations, darunavir, efavirenz, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir may INCREASE vilazodone concentrations. Maximum dose 20 mg per day with strong or moderate CYP 3A4 inhibitors. Strong inducers of CYP 3A4 including efavirenz, etravirine and nevirapine may DECREASE vilazodone concentrations. Effects may be variable. Nefazodone 50 mg twice per day 300 to 400 mg per day in divided doses Somewhat sedating. Low risk of sexual dysfunction. Rare reports of fatal hepatotoxicity led to market withdrawal in many countries. Nefazodone is metabolized by CYP2D6 and 3A4 Nefazodone is a potent inhibitor of CYP3A4 Nefazodone is an inducer of Pgp

NOTE: AVOID nefazodone in patients treated with HIV antiretrovirals, whenever possible. Not a first- or second-line choice. Numerous dose dependent drug interactions can increase risk of toxicities due to both nefazodone and HIV antiretrovirals. Nefazodone may alter concentrations of CYP 3A4 and/or Pgp substrates including atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, maraviroc, nelfinavir, nevirapine, ritonavir, and saquinavir. All HIV protease inhibitors Δ and cobicistat containing coformulations, may INCREASE concentrations of nefazodone. Dopamine-norepinephrine reuptake inhibitors Bupropion SR (sustained release) 100 mg each morning 150 to 400 mg per day in divided doses (depending on preparation) Stimulant effect may be useful for treatment of depressed patients with low energy and apathy. Low risk of cognitive toxicity. Low risk of sexual dysfunction. Bupropion is metabolized by CYP2B6 and/or UDP-UGT glucuronidation Bupropion is an inhibitor of CYP2D6 Nelfinavir is an inhibitor of CYP2B6 and may INCREASE bupropion concentrations. Strong inducers of CYP2B6 and/or UDP-UGT including efavirenz, lopinavir, lopinavir-ritonavir, tipranavir-ritonavir, and nevirapine may DECREASE concentrations of bupropion. A 46 to 57 percent reduction in bupropion concentrations was reported in small studies of healthy volunteers when bupropion was co-administered with tipranavir-ritonavir, or efavirenz. Titrate bupropion dose based upon response. Bupropion XL (extended release) 150 mg each morning 300 to 450 mg once daily Tricyclic antidepressants (TCAs) ◊ Desipramine 10 to 25 mg daily 50 to 300 mg daily Mildly activating; promotes weight gain. Stimulant effects may be useful for depressed patients with low energy and hypersomnia who have not responded to first line antidepressants. Useful for patients with comorbid painful conditions such as diabetic neuropathy. Established therapeutic serum concentration 125 to 300 ng/mL. ◊ Desipramine is metabolized by CYP2D6 Strong inhibitors of CYP2D6, all HIV protease inhibitors Δ may INCREASE desipramine concentrations. Use lowest tricyclic antidepressant dose and titrate based on response and/or antidepressant concentrations. Elevated risk of serious cardiac arrhythmias in combination with other agents that can cause QTc prolongation or increase desipramine concentrations. • Nortriptyline 10 to 25 mg at bed time 50 to 150 mg at bedtime

Strong inhibitors of CYP2D6, all HIV protease inhibitors Δ may INCREASE desipramine concentrations. Use lowest tricyclic antidepressant dose and titrate based on response and/or antidepressant concentrations. Elevated risk of serious cardiac arrhythmias in combination with other agents that can cause QTc prolongation or increase desipramine concentrations. • Nortriptyline 10 to 25 mg at bed time 50 to 150 mg at bedtime Mildly sedating; promotes weight gain. Taken at bed time for depressed patients with insomnia. May be useful for melancholic, anxious, depressed patients who have not responded to first line antidepressants. Useful for patients with comorbid painful conditions such as diabetic neuropathy. Established therapeutic serum concentration 50 to 150 ng/mL. ◊ Nortriptyline is metabolized by CYP2D6 Strong inhibitors of CYP2D6 including all HIV protease inhibitors Δ and cobicistat containing coformulations, may INCREASE nortriptyline concentrations. Use lowest tricyclic antidepressant dose and titrate based on response and/or antidepressant concentrations. Elevated risk of serious cardiac arrhythmias in combination with other agents that can cause QTc prolongation or increase nortriptyline concentrations. • Amitriptyline 10 to 25 mg daily 150 to 300 mg daily Sedating; promotes weight gain. ◊ Amitriptyline is metabolized by CYP2D6 Strong inhibitors of CYP2D6 including all HIV protease inhibitors Δ and cobicistat containing coformulations, may INCREASE amitriptyline concentrations. Use lowest tricyclic antidepressant dose and titrate based on response. Elevated risk of serious cardiac arrhythmias in combination with other agents that can cause QTc prolongation or increase amitriptyline concentrations. • Clomipramine 25 mg at bedtime 100 to 300 mg at bedtime Sedating; promotes weight gain. ◊ Clomipramine is metabolized by CYP1A2, 2C19 and 2D6 Strong inhibitors of CYP1A2, 2C19 and/or 2D6, including all HIV protease inhibitors Δ and cobicistat containing coformulations, may INCREASE clomipramine concentrations. Use lowest tricyclic antidepressant dose and titrate based on response. Elevated risk of serious cardiac arrhythmias in combination with other agents that can cause QTc prolongation or increase clomipramine concentrations. • Imipramine 10 to 25 mg at bedtime 150 to 300 mg at bedtime Sedating; promotes weight gain. ◊ Imipramine is metabolized by CYP2C19 and 2D6

Use lowest tricyclic antidepressant dose and titrate based on response. Elevated risk of serious cardiac arrhythmias in combination with other agents that can cause QTc prolongation or increase clomipramine concentrations. • Imipramine 10 to 25 mg at bedtime 150 to 300 mg at bedtime Sedating; promotes weight gain. ◊ Imipramine is metabolized by CYP2C19 and 2D6 Strong inhibitors of CYP2C19 and/or 2D6 including all HIV protease inhibitors Δ and cobicistat containing coformulations, may INCREASE imipramine levels. Use lowest tricyclic antidepressant dose and titrate based on response. Elevated risk of serious cardiac arrhythmias in combination with other agents that can cause QTc prolongation or increase imipramine concentrations. • Doxepin 10 to 25 mg at bedtime 150 to 300 mg at bed time Sedating; promotes weight gain. ◊ Doxepin is metabolized by CYP2D6 Strong inhibitors of CYP2D6 including all HIV protease inhibitors Δ and cobicistat containing coformulations, may INCREASE doxepin concentrations. Use lowest tricyclic antidepressant dose and titrate based on response. Elevated risk of serious cardiac arrhythmias in combination with other agents that can cause QTc prolongation or increase doxepin concentrations. • Herbal products St John's wort (Hypericum perforatum) Do NOT co-administer St John's wort with HIV antiretroviral drugs. St John's wort is an inducer of CYP1A2, 2C9, and 3A4 Concomitant use of St John's wort and HIV antiretroviral drugs is contraindicated. Use of St John's wort with all HIV protease inhibitors Δ , efavirenz, etravirine, nevirapine, and maraviroc can DECREASE antiretroviral concentrations and cause virologic resistance and treatment failure.

IMPORTANT NOTE: Not all potential interactions are listed. Additional interactions of antidepressants with other medications taken by HIV patients and management suggestions may be determined using the drug interactions tool (Lexi-Interact Online) included in UpToDate. Agents are listed within each class in order of preference based upon tolerability in most patients. Use doses at the lower end of ranges shown for starting and maintenance treatment of depression in patients with HIV who are medically ill, older or debilitated. AUC: area under the time versus concentration curve; CYP: cytochrome P450; Pgp: P-glycoprotein efflux transporter; UDP-UGT: uridine 5'-diphospho-glucuronosyltransferase catalyst of glucuronidation. * Maximum recommended dose of citalopram is 20 mg for patients >60 years of age, with significant hepatic insufficiency, or taking medications that can increase citalopram levels. For additional information, refer to UpToDate topic on selective serotonin reuptake inhibitors (SSRIs) section on cardiac side effects. • QTc prolonging antidepressant drugs can have additive effects with other drugs that prolong the QTc interval, including saquinavir, and may cause life-threatening ventricular arrhythmias. Refer to topics on selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants for treating depressed adults. Δ HIV protease inhibitors include: atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and tipranavir. ◊ Due to significant anticholinergic side effects, tricyclic antidepressants (TCAs) may NOT be well tolerated in patients with HIV who are also medically ill. TCAs may be fatal in overdose and can cause cardiac arrhythmias or orthostatic hypotension. Serum drug concentration monitoring may be useful for guiding treatment with amitriptyline, desipramine, imipramine, and nortriptyline. For additional information refer to UpToDate topic on unipolar depression and tricyclic and tetracyclic drugs for treating depressed adults. Data from: Lacy CF, et al (eds) Lexicomp Online. Copyright © 1978-2013 Lexicomp, Inc. All Rights Reserved. Wynn GH, et al (eds) Clinical Manual of Drug Interaction Principles for Medical Practice APA publishing, Washington DC. Copyright © 2009.

IMPORTANT NOTE: Not all potential interactions are listed. Additional interactions of antidepressants with other medications taken by HIV patients and management suggestions may be determined using the drug interactions tool (Lexi-Interact Online) included in UpToDate. Agents are listed within each class in order of preference based upon tolerability in most patients. Use doses at the lower end of ranges shown for starting and maintenance treatment of depression in patients with HIV who are medically ill, older or debilitated. AUC: area under the time versus concentration curve; CYP: cytochrome P450; Pgp: P-glycoprotein efflux transporter; UDP-UGT: uridine 5'-diphospho-glucuronosyltransferase catalyst of glucuronidation. * Maximum recommended dose of citalopram is 20 mg for patients >60 years of age, with significant hepatic insufficiency, or taking medications that can increase citalopram levels. For additional information, refer to UpToDate topic on selective serotonin reuptake inhibitors (SSRIs) section on cardiac side effects. • QTc prolonging antidepressant drugs can have additive effects with other drugs that prolong the QTc interval, including saquinavir, and may cause life-threatening ventricular arrhythmias. Refer to topics on selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants for treating depressed adults. Δ HIV protease inhibitors include: atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and tipranavir. ◊ Due to significant anticholinergic side effects, tricyclic antidepressants (TCAs) may NOT be well tolerated in patients with HIV who are also medically ill. TCAs may be fatal in overdose and can cause cardiac arrhythmias or orthostatic hypotension. Serum drug concentration monitoring may be useful for guiding treatment with amitriptyline, desipramine, imipramine, and nortriptyline. For additional information refer to UpToDate topic on unipolar depression and tricyclic and tetracyclic drugs for treating depressed adults. Data from: Lacy CF, et al (eds) Lexicomp Online. Copyright © 1978-2013 Lexicomp, Inc. All Rights Reserved. Wynn GH, et al (eds) Clinical Manual of Drug Interaction Principles for Medical Practice APA publishing, Washington DC. Copyright © 2009. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. 1–239. Available at file://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf . Drug interactions section accessed April 18, 2012.

Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. 1–239. Available at file://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf . Drug interactions section accessed April 18, 2012. Hill L and Lee KC Pharmacotherapy considerations in patients with HIV and psychiatric disorders: Focus on antidepressants and antipsychotics. Ann Pharmacother 2013;47:75.