Selective serotonin reuptake inhibitor (SSRI)
Sertraline is an antidepressant (SSRI) used for depression, anxiety, obsessive-compulsive disorder and other conditions. It is effective, but effects take a few weeks and nausea, insomnia or changes in sexual desire may occur at the start.
Also known as: Zoloft
Isoniazid has a weak monoamine oxidase-inhibiting effect; with SSRIs (Sertraline) it may raise the risk of serotonin syndrome.
Isoniazid has some monoamine oxidase inhibiting activity (the isoniazid label states it has MAO-inhibiting activity, with interaction with tyramine-rich foods), and SSRIs such as sertraline increase serotonin availability; together, the combination may increase the risk of serotonin syndrome. The sertraline label warns about the increased risk with serotonergic drugs and with drugs that impair serotonin metabolism (such as MAO inhibitors). Monitor for serotonin symptoms (agitation, tachycardia, hyperthermia, hyperreflexia, myoclonus, rigidity), especially at treatment initiation or dose increases, and consider alternatives if needed.
Isoniazid + sertraline: risk of serotonin syndrome (isoniazid has MAO-inhibiting activity). Monitor symptoms.
Weak MAO inhibition by isoniazid and serotonin reuptake inhibition.
Signs of serotonin syndrome.
Agitation, tremor, hyperthermia, rigidity, diarrhoea.
Watch for serotonergic signs; use with caution.
DailyMed/FDA (NIH/NLM) — approved Isoniazid label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=93252cc8-c8d4-401b-bde5-ca8a3b57651e ; approved Sertraline label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=61835f25-bfe4-49ac-9dbf-3d6387866e78
Sedating antihistamine + SSRI: mild additive sedation.
Diphenhydramine is a first-generation antihistamine with central sedative effect, and sertraline can cause drowsiness or fatigue, especially at treatment start. The combination adds up the sedative effect, potentially causing daytime drowsiness, reduced concentration and a higher risk of falls in the elderly. It is not contraindicated, but caution is recommended: prefer less sedating antihistamines if needed, avoid driving and monitor symptoms. In the elderly, consider the anticholinergic burden of diphenhydramine (confusion, urinary retention, dry mouth).
Sedating antihistamine + SSRI: mild additive sedation. Watch for daytime drowsiness.
Both may cause sedation and additive anticholinergic effects.
Symptoms of excessive sedation.
Daytime drowsiness, confusion in the elderly.
Use with caution; watch for daytime drowsiness.
DailyMed (FDA) — approved Diphenhydramine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d8944f3c-acef-4ebe-9633-7d641ae95edf ; approved Sertraline label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=91e24d17-ff0a-449c-9472-b9df74c98456 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Decongestant + SSRI: possible increased pressor and serotonergic effect.
Pseudoephedrine has a sympathomimetic effect (vasoconstriction, tachycardia) and sertraline, as an SSRI, can potentiate the adrenergic effects and theoretically increase the risk of serotonin syndrome. In most patients the interaction is mild and self-limited, but in hypertensive, cardiac or elderly patients monitor blood pressure and adrenergic symptoms (palpitations, tremor, agitation). Use the decongestant at the lowest dose and for the shortest time, preferring local alternatives (nasal corticosteroids) in at-risk patients.
Decongestant + SSRI: possible increased pressor and serotonergic effect. Monitor blood pressure.
Pseudoephedrine may add a pressor effect; the SSRI interferes with metabolism.
Blood pressure in at-risk patients.
Hypertension, agitation, tremor.
Monitor blood pressure and serotonergic symptoms.
DailyMed (FDA) — approved Pseudoephedrine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=78faa497-6743-b85b-e053-2a91aa0ae822 ; approved Sertraline label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=91e24d17-ff0a-449c-9472-b9df74c98456 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Sertraline may reduce the effectiveness of tamoxifen in breast cancer by lowering its active form. Always tell your doctor if you take both medicines.
Like other SSRIs, sertraline interferes with CYP2D6-mediated activation of tamoxifen, lowering endoxifen. The effect is smaller than with fluoxetine or paroxetine (moderate inhibition, more evident at high sertraline doses, above 100 mg/day), but the loss of efficacy is clinically relevant in a disease as sensitive to adjuvant therapy as breast cancer. The tamoxifen SmPC recommends avoiding potent CYP2D6 inhibitors and exercising caution with the others.
Sertraline inhibits CYP2D6 moderately and dose-dependently, reducing endoxifen levels. When possible, prefer an SSRI with weaker CYP2D6 inhibition; if the combination is unavoidable, monitor response.
Moderate CYP2D6 inhibition by sertraline, reducing endoxifen formation.
Tamoxifen response and adherence; signs of breast cancer recurrence.
New breast lump, bone pain, clinical worsening — oncology reassessment.
Prefer alternatives with less CYP2D6 impact (citalopram, escitalopram, venlafaxine); if sertraline is kept, use the lowest effective dose and inform the oncologist.
EMC-UK (MHRA) — approved Tamoxifen SmPC: https://www.medicines.org.uk/emc/product/101398/smpc ; DailyMed/FDA (NIH/NLM) — approved Sertraline label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=91e24d17-ff0a-449c-9472-b9df74c98456 ; PubMed — https://pubmed.ncbi.nlm.nih.gov/20141708/ ; Prontuário Terapêutico do INFARMED (11th ed., 2012)
High risk of serotonin syndrome: combining two SSRIs (Sertraline + Fluoxetine) accumulates serotonin and can be dangerous.
Fluoxetine and sertraline increase synaptic serotonin through the same mechanism (blockade of the SERT transporter); in combination, the risk of serotonin syndrome increases, especially at high doses or with other serotonergic drugs. Fluoxetine has a long half-life (1 to 3 days; 4 to 16 days for norfluoxetine), so the washout when switching drugs must be longer. In practice, two SSRIs should not be used simultaneously; the combination is only justified in very short, supervised transitions, and warning symptoms (agitation, tremor, hyperreflexia, hyperthermia, diarrhoea) should lead to immediate discontinuation.
Two SSRIs simultaneously: risk of serotonin syndrome (agitation, tremor, hyperthermia, rigidity, diarrhoea) and additive effects. Avoid; when switching SSRIs, respect the washout period (fluoxetine has a long half-life).
Both inhibit serotonin reuptake; Fluoxetine has long-acting metabolites that potentiate the second SSRI.
Monitor serotonin signs in the first weeks; advise against dose doubling.
Agitation, hyperthermia, tachycardia, tremor, clonus, diarrhoea, confusion.
Avoid the combination. When switching is necessary, respect a washout period and use single low doses.
DailyMed/FDA (NIH/NLM) — approved Sertraline label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=91e24d17-ff0a-449c-9472-b9df74c98456 ; approved Fluoxetine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=09fb3100-1e06-4cdc-8016-7e4f5d097490
High risk of serotonin syndrome between Linezolid and Sertraline (an SSRI).
Sertraline increases synaptic serotonin by blocking reuptake and linezolid inhibits monoamine oxidase: the combination of the two actions can precipitate severe serotonin syndrome (agitation, tremor, hyperthermia, rigidity, hyperreflexia) with risk of death. The approved linezolid label warns of the increased risk with serotonergic drugs, including SSRIs. Whenever possible, choose an alternative antibiotic; if the combination is unavoidable, use the lowest effective dose, monitor for serotonergic symptoms and discontinue immediately if they occur.
Linezolid (MAO inhibitor) + SSRI: risk of potentially fatal serotonin syndrome. Avoid; if unavoidable, close monitoring and immediate discontinuation if symptoms occur.
MAO inhibition (linezolid) and serotonin reuptake inhibition.
Signs of serotonin syndrome.
Agitation, tremor, hyperthermia, rigidity, myoclonus.
Avoid; washout of at least 14 days between drugs.
DailyMed/FDA (NIH/NLM) — approved Linezolid label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=374af2a7-d994-40bd-a86a-cd9038d0b72c ; approved Sertraline label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=61835f25-bfe4-49ac-9dbf-3d6387866e78
Buprenorphine with sertraline increases the risk of serotonin syndrome.
Concomitant use of opioids with drugs that affect the serotonergic system, such as SSRIs (sertraline), can result in serotonin syndrome, potentially life-threatening; the buprenorphine label reports cases of serotonin syndrome with concomitant opioids and serotonergic drugs and recommends carefully observing the patient, especially at treatment initiation and dose adjustments, and discontinuing buprenorphine if the syndrome is suspected. Symptoms include mental status changes (agitation, hallucinations, coma), autonomic instability (tachycardia, blood pressure lability, hyperthermia) and neuromuscular aberrations (hyperreflexia, incoordination, rigidity).
Buprenorphine + sertraline: risk of serotonin syndrome (opioid + SSRI). Monitor symptoms, especially at initiation and dose adjustments.
Both raise CNS serotonin; buprenorphine also causes respiratory depression that sertraline may mask.
Agitation, fever, tremor, hyperreflexia, clonus.
Signs of severe serotonin excess require immediate withdrawal and supportive care.
Monitor for serotonin excess; titrate doses with caution.
DailyMed/FDA (NIH/NLM) — approved Buprenorphine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=713db2c6-0544-4633-b874-cfbeaf93db89 ; approved Sertraline label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=91e24d17-ff0a-449c-9472-b9df74c98456 — with additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Codeine with sertraline increases the risk of serotonin syndrome and may alter the analgesic effect.
Concomitant use of opioids with drugs that affect the serotonergic system, such as SSRIs (sertraline), can result in serotonin syndrome; the codeine label explicitly identifies SSRIs among the serotonergic drugs whose combination with opioids has resulted in serotonin syndrome, and recommends frequently evaluating the patient, especially at treatment initiation and dose adjustments, and discontinuing immediately if the syndrome is suspected. Inform the patient of the symptoms (agitation, hallucinations, tachycardia, hyperthermia, hyperreflexia, rigidity) and the need to seek medical help.
Codeine + sertraline: risk of serotonin syndrome (opioid + SSRI). Monitor symptoms, especially at initiation and dose adjustments.
Codeine and sertraline both raise CNS serotonin; also sertraline (CYP2D6 inhibition) may reduce codeine to morphine conversion.
Agitation, fever, tremor, hyperreflexia, muscle rigidity.
High fever with rigidity and altered mental state require discontinuation and urgent treatment.
Monitor for serotonin excess; if analgesia is inadequate, consider an alternative analgesic.
DailyMed/FDA (NIH/NLM) — approved Codeine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4c966d73-77c6-4514-954e-57aa06a080c6 ; approved Sertraline label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=91e24d17-ff0a-449c-9472-b9df74c98456 — with additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Sertraline may potentiate the serotonergic effects of dextromethorphan.
Dextromethorphan has serotonergic action (serotonin reuptake inhibition) and is also a CYP2D6 substrate, an enzyme inhibited by sertraline; the combination with SSRIs such as sertraline increases the risk of serotonin syndrome, potentially life-threatening, with symptoms such as agitation, hallucinations, tachycardia, hyperthermia, hyperreflexia, myoclonus and rigidity. The sertraline label lists serotonergic drugs whose concomitant use increases the risk of serotonin syndrome, and the dextromethorphan label warns about interaction with MAO inhibitors. In patients on SSRIs, prefer alternative antitussives or use with caution, monitoring for serotonin symptoms.
Dextromethorphan + sertraline: risk of serotonin syndrome (serotonergic antitussive + SSRI). Avoid or monitor closely.
Additive serotonergic effect; partial CYP2D6 inhibition by sertraline.
Monitor agitation, diarrhoea, tremor, hyperreflexia and confusion.
Serotonin syndrome.
Monitor for symptoms of serotonergic excess with the combination.
DailyMed (FDA) — approved Dextromethorphan label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0d99237c-0b52-0af6-e063-6394a90aba14 ; approved Sertraline label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=91e24d17-ff0a-449c-9472-b9df74c98456 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Fentanyl with sertraline increases the risk of serotonin syndrome.
The sertraline label explicitly lists fentanyl among the serotonergic drugs whose concomitant use increases the risk of serotonin syndrome; the fentanyl label reports cases of serotonin syndrome, potentially life-threatening, with concomitant use of serotonergic drugs, including SSRIs, and recommends immediately discontinuing fentanyl if the syndrome is suspected. Symptoms usually appear within hours to a few days of starting the combination: mental status changes (agitation, hallucinations, coma), autonomic instability (tachycardia, blood pressure lability, hyperthermia) and neuromuscular aberrations (hyperreflexia, incoordination, rigidity).
Fentanyl + sertraline: risk of serotonin syndrome (opioid + SSRI). Monitor symptoms; stop fentanyl if suspected.
Both raise CNS serotonin; fentanyl also lowers the seizure threshold that sertraline may influence.
Tremor, hyperreflexia, myoclonus, agitation, hyperthermia.
Severe serotonin syndrome requires immediate withdrawal of both drugs.
Monitor for signs of serotonin excess during the first weeks of combination.
DailyMed/FDA (NIH/NLM) — approved Fentanyl label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e15a7e9b-8025-49dd-9a6d-bafcccf1959f ; approved Sertraline label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=91e24d17-ff0a-449c-9472-b9df74c98456 — with additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Risk of serotonin syndrome and a lowered seizure threshold when Sertraline is combined with Tramadol.
The sertraline label lists tramadol among the serotonergic drugs whose concomitant use increases the risk of serotonin syndrome, and the tramadol label states that concomitant use with CYP2D6 inhibitors (sertraline inhibits CYP2D6) can raise tramadol levels and lower the active metabolite M1, with an increased risk of serious adverse events, including seizures and serotonin syndrome. The combination should be avoided whenever possible; if unavoidable, use the lowest effective dose, monitor for serotonin symptoms (agitation, tachycardia, hyperthermia, hyperreflexia) and signs of seizures, and reassess the need for the opioid.
Sertraline + tramadol: risk of serotonin syndrome and seizures (tramadol + SSRI). Monitor closely; consider alternatives.
Sertraline raises central serotonin and Tramadol does as well, further lowering the seizure threshold.
Watch for serotonin signs and seizures in the first days of association.
Agitation, tremor, hyperthermia, clonus, seizures, confusion.
Avoid the combination if possible; if unavoidable, use the lowest dose and monitor signs.
DailyMed/FDA (NIH/NLM) — approved Sertraline label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=91e24d17-ff0a-449c-9472-b9df74c98456 ; approved Tramadol label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=552955e6-2bb3-8755-e063-6394a90ab21c
Alcohol potentiates the central nervous system depression of sertraline and can worsen anxiety and hepatotoxicity.
Avoid alcohol intake during treatment.
DailyMed/FDA (NIH/NLM) — approved Sertraline label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=91e24d17-ff0a-449c-9472-b9df74c98456
Sertraline can be administered with or without food; taking it with food may reduce gastrointestinal irritation.
Take at the same time every day, with or without food.
DailyMed/FDA (NIH/NLM) — approved Sertraline label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=91e24d17-ff0a-449c-9472-b9df74c98456
Sertraline is metabolised in the liver; hepatic impairment reduces elimination and increases the risk of accumulation.
Reduce the dose in hepatic impairment and monitor adverse effects.
DailyMed/FDA (NIH/NLM) — approved Sertraline label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=91e24d17-ff0a-449c-9472-b9df74c98456
Selective serotonin reuptake inhibitors can lower the seizure threshold.
Use with caution in patients with epilepsy.
DailyMed/FDA (NIH/NLM) — approved Sertraline label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=91e24d17-ff0a-449c-9472-b9df74c98456
SSRIs in the third trimester are associated with neonatal adaptation syndrome; sertraline is one of the most studied SSRIs in pregnancy.
Assess risk/benefit; avoid if possible in the third trimester in mild-moderate depression.
Present in breast milk in small amounts; generally considered compatible.
No specific contraception required.
DailyMed/FDA (NIH/NLM) — approved Sertraline label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=91e24d17-ff0a-449c-9472-b9df74c98456
Clinical and educational support tool. The information does not replace a medical prescription or the opinion of a qualified healthcare professional.
SSRI antidepressant. Potentiates serotonergic activity in the CNS by inhibiting neuronal reuptake of serotonin (5-HT); very weak effect on norepinephrine and dopamine reuptake and no significant affinity for adrenergic, cholinergic, GABA, dopaminergic, histaminergic or benzodiazepine receptors. Maximum ΔΔQTc of 10 ms at 2-fold the maximum recommended dose.
Potent and selective inhibition of neuronal serotonin reuptake; it blocks serotonin uptake into human platelets at clinically relevant doses. It does not inhibit monoamine oxidase. The main metabolite, N-desmethylsertraline, is substantially less active.
Peak plasma concentrations 4.5 to 8.4 hours after daily dosing; mean terminal half-life of about 26 hours, with approximately 2-fold accumulation to steady state (reached after one week). Food causes a small increase in Cmax and AUC. Serum protein binding of 98%.
Extensive first-pass metabolism; the main initial pathway is N-demethylation to N-desmethylsertraline (half-life 62 to 104 hours). About 40 to 45% of the radioactivity is recovered in urine within 9 days; 40 to 45% in faeces (12 to 14% as unchanged sertraline). Exposure increases about 3-fold in mild hepatic impairment.
Mean terminal half-life of about 26 hours (sertraline); N-desmethylsertraline 62 to 104 hours. Clearance is about 40% lower in the elderly (steady state in 2 to 3 weeks) and is not relevantly affected by renal impairment.
Medicines from the same therapeutic group (ATC classification) or the same pharmacological class.
