Oral Panic disorder with or without agoraphobia, Posttraumatic stress disorder, Social anxiety disorder
Adult: Initially, 25 mg once daily, increased to 50 mg once daily after 1 week. Subsequent doses may be increased in increments of 50 mg at intervals of at least 1 week according to response and tolerability. Maintenance (during long-term therapy): Use the lowest effective dose with subsequent adjustments based on response. Max: 200 mg daily. Dosage and treatment recommendations may vary among individual products or between countries (refer to detailed local product guidelines).
Oral Obsessive compulsive disorder
Adult: Initially, 50 mg once daily, may be increased in increments of 25 mg or 50 mg at intervals of at least 1 week according to response and tolerability. Maintenance (during long-term therapy): Use the lowest effective dose with subsequent adjustments based on response. Max: 200 mg daily. Dosage and treatment recommendations may vary among individual products or between countries (refer to detailed local product guidelines). Child: 6-12 years Initially, 25 mg once daily, may be increased to 50 mg once daily after 1 week as necessary. Max: 200 mg daily; 13-17 years Initially, 50 mg once daily, may be increased in increments of 50 mg daily up to Max of 200 mg daily. Consider the lower body weight of children compared to adults when increasing the dose from 50 mg. Dosage and treatment recommendations may vary among individual products or between countries (refer to detailed local product guidelines).
Oral Major depressive disorder
Adult: Initially, 50 mg once daily, may be increased in increments of 25 mg or 50 mg at intervals of at least 1 week according to response and tolerability. Maintenance (during long-term therapy): Use the lowest effective dose with subsequent adjustments based on response. Max: 200 mg daily. Dosage and treatment recommendations may vary among individual products or between countries (refer to detailed local product guidelines).
Oral Premenstrual dysphoric disorder
Adult: Continuous daily dosing regimen: Initially, 50 mg once daily, may be increased in increments of 50 mg per menstrual cycle up to a Max of 150 mg daily in patients who do not respond to the 50 mg dose. Luteal phase dosing regimen: Initially, 50 mg once daily. Patients who do not respond to the 50 mg dose may have dose increases of up to 100 mg daily during the luteal phase of the menstrual cycle. If a 100 mg daily dose has been established during the luteal phase dosing, patients must initially be given a 50 mg daily dose for the 1st 3 days of each luteal phase dosing period. Dosage and treatment recommendations may vary among individual products or between countries (refer to detailed local product guidelines).
Special Patient Group
Pharmacogenomics:
Sertraline is extensively metabolised in the liver via N-demethylation significantly by CYP2C19 and to a lesser extent by other CYP450 isoenzymes (e.g. CYP2B6, CYP2C9, CYP2D6, CYP3A4) to form N-desmethylsertraline (primary inactive metabolite). Genetic variation in CYP2C19 may affect sertraline exposure and potentially its dosing, efficacy, and tolerability. Some evidence has shown that CYP2B6 genetic variation may also be associated with sertraline exposure; however, studies showed that CYP2D6 genetic variation has found little to no effect on the exposure and dose of sertraline. Genetic testing may be considered.
Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline as of April 2023:
Dosage recommendations based on CYP2C19 phenotype:
Phenotype and Genotype
Implications
Recommendations
CYP2C19 ultrarapid metaboliser
Patients carrying 2 increased function alleles e.g. *17/*17
A small increase in sertraline metabolism to less active compounds as compared with CYP2C19 normal metabolisers.
Initiate treatment with the recommended starting dose.
CYP2C19 rapid metaboliser
Patients carrying 1 normal function allele and 1 increased function allele e.g. *1/*17
A small increase in sertraline metabolism to less active compounds as compared with CYP2C19 normal metabolisers.
Initiate treatment with the recommended starting dose.
CYP2C19 normal metaboliser
Patients carrying 2 normal function alleles e.g. *1/*1
Normal sertraline metabolism.
Initiate treatment with the recommended starting dose
CYP2C19 likely intermediate metaboliser
Patients carrying 1 normal function allele and 1 decreased function allele, or 1 increased function allele and 1 decreased function allele, or 2 decreased function alleles e.g. *1/*9, *9/*17, *9/*9
Reduced sertraline metabolism to less active compounds as compared with CYP2C19 normal metabolisers.
Initiate treatment with the recommended starting dose. Consider a slower titration schedule and reduced maintenance dose than the CYP2C19 normal metabolisers.
CYP2C19 likely poor metaboliser
Patients carrying 1 decreased function allele and 1 non-functional allele e.g. *2/*9, *3/*9
Greatly reduced sertraline metabolism to less active compounds as compared with CYP2C19 normal metabolisers. Higher plasma levels may increase the probability of side effects.
Consider a lower initial dose, slower titration schedule, and 50% reduction in the standard maintenance dose as compared with CYP2C19 normal metabolisers. May also consider to select an appropriate alternative antidepressant not predominantly metabolised by CYP2C19.
Greatly reduced sertraline metabolism to less active compounds as compared with CYP2C19 normal metabolisers. Higher plasma levels may increase the probability of side effects.
Consider a lower initial dose, slower titration schedule, and 50% reduction in the standard maintenance dose as compared with CYP2C19 normal metabolisers. May also consider to select an appropriate alternative antidepressant not predominantly metabolised by CYP2C19.
For all CYP2C19 phenotypes, the CYP2B6 metaboliser status, drug-drug interactions and other patient characteristics (e.g. age, liver or renal function) must also be considered, particularly for CYP2C19 likely poor and poor metabolisers when adjusting the dose or selective alternative treatment.
Dosage recommendations based on CYP2B6 phenotype:
Phenotype and Genotype
Implications
Recommendations
CYP2B6 ultrarapid metaboliser
Patients carrying 2 increased function alleles e.g. *4/*4, *22/*22, *4/*22
Increased sertraline metabolism to less active compounds as compared with CYP2B6 normal metabolisers.
Initiate treatment with the recommended starting dose.
CYP2B6 rapid metaboliser
Patients carrying 1 normal function allele and 1 increased function allele e.g. *1/*4, *1/*22
A small increase in sertraline metabolism to less active compounds as compared with CYP2B6 normal metabolisers.
Initiate treatment with the recommended starting dose.
CYP2B6 normal metaboliser
Patients carrying 2 normal function alleles e.g. *1/*1
Normal sertraline metabolism to less active compounds.
Initiate treatment with the recommended starting dose.
Initiate treatment with the recommended starting dose.
CYP2B6 intermediate metaboliser
Patients carrying 1 normal function allele and 1 decreased function allele, or 1 normal function allele and 1 non-functional allele, or 1 increased function and 1 decreased function allele, or 1 increased function and 1 non-functional allele e.g. *1/*6, *1/*18, *4/*6, *4/*18, *6/*22, *18/*22
Reduced sertraline metabolism to less active compounds as compared with CYP2B6 normal metabolisers.
Initiate treatment with the recommended starting dose. Consider a slower titration schedule and reduced maintenance dose than the CYP2B6 normal metabolisers.
CYP2B6 poor metaboliser
Patients carrying 2 decreased function alleles, or 2 non-functional alleles, or decreased function allele and 1 non-functional allele e.g. *6/*6, *18/*18, *6/*18
Greatly reduced sertraline metabolism to less active compounds as compared with CYP2B6 normal metabolisers. Higher plasma levels may increase the probability of side effects.
Consider a lower initial dose, slower titration schedule, and 25% reduction in the standard maintenance dose as compared with CYP2B6 normal metabolisers. May also consider to select an appropriate alternative antidepressant not predominantly metabolised by CYP2B6.
For all CYP2B6 phenotypes, the CYP2C19 metaboliser status, drug-drug interactions and other patient characteristics (e.g. age, liver or renal function) must also be considered, particularly for CYP2B6 poor metabolisers when adjusting the dose or selective alternative treatment.
Dosage recommendations based on a combination of CYP2C19 and CYP2B6 phenotypes:
Phenotype combination
Recommendations
CYP2C19 ultrarapid/rapid metabolisers and CYP2B6 ultrarapid/rapid metabolisers
Initiate treatment with the recommended starting dose. If the patient has an inadequate response to the recommended maintenance dose, consider titrating to a higher maintenance dose or switching to an appropriate alternative antidepressant agent not predominantly metabolised by CYP2C19 or CYP2B6.
CYP2C19 ultrarapid/rapid metabolisers and CYP2B6 ultrarapid/rapid metabolisers
CYP2C19 likely intermediate/intermediate metabolisers and CYP2B6 normal/intermediate metabolisers
Initiate treatment with the recommended starting dose. Consider a slower titration schedule and lower maintenance dose.
CYP2C19 likely intermediate/intermediate metabolisers and CYP2B6 poor metabolisers
Consider a lower initial dose, slower titration schedule, and 50% reduction in the standard maintenance dose as compared with CYP2C19 normal metabolisers.
CYP2C19 likely poor/poor metabolisers and CYP2B6 ultrarapid/rapid/intermediate/normal metabolisers
Consider a lower initial dose, slower titration schedule, and 50% reduction in the standard maintenance dose as compared with CYP2C19 normal metabolisers. May also consider to select an appropriate alternative antidepressant not predominantly metabolised by CYP2C19.
CYP2C19 likely poor/poor metabolisers and CYP2B6 poor metabolisers
Select an appropriate alternative antidepressant agent not predominantly metabolised by CYP2C19 or CYP2B6.
Royal Dutch Pharmacists Association - Pharmacogenetics Working Group (DPWG) Guideline as of November 2018:
Phenotype
Description
Recommendation
CYP2C19 poor metaboliser
Individuals who are poor CYP2C19 metabolisers have an increased risk of side effects. The gene variation results in increased sertraline plasma concentrations.
Do not administer doses exceeding 75 mg daily. Guide the dosing based on response, side effects, and/or sertraline plasma levels.
Hepatic Impairment
Mild to moderate: Dose reduction or less frequent dosing may be required. Severe: Not recommended.
Administration
May be taken with or without food.
Reconstitution
Oral concentrate solution: Dilute with approx 120 mL of water, ginger ale, lemonade juice, orange juice, or lemon/lime soda immediately prior to administration. Do not mix with any other liquids. After mixing, a slight haze may appear which is normal.
Contraindications
Concomitant use or within 14 days of discontinuing MAOIs, including methylthioninium chloride and linezolid. Concurrent use with pimozide.
Special Precautions
Patient with personal or family history of mania, hypomania, and bipolar disorder; seizure disorder, conditions predisposing to seizures (e.g. brain damage, alcoholism); history of bleeding disorders (particularly gastrointestinal bleeding), pre-existing platelet dysfunction or coagulation disorders (e.g. von Willebrand factor); volume depletion, diabetes; angle-closure glaucoma, history of glaucoma; risk factors for QTc prolongation (e.g. family history of QTc prolongation, cardiac disease, congenital long QT syndrome, bradycardia, hypomagnesaemia, hypokalaemia). CYP2C19 intermediate, likely intermediate, likely poor, and poor metabolisers. CYP2B6 intermediate and poor metabolisers. Patients who have a combination of CYP2C19 and CYP2B6 phenotypes. Avoid abrupt withdrawal. Hepatic and renal impairment. Children and elderly. Pregnancy and lactation.
Adverse Reactions
Significant: Suicidal thoughts and behaviour, activation of hypomania or mania, seizures, CNS depression, akathisia or psychomotor restlessness; QTc prolongation, torsades de pointes; abnormal bleeding events (e.g. ecchymoses, purpura, haematoma, epistaxis), increased risk of postpartum haemorrhage (particularly 1 month before birth; new-onset diabetes, altered/loss of glycaemic control; bone fractures, acute angle-closure glaucoma, sexual dysfunction (e.g. erectile dysfunction, ejaculation delay or failure, delayed or absent orgasm in females), withdrawal syndrome (particularly if abruptly discontinued). Cardiac disorders: Palpitation, chest pain. Ear and labyrinth disorders: Tinnitus. Eye disorders: Visual disturbance. Gastrointestinal disorders: Nausea, diarrhoea, dry mouth, dyspepsia, constipation, vomiting, abdominal pain, flatulence, dysgeusia. General disorders and administration site conditions: Fatigue, malaise, asthenia, pyrexia. Investigations: Weight increased. Metabolism and nutrition disorders: Decreased or increased appetite. Musculoskeletal and connective tissue disorders: Back pain, arthralgia, myalgia. Nervous system disorders: Headache, dizziness, somnolence, paraesthesia, tremor, extrapyramidal symptoms, disturbance in attention. Psychiatric disorders: Insomnia, anxiety, agitation, depression, nervousness, nightmare, bruxism, depersonalisation. Reproductive system and breast disorders: Irregular menstruation, decreased libido. Respiratory, thoracic and mediastinal disorders: Pharyngitis, rhinitis, URTI, yawning. Skin and subcutaneous tissue disorders: Rash, hyperhidrosis. Vascular disorders: Hot flush. Potentially Fatal: Serotonin syndrome, neuroleptic malignant syndrome (NMS), haemorrhage (e.g. gastrointestinal or gynaecological bleeding), hyponatraemia (usually as a result of SIADH).
PO: Z (Risk of postpartum haemorrhage, persistent pulmonary hypertension in infant, neonatal withdrawal/toxicity in late pregnancy use. Monitor closely.)
Patient Counseling Information
This drug may cause drowsiness and may impair the mental or physical abilities in performing certain tasks, if affected, do not drive or operate machinery.
Monitoring Parameters
Monitor BMI (longitudinal monitoring), height, weight; serum Na in at-risk patients. Closely monitor mental status for worsening of depression, psychosis, suicidal ideation, and other unusual behavioural changes at the start of treatment or when doses are adjusted. Assess for signs and symptoms of serotonin syndrome.
Overdosage
Symptoms: Somnolence, dizziness, gastrointestinal disturbances (e.g. nausea, vomiting), tachycardia, tremor, agitation, seizures, QTc prolongation or torsades de pointes, and coma. Management: Symptomatic and supportive treatment. Establish and maintain an airway; ensure adequate oxygenation or ventilation if necessary. Administration of activated charcoal with a cathartic may be considered. Monitor cardiac (e.g. ECG) and vital signs.
Drug Interactions
May increase the risk of hyponatraemia with diuretics. Increased risk of QTc prolongation and/or ventricular arrhythmias with specific antipsychotics (e.g. chlorpromazine, ziprasidone, mesoridazine, droperidol), specific antibiotics (e.g. erythromycin, moxifloxacin), Class IA antiarrhythmics (e.g. quinidine, procainamide), Class III antiarrhythmics (e.g. amiodarone, sotalol), and other drugs that prolong QTc interval (e.g. pentamidine, methadone, halofantrine, mefloquine, tacrolimus). May increase the exposure of CYP2D6 substrates (e.g. propafenone, flecainide, dextromethorphan). May decrease the plasma concentration resulting in lowered efficacy with metamizole. May increase the serum concentration of phenytoin. May prolong the neuromuscular blocking effects of mivacurium or other neuromuscular blockers. May result in increased prothrombin time which may affect INR with warfarin. May increase sertraline exposure with potent CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, clarithromycin, nefazodone). Potentially Fatal: Increased risk of serotonin syndrome with other serotonergic agents (e.g. triptans, TCAs, lithium, fentanyl, tramadol, buspirone, amphetamines, tryptophan, fenfluramine, serotonin [5-HT] agonists), agents which impair metabolism of serotonin (e.g. MAOIs, linezolid, IV methylthioninium chloride), antipsychotics, other dopamine antagonists, and opiate/opioid drugs (e.g. buprenorphine). Increased risk of bleeding with aspirin, anticoagulants (e.g. warfarin, heparin), other antiplatelet agents (e.g. clopidogrel, ticlopidine), and NSAIDs. May increase the plasma levels of pimozide which increases the risk of QTc prolongation and ventricular arrhythmias (e.g. torsades de pointes).
Food Interaction
Increased risk of serotonin syndrome with St. John's wort. May enhance the risk of psychomotor impairment with alcohol. Increased plasma levels with grapefruit juice.
Lab Interference
May lead to a false-positive test result with urine detection of benzodiazepines.
Action
Description: Mechanism of Action: Sertraline, a naphthaleneamine derivative, is a selective serotonin reuptake inhibitor (SSRI) antidepressant agent. It potentiates the serotonergic activity in the central nervous system by inhibiting presynaptic serotonin (5-HT) reuptake. It has very weak effects on norepinephrine and dopamine neuronal uptake. Onset: Initial effects: Within 1-2 weeks (depression); within 2 weeks (obsessive compulsive disorder, panic disorder, posttraumatic stress disorder); within the 1st few days of treatment (premenstrual dysphoric disorder). Pharmacokinetics: Absorption: Slowly and well absorbed from the gastrointestinal tract. Time to peak plasma concentration: Approx 4.5-8.4 hours (sertraline). Distribution: Widely distributed throughout body tissues. Crosses the placenta and enters breast milk. Plasma protein binding: Approx 98%. Metabolism: Metabolised in the liver mainly via N-demethylation by multiple CYP450 isoenzymes (involving CYP2C19, CYP2B6, CYP3A4, CYP2C9, and CYP2D6) to form the primary inactive metabolite, N-desmethylsertraline; further metabolised via oxidative deamination and subsequent reduction, hydroxylation, and glucuronide conjugation. Undergoes extensive first-pass metabolism. Excretion: Via urine (40-45% as metabolites); faeces (40-45%; 12-14% as unchanged drug). Elimination half-life: Approx 26 hours (sertraline); 62-104 hours (N-desmethylsertraline).
Chemical Structure
Sertraline Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 68617, Sertraline. https://pubchem.ncbi.nlm.nih.gov/compound/Sertraline. Accessed May 28, 2024.
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