AVENTYL HYDROCHLORIDE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for AVENTYL HYDROCHLORIDE (AVENTYL HYDROCHLORIDE).
Nortriptyline hydrochloride, the active ingredient in Aventyl Hydrochloride, is a tricyclic antidepressant that inhibits the reuptake of norepinephrine and serotonin at the presynaptic neuronal membrane, increasing their concentrations in the synaptic cleft. It also has antihistaminic, anticholinergic, and sedative properties.
| Metabolism | Primarily hepatic metabolism via CYP2D6, CYP3A4, and CYP1A2 isoenzymes; undergoes hydroxylation and N-demethylation; active metabolite: 10-hydroxynortriptyline. |
| Excretion | Primarily renal (approximately 70% as metabolites, <5% unchanged); biliary/fecal excretion accounts for ~30%. |
| Half-life | Terminal elimination half-life is approximately 19–24 hours; may be prolonged in elderly and patients with hepatic impairment. |
| Protein binding | Approximately 90–95% bound to plasma proteins (albumin and alpha-1-acid glycoprotein). |
| Volume of Distribution | Approximately 14 L/kg; indicates extensive tissue distribution. |
| Bioavailability | Oral: ~40–60% due to first-pass metabolism. |
| Onset of Action | Oral: 1–3 hours (therapeutic response may require 2–4 weeks). |
| Duration of Action | Duration of a single dose is approximately 24 hours; steady-state achieved in 4–7 days. |
| Molecular Weight | 263.38 |
25 mg orally three times daily; may increase gradually to 150 mg/day in divided doses. Maximum dose 150 mg/day.
| Dosage form | CAPSULE |
| Renal impairment | No specific guidelines; use caution in severe renal impairment (eGFR <30 mL/min/1.73m²) with dose reduction and monitoring. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: reduce dose by 50%; Child-Pugh C: contraindicated. |
| Pediatric use | Not recommended for children under 12 years. For adolescents 12-18 years: initial 10 mg orally three times daily, increase to maximum 100 mg/day. |
| Geriatric use | Initial 10 mg orally three times daily; maximum 100 mg/day. Monitor for anticholinergic effects, sedation, and orthostatic hypotension. |
| 1st trimester | Avoid; risk of fetal cardiovascular malformations. |
| 2nd trimester | Avoid; risk of fetal arrhythmias and growth restriction. |
| 3rd trimester | Avoid; neonatal withdrawal syndrome and respiratory depression. |
Clinical note
Comprehensive clinical and safety monograph for AVENTYL HYDROCHLORIDE (AVENTYL HYDROCHLORIDE).
| Placental transfer | Nortriptyline crosses the placenta; fetal concentrations approximately 50-100% maternal levels. |
| Breastfeeding | Nortriptyline (active metabolite) is excreted into breast milk; monitor infant for drowsiness, decreased feeding, and weight gain; benefit-risk assessment needed. |
| Lactation Rating |
■ FDA Black Box Warning
Suicidality and Antidepressant Drugs: Nortriptyline increases the risk of suicidal thinking and behavior in children, adolescents, and young adults with major depressive disorder and other psychiatric disorders. Short-term studies did not show an increase in suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older.
| Serious Effects |
Hypersensitivity to nortriptyline or TCAsConcomitant MAO inhibitors (risk of serotonin syndrome)Recent myocardial infarctionNarrow-angle glaucomaSevere urinary retention
| Precautions | Clinical worsening and suicide risk: Monitor for clinical worsening, suicidality, or unusual changes in behavior, especially at the beginning of therapy or during dose changes., Cardiovascular effects: May cause QTc prolongation, arrhythmias, tachycardia, and orthostatic hypotension; use with caution in patients with cardiovascular disease., Serotonin syndrome: Risk when co-administered with other serotonergic drugs., Anticholinergic effects: May exacerbate urinary retention, angle-closure glaucoma, hyperthyroidism, and seizures., Hematologic effects: Rare cases of agranulocytosis, leukopenia, and thrombocytopenia reported., Discontinuation syndrome: Abrupt discontinuation may cause withdrawal symptoms (dizziness, nausea, headache, malaise). |
Loading safety data…
| L3 (Moderately Safe) |
| Teratogenic Risk | First trimester: Limited human data; animal studies show no clear teratogenicity at clinically relevant doses. Second and third trimesters: No evidence of structural teratogenicity. Neonatal withdrawal syndrome (jitteriness, irritability) possible with third-trimester exposure; preterm labor risk not established. Avoid use if possible, especially in first trimester. |
| Fetal Monitoring | Maternal: Blood pressure, heart rate, signs of anticholinergic toxicity (constipation, urinary retention), mood/mental status. Fetal/neonatal: Ultrasound for growth restriction if used in advanced pregnancy; monitor neonate for jitteriness, irritability, respiratory depression at birth. |
| Fertility Effects | Animal studies: no adverse effects on fertility at therapeutic doses. Human data: limited; may cause menstrual irregularities or sexual dysfunction, potentially transiently impairing fertility. No established association with permanent infertility. |
| Food/Dietary | Avoid alcohol and excessive caffeine. No specific food restrictions; however, high-fiber foods may reduce absorption if taken simultaneously. Grapefruit juice may increase nortriptyline levels (inhibit CYP3A4) – limit or avoid grapefruit products. Maintain adequate hydration to counter anticholinergic effects (dry mouth, constipation). |
| Clinical Pearls | AVENTYL (nortriptyline) is a secondary amine tricyclic antidepressant (TCA) with a higher ratio of norepinephrine reuptake inhibition to serotonin reuptake inhibition. It causes less orthostatic hypotension, sedation, and anticholinergic effects than tertiary amines like amitriptyline. Therapeutic plasma range: 50-150 ng/mL; toxicity risk rises >200 ng/mL. Monitor ECG for QTc prolongation at baseline and with dose increases. Use with caution in patients with cardiovascular disease, narrow-angle glaucoma, urinary retention, or hyperthyroidism. Abrupt discontinuation may cause withdrawal symptoms (e.g., nausea, headache, malaise). Avoid coadministration with MAOIs (risk of serotonin syndrome) and drugs that inhibit CYP2D6 (e.g., fluoxetine, paroxetine) – reduce nortriptyline dose by 50% if adding a strong CYP2D6 inhibitor. Onset of antidepressant effect: 2-4 weeks. |
| Patient Advice | Take exactly as prescribed; do not stop suddenly without consulting your doctor. · May cause drowsiness or dizziness; avoid driving or operating machinery until you know how this medication affects you. · Avoid alcohol; it can increase side effects like drowsiness and dizziness. · Report any signs of serotonin syndrome: agitation, hallucinations, fast heart rate, fever, muscle stiffness, or loss of coordination. · This medication takes 2-4 weeks to improve mood; continue taking it even if you don't feel immediate benefit. · Do not take with MAO inhibitors or within 14 days of stopping them. · Store at room temperature away from light and moisture. · If you miss a dose: take it as soon as you remember unless it's almost time for the next dose – then skip the missed dose. Do not double up. · Use caution when standing up from a lying or sitting position to avoid dizziness from low blood pressure. · Tell your doctor if you have a history of seizures, heart problems, or glaucoma. |