Tesofensine (NS2330) is a triple monoamine reuptake inhibitor that blocks the reuptake of dopamine, norepinephrine, and serotonin. Originally developed for P...

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Safety Profile

Safety Profile: Tesofensine

Common Side Effects

• Dry mouth, insomnia, and constipation are the most frequently reported adverse effects in clinical trials
• Increased heart rate (mean increase of 7–8 bpm) and elevated blood pressure observed in dose-dependent fashion
• Nausea, diarrhea, and abdominal discomfort
• Headache, dizziness, and mood changes including irritability and anxiety
• Reduced appetite (pharmacological effect, but may become excessive)

Serious Adverse Effects

• Cardiovascular effects: sustained elevations in heart rate and blood pressure at higher doses (0.5–1.0 mg/day) raise concern for long-term cardiovascular safety; tachycardia and hypertension were dose-limiting in Phase II/III trials
• Psychiatric adverse effects including depression, anxiety, suicidal ideation, and insomnia at higher doses; relates to its triple monoamine reuptake inhibition (serotonin, norepinephrine, dopamine)
• Risk of serotonin syndrome when combined with other serotonergic agents
• Potential for abuse and dependence due to dopamine reuptake inhibition, though clinical data suggest lower abuse potential than amphetamines
• QTc prolongation has not been definitively established but cardiovascular monitoring is recommended

Contraindications

• Known hypersensitivity to tesofensine or excipients
• Uncontrolled hypertension or significant cardiovascular disease (coronary artery disease, heart failure, arrhythmias)
• History of stroke or transient ischemic attack
• Concurrent use of MAO inhibitors (risk of hypertensive crisis and serotonin syndrome; washout of at least 14 days required)
• Glaucoma (mydriatic effects possible due to noradrenergic activity)
• Pregnancy and lactation (no human safety data; animal studies showed developmental toxicity)
• History of severe psychiatric disorders including major depression with suicidal ideation, bipolar disorder, or psychosis

Drug Interactions

• MAO inhibitors (phenelzine, tranylcypromine, selegiline): Contraindicated; risk of hypertensive crisis and serotonin syndrome
• Serotonergic drugs (SSRIs, SNRIs, triptans, tramadol): Increased risk of serotonin syndrome due to serotonin reuptake inhibition
• Sympathomimetics (pseudoephedrine, amphetamines): Additive cardiovascular effects; avoid concurrent use
• Antihypertensives: May partially counteract blood pressure effects; dose adjustments may be needed
• CYP3A4 inhibitors: Tesofensine is metabolized via CYP3A4; inhibitors may increase plasma levels

Population-Specific Considerations

• Elderly: Increased cardiovascular risk; not recommended without careful cardiac evaluation
• Pediatric: No safety or efficacy data; not approved for use in children
• Obese patients: Primary studied population (Phase II/III); significant weight loss (10–13% at 0.5 mg) but cardiovascular concerns limited further development
• Cardiac patients: Contraindicated in patients with significant cardiovascular disease
• Psychiatric patients: Monitor closely for mood changes, anxiety, and suicidal ideation

Pharmacokinetic Profile