What are the potential side effects of phentermine in adults with a body mass index (BMI) of 30 or higher, or those with a BMI of 27 or higher and at least one weight-related condition?

Side Effects of Phentermine

The most common side effects of phentermine include dry mouth, insomnia, dizziness, irritability, and constipation, while serious cardiovascular concerns are primarily related to blood pressure and heart rate changes that require monitoring. 1, 2

Common Side Effects

Neuropsychiatric Effects

• Dry mouth is the most frequently reported side effect across clinical trials 1
• Insomnia and difficulty sleeping occur commonly, which can be minimized by taking phentermine early in the morning (approximately 2 hours after breakfast) and avoiding late evening administration 1, 2
• Dizziness affects a significant proportion of patients 1
• Irritability and anxiety may develop, particularly in patients with pre-existing anxiety disorders 1, 3
• Disturbance in attention and cognitive effects have been reported 4

Gastrointestinal Effects

• Constipation is a common sympathomimetic side effect 1, 4
• Dysgeusia (altered taste) occurs frequently 1, 4

Neurological Effects

• Paresthesias (tingling sensations) are reported, particularly when phentermine is combined with topiramate 1, 4
• Hypoesthesia (reduced sensation) may occur 4

Cardiovascular Effects

Blood Pressure and Heart Rate

• Mild increases in heart rate and blood pressure can occur due to phentermine's sympathomimetic properties 1, 5
• However, observational data from long-term phentermine monotherapy shows minimal significant increases in blood pressure in most treated individuals, with some studies showing blood pressure reductions of 6.9/5.0 mm Hg at 26 weeks when combined with weight loss 5, 6
• Heart rate changes are generally modest, with increases of approximately 1.2 bpm at 52 weeks in treated patients 6
• Blood pressure and heart rate should be monitored periodically during treatment, especially in the initial weeks 1, 5, 3

Serious Cardiovascular Concerns

• The historical association with valvular heart disease was primarily linked to fenfluramine (the "fen-phen" combination), not phentermine monotherapy 1, 5
• Fenfluramine metabolites directly activated serotonin receptors in cardiac tissues, while phentermine works through norepinephrine pathways 5
• Phentermine is contraindicated in patients with cardiovascular disease including coronary artery disease, stroke, arrhythmias, congestive heart failure, or uncontrolled hypertension 1, 7, 2

Serious Adverse Events

Drug Interactions

• Hypertensive crisis can occur when phentermine is used with monoamine oxidase inhibitors (MAOIs) or within 14 days of MAOI discontinuation 1, 7, 2
• Potential drug-drug interactions exist with other sympathomimetic amines 1, 2
• Serotonergic agents (SSRIs, SNRIs) may interact, though some trials included patients on these medications 1, 8

Severe Side Effects Leading to Discontinuation

• In clinical studies, approximately 14% of patients were withdrawn due to side effects 9
• Severe headaches requiring discontinuation occurred in some patients 9
• Hypertension development necessitated withdrawal in select cases 9
• Depressive symptoms, breathlessness, and palpitations with irritability led to discontinuation in individual patients 9

Contraindications and High-Risk Situations

Absolute Contraindications

• History of cardiovascular disease (coronary artery disease, stroke, arrhythmias, heart failure) 1, 7, 2
• Uncontrolled hypertension 7, 2
• Hyperthyroidism due to concerns for arrhythmias and seizures 7, 2
• History of drug abuse (phentermine is Schedule IV controlled substance) 7, 2
• Glaucoma 2
• Agitated states 2
• Pregnancy and lactation (Category X) 1, 2
• Known hypersensitivity to sympathomimetic amines 2

Special Populations

• Renal impairment: Maximum dose of 15 mg daily for severe renal impairment (eGFR 15-29 mL/min/1.73 m²); avoid use in end-stage renal disease 2
• Patients requiring general anesthesia require special management considerations 7
• Seizure disorders: Exercise caution, particularly with combination therapy 7

Dose-Related Considerations

• Side effects are generally dose-dependent, with higher doses (37.5 mg vs 15 mg) associated with increased frequency of adverse events 1, 4
• Low-dose phentermine (8 mg up to 3 times daily) may reduce side effect burden while maintaining efficacy 1
• Starting with the lowest effective dose (15 mg daily) and titrating based on response and tolerability is recommended 3

Long-Term Safety Concerns

• FDA approval is only for short-term use (12 weeks), though many practitioners prescribe off-label for longer duration 1, 3
• No large cardiovascular outcome trials exist for long-term phentermine monotherapy 5, 7
• Long-term use beyond 12 weeks increases exposure to potential drug-drug interactions and adverse drug reactions 8
• The unpredictability of individual response to phentermine means poor initial response is unlikely to improve with higher dosage 9