- ACRONYMS AND DEFINITIONS
- CAD - Coronary Artery Disease
- Cal - Calories
- CIII - DEA schedule III
- CIV - DEA schedule IV
- DBP - Diastolic Blood Pressure
- FDA - U.S. Food and Drug Admin
- HTN - Hypertension
- Hypocaloric - to consume fewer calories than what is expended
- PPH - Primary Pulmonary Hypertension
- RCT - Randomized controlled trial
- SBP - Systolic Blood Pressure
- DRUGS IN CLASS
- Standard-release products
- Benzphetamine (Didrex®) CIII
- Diethylpropion HCL (Tenuate®) CIV
- Phendimetrazine (Bontril® PDM) CIII
- Phentermine HCL (Adipex-P®, Suprenza™, Lomaira™) CIV
- Extended-release products
- Diethylpropion HCL (Tenuate Dospan®) CIV
- Phendimetrazine (Bontril®) CIII
- Phentermine resin complex (Ionamin®) CIV
- Combination products
- MECHANISM OF ACTION
- Appetite suppressants
- Appetite suppressants are sympathomimetic amines, a class of drugs that stimulates the sympathetic nervous system by mimicking the action of endogenous catecholamines (e.g. epinephrine, norepinephrine, dopamine). Their hunger-suppressing effects are believed to occur through increased norepinephrine activity in the hypothalamus. [16]
- WEIGHT LOSS
- Overview
- Two small studies that evaluated the effects of phentermine and diethylpropion on weight loss are detailed below
- The trial enrolled 74 obese patients with an average BMI of 33
Main inclusion criteria
- BMI ≥ 30 or BMI 27 - 30 and treated for type 2 diabetes, hypertension, or dyslipidemia
Main exclusion criteria
- HgA1C > 7.5%
- SBP ≥ 140, DBP ≥ 90
- History of weight loss surgery or medications
- Psychiatric illness
Baseline characteristics
- Average age 35 years
- Average BMI - 33
- Average weight - 191 lbs (87 kg)
- Female sex - 74%
- Average blood pressure - 123/80
Randomized treatment groups
- Group 1 (37 patients) - Phentermine 30 mg once daily for 12 weeks
- Group 2 (37 patients) - Placebo for 12 weeks
- Phentermine was given in a diffuse-controlled release (DCR) capsule
- All patients were instructed to follow a hypocaloric diet (1500 cal/day for men, and 1200 cal/day for women)
Primary outcome: Change in body weight and waist circumference at 12 weeks
Results
Duration: 12 weeks | |||
Outcome | Phentermine | Placebo | Comparisons |
---|---|---|---|
Primary outcome (body weight loss) | 17.8 lbs (8.1 kg) | 3.74 lbs (1.7 kg) | p<0.001 |
% weight loss | 10.7% | 1.9% | p<0.001 |
Primary outcome (decrease in waist circumference) | 7.2 cm | 2.1 cm | p<0.001 |
Dropout rate | 19% | 27% | N/A |
|
Findings: Short-term phentermine DCR treatment resulted in significant reduction in weight and improvement of metabolic parameters, including waist
circumference and some lipid profiles, without clinically severe adverse events. Further study is needed to show long-term efficacy and safety of phentermine DCR in Korean patients with obesity.
- The trial enrolled 69 obese patients with an average BMI of 37
Main inclusion criteria
- BMI ≥ 30 and ≤ 45
Main exclusion criteria
- Body weight fluctuations > 4 kg in previous 3 months
- Use of other weight loss medications
- Diabetes
- Significant depression, anxiety, or substance abuse disorder
Baseline characteristics
- Average age 37 years
- Average BMI - 37
- Average weight - 211 lbs (96 kg)
- Female sex - 90%
- Average blood pressure - 126/72
Randomized treatment groups
- Group 1 (37 patients) - Diethylpropion SR 50 mg twice a day for six months
- Group 2 (32 patients) - Placebo for six months
- All patients were instructed to follow a 600 calorie deficit per day diet
- EKGs and echocardiograms were performed at baseline, 6 months, and 12 months
Primary outcome: Percent change in body weight at 6 months
Results
Duration: 6 months | |||
Outcome | Diethylpropion | Placebo | Comparisons |
---|---|---|---|
Primary outcome (% weight loss) | 9.8% | 3.2% | p<0.0001 |
Average weight loss at 6 months | 20.5 lbs (9.3 kg) | 6.8 lbs (3.1 kg) | p<0.0001 |
Dropout rate | 19% | 31% | N/A |
Dry mouth (first 3 months) | 69.4% | 41% | p=0.02 |
Insomnia (first 3 months) | 53% | 22% | p=0.009 |
|
Findings: Diethylpropion plus diet produced sustained and clinically significant weight loss over 1 year. It seems to be safe in relation to cardiovascular
and psychiatric aspects in a well-selected population.
- Summary
- In the two small studies above, phentermine and diethylpropion caused an average weight loss of around 10% over 3 - 6 months. Side effects were generally mild and included insomnia and dry mouth.
- SIDE EFFECTS
- Stimulant side effects
- Stimulant-related side effects include the following (frequency not well defined):
- Insomnia
- Dry mouth
- Unpleasant taste in mouth
- Palpitations
- Anxiety or agitation
- Elevated blood pressure (see hypertension below)
- Increased heart rate
- Drug dependence and addiction
- Possible precipitation of psychosis in susceptible patients
- Valvular heart disease
- In the 1990s, phentermine was combined with fenfluramine in the popular "Phen-fen" diet pill. Fenfluramine and another drug called dexfenfluramine, both serotonergic agonists, were later found to cause valvular heart disease; this effect is believed to occur through direct stimulation of serotonin receptors (5-HT2b) in the heart. In 1997, the FDA pulled fenfluramine and dexfenfluramine from the market.
- Because phentermine was often taken with fenfluramine, the FDA also placed a valvular heart disease warning on all sympathomimetic amines. No evidence prior to or after that time has linked sympathomimetic amines to valvular heart disease. Furthermore, studies that have looked specifically for an association have found none. [6,7,8,11,16]
- Primary pulmonary hypertension (PPH)
- PPH was another cardiac condition associated with fenfluramine and dexfenfluramine use (see valvular heart disease). When the FDA pulled the drugs from the market, they also placed a PPH warning on all sympathomimetic amines. In studies, sympathomimetic amines have not been shown to cause PPH. [6,7,9,16]
- CONTRAINDICATIONS
- All sympathomimetic amines
- History of cardiovascular disease (e.g. CAD, stroke, heart arrhythmia, heart failure, uncontrolled hypertension, pulmonary hypertension)
- During or within 14 days following the administration of monoamine oxidase inhibitors - may cause severe hypertension
- Hyperthyroidism
- Glaucoma
- Agitated state
- History of drug abuse [6,7,14,15]
- PRECAUTIONS
- Kidney disease
- Benzphetamine
- Benzphetamine has not been studied in kidney disease
- Diethylpropion
- Diethylpropion is extensively excreted in the urine, and exposure is increased in kidney disease. Use caution.
- Phendimetrazine
- Phendimetrazine is primarily excreted by the kidneys, and exposure is increased in renal disease. Use caution.
- Phentermine
- CrCl ≥ 30 ml/min: no dose adjustment necessary
- CrCl 15 - 29 ml/min: maximum dose is 15 mg/day
- CrCl < 15 ml/min: DO NOT USE
- Liver disease
- Benzphetamine
- Benzphetamine has not been studied in liver disease
- Diethylpropion
- Diethylpropion has not been studied in liver disease
- Phendimetrazine
- Phendimetrazine has not been studied in liver disease
- Phentermine
- Phentermine has not been studied in liver disease
- Hypertension
- Sympathomimetic amines are stimulants, which raises the concern that they can increase blood pressure and worsen hypertension. In randomized controlled trials, blood pressure elevations were uncommon, and a reduction was often seen secondary to weight loss. Furthermore, a small observational study (N=269) found that phentermine-treated patients with hypertension saw average declines in their blood pressure that started as early as 1 week after initiation and persisted through 52 weeks. [PMID 21527891] [2,10,13]
- Hyperthyroidism
- Sympathomimetic amines may worsen symptoms of hyperthyroidism [6,7]
- Psychiatric illness
- Sympathomimetic amines may increase symptoms of agitation and anxiety
- Drug abuse
- Sympathomimetic amines are chemically related to amphetamines, and therefore, they have the potential for abuse in susceptible patients. That being said, the abusive properties of stimulants like cocaine and methamphetamine are related to their effects on dopamine release. Sympathomimetic amines have minimal dopamine effects, and studies evaluating their long-term use have not identified psychological or physical dependence. [16,17]
- Abrupt discontinuation
- Abruptly stopping sympathomimetic amines after prolonged use may lead to extreme fatigue and depression. Drug tapering may be necessary in some patients. In a study of long-term phentermine users (up to 21 years), abrupt discontinuation did not cause amphetamine-like withdrawal symptoms. [PMID 23736363]
- DRUG INTERACTIONS
- NOTE: The drug interactions presented here are NOT all-inclusive. Other interactions may exist. Drug interaction checkers provide the most efficient and practical way to check for interactions among multiple medications. A free interaction checker is available from Drugs.com (see Drugs.com interactions checker).
- All sympathomimetic amines
- MAO inhibitors - concomitant use of MAO inhibitors and phentermine increases the risk of hypertensive crisis; therefore, they should not be taken within 14 days of each other.
- Medications that affect the CNS - any medication that has CNS effects (e.g. antidepressants, antipsychotics, seizure medications, insomnia drugs, bipolar medications) may potentially be affected by the stimulant properties of sympathomimetic amines
- Serotonergic medications - case reports of serotonin syndrome have been reported in patients taking sympathomimetic amines with other serotonergic medications
- Metabolism and clearance
- The metabolism of sympathomimetic amines is not well-defined
- LONG-TERM SAFETY
- Phentermine and diethylpropion have been available since the 1960s, and benzphetamine and phendimetrazine were approved in the 1970s. Sympathomimetic amines have been widely prescribed and proven safe.
- DOSING
- BIBLIOGRAPHY
- 1 - PMID 11493122
- 2 - PMID 19564877
- 3 - PMID 15526396
- 4 - PMID 7471128
- 5 - PMID 17066505
- 6 - Phentermine package insert
- 7 - Diethylpropion package insert
- 8 - PMID 11104741
- 9 - PMID 10713017
- 10 - PMID 20920040
- 11 - PMID 9731087
- 12 - Suprenza PI
- 13 - PMID 21481449
- 14 - Didrex PI
- 15 - Bontril PI
- 16 - PMID 24621808 - Cardiovascular effects of phentermine and topiramate: a new drug combination for the treatment of obesity, J Hypertens (2014)
- 17 - PMID 23736363 - Addiction potential of phentermine prescribed during long-term treatment of obesity, Int J Obes (Lond) (2014)