Phentermine and fenfluramine

The Chairman of FDA s Advisory Committee commented on the risk of death from developing PPH. "We have had what 1 think appears to be a reasonable estimate of the risk of deaths from pulmonary hypertension. We need to understand clearly that if a million patients take this drug, at least a couple dozen of them will die annually as a result of this complication. That seems the best estimate. This is something that has to be weighed seriously." The appearance of heart valvulopathies in otherwise asymptomatic people in their thirties or forties was unexpected and caught patients and practitioners by surprise. Both fenfluramine and phentermine cause an increase in the amount of serotonin available in the body, which can cause cardiac valvulopathies. 

The amphetamines were replaced by amphetamine analogs—substances somewhat less potent than amphetamines. Fen-Phen, the combination of fenfluramine and phentermine, was a popular appetite suppressant in the 1990s, but was associated with severe health problems such as pulmonary hypertension, heart valve dysfunction, and nerve damage. As a result, both drugs were withdrawn from the market. 

Other dmgs were developed. Some—including "fen-phen" (fenfluramine and phentermine) and drugs containing the stimulant ephedra—initially enjoyed raging popularity. Yet, they too were later banned due to serious health risks. 

A pharmacy journal reports the work of the University of Rochester s Dr. Michael Weintraub, who has discovered that the combination of fenfluramine and phentermine is effective for weight loss. 

Weintraub M, Hasday JD, Mushlin Al, Lockwood DH. A double-blind clinical trial in weight control. Use of fenfluramine and phentermine alone and in combination. Arch Intern Med 1984 144 1143-1148. 

Jollis JG, Landolfo CK, Kisslo J, Constantine GD, Davis KD, Ryan T. Fenfluramine and phentermine and cardiovascular findings effect of treatment duration on prevalence of valve abnormalities. Circulation 2000 101 2071-2077. 

Tomita T, Zhao Q. Autopsy findings of heart and lungs in a patient with primary pulmonary hypertension associated with use of fenfluramine and phentermine. Chest 2002 121 649-652. 

Mark EJ, Patalas ED, Chang HT, Evans RJ, Kessler SC. Fatal pulmonary hypertension associated with short-term use of fenfluramine and phentermine. N Engl... 

Fenfluramine, dexfenfluramine, and phentermine have been used alone or in combination as an alternative to diet and surgery in the management of obesity. This therapy was halted in 1997 after reports of valvular lesions affecting almost one-third of patients treated with these drugs. The combination of fenfluramine and phentermine is called fen-phen. 

The fenfluramines and phentermine can cause valvular heart disease (8-10), and this has been reviewed (11). Fenfluramine was voluntarily withdrawn by the manufacturers on 15 September 1997, and the US Department of Health and Human Services issued interim recommendations for people previously exposed to fenfluramine or dexfenfluramine with cardiac valvulopathies (SEDA-22, 3). 

The autopsy findings in the heart and lungs of a patient with pulmonary hypertension associated with fenfluramine and phentermine have been described (13). 

Effects of withdrawal of therapy on valvulopathy In a patient who was followed-up for 2 years after withdrawal, multivalvular regurgitation associated with fenfluramine and phentermine may have regressed (23). 

Pulmonary artery pressure and cardiac valvular status were determined in a series of 156 mostly asymptomatic patients taking fenfluramine and phentermine (59). The anorexigen was withdrawn when abnormalities were noted. Pulmonary artery pressure was estimated and valvular examination was performed using Doppler echocardiography. There was borderline or mildly elevated pulmonary artery pressure in 21 patients and 31 patients had notable valvular abnormalities. It has therefore been established that asymptomatic patients may have significant echocardiographic abnormalities, representing early lesions. 

Steel JM, Munro JF, Duncan LJ. A comparative trial of different regimens of fenfluramine and phentermine in obesity. Practitioner 1973 211(262) 232-6. 

Cannistra LB, Cannistra AJ. Regression of multivalvular regurgitation after the cessation of fenfluramine and phentermine treatment. N Engl J Med 1998 339(11) 771. 

Dahl CF, Allen MR. Regression and progression of valvulopathy associated with fenfluramine and phentermine. Ann Intern Med 2002 136(6) 489. 

Weintraub et al. 1984). This combination (later to become known as fen-phen) appeared to be more effective and better tolerated in comparative clinical trials than either drug given alone. The combination of fenfluramine and phentermine soon became extremely popular in the US. By 1996, over 18 million prescriptions for this combination were being issued annually. Unfortunately, the fenfluramine moiety of the combination appeared to cause pulmonary hypertension and/or mitral valve prolapse in some patients. It was withdrawn from the market in 1997. 

Amphetamines 2-5 days Up to 2 weeks with prolonged or heavy use Many sympathomimetic amines such as pseudoephedrine, ephedra, phenylephrine, fenfluramine, and phentermine may cause positive results. Other drugs such as selegiline, chlorpromazine, trazodone, bupropion, and amantadine may cause false-positive results depending on the assay. 

In September 1997, the FDA requested the manufacturers of fenfluramine and dexfenfluramine to voluntarily withdraw their products from the market. This was done following case reports of valvular heart disease in patients taking either medication as monotherapy or in combination with another anorexic agent, phentermine. Because no association has been found between phentermine alone and valvular heart disease, it is still available. Isolated case reports of pulmonary hypertension and phentermine monotherapy have been reported, but present data do not support an association. Although fenfluramine and phentermine were both approved by the FDA to be used as anorectic agents, the combination therapy, fen-phen, was never approved. 

In the last 30 years there have been continued instances of drug recalls or precautionary statements due to pharmacovigilance reports and some more notable examples include benoxaprofen and hepatic disorders/ deaths in the elderly and temafloxacin associated hemolytic anemia. Other recent examples are cardiac valve disorders from fenfluramine and phentermine (Fen-Fen), anaphylaxis from zomepirac, rhabdomyoly-sis associated with ceiivastatin and cardiac arrests from drug interactions with terfenadine and drugs which inhibit P450 3A4 like ketoconazole and erythromycin... 

Many physiologically active substituted benzenes are not found in nature, but exist because chemists have synthesized them. The now-banned diet dmg fen-phen is a mixture of two synthetic substituted benzenes fenfluramine and phentermine. Agent Orange, a defoliant widely used in the 1960s during the Vietnam War, is also a mixture of two synthetic substituted benzenes 2,4-D and 2,4,5-T. The compound TCDD... 

Kaddoumi, A. Nakashima, M.N. Wada, M. Kuroda, N. Nakahara, Y. Nakashima, K. HPLC of ( )-fenfluramine and phentermine in plasma after derivatization with dansyl chloride, J.Liq.Chromatogr. Rd.Technol, 2001, 24, 57-67. 

---