The FDA has authorized over-the-counter (OTC) sale of a nonmedicated alcohol-based gel (Eroxon – Futura) for treatment of erectile dysfunction (ED) in males ≥22 years old. Eroxon is the only FDA-approved OTC and topical treatment for erectile dysfunction. It is also available in the UK and the EU.

Low-intensity extracorporeal shockwave therapy similar to that used to fragment kidney stones or gallstones is a new option for treatment of erectile dysfunction that is now being advertised extensively in the US. It has not been approved by the FDA for treatment of erectile dysfunction.

The FDA has approved a sublingual powder formulation of nitroglycerin (GoNitro – Espero) for prevention or acute relief of an attack of angina pectoris. It is the first powder formulation of nitroglycerin to become available in the US. Most patients with angina use sublingual nitroglycerin tablets (Nitrostat, and generics). Translingual spray formulations of nitroglycerin (NitroMist, Nitrolingual Pumpspray, and generics) are also available.

The FDA has approved an intranasal gel formulation of testosterone (Natesto – Trimel/Endo) for replacement therapy in men with hypogonadism. Packaged in a metered-dose pump, Natesto is the first intranasal testosterone to become available in the US. Like other testosterone products, it is classified as a schedule III controlled substance. The FDA recently cautioned against using testosterone to treat low testosterone levels solely due to aging because the benefits and safety of such use have not been established, and there is a possible increased risk of myocardial infarction (MI) and stroke.

Heart failure is usually associated with left ventricular dysfunction. According to recent guidelines, patients with a left ventricular ejection fraction (LVEF) ≤40% are considered to have heart failure with reduced ejection fraction (HFrEF) or systolic heart failure. Patients with a LVEF ≥50% and symptoms of heart failure are considered to have heart failure with preserved ejection fraction (HFpEF) or diastolic heart failure; there is little evidence that drug treatment improves clinical outcomes in these patients. The treatment of acute heart failure is not included here.

The FDA has approved avanafil (Stendra – Vivus), an oral phosphodiesterase type-5 (PDE5) inhibitor, for treatment of erectile dysfunction. It is the fifth PDE5 inhibitor to be approved for this indication. Advertisements on Stendra’s website imply that it has a faster onset of action than other PDE5 inhibitors.

Prompted by the recent publication of 2 retrospective studies, the FDA has announced that it is investigating the risk of stroke, heart attack, and death in men taking FDA-approved testosterone products.1

The first study examined the records of 8709 men with low testosterone levels (<300 ng/dL) who underwent coronary angiography between 2005 and 2011; 1223 of these men started testosterone therapy after a median of 531 days following coronary angiography. Three years after coronary angiography, the Kaplan-Meier estimated cumulative percentages of men who died or had a myocardial infarction (MI) or ischemic stroke were 26% of those treated with testosterone and 20% of those who were not treated with the hormone, a hazard ratio of 1.29 (95% CI 1.04-1.58; P=0.02).2

The second study compared the rate of nonfatal MI during the 90 days after filling a prescription with the rate in the prior year in 56,000 men given a prescription for testosterone and in 167,000 given a phosphodiesterase type 5 inhibitor (sildenafil [Viagra] or tadalafil [Cialis]). In the testosterone group as a whole, the post/pre-prescription rate ratio was 1.36, but in men ≥65 years old it was 2.19 and in younger men with a history of heart disease it was 2.90. In men who received a prescription for sildenafil or tadalafil, the rate ratio was 1.08 for all ages, 1.15 for those ≥65 years old, and 1.40 for younger men with a history of heart disease.3

A recent meta-analysis of randomized, placebo-controlled trials of testosterone therapy also found an increased risk of cardiovascular-related events in men treated with the hormone (odds ratio [OR] 1.54; 95% CI 1.09-2.18); an analysis by funding source found that the risk was greater in trials not funded by the pharmaceutical industry (OR 2.06 vs. 0.89).4

1. FDA Drug Safety Communication January 31, 2014: FDA evaluating risk of stroke, heart attack and death with FDA-approved testosterone products. Available at www.fda.gov. Accessed February 24, 2014.

2. R Vigen et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA 2013; 310:1829.

3. WD Finkle et al. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS One 2014; 9:e85805.

4. L Xu et al. Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials. BMC Med 2013; 11:108.

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The FDA has approved the use of nitroglycerin ointment 0.4% (Rectiv – ProStrakan/Aptalis) for treatment of moderate to severe pain associated with chronic anal fissure; the same drug is marketed as Rectogesic in Europe. Nitroglycerin ointment 2% (Nitro-Bid) is available in the US for prevention of angina.

Sildenafil (Viagra), tadalafil (Cialis) and vardenafil (Levitra, Staxyn) have become the standard treatment for erectile dysfunction. Head-to-head comparisons of these agents are still lacking, but some differences between them and new recommendations for their dosing (see Table 2) are worth noting.

The FDA has approved the use of the phosphodiesterase-5 (PDE-5) inhibitor tadalafil (Cialis – Lilly) for treatment of signs and symptoms of benign prostatic hyperplasia (BPH) in men with or without erectile dysfunction. Tadalafil is approved for use under another brand name (Adcirca) for treatment of pulmonary arterial hypertension. The other PDE-5 inhibitors available in the US for treatment of erectile dysfunction (sildenafil [Viagra]; vardenafil [Levitra]) have also been reported to be effective for treatment of BPH signs and symptoms, but have not been approved for this indication by the FDA.

The FDA has approved a lingual aerosol formulation of nitroglycerin (NitroMist – Akrimax) for acute relief of an attack or acute prophylaxis of angina pectoris. It is the second nitroglycerin lingual spray to become available in the US; Nitrolingual Pumpspray was approved in 1985. Most patients with angina use sublingual nitroglycerin tablets.

Sexual complaints related to desire, arousal, orgasm and painful intercourse are common in women. Since the last Medical Letter article on this subject, some new information has become available.

Many drugs can cause psychiatric symptoms, but a causal connection is often difficult to establish. Psychiatric symptoms that emerge during drug treatment could also be due to the underlying illness, previously unrecognized psychopathology, or psychosocial factors. The withdrawal of some drugs can cause symptoms such as anxiety, psychosis, delirium, agitation or depression.

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The phosphodiesterase type 5 (PDE5) inhibitor tadalafil (Cialis - Lilly) is now being promoted for once daily treatment of erectile dysfunction. Tadalafil differs from sildenafil (Viagra) and vardenafil (Levitra), the other PDE5 inhibitors marketed for erectile dysfunction in the US, in having a much longer duration of action.

The FDA recently advised health care professionals and consumers not to use a number of dietary supplements found to contain the phosphodiesterase-5 inhibitor sildenafil (Viagra) or an analog of the drug (www.fda.gov). Although the effects of sildenafil may be noticeable (in men), the presence of other, possibly more toxic adulterants in dietary supplements may be more difficult or impossible to detect.

Other drugs previously found in dietary supplements have included lovastatin (Mevacor, and others), estrogen, alprazolam (Xanax, and others), indomethacin (Indocin, and others) and warfarin (Coumadin, and others). Aristolochic acid in Chinese herbal weight loss products caused acute renal failure in about 100 women in Belgium; at least 70 of them required dialysis or transplantation, and at least 18 developed urothelial cancer (Med Lett Drugs Ther 2002; 44:84).

Dietary supplements do not require FDA approval before marketing. The agency does have the power to remove mislabeled or adulterated products from store shelves, but the burden of discovery and proof is entirely on the government.

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Sexual complaints related to desire, arousal, orgasm and pain are common in women. No drugs are approved by the FDA for any of these indications, but many are used off-label.

BiDil (NitroMed), a fixed-dose combination of isosorbide dinitrate and hydralazine, was approved by the FDA for adjunctive use in the treatment of heart failure in black patients.Both drugs are oral vasodilators that have been used together off-label for many years to treat heart failure in patients not responding to other drugs.

The Medical Letter reported last year that sildenafil (Viagra - Pfizer) appeared to be effective for idiopathic pulmonary arterial hypertension (PAH), but confirmation from a controlled trial was needed. Now the results of such a study are about to be published, and the drug has been approved by the FDA for this indication under the trade name Revatio.

Serious adverse interactions between drugs continue to be reported. Many of these are due to inhibition or induction of cytochrome P450 (CYP) enzymes, particularly CYP3A4. CYP3A is thought to be involved in the metabolism of more than 50 percent of currently prescribed drugs.2 CYP3A4, which is more abundantly expressed than CYP3A5, accounts for most CYP3A activity in vivo.

The FDA recently announced that it was investigating 38 reports of loss of vision in men who took sildenafil (Viagra), which has been used to treat erectile dysfunction since 1998.

Breaking drug tablets in half is a common practice. In some cases, a lower drug dose may be as effective as a higher one, with fewer adverse effects. Sometimes tablets are split to achieve an intermediate dose between marketed strengths. When 2 tablet sizes cost the same, as they often do, splitting the larger size saves money. Is this a reasonable practice?

Several recent case reports suggest that oral sildenafil may be effective for treatment of pulmonary arterial hypertension (PAH). Sildenafil is currently marketed as Viagra for treatment of erectile dysfunction (Medical Letter 1998; 40:51).

The ability of grapefruit juice to increase serum concentrations of drugs was first discovered during a study of the effect of ethanol on felodipine (Plendil) pharmacokinetics. Double-strength grapefruit juice used to disguise the taste of ethanol resulted in higher than expected serum concentrations of felodipine (DG Bailey et al, Clin Invest Med 1989; 12:357).

Alfuzosin hydrochloride (Uroxatral - Sanofi-Synthelabo) is now available in the US in a new formulation for once-daily treatment of benign prostatic hyperplasia (BPH). The drug has been used in Europe since 1987. Alpha₁-blockers cause relaxation of smooth muscle tone in the bladder neck, prostatic capsule and prostatic urethra, relieving symptoms of urinary obstruction.

Tadalafil (Cialis - Lilly Icos) is the third oral drug to be approved by the FDA for treatment of erectile dysfunction. It has a longer duration of action than sildenafil (Viagra) or vardenafil (Levitra - Medical Letter 2003; 45:77).

Vardenafil (Levitra -Bayer) is the second oral drug approved by the FDA for treatment of erectile dysfunction. Sildenafil (Viagra - Medical Letter 1998; 40:51), the first oral drug, has been available for 5 years. Pharmacokinetics, effectiveness, adverse effects, dosage and cost of the new drug are reviewed. Whether it offers any benefits over sildenafil is discussed.

The number of drugs marketed for psychiatric indications has increased sharply in recent years. The recommendations in this article are based on the results of controlled trials and on the experience and opinions of Medical Letter consultants. Interactions with other drugs can be found in The Medical Letter Handbook of Adverse Drug Interactions, 2003.

Many drugs can cause psychiatric symptoms, but a causal connection is often difficult to establish. Psychiatric symptoms that emerge during drug treatment may also be due to the underlying illness, previously unrecognized psychopathology, or psychosocial factors. The withdrawal of some drugs can cause symptoms such as anxiety, psychosis, delirium, agitation or depression.

Amprenavir is the fifth protease inhibitor to become available for treatment of HIV infection. It was approved by the FDA for use with other drugs in the treatment of HIV-infected adults and children at least four years old.

Sildenafil citrate (Viagra - Pfizer) is the first oral drug approved by the FDA for treatment of erectile dysfunction. Alprostadil is also marketed for this indication but must be injected into the corpus cavemosum (Caverject) or pushed into the urethra (MUSE).