Pharmacology Watch

Critical Drug Shortages Are on the Rise

In this issue: Drug shortages; metformin and cancer prevention; migraine prevention guidelines; and FDA actions.

What's causing the shortages?

Drug shortages are happening at an unprecedented rate. Just in the last 2 months, we have seen shortages of diazepam, methotrexate, leucovorin, naltrexone, oxymorphone, mitomycin, fentanyl, metoclopramide, pantoprazole, ondansetron, and dexamethasone among others. What is causing the shortages and is there any end in sight? Although it seems like a new problem, we have seen an increasing number of drug shortages going back to 2005. But while there were about 50 drug shortages in the mid 2000s, last year more than 260 drugs were in short supply, including many commonly used and clinically vital drugs. The cause of these shortages is multifactorial. Some sources in the industry blame price controls, especially for generic drugs. Medicare and Medicaid impose strict controls on most generics, squeezing pharmaceutical companies' ability to make a profit. Some companies have simply decided to drop out of the generic market altogether. Others blame fewer manufacturers. The Wall Street Journal reports that there were 26 vaccine makers in the United States in 1967, while currently there are only six. But even these issues do not explain the severe shortages we are seeing. Most experts agree the two major issues causing the current shortages are supply chain disruptions, especially disruptions in raw materials, and problems with manufacturing, especially safety issues, which force the FDA to shut down production of a product line or an entire factory. Safety shutdowns are the most common cause of shortages of sterile injectable drugs. But in other cases, companies limit production themselves when they either have an absolute shortage of raw materials or they decide to divert limited supplies of raw materials from less expensive generics to more expensive brand-name drugs. This is a current issue with some of the attention deficit hyperactivity disorder drugs that have been in short supply for several months. Last month, the FDA initiated a series of steps to increase the supply of critically needed cancer drugs, including allowing the importation of drugs in shortage from Europe and elsewhere. The agency is also fast tracking approval of new manufacturers for short-supply drugs like methotrexate. The FDA, as well as the Obama administration, is also requiring companies to give early warning of potential drug shortages. Finally, the Justice Department will aggressively pursue possible incidences of collusion or price gouging among drug distributors who may be taking advantage of shortages. Despite these steps, there will likely be no short-term easing in drug shortages.

Does metformin prevent cancer?

Last month, we reported that low-dose aspirin may be protective against some cancers. Now it looks like metformin may have similar properties. A new study from the American Association for Cancer Research suggests that the diabetes drug may improve the prognosis with pancreatic cancer. In a retrospective study, researchers at the University of Texas studied 302 patients with diabetes and pancreatic cancer; 117 of these patients were taking metformin. The 2-year survival rate was 30.1% for the metformin group vs 15.4% for the non-metformin group (P = 0.004; x² test). The pancreatic cancer patients on metformin lived 4 months longer than non-metformin patients (15.2 months vs 11.1 months). The authors suggest that metformin should be evaluated as a supplemental therapy for patients with pancreatic cancer (Clin Cancer Res published online March 31, 2012; doi: 10.1158/1078-0432.CCR-11-2994). Data presented at the AACR meeting in Chicago earlier this year suggest that the drug may also be beneficial for men with prostate cancer, although further research is needed.

Migraine prevention in adults

The American Academy of Neurology and the American Headache Society have published their new guideline on pharmacologic treatment for episodic migraine prevention in adults. The highest level (Level A) recommendation for prevention was given to antiepileptic drugs, including divalproex sodium, sodium valproate, and topiramate. Other level A drugs included the beta-blockers metoprolol, propranolol, and timolol as well as the triptan frovatriptan, but this last agent is just for short-term use for menstrually associated migraine (MAM) prevention. Level B drugs included the antidepressants amitriptyline and venlafaxine, the beta-blockers atenolol and nadolol, and the triptans naratriptan and zolmitriptan (also only for short-term MAM prevention). Possibly effective medications included lisinopril, candesartan, some beta-blockers, and carbamazepine. There was little or no evidence to support any other drugs including selective serotonin reuptake inhibitors, calcium channel blockers, or acetazolamide. Drugs that should not be offered include lamotrigine and clomipramine. In a separate section on nonsteroidal anti-inflammatory drugs (NSAIDs) and complementary treatments, Petasites hybridus (butterbur) were given recommended status, while NSAIDs were listed as probably effective (Neurology published online April 24, 2012; doi: 10.1212/WNL.0b013e3182535d20, and doi: 10.1212/WNL.0b013e3182535d0).

Fibrate use in elderly patients

Fibrate use in elderly patients is associated with worsening renal function and increased risk of hospitalization, according to a new study. Researchers reviewed data from a large Canadian database of patients over the age of 65 who were started on a fibrate or ezetimibe (comparator). Many patients in both groups were also on statins. Fibrate users were more likely to be hospitalized for an increase in serum creatinine (odds ratio [OR] 2.4 [95% confidence interval (CI), 1.7 to 3.3]). Fibrate patients were also more likely to consult a nephrologist, but there was no difference in all-cause mortality or need for dialysis. In a subgroup of 1110 patients in which serum creatinines were available at baseline and within 90 days, 9.1% of fibrate users and 0.3% of ezetimibe users had an increase in serum creatinine of 50% or more (OR 29.6 [CI, 8.7 to 100.5]). The risk was higher if patients had chronic kidney disease. The authors conclude that new fibrate use in the elderly is associated with an increase in serum creatinine and a small increase in hospitalization and nephrology consultation (Ann Intern Med 2012;156:560-569).

FDA actions

The FDA has approved the first PDE5 inhibitor in a decade for the treatment of erectile dysfunction (ED). Avanafil (Stendra) joins sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra) as the fourth drug approved for this indication. Avanafil will be marketed as having a shorter onset and a shorter half-life than the other drugs in this class. Men should take avanafil as needed 30 minutes before sexual activity with onset of action as quickly as 15 minutes. The approval was based on three randomized, placebo-controlled clinical trials of 1267 patients with ED in which 57% of men achieved erections sufficient for intercourse, up from a baseline of 15% (compared to 27% with placebo). Like other PDE5 inhibitors, avanafil should not be taken with nitrates. Commonly reported side effects include headache, flushing, nasal congestion, nasopharyngitis, and back pain. Avanafil will be marketed by VIVUS of Mountain View, California, as Stendra.

The FDA is requiring new labeling on finasteride — Merck's testosterone blocker used for the treatment of benign prostatic hypertrophy (5 mg as Proscar) and male pattern baldness (1 mg as Propecia). The new labeling addresses sexual adverse events such as libido disorders, ejaculation disorders, orgasm disorders, and even male infertility and poor semen quality. Some of these issues, such as libido disorders and ejaculation disorders, may continue after stopping the drug, while infertility and poor semen quality improve or normalize after discontinuation. The labeling change is based on event reports filed with the FDA, although a clear causal relationship has not been made. Still, the agency is recommending that a discussion of the risks and benefits of finasteride include the possibility of sexual side effects.

This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. In order to reveal any potential bias in this publication, we disclose that Dr. Elliott reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study. Questions and comments, call: (404) 262-5404. E-mail: