Kathryn L. Hahn, PharmD, CPE, DAAPM

Unique formulations, new indications, and the 'rediscovery' of already approved drugs are just a few of the innovations pharmacists can expect as drug makers revitalize their product portfolios.

	The current environment for drug development is putting increasing pressure on the pharmaceutical industry to consider innovative ways to supplement the development of new molecular entities by repurposing or repositioning older drugs with known track records for efficacy and safety.

	New drug development is a high-risk business with the potential for high reward but also with the possibility of significant loss. On average, it takes 10 to 15 years to bring either a new molecular entity or a biologic to market, at an estimated cost of approximately $800 million to $1.7 billion.

 Of the drugs that receive approval from the FDA, approximately 2 in 10 are able to recoup development costs.

	In order to bring 1 new drug to market, many thousands of compounds are screened and discarded before a promising few reach the first round of clinical trials.

	Of the compounds that do enter clinical testing, it is estimated that, overall, the new drug approval rate is only 19%.

 In 2009, just 19 new molecular entities were approved by the FDA’s Center for Drug Evaluation and Research—a number that has remained relatively constant since 2005, but represents a significant decline from the peak of 53 in 1996.

	A key concern in the approval process—and an important cause of drug failure&mdash;is the toxicity-to-benefit ratio and long-term safety profile of an investigational drug. The high-profile withdrawal of drugs such as cerivastatin (Baycol) and rofecoxib (Vioxx) from the market due to safety concerns has reinforced the need for phase 4 postmarketing or safety surveillance studies and has triggered increased scrutiny of safety data by regulatory authorities.

	In addition to the challenges of the time and cost required to bring new drugs to market, the pharmaceutical industry is faced with dwindling product pipelines and imminent patent expirations on many drugs, including several “blockbusters,” such as atorvastatin (Lipitor). It is estimated that 71 drugs will face first-time generic competition between 2010 and 2015.

 It is further projected that drugs with sales of more than $73 billion from the 10 largest pharmaceutical companies will be exposed to generic competition between 2009 and 2012.

	Repurposing drugs is not new to the pharmaceutical industry. There are numerous effective therapeutic agents whose side effect profiles have been documented over long-term use in clinical settings that are potential candidates for repurposing. In fact, approximately two-thirds of new drug applications submitted to the FDA are for modifications of existing drugs or their indications.

	Classic life-cycle management of a branded drug often includes extending the value and life of the drug by innovative strategies such as reformulation, finding new indications, or rediscovering the inherent value of an old drug—all of which are intended to provide added benefit to patients.

	Many drugs may benefit from new and innovative technologies that improve drug delivery systems, such as chewable tablets, oral liquids, or conversion of intravenous to noninjectable forms of delivery. For example, a different route of administration, such as conversion from oral to transdermal, may lower the dose required, permit a new indication, or reduce toxicity. Conversion to extendedrelease technology decreases dosing frequency, which may increase adherence and decrease side effects by altering intestinal absorption.

	New applications or indications for drugs can be discovered systematically by means of sophisticated computer programs or serendipitously by noting unexpected, but beneficial, side effects of treatment. In some cases, targets of a known drug that are clinically relevant in one biologic pathway or disease may be relevant in other pathways or diseases as well. It is also possible to take advantage of drugs that interact with multiple targets by developing a new indication where a secondary target is more relevant.

 A partial list of repurposed drugs is shown in the Table.

	Older drugs that have been overshadowed by advances in new drug development technologies, such as rational structurebased drug design and high-throughput screening (drug discovery experimentation that uses automated systems), may be revitalized when newer drugs either do not live up to their therapeutic potential or elicit an increased risk-to-benefit ratio over time.

	For industry, repurposing or repositioning of already-approved drugs is a lower-risk strategy that can reduce the cost and accelerate the time needed to bring the drug to market. Pharmacologic and safety profiles have been established; smaller, more rapid clinical trials may be carried out; and the manufacturing process may require only minimal modification.

Furthermore, for drugs that may be nearing expiry, the Hatch—Waxman Act offers additional protection by granting 3-year market exclusivity rights to the new version of the drug.

	Although there are many diseases and conditions that have benefited from repurposed drugs, the management of hypertension in the primary care setting and supportive care in the oncology setting represent therapeutic areas in which there are significant unmet patient needs that repurposed drugs have the potential to address.

Management of Hypertension and Chronic Heart Failure 

	The prevalence of hypertension in the United States has essentially remained unchanged since 1999, varying from 28% to 30% of the adult population. An additional 28% have prehypertension (systolic blood pressure [BP] of 120-139 mm Hg or diastolic BP of 80-89 mm Hg).

	Despite the fact that high BP is a modifiable risk factor for cardiovascular disease (CVD), only 68% of adults with hypertension are treated with antihypertensives, and, of those, only 64% are treated successfully, indicating that appropriate management of hypertension is a significant ongoing medical need.

 Numerous drugs representing several classes of antihypertensive agents are currently available. These drugs must be used in combination therapy to control BP in the majority of patients.

	The antihypertensive drug classes include:

	• Diuretics (thiazide, loop, potassium-sparing)

	• Beta-blockers (with/without intrinsic sympathomimetic activity)

	• Angiotensin-converting enzyme (ACE) inhibitors

	• Calcium channel blockers (nondihydropyridines, dihydropyridines)

 -agonists and other centrally acting drugs

	Currently, the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recommends thiazide diuretics as the preferred initial agent for treating uncomplicated hypertension. Results from ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial), among others, have consistently shown that thiazide diuretics are unsurpassed in reducing the risk of CVD and renal complications.

 However, despite their efficacy, tolerability, and modest cost, they remain underutilized.

	Spironolactone (Aldactone), a potassium-sparing diuretic that acts as an aldosterone receptor antagonist, is an example of an old drug that has seen a recent resurgence of interest.

 With the introduction of ACE inhibitors—which decrease urinary excretion of potassium by blocking angiotensin II—mediated production of aldosterone&mdash;the use of spironolactone fell out of favor after a spike in patients with serious hyperkalemia was observed when ACE inhibitors and spironolactone were used concomitantly.

 However, spironolactone usage increased following publication of RALES (Randomized Aldactone Evaluation Study), which demonstrated a 30% lower risk of morbidity and mortality in patients with severe heart failure and systolic left ventricular dysfunction who had received low-dose spironolactone.

 LowTable partial list of repurpose drugs spironolactone has also been shown to be effective in the treatment of resistant hypertension.

	Nonselective beta-blockers are an example of the rediscovery of an older class of drugs. The first beta-blocker, propranolol (Inderal), was characterized by J.W. Black, MD, in the mid-1960s.

-adrenergic receptors, was overshadowed by the morespecific second-generation beta

 -adrenergic receptor blockers, such as metoprolol and atenolol.

Carvedilol (Coreg), a third-generation beta-blocker, nonselectively blocks both beta

-adrenergic receptors as well as the alpha

-adrenergic receptor, which increases peripheral vasodilation and renal sodium excretion.

In the COMET (Carvedilol or Metoprolol European Trial) study, carvedilol significantly improved both survival and vascular outcomes, including stroke, myocardial infarction, and unstable angina compared with metoprolol.

	Minoxidil is an example of an old drug repurposed with a new indication and reformulation. Minoxidil (Loniten), a powerful peripheral vasodilator, is used in combination with other antihypertensives to treat severe or refractory high BP. In early studies, sodium retention and hirsutism were noted as significant side effects of minoxidil therapy.

 In the late 1980s, a topical preparation of minoxidil (Rogaine) was cleared by the FDA for male pattern baldness and androgenic alopecia; in the mid-1990s, 5% and 2% topical solutions of minoxidil were approved as OTC products.

Reformulation to a 5% topical foam-based vehicle was assessed in a randomized, blinded clinical study that demonstrated significant improvement in hair counts and subjective assessment of hair loss condition and good tolerability compared with placebo. Thus, the foam formulation was found to be comparable to the solution with respect to performance and had the added benefit of enhanced cosmetic acceptability.

	Patients with cancer may experience numerous treatment- and cancer-related complications that can have a substantial impact on quality of life. Two of the most-feared complications are chemotherapy-induced nausea and vomiting (CINV) and cancerrelated pain. Although pharmacologic interventions are available for both CINV and pain, response is still often inadequate.

 Cannabis was first used medicinally by the Chinese approximately 5000 years ago. Around 1000 BC, cannabis was widely used in India for both its numerous therapeutic and psychoactive properties, for which it was often incorporated into religious rituals.

 In Western medicine, cannabis was commercialized during the late 19th and early 20th centuries and was removed from the US Pharmacopeia in 1941 only following passage of the Marijuana Tax Act.

	The discovery and characterization of the human endocannabinoid system and its receptors, CB1 and CB2 , in the early 1990s led to renewed interest in the medical benefits of cannabis derivatives.

The CB1 receptor, which is expressed in both central and peripheral neuronal tissue, is particularly abundant in the brain; CB1 receptors are also present to a lesser extent in many organs.

Thus, the synthetic cannabinoid agonists of CB1 receptors are examples of drugs whose target is expressed in several biologic pathways that can be used in more than 1 clinical context. Currently, cannabinoids are indicated in the United States for CINV (nabilone [Cesamet], dronabinol [Marinol]) and appetite stimulation (dronabinol) and in Canada for neuropathic pain secondary to multiple sclerosis (cannabidiol [Sativex]).

 The expected side effect profile of cannabinoids (eg, dizziness, euphoria, drowsiness) has also been well characterized.

 approximately 70% to 80% of all patients with cancer undergoing chemotherapy will experience CINV.

It has been further estimated that approximately 30% to 50% of patients with cancer will continue to experience CINV despite the use of appropriate standard antiemetic therapy.

	The use of cannabinoids such as nabilone for CINV is being rediscovered after being sidelined by newer, more effective agents such as the selective 5-HT 3 receptor antagonists (eg, ondansetron [Zofran] and palonosetron [Aloxi]) and the neurokinin-1 receptor antagonist aprepitant [Emend].

The current National Comprehensive Cancer Network Clinical Practice Guidelines for Antiemesis include cannabinoids in their recommendations for breakthrough or refractory CINV in patients with inadequate response to standard therapies.

 Patients with chronic cancer- or non—cancer-related pain are frequently treated with opioids to obtain relief. Synthetic methadone, first developed during World War II as an alternative opioid analgesic to morphine, has recently undergone a renaissance because of a better understanding of both its unique pharmacologic properties and the challenges associated with its management, as well as its relatively low cost.

 As clinicians are now taking a more enlightened approach to pain management, the usage of methadone has increased dramatically over the past decade.

	Once used almost exclusively in detoxification and maintenance programs for narcotic addiction, 45 methadone has recently been shown to be highly effective in opioid rotation schedules in the palliative care setting.

The potent efficacy of methadone can be attributed to at least 3 different mechanisms of action: mu-opioid receptor agonism (levo-isomer), N-methyl-Daspartate antagonism (dextro-isomer), and monoamine reuptake inhibition.

The variable pharmacokinetics and difficulty in establishing equianalgesic ratios when converting from another opioid present challenges to the use of methadone; however, these concerns have been addressed procedurally in guidelines and recommendations.

 Fentanyl, which was first synthesized in 1960, has more than 100 times the potency of morphine and was initially developed as an anesthetic.

 Fentanyl is a rapid-onset, short-acting, lipophilic opioid with selective activity for mu-receptors expressed primarily in the brain and spinal cord, but also in the gastrointestinal tract.

	Breakthrough pain, defined as a sudden and often intense exacerbation of pain that occurs against a background of otherwise controlled persistent pain, is a challenging aspect of cancer pain that occurs in approximately 65% of patients with persistent pain.

 Breakthrough pain is usually treated with oral short-acting opioids that are often ineffective because of delayed pain relief resulting from variable absorption, limited bioavailability due to first-pass metabolism, or patient symptoms such as dysphagia or nausea and vomiting.

	Reformulations of fentanyl such as those using transdermal (Duragesic) and transmucosal (Actiq [stick lozenge], Fentora [effervescent tablets]) modes of administration have improved drug delivery; fentanyl buccal soluble film [Onsolis] is a transmucosal delivery system that uses a small soluble adhesive polymer film applied to the buccal membrane to deliver fentanyl. This new technology delivers fentanyl faster and at higher plasma concentrations than does the lozenge with less patient effort

 and provides significant breakthrough pain relief at 30 minutes compared with placebo. In clinical trials, Onsolis was well-tolerated in the oral cavity, and there were no unexpected adverse events.

Hydromorphone is an example of a short-acting potent opioid that requires frequent dosing (4- to 6-hour intervals) to achieve around-the-clock control of pain. Although extended-release formulations for opioids, which provide sustained drug delivery with either daily or twice-daily dosing, have been available for many years, a 24-hour extended-release hydromorphone product (Palladone) was withdrawn from the market in 2005 for potentially fatal reactions when taken with alcohol.

In March 2010, a new extended-release formulation of hydromorphone (Exalgo) that uses an innovative and patented osmotic controlled-release oral delivery system (OROS Push-Pull) technology became available. With this technology, more uniform drug effects and better bioavailability have been reported, and the likelihood of alcohol-induced “dose-dumping” appears to be reduced.

Counseling Patients About Prescriptions for Older Drugs 

Articles

Old Drugs Are New Again 

Fibromyalgia (FM) is a multisymptom condition characterized by chronic widespread pain, functional disability, physical deconditioning, and a variety of other symptoms. FM has emerged as a major diagnostic source of prescriptions for analgesics, muscle relaxants, reuptake inhibitors, and other medications. Standards for diagnosis and treatment remain controversial in the medical community. Increasing evidence supports FM as a specific physical condition with demonstrated chemical abnormalities and physiologic processes that differ from other illnesses and those in healthy control subjects. Recent laboratory, positron emission tomography, voxel-based morphometry, and functional magnetic resonance imaging (fMRI) research has supported the legitimacy of FM as a genuine, distinct disorder. Nevertheless, that legitimacy is still not universally accepted, perhaps in part because FM cannot be diagnosed with a simple laboratory test.

FM is more prevalent than some pharmacists and physicians are aware. In the United States, approximately 2% to 4% of the population suffers from FM, and up to 73% of patients are undiagnosed. Controversy in the medical community about the definition and diagnosis of FM, along with societal stigma attached to psychophysical symptoms, make FM an especially harsh condition for those who suffer from it. Patients may meet the criteria for FM without receiving an accurate diagnosis for years. The frustrating lack of diagnosis and physician skepticism can cause greater distress. It is not surprising that many patients are confused about their condition, or that medication adherence is generally poor.

Community pharmacists can play an important role in helping to identify patients with FM and assisting clinicians with rational treatment plans that incorporate the most effective treatments for the individual patient while minimizing adverse effects and avoiding drug—drug interactions. Education and counseling from pharmacists can help patients understand FM, gain control over the stressors that cause flareups, and more successfully manage symptoms. Importantly, through patient counseling, pharmacists can promote medication adherence and thus enable better treatment outcomes.

This monograph will explore the symptoms and diagnosis of FM; epidemiology, burden, and pathophysiology; and pharmacologic and nonpharmacologic treatment options. In addition, it will provide a comprehensive description of milnacipran HCl, including its clinical pharmacology, clinical efficacy, dosing, and safety information. Lastly, it will offer practical information on the role of the pharmacist in the care of patients with FM.

This supplement was supported by Forest Pharmaceuticals, Inc.