Conflicting recommendations on when to screen for breast cancer are problematic for healthcare providers. The recent recommendation by the US Preventive Services Task Force (USPSTF) against routine screening mammography for women 40-49 years old conflicts with recommendations made by other organizations such as the American Cancer Society and earlier recommendations made by the USPSTF in 2002.

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Three rapid-acting insulin analogs are currently available: insulin lispro, insulin aspart and insulin glulisine. 1-3 All three are approved for use in both type 1 and type 2 diabetes, either by subcutaneous injection, insulin pump or intravenous administration. All three cost more than regular insulin.

Harvesting of autogenous bone, most commonly from the iliac crest, for use as the interbody graft in spinal fusion procedures has been standard practice, but is associated with a high rate of morbidity, including graft site pain, infection, fracture, bleeding and damage to the femoral nerve. Use of recombinant human bone morphogenetic protein (rhBMP-2; Infuse Bone Graft - Medtronic) was first approved by the FDA in 2002 for single-level anterior lumbar spinal fusion in adults with degenerative disc disease who had not responded to at least 6 months of nonoperative treatment. Now it has also been approved for treatment of open tibial fractures and for use in oral and maxillofacial bone grafting procedures.

Healthcare providers are often asked if patients can use drugs after their expiration date. Pharmaceutical companies, because of legal restrictions and liability concerns, will not sanction such use and might not even comment on the safety or effectiveness of using their products beyond the date on the label. Since the last Medical Letter publication on this subject, more data have become available.

The FDA has approved the fluoroquinolone besifloxacin 0.6% ophthalmic suspension (Besivance - Bausch & Lomb) for treatment of bacterial conjunctivitis caused by susceptible bacteria. According to the manufacturer, this product was developed specifically for ophthalmic use in a specialized vehicle designed to prolong contact time on the ocular surface. Besifloxacin is not available for systemic use.

Recent news articles about mercury in fish may lead some patients to seek more information from their healthcare providers. For most Americans, seafood is the major source of exposure to mercury. The mercury in seafood is in the form of methylmercury, a potential neurotoxin formed by the organification of elemental mercury by marine microorganisms like plankton, which are then consumed by aquatic animals and concentrated up the food chain.

Until the recent introduction of febuxostat (Uloric), no new drugs had been marketed for treatment of gout in the past 40 years. Colchicine, which has been available for decades as an unapproved drug, has now been approved by the FDA (Colcrys) for treatment and prophylaxis of gout flares. It was approved earlier only in combination with probenecid (Colbenemid, and others). The goals of gout treatment are three-fold: treating acute disease, preventing flares and reducing uric acid stores.

The FDA has approved the use of aliskiren (Tekturna), a direct renin inhibitor, with valsartan (Diovan), an angiotensin-receptor blocker (ARB), in a fixed-dose combination as Valturna (Novartis) for treatment of hypertension in patients already taking both drugs or not adequately controlled on monotherapy, and as initial therapy in those likely to need multiple drugs to control their blood pressure.

The FDA has approved the marketing of tolvaptan (Samsca - Otsuka), an oral vasopressin receptor antagonist, for treatment of hypervolemic or euvolemic hyponatremia due to congestive heart failure (CHF), cirrhosis or the syndrome of inappropriate antidiuretic hormone secretion (SIADH). A similar drug, conivaptan (Vaprisol) is already available for intravenous (IV) treatment of euvolemic hyponatremia in hospitalized patients. Tolvaptan was approved by the FDA for both inpatient and outpatient use, but it should be started in a hospital.

Currently circulating influenza virus is almost universally pandemic 2009 influenza A H1N1, but seasonal influenza strains could also appear soon. Antiviral drugs are an important adjunct to influenza vaccination for treatment and chemoprophylaxis of both pandemic and seasonal influenza. They may, however, interfere with the efficacy of FluMist, the live-attenuated intranasal vaccine, if they are administered within 48 hours before or <2 weeks after FluMist administration. Inactivated vaccines are not affected by antiviral drug therapy.

Saxagliptin (Onglyza - Bristol-Myers Squibb), the second oral dipeptidyl peptidase-4 (DPP-4) inhibitor to be marketed in the US, has been approved by the FDA for treatment of adults with type 2 diabetes.

The FDA has approved use of tadalafil (Adcirca - Lilly/United Therapeutics) for treatment of pulmonary arterial hypertension (PAH).

Paliperidone palmitate (Invega Sustenna – Ortho-McNeil Janssen) has been approved by the FDA as a once-monthly injection for acute and maintenance treatment of schizophrenia in adults. An extended-release oral formulation (Invega) has been available since 2006.1 Long-acting injections of antipsychotic drugs typically are used to treat patients who cannot adhere to an oral regimen.2,3 Paliperidone is the primary active metabolite of risperidone (Risperdal), which is also available as a long-acting (every 2 weeks) injection. It is unclear whether either risperidone or paliperidone is a better choice for long-term treatment of schizophrenia than a first-generation drug such as haloperidol, which can also be injected once a month and costs much less.4

1. Paliperidone (Invega) for schizophrenia. Med Lett Drugs Ther 2007; 49:21.
2. JC West et al. Use of depot antipsychotic medications for medication non-adherence in schizophrenia. Schizophr Bull 2008; 34:995.
3. D Hough et al. Safety and tolerability of deltoid and gluteal injections of paliperidone palmitate in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33:1022.
4. Drugs for psychiatric disorders. Treat Guidel Med Lett 2006; 4:35.

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In 2007, Merck voluntarily recalled some lots of PedvaxHIB and Comvax, two Haemophilus influenzae type b (Hib) vaccines, and temporarily stopped their production because of possible contamination, resulting in a shortage during which pediatricians were urged to defer giving Hib booster doses (normally given at 12-15 months) to healthy children. Now the FDA has granted accelerated licensure of Hiberix (GlaxoSmithKline), a monovalent vaccine conjugated with tetanus toxoid that has been used in Europe since 1996, as a booster (final) dose of the Hib series in children 15 months-4 years old. Hiberix can also be given to children 12-15 months old as a scheduled booster dose.1

1. Licensure of a Haemophilus influenzae type b (Hib) vaccine (Hiberix) and updated recommendations for use of Hib vaccine. MMWR Morb Mortal Wkly Rep 2009; 58:1008.

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The equivalence of generic drugs to their brand-name precursors continues to be controversial. The last Medical Letter review of this subject (2002) concluded that well-documented therapeutic inequivalence between brand-name and FDA-approved generic drugs had not been reported. Is that still true? New data have become available for some drugs.

The FDA has approved degarelix (Firmagon - Ferring), a synthetic decapeptide gonadotropin-releasing hormone (GnRH) receptor antagonist, for rapid medical castration of men with advanced prostate cancer. Abarelix (Plenaxis), the first GnRH antagonist approved by the FDA, was withdrawn from the US market because of immediate hypersensitivity reactions.

The FDA has approved the use of recombinant human antithrombin (rhAT; ATryn - Lundbeck) in patients with inherited antithrombin (AT) deficiency to prevent thrombosis during or after surgery or childbirth. The protein is produced in the milk of transgenic goats carrying a copy of the human cDNA for AT. This is the first US drug approval for a protein produced by a transgenic animal. ATryn has been used in Europe since 2006.

The FDA has licensed 4 new monovalent vaccines for prevention of respiratory illness caused by a new influenza A H1N1 virus that appears to be derived from a swine strain. The 5th vaccine should be licensed soon. All of these vaccines are expected to become available in October. An intranasal formulation is expected in the first week of October.

Dronedarone (Multaq - Sanofi-Aventis) has been approved by the FDA for oral treatment of atrial fibrillation and flutter. Amiodarone (Cordarone, and others) is the most effective drug for this indication, but has considerable toxicity.

Two separate influenza vaccines will be available this season: the usual seasonal trivalent vaccine and a monovalent vaccine (not yet licensed by the FDA) directed at the novel H1N1 virus currently causing pandemic infection. The next issue of the Medical Letter will review the pandemic H1N1 vaccine.

Resveratrol is a phytochemical found in the skin of red grapes and in many other plants, including berries, plums and peanuts. As a constituent of red wine, it has been associated with cardioprotective effects. Dietary supplements containing resveratrol are now being widely promoted as antioxidants that can prevent agerelated diseases.

The FDA has approved artemether-lumefantrine (Coartem - Novartis) for oral treatment of uncomplicated Plasmodium falciparum malaria. It is not approved for prophylaxis. Artemether-lumefantrine is the first artemisinin-based drug approved for use in the US. Artemisinins are Chinese herbal products used worldwide to treat malaria. The intravenous formulation of artesunate, another artemisinin, is available in the US through the CDC.

The FDA has approved prasugrel (Effient - Lilly/Daiichi Sankyo), an oral antiplatelet drug, for use with aspirin to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndromes (ACS) being managed with percutaneous coronary intervention (PCI). It will compete with clopidogrel (Plavix) for such use.

The FDA has approved calcitriol ointment (Vectical - Galderma), a vitamin D analog, for topical treatment of mild-to-moderate plaque psoriasis in adults ≥18 years old. Ointments are generally considered more potent than creams or solutions.

Red yeast rice is a food product that has been used in Chinese cooking and medicine for centuries. It is available in the US in a capsule formulation and is often used by patients who want a "natural" product to lower cholesterol.

Some readers have asked why the June 2009 issue of Treatment Guidelines (Antimicrobial Prophylaxis for Surgery) did not recommend use of ertapenem (Invanz) for prevention of infection after elective colorectal surgery. Ertapenem is a broad-spectrum carbapenem that has been approved for such use by the FDA. Medical Letter consultants do not recommend use of broad-spectrum drugs such as ertapenem, third-generation cephalosporins such as cefotaxime (Claforan), ceftriaxone (Rocephin), cefoperazone (Cefobid), ceftazidime (Fortaz, and others) or ceftizoxime (Cefizox), or fourth-generation cephalosporins such as cefepime (Maxipime) for routine surgical prophylaxis because they are expensive, some are less active than first- or second-generation cephalosporins against staphylococci, and their spectrum of activity includes organisms rarely encountered in elective surgery. These drugs should be reserved for treatment of serious infections, particularly those likely to be caused by organisms resistant to other antimicrobials.

The most effective drugs available for treatment of tobacco dependence are bupropion (Zyban, and others and varenicline (Chantix). The FDA recently ordered the manufacturers of both to add boxed warnings about the risk of psychiatric symptoms and suicide to their prescribing information (FDA Alert, 7/1/2009).

The FDA has approved a new Japanese encephalitis vaccine (Ixiaro - Intercell/Novartis). It will replace JEVax (Sanofi Pasteur), which has had tolerability and safety problems and is no longer being manufactured.

Several large European observational studies published on-line this summer have raised questions about whether use of insulin glargine increases the risk of cancer.

The FDA has approved tapentadol hydrochloride (Nucynta - Ortho-McNeil Janssen) for oral treatment of moderate to severe acute pain in patients ≥18 years old. It has been classified as a Schedule II controlled substance

Readers have asked us to update our 2004 article on tablet splitting. Breaking drug tablets in half is a common practice, but the FDA recently advised consumers against it (FDA Consumer Health Information, July 2009).

Transdermal fentanyl (Duragesic, and others) offers a convenient delivery system for patients with chronic pain1 but it has some drawbacks. One is that exposing the patch to heat, either from an external source, increased exertion or possibly high fever, could increase release of the drug, which might lead to an overdose and fatal respiratory depression.2 A recent article in the NY Times about this problem may have aroused the concerns of some patients using the patches.3

First approved for marketing by the FDA in 19914, transdermal fentanyl provides continuous delivery of the drug for about 3 days. After application of the patch, a depot of fentanyl forms in the upper layers of the skin. Serum concentrations of the drug increase gradually, reaching a peak (Cmax) in 24-72 hours. According to a pharmacokinetic model mentioned in the labeling, an increase in body temperature to 40°C (104°F) could increase fentanyl serum concentrations by 33%. Local application of heat near or on a fentanyl transdermal patch also increases systemic absorption; in one study, heating the patch during the first 4 hours after application increased maximum serum concentrations nearly three-fold.5 Unintentional increases in systemic fentanyl absorption caused by a heating pad, a warming blanket used during surgery and strenuous exertion have led to respiratory depression in 3 patients.6 No reports of clinical overdosage caused by fever have been published.

Serious adverse events may require removal of the patch and administration of an opioid antagonist such as naloxone (Narcan, and others). Monitoring for hypoventilation or cognitive impairment for at least 24 hours is recommended after removing the patch because fentanyl concentrations decrease slowly (50% decrease in about 17 hours) due to continued systemic absorption from the intracutaneous reservoir.

1. Drugs for pain. Treat Guidel Med Lett 2007; 5:23.
2. FDA Alert 7/15/2005; Update 12/21/2007. Information for healthcare professionals: Fentanyl transdermal system (marketed as Duragesic and generics). Available at www.fda.gov/cder/drug/InfoSheets/HCP/fentanyl_2007HCP.htm. Accessed July 27, 2009.
3. T Brown. Doctors and nurses, still learning. New York Times, April 29, 2009. Available at NYTimes.com. Accessed July 29, 2009.
4. Transdermal fentanyl. Med Lett Drugs Ther 1992; 34:97.
5. MA Ashburn et al. The pharmacokinetics of transdermal fentanyl delivered with and without controlled heat. J Pain 2003; 4:291.
6. KA Carter. Heat-associated increase in transdermal fentanyl absorption. Am J Health Syst Pharm 2003; 60:191.

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The thionamides propylthiouracil and methimazole are both used to treat hyperthyroidism.1 Propylthiouracil causes severe hepatic toxicity or hepatic failure in about 0.1% of adults and children.2,3 It is the third leading cause of liver transplants due to drug toxicity (acetaminophen and isoniazid are the first two). Methimazole may cause less serious hepatic toxicity; reversible cholestatic jaundice has been reported. There is generally no good reason to continue to use propylthiouracil, with 2 possible exceptions. First, propylthiouracil may be preferred for treatment of life-threatening thyroid storm because it inhibits conversion of T4 to T3, while methimazole does not. Second, propylthiouracil may be preferable for use in pregnancy because use of methimazole has rarely been associated with aplasia cutis and with choanal and esophageal atresia.

1. Drugs for thyroid disorders. Treat Guidel Med Lett 2009; 7:57.
2. SA Rivkees and DR Mattison. Ending propylthiouracil-induced liver failure in children. N Engl J Med 2009; 360:1574.
3. DS Cooper and SA Rivkees. Putting propylthiouracil in perspective. J Clin Endocrinol Metab 2009; 94:1881.

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The FDA has approved benzyl alcohol lotion, 5% (Ulesfia Lotion - Sciele) for treatment of head lice in patients ≥6 months old. The active ingredient is 5% benzyl alcohol; the vehicle is 5% mineral oil.

The National Cholesterol Education Program recommends that LDL-C be lowered to less than 100 mg/dL (2.6 mmol/L) and considers a value <70 mg/dL (1.8 mmol/L) a reasonable goal for patients at very high risk.

Concerns have surfaced again at the FDA and in the media about the safety of acetaminophen and the multiplicity of products on the market in the US that contain various amounts of it.

Golimumab (Simponi - Centocor), a fully humanized anti-tumor necrosis factor (TNF)-a antibody, has been approved by the FDA for the treatment of: (1) moderate to severe active rheumatoid arthritis (RA) in combination with methotrexate; (2) active psoriatic arthritis (PsA) alone or in combination with methotrexate; and (3) active ankylosing spondylitis (AS).

The FDA, which had previously approved intravenous (IV) administration of 5 mg of zoledronic acid (Reclast – Novartis) once a year for treatment of postmenopausal osteoporosis (Med Lett Drugs Ther 2007; 49:89), has now approved the same dose for use once every 2 years to prevent osteoporosis in postmenopausal women with osteopenia.

Clinical Studies – In an unpublished study summarized in the package insert, 224 women with osteopenia ≤5 years after menopause were given an IV infusion of zoledronic acid 5 mg or placebo; 2 years later, total hip bone mineral density (BMD) had increased by 2.6% with the drug and decreased by 2.1% with placebo. Among 357 osteopenic women >5 years after menopause, hip BMD 2 years after one IV dose of zoledronic acid increased by 2.1% and decreased by 1.0% with placebo. Both of these differences from placebo were statistically significant. Similarly significant increases occurred in vertebral BMD. No data are available on the incidence of hip or vertebral fractures in these women, but zoledronic acid once a year for treatment of osteoporosis has been shown to decrease the incidence of such fractures.

Adverse Effects — An acute-phase reaction including fever, flu-like symptoms, headache, arthralgia and myalgia can occur with IV administration of zoledronic acid; symptoms usually subside within a few days. Renal damage can occur after a single dose, especially with concomitant use of other nephrotoxic drugs, including nonsteroidal anti-inflammatory drugs (NSAIDs). Jaw osteonecrosis has occurred rarely. Whether long-term use of bisphosphonates, which interfere with bone remodeling, could increase the incidence of long-bone fractures remains to be established. None of these events, except for acutephase reactions, occurred during the clinical trial, according to the manufacturer.

Cost – The cost of one 5-mg injection of Reclast is about $1200 for the drug alone.

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Axona (Accera), a "medical food" containing a proprietary formulation of medium-chain triglycerides (>95% caprylic triglyceride), is currently being marketed for the "clinical dietary management of the metabolic processes associated with mild to moderate Alzheimer's disease."

The FDA has approved lacosamide (Vimpat - UCB Pharma) for oral or intravenous (IV) use as add-on therapy in adults with partial-onset seizures.

Use of a selective serotonin reuptake inhibitor (SSRI) is common in women taking tamoxifen (Nolvadex, and others) for breast cancer, both to treat depression and to decrease hot flashes. However, tamoxifen must be metabolized by CYP2D6 to become pharmacologically fully active (MJ Higgins et al. J Natl Compr Canc Netw 2009; 7:203), and the SSRIs fluoxetine (Prozac, and others) and paroxetine (Paxil, and others) are strong inhibitors of CYP2D6. Sertraline (Zoloft, and others) inhibits CYP2D6 to a lesser extent. Citalopram (Celexa, and others) and escitalopram (Lexapro), the 2 other SSRIs approved for treatment of depression, are only weak inhibitors of CYP2D6.

Two observational studies presented at a recent meeting of the American Society of Clinical Oncology (45th annual meeting, May 29-June 2, 2009, Orlando, FL abstracts CRA508, CRA509) examined the effect of strong inhibitors of CYP2D6 on the success rate of tamoxifen in preventing recurrence of breast cancer. One found that women who took fluoxetine, paroxetine or sertraline (or bupropion, duloxetine, terbinafine, quinidine or long-term diphenhydramine) with tamoxifen had a higher 2-year recurrence rate (13.9% vs. 7.5%). The other study found no association between cancer recurrence and use of a CYP2D6 inhibitor.

There is no good evidence that any one SSRI is more effective than any other for treatment of depression. For women who are taking tamoxifen and need to begin treatment with an SSRI to treat depression, citalopram or escitalopram might be the safest choice (Treat Guidel Med Lett 2006; 4:35). Use of an SSRI to treat hot flashes in women taking tamoxifen should probably be reconsidered.

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Milnacipran (Savella - Forest), an oral selective serotonin and norepinephrine reuptake inhibitor (SNRI), is the third drug approved by the FDA for management of fibromyalgia. The 2 others are pregabalin, a gammaaminobutyric acid (GABA) analog also approved for treatment of diabetic neuropathy, post-herpetic neuralgia and epilepsy, and duloxetine, an SNRI also approved for treatment of depression, diabetic neuropathy and generalized anxiety disorder.

Most patients with hypertension require more than one drug to control their blood pressure. Exforge HCT (Novartis) is a new 3-drug fixed-dose combination tablet approved by the FDA for treatment of hypertension. It combines the calcium-channel blocker amlodipine (Norvasc, and others) and the angiotensin receptor blocker (ARB) valsartan (Diovan), which are already available in a combination tablet (Exforge), with the most commonly prescribed diuretic hydrochlorothiazide (HCTZ). Exforge HCT is not approved for initial treatment of hypertension, but rather for patients not adequately controlled on a 2-drug combination of a calcium-channel blocker, an ARB or a diuretic. It can also be substituted for amlodipine, valsartan and HCTZ in patients already taking all 3 of these drugs.

A 23-valent polysaccharide vaccine (PPSV23; Pneumovax 23 - Merck) is the only pneumococcal vaccine approved for use in adults. It has reduced the risk of invasive pneumococcal disease (meningitis or bacteremic pneumonia), but not mortality, in immunocompetent older adults.2 PPSV23 has not been shown to reduce the risk of invasive pneumococcal disease (IPD) in immunocompromised patients.

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Atrial fibrillation increases the risk of stroke by a factor of 5. A randomized controlled trial (ACTIVE W) in 6706 patients with atrial fibrillation and one or more additional risk factors (≥75 years old; hypertension; previous stroke, transient ischemic attack or non- CNS embolus; left ventricular ejection fraction <45%; peripheral vascular disease; or 55-74 years old plus diabetes or coronary artery disease) found that a vitamin K antagonist such as warfarin (Coumadin, and others) was superior to clopidogrel (Plavix) plus aspirin in preventing vascular events, especially ischemic stroke.1

Now another study (ACTIVE A) from the same group of investigators has compared addition of clopidogrel to aspirin with aspirin alone in 7554 patients with atrial fibrillation and one or more additional risk factors for stroke. All of these patients were considered “unsuitable” for treatment with a vitamin K antagonist. Vascular events, primarily stroke, occurred significantly more often with aspirin alone. Major bleeding occurred significantly more often with aspirin plus clopidogrel.2

Oral anticoagulation with a vitamin K antagonist such as warfarin continues to be the treatment of choice for patients with atrial fibrillation and one or more additional risk factors for stroke.3-5 In patients who cannot or will not take a vitamin K antagonist, clopidogrel plus aspirin appears to be more effective in preventing stroke than aspirin alone.

1. ACTIVE Writing Group of the ACTIVE Investigators. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 2006; 367:1903.

2. ACTIVE Investigators. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med 2009; 360:2066.

3. Antiplatelet and anticoagulant drugs. Treat Guidel Med Lett 2008; 6:29.

4. DE Singer et al. Antithrombotic therapy in atrial fibrillation: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133 (6 suppl): 546S.

5. AS Go. The ACTIVE pursuit of stroke prevention in patients with atrial fibrillation. N Engl J Med 2009; 360:2127.

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A new fixed-dose tablet (PrandiMet - Novo Nordisk) combining metformin (Glucophage, and others) and repaglinide (Prandin) has been approved by the FDA for treatment of type 2 diabetes in patients already taking both metformin and repaglinide, or for patients not adequately controlled on either drug alone.

The FDA has approved the prostaglandin analog bimatoprost in a 0.03% solution (Latisse - Allergan) for increasing eyelash length, thickness and darkness in patients with hypotrichosis of the eyelashes.

Apriso (Salix) is a new formulation of mesalamine (5-aminosalicylic acid; 5-ASA) approved by the FDA for maintenance of remission in mild to moderate ulcerative colitis (UC). Mesalamine is a locally acting antiinflammatory agent that is widely used both to maintain and induce remission in inflammatory bowel disease. Various mesalamine formulations have been developed to target drug delivery to areas of the small intestine and colon. Most of these agents require frequent dosing and have a high pill burden. The newest products - Lialda, introduced in 2007,1 and now Apriso - can be dosed once daily.

Web sites and blogs are advising patients that periodic "cleansing" of the colon is necessary to rid the body of toxins.

The FDA has announced that it will lower the age for over-the-counter access to the emergency contraceptive Plan B1 from 18 to 17 years old. In a randomized, controlled trial, the two 0.75-mg levonorgestrel tablets in Plan B, taken 12 hours apart beginning within 72 hours after unprotected intercourse, decreased the overall pregnancy rate to 1.1% (11/976) of women who requested emergency contraception.2 The sooner the drug is taken after coitus, the more effective it is. Nausea and vomiting can occur with Plan B. Fetal malformations have not been associated with pregnancies that occurred despite use of levonorgestrel-only emergency contraception.3

1. Emergency contraception OTC. Med Lett Drugs Ther 2004; 46:10.
2. Task Force on Postovulatory Methods of Fertility Regulation. Randomised controlled trial of levonorgestrel versus the Yuzpe regimen of combined oral contraceptives for emergency contraception. Lancet 1998; 352:428.
3. L Zhang et al. Pregnancy outcome after levonorgestrel-only emergency contraception failure: a prospective cohort study. Hum Reprod 2009 Mar 31 (epub).

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The FDA has approved the marketing of fenofibric acid (Trilipix - Abbott) to reduce triglycerides and increase HDL-C in patients with mixed dyslipidemia on optimal doses of a HMG-CoA reductase inhibitor (statin) who have, or have risk factors for, coronary heart disease. It is the first fibrate approved by the FDA specifically for combined use with a statin. Trilipix is also approved as monotherapy for hypertriglyceridemia, hypercholesterolemia and low HDL-C. The patent for Tricor, Abbott's older formulation of fenofibrate, will expire in 2011.

The FDA has approved the marketing of fesoterodine (Toviaz - Pfizer), a muscarinic receptor antagonist, for treatment of overactive bladder. It is the sixth antimuscarinic drug approved for this indication.

The recent Medical Letter article on vancomycin dosing and monitoring briefly mentioned use of an alternative antibiotic for treatment of methicillin-resistant Staphylococcus aureus (MRSA) with reduced susceptibility to vancomycin. Some readers have asked for more information on this subject.

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A new formulation of the H1-antihistamine azelastine hydrochloride 0.1% nasal spray (Astepro - Meda) has been approved by the FDA for treatment of seasonal allergic rhinitis (SAR) in patients ≥12 years old and is being heavily advertised to the public on radio, television and the Internet. All azelastine products require a prescription.

Epiduo gel (Galderma), a fixed-dose combination of adapalene 0.1% (Differin), a synthetic retinoid analog, and benzoyl peroxide (BPO) 2.5%, an oxidizing agent, has been approved by the FDA for topical treatment of acne vulgaris in patients ≥12 years old.

(Med Lett Drugs Ther 2009; 51:25) In the paragraph on dosing, the second-to-last sentence should have said that the new recommendations suggest considering use of an alternative antibiotic when the MIC for the infecting organism is ≥2 mg/L, not >2 mg/L.

Consensus recommendations for dosing and therapeutic monitoring of intravenous (IV) vancomycin (Vancocin, and others) were recently published. IV vancomycin has been used for decades as an alternative to penicillins for treatment of serious infections due to gram-positive cocci. In recent years, the widest use of the drug has been for treatment of serious methicillin-resistant Staphylococcus aureus (MRSA) infections.

Deep brain stimulation (DBS) is increasingly used to treat advanced Parkinson's disease (PD), but few controlled clinical trials have been published. New evidence from a large controlled study has recently become available.

The FDA has approved a delayed-release capsule formulation of valproic acid (VPA; Stavzor - Noven Therapeutics) for all of the indications for which divalproex sodium (Depakote, and others; Depakote ER) is approved: monotherapy and adjunctive therapy of complex partial seizures and simple and complex absence seizures, and adjunctive therapy in patients with multiple seizure types that include absence seizures; acute treatment of manic episodes associated with bipolar disorder; and prophylaxis of migraine headaches. In addition, valproate (valproic acid or divalproex sodium) is considered a drug of choice for treatment of other types of seizures including generalized tonic-clonic, myotonic and atonic seizures.

The FDA has approved the proton-pump inhibitor (PPI) dexlansoprazole (Kapidex - Takeda), a delayed release formulation of the R-enantiomer of lansoprazole (Prevacid - Takeda), for treating and maintaining healing of erosive esophagitis and for treatment of heartburn associated with non-erosive gastroesophageal reflux disease (GERD).

Short-acting methylphenidate (MPH) is effective for treatment of attention-deficit/hyperactivity disorder (ADHD), but its 3-5 hour duration of action usually requires mid-day dosing in school, which children may find disruptive or stigmatizing.

A recent article in the New England Journal of Medicine confirms something that others, including The Medical Letter (Treat Guidel Med Lett 2008; 6:23), have been saying for years: no particular combination of protein, carbohydrate and fat in the diet offers any advantage in losing weight. This randomized 2-year trial followed 800 overweight and obese subjects on low fat/average protein, low fat/high protein, high fat/average protein, and high fat/high protein diets. Carbohydrate intake varied from 35% (in the high fat/high protein diet) to 65% (in the low fat/average protein diet). All patients were advised to undertake 90 minutes of moderate exercise per week and given a “caloric prescription” to produce a deficit of 750 kcal per day. Most participants lost weight in the first 6 months and regained some thereafter. There was no significant difference in weight loss between different diets and no indication that any particular diet was more pleasant or less painful than any other. Average weight loss at the end of the trial was 4 kg among the remarkably high 80% of subjects who completed the trial, and 9 kg among those who also attended two thirds of the counseling sessions offered to the participants (FM Sacks et al, N Engl J Med 2009; 360:859).

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Alemtuzumab (Campath), a genetically engineered, humanized monoclonal antibody currently approved to treat B-cell chronic lymphocytic leukemia (BCLL) and used off-label for induction therapy in solid organ transplants, is now also being tried off-label for treatment of relapsing multiple sclerosis (MS).

Rufinamide (Banzel - Eisai), a triazole derivative structurally unrelated to other marketed antiepileptic drugs (AEDs), has been approved by the FDA for treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients ≥4 years old.

The FDA has approved an extended-release formulation of amoxicillin (Moxatag – MiddleBrook) for once-daily treatment of pharyngitis or tonsillitis caused by Streptococcus pyogenes in adults and children ≥12 years old. Approval was based on an unpublished study that found once-daily treatment with Moxatag 775 mg for 10 days non-inferior to penicillin V 250 mg four times a day for 10 days in eradication of S. pyogenes.

For decades, the drug of choice for oral treatment of streptococcal pharyngitis in adolescents and adults has been penicillin V 250 mg taken three or four times a day.1 Amoxicillin is equally effective, but penicillin is generally recommended because of its narrower spectrum. In adults, immediate-release amoxicillin is usually dosed 375-500 mg two to three times a day, but giving it in a higher dose (750-1000 mg) once a day appears to be equally effective for treatment of strep throat.2-4

Each Moxatag tablet contains 775 mg of amoxicillin divided into one immediate-release and two delayedrelease components. Compared to a similar dose of immediate-release amoxicillin suspension, absorption of amoxicillin from the new formulation is slower, resulting in a lower peak serum concentration, but the elimination half-life and amoxicillin exposure (AUC) are similar. S. pyogenes is susceptible to these serum concentrations, but they may be too low to treat other types of infections.

A 10-day supply of Moxatag is expected to cost about $100 compared to $4 for a similar course of penicillin V or immediate-release amoxicillin.5 There is no good reason to prescribe Moxatag.

1. A Bisno et al. Practice guidelines for the diagnosis and management of group A streptococcal pharyngitis. Infectious Disease Society of America. Clin Infect Dis 2002; 35:113.
2. P Shvartzman et al. Treatment of streptococcal pharyngitis with amoxycillin once a day. BMJ 1993; 306:1170.
3. HM Feder Jr. et al. Once-daily therapy for streptococcal pharyngitis with amoxicillin. Pediatrics 1999; 103:47.
4. HW Clegg et al. Treatment of streptococcal pharyngitis with once-daily compared with twice-daily amoxicillin: a noninferiority trial. Pediatr Infect Dis J 2006; 25:761.
5. Retail cost at one Walgreens pharmacy. February 27, 2009.

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Current guidelines recommend use of a proton pump inhibitor (PPI) to decrease the risk of gastrointestinal bleeding in patients taking clopidogrel (Plavix) with aspirin. A recent issue of The Medical Letter considered whether omeprazole (Prilosec, and others) or other PPIs could interfere with the antiplatelet effect of clopidogrel. The conclusion was that patients taking both drugs should probably continue to do so until more data became available. Several new publications require reconsideration of that recommendation.

An old conjugated estrogens vaginal cream (Premarin Vaginal Cream - Wyeth) has been newly approved by the FDA specifically for treatment of moderate to severe dyspareunia due to vulvar and vaginal atrophy associated with menopause. Synthetic conjugated estrogens A vaginal cream (Barr) has also been approved for this indication, but has not yet been marketed.

The incidence of oral cancer appears to be increasing, especially in younger patients. Risk factors include use of tobacco and alcohol, and exposure to human papillomavirus. ViziLite Plus (Zila Pharmaceuticals) is a combination device that uses fluorescent light and toluidine blue tissue staining to help dentists identify abnormal changes in the mucous membranes of the oral cavity. Originally developed for detecting abnormal growths on the uterine cervix, in 2001 it received FDA clearance for "identification, evaluation, and monitoring of oral mucosal abnormalities in a patient population at increased risk for oral cancer." The toluidine blue marking system was cleared for inclusion in 2005.

A recently published retrospective cohort study in patients 30-74 years old has led to headlines in the media warning that use of atypical antipsychotic drugs doubles patients’ risk of sudden cardiac death. Typical antipsychotics have long been associated with this risk. In this study, however, the incidence of sudden cardiac death was similar with typical and atypical antipsychotics: about 1 in 340 person-years among the patients who took typical (first generation) antipsychotics such as haloperidol (Haldol, and others) and 1 in 360 personyears among those who took atypical (second-generation) drugs such as olanzapine (Zyprexa), compared to 1 in 700 patient-years among otherwise similar nonusers of antipsychotic drugs. The risk increased with the dose of the drug and also with the age of the patient; the authors state that they did not include patients younger than 30 because sudden cardiac death is very rare in the younger age group.1

Second-generation drugs are less likely than first generation drugs to cause extrapyramidal symptoms, tardive dyskinesia and neuroleptic malignant syndrome, but more likely to cause weight gain and other metabolic abnormalities.2 Aripiprazole (Abilify)3 is least likely to prolong the QT interval, which is one of the mechanisms that could be responsible for the small increase in the absolute risk of sudden death among patients who take antipsychotic drugs.

In a patient with a good indication for its use, the consequences of not taking an antipsychotic drug may be greater than the risks of taking one.

1. WA Ray et al. Atypical antipsychotic drugs and the risk of sudden cardiac death. N Engl J Med 2009; 360:225.
2. Drugs for psychiatric disorders. Treat Guidel Med Lett 2006; 4:35.
3. Second-generation antipsychotics — aripiprazole revisited. Med Lett Drugs Ther 2005; 47:81.

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Effective treatment of hypertension can prevent organ damage and death. The choice of drugs for initial treatment continues to be controversial.

Romiplostim (Nplate - Amgen), a recombinant fusion protein injected subcutaneously, and eltrombopag (Promacta - GlaxoSmithKline), a non-peptide taken orally, have been approved by the FDA for treatment of chronic immune thrombocytopenic purpura (ITP) refractory to corticosteroids, immunoglobulins and/or splenectomy.

The FDA has cleared a new device for treatment of major depressive disorder (MDD) resistant to antidepressant medication. The NeuroStar TMS System (Neuronetics) produces pulsed magnetic fields that can induce electrical currents in the brain. Unlike electroconvulsive therapy (ECT), it does not require anesthesia or induction of seizures. Other similar devices are under development.

Since publication of our recent article on antiviral drugs for influenza, increased levels of resistance to oseltamivir (Tamiflu) have been detected in influenza A H1N1 strains.

Implantable cardioverter defibrillators (ICDs) are widely used in patients at risk for sudden cardiac death (SCD) because these devices have been highly successful in terminating life-threatening ventricular arrhythmias and in increasing survival.

Tetrabenazine (Xenazine - Ovation Pharmaceuticals), an old drug first synthesized 50 years ago for treatment of schizophrenia, was recently approved by the FDA for the treatment of chorea associated with Huntington's disease. It has been available in other countries for decades.

The Medical Letter was founded in 1959 by Arthur Kallet, an engineer, and Dr. Harold Aaron, an internist. In 1932, Kallet had written the book 100,000,000 Guinea Pigs, a best-seller that was partly responsible for the Food and Drug Act of 1938, which required for the first time that new drugs show proof of safety. He was the founding director of Consumers Union and started the publication of Consumer Reports. Dr. Aaron, who became the medical director of Consumer Reports, suggested to Kallet that doctors could use a similar publication to evaluate the new drugs that were coming on the market with no counterweight to the manufacturers' claims. They borrowed $18,000 and started The Medical Letter. Apparently Dr. Aaron was correct in his perception; within 25 years, the new publication had 150,000 subscribers in the US and Canada.

After half a century, The Medical Letter is still supported solely by subscription fees and sales of its other products, which now include foreign editions (in Italian, French, Spanish and Japanese), a second newsletter (Treatment Guidelines), a drug interactions database, handbooks, software, licenses and continuing education materials. We still do not accept grants, gifts or donations. And we continue to refuse opportunities to sell large numbers of reprints to pharmaceutical companies.

Our mission remains to help practitioners offer the best possible care to their patients. For at least another 50 years.

Continued use of a long-acting beta-2 agonist for treatment of asthma may cause down-regulation of the beta-2 receptor with loss of the bronchoprotective effect from rescue therapy with a short-acting beta-2 agonist. After a large study (SMART) found an increased risk of asthma-related deaths in patients receiving the long-acting beta-2 agonist salmeterol, a boxed warning was added to the labeling of all medications containing a long-acting beta-2 agonist. Now the FDA has completed a meta-analysis of 110 asthma treatment studies in 60,954 patients taking any of the long-acting beta-2 agonist formulations listed in the table.

Clopidogrel (Plavix), which prevents arterial thrombosis by inhibiting platelet activation, is commonly prescribed (usually with aspirin) for months after acute coronary syndromes and stent implantation. It may also, however, increase the risk of bleeding. Therefore, a proton pump inhibitor (PPI) such as omeprazole (Prilosec, and others) is often given concurrently to decrease the risk of gastrointestinal (GI) bleeding. Some reports have suggested that omeprazole may interfere with the antiplatelet effect of clopidogrel.

Silodosin (Rapaflo - Watson Pharmaceuticals), an alpha1a-adrenoreceptor selective antagonist, has been approved by the FDA for treatment of benign prostatic hyperplasia (BPH). Some medications for BPH are listed in the table on page 4. Alpha1 blockers are commonly used with 5a-reductase inhibitors such as finasteride, which can shrink the size of the prostate, but may take months to do so.

(Med Lett Drugs Ther 2008; 50:94) In Table 1, "Invasive" should be "less" and "more" rather than "no" and "yes" for CT colonography and colonoscopy, respectively. In the conclusion, CT colonography should be changed to "less invasive" rather than "noninvasive".