The FDA has approved Exforge (Novartis) and Azor (Daiichi Sankyo), the first combinations of a calcium channel blocker (CCB) with an angiotensin receptor blocker (ARB) for treatment of hypertension. Amlodipine is the CCB in both products. The ARBs are valsartan in Exforge and olmesartan in Azor. All 3 of these drugs are available in fixed-dose combinations with other antihypertensive drugs.

An extended-release formulation of the centrally-acting muscle relaxant cyclobenzaprine (Amrix - Cephalon) has been approved by the FDA for treatment of muscle spasms. Immediate-release (IR) cyclobenzaprine (Flexeril, and others) has been available since 1977.

Temsirolimus (Torisel - Wyeth), an mTOR (mammalian target of rapamycin) kinase inhibitor that is metabolized to sirolimus (rapamycin), has been approved by the FDA for intravenous treatment of advanced renal cell carcinoma.

On page 100 of the article "Major Changes in Endocarditis Prophylaxis for Dental, GI and GU Procedures", under the section Highest-Risk Procedures, the word "rubber" should have been omitted. Placement of orthodontic rubber bands is not a highest-risk procedure that justifies prophylaxis; placement of orthodontic (metal) bands is. An orthodontic band is a metal ring that surrounds the tooth and is pressed into place causing movement in closely-spaced teeth and sometimes bleeding when the bands are placed close to the gumline.

Levocetirizine (Xyzal - UCB/Sanofi-aventis), the active enantiomer of the second-generation H₁-antihistamine cetirizine (Zyrtec), has been approved by the FDA for treatment of seasonal and perennial allergic rhinitis (SAR and PAR) and chronic idiopathic urticaria in adults and children 6 years of age and older. Cetirizine has been approved by the FDA for over-the-counter use and may also become available generically in the US. Levocetirizine has been available in Europe since 2001.

The American Heart Association has issued its revised guidelines for prevention of infective endocarditis. Antimicrobial prophylaxis for dental procedures is now recommended only for patients at the highest risk of severe consequences from endocarditis who are undergoing the highest-risk procedures. Endocarditis prophylaxis is no longer recommended for gastrointestinal (GI) and genitourinary (GU) procedures. When these changes are implemented, the number of patients receiving antimicrobial prophylaxis to prevent endocarditis should decline sharply.

The FDA has approved a new formulation of dexrazoxane (Totect) for treatment of extravasation from intravenous (IV) anthracyclines such as doxorubicin (Adriamycin, and others). Dexrazoxane has been available since 1995 as Zinecard for protection against the cardiac toxicity of anthracyclines (Med Lett Drugs Ther 1995; 37:110). It is also available generically. The drug’s precise mechanism of action is not known, but anthracyclines are vesicants that bind to DNA and act as oxidizing agents in the presence of iron. Dexrazoxane is a topoisomerase inhibitor, possibly interfering with anthracycline effects on DNA, and is also a potent iron-chelating agent, preventing free-radical formation. In uncontrolled clinical trials, dexrazoxane appears to have prevented severe necrosis that would require surgical debridement (HT Mouridsen et al. Ann Oncol 2007; 18:546. epub). It is given in a dose of 1000 mg/m² (2000 mg maximum) as an IV infusion over 1-2 hours as soon as possible (no later than 6 hours) after extravasation has occurred and again 24 hours later, and then in a dose of 500 mg/m² (1000 mg maximum) 48 hours after the first dose. The dose should be reduced by half in patients with a creatinine clearance <40 mL/min.

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(Vol. 49, p. 66, August 13, 2007) A reader has pointed out that Saccharomyces boulardii is not a separate species, but a strain of Saccharomyces cerevisiae. S. cerevisiae (including S. boulardii) has been reported to cause systemic infection after oral ingestion in both immunocompromised patients and healthy hosts (MJ McCullough et al. J Clin Microbiol 1998; 36:2613).

Direct-to-consumer advertisements are urging women to be tested for mutations in BRCA1 and BRCA2 genes, which are the most common known causes of an inherited predisposition to breast and ovarian cancer. Clinically important BRCA mutations have been found in about 2% of Ashkenazi Jewish women, and are estimated to occur in about 1 in 300 to 500 women in the general non-Jewish US population. The prevalence appears to be lower in non-whites.

Formoterol fumarate (Perforomist - Dey), a long-acting beta₂-agonist, was recently approved by the FDA as an inhalation solution for nebulization for maintenance treatment of bronchoconstriction associated with chronic obstructive pulmonary disease (COPD). Arformoterol (Brovana), the (R, R)-enantiomer of formoterol, was approved earlier this year for the same indication.

Some recently published studies suggest that taking selective serotonin reuptake inhibitors (SSRIs) may increase the risk of developing osteoporosis. A relationship between SSRIs and osteoporosis is biologically plausible because bone has serotonin receptors, and SSRI-treated mice have reduced bone mass.

When the nicotine receptor partial agonist varenicline (Chantix – Pfizer) was first marketed, The Medical Letter concluded that it was moderately effective in increasing smoking cessation rates.1 More recent publications and the clinical experience of Medical Letter consultants now suggest that varenicline is the most effective drug available for this indication, more effective than nicotine replacement therapy or bupropion SR (Zyban).2,3 A word of caution: exacerbations of psychiatric illness have been reported in patients who took higher-than-recommended starting doses of varenicline.4,5

1. Varenicline (Chantix) for tobacco dependence. Med Lett Drugs Ther 2006; 48:66.
2. P Wu et al. Effectiveness of smoking cessation therapies: a systemic review and meta-analysis. BMC Public Health 2006; 6:300.
3. K Cahill et al. Nicotine receptor partial agonists for smoking cessation. Cochrane Database Syst Rev 2007; (1):CD006103.
4. R Freedman. Exacerbation of schizophrenia by varenicline. Am J Psychiatry 2007; 164:1269.
5. I Kohen and N Kremen. Varenicline-induced manic episode in a patient with bipolar disorder. Am J Psychiatry 2007; 164:1269.

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Zoledronic acid (Reclast - Novartis) is the first bisphosphonate approved by the FDA for once-yearly intravenous (IV) treatment of osteoporosis in postmenopausal women. Reclast is also approved for treatment of Paget's disease. Another IV formulation of zoledronic acid (Zometa) is approved for treatment of hypercalcemia of malignancy, multiple myeloma and bone metastases from solid tumors.

Fluticasone furoate nasal spray (Veramyst - GSK) is now available for once-daily treatment of seasonal and perennial allergic rhinitis in adults and children ≥2 years old. It is similar to fluticasone propionate nasal spray (Flonase, and others), which is now available generically.

Antiviral drugs can be used for treatment of patients with influenza and for prophylaxis of influenza exposures that occur before or less than 2 weeks after vaccination. They can also be used to control institutional influenza outbreaks and for prophylaxis in years when circulating strains differ from those included in the vaccine.

Ambrisentan (Letairis - Gilead), a selective endothelin type A (ET_A) receptor antagonist, has been approved by the FDA for treatment of symptomatic patients (WHO class II or III) with pulmonary arterial hypertension (PAH).

Annual immunization against influenza A and B is the most effective method of preventing infection and has been shown to reduce associated complications.

Quantiferon - TB Gold (Cellestis) is a T-cell interferon-gamma release assay approved by the FDA as an alternative to the tuberculin skin test for diagnosis of infection with Mycobacterium tuberculosis (TB). An earlier assay (Quantiferon-TB), which is no longer commercially available, was approved by the FDA in 2001. Other interferon-gamma release assays (IGRAs) are available abroad.

An article (Med Lett Drugs Ther 2007; 49:41) on sunscreens in the May 21 issue of The Medical Letter included a statement that if sunscreens and the insect repellent DEET are used together, DEET should be applied first to avoid decreasing the effectiveness of the sunscreen. However, a recent in vitro study in human skin found that sunscreen increases absorption of DEET, especially when DEET is applied first (T Wang and X Gu. J Pharm Pharm Sci 2007; 10:17). Whether this practice could cause clinical toxicity is unclear. Some travel experts recommend applying sunscreen first.

The Medical Letter article (Med Lett Drugs Ther 2007; 49:71) on Low-Dose Transdermal Estrogens said that Elestrin has been marketed in Europe since 1976. Actually it is EstroGel (Ascend Therapeutics), a similar product, that has been available in Europe since 1976.

Pregabalin (Lyrica - Pfizer) is the first drug approved by the FDA for management of fibromyalgia. When it was first marketed, pregabalin, which is structurally similar to gabapentin (Neurontin, and others), was approved for treatment of neuropathic pain associated with postherpetic neuralgia and diabetic peripheral neuropathy and for adjunctive treatment of partial onset seizures in adults with epilepsy. It has also been prescribed off-label for other types of neuropathic pain such as sciatica.

The FDA has approved a transmucosal tablet formulation of fentanyl citrate (Fentora - Cephalon) for management of breakthrough pain in opioid-tolerant patients with cancer. An oral transmucosal fentanyl lozenge on a stick (Actiq, and others) is also available for this indication, and is widely used off-label for chronic, non-cancer pain as well.

Eculizumab (Soliris - Alexion) has been approved by the FDA for reduction of hemolysis in patients with paroxysmal nocturnal hemoglobinuria (PNH), a rare form of hemolytic anemia. A recombinant humanized monoclonal antibody, eculizumab is the first drug to be marketed for this indication.

Tinidazole (Tindamax - Mission Pharmacal), an oral antiprotozoal drug available in the US since 2004 for treatment of trichomoniasis, giardiasis, amebiasis and amebic liver abscess, was recently approved by the FDA for treatment of bacterial vaginosis.

Lapatinib (Tykerb - GlaxoSmithKline), an oral inhibitor of both HER-2 and epidermal growth factor receptor type 1 (EGFR-1 or ErbB-1), has been approved by the FDA for use in combination with capecitabine (Xeloda) to treat advanced or metastatic breast cancer that overexpresses HER-2 in patients who have received prior therapy that included an anthracycline, a taxane and trastuzumab (Herceptin), an intravenous monoclonal antibody that also inhibits HER-2.

In the US, over one third of adults under the age of 35 and about one quarter of those aged 18-50 now have at least one tattoo. In later life, some people come to regret their tattoos, but tattoo inks can be difficult and expensive to remove.2 Recently, some new tattoo inks have been designed for improved safety and ease of removal.

Rotigotine (Neupro - Schwarz Pharma), a nonergot dopamine agonist in a transdermal patch formulation, was recently approved by the FDA for treatment of early Parkinson's disease (PD).

Three low-dose transdermal estrogens were recently approved by the FDA for treatment of menopausal vasomotor symptoms. Elestrin and Divigel are transdermal estradiol gels and Evamist is an estradiol spray. Elestrin has been marketed in Europe since 1976.

The New York City Board of Health has recently required that city restaurants reduce the content of industrially produced trans fatty acids so that each serving contains <0.5 g. This initiative is intended to reduce the number of coronary heart disease events in New York City. A more comprehensive approach used in Denmark since 2004 requires by law that fats and oils in all food contain <2% industrially produced trans fatty acids. The FDA requires that labels of packaged food include their trans fatty acid content. This requirement has led food manufacturers to develop brands containing zero or small amounts of trans fat.

Probiotics are live, nonpathogenic microorganisms (usually bacteria or yeasts) that have been used for centuries for their potential health benefits. They are currently marketed for prevention and treatment of a variety of disorders, including diarrhea, irritable bowel syndrome and inflammatory bowel disease.

Lybrel (Wyeth) is the first FDA-approved low-dose combination oral contraceptive taken 365 days a year without a placebo or pill-free interval. All tablets contain low doses of levonorgestrel (0.09 mg) and ethinyl estradiol (20 mcg). Most oral contraceptives are packaged as a 21/7 cycle (21 days of active tablets and 7 days of placebo), resulting in 13 withdrawal bleeding episodes each year. Two formulations are taken for 24 days followed by 4 days of inert tablets (Yaz and Loestrin 24). Two others (Seasonique and Seasonale) have a 91-day cycle with only 4 withdrawal bleeds per year.

Most patients with community-acquired pneumonia (CAP) are treated empirically. New guidelines published jointly by the Infectious Diseases Society of America and the American Thoracic Society have recently become available.

The thiazolidinediones rosiglitazone (Avandia) and pioglitazone (Actos) are peripheral insulin sensitizing agents used to treat hyperglycemia in patients with type 2 diabetes; one or the other is often used as a second or third agent with metformin (Glucophage, and others) and/or a sulfonylurea such as glimepiride (Amaryl, and others). A recent report suggested that rosiglitazone may increase the incidence of myocardial infarction (MI) and cardiovascular mortality.

Lisdexamfetamine dimesylate (Vyvanse - Shire), a prodrug in which d-amphetamine is covalently bonded to L-lysine, has been approved by the FDA for treatment of attention-deficit/hyperactivity disorder (ADHD) in children 6-12 years old. It was designed to have less potential than amphetamine itself for abuse, diversion or overdose toxicity. Like methylphenidate and amphetamines, lisdexamfetamine is a Schedule II controlled substance.

The FDA has received new reports of serious and life-threatening hypersensitivity reactions to omalizumab (Xolair – Genentech), a monoclonal anti-IgE antibody injected subcutaneously for treatment of asthma (Med Lett Drugs Ther 2003; 45:67), and has added a black-box warning to the package insert.

Postmarketing reports submitted to the FDA included 124 reports of anaphylaxis among an estimated 57,300 patients (0.2%) who might have been treated with the drug between June 2003 and December 2006. Anaphylaxis occurred after the first dose of Xolair in 39% of cases, after a 2nd dose in 19%, after a 3rd dose in 10% and after subsequent doses in the rest; one case occurred after 39 doses (19 months of continuous therapy) when treatment was restarted after a 3-month gap. Most cases (59%) occurred within 2 hours of the injection, but 32% occurred later, up to 4 days after the injection. No deaths have been reported (www.fda.gov/cder/drug/infopage/omalizumab).

Use of omalizumab should be limited to patients with severe asthma that is not adequately controlled by other drugs and has a clear allergic component. Patients should be observed for 2 hours after injection in a setting where anaphylaxis can be diagnosed and treated promptly and should carry an epinephrine autoinjector (EpiPen; Twinject) for a few days following an injection.

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Some Medical Letter consultants have suggested that our recent article on dermal fillers (Med Lett Drugs Ther 2007; 49:39) should have included stronger warnings about the risk of fillers that are not biodegradable, such as Artefill. The polymethylmethacrylate (PMMA, the same material that makes up Plexiglas) beads in Artefill can over time, even with the best technique, cause foreignbody granulomas and hypertrophic scarring, which may require surgical removal. Granulomas and nodules have been especially frequent when Artefill was injected into the lips. Complications are less likely with hyaluronic acid products such as Hylaform, Juvéderm or Restylane.

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Arformoterol tartrate (Brovana - Sepracor), a singleisomer, long-acting beta₂-agonist, has been approved by the FDA as an inhalation solution for nebulization for treatment of bronchoconstriction pulmonary disease (COPD). Arformoterol is the (R,R)-enantiomer of formoterol (Foradil), which is available as a powder for inhalation and was recently also approved as a solution for nebulization (Perforomist - Dey; available fall 2007)

The FDA has approved the marketing of Resperate (InterCure), a device that helps patients breathe slowly, as an adjunct for treatment of hypertension. The FDA does not require proof of effectiveness for approval of devices with minimal potential for harm, such as this one.

Recent publicity about symptoms of ovarian cancer will prompt many questions from patients about testing for the disease. Early-stage epithelial ovarian cancer is potentially curable, with survival rates of 90-95%, but about 75% of women have advanced or metastatic disease at diagnosis. Between physical examination and exploratory surgery, 2 tests are commonly used.1

Transvaginal ultrasound (TVUS) images the ovaries better than transabdominal ultrasound. In a study in which 25,327 asymptomatic women were screened with TVUS annually from 1987 to 2005, 364 patients had exploratory surgery, and 44 had primary ovarian cancer: 28 had stage I, 8 had stage II, and 8 had stage III disease. The most common finding among those who did not have cancer was ovarian serous cystadenoma. Screening with TVUS had a sensitivity of 85.0% and a specificity of 98.7%.2

Serum concentrations of the tumor marker CA-125 are not elevated in 20-50% of women with early disease and are elevated in many noncancerous conditions, including menstruation and uterine fibroids. In one study screening 22,000 postmenopausal women, the sensitivity of serial tests in detecting ovarian cancer was 86% with a specificity of 98%; the sensitivity of a single CA-125 determination was only 62%.3 In a prospective study screening 6,537 postmenopausal women with serial CA-125 determinations, the specificity was 99.8%; only 16 women underwent surgery and 4 of them had ovarian cancer.4

A controlled trial screening for ovarian cancer with both TVUS and CA-125 measurements is underway in the UK.5 The specificity and sensitivity of either one or both of these tests in detecting early-stage ovarian cancer in women who present with symptoms remain to be established.

1. GD Aletti et al. Current management strategies for ovarian cancer. Mayo Clin Proc 2007; 82:751.

2. JR van Nagell et al. Ovarian cancer screening with annual transvaginal sonography: findings of 25,000 women screened. Cancer 2007; 109:1887.

3. SJ Skates et al. Calculation of the risk of ovarian cancer from serial CA-125 values for preclinical detection in postmenopausal women. J Clin Oncol 2003; 21 suppl 10:206s.

4. U Menon et al. Prospective study using the risk of ovarian cancer algorithm to screen for ovarian cancer. J Clin Oncol 2005; 23:7919.

5. UK collaborative trial of ovarian cancer screening. Available at www.ukctocs.org.uk. Accessed June 25, 2007.

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Most cases of Lyme disease in North America occur between May and September. In 2005, 12 states (CT, DE, ME, MD, MA, MI, NH, NJ, NY, PA, VA, WI) reported about 95% of all the Lyme disease in the US, but some cases occurred in all states except AR, CO, HI, MS, MT and OK. New guidelines for treatment of Lyme disease have been published.

The FDA has approved ThermaClear (Therative), a battery-powered, handheld device, to treat individual acne lesions with heat. ThermaClear is indicated only for use on mild to moderate inflammatory acne, not severe nodular or severe cystic acne, and it is not meant to be used on blackheads and whiteheads. Two similar devices are already on the market: Zeno, another handheld device that delivers heat to acne lesions, and the Radiancy Clear Touch Lite Acne Clearance System, a larger heat-delivery device.

The FDA has approved over-the-counter (OTC) sale of the weight-loss drug orlistat (Xenical – Roche)1 as alli (GlaxoSmithKline), to be used in combination with a reduced-calorie, low-fat diet. Orlistat binds to gastric and pancreatic lipases, preventing absorption of about 30% of dietary fat with the 120-mg prescription dose, and 25% with the 60-mg OTC dose. A 16-week controlled trial of the OTC dose (60 mg 3 times daily with meals) in overweight, not obese, patients (average BMI 26.8) on a reduced-calorie, low-fat diet found that patients taking the drug lost 1.15 kg more than those taking placebo.2

Orlistat causes flatulence with oily spotting, loose stools, fecal urgency and occasional incontinence in 20-40% of patients on a low-fat diet; these effects presumably would be more frequent and more severe with a higher fat intake or self-prescription of higher-thanrecommended doses. The drug also interferes with absorption of fat-soluble vitamins (A, D, E, K); the manufacturer recommends that patients also take a multivitamin supplement at bedtime. Orlistat can increase the anticoagulant effect of warfarin and may interfere with the absorption of other drugs.

A “starter pack” of 90 capsules of alli (60 mg each) costs $62.99, compared to $224.64 for 90 capsules of Xenical (120 mg each).3

1. Orlistat for obesity. Med Lett Drugs Ther 1999; 41:55.

2. JW Anderson et al. Low-dose orlistat effects on body weight of mildly to moderately overweight individuals: a 16 week, double-blind, placebo-controlled trial. Ann Pharmacother 2006; 40:1717.

3. Cost based on information from drugstore.com (June 11, 2007).

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Sitagliptin (Januvia) and metformin (Glucophage, and others) are now available in a single tablet (Janumet - Merck) for treatment of type 2 diabetes. The combination is approved by the FDA for use in patients not adequately controlled by sitagliptin or meformin alone or in those already taking both drugs. Metformin is also available in combination with the thiazolidinediones pioglitazone and rosiglitazone and with the sulfonylureas glipizide and glyburide.

MoviPrep (Salix) is a new polyethylene glycol (PEG)-based bowel cleansing preparation approved for use in adults prior to colonoscopy. It contains ascorbic acid, which acts as an additional cathartic and flavoring agent, and requires a lower volume of fluid (3 L compared to the traditional 4 L) than most other PEG products. HalfLytely is an FDA-approved 2-L PEG product, but it must be taken with bisacodyl.

Gadolinium-based contrast agents, which are used mainly for magnetic resonance imaging and angiography, were first introduced partly because of the discovery in the 1990’s that iodine-based contrast agents could cause nephrotoxicity and acute renal failure. Some recent reports have suggested, however, that gadolinium-based agents may also be nephrotoxic.1 One patient who developed acute renal failure after use of gadolinium-based contrast had a renal biopsy that showed acute tubular injury.2

Moreover, after exposure to gadolinium-based contrast, some patients with severe renal insufficiency, or liver disease with any degree of renal insufficiency, have developed nephrogenic systemic fibrosis, with sclerodermalike changes in the skin, connective tissues and other organs, which has sometimes been fatal.3,4 The mechanism is unknown; release of free gadolinium ions, which are toxic, has been suggested.5

Gadolinium-containing contrast agents are marketed in the US as Magnevist, MultiHance, Omniscan, OptiMARK, and ProHance (www.fda.gov). In patients with renal insufficiency, especially those requiring dialysis, use of any contrast agent should be avoided if possible.

1. C Briguori et al. Gadolinium-based contrast agents and nephrotoxicity in patients undergoing coronary artery procedures. Cath Cardiovasc Interven 2006; 67:175.

2. H Akgun et al. Are gadolinium-based contrast media nephrotoxic? A renal biopsy study. Arch Pathol Lab Med 2006; 130:1354.

3. AS Boyd et al. Gadolinium deposition in nephrogenic fibrosing dermopathy. J Am Acad Dermatol 2007; 56:27.

4. A Deo et al. Nephrogenic systemic fibrosis: a population study examining the relationship of disease development to gadolinium exposure. Clin J Am Soc Nephrol 2007; 2:264.

5. T Grobner and FC Prischl. Gadolinium and nephrogenic systemic fibrosis. Kidney Int 2007 May 16; epub ahead of print.

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Ecamsule (terephthalylidene dicamphor sulfonic acid), the first new sunscreen agent to be approved by the FDA in 18 years, is now available in the US in a moisturizer called Anthelios SX. Ecamsule has been used in Canada and Europe for more than 10 years.

Mecasermin (Increlex - Tercica), which is injected subcutaneously, has been approved by the FDA for treatment of growth failure in children with severe primary insulin-like growth factor (IGF-1) deficiency. Mecasermin is recombinant human (rh) IGF-1. It has also been approved to treat children with short stature who are deficient in growth hormone (GH), but have developed neutralizing antibodies in response to GH treatment. A similar product, mecasermin rinfabate (Iplex - Insmed), that was approved by the FDA for the same indications was withdrawn from the market due to patent issues.

The erythropoiesis-stimulating agents (ESAs) epoetin alfa (Epogen, Procrit) and darbepoetin alfa (Aranesp) are widely used for treatment of anemia and to reduce the need for red blood cell transfusions. Based on the results of recent clinical trials indicating an increased risk of serious adverse events and death associated with ESAs, particularly when used to achieve a hemoglobin concentration ≥12 g/dL, the FDA has revised the prescribing information for these drugs to include a black box warning.

Several injectable products are available for soft tissue augmentation of wrinkles and folds. These fillers are often used in conjunction with botulinum toxin type A (Botox) injections.

Tegaserod maleate (Zelnorm – Novartis), a partial serotonin 5-HT4 receptor agonist that increases gastrointestinal motility, was approved by the FDA in 2002 for short-term treatment of constipation-predominant irritable bowel syndrome in women,1 and in 2004 for treatment of chronic constipation in adults ≤65 years old. Its efficacy has not been impressive statistically, but according to Medical Letter consultants some patients with slow-transit constipation have benefited from taking the drug. Diarrhea has been its main adverse effect.2

The FDA now has requested that the manufacturer stop marketing the drug based on an unpublished postmarketing analysis of earlier clinical trials that showed a higher rate of serious cardiovascular events (including angina, myocardial infarction and stroke) in patients who took tegaserod compared to placebo. Among more than 11,600 patients treated with tegaserod for 1-3 months, 13 (0.11%) had a confirmed ischemic event compared to only 1 patient (0.01%) among more than 7000 treated with placebo. The mechanism by which tegaserod would cause cardiovascular ischemia is unknown; serotonin 5-HT₁ receptor agonists used to treat migraine, such as sumatriptan (Imitrex), can constrict coronary arteries, and tegaserod has some affinity for 5-HT₁ receptors.3

Tegaserod may still be available, possibly through a special access program, for patients who do not have other treatment options.

1. Tegaserod maleate (Zelnorm) for IBS with constipation. Med Lett Drugs Ther 2002; 44:79.

2. Drugs for irritable bowel syndrome. Treat Guidel Med Lett 2006; 4:11.

3. AJ Busti et al. Tegaserod-induced myocardial infarction: case report and hypothesis. Pharmacotherapy 2004; 24:526.

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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.

Panitumumab (Vectibix - Amgen), a fully human IgG₂ monoclonal antibody that inhibits the epidermal growth factor receptor (EGFR), has been approved by the FDA for treatment of patients with EGFR-expressing metastatic colorectal cancer that has progressed despite standard chemotherapy. It is the second monoclonal antibody EGFR inhibitor to be approved for metastatic colorectal cancer; cetuximab (Erbitux), a human-murine chimeric IgG₁ monoclonal antibody, was approved in 2004.

Aliskiren (ah LIS ker in; Tekturna - Novartis), the first direct renin inhibitor, has been approved by the FDA for treatment of hypertension. It is indicated for oral use either as monotherapy or in combination with other antihypertensive agents.

Some patients with primary immune deficiency are injected with intravenous immune globulin (IVIG) every 3-4 weeks. Now a subcutaneous immune globulin (SCIG) has also been approved in the US for this indication (Vivaglobin - CSL Behring). SCIG has been used in Europe for about 10 years.

A once-daily oral formulation of mesalamine (Lialda - Shire) was recently approved by the FDA for induction of remission in patients with mild to moderate ulcerative colitis.

The dopamine agonist pramipexole (Mirapex - Boehringer Ingelheim) is the second drug approved by the FDA for treatment of moderate to severe restless legs syndrome (RLS). Ropinirole (Requip), another dopamine agonist, was approved for RLS in 2005. Both of these drugs were first approved for treatment of Parkinson's disease.

Vorinostat (Zolinza - Merck), an oral histone deacetylase (HDAC) inhibitor, has received accelerated approval from the FDA for treatment of skin manifestations of cutaneous T-cell lymphoma (CTCL) that is persistent, progressive or recurrent after two systemic therapies. The most common types of CTCL are mycosis fungoides and SΘzary syndrome, the leukemic form of mycosis fungoides.

Paliperidone (Invega - Janssen) has been approved by the FDA in an extended-release formulation for treatment of schizophrenia. It is the primary active metabolite of the second-generation antipsychotic risperidone (Risperdal - Janssen), which is scheduled to lose its patent exclusivity in December 2007.

A recent advertisement for the proton pump inhibitor (PPI) lansoprazole (Prevacid - TAP) suggests that children who cough at night, complain of abdominal pain, refuse to eat, or have a bad taste in their mouths may all have gastroesophageal reflux disease (GERD). A Bunny's Tummy Trouble, a children's book about GERD published by TAP, is now available as a patient handout in pediatricians' waiting rooms. The use of acid-suppressive drugs in infants and children has increased markedly in recent years and many of these drugs are now available in child-friendly formulations. A table in the article lists some of the drugs used to treat GERD in children.

Sunitinib (Sutent - Pfizer) and sorafenib (Nexavar - Bayer), two oral tyrosine kinase inhibitors, have been approved by the FDA for treatment of advanced renal cell carcinoma (RCC). Sunitinib is also approved for use in patients with gastrointestinal stromal tumor (GIST) who are not responding to or are intolerant of standard therapy with imatinib (Gleevec).

Femcon Fe (Warner Chilcott) is being advertised as the world's only chewable oral contraceptive. It was formerly marketed as Ovcon 35 Fe. Each packet provides 21 tablets containing 0.4 mg norethindrone and 35 mcg ethinyl estradiol, and 7 tablets with only 75 mg of ferrous fumarate. Femcon Fe has the same active hormonal ingredients as Ovcon 35 (Warner Chilcott), which has been available since 1976, and its generic equivalent Balziva (Barr); neither formulation contains iron. The spearmint-flavored Femcon Fe pill can be chewed or swallowed whole. According to the package labeling, if the pill is chewed, it should be followed by a full glass of water. The generic equivalent is not chewable, but it costs about 15 cents less per pill, and presumably comes with a lower co-pay in most insurance plans. Download U.S. English

A variety of glucose monitoring devices have been used in an effort to reduce the hypoglycemia and wide glucose excursions that complicate insulin treatment of diabetes. Since the last Medical Letter issue reviewing such devices, more continuous glucose monitoring (CGM) systems have become available. Five devices available now, and two expected to be marketed soon, are listed in the table on page 14. The FDA has approved continuous glucose devices only for the observation of glucose trends.

A combination tablet containing estradiol and drospirenone (Angeliq - Berlex) recently became available for treatment of moderate to severe menopausal symptoms in women with an intact uterus. Since the last Medical Letter issue reviewing such devices,1 more continuous glucose monitoring (CGM) systems have become available. Five devices available now, and two expected to be marketed soon, are listed in the table on page 14. The FDA has approved continuous glucose devices only for the observation of glucose trends.

Duetact (Takeda), a new fixed-dose combination of the thiazolidinedione pioglitazone (Actos) and the sulfonylurea glimepiride (Amaryl, and others), was recently approved by the FDA for treatment of type 2 diabetes. It is approved as an adjunct to diet and exercise to improve glycemic control in patients already taking pioglitazone and/or a sulfonylurea. Avandaryl, a combination of glimepiride and the thiazolidinedione rosiglitazone, was approved in 2006.

The FDA has approved the nucleoside analog telbivudine (Tyzeka - Novartis/Idenix) for treatment of patients ≥16 years old with active chronic hepatitis B virus (HBV) infection. It is the fourth oral drug marketed for this indication in the US.

In the recent Medical Letter article on the treatment of Clostridium difficile–associated disease (CDAD) we wrote: “Healthcare workers caring for patients with C. difficile infection should follow contact isolation precautions, especially use of gloves and hand washing with soap and water after glove removal. Alcohol-based products such as hand sanitizers will not eradicate C. difficile spores.”1 One reader pointed out that alcoholbased products do eradicate some C. difficile spores and have been invaluable against other pathogens.

In an unpublished study available as an abstract, both alcohol-based hand gels and chlorhexidine washes reduced the number of C. difficile spores on contaminated hands, but chlorhexidine was more effective (8 spores/cm2 remaining vs. 30-44 spores/cm2 with 3 formulations of alcohol-based hand gels).2 A previous study showed that chlorhexidine was not different from soap in removal of spores.3 Alcohol itself should have no effect on spores (purified spores are frequently stored in alcohol), but the mechanical action of washing hands with alcohol-based products may be effective in removing them. The CDC has recommended that healthcare workers caring for patients with known or suspected CDAD use contact precautions and perform hand hygiene with either an alcohol-based hand rub or soap and water, except in an outbreak setting, where exclusive use of soap and water should be considered.4

1. Treatment of Clostridium difficile–associated disease (CDAD). Med Lett Drugs Ther 2006; 48:89.

2. J Leischner et al. Effect of alcohol hand gels and chlorhexidine hand wash in removing spores of Clostridium difficile (CD) from hands. Intersci Conf Antimicrob Agent Chemother (ICAAC), Washington, DC 2005, abstract LB-29-2005.

3. K Bettin et al. Effectiveness of liquid soap vs. chlorhexidine gluconate for the removal of Clostridium difficile from bare hands and gloved hands. Infect Control Hosp Epidemiol 1994; 15:697.

4. CDC. Clostridium difficile information for healthcare providers (www.cdc.gov/ncidod/dhqp/id_CdiffFAQ_HCP.html; accessed January 22, 2007).

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A new once-daily, low-dose oral formulation of doxycycline monohydrate (Oracea - CollaGenex) has been approved by the FDA for treatment of inflammatory papules and pustules associated with rosacea in adults.

Dasatinib (Sprycel - Bristol-Myers Squibb), an inhibitor of multiple tyrosine kinases, has been approved by the FDA for second-line treatment of chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in adults.

Medical Letter consultants have brought to our attention some confusion that has accompanied the release of Adacel, a combination of tetanus toxoid, diphtheria toxoid and acellular pertussis antigens (Tdap) recently approved for use as a booster in adolescents and adults 11-64 years old (Med Lett Drugs Ther 2006; 48:5). Another Tdap vaccine, Boostrix, is approved for use in adolescents 10-18 years old. Some adults have inadvertently been immunized with Daptacel or Infanrix (DTaP), which are intended for active immunization of infants and children 6 weeks to 6 years old. Such mix-ups were reported by the Institute for Safe Medication Practices (www.ismp.org) in the August 24 and December 2006 issues of its newsletter.

The problem with giving these pediatric vaccines to adults is that they contain more diphtheria and pertussis antigens than the adult vaccine, and adults may have untoward reactions to these higher antigen levels. One consultant who inadvertently gave the pediatric vaccine to 80 adults reports that a few developed fever to 102ºF, and several developed severe erythema and swelling at the injection site. In the absence of a comparative trial, whether these reactions were due to the higher antigen load can only be a matter of speculation.

The reasons for the mix-ups, according to the Institute, include the similarities in the brand names and packaging of Adacel and Daptacel in addition to the similar component antigens in the 2 products (the components of Adacel are listed in a different order and are labeled as “reduced” diphtheria toxoid and acellular pertussis). The manufacturer of Adacel and Daptacel intends to make changes in the packaging and labeling to clarify the differences between the products. The inadvertent administration of Infanrix to adults was caused by an electronic order entry program’s failure to differentiate between the adult and pediatric vaccines.

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Oxymorphone hydrochloride, a semi-synthetic opioid agonist, has been available for many years in the US as Numorphan (Endo) for parenteral use and as a rectal suppository. Now it has been approved by the FDA for oral administration as an immediate-release (IR) tablet (Opana) for treatment of moderate to severe acute pain, and as an extended-release tablet (Opana ER) for treatment of moderate to severe pain in patients requiring continuous opioid treatment for an extended period of time.

Sitagliptin phosphate (Januvia - Merck) is the first dipeptidyl-peptidase-4 (DPP-4) inhibitor to be marketed for treatment of type 2 diabetes. It has been approved by the FDA for oral use as monotherapy or in combination with metformin (Glucophage, and others), pioglitazone (Actos) or rosiglitazone (Avandia).