Several Medical Letter readers have asked about the meaning of non-inferiority trials. A non-inferiority trial is a comparison with an active control to determine whether the difference in response between the new drug and the active control is small enough (less than some pre-specified margin) to demonstrate that the new treatment is not less effective (or is only slightly less effective) than the control in achieving the primary outcome.1,2 Non-inferiority trials are appropriate when a proven effective treatment already exists and assigning some patients to a placebo group would be unethical because the treatment is life-saving or prevents irreversible injury.3 The FDA recently issued guidelines on how to interpret a non-inferiority trial, how to choose a non-inferiority margin and how to analyze the results.4

1. Guidance for industry non-inferiority clinical trials. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM202140.pdf. Accessed December 17, 2010.

2. ICH Harmonised Tripartite Guideline. Choice of control group and related issues in clinical trials E10. http://private.ich.org/LOB/media/MEDIA486.pdf. Accessed December 17, 2010.

3. R Temple and SS Ellenberg. Placebo-controlled trials and active-control trials in the evaluation of new treatments. Part 1: ethical and scientific issues. Ann Intern Med 2000; 133:464.

4. FDA issues first draft guidance on noninferiority trial. http://www.fdanews.com/newsletter/article?articleId=124913 &issueId=13475. Accessed December 17, 2010.

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Glycopyrrolate (Robinul, and others), a synthetic muscarinic receptor antagonist, has been used off-label for many years for treatment of excessive drooling in patients with Parkinson’s disease, in patients taking clozapine for schizophrenia, and in developmentally disabled children.1-3 It has now been approved by the FDA as Cuvposa (Shionogi) for use specifically in children 3-16 years old with severe chronic drooling due to a neurologic condition, such as cerebral palsy. It is being marketed as an oral solution, which will permit more precise weight-based dosing than was possible with the oral tablets used in the past. As with other anticholinergic drugs, dry mouth, constipation, flushing and nasal congestion can occur. Since glycopyrrolate decreases secretion not only of saliva, but also of sweat, overheating due to high ambient temperatures or excessive exercise could be dangerous for patients who take it.

1. ME Arbouw et al. Glycopyrrolate for sialorrhea in Parkinson disease: a randomized, double-blind, crossover trial. Neurology 2010; 74:1203.

2. CS Liang et al. Comparison of the efficacy and impact on cognition of glycopyrrolate and biperiden for clozapine-induced sialorrhea in schizophrenic patients: a randomized, double-blind, crossover study. Schizophren Res 2010; 119:138.

3. RJ Mier et al. Treatment of sialorrhea with glycopyrrolate: a double-blind, dose-ranging study. Arch Pediatr Adolesc Med 2000; 154:1214.

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The FDA has approved velaglucerase alfa (Vpriv – Shire), a new formulation of glucocerebrosidase prepared from human fibroblasts, for treatment of the nonneurologic form of Gaucher’s disease (Type 1). Patients with Gaucher’s disease have a congenital deficiency of glucocerebrosidase that leads to accumulation of glucosylceramide, the end-product of sphingolipid catabolism, in the lysozymes of reticuloendothelial cells in the liver, spleen and bone marrow.Velaglucerase is the second form of the enzyme now available in the US; imiglucerase (Cerezyme – Genzyme), which is produced by recombinant DNA technology from Chinese hamster ovary cells, was marketed earlier but has recently been in short supply.1 These agents are usually given as an IV infusion every 2 weeks. Both velaglucerase and imiglucerase have been shown to increase serum hemoglobin concentrations and platelet counts and decrease the size of the spleen. Velaglucerase contains the exact amino acid sequence of the human enzyme, while imiglucerase has one amino acid difference, but their activities are similar.2 The main difference between them may be in their cost. Cerezyme costs about $200,000 per year, while Vpriv is expected to cost about 15% less.2

1. Differentiation will be key challenge for Shire’s Gaucher disease drug Vpriv. The Pink Sheet. March 8, 2010; 72: 27.
2. B Brumshtein et al. Characterization of gene-activated human acid-beta-glucosidase: crystal structure, glycan composition, and internalization into macrophages. Glycobiology 2010; 20:24.

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A little more than a year ago, The Medical Letter reported the results of an FDA meta-analysis which found that use of a long-acting beta-2 agonist (LABA) such as salmeterol (Severent) or formoterol (Foradil) in patients with asthma was associated with an increased risk of a composite endpoint of asthma-related death, intubation or hospitalization; the highest risk was in children 4-11 years old.There was no significant increase in risk when a long-acting beta-2 agonist was used with an inhaled corticosteroid.The Medical Letter recommended that long-acting beta-2 agonists should not be used as monotherapy for asthma, especially in children, and that long-acting beta-2 agonists should be used for asthma only in combination with an inhaled corticosteroid, preferably in a fixed-dose combination in the same inhaler.1

Now the FDA has issued new Safe Use Requirements2 and labeling requirements for long-acting beta-2 agonists that include the following: “Stop use of the LABA, if possible, once asthma control is achieved and maintain the use of an asthma-controller medication such as an inhaled corticosteroid.”3

It has not been determined that patients taking a longacting beta-2 agonist in a fixed-dose combination with an inhaled corticosteroid have an increased risk of death or that stopping long-acting beta-2 agonists in such patients will improve long-term outcomes. A controlled clinical trial of these new requirements would be welcome.

1. Long-acting beta-2 agonists in asthma. Med Lett Drugs Ther 2009; 51:1.
2. www.fda.gov/safety/medwatch/default.htm
3. BA Chowdhury and G Dal Pan. The FDA and safe use of long-acting beta-agonists in the treatment of asthma. N Engl J Med 2010; Feb 24 (epub).

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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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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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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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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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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 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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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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The FDA has added a boxed warning to fluoroquinolone package inserts about tendon injuries that may occur as a result of their use. Tendinitis or tendon rupture may occur rarely with systemic use of any fluoroquinolone, either while the drug is being taken or for up to several months afterwards.

Fluoroquinolone-related tendon injury is rare; estimates for its incidence in the general population range from 0.14% to 0.4%. The risk is higher for patients >60 years old and for those taking corticosteroids. For patients with organ transplants, the incidence may be as high as 15%.1 A case-control study in Italy involving 22,194 cases of non-traumatic tendinitis and 104,906 controls found that fluoroquinolone use was significantly associated with tendon disorders in general (OR 1.7; 95% CI 1.4-2.0), tendon rupture (OR 1.3; 95% CI 1.0-1.8), and Achilles tendon rupture (OR 4.1; 95% CI 1.8-9.6). Achilles tendon rupture occurred with fluoroquinolone treatment in one of every 5989 patients in general and in one of every 1638 patients >60 years old.2

Widespread use of fluoroquinolones, particularly for treatment of respiratory infections, has produced substantial bacterial resistance to this class of drugs and has been associated with an increase in the incidence and severity of Clostridium difficile disease.3 Even when bacterial pneumonia is considered a likely possibility, other drugs are generally preferred, at least in non-elderly, otherwise healthy patients.4

1. F Muzi et al. Fluoroquinolones-induced tendinitis and tendon rupture in kidney transplant recipients: 2 cases and a review of the literature.Transplant Proc 2007; 39:1673.
2. G Corrao et al. Evidence of tendinitis provoked by fluoroquinolone treatment: a case-control study. Drug Saf 2006; 29:889.
3. Treatment of Clostridium difficile-associated disease (CDAD). Med Lett Drugs Ther 2006; 48:89.
4. Drugs for community-acquired bacterial pneumonia. Med Lett Drugs Ther 2007; 49:62.

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Inhaled drugs for asthma are available in the US mainly in pressurized metered-dose inhalers (MDIs), which require a propellant, and dry powder inhalers, which do not. The chlorofluorocarbon (CFC) propellants in MDIs are being replaced by hydrofluoroalkane (HFA) propellants for environmental reasons: CFCs contribute to the depletion of the ozone layer. December 31, 2008 will be the last day that albuterol MDIs using CFC propellants can be sold in the US. The FDA is expected to announce a termination date for other CFC-containing products in the near future.

Three HFA albuterol inhalers and one HFA levalbuterol inhaler have been approved by the FDA. None is available generically. HFA inhalers require priming — firing 4 puffs into the air (3 with ProAir) — the first time they are used, and after 2 weeks of non-use (3 days with Xopenex HFA).

In general, HFA sprays taste different, are less forceful, and are warmer and mistier than CFC sprays. Some patients may have to be reassured that they are getting enough of their medication, but actually the smaller particles of the HFA sprays may reach the lungs more readily than CFC sprays.

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Melamine present in infant formula and other milk products has been associated with widespread illness and some deaths among infants in China. It was also identified in pet food sold in North America after a large number of pets became ill and some died. In both the infants and the pets, renal injury appeared to be the cause.1

Melamine (C₃H₆N₆) is a heterocyclic compound, two-thirds nitrogen by weight, that is slightly soluble in water. When combined with formaldehyde, it forms melamine resin, which has a wide variety of industrial applications including the manufacturing of kitchenware, whiteboards and laminate flooring.1 Because of its nitrogen content, melamine has been illegally added to products such as milk, wheat gluten and rice protein to factitiously boost the apparent protein content; common assays for protein content do not distinguish between amino-acid nitrogen and non-protein nitrogen.

Melamine itself is relatively nontoxic; the FDA has established, based on an extrapolation from studies in rats, a tolerable daily intake of 0.63 mg/kg/day.1 However, the combination of melamine with cyanuric acid (a water disinfectant and/or impurity associated with melamine production that itself is also nontoxic) results in the formation of insoluble crystals that precipitate in renal tubules following ingestion and may cause acute renal failure.2-4 Infants may be especially sensitive to this mechanism of toxicity.

Treatment of humans or animals poisoned with these compounds is largely supportive. Hemodialysis may be indicated, depending on the degree of renal failure. Whether hemodialysis removes melamine or related compounds is unknown.

1. U.S. Food and Drug Administration. Interim safety and risk accessment of melamine and its analogues in food for humans. October 3, 2008. Available at www.cfsan.fda. gov/~dms/melamra3.html. Accessed October 14, 2008.
2. CA Brown et al. Outbreaks of renal failure associated with melamine and cyanuric acid in dogs and cats in 2004 and 2007. J Vet Diagn Invest 2007;19:525.
3. RL Dobson et al. Identification and characterization of toxicity of contaminants in pet food leading to an outbreak of renal toxicity in cats and dogs. Toxicol Sci 2008; 106:251.
4. World Health Organization. Melamine and cyanuric acid: toxicity, preliminary risk assessment and guidance on levels in food. September 25, 2008. Available at www.who.int/foodsafety/fs_management/Melamine.pdf. Accessed October 14, 2008.

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The FDA has issued an update (August 18, 2008; www.fda.gov) on occurrences of acute pancreatitis in patients with diabetes taking exenatide (Byetta – Amylin/Lilly). The latest update, which follows an FDA Alert in October 2007, reports 6 cases of hemorrhagic or necrotizing pancreatitis with 2 deaths in patients taking the drug. Whether pancreatitis occurs more often in patients taking exenatide than in patients with diabetes not taking exenatide is not clear.1

Given by subcutaneous injection, exenatide is a synthetic peptide that stimulates release of insulin from pancreatic beta cells.2 It is FDA-approved as adjunctive therapy in patients with type 2 diabetes. In addition to potentiating insulin release, exenatide slows gastric emptying, which may cause nausea and sometimes vomiting. The presenting symptoms of acute pancreatitis typically are nausea, vomiting and severe upper abdominal pain. Severe abdominal pain is not a usual side effect of exenatide. If pancreatitis is suspected in a patient taking exenatide, the drug should be discontinued promptly, and should not be restarted after recovery.

1. SR Ahmad and J Swann. Exenatide and rare adverse events. N Engl J Med 2008; 358:1970.
2. Exenatide (Byetta) for type 2 diabetes. Med Lett Drugs Ther 2005; 47:45.

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The goal for drug therapy of type 2 diabetes is achieving and maintaining a near-normal glycated hemoglobin (HbA_1C) concentration without inducing hypoglycemia; the target has generally been an HbA_1C of 6.5-7.0% or lower. Whether treating to this level prevents macrovascular (cardiovascular) events has been unclear. Now, 2 large randomized, double-blind trials in patients with long-standing diabetes and at high risk for cardiovascular disease have found no decrease in macrovascular events with intensive glucose control.

The ACCORD trial in about 10,000 patients found that patients intensively treated with anti-hyperglycemic drugs, including frequent use of thiazolidinediones, mostly rosiglitazone (Avandia), and insulin, with an HbA_1C target of 6.0% (actual median HbA_1C 6.4%) did not obtain a significant reduction in major cardiovascular events (the primary endpoint) over a period of 3.5 years. The trial was stopped early because of an unexpected increase in all-cause mortality (257 deaths vs. 203) in intensively treated patients compared to patients with an HbA_1C target of 7.0-7.9% (actual median HbA_1C 7.5%). The etiology of the higher mortality is unclear.1

The ADVANCE trial in about 11,000 similar patients treated to an HbA_1C target of 6.5% with a sulfonylurea-based regimen, and infrequent use of thiazolidinediones, also found no decrease in macrovascular events, but no increase in all-cause mortality.2

Whether intensive glycemic control would reduce macrovascular events in patients at lower risk has not been established.

1. The ACCORD Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358:2545.
2. The ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008; 358:2560.

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The US Centers for Disease Control and Prevention (CDC) has reported that measles outbreaks have occurred in New York City, California and Arizona in 2008, and additional cases have been confirmed in Michigan, Wisconsin, Hawaii, New York State, Pennsylvania, Illinois and Virginia (CDC Health Advisory, May 1, 2008). To date, 63 of the 64 infected patients were unvaccinated, and 54 of the cases were associated with importation of the disease. Both measles infection and vaccination (2 doses at least 28 days apart, with the first dose no earlier than 12 months of age) generally provide lifelong immunity.Patients >12 months old with no evidence of immunity (not born before 1957, no convincing history of clinical measles, no documentation of vaccination, and no laboratory evidence of immunity) should be vaccinated with MMR or monovalent measles vaccine. In an outbreak, children 6-12 months old can also be vaccinated, but they will still need 2 subsequent doses after the age of 12 months to be fully immunized.¹ Contraindications to the attenuated live-virus vaccine include pregnancy, immunosuppressive therapy, leukemia or lymphoma, and congenital or acquired immunodeficiency. Transient fever and/or rash can occur after vaccination.

1. Committee on Infectious Diseases in LK Pickering et al eds, 2006 Red Book: Report of the Committee on Infectious Diseases 27th ed, Elk Grove, Ill: American Academy of Pediatrics 2006, page 446.

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The drug of choice for patients who require parenteral treatment for malaria is IV artesunate, which is available now from the CDC Malaria Branch (M-F, 8 AM-4:30 PM eastern time, 770-488-7788 or, after hours, 770-488-7100). Artesunate appears to be more effective than quinine1 and safer than quinidine, the other parenteral alternatives in the US. The CDC has supplies of artesunate in Atlanta and in 8 quarantine stations in major airports around the US. It will release the drug for appropriate patients (severe disease or unable to take oral drugs) if it can be supplied as quickly as quinidine, or if quinidine has failed, been poorly tolerated, or is contraindicated.

The herbal artemisinin derivatives artemether and artesunate are used worldwide for treatment of malaria caused by Plasmodium falciparum, but have not been marketed in the US.2,3 About 1500 cases of malaria are diagnosed each year in the US in returning travelers, and about 5% of these have severe disease.4

Artesunate is generally given over 3 days in 2.4 mg/kg doses at 0, 12, 24 and 48 hours. It should be accompanied as soon as possible by an oral drug such as atovaquone/proguanil (Malarone), doxycycline (Vibramycin, and others; not for children <8 years old), clindamycin (Cleocin, and others) or mefloquine (Lariam, and others).

1. A Dondorp et al. South East Asian Quinine Artesunate Malaria Trial (SEAQUAMAT) Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet 2005; 366:717.
2. Drugs for parasitic infections. New Rochelle, NY: The Medical Letter; 2007:34.
3. NJ White. Qinghaosu (artemisinin): the price of success. Science 2008; 320:330.
4. PJ Rosenthal. Artesunate for the treatment of severe falciparum malaria. N Engl J Med 2008; 358:1829.

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Colesevelam (Welchol - Daiichi Sankyo - Med Lett Drugs Ther 2000; 42:102), a bile-acid sequestrant used to lower LDL cholesterol, has been approved by the FDA as an adjunct to diet and exercise in the treatment of type 2 diabetes. In unpublished studies summarized in the package insert, patients with type 2 diabetes taking metformin (Glucophage, and others), a sulfonylurea or insulin (each as either monotherapy or in combination with other anti-diabetic agents) were given colesevelam 3800 mg per day or placebo; colesevelam significantly reduced glycosylated hemoglobin (A1c) by about 0.5% more than placebo in all three trials. The mechanism is unclear.

Colesevelam can cause constipation, nausea and dyspepsia, increase serum triglyceride concentrations, and interfere with absorption of other oral drugs. One month's treatment with Welchol obtained from drugstore.com would cost about $200. Medical Letter consultants are not enthusiastic about prescribing it for this indication.

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Genetic Test for Carbamazepine-Induced Stevens-Johnson Syndrome Carbamazepine (Tegretol, Carbatrol, Equetro, and others), which is now used to treat not only epilepsy but also trigeminal neuralgia and manic episodes in patients with bipolar disorder,1 is a known cause of Stevens-Johnson syndrome (SJS). The incidence of carbamazepine-induced SJS in countries with mainly white populations is 1 to 6 per 10,000 new users of the drug, but Asian patients have a 10-fold higher incidence of this reaction. An association has been found between the human leukocyte antigen (HLA)-B*1502 allele and carbamazepine-induced SJS in a Chinese population.2 This allele occurs almost exclusively in Asians.3,4 The FDA is now recommending that Asian patients be tested for genetic susceptibility to carbamazepine-induced SJS before starting the drug. The genetic test should be available in most clinical chemistry labs.

1. Extended-release carbamazepine (Equetro) for bipolar disorder. Med Lett Drugs Ther 2005; 47:27.
2. WH Chung et al. Medical genetics: a marker for Stevens- Johnson syndrome. Nature 2004; 428:486.
3. C Lonjou et al. A marker for Stevens-Johnson syndrome. . . : ethnicity matters. Pharmacogenomics J 2006; 6:265.
4. A Alfirevic et al. HLA-B locus in Caucasian patients with carbamazepine hypersensitivity. Pharmacogenomics 2006; 7:813.

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The CDC recently reported that fluoroquinoloneresistant strains of Neisseria meningitidis have been detected for the first time in the US in an area around the border of North Dakota and Minnesota (CDC. MMWR, Feb 22, 2008). These isolates were all serogroup B, for which meningococcal vaccines (Med Lett Drugs Ther 2005; 47:29) do not offer protection. Since many laboratories do not test N. meningitidis for antimicrobial susceptibility, it is possible that such resistance is more widespread.

A single oral dose of ciprofloxacin (Cipro, and others) 500 mg has been used for prophylaxis after close contact with infected patients. Oral rifampin (Rifadin, and others) 600 mg (10 mg/kg for children) q12h for 2 days, a single IM injection of ceftriaxone (Rocephin, and others) 250 mg (125 mg for children), or a single oral dose of azithromycin (Zithromax, and others) 500 mg (10 mg/kg for children) are reasonable alternatives.

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Recent reports (D Kaye.Clin Infect Dis April 1, 2008;46:iii) indicate that 2 of the 3 components of this year's influenza vaccine (Med Lett Drugs Ther 2007;49:81), the influenza B and A/H3N2 antigens, do not matchup well with circulating strains. The B component is probably not protective. The A/H3N2 antigen in the vaccine probably provides some protection, particularly for high-risk patients. The third component, the A/H1N1 antigen, is protective against circulating A/H1N1 influenza viruses, but these viruses, unlike previous A/H1N1 strains, are developing some resistance to oseltamivir (Tamiflu), particularly in Europe; in the US and Canada, about 5% of influenza A/H1N1 isolates are resistant to oseltamivir in vitro.

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Sevelamer carbonate (Renvela – Genzyme), a buffered form of the anion-exchange resin sevelamer hydrochloride (Renagel – Genzyme),1 has been approved by the FDA for use in patients with chronic kidney disease on dialysis. According to the manufacturer, Renvela will replace Renagel, which has been shown to induce or exacerbate metabolic acidosis in patients on dialysis. Two randomized, crossover studies found the two sevelamer salts equivalent in their ability to lower serum phosphate.2,3 Patients taking the carbonate had higher serum bicarbonate concentrations and fewer gastrointestinal adverse effects. Sevelamer carbonate, which is available in 800-mg tablets, can be substituted for the hydrochloride salt gram for gram. Recent studies in patients beginning hemodialysis have suggested a possible mortality benefit for sevelamer compared to less expensive calcium- based phosphate binders,4,5 but some critics are skeptical.6

1. Phosphate binders. Med Lett Drugs Ther 2006; 48:15.
2. J Delmez et al. A randomized, double-blind, crossover design study of sevelamer hydrochloride and sevelamer carbonate in patients on hemodialysis. Clin Nephrol 2007; 68:386.
3. S Fan et al. Renvela (sevelamer carbonate) powder and Renagel (sevelamer hydrochloride) tablets: report of a randomized, cross-over study in chronic kidney disease (CKD) patients on hemodialysis (poster). American Society of Nephrology Renal Week. October 31- November 5 2007. San Francisco.
4. GA Block et al. Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients. Kidney Int 2007; 71:438.
5. AM Borzecki et al. Survival in end stage renal disease: calcium carbonate vs. sevelamer. J Clin Pharm Ther 2007; 32:617.
6. J Silver. The details bedevil DCOR. Kidney Int 2007; 72:1041.

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

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

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

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An unpublished 2-year randomized study (ENHANCE) on the effect of adding ezetimibe 10 mg to simvastatin 80 mg in 720 patients with heterozygous familial hypercholesterolemia has been in the news recently. About 80% of these patients had previously been treated with statins. The primary endpoint was the change in the intima-media thickness (IMT) of the carotid artery (baseline 0.68 and 0.69 mm); the IMT increased by 0.0111 mm with ezetimibe plus simvastatin and 0.0058 mm with simvastatin 80 mg alone (p=0.29). The ezetimibe- simvastatin combination lowered LDL-C by 58% compared to 41% lowering with simvastatin alone (p<0.01). The study was not powered to assess cardiovascular events; cardiovascular deaths occurred in 2 patients treated with both drugs and 1 on simvastatin alone.

Ezetimibe, an inhibitor of cholesterol absorption, is available both alone (Zetia) and in combination with 10, 20, 40 and 80 mg of simvastatin (Vytorin). No data have been published on the effect of ezetimibe on cardiovascular events with or without simvastatin. Whether addition of ezetimibe to a statin is as effective as raising the dose of the statin in decreasing the number of cardiovascular events remains to be determined in larger studies that are underway.

Neither Zetia or Vytorin is recommended for initial treatment of hypercholesterolemia.

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Cetirizine (Zyrtec, and others) and cetirizine/pseudoephedrine (Zyrtec-D) are becoming available without a prescription this month for treatment of allergic rhinitis and urticaria in adults and children. Cetirizine is the second of the second-generation H1-antihistamines to become available over the counter. Loratadine (Claritin, and others) was the first.

Cetirizine has been shown to be more effective than loratadine in suppressing histamine-induced wheals in healthy volunteers (W Carey et al. Drugs Exp Clin Res 2002; 28:243), but no well-controlled clinical trials have established that any second-generation H1-antihistamine is more effective overall than any other (M Plaut and MD Valentine. N Engl J Med 2005; 353:1934).

Cetirizine may be mildly sedating in some patients, but it is significantly less sedating than first-generation H1-antihistamines such as diphenhydramine (Benadryl, and others) or chlorpheniramine (Chlor-Trimeton, and others), which have been available without a prescription for many years. Its safety in young children is better documented than that of any other first- or second-generation H1-antihistamine (Treat Guidel Med Lett 2007; 5:71).

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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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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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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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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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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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Statins have been shown to reduce the risk of stroke in patients at high risk for cardiovascular disease (Treat Guidel Med Lett 2005; 3:15). A recent issue of The New England Journal of Medicine includes the results of a study sponsored by the manufacturer in which 80 mg of atorvastatin (Lipitor – Pfizer) or placebo was given to 4731 patients without coronary artery disease who had had a stroke or transient ischemic attack (TIA) within one to six months before study entry (The Stroke Prevention by Aggressive Reduction in Cholesterol Levels [SPARCL] Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 2006; 355:549). Patients were not required to have elevated cholesterol levels to enroll. The authors conclude that the study results support starting atorvastatin treatment soon after a stroke or TIA.

The primary study endpoint was a nonfatal or fatal stroke. During a median follow-up of 4.9 years, patients treated with atorvastatin had 265 strokes compared to 307 strokes with placebo. Patients treated with atorvastatin had 56 fewer ischemic strokes and 22 more hemorrhagic strokes. They also had 39 fewer coronary events. There were 216 deaths among patients treated with atorvastatin and 211 among those treated with placebo.

Whether patients with a recent ischemic stroke or TIA would be as well protected against a recurrence and against coronary events by a lower dose of atorvastatin or by another less potent statin remains to be determined. The risk of myopathy and rhabdomyolysis with statins is dose-related; atorvastatin is the second-most potent statin on the US market (rosuvastatin is the most potent), and 80 mg is its maximum dose. Statins have an antithrombotic effect, and an increase in hemorrhagic stroke in patients with cerebrovascular disease treated with statins has been reported previously (Heart Protection Collaborative Study, Lancet 2004; 363:757). It is doubtful whether patients with a recent hemorrhagic stroke should be treated with statins at all, let alone a maximum dose of atorvastatin.

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Soon after The Medical Letter first reviewed use of natalizumab (Tysabri – Biogen Idec and Elan) for treatment of relapsing forms of multiple sclerosis (MS) (Med Lett Drugs Ther 2005; 47:13), the drug was withdrawn from the market. The unpublished clinical trials that led to its approval by the FDA have since been published, and now the drug has been returned to the market with prescribing restrictions.

Natalizumab decreases the number of relapses and new brain lesions in patients with MS. It was withdrawn because progressive multifocal leukoencephalopathy (PML) occurred in 3 (of about 3000) patients being treated with the drug; two were taking the drug in combination with interferon beta for MS, and one was taking it with azathioprine for Crohn’s disease. PML is an opportunistic infection of the brain, caused by reactivation of the JC virus in immunosuppressed patients, that often causes death or severe neurological disability. There is no treatment for PML.

The publication of the natalizumab clinical trials in MS provided information on the drug’s effect on the progression of disability, which was not available when it was first reviewed here. In one study, combination therapy with natalizumab and interferon beta-1a for 2 years led to an estimated cumulative probability of progression of 23%, compared to 29% with interferon beta-1a alone (RA Rudick et al. N Engl J Med 2006; 354:911). In the second study, the estimated cumulative probability of progression over 2 years was 17% with natalizumab alone and 29% with placebo (CH Polman et al. N Engl J Med 2006; 354:899).

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The FDA has approved over-the-counter (OTC) sales of Plan B (Duramed), an emergency contraceptive package that contains two 0.75-mg tablets of levonorgestrel, to women ≥18 years old. Younger women still require a prescription. In one trial, two levonorgestrel 0.75-mg tablets taken 12 hours apart, the first within 72 hours after unprotected intercourse, decreased the pregnancy rate to 1%, compared to an expected rate of 8% (Task Force on Postovulatory Methods of Fertility Regulation, Lancet 1998; 352:428). How high doses of a progestin taken after coitus prevent pregnancy is unclear; they may interfere with ovulation, fertilization or implantation.

Nausea and vomiting can occur. The drug will not terminate an established pregnancy. No fetal malformations have been reported after unsuccessful use.

Plan B will not be available OTC until the end of the year, according to the manufacturer, and the OTC price is not yet available. The retail price for the prescription product varies from about $25 to $40. In order to enforce the age restriction, the drug will be kept behind the pharmacist’s counter, and a valid photo ID will be required.

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The results of a randomized, placebo-controlled trial of calcium and vitamin D supplements in more than 36,000 postmenopausal women, conducted as part of the Women’s Health Initiative (RD Jackson et al. N Engl J Med 2006; 354:669), have been misinterpreted by some patients to mean that they should stop taking such supplements.

At the time of recruitment, the participants in this study had an average daily calcium intake of 1100-1200 mg. They were randomized to take either 1000 mg of calcium carbonate plus 400 IU of vitamin D₃ or a placebo for an average of 7 years. Both groups were permitted to take calcium and vitamin D supplements on their own as well. In the intention-to-treat population, the study supplements increased hip bone density but did not decrease the incidence of hip fractures. The subgroup of women who adhered to the protocol and actually took the study supplements showed a significant reduction in hip fractures compared to the control group.

Men and women over age 50 should have a total calcium intake of about 1200 mg per day (Treat Guidel Med Lett 2005; 3:69). If they need a supplement to achieve that, calcium citrate is more expensive, but it offers some advantages over calcium carbonate: it can be taken without food, causes less GI disturbance and may be less likely to cause kidney stones.

With any calcium salt, vitamin D is necessary for optimal absorption. The recommended minimum daily requirement of vitamin D (vitamin D₃ is preferred) is 400 IU for people 50-70 years old and 600 IU for those over 70. But those infrequently exposed to the sun may need 800- 1000 IU of vitamin D daily, and many experts recommend 800 IU or more for all postmenopausal women.

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Last year, a Medical Letter article reviewing colonoscopy preparations warned that oral sodium phosphate preparations, such as Fleet Phospho-Soda solution and Visicol tablets, could cause significant electrolyte disturbances and, rarely, renal failure (Med Lett Drugs Ther 2005; 47:53). A subsequent report documented acute phosphate nephropathy and renal failure in 21 patients who had used sodium phosphate before colonoscopy (GS Markowitz et al. J Am Soc Nephrol 2005; 16:3389). Seventeen of these patients were women and 14 were taking an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB). The FDA recently issued an alert advising against use of oral sodium phosphate in patients with kidney disease or uncorrected electrolyte abnormalities and urges caution in patients taking drugs that may affect renal function such as diuretics, NSAIDs, ACE inhibitors or ARBs.