KASR ALAINY DRUG INFORMATION CENTER Newsletter

“Volume 2 Issue 6, July 2011”

In This Issue *Drug overview….”Clostridium difficile and Dificid” P.g 1-3.

*FDA News ….P.g 4.

*Egyptian Drug Authority (EDA) News…. P.g 4, 5.

*From Our Answered Questions….P.g 5, 6.

”Europe’s E.coli outbreak” P.g 7. *Brief Note….

*Recent study…. P.g 8.

Drug Overview

Clostridium difficile and Dificid “Treatment and Prevention of recurrence”  A common complication of treatment with antimicrobial agents is the development of antibiotic-associated diarrhea (AAD) in 5–25% of patients. [1]  Antimicrobial Agents that Predispose to Clostridium difficile Diarrhea and Colitis : [2] Frequency Infrequently Rarely Ampicillin Tetracyclines Parenteral aminoglycosides Amoxicillin Sulfonamides Metronidazole Cephalosporins Macrolides Bacitracin Clindamycin Chloramphenicol Vancomycin Other penicillins Trimethoprim Quinolones  Clostridium difficile is responsible for 15–25% of cases of AAD and for almost all cases of pseudomembraneous colitis. [3] KDIC Newsletter Vol.2 Iss.6

 Clostridium difficile associated diarrhea can occur up to 8 weeks after the discontinuation of antibiotics. Most cases of Clostridium difficile infection occur on days 4 through 9 of antibiotic therapy. [3]  The first step in treatment of Clostridium difficile associated diarrhea is to discontinue the precipitating antibiotic, and administer fluids and electrolytes to maintain hydration. [3]  Specific treatment should be initiated if diarrhea persists despite discontinuation of the precipitating antibiotic or if there is evidence of colitis.[3]  First-line therapy consists of Metronidazole, 500 mg orally 3 or 4 times daily for 10 - 14 days, with a greater than 90% positive response rate. [3]  Vancomycin also is an effective treatment, with a response rate greater than 90%. [3] If a patient is pregnant or does not respond to or tolerate Metronidazole, Vancomycin should be initiated in a dosage of 125 - 500 mg orally four times daily for 10 - 14 days. [3]  Though Teicoplanin, an antibiotic of limited availability and great cost, showed in some outcomes significant benefit over Vancomycin and Fusidic acid, and a trend towards benefit compared to Metronidazole. [6]  New treatment:  The U.S. Food and Drug Administration on May 27, 2011 approved Dificid (fidaxomicin) tablets for the treatment of Clostridium difficile-associated diarrhea (CDAD). [7]  Dificid, a macrolide antibacterial, should be taken 200 mg every 12 hours for 10 days with or without food. [5,7]  The most common side effects reported with Dificid included nausea, vomiting, headache, abdominal pain, and diarrhea. [7]  Advantages: Dificid (fidaxomicin) may offer advantages over established treatment options due to its: . Demonstrated activity against hypervirulent C. difficile. . Limited impact on normal intestinal flora. . High retention in the gut. . Reduced cross-resistance with known antibiotics.

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. Reduced likelihood of Vancomycin-resistant Enterococcus colonization and twice daily dosing regimen. [5]  Dificid vs. Vancomycin:  Patients treated with Dificid had a sustained cure 3 weeks after treatment ended versus those patients treated with Vancomycin. [7]  A Randomised active-controlled study comparing safety and efficacy of Dificid vs Vancomycin. Results was for Dificid and Vancomycin respectively: clinical cure rate (resolution of diarrhea) 87.7% vs. 86.8%; recurrence rate 12.7% vs. 26.9%; global cure rate (clinical cure with no subsequent recurrence during 28 days follow-up end of therapy) 76.6% vs. 63.4%. [5]  Important Safety Information DIFICID should not be used for systemic infections. Only use DIFICID for infection proven or strongly suspected to be caused by Clostridium difficile. [8] References: 1) SULLIVAN Å., NORD C. E. 2005. Probiotics and gastrointestinal diseases. Journal of Internal Medicine Volume 257, Issue 1, pages 78–92, January. 2) Kelly CP, LaMont JT. Treatment of Clostridium difficile diarrhea and colitis. In: Wolfe MM, ed. Gastrointestinal Pharmacotherapy. Philadelphia, Pa.: WB Saunders; 1993:199-212. 3) MICHAEL S. SCHROEDER, M.D. 2005. Clostridium difficile–Associated Diarrhea. Am Fam Physician. 2005 Mar 1;71(5):921-928. 4) Bartlett J.C.; Clostridium difficile: history of its role as an enteric pathogen and the current state of knowledge about the organism. Clin. Infect. Dis., 18: s265-s272, 1994. 5) (Dificid) for Clostridium difficile infection – treatment and prevention of recurrence, dec 2010,The National Horizon Scanning Centre Research Programme is part of the National Institute for Health Research 6) Cochrane Database Syst Rev. 2007 Jul 18;(3):CD004610. Nelson RL. Antibiotic treatment for Clostridium difficile-associated diarrhea in adults. Cochrane Database of Systematic Reviews 2007, Issue 3. Art. No.: CD004610. DOI: 10.1002/14651858.CD004610.pub3 7) www. FDA.gov 8) Nerandzic MM, Mullane K, Miller M et al. Acquisition and overgrowth of vancomycin-resistant enterococci in patients treated with either fidaxomicin or vancomycin for C. difficile infection. Presentation K-1915. 49th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). San Francisco, CA,USA. 2009.

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KDIC Newsletter Vol.2 Iss.6

FDA News

Label Change for Zocor (simvastatin)

FDA notified healthcare professionals that it is recommending limiting the use of the highest approved dose of the cholesterol-lowering medication simvastatin (80 mg) because of increased risk of muscle damage. Patients taking simvastatin 80 mg daily have an increased risk of “Simvastatin is under the brand- myopathy compared to patients taking lower name Zocor (conc. 80mg not doses of this drug or other drugs in the same available in Egypt), and as a class. This risk appears to be higher during the single-ingredient generic product first year of treatment, is often the result of Simvacor 80mg and Corvast 80 interactions with certain medicines, and is mg” frequently associated with a genetic predisposition toward simvastatin-related myopathy. The most serious form of myopathy, called rhabdomyolysis, can damage the kidneys and lead to kidney failure which can be fatal. RECOMMENDATION: Simvastatin 80 mg should not be started in new patients, including patients already taking lower doses of the drug. Reference: FDA- label change, 8 June 2011 (Click here)

Egyptian Drug Authority (EDA) News

Duxil…withdrawal due to unfavorable risk benefit ratio

Duxil® is a vasodilator containing "Almitrine and Raubasine". Almitrine is a triazine, a synthetic substance, acting on pulmonary exchange and increasing

arterial oxygen pressure; Raubasine is an alkaloid derivative of Rauwolfia serpentina, acting at tissue level, favouring the utilization of oxygen. Its principal impact is mitochondrial. It was indicated for sub-acute and chronic cerebrovascular insufficiency with its varied symptoms: loss of memory; decrease in intellectual efficiency and concentration; and vascular disorders of the retina and inner ear. On May 2011, the Technical Committee (TC)

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KDIC Newsletter Vol.2 Iss.6

at the Central Administration of Pharmaceutical Affairs (CAPA) has decided to withdraw Duxil®. This decision was based on the re-assessment of the French Agency for the Safety of Health Products (AFSSAPS) for the risk / benefit ratio of Duxil ®. AFSSAPS decided to withdraw the permission to market this product under its two forms (Coated tablets and oral suspension) which are no longer traded.

The above decision is only applied on the brand (Duxil®), because it is the only product that contains this combination.

References: 1- Egyptian drug authority (Click here) 2- The French Agency for the Safety of Health Products (Click here)

From our answered questions

Question 1: What is the alternative to be used instead of V-FEND (Voriconazole) in aspergillus infection?

Patient History: A 7 years old boy suffers from interstitial pulmonary disease, a culture from his sputum revealed an aspergillus infection. On previous admission, he suffered

from hypersensitivity reaction from V-FEND (Voriconazole).

(1, 2)  VFEND (Voriconazole) is the preferred therapy of Aspergillosis ; however Voriconazole is contraindicated in patients with known hypersensitivity to Voriconazole or its excipients. (3) Serious cutaneous reactions, including Stevens- Johnson syndrome, toxic epidermal necrolysis and erythema multiforme have been reported during treatment with VFEND (Voriconazole). If a patient develops an exfoliative cutaneous reaction, VFEND (Voriconazole) should be discontinued. (3)  Amphotericin B may be used as alternative therapy when Voriconazole not to be appropriate (2, 3, 4); it may cause acute liver failure, hepatitis and jaundice, cholestasis which has been reported in infants treated with Amphotericin for systemic Candida infections. Most of these reports were incidental, and Amphotericin cannot be regarded as a known cause of liver damage. (5)

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 Oral Itraconazole has been used in selected patients with mild immunosuppression and non-life-threatening Aspergillus infection or in patients who had already been stabilized with Amphotericin B. Efficacy of Itraconazole has not been established in children. (1, 2) References: 1) Up-to-date Database. 2) BNF for children 2009. 3) www.drugs.com 4) Antibiotic Essentials 2009. 5) Meyler’s side effects of drugs 2006.

Question 2: Are there any interactions between the following drugs?

Patient History: A 55 years old patient suffering from osteoarthritis. He is on ULTRAFEN

(Ibuprofen), MARK-FAST (Ibuprofen-Chlorzoxazone) and ASPIRIN.

 Both Markfast and Ultrafen contain Ibuprofen, and this would potentiate their effects and adverse effects.  Use of aspirin with Ibuprofen (in Markfast and Ultrafen): (1)  The concomitant use of Aspirin with Ibuprofen can reduce the cardiovascular benefits of aspirin.  However, Ibuprofen 400mg can be administered 30 minutes after or 8 hours before immediate-release aspirin to avoid competitive inhibition of platelet’s Cyclooxygenase (COX) acetylation site.  Data on enteric-coated aspirin are not available.  Infrequent use of ibuprofen has little effect on overall cardioprotective effects of aspirin because of aspirin’s long-lasting effect on platelets.  Other non-selective NSAIDs theoretically will have the same effect as ibuprofen and should be dosed accordingly. Consider alternative medications in high-risk cardiovascular populations. References: 1) Fda.gov

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KDIC Newsletter Vol.2 Iss.6 Brief Note

Europe's E. coli outbreak

The strain of Escherichia coli (E.coli) that is making people ill in Germany and other parts of Europe is known as 0104:H4, and

part of a class of bacteria known as Shiga toxin-producing E. coli, or STEC. Symptoms of STEC infection include stomach cramps, diarrhea (which is often bloody), and vomiting. If there is fever, it usually is not very high. Most people get better within 5-7 days. (2) Complications result when the Shiga toxin enters the bloodstream and include 'hemolytic uremic syndrome' or HUS. HUS causes kidney damage that may be temporary or permanent. (2, 4) Other patients, especially the elderly, may develop a related condition called thrombotic thrombocytopenic purpura (TTP). (1, 2)

What is the best treatment for STEC infection? (3, 4, 5)

Treatment involves replacing fluid losses (I.V.) and other supportive measures. Antibiotics are not usually helpful in treating E. coli infections caused by STEC. In fact, there is some evidence that antibiotics might make the situation worse by increasing the risk of HUS by increasing toxin production. Antibiotics may be needed if the patient develops sepsis. Patients with HUS may require dialysis. TTP may require Plasmapheresis. There is an experimental treatment for HUS that involves a monoclonal antibody directed against complement activity by cleavage of the complement protein C5. The antibody, called eculizumab (Soliris), appears to have been helpful in a few cases but large-scale studies are lacking. Antidiarrheal agents like Imodium® may also increase the risk of HUS.

References

1. www.cdc.gov/ecoli/2011/ecoliO104/index.html 2. www.cdc.gov/ecoli/2011/ecoliO104/index.html#clinical 3. www.cdc.gov/nczved/divisions/dfbmd/diseases/ecoli_o157h7/#treat 4. Shiga Toxin: E. coli 0104:H4.emedicinehealth.com 5. www.webmd.com/food-recipes/food-poisoning/ treatment overview

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KDIC Newsletter Vol.2 Iss.6 Recent study

NEXIUM (esomeprazole) I.V “First Proton Pump Inhibitor approved for children less than one year”

This approval of Nexium (esomeprazole sodium) I.V. for the treatment of children 1 month to 17 years old who are suffering from gastroesophageal reflux disease (GERD) with erosive esophagitis.(1)

NEXIUM® I.V for Injection is used in general for the short-term treatment (up to 10 days) of GERD when oral therapy is not possible or appropriate. (1, 2, 3)

Dosage and Administration

•Adults: Dose is either 20 mg or 40 mg esomeprazole given once daily by intravenous injection (no less than 3 minutes) or intravenous infusion (10 minutes to 30 minutes). • Pediatric: Give the following doses once daily as an intravenous infusion over 10 minutes to 30 minutes ° 1 year to 17 years: – Body weight less than 55 kg: 10 mg – Body weight 55 kg or greater: 20 mg ° 1 month to less than 1 year of age: 0.5 mg/kg Precautions with use of Nexium I.V.:  Nexium I.V. should not be administered concomitantly with any other medications through the same intravenous site and or tubing.  The intravenous line should always be flushed with either 0.9% Sodium Chloride Injection, USP, Lactated Ringers Injection, USP or 5% Dextrose Injection, USP both prior to and after administration of Nexium I.V. for Injection. References:

1. www.astrazeneca-us.com/about-astrazeneca-us/newsroom 2. www.drugs.com/newdrugs/fda-approves-nexium 3. www.rxlist.com/nexium-iv-drug.htm

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Advisory Board Prof.Dr. Magda Zaki Professor of Pharmacology, Our Vision Ex Head of Pharmacology The pharmacist working in Kasr Alainy Drug Information department, Center (KDIC) provides accurate, unbiased, relevant, Faculty of medicine, Cairo University evidenced based and timely information about drugs and drug related problems to assist the center users in optimizing Dr. Amani Nabil health outcomes. Ass.Professor of Pharmacology, Our Mission Faculty of medicine Cairo University Pharmacists in the KDIC are part of the health care team Dr. Samia Rashed working through the Clinical Pharmacology and Pharmacy Ex Head of Pharmacy department, committee, to provide useful service and the pharmaceutical Technical director of KDIC, information needed for the hospitals’ patients. Cairo University Hospitals Visit us on: Editorial Board http://www.medicine.cu.edu.eg/beta/en/hospitals/kasr Chief Editor alainy-drug-information-center.html Dr.Rania Ramzi Director of KDIC, Drug information specialist, Cairo University Hospitals Editors Pharmacist: Maha Ollaek Drug information pharmacist, Cairo university Hospitals

Pharmacist: Samar Samy Drug information pharmacist, Cairo university Hospitals To contact us Internal line: 1260 Pharmacist: Doaa Bazan External line & Fax: 23687397 Drug information pharmacist, E-mail: [email protected] Cairo university Hospitals

Pharmacist: Shaimaa Ragab Drug information pharmacist, Cairo university Hospitals

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