Drug Information Bulletin

Drug Information Centre (DIC) Indian Pharmaceutical Association

th

Year

Volume: 05

Number: 42

29th January 2012

Content Citalopram: dose-related cardiac risk Ondansetron: QT prolongation United States of America USP-NF revised six more monographs U.S. files consent decree in Ranbaxy case Govt. statistics show cases of spurious and sub-standard drugs are coming down in the country Forthcoming Event hydrochloride and their generics. Ondansetron may increase the risk of developing abnormal changes in the electrical activity of the heart, which can result in a potentially fatal abnormal heart rhythm. Ondansetron and ondansetron hydrochloride are 5-HT3 receptor antagonists used to prevent nausea and vomiting caused by cancer chemotherapy, radiation therapy and surgery (1). The manufacturer of Zofran is being required to conduct a thorough QT study to assess the potential to prolong the QT interval. Results from this study are expected in the summer of 2012. Label changes may result after the additional information has been reviewed. Ondansetron labelling already contains information about the potential for QT prolongation. Additionally, published articles describe QT interval prolongation with ondansetron or droperidol (24). References

Citalopram: dose-related cardiac risk Health Canada is reviewing the heartrelated safety of the prescription antidepressant citalopram. The review is in light of new study data suggesting that high doses (60 mg/day) can affect the electrical activity of the heart which could potentially lead to serious, possibly fatal abnormal heart rhythms. Citalopram, an SSRI, is used to treat depression. The current Canadian prescribing information recommends 20 mg/day of citalopram in adults. Some people who have not responded to this dose are prescribed 40 or even 60 mg/day. Reference: Information Update 2011134, 13 October 2011 at http://www.hcsc.gc.ca/ahcasc/media/advisoriesavis/_2011/2011_134eng.php Ondansetron: QT prolongation United States of America The Food and Drug Administration (FDA) is informing the public of an ongoing safety review of the anti-nausea drug ondansetron (Zofran), ondansetron

2 1. National Center for Biotechnology Information. U.S. National Library of Medicine.PubMed Drug & Supplements Monograph Ondansetron. Available at: http://www.nlm.nih.gov/medlineplus/drugi nfo/meds/a601209.html.Accessed September 10, 2011. 2. Charbit et al. Droperidol and ondansetroninduced QT interval prolongation. Anesthesiology 2008; 109(2): 206-212. 3. Charbit et al. Prolongation of QTc interval after postoperative nausea and vomiting treatment by droperidol or ondansetron. Anesthesiology 2005; 102(6): 1094-1100. 4. Nathan et al. Implication of Anesthesia in Children with Long QT syndrome. Anesthesia and Analgesia 2011; 112(5): 1163-1168. 5. FDA Drug Safety Communication: Abnormal heart rhythms may be associated with use of Zofran (ondansetron). Safety Announcement, 15 September 2011 at http://www.fda.gov/Drugs/DrugSafety USP-NF revised six more monographs - Amoxicillin and Clavulanate Potassium for Oral Suspension (posted 27-Jan-2012; official 01Feb-2012) - Carbidopa (posted 27-Jan-2012; official 01-Feb-2012) - Doxycycline Hyclate DelayedRelease Tablets (posted 27-Jan2012; official 01-Feb-2012) - Metolazone Tablets (posted 27-Jan2012; official 01-Feb-2012) - Olopatadine Hydrochloride Ophthalmic Solution (posted 27-Jan2012; official 01-Feb-2012) - Zolpidem Tartrate Extended-Release Tablets (posted 27-Jan-2012; official 01-Feb-2012) - Valacyclovir Hydrochloride IRA (posted 27-Jan-2012; official 01Mar-2012) For details: http://www.usp.org/USPNF/newOfficialTe xt/revisionBulletins U.S. files consent decree in Ranbaxy case The United States Justice Department has filed a ground-breaking consent decree in court for a permanent injunction mandating Indian drug-maker Ranbaxy to adhere to U.S. manufacturing standards and ensure integrity of data at its plants in the U.S. and India. This action against Ranbaxy is groundbreaking in its international reach it requires the company to make fundamental changes to its plants in both the United States and India, Assistant Attorney General for the Justice Departments Civil Division Tony West said on Wednesday after it filed the consent decree at the request of the Food and Drug Administration (FDA). Our commitment to ensuring that the drugs the American people rely on are safe, effective and manufactured according to the FDAs standards... beyond our borders, Mr. West said. The consent decree is unprecedented in its scope, the Justice Department said. It requires Ranbaxy to hire an outside expert to conduct a thorough internal review at the affected facilities and to audit applications containing data from those facilities, withdraw any applications found to contain false data, set up a separate office of data reliability within Ranbaxy and hire an outside auditor to audit the affected facilities in the future, the Justice Department said. These are part of a wide range of actions to correct its violations and ensure that they do not happen again, it added. Meanwhile, Ranbaxy has committed to further strengthen procedures and policies to ensure data integrity and to comply with current good manufacturing practices. Todays announcement is the next step in the process of finalising our agreement

with the FDA to resolve this legacy issue, Ranbaxy CEO and Managing Director Arun Sawhney said in a statement. Ranbaxys Paonta Sahib, Batamandi and Dewas facilities in India have been on FDA import alert since 2008 and Ranbaxy has closed its Gloversville facility. The USFDA had banned 30 generic drugs produced by Ranbaxy at these three units, citing gross violation of approved manufacturing norms. In the same year, the U.S. Department of Justice had also moved a motion against the company in a local court alleging forgery of documents and fraudulent practice. The consent decree also prevents Ranbaxy from manufacturing drugs for introduction to the US market and for the Presidents Emergency Plan for AIDS Relief (PEPFAR) Programme at the Paonta Sahib, Batamandi, Dewas and Gloversville facilities until drugs can be manufactured at such facilities in compliance with US manufacturing quality standards, the USFDA said in a statement. Because this company continued to violate current good manufacturing practice regulations and falsify information on drug applications, the FDA took these actions in an effort to protect consumers, FDA Associate Commissioner for Regulatory Affairs Dara Corrigan said. The USFDA also said Ranbaxy has agreed to relinquish any 180-day marketing exclusivity that it might have for three pending generic drug applications and the firm has further agreed to relinquish any 180-day marketing exclusivity that it may have for several additional generic drug applications if it fails to meet certain decree requirements by specified dates. The consent decree also contains damages provisions to cover many potential violations of the law and the decree, the USFDA added. If defendants distribute any drug from the facilities covered by the decree, Ranbaxy

3 shall pay liquidated damages equal to two times the retail value of such drug, not to exceed USD 10 million in any one calendar year, the USFDA said. Further, if the company submits an untrue statement in connection with any application filed with the FDA, Ranbaxy shall pay up to USD 3 million in liquidated damages for each such statement, not to exceed 30 million dollars in any one calendar year, the USFDA added. Once the consent decree is approved by the court, it becomes a court order with which Ranbaxy must comply or face contempt. Submitting false data to the FDA in drug applications will not be tolerated, said Mr. West. The Department of Justice, in partnership with the FDA, will use all available tools, including civil injunction actions and consent decrees, to ensure the integrity of drug applications and to ensure that all drugs sold in the US meet US standards, he added. Through investigation by the department and the FDA, the US government said it uncovered numerous problems with Ranbaxys drug manufacturing and testing facilities in India and at units owned by its US subsidiary, Ranbaxy Inc. These problems included failure to keep written records showing that drugs had been manufactured properly and failure to investigate evidence indicating that drugs did not meet their specifications, the Justice Department said. The company also failed to adequately separate the manufacture of penicillin drugs from nonpenicillin drugs in order to prevent cross-contamination. It also failed to have adequate procedures to prevent contamination of sterile drugs, it added. Ranbaxy also conducted inadequate testing of drugs to ensure they kept their strength and effectiveness until their expiration date, the department added.

4 The government also determined that Ranbaxy submitted false data in drug applications to the FDA, including the backdating of tests and the submitting of test data for which no test samples existed, it said. All of these actions constituted violations of the Federal Food, Drug and Cosmetic Act, making many of Ranbaxys drugs adulterated, potentially unsafe and illegal to sell in the United States, the Justice Department said. Last year, Ranbaxy signed a consent decree with the USFDA to lift a ban on the import of drugs from certain manufacturing plants. It had also announced a provision of USD 500 million to settle its case with US Department of Justice. A consent decree is a settlement of a lawsuit or criminal case in which a person or company agrees to take specific actions without admitting fault or guilt for the situation that led to the lawsuit. Govt. statistics show cases of spurious and sub-standard drugs are coming down in the country With sterner measures in place to check production and supply of spurious drugs, the instances of sub-standard drugs being sold in the market have come down during the last year, according to the statistics collected by the Health Ministry. As per the countrywide survey conducted by the Government in 2009 to assess the extent of spurious drugs in the country, out of 24,136 samples collected for analysis, only 0.046 per cent samples were found spurious. Further, as per the available information received from state drug controllers, the drug samples tested all over the country in four years 20072008 to 2010-2011 reveal that only about 0.25 per cent of around 43,000 samples per annum have been found to be spurious/adulterated, sources said. During the year 2010-11, the official machinery took 49682 samples through random checks in the chemist shops across the country and 2372 samples were declared not of standard quality. The number of spurious or adulterated drugs stood at 95 while prosecutions were launched against 167 persons in this regard. The officials conducted 1295 raids throughout the country. During 2009-10, the total number of drugs of substandard quality was 1942 and the total number of spurious or adulterated drugs was 117, out of the total 39248 samples collected. As many as 147 persons were arrested and a total of 2513 raids were mounted on the medical shops. Likewise, the quantum of fake drugs during the period of 2008-09 was also higher. Out of 45145 total samples collected, as many as 2597 were declared as not of standard quality while 157 samples were found to be either spurious or adulterated in the tests. The officials held 2836 raids and arrested 133 persons during the period, according to the statistics collected. The Drugs and Cosmetics Act, 1940 (D&C Act) has been amended under Drugs & Cosmetics (Amendment) Act 2008 and it has come into force since 10th Aug, 2009. Under this Act, stringent penalties for manufacture of spurious and adulterated drugs have been provided. Certain offences have been made cognizable and non-bailable. Guidelines for taking action on samples of drugs declared spurious or not of standard quality in the light of enhanced penalties under the D&C Act have been forwarded to the state drugs controllers for implementation, he said. Forthcoming Event:

4th Student Congress