Safety and Efficacy Issues

WHO Drug Information Vol. 27, No. 4, 2013

Contaminated dextromethorphan and had consumed medical products produced by a local manufacturer World Health Organization — On 24 containing dextromethorphan. The January 2013, a WHO Drug Alert was children were aged from 2–9 years and issued following the discovery in Pakistan serious adverse reactions included of two types of locally produced cough altered consciousness, cyanosis, syrup containing the contaminated active respiratory distress and seizures. Onset pharmaceutical ingredient (API) dextro- of symptoms occurred from 2–7 hours methorphan. after ingesting dextromethorphan. Since then, the number of patients experiencing This incident led to the death of approxi- adverse reactions rose to 44 confirmed mately 50 persons in Pakistan, all with a cases, ranging in age from 5 months to history of drug addiction, who had been 48 years. There was one fatality that may abusing dextromethorphan-containing be linked to the event. syrup for many years without any reported unexpected adverse reactions. The Paraguayan Ministry of Health issued The subsequent investigation found that warnings concerning the medicines manufacturers in Pakistan were obtaining thought to be connected to this incident. the dextromethorphan API from a source Investigations by the Paraguayan in India. authorities subsequently indicated the source of the API dextromethorphan to be Full laboratory testing of the dextro- the same Laboratories in India. The batch methorphan showed that it was conta- number of the dextromethorphan API minated with levomethorphan, the used by the Paraguayan manufacturer enantiomer of dextromethorphan, which was the same as one of the contaminated is a potent opioid analgesic internationally batches found in Pakistan. However, the controlled under Schedule 1 of the Single Paraguayan manufacturer appears to Convention on Narcotic Drugs (1961). have ordered the API in 2012, prior to events in Pakistan. In January 2013, as a result of this incident, the Indian regulatory authorities According to the local manufacturer in suspended the manufacture, distribution, Paraguay none of the products have sale or use of the dextromethorphan in been exported, however they could question. possibly be available in neighbouring countries through local traders and WHO called on all countries to increase travellers. vigilance concerning dextromethorphan in general and to ensure that the API met all WHO advises extra vigilance for the API required quality specifications. dextromethorphan and strongly urges that extreme caution be exercised by On 26 September 2013, WHO was importing countries and manufacturers. notified of suspected drug intoxication Dextromethorphan should be carefully involving eleven paediatric patients tested for the presence of the contain Paraguay. All of the patients were minant levomethorphan, and it should experiencing influenza-like symptoms meet the recognized specifications.

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Samples of contaminated dextromethor- Details of falsified batches of Coartem® phan API from the original Pakistan circulated by WHO in May 2013 are as incident have been analysed at the follows: request of WHO and revealed limits of levomethorphan varying between 9.5% to Batch number: F1901 22.6%. All of the samples tested in both Manufacturing Date: 01.2012 incidents have failed to comply with the Expiry Date: 01.2014 requirements for the specific optical The packaging is in English and bears a rotation as specified in the monograph falsified stamp of the Nigerian National for dextromethorphan hydrobromide Medicines Regulatory Agency, NAFDAC. published in The International Pharma- copeia. Batch Number: F2261 Reference: WHO Information Exchange Manufacturing Date: 01.2012 System ([email protected]). Drug Alert, Expiry Date: 01.2014 Nos.126 & 129, 17 October 2013 at http:// www.who.int/medicines/publications/ The packaging is in English and bears the drugalerts/drugalertindex/en/. falsified green leaf logo of the Affordable Medicines Facility – Malaria (AMFm) Falsified artemether and Programme. Novartis has informed WHO that this batch has also been seen again lumefantrine circulating in recently in Cameroon. Cameroon World Health Organization — A WHO All four batches are packaged for adult Drug Alert has been circulated concerning use and distribution within the public falsified batches of Coartem® that are sector. The falsified batches contain little circulating in Western and Central Africa. or no active pharmaceutical ingredient Coartem® is a fixed-dose artemesinin and are therefore ineffective. based combination therapy (ACT) (artemether 20 mg and lumefantrine Some of these batches have been found 120 mg) used for the treatment of in a number of West and Central African Plasmodium falciparum malaria. The countries in hospitals and street markets. genuine product is manufactured by Increased vigilance throughout the region Novartis and is a WHO prequalified is strongly advised. Hospitals, clinics, and medicine. pharmacies should check their stocks for these batches and report any suspicions On 5 November 2013, Novartis informed to their national medicines regulatory WHO of further falsified versions of authority. Coartem® recently circulating in Cameroon as follows: Reference: WHO Information Exchange System ([email protected]). Drug Alert Batch Number: NOF 2153 No.130, 8 November 2013 at http://www. Manufacturing Date 01.2013 who.int/medicines/publications/drugalerts/ Expiry Date: 11. 2015 drugalertindex/en/. Batch Number F2929 Manufacturing Date: 01.2012 Ponatinib: increased reports Expiry Date: 01.2016 of serious blood clots The packaging of both batches is in United States of America — The English and bears the falsified green Food and Drug Administration (FDA) is leaf logo of the Global Fund Affordable investigating the increased frequency of Medicines Facility – Malaria (AMFm) reports of serious and life-threatening Programme. blood clots and severe narrowing of

347 Safety and Efficacy Issues WHO Drug Information Vol. 27, No. 4, 2013 blood vessels of patients taking ponatinib Intravenous tigecycline: (Iclusig®). Health care professionals increased risk of death should consider whether the benefits of ponatinib treatment are likely to exceed United States of America — The Food the risks. and Drug Administration (FDA) is warning that an additional analysis shows an Ponatinib is used to treat adults diag- increased risk of death when intravenous nosed with chronic phase, accelerated tigecycline (Tygacil®) is used for phase, or blast phase chronic myeloid approved or non-approved uses. leukaemia or Philadelphia chromosome- positive (Ph+) acute lymphoblastic Healthcare professionals should leukaemia, who are no longer benefiting reserve tigecycline for use in situations from previous treatment or who do not when alternative treatments are not tolerate other treatment. suitable. Tigecycline is approved to treat complicated skin and skin structure At the time of approval in December infections, complicated intra-abdominal 2012, the Iclusig® label contained infections, and community-acquired information about the risks of blood bacterial pneumonia. Tigecycline is clots. In clinical trials conducted before not indicated for treatment of diabetic approval, serious arterial blood clots foot infection or for hospital-acquired or occurred in eight percent of Iclusig®- ventilator-associated pneumonia. treated patients and venous blood clots occurred in three percent of patients. In 2010, FDA informed the public that a In the most recent clinical trial data meta-analysis of 13 Phase III and IV trials submitted by the manufacturer to FDA, at showed a higher risk of death among least 20 percent of all participants treated patients receiving Tygacil® compared to with ponatinib have developed blood clots other antibacterial drugs. The increased or narrowing of blood vessels. risk was greatest in patients treated for Data from clinical trials and postmarket ventilator-associated pneumonia, a use adverse event reports show that serious for which FDA has not approved the drug. adverse events have occurred in patients treated with ponatinib, including heart Since 2010, FDA has analysed data from attacks resulting in death, worsening ten clinical trials conducted only for FDA- coronary artery disease, stroke, approved uses showed a higher risk of narrowing of large arteries of the brain, death among patients receiving Tygacil® severe narrowing of blood vessels in compared to other antibacterials. In the extremities, and the need for urgent general, the deaths resulted from surgical procedures to restore blood worsening infections, complications of flow. Other problems include congestive infection, or other underlying conditions. heart failure and loss of blood flow to Reference: FDA Drug Safety Communication, extremities resulting in tissue death 27 August 2013 at http://www.fda.gov/Drugs/ requiring amputation. Newly identified DrugSafety.htm serious adverse reactions have also been reported including decreased vision and clots in blood vessels of the eye. Cinacalcet: hypocalcaemia and These adverse events were seen in all arrhythmia age groups treated and in those with and Canada — A safety review of the drug without cardiovascular risk factors. cinacalcet (Sensipar®) has identified a Reference: FDA Drug Safety Communication, possible link to arrhythmia associated 11 October 2013 at http://www.fda.gov/Drugs/ with low blood calcium. Cinacalcet DrugSafety/ucm370945.htm is used for treating disorders of the

348 WHO Drug Information Vol. 27, No. 4, 2013 Safety and Efficacy Issues parathyroid gland that result in abnormal In patients with prior HBV infection, HBV blood calcium levels. It is well known reactivation may occur when the body’s to cause hypocalcemia and this risk immune system is impaired. Infection is clearly outlined on the Canadian can cause serious liver problems, Sensipar® label. including liver failure and death. The risk of HBV reactivation is already described Hypocalcemia can cause QT prolongation in the labelling for both drugs; however, and arrhythmia which can be serious cases continue to occur, including deaths. and may lead to sudden death. Stronger warnings have been added to the Reference: FDA Drug Safety Communication, drug label to inform of the risk of QT 25 August 2013 at http://www.fda.gov/Drugs/ prolongation and arrhythmia associated DrugSafety/ucm366406.htm with use. Hydroxyethyl-starch solutions: Healthcare professionals should only for hypovolaemia prescribe cinacalcet with caution in patients with other risk factors for QT European Union — The European prolongation, such as known congenital Medicines Agency’s Pharmacovigilance long QT syndrome, or in patients who are Risk Assessment Committee (PRAC) taking other drugs known to cause QT has completed its review of hydroxyethyl- prolongation. For patients treated with starch (HES) solutions following an cinacalcet for chronic kidney disease and assessment of new information and receiving dialysis, reduce dose or stop commitments from companies for use if low blood calcium, signs of QT additional studies and risk minimization prolongation, or arrhythmia continue. For activities. The Committee confirmed these patients, cinacalcet should not be that HES solutions must no longer be started if they have severe hypocalcemia. used to treat patients with sepsis or burn injuries, or critically ill patients, because Reference: Health Canada Important of an increased risk of kidney injury and Safety Information, 15 October 2013 at http:// mortality. HES solutions may, however, healthycanadians.gc.ca/recall-alert-rappel- continue to be used in patients to treat avis/hc-sc/2013/36267a-eng.php hypovolaemia caused by acute blood loss, provided that appropriate measures Ofatumumab and rituximab: are taken to reduce potential risks and reactivation of HBV infection that additional studies are carried out.

United States of America — The Food The review of HES solutions was initially and Drug Administration (FDA) has triggered by the German medicines approved changes to the prescribing agency, the Federal Institute for Drugs information for ofatumumab (Arzerra®) and Medical Devices (BfArM), following and rituximab (Rituxan®) to warn of the studies showing an increased risk of risk of reactivation of hepatitis B virus mortality in patients with sepsis and an (HBV) infection. The revised labelling will increased risk of kidney injury requiring also include additional recommendations dialysis in critically ill patients following for screening, monitoring and managing treatment with HES solutions. patients. Both ofatumumab and rituximab are used to treat certain cancers of the Reference: EMA Press Release, 11 Octo- blood and lymph system. Rituximab is ber 2013 at http://www.ema.europa.eu/ema/ also approved to treat other medical index.jsp?curl=pages/news_and_events/ conditions, including rheumatoid arthritis. news/2013/10/news_detail_001917. Both drugs suppress the immune system. jsp&mid=WC0b01ac058004d5c1

349 Safety and Efficacy Issues WHO Drug Information Vol. 27, No. 4, 2013

Artesunate: haemolytic anaemia requirements for all extended-release and long-acting (ER/LA) opioid analgesics World Health Organization — Injectable intended to treat pain. artesunate is a life-saving therapy for patients with severe Plasmodium The updated indication states that ER/LA falciparum malaria and provides a opioids are indicated for the management substantial reduction of mortality. In of pain severe enough to require daily, the two largest randomized controlled around-the-clock, long-term opioid trials conducted in patients with severe treatment and for which alternative malaria, parenteral artesunate treatment treatment options are inadequate. reduced deaths by 34.7% (Asia) and by 22.5% (Africa) compared with parenteral The updated indication further quinine. WHO currently recommends clarifies that, because of the risks of artesunate (intravenous or intramuscular) addiction, abuse, and misuse, even as the first line treatment for the initial at recommended doses, and because management of severe malaria. of the greater risks of overdose and death, these drugs should be reserved A number of cases of delayed haemolytic for use in patients for whom alternative anaemia have been identified following treatment options (e.g., non-opioid treatment of severe malaria with analgesics or immediate-release opioids) injectable artesunate. In March 2013, the are ineffective, not tolerated, or would Medicines for Malaria Venture (MMV) be otherwise inadequate to provide convened a meeting of experts to review sufficient management of pain; ER/LA the available evidence on delayed opioid analgesics are not indicated for as- haemolytic anaemia following treatment needed pain relief. with injectable artesunate. The FDA is also requiring a new boxed The full report of the expert meeting warning on ER/LA opioid analgesics to is now available on the MMV web site caution that chronic maternal use of these together with an information note which products during pregnancy can result in reflects the current WHO position based neonatal opioid withdrawal syndrome. on the outcome of the review meeting Reference: FDA News Release, 10 Septem- and consultation with the GMP Technical ber 2013 at http://www.fda.gov/NewsEvents/ Expert Group on Malaria Chemotherapy. Newsroom/PressAnnouncements

Reference: Medicines for Malaria Venture. Information Note, 13 October 2013 at (1) Carbamazepine: HLA-B*1502 http://www.who.int/entity/malaria/publications/ genotype testing atoz/who_note_delayed_haemolytic_ anaemia_oct13.pdf. (2) http://www.who. Singapore — The Ministry of Health int/malaria/publications/atoz/who_note_ (MOH) has announced that genotyping haemolytic_anaemia/en/index.html. (3) http:// for the HLA-B*1502 allele prior to the www.mmv.org/newsroom/events/expert-group- initiation of carbamazepine (CBZ) therapy meeting- safety-profile-injectable-artesunate. in new patients of Asian ancestry is now considered the standard of care. These Opioid analgesics: new recommendations by MOH and the new safety warnings Health Sciences Authority (HSA) have been made in consultation with experts United States of America — The Food in various fields such as neurology, and Drug Administration (FDA) has psychiatry and dermatology, following announced class-wide safety labelling the review of findings from local and changes and new postmarket study international studies.

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CBZ has been registered in Singapore Confirmed PRCA cases associated since 1988 and is currently available as with epoetin alfa accounted for 90% Tegretol® and six generic products. It is of total epoetin alfa-associated PRCA indicated for the treatment of epilepsy cases in the HSA Pharmacovigilance and other conditions such as diabetic database since the re-instatement of neuropathy, trigeminal neuralgia and the subcutaneous route for Eprex® in bipolar disorders. While CBZ is an April 2009. This is a disproportionately effective drug and the drug of choice for high number of PRCA cases reported several conditions, Stevens-Johnson compared to the baseline reporting trend. syndrome (SJS) and toxic epidermal necrolysis (TEN), which are associated During this period, nine PRCA cases with significant mortality and long-term were reported from two local healthcare morbidity, have been reported with its institutions. All cases were reported with use. subcutaneous use of Eprex® in chronic kidney disease patients with duration of Between 2003 and 2012, HSA received onset ranging from seven months to 19 131 local serious reports of CBZ-induced months. SJS/TEN (average of 15 reports per year). Since the beginning of 2013, HSA Reference: HSA Safety Alert, 29 August 2013 has received five reports of SJS/TEN at http://www.hsa.gov.sg/publish/hsaportal/ associated with the use of CBZ. A one- en/health_products_regulation/safety_ time HLA-B*1502 genotyping test helps information/product_safety_alerts/Safety_ distinguish high-risk patients who should Alerts_2013/recommendations_for.html avoid CBZ from low-risk patients who are able to continue to use this low-cost yet Sunitinib malate: cutaneous effective medicine. reactions

SJS and TEN often begin with flu-like Canada — A statement has been added symptoms, followed by development of to the product monograph indicating a a red or purplish rash and painful ulcers potential association between sunitinib of mucous membranes. The skin lesions malate (Sutent®) and severe cutaneous then progress to epidermal necrosis and reactions suggestive of Stevens-Johnson detachment. These conditions require syndrome (SJS) and toxic epidermal hospitalization and can be life-threatening necrolysis (TEN). If signs or symptoms and even fatal. are present, treatment should be discontinued. If the diagnosis of SJS or Reference: HSA Safety Alert, 29 August 2013 at http://www.hsa.gov.sg/publish/ TEN is confirmed treatment must not be hsaportal/en/health_products_regulation/ restarted. safety_information/product_safety_alerts/Sa- fety_Alerts_2013/recommendations_for.html Sunitinib malate is indicated for the treatment of gastrointestinal stromal Epoetin alfa: increase tumour after failure of imatinib in pure red cell aplasia mesylate treatment due to resistance or intolerance. It is also indicated Singapore — The Health Sciences for the treatment of metastatic renal Authority (HSA) has advised of an cell carcinoma of clear cell histology unexpected increase in local cases of and for the treatment of patients with antibody-mediated pure red cell aplasia unresectable locally advanced or (PRCA) associated with subcutaneous metastatic, welldifferentiated pancreatic administration of epoetin alfa (Eprex®) neuroendocrine tumours, whose disease during the period 2012 and 2013. is progressive.

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Reference: Health Canada. Advisories, War- Reference: FDA Drug Safety Communication, nings and Recalls, 9 September 2013 at http:// 23 August 2013 at http://www.fda.gov/Drugs/ www.hcsc.gc.ca DrugSafety/ucm368902.htm

Panitumumab: RAS status Ornidazole: adverse eye effects before treatment New Zealand — Since 1987, the Centre United Kingdom — The Medicines for Adverse Reactions Monitoring and Healthcare Products Regulatory (CARM) has received 10 reports where Agency (MHRA) has announced that the patient experienced eye problems — evidence of wildtype rat sarcoma viral mainly described as visual impairment oncogene (RAS) status is required before and blurred vision — following treatment initiating treatment with panitumumab with ornidazole, used to treat bacterial (Vectibix®) alone or in combination with infections. other chemotherapy in the treatment of metastatic colorectal cancer. Inferior Visual impairment and/or blurred vision progression-free survival and overall can affect the user’s ability to drive or survival have been shown in patients operate machinery. Anyone experiencing with RAS mutations beyond KRAS these problems should not drive or exon 2 who received panitumumab operate machinery. combined with oxaliplatin-containing Reference: Medsafe Monitoring Communica- (Folfox®) chemotherapy versus Folfox® tion,1 November 2013 at http://www. alone. medsafe.govt.nz/Projects/B2/monitoring- communications.asp#1-November-2013. These findings emphasize that panitumumab is contraindicated in Statins: risk of acute kidney injury combination with oxaliplatin-based chemotherapy in patients with mutant New Zealand — Medsafe has identified RAS or in whom RAS status is unknown. a possible signal of acute kidney injury (without rhabdomyolysis) with the use Reference: Medicines and Healthcare of high-dose statins following a review Products Regulatory Agency (MHRA). Drug of published literature. Myopathy or Safety Update, Volume 7, Issue 2, September rhabdomyolysis is a well-known adverse 2013 at http://www.mhra.gov.uk effect of statin therapy, with acute kidney injury occurring secondary to these Fentanyl patches: colour changes symptoms. Recent studies however to avoid exposure have suggested that there is a risk of acute kidney injury occurring without United States of America — The prior or concurrent onset of myopathy or Food and Drug Administration (FDA) is rhabdomyolysis. The overall benefit-risk requiring colour changes to the writing balance of statins remains positive. on fentanyl (Duragesic®) pain patches in an effort to prevent accidental exposure. The Centre for Adverse Reactions Used fentanyl patches require proper Monitoring (CARM) has received a total disposal after use. of 38 reports which fulfil the criteria for acute kidney injury with statins. Of these, FDA continues to learn of deaths from 24 also report rhabdomyolysis or creatine accidental exposure to fentanyl patches kinase elevations, which are suggestive and is requiring the manufacturer to print of muscle problems. the name and strength of the drug on the patch in long-lasting ink, in a color that is Acute kidney injury is defined in different clearly visible to patients and caregivers. ways, from acute renal failure with tubular

352 WHO Drug Information Vol. 27, No. 4, 2013 Safety and Efficacy Issues necrosis or unspecified, through to need Longer delays (24 hours) are appropriate for renal replacement therapy such as to consider for patients receiving higher haemodialysis, peritoneal dialysis or therapeutic doses of enoxaparin (1 mg/kg kidney transplantation. twice daily or 1.5 mg/kg once daily).

Reference: Medsafe Monitoring Communica- A post-procedure dose of enoxaparin tion,1 November 2013 at http://www. should usually be given no sooner than medsafe.govt.nz/Projects/B2/monitoring- 4 hours after catheter removal. In all communications.asp#1-November-2013. cases, a benefit-risk assessment should consider both the risk for thrombosis and Low molecular weight heparin: the risk for bleeding in the context of the risk of spinal column bleeding procedure and patient risk factors. and paralysis Epidural or spinal hematomas are a United States of America — The known risk of enoxaparin in the setting Food and Drug Administration (FDA) of spinal procedures and are already is recommending that health care described in warnings and precautions professionals carefully consider the for Lovenox® and generic enoxaparin timing of spinal catheter placement and products. However, these serious removal in patients taking anticoagulant adverse events continue to occur. drugs, such as enoxaparin, and delay dosing of anticoagulant medications for It is important to note that all some time interval after catheter removal anticoagulants carry the risk of causing to decrease the risk of spinal column spinal bleeding when used in conjunction bleeding and subsequent paralysis with epidural/spinal anesthesia or spinal after spinal injections, including epidural puncture. procedures and lumbar punctures. These new timing recommendations, which can Reference: FDA Drug Safety Communication, decrease the risk of epidural or spinal 6 November 2013 at http://www.fda.gov/ hematoma, will be added to the labelling Drugs/DrugSafety/ucm373595.htm of anticoagulant drugs known as low molecular weight heparins, including Pazopanib: hepatotoxicity Lovenox® and generic enoxaparin products and similar products. Canada — Healthcare professionals have been reminded that pazopanib Health care professionals and institutions hydrochloride (Votrient®) is associated involved in performing spinal/epidural with hepatotoxicity including hepatic anesthesia or spinal punctures should failure and fatalities. determine, as part of a pre-procedure checklist, whether a patient is receiving Physicians are asked to monitor serum anticoagulants and identify the liver tests before initiation and during appropriate timing of enoxaparin dosing treatment. Testing of serum liver enzyme in relation to catheter placement or and bilirubin levels during treatment has removal. To reduce the potential risk of increased in frequency and periodic bleeding, consider both the dose and the monitoring should continue after month elimination half-life of the anticoagulant: four.

For enoxaparin, placement or removal of Pazopanib hydrochloride is a tyrosine a spinal catheter should be delayed for kinase inhibitor indicated for treatment at least 12 hours after administration of of metastatic renal cell (clear cell) prophylactic doses such as those used carcinoma as first-line systemic therapy for prevention of deep vein thrombosis. or second line systemic therapy after

353 Safety and Efficacy Issues WHO Drug Information Vol. 27, No. 4, 2013

treatment with cytokines for metastatic Reference: FDA Drug Safety Communication, disease. It is also indicated for treatment 20 November 2013 at http://www.fda.gov/ of patients with selective subtypes of Drugs/DrugSafety/ucm375654.htm advanced soft tissue sarcoma who have received prior chemotherapy Thiocolchicoside: risk of for metastatic disease, or who have aneuploidy progressed within 12 months after (neo) adjuvant therapy. European Union — The European Medi- cines Agency’s Committee on Human Concomitant use of pazopanib hydro- Medicinal Products (CHMP) has recom- chloride and statins should be under- mended that thiocolchicoside-containing taken with caution and close monitoring. medicines for use by mouth or injection should be restricted across the European Reference: Health Canada. Advisories, War- Union. nings and Recalls, 9 August 2013 at http:// www.hcsc.gc.ca These medicines are now recommended only as an add-on treatment for painful Regadenoson and adenosine: muscle contractures resulting from spinal fatal cardiac reactions conditions in adults and adolescents 16 years of age or older. In addition, the United States of America — The Food dose of thiocolchicoside by mouth or and Drug Administration (FDA) has warn- injection should be restricted. ed healthcare professionals of the rare but serious risk of heart attack and death The review of thiocolchicoside was with use of the cardiac nuclear stress triggered by the Italian medicines test agents regadenoson (Lexiscan®) regulatory agency, AIFA, following new and adenosine (Adenoscan®). experimental evidence which suggested that thiocolchicoside was broken down Patients with signs or symptoms of un- in the body into a metabolite (M2 or stable angina or cardiovascular instability SL59.0955) that could damage dividing may be at greater risk for serious cardio- cells, resulting in aneuploidy. Aneuploidy vascular adverse reactions. is a risk factor for harm to the develop- ing fetus, reduced fertility in men and in Regadenoson and adenosine are theory could increase the risk of develop- approved for use during cardiac nuclear ing cancer. stress tests in patients who cannot exercise adequately. They cause blood Preparations for local application to the to flow preferentially to the healthier, skin, which do not produce substantial unblocked or unobstructed arteries. In levels of M2 in the body, are not affected some cases, this reduced blood flow can by this review. lead to a heart attack, which can be fatal. Reference: EMA Press Release, 22 Novem- Cardiac resuscitation equipment and ber 2013 at http://www.ema.europa.eu/ema/ trained staff should be available before index.jsp?curl=pages/news_and_events/ administering regadenoson or adeno- news/2013/11/news_detail_001967. sine. jsp&mid=WC0b01ac058004d5c1

Spontaneous monitoring systems are useful in detecting signals of relatively rare, serious or unexpected adverse drug reactions. A signal is defined as “reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented pre- viously. Usually, more than a single report is required to generate a signal, depending upon the seriousness of the event and the quality of the information”. All signals must be vaidated before any regulatory decision can be made.

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