Published by the Centre for Drug Administration, HSA and the HSA Pharmacovigilance Advisory Committee

Letter from Editor

HSAs communication of drug safety information

he safety profile of many drugs are never fully known at the time of marketing. This is largely due to the limited applicability of animal models to predict human responses to drugs and the limitations of clinical trials. It is only when a drug is used in real-life clinical situations or when further post-marketing studies on a larger number of patients are conducted, that new safety concerns start to emerge. At HSA, we recognise it is important that healthcare professionals are informed in a timely manner on important drug safety information so that you can make better informed decisions on the use of the affected health product. To enhance your access to timely drug safety information, we have developed several communication channels for dissemination of such information.

information using a single-sign-on password entry and interface. The drug safety information available at HPP include: Dear Healthcare Professional Letters (issued by HSA and pharmaceutical companies) MedAlerts (issued by MOH)

Past copies of the Dear Healthcare Professional letters can be found at the HPP .

C) Electronic dissemination of information

In addition to the mailing of the HSA ADR News bulletin and Dear Healthcare Professional Letters via post, HSA also sends out urgent drug safety information e.g. product suspension and withdrawals, to healthcare professionals via electronic cascade (email, facsimile, SMS). To ensure that you continue to receive the most recent drug safety information, healthcare professionals are encouraged to update your contact details such as email address, facsimile number and/or mobile number at the HPP .

A ) H S As w e b s i t e (http://www.hsa.gov.sg/safetyinfo_and_recalls)
The HSA s website provides the following drug safety information: Product Safety Alerts (alerts on major drug safety concerns) Dear Healthcare Professional Letters (advisories available in abstracts only, full contents are available at the MOH Health Professionals Portal) Product Recalls (recall of batches of products due to quality and safety concerns) Product Safety Labelling Amendments (amendments to the package inserts to include new safety information) HSA Adverse Drug Reaction News bulletin and New Drugs List

D) Online search for local ADR reports

An online facility to search for local ADR reports is also available at the HPP . This database contains over 11,000 local spontaneous ADR reports that have been received by the Pharmacovigilance Unit, HSA since the national ADR monitoring programme started in 1993. We hope that healthcare professionals will find the above drug safety communication channels that we have developed useful for keeping abreast of drug safety information. We welcome your feedback on how we can improve our services better.

B) MOH Health Professionals Portal (http://www.hpp.moh.gov.sg)

The HPP is a one-stop portal developed by the Ministry of Health for healthcare professionals such as dentists, doctors and pharmacists to access multiple secure e-services and

Editor-in-Chief

Chan Cheng Leng

ISSN: 0219 - 2152 March 2008 Vol.10 No.1

1 2 3 4

HSA's communication of drug safety information Update on rosiglitazone and cardiovascular risks Strontium (Protos): A safety update Analysis of ADR reports 2007

6 6 7 8

Suicidality associated with antiepileptic drugs Update on suspension of sales of nimesulide in Singapore Package insert amendments reflecting safety issues Update on Evra and thromboembolism

CONTENTS

Adverse Drug Reaction News March 2008 Vol.10 No.1

Update on rosiglitazone and cardiovascular risks

Reduction Assessment with Rosiglitazone and Ramipril Medication), RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes). For all three trials, analyses were performed using a composite of major adverse cardiovascular events, (i.e. cardiovascular death, myocardial infarction and stroke, known as MACE) as endpoint. In their entirety, the available data on the risk of myocardial ischaemia were not conclusive.

B) Publication of Long-term Risk of Cardiovascular Events with Rosiglitazone in JAMA

On 12 September 2007, the Journal of the American Medical Association (JAMA) published a systemic review and metaanalysis of the long-term cardiovascular risks for rosiglitazone, including myocardial infarction, heart failure and cardiovascular mortality. Rosiglitazone appeared to significantly increase the risk of myocardial infarction (RR 1.42, p=0.02) and heart failure (RR 2.09, p<0.001) without a significant increase in risk of cardiovascular mortality (RR 0.90, p=0.53).3

osiglitazone (Avandia, GlaxoSmithKline) has been registered by HSA since 2000 for use as an adjunct to diet and exercise in the treatment of type 2 diabetes mellitus; as monotherapy or in combination with metformin or a sulfonylurea to reduce insulin resistance; and to lower elevated blood glucose in patients with type 2 diabetes mellitus. Avandamet, also by GlaxoSmithKine (GSK), contains a combination of rosiglitazone and metformin.

C) Other on-going long-term clinical trials

GSK has several other on-going long-term studies which are intended to increase the available data on the cardiovascular safety of rosiglitazone with most of them ending in 2008. RECORD is the largest prospective long-term study for type 2 diabetes patients specifically to determine the cardiovascular outcomes of death and hospitalisation in rosiglitazone containing regimens versus patients treated with the combination of metformin and sulfonylurea. The study is due to finish in late 2008 with results expected in early 2009.

Background
In May 2007, the New England Journal of Medicine published an article by Nissen and Wolski1 which suggested the possibility of an increased risk of adverse cardiac events associated with rosiglitazone. The increased risk of myocardial infarction (odds ratio 1.43, p=0.03) and cardiovascular death (odds ratio 1.64, p=0.06) was arrived at in a meta-analysis of 42 clinical studies which had about 15,500 patients treated with rosiglitazone compared with 12,282 patients on regimens that did not include rosiglitazone.

Actions taken by international regulatory agencies

The UK Medicines and Healthcare Products Regulatory Agency (MHRA), European Medicines Agency (EMEA), Health Canada and the US FDA have all taken the similar stance that there were insufficient evidence to indicate that the risks of myocardial infarction or death are different between rosiglitazone and some other oral type 2 diabetes mellitus treatments, and the benefits of rosiglitazone in the treatment of type 2 diabetes continue to outweigh their risks. However, in all the various jurisdictions, the product information of rosiglitazone-containing products will be updated to include warning that in patients with ischaemic heart disease, rosiglitazone should only be used after careful evaluation of each patient's individual risk. In Canada, it has been announced that rosiglitazone is no longer approved as monotherapy for type 2 diabetes, nor for use in combination with sulfonylurea, except when metformin use is contraindicated or not tolerated. Treatment with all rosiglitazone products is now contraindicated in patients with any stage of heart failure (i.e. NYHA Class I, II, III or IV). The product information for Avandia is currently under review by Health Canada.

Various analyses to verify the association of rosiglitazone with cardiovascular risks A) US FDA advisory committee meeting2 Pooled data from 42 clinical trials
The US Food and Drug Administration (FDA) convened a public Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee meeting on 30 July 2007 to review the cardiovascular profile of rosiglitazone. The FDA conducted their own analysis of the 42 double-blind, randomized, controlled clinical trials which were used in Nissen and Wolski's paper. In their analysis, an increased risk of myocardial ischaemia with rosiglitazone versus pooled comparators was observed (odds ratio 1.4, 95% CI 1.1, 1.8). An increased risk of myocardial ischaemic* events with rosiglitazone was observed in the placebo-controlled studies, but not in the active-controlled studies. (*Angina pectoris aggravated, unstable angina, cardiac arrest, chest pain, coronary artery occlusion, dyspnoea, myocardial infarction, coronary thrombosis, myocardial ischaemia, coronary artery disease/disorder.)

Conclusion
Based on the available data to-date, there is insufficient evidence at this point to conclude that the risks of myocardial infarction and cardiovascular death is higher for rosiglitazone compared to other type 2 diabetes treatments. However, to promote safe use of this drug, HSA is working with the company to strengthen the prescribing information in the local package inserts of Avandia
continued on Page 3

Large long-term prospective randomized controlled trials

Data from three other large long-term prospective randomized controlled trials were also analysed for myocardial ischaemic events - ADOPT (A Diabetes Outcomes Progression Trial), DREAM (Diabetes

March 2008 Vol.10 No.1 Adverse Drug Reaction News

Strontium (Protos): A safety update

Risk of severe hypersensitivity reaction syndromes

and there is a risk of symptoms returning during the recovery period. As of November 2007, 16 cases of DRESS were reported to the CHMP . The latency period between the first ingestion of Protos and the display of symptoms of DRESS is about 3 to 6 weeks. All of the cases were classified as severe and required hospital treatment. Two of the patients died. The CHMP had evaluated that the link between Protos and DRESS was not recognized immediately and the delay before the medicine was stopped could have resulted in the severity of outcome in these patients.

Other regulatory actions

In light of the post-marketing reports described above, the CHMP concluded that the use of Protos is linked to an increased risk of DRESS and recommended that warnings on severe hypersensitivity syndromes, including DRESS and Stevens Johnson syndrome be included in the product and patient information for Protos. Protos is not registered in the United States and Canada.

trontium ranelate (Protos, Ser vier) has been registered in Singapore since July 2006 for the treatment of postmenopausal osteoporosis to reduce the risk of vertebral and hip fractures. Since its launch in Europe in 2004, Protos is registered in 64 countries and has a total of about 570,000 patient-years of exposure.

HSA's advisory and actions

To date, HSA has not received any ADR reports associated with Protos and DRESS. There is one case of a patient who developed Stevens Johnson syndrome after taking both Protos and Arcoxia (etoricoxib) concurrently for about one month. She has since recovered. In view of this emerging safety concern, prescribers are advised to inform their patients of the risk of severe allergic reactions and to inform them to stop Protos immediately should a rash occur and to seek medical advice. For patients who have stopped treatment due to hypersensitivity reactions, Protos should not be re-introduced. HSA has worked with the company to update the package insert of Protos to include warnings on cases of severe hypersensitivity syndromes linked to the use of Protos, as well as the postmarketing adverse reactions to Protos.

Safety concern
In November 2007, the European Medicines Agency's (EMEA) Committee for Medicinal Products for Human Use (CHMP) was alerted to an increasing number of reports of drug rash with eosinophilia and systemic symptoms (DRESS) associated with the use of Protos. DRESS is a rare but serious and life-threatening type of allergic reaction to a drug. The condition starts with a skin rash, accompanied by a fever, swollen glands, eosinophilia, adenopathy and systemic involvement which may include hepatic, renal and pulmonary impairment. In most cases, the symptoms resolved upon discontinuation of Protos and with the initiation of corticosteroid therapy. However, it has been reported that recovery can be slow

continued from Page 2 Update on rosiglitazone and cardiovascular risks

and Avandamet. Information on cardiac ischaemia will be included in the adverse reactions and clinical studies sections of the package insert, and the initiation of rosiglitazone will be contraindicated in patients with NYHA Class III and IV heart failure. Healthcare professionals are encouraged to report all serious adverse effects suspected to be associated with the thiazolidinediones class of medicines, namely, rosiglitazone and pioglitazone, to the Pharmacovigilance Unit.
References 1. N Engl J Med 2007 Jun;356(24):2457-71.

Suspect an Adverse Reaction? Report it.

HSA wants to be informed of suspected adverse reactions that ar e: are: serious (even if the r eactions ar e well known) reactions are - for medicines and natural health pr oducts products serious and non-serious - for r ecently recently marketed medicines (< 5 years) [Please r efer to HSA s lists of newly appr oved refer HSA approved drugs at www .hsa.gov .sg/adrbulletin] www.hsa.gov .hsa.gov.sg/adrbulletin] Please pr ovide as much information as you can provide to allow the Pharmacovigilance Unit of HSA to do case assessment. However , please do not be However, ed fr om r eporting because some details deterr from reporting deterred ar e not known. are

2. FDA briefing document. http://www.fda.gov/ohrms/dockets/ac/07/ briefing/2007-4308b1-02-fda-backgrounder.pdf (accessed on 16 January 2007) 3. JAMA 2007 Sep;298(10):1189-95.

Adverse Drug Reaction News March 2008 Vol.10 No.1

Analysis of ADR reports for year 2007

Based on a breakdown of the ethnic groups, Chinese patients constituted the highest proportion (61.6%), followed by Malays (12.5%) and Indians (8.3%). Majority of ADRs were reported to occur in patients between 30 and 69 years of age (62.6%) as shown in Chart 1. There were more reports of ADRs occurring in females (57.6%) than males. Most of the reports received were associated with pharmaceutical medicines (96.9%) and Table 1 shows the top 15 drugs commonly suspected of causing ADR. Most of the ADRs reported were skin-related disorders (25.0%) as listed in Table 2. Examples of serious ADR reports are listed in Table 3.

n the year 2007, the Pharmacovigilance Unit of HSA received a total of 13,475 local spontaneous reports of suspected adverse drug reaction (ADR) to health products (pharmaceuticals, biologics, complementary medicines and cosmetics). Of these, 1,740 ADR reports were reviewed and analysed. The reviewed reports were mainly from healthcare professionals in the public hospitals (50.6%), followed by public institution/government clinics (31.5%), private clinics/hospitals (9.4%), pharmaceutical companies (8.4%) and community pharmacies (0.1%). Of all the reports reviewed, 736 (42%), were classified as serious by the reporters.

Chart 1: Breakdown of the no. of patients who experienced ADRs by age group (n = 1,740)

Table 1: Top 15 drugs (by active ingredients) suspected of causing ADRs Top 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Active ingredient Diclofenac Naproxen Cotrimoxazole Metoclopramide Hydrochlorothiazide Atenolol Simvastatin Amoxicillin Aspirin Paracetamol Coamoxiclav Mefenamic acid Docetaxel Paclitaxel Ciprofloxacin No. of reports (% **) 76 (4.4) 70 (4.0) 63 (3.6) 63 (3.6) 59 (3.4) 58 (3.3) 48 (2.8) 41 (2.4) 41 (2.4) 38 (2.2) 38 (2.2) 36 (2.1) 34 (2.0) 34 (2.0) 32 (1.8)

Table 2: Top 10 ADRs by system-organ classes* Top 1 2 3 4 5 6 7 8 9 10

*

Active ingredient Skin & appendages Body as a whole Respiratory Nervous Gastrointestinal Psychiatric Vascular (extracardiac) Urinary Musculoskeletal Metabolic & nutritional

No. of reports (% **) 758 (25.0) 544 (17.9) 303 (10.0) 244 (8.0) 234 (7.7) 113 (3.7) 110 (3.6) 108 (3.6) 99 (3.3) 99 (3.3)

* More than one suspected drug may be implicated in an ADR report. ** % of total no. of ADR reports (n=1,740)

The system-organ class refers to the adverse reaction terminology developed by the WHO. (NB: More than one ADR term may be described in an ADR report) ** % of total no. of ADR terms (n=3,038) quoted

March 2008 Vol.10 No.1 Adverse Drug Reaction News

Table 3: Drugs suspected of causing serious blood, hepatic and skin adverse reactions Description WHO ADR preferred term Agranulocytosis / neutropenia Haemolytic anaemia Leucopenia Pancytopenia Thrombocytopenia Suspected active ingredient (the number in the bracket represents the number of times the drug has been implicated *) Benzylpenicillin (1), carbamazepine (1), carbimazole (2), cloxacillin (1), cyclophosphamide (1), erythromycin (1), mefenamic acid (1), methimazole (1), phenytoin (1), ticlopidine (1) Dapsone (1) Allopurinol (1), colchicine (2), leflunomide (1), quetiapine (2), sulfasalazine (3), ticlopidine (1), zidovudine (1) Amoxicillin (1), azathioprine (1), cloxacillin (1), cyclophosphamide (1), methotrexate (1), phenytoin (1), teicoplanin (1) Amoxicillin (1), azathioprine (1), bevacizumab (1), carbamazepine (2), clopidogrel (1), heparin (1), pentazocine (1), phenytoin (1), pyrimethamine (1), sunitinib (1) Buprenorphine (1), carbamazepine (1), coamoxiclav (1), cotrimoxazole (1), isoniazid (1), pyrazinamide (1), rifampicin (1), streptomycin (1) Allopurinol (1), sorafenib (1)

Blood disorders

Hepatic disorders

Cholestatic hepatitis Hepatic failure

Hepatic encephalopathy Sorafenib (1) Hepatitis/ Hepatitis with jaundice Abacavir (1), atorvastatin (1), azathioprine (3), ciprofloxacin (1), cotrimoxazole (2), dapsone (1), enalapril (1), ertapenem (1), ketoconazole (1), lovastatin (1), methotrexate (1), nevirapine (1), nimesulide (1), phenytoin (2), rifampicin (1), rosiglitazone (1), simvastatin (2), valaciclovir & valganciclovir (1) Aciclovir (1), allopurinol (10), amitriptyline (1), amoxicillin (5), buprenorphine (1), carbamazepine (7), ceftriaxone (1), chloramphenicol (1), ciprofloxacin (1), clarithromycin (1), coamoxiclav (2), colchicine (1), cotrimoxazole (6), dapsone (1), erythromycin (1), ethambutol (4), etoricoxib (1), isonazid (3), levofloxacin (1), mefenamic acid (1), meropenem (1), naproxen (1), nevirapine (1), omeprazole (3), phenytoin (7), piperacillin & tazobactam (1), pyrazinamide (3), pyrimethamine (1), rifampicin (2), streptomycin (1), tazobactam (1), ticlopidine (1)

Skin disorders

Stevens Johnson syndrome (SJS)/Toxic epidermal necrolysis (TEN)/SJS-TEN

* More than one suspected drug may be implicated in a single ADR report.

You can log in to the Health Professionals Portal to search for local spontaneous ADR reports (http://www.hpp.moh.gov.sg).
The local ADR reports are submitted by healthcare professionals and pharmaceutical companies. Each report represents the suspicion, opinion or observation of the individual reporter. It is important to note that cause and effect relationships have not been established in the vast majority of reports submitted. Other factors, such as underlying disease or other concomitant medications may also have contributed towards or caused the reaction. In addition, as only a certain proportion of suspected ADRs are reported to the Pharmacovigilance Unit of HSA, the information obtained from this website must not be used to estimate the incidence of ADRs in Singapore. Nonetheless, these ADR reports are important to HSA as they allow HSA to monitor for signals of potential safety concern with any health product and to carry out further investigations on the product.

Adverse Drug Reaction Online Enquiry (ADR)

Adverse Drug Reaction News March 2008 Vol.10 No.1

Suicidality associated with antiepileptic drugs

This increased risk of suicidal behaviour and ideation was observed between one to 24 weeks after taking the drugs and could not be reliably assessed beyond 24 weeks. The results were found to be consistent among the drugs and were reflected in all demographic subgroups. There was no clear pattern of risk across the age groups observed. It was also noted that the relative risk for suicidal thoughts or behaviour was higher for patients with epilepsy compared to those with psychiatric or other disorders (see Table 2).

SA would like to inform healthcare professionals about the recent findings of the US Food and Drug Administration (FDA) on the increased risk of suicidal thoughts and behaviour associated with antiepileptic drugs (AEDs) from the analysis of 199 placebo-controlled clinical trials. This analysis was triggered by a preliminary finding in March 2005 that several drugs in this class were associated with an increased risk of suicidality.

Findings from FDA's review of clinical trials

The US FDAs analysis involved 11 AEDs (see Table 1) which examined the effectiveness of drugs in epilepsy, psychiatric disorders (e.g. bipolar disorder, depression and anxiety) and other conditions (e.g. migraine and neuropathic pain syndrome). The analysis included a total of 43,892 patients (5 years old and above) with 27,863 patients in the drug treatment groups and 16,029 in the placebo groups.

Table 2: Relative risk and risk difference for suicidality Indication Placebo Drug Relative risk: Risk
patients with events per 1,000 patients patients with events per 1,000 patients Incidence of events in drug patients/ incidence in placebo patients 3.6 1.6 2.3 2.0 difference: Additional drug patients with events per 1,000 patients 2.5 3.1 1.1 2.1

Table 1: AEDs included in US FDA analysis and AEDs available in Singapore AEDs studied by the US FDA
Carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, zonisamide

AEDs available in Singapore

Carbamazepine, gabapentin, lamotrigine, levetiracetam, pregabalin, topiramate, valproate, *phenytoin, *vigabatrin * AEDs not included in the
US FDA's review.

Epilepsy Psychiatric Other Total

1.0 5.2 0.8 2.2

3.5 8.3 2.0 4.3

The local situation and HSAs advisory

To date, HSA has not received any local ADR reports of suicidality associated with AEDs. Nevertheless, healthcare professionals should take into consideration the above safety information when prescribing and managing patients on AEDs. Healthcare professionals are also encouraged to report adverse events of suicidality suspected to be associated with AEDs to HSA. In the meanwhile, HSA will be working with the drug companies to update the prescribing information in the package inserts of the class of AEDs.

The findings revealed four completed suicides among patients in the drug treatment groups and none among the patients in the placebo groups. Patients receiving AEDs had approximately twice the risk of suicidal behaviour or ideation (0.43%) as compared to patients receiving placebo (0.22%), corresponding to an estimated 2.1 per 1,000 (95% CI 0.7, 4.2) more patients in the drug treatment groups who experienced suicidal behaviour or ideation than in the placebo groups.

Update on suspension of sales of nimesulide in Singapore

n June 2007, HSA suspended the local sales of nimesulide-containing oral preparations pending the safety review of nimesulide following both local and overseas signals of liver toxicities. Nimesulide, a non-steroidal antiinflammatory drug, is indicated for the treatment of acute pain, symptomatic treatment of painful osteoarthritis and primary dysmenorrhoea. The European Medicines Agency's (EMEA) Committee for Medicinal Products for Human Use (CHMP) was tasked to review the safety profile of nimesulide following the suspension of nimesulide in Ireland in May 2007 due to concerns with liver toxicities. CHMP concluded in September 2007 that nimesulide is associated with an increased risk of liver toxicity. However, the committee recommended that nimesulide could continue to be marketed in the European Union but with strict restrictions imposed on the use of the drug: nimesulide

should not be prescribed to patients with compromised liver function nor patients prescribed other medicines that can also cause liver damage, and to limit the treatment of nimesulide to a maximum of 15 days.

Outcome of HSA's review

HSA completed the review of available data, which comprised local adverse drug reaction reports, the WHO international adverse drug reactions database, literatures, EMEA's review and local consumption data of nimesulide in December 2007. The review concluded that: Nimesulide is associated with an increased risk of liver toxicity, though the incidence is rare, and there is no clear elucidation of the mechanism of action. The risks versus benefits profile of nimesulide is unfavourable in view of the presence of isolated cases of liver injuries associated with nimesulide in

Singapore, the inability to identify patients who might be at risk, and the difficulty in implementing restricted use of nimesulide in the local context. There are alternative treatment options available for treating the conditions that nimesulide is indicated for. Hence, the sales of oral preparations containing nimesulide will remain suspended and the product licences of Nidol tablet, Nidol satchet, NimotasCD Ttablet, Nise tablet and Qnim MD tablet will not be renewed upon expiry. Effectively, this means that no marketing of nimesuilde has been authorised by HSA since June 2007. HSA has posted a Dear Healthcare Professional Letter to inform all healthcare professionals of this decision on 26 December 2007 in the Health Professionals Portal. For details of the letter, please log onto the portal at http://www.hpp.moh.gov.sg

March 2008 Vol.10 No.1 Adverse Drug Reaction News

Package insert amendments reflecting safety issues

SA has approved the following package insert changes due to safety updates from August 2007 to January 2008. Please note that due to space constraints, the list published is not exhaustive and readers are encouraged to refer to the following website for the complete listing with details: http://www.hsa.gov.sg/ safetyinfo_and_recalls . Please also note that there might be some lag time in the availability of the package insert which reflects the latest change(s).

1 2 3

Bromocriptine (Parlodel, Novartis) ADR: Cardiac valve fibrosis. Budesonide (Rhinocort Aqua, AstraZeneca) Pregnancy & lactation: Small increase in occurrence of minor heart malformations detected in children where the mother has been exposed to Rhinocort Aqua in early pregnancy. Consider breastfeeding during treatment only after assessing risk vs benefit. Cabergoline (Dostinex, Pfizer) Contraindications: History of pulmonary, pericardial & retroperitoneal fibrotic disorders. Anatomical evidence of cardiac valvulopathy of any valve. Warnings & precautions: Erythrocyte sedimentation rate (ESR) found to be abnormally increased in association with pleural effusion/fibrosis may warrant a chest X-ray. Serum creatinine measurements can be used to help in the diagnosis of fibrotic disorder. All patients recommended to undergo cardiovascular evaluation, including an ECG, to assess potential presence of an occult valvular disease before initiating treatment with cabergoline. Subsequent regular clinical diagnostic monitoring (e.g. physical examination, X-ray, ECG, CT scan) for development of valvular disease or fibrosis is recommended. ADR: Asymptomatic valvular regurgitation. Cefuroxime (Zinacef, GSK) Interaction: Zinacef may affect the gut flora, leading to lower oestrogen reabsorption & reduced efficacy of combined OCs. ADR: Cutaneous vasculitis. Celecoxib (Celebrex, Pfizer) Co-administration of an ACE inhibitor &/or an angiotensin II antagonist together with a selective or non-selective COX-II inhibitor can further impair renal function, potentially resulting in acute renal failure (effect usually reversible). Ciclosporin (Gengraf, Abbott) Warnings: Increased risk for development of lymphomas & other malignancies, particularly of skin. Increased risk is related to the intensity & duration of immunosuppression. Use multiple concomitant immunosuppressants with caution in case of immune-oversuppression. Cases of convulsions reported in adults & paediatric patients receiving concomitant high doses methylprednisolone. Care should also be taken in using ciclosporin with nephrotoxic drugs. Encephalopathy has been described post-market, esp. in patients receiving liver transplants. Predisposing factors include hypertension, hypomagnesemia, hypocholesterolaemia, high dose corticosteroids, high ciclosporin blood concentrations, & graft-vs-host disease. ADR: Optic disc edema including papilloedema, with possible visual impairment, secondary to benign intracranial hypertension (rare).

Antidepressants increased the risk of suicidal thinking & behaviour (suicidality) in children, adolescents & young adults in short-term studies of major depressive disorder (MDD) & other psychiatric disorders. There was a reduction in risk with antidepressants compared to placebo in adults 65 yrs. Monitor patients of all ages who are started on antidepressant therapy for clinical worsening, suicidality or unusual changes in behaviour. Precautions: History of liver or kidney problems, seizures or blackouts, diabetes, heart problems, abnormal bleeding, patients on herbal products e.g. St. John's Wort, pregnancy & lactation: Some neonates exposed to fluoxetine, late in the third trimester have been reported to develop complications requiring prolonged hospitalisation, respiratory support & tube feeding. Interactions: MAOIs, thioridazine, other antidepressants, sedatives, drugs which may affect blood clotting & increase bleeding, aspirin, NSAIDs, drugs used to treat diabetes & linezolid. Limit alcohol intake while taking pms-fluoxetine. ADRs: Upset stomach, anxiety, weakness, loss of appetite, affect sexual functioning. Symptoms such as headache, insomnia, paraesthesias (numbness, tingling, burning or prickling sensation), nervousness, anxiety, nausea, sweating, dizziness, jitteriness & weakness & other symptoms have been reported after stopping pms-fluoxetine. Formoterol (Foradil, Novartis) Warnings & precautions: A study observed a higher rate of death due to asthma in patients treated with salmeterol compared with placebo. Foradil should not be used in conjunction with another long-acting beta2agonist. Placebo-controlled clinical studies with Foradil suggested a higher incidence of serious asthma exacerbations in patients who received Foradil than in those who received placebo. Foradil must not be initiated or the dose increased during an asthma exacerbation. Foradil must not be used to relieve the acute symptoms of an asthma attack. ADRs: Dysgeusia & peripheral oedema. Isotretinoin (Oratane, Apex Pharma) Warnings & precautions: Use of topical tretinoin is not recommended during pregnancy, esp. 1st trimester. Risk of sudden onset of decreased night vision. Avoid waxing, dermatological abrasions, facial peels & some hair treatments while using Oratane & for 6 months after isotretinoin treatment is stopped. Interaction: May reduce effect of carbamazepine. Lactulose (pms-lactulose, IDS) Precautions: If diarrhoea occurs when using lactulose in Portal Systemic Encephalopathy (PSE), it may severely deplete fluids & potassium & may intensify symptoms of PSE hence potassium levels should be monitored during long-term treatment with lactulose. Caution needed if an unusual diarrhoeal condition occurs during lactulose therapy. Debilitated patients who receive lactulose for > 6 months should have serum electrolytes (e.g. potassium, chloride, carbon dioxide) measured periodically during therapy. ADRs: Gaseous distention, belching, borborygmi, &/or abdominal discomfort (may occur during first few days of therapy but subside with continued therapy or dosage reduction). Infants receiving lactulose may develop dehydration & hyponatraemia. Lopinavir & ritonavir (Kaletra, Abbott) Rosuvastatin can interact with Kaletra. Use lowest possible dose of rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors like pravastatin or fluvastatin in combination with Kaletra. Lovastatin (Ellanco, CCM Pharmaceuticals) Revisions to dosage section: Reduce dose if LDL-cholesterol levels fall below 75mg/dL (1.94mmol/L) or total plasma cholesterol levels falls below 140mg/dL (3.6mmol/L). Warnings & precautions: Perform transaminase tests before treatment begins & periodically thereafter, particularly in patients who have abnormal liver function tests &/or consume substantial amounts of alcohol & in patients in whom the dose is increased to 40mg/day or more. Myopathy & rhabdomyolysis have occurred in transplant & non-transplant patients following concomitant treatment with itraconazole. Lovastatin has only a moderate TG-lowering effect & is not indicated where hypertriglyceridaemia is the abnormality of most concern (i.e. hyperlipidemia types I, IV & V).

ADRs: Flatulence, diarrhoea, constipation, nausea, dyspepsia, muscle cramps, myalgia, abdominal pain, fatigue, pruritus, dry mouth, insomnia, sleep disorders, myopathy & rhabdomyolysis (rare).

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Methylphenidate (Concerta, J&J) ADRs: Nervousness, disorientation, confusional state, alopecia, hypersensitivity reactions such as angioedema, anaphylactic reactions, auricular swelling, bullous conditions, exfoliative conditions, urticarias, pruritus, rashes, eruptions & exanthemas. Nifedipine (Adalat, Bayer) Warnings: In pregnancy, careful monitoring of blood pressure required when administering nifedipine with IV magnesium sulfate due to possible excessive fall in blood pressure which could harm mother & fetus. ADRs: Angioedema, larynx oedema, anaphylactic/ anaphylactoid reaction, anxiety reactions, sleep disorders, migraine, dysaesthesia, nosebleed, GI & abdominal pain, vomiting, joint swelling, polyuria, dysuria, erectile dysfunction, unspecific pain, & chills. Interactions: CYP 3A4 inhibitors or CYP 3A4 inducers, phenytoin, carbamazepine, phenobarbitone, tacrolimus & grapefruit juice. Norelgestromin & ethinyl estradiol (Evra, J&J) Interaction: Bosentan. ADRs: Abnormal blood cholesterol decreased blood glucose, increased low density lipoprotein, migraine with aura, cerebral haemorrhage, haemorrhage intracranial, haemorrhagic stroke, subarachnoid haemorrhage, dermatitis allergic, exfoliative rash, photosensitivity reaction, hyperglycaemia, insulin resistance, fibroadenoma of breast, uterine leiomyoma, cervical dysplasia, hypomenorrhoea, menometrorrhagia, oligomenorrhoea, suppressed lactation, emotional disorder, & insomnia. Olmesartan medoxomil (Olmetec, Pfizer) Contraindication: Pregnancy. Caution: Increased risk of renal insufficiency may occur when patients with bilateral renal artery stenosis (or stenosis of the artery to a single functioning kidney) are treated with drugs that affect the renin-angiotensin system. ADRs: Vomiting, pruritus, acute renal failure, increased blood creatinine & hyperkalaemia. Risperidone (Risperdal, J&J) Warnings: Caution in patients with a history of cardiac arrhythmias, congenital long QT syndrome. Clinically significant hypotension reported for concomitant use with antihypertensive treatment. ADRs: URTI, UTI, anaemia, dyspnoea, epistaxis, seborrhoeic dermatitis, arthralgia, increased blood creatine phosphokinase, pneumonia, confusional state, transient ischaemic attack, conjunctivitis, faecaloma, agranulocytosis, thrombocytopenia, anaphylactic reaction, diabetic ketoacidosis, mania, atrial fibrillation, sleep apnoea syndrome, intestinal obstruction, & jaundice. Strontium ranelate (Protos, Servier) Warnings & precautions: Cases of severe hypersensitivity syndromes, including drug rash with eosinophilia & systemic symptoms (DRESS), sometimes fatal, was reported. Stop Protos immediately & permanently when a rash occurs & seek medical advice. Discontinue Protos therapy in case of serious allergic reaction. ADRs: Vomiting, abdominal pain, stomatitis, mouth ulceration, angioedema, SJS, muscle spasm, myalgia, bone pain, arthralgia, & pain in extremity. Terbinafine (Lamisil, Novartis) Warnings & precautions: Evaluate aetiology of any very rare cases of blood dyscrasias (neutropenia, agranulocytosis, thrombocytopenia, pancytopenia) that occur in patients treated with Lamisil & consider a possible change in medication regimen. Lamisil tablets has not been adequately studied in renal impairment & therefore not recommended. Serious skin reactions (e.g. SJS, TEN) have been very rarely reported. If progressive skin rash occurs, discontinue Lamisil. Very rare cases of serious liver failure (some with a fatal outcome, or requiring liver transplant) have been reported. ADRs: Pancytopenia, dizziness, paraesthesia & hypoaesthesia. Zolpidem (Stilnox, Sanofi-Aventis) Caution: In view of lack of data, preferable not to use zolpidem at any stage during pregnancy. If treatment is necessary towards the end of pregnancy, avoid high doses & monitor neonate for signs of impregnation, respiratory depression, apnoea, hypothermia, & withdrawal syndrome. ADRs: Hallucinations & somnambulism.

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17 18

4 5 6

10

11

19

12 13

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7 8

Drotrecogin alfa (Xigris, Eli Lilly) Warnings: Prophylactic heparin should not be discontinued unless considered medically necessary. Interaction: Prophylactic heparin increased the risk of nonserious bleeding. Fluoxetine (pms-fluoxetine, IDS) Contraindication: Concomitant therapy with thioridazine. Warnings: Not for children < 18 years of age. Not to use concomitantly with pimozide due to rare reports of prolonged seizures. Patients may experience unusual feelings of agitation, hostility or anxiety, or have impulsive or disturbing thoughts such as thoughts of self-harm or harm to others, particularly in the first few weeks or when doses are adjusted. Caution: Patients with history of allergic reactions.

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Adverse Drug Reaction News March 2008 Vol.10 No.1

Update on Evra and thromboembolism

Since marketing, there has been a higher number of spontaneous case reports of VTE associated with patients on Ortho Evra and Evra compared to other COC, which raised the concern as to whether hormonal transdermal patches could be associated with a higher VTE risk.

Review of epidemiology studies conducted

Since the update in March 2007, an additional unpublished epidemiology study (BCDSP LNG-30 OC study) and an analysis of new data from the previously completed epidemiology study (BCDSP NGM-35 OC1 study) has been conducted to evaluate the relative risk of VTE in Ortho Evra users compared to other COC users. BCDSP LNG-30 OC study showed odds ratio 2.0 (95% C.I 0.9-4.1) while the analysis of new data from BCDSP NGM-35 OC study showed odds ratio 1.1 (95% C.I 0.6-2.1). To date, three nested case-control epidemiology studies, using electronic health claims database, have been conducted to compare the relative risk of VTE in Ortho Evra users against other COC users (using 30-35mcg EE and either levonorgestrel or norgestimate) in women aged 15-44. The studies are i3 Ingenix study, BCDSP NGM-35 OC study and BCDSP LGN-30 OC study. Of the studies, only i3 Ingenix study reached statistical significance at an odds ratio of 2.4 (95% CI 1.1-5.5).

his is an update on the further findings from the recently completed studies reviewing the relative risk of venous thromboembolism (VTE) associated with use of Ortho Evra compared to combined oral contraceptives (COC) [please refer to HSA ADR News Bulletin (March 2007; Vol.9 No.1) for the earlier review.] Evra (Johnson & Johnson) is a transdermal combined contraceptive patch containing 6mg norelgestromin (NGMN) and 600mcg ethinyl estradiol (EE) that has been registered locally since 2003. Ortho Evra is the formulation of Evra marketed in U.S, containing 6mg NGMN and 750mcg EE.

Table 1: Summary of epidemiology studies comparing estimates (odds ratios) of VTE risk in users of Ortho Evra versus COC Epidemiologic Study i3 Ingenix BCDSP NGM-35 OC BCDSP LNG-30 OC
a b NGM LNG EE

Comparator Product NGM/35 mcg EE NGM/35mcg EE LNG/30mcg EE

Odds Ratio (95% CI) 2.4 (1.1-5.5)a 0.9 (0.5-1.6) 1.1 (0.6-2.1)b,3 2.0 (0.9-4.1)

Application of findings on Ortho Evra to Evra

The post-marketing safety data available are largely based on Ortho Evra. Although the dosage and manufacturing processes are different for Evra and Ortho Evra, the patches are designed to deliver similar systemic amounts of EE and NGMN, and have been demonstrated to be bioequivalent. Evra was approved for marketing based on studies conducted with Ortho Evra. Similarly, the post-marketing data would be considered applicable to Evra.

Increase in risk of VTE is statistically significant Separate estimate from 17 months of data on new cases not included in the previous estimate Norgestimate Levonorgestrel Ethinyl estradiol

VTE associated with use of hormonal contraceptives

COC are known to be associated with an increased risk of VTE. The incidence of VTE in healthy, non-pregnant women who are not taking a COC is about 4 cases per 100,000 women per year of use. The incidence of VTE associated with COC, ranges from 10.3 to 21 cases per 100,000 women per year of use and remains lower than that of pregnancy (60 cases per 100,000 women per year of use).

Conclusion
Healthcare professionals should take into consideration the findings above when selecting the appropriate contraceptives for their patients. The local package insert of Evra has been amended to include the findings of the latest epidemiology studies on Ortho Evra. HSA will continue to monitor the safety profile of this drug and update healthcare professionals when more information becomes available.
References 1. Contraception 2006 Mar;73:223-8. 2. Obstet Gynecol 2007 Feb;109:339-46. 3. Contraception 2007 Jul;76:4-7.

Editor-in-Chief Ms Chan Cheng Leng, BSc (Pharm) Hons Executive Editor Ms Ang Pei San, BSc (Pharm) Staff Editors Mr Choong Chih Tzer, BPharm Dr Yvonne Koh, BSc (Pharm) Hons, PhD Ms Adena Lim, BSc (Pharm) Hons, MPharm (Clin Pharm) Ms Belinda Tan, BSc (Pharm) Ms Tan Wei Chuen, BSc (Pharm)

Editorial Board Clinical Prof. Goh Chee Leok Prof. Edmund Lee Joo Deoon Clinical Prof. Chng Hiok Hee Clinical A/Prof. Gilbert Lau Kwang Fatt Dr Lee Kheng Hock

Enquiries, comments and suggestions to: Pharmacovigilance Unit Centre for Drug Administration Health Products Regulation Group Health Sciences Authority 11 Biopolis Way, #11-03, Helios, Singapore 138667 Tel: (65) 6866 3538 Fax: (65) 6478 9069 Website: http://www.hsa.gov.sg Email: HSA_drugsafety@hsa.gov.sg

The contents are not to be reproduced in part or in whole, without prior written approval from the editor. Whilst every effort is made in compiling the content of this publication, the publishers, editors and authors accept no liability whatsoever for the consequences of any inaccurate or misleading data, opinions or statements. The mention of any product by the authors does not imply any official endorsement of the product by the Health Sciences Authority. Copyright 2008 Health Sciences Authority of Singapore. All Rights Reserved.