November 2003 Vol 5 No.

ISSN : 0219-2152

ADVERSE DRUG REACTION NEWS

he atypical antipsychotics currently available i n Si ng a p ore a re c l o z a p i n e ( C l o z a r i l , N o v a r t i s ) , risperidone (Risperdal , Janssen-Cilag), quetiapine (Seroquel, AstraZeneca), olanzapine (Zyprexa, Eli Lilly) and ziprasidone (Zeldox, Pfizer). In recent years, based on postmarketing studies, there have been increasing reports on the increased risks of hyperglycaemia and diabetes in patients treated with this group of drugs. Two large-scale studies led by Francesca Cunningham1 (n = 12,235) and Michael Sernyak2 (n = 38,632) reported the increased prevalence of diabetes mellitus associated with patients taking atypical antipsychotics compared to those treated with conventional antipsychotics. Cunningham et al demonstrated that the risk of diabetes appears to be significantly increased with the use of olanzapine (hazard ratio 1.27; 95% CI 1.04 1.56), quetiapine (3.34; 2.51 4.45) and risperidone (1.49; 1.22 1.81) but not clozapine (1.48; 0.65 3.37). The conventional antipsychotics used in the study included haloperidol, thioridazine, perphenazine, chlorpromazine, fluphenazine, thiothixene, trifluoperazine, loxapine, mesoridazine and molindone. In the study reported by Sernyak et al, a total of 22,648 (58.6%) patients were treated with atypical antipsychotics. When the effects of age were controlled (patients age range from < 40 to > 70 years old), patients who received atypical antipsychotics were 9% (95% CI 1.03 1.15) more likely to develop diabetes than those who were treated with the conventional drugs. The odds of having a diagnosis of diabetes mellitus were significantly greater for all patients receiving clozapine (odds ratio 1.25; 95% CI 1.07 1.46), olanzapine (1.11; 1.04 1.18) and quetiapine (1.31; 1.11 1.55) but not risperidone (1.05; 0.98 1.12). However, in younger patients (< 40 years old), the use of all four types of atypical antipsychotics was associated with a significant increased prevalence of diabetes mellitus (odds ratio 1.63; 95% CI 1.23 2.16).

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

INCREASED RISK OF HYPERGLYCAEMIA AND DIABETES WITH ATYPICAL ANTIPSYCHOTICS

Regulatory decisions
The US Food and Drug Administration (FDA) has recently requested the manufacturers of all atypical antipsychotics to include warnings of potential increased risk of hyperglycaemia and diabetes in the package inserts. While FDA acknowledges that the relationship between atypical antipsychotics and diabetes mellitus adverse events has not been completely described, it believes that the safe use of these drugs can be enhanced by informing prescribers and patients about these events.

HSAs advisory
HSA will be reviewing the package inserts of the atypical antipsychotics. In the meantime, we advise that patients treated with these drugs be monitored for symptoms of hyperglycaemia including polydipsia, polyuria, polyphagia and weakness. Healthcare professionals are encouraged to report any serious suspected adverse drug reactions to this class of drugs
References: 1. Cunningham F et al. Pharmacoepidemiology and Drug Safety, 2003, 12, S154-5 2. Sernyak MJ et al. Am J Psychiatry, 2002; 159(4):561-6

CONTENTS
Risk of hyperglycaemia & diabetes with atypical antipsychotics Safety concern of venlafaxine in children with depression Hypospadias & loratadine / desloratadine The SMART safety study & asthma management Update on HRT: The Million Women Study Risk of oligohidrosis & hyperthermia with Topamax Fruit juices & drug interactions Casodex & increased deaths in early prostate cancer

1 2 2 3 4 4 5 6

Reporting Made Easy: Online adverse drug reaction reporting is available at http://www.hsa.gov.sg/ADR_online

SAFETY CONCERN OF VENLAFAXINE IN CHILDREN

e have previously updated you on the safety concern of the use of paroxetine (Seroxat) in children with major depressive illness and the associated risk of increased emotional liability. Recent emerging safety information has raised similar concerns of the use of another antidepressant, venlafaxine, in children. Venlafaxine (Efexor / Efexor XR, Wyeth), a serotonin and noradrenaline reuptake inhibitor (SNRI), is indicated for the treatment of depression and generalised anxiety disorder in adults. It is not licensed for the treatment of major depressive disorder (MDD) in patients less than 18 years old as safety and effectiveness have not been demonstrated in this population. Recent results from two clinical trials in children and adolescents (6 - 17 years) have failed to demonstrate its efficacy in depressive illness and the results showed an increase in harmful outcomes including hostility, suicidal ideation and self-harm in the venlafaxine group compared to the placebo group.

twice that of placebo, were as follows (percentages listed for venlafaxine and placebo respectively): hostility (2%, <1%) and suicide ideation (2%, 0%). In addition, there were three suicide attempts in the venlafaxine group, compared with none in the placebo group, although there were no deaths in these trials. Other events which occurred more commonly in the venlafaxine group were abdominal pain, loss of appetite and weight loss.

Regulatory decisions
On the basis of these findings, the UK Committee of Safety of Medicine (CSM) has assessed that the balance of risks and benefits of venlafaxine is unfavourable for the treatment of depressive illness in this age group. It also advised that paediatric patients who are currently on venlafaxine should not have their medication discontinued abruptly because of the risk of withdrawal reactions. HSA is working with Wyeth to update the labelling in the package insert of Efexor and Efexor XR to reflect the above information. The current evidence suggests that the balance between risks and benefits of venlafaxine remains favourable in the treatment of adults with depressive illness and anxiety disorders

Results from the trials

The MDD trials found that the most common adverse events leading to discontinuation in at least 1% of children and adolescents treated with venlafaxine and occurring at a rate

HYPOSPADIAS AND LORATADINE / DESLORATADINE

Precaution on the use of loratadine and desloratadine in pregnancy oratadine has been used as a therapeutic agent for more than 14 years. It is a tricyclic antihistamine with selective peripheral H1 receptor antagonist activity. It is marketed as a non-sedative antihistamine for the relief of symptoms associated with allergic rhinitis and ocular itching and burning. In 1999, the Swedish Medical Products Agency (MPA) reported an increased in frequency of hypospadias in boys born to 2,780 Swedish women who took loratadine (Clarityn, Schering Plough) during their pregnancy. Fifteen cases were observed among these births. Hypospadias is a developmental anomaly in which the urethra opens on the underside of the penis or on the perineum. It is a frequently found malformation with an incidence of 3 per 1,000 males and may be due to genetic or environmental factors. Following these reports, a review was conducted by the Committee of Proprietary Medicinal Products (CPMP) of the European Agency for the Evaluation of Medicinal Products (EMEA). The concern for this adverse effect was also extended to the major metabolite of loratadine, i.e. desloratadine, which is also marketed as a non-sedative antihistamine and indicated for the relief of symptoms associated with seasonal allergic rhinitis.
2

The companys preclinical study showed that loratadine has no anti-androgenic activity. The scientific assessment of the safety signal of hypospadias following use of loratadine during pregnancy by CPMP concluded that based on the available data, a causal relationship between loratadine and hypospadias could neither be confirmed nor excluded. CPMP also considered that the benefit/risk balance of desloratadine containing medicinal products remains favourable. To-date, other than the Swedish reports, the WHO ADR database, which captures ADR reports from more than 71 participating countries, reveals 10 other cases of hypospadias suspected to be associated with loratadine. There are no reports with desloratadine.

Recommendations
The Pharmacovigilance (PV) Unit has not received any reports of hypospadias suspected to be associated with these drugs. As a precautionary measure, in-line with the recommendations in the package insert of these products, which state that the safe use of loratadine and desloratadine in pregnancy has not been established, it is advised that the use of desloratadine or loratadine during pregnancy be avoided

THE SMART SAFETY STUDY AND ASTHMA MANAGEMENT

The interim analysis of a planned 28-week safety study, the Salmeterol Multi-center Asthma Research Trial (SMART) revealed rare but potentially serious, respiratory adverse events suspected to be associated with salmeterol

almeterol (Serevent, GlaxoSmithKline) is a long-acting 2 agonist bronchodilator, registered in Singapore in 1991. It is licensed for use as a complementary treatment with oral or inhaled steroids in the management of asthma.

Inhaled corticosteroid use

In contrast to recommendations on current asthma management guidelines, there was a low level of inhaled corticosteroid use (47%) in the entire population in the SMART study. Only 50% of Caucasians and 38% of the AfricanAmericans were receiving treatment with an inhaled corticosteroid. In the total population of patients receiving inhaled corticosteroids at baseline, no significant differences were seen in primary events and asthma-related events, including deaths. However, in the total population of patients not receiving inhaled corticosteroids at baseline, there was a statistically significant greater number of asthma-related deaths in all patients taking Serevent to those taking placebo (10 vs 1).

Results of the interim analysis

The SMART study was designed to assess the safety profile of Serevent following concerns of regular use of short-acting and long-acting 2 agonists in the management of asthma. The interim analysis included 25,858 long-acting 2 agonist naive patients (average age of 39 years, 71% Caucasian, 18% African-American, 8% Hispanic and 3% Asian & Others). In addition to their usual asthma therapy, 13,174 patients were treated with Serevent Inhalation Aerosol, 42 mcg twice daily and 13,179 patients were given placebo. The primary endpoint was the combined number of respiratory-related deaths and respiratory-related life threatening experiences (intubations and mechanical ventilation). Secondary endpoint was all-cause of death including asthma-related deaths or life-threatening experience. The key findings included:

Recommendations
Given the similar basic mechanisms of action of all 2 agonists, it is possible that the findings seen in the SMART study may be consistent with a class effect. Consistent with the MOH Clinical Practice Guidelines on the management of asthma and reinforced by trends seen in the interim analysis of the SMART study, it is recommended that patients receiving long-acting 2 agonist for asthma should normally also be receiving regular and adequate doses of an effective asthma controller medication, such as inhaled corticosteroid. Bronchodilators should not be the only or main treatment in patients with severe or persistent asthma
Reference: Ministry of Health, Singapore. MOH Clinical Practice Guidelines 1/2002: Management of asthma. (http://www.moh.gov.sg/newmoh/pdf/abo/clinic2002/asthma.pdf)

For the primary endpoint, the analysis showed no significant difference between treatment groups. However, a higher number of asthma-related deaths (13 vs 4 cases) and a higher number of combined asthma-related deaths or life threatening experiences (36 vs 23) was reported in the Serevent group compared to the placebo arm. Although the SMART study was not designed to analyse subpopulations differences, a post hoc analysis based on race and ethnicity was performed. The analysis showed no increase in respiratory and asthma-related episodes in Caucasians. However, amongst African-Americans, there was a statistically significant increase in primary endpoint in the Serevent group (20 vs 7). The occurrence of asthmarelated deaths (8 vs 1) and asthma-related episodes (19 vs 4) was also statistically significantly higher in Serevent patients compared to placebo. (The African-Americans were noted to have more severe asthma at baseline than the Caucasians.)

Adverse Drug Reaction News Nov 2003 Vol 5 No.3

UPDATE ON HRT: THE MILLION WOMEN STUDY

he results of the UK Million Women Study have recently been published in The Lancet in August 2003. They confirm and expand on the results of the previous Womens Health Initiative (WHI) study which investigated only combination hormone replacement therapy (HRT). The Million Women Study is a cohort study investigating the effects of specific types of HRT on breast cancer incidence and mortality. More than a million women aged 50 64 years were recruited between 1996 and 2001 in UK and half the women had used HRT. A summary of the key findings is included below: Among the postmenopausal women (n = 828,923) included in the main analysis, the risk of breast cancer was significantly higher among ever users than never users of HRT at baseline [relative risk of 1.43; 95% CI (1.36 1.5)]. However, among the ever users of HRT, the relative risk was increased in current users [1.66 (1.58 1.75)] but not in past users [1.01 (0.94 1.09)]. The study showed that the risk of breast cancer begins to decline when HRT is stopped and by 5 years reaches the same level as women who have never taken HRT. In current users, the risk of breast cancer increased with increasing total duration of use, regardless of HRT type. The relative risk of breast cancer was significantly raised for current users of oestrogen only preparations [relative risk of 1.30 (1.21 1.40)], tibolone [1.45 (1.25 1.68)], and oestrogen-progestagen combinations [2.00 (1.88 2.12)]. This study demonstrated a higher risk of breast cancer associated with the use of combined HRT than oestrogen only therapy.

For oestrogen only preparations, the relative risk of breast cancer was significantly raised separately for users of oral, transdermal and implanted formulations compared to never users of HRT [1.32 (1.21 1.45), 1.24 (1.11 1.39) and 1.65 (1.26 2.16), respectively]. With 4.1 years of follow-up for mortality, the relative risk of death from breast cancer was increased in current users of HRT at recruitment [1.22 (1.00-1.48)] compared with never users. The estimated number of extra cases of breast cancer occurring after 5 and 10 years using oestrogen only and combined HRT are shown in Table 1.

Table 1: Estimated excess incidence of invasive breast cancer in 1,000 women who had ever used HRT relative to never users. Baseline incidence of invasive breast cancer in never users is ~ 32 per 1,000 between the ages of 50 and 65 years.

Number of additional cases of breast cancer per 1,000 women by age 65 Duration of use of HRT (from age 50) Oestrogen only Oestrogen-progestagen 5 years 1.5 6 10 years 5 19

Reference: Lancet, 2003; 362: 419-427

OLIGOHIDROSIS AND HYPERTHERMIA WITH TOPAMAX

Physicians are alerted to the risk of oligohidrosis and hyperthermia especially in paediatric patients opiramate (Topamax, Janssen-Cilag), a sulphamatesubstituted monosaccharide antiepileptic was registered in 1998 in Singapore for the treatment of adults and children with partial onset seizures and generalised seizures. Safety information from clinical trials and worldwide postmarketing reports revealed cases of oligohidrosis and hyperthermia in topiramate-treated patients, primarily involving children. Most cases have occurred in association with exposure to elevated environmental temperatures and/or vigorous activity. As of February 2002, the rate for spontaneous postmarketing reports of all potential cases of oligohidrosis was estimated to be at 35 per 1,000,000 patients treated. Serious or medically significant oligohidrosis or its sequelae were reported at a rate of 1.6 per 1,000,000 patients treated (This figure may be an under-estimation as it is generally recognised that postmarketing data are subject to substantial under-reporting).

The local package insert of Topamax has been updated to reflect this new safety information.

HSAs Advisory
Topamax should be prescribed with caution with drugs such as carbonic anhydrase inhibitors and anticholinergic drugs which can predispose patients to heat-related disorders. When prescribing Topamax , patients (especially paediatric patients) should be appropriately advised to ensure proper hydration before and during activities such as exercise or exposure to warm temperatures.
4 2

FRUIT JUICES AND DRUG INTERACTIONS

Grapefruit juice
Healthcare professionals are reminded of the potential drug interactions with grapefruit juice

rapefruit juice contains a psoralen which inhibits the metabolism of certain drugs by enzymes of the CYP3A4 subfamily of cytochrome P450. As CYP3A4 is involved in the metabolism of many drugs that are currently in use therapeutically, there are many clinically significant drugs interactions that have been reported with grapefruit juice. These drugs include cyclosporin, terfenadine, ergot derivatives, calcium channel blockers and statins. Evidence for these interactions comes largely from studies of simultaneous administration of grapefruit juice and the relevant drugs. As little as one glass of grapefruit juice (250 mL) has been reported to result in a drug interaction. The importance of the interaction appears to be influenced by various factors including individual patient susceptibility, type and amount of grapefruit juice.

Recommendations
Some sources recommend not to ingest grapefruit juice within 2 hours before and 5 hours after intake of a drug while others suggest that the inhibitory effects of grapefruit juice may last for 3 days or longer. A safer alternative is to avoid consuming grapefruit and its juice when taking drugs known to be metabolised by CYP3A4. Whilst sweet oranges and their juice do not appear to cause similar type of drug interactions, sour orange juice such as that from Seville oranges, may have similar effect to grapefruit juice. Tangelos are a hybrid of grapefruit and may also interfere with drugs. Most other citrus fruits, such as lemons, limes, naturally sweet oranges and tangerines are considered safe.

One fatal case involved a man whose INR dramatically increased (INR > 50) 6 weeks after starting to drink cranberry juice. The patient died from gastrointestinal and pericardial haemorrhage. In another 2 cases, less dramatic INR increases were noted whilst the patients were taking cranberry juice. One of these 2 patients was stabilized on a lower dose of warfarin and the other, after stopping cranberry juice. In the 4th case, the INR was reported to be generally unstable after cranberry ingestion and in the 5th case, an INR decrease was reported. The CSM conjectured that the interaction was biologically plausible based on 2 grounds: i) Cranberry juice contains various antioxidants including flavonoids, which are known to inhibit cytochrome P450 activity; and warfarin is predominantly metabolised by CYP2C9. ii) The constituents of different brands of cranberry juice may vary, and that such variations might affect the potential for drug interactions.

Cranberry juice
Patients on warfarin should limit or avoid drinking cranberry juice ince 1999, the UK Committee o f Safety of Medicine (CSM) has received 5 reports suggesting an interaction between warfarin and cranberr y juice, leading to changes in international normalised ratio (INR) values.

Recommendations
Whether constituents in cranberry juice can inhibit CYP2C9 and thus warfarin metabolism, or interact in another way will require further investigation. Until this possible interaction between cranberry juice and warfarin has been investigated, it would be prudent to advice patients taking warfarin to limit or avoid drinking cranberry juice

1 5

Adverse Drug Reaction News Nov 2003 Vol 5 No.3

CASODEX AND EARLY PROSTATE CANCER

Trial results reveal increased risk of deaths when Casodex is used in patients with localised (early) prostate cancer who would otherwise undergoing watchful waiting

>
In the subgroup analysis of patients with localised prostate cancer at low risk of disease progression, otherwise managed by watchful waiting, there were more numbers of accelerated deaths in the Casodex group vs the placebo group [196 (25.2%) deaths vs 174 (20.5%) deaths, HR = 1.23, 95% CI 1.00-1.50]. In the higher risk subgroup of patients with locally advanced disease showed a trend towards improved survival with Casodex compared to the placebo arm [113 (33.7%) deaths vs 133 (41.3%) deaths, HR = 0.80, 95% CI 0.62-1.04). No survival differences were apparent in patients receiving adjuvant therapy, although the data in this setting is relatively immature (approximately 10% deaths in adjuvant setting).

icalutamide (Casodex , AstraZeneca), an oral anti-androgen has been approved by some regulatory authorities for the treatment of localised (early) prostate cancer. The Canadian and UK Health Authority have recently withdrawn the approval of Casodex for this indication as data obtained from the follow-up second analysis of the Casodex Early Prostate Cancer (EPC) trial programme revealed a trend towards increased risk of death in patients with localised (early) prostate cancer who were put on Casodex as compared to those on placebo.

EPC Trial
The EPC trial is an on-going international programme comprising 3 geographically distinct trials. All trials are prospective, randomised, double blind, placebocontrolled clinical trials (n = 8,113) that compare Casodex 150 mg/day and placebo, when given in addition to standard care in men with localised or locally advanced prostate cancer. The programme considered standard care to be radical prostatectomy, radiotherapy or watchful waiting (initiation of therapy only if symptoms or signs of progression occurred). Primary endpoints are progression free survival and overall survival. The findings are as follows:

There was a significant reduction in the risk of progression free survival in the combined analysis of the 3 trials after 5.4 years of follow-up [797 (19.7%) events vs 960 (23.6%) events, hazard ratio (HR) = 0.73]. Benefits in terms of reduced risk of disease progression were largest in those at high risk of disease progression (e.g. locally advanced disease, elevated serum levels of Prostate Specific Antigen (PSA) at baseline or high Gleason grade). For overall survival, as reported in the first analysis, the second analysis showed no difference between treatment groups for either the combined analysis all 3 trials or separate analysis for each of the trial.

>

>

> > >

>
Implications

Casodex is only licensed for the treatment of locally advanced prostate cancer in Singapore. Patients with locally advanced prostate cancer are not affected by this new safety information. In view of these data, and in the absence of factors to suggest high risk of disease progression, AstraZeneca has advised physicians in countries where Casodex is licensed for early prostate cancer to discontinue Casodex in patients with localised (early) prostate cancer who would otherwise be undergoing watchful waiting.

>

Editor-in-Chief
Ms Chan Cheng Leng BSc (Pharm) Hons

>

Adverse Drug Reaction News is produced by the Centre for Pharmaceutical Administration, HSA and the Pharmacovigilance Advisory Committe

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

Enquiries, comments and suggestions to:

Pharmacovigilance Unit Centre for Pharmaceutical Administration Health Sciences Authority 2 Jalan Bukit Merah Singapore 169547 Tel: (65) 6325 5604 Fax: (65) 6325 5448 Website: http://www.hsa.gov.sg Email: HSA_DRUGSAFETY@hsa.gov.sg

Executive Editor
Ms Ang Pei San BSc (Pharm)

Its contents are not to be reproduced in part or in whole, without prior written approval to 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 2003 Health Sciences Authority of Singapore. All Rights Reserved.