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Other similar drugs that are registered include risedronate(Actonel, Sanofi-aventis) in 2001 and ibandronate (Bonviva,Roche) in 2005. These drugs belong to the bisphosphonateclass of drugs which acts as specific inhibitors of osteoclast-mediated bone resorption.

Bisphosphonates have demonstrated to have fracture reductionbenefits for post-menopausal women with prior vertebral fractureor T-scores of 2.5 or lower. There are however anecdotalreports in recent years that suggest bisphosphonates may beassociated with the risk of fractures in certain susceptibleindividuals.

Literature reviewA review of the published medical literature indicates that thereare about ten cases of spontaneous nonspinal fractures inpatients on alendronate therapy. For the nine patients who werereported to continue taking alendronate after the fractures,six displayed either delayed or absent fracture healing for

3 months to 2 years.1,2 The description of these cases appearssimilar to some of our local cases in that these were mainlypost-menopausal female patients who developed atraumaticnonspinal fractures after 3-8 years of alendronate treatment.

Local practice guideli nes

The MO H Clinical Practice Guidelines for Osteoporosis3

recommends that for treatment with bisphosphonates,alendronate or risedronate therapy is recommended whenpatients T-score is less than or equal to 2.5, whether or notpatient has a fracture. For such cases, it is recommended toconsider monitoring BMD after one year.

CONTENTS

Published b y the Centre fo r Drug Administration, HSA and the HSA Pharma covigilance Advisory Committee

ISSN: 0219 - 2152March 2007

Vol.9 No.1

R

ecently, the Pharmacovigilance Unit, HSA has received25 reports of fractures and one of delayed bone healing

with long-term use of alendronate in our local patients.We are currently following up with these reports to determinethe causality and the date of occurrence of these events asmany of them lacked details such as onset of the adverse event,dose and duration of alendronate given, use of concomitantmedicines and whether bone mineral density (BMD) wasmeasured.

Analysis of reportsBased on an interim analysis of the available data, the adverseevents were observed in female patients who were onalendronate for 110 years (duration reported in 22 patients),with median age of 66.5 years (range: 3782 years). Only

12 reports included patients BMD T-scores for hip which rangedfrom 1.29 to 2.8.

Seven patients were reported to have pain in the fractured limbup to four months prior to sustaining the fracture. Six out of the26 patients did not encounter any trauma prior to experiencingthe fracture. Ten patients had minimal trauma, mainlyspontaneous falls, and one patient had delayed bone healing.In nine patients, the events leading to the sustaining of thefractures were not stated.

The types of fractures experienced by these patients were mainlysub-trochanteric in nature. Most of these fractures were eithersimple transverse fractures or short oblique fractures and

reporting physicians described them as distinctly different fromtypical osteoporotic fractures.

Background informationAlendronate (Fosamax, Merck Sharp & Dohme) has beenregistered by HSA since 1996 for the treatment and preventionof osteoporosis in post-menopausal women. The recommendeddosage for treatment of osteoporosis in post-menopausal womenis one 70mg tablet once weekly or one 10mg tablet once daily.For the prevention of osteoporosis in post-menopausal women,the recommended dosage is one 5mg tablet once daily (the5mg tablet is not marketed locally).

5 Evra & risk of thromboembol ism6 Package insert amendments reflecting

safety issues

8 Bevacizumab: association withhypertensive encephalopathy & reversible

posterior leukoencephalopathy syndrome

1 Reports of fractures with alendronate2 Linezolid: safety findings from a clinical

trial in catheter-related infections

3 New safety issues associated with rituximab

4 Analysis of ADR reports for 2006

Monitoring of patients bone mineraldensity recommended before and

during drug therapy

continued on Page 2

Reports of fractures with alendronate


2/8Page2 Adverse Drug Reaction News March 200 7 Vol.9 No.1

Linezolid: safetyfindings from a clinicaltrial in catheter-related

infections

Linezol id (Zyvox, Pf izer) is a synthetic

antibacterial agent belonging to theoxazolidinones class of antimicrobial agents.

It is licensed for the treatment of nosocomial- andcommunity-acquired pneumonia and for complicatedor uncomplicated skin and skin structure infectionscaused by methicillin or vancomycin resistant gram-positive bacteria.

Study in ca theter - re la ted gram-pos i t i vebloodstream infections shows higher mortalityrate in linezolid groupA clinical trial in adult patients with catheter-related gram-positive bloodstream infections showed a higher mortality

rate in the linezolid arm [78/ 363 (21.5%)] versus thecomparator drugs [58/ 363 (16.0%)] at 84 days post-study admission with an estimated odds ratio of 1.426[95% CI 0.9702.098] based on results from logisticregression. The study was an open-label, randomised,comparator-controlled phase 3 study of intravenous/ orallinezolid (600mg q12h) versus comparator [intravenousvancomycin (1g q12h) or intravenous oxacillin (2g q6h)followed by oral dicloxacillin (500mg q6h)] with atreatment duration of 7 to 28 days.

While causality has not been established, the observedmortality imbalance occurred primarily in linezolid-treated

No clinical activity againstgram-negative pathogens.

Specific gram-negative therapyrequired if a concomitant

gram-negative pathogen isdocumented or suspected

patients in whom either gram-negative pathogens, mixed gram-

negative and gram-positive pathogens, or no pathogen were identifiedat baseline. Patients randomised to linezolid who had only a gram-positive infection at baseline, including the subgroup of patients withgram-positive bacteraemia experienced a survival rate similar to thecomparator group.

From the companys analysis of the mortality data, a major findingwas a lower than predicted mortality incidence in the comparatorgroup and a greater overall incidence of gram-negative bloodstreaminfections in the linezolid group with a higher mortality in the linezolidpatients who had gram-negative infections.

The company also noted that the antibiotic treatment for patients withgram-negative infection who died was assessed as inadequate inboth arms of the study and may have been a contributing factor tothe overall number of deaths in the study.

Local situationArising from this study, HSA is working with the company to updatethe safety information in the local package insert of Zyvox to includethe findings of this study to remind healthcare professionals thatlinezolid has no clinical activity against gram-negative pathogensand is not approved for the treatment of gram-negative infections orfor the treatment of patients with catheter-related bloodstreaminfections. Specific gram-negative therapy is required if a concomitantgram-negative pathogen is documented or suspected

continued from Page 1 Reports of fractures with alendronate

For patients with T-score between 1 to 2.5 (with respect tobisphosphonate use in prevention of osteoporosis),it recommends that it might be a reasonable option to deferintervention in those at low risk for fracture prevention as

bisphosphonates havenot demonstrated toreduce fractures whenused in prevention,despite reducing boneloss.

ConclusionHSA will be followingup with the case reportsto investigate whetherthere is a causal linkbetween the reported

adverse events and the drug, and whether there could beother factors that may have predisposed to the fracture.Although the reports received were for alendronate, it maybe premature to form the direct causal link betweenalendronate and these fractures. At the same time, the possibleassociation of such adverse events with other bisphosphonatescannot be excluded.

Healthcare professionals are encouraged to report allserious adverse effects especially fractures suspected to beassociated with bisphosphonates to the PharmacovigilanceUnit of HSA

References1. J Clin Endocrinol Metab 2005; 90:1294-301.2. Geriatrics 2006; 61:31-3.3. MO H Clinical Practice Guidelines. Osteoporosis. Singapore.

February 2002.Radiograph of a subtrochanteric fracture


3/8Adverse Drug Reaction News March 2007 Vol.9 No.1 Page3

New safety issuesassociated with rituximab

Reports of possible hepatic failure,

bowel obstruction and perforation,and progressive multifocal

leukoencephalopathy

Ri tuximab (Mabthera, Roche) is a recombinant

chimeric anti-CD20 monoclonal antibody licensed in

Singapore for: i) treatment of patients with relapsed or

chemo-resistant indolent B-cell non-Hodgkins lymphomas (NHL),

ii) treatment of patients with CD20 positive diffuse large B-cell

non-Hodgkins lymphomas (DLCL) in combination with CHOP*

therapy, iii) treatment of previously untreated patients with

stage IIIIV follicular lymphoma in combination withCVP** chemotherapy.

In the past few months, there have been reports of hepatic

failure, bowel obstruction and perforation, and progressive

multifocal leukoencephalopathy (PML) suspected to be

associated with its use. The causality of some of these adverse

events has not been established although its immunosuppressant

effects may account for PML.

a) Reports of bowel obstruction and gastrointestinal

perforations1

In November 2006, Health Canada together with Hoffmann-

La Roche in Canada issued an advisory to healthcare

professionals about the observation of bowel obstruction and

gastrointestinal perforations in patients treated with rituximab.

The advisory included data from the analysis of the companys

worldwide pharmacovigilance database for rituximab which

indicated that 47 cases of bowel obstruction (nine deaths) and

37 cases of gastrointestinal perforation (four deaths) have been

reported in rituximab patients for an estimated 730,000

cumulative patient exposure. These reports originated from both

spontaneous sources and clinical studies, and the majority of

these cases were reported for the NHL indication. O f these,

two reports of bowel obstruction (one death) and two reportsof gastrointestinal perforation originated from Canada.

The advisory also mentioned that the presence of risk factors

such as underlying medical history (e.g. gastrointestinal

lymphoma) and intake of concomitant medications (e.g.

chemotherapy and steroids) in the cases of bowel obstruction

and gastrointestinal perforation made interpretation of data

difficult. However, these confounding factors, a contributory

role of rituximab in causing gastrointestinal perforation in

patients diagnosed with NHL has not been excluded. In addition,

a pooled analysis of clinical trials in patients with NHL has

indicated a higher incidence of gastrointestinal perforation inthe arms treated with rituximab/ chemotherapy compared to

the arms treated with chemotherapy alone (0.38% verus 0.15%).

In post-marketing reports of patients with NHL, the mean time

to onset of symptoms was six days from the start of therapy

(range 1 to 77 days) for documented gastrointestinal

perforation. The site of gastrointestinal perforation in the cases

of NHL included both the upper and lower gastrointestinal tracts.

b) New reports of fulminant hepatitis in hepatitis B virus

carriers

In Japan, there were 18 new reports of exacerbation of HBV

infection over the last two years. Of these, nine were of fulminant

hepatitis and eight of death in patients with NHL.

The Ministry of Health, Labour and Welfare of Japan has in

December 2006, requested the product licence holder to

disseminate a dear healthcare professional letter and to

strengthen the package insert of rituximab to warn of cases of

fatal liver failure caused by fulminant hepatitis or exacerbation

of hepatitis in hepatitis B virus carrier treated with rituximab

(marketed as Mabthera in Japan).

c) Repor ts of Progressive Multifocal Leukoencephalopathy

(PML)2,3

The US Food and Drug Administration has in December 2006

alerted healthcare professionals of two fatal cases of progressivePML in patients treated with rituximab (marketed as Rituxan

in US) for systemic lupus erythematosus (SLE) which was not an

approved indication of the drug. PML is a demyelinating disease

caused by reactivated JC virus which is a latent virus present in

80% of adults.

Reactivation or exacerbation of viral infections including

JC virus leading to PML may occur when patients receive

Rituxan for any reason. To date, there are 23 confirmed reports

of PML in patients with lymphoid malignancies treated with

rituximab although PML has also been reported in SLE patients

not treated with rituximab.

Local situation

HSA has not received any reports on the above-mentioned

adverse events. Nonetheless, physicians are advised to closely

monitor patients treated with rituximab for these adverse effects

and to report these events to the Pharmacovigilance Unit of

HSA should they be encountered

* CHOP cyclophosphamide, doxorubicin, vincristine, prednisolone* * CVP vincristine, cyclophosphamide, prednisolone

References1. Health Canada Advisory for Healthcare Professionals (10/ 11/ 06)

http:/ / www.hc-sc.gc.ca/ dhp-mps/ medeff/ advisories-avis/ prof/2006/ rituxan_3_hpc-cps_e.html

2. US FDA information for Healthcare Professionals (18/ 12/ 06) http:/ /www.fda.gov/ cder/ drug/ infopage/ rituximab/ default.htm

3. US FDA Public Health Advisory (18/ 12/ 06) http:/ / www.fda.gov/cder/ drug/ advisory/ rituximab.htm



The Pharmacovigilance (PV) Unit of HSA administers the

national adverse drug reaction (ADR) monitoring programby collating and reviewing ADR reports received from

healthcare professionals and pharmaceutical companies.

In addition to the conventional mode of ADR reporting throughemail, fax or mail, ADR reports can now be routed electronicallyto the PV Unit via the ADR/ drug allergy reporting module inthe Critical Medical Information Store (CMIS)* componentof the Electronic Medical Record Exchange (EMRX)**.

This platform of e-reporting is being implemented nationwide in phases, starting with National Healthcare Group (NHG)in January 2006.

Overview of ADR reports received via conventional andCMIS sourcesIn the year 2006, the PV Unit received 984 ADR reports viathe conventional route (i.e. mail, fax and email) and 11,000reports from CMIS.

This issues analysis of ADR reports have incorporated thosethat came through CMIS in addition to the conventional routeof reporting. Although 11,000 reports were received throughCMIS, not all were included in the analysis as many of thereports lacked details such as specific ADR terms, suspecteddrug or had erroneous date of onset of ADR. This could partlybe due to the transfer of data from the old patient medicalrecords system and other inherent teething problems. In addition,non-serious reports such as rash and periorbital oedema werenot included in the data analysis.

A total of 1,523 reports were analysed. These reports weremainly from public hospitals (56.8%), followed by governmentclinics (20.4%), national specialty centres (12.7%),

pharmaceutical companies (5.3%), private clinics/ specialistclinics (3.2%) and private hospitals (1.6%). The majority of thereports received were associated with pharmaceutical products(96.6%), followed by biologics/ vaccines (1.4%),

Analysis of ADR reports for year 2006

complementary medicines (1.2%), health supplements andcosmetics.

Based on a breakdown of the reports according to ethnic groups,Chinese patients constituted 60.9% of the reports, followed byMalay (12.5%), and Indian (8.7%) patients. There were morereports received in females than males (768 vs 661 reports).Patients between 5059 years of age made up 19.2% of thereports, followed by those aged 4049 (15.5%), and aged6069 (14.3%).

ConclusionActive participation of ADR reporting by our healthcareprofessionals is important in maintaining surveillance on thesafety profile of marketed drugs. In addition to the quantity ofreporting, the quality of reporting is also important to enablebetter signal detection.

Healthcare professionals are reminded that details of the casessuch as the date of occurrence of ADR, start and end dates ofingestion of suspected drug, concomitant medications andexisting medical conditions are useful to the PV Unit in theassessment of the causal relationship between the suspecteddrug and observed ADRs. Whenever possible, healthcareprofessionals are encouraged to provide these data.

* CMIS (Cr i t i ca l Med ica l In fo rmat ion Sto re )of the EMRX serves as ashared electronic repository of patients medical alerts, adverse drugreaction and drug allergy data. The CMIS online ADR reporting formis also available at the Health Professional Portal (HPP) to allowhealthcare professionals from the private sector to enter an ADR report.The HPP is a one-stop portal for the healthcare professional communityto access multiple e-services relating to professional practice andinformation repository using single-sign-on through a common interface.

** EMRX (Elect ronic Medical Record Exchang e), launched in April

2004, is an electronic platform which enables hospitals and governmentclinics across the two public healthcare clusters, namely, NationalHealthcare Group (NHG) and Singapore Health Services (Singhealth)to share vital patient medical information such as inpatient dischargesummaries, medical history and laboratory results.

More than one ADR term ma y be described in a single ADR report.

Table 1: Top system- org an classes affected inserious ADRs

Chart 1: Breakdown of the no. of patients whoexperienced ADRs by age group (n= 1,523)

System-organ classNo. of serious

ADR reports

Respiratory 148

Body as a whole 141

Skin & appendages 83

Haematological 80

Musculoskeletal 50

Liver & biliary 49

Psychiatric 27

Nervous 15

Ocular 13

Renal 12



Table 2: Top 15 drugs (by active ing redients) suspected of causing serious ADRs

TopActive No. of serious

ingredient ADR reportsExamp les of serious ADRs

1 Diclofenac 28Agranulocytosis; anaphylaxis; laryngeal oedema, wheeze; hepatitis;interstitial nephritis, nephropathy; Stevens Johnson syndrome

2 Atenolol 28Anaphylaxis; bradycardia (marked); bronchospasm; erectile dysfunction;exfoliative dermatitis

3 Cotrimoxazole 28Anaphylaxis; tongue oedema, wheezes; hepatitis, jaundice; conjunctivitis;leucopenia, neutropenia; Stevens Johnson syndrome, toxic epidermal necrolysis

4 Phenytoin 25 Anaphylaxis; conjunctivitis; fatty liver, hepatitis; leucopenia, neutropenia, pancytopenia;exfoliative dermatitis, Stevens Johnson syndrome, toxic epidermal necrolysis

5 Carbamazepine 21Hepatitis; leucopenia, neutropenia, pancytopenia, thrombocytopenia;exfoliative dermatitits, Stevens Johnson syndrome

6 Aspirin 21Anaphylaxis; asthma aggravated, bronchospasm; erosive gastritis, gastric ulcer;exfoliative dermatitis, toxic epidermal necrolysis

7 Allopurinol 21

Allopurinol hypersensitivity syndrome; anaphylaxis; hepatitis; acute renal failure,glomerulonephritis, interstitial nephritis; mucositis; pancytopenia; Stevens Johnsonsyndrome, toxic epidermal necrolysis

8 Amoxicillin 20Anaphylaxis; dyspnoea; exfoliative dermatitis, Stevens Johnson syndrome,toxic epidermal necrolysis

9 Ceftriaxone 20 Anaphylaxis; leucopenia; Stevens Johnson syndrome, toxic epidermal necrolysis

10 Paracetamol 20 Anaphylaxis; bronchospasm; confusion, hallucination; exfoliative dermatitis

11 Simvastatin 18 Cholestatic hepatitis, hepatitis; exfoliative dermatitis; rhabdomyolysis

12 Coamoxiclav 18Anaphylaxis; agranulocytosis; leukocytoclastic vasculitis; rhabdomyolysis;exfoliative dermatitis, Stevens Johnson syndrome

13 Warfarin 17 Cerebral haemorrhage, intraventricular haemorrhage, subdural haematoma

14 Cloxacillin 13Anaphylaxis; pancytopenia; exfoliative dermatitis, Stevens Johnson syndrome,toxic epidermal necrolysis

15 Ticlopidine 13 Agranulocytosis, leucopenia; cholestatic hepatitis, jaundice; pemphigus

Table 3 : Drugs suspected of causing serious blood, hepatic and skin adverse reactions

Descr ip ti on WHO prefer red termSuspected active ingredient (the number i n the br acket representsthe number of times the drug has been im plicated *)

Blood Agranulocytosis/ (6) Ticlopidine; (4) Carbimazole; (2) Valproic acid; (1) Carbamazepine,disorders neutropenia Chlorpromazine, Esomeprazole, Coamoxiclav, Cotrimoxazole, Diazepam, Diclofenac,

Imipenem/ cilastatin, Methotrexate, Mirtazapine, Nalidixic acid, Phenytoin,Propylthiouracil, Topiramate, Trifluoperazine, Trihexyphenidyl, Vancomycin

Anaemia, aplastic (1) Ethosuximide, Naproxen

Anaemia, haemolytic (1) Dapsone, Methyldopa

Leucopenia (3) Ticlopidine; (1) Azathioprine, Carbamazepine, Carbimazole, Ceftriaxone,Hydrocortisone, Phenytoin, Sirolimus, Sulfasalazine, Piperacillin/ tazobactam,Quetiapine, Trifluoperazine, Valproic acid, Vancomycin

Pancytopenia (2) Allopurinol; (1) Azathioprine, Carbamazepine, Chlorpromazine, Ciprofloxacin,Cloxacillin, Esomeprazole, Phenytoin

Pure red cell aplasia (1) Epoetin alfa

Thrombocytopenia (2) Valproic acid; (1) Carbamazepine, Carbimazole, Chlorpromazine, Heparin,Hydrochlorothiazide, Omeprazole

Hepatic Autoimmune hepatitis (1) Pil Setelan (adulterated with paracetamol, chlorpheniramine and phenylbutazone)

disorders Cholestatic hepatitis (2) Ticlopidine; (1) Chlorpromazine, Cyclophosphamide, Glipizide, Leflunomide,Sodium aurothiomalate, Simvastatin

Fatty liver (1) Phenytoin

Fulminant hepatitis (1) Propylthiouracil

Hepatic failure (1) Methyldopa, Dapsone/ pyrimethamine

Hepatic neoplasm (1) Ciclosporin

Hepatitis (3) Allopurinol, Simvastatin; (2) Complementary medicine, Cotrimoxazole,Isoniazid, Lovastatin; (1) Atorvastatin, Carbamazepine, Cotrimoxazole, Diclofenac,Dr Xeniji, Fluconazole, Gabapentin, Pyrazinamide, Rifampicin, Isotretinoin,Losartan, Memantine, Phenytoin, Thalidomide, Valproic acid

Hepatitis with jaundice (3) Complementary medicine; (1) Isoniazid, Ketoconazole, Moxifloxacin, NaturlandSlimexcell Phytotherapy, Nitrofurantoin, Penicillin V, Shou Wu Plus, Ticlopidine

Skin Stevens Johnson (11) Carbamazepine; (9) Cotrimoxazole; (8) Phenytoin; (6) Amoxicillin;disorders syndrome (SJS)/ Toxic (5) Allopurinol; (4) Omeprazole; (2) Cefalexin, Ceftazidime, Ceftriaxone,epidermal necrolysis Celecoxib, Ciprofloxacin, Cloxacillin, Enalapril, Lamotrigine, Naproxen, Spironolactone;(TEN)/ SJS-TEN (1) Ampicillin, Aspirin, Clopidogrel, Coamoxiclav, Diclofenac, Esomeprazole,

Ethambutol, Etoricoxib, Frusemide, Griseofulvin, Imipenem/ cilastatin, Isoniazid,Meloxicam, Methotrexate, Pyrazinamide, Rifampicin, Sotalol, Sulfasalazine

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



Evra (Johnson & Johnson) is a combination

transdermal contraceptive patch containing6mg norelgestromin (NGMN) and 0.6mg

ethinylestradiol (EE) and is designed to release thesehormones over a 7-day period. It has been registeredin Singapore since 2003.

Hormonal contraceptives are known to be associatedwith an increased risk of venous thromboembolism(VTE), particularly during the first year of use of oralcontraceptives (OC). In all cases, the risk of VTEincreases with age and in the presence of other riskfactors for VTE (e.g. obesity). The incidence of VTE inhealthy, non-pregnant women who are not taking an

OC is about 5 cases per 100,000 women per year.For those taking combined OC containing secondgeneration progestogens, this incidence is about15 per 100,000 women per year of use. Some studieshave reported a greater risk of VTE in women usingpreparations containing third generationprogestogens; the incidence is about 25 per 100,000women year of use. The risk of VTE with transdermalpatches is yet to be established although it remainsvery small and less than the risk of VTE associatedwith pregnancy, which is estimated as 60 per100,000 pregnant women years.

In the last two years, there has been a higher number

of spontaneous case reports of VTE associated withpatients on this transdermal hormonal contraceptivecompared to combined OC which raised the concernas to whether transdermal patch could be associatedwith a higher VTE risk.

Studies

Recent studies have been conducted to attempt to shedsome light to the post-marketing observation. Most ofthe studies were on Ortho Evra, the product marketedin the United States, comprising 6mg NGMN and ahigher content of EE at 0.75mg. Although the dosageand the manufacturing process for Evra is different

from that for Ortho Evra, the patches were designedto deliver similar systemic amounts of EE and NGMN,and have been demonstrated to be bioequivalent.Hence the post-marketing data and studies on OrthoEvra are considered to apply equally to Evra.

a) Pharmacokinetic studiesThe Pharmacokinetic (PK) profile for the transdermalpatches appears to be different from the PK profilefor OCs as demonstrated in the studies below:

i) Or tho Evra versus OCs

A PK study designed to analyse the difference indelivery of EE using Ortho Evra and a conventionalOC (containing norgestimate (NGM) 250mcg andEE 35mcg) over a 7-day period found that OrthoEvra has higher steady state concentrations andlower peak concentrations compared to OCs. Understeady state conditions, there was an increasedexposure of oestrogen (AUC

0168and C

ssfor EE were

55% and 60% higher, respectively) in women using

Evra and risk ofthromboembolism

Ortho Evra compared to those taking conventional OC. The peak bloodlevels of oestrogen (C

max) however were about 25% lower in women

using Ortho Evra. While the oestrogen level with the patch remainedconstant for one week until the patch was removed, the peak blood

levels with a daily birth control pill rapidly declined to levels that werelower than on the Ortho Evra.

As a result of this finding, the US Food and Drug Administration hasamended the US package insert of Ortho Evra to include this newinformation and a statement that although this increased oestrogenexposure may carry a theoretical risk of increased VTE, the clinicalsignificance is not known.

ii) Evra versus OCsA PK study comparing Evra and OC (containing NGM 250mcg andEE 35mcg) showed that C

maxvalues were found to be two-fold higher for

NGMN and EE in subjects administered with the OC compared to Evra,while overall exposure (AUC and C

ss) was comparable in subjects treated

with Evra. Inter-subject variability (%CV) for the PK parameters followingdelivery from Evra was higher relative to the variability determinedfrom the OC.

The clinical relevance of this finding is yet to be determined; and cautionshould be exercised when making a direct comparison of these PKparameters.

b) Epidemiology studiesThe results of two separate epidemiological studies sponsored by Johnson& Johnson that were designed to evaluate the risk of VTE in Ortho Evraand OC (containing NGM 250mcg and EE 35mcg) were recentlycompleted. These two studies with a nested case-control design wereconducted in the US in women aged 15 to 44 years using electronichealth claims data. The study by Cole et al1 found a two-fold increase in

the risk of VTE in current users of O rtho Evra compared to currentOC users (OR 2.4, 95% CI 1.15.5). However, the study by Jick et al2

did not find an increase in risk of VTE for current users of OrthoEvra compared to current OC users (OR 0.9, 95% CI 0.51.6).

The epidemiology studies, comparing the risk of VTE in women usingthe transdermal hormonal contraceptive patch to the risk in womenusing conventional OC, are being extended as new electronic healthclaims data becomes available.

ConclusionHSA will continue to monitor the safety profile of these drugs and updateour healthcare professionals when more information becomes available.Although HSA has not received any reports of serious adverse reactions

associated with Evra, the local package insert of Evra will be amendedto include the findings of the studies on Ortho Evra and Evra as bothproducts are bioequivalent

References1. Obstet Gynecol. 2007 Feb; 109(2 pt 1): 339-46.2. Contraception. 2006 Mar; 73(3): 223-8.



Package insert amendmentsreflecting safety issues

HSA has approved the following packageinsert changes due to safety updates fromO ctober 2006 to January 2007.

Details of the updates are listed ath t t p : / / ww w .hsa . gov. sg / cda / l abe l changes.Please note that there might be some lag timein the availability of the package insertwhich reflects the latest change(s).

1. Alend ronate (Fosamax, M SD)UnderPrecautions, it is stated that localised osteonecrosisof the jaw (ONJ) has occurred in patients with post-menopausal osteoporosis.

2. Ambroxol (Mucosolvan , Boehr ing erIngelheim) Cautionary use in those with rarehereditary fructose intolerance due to sorbitol contentof Mucosolvan. Severe skin lesions were reportedwith Mucosolvan which requires discontinuation.New ADRs: vomiting & heartburn. Use in firsttrimester of pregnancy is not recommended.

3. Carbo plat i n (Parap lat in , Br is to l -M ye r s Squ i b b ) Post-market injection sitereactions associated with extravasation, malaise,

dehydration & stomatitis were reported. Studiesinvolving therapy with carboplatin &cyclophosphamide have shown that elderly patientstreated with carboplatin were more likely to developsevere thrombocytopenia than younger patients.Increased risk of allergic reactions includinganaphylaxis was reported in patients previouslyexposed to platinum therapy.

4 . C lobu t i no l (Si l omat , Boehr i n gerInge lhe im) Contraindicated in patients withknown congenital long Q T syndrome & rarehereditary conditions (e.g. fructose intolerance dueto sorbitol content). Clobutinol may lengthen QTinterval in patients with congenital long Q Tsyndrome. New ADRs: somnolence & hallucinations(primarily seen in children & geriatrics), torsade de

pointes (very rare).5. Codergocr ine (Hydergine , N ovart is)Use a lower starting dose & maintenance dose forpatients with moderate-severe hepatic impairment,with appropriate monitoring. It is cautioned thatHydergine containing lactose, is not recommendedin patients with galactose intolerance, lactasedeficiency or glucose-galactose malabsorption.

Interactions (possibly causing increaseddopaminergic effects) may occur betweencodergocrine & macrolides, HIV protease or reversetranscriptase inhibitors, & azole antifungals. Do notuse during pregnancy & lactation. May causedizziness; caution in driving or operatingmachinery. New ADRs: bradycardia, headache,dizziness, hypotension (after IV administration),

vomiting, diarrhoea, retroperioneal fibrosis & rash.

6. Diclofenac (Vol taren EC, No vart is)Contraindicated in treatment of peri-operative painin coronary artery bypass graft surgery. Caution inthe use of aspirin & other NSAIDs in aspirin-sensitiveasthmatic patients due to potentially fatalbronchospasm.

7. Didan osine (Videx EC , Bristol-M yersSqu ibb) Co-administration of didanosine &tenofovir results in a 40-60% increase in systemicexposure to didanosine. Thus concomitant use isnot recommended, especially in patients with highviral load & low CD4 cell count as it may result invirological failure & emergence of early resistance.If combination is used, efficacy & adverse eventsrelated to didanosine should be monitored. Rarely,pancreatitis & lactic acidosis.

8 . Et o r i c o x i b ( A r c o x i a , MSD ) Contraindicated in peripheral arterial disease.A maximum duration of treatment for acute pain is8 days, including that related to primarydysmenorrhoea & minor dental procedures.Discontinue therapy if the condition deteriorated

during treatment in the elderly & patients with renal,hepatic, or cardiac dysfunction.

Arcoxia may reduce the antihypertensive effectof ACE inhibitors & angiotensin II antagonists. Co-administration with an ACE inhibitor or angiotensinII antagonist may result in possible acute renal failure

in renal patients & should be given with caution inthe elderly. Rates for serious thromboticcardiovascular events were higher in patients onetoricoxib vs naproxen 500mg 2 times/ day. N ewADRs: fluid retention, pancreatitis, confusions &hallucinations.

9. Fenta nyl (Durog esic Tran sdermalSystem , J&J) Appropriate initiating doseshould be based on the patients current opioid use.Preferably use in patients who have demonstratedopioid tolerance. O ther additional factors includebody size, age & extent of debilitation.

10. Flut icasone (Flixona se, GSK)Heightmonitoring is recommended in children onprolonged treatment (nasal corticosteroid used athigh dose & long duration may affect growth).

11 . Fondapa r i n ux (A r i x t a , GSK)Inpatients undergoing surgery, the timing of the firstdose of Arixtra requires strict adherence.UnderWarnings, it is added that Arixtra does not bindto platelet factor 4 and doesn't cross-react with serafrom patients with Heparin InducedThrombocytopenia (HIT)-type II. N ew ADRs: post-operative wound infections, thrombocythaemia,abnormal platelets, coagulation disorder,hypokalaemia, anxiety, bilirubinaemia, syncope, &leg pain.

12. G lyceryl tr ini t ra te (Angised , GSK)Contraindicated in patients taking sildenafil. Maycause dizziness & syncope. Caution in driving oroperating machinery. A local burning or tinglingsensation may occur in the tongue or mouth.

13 . I l op ros t t r ometamo l (Ven tav i s ,Zue l l i g )Caution in patients with Child-Pughclass B or more severe hepatic impairment & thosewith mild-moderate hepatic impairment.

14. Ipratropium (Atrovent , Boehr ingerI n g e l h e i m ) It is cautioned that colouredimages in association with red eyes from cornealoedema, in addition to conjunctival congestion, maybe signs of acute narrow-angle glaucoma.

15. Itra conazole (Spor anox , J&J)Cautionin patients with renal & hepatic impairment.Concomitant use with bepridil or nisoldipine iscontraindicated. N ot to be used in patients withevidence of ventricular dysfunction such as CHF ora history of CHF except for treatment of life-

threatening or other serious infection. Risk of heartfailure might increase with total daily dose ofitraconazole. New ADRs: leukopenia, neutropenia,thrombocytopenia, serum sickness, angioneuroticoedema, hypertriglyceridaemia, paraesthesia,visual disturbances, tinnitus, dysgeusia, toxicepidermal necrolysis, erythema multiforme, &exfoliative dermatitis.

16. Ketoconazole (Nizoral , J&J)Liverfunction should be assessed prior to treatment &monitored regularly during treatment & at the firstsigns of hepatotoxicity. Stop treatment immediatelyif hepatotoxicity is suspected. Cumulative dose oftreatment is a risk factor for serious hepatotoxicity.Should not co-administer with CYP3A4 substratese.g. bepridil, disopyramide, halofantrine,

levacetylmethadol, sertinidole (can lead to QTprolongation), ergometrine, methylergometrine,nisoldipine & eplerenone. Combination with potentenzyme inducers e.g. nevirapine significantlyreduces the bioavailability of ketoconazole. Cautionwhen co-administering with glucocorticoids (e.g.budesonide, dexamethasone & methylprednisolone),HMG-CoA reductase inhibitors, cilostazol,

eletriptan, fentanyl & tolterodine. Caution inpregnancy. New ADRs: angioneurotic oedema,adrenocortical insufficiency, photophobia &cirrhosis.

17. Lignocaine (Ligno caine , Pf izer )Cardiovascular toxic effects are generally preceded

by signs of toxicity in the central nervous system,unless the patient is receiving a general anaestheticor is heavily sedated with drugs such as abenzodiazepine or barbiturate. Rarely, cardiacarrest has occurred without prodromal CNS effects.In children, early signs of local anaesthetic toxicitymay be difficult to detect in cases where the blockis given during general anaesthesia.

18 . Lop ina v i r & r i tonav i r (Ka le t r a ,Abbo t t ) Therapeutic concentration monitoringshould be exercised in co-administration of Kaletrawith anti-arrhythmics. Systemic corticosteroid effectse.g. Cushing's syndrome & adrenal suppression hasbeen reported in patients receiving ritonavir &inhaled or intranasally administered fluticasone thusco-administration is not recommended. Newprecautions: (1) post-marketing reports of hepaticdysfunction, including fatalities & consideration forincreased AST/ ALT monitoring in patients at risk,especially during first few months of treatment, (2)reports of immune reconstitution syndrome in patientstreated with combination antiretroviral therapy. Post-marketing reports include bradyarrhythmia, StevensJohnson syndrome & redistribution/ accumulation ofbody fat. ADRs in paediatrics include taste aversion,vomiting, diarrhoea & rash.

1 9 . Me t o p r o l o l ( Be t a l o c ZO K ,As t r aZ enec a ) Adjust dosage to avoidbradycardia. Contraindicated in unstabledecompensated cardiac heart failure (pulmonaryoedema, hypoperfusion or hypotension), & in thosewith continuous or intermittent inotropic therapyacting through beta-receptor agonism.

Give lower doses or gradually withdraw treatmentif patient developed increasing bradycardia.Sudden withdrawal of beta-blockade in high-riskpatients may aggravate chronic heart failure, &increase the risk of myocardial infarction & suddendeath. Plasma levels of metoprolol may be raisedby co-administration of antiarrhythmics,antihistamines, histamine-2-receptor antagonists,antidepressants, antipsychotics, & COX-2 inhibitors.New ADR: hepatitis & arthralgia.

20. Miconazole (Daktarin oral gel, J&J)Contraindicated in infants < 6 months old or in thosewhose swallowing reflex is not yet sufficientlydeveloped. Hypoglycemia may occur in patientsusing oral hypoglycemics e.g. sulfonylureas &miconazole concomitantly. Miconazole interacts

with bepridil, halofantrine, sertindole, ergotalkaloids & isopyramide. New ADRs: angioneuroticoedema, anaphylactic reactions, choking, Lyellsyndrome (toxic epidermal necrolysis), StevensJohnson syndrome, urticaria, & rash.

21. Pramipexole (Si f ro l , Boehr ingerInge lhe im)Patients & caregivers should beaware of behavioural changes e.g. pathologicalgambling, increased libido, binge eating & mayrequire dose reduction or discontinuation. N ewADRs: abnormal behaviour & dreams, delusion,fatigue, hyperkinesia, increased eating, paranoia,pathological gambling, & weight increase.

22 . Stavud in e (Zer i t , Br i sto l -M yersSquibb)Peripheral neuropathy was reportedin HIV-infected patients receiving stavudine together

with didanosine & hydroxyurea. Increased risk ofhepatotoxicity & possibly death may occur inpatients treated with Zerit in combination withdidanosine & hydroxyurea vs Zerit alone. NewADRs: abdominal pain, chills/ fever, redistribution/accumulation of body fat, anorexia, pancreatitis,myalgia, anaemia, leucopenia, symptomatichyperlactatemia, & insomnia


8/8 Vol.9 No.3

Editor-in-ChiefMs Chan Cheng Leng, BSc (Pharm) Hons

Executive Edito rMs Ang Pei San, BSc (Pharm)

Staff EditorsMs Yvonne Koh, BSc (Pharm) HonsMs Adena Lim, MPharm (Clin Pharm)Ms Tan Bee Him, BSc (Pharm)

Editorial BoardClinical Prof. Goh Chee LeokProf. Edmund Lee Joo DeoonClinical A/ Prof. Chng Hiok HeeClinical A/ Prof Gilbert Lau Kwang FattDr Lee Kheng Hock

Enquiries, comments and suggestions to:

Pharmacovigilance Unit

Centre for Drug AdministrationHealth 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 [email protected]

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 authorsaccept 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 2007 Health Sciences Authority of

Singapore. All Rights Reserved.

Bevacizumab association with

hypertensiveencephalopathy and

reversible posteriorleukoencephalopathy

syndromeRare but serious adverse reactions

B

evacizumab (Avastin) is a recombinant

humanised monoclonal antibody that is directed

against the vascular endothelial growth factor

(VEGF). It has been licensed since March 2005by HSA for use in combination with intravenous

5-fluorouracil/ folinic acid or intravenous

5-fluorouracil/ folinic acid/ irinotecan for the first-line

treatment of patients with metastatic carcinoma

of the colon or rectum.

New safety information

Based on reviews of post-market and clinical trial

reports, rare cases of hypertensive encephalopathy

and reversible posterior leukoencephalopathy

syndrome (RPLS) have been seen in patients on

Avastin.A total of three confirmed cases of hypertensive

encephalopathy have been reported in Avastin

clinical studies and in post-marketing experience

worldwide, based on an estimated patients exposure

of 67,000. Hypertensive encephalopathy is

manifested as severe hypertension associated with

headache, nausea, vomiting, convulsions or confusion.

In all the cases reported, the patients had a medical

history of hypertension and experienced markedly

increased blood pressure of 200mmHg systolic.

One of these three cases resulted in a fatal outcome.1

RPLS, a neurologic disorder, typically presents as

headache, seizures and visual loss, and often occurs

in the setting of accelerated hypertension.2 It may

develop in patients who have kidney failure, high

blood pressure or who have a compromised immune

system. This condition encompasses a spectrum of

disorders, including hypertensive encephalopathy,

eclampsia, thrombotic thrombocytopenic

purpura/ haemolytic uraemic syndrome, and is also

associated with the use of other medicines like

immunosuppressants. Brain imaging, particularly

MRI, confirms the diagnosis of RPLS. Reports ofpatients with RPLS have been confirmed in four and

suspected in ten patients receiving Avastin. Two of

these reports were recently published in the literature.3

The onset of symptoms was reported to occur from 16

hours to 1 year after starting Avastin. None of these

cases had resulted in death.

A direct cause and effect between Avastin and these

events has not been established but it cannot be ruled

out. The majority of the reports stated above were for

the treatment of conditions other than the licensed

indications metastatic carcinoma of the colon orrectum. Both hypertensive encephalopathy and RPLS

are reversible if recognised and treated promptly.

Local situation

HSA has not received any local reports pertaining to

hypertensive encephalopathy and RPLS associated

with the use of Avastin. In-line with regulatory actions

taken by regulatory agencies such as the Therapeutics

Goods Administration of Australia, Health Canada

and the US Food and Drug Administration, the local

package insert of Avastin will be updated to reflect

this new safety information

References

1. Health Canada advisory, warnings and recalls for health

professionals, October 2006. http:/ / www.hc-sc.gc.ca/ dhp-

mps/ medeff/ advisories-avis/prof/ 2006/

avastin_hpc-cps_e.html

2. Intern Med J 2005; 35:83-90.

3. N Engl J Med 2006; 354:980-2.

ADR News Mar2007 Vol9 No1

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