Staff
NATIONALLY CIRCULATED INFORMATION
Australia
ADRAC Bulletin Vol 16, No 1, February 1997.
Electrolyte disturbances with oral
phospate bowel preparations
The use of oral sodium phosphate solution (Fleet
Phospho-Sosa Buffered Saline Laxative Mixture) as a
bowel preparation for colonoscopy has become more
common. The product is available without
prescription and can also be used as a laxative at a
lower dose.
Prescribers should be aware that oral sodium
phosphate products can cause dehydration,
hyperphosphataemia, hypocalcaemia, other
electrolyte abnormalities and associated
complications. Infants, the elderly, the frail, those
with congestive heart failure, and compromised renal
function are particularly at risk.
Calcitriol and hypercalcaemia
The active metabolite of vitamin D is calcitriol and is
now widely used in the management of osteoporosis.
It is well known to cause hypercalcaemia but
monitoring may not be as assiduous as necessary.
Over the past 4 years ADRAC has received 51
reports of adverse reactions in association with
calcitriol. Most commonly reported reactions have
included rash, pruritus, headache and hypercalcaemia,
and arthralgia, chest pain, constipation and nausea.
The product information for calcitriol has a
precaution about the development of hypercalcaemia
with the use of the drug and recommends twice
weekly determinations of serum calcium levels early
in calcitriol therapy, with at least weekly
determinations for the first 12 weeks and monthly
thereafter.
Fluvastatin and muscle disorder - a class
effect
Fluvastatin is a HMG-CoA reductase inhibitor which
has recently been marketed in Australia.
ADRAC has received 85 reports in association with
fluvastatin from March to December 1996. Most
commonly reported reactions have included muscle
disorders (myalgia, myopathy, myositis, leg cramps
and/or increased creatine kinase (CK)).
Early clinical trials did not show myopathy as an
adverse effect of fluvastatin but this effect has become
evident from postmarketing surveillance. Prescribers
should be aware that muscle involvement is a class
effect of all HMG-CoA reductase inhibitors,
including simvastatin and pravastatin.
Lamotrigine and severe skin reactions
Lamotrigine is an anticonvulsant which was initially
approved in 1994 as `add on therapy´ for treatment
of epilepsy, although it is now also used as
monotherapy. ADRAC has received 111 reports
involving lamotrigine. Of these, 36 described skin
reactions, mostly rashes and often described as
maculopapular. Lamotrigine is known as a relatively
frequent cause of a mild rash but of particular interest
are the eight reports of severe skin reactions such as
erythema multiforme, Stevens Johnson syndrome,
toxic epidermal necrolysis and bullous eruption.
Worldwide, there have been over 100 reports of
Stevens Johnson syndrome or toxic epidermal
necrolysis with lamotrigine.
Prescribers are reminded that careful incremental
titration of the dose may decrease the severity of skin
reactions, that the dose of lamotrigine in patients
taking valproate should be reduced as directed in the
Product Insert and that all patients who develop a
rash should be promply evaluated with consideration
given to withdrawal of the drug.
Canada
Canadian Adverse Drug Reaction Newsletter, Vo l7,
No 1, January 1997
Primary pulmonary hypertention and long-
term use of appetite suppressants
Primary pulmonary hypertension (PPH) is a life-
threatening condition with an estimsted 4-year
survival rate of 55%. Recent data indicate an increase
in the risk of PPH associated with the use of appetite-
suppressant drugs (mainly dexfenfluramine and
fenfluramine) when used for more than 3 months.
Thus, the estimated risk is 23 to 46 cases per million
patients each year.
As recommended by expert advice from the Drugs
Programme, Health Canada warns physicians that:
A- Ponderal and Pondimin are indicated only for
short-term use: now defined as no more than 3
months.
B- The indication for appetite-suppressant drugs has
been further restricted to the medical management
of obese patients with an initial BMI of > 30 kg/m2.
Such drugs can also be prescribed for patients with a BMI of 27
to 29 kg/m2, if they have other risk factors.
Treatment with appetite-suppressant drugs should be
stopped if new, unexplained symptoms of dyspnea,
angina pectoris, syncope or lower-extremity oedema
develop.
See National circulated information, United Kingdom
below.
HIV protease inhibitors and increased
bleeding in hemophilia?
Protease inhibitors (PIs), a new class of antiretroviral
agents, are currently indicated in combination with
other antiretroviral agents for the management of
HIV infection.
Invirase, Norvir and Crixivan were first approved in
Canada in March, August and September 1996
respectively.There have been concern about the
occurance of increased bleeding in hemophiliac
patients treated with PIs. To date, the total number
of incidents of increased bleeding in hemophiliac
patients receiving PIs is 55 cases worldwide, 5 of
which occurred in Canada.
Erythema multiforme and nifedipine
A case report of a 46-year-old woman who developed
erythema multiforme (EM) a few weeks after her
antihypertensive therapy was changed to nifedipine
XL was published in The Canadian Journal of
Hospital Pharmacy.
The patient was admitted to hospital with a 3-day
history of fever, malaise, headache and a
maculopapular rash. The rash progressed to a painful,
non-itchy rash that covered 85% of her body, with
vesicles on her lower limbs. The results of a punch
biopsy led to the diagnosis of EM. Nifedipine was
stopped and the patient was treated with
acetaminophen, iv hydrocortisone, prednisone,
hydroyzine, iv cloxacillin and mupirocin ointment.
Her skin continued to peel, and she was subsequently
treated as a burn patient with daily tub baths,
bacitracin dressings on the open areas of the rash and
clobetasol cream on the non-blistered areas. The rash
improved, although her skin continued to peel, and
the patient was discharged from the hospital.
The Canadian ADR database received 290 cases of
suspected adverse reactions associated with the use of
nifedipine from 1982 to 1996, 109 involved skin and
appendages disorders, including 2 reports of EM.
The CADRMP remids health care professionals that
EM is a hypersensitivity reaction that can range from
being mild to severe, and sometimes fatal .
Congenital anomalies and fluconazole
Since 1990 fluconazole has been available in Canada
as a systemic antifungal agent for the treatment of
oropharyngeal and oesophageal candidiasis, other
serious candidal infections and cryptococcal
meningitis. In 1995 Diflucan 150 became available as a
single-dose treatment for vaginal candidiasis.
In 1992 and 1996, Lee and Pursley and their
colleagues described infants with multiple congenital
anomalies whose mothers took high doses of
fluconazole for the treatment of coccidioidal
meningitis for at least the first 4 months of their
pregnancies.
There are some suggestions that the drug may cause
teratogenic effects in humans, including craniofacial,
skeletal and cardiac anomalies. There is some evidence
to indicate that the teratogenic effects may be dose
dependent.
Fluconazole is not recommended in pregnant women
unless the potential benefit outweighs the risk to the
mother and fetus.
Germany
Deutsches Ärzteblatt 93, Heft 7, S. A-419, 1996
Registration of tacrine under special
conditions
Tacrine (Cognex) has been available in the Federal
Republic of Germany since June 1995 for the
treatment of mild and moderate of Alzheimer´s
disease. It attacks central structures in the form of a
cholinesterase inhibitor.
Some facts to be considered are:
1- The clinical studies have shown therapeutic
effects only in some of the patients.
2- In addition to the therapeutic effects, there are
often adverse reactions.
3- Besides cholinergically mediated adverse drug
reactions, more than 40% of the patients suffer
from reversible increases in transaminases.
4- Granulomatous hepatitis and hepatocellular
necrosis have been observed, which were assumed
to be caused by immunological reactions.
5- Psychological reactions can also occur.
In view of this risk/benefit ratio, the indication for
the application of tacrine has to be made very
carefully. If a therapeutic effects has not been
achieved within 3 months, treatment should be
discontinued.
Deutsches Ärzteblatt 93, Heft 8, S. A-491, 1996
Acute myocardial infarction or instable
angina pectoris not to be treated with
short-acting calcium antagonists
Nifedipine and other dihydropyridines are indicated
in patients with hypertension and stable angina
pectoris; they are generally contra-indicated for
instable angina pectoris, as well as for acute
myocardial infarction. For secondary prophylaxis
after an acute myocardial infarction, beta blockers,
and not calcium antagonists, are first choice drugs.
Calcium antagonists should generally be avoided in
patients with heart failure in addition to a post-
infarction condition.
Their use contrary to the indications can lead to
excess mortality.
The Drug Commission of the German Medical
Profession recommends strict compliance with the
restrictive indication when prescribing nifedipine and
other short-acting dihydropyridines.
Deutsches Ärzteblatt 93, Heft 9, S. A-561, 1996
Risks with antiarrhythmic therapy with
quinidine/verapamil
The Drug Commission of the German Medical
Profession (AkdÄ) has so far received a total of 102
cases of adverse drug reactions caused by the fixed
combination of quinidine/verapamil.
Its indications are symptomatic and tachycardiac
supraventricular cardiac arrhythmias which need
treatment and involve fast conduction.
In principle, single-entity drugs should be used for
treatment of arrhythmia.
The AKdÄ points out that, in case of urgent need for
the combined use of quinidine and verapamil, both
components should be used as individual substances.
Ireland
Drug Safety - January 1997 - Issue No. 3
Lamotrigine (Lamictal)
Lamotrigine, a novel antiepileptic drug was first
authorised for use in Irland in 1990 an "an add on"
therapy. In 1995 the product was additionally
authorised for use as monotherapy.
Evidence from clinical trails and post-marketing
surveillance suggests that about 1 in 1,000 patients
develop serious skin reactions.
To minimise the risk of serious skin reactions,
prescribers are reminded to:
1- Strickly adhere to the dosage instructions
2- Advice patients to see their doctor immediately if
they develop a skin rash.
3- Comprehensively evaluate any patients
presenting with a rash.
See also: Australia above.
Japan
Information on Adverse Reactions to Drugs in Japan,
No. 137, May 1996.
Epileptic seizures due to interaction of
sodium valproate with panipenem/
betamipron or with meropenem
It has been reported that concomitant use of
panipenem/betamipron or meropenem in patients
receiving sodium valproate has led to lowering of
plasma valproic acid concentration, resulting in
recurrence of epileptic seizures.
An adequate plasma level of valproic acid is
important to control seizures, and reduction of the
plasma level due to interaction with other drugs has
clinical consequences.
Severe adverse reaction Interstitial
pneumonia caused by Sho-saiko-to
Sho-saiko-to is a Chinese preparation for improving
hepatic dysfunction in chronic hepatitis.
Interstitial pneumonia has been reported with serious
outcome.
Information on Adverse Reactions to Drugs in Japan,
No. 138, July 1996.
Interstitial pneumonia after cancer chemo-
therapy in combination with G-CSF
The drug is used against neutropenia caused by cancer
chemotherpy. It has been reported that interstitial
pneumonia or its aggravation was found in patient
receiving this drug. Judging from the
pharmocological action of the drug, it appears to be
involved in interstitial pneumonia or its aggravation.
Because G-CSF (Granulocyte colony stimulating
factor) may cause or exacerbate interstitial
pneumonia, patients who have received it should be
carefully observed. If they show fever, cough,
dyspnea, or abnormal chest X-ray findings,
administration must be stopped and appropriate
measures, such as adrenocortical hormone treatment
must be taken.
Cisapride and asthmatic attacks
Cisapride was approved in 1989 for gastrointestinal
symptoms, associated with chronic gastritis or
postgastrectomy syndrome, reflux oesophagitis, and
intestinal pseudo-obstruction. Asthmatic attacks and
aggravation of asthma were reported in 3 patients
who received the drug. Cisapride may cause asthma
though hypersensitivity or when its selective
pharmacological effect on the gastrointestinal smooth
muscles adversely affects bronchial smooth muscles.
Care should be taken when treating patients with
history of hypersensitivity or asthma.
Malaysia
Berita Ubat-Ubatan, Newsletter of the Drug Control
Authority Malaysia, Vol 10, No 3, September 1996.
Carbamazepine
Carbamazepine is a very commonly used anti-
convulsant drug. The drug can cause severe and life-
threatening adverse reactions.
Malaysian Adverse Drugs Reaction Advisory
Committee (MADRAC) received 103 reports
associated with the use of carbamazepine between
June 1988 and June 1996. It was the sole suspected
drug in 96 of the 103 reports.
MADRAC advises that patients on carbamazepine
are monitored closely for signs of hypersensitivity
reactions.
Atenolol - memory impairment
A 54-year-old man was hospitalised with a 3-month
history of progressive memory impairment. He was
on atenolol 100 mg daily for the past 14 years for
hypertension. At work, the man had difficulty in
concentrating and understanding new concepts or
ideas. The man had a 75% improvement in his
memory one month after atenolol was replaced with
amiloride HCl + Hydrocholrothiazide. Three
months later, the man had completely recovered
from the problem.
New Zealand
Prescriber update, No 14, February 1997
Adverse reactions of current concern
The following table lists the Medicines Adverse
Reactions Committee Adverse Reactions of Current
Concern.
There are two reasons for this list.
A- To raise the level of awareness of these adverse
reactions.
B- To evoke reports so that more information may
be gathered and appropriate action taken.
Medicine Adverse Reaction Prescriber
update reference
Clozapine myocarditis No. 7, Dec 1994
Flucloxacillin cholestatic hepatitis No. 7, Dec 1994
Herbal medicines all adverse reactions No. 13, Dec 1996
Non-sedating cardiac effects
anti-histamins No. 7, Dec 1994
Intramuscular injections site reactions No. 13, Dec 1996
NSAIDs
Intramuscular renal damage No.13, Dec 1996
NSAIDs
Oral contraceptives venous No.11, Feb 1996
thromboembolism
Roxithromycin cardiac arrhythmias No. 11, Feb 1996
Terbinafine haematological reactions No. 8, May 1995
Tiaprofenic acid cystitis No. 7, Ddec 1994
When reporting cardiac events associated with the
non-sedating antihistamines, include ECG results.
Cisapride and cardiac arrhythmias
Cisapride is used to restore or facilitate motility in
the gastrointestinal tract. Cases of cardiac
arrhythmias with cisapride have been reported
including several fatalities.
Recommendations:
1- Cisapride should not be used concomitantly with
erythromycin, clarithromycin, fluconazole,
itraconazole, ketoconazole or miconazole
(including Daktarin Oral Gel);
2- Cisapride should be used cautiously in patients
with electrolyte disturbances or cardiac disease;
3- Metoclopramide or domperidone should be con-
sidered as alternatives to cisapride in patients with
congenital prolonged QT syndrome, or those
taking other agents causing prolongation of the
QT interval, for example terfenadine, astemizole,
quinidine or sotalol;
4- Cisapride should not be used at doses that exceed
the recommended maximum (40 mg daily).
Risk factors for sotalol proarrhythmia
Important risk factors for the development of serious
ventricular arrhythmias associated with sotalol are;
dose, renal impairment, female gender, hypokalaemia,
QT interval and a history of heart failure.
Although sotalol is undoubtedly a useful anti-
arrhythmic agent, the benefits should be weighed
against these potentially serious adverse effects.
Ticlopidine-induced blood dyscrasias
Ticlopidine may cause life-threatening haematological
reactions. Blood counts should be checked every 2
weeks in the first 3 months of administration and
patients should be alerted to seek immediate medical
attention if they develop symptoms of infection or
bleeding.
Interactions with fluoxetine and other SSRIs
The list of medicines with a potential to interact with
the SSRIs is long. Practitioners should bear this in
mind before co-prescribing and be prepared to
modify treatment promptly if necessary.
Top ten adverse reactions to omeprazole
in the IMMP
The monitoring of omeprazole in the Intensive
Medicines Monitoring Programme (IMMP) has
revealed a very good safety record. None of the top
ten adverse reactions reported are common.
However, awareness of possible adverse reactions is
beneficial in the management of some patients.
Polymyosititis, a previously unrecognised reaction to
omeprazole, was reported three times.
Philippines
SIGNALS in Adverse Drug Reactions Monitoring,
Vol 1, No 12, December 1996
ADR s of herbal medicines
Herbal medicines are seen as WHO document
panacea for the following reasons:
1- The belief that herbal medicines are as effective as
synthetic drug products.
2- The belief that since herbal medicines have been
used over the centuries and are of natural
origin, they are devoid of toxic potentials of
conventional medicines and therefore must be
harmless.
3- Because herbal medicines are accessible to the common man.
4- Because of the low cost.
WHO categorizes herbal medicines in the following
three classes:
1- Herbal medicines that are available on medical
prescription only and are comparable with synthetic
prescription medicines as to their use in medical practice.
2- Herbal medicines that are licenced to be sold over-the-counter
and are used for self-medication.
3- Herbals that are not licenced as a pharmaceutical product and
are sold mainly as health supplements.
The WHO warns the public that though botanicals
appear to have an excellent safety records, some are
potentially dangerous as they possess important
intrinsic toxicity.
The WHO recommended the following:
1- Countries adopt within a national drug policy,
specific provisions on the availability and use of
herbal medicines having regard to the need for
appropriate statutory controls.
2- The public is made aware that herbal medicines are
not inherently innocuous.
3- Composition of potent pharmacologically active
substances in herbal remedies should be controlled
and information should be included on retail packaging.
4- Monographs on herbal medicines should be developed for
inclusion in national pharmacopoeia.
5- Criteria for monitoring adverse effects associated with the
use of herbal must be developed.
Sweden
Information from the MPA, Vol 7, No 6 December
1996.
Acarbose - hepatic disorders in focus of
the two year follow up
Acarbose (GlucobayR) was launched in June 1994 for
use in non-insulin dependent diabetes mellitus. Since
then 12 adverse reaction reports have been recieved
describing 14 reactions. Acarbose is suspected of
causing 9 of the reaction: 5 flatulence/stomach pain/
diarrhoea, 2 reversible elevation of transaminases, 1
exanthema and 1 paraesthesia.
One of the hepatic disorder cases concern a 51-year-
old woman with diabetes mellitus and hypertension.
She used to take Glucophage but the prescription was
changed to acarbose 300 mg daily and after eight
months of treatment elevation of ALAT and ASAT
was noted. Glucobay was discontinued and
Glucophage restarted. About one month later the
transaminase levels had normalised. The liver tests
were normal both before the start of acarbose use and
six months after withdrawal.
In the data sheet for Glucobay elevation of
transaminase levels is mentioned as rare (<1/1000).
The manufacturer has recently reported an
internationals study describing cases of liver damage
associated with acarbose. It is unclear weather it is
acarbose or its metabolites that cause the liver
damage. No risk factors have been identified, but
early clinical trials indicate that elevated transaminase
levels are dose related. Such a relationshi han not
been seen in the patients who experienced
symptomatic liver damage, as no one exceeded the
recommended dose.
It is important to remember that these disorders
often start after several months of treatment.
Therefore it is adviced to regularly monitor liver
function.
United Kingdom
Current Problems in Pharmacovigilance, Vol 23,
February 1997.
Anorectic agents: risks and benefits
Recommendations for the use of fenfluramine,
dexfenfluramine and phentermine have been revised.
Primary pulmonary hypertension (PPH) is
recognised to be associated with the use of anorectic
agents.
The use of these products is contraindicated in
patients with this disease, a current or past history of
cardiovascular or cerebrovascular disease, a current or
past psychiatric disorder, a history of alcoholism or
drug abuse, in children under 12 years, and in patients
receiving any other centrally acting anorectic agent.
It is recommended that treatment should be
conducted under the care of physicians experienced in
the treatment of obesity.
Ticlopidine and white blood cell disorders
Ticlopidine is not licensed in the United Kingdom.
It is an antiplatelet drug which has recently been used
quite widely on a named-patient basis for prophylaxis
following intracoronary stenting.
The legal responsibility for the consequences of using
this, or any other unlicensed medicine rests with the
prescribing doctor.
Severe withdrawal reactions with baclofen
In order to minimise the risk of withdrawal reactions,
baclofen therapy should always be discontinued by
gradual dose reduction over at least one to two
weeks. If symptoms occur, a longer period of
withdrawal may be necessary.
SPECIAL COMMUNICATIONS
France
Minutes from the French Pharmacovigilance
Commission meeting, July 4th and October 3rd 1996:
PrepulsidR(Cisapride) and adverse cardiac
effects
The French Pharmacovogilance Commission has
reviewed the cases of adverse cardiac effects reported
during 1995 with PrepulsidR (cisapride, Janssen
Pharmaceuticals).
Of the 30 cases reported, 14 described prolonged QT
intervals in prematures.
Four of the reports mentioned concomitant use of
the anti-cholinergic diphemanil methylsulfate. As a
result of this the Commission has decided to ask the
manufacturer to initiate studies of the
pharmacokinetics in prematures. The Commission
decided to change labelling:
* strict dose labelling for prematures
* contraindicating the drug in case of known
congenital QT prolongation and for use together
with diphemanil.
* under 'cautions' call for monitoring of QT intervals
* add notes under 'adverse reactions' and 'overdosage'
about the reports of QT prolongation.
Reference: Olsson S, Edwards IR; Tachycardia during
cisapride treatment, Br Med J, 1992; 305: 748-749
Naftidrofuryl and hepatic side effects
The Commission has reviewed six cases of adverse
hepatic effects reported with naftidrofuryl. Three of
these reports came from France, one of them
describing a positive rechallenge.
Following the review the Commission decided to add
a note about the signal under 'adverse reactions' in
the labelling.
Topical ketoprofen and skin reactions
Because of the skin adverse reactions seen with
topical ketoprofen products the Commission has
decided to make general label changes for all such
products:
* wash hands after each use
* contraindicated in known allergy against
ketoprofen or other NSAIDs and aspirin
* delete the statement 'may be used with occlusive
bandage'
* add under 'precations' to avoid exposure to sunligt
during and two weeks after treatment
* add 'photosensitivity' and 'severe bullous eruption'
(rare) under 'adverse reactions'.
Carmustine and pulmonary fibrosis
The Commission has reviewed the results of a French
pilot study on the association of carmustine and
pulmonary toxicity in children. The study gives
evidence of a delayed toxicity mainly seen in
children, that seems to be age and dose related. This
has led to suggest the following:
* contraindicate carmustine use in children
* allowing six weeks treatment intervals between
treatments in other groups
* reevaluation of the risk-benefit report of the drug
Opioid analgesics and antitussives - biliary
disorders
The Commission has decided to change labelling for
all per orally and rectally administered drugs
containing codeine, opium or dextropropoxyphene
to mention the adverse biliary disorder 'spasm of
Oddi´s sphinter manifested by biliary or pancreatic
pain'.
Minocycline
Following an article in the British Medical Journal
describing 23 cases of hepatitis and 11 cases of lupus
caused by minocycline the Commission has proposed
to the manufacturer (Wyeth Lederle) to make
labelling changes concerning 'precautions' and
'adverse reactions', to include these reactions are
included.
Fusidic acid - haematological disorders
After analysing 41 cases recieved by the National
Pharmacovigilance System, it seems that also the oral
forms of fusidic acid (like the intravenous forms)
cause hematological disorders. Most frequent are
neutropenias and pancytopenias. Age, sex, duration
of treatment and doses above 1g daily seem to be risk
factors.
Leo Laboratoires has 53 notifications about
hematological effects, internationally collected since
1970.
These findings has led the Commission to propose a
change of labelling to mention haematological
disorders under 'adverse reactions' and to call for
observation of this during and 15 days after
treatment.
Germany
Deutsches Ärzteblatt 93, Heft 26, S. A-1790, 1996
Fulminant liver failure during treatment
with paroxetine
The AkdÄ would like to draw doctor´s attention to
the fact that severe liver damage may occur during
treatment with paroxetine, necessitating immediate
withdrawal of the drug.
Deutsches Ärzteblatt 93, Heft 42, A-2723, 1996
How tolerable are drugs containing
echinacea?
Echinacea preparations are used in supportive
treatment of recurrent infections of the airways and
the efferent urinary tract, in superficial wounds
which are slow to heal and for increasing the body's
natural resistance, in bacterial skin infections, herpes
simplex labilis and in leucopenia following the use of
radiation and cytostatic drugs.
Allergic reactions including erythema multiforme and
complaints affecting the airways including bronchial
asthma have been reported.
Since 1990, 97 reports on suspected cases of adverse
drug reactions have been submitted to the Drug
Commession of the German Medical Profession on
different drugs containing Echinacea. In two cases
among these reports, a fatal outcome is linked to the
treatment with Echinacea.
Doctor and patient must always critically weigh the
risks and benefits of these herbal drugs.
Deutsches Ärzteblatt 93, Heft 43, S. A-2809, 1996
Don´t overlook ACE-inhibitor induced
angioneurotic oedema even during long-
term administration
Angioneurotic oedema, usually of the face, mouth,
tongue, throat and larynx, can occur during
treatment with ACE-inhibitors, often in the early
stages, always represent an adverse drug reaction of
this substance class which must be taken seriously.
The potential risk to a patient with angioneurotic
oedema in this area is the result of the following
obsevations:
1- The oedema can progress and spread in the mouth/
throat/larynx very quickly, meaning that even
emergency intubation can fail.
2- Swelling which is initially regarded as "mild" and
reversible can result in a life-threatening obstruction
of the airways as it develops further.
3- The value of drug-based measures still cannot be
properly estimated.
4- Case reports of recurrent angioneurotic oedemas were
already published in the literature.
The Drug Commisssion has pointed out that the
potential development of an angioneurotic oedema
typical for this substance class as an ADR must be
kept in mind when administering ACE inhibitors,
not only after the start of the treatment, but also at
all times during long-term administration.
USA
Med Watch, December 12, 1996
Flonase (fluticasone propionate) nasal
spray
A statement added has been added to the product
information that alteration or loss of sense of taste
and/or smell and, rarely, nasal septal perforation have
been reported during post-marketing experience
Reports in who file: Taste loss 5, Parosmia 13.
Med Watch, December 20, 1996
Xanax (alprazolam)
Regarding risk of dependence and its severity, in
notation regarding spontaneous reporting system
(replacing "post-marketing surveillance") data, long
periods now defined as more than 12 (rather than "8-
12", as before) weeks.
In a controlled post-marketing discontinuation study
of panic disorder patients, the patients treated with
doses of Xanax greater than 4 mg/day had more
difficulty tapering to zero dose than patients treated
with less than 4 mg/day.
Med Watch, February 21, 1997
Pondimin (fenfluramine HCl)
Pondimin is an appetite suppressant, and appetite
suppressants increase the risk of developing primary
pulmonary hypertension (PPH), an often fatal
disorder.
DRUG WITHDRAWALS
France
Agence du Medicament, February 7, 1997
Terfenadine withdrawn
The French Pharmacovigilance Advisory Board
examined on the 6th February, 1997, the safety
profile of the non sedative antihistamines marketed in
France (terfenadine, astemizole, loratadine,
cetirizine), particularly with respect to their serious
cardiac adverse reactions.
Results of the survey confirm the current existence of
serious cardiac adverse effects such as torsade de
pointes and other ventricular arrythmias with
terfenadine. The conditions facilitating their
occurrence are welknown.
Given that :
A- The risk of serious cardiac effects has not been controlled
B- Other safer therapeutic alternatives are available
on the market, the French Pharmacovigilance
Advisory Board has proposed to suspend the
marketing and use of terfenadine
Ireland
Drug Safety - January 1997 - Issue No.3
Tolrestat
Tolrestat was first authorised for use in Ireland in
1988 as for the treatment of diabetic neuropathy.
As there was no positive results from the studies
undertaken by the company to confirm previous
studies, the company decided to voluntarily
withdraw the product worldwide from October 11,
1996 and to notify physicians and pharmacists
accordingly.
Malaysia
Berita Ubat-Ubatan, Newsletter of the Drug Control
Authority Malaysia, Vol 10, No 3, September 1996
Paracetamol 500 mg/5 ml liquid preparations
The Drug Control Authority has decided to cancel
the registration of all paracetamol 500 mg/5ml liquid
preparations. This decision was taken after the
adverse reaction committee received three reports of
paracetamol toxicity in children, one fatal, associated
with the use of paracetamol 500 mg/5 ml.
LITERATURE REFERENCES
Argentina
Lancet Vol 349, 399-400, February 8, 1997
Worldwide pharmacovigilance systems
and tolrestat withdrawal
Tolrestat is an aldose-reductase inhibitor, developed
as a new tool for the treatment of serious diabetes
complications such as neuropathy, retinopathy, and
nephropathy.
In March, 1995, a report was received through the
National Pharmacovigilance System of Argentina of
hepatic necrosis and death of a patient on tolrestat.
When the centre asked about other reports of torestat
and hepatic abnormalities: The centre has received
from WHO collaborating Centre for International
Drug Monitoring in Uppsala the first and useful
information about hepatic abnormalities related to
tolrestat. Tolrestat was being marketed in several
countries including: Argentine, Chile, Greece,
Ireland, Italy, Mexico, Philippines and Uruguay. In
October, 1996, the manufacturer´s medical doctor
informed to the centre that the manufacturer, because
of another two fatal cases of tolrestat and hepatic
necrosis and the poor efficacy in clinical trials, had
decided to suspend worldwide marketing of tolrestat.
Statement from the National Pharmocovigilance
System of Argentina "Our case illustrates the need for
pharmacovigilance systems worldwide, not only in
developed countries, and the importance of
connection with the WHO drug-monitoring centre
in Uppsala".
Croatia
Pharmacoepidemiology and Drug Safety, Vol 6: 49-56
(1997)
Problems with drugs in Croatia
The drug situation is controlled with the help of:
1- Donations from Europe and US
2- Essential drug formulations, 250 for
outpatients, and 580 generic names for
various levels of hospital use
3- Special efforts to purchase drugs of good quality
at a reasonable price
4- Control of prescribing especially by GPs.
A new Medicines Act is in preparation and about
1000 generic names are on the market.
Drug education:
1- The Croatian Journal of Pharmacotherapy has
been published since 1962,
2- There are several drug bulletins
3- Special chapters on clinical pharmacology in textbooks,
4- Translation of three editions of Laurence´s
textbook with special commentary and
adaptation to local needs;
5- ADR spontaneous and intensive monitoring
(WHO programme) with a personal feedback to the
reporters and regular articles on drug use in a number
of periodicals.
There is an enthusiasm for `vasoactive drugs`, after
dipirydamole came oxpentifylline and antimicrobials
are always overprescribed.
France
Therapie 1996; 51; 414-416
Adverse drug reactions with fluoro-
quinolones
The French system of drug surveillance has analysed
the reports of adverse drug reactions (ADRs) to
fluoroquinolones since they were launched. The
frequency of reactions ranges from 1/15000 to
1/208000 case per days of treatment. Cutaneous
disorders and tendon disorders dominate in France,
whereas cutaneous effects and neuropsychiatric
disorders are predominant in the UK; tendon
disorders take up only the 5th position.
Among the most unexpected ADRs are the
following:
1- Shock
2- Acure renal failure
Tendon ruptures represent 81 cases for 921 reports of
tendon disorders which are related in decreasing
order to pefloxacin 1/23130 case per days of
treatment, ofloxin, norfloxacin and ciprofloxacin
1/779600 case per days of treatment. Age and
corticosteroids increase the risk of tendon rupture.
Therapie 1996; 51; 419-420
Tendon disorders with fluoroquinolones
421 cases have been collected by the Centre de
Pharmacovigilance: 340 of tendinitis and 81 of tendon
rupture. These cases were attributed to Peflacine,
Oflocet, Noroxine, Ciflox.
Tendinitis was characterized by a bilateral malleolar
oedema associated with a sudden pain. Sometimes this
oedema evoked phlebitis. The tendon rupture was
generally preceded by a tendinitis but in half of the
cases it occurred without warning.
Philippines
Clinical Pharmacology & Therapeutics, Vol 60, No
5, November 1996.
Concentration-related pharmacodynamic
effects of thioridazine and its metabolites
in humans.
Thioridazine has dose-related effects on ventricular
repolarization and the parent drug causes an
important proportion of these effects, although its
metabolites may also contribute.