References:
1 Drug Safety 1996; 15(1): 72-8
2 J Clin Pharmacol 1996; 36(4): 361-4
3 Eur Heart J 1994; 15(Suppl C): 52-6
4 J Hypertension 1995; 13(Suppl 3); S 17-21
5 Br J Clin Pharmacol 1995; 39(3): 265-70
6 BMJ 1994; 308: 18-21
7 Am Fam Physician 1996; 54(3): 947-53
Canadian Adverse Drug Reaction Newsletter, Vol 7, No 4
, October 1997
Protease inhibitors
The Therapeutic Products Programme (TPP) is aware of approximately
152 cases worldwide of new or exacerbated diabetes mellitus and hyperglycemia
in HIV-infected patients receiving protease inhibitors. The reports received
include 6 for Crixivan (indinavir sulfate) and 2 for Invirase (saquinavir
mesylate).Three patients recovered from hyperglycemia. 1 started insulin
therapy, but hyperglycemia persisted, 1 died from sepsis, and 3 cases were
of unknown outcome. In 4 of these 8 cases, the patients were known to have
diabetes. However, there is no conclusive evidence to establish a causal
relationship between protease inhibitor therapy and these events.
:
Terconazole
A 25-year-old woman gradually developed erythema multiforme
covering 90% of her body surface a few days after intravaginal administration
of terconazole ovules and suspected topical administration of terconazole
vaginal cream. The situation progressed to Stevens Johnson syndrome and
toxic epidermal necrolysis within 24 hours. Sepsis developed, and the patient
died from severe complications following acute renal failure and subsequent
cardiac arrest.
Concomitant medication use included the contraceptive
ortho 1/35. The patient had used a lactobacillus herbal preparation 4 to
5 days before using the terconazole.
Paroxetine
A 13 month old boy with prenatal exposure to paroxetine
exhibited delayed global development. No other drugs had been taken by
the mother; as well, no other obvious causative factors were identified.
A female infant born at 35 weeks' gestation had intraventricular
and subarachnoid bleeding. The mother had been taking paroxetine from the
16th week of pregnancy until delivery. The baby recovered from
the bleeding, but according to the physician permanent neurological damage
may occur.
A 29-year-old woman, while taking paroxetine, experienced
a miscarriage during the first trimester of pregnancy. No other drugs were
taken concomitantly.
References:
1. Ottawa: Therapeutic Products Programme; 1997 July 4.
2. Laval(QC): Hoechst Marion Roussel Canada; 1997 June
27.
3.Can Med Assoc J 1997; 157: 362
4. Ottawa: Therapeutic Products Programme, 1997 July 11.
5. Martindale. The extra pharmacopoeia (electronic version).
1995.
Vigabatrin
A number of reports of ophthalmological abnormalities
including visual field constriction, bilateral optic disc pallor, subtle
peripheral retinal atrophy and optic atrophy associated with the use of
vigabatrin have been collected from various countries by Hoechst Marion
Roussel in the course of international postmarketing surveillance.
Ref: See Australia above.
Finland
Tabu, Vol 5, No 4, 1997
Adverse drug reactions and age
Adverse effects of drugs become more common with age.
Drug therapy becomes more frequent with increasing age, which is particularly
true of the concurrent use of several drugs. Higher age may reduce the
reserve capacity for various bodily functions and weaken the homeostasis
of the patients, while the pharmacokinetics of many drugs undergo changes.
The risk of adverse effects related to drug dose increases with age.
New Zealand
Prescriber update, No 15 August 1997.
Adverse reactions of current concern
A list of adverse reactions of current concern was first
initiated in December 1994.
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.
The list is as follows:
Medicine Adverse Prescriber
Reaction update reference
Clozapine myocarditis No. 7, Dec 1994
Dexfenfluramine/ primary pulmo- No.15, Aug 1997
fenfluramine nary hypertension
Herbal all adverse No.13, Oct 1996
medicines reactions
Intramuscular injection site No.13, Oct 1996
NSAIDs reactions
Intramuscular renal damage No.13, Oct 1996
NSAIDs
Mefloquine neuropsychiatric No.15, Aug 1997
reactions
Non-sedating cardiac effects No.7, Dec 1994
antihistamines
Oral contracep- venous thrombo- No.11, Feb 1996
tives embolism
Roxithromycin cardiac arrhyth- No.11, Feb 1996
mias
Terbinafine haematological No. 8, May 1995
reactions
Dexfenfluramine and fenfluramine and the risk of
primary pulmonary hypertension
Patients should be informed of the risks of potentially
fatal primary pulmonary hypertension with long term use of anorexiants
such as dexfenfluramine and fenfluramine and advised to promptly report
symptoms such as dyspnoea, chest pain and leg oedema.
Primary pulmonary hypertension (PPH) is a rare, often
fatal disease that occurs more frequently in women during their third and
fourth decade. The anorexiant aminorex fumarate was withdrawn about thirty
years ago because of the association with an epidemic increase in PPH in
Europe.
Withdrawal reactions with selective serotonin reuptake
inhibitors
The abrupt discontinuation of an SSRI, particularly those
with a short elimination half-life such as paroxetine, may be associated
in some patients with a withdrawal reaction.
A. The Centre for Adverse Reactions Monitoring (CARM)
has received 9 reports of withdrawal reactions after stopping paroxetine
and 4 with fluoxetine.
B. To February 1996, the Australian Adverse Drug Reactions
Advisory Committee has received 22 reports of withdrawal reactions with
paroxetine, 3 with fluoxetine and 7 with sertraline.
C. At the end of September 1996, the WHO database had
1096, 275 and 183 reports with paroxetine, fluoxetine and sertraline, respectively.
D. The Committee of Safety of Medicines in the United
Kingdom recently published (Brit J Clin Pharmacol 1996; 42:757-63) results
of a survey of reports of withdrawal effects with selective serotonin reuptake
inhibitors (SSRIs). Withdrawal effects represented a much larger proportion
of all reports received for paroxetine than for other SSRIs
Oral Fleet and marked hypokalaemia
Oral sodium phosphate (Fleet) may cause electrolyte/ fluid
imbalance, including hypokalaemia. Copious fluid intake is advisable and
consideration should be given to checking electrolytes where appropriate.
The CARM has received 3 reports of adverse reactions to
oral sodium phosphate. All occured following a standard dose of 2 x 45
ml for bowel preparation prior to barium enema or endoscopy. Two patients
developed marked hypokalaemia. The third developed acute renal failure
secondary to dehydration with hypokalaemia, hyper-phosphataemia and hypo-calcaemic
tetany. A fourth case developed severe hypokalaemia and went into artrial
fibrillation during surgery following two 45 ml doses.
The ADRAC has similar reports with oral phosphate bowel
preparations.(Aust. Adv. Drug Reactions Bull 1997; 16 (1): 2).
.
Top ten adverse reactions with multiload Cu375 in
the IMMP
The monitoring of multiload Cu375 in normal clinical practice
in New Zealand has produced rates of adverse events consistent with those
reported from clinical trials, except there was a higher rate of uterine
perforations. If a woman using a copper IUCD develops an unexplained or
persistent allergic condition, practitioners should suspect the device.
With abdominal pain, the presence of infection related to an IUCD should
also be considered.
The 10 most frequent adverse reactions are presented in
the table below. Except for insertion problems, the rates per 1000 insertions
are not true rates of occurrence but are provided to give an idea of the
comparative frequency of the events.
There were 40 instances of failed insertion giving a rate
of 3.4 per 1000. Amongst the pregnancies, five were ectopic with a rate
of 0.05 per 100 woman-years which is lower than the natural
rate. Bleeding at insertion does not include bleeding of the cervix from
puncture with the tenaculum.
Reactions Reactions for the whole cohort
Number Rate/1000 insertions
Abnormal bleeding 589 47.7
Pain 369 29.9
Infection 273 22.1
Device expelled 235 19.0
Difficult/failed insertion 207 16.8
Pregnancy 110 8.9
Pain on insertion 70 5.7
Vasovagal response to
insertion 43 3.5
Bleeding at insertion 12 1.0
Uterus perforated 9 0.7
Follow-up information, which provides more accurate adverse
reaction rates, is included in table below, but only for the 3850 women
who had the device inserted prior to July 1994. The 2 rates (Pearl and
Life Table) refer only to events necessitating removal of the device in
the first year. Pearl rates are the number of events per 100 women-years.
For the first year of use the total number of women-year was 3521. The
Life Table method was used to calculate the percentage of women who can
expect to experience each event in the first year of use based on the Intensive
Medicines Monitoring Programme data.
Reaction Rate per 100 Expectation of
Woman-years occurrence within 12
(Pearl) Months (Life Table)
Abnormal
bleeding 3.5 3.9%
Pain 2.2 2.5%
Infection 0.8 1.0%
Device expelled 1.9 2.2%
Pregnancy 0.6 0.7%
Sweden
Information from the Medical Products Agency, Vol 8, No
4, July 1997.
Hyperglycemia and diabetes mellitus in the treatment
with protease inhibitors
More than 100 cases of diabetes mellitus or hyperglycemia
have been reported in HIV infected patients treated of protease inhibitors.
Approximately 20% of the patients had a known diabetes which was aggravated.
The average treatment time with protease inhibitors before
onset of hyperglycemia/diabetes mellitus was 80 days. A few patients without
prior signs of diabetes experienced ketoacidosis, but information about
these cases is of varying quality.
Many of the patients had other risk factors for hyperglycemia/diabetes
mellitus and some of them were treated with other drugs which can induce
hyperglycemia or diabetes mellitus.
Some patients needed treatment with insulin or per oral
antidiabetics or dosage adjustment of previously introduced medication.
In about half of the cases the treatment with protease inhibitors was discontinued.
Despite these actions the symtoms remained for some patients, also for
some without prior diabetes mellitus.
Ref: See Canada above
Pertussis vaccines
In January 1996 two new multiple component vaccines against
pertussis, diphteria and tetanus was approved by the Medical Products Agency,
MPA. Only one of these vaccines was however launched - Infanrix - wich
contains the components PT, FHA and pertactin. During the introductory
year, 1996, the MPA received 89 adverse reaction reports regarding Infanrix.
These described 119 adverse reactions with a probable relationship.
52 general symptoms, whereof 25 fever reactions and 18
HHE (Hypotonic Hyporesponsive Episode) were reported, together with 18
local reactions, whereof 5 exanthema and 1 urticaria.
20 children reacted with persistent crying and 4 with
anxiety. Four children had febrile cramps and 2 muscular hypertonia.
"Vaccine mot pertussis" is a single pertussis vaccine
approved for immunization of children already given DT.vaccin. It was launched
in the spring of 1996. It contains the same pertussis vaccine as Infanrix.
Surprisingly the number of reports is higher than for Infanrix even though
the number of exposures is lower. During 1996, 101 reports with 134 adverse
reactions with a probable relationship were reported.
44 general symptoms
1 collapse
1 absence attack
2 cases of in somnolence
36 local skin reactions
8 urticaria
3 persistent crying
2 anxiety
Gingko Biloba - joint disorders
A 76 -year- old woman with hypertonia, colpitis and arthrosis
started taking Seredrin (Gingko Biloba) for dizziness. She stopped after
12 days as she experienced polyarthralgia and swollen joints. The symtoms
resolved after one week. She was restarted on Seredrin 3 weeks later but
reactions reappeared. The concomittant drugs felodipine, atenolol, estriol
and naproxen were continued after the withdrawal of Seredrin. No similar
cases have been found in the Swedish (SWEDIS) or in the WHO database.
USA
FDA Medical Bulletin, Vol 27, No 2, SUMMER 1997
Reports of valvular heart disease in patients receiving
concomitant fenfluramine and phentermine.
Fenfluramine and phentermine were approved more than 20
years ago as individual agents for short-term use in the medical management
of obesity.
As of July 8, 1997, there have been 33 cases reported
to FDA of unusual valvular morphology and regurgitation involving the mitral,
aortic, and/or tricuspid valves, usually being multivalvular. All 33 patients
were American women with a mean age of 43.3 years, all of whom had received
combined fenfluramine and phentermine therapy for between 1 and >16 months
before presentation with their valvular disease. About half of the women
were reported to have pulmonary hypertension with their valvular disease.
Echocardiographic confirmation of valvular disease was seen in nearly all
of these patients. To date, surgical intervention has been required in
six patients; the histopathology of the diseased valves resembled that
seen in carcinoid syndrome or ergotamine toxicity. The course of the cardiac
valvul- opathy in individuals after the drugs are stopped is presently
unknown.
The FDA reminds all health care practitioners that the
safety and effectiveness of the use of fenfluramine and phentermine in
combination have not been established and that serious concerns about the
safety of such combined use have been raised.
FDA is taking measures to strengthen its recent warning
that treatment of patients for obesity with a combination of fenfluramine
and phentermine has been associated with the development of a serious heart
valve disease.
See also Withdrawals below
Protease inhibitors may increase blood glucose in
HIV patients
FDA has received 83 reported cases of new or exacer-bated
diabetes mellitus and hyperglycemia in HIV-infected patients taking any
one of this newest class of AIDS drugs. Of the 83 patients, 27 required
hospitalization, including six life-threatening cases. 5 cases resulted
in ketoacidosis, a serious diabetes-related condition that is characterized
by a fruity mouth odour, nausea, vomiting, dehydration, weight loss, confusion,
and if untreated, coma or death. However, none of this data definitely
demonstrates that the drugs caused the condition.
Many patients who developed diabetes while on protease
inhibitors (sasquinavir, indinavir, ritonavir and nelfinavir) were able
to control the diabetes through insulin or other agents.
HIV patients on protease inhibitor therapy should know
that increased thirst and hunger, unexplained weight loss, increased urination,
fatigue and dry, itchy skin are warning signs of hyperglycemia and diabetes.
Ref: See information from Canada above
Sucostrin (succinylcholine)
Two life-threatening events that may occur with the use
of succinylcholine:
1- Cardiac arrest in children and adolescents receiving
succinylcholine.
2- Succinylcholine-induced hyperkalemia.
Lamictal (lamotrigine)
New warning in the labeling for the antiepileptic lamotrigine
(Lamictal) pertain to reports of severe, potentially lifethreatening rash,
including Stevens-Johnson syndrome, and, rarely, toxic epidermal necrolysis,
reported in association with the use of lamictal.
FDA proposes ban on OTC sale of laxative ingredient
Phenolphthalein is an ingredient widely used in several
laxative products for many years, which potentially could cause cancer
in human. Because consumers have access to more than two dozen laxative
products without this ingredients, the FDA is proposing to ban the over-the-counter
(OTC) sale of this product.
Zafirlukast (Accolater) a new asthma drug
Approved in September 1996, zafirlukast is the first in
a new class of drugs designed as a nonsteroidal, asthma prophylaxis and
treatment for patients aged 12 or older. It has recently been associated
with a rare and sometimes fatal condition known as Churg-Strauss syndrome.
Churg-Strauss syndrome occurs in adult asthma patients
and may appear as generalized, flu-like symptoms such as fever, muscle
aches and pains, and weight loss. Patients also experience inflammation
of blood vessels, primarily in the lungs. If left untreated, Churg-Strauss
syndrome can result in major organ damage and even death.
Seldane labeling changes
Terfenadine containing products, such as Seldane and Seldane-D,
have long been associated with severe risks when taken with certain antibiotics
and antif ungals. The makers of the antihistamine Seldane and Seldane-D,
are adding new warning information to the products´ labeling. This
provides new contraindication of simultaneously using Seldane/Seldane-D
with the recently approved hypertension drug, Posicor (mibefradil dihydrochloride).
It also provides additional warning against using Seldane/Seldane-D with
a number of other newer drugs.
These include:
1 HIV protease inhibitors such as;
Crixivan (indinavir), Norvir (ritonavir), Invirase (saquinavir),
Viracept (nelfinavir)
2 Serotonin reuptake inhibitors such as ;
Luxor (fluvoxamine), Zoloft (sertaline), Serzone (nefazodone),
along with the additional medications Zyflo (zileuton),
Propulsid (cisapride) and Zagam (sparfloxacin).
Patients with renal difficulties should not take more
than one seldane/seldane-D tablet daily and that seldane/seldane-D should
not be taken with grapefruit juice.
SPECIAL COMMUNICATION
United Kingdom
Message from the chairman of the Committee on Safety of
Medicines (9 October 1997)
Hormone replacement therapy (HRT) and breast cancer
The Lancet (11 October 1997) is carrying an article by
the Collaborative Group on Hormonal Factors in Breast Cancer with Professor
Valerie Beral as principal author.
The report is based on pooled original data from 51 studies.
It shows an increase in the risk of breast cancer that is related to the
duration of HRT use, but which disappears within about 5 years of stopping.
There is no clear evidence that different HRT preparations have varying
risks. The authors have noted that breast cancers in HRT users were less
likely to have spread beyond the breast than those in non-users.
Women who use HRT for a short time around the menopause
have a very low excess risk. For women aged 50 not using HRT, about 45
in every 1000 will have cancer diagnosed over the next 20 years, that is
up to age 70. For those who use HRT for long periods of time, the estimated
number of extra cancers is shown below:
Time Breast cancers over Extra Breast cancers
on HRT the 20 yr from age in HRT users
50 to 70
Never 45 per 1000 -
5 yrs use 47 per 1000 2 per 1000
10 yrs use 51 per 1000 6 per 1000
15 yrs use 57 per 1000 12 per 1000
The association between breast cancer and HRT use that
is described in the report is not a new finding.The Committee´s view
is that, overall, these new results do not markedly alter the balance of
benefits and risks for HRT and that they do not provide a reason for women
to stop their treatment.
WITHDRAWALS
USA
FDA MedWatch News, September 15. 1997
Withdrawal of fenfluramine and dexfenfluramine
The Food and Drug Administration, acting on new evidence
about significant side-effects associated with fenfluramine and dexfenfluramine,
has asked the manufacturers to voluntarily withdraw both treatments for
obesity from the market. Dexfenfluramine is manufactured for Interneuron
Pharmaceuticals and marketed under the name of Redux by Wyeth-Ayerst Laboratories,
a subsidiary of American Home Products Corp. Of Madison, N.J., which also
manufactures and markets fenfluramine under the brand name Pondimin. Both
companies have agreed to voluntarily withdraw their drugs. The FDA is not
requesting the withdrawal of phentermine, the third widely used medication
for obesity.
LITERATURE REFERENCES
Denmark
U.Pedersen-Bjergaard, M. Andersen & P.B. Hansen.
Eur.J.Clin.Pharmacol (1997) 52: 183-189
Drug-induced thrombocytopenia: clinical data on
309 cases and the effect of corticosteroid therapy
Thrombocytopenia induced by non-cytotoxic drugs is characterised
by a heterogeneous clinical picture and recovery is generally rapid. Although
corticosteroids seem inefficient, the authors still recommend that severe
symptomatic cases of drug-induced thrombocytopenia are treated as idiopathic
thrombocytopenic purpura due to the difficult initial differentiation between
the two conditions.
Netherlands
Principles of signal detection in pharmacovigilance.
Ronald H.B. Meyboom, Antoine C.G. Egberts, I. Ralph Edwards,
Yechiel A. Hekster, Fred H.P. de Koning and Frank W.J. Gribnau.
Drug Safety 1997 Jun; 16(6)355-366.