Mersey ADR Newsletter
Issue 27 Winter 2007
(Vasovist®), gadoteric acid (Dotarem®), gadoteridol
In this issue: (ProHance®) and gadoxetic acid disodium (Primovist®).
▼ Gadolinium-based contrast agents and
By the start of 2007, there had been approximately 200
nephrogenic systemic fibrosis cases of NSF reported worldwide. In the European
▼ Intraoperative floppy iris syndrome associated Union, most have been attributed to Omniscan, although
with tamsulosin there have been cases associated with Magnevist and
▼ Glitazones and fracture risk in women MultiHance (all of which have linear structures). In the UK
▼ Dopamine agonist-associated pathological there have been seven cases of NSF reported via the
gambling Yellow Card scheme, none of these reports originated
from the Yellow Card Centre (YCC) Mersey region.
Gadolinium-based contrast agents
The SmPCs for Omniscan and Magnevist contraindicate
and nephrogenic systemic fibrosis their use in patients with severe renal impairment
(glomerular filtration rate less than 30ml/min/1.73m2) or in
Gadolinium-based contrast agents are used for magnetic patients who have had or are awaiting liver
resonance imaging (MRI) scans. A causal relationship transplantation. Due to immature kidney function in
between these agents and nephrogenic systemic fibrosis neonates and infants up to one year of age, they should
(NSF) was first identified in early 2006. only be used in these patients after careful consideration.
NSF (also known as nephrogenic fibrosing dermopathy) Further information is available:
is a rare but debilitating and potentially fatal condition. It MHRA safety warning: Increased risk of nephrogenic fibrosing
was first described in the medical literature in 2000 and dermopathy/nephrogenic systemic fibrosis and gadolinium-containing
involves connective tissue in the skin which becomes MRI contrast agents
thickened, coarse and hard, sometimes leading to Public assessment report: Nephrogenic Systemic Fibrosis (NSF)
and gadolinium-containing MRI contrast agents
contracture and joint immobility. NSF is a progressive
Public Health Link alert: Gadolinium-containing MRI contrast
disease and can go on to affect the lungs, liver, heart and agents and nephrogenic systemic fibrosis (NSF)
muscles.
All patients, particularly those aged over 65
Gadolinium is a highly toxic metal ion. When used as a years, should be screened for renal dysfunction
contrast agent it is held within a chelate complex which by obtaining a history and/or laboratory tests
before these contrast agents are used.
reduces its toxicity. The stability of the complex is related
to its structural properties - cyclical structures being more
stable than linear. The chelate complex is excreted by Intraoperative floppy iris syndrome
the kidneys, and therefore renal impairment can influence associated with tamsulosin
toxicity by reducing its excretion.
Tamsulosin is an alpha-blocker licensed for benign
Signs and symptoms of gadolinium-induced NSF begin prostatic hyperplasia (BPH). It has been identified as a
two to four weeks after administration and include: cause of intraoperative floppy iris syndrome (IFIS), a
Burning or itching of skin, reddened or dark newly diagnosed variant of small pupil syndrome that
patches, swelling, hardening and/or tightening. may lead to increased procedural complications during
Yellow raised spots on the whites of the eyes. cataract extraction.1
Joint stiffness, limited movement in hands, legs
or feet, pain deep in hip bone or ribs, and muscle One of the most critical elements of safe cataract surgery
weakness. is adequate pupil dilation. In IFIS, the pupil does not
appear to respond to standard intraoperative
NSF has only been reported in patients with renal pharmacological interventions, and following mechanical
insufficiency; most affected patients have had advanced stretching techniques, the pupil snaps back to its original
or end-stage renal disease. There is no successful size. Therefore, the employment of other measures are
treatment for NSF although improving renal function may required to maintain pupil dilation.1
slow or arrest development of the condition and may
even gradually reverse it. The role of haemodialysis Evidence suggests that tamsulosin-associated IFIS may
remains unclear. be dose related. In patients taking tamsulosin 400
micrograms/day for BPH 63% developed IFIS2,
Gadolinium-based contrast agents available in the UK compared with only 38% of patients taking tamsulosin
are: gadodiamide (Omniscan®), gadopentetate 200 micrograms/day.3
dimeglumine (Magnevist®), gadobenate dimeglumine
(MultiHance®), gadobutrol (Gadovist®), gadofosveset Prescribers are advised that the initiation of tamsulosin in
patients awaiting cataract surgery is not recommended.
A bulletin discussing typical adverse drug reactions.
Published by YCC Mersey in conjunction with the University of Liverpool Department of Clinical Pharmacology.
Editor: Justine Howard. Telephone 0151 794 8122. E-mail YCCMersey@lrippu.nhs.uk
nd
YCC Mersey, Pharmacy Practice Unit, 2 Floor 70 Pembroke Place, Liverpool, L69 3GF
Temporarily discontinuing tamsulosin one to two weeks The results of a prospective study involving 297 patients
prior to cataract surgery has been shown to be helpful with Parkinson’s disease showed a lifetime prevalence of
but is not completely effective in preventing the PG in this patient group of 3.4% which increased to 7.2%
syndrome.2 During pre-operative assessment, cataract in those treated with dopamine agonists. The lifetime
surgeons and ophthalmic teams are advised to consider prevalence of PG in the general population is 1% to 2%.
whether patients scheduled for cataract surgery are These results indicate that Parkinson’s disease itself may
being or have been treated with alpha-blockers in order contribute to such behavioural disorders. The group of
to ensure that appropriate measures are in place to gamblers comprised men and women. They preferred
manage IFIS during surgery.4 slot machines characterised by high reward uncertainty,
limited need for higher cognitive processing and a
Nationally there have been 23 Yellow Card reports of repetitive nature, to more interactive types of gambling,
floppy iris syndrome associated with tamsulosin, none of such as playing cards. On average, they lost
8
which originated from the YCC Mersey region. approximately £52,000 each.
Prior to cataract surgery, ophthalmic surgeons
should identify what medicines the patient is
A temporal association is suggested as PG starts after
using and be prepared for difficulty if they dopaminergic drug therapy commences and recovers
include tamsulosin or other alpha-blockers. after drug withdrawal. Onset most frequently occurs one
to three months after starting therapy, although onset as
late as nine years after drug commencement has been
Glitazones and fracture risk in women reported.9 There is also evidence suggesting a dose
effect, with reports of PG starting after a dose increase
Recent trials designed specifically to assess the efficacy and recovery after dose reduction.10
of the glitazones (pioglitazone and rosiglitazone) in the
management of type 2 diabetes have identified that The majority of published case reports of PG are
women assigned to take glitazones experienced a higher associated with pramipexole; however, reports of PG
incidence of fracture compared with women taking other associated with other dopamine agonists suggest that it
anti-diabetic treatments or placebo. This increased rate may be a class effect.10
of fracture was not seen in men.
In July 2006, the European Union’s Pharmacovigilance
For both drugs, fractures have been reported in the upper Working Party recommended that PG should be listed as
limbs (upper and lower arm, wrist and hand) and the an undesirable effect in the SmPC for all dopamine
distal lower limbs (fibula, tibia, ankles and feet). These agonist containing products.10
sites are different to those associated with post-
menopausal osteoporosis (hip and spine). The data Table 2. Number of Yellow Cards submitted nationally reporting
come from studies where pioglitazone was taken for a pathological gambling associated with dopamine agonists.
maximum of 3.5 years and rosiglitazone was taken for Drug name No. of Yellow Card reports
between four and six years. Apomorphine 1
5,6
Bromocriptine 0
Table 1. Fracture incidence for rosiglitazone and pioglitazone.
Cabergoline 7
Female Male
Pergolide 7
Rosiglitazone
9.3% 3.95% Pramipexole 10
(n=1,456)
Ropinirole 10
Pioglitazone
2.6% 1.3% Rotigotine 0
(n=8,100)
Pathological gambling can occur in patients
The MHRA has received eight Yellow Cards reporting taking dopamine agonists irrespective of their
fracture in patients receiving rosiglitazone and three gambling history although those with a history
reports of fracture in patients receiving pioglitazone. seem to be predisposed.9
References
Until the mechanism of the adverse effect is established, (1) Schwinn DA, Afshari NA. α1-adrenergic receptor antagonists and
all women taking a glitazone should be considered at the iris: new mechanistic insights into floppy iris syndrome. Surv
increased risk of fracture. Ophthalmol 2006; 51: 501-512.
(2) Chang DF, Campbell JR. Intraoperative floppy iris syndrome
Women taking or being considered for associated with tamsulosin. J Cataract Refract Surg 2005; 31: 664-
rosiglitazone or pioglitazone should have their 673.
bone health assessed prior to starting therapy. (3) Oshika T, Ohashi Y, Inamura M, et al. Incidence of intraoperative
floppy iris syndrome in patients on either systemic or topical α1-
adrenoceptor antagonist. Am J Ophthalmol 2007; 143: 150-151.
(4) Anon. Tamsulosin (Flomax) and intraoperative floppy iris syndrome
Dopamine agonist-associated (IFIS). Current Problems in Pharmacovigilance 2006: 31: 6-7.
pathological gambling (5) MHRA safety information on medicines for healthcare professionals,
11/04/07: Risk of fractures in women on long term pioglitazone
treatment.
Pathological gambling (PG), defined as an irresistible (6) MHRA safety information on medicines for healthcare professionals,
urge to gamble despite severe personal and financial 15/03/07: Risk of fractures in feet, hands and upper arms in women
consequences, has been associated with the use of on rosiglitazone.
(7) Voon V, Thomsen T, Miyasaki JM, et al. Factors associated with
dopamine agonists indicated for restless legs syndrome, dopaminergic drug-related pathological gambling in Parkinson
endocrine disorders and Parkinson’s disease. disease. Arch Neurol. 2007; 64: 212-216.
(8) Voon V, Hassan K, Zurowski M, et al. Prospective prevalence of
PG is thought to be caused by an altered function of the pathologic gambling and medication association in Parkinson
disease. Neurology 2006; 66: 1750-1752.
dopaminergic reward system; dopamine agonists appear (9) Tippmann-Peikert M, Park JG, Boeve BF, et al. Pathologic gambling
to exacerbate reward-seeking behaviours such as in patients with restless legs syndrome treated with dopaminergic
gambling.7 agonists. Neurology 2007; 68: 301-303.
(10) Public Assessment Report Nov 2006. Dopamine agonists:
pathological gambling and increased libido.