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Published: November 2006

Watching Briefs - November 2006

Prescriber Update 27(2): 18-20.
November 2006

Medsafe Pharmacovigilance Team

Psychiatric reactions with cholesterol-lowering agents
Statin reminder – myopathy, rhabdomyolysis, and interactions
Watch for muscle disorders with ezetimibe too
Terbinafine: serious hepatic and haematological reactions
Care needed with liquid paracetamol dosing advice for children
Bisphosphonates and osteonecrosis of the jaws
Increased risk of bleeding with SSRIs

Psychiatric reactions with cholesterol-lowering agents

The Centre for Adverse Reactions Monitoring (CARM) in Dunedin is receiving an increasing number of reports of psychiatric reactions occurring with the statins, fibrates and, more recently, ezetimibe.  These reports account for up to one-fifth of the total adverse reaction reports for some of these agents.  The reactions of particular concern are those of aggressive behaviour; but also memory impairment, as well as mood, cognitive, sleep and perception disorders.  In Australia, nine cases of depression and three cases of depressed mood have been reported in association with ezetimibe use; onset within four days of commencing ezetimibe was noted in seven of the cases.1  Prescribers are asked to consider the cholesterol-lowering agents as a possible causal explanation in patients presenting with psychiatric symptoms.

Reference
  1. ADRAC. Ezetimibe and depression – A possible signal. Aust Adv Drug React Bull 2006;5(5):19.

Statin reminder – myopathy, rhabdomyolysis, and interactions

Information on this subject has been updated. Read the most recent information.

Prescribers are reminded of the risk of myopathy and rhabdomyolysis with the statins. CARM continues to receive reports of these adverse events.  Patients should be monitored for muscle pain, weakness or tenderness especially during the initial months after commencing a statin or increasing the dose.  If these symptoms occur the patient should undergo prompt investigation, including the determination of creatine kinase (CK) levels.  Statin treatment should be discontinued immediately if myopathy is suspected or diagnosed, or if the CK is more than ten times the upper limit of normal.1

Rhabdomyolysis is a severe form of myopathy with muscle breakdown, and may result in renal failure and death.  Older age, high statin doses, co-morbidities (e.g. diabetes, hypothyroidism, liver or renal disease), concurrent use of fibrates and/or other interacting medicines can increase the risk of rhabdomyolysis; therefore, these patients require closer monitoring.1  Simvastatin and atorvastatin are substrates for CYP 3A4, and thus should be discontinued if azole antifungals, macrolide antibiotics, HIV protease inhibitors or nefazodone (i.e. potent CYP 3A4 inhibitors) are indicated.  Where co-prescription of amiodarone, fibrates, verapamil or cyclosporin is necessary, only very low doses of simvastatin or atorvastatin should be used.2  Diltiazem, a weak CYP 3A4 inhibitor, increases the risk of rhabdomyolysis when prescribed with high doses of simvastatin or atorvastatin, or where other risk factors are also present.3  Suspect co-prescribed medicines in the CARM reports of rhabdomyolysis were cyclosporin, itraconazole and diltiazem.  Patients who are prescribed statins need to be informed of the importance of promptly reporting unexplained muscle symptoms, particularly if accompanied by malaise or fever.1  Prescribers need to particularly consider those patients at greater risk, as well as the potential for co-prescribed medicines to interact.

References
  1. Savage R, Tatley M. Myopathy with Statins: Check CK Levels and Interactions. Prescriber Update 2004;25(1):4-5. www.medsafe.govt.nz/profs/PUarticles/Statinmyop.htm
  2. Merck Sharp & Dohme (New Zealand) Limited. Lipex (simvastatin) data sheet 4 May 2005. www.medsafe.govt.nz/Profs/Datasheet/l/Lipextab.htm
  3. Gladding P. Potentially lethal interaction between diltiazem and statins [Letter]. Ann Int Med 2004;140(8):676.

Watch for muscle disorders with ezetimibe too

Ezetimibe (Ezetrol®; also Vytorin® which contains ezetimibe with simvastatin) is a relatively recent addition to the range of medicines used in the management of hypercholesterolemia. It can be used alone or in combination with a statin.1  Up to 30 June 2006, CARM had received 44 reports of suspected adverse reactions to ezetimibe.  These unexpectedly included one report of suspected myopathy; one of myalgia and muscle weakness; and nine reports of myalgia.  Six patients were not taking a statin or fibrate, both of which are known to cause muscle disorders; and recovery was recorded for four of these when ezetimibe was discontinued, including the patient with muscle weakness.  Consequently, prescribers are advised to be aware of the potential for ezetimibe to cause myopathy or even rhabdomyolysis, which has been reported overseas.1  Patients should be advised of this risk and asked to promptly seek medical advice for unexplained muscle pain, tenderness or weakness.  As with the other cholesterol-lowering agents, ezetimibe should be immediately discontinued if myopathy is suspected or diagnosed.1  Prescribers are encouraged to report these adverse reactions so that more data can be gathered and possible risk factors identified.  It is currently unclear how or why ezetimibe causes muscle disorders, as its mechanism of therapeutic action differs from that of the statins and fibrates.

Reference
  1. Merck Sharp & Dohme (New Zealand) Limited. Ezetrol (ezetimibe) tablets data sheet 23 November 2005. www.medsafe.govt.nz/profs/Datasheet/e/Ezetroltab.htm

Terbinafine: serious hepatic and haematological reactions

Prescribers are reminded that the oral antifungal agent terbinafine (Lamisil®, Terbafin®, Apo-Terbinafine®) can cause serious side effects such as agranulocytosis, hepatic failure and Stevens-Johnson syndrome.1  Case reports to CARM in the last five years include nine reactions that led to hospital admission.  Another two cases were life-threatening, consisting of agranulocytosis in one patient, and in the other neutropenia with elevated hepatic enzymes and ulcerative stomatitis.  Serious adverse reactions reported include exfoliative dermatitis (3 cases), hepatitis (2), neutropenia (2), pustular rash (2) and agranulocytosis (1).  Almost all of the adverse reactions occurred within two months of commencing terbinafine, where duration of treatment was known.  In Australia, there have been 16 reports of white blood cell dyscrasias, including seven cases each of agranulocytosis and neutropenia.2

Oral terbinafine is not recommended for patients with chronic or active liver disease.  Patients should be asked to promptly report symptoms suggestive of impaired liver function or blood dyscrasias, so that clinical investigations can be commenced immediately and terbinafine therapy stopped.1  To maximise the safety and efficacy of oral terbinafine, prescribers should ensure that the infection is caused by susceptible fungal organisms before prescribing this medicine.  An unpublished New Zealand study found that when mycology was performed on patients referred to a dermatologist for treatment of tinea unguium (onychomycosis), 54% of the patients did not have a fungal infection.3  Non-fungal causes of similar presenting nail symptoms include repeated trauma, psoriasis, lichen planus and vascular disorders.4  Prescribers are also asked to bear in mind the risks of serious adverse reactions when deciding on the appropriateness of prescribing oral terbinafine for asymptomatic fungal infections.

References
  1. Novartis New Zealand Limited. Lamisil (terbinafine) tablets data sheet 15 February 2006.
  2. ADRAC. Life-threatening blood dyscrasias with oral terbinafine. Aust Adv Drug React Bull 2006;25(4):15.
  3. Personal communication, 10 August 2006. Dermatologist, Hamilton.
  4. Scher RK, Baran R. Onychomycosis in clinical practice: factors contributing to recurrence. Br J Dermatol 2003; 149(Suppl 65):5-9.

Care needed with liquid paracetamol dosing advice for children

Prescribers are asked to be aware that there is a range of strengths of liquid paracetamol products available for purchase by consumers.  The strengths are:

To avoid the risk of inadvertent overdosing, prescribers and pharmacists should always clarify with consumers what strength of liquid paracetamol product they are using – this information is specified on the bottle label.  Don't rely on other descriptions such as colour, flavour or product name (e.g. "Junior" or "Infant") to identify the strength of the paracetamol liquid.  There are anecdotal reports of prescribers giving dosage advice on the basis of the colour of the product, believing it to be the 120mg/5ml (i.e. 24mg/ml) strength when in fact the consumer has a 50mg/ml strength product.  This can result in infants receiving double the recommended dose of paracetamol.

Bisphosphonates and osteonecrosis of the jaws

Information on this subject has been updated. Read the most recent information.

An article on the dental practice of tooth removal in patients taking oral alendronate was published in the June 2006 issue of NZDA News, a publication of the New Zealand Dental Association. 

Increased risk of bleeding with SSRIs

Information on this subject has been updated. Read the most recent information.

There is evidence from observational studies and case reports that the use of antidepressants, especially selective serotonin reuptake inhibitors (SSRIs), is associated with an increased risk of bleeding due to blockade of serotonin reuptake in platelets and subsequent platelet dysfunction.1  Various haemorrhagic adverse effects have been reported with the SSRIs, including bruising, purpura, epistaxis, haematoma, vaginal bleeding, peri-operative bleeding and gastrointestinal bleeding.1-3

All SSRIs exhibit anti-platelet properties and all have been implicated in bleeding events.1  A case-control study found that those antidepressants with a higher degree of serotonin reuptake inhibition (such as SSRIs) were significantly associated with an increased risk of hospital admission for abnormal bleeding.1

Evidence shows that the risk of bleeding is higher when SSRIs are used concomitantly with other medicines known to increase the risk of bleeding, such as NSAIDs, aspirin, warfarin or low molecular weight heparins.1-3  SSRIs should therefore be used with caution in patients concomitantly treated with such medicines; in patients with a known tendency for bleeding; and those with predisposing medical conditions.  Pharmacological gastroprotection should be considered for high-risk patients.1

Following a Medicines Adverse Reactions Committee review in 2005 of the risk of abnormal bleeding with SSRIs, all of the New Zealand data sheets for SSRIs have been updated to include warnings about this potential adverse reaction.

References
  1. Serebruany V. Selective Serotonin Reuptake Inhibitors and Increased Bleeding Risk: Are We Missing Something? Am J Med 2006;119:113-116.
  2. Meijer WEE, Heerdink ER, Nolen WA, et al. Association of risk of abnormal bleeding with degree of serotonin reuptake inhibition by antidepressants. Arch Intern Med 2004;164:2367-2370.
  3. Paton C. Ferrier IN. SSRIs and gastrointestinal bleeding. BMJ 2005;331(7516):529-530.

 

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