Published: October 2007

Publications

Watching Briefs - November 2007

Quick updates, alerts and short reminders about medicine safety issues

 

Prescriber Update 28(1): 2-6
October 2007

Medsafe Pharmacovigilance Team

Quinine - not for leg cramps anymore
Tendon disorders with quinolone antibiotics
Ototoxicity with aminoglycoside ear drops
Warfarin, cranberry and herbs - watch for interactions
Patient consent and off-label use of medicines
Eltroxin tablets - new formulation so don't halve or crush
Prexige - monthly liver function tests required
LABAs - reminder about safe prescribing

 

Quinine - not for leg cramps anymore

Local and international reports of thrombocytopenia following quinine use for the relief of nocturnal legs cramps prompted Medsafe and the Medicines Adverse Reactions Committee (MARC) to review the safety of quinine in 2006.  In the absence of robust data to support the efficacy of quinine for leg cramps, combined with clear evidence of harm due to unpredictable and potentially life-threatening thrombocytopenia, the MARC concluded that the benefit-risk profile of quinine no longer supported its continued use for nocturnal leg cramps.  As a result, Medsafe has required the sponsors of quinine products to remove the indication of leg cramps; this means that quinine should no longer be prescribed for this purpose.  The data sheets for quinine products in New Zealand have recently been updated to remove reference to the use of quinine for nocturnal leg cramps.

Background

Despite the use of quinine for leg cramps for many decades, there have been few studies conducted to fully assess the efficacy of quinine, resulting in a paucity of convincing data to support the place of quinine for leg cramps.¹  In contrast, there has been increasing evidence of harm occurring, specifically thrombocytopenia, which is thought to be an idiosyncratic hypersensitivity reaction.²  A review³ of published reports of drug-induced thrombocytopenia (excluding heparin) reported quinine to be the second most commonly implicated medicine.  In this review of 53 cases of quinine-induced thrombocytopenia, there was a median time-to-onset of seven days.  For the 30 cases where it was known how many doses were taken, the median was 3 (range 1-30 doses).  The absence of known predisposing factors makes identification of at-risk patients very difficult, and is further complicated by the unpredictable occurrence of thrombocytopenia.³

As at 30 July 2007, the Centre for Adverse Reactions Monitoring (CARM) had received 128 reports of adverse reactions to quinine; 45 of these were of thrombocytopenia and included two deaths.  In 10 of the 14 most recent CARM reports, onset occurred within seven days; and 10 of the 14 patients were hospitalised.

In both the published³ and local cases, the short duration to onset and extent of the severity of the reactions suggest that providing patients with advice at the time of prescribing to discontinue the medicine should symptoms of thrombocytopenia occur does not necessarily avoid serious consequences.  Therefore, Medsafe is advising prescribers and pharmacists that quinine must no longer be used for the relief of leg cramps.  Quinine remains licensed for combination therapy in the treatment of chloroquine-resistant malaria caused by Plasmodium falciparum.  This is because the benefits of treating malaria outweigh the risks of both thrombocytopenia and dose-related cinchonism.

While Medsafe acknowledges that the removal of quinine as a treatment option in patients with leg cramps may cause adjustment difficulties in general practice, there is no regulatory justification for continuing to approve the indication of leg cramps in the presence of harm and absence of robust efficacy data.  This action is consistent with that taken in Australia⁴ and the United States.²

Prescribers may like to take this opportunity to review their quinine patients to exclude other possible causes of leg cramps.  Medical conditions associated with leg cramps include diabetes, Parkinson's disease, hypoglycaemia, anaemia, thyroid and endocrine disorders.^5,6  Medicines such as beta-agonists, cimetidine, diuretics, morphine, nifedipine, statins and steroids have also been implicated.^1,6  Other possible risk factors may include structural disorders (e.g. flat feet), prolonged sitting, awkward leg positions while sedentary, or dehydration.^7,8  It has also been suggested that tight-fitting bed sheets or blankets, particularly when lying supine, may trigger leg cramps by causing the calf muscle to tighten.⁸

References

1. El-Tawil S, Musa TA, El-Tawil T, Weber M. Quinine for muscle cramps (Protocol). Cochrane Database of Systematic Reviews 2004, Issue 2. Art. No. CD005044 (accessed on-line 25 June 2007).
2. FDA Federal Register 19 April 1995 - Proposed Rules: Drug products containing quinine for the treatment and/or prevention of malaria for over-the-counter human use. www.fda.gov/cder/otcmonographs/quinine/Malaria_PR_19950419.pdf
3. Brinker AD, Beitz J.  Spontaneous reports of thrombocytopenia in association with quinine: Clinical attributes and timing related to regulatory action. American Journal of Hematology 2002;70(4):313-317.
4. Australian Adverse Drug Reactions Advisory Committee (ADRAC).  Quinine indications - cramps deleted. Aust Adverse Drug React Bull 2004;23(5):4. www.tga.gov.au/adr/aadrb/aadr0410.htm#a5
5. Neurologic disorders - parasomnias. In Beers MH, Berkow R (Eds) The Merck Manual of Diagnosis and Therapy 17^th edn. 1999: Merck Research Laboratories, New Jersey, USA, p.1416-1417.
6. Butler JV, Mulkerrin EC, O'Keeffe S T.  Nocturnal leg cramps in older people. Postgraduate Medical Journal 2002;78:596-598.
7. Patient Notes: Nocturnal Leg Cramps. Postgraduate Medicine 2002;111(2):125-126.
8. Harvard Medical School Health.  Five ways to prevent night-time leg cramps. Harvard Health Letter 2004;30(2):6.

 

Tendon disorders with quinolone antibiotics

Prescribers are reminded of the risk of tendon disorders, such as tendonitis, tendon rupture and tendinopathy, associated with the use of quinolone antibiotics. The onset of these adverse effects can occur as early as the first few hours after the initial dose and as late as six months after treatment.¹ It is important that patients are asked to inform their prescriber immediately if they experience symptoms suggestive of tendon disorders, such as oedema, erythema, and sharp pain, particularly with walking and palpation.¹

Of the 104 cases of tendon disorders reported to the Centre for Adverse Reactions Monitoring (CARM) to date, 69% involved quinolones, mainly ciprofloxacin, norfloxacin and enoxacin. Similar figures have been seen in Australia with 75% of reported tendon disorders involving quinolones.²

Prescribers should be cautious when prescribing quinolones to patients already receiving steroid therapy, those with renal insufficiency or who are elderly as these risk factors increase the likelihood of quinolone-associated tendon disorders.¹ It is also recommended that the history of patients presenting with symptoms suggestive of tendon damage be checked for current or previous use of quinolones.

Emerging reports suggest that the newer generation quinolones such as levofloxacin also carry a risk of tendon disorders.¹

References

1. Gold L, Igra, H. Levofloxacin-induced tendon rupture: A case report and review of the literature. Journal of the American Board of Family Practice 2003;16:458-460.
2. Personal communication, 6 July 2007. Executive Officer, Adverse Drug Reactions Unit, Therapeutic Goods Administration, Australia.

 

Ototoxicity with aminoglycoside ear drops

A position statement on the use of ototoxic ear drops has recently been released by the New Zealand Society of Otolaryngology Head and Neck Surgery, and published in the New Zealand Medical Journal. ¹ This is in response to recognition that use of aminoglycoside-containing ear drops when the middle ear is compromised carries a risk of local damage to the cochlea and vestibular labyrinth. Consequently, the Society recommends avoiding, wherever possible, the use of ear drops containing aminoglycosides in patients where there is a direct pathway to the middle ear. This includes conditions such as tympanic membrane perforation and mastoid conditions with open middle ear, and in the presence of ventilation tubes. It is now understood that there is a small risk (1:1,000 to 1:10,000) of damage to the inner ear in circumstances where the ear drops may penetrate into the middle ear. The Society has asked that general practitioners' attention be drawn to the position statement, which includes guidelines for the use of potentially ototoxic agents in patients with ears at risk. There is no risk from the use of these drops where the tympanic membrane is intact. Ear drops containing aminoglycosides currently available in New Zealand are Sofradex^®, Soframycin^® and Kenacomb Otic^®.

Reference

1. Gilbert J, Dawes PJ, Mahadevan M, et al. Use of ototoxic eardrops: a position statement from the New Zealand Society of Otolaryngology Head and Neck Surgery. NZMJ 2007;120(1258). www.nzma.org.nz/journal/120-1258/2646

 

Warfarin, cranberry and herbs - watch for interactions

It is well recognised that warfarin interacts with many medicines and foods. In the United Kingdom, there have been reports of concurrent consumption of cranberry juice increasing the INR, resulting in an elevated risk of bleeding in patients taking warfarin.¹ In one case, the patient's INR was >50; and he died of gastrointestinal and pericardial haemorrhage.² The mechanism may involve inhibition of cytochrome P450 enzymes by the antioxidants contained in cranberries; warfarin is predominantly metabolised by P450 CYP2C9.² Due to the potential for serious consequences, patients should be advised to avoid consuming cranberry juice while taking warfarin. It is possible that other cranberry products (e.g. capsules) may also interact with warfarin, therefore should similarly be avoided.¹ Grapefruit juice does not appear to affect the metabolism of warfarin.³

Reports of increased INR in warfarin patients who are also taking herbal products or complementary and alternative medicines are becoming more common. Implicated agents in published case reports include German chamomile (Matricaria recutita),⁴ dong quai (Angelica sinensis), ⁵ fish oil,⁶ and royal jelly.⁷ Other herbs that may have antiplatelet activity, and thus potentially increase bleeding time, include garlic (Allium sativum), ginger (Zingiber officinale), ginkgo (Ginkgo biloba) and ginseng (Panax ginseng). Some herbs such as alfalfa (Medicago sativa), celery (Apium graveolens) and chamomile (both German - M. recutita, and Roman - Chamaemelum nobile) may contain coumarins, which could possibly potentiate the effect of warfarin.³ However, to date, the coumarin compounds detected in herbs such as alfalfa lack the necessary chemical structural requirements for anticoagulant activity.⁸ Despite an absence of good evidence of a causal association for all of these interactions, the potential consequences are significant so health professionals and patients should be aware of possible harm.³ More frequent INR monitoring is warranted in patients who take, stop or start any complementary and alternative medicine while on warfarin. Health professionals are encouraged to report suspected reactions or interactions to the Centre for Adverse Reactions Monitoring (CARM) so that more information can be gathered about complementary and alternative medicines.

In New Zealand, there have been eight reports received by CARM involving warfarin interactions with complementary and alternative medicines. These included St John's Wort (Hypericum perforatum); ginger; aloe vera and manuka honey; creatine; glucosamine with chondroitin; and a product containing L. acidophilus and B. bifidum. The most common reaction was increased INR (seven cases); but epistaxis occurred in one patient.

To minimise the risk of potential interactions with complementary and alternative medicines, or food products, patients taking warfarin should be advised of the following:⁹

• talk to their health professional before starting any complementary and alternative medicines because the dose of warfarin may require adjustment
• if already taking a complementary or alternative medicine, not to stop taking it unless first discussed with their health professional
• if taking a complementary or alternative medicine, or if regularly consuming food products that can change the effects of warfarin, to keep their usage or intake consistent from day to day
• report any unusual bruising or bleeding to their health care professional right away.

References

1. Committee on Safety of Medicines. Interaction between warfarin and cranberry juice: new advice. Current problems in pharmacovigilance 2004;30:10. www.mhra.gov.uk
2. Suvarna R, Pirmohamed M, Henderson L. Possible interaction between warfarin and cranberry juice. BMJ 2003;327(7429):1454.
3. Myers SP. Interactions between complementary medicines and warfarin. Aust Prescr 2002;25(3):54-56.
4. Segal R, Pilote L. Warfarin interaction with Matricaria chamomilla. CMAJ 2006;174(9):1281-1282.
5. Page RL 2nd, Lawrence JD. Potentiation of warfarin by dong quai. Pharmacotherapy 1999;19(7):870-876.
6. Buckley MS, Goff AD, Knapp WE. Fish oil interaction with warfarin. Ann Pharmacother 2004;38(1):50-52.
7. Lee NJ, Fermo JD. Warfarin and royal jelly interaction. Pharmacotherapy 2006;26(4):583-586.
8. Barnes J, Anderson LA, Phillipson JD. Herbal medicines. A guide for health-care professionals, 3rd edn. London: Pharmaceutical Press; 2007.
9. Health Canada. It's your health - Warfarin interactions with drugs, natural health and food products September 2004. www.hc-sc.gc.ca/iyh-vsv/med/warfarin_e.html

 

Patient consent and off-label use of medicines

Medsafe recognises that the unapproved (or 'off-label') use of medicines is sometimes appropriate. In such instances, section 25 of the Medicines Act 1981 allows a registered medical practitioner to "procure the sale or supply of any medicine" (approved or unapproved) for a particular patient in his or her care. "Procure the sale or supply" refers to obtaining the medicine through the usual channels such as a pharmacy or a pharmaceutical company, and it also permits the practitioner to use other means of obtaining a medicine such as importation. Section 25 is intended to allow medical practitioners to either obtain unapproved medicines, or to use medicines for an unapproved indication, for the treatment of a particular patient in the care of that or another practitioner.

There are limitations to this authority embedded in the Code of Health and Disability Services Consumers' Rights 1996. Unapproved use of medicines must comply with this Code, which states that the patient has the right to treatment of an appropriate ethical and professional standard, and the doctor has the responsibility of ensuring that the treatment, whether approved or unapproved, meets this standard. The patient also has the right to be fully informed.

If a prescriber is considering an unapproved medicine (i.e. a medicine that has not been assessed by Medsafe against regulatory standards for safety, efficacy and quality), the onus is on the prescriber to satisfy themself that the medicine is of appropriate safety, quality and efficacy before deciding to prescribe it.

Medsafe considers that, in order for prescribers to comply with the Code, during the consultation the patient should be advised about 1) the unapproved status of the medicine; and 2) the information that led the prescriber to decide why that particular unapproved medicine is the most appropriate treatment for the patient. It is only after this information has been communicated that the patient's informed consent for treatment with an unapproved medicine is considered to have been obtained.

 

Eltroxin tablets - new formulation so don't halve or crush

Since July 2007, a new formulation of Eltroxin^® (levothyroxinel; also know as thyroxine) 50mcg and 100mcg tablets has been available. The reformulated tablets are no longer scored and are not intended to be halved, so patients who require a dose of 25mcg daily must instead be prescribed one 50mcg tablet to be taken every second day. It is also recommended by the manufacturer that, due to lack of data on crushing the tablets, Eltroxin tablets should only be prescribed to patients who are able to swallow the tablets whole. Eltroxin tablets should be taken on an empty stomach, preferably before breakfast.¹

Table: Dosage and administration for new formulation of Eltroxin tablets¹

Daily dose	Dosing regimen
25 microgram	One 50 microgram tablet on alternate days
50 microgram	One 50 microgram tablet daily
75 microgram	One 50 microgram tablet daily and one 50 microgram tablet on alternate days
100 microgram	One 100 microgram tablet daily
125 microgram	One 100 microgram tablet daily and one 50 microgram tablet on alternate days

Reference

1. GlaxoSmithKline NZ Limited. Eltroxin (thyroxine sodium) data sheet. 5 July 2006. www.medsafe.govt.nz/profs/Datasheet/e/Eltroxin(new)tab.pdf

 

Prexige - monthly liver function tests required

Post-marketing events of severe liver dysfunction, including fatal outcome and transplantation, have been observed internationally with Prexige® (lumiracoxib). Consequently, Prexige is now only indicated for the symptomatic treatment of osteoarthritis and limited to a maximum daily dose of 100mg. Patients with severe hepatic disease (Child-Pugh > 9) or with a baseline AST/ALT > 1.5xULN should not be commenced on lumiracoxib.

Liver function monitoring is recommended at baseline and monthly thereafter while on Prexige. The 100mg dose should not be exceeded as higher doses do not provide any additional benefit and may increase the risks of adverse events. Patients using Prexige should be informed about the signs and symptoms of liver dysfunction. Patients who develop signs and/or symptoms suggestive of liver dysfunction should be investigated promptly. Prexige should be discontinued if elevations of AST/ALT > 3xULN occur.

CARM has received three reports of abnormal liver function since August 2007, when the 400mg Prexige tablets were withdrawn from the New Zealand market and restrictions placed on the 100mg tablets.

LABAs - reminder about safe prescribing

Recently published papers^1,2 suggest that long-acting beta agonist (LABA) inhaled bronchodilators might increase the risk of serious asthma exacerbations, including life-threatening episodes, particularly in patients who do not use a concomitant inhaled corticosteroid. LABAs include salmeterol and eformoterol. Medsafe and the Medicines Adverse Reactions Committee would like to remind prescribers of the following key points regarding the use of LABAs:

• LABAs should not be used as monotherapy or first-line treatment for asthma; a LABA should be added to asthma treatment only if an appropriate dose of an inhaled corticosteroid does not provide adequate control.
• Patients should be warned not to stop or reduce corticosteroid therapy without medical advice, even when symptoms improve.
• LABA therapy should not be initiated, or the dose increased, in patients with significantly worsening or acutely deteriorating asthma.
• Patients should be advised to seek medical attention immediately if their asthma deteriorates suddenly.
• A reassessment of therapy should be undertaken if asthma worsens despite regular use of a LABA and an inhaled corticosteroid.

References

1. Nelson HS et al. The Salmeterol Multicenter Asthma Research Trial - A Comparison of Usual Pharmacotherapy for Asthma or usual Pharmacotherapy Plus Salmeterol. Chest 2006;129:15-26.
2. Salpeter SR et al. Meta-analysis: Effect of Long-Acting Beta-Agonists on Severe Asthma Exacerbations and Asthma-Related Deaths. Ann Int Med 2006;144:904-912.