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Australian Adverse Drug Reactions Bulletin, Vol 16, No 1

February 1997

Prepared by the Adverse Drug Reactions Advisory Committee (ADRAC) and the Office of Medicine Safety Monitoring (OMSM) of the TGA.

Contents

Electrolyte disturbances with oral phosphate bowel preparations

In recent years, the use of oral sodium phosphate solution (Fleet Phospho-Soda Buffered Saline Laxative Mixture) as a bowel preparation for colonoscopy has become more common. Over the past 18 months, ADRAC has received three serious reports, two with fatal outcomes, highlighting severe electrolyte disturbances associated with this oral bowel cleansing solution. The product is available without prescription and can also be used as a laxative at a lower dose.

In one report, a 90 year old man developed hyperphosphataemia (serum phosphate 4.25; reference range: 0.8-1.45 mmol/L) with consequent severe hypocalcaemia (serum Ca 0.97, reference range 2.10-2.55 mmol/L) and renal impairment after taking an oral sodium phosphate solution at the dose and in the manner recommended in preparation for colonoscopy. He also developed ischaemic gangrene of the toes and died some 4 days after the onset of the reaction. The other report describing a fatal outcome involved a 77 year old woman who died after developing dehydration with electrolyte depletion (hypocalcaemia, hyponatraemia and hypokalaemia) following two doses of orally administered phosphate solution. Another case involved a 49 year old female with renal impairment who developed hyperphosphataemia (phosphate: 9.1 mmol/L), hypocalcaemia (Ca: 0.8 mmol/L), paraesthesia, carpal spasm and QT prolongation following two 45 mL doses of the oral solution prior to colonoscopy. She required 6 hours haemodialysis.

Prescribers should be aware that oral sodium phosphate products can cause dehydration (between 1 and 4 L fluid loss), 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.

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Calcitriol and hypercalcaemia

Calcitriol (Rocaltrol) is the active metabolite of vitamin D 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. ADRAC has recently received reports of hypercalcaemia including one with a fatal outcome.

This fatal report described an 82 year old woman with known normal serum creatinine and calcium who began taking calcitriol (0.5 æg daily) and nandrolone decanoate (9 injections per 3 months) for osteoporosis. Other medication included paracetamol and dioctyl sodium sulphosuccinate. Several months later, she presented to hospital with confusion, hypotension and tachycardia and was found to have hypercalcaemia (Ca 4.21; reference range 2.10-2.55 mmol/L) and renal impairment (creatinine: 0.37; reference range 0.06-0.12mmol/L). Despite treatment with fluids, steroids and calcitonin, the patient had a cardiac arrest and died. The autopsy revealed no other cause for hypercalcaemia.

ADRAC has received 51 reports of adverse reactions in association with calcitriol over the past 4 years. Most commonly reported reactions have included rash (7 reports), pruritus (6), headache and hypercalcaemia (4 each), and arthralgia, chest pain, constipation and nausea (3 each). Apart from the fatal case described above, each of the other 3 patients with hypercalcaemia recovered after withdrawal of calcitriol and symptomatic treatment.

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 the commencement of calcitriol therapy with at least weekly determinations for the first 12 weeks and monthly determinations thereafter.

Fluvastatin and muscle disorders - a class effect

The Committee has previously drawn attention to the problem of muscle disorders associated with the lipid lowering agents simvastatin and clofibrate. Fluvastatin (Lescol, Vastin) is a HMG-CoA reductase inhibitor which has recently been marketed in Australia.

From March to December 1996 the Committee has received 85 reports in association with fluvastatin. Over one third of these (30 reports) describe muscle disorders (myalgia, myopathy, myositis, leg cramps and/or increased creatine kinase (CK)). Fluvastatin was the only drug suspected in all but two of these and three reports documented recurrence of symptoms on rechallenge. Ages of the patients ranged from 42 to 77 (median 62) years. Daily doses were 20 to 40 mg and for the majority (20 of 24) of reports which provided the information, onset occurred within the first month of therapy.

The most frequent presenting symptom was myalgia which was noted in 21 cases. Most of the reports did not specify the muscle groups involved although 8 of them described leg pains and back pain was noted in 4 patients. In some cases cramps and/or weakness were also reported. Mild to marked elevations of CK ranging from 217 to 8177 U/L (median: 317, reference range 0-195) were noted in 11 reports. Interestingly, 13 reports documented similar problems with previous use of simvastatin or another "statin".

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 (307 reports) and pravastatin (29 reports).

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Lamotrigine and severe skin reactions

Lamotrigine (Lamictal) 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. From 1994 to December 1996 the Committee 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 (10% in clinical trials) 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.

For these serious cases, ages ranged from 3 to 35 (median 15) years with five of the eight patients being under 18 years of age. Onset occurred as early as the first day and as late as 2 years after commencing therapy although 6 had their onset within the first month. Six of the eight reports documented concurrent administration of sodium valproate. In four cases the severity of the reaction was such that hospital admission was required for administration of intravenous fluids and systemic corticosteroid therapy. Recovery was documented in three of the reports whereas the outcome remained unknown at the time of reporting for the other five.

Worldwide, there have been over 100 reports of Stevens Johnson syndrome or toxic epidermal necrolysis with lamotrigine. The product information mentions the possibility of serious skin reactions. It also acknowledges that adverse reactions are more likely to occur in patients who are taking valproate concurrently as this may reduce the hepatic clearance of lamotrigine thereby increasing plasma concentrations of the drug by approximately two-fold for a given dose. 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 PI and that all patients who develop a rash should be promptly evaluated with consideration given to withdrawal of the drug.

Drugs of current interest

Please report all suspected reactions to these Drugs of Current Interest

  • Azithromycin (Zithromax)
  • Cabergoline (Dostinex)
  • Cilazapril (Inhibace)
  • Enoxacin (Enoxin)
  • Famciclovir (Famvir)
  • Fluvastatin (Lescol, Vastin)
  • Gestrinone (Dimetriose)
  • Goserelin (Zoladex)
  • Leuprorelin (Lucrin)
  • Losartan Potassium (Cozaar)
  • Nafarelin (Synarel)
  • Pantoprazole (Somac)
  • Salmeterol (Serevent)
  • Sevoflurane (Sevorane)
  • Tacrine (Cognex)
  • Ticlopidine (Ticlid)
  • Valaciclovir (Valtrex)
  • Venlafaxine (Efexor)
  • Zopiclone (Imovane)

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What to report?

(you do not need to be certain, just suspicious!)

ADRAC encourages the reporting of all suspected adverse reactions to medicines, including vaccines, OTC medicines, herbal, traditional or alternative remedies. ADRAC particularly requests reports of:

  • ALL suspected reactions to new drugs (see drugs of current interest)
  • ALL suspected drug interactions
  • Suspected reactions causing
    • Death
    • Admission to hospital or prolongation of hospitalisation
    • Increased investigations or treatment
    • Birth defects

For blue cards

Reports of suspected adverse drug reactions are best made by using a prepaid reporting form ("blue card") which is available from the website or from the Office of Medicines Safety Monitoring (02 6232 8744).

Reports can also be submitted electronically, by clicking on "Report a problem" on this website, by fax: 02 6232 8392, or email: ADR.Reports@tga.gov.au.

ISSN 0812-3837

© Commonwealth of Australia 1999

All correspondence to be addressed to: The Secretary, ADRAC, PO Box 100, Woden ACT 2606

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