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New drugs
(Aust Prescr 2000;23:21-3)
Some of the views expressed in the following notes on newly approved products should be regarded as tentative, as there may have been limited published data and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. As a result of fuller experience, initial comments may need to be modified. The Committee is prepared to do this. Before new drugs are prescribed, the Committee believes it is important that full information is obtained either from the manufacturer's approved product information, a drug information centre or some other appropriate source.
Zenapax (Roche)
vials containing 25 mg/5 mL
Approved indication: renal transplant
Australian Medicines Handbook Section 14
Despite advances in immunosuppression, acute rejection remains a major problem for patients receiving a kidney transplant. The chances of a successful transplant may be increased by interfering with cellular immunity. Monoclonal antibodies such as basiliximab (see `New drugs' Aust Prescr 1999;22:95) and daclizumab inhibit the proliferation of T lymphocytes by binding to the interleukin-2 receptor on these cells.
Daclizumab is infused before surgery. The dose is then repeated every two weeks for a total of five doses with the aim of saturating the receptors. The half-life of daclizumab is 20 days, resembling that of IgG.
In one trial, 126 patients given daclizumab were compared with 134 who received an intravenous placebo. Both groups were also given cyclosporin, azathioprine and prednisone. Acute rejection occurred in 35% of the patients given a placebo, but in only 22% of patients given daclizumab. After a year, the graft survival was 90% in the placebo group and 95% in the daclizumab group.1
The toxicity of the other immunosuppressive drugs is not increased by daclizumab. Treatment did not cause significantly more adverse effects than placebo.1
While daclizumab reduces the incidence of acute rejection its long-term effectiveness requires further study. Although 90% of the daclizumab molecule contains a human antibody sequence this does not appear to make it significantly superior to basiliximab.
R E F E R E N C E
1. Daclizumab triple therapy study group. Interleukin-2-receptor blockade with daclizumab to prevent acute rejection in renal transplantation. N Engl J Med 1998;338:161-5.
Arava (Hoechst Marion Roussel)
10 mg, 20 mg and 100 mg tablets
Approved indication: rheumatoid arthritis
Australian Medicines Handbook Section 14
Disease modifying antirheumatic drugs, such as gold and methotrexate, are increasingly prescribed for patients with rheumatoid arthritis. These drugs are toxic and may not slow the progression of the disease. Leflunomide is an attempt to produce an effective, well tolerated treatment. It is an immunomodulating drug which inhibits the pyrimidine synthesis that is associated with cell proliferation. Leflunomide also has a weak anti-inflammatory action.
Patients begin taking leflunomide with a loading dose for
three days. This is because the drug has a long half-life (2-3 weeks). There
is extensive first pass metabolism which converts leflunomide to its active
form. The active metabolite is slowly excreted into the urine and faeces. Smoking
increases clearance.
Leflunomide has been compared with placebo and sulfasalazine, a drug with the
capability of retarding disease progression. A total of 359 patients were randomised
to be treated for 24 weeks. Although many patients did not complete the study,
the arthritic symptoms and signs responded to treatment in 20% of the patients
in the placebo group compared with 55% of the leflunomide group and 56% of
the sulfasalazine group. X-rays revealed that there was less disease progression
in the active treatment groups. The study did not have enough power to show
a difference between leflunomide and sulfasalazine.1 Other
studies suggest the efficacy of leflunomide and methotrexate may be similar.
While 96 of the 133 patients taking leflunomide completed the trial, 19 (14%) had to withdraw because of adverse events.1 Common problems were diarrhoea, nausea, rashes and alopecia. Other adverse effects include headache, dizziness, leucopenia and altered liver function. Regular white blood counts and liver function tests are recommended.
In October 1999 the European Medicines Evaluation Agency issued a statement warning the public about serious adverse reactions to leflunomide. There was particular concern about reports of pancytopenia and serious skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis.
Few significant drug interactions have emerged, but live vaccines are not recommended until six months after the conclusion of treatment. Leflunomide is contraindicated in pregnancy.
Until more information is available about leflunomide it will probably be reserved for patients with severe active rheumatoid arthritis who cannot tolerate or do not respond to other disease modifying drugs.
R E F E R E N C E
1. Smolen JS, Kalden JR, Scott DL, Rozman B, Kvien TK, Larsen A, et al. Efficacy and safety of leflunomide compared with placebo and sulphasalazine in active rheumatoid arthritis: a double-blind, randomised, multicentre trial. Lancet 1999;353:259-66.
Temodal (Schering-Plough)
5 mg, 20 mg, 100 mg and 250 mg capsules
Approved indication: brain tumours
Australian Medicines Handbook Section 14.1.3
The primary brain tumours include anaplastic astrocytoma and glioblastoma multiforme. Both of these tumours have a poor prognosis. Patients may be treated with surgery followed by radiotherapy and chemotherapy. Temozolomide has been developed as an option for treating patients who relapse after this therapy.
Temozolomide is an alkylating agent, with similarities to dacarbazine. It is taken once a day at least one hour before food for five days each month. The drug is rapidly absorbed and crosses the blood-brain barrier. Most of the drug is metabolised with less than 10% being excreted unchanged in the urine.
In 162 patients with anaplastic astrocytoma there was a response rate of 33% with temozolomide. The median survival time for these patients was 14.6 months. In the more common glioblastoma multiforme, the median survival time was much shorter. When the drug was compared with procarbazine in the treatment of 225 patients, the median progression-free survival was 2.7 months for temozolomide and 1.8 months for procarbazine.
In the few months that they survive, most patients will have adverse effects from the treatment. Myelosuppression is very common, so patients must have their blood count checked before each monthly treatment. Nausea and vomiting are also common and some patients will need antiemetic drugs.
While temozolomide has been approved for both types of tumour in Australia, the evidence of its effectiveness in glioblastoma multiforme was insufficient to warrant an accelerated approval in the U.S.A.
NEW FORMULATIONS
Loratadine/pseudoephedrine sulfate
Clarinase 24 Hour Relief (Schering-Plough)
10 mg loratadine/240 mg pseudoephedrine sulfate sustained-release tablets
Acimax (AstraZeneca)
20 mg tablets
Losec (AstraZeneca)
10 mg and 20 mg tablets
NEW COMBINATIONS
Interferon alfa-2b and ribavirin
Rebetron Combination Therapy (Schering-Plough)
composite packs containing
interferon alfa-2b 18 million IU/pen
ribavirin 200 mg capsules
NEW FORMULATIONS
Topamax (Janssen-Cilag)
15 mg and 25 mg sprinkle capsules
NEW COMBINATIONS
Loperamide hydrochloride/simethicone
Imodium Advanced (Janssen-Cilag)
2 mg loperamide hydrochloride/125 mg simethicone
NEW PROPRIETARY BRANDS
Antroquoril (Schering-Plough)
200 microgram/g cream and ointment
Captopril (Douglas)
12.5 mg, 25 mg and 50 mg tablets
SBPA Metoprolol (Schein Bayer)
50 mg and 100 mg tablets
Crysanal (Syntex)
550 mg tablets
Ranoxyl (Douglas)
150 mg and 300 mg tablets
SBPA Ranitidine (Schein Bayer)
150 mg and 300 mg tablets
Typherix (SmithKline Beecham)
25 microgram/0.5 mL pre-filled syringes
