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.
Distaph (Alphapharm)
250 mg and 500 mg capsules
Indication: specified infections
Following concern about the risk of cholestatic hepatitis after treatment with flucloxacillin, effective alternatives are being sought.1 Dicloxacillin is one alternative, but it is not
known if the risk of jaundice is significantly less than with flucloxacillin.
Dicloxacillin is an isoxazolyl penicillin which is not inactivated by beta lactamase. This makes the drug effective in the treatment of staphylococcal infections. Its indications therefore resemble those of flucloxacillin.
When dicloxacillin is taken 1-2 hours before food, it is rapidly absorbed. The bioavailability is 50-94% and dicloxacillin is almost completely bound to plasma proteins. Approximately half the absorbed dose is metabolised and excreted, with the unchanged fraction, in the urine. In patients with severe renal impairment, it is suggested that the dose interval be increased from every 6 hours to every 8 hours.
The adverse effects of dicloxacillin are similar to those of flucloxacillin. They include hypersensitivity reactions (penicillin allergy is a contraindication) and gastrointestinal symptoms. As well as rarely causing hepatitis, dicloxacillin can also cause pseudomembranous colitis.
Until the incidence of hepatitis is known, it may be best to use other alternatives to flucloxacillin.1
R E F E R E N C E
1 . Turnidge J. What to use instead of flucloxacillin. Aust Prescr
1995;18:54-6.
Femara (Novartis)
2.5 mg tablets
Indication: breast cancer
Antioestrogens such as tamoxifen are often used in the treatment of advanced breast cancer. In postmenopausal women, including those whose menopause has been induced by treatment, oestriol can be
produced by other tissues. This synthesis can be stopped by inhibiting the aromatase enzymes. Anastrozole is already available for postmenopausal women with advanced breast cancers which have
progressed following treatment with tamoxifen. Letrozole, another non-steroidal aromatase inhibitor, is now also approved for the same indication.
In a pivotal clinical trial, letrozole was not compared with anastrozole. The comparator was megestrol acetate, a synthetic progestogen. The 551 patients were randomised to receive daily doses of 0.5 mg or 2.5 mg of letrozole or 160 mg megestrol. The overall response rate was 24% in patients given 2.5 mg letrozole. Only 13% of the women given 0.5 mg letrozole and 16% of those given megestrol had a response to treatment. The median time before treatment failed was longest (155 days) in the patients given 2.5 mg letrozole.
Letrozole is taken once a day until the cancer progresses. It is well absorbed and rapidly distributed. The drug is slowly metabolised and then excreted mainly in the urine. As the metabolism may involve cytochrome P450 3A4 and 2A6, there is a potential for interactions with other drugs metabolised by these enzymes. The half-life of letrozole is two days and its concentration takes 2-6 weeks to reach a steady state.
Some of the adverse reactions of letrozole can be predicted by its effects on oestradiol synthesis e.g. hot flushes. The most common adverse effects are headache, nausea and peripheral oedema. In the pivotal study, letrozole was generally better tolerated than megestrol.
Women with breast cancer and their doctors will need to consider carefully the risks and benefits of letrozole. Its efficacy in oestrogen-receptor negative tumours is not yet known. Although letrozole has a higher response rate than megestrol, the median time to progression is not significantly different. When the data from the pivotal trial were collected, there were no statistically significant differences in the risk of death or the median time to death. At that stage, 58% of the women taking letrozole (2.5 mg) and 50% of those taking megestrol were still alive. If further study finds that letrozole has no greater effect on survival than megestrol, patients may still prefer letrozole (or anastrozole) as it is better tolerated.
Gabitril (Novo Nordisk Pharmaceuticals)
5 mg, 10 mg and 15 mg tablets
Indication: epilepsy
Not all patients with partial seizures can be controlled by conventional antiepileptic drugs. Tiagabine adds to the list of second-line drugs which includes gabapentin, vigabatrin and
lamotrigine.
Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter. By inhibiting reuptake of GABA, tiagabine can reduce the frequency of seizures.
In clinical trials, patients have had tiagabine or a placebo added to their usual treatment. These trials had a baseline period of 8-12 weeks followed by a double-blind titration period of 4-6 weeks, then a 8-12 week assessment period. The results showed tiagabine was significantly more effective than placebo in reducing the frequency of partial seizures. Tiagabine may also reduce the frequency of secondary generalised tonic-clonic seizures.
Although the trials have used a variety of dose frequencies, patients are recommended to take tiagabine 3 times a day. Treatment begins with a total dose of 7.5-15 mg and is increased at weekly intervals by 5-15 mg. The dose is increased until the patient responds or adverse effects develop. Most patients are maintained on 30-50 mg daily, but doses of 70 mg daily have been tolerated.
Tiagabine is well absorbed. Although food delays absorption, the tablets should be taken with food. Tiagabine is almost totally metabolised by the liver. Its clearance is increased by drugs which induce liver metabolism including phenytoin and carbamazepine. Enzyme induction can reduce the half-life from 7-9 hours to 2-3 hours.
Adverse events more frequently associated with tiagabine than placebo include dizziness, tiredness, nervousness and diarrhoea. Paradoxical status epilepticus has occurred when the dose of tiagabine has been increased. Although withdrawal seizures have not been reported, it is also recommended that the dose be gradually reduced.
With several second-line drugs now available, there is a need to establish the best approach to treatment. This may include studies of any synergistic effects between the drugs.
Fareston (Schering-Plough)
60 mg tablets
Indication: breast cancer
Tamoxifen is an anti-oestrogen with a well-established role in breast cancer. Toremifene has a similar structure and can be used as an alternative to tamoxifen in the treatment of postmenopausal
women with hormone-dependent breast cancer.
The antitumour effect is mainly due to toremifene binding to oestrogen receptors. This inhibits the oestrogen-induced stimulation of cell replication.
Toremifene is taken once daily. It is quickly absorbed and food does not have a significant effect on the extent of absorption. Toremifene is almost totally bound to albumin. There is extensive metabolism and an active metabolite is produced. The metabolites are mainly excreted in the faeces. As the half-life of toremifene is long, it takes 4-6 weeks for the concentration to reach a steady state.
Toremifene and tamoxifen have been compared in 3 main trials. In terms of response and survival, the two drugs were generally equivalent.
Some of the adverse effects of toremifene can be expected because of its mechanism of action. Common adverse effects include hot flushes, leucorrhoea, oedema, nausea and vomiting.
Approximately 3% of the women in clinical trials had to withdraw due to adverse reactions. There is a risk of hypercalcaemia in the first week of treatment, particularly if the patient has bony metastases. There is insufficient evidence to determine if toremifene shares the potential of tamoxifen to increase the risk of endometrial cancer during long-term treatment. So far, toremifene appears to have no clear advantage over tamoxifen.
