New drugs

(Aust Prescr 1997;20:101-3)

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.

Cysteamine bitartrate

Cystagon (Orphan Australia)
50 mg and 150 mg capsules

Indication: nephropathic cystinosis
Cystinosis is inherited as an autosomal recessive trait. The body is unable to remove cystine from lysosomes, so it accumulates. The accumulation of cystine crystals can affect many organs, particularly the kidney (Fanconi's syndrome). Giving patients cysteamine can slow the deterioration in renal function; however, it is unpalatable and cysteamine bitartrate has been developed as an alternative.

Cysteamine, which was once used in the treatment of paracetamol poisoning, works by reacting with the cystine in lysosomes. The reaction produces cysteine which can be transported out of affected cells.

As cystinosis is a rare condition, it is difficult to study its treatment in adequate numbers of patients. Studies that have been done tend to have used cysteamine hydrochloride rather that cysteamine bitartrate. In general, cysteamine can be expected to reduce the concentration of cystine in white blood cells. If these concentrations can be near normal, renal function and growth are likely to be maintained. It is not clear how long this benefit will last and whether or not renal transplant can be avoided.

The children start on a low dose which is gradually increased. The concentration of cystine in the leucocytes is measured 5-6 hours after a dose. Once a maintenance dose is established, cystine concentrations should be checked every 3 months.

The most common adverse effects occur in the gastrointestinal tract. They include vomiting, anorexia and diarrhoea.

As the number of `orphan' drugs is likely to increase, they will pose a challenge to systems of drug regulation. It will be difficult to balance the need for such drugs with the relative lack of data to support their use.

Dolasetron mesylate

Anzemet (Hoechst Marion Roussel)
50 mg and 200 mg tablets
20 mg/mL in 0.625 mL and 5 mL ampoules

Indication: prevention of nausea and vomiting
Vomiting is often a problem during chemotherapy for cancer, especially if highly emetogenic drugs such as cisplatin are used. There are several approaches to dealing with this problem including the use of 5HT₃ receptor blockers. Dolasetron is a new drug in this class which already contains ondansetron and tropisetron. In addition to patients having chemotherapy, dolasetron can also be used in the management of postoperative nausea and vomiting. It is not approved for use in children.

Dolasetron is given once a day. Patients can receive the injection 30 minutes before, or take a tablet one hour before, chemotherapy. The tablet is well absorbed and, like injectable dolasetron, is rapidly converted to an active metabolite. This metabolite has a half-life of 7-9 hours with 30% being excreted in the urine and the rest by further metabolism. Although clearance is reduced by hepatic or renal impairment, no dose adjustments are advised.

Most patients will benefit from having a 5HT₃ receptor blocker before chemotherapy. Dolasetron is probably as effective as the other drugs and, similarly, the addition of a corticosteroid will enhance its efficacy. To reduce delayed nausea and vomiting, dolasetron can be continued for up to 7 days.

Adverse effects which have been reported in patients taking dolasetron include headache, dizziness and diarrhoea. Arrhythmias have been reported, but their association with dolasetron is unclear.

Nevirapine

Viramune (Boehringer Ingelheim)
200 mg tablets

Indication: HIV infection
Nevirapine is an inhibitor of HIV-1 reverse transcriptase. As it binds directly to the enzyme, its action differs from that of a nucleoside analogue such as zidovudine.¹

If nevirapine is used alone, the virus quickly develops resistance to the drug. Accordingly, nevirapine should be prescribed in combination with two other antiviral drugs.

In patients who have not been previously treated, the combination of nevirapine, zidovudine and didanosine has been compared with nevirapine and zidovudine, and zidovudine and didanosine. After 52 weeks, the CD4 lymphocyte count had improved significantly more in the patients given the combination of 3 drugs. Concentrations of viral RNA were also significantly lower.

Nevirapine was also studied in patients who had taken nucleoside analogues. Combining nevirapine with zidovudine and didanosine maintains the CD4 count longer than zidovudine plus didanosine and lowers the concentration of viral RNA.²

Treatment begins with a single 200 mg dose increasing to twice daily after 14 days. The tablet is well absorbed and has a high bioavailability. Food has no significant effect on absorption. Nevirapine is metabolised by the cytochrome P450 system so there is a potential for an interaction with other drugs metabolised by this system. As nevirapine induces its own metabolism, its clearance increases during the first few weeks of treatment. This reduces the half-life from 45 hours to 25-30 hours.

Nevirapine has not been evaluated in patients with liver disease; however, liver function is commonly affected. All patients should have their liver function monitored during treatment.

The most common adverse effect is rash. When compared with those treated with zidovudine and didanosine, 35% of patients taking nevirapine developed a rash. This rash was considered to be severe or life-threatening (e.g. Stevens-Johnson syndrome) in almost 7% of patients. Most of the severe rashes erupt in the first month of treatment. A quarter of the patients with severe rashes will need admission to hospital.

Approximately 7% of patients have to stop treatment because of rashes. Patients may also discontinue treatment because of other adverse effects such as fever and hepatitis. Patients may also experience headache, nausea and vomiting.

Although nevirapine has some beneficial effects, these start to decline after the first few weeks of treatment. At present, there is no evidence of an improvement in clinical end points such as survival. Nevirapine has to be used with two other antiviral drugs because combination with zidovudine alone does not alter the emergence of resistance. There are no results of trials combining nevirapine and protease inhibitors, but the drugs do interact. Until more data become available, the best way to use nevirapine in combined regimens will remain unclear.

R E F E R E N C E S
1. Locarnini S. Antiviral drugs - mechanisms of action. Aust Prescr 1993;16:78-81.

2. D'Aquila RT, Hughes MD, Johnson VA, Fischl MA, Sommadossi JP, Liou SH, et al. Nevirapine, zidovudine, and didanosine compared with zidovudine and didanosine in patients with HIV-1 infection. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1996;124: 1019-30.

Topotecan hydrochloride

Hycamtin (SmithKline Beecham)
vials containing 4 mg as lyophilised powder

Indication: ovarian cancer
The treatment of advanced ovarian cancer includes platinum-based chemotherapy. Although many patients will respond to this chemotherapy, the disease recurs. Topotecan can now be offered to women with metastatic carcinoma of the ovary who have failed to respond to treatment.

Topotecan is an inhibitor of topoisomerase. This enzyme is involved in the replication of DNA and its concentrations are higher than normal in cancer cells. Topotecan destroys cancer cells, but also damages normal cells.

The drug is given as a 30-minute infusion every day for 5 days. After a 3-week break, the course is repeated and a minimum of 4 courses is recommended.

Topotecan has a high volume of distribution (up to 243 L after a single dose). The half-life of a dose is 2-7 hours with clearance mainly by metabolism, but 20-60% of the dose will appear in the urine. Plasma clearance is therefore reduced by both hepatic and renal impairment.

Paclitaxel is already available to treat women who have not responded to platinum-based chemotherapy, so this drug has been compared with topotecan. The median time to response for topotecan is approximately 10 weeks compared with 7 weeks for paclitaxel. However, the overall response rate may be a little higher with topotecan than paclitaxel. For example, 6 of 112 patients given topotecan had a complete response compared with 4 of the 114 patients given paclitaxel. The median time for the disease to progress was longer in patients given topotecan.

Unfortunately, topotecan is very toxic. The dose limiting toxicity is haematological with nearly all patients being affected. A neutropenia of <500 cells/mm³ occurs in 81% of patients. The neutropenia develops in 11 days and lasts for about a week. The full blood count should be monitored closely and patients who have had severe neutropenia should have their dose reduced or be given granulocyte-colony stimulating factor (G-CSF). Most patients will also develop anaemia and thrombocytopenia. Nearly 80% of the patients will have nausea and many will vomit. A majority of the women will develop alopecia.

Although some patients will respond to topotecan, the effect on survival is unclear.

Answers to self-test questions
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