New drugs

(Aust Prescr 1996;19:24-7)

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.

Amorolfine

Loceryl (Roche Products)
5% nail lacquer in 5 mL

Indication: fungal infections
Amorolfine is a member of a new class of antifungal drugs. It interferes with sterol biosynthesis and therefore the fungal cell membrane. The effect may be fungistatic or fungicidal.

The nail lacquer can be applied once or twice a week to nails infected by moulds, yeasts or dermatophytes. Treatment may have to continue for many months, particularly when the toenails are involved. There are limited data on the longterm use of amorolfine.

In general, amorolfine is effective, although not all patients, especially those with onychomycosis, will respond. It is unknown how effective the nail lacquer is for patients with infections involving more than 80% of the nail, as this group were excluded from some studies. The nail lacquer must be applied by a certain method. To assist the patient, the lacquer is supplied in a kit containing cleaning pads, spatulas and nail files.

Some of the amorolfine applied is absorbed, particularly through the skin; however, the majority of adverse effects occur at the site of application. The drug has been given a B3 classification for use in pregnancy.

Overseas information suggests that amorolfine may be a relatively expensive drug. There is, therefore, a need for clinical studies to compare amorolfine with other antifungal drugs.

Cabergoline

Dostinex (Pharmacia)
0.5 mg tablets

Indication: hyperprolactinaemia
Cabergoline is a synthetic ergoline derivative which stimulates D2 dopamine receptors. This stimulation reduces prolactin secretion.

The effect of cabergoline begins within 3 hours of taking the drug and may last for up to 28 days after a single dose. The elimination halflife is estimated to be between 80 and 115 hours in hyperprolactinaemic patients. Most of the drug is metabolised and elimination is mainly in the faeces.

Cabergoline should be started at a low dose and increased at monthly intervals. The drug can be given once or twice a week in hyperprolactinaemia.

If the drug is used to prevent lactation, a single 1 mg dose is recommended on the first day after delivery. The drug is not approved for the inhibition of established lactation and should only be used to prevent lactation when there are medical reasons e.g. after a stillbirth.

Cabergoline has been compared with bromocriptine in doubleblind studies. For the prevention of lactation, one day's treatment with cabergoline was as effective as two weeks' treatment with bromocriptine. Cabergoline was better tolerated.1 In women with hyperprolactinaemic amenorrhoea, pregnancy or ovulatory cycles are more likely to occur during cabergoline treatment. Significantly more women achieve normoprolactinaemia with cabergoline.2

The adverse effects of cabergoline include nausea, headache, dizziness and reduced blood pressure. Adverse effects were reported by 16% of women in the study of inhibition of lactation and 68% in the study of hyperprolactinaemia. The corresponding figures for bromocriptine were 27% and 78%.

If postmarketing surveillance confirms the advantages of cabergoline, it may eventually supersede bromocriptine.

 R E F E R E N C E S
1. European multicentre study group for cabergoline in lactation inhibition. Single dose cabergoline versus bromocriptine in inhibition of puerperal lactation: randomised, doubleblind, multicentre study. Br Med J 1991;302:1367-71.

2. Webster J, Piscitelli G, Polli A, Ferrari CI, Ismail I, Scanlon MF. A comparison of cabergoline and bromocriptine in the treatment of hyperprolactinaemic amenorrhoea. N Engl J Med 1994;331:904-9.

Fluvastatin

/span>Lescol (Sandoz Australia)
20 mg and 40 mg capsules

Indication: hypercholesterolaemia
This product is an addition to the class of drugs which inhibit hydroxymethyl glutaryl coenzyme A and thereby reduce cholesterol synthesis.1 The class also includes simvastatin and pravastatin.

Fluvastatin is well absorbed and extensively metabolised by the liver. The bioavailability is approximately 24%. Most of the metabolites are excreted in the faeces and the elimination halflife is 2-3 hours. The manufacturer recommends that liver function tests are performed before and during therapy. If the liver enzyme concentrations persistently exceed 3 times the upper limit of normal, therapy should be stopped.

The drug reduces total cholesterol and low density lipoprotein cholesterol while slightly increasing concentrations of high density lipoprotein cholesterol. This means it is suitable for the treatment of hyperlipidaemia when hypercholesterolaemia predominates. Fluvastatin should be considered if other treatments including diet are unsatisfactory. Dietary therapy must continue during fluvastatin treatment.

The most common adverse effects are dyspepsia, nausea and insomnia. It is not known if fluvastatin can cause the myopathic syndromes which have been observed in patients taking similar drugs. There are no longterm safety data available.

Fluvastatin may be less effective at lowering the concentration of cholesterol than other reductase inhibitors, so its price may determine how frequently it is prescribed. A review in the U.S.A. concluded that fluvastatin may be less effective in lowering serum cholesterol, but costs less than other HMGCoA reductase inhibitors.²

 R E F E R E N C E S
1. Fidge NH. Lipidlowering drugs mechanisms of action. Aust Prescr 1990;13:73-7.

2. Fluvastatin for lowering cholesterol. Medical Letter 1994;36:45-6.

Gestrinone

Dimetriose (Roussel Uclaf)
2.5 mg capsules

Indication: endometriosis
Gestrinone is a synthetic steroid hormone which inhibits the release of pituitary gonadotrophins. The effect on ovarian secretion results in the atrophy of endometrial tissue, including regression of endometriosis. Gestrinone is structurally related to norgestrel and has some androgenic and progestogenic activity. However, the drug has an antiprogesterone effect on endometrial tissue.

The halflife is approximately 27 hours and a steady state is achieved if a second capsule is taken 3 days after the first dose. The drug is metabolised and the metabolites are excreted in the urine and faeces.

Treatment begins on the first day of a period and continues for 6 months. Most women develop amenorrhoea within two months. If spotting occurs, the dose can be increased to one capsule 3 times a week for a few weeks. Repeat courses of gestrinone are not recommended.

Although gestrinone is effective in relieving the symptoms of endometriosis, its effect on infertility is not clear. The efficacy of the drug is probably similar to danazol.

Like danazol, many of gestrinone's adverse effects are due to its androgenic activity. These include acne, seborrhoea, hirsutism, weight gain and changes to the voice. Most patients will have at least one adverse event. Although gestrinone inhibits ovulation, patients need to use barrier contraception while taking the drug. This is because the drug is embryotoxic in some animals and can cause masculinisation of a female fetus. Gestrinone also significantly reduces HDL concentrations.

Interferon beta-1b

Betaferon (Schering)
9.6 million IU (0.3 mg) in 3 mL glass vials

Indication: multiple sclerosis
The clinical course of multiple sclerosis is variable. Some patients have attacks of neurological dysfunction followed by remission. Interferon beta-1b has been approved for use in patients with this relapsing-remitting type of multiple sclerosis, who have at least two attacks in a two-year period.

This is a recombinant product that is almost identical to human interferon beta which has antiviral and immunoregulatory effects. A subcutaneous injection given on alternate days can reduce the number of attacks experienced by the patient. In a randomised, doubleblind, placebocontrolled trial of interferon beta-1b in 372 patients, treatment significantly reduced exacerbation rates and a dose of 8 million IU doubled the number of patients who experienced no exacerbations at all.1 Magnetic resonance imaging revealed that the area of the lesions in patients using 8 million IU decreased while the affected area increased in patients given placebo. However, after two years, the study did not show a significant change in disability.

Most patients will experience injection site reactions during treatment and flu-like symptoms are frequently reported. Laboratory studies reveal that lymphopenia occurs at some time in most patients; concentrations of liver enzymes may also increase. Tests for neutralising antibodies to interferon will detect some neutralising activity in 45-50% of patients at some time during treatment. The product information contains a warning that suicidal ideation may be an adverse effect of treatment.

Although the number of patients studied is relatively small, interferon beta-1b appears to be effective in relapsing-remitting multiple sclerosis. Its longterm safety and effectiveness are not yet known. Although the number of admissions to hospital is reduced, this is unlikely to offset the high cost of the treatment. Interferon beta-1b is not approved for use in progressive multiple sclerosis.

R E F E R E N C E
1. IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. Neurology 1993;43:655-61.

Pantoprazole

Somac (Pharmacia)
40 mg tablets

Indication: peptic ulcers, reflux oesophagitis
This drug increases the prescriber's choice of proton pump inhibitors. Short courses of pantoprazole can be used to treat gastrointestinal lesions which have not responded to H 2
receptor antagonists.

Pantoprazole is highly protein bound and rapidly cleared from the serum by liver metabolism. The halflife is 1-2 hours with most of the metabolites being excreted in the urine. Some patients eliminate pantoprazole more slowly so that the halflife extends to 10 hours. The drug is contraindicated for patients with severe liver disease.

The effect of pantoprazole on acid secretion is prolonged and the minimum effective dose may be less than the recommended daily dose. Treatment is usually given for up to 4 weeks, but some conditions such as reflux oesophagitis may take longer to heal. Safety data to support prolonged use of pantoprazole are not available. Its efficacy is similar to that of omeprazole.

The most common adverse effects reported in clinical trials were headache and diarrhoea. Some serious adverse reactions, such as hepatocellular tumours, thyroid adenomas and ocular toxicity, occurred in animal studies.

Proguanil hydrochloride

Paludrine (ICI Pharmaceuticals)
100 mg tablets

Indication: malaria prophylaxis
This product is returning to the Australian market after an absence of 10 years. The use of proguanil declined as longeracting drug combinations such as dapsone/pyrimethamine and sulfadoxine/pyrimethamine became available. Recent concern about the adverse effects of these combinations has resulted in an increased demand for proguanil. As Plasmodium falciparum is now resistant to proguanil in many areas of Africa and SouthEast Asia, the World Health Organization recommends that patients taking proguanil should also take chloroquine.

Proguanil is taken daily starting at least one day before entering the malarious area and continuing until 4 weeks after leaving the area. The drug is metabolised to the active antimalarial cycloguanil. This inhibits the synthesis of nucleic acids by the malaria parasite. The main effect of the drug is against pre-erythrocytic schizonts. Proguanil and cycloguanil are predominantly renally excreted, so the dose should be lowered in patients with reduced renal function.

In contrast to some of the other drugs used for prophylaxis, proguanil can be used by pregnant women and children.

The drug is usually well tolerated, the commonest adverse effects are gastrointestinal upsets and mouth ulcers. Patients who are anticoagulated may need to have their treatment adjusted when they commence proguanil.

It is anticipated that a working party of the National Health and Medical Research Council will consider the role of proguanil for Australian travellers.

Recombinant factor VIII

Recombinate (CSL)
bottles containing 250 IU, 500 IU and 1000 IU for reconstitution

Indication: haemophilia A
Haemophilia A is due to a deficiency or dysfunction of factor VIII. The patients are at risk of bleeding after minor injuries. If bleeding, e.g. into a joint, is suspected, the patient needs to be given factor VIII.

Although the safety of factor VIII products derived from human plasma has increased, there is still the potential for infection. Patients are also at risk of developing antibodies which inhibit factor VIII and so reduce the effectiveness of treatment. Although inhibitors can still occur, the risk of infection will be reduced by a recombinant factor VIII.

The factor VIII in this product is synthesised using Chinese hamster ovary cells. It has the same effects as human factor VIII, so it can be infused to prevent or treat bleeding.

The dose is determined by calculating how much factor VIII has to be given to raise its plasma concentration to a particular percentage of normal. While an early haemarthrosis may be stopped by raising the concentration to 20% of normal, severe bleeding may require the concentration to be raised to 100%. While the dose can be estimated using these calculations, the manufacturer recommends serial assays to ensure that adequate concentrations are reached. As the halflife is 14 hours, the infusion should be repeated until the threat of bleeding has resolved.

Patients can develop inhibitors to recombinant factor VIII. If an inhibitor is present, bleeding might not be controlled as expected and additional factor VIII may be needed. Hypersensitivity is unusual, but patients should be informed of the possibility.

There have been shortages of plasmaderived factor VIII in Australia, so this product will increase supply. The product is expensive and will probably only be available to patients registered at recognised treatment centres. Treatment may be reserved for children and new patients who are not 'virally compromised'.

Answers to self-test questions
1. False	2. True	3. False
4. True	5. True	6. False
7. False	8. True	9. False
10. False