New drugs

(Aust Prescr 1997;20:77-9)

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.

Fluvoxamine

Luvox (Solvay Pharmaceuticals)
100 mg tablets

Indication: depression, obsessive compulsive disorder
Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) which has been available overseas for at least 10 years. Its chemical structure is different to that of the other SSRIs.

The usual starting dose is 50 mg. This is well absorbed even in the presence of food. Fluvoxamine has a bioavailability of 53% as it is extensively metabolised by the liver. Most of the metabolites are inactive and excreted in the urine. If the drug is given to patients with renal or hepatic impairment, the dose should only be increased slowly. In healthy people taking repeated doses, the half-life is approximately 22 hours. Unless the treatment exceeds 150 mg per day, a single daily dose can be prescribed.

Fluvoxamine has mainly been compared with placebo or imipramine in studies of depression. It is unclear how fluvoxamine compares with other SSRIs. Most of the studies have only lasted for approximately 6 weeks. In general, the response to fluvoxamine will be greater than to placebo and similar to the response to imipramine. Patients who respond to fluvoxamine and continue to take it for up to a year are less likely to relapse than those who are switched to placebo.

Obsessive-compulsive disorder is difficult to treat.¹ Fluvoxamine has been studied for this disorder in comparison with placebo or clomipramine. Significantly more patients responded to fluvoxamine than placebo and the effectiveness of fluvoxamine was similar to that of clomipramine.

The dose of fluvoxamine is increased until a response occurs. Nausea is a common complaint when starting treatment, but may decline over two weeks. The maximum dose is 300 mg.

After nausea, the most frequent adverse effects are headache, somnolence and insomnia. Other common adverse reactions include dry mouth, dizziness, asthenia, diarrhoea, constipation, palpitations and sweating. Rare events include convulsions, postural hypotension and abnormal liver function.

Fluvoxamine can inhibit the metabolism of other drugs metabolised in the liver. It can interact with carbamazepine, warfarin, phenytoin and oxidatively metabolised benzodiazepines.

R E F E R E N C E
1. O'Sullivan BT, Johnson GF. The management of obsessive-compulsive disorder. Aust Prescr 1990;13:6-9.

Ivermectin

Stromectol (Merck Sharp & Dohme)
6 mg tablets

Indication: strongyloidiasis and onchocerciasis
Onchocerciasis is one of the world's major causes of blindness. As the vector for the causative nematode is found near rivers, the condition is also known as river blindness. Ivermectin is the first-line treatment. The drug can also be used as an alternative to thiabendazole or albendazole in the treatment of infestation with the helminth Strongyloides stercoralis.

Invermectin is derived from moulds found in soil. It is thought to act by stimulating the release of gamma-aminobutyric acid (GABA) from the pre-synaptic nerve terminals of the parasites. The inhibition of neurotransmission by GABA gives ivermectin a broad spectrum of activity against helminths. It is not thought to interfere with human neurotransmission.

One advantage of ivermectin is that a single dose is effective. The drug is taken on an empty stomach in a dose determined by the patient's weight. As paediatric data are limited, ivermectin is not recommended for children under 5 years old with onchocerciasis or children under 12 years with strongyloidiasis. The drug also causes fetal damage in animals and is present in breast milk. Pharmacokinetic data are

limited, but it is known that ivermectin and its metabolites are excreted in the faeces over approximately two weeks. The plasma half-life of the metabolites (3 days) is approximately 6 times longer than that of the parent compound.

Repeat doses of ivermectin are not recommended for strongyloidiasis, although, if possible, the stools should be re-examined to ensure the treatment has worked. In areas endemic for onchocerciasis, the dose can be repeated after 6 or 12 months.

The adverse effects of ivermectin vary slightly depending on the condition being treated. This is because the death of the parasite in patients with onchocerciasis can cause allergic or inflammatory responses. These can present as arthralgia, lymphadenopathy, fever, pruritus and skin rashes. Other adverse effects include headache, myalgia, oedema, tachycardia, fatigue, dizziness and tremor.

Nefazodone hydrochloride

Serzone (Bristol-Myers Squibb)
100 mg, 200 mg and 300 mg tablets

Indication: major depression
This drug inhibits the reuptake of serotonin, but its structure is different to that of the selective serotonin reuptake inhibitors (SSRIs).

Nefazodone is completely absorbed from the gut, but food reduces its bioavailability. Most of the drug is eliminated by a complex metabolism. Some of the metabolites are active and one of these has a half-life of up to 9 hours compared with the 2-4 hours of the parent compound. As the metabolites are excreted in the urine and the faeces, extra caution is needed if the drug is prescribed to a patient with renal or hepatic failure. There is a potential for interaction with drugs metabolised by cytochrome P450 3A4 as this isoenzyme is inhibited by nefazodone. Examples of these drugs include triazolam, alprazolam, calcium channel antagonists, terfenadine, astemizole, ketoconazole and erythromycin.

Treatment starts with 100 mg twice a day. It is increased by 100 mg or 200 mg at weekly intervals depending on the patient's response. Although it may take several weeks for a depressed patient to respond to therapy, the effectiveness of nefazodone has not been systematically evaluated beyond
6-8 weeks.

In short-term clinical trials, nefazodone has comparable efficacy to imipramine. Its efficacy is also said to be similar to that of the SSRIs.
While the drug may be ineffective if the dose is increased too slowly, a rapid increase can cause adverse effects. The adverse effects of nefazodone include nausea, dry mouth, constipation, somnolence, dizziness and postural hypotension.

On currently available short-term data, it appears that nefazodone has no obvious advantages over SSRIs and is unlikely to be a first-line drug for depression.

Olanzapine

Zyprexa (Eli Lilly)
5 mg, 7.5 mg and 10 mg tablets

Indication: schizophrenia
The long-term outcome of treatment for schizophrenia is often unsatisfactory. For example, the disease can often relapse. To try to improve outcomes, atypical antipsychotics such as clozapine have been studied. Olanzapine is a new drug with a structure similar to clozapine.

Patients begin with a dose of 10 mg once a day. This is then adjusted according to the response. The absorption of olanzapine is not affected by food and the peak plasma concentration is reached within 5-8 hours. In-vitro olanzapine binds with

dopamine, serotonin, cholinergic and histamine receptors. The drug reduces the activity of dopaminergic neurones. Olanzapine is metabolised by the liver, but its half-life depends on the sex and age of the patient. The half-life is longer in women and can exceed 50 hours in the elderly.

In studies lasting for 6 weeks, olanzapine was more effective than placebo and at least as effective as haloperidol. These trends have persisted when treatment has continued beyond 6 weeks. There appear to be no data comparing olanzapine with clozapine.

The adverse effects of olanzapine resemble those of other antipsychotic drugs. However, unlike clozapine, agranulocytosis does not currently appear to be a problem. The most common adverse effects are somnolence and weight gain. Patients may also complain of constipation, dry mouth, dizziness and oedema. Olanzapine may affect the concentrations of prolactin and liver enzymes.

Although olanzapine is metabolised by cytochrome P450, it does not have a significant effect on the metabolism of warfarin, theophylline, imipramine or diazepam. The clearance of olanzapine is affected by smoking and carbamazepine.

There is a need to establish if olanzapine is as effective as clozapine. If it is, then it seems to offer a safer alternative in the treatment of schizophrenia.

Penciclovir

Vectavir (SmithKline Beecham)
1% cream in 2 g tubes

Indication: herpes labialis
Patients with shingles can be treated with famciclovir. However, the drug is a prodrug which must be metabolised to its active form, penciclovir. Treatment with oral penciclovir is not used as it has a very low bioavailability; however, topical penciclovir can be effective in the treatment of herpes infections of the lips.

To be effective, the cream must be applied every two hours, at least 6 times a day, for 4 days. Patients using penciclovir heal significantly faster than those using a placebo cream. However, in absolute terms, this means the cold sore heals up one day earlier.

There is minimal systemic absorption of penciclovir and no more local adverse reactions than placebo. The risks of phototoxity and photoallergy in the Australian environment are unknown.

As cold sores usually heal spontaneously, there is no clear indication for using this product. Although some patients with recurrent cold sores may wish to try penciclovir, the benefit is likely to be small. The safety and efficacy of penciclovir cream has not been established in children, pregnant women or immunocompromised patients.

NEW FORMULATIONS

Fluticasone propionate

Flixotide Accuhaler (Glaxo Wellcome)
100, 250 and 500 microgram/blister

NEW STRENGTHS

Albumin

Albumex 4 (CSL)
40 g/L injection

Simvastatin

Zocor (Merck Sharp & Dohme)
40 mg tablets

NEW PROPRIETARY BRANDS

Cefaclor monohydrate

Keflor (Alphapharm)
125 mg/5 mL and 250 mg/5 mL granules for suspension

Ipratropium bromide

Ipratrin uni-dose (Alphapharm)
250 microgram/mL in 1 mL and 2 mL ampoules

Selegiline hydrochloride

Selgene (Alphapharm)
5 mg tablets