New drugs

(Aust Prescr 1999;22:43-7)

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.

Brimonidine tartrate

Alphagan (Allergan)
2 mg/mL eye drops in 5 mL dropper bottles

Approved indication: glaucoma

Australian Medicines Handbook Section 11.2.2

A variety of drugs are available to treat raised intraocular pressure.¹ The options include alpha adrenergic agonists which affect the flow of aqueous humour. Brimonidine is an alpha₂ adrenergic agonist. As brimonidine has a selective action, the mydriasis seen with other agonists does not occur.

The drops are instilled twice a day. While the half-life of brimonidine is 3 hours, its effect lasts for at least 12 hours. The absorbed drug is metabolised by the liver and then excreted in the urine.

Clinical studies reveal that brimonidine reduces intraocular pressure by 4-6 mmHg. Although this effect has been observed for up to a year of treatment, approximately 8% of patients discontinued brimonidine because their glaucoma was not controlled.

Compared with beta blocking eye drops, adrenergic agonists have more adverse effects. Patients using brimonidine may complain that their eyes are red, burning or stinging and that their vision is blurred. In addition to other ocular adverse effects, including allergic reactions, the patients can have systemic adverse effects such as dry mouth and dizziness. Blood pressure may be reduced and palpitations have been reported.

The product information advises that, because of the preservative used, brimonidine should not be instilled within 10 minutes of other eye drops; however, there are no data to support its use in combination with other treatments for glaucoma. Patients with soft contact lenses should not put them in until at least 15 minutes after using brimonidine because the preservative may be absorbed into the lens.

In view of the comparisons, brimonidine should only be prescribed as monotherapy for patients who cannot take beta blockers for their chronic open angle glaucoma.

R E F E R E N C E

1. Goldberg I. The medical treatment of glaucoma. Aust Prescr 1993;16:34-7.

Cidofovir

Vistide (Pharmacia & Upjohn)
75 mg/mL sterile concentrate for infusion in 5 mL vials

Approved indication: cytomegalovirus retinitis

Australian Medicines Handbook Section 5.3.2

Patients who are immunocompromised may develop significant cytomegalovirus infections. In patients with AIDS, there is a risk of retinitis which may lead to blindness. Cytomegalovirus retinitis can be treated with ganciclovir or foscarnet. Cidofovir provides another option.

Cidofovir is an analogue of cytosine. It is active against herpes viruses including cytomegalovirus (CMV). Unlike ganciclovir, which is activated by viral enzymes, cidofovir is converted by host enzymes. This may slow the development of resistance.

A randomised controlled trial studied cidofovir in 48 patients with AIDS and retinitis. The patients were either treated immediately or after the retinitis progressed. The median time to progression was 120 days in the immediate treatment group and 22 days in the deferred treatment group.¹ (In patients taking ganciclovir or foscarnet, the median time to progression is approximately 50 days.)

In a study of patients who were intolerant of, or failed to respond to, ganciclovir or foscarnet, the median time to retinal progression was 115 days.

Cidofovir is infused once a week for two weeks. After this induction, maintenance treatment is given every two weeks. As nephrotoxicity is a common adverse event, patients must be well hydrated and be given probenecid. The probenecid reduces the clearance, probably by blocking renal tubular secretion. The half-life of the active drug in cells is 17-65 hours.

Proteinuria occurs in 41% of patients. Approximately 25% of patients had to withdraw from clinical trials of the drug because of this nephrotoxicity or other adverse effects such as neutropenia. Patients may complain of asthenia, nausea, alopecia, rashes and fever. They may also have adverse reactions to probenecid.

Cidofovir does delay the progression of retinitis due to CMV infection; however, visual acuity may not significantly change. The drug has an advantage over foscarnet and ganciclovir as it needs to be given less frequently, but there are insufficient data to establish which drug is the most effective in practice.

R E F E R E N C E

1. Lalezari JP, Stagg RJ, Kuppermann BD, Holland GN, Kramer F, Ives DV, et al. Intravenous cidofovir for peripheral cytomegalovirus retinitis in patients with AIDS. Ann Intern Med 1997;126:257-63.

Clopidogrel

Iscover (Bristol-Myers Squibb)
Plavix (Sanofi Winthrop)
75 mg tablets

Approved indication: vascular ischaemia

Australian Medicines Handbook Section 7.2

The aggregation of platelets in patients with vascular disease can cause ischaemic events such as myocardial infarction and stroke. Therefore, antiplatelet drugs have an important role in preventing these events.¹ Clopidogrel is a new antiplatelet drug similar to ticlopidine. The platelet's glycoprotein receptor for fibrinogen is affected because clopidogrel blocks the activation of platelets by adenosine diphosphate.

Clopidogrel has been compared with aspirin in a study of more than 19 000 patients. The patients had a history of peripheral vascular disease, myocardial infarction or ischaemic stroke. They took either 325 mg aspirin and a placebo, or 75 mg clopidogrel and a placebo. The patients were followed up for approximately two years. The annual risk of death from vascular causes was 5.83% in the patients taking aspirin and 5.32% in the patients taking clopidogrel (1021 vs. 939 events). The 8.7% reduction in relative risk was statistically significant.² There was no difference in all cause mortality between the two treatments.

The once daily dose is quickly absorbed, but very little clopidogrel can be detected in the plasma. This is because of extensive liver metabolism. As the main metabolite is inactive, it is thought that another unidentified metabolite is responsible for inhibiting platelet activation. Half of each dose is excreted in the urine, but a reduced dose is not required in the elderly or in those with reduced renal function. Although half the dose is excreted in the faeces, there is no advice on the effects of hepatic insufficiency.

In the clinical trial of clopidogrel², 21% of the patients dropped out, usually due to adverse events. When compared with aspirin, there was a similar frequency of adverse reactions. More patients taking clopidogrel complained of a rash or diarrhoea, but patients taking aspirin were more likely to have gastrointestinal discomfort or bleeding. Four patients taking clopidogrel have developed severe neutropenia. Compared with similar studies of ticlopidine, clopidogrel appears to cause less neutropenia. The overall incidence of thrombocytopenia is similar for clopidogrel and aspirin.

Clopidogrel can inhibit the activity of cytochrome P450 2C9. This creates the potential for interactions with other drugs metabolised by this system, such as tolbutamide and phenytoin. Caution is needed when prescribing clopidogrel with other drugs which increase the risk of bleeding e.g. heparin, warfarin and non-steroidal anti-inflammatory drugs including aspirin.

Although clopidogrel reduces the relative risk of death more than aspirin, the reduction is not the same in all patients. People with peripheral vascular disease had a big reduction in risk, while there was no reduction for patients who had had a myocardial infarction.

If 1000 patients are treated for a year, aspirin will prevent 19 major clinical events and clopidogrel will prevent 24. Given the low price of aspirin, it will be interesting to see what the cost of purchasing the apparent additional benefit of clopidogrel will be.

R E F E R E N C E S

1. Lefkovits J. Recent advances in antiplatelet therapy. Aust Prescr 1996;19:98-101.

2. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329-39.

Interferon beta-1a

Avonex (CSL)
vials containing 30 microgram as lyophilised powder

Approved indication: relapsing multiple sclerosis

Australian Medicines Handbook Section 14.2.2

Autoimmune mechanisms have an important role in multiple sclerosis. This led to the approval in 1995 of interferon beta-1b for the treatment of the relapsing-remitting type of multiple sclerosis. The structurally similar interferon beta-1a has now been approved for the same indication. These interferons are cytokines which act by altering the immune response, but their exact mechanism of action in multiple sclerosis is unknown.

The main trial of interferon beta-1a involved 158 patients who were compared with 143 patients who were given a placebo. The patients were given weekly injections for two years. At the end of the study, there had been fewer exacerbations in the treated group. There was evidence that the progression of disability was slower in the treated group. Disability increased in 22% of the treated group and 35% of the placebo group. Magnetic resonance imaging showed fewer lesions in the brains of patients given interferon beta-1a.¹

The half-life of interferon beta-1a is 10 hours. As its biological effects last much longer, it only has to be injected weekly. After instruction, able patients can give their own intramuscular injections.

The manufacturer suggests that paracetamol be given before the injection and for the next day. This is to counteract the flu-like symptoms which occur in most patients. In addition to fever, chills and muscle aches, the risk of developing anaemia is also significantly greater for patients using the drug than for those given a placebo. Only 4% of the patients taking interferon beta-1a in clinical trials had to withdraw because of adverse effects. Safety and effectiveness have not been established beyond two years of therapy.

One of the problems with interferon beta-1b is the development of antibodies which may reduce its effectiveness. After two years, 22% of the patients given interferon beta-1a had developed antibodies, but the effect on efficacy is unclear.

When interferon beta-1b was marketed, there was no evidence of its effect on disability, whereas interferon beta-1a has been shown to have some effect. The clinical importance of reducing exacerbations from 0.9 per year to 0.6 per year will also have to be weighed against treatment costs. Overseas information suggests one month's treatment with interferon beta-1a is likely to be cheaper than with interferon beta-1b. When deciding which interferon to recommend, Australian prescribers will also have to consider that the recombinant interferon beta-1a available here differs from that used in the clinical trials.

R E F E R E N C E

1. The Multiple Sclerosis Collaborative Research Group. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. Ann Neurol 1996;39:285-94.

Naltrexone hydrochloride

ReVia (Orphan Australia)
50 mg tablets

Approved indication: substance abuse

Australian Medicines Handbook Section 18.5

Naltrexone is an opioid antagonist. It can be used in the management of patients who have ceased using opioids and as part of a treatment program for alcohol dependence. While naltrexone blocks the effects of opioids, e.g. injected heroin, its mechanism of action in alcohol-dependent patients is unknown. In animals, opioid antagonists reduce alcohol consumption.

The main steps in the treatment of opioid addiction are detoxification and maintenance of abstinence. Although naltrexone has been used in rapid detoxification regimens, the evidence is not strong enough for this technique to be considered to be more than experimental.¹ Naltrexone's main use will therefore be in maintenance. By blocking opioid receptors, naltrexone stops the euphoric effects of heroin which may reduce the patient's desire for the illicit drug.

A Cochrane review is investigating the effectiveness of naltrexone maintenance as there are no data which clearly show a beneficial effect on the rate of relapse. Patients must be motivated to comply with one of a variety of treatment regimens, so it is best if the drug is part of a comprehensive rehabilitation program.

Great care is needed when starting treatment. The patient should not have taken any opioids in the preceding 7-10 days. If they have, there is a risk of precipitating an acute withdrawal reaction. The product information recommends a naloxone challenge test if there is any doubt about the patient's abstinence.

Patients need to be warned not to try to overcome the blockade by taking large quantities of opioid; they may overdose. They should also be aware that their sensitivity to opioids may increase, so if they relapse after treatment, their `usual' dose may cause life-threatening adverse effects.

In the treatment of alcohol dependence, 50 mg naltrexone is taken daily for up to 12 weeks. In clinical trials, this regimen has produced better abstinence rates than placebo and reduced the risk of relapse. As with opioid maintenance treatment, patients must be motivated so naltrexone should only be used as one part of a treatment program. Patients who drink heavily may have abnormal liver function. If liver function tests are more than 3 times normal, it may be inappropriate to use naltrexone as the drug can damage the liver.

First-pass metabolism reduces the oral bioavailability of naltrexone to 40%. Extensive metabolism results in only 2% being excreted unchanged with most of the metabolites appearing in the urine.

Commonly reported adverse events include nausea, headache, fatigue, insomnia and anxiety. Although depression and suicidal ideation have been reported, no causal link with naltrexone has been shown.

R E F E R E N C E

1. O'Connor PG, Kosten TR. Rapid and ultrarapid opioid detoxification techniques. JAMA 1998;279:229-34.

Trovafloxacin and alatrofloxacin mesylate

Trovan and Trovan IV (Pfizer)
200 mg tablets
40 mL and 60 mL vials containing 5mg/mL

Approved indication: specified infections

Australian Medicines Handbook Section 5.1.12

At a time when antibiotic use in Australia is declining, the range of quinolones has been expanded with the introduction of trovafloxacin. It acts like the other quinolones by inhibiting an enzyme essential in the replication of bacterial DNA.

Two formulations are available. The tablets are taken once a day, while the concentrate is diluted and then infused over one hour. This intravenous formulation contains alatrofloxacin which is the prodrug of trovafloxacin. Alatrofloxacin is used because it is more soluble than trovafloxacin. Some intravenous fluids, e.g. normal saline, are not suitable for diluting alatrofloxacin.

Trovafloxacin tablets have a bioavailability of 88%. This is not affected by food, but the tablets should not be taken with antacids. Morphine also reduces absorption. Trovafloxacin is widely distributed with concentrations in some tissues exceeding those in the plasma. Half the dose is excreted unchanged, while the rest is metabolised and excreted mainly in the faeces. The half-life is 11 hours, but the drug needs to be given only once a day.

There is a broad spectrum of antibacterial activity including both Gram positive and Gram negative organisms. Susceptible organisms include streptococci, staphylococci, Escherichia coli, Haemophilus influenzae, Moraxella catarrhalis, Neisseria gonorrhoea, Pseudomonas aeruginosa and Chlamydia pneumoniae. This profile enables trovafloxacin to be used in a wide variety of conditions. These include pneumonia, pelvic inflammatory disease, gonorrhoea, chlamydial cervicitis and infections of the skin and skin structures.

In clinical trials, 5% of patients discontinued treatment because of adverse events. The common adverse events are dizziness, headache and nausea. Trovafloxacin should be used cautiously in patients with neurological disorders, including cerebral atherosclerosis, as seizures can occur. The drug should be discontinued if a rash develops because of the risk of hypersensitivity reactions.

Trovafloxacin is not appropriate for common infections. For example, it should not be used to treat uncomplicated lower urinary tract infections unless resistance to other antibiotics has been proven. The quinolones are useful drugs for organisms that may be difficult to eradicate e.g. Pseudomonas aeruginosa. Their use should therefore be restricted in order to slow the development of resistant bacteria. Although experience with trovafloxacin is limited, a possible advantage is its metabolism. There is minimal involvement of the cytochrome P450 system, so the potential for interactions with drugs such as warfarin, cimetidine and theophylline may be reduced.

Zafirlukast

Accolate (Zeneca)
20 mg and 40 mg tablets

Approved indication: asthma

Australian Medicines Handbook Section 19.3

In patients with asthma, leukotrienes are associated with airways inflammation and smooth muscle constriction. Zafirlukast has been developed to counteract these effects by competing for the leukotriene receptors.

The drug is taken twice a day. Zafirlukast should not be taken with meals as its bioavailability is reduced by 40%. Zafirlukast is extensively metabolised with most of the metabolites being excreted in the faeces. Although clearance is reduced in the elderly, a lower starting dose is not recommended. The drug is not recommended for patients with hepatic impairment.

The liver metabolism involves the cytochrome P450 system. This explains some of the drug interactions which can occur with zafirlukast. Interacting drugs include warfarin, terfenadine, erythromycin and aspirin.

Zafirlukast has been compared with placebo in short-term studies (13 weeks' duration) of mild-to-moderate asthma. In one of these company-supported studies, 103 patients were given zafirlukast and compared with 43 patients given a placebo. At the end of the study, the zafirlukast group had significantly more days when they did not need their beta agonist inhalers and were free of symptoms.¹

This means that some patients with asthma will benefit from taking a preventive medication, but how does zafirlukast compare with other forms of prevention? It is probably no more potent than inhaled steroids and its potential to allow a reduction in the dose of inhaled corticosteroids is uncertain.

Patients should not be suddenly switched from corticosteroids to zafirlukast. There are occasional reports that reducing the dose of corticosteroid may precipitate or exacerbate the Churg-Strauss syndrome (systemic eosinophilic vasculitis). Other adverse events observed during treatment with zafirlukast include headache, gastrointestinal upsets and altered liver function and elevated creatine phosphokinase.

Although zafirlukast has been approved for the treatment and prophylaxis of asthma in patients over 12 years of age, its main role will be in prevention. Zafirlukast has no role in acute asthma attacks and has not been evaluated in unstable asthma. It can be used in patients whose asthma is not controlled by beta agonists. As zafirlukast has no clear advantage, it should probably only be prescribed if the patients cannot use other preventive treatments.

R E F E R E N C E

1. Suissa S, Dennis R, Ernst P, Sheehy O, Wood-Dauphinee S. Effectiveness of the leukotriene receptor antagonist zafirlukast for mild-to-moderate asthma. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1997;126:177-83.

NEW FORMULATIONS

Alprostadil

MUSE (Astra)

urethral delivery system containing 125 microgram, 250 microgram, 500 microgram and 1000 microgram

Approved indication: erectile dysfunction

Australian Medicines Handbook Section 13.3

Until the approval of sildenafil in 1998, the most effective drug treatment for erectile dysfunction was prostaglandin E₁ (alprostadil) (see `The management of erectile dysfunction' Aust Prescr 1998;21:46-8). This treatment had the disadvantage of having to be given by intracavernosal injection. The same effect can now be achieved by inserting this new formulation into the urethra.

When practitioners consider prescribing the new formulation, they will still need to instruct patients how to use it. Patients must urinate before inserting the alprostadil pellet. If the detailed instructions are followed, the drug is quickly absorbed through the urethral mucosa.

A starting dose of 250 micrograms is recommended. If this is ineffective, the dose can be increased on a later occasion; no more than two doses can be given in 24 hours.

Penile pain is a common adverse effect and urethral bleeding occurs in 5% of patients. Priapism is infrequent. Although alprostadil is not contraindicated for patients with cardiovascular disease, it can cause hypotension.

A condom must be used during intercourse with a pregnant woman because of the effect of alprostadil on the uterus.

Although it can be expected to work more quickly than oral sildenafil, this product is more difficult to use. It may have a role in patients who require drug treatment, but cannot take sildenafil, for whom it is contraindicated or does not work.