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.
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 intraocularpressure.1 The options include alpha adrenergicagonists which affect the flow of aqueous humour. Brimonidine is an alpha2 adrenergicagonist. As brimonidine has a selective action, the mydriasis seen with otheragonists does not occur.
The drops are instilled twice a day. While the half-life ofbrimonidine is 3 hours, its effect lasts for at least 12 hours. The absorbeddrug is metabolised by the liver and then excreted in the urine.
Clinical studies reveal that brimonidine reduces intraocular pressure by 4-6mmHg. Although this effect has been observed for up to a year of treatment,approximately 8% of patients discontinued brimonidine because their glaucomawas not controlled.
Compared with beta blocking eye drops, adrenergic agonistshave more adverse effects. Patients using brimonidine may complain that theireyes are red, burning or stinging and that their vision is blurred. In additionto other ocular adverse effects, including allergic reactions, the patientscan have systemic adverse effects such as dry mouth and dizziness. Blood pressuremay be reduced and palpitations have been reported.
The product information advises that, because of the preservativeused, 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 treatmentsfor glaucoma. Patients with soft contact lenses should not put them in untilat least 15 minutes after using brimonidine because the preservative may beabsorbed into the lens.
In view of the comparisons, brimonidine should only be prescribedas monotherapy for patients who cannot take beta blockers for their chronicopen angle glaucoma.
Reference
1. Goldberg I. The medical treatment of glaucoma.Aust Prescr 1993;16:34-7.
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 significantcytomegalovirus infections. In patients with AIDS, there is a risk of retinitiswhich may lead to blindness. Cytomegalovirus retinitis can be treated withganciclovir or foscarnet. Cidofovir provides another option.
Cidofovir is an analogue of cytosine. It is active againstherpes viruses including cytomegalovirus (CMV). Unlike ganciclovir, which isactivated by viral enzymes, cidofovir is converted by host enzymes. This mayslow the development of resistance.
A randomised controlled trial studied cidofovir in 48 patientswith AIDS and retinitis. The patients were either treated immediately or afterthe retinitis progressed. The median time to progression was 120 days in theimmediate treatment group and 22 days in the deferred treatment group.1 (Inpatients taking ganciclovir or foscarnet, the median time to progression isapproximately 50 days.)
In a study of patients who were intolerant of, or failed torespond to, ganciclovir or foscarnet, the median time to retinal progressionwas 115 days.
Cidofovir is infused once a week for two weeks. After thisinduction, maintenance treatment is given every two weeks. As nephrotoxicityis 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% ofpatients had to withdraw from clinical trials of the drug because of this nephrotoxicityor other adverse effects such as neutropenia. Patients may complain of asthenia,nausea, alopecia, rashes and fever. They may also have adverse reactions toprobenecid.
Cidofovir does delay the progression of retinitis due to CMVinfection; however, visual acuity may not significantly change. The drug hasan 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 effectivein practice.
Reference
1. Lalezari JP, Stagg RJ, Kuppermann BD,Holland GN, Kramer F, Ives DV, et al. Intravenous cidofovir for peripheralcytomegalovirus retinitis in patients with AIDS. Ann Intern Med 1997;126:257-63.
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 ischaemicevents such as myocardial infarction and stroke. Therefore, antiplatelet drugshave an important role in preventing these events.1 Clopidogrelis a new antiplatelet drug similar to ticlopidine. The platelet's glycoproteinreceptor for fibrinogen is affected because clopidogrel blocks the activationof platelets by adenosine diphosphate.
Clopidogrel has been compared with aspirin in a study of morethan 19 000 patients. The patients had a history of peripheral vascular disease,myocardial infarction or ischaemic stroke. They took either 325 mg aspirinand a placebo, or 75 mg clopidogrel and a placebo. The patients were followedup for approximately two years. The annual risk of death from vascular causeswas 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 statisticallysignificant.2 There was no difference in allcause mortality between the two treatments.
The once daily dose is quickly absorbed, but very little clopidogrelcan be detected in the plasma. This is because of extensive liver metabolism.As the main metabolite is inactive, it is thought that another unidentifiedmetabolite is responsible for inhibiting platelet activation. Half of eachdose is excreted in the urine, but a reduced dose is not required in the elderlyor in those with reduced renal function. Although half the dose is excretedin 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 comparedwith aspirin, there was a similar frequency of adverse reactions. More patientstaking clopidogrel complained of a rash or diarrhoea, but patients taking aspirinwere more likely to have gastrointestinal discomfort or bleeding. Four patientstaking clopidogrel have developed severe neutropenia. Compared with similarstudies of ticlopidine, clopidogrel appears to cause less neutropenia. Theoverall 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 bythis system, such as tolbutamide and phenytoin. Caution is needed when prescribingclopidogrel 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 morethan aspirin, the reduction is not the same in all patients. People with peripheralvascular disease had a big reduction in risk, while there was no reductionfor patients who had had a myocardial infarction.
If 1000 patients are treated for a year, aspirin will prevent19 major clinical events and clopidogrel will prevent 24. Given the low priceof aspirin, it will be interesting to see what the cost of purchasing the apparentadditional benefit of clopidogrel will be.
References
1. Lefkovits J. Recent advances in antiplatelettherapy. Aust Prescr1996;19:98-101.
2. CAPRIE Steering Committee. A randomised,blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemicevents (CAPRIE). Lancet 1996;348:1329-39.
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 ofthe relapsing-remitting type of multiple sclerosis. The structurally similarinterferon beta-1a has now been approved for the same indication. These interferonsare cytokines which act by altering the immune response, but their exact mechanismof action in multiple sclerosis is unknown.
The main trial of interferon beta-1a involved 158 patientswho were compared with 143 patients who were given a placebo. The patientswere given weekly injections for two years. At the end of the study, therehad been fewer exacerbations in the treated group. There was evidence thatthe progression of disability was slower in the treated group. Disability increasedin 22% of the treated group and 35% of the placebo group. Magnetic resonanceimaging 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 biologicaleffects 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 beforethe injection and for the next day. This is to counteract the flu-like symptomswhich occur in most patients. In addition to fever, chills and muscle aches,the risk of developing anaemia is also significantly greater for patients usingthe drug than for those given a placebo. Only 4% of the patients taking interferonbeta-1a in clinical trials had to withdraw because of adverse effects. Safetyand effectiveness have not been established beyond two years of therapy.
One of the problems with interferon beta-1b is the developmentof antibodies which may reduce its effectiveness. After two years, 22% of thepatients given interferon beta-1a had developed antibodies, but the effecton efficacy is unclear.
When interferon beta-1b was marketed, there was no evidenceof its effect on disability, whereas interferon beta-1a has been shown to havesome effect. The clinical importance of reducing exacerbations from 0.9 peryear to 0.6 per year will also have to be weighed against treatment costs.Overseas information suggests one month's treatment with interferon beta-1ais likely to be cheaper than with interferon beta-1b. When deciding which interferonto recommend, Australian prescribers will also have to consider that the recombinantinterferon beta-1a available here differs from that used in the clinical trials.
Reference
1. The Multiple Sclerosis CollaborativeResearch Group. Intramuscular interferon beta-1a for disease progression inrelapsing multiple sclerosis. Ann Neurol 1996;39:285-94.
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 themanagement of patients who have ceased using opioids and as part of a treatmentprogram for alcohol dependence. While naltrexone blocks the effects of opioids,e.g. injected heroin, its mechanism of action in alcohol-dependent patientsis unknown. In animals, opioid antagonists reduce alcohol consumption.
The main steps in the treatment of opioid addiction are detoxificationand maintenance of abstinence. Although naltrexone has been used in rapid detoxificationregimens, the evidence is not strong enough for this technique to be consideredto be more than experimental.1 Naltrexone's mainuse will therefore be in maintenance. By blocking opioid receptors, naltrexonestops the euphoric effects of heroin which may reduce the patient's desirefor the illicit drug.
A Cochrane review is investigating the effectiveness of naltrexonemaintenance as there are no data which clearly show a beneficial effect onthe rate of relapse. Patients must be motivated to comply with one of a varietyof treatment regimens, so it is best if the drug is part of a comprehensiverehabilitation program.
Great care is needed when starting treatment. The patientshould 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 productinformation recommends a naloxone challenge test if there is any doubt aboutthe patient's abstinence.
Patients need to be warned not to try to overcome the blockadeby taking large quantities of opioid; they may overdose. They should also beaware that their sensitivity to opioids may increase, so if they relapse aftertreatment, their `usual' dose may cause life-threatening adverse effects.
In the treatment of alcohol dependence, 50 mg naltrexone istaken daily for up to 12 weeks. In clinical trials, this regimen has producedbetter abstinence rates than placebo and reduced the risk of relapse. As withopioid maintenance treatment, patients must be motivated so naltrexone shouldonly be used as one part of a treatment program. Patients who drink heavilymay have abnormal liver function. If liver function tests are more than 3 timesnormal, it may be inappropriate to use naltrexone as the drug can damage theliver.
First-pass metabolism reduces the oral bioavailability ofnaltrexone to 40%. Extensive metabolism results in only 2% being excreted unchangedwith most of the metabolites appearing in the urine.
Commonly reported adverse events include nausea, headache,fatigue, insomnia and anxiety. Although depression and suicidal ideation havebeen reported, no causal link with naltrexone has been shown.
Reference
1. O'Connor PG, Kosten TR. Rapid and ultrarapidopioid detoxification techniques. JAMA 1998;279:229-34.
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, therange of quinolones has been expanded with the introduction of trovafloxacin.It acts like the other quinolones by inhibiting an enzyme essential in thereplication of bacterial DNA.
Two formulations are available. The tablets are taken oncea day, while the concentrate is diluted and then infused over one hour. Thisintravenous formulation contains alatrofloxacin which is the prodrug of trovafloxacin.Alatrofloxacin is used because it is more soluble than trovafloxacin. Someintravenous fluids, e.g. normal saline, are not suitable for diluting alatrofloxacin.
Trovafloxacin tablets have a bioavailability of 88%. Thisis not affected by food, but the tablets should not be taken with antacids.Morphine also reduces absorption. Trovafloxacin is widely distributed withconcentrations in some tissues exceeding those in the plasma. Half the doseis excreted unchanged, while the rest is metabolised and excreted mainly inthe faeces. The half-life is 11 hours, but the drug needs to be given onlyonce a day.
There is a broad spectrum of antibacterial activity includingboth Gram positive and Gram negative organisms. Susceptible organisms includestreptococci, staphylococci, Escherichia coli, Haemophilus influenzae, Moraxellacatarrhalis, Neisseria gonorrhoea, Pseudomonas aeruginosa and Chlamydiapneumoniae. This profile enables trovafloxacin to be used in a wide varietyof 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 treatmentbecause of adverse events. The common adverse events are dizziness, headacheand nausea. Trovafloxacin should be used cautiously in patients with neurologicaldisorders, including cerebral atherosclerosis, as seizures can occur. The drugshould be discontinued if a rash develops because of the risk of hypersensitivityreactions.
Trovafloxacin is not appropriate for common infections. Forexample, it should not be used to treat uncomplicated lower urinary tract infectionsunless resistance to other antibiotics has been proven. The quinolones areuseful drugs for organisms that may be difficult to eradicate e.g. Pseudomonasaeruginosa. Their use should therefore be restricted in order to slow thedevelopment of resistant bacteria. Although experience with trovafloxacin islimited, a possible advantage is its metabolism. There is minimal involvementof the cytochrome P450 system, so the potential for interactions with drugssuch as warfarin, cimetidine and theophylline may be reduced.
Accolate (Zeneca)
20 mg and 40 mg tablets
Approved indication: asthma
Australian Medicines Handbook Section 19.3
In patients with asthma, leukotrienes are associated withairways inflammation and smooth muscle constriction. Zafirlukast has been developedto counteract these effects by competing for the leukotriene receptors.
The drug is taken twice a day. Zafirlukast should not be takenwith meals as its bioavailability is reduced by 40%. Zafirlukast is extensivelymetabolised with most of the metabolites being excreted in the faeces. Althoughclearance 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-supportedstudies, 103 patients were given zafirlukast and compared with 43 patientsgiven a placebo. At the end of the study, the zafirlukast group had significantlymore days when they did not need their beta agonist inhalers and were freeof symptoms.1
This means that some patients with asthma will benefit fromtaking a preventive medication, but how does zafirlukast compare with otherforms of prevention? It is probably no more potent than inhaled steroids andits potential to allow a reduction in the dose of inhaled corticosteroids isuncertain.
Patients should not be suddenly switched from corticosteroidsto zafirlukast. There are occasional reports that reducing the dose of corticosteroidmay precipitate or exacerbate the Churg-Strauss syndrome (systemic eosinophilicvasculitis). Other adverse events observed during treatment with zafirlukastinclude headache, gastrointestinal upsets and altered liver function and elevatedcreatine phosphokinase.
Although zafirlukast has been approved for the treatment andprophylaxis of asthma in patients over 12 years of age, its main role willbe in prevention. Zafirlukast has no role in acute asthma attacks and has notbeen evaluated in unstable asthma. It can be used in patients whose asthmais not controlled by beta agonists. As zafirlukast has no clear advantage,it should probably only be prescribed if the patients cannot use other preventivetreatments.
Reference
1. Suissa S, Dennis R, Ernst P, SheehyO, Wood-Dauphinee S. Effectiveness of the leukotriene receptor antagonist zafirlukastfor mild-to-moderate asthma. A randomized, double-blind, placebo-controlledtrial. Ann Intern Med 1997;126:177-83.
NEW FORMULATIONS
MUSE (Astra)
urethral delivery system containing 125 microgram, 250 microgram, 500 microgram and 1000 microgramApproved indication: erectile dysfunction
Australian Medicines Handbook Section 13.3
Until the approval of sildenafil in 1998, the most effectivedrug treatment for erectile dysfunction was prostaglandin E1 (alprostadil)(see `The management of erectile dysfunction' AustPrescr 1998;21:46-8). This treatment had the disadvantage of having tobe given by intracavernosal injection. The same effect can now be achievedby 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 urinatebefore 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 thisis ineffective, the dose can be increased on a later occasion; no more thantwo doses can be given in 24 hours.
Penile pain is a common adverse effect and urethral bleedingoccurs in 5% of patients. Priapism is infrequent. Although alprostadil is notcontraindicated for patients with cardiovascular disease, it can cause hypotension.
A condom must be used during intercourse with a pregnant womanbecause of the effect of alprostadil on the uterus.
Although it can be expected to work more quickly than oralsildenafil, this product is more difficult to use. It may have a role in patientswho require drug treatment, but cannot take sildenafil, for whom it is contraindicatedor does not work.
The T-score (
) is explained in 'New drugs: transparency', Vol 30 No 1, Aust Prescr 2007;30:26-7.
