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.
Sporanox (Janssen-Cilag)
100 mg capsules
Indication: specified fungal infections
Itraconazole is a triazole which inhibits the synthesis of fungal cell membranes.It is best absorbed after food, but bioavailability varies. The pharmacokineticsmay be non-linear due to a saturation of metabolism.
The drug is highly protein bound with only 0.2% circulating as free drug.The concentration in the skin is usually higher than the plasma concentration.ltraconazole is extensively metabolised by the liver to inactive metabolites.The elimination half-life may increase with repeated dosing to over 24 hours.
Itraconazole is effective against superficial dermatophytes and Candidaalbicans. It has been approved for use in pityriasis versicolor unresponsiveto other therapy and cases of superficial dermatomycoses, vulvovaginal candidiasisand fungal keratitis which have failed to respond to topical treatment. Inimmunocompromised patients, itraconazole has been approved for the treatmentof oral candidiasis. The recommended duration of treatment varies from 3days for vulvovaginal candidiasis to at least 4 weeks in immunocompromisedpatients with oral candidiasis.
Whether itraconazole is more effective than ketoconazole is uncertain, butit is thought to be less toxic.1 Nevertheless, 15% of patientstreated with itraconazole will experience an adverse reaction. These reactionsare mostly gastrointestinal, but itraconazole can produce hypertension, hypokalaemiaand ankle oedema probably due to an effect on the adrenal glands.
Interacting drugs which require itraconazole to be prescribed with additionalcaution include digoxin, phenytoin, H 2 antagonists, warfarin, isoniazid, rifampicin,norethisterone and oral hypoglycaemic drugs. ltraconazole should not be prescribedwith astemizole or terfenadine because of the potential for cardiac arrhythmias.
Reference
1. Dismukes WE. Azole antifungal drugs: old and new. AnnIntern Med 1988;109:177-9.
Betagan (Allergan)
2.5 mg/mL and 5 mg/mL eye drops
Indication: reduction of elevated intraocular pressure
Glaucoma affects approximately 1-2% of people over 60 years of age. It iscaused by raised intraocular pressure and can lead to blindness. Beta adrenergicantagonists are one option for treating glaucoma. They are thought to act byreducing the production of aqueous humour and have an advantage over parasympathomimeticagents as they have less effect on pupil size. Levobunolol is an addition tothe range of beta blockers suitable for ophthalmic use.
It has been approved for the control of intraocular pressure in chronic openangle glaucoma and ocular hypertension and the treatment of acutely elevatedintraocular pressure following laser capsulotomy and extra-capsular cataractextraction.
Systemic adverse effects can result from the use of eye drops containing betablockers. Levobunolol is therefore contraindicated in patients with conditionssuch as asthma.
Ditropan (Fisons)
5 mg tablets
Indication: detrusor overactivity
Although there is little evidence of efficacy from controlled clinical trials,oxybutynin has been marketed overseas for many years and has been availablein Australia through the Special Access Scheme. It inhibits the muscarinicactions of acetylcholine and has antispasmodic effects on smooth muscle. Thedrug can be considered for the treatment of conditions such as urge incontinence1,where there is detrusor instability which has failed to respond to behaviouralinterventions.
There is extensive first pass metabolism so the oral bioavailability is only6%.The drug is rapidly eliminated with a half-life of less than 2 hours.
Oxybutynin therapy can begin with a dose of 2.5-5mg twice a day, graduallyincreasing as necessary to control symptoms.2 The drug ismore effective than placebo, but may not have a significant advantage overother anticholinergic drugs such as propantheline.
The usefulness of the drug may be limited by its atropine-like adverse effects.Elderly patients in particular may be prone to constipation, urinary retention,blurred vision, dry mouth and dizziness. A low dose is recommended for theelderly.
References
1. Millard RJ. Uropharmacology in the management ofincontinence. Aust Prescr 1992;15:66-9.
2. Bent AE. Etiology and management of detrusor instabilityand mixed incontinence. Obstet Gynecol 1989;16:853-68.
Indication: ovarian cancer
This chemical is extracted from the bark of the Pacific yew tree (Taxus brevifolia). Asit disrupts cell division, paclitaxel has been studied as an anticancer drug.
Paclitaxel is given by intravenous infusion and is rapidly distributed tothe periphery. The half-life is 6-13 hours and elimination is thought to bemainly by liver metabolism.
The drug is approved for use in patients with metastatic ovarian carcinomaif standard therapy fails. Response rates in these patients are low and itis unknown if paclitaxel has any advantages over existing treatments.
Although paclitaxel is a 'natural' substance, it is cytotoxic and can causeserious adverse effects. Severe hypersensitivity can occur and all patientsneed premedication to cover this possibility; a corticosteroid, antihistamineand H2 antagonist are recommended. The dose-limiting toxicity is neutropeniawhich develops in approximately 70% of patients. Anaemia occurs in 90% of patients,but thrombocytopenia is less frequent. Approximately half of the patients willdevelop a peripheral neuropathy, although this usually improves after treatmentis discontinued. Other adverse reactions include alopecia, hypotension, bradycardia,nausea and vomiting.
More study is required to define the clinical use of paclitaxel.
Permax (Eli Lilly)
0.05 mg, 0.25 mg and 1 mg tablets
Indication: adjunct to levodopa therapy in Parkinson's disease
Parkinson's disease is associated with a deficiency of dopamine in the basalganglia. Patients who require treatment are often treated with levodopa, usuallyin combination with a decarboxylase inhibitor. During long-term therapy, complicationscan develop including a reduced responsiveness to levodopa. One approach tothis problem is to introduce a drug which directly stimulates the dopaminereceptors. One group of dopaminergic agonists are the ergolines e.g. bromocriptine.
Pergolide is an ergoline which is active at D1, and D2 receptors. Little isknown about the pharmacokinetics of the drug as it is difficult to assay. Thesuppression of prolactin secretion has been used as an indicator of the drug'sactivity. A single dose will inhibit prolactin secretion for at least 24 hours,but any clinical benefits are not so prolonged. Usually the drug is taken 3times a day.
Postural hypotension can occur, so it is important to begin treatment witha low dose. The dose is then increased every 3 days until an optimal levelis reached. It may then be possible to reduce the concurrent dose of levodopa.The response to pergolide may decline with time requiring an increase in thedose, but the long-term efficacy of doses over 5 mg/day has not been evaluated.
Dopaminergic agonists can cause hallucinations, confusion, nausea and vomiting.Liver function and white blood cell counts should be monitored before and duringpergolide treatment.
There are no convincing data to show a clinical advantage for any particulardopaminergic agonist. Information from overseas shows that pergolide is muchmore expensive than bromocriptine. Therefore, pergolide will probably onlybe used as an adjunctive treatment when the effect of levodopa therapy hasdeclined and the patient does not respond to bromocriptine.
Data on the use of pergolide with levodopa-benserazide combinations are limitedand there is insufficient evidence to allow pergolide to be approved for useas sole therapy in Parkinson's disease.
Mycobutin (Pharmacia)
150 mg capsules
Indication: specified infections
Rifabutin is related to rifampicin and therefore has activity against mycobacteria.It has been approved for use in cases of pulmonary tuberculosis where the Mycobacteriumtuberculosis strains are resistant to rifampicin. Rifabutin can also be usedin the treatment of Mycobacterium avium-intracellulare complex (MAC)and other atypical mycobacteria. MAC is found in up to 50% of AIDS patientsat autopsy, so rifabutin has also been approved for prophylaxis in patientswith advanced HIV infection who have less than 200 CD4 cells/ microlitre.
Rifabutin is rapidly absorbed from the gut, but the absorption is incompleteand the bioavailability is less than 20%. The daily dose can be given at anytime, independently of meals. After absorption, the drug is bound to plasmaproteins and distributed widely with concentrations in the lung exceeding plasmaconcentration. Although rifabutin is metabolised with only 4% of the dose appearingas unchanged drug in the urine, it is recommended that the dose should be halvedin patients with severe renal impairment. Rifabutin has a half-life of 35-40hours.
Most of the patients studied in trials of rifabutin have also been takingother drugs, so attributing adverse reactions can be difficult. Rifabutin maybe associated with arthralgia, myalgia, uveitis, changes in liver function,nausea and vomiting. Like rifampicin, rifabutin can cause an orange-red discolourationof the urine and body secretions. Contact lenses may become permanently stained.The frequency of adverse haematological reactions, such as leucopenia, maybe increased by concurrent treatment with isoniazid. Full blood counts andliver function tests should be monitored during long-term multidrug treatments.Rifabutin induces the cytochrome P450 enzymes, so there is a potential forinteractions with drugs metabolised by that system.
Risperdal (Janssen-Cilag)
1 mg, 2 mg, 3 mg and 4 mg film-coated tablets
Indication: schizophrenia
Benzisoxazole derivatives such as risperidone represent a new class of antipsychoticdrugs. Risperidone is an antagonist at serotonin (5-HT2) and dopamine (D2)receptors. It also binds to alpha1 adrenoceptors, but has no affinity for cholinergicreceptors.
Risperidone is well absorbed from the gut, even in the presence of food. Theelimination half-life depends on whether the patient is an extensive (3 hours)or a poor (19 hours) metaboliser (8% of the Causasian population are poor metabolisers).The metabolism is partly carried out by cytochrome P450 and produces an activemetabolite. A twice daily dose is recommended. Although clinical data are lacking,the company advises halving the recommended dose in the elderly and in patientswith hepatic or renal impairment.
The drug is more effective than placebo in the treatment of schizophreniaand has a similar efficacy to haloperidol.
As risperidone blocks alpha1 adrenoceptors, hypotension can occurand practitioners are advised to titrate the dose slowly over several days.
Blockade of D2 receptorsby antipsychotics causes extrapyramidal adverse effects and stimulates prolactinrelease. Risperidone may cause fewer extrapyramidal symptoms than other drugs,but the elevation of prolactin can cause amenorrhoea.
Other adverse effects include insomnia, lethargy, headache and sexual dysfunction.In clinical trials, approximately 7% of the patients had to cease risperidonetherapy because of adverse effects.
Odrik (Roussel Uclaf Australia)
0.5 mg, 1 mg and 2 mg capsules
Indication: hypertension
Trandolapril is a new entrant into the important market of antihypertensivedrugs. (In 1992-3, public expenditure on antihypertensive drugs, excludingbeta blockers, exceeded $250 million.) It is unclear whether any of trandolapril'scharacteristics, e.g. a long duration of action, are significant advantagesover the competition.
Trandolapril is rapidly absorbed and converted into trandolaprilat, an activemetabolite. Trandolaprilat is highly lipophilic and is a potent inhibitor ofangiotensin converting enzyme (ACE). One day after a single 2 mg dose, 80%of ACE activity will remain inhibited. A steady state is reached after 4 daysof single daily dosing. Elimination has a slow terminal phase, excretion ofradiocarbon-labelled drug takes 7 days, but over 80% is eliminated within 2days. Although trandolaprilat and its metabolites are mainly excreted in thefaeces, dose reductions are required for patients with renal insufficiencyas well as for those with liver disease.
The usual starting dose is 1 mg daily for patients with mild to moderate essentialhypertension. A lower dose is used if the patient has been taking a diuretic.Trandolapril lowers blood pressure, probably as effectively as other ACE inhibitors,with a maximum response after 2-4 weeks. If no response occurs, another drugmay be added or the dose can be increased.
Trandolapril can cause the same adverse effects as other ACE inhibitors e.g.first dose hypotension, angioedema, hyperkalaemia. Cough occurred in approximately5% of patients involved in long-term studies.
Navoban(Sandoz)
5 mg capsules
1 mg/1 mL in 5 mL ampoules
Indication: prevention of nausea and vomiting
Oncologists now have a choice of serotonin (5-HT3) receptor antagonists tohelp reduce the nausea and vomiting associated with chemotherapy. Unfortunately,there is a dearth of comparative data to guide the prescriber in the selectionof tropisetron or the previously marketed ondansetron (see 'New drugs' AustPrescr 1991;14:70).
Anticancer treatments are believed to cause vomiting by triggering the releaseof serotonin from the gut. This acts on 5-HT3 receptors in the gut and brainstem so receptor antagonists will reduce the emetic effects of anticancer treatment.
Compared to an antiemetic 'cocktail' of drugs including metoclopramide, tropisetronis probably as effective in the control of acute vomiting, but less effectivein controlling acute nausea, and delayed nausea and vomiting. However, theantiemetic 'cocktail' may cause more adverse effects than a single daily doseof tropisetron.
Oral tropisetron is rapidly absorbed from the gut, but its bioavailabilityvaries due to saturation of first pass metabolism. The elimination of tropisetronmay also vary between individuals as its metabolism can be influenced by polymorphism.About 8% of Caucasians are slow metabolisers and in these patients the eliminationhalf-life may be 45 hours compared with 8 hours in extensive metabolisers.In extensive metabolisers, most of the dose is excreted in the urine - 8% asunchanged drug and 70% as metabolites. In poor metabolisers, a greater proportionof unchanged drug is excreted. Higher plasma concentrations can be expectedin patients with impaired renal function.
Tropisetron appears to be well tolerated. The most frequently reported adverseeffects are headache, constipation, diarrhoea and fatigue.
Imovane (Rhone-Poulenc Rorer)
7.5 mg film-coated tablets
Indication: insomnia
Drugs are not the first-line treatment of insomnia.1 Ifa hypnotic is prescribed, it is usually a benzodiazepine. Zopiclone now offersan alternative as it is a non-benzodiazepine hypnotic.
Zopiclone is a cyclopyrrolone which binds to benzodiazepine receptors in thebrain. It is rapidly absorbed reaching a peak plasma concentration within twohours. The drug is also rapidly eliminated by metabolism with a half-life ofapproximately 5 hours. The metabolites have little pharmacological activity.
Few adverse effects have been reported, but lighter sleep and anxiety canoccur when the drug is withdrawn. Common adverse effects are bitter taste,dry mouth, drowsiness, headaches and fatigue.
Zopiclone is as effective as the benzodiazepine hypnotics, but the risk ofdependence is unknown. As the lack of data on dependence has been a cause forconcern2, the drug is approved for short-term use (2-4 weeks)only.
References
1. Mant A, Bearpark H. Management of insomnia. Aust Prescr1990;13:51-4.
2. Zopiclone: another carriage on the tranquilliser train[editorial]. Lancet 1990;335:507-8.
NEW FORMULATIONS
EMLA Patch (Astra)
self-adhesive patch containing 25 mg lignocaine and 25 mg prilocaine
Adalat OROS (Bayer)
30 mg and 60 mg controlled release tablets
Kapanol (Glaxo)
20 mg, 50 mg and 100 mg modified release capsules
Orudis (Rhone-Poulenc Rorer)
2.5% gel
The T-score (
) is explained in 'New drugs: transparency', Vol 32 No 3, Aust Prescr 2009;32:80-1.
