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New drugs
(Aust Prescr 1994;17:87-90)
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 pharmacokinetics may 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 Candida albicans. It has been approved for use in pityriasis versicolor unresponsive to other therapy and cases of superficial dermatomycoses, vulvovaginal candidiasis and fungal keratitis which have failed to respond to topical treatment. In immunocompromised patients, itraconazole has been approved for the treatment of oral candidiasis. The recommended duration of treatment varies from 3 days for vulvovaginal candidiasis to at least 4 weeks in immunocompromised patients with oral candidiasis.
Whether itraconazole is more effective than ketoconazole is uncertain, but it is thought to be less toxic.1 Nevertheless, 15% of patients treated with itraconazole will experience an adverse reaction. These reactions are mostly gastrointestinal, but itraconazole can produce hypertension, hypokalaemia and ankle oedema probably due to an effect on the adrenal glands.
Interacting drugs which require itraconazole to be prescribed with additional caution include digoxin, phenytoin, H 2 antagonists, warfarin, isoniazid, rifampicin, norethisterone and oral hypoglycaemic drugs. ltraconazole should not be prescribed with astemizole or terfenadine because of the potential for cardiac arrhythmias.
R E F E R E N C E
1. Dismukes WE. Azole antifungal drugs: old and new. Ann Intern 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 is caused by raised intraocular pressure and can lead to blindness. Beta adrenergic antagonists are one option for treating glaucoma. They are thought to act by reducing the production of aqueous humour and have an advantage over parasympathomimetic agents as they have less effect on pupil size. Levobunolol is an addition to the range of beta blockers suitable for ophthalmic use.
It has been approved for the control of intraocular pressure in chronic open angle glaucoma and ocular hypertension and the treatment of acutely elevated intraocular pressure following laser capsulotomy and extra-capsular cataract extraction.
Systemic adverse effects can result from the use of eye drops containing beta blockers. Levobunolol is therefore contraindicated in patients with conditions such 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 available in Australia through the Special Access Scheme. It inhibits the muscarinic actions of acetylcholine and has antispasmodic effects on smooth muscle. The drug can be considered for the treatment of conditions such as urge incontinence1, where there is detrusor instability which has failed to respond to behavioural interventions.
There is extensive first pass metabolism so the oral bioavailability is only 6%.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, gradually increasing as necessary to control symptoms.2 The drug is more effective than placebo, but may not have a significant advantage over other 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 the elderly.
R E F E R E N C E S
1. Millard RJ. Uropharmacology in the management of incontinence. Aust Prescr 1992;15:66-9.
2. Bent AE. Etiology and management of detrusor instability and mixed incontinence. Obstet Gynecol 1989;16:853-68.
6 mg/mL in 5 mL vials
Indication: ovarian cancer
This chemical is extracted from the bark of the Pacific yew tree (Taxus brevifolia). As it disrupts cell division, paclitaxel has been studied as an anticancer drug.
Paclitaxel is given by intravenous infusion and is rapidly distributed to the periphery. The half-life is 6-13 hours and elimination is thought to be mainly by liver metabolism.
The drug is approved for use in patients with metastatic ovarian carcinoma if standard therapy fails. Response rates in these patients are low and it is unknown if paclitaxel has any advantages over existing treatments.
Although paclitaxel is a 'natural' substance, it is cytotoxic and can cause serious adverse effects. Severe hypersensitivity can occur and all patients need premedication to cover this possibility; a corticosteroid, antihistamine and H2 antagonist are recommended. The dose-limiting toxicity is neutropenia which develops in approximately 70% of patients. Anaemia occurs in 90% of patients, but thrombocytopenia is less frequent. Approximately half of the patients will develop a peripheral neuropathy, although this usually improves after treatment is 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 basal ganglia. Patients who require treatment are often treated with levodopa, usually in combination with a decarboxylase inhibitor. During long-term therapy, complications can develop including a reduced responsiveness to levodopa. One approach to this problem is to introduce a drug which directly stimulates the dopamine receptors. One group of dopaminergic agonists are the ergolines e.g. bromocriptine.
Pergolide is an ergoline which is active at D1, and D2 receptors. Little is known about the pharmacokinetics of the drug as it is difficult to assay. The suppression of prolactin secretion has been used as an indicator of the drug's activity. 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 3 times a day.
Postural hypotension can occur, so it is important to begin treatment with a low dose. The dose is then increased every 3 days until an optimal level is 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 the dose, 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 during pergolide treatment.
There are no convincing data to show a clinical advantage for any particular dopaminergic agonist. Information from overseas shows that pergolide is much more expensive than bromocriptine. Therefore, pergolide will probably only be used as an adjunctive treatment when the effect of levodopa therapy has declined and the patient does not respond to bromocriptine.
Data on the use of pergolide with levodopa-benserazide combinations are limited and there is insufficient evidence to allow pergolide to be approved for use as 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 Mycobacterium tuberculosis strains are resistant to rifampicin. Rifabutin can also be used in the treatment of Mycobacterium avium-intracellulare complex (MAC) and other atypical mycobacteria. MAC is found in up to 50% of AIDS patients at autopsy, so rifabutin has also been approved for prophylaxis in patients with advanced HIV infection who have less than 200 CD4 cells/ microlitre.
Rifabutin is rapidly absorbed from the gut, but the absorption is incomplete and the bioavailability is less than 20%. The daily dose can be given at any time, independently of meals. After absorption, the drug is bound to plasma proteins and distributed widely with concentrations in the lung exceeding plasma concentration. Although rifabutin is metabolised with only 4% of the dose appearing as unchanged drug in the urine, it is recommended that the dose should be halved in patients with severe renal impairment. Rifabutin has a half-life of 35-40 hours.
Most of the patients studied in trials of rifabutin have also been taking other drugs, so attributing adverse reactions can be difficult. Rifabutin may be associated with arthralgia, myalgia, uveitis, changes in liver function, nausea and vomiting. Like rifampicin, rifabutin can cause an orange-red discolouration of the urine and body secretions. Contact lenses may become permanently stained. The frequency of adverse haematological reactions, such as leucopenia, may be increased by concurrent treatment with isoniazid. Full blood counts and liver function tests should be monitored during long-term multidrug treatments. Rifabutin induces the cytochrome P450 enzymes, so there is a potential for interactions with drugs metabolised by that system.
Risperidal (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 antipsychotic drugs. Risperidone is an antagonist at serotonin (5-HT2) and dopamine (D2) receptors. It also binds to alpha1 adrenoceptors, but has no affinity for cholinergic receptors.
Risperidone is well absorbed from the gut, even in the presence of food. The elimination 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 active metabolite. A twice daily dose is recommended. Although clinical data are lacking, the company advises halving the recommended dose in the elderly and in patients with hepatic or renal impairment.
The drug is more effective than placebo in the treatment of schizophrenia and has a similar efficacy to haloperidol.
As risperidone blocks alpha1 adrenoceptors, hypotension can occur and practitioners are advised to titrate the dose slowly over several days.
Blockade of D2 receptors by antipsychotics causes extrapyramidal adverse effects and stimulates prolactin release. 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 risperidone therapy 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 antihypertensive drugs. (In 1992-3, public expenditure on antihypertensive drugs, excluding beta blockers, exceeded $250 million.) It is unclear whether any of trandolapril's characteristics, e.g. a long duration of action, are significant advantages over the competition.
Trandolapril is rapidly absorbed and converted into trandolaprilat, an active metabolite. Trandolaprilat is highly lipophilic and is a potent inhibitor of angiotensin 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 days of single daily dosing. Elimination has a slow terminal phase, excretion of radiocarbon-labelled drug takes 7 days, but over 80% is eliminated within 2 days. Although trandolaprilat and its metabolites are mainly excreted in the faeces, dose reductions are required for patients with renal insufficiency as well as for those with liver disease.
The usual starting dose is 1 mg daily for patients with mild to moderate essential hypertension. 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 drug may 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 approximately 5% 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 to help reduce the nausea and vomiting associated with chemotherapy. Unfortunately, there is a dearth of comparative data to guide the prescriber in the selection of tropisetron or the previously marketed ondansetron (see 'New drugs' Aust Prescr 1991;14:70).
Anticancer treatments are believed to cause vomiting by triggering the release of serotonin from the gut. This acts on 5-HT3 receptors in the gut and brain stem so receptor antagonists will reduce the emetic effects of anticancer treatment.
Compared to an antiemetic 'cocktail' of drugs including metoclopramide, tropisetron is probably as effective in the control of acute vomiting, but less effective in controlling acute nausea, and delayed nausea and vomiting. However, the antiemetic 'cocktail' may cause more adverse effects than a single daily dose of tropisetron.
Oral tropisetron is rapidly absorbed from the gut, but its bioavailability varies due to saturation of first pass metabolism. The elimination of tropisetron may also vary between individuals as its metabolism can be influenced by polymorphism. About 8% of Caucasians are slow metabolisers and in these patients the elimination half-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% as unchanged drug and 70% as metabolites. In poor metabolisers, a greater proportion of unchanged drug is excreted. Higher plasma concentrations can be expected in patients with impaired renal function.
Tropisetron appears to be well tolerated. The most frequently reported adverse effects 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 If a hypnotic is prescribed, it is usually a benzodiazepine. Zopiclone now offers an alternative as it is a non-benzodiazepine hypnotic.
Zopiclone is a cyclopyrrolone which binds to benzodiazepine receptors in the brain. It is rapidly absorbed reaching a peak plasma concentration within two hours. The drug is also rapidly eliminated by metabolism with a half-life of approximately 5 hours. The metabolites have little pharmacological activity.
Few adverse effects have been reported, but lighter sleep and anxiety can occur 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 of dependence is unknown. As the lack of data on dependence has been a cause for concern2, the drug is approved for short-term use (2-4 weeks) only.
R E F E R E N C E S
1. Mant A, Bearpark H. Management of insomnia. Aust Prescr 1990;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
