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New drugs
(Aust Prescr 1999;22:147-51)
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.
Campral (Alphapharm)
333 mg enteric-coated tablets
Approved indication: alcohol dependence
Australian Medicines Handbook Section 18.6
Patients with alcohol dependence often relapse after treatment. Although psychological interventions are important, new drugs such as naltrexone (see `New drugs' Aust Prescr 1999;22:45-6) can help maintain abstinence. Acamprosate has also been approved for the prevention of relapse after detoxification.
Like naltrexone, the precise mechanism of action of acamprosate is uncertain. It has a chemical structure similar to gamma-aminobutyric acid (GABA), so acamprosate may stimulate inhibitory neurotransmission.
Patients begin treatment as soon as possible after the withdrawal period. The tablets are taken three times a day, with the dose being adjusted for body weight. Acamprosate is contraindicated if hepatic or renal function is significantly impaired. The tablets are slowly absorbed even if taken without food. It takes a week to reach a steady state. Most of the small proportion of the dose which is absorbed is excreted unchanged in the urine.
In a clinical trial, 224 patients were given acamprosate and compared with 224 patients who took a placebo. The patients had not drunk alcohol for at least five days before starting treatment. Approximately 40% of the patients managed to continue treatment for a year. Of the 94 patients who had taken acamprosate for a year, 41 had been continuously abstinent. In the placebo group, only 16 of the 85 who completed treatment had been abstinent. In each group, 52 patients relapsed; most of the others were either lost to follow-up or stopped treatment.1
Not many patients withdrew from the studies of acamprosate because of adverse effects. More than 10% of patients will develop diarrhoea at the start of treatment. Less frequent adverse effects include rashes, abdominal pain and nausea and vomiting.
Although acamprosate can improve abstinence, its effects may decline with time. Of the 79 patients who completed 27 months of follow-up, only 27 remained abstinent.1 As the long-term benefits of acamprosate are unclear, it is important that it is only used as an adjunct to psychological and social treatments.
R E F E R E N C E
1. Whitworth AB, Fischer F, Lesch OM, Nimmerrichter A, Oberbauer H, Platz T, et al. Comparison of acamprosate and placebo in long-term treatment of alcohol dependence. Lancet 1996;347:1438-42.
Celebrex (Searle)
100 mg and 200 mg capsules
Approved indication: arthritis
Australian Medicines Handbook Section 15.1
Non-steroidal anti-inflammatory drugs act by inhibiting the enzyme cyclo-oxygenase (COX).1 This enzyme is required for the synthesis of prostaglandins and its activity increases in inflammation. It has two isoforms, COX-1 and COX-2, both of which are blocked to varying degrees by non-steroidal anti-inflammatory drugs. As COX-1 may produce protective prostaglandins in the stomach, its inhibition could be responsible for some of the adverse effects of the drugs. Celecoxib is much more selective for COX-2, so it may cause fewer adverse effects than the older drugs.
Patients with symptoms of rheumatoid arthritis take celecoxib in two divided doses. A single daily dose may be used in osteoarthritis. The drug is quickly absorbed. Although taking the capsules with food delays absorption, the bioavailability is increased. Celecoxib is metabolised in the liver by cytochrome P450 CYP2C9 so there is a potential for interactions with drugs such as fluconazole.
In studies lasting up to 12 weeks, celecoxib has reduced the pain of osteoarthritis more effectively than placebo. Trials, of up to 24 weeks, in patients with rheumatoid arthritis have found the efficacy of celecoxib to be similar to that of naproxen 500 mg twice daily.
The effect of celecoxib on the gut has been assessed by endoscopy. Gastric ulcers were seen significantly less frequently during treatment with celecoxib, than they were in patients taking naproxen or diclofenac. Celecoxib, however, is not free of gastrointestinal adverse effects. Dyspepsia, abdominal pain and diarrhoea occur more frequently than with placebo. In animal studies, COX-2 inhibitors retard ulcer healing.1
Most of the enzyme activity in platelets is COX-1, so celecoxib should have little effect on bleeding time. The potential of COX-2 inhibitors to cause fluid retention, renal impairment or hypertension is unknown. In clinical trials peripheral oedema occurred with equal frequency (2.1%) in patients taking celecoxib or naproxen. Celecoxib is not recommended for patients with aspirin-sensitive asthma.
The COX-2 inhibitors have the potential to replace non-steroidal anti-inflammatory drugs for the relief of arthritic symptoms. Whether or not they fulfil this potential will depend on their long-term safety. For example, will they cause fewer gastrointestinal haemorrhages than the non-steroidal anti-inflammatory drugs?
R E F E R E N C E
1. Hawkey CJ. COX-2 inhibitors. Lancet 1999;353:307-14.
Stocrin
(Merck Sharp & Dohme)
50 mg, 100 mg and 200 mg capsules
Approved indication: HIV infection
Australian Medicines Handbook Section 5.3.4
The treatment of HIV infection often requires the patient to take a combination of drugs several times a day.1 Efavirenz is a non-nucleoside reverse transcriptase inhibitor which only needs to be given once a day. After absorption the peak plasma concentration is reached in 3-5 hours, but efavirenz is eliminated slowly. It has a half-life of 40-55 hours with only 1% being excreted unchanged in the urine. Cytochrome P450 is involved in the metabolism of efavirenz and the drug induces liver enzymes. There is therefore a potential for interactions with many drugs including indinavir, cisapride, triazolam, rifampicin, macrolide antibiotics and oral contraceptives. Liver enzymes should be monitored in patients with liver disease.
There have been three main trials of efavirenz. They have involved untreated and previously treated patients.
One study of 450 patients compared the combination of zidovudine, lamivudine and indinavir with zidovudine, lamivudine and efavirenz, or indinavir and efavirenz. After 24 weeks the proportion of patients with reduced concentrations of HIV RNA was greatest for those who had taken the three-drug combination containing efavirenz.
Another trial, involving 184 patients, studied the addition of efavirenz or a placebo to a combination of indinavir and two nucleoside analogue reverse transcriptase inhibitors. After 24 weeks a greater proportion of the patients taking efavirenz had significantly less viral RNA.
The third trial studied efavirenz in combination with nelfinavir (a protease inhibitor). The 196 patients took two nucleoside reverse transcriptase inhibitors plus efavirenz or nelfinavir, or efavirenz and nelfinavir. After 24 weeks the CD4 count increased, but there were no significant differences between the treatment groups. The four-drug regimen produced the greatest proportion of patients with low concentrations of viral RNA.
The most common adverse effects of efavirenz are skin rashes. Although Stevens-Johnson syndrome has been reported, less than 2% of the patients in the clinical trials had to stop taking efavirenz because of skin rashes.
Patients also commonly develop symptoms related to the nervous system. These include dizziness, headache, insomnia, nightmares and altered concentration. Approximately 3% of patients in the trials stopped the drug because of these symptoms.
There is little information about viral resistance to efavirenz. It should never be used as monotherapy and is probably unlikely to work in patients who have developed resistance to nevirapine or delavirdine.
R E F E R E N C E
1. Smith D. New approaches in the treatment of HIV infection. Aust Prescr 1998;21:44-6.
Comtan (Novartis)
200 mg tablets
Approved indication: Parkinson's disease
Australian Medicines Handbook Section 16.2
Inhibitors of catechol-O-methyl transferase (COMT) reduce the metabolism of levodopa. This prolongs the clinical response to levodopa and may benefit patients with Parkinson's disease who experience symptoms as the levodopa wears off. The first of the COMT inhibitors was tolcapone (see `New drugs' Aust Prescr 1998;21:54) but it was withdrawn after some patients developed severe hepatic reactions.
Entacapone is taken with each dose of the patient's usual levodopa/dopa decarboxylase inhibitor. The dose of the patient's usual treatment should be reduced when entacapone is started. Patients taking levodopa/benserazide may need a greater reduction as entacapone increases the bioavailability of the combination. Entacapone has a bioavailability of 35% with extensive first-pass metabolism. Most of the drug is excreted as metabolites in the urine.
One study randomised 205 patients, treated with levodopa, to take entacapone or a placebo for 24 weeks. The amount of time patients had reduced symptoms (`on' time) was increased by 5% in those taking entacapone.1
Most of the adverse effects of entacapone are as a result of increased dopaminergic activity. For example, dyskinesia occurs in 25% of patients. During clinical trials gastrointestinal symptoms were another common reason for patients stopping treatment with entacapone. Patients may develop diarrhoea, abdominal pain, nausea and vomiting. The haemoglobin falls significantly in approximately 2% of patients. Entacapone can affect liver enzymes and there is not yet enough experience with the drug to be certain that it does not share tolcapone's problems.
Although entacapone is efficacious, its usefulness in practice will need further evaluation. Does add-on medication provide a greater benefit than simply increasing the dose of levodopa?
R E F E R E N C E
1. Parkinson Study Group. Entacapone improves motor fluctuations in levodopa-treated Parkinson's disease patients. Ann Neurol 1997;42:747-55.
Copaxone (Hoechst Marion Roussel)
vials containing 20 mg powder for reconstitution
Approved indication: multiple sclerosis
Australian Medicines Handbook Section 16.4.3
Multiple sclerosis has the features of an autoimmune disease. Two of the interferons are approved for treatment, but their mechanism of action is uncertain. This is also true of glatiramer which has been approved for the relapse-remitting type of multiple sclerosis.
Glatiramer is a mixture of polypeptides built from the amino acids, alanine, glutamine, lysine and tyrosine. This mixture reduces allergic encephalomyelitis in animals. Although glatiramer has been studied in clinical trials, there are no human pharmacokinetic data.
The largest study of glatiramer randomised 251 patients to take the drug or a placebo. These patients injected themselves once a day for two years. During this period, glatiramer reduced the mean relapse rate by 29%. This reduction increased to 32% when the trial was extended for several months. During the whole period of the study, 34% of the patients injecting glatiramer had no relapses compared to 25% of the placebo group. Neurological disability was more likely to improve in the patients taking glatiramer.1
In this trial, the most common adverse events were reactions at the injection site. Some patients developed chest pain and facial flushing. Reactive antibodies develop in all patients, but the antibody concentration declines with time. These antibodies do not seem to neutralise the drug.
Although the 29% reduction in relapse rate appears impressive, it is the difference between 1.19 (glatiramer) and 1.68 (placebo).1 The clinical significance of this reduction will require further study. The ability of glatiramer and the interferons to reduce the progression of multiple sclerosis also remains unclear.
R E F E R E N C E
1. Johnson KP, Brooks BR, Cohen JA, Ford CC, Goldstein J, Lisak RP, et al. Extended use of glatiramer acetate (Copaxone) is well tolerated and maintains its clinical effect on multiple sclerosis relapse rate and degree of disability. Neurology 1998;50:701-8.
Micardis (Boehringer Ingelheim)
Pritor (Glaxo Wellcome)
40 mg and 80 mg tablets
Approved indication: hypertension
Australian Medicines Handbook Section 6.4.5
Telmisartan adds to the choice of angiotensin receptor antagonists1 available in Australia. It is suitable for patients with mild to moderate hypertension who cannot tolerate other treatments.
Patients take telmisartan once a day. There is extensive first-pass metabolism so the bioavailability of a 40 mg dose is 40%. Less than 1% of the dose is excreted unchanged in the urine. The half-life is approximately 20 hours.
Blockade of the AT1 receptor reduces vascular resistance. This lowers the blood pressure, but it does not increase the pulse. The effect on blood pressure is slow and the full effect is not reached for 4-8 weeks. Orthostatic hypotension is uncommon.
Telmisartan has been compared with other antihypertensive drugs and placebo. In a comparison with enalapril, 278 elderly patients were treated for 26 weeks. Both drugs provided effective 24-hour control of blood pressure. The mean reductions in blood pressures were 22/12 for telmisartan and 20/11 for enalapril.2 An unpublished trial compared telmisartan and losartan. Although the treatment period was only six weeks, telmisartan had a greater effect on blood pressure. The mean reductions were 11/7 for telmisartan and 6/4 for losartan.
Telmisartan is generally well tolerated. In clinical trials the incidence of cough was approximately 1%. Diarrhoea and dyspepsia occur more frequently than with placebo.
Gastrointestinal adverse effects are more common in patients with a history of gastrointestinal problems.
In clinical trials patients have been treated with telmisartan and hydrochlorothiazide without causing significant problems. There is, however, an interaction with digoxin so digoxin concentrations should be checked when starting or changing the dose of telmisartan.
R E F E R E N C E S
1. Johnston CI. Angiotensin receptor antagonists for the treatment of hypertension. Aust Prescr 1998;21:95-7.
2. Karlberg BE, Lins LE, Hermansson K. Efficacy and safety of telmisartan, a selective AT1 receptor antagonist, compared with enalapril in elderly patients with primary hypertension. J Hypertens 1999;17:293-302.
Rezulin (Parke Davis)
200 mg and 400 mg tablets
Approved indication: type 2 diabetes
Australian Medicines Handbook Section 10.1
The drug treatment of non-insulin dependent diabetes aims at increasing insulin secretion or making the peripheral cells more sensitive to insulin.1 Although it has a different action to metformin, troglitazone also improves the cellular response to insulin.
In a placebo-controlled trial, six months treatment with troglitazone produced significant decreases in postprandial and fasting blood glucose concentrations.2 Adding troglitazone to treatment with a sulfonylurea, such as glibenclamide, can improve glycaemic control. Patients with type 2 diabetes who eventually require insulin may also benefit from the addition of troglitazone. In placebo-controlled studies, some patients taking troglitazone and insulin have been able to reduce their dose of insulin. There were improvements in the concentrations of blood glucose and HbA1c.
Troglitazone is taken once a day. Its absorption is increased by food so it should be taken with a meal. Troglitazone is completely metabolised with most of the metabolites being excreted in the faeces. An interaction with terfenadine and oral contraceptives suggests that troglitazone may induce CYP3A4. This raises the possibility of an interaction with other drugs metabolised by the enzyme e.g. triazolam, calcium channel blockers, HMG CoA reductase inhibitors and corticosteroids. There are no pharmacokinetic effects on digoxin or warfarin.
The drug is contraindicated in liver disease, but all patients should have their liver palpated and their liver function tests checked regularly. This is because severe idiosyncratic liver damage can occur. Although this is usually reversible, it has resulted in liver transplant or death on rare occasions. Concern about these hepatic adverse effects led to the withdrawal of troglitazone in the U.K. Troglitazone should therefore be used with extreme caution if prescribed with other drugs that can alter liver function e.g. HMG CoA reductase inhibitors.
Although troglitazone can be used in the U.S.A. with oral hypoglycaemic agents, its use in Australia will be more restricted. In Australia, the drug is only approved for patients with type 2 diabetes who require insulin. Troglitazone should only be considered if the patient's blood glucose is not controlled by insulin.
R E F E R E N C E S
1. Proietto J. The management of type 2 diabetes. Aust Prescr 1997;20:65-7.
2. Maggs DG, Buchanan TA, Burant CF, Cline G, Gumbiner B, Hsueh WA, et al. Metabolic effects of troglitazone monotherapy in type 2 diabetes mellitus. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1998;128:176-85.
NEW FORMULATIONS
Nicorette Inhaler (Pharmacia & Upjohn)
10 mg cartridge
NEW STRENGTHS
Rohypnol (Roche)
1 mg tablets
Stromectol (Merck Sharp & Dohme)
3 mg tablets
NEW COMBINATIONS
Ipratropium bromide/salbutamol sulfate
Combivent Metered Aerosol (Boehringer Ingelheim)
ipratropium bromide 21 microgram/salbutamol sulfate 120 microgram per actuation
NEW PROPRIETARY BRANDS
DBL Atenolol (Faulding)
50 mg tablets
Azamun (Douglas)
50 mg tablets
Carbium (Hexal)
200 mg tablets
Dinac (Douglas)
25 mg and 50 mg tablets
Vasocardol CD (Hoechst Marion Roussel)
180 mg and 240 mg modified-release capsules
Flecatab (Alphapharm)
100 mg tablets
Onco-Tain (Faulding)
1 g in 20 mL vials
Indahexal (Hexal)
2.5 mg tablets
Oestradiol/norethisterone acetate
Kliovance (Novo Nordisk)
tablets containing oestradiol 1 mg and norethisterone acetate 0.5 mg
Ranihexal (Hexal)
150 mg and 300 mg tablets
DBL Sotalol (Faulding)
160 mg tablet
