(Aust Prescr 2001;24:20-3)
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.
Zyban (Glaxo Wellcome)
150 mg sustained-release tablets
Approved indication: nicotine dependence
Australian Medicines Handbook Section 18.6.2
Bupropion is not a new drug. It was approved in the USA for the treatment of depression more than 10 years ago. The antidepressant effect probably involves the drug's action on neurotransmitters. These actions may also help smokers to quit; depressed smokers gave up smoking during the clinical trials of bupropion.
To study the usefulness of bupropion in assisting smoking cessation, 615 smokers were enrolled in a randomised placebo-controlled trial. All the participants were given counselling in addition to drug treatment. After seven weeks of treatment, 19% of the placebo group had given up smoking. In the bupropion group the success rate increased with the dose. Approximately 29% of those taking 100 mg daily gave up, compared with 39% of those taking 150 mg and 44% of those taking 300 mg. All the participants put on weight, but the least weight gain (1.5 kg) was in the patients taking the highest (300 mg) dose of bupropion.1
Bupropion has also been compared with nicotine patches. In this trial 244 people were randomised to take bupropion, 244 used a nicotine patch, 245 used both medications and 160 were given placebos. During the nine weeks of treatment the participants were also counselled. When the participants were reviewed after six months, 35% of the bupropion group had stopped smoking compared with 21% of those using the nicotine patch and 19% of the placebo group. In the combined treatment group, 39% had stopped smoking. Treatment with bupropion alone, or in combination with a nicotine patch, was significantly better than treatment with the patch alone.2
Patients begin bupropion when they are still smoking. They start with 150 mg once a day, and after three days they take 150 mg twice a day. Smoking should stop in the second week of treatment. If the patient is still smoking after seven weeks they are unlikely to benefit by continuing bupropion.
There is extensive first-pass metabolism and metabolism is the main method
of clearance. Less than 1% of the drug is excreted unchanged in the urine.
Bupropion is metabolised by cytochrome P450 2B6. Although clinical interactions
have not been studied, caution is needed when prescribing other drugs metabolised
by this system. The metabolism of bupropion may be altered by drugs such as
phenytoin and carbamazepine. There is a risk of seizures, so bupropion is contraindicated
in patients with epilepsy or other conditions which alter the seizure threshold.
The drug's effect on neurotransmitters may cause insomnia as an adverse effect.
In clinical trials 40% of patients complained of insomnia. Other complaints
included altered concentration, anxiety and dizziness. Some patients will experience
nausea and a dry mouth. Severe allergic reactions have also been reported.
In the comparative study2 approximately 12% of
the people taking bupropion stopped treatment because of its adverse effects.
As with other interventions for smoking, the effectiveness of bupropion declines with time. A year after the start of the placebo-controlled trial 23% of those given bupropion had not resumed smoking.1 In the comparative trial 30% of the bupropion group were still abstinent after one year.2
Bupropion has only been approved for short-term use by patients who are committed to stopping smoking. It should always be used in conjunction with counselling.
References
1. Hurt RD, Sachs DP, Glover ED, Offord KP, Johnston JA, Dale LC, et al. A comparison of sustained-release bupropion and placebo for smoking cessation. N Engl J Med 1997;337:1195-202.
2. Jorenby DE, Leischow SJ, Nides MA, Rennard SI, Johnston JA, Hughes AR, et al. A controlled trial of sustained-release bupropion, a nicotine patch, or both for smoking cessation. N Engl J Med 1999;340:685-91.
NovoRapid (Novo Nordisk)
100 IU/mL in 10 mL vials, 1.5 mL and 3 mL cartridges, and 1.5 mL and 3 mL prefilled
syringes
Approved indication: diabetes mellitus
Australian Medicines Handbook Section 10.1.1
Genetic engineering allows scientists to develop analogues of natural substances. Insulin aspart is an analogue of human insulin. The properties of the insulin molecule have been altered by the substitution of one amino acid.
Substituting aspartic acid for proline increases the rate of absorption of insulin after subcutaneous injection. This gives insulin aspart a rapid onset of action mimicking the physiological secretion of insulin. The effect begins within 20 minutes of an injection and reaches a peak within one to three hours, with a total duration of action of three to five hours. This effect gives better control of postprandial glucose concentrations than human insulin injected 30 minutes before a meal.1
In patients with type 1 diabetes, the reduction in glycated haemoglobin (HbA1c) was greater with insulin aspart than with soluble human insulin. Although the difference was significant it was small; the HbA1c was reduced by 0.12-0.16. In type 2 diabetes, insulin aspart also caused a greater reduction in HbA1c, but this was not statistically significant.
The adverse effects of insulin aspart are similar to those of soluble human insulin, but there are no long-term safety data. To reduce the risk of hypoglycaemia, insulin aspart should be injected immediately before a meal.
Reference
1. Lindholm A, McEwen J, Riis AP. Improved postprandial glycemic control with insulin aspart. A randomized double-blind cross-over trial in type 1 diabetes. Diabetes Care 1999;22:801-5.
Actonel (Aventis Pharma)
5 mg film-coated tablets
Approved indication: osteoporosis, Paget's disease
Australian Medicines Handbook Section 10.4.2
Bisphosphonates inhibit the resorption of bone by osteoclasts. By reducing the turnover of bone and increasing bone density the bisphosphonates can help patients with Paget's disease or osteoporosis.
Like the other bisphosphonates, risedronate is poorly absorbed. The bioavailability of the tablet is only 0.63% and this is reduced by food. Patients should only take the tablets with water. After absorption risedronate is distributed to bone. Although half the absorbed dose is excreted within 24 hours the elimination of the drug from bone is slow. The half-life is approximately 20 days.
Patients must take the tablets while they are standing. They should remain upright for at least 30 minutes. This helps to ensure the tablet reaches the stomach and does not irritate the oesophagus. Approximately 12% of patients will complain of abdominal pain. Other adverse events reported in clinical trials include arthralgia, itching, flu-like symptoms, diarrhoea and dizziness.
Risedronate is approved for several indications. There is evidence from clinical trials to support each indication.
More than 3500 women were randomised to take risedronate or a placebo for three years. The women enrolled in the trials had a history of vertebral fractures. Their fracture risk was reduced significantly by risedronate. In one study the cumulative frequency of new vertebral fractures after three years was 11% in patients taking risedronate and 16% in those taking a placebo. Compared to placebo, risedronate also increased bone density in the lumbar spine by 5%.1
Glucocorticoid-induced osteoporosis
When patients who are taking long-term corticosteroids are given risedronate, calcium and vitamin D, their bone density increases. Although they are statistically significant, these increases are small. After a year of treatment the mean increase, compared to placebo, was 2.4% in the femoral trochanter and 2.7% in the lumbar spine.
Risedronate has also been given to patients who had recently started corticosteroids. This prevented the bone loss seen in patients who were only given calcium supplements.
In Paget's disease bone resorption and formation are increased. Compared with osteoporosis, a higher dose is needed to control the activity of the disease. This activity can be assessed by measuring the serum alkaline phosphatose.
One study compared the effect of taking risedronate for two months with taking etidronate for six months. After 12 months, the concentrations of alkaline phosphatase were normal in 73% of the patients taking risedronate, but in only 15% of those taking etidronate. Relapses were less common in the risedronate group. After 18 months, 53% of the group were still in remission compared with only 14% of the etidronate group. Risedronate also produced significant reductions in bone pain.2
Although risedronate has an advantage over etidronate so do other oral bisphosphonates such as alendronate and tiludronate. Further studies are needed to find the best bisphosphonate and to assess the safety of long-term treatment.
References
1. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis. JAMA 1999;282:1344-52.
2. Miller PD, Brown JP, Siris ES, Hoseyni MS, Axelrod DW, Bekker PJ. A randomised, double-blind comparison of risedronate and etidronate in the treatment of Paget's disease of bone. Am J Med 1999;106:513-20.
Avandia (SmithKline Beecham)
4 mg and 8 mg film-coated tablets
Approved indication: type 2 diabetes
Australian Medicines Handbook Section 10.1
Rosiglitazone is the second drug of its class to be approved for use in Australia. It has wider indications than troglitazone, the first drug to be approved (see 'New drugs' Aust Prescr 1999;22:150). Rosiglitazone can be prescribed when a patient's blood glucose is not controlled by diet. It can also be used in combination with metformin and sulfonylureas.
Like troglitazone, rosiglitazone reduces insulin resistance. Although reductions in fasting blood glucose occur soon after starting treatment, the full effect on insulin sensitivity is not seen for six to eight weeks. The starting dose of 4 mg daily may be increased to 8 mg daily after this interval.
The tablets can be taken once or twice daily. They are completely absorbed and have a bioavailability of 99%. Rosiglitazone is completely metabolised by the liver. Cytochrome P450 2C8 is the main enzyme involved. The drug is not recommended for people with liver disease. Most of the metabolites are excreted in the urine, but a dose reduction is not required if there is renal impairment.
There are not many published clinical trials of rosiglitazone. A 26-week study of 493 patients with type 2 diabetes found that a twice-daily dose of 2 mg or 4 mg reduced glycated haemoglobin (HbA1c) by 0.9-1.5% more than placebo. Twice-daily doses appeared to have greater efficacy than once daily.
Rosiglitazone was as effective as glibenclamide in reducing HbA1c in a comparative study. After a year, HbA1c was reduced 0.7% by glibenclamide and 0.5% by rosiglitazone 4 mg twice daily. The HbA1c of patients given 2 mg rosiglitazone twice daily fell by only 0.3%, but both doses of rosiglitazone had a greater effect on fasting plasma glucose than glibenclamide did.
Other trials have studied the use of rosiglitazone in combination with metformin or sulfonylureas. The combinations usually improve glycaemic control more than monotherapy. For example, adding rosiglitazone 4 mg twice daily to metformin will reduce HbA1c by 0.8% more than metformin alone.
In the clinical trials rosiglitazone was generally well tolerated. Some patients will develop fluid retention so there is a risk of precipitating heart failure. Rosiglitazone increases LDL and HDL cholesterol and can cause anaemia.
The first drug of this class, troglitazone, was withdrawn following reports of hepatic toxicity. Although only 0.2% of patients taking rosiglitazone have had hepatic adverse events, there is a concern that the toxicity may be a class effect. Patients should therefore have their liver function checked before treatment and every two months during the first year of therapy, then periodically thereafter. Rosiglitazone has not been approved for use in Europe and an American consumer drug bulletin has advised its readers not to use rosiglitazone for five years.1
Reference
1. Health Research Group. The new diabetes drug rosiglitazone (Avandia) rejected by European regulators. Worst Pills Best Pills 1999;12:93-4.
Stilnox (Sanofi Synthelabo)
10 mg tablets
Approved indication: insomnia
Australian Medicines Handbook Section 18.4.2
Zolpidem acts on benzodiazepine receptors. Although it has a different structure and is said to be more selective in its action, zolpidem has similar effects to the benzodiazepines.
The drug is rapidly absorbed and peak plasma levels are reached within 3 hours. First-pass metabolism reduces bioavailability to 70%. The liver also eliminates most of the drug with only 1% appearing unchanged in the urine. A lower dose is recommended for the elderly and patients with hepatic impairment. Zolpidem has a half-life of two hours, but its hypnotic effect can last up to 6 hours.
In clinical trials, zolpidem has been more effective than placebo in treating chronic insomnia, but does not appear to have any advantage over temazepam.
Adverse effects caused 4% of patients in clinical trials to discontinue zolpidem. These effects included dizziness, headache, nausea and daytime drowsiness. Dizziness was the most common adverse effect reported in patients taking zolpidem for 28-35 nights. All patients should be warned of the possible risk of feeling drowsy the morning after taking zolpidem. The drug interacts with others, such as alcohol, which depress the central nervous system.
Patients complaining of insomnia need to be assessed to exclude underlying causes such as depression. Often insomnia does not require drug treatment. If a patient is prescribed zolpidem, they should take it for less than 4 weeks. The potential for withdrawal, tolerance or rebound insomnia is uncertain. Higher doses should not be used because, like other benzodiazepines, they have been associated with amnesia.
NEW FORMULATIONS
MS Mono (Mundipharma)
30 mg, 60 mg, 90 mg and 120 mg capsules
Viramune (Boehringer Ingelheim)
10 mg/mL suspension
Rapilysin (Roche)
0 U powder for injection
NEW STRENGTHS
Cardizem CD (Aventis Pharma)
360 mg modified-release capsules
Femtran 25 and Femtran 75 (3M Pharmaceuticals)
2 mg and 5.7 mg transdermal patches
NEW COMBINATIONS
Enalapril maleate/hydrochlorothiazide
Renitec Plus 20/6 (Merck Sharp & Dohme)
20 mg enalapril maleate/6 mg hydrochlorothiazide tablets
NEW PROPRIETARY BRANDS
GenRx Cefaclor CD (Faulding)
375 mg sustained-release tablets
GenRx Ipratropium (Faulding)
250 microgram/mL solution for inhalation
