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New drugs
(Aust Prescr 1999;22:95-8)
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.
Simulect (Novartis Pharmaceuticals)
vials containing 20 mg as lyophilised powder
Approved indication: organ transplant
Australian Medicines Handbook Section 14.1.4
Episodes of acute rejection occur in 30-50% of patients after a renal allograft. This rejection involves T lymphocytes which are specific for the antigens on the donor kidney. The signal for the proliferation of T cells is the binding of the cytokine interleukin-2 to its receptor on the surface of the lymphocyte. Basiliximab is a chimeric (mouse/human) monoclonal antibody which acts as an immunosuppressant by blocking the interleukin-2 receptor.
The antibody is given intravenously two hours before transplant surgery and 4 days afterwards. This suppresses the immune response for 4-6 weeks. The half-life of basiliximab is approximately one week.
Basiliximab has been studied in trials which investigated if it had any additional effect on patients given cyclosporin and steroids. One study randomised 193 renal transplant patients to receive basiliximab and 187 to be given a placebo. Acute rejection occurred in 51 of the patients given basiliximab and in 73 of the placebo group. There was also a significantly lower incidence of steroid-resistant rejection episodes which required antibody therapy in the patients given basiliximab.1
In patients taking a combination of immunosuppressant drugs, it can be difficult to attribute adverse effects to one particular drug. Data from the 363 patients given basiliximab in clinical trials show that the pattern of adverse reactions is similar to that seen in the 359 patients given a placebo. The commonly reported adverse events in the trials included nausea, constipation, pain and urinary tract infection. Some patients will develop antibodies e.g. human anti-mouse antibodies. Post-transplant lymphoproliferative disorders have also been reported.
The evidence is that basiliximab is efficacious at reducing graft rejection in the first 6 months. After a year, however, there is no difference in graft survival. As other drugs such as tacrolimus and mycophenolate are now available for use in transplant patients, further research will be needed to determine the best regimens for allograft recipients.
R E F E R E N C E
1. CHIB 201 International Study Group. Randomised trial of basiliximab versus placebo for control of acute cellular rejection in renal allograft recipients. Lancet 1997;350:1193-8.
Xeloda (Roche)
150 mg and 500 mg tablets
Approved indication: breast cancer
Australian Medicines Handbook Section 14.1.3
Drug treatment has an increasing role in the management of breast cancer.1 New drugs for breast cancer are usually first used when all else fails. Capecitabine may be indicated for women with locally advanced or metastatic breast cancer after an anthracycline-containing regimen and paclitaxel have failed.
After capecitabine is absorbed from the gut, it is converted to the active cytotoxic 5-fluorouracil (5FU). One of the enzymes involved in the conversion is more concentrated in tumours than normal tissues. The metabolism of 5FU damages cells, especially those which are rapidly proliferating. Most of a dose is excreted as metabolites in the urine. Capecitabine and 5FU both have a half-life under one hour, but only two doses a day are needed. Patients take the drug for two weeks, then have a week's rest. The dose is adjusted according to its toxicity.
Diarrhoea, nausea and vomiting are the most common adverse effects of capecitabine. Approximately 45% of patients develop a hand and foot syndrome. There is peripheral numbness, paraesthesia, erythema, swelling and blistering. If these symptoms are severe, treatment should be interrupted. Other adverse effects include stomatitis, fatigue and abdominal pain.
There has only been one large uncontrolled clinical trial of capecitabine. Most of the 162 patients were resistant or had failed previous treatment; 82% had already been exposed to 5FU. There were only 3 complete responses and the overall response rate was 20%. The patients survived for a median of 13 months. Patients should be informed about the marginal efficacy and frequent adverse effects.
R E F E R E N C E
1. Ackland SP. Drug treatment of breast cancer. Aust Prescr 1998;21:15-9.
Lipobay (Bayer)
200 and 300 microgram tablets
Approved indication: hypercholesterolaemia
Australian Medicines Handbook Section 6.6.1
Cerivastatin adds to the choice of HMG-CoA reductase inhibitors available for the treatment of hypercholesterolaemia. It reduces low-density lipoprotein (LDL) cholesterol concentrations in the plasma by reducing hepatic cholesterol production. Plasma triglycerides and apolipoprotein B may be reduced while high-density lipoprotein-cholesterol concentrations may increase.
The drug should only be prescribed to patients who are following a cholesterol-lowering diet. Other causes of hypercholesterolaemia, such as diabetes, should be excluded.
Cerivastatin is given each evening. Food does not affect the pharmacokinetics of this drug, but bioavailability is reduced to 60% by first-pass metabolism. Cerivastatin is almost completely metabolised by the liver. Although there is no unchanged drug excreted in the urine, some of the metabolites are renally excreted. A reduced dose is recommended for patients with significant renal dysfunction. Cerivastatin is contraindicated in liver disease.
The hepatic metabolism of cerivastatin includes cytochrome P450 3A4. There is a potential for interactions with other drugs involved with this enzyme system. Erythromycin will increase the concentration of cerivastatin and a similar effect may be expected with other inhibitors of this system e.g. ketoconazole.
Cerivastatin has been studied in randomised double-blind placebo-controlled trials. The drug significantly reduced concentrations of total and LDL cholesterol after one week. LDL cholesterol concentrations reduced by 20-30% compared to placebo. The effect peaked after 4 weeks and was then maintained.
A blood sample should be taken after 6 weeks of treatment to assess the response and also to check liver function. As treatment should be discontinued if liver enzyme concentrations exceed 3 times normal, liver function should also be checked before treatment, after 12 weeks, and periodically thereafter.
Approximately 3% of patients left the clinical trials because of adverse effects. The overall incidence of adverse effects is similar to placebo. Prescribers should be alerted by complaints of muscle aches as myopathy has been reported with other HMG-CoA reductase inhibitors.
Cerivastatin does lower cholesterol, but its effect on cardiovascular disease is not yet known. As data are accumulating on the long-term effects of other HMG-CoA reductase inhibitors, there seems to be little reason for prescribing cerivastatin until such outcome data are available.
Cerezyme (Genzyme)
vials containing 200 units as powder for reconstitution
Approved indication: Gaucher's disease type I
Patients with Gaucher's disease lack the enzyme glucocerebrosidase. This deficiency results in an accumulation of glucocerebroside which can cause hepatosplenomegaly and bone marrow suppression. A few years ago alglucerase, a modified form of glucocerebrosidase, became available for replacement therapy (see `New drugs' Aust Prescr 1995;18:7). Imiglucerase is a recombinant form of alglucerase, so it should not have the potential risks of a product derived from pooled human placental tissue.
The two enzymes were compared in a double-blind trial. There were 15 patients in each treatment group. They were given an infusion of 60 U/kg every two weeks for 9 months. At the end of the study there were no significant differences in the effects of treatment on the size of the liver and spleen, the haemoglobin or the platelet count.1
The dose has to be titrated for each individual patient. A small comparative trial found 15 U/kg every two weeks to be as effective as 2.5 U/kg 3 times a week.2 The lower doses may have less effect on the skeletal effects of Gaucher's disease.
Apart from injection site reactions, symptoms suggestive of hypersensitivity have been reported in 4% of patients. These symptoms usually occur during the two-hour infusion. Although 20% of the patients given imiglucerase develop antiglucocerebrosidase antibodies, this is half the frequency seen with alglucerase.1 While the presence of antibodies increases their risk of a hypersensitivity reaction most patients can continue treatment.
There are only about 30 people in Australia being treated with alglucerase, but the annual cost of treatment is approaching $8 million. The launch of imiglucerase should help to reduce the cost per patient.
R E F E R E N C E S
1. Grabowski GA, Barton NW, Pastores G, Dambrosia JM, Banerjee TK, McKee MA, et al. Enzyme therapy in type I Gaucher disease: comparative efficacy of mannose-terminated glucocerebrosidase from natural and recombinant sources. Ann Int Med 1995;122:33-9.
2. Zimran A, Elstein D, Levy-Lahad E, Zevin S, Hadas-Halpern I, Bar-Ziv Y, et al. Replacement therapy with imiglucerase for type I Gaucher's disease. Lancet 1995;345:1479-80.
Evista (Eli Lilly)
60 mg tablets
Approved indication: prevention of bone loss
Australian Medicines Handbook Section 10.4
The Australian National Consensus Conference on the Prevention and Management of Osteoporosis1 recommended oestrogen therapy for postmenopausal women with a low bone mass. Oestrogens have a beneficial effect, but they increase the risk of endometrial cancer. Research efforts have therefore been directed at finding a drug with oestrogenic effects which is selective for bone.
Raloxifene acts on oestrogen receptors. It produces different effects in different tissues because of the way it binds with the receptors. Raloxifene has an agonist effect on bone, but does not stimulate the endometrium. Experimentally, it inhibits the growth of breast cancer cells.
A multinational study enrolled 601 postmenopausal women with low or normal bone density.2 They were randomised to take 30 mg, 60 mg or 150 mg of raloxifene or placebo daily for two years. The response to treatment was evaluated by measurement of bone density and biochemical markers of bone metabolism. Bone density increased in women given raloxifene while it decreased in those given placebo. There was a significant decrease in bone turnover in the women who took raloxifene. The greatest increase in bone density at the hip occurred in women taking 60 mg raloxifene. This is now the recommended daily dose.
Postmenopausal women taking oestrogens may also benefit from the effect of treatment on the risk of cardiovascular disease. Like oestrogen, raloxifene alters the lipoprotein profile. In the efficacy study2, raloxifene significantly decreased the concentration of total and LDL cholesterol. Another study compared these findings with hormone replacement therapy (HRT).3 The reductions in LDL cholesterol were similar, but raloxifene did not `significantly' change the HDL cholesterol which was increased 11% by HRT. Raloxifene significantly lowered fibrinogen while HRT had no effect.
The bioavailability of raloxifene is only 2%. This is because only 60% of the dose is absorbed and this undergoes first-pass metabolism. The daily dose may be taken with or without food. Raloxifene is highly protein bound and it mainly circulates as glucuronide metabolites. The plasma elimination half-life is approximately 28 hours with excretion mainly in the faeces.
Raloxifene is not recommended for patients with liver disease. As there is an increased risk of thromboembolism, raloxifene is contraindicated in women with a history of venous thrombosis. Compared with women taking placebo, women taking raloxifene are significantly more likely to experience leg cramps, peripheral oedema and vasodilatation.
While raloxifene provides another option for preventing osteoporosis in postmenopausal women, its role in therapy needs to be elucidated. More research is needed to see if it reduces fractures or protects against cardiovascular disease. Tamoxifen may also protect against osteoporosis, but it can increase the incidence of endometrial cancer. While raloxifene does not cause endometrial proliferation2, it is not as effective as oestrogen in reducing hot flushes. There are no data on using raloxifene and oestrogens in combination. Recent results are encouraging4, but further studies will be needed to discover how raloxifene affects the long-term risk of breast cancer.
R E F E R E N C E S
1. The Australian National Consensus Conference on the Prevention and Management of Osteoporosis 1996. Aust Prescr 1997;20(3 Suppl).
2. Delmas PD, Bjarnason NH, Mitlak BH, Ravoux A, Shah AS,
Huster WJ, et al. Effects of raloxifene on bone mineral density, serum cholesterol
concentrations, and uterine endometrium in postmenopausal women.
N Engl J Med 1997;337:1641-7.
3. Walsh BW, Kuller LH, Wild RA, Paul S, Farmer M, Lawrence JB, et al. Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women. JAMA 1998;279:1445-51.
4. Cummings SR, Eckert S, Krueger KA, Grady D, Powles TJ, Cauley JA, et al. The effect of raloxifene on risk of breast cancer in postmenopausal women. JAMA 1999;281:2189-7.
NovoSeven (Novo Nordisk)
vials containing 1.2 mg, 2.4 mg and 4.8 mg for reconstitution
Approved indication: haemophilia
Australian Medicines Handbook Section 7.4
Patients with haemophilia lack clotting factor VIII or IX. This increases the risk of having a severe haemorrhage after minor injury. To control bleeding the patient is given clotting factors, e.g. a factor VIII concentrate. Over time, some patients will develop antibodies to the clotting factors. These inhibitors can make haemostasis difficult to achieve. Recombinant factor VIIa can circumvent this problem because it activates the extrinsic pathway to coagulation. (Factors VIII and IX are in the intrinsic pathway.)
The new product is genetically engineered. It is almost completely identical to human factor VIIa.
Recombinant factor VIIa is given by slow intravenous injection. It has a half-life of approximately 3 hours, which corresponds to the initial dosage interval. The dose interval is then adjusted according to the clinical response. In bleeding episodes, a dose can be given every 2 hours until control is achieved. After major surgery patients may need to be treated for up to 3 weeks.
The product has been tested in 141 males who had a total of 308 bleeds. It was effective in most cases, but patients can still die from haemorrhagic complications.
The serious adverse events which have occurred in clinical trials include pulmonary embolism and other thrombotic events, disseminated intravascular coagulation, renal failure and shock. More common adverse events include fever, hypertension and headache. Allergic reactions including anaphylaxis can also occur. Two patients have developed antibodies to factor VII after treatment.
Aggrastat (Merck Sharp & Dohme)
50 mL glass vials containing 0.25 mg/mL
500 mL plastic containers containing 0.05 mg/mL
Approved indications: unstable angina, myocardial ischaemia
Australian Medicines Handbook Section 7.2
Tirofiban inhibits platelet aggregation by blocking the glycoprotein IIb/IIIa receptor. This prevents fibrinogen binding to the platelets.1 As platelet activation leads to arterial thrombus formation, tirofiban has a potential role in acute coronary syndromes. This has been studied in two large trials.
In the PRISM study2, 3232 patients with unstable angina were randomised to receive aspirin and either tirofiban or heparin. Within 48 hours, 5.6% of the patients given heparin were dead, had a myocardial infarction or had refractory ischaemia. Only 3.8% of the patients given tirofiban reached this composite end point.
The PRISM-PLUS study3 included 1915 patients with unstable angina or non-Q wave myocardial infarction. These patients were given aspirin with heparin, or tirofiban, or both. In comparison with the heparin group, tirofiban plus heparin significantly reduced the composite end points at 7 days, 30 days and 6 months.
Tirofiban is given intravenously. After an initial infusion lasting 30 minutes, a maintenance infusion is continued for at least 48 hours. Tirofiban has a half-life of approximately two hours. It is excreted unchanged mainly in the urine, but also in the bile. The dose should be reduced in patients with renal impairment.
Bleeding is the most common complication of therapy. In the PRISM study, 2.4% of the patients given tirofiban needed a transfusion. In the PRISM-PLUS study, 4% of those given heparin and tirofiban needed a transfusion. (This study was stopped because of a significant increase in deaths in patients taking tirofiban alone.) In addition to regular checks of the haemoglobin, the platelet count is also monitored as there is a risk of thrombocytopenia.
The precise role of tirofiban is unclear. As it has been approved for use with heparin, the PRISM-PLUS study deserves further examination. Dissection of the composite end points reveals that, at 6 months, the absolute reduction in death or myocardial infarction was 3% (12.3% of the tirofiban plus heparin group and 15.3% of the heparin group had died or had an infarction). The cost of purchasing this extra benefit will undoubtedly determine whether or not tirofiban becomes part of standard treatment.
R E F E R E N C E S
1. Lefkovits J. Recent advances in antiplatelet therapy. Aust Prescr 1996;19:98-101.
2. The Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) Study Investigators. A comparison of aspirin plus tirofiban with aspirin plus heparin for unstable angina. N Engl J Med 1998;338:1498-505.
3. The Platelet Receptor Inhibition in Ischemic Syndrome
Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS)
Study Investigators. Inhibition of the platelet glycoprotein IIb/IIIa receptor
with tirofiban in unstable angina and non-Q-wave myocardial infarction.
N Engl J Med 1998;338:1488-97.
Ursofalk (Orphan Australia)
250 mg capsules
Approved indication: chronic cholestasis
Australian Medicines Handbook Section 12
In primary biliary cirrhosis, there is chronic inflammation which destroys the intrahepatic bile ductules. At first, patients may be asymptomatic, but the reduced excretion of bile can cause steatorrhoea. The disease slowly progresses and death can result from hepatic failure or the complications of cirrhosis. Primary biliary cirrhosis is now a common indication for a liver transplant. Although there is no effective drug treatment, some patients will benefit from ursodeoxycholic acid.
Ursodeoxycholic acid is a bile acid which is synthesised from its precursor by intestinal bacteria. Its mechanism of action in primary biliary cirrhosis is uncertain. Ursodeoxycholic acid may have an effect by increasing the flow and altering the composition of bile. It has also been used in the treatment of gallstones.
In clinical trials with at least two years of follow up, patients who took ursodeoxycholic acid had improved liver function tests. This may not always improve the patient's symptoms or the histology of the liver.
Ursodeoxycholic acid has few known adverse effects. Diarrhoea is the main adverse reaction. Patients can complain of an increase in itching when they begin treatment. This may respond to a reduction in the dose. Ursodeoxycholic acid is contraindicated if there is acute inflammation of the gall bladder or obstruction of the common bile duct.
Ursodeoxycholic acid will probably have a role in delaying the need for liver transplantation. A placebo-controlled study of 145 patients with primary biliary cirrhosis found that the disease progressed more slowly in patients given ursodeoxycholic acid. This group also had a significantly lower probability of transplantation or death during the two-year study.1
R E F E R E N C E
1. Poupon RE, Poupon R, Balkau B. Ursodiol for the long-term treatment of primary biliary cirrhosis. The UDCA-PBC Study Group. N Engl J Med 1994;330:1342-7.
NEW FORMULATIONS
Augmentin Duo 400 (SmithKline Beecham) powder for oral suspension containing 400 mg amoxycillin and 57 mg clavulanic acid
Flixotide CFC-free inhaler (Glaxo Wellcome)
125 microgram and 250 microgram/actuation
Erotab (Douglas)
20 mg dispersible tablets
Prozac (Eli Lilly)
20 mg tablets
Measles, mumps, rubella vaccine
Priorix (SmithKline Beecham)
vials and pre-filled syringes
Zofran Zydis (Glaxo Wellcome)
4 mg and 8 mg wafers
Zerit (Bristol-Myers Squibb)
1 mg/mL powder for oral solution
