New drugs

(Aust Prescr 1998;21:80-3)

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.

Carvedilol

Kredex (SmithKline Beecham)
3.125 mg, 6.25 mg, 12.5 mg and 25 mg tablets

Dilatrend (Boehringer Mannheim)
6.25 mg, 12.5 mg and 25 mg tablets

Indication: hypertension, heart failure

Catecholamine neurotransmitters may act at either alpha or beta adrenoceptors. The alpha receptor mediates vasoconstriction, whereas stimulation of the beta receptor results in increased cardiac contractility, vasodilatation and increased heart rate. Certain adverse effects may be anticipated during treatment with a beta blocker e.g. impaired peripheral circulation. However, carvedilol has both alpha and beta blocking actions, so the problem of cold extremities may be reduced. This dual action is due to the fact that carvedilol is a racemic compound whose enantiomers have different effects.

Carvedilol is a lipophilic, non-selective antagonist with no intrinsic sympathomimetic activity. It is absorbed rapidly from the gut and undergoes first-pass metabolism. Bioavailability is approximately 25% and is increased by liver impairment as the drug undergoes hepatic clearance.

Carvedilol is effective in reducing blood pressure, and has recently been investigated for the treatment of heart failure. In severe heart failure, catecholamine concentrations rise so sympathetic antagonists may counter some of the adverse haemodynamic effects.

In one trial, 696 patients with chronic heart failure were given carvedilol and 398 were given placebo.¹ It is important to note that only patients who could tolerate carvedilol for an initial test period were randomised. This study was stopped early because there was a clear difference in mortality. Approximately 8% of the placebo group died compared with 3% of the carvedilol group. The risk of hospitalisation was reduced by 27% in the carvedilol group. As the patients were also taking digoxin, diuretics and an ACE inhibitor, carvedilol has only been approved for use as an adjunct to these treatments.

Approximately 5% of the patients with heart failure had to withdraw from clinical trials because of adverse events. Patients may complain of dizziness, blurred vision or diarrhoea. They may also develop bradycardia, hypotension or worsening heart failure.

R E F E R E N C E
1. U.S. Carvedilol Heart Failure Study Group. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med 1996;334:1349-55.

Cefepime

Maxipime (Bristol-Myers Squibb)
500 mg in 15 mL vials
1 g in 15 mL vials
2 g in 77 mL vials

Indication: specified infections

Cefepime is an injectable cephalosporin with a broad spectrum of activity. Bacteria sensitive to cefepime include staphylococci, streptococci, Escherichia coli, Klebsiella pneumoniae, Haemophilus influenzae and Proteus mirabilis. Its efficacy against Pseudomonas aeruginosa is similar to that of ceftazidime.

The drug can be used to treat septicaemia and intra-abdominal infections such as peritonitis. It can also be used to treat gynaecological infections and infections in the urinary tract, lower respiratory tract or the skin. Cefepime can also be considered as part of a regimen for the empirical treatment of febrile neutropenia. The drug has not been approved for use in children under 12 years old.

Cefepime is injected every 12 hours. The drug is eliminated by renal clearance and has a half-life of two hours. If the creatinine clearance is less than 30 mL/minute, the dose should be reduced. The usual duration of treatment is 7-10 days, but this may be extended for more severe infections.

The most common adverse effects of cefepime are diarrhoea, headache, rash, nausea and vomiting. Some cases of diarrhoea may be due to Clostridium difficile.

Although cefepime has many potential uses, it should probably be reserved as an option for infections where ceftazidime would currently be considered.¹

R E F E R E N C E
1. Turnidge J. The choice of cephalosporins [editorial]. Aust Prescr 1992;15:26-8.

Liposomal daunorubicin

DaunoXome (NeXstar Pharmaceuticals)
vials containing 50 mg/25 mL concentrated solution

Indication: Kaposi's sarcoma

Kaposi's sarcoma is the most frequent neoplasm affecting homosexual or bisexual men with HIV infection. The patients who develop progressive disease have a poor prognosis. Various regimens of chemotherapy have been used in palliation.

There are obvious problems in giving cytotoxic drugs to patients who already have a suppressed immune system. In an effort to deliver more of the drug to the affected tissues, daunorubicin has been encapsulated in liposomes. These liposomes are 50-80 nm in diameter and are made of cholesterol and distearoylphosphatidylcholine. Encapsulated daunorubicin shows selectivity for tumour tissue in animal models. The intact liposome enters the tumour cells. Its structure is then disrupted to release daunorubicin.

Liposomal daunorubicin has different pharmacokinetics to daunorubicin. It has a higher peak plasma concentration, a smaller volume of distribution and a lower clearance. The exposure following a dose of 80 mg/m² is approximately 36 times greater than with conventional daunorubicin.

Liposomal daunorubicin has been compared with a combination of doxorubicin, bleomycin and vincristine in the treatment of advanced Kaposi's sarcoma in 227 patients.¹ Treatment was given every two weeks until there was a response, the disease progressed or toxicity developed. There was no significant difference in the response rate with 25% of the patients given liposomal daunorubicin having a response (28% in the control group). The median duration of response was similar in both groups. When the data were analysed, 107 of the patients were dead. The median duration of survival was 369 days for patients given liposomal daunorubicin and 342 days for the combination treatment. The researchers estimated survival to be 53% at one year for daunorubicin.

Neutropenia occurred in approximately 35% of both treatment groups, but patients given liposomal daunorubicin were more likely to develop severe neutropenia (<500 cells/mm³). More of the patients given liposomal daunorubicin developed opportunistic infections and more required G-CSF.

Care should be taken when infusing the drug as inflammation can occur at the injection site. There is also a need to be alert for allergic reactions.

Daunorubicin is associated with cardiomyopathy and there is no clear evidence that the new formulation will be less toxic. All patients should have their cardiac function assessed.

Neuropathy occurs in 13% of patients. This is significantly less than in patients given daunorubicin, bleomycin and vincristine. Liposomal daunorubicin also has the advantage of causing less alopecia.

R E F E R E N C E
1. Gill PS, Wernz J, Scadden DT, Cohen P, Mukwaya GM, Hayden von Roenn J, et al. Randomised phase III trial of liposomal daunorubicin versus doxorubicin, bleomycin and vincristine in AIDS-related Kaposi's sarcoma. J Clin Oncol 1996;14:2353-64.

Reteplase

Rapilysin (Boehringer Mannheim)
vials containing 10 units for reconstitution

Indication: myocardial infarction

Thrombolytic therapy is a key part of the management of myocardial infarction. Streptokinase and tissue plasminogen activator (t-PA) are already available and are now joined by reteplase. This new product is a modified form of tissue plasminogen activator. Reteplase is a recombinant product which has a longer half-life than t-PA. This enables reteplase to be given by injection rather than infusion. Two injections are given slowly, 30 minutes apart. This reduces plasma fibrinogen concentrations by 75-90%. The concentrations of fibrinogen return to normal within 48 hours.

Reteplase has been compared with streptokinase in patients with acute myocardial infarction.¹ In this trial, 3004 people received reteplase and 3006 received streptokinase. The patients were also given aspirin and warfarin. Within 35 days of their infarction, 9-10% of the patients in each group had died. Strokes and bleeding complications were similar in each group. This trial suggests that reteplase is as effective as streptokinase. Although the trial included patients presenting up to 12 hours after infarction, reteplase has only been approved for use within 6 hours.

The contraindications to reteplase are similar to those of other thrombolytic agents e.g. severe hypertension, recent surgery or stroke. The method of elimination is unknown so the drug is contraindicated in patients with liver or renal dysfunction.

The most common adverse events are bleeding at the injection site and hypotension. Other adverse effects include internal bleeding and arrhythmias.

Reteplase is easier to give than tissue plasminogen activator, but it is unlikely to be preferred if it is significantly more expensive than streptokinase.

R E F E R E N C E
1. International Joint Efficacy Comparison of Thrombolytics. Randomised, double-blind comparison of reteplase double-bolus administration with streptokinase in acute myocardial infarction (INJECT): trial to investigate equivalence. Lancet 1995;346:329-36.

Tacrolimus

Prograf (Janssen-Cilag)
1 mg and 5 mg capsules
solution for injection containing 5 mg/mL

Indication: immunosuppression for liver transplantation

Immunosuppressive drugs are used to reduce the risks of rejection after organ transplants. Cyclosporin is often used, but can have serious adverse effects such as renal dysfunction. Tacrolimus has been developed to try to provide immunosuppression with fewer adverse effects.

Tacrolimus is an antibiotic derived from a fungus found in soil. Its structure is not related to cyclosporin, but it has similar properties. The method of action is uncertain, but may involve inhibition of cytokine secretion. Both humoral and cell-mediated immune responses are suppressed.

As the drug is hepatotropic, it has been studied in patients having liver transplants. One study compared tacrolimus plus low-dose corticosteroids with a cyclosporin-based regimen in over 500 patients. After 12 months, acute rejection had occurred in 107 of the 264 patients given tacrolimus and 132 of the 265 given cyclosporin. There were also significant differences in the rates of refractory acute rejection and chronic rejection.¹ Although there was not a significant improvement in survival, tacrolimus has been approved for primary immunosuppression in liver allograft recipients.

Treatment with tacrolimus begins 6 hours after transplant surgery. Usually a continuous infusion will be given. Tacrolimus is incompatible with PVC, so tubing and syringes containing such plastics should not be used. Once the patient can swallow, the capsules are given twice a day. Absorption is erratic and is reduced by food. Tacrolimus is highly bound to red blood cells and plasma proteins. The half-life varies between 3.5 and 40.5 hours with most of the drug being metabolised in the liver.

Although tacrolimus and cyclosporin appear to have similar adverse effects, they are more likely to develop in patients given tacrolimus. In the comparative study¹, all patients had adverse reactions and 76 taking tacrolimus had to withdraw compared with 64 taking cyclosporin. The most common complaints are diarrhoea, headache, tremor and nausea. Glucose metabolism and renal function may be impaired. At least 30% of patients will develop hypertension, but this is less than the incidence in patients given cyclosporin.

In addition to routine monitoring of patients after transplantation, concentrations of tacrolimus should be monitored. Trough concentrations in whole blood can be used when adjusting the dose. Monitoring the blood concentration is important if certain drugs are given with tacrolimus. As tacrolimus is metabolised by cytochrome P450 3A4, the drugs it interacts with include ketoconazole and erythromycin.

Physicians and their patients must now decide if the effectiveness of tacrolimus outweighs the higher incidence of toxicity relative to cyclosporin.

R E F E R E N C E
1. European FK506 Multicentre Liver Study Group. Randomised trial comparing tacrolimus (FK506) and cyclosporin in prevention of liver allograft rejection. Lancet 1994;344:423-8.

Tiludronate disodium

Skelid (Sanofi Winthrop)
200 mg tablets

Indication: Paget's disease

Tiludronate adds to the choice of biphosphonates available for the treatment of Paget's disease. The biphosphonates work by inhibiting the resorption of bone.

In clinical trials, the effectiveness of tiludronate has been objectively assessed by measuring concentrations of serum alkaline phosphatase. This enzyme is increased in Paget's disease. A 3-month course of tiludronate will at least halve alkaline phosphatase in over half the patients. The concentration of alkaline phosphatase may remain reduced for up to 18 months. In some patients, the concentration will fall to the normal range. Some patients will experience a reduction in bone pain.

Tiludronate has been compared with etidronate in a company-sponsored trial of 234 patients. After 6 months, significantly more patients had responded to tiludronate than etidronate. However, neither drug had an advantage over the other in the reduction of bone pain.¹

Only 6-7% of a dose of tiludronate is absorbed. As food reduces absorption, the tablets should not be taken less than two hours before or after a meal. Absorption is also reduced by calcium, so the tablets should be swallowed with water, not milk.

Tiludronate binds to bone. This means that it has a long half-life. The drug is gradually excreted unchanged in the urine.

The most frequent adverse effects are gastrointestinal, including abdominal pain, nausea and diarrhoea. Other adverse effects include asthenia, headaches and rashes. Bone mineralisation is not affected at therapeutic doses.

R E F E R E N C E
1. Roux C, Genneri C, Farrerons J, Devogelaer JP, Mulder H, Kruse HP, et al. Comparative prospective, double-blind, multicenter study of the efficacy of tiludronate and etidronate in the treatment of Paget's disease of bone. Arthritis Rheum 1995;38:851-8.

Topiramate

Topamax (Janssen-Cilag)
25 mg, 50 mg, 100 mg and 200 mg tablets

Indication: epilepsy

Although therapy with a single drug is preferred for patients with epilepsy, this may not be enough to control their seizures. Topiramate adds to the choice of drugs which may be used as adjunctive treatment. It is specifically approved for adults with partial onset epileptic seizures with or without secondary generalised seizures.

Topiramate is based on a monosaccharide molecule. It is thought to act by increasing the activity of gamma-aminobutyric acid (GABA), blocking sodium channels to reduce the frequency of action potentials, and inhibiting a subtype of glutamate receptors.

The efficacy of topiramate is based on 5 randomised placebo-controlled, double-blind parallel group studies. In one of the larger studies, 181 patients were randomised to receive either placebo or topiramate (200 mg, 400 mg or 600 mg daily) as adjunctive therapy. Once stabilised, the dose was continued for 12 weeks. The rate of seizures per month declined significantly, compared with placebo, in patients taking 400 mg (48% decline) or 600 mg (45% decline). Between 40% and 50% of the patients on these doses had their seizure rate at least halved.¹

Therapy begins with a dose of 50 mg at night. This is then increased weekly by 50-100 mg depending on the clinical response. Twice a day dosing is recommended.

The tablets are well absorbed. There is some metabolism, but most of the drug is excreted unchanged in the urine. The elimination half-life is 21 hours. Clearance is decreased in patients with renal disease and, although less than 20% of the drug is metabolised, liver disease. Currently, the need for plasma level monitoring is uncertain. Adding topiramate usually has no effect on the steady state concentrations of carbamazepine, phenobarbitone, phenytoin, primidone or sodium valproate. Occasionally, some patients with a particular enzyme will develop increased phenytoin concentrations. Both phenytoin and carbamazepine reduce the plasma concentration of topiramate. Other drugs with the potential for interaction include digoxin and low-dose oral contraceptives.

The most common adverse effects include ataxia, confusion, dizziness, fatigue, paraesthesia, impaired concentration and abnormal thinking. Patients should be cautioned about driving or operating machines. They should also be advised that there is a risk of forming renal stones. Although regular laboratory tests are not required, topiramate can cause changes in the white cell count.

There are no data on the efficacy or safety of topiramate in combination with gabapentin, lamotrigine or vigabatrin. It is also unclear which is the most effective adjunctive drug.

R E F E R E N C E
1. Faught E, Wilder BJ, Ramsay RE, Reife RA, Kramer LD, Pledger GW, et al. Topiramate placebo-controlled dose-ranging trial in refractory partial epilepsy using 200, 400, and 600 mg daily dosages. Neurology 1996;46:1684-90.

NEW FORMULATIONS

Fentanyl

Durogesic (Janssen-Cilag)
2.5 mg, 5 mg, 7.5 mg and 10 mg patches

Itraconazole

Sporanox (Janssen-Cilag)
10 mg/mL oral solution in 150 mL bottles

Loperamide

Imodium (Janssen-Cilag)
2 mg caplets

NEW STRENGTHS

Ipratropium bromide

Ipratrin Adult uni-dose (Alphapharm)
500 microgram/mL single dose ampoules

Pravastatin sodium

Pravachol (Bristol-Myers Squibb)
40 mg tablets