New drugs

(Aust Prescr 1995;18:35-8)

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.

Adenosine

Adenocor (Sanofi Winthrop)
3 mg/mL in 2 mL vials

Indication: supraventricular tachycardia
Adenosine is a nucleoside with an important role in metabolism. It has several effects on the heart including depression of conduction at the atrioventricular node, reduced automaticity of the sinoatrial node and decreased atrial contractility.

Adenosine has been approved for both diagnostic and therapeutic indications, which overlap somewhat. In patients with classical paroxysmal supraventricular tachycardia (SVT), the ECG usually shows normal narrow QRS complexes. Most of these cases are due to a reentry circuit which involves antegrade conduction through the AV node and retrograde conduction through an accessory pathway (e.g. classical Wolff Parkinson White syndrome). Measures which slow conduction through the AV node, e.g. carotid sinus pressure or Valsalva manoeuvre, often terminate the tachycardia. Intravenous verapamil works in this way and is often effective. Adenosine is equally effective for paroxysmal SVT1 but has some advantages over verapamil. The advantages are that adenosine is much shorter acting (minutes) and can be safely given to patients with heart failure or to patients taking beta blockers.

There are two situations where adenosine may be a useful diagnostic test. Firstly, some patients with narrow complex tachycardia around 150 beats per minute have atrial flutter with 2:1 block rather than SVT. In these patients, adenosine will transiently slow the ventricular rate, revealing flutter waves on the ECG, thus confirming the diagnosis.

Secondly, some patients will have wide QRS complexes, socalled wide complex tachycardia, for which the cause may not be clear. If this is due to SVT with aberrant conduction, adenosine will usually terminate the tachycardia. By contrast, if the problem is ventricular tachycardia, the patient will usually have serious underlying heart disease, and will often be hypotensive and very unwell. These patients should never be given intravenous verapamil. Intravenous adenosine will have no effect on the arrhythmia, but will generally not harm the patient. As a diagnostic test in wide complex tachycardias, adenosine has a sensitivity, specificity and predictive value of approximately 90%.2

The most common adverse effects include chest tightness, dyspnoea, bronchospasm and facial flushing. Bradycardia is a serious adverse event and the effects of adenosine are not blocked by atropine. Adenosine should only be used where cardiac monitoring and resuscitation equipment are immediately available.

R E F E R E N C E S
1. Adenosine for PSVT Study Group. Adenosine for paroxysmal supraventricular tachycardia: dose ranging and comparison with verapamil. Ann Intern Med 1990;113:104-10.

2. Griffith MJ, Linker NJ, Ward DE, Camm AJ. Adenosine in the diagnosis of broad complex tachycardia. Lancet 1988;1:672-5.

Cefpirome sulfate

Cefrom (Roussel Uclaf Australia)
vials containing 500 mg, 1 g and 2 g as powder

Indication: specified infections
Cefpirome is another broad spectrum cephalosporin for intravenous use. Its antimicrobial activity is similar to that of cefotaxime.

The reconstituted drug can be injected over 3-5 minutes or given as a 20-30 minute infusion. Clearance is mainly renal so a lower dose is given if creatinine clearance is reduced. The halflife is 2 hours, but cefpirome can usually be given twice a day.

Cefpirome is stable to beta lactamases and has activity against staphylococci, streptococci, and Gramnegative organisms including Escherichia coli, Haemophilus influenzae and Moraxella catarrhalis . The drug is active against Pseudomonas aeruginosa , but may be less active than ceftazidime.

The results of clinical trials have led to cefpirome being approved for the treatment of serious or lifethreatening infections. It can be given for septicaemia, infections of the lower respiratory tract, skin and soft tissues and complicated infections of the urinary tract. Cefpirome can also be used to treat infections in neutropenic patients.

Adverse reactions occurred in over 12% of patients during clinical trials and cefpirome was withdrawn from 5%. These reactions can range from pain at the injection site to pseudomembranous colitis and jaundice. Renal function should be monitored if cefpirome is given with an aminoglycoside or a loop diuretic.

With the addition of cefpirome to the market, cost may become a significant influence on the choice of cephalosporins 1 for severe infections.

R E F E R E N C E
1. Turnidge J. The choice of cephalosporins [editorial]. Aust Prescr 1992;15:268.

Cladribine

Leustatin (JanssenCilag)
intravenous solution containing 1 mg/mL in 10 mL vials

Indication: hairy cell leukaemia
Hairy cell leukaemia is a relatively uncommon type of leukaemia involving B lymphocytes. The leukaemic cells have characteristic cytoplasmic projections and infiltrate the blood and bone marrow.

Lymphocytes contain high concentrations of deoxycytidine kinase. This enzyme phosphorylates deoxyadenosine while deoxynucleotidase reverses the reaction. Cladribine is a purine analogue which passively enters cells and is phosphorylated by deoxycytidine kinase. However, the product of the reaction is resistant to deamination and accumulates as there is little deoxynucleotidase activity in lymphocytes. This causes breaks in DNA strands and leads to cell death.

Cladribine is relatively specific for lymphocytes on account of their high ratio of deoxycytidine kinase to deoxynucleotidase. In hairy cell leukaemia, a 7day infusion can induce a response rate in over 60% of patients. Previously untreated patients have a higher response rate. After complete remission, only 2 of 126 patients have relapsed during a median followup time of 14 months.1

Inevitably, there are serious adverse effects. Myelosuppression is common with neutropenia occurring in 69% of patients, anaemia in 41% and thrombocytopenia in 14%. Infections can be fatal, but to confuse the diagnosis, patients may develop a high fever without infection. Other adverse reactions include rashes, headache, thrombosis at the infusion site, nausea and vomiting.

Patients with hairy cell leukaemia who are symptomfree and not pancytopenic may not require treatment.1 When therapy is needed, cladribine is an effective drug.

R E F E R E N C E
1. Beutler E. Cladribine (2chlorodeoxyadenosine). Lancet 1992;340:952-6.

Dornase alfa

Pulmozyme (Roche Products)
nebuliser solution containing 2.5 mg (2500 units) per 2.5 mL

Indication: respiratory complications of cystic fibrosis
This product is a recombinant human deoxyribonuclease, manufactured using Chinese hamster ovary cells. The enzyme breaks down DNA.

Patients with cystic fibrosis produce secretions which are viscous and difficult to clear. As respiratory disease is the most frequent cause of death, it is important to keep the airways as clear as possible. The sputum of patients with cystic fibrosis contains inflammatory cells and is therefore rich in DNA. Inhaling recombinant deoxyribonuclease may therefore reduce the complications due to the accumulation of DNA in purulent sputum.

Daily treatment for 24 weeks improves FEV1 by 5-6% and parenteral antibiotics are less frequently needed. The product has been approved for use in patients between 5 and 23 years old, with a forced vital capacity (FVC) greater than 40% of the predicted value, as they are the most likely to benefit from treatment. After treatment, lung function returns to baseline levels.

Compared with patients given placebo, patients receiving the nebulised enzyme are more likely to complain of pharyngitis, laryngitis and an altered voice. Allergic reactions are possible and some patients will develop antideoxyribonuclease antibodies.

There is a need to develop protocols for the use of this product. The product information gives little guidance on whether all eligible patients should be treated, for how long and the timing of treatment in relation to other interventions such as chest physiotherapy. Treatment should continue
only if there is evidence of a sustained benefit for the patient. The longterm safety and efficacy are unknown.

Nedocromil sodium

Tilade (Fisons)
metered dose aerosol delivering 2 mg/dose

Indication: asthma prophylaxis
The airways of asthmatic patients are hyperresponsive to a variety of stimuli and increased reactivity is related to an inflammatory response. Nedocromil acts by inhibiting the release of inflammatory mediators e.g. histamine. It has a stabilising effect on mast cells and so resembles sodium cromoglycate.

Like sodium cromoglycate, the dose is two inhalations 4 times a day. Both drugs can have beneficial effects on asthma symptoms, but data on their relative efficacies are inconclusive.1

Nedocromil has also been compared to inhaled steroids in small numbers of patients. While both treatments improve lung function, inhaled steroids may give better control. It would be unwise to substitute nedocromil abruptly in a patient stabilised on inhaled steroids. Nedocromil has no role in the management of acute asthma.

The drug can be used in adults and children over 12 years old as prophylactic therapy for mild to moderate asthma. It is also approved for the prevention of acute bronchospasm caused by recognised trigger factors. Two inhalations can give several hours' protection against bronchospasm if taken a few minutes before exercise or exposure to cold air or allergens.

About 5% of the inhaled dose is absorbed and some is also swallowed. A bitter taste is patients' most common complaint. Upper gastrointestinal symptoms and headache can also occur during treatment.

R E F E R E N C E
1. Wasserman SI. A review of some recent clinical studies with nedocromil sodium. J Allergy Clin Immunol 1993;92:210-5.

Ofloxacin

Ocuflox (Allergan)
ophthalmic solution containing 3 mg/mL in 5 mL

Indication: bacterial conjunctivitis
Not all cases of conjunctivitis are due to bacteria. However, when a topical antibiotic is indicated, ofloxacin solution can be considered for severe cases. Ofloxacin is a fluoroquinolone antibiotic similar to norfloxacin. The drug inhibits DNA gyrase which leads to the death of the organism. Ofloxacin has a broad spectrum of activity which includes the
common pathogens.

The manufacturer recommends that one drop be used 4 hourly for 2 days and then one drop 6 hourly for up to 8 days. Longterm use is not advised as a resistant infection may develop. Contact lenses should not be worn during treatment. The drug is not approved for use in children.

A small amount of ofloxacin is absorbed. Although there is a potential for systemic adverse reactions, more common problems are burning, stinging, itching and dry eyes. Although 10-14% of patients report adverse effects, under 2% of patients cease therapy because of these reactions.

It is not clear if ofloxacin has an advantage over established (and probably cheaper) treatments for bacterial conjunctivitis.

NEW FORMULATIONS

Tacrine hydrochloride

Cognex (Parke Davis)
10 mg, 20 mg, 30 mg and 40 mg capsules

Indication: Alzheimer's disease
The pathology of Alzheimer's disease involves the loss of neurones, and biochemical studies suggest that acetylcholine synthesis is reduced. Researchers have been investigating the theory that increasing the concentration of acetylcholine may benefit the patient.

Tacrine is an anticholinesterase which has been used in anaesthesia. The new capsule formulations have been studied in patients with mild to moderately severe Alzheimer's disease.

Many of the clinical trials of tacrine have been criticised and the results are conflicting. Some show that the drug is no better than placebo, while others report significant benefits. An Australian study found no clinically relevant improvement after 36 weeks.1 As tacrine cannot prevent the loss of neurones, at best it can improve cognitive function to what it was 6 months previously, but the patient will continue to decline at the same rate.2

Tacrine must be given 4 times a day between meals as the halflife is 2-3 hours and absorption is reduced by food. The extent of first pass metabolism is dose dependent because the liver enzymes become saturated at low doses. As cytochrome P450 is involved in the metabolism of tacrine, interactions can occur with theophylline and cimetidine.

Liver enzyme abnormalities occur in nearly 30% of patients, so regular liver function tests are advised. At first, patients should be tested every 2 weeks, then monthly after the first 12 weeks, then quarterly if treatment is continued for more than 6 months. While elevated transaminase concentrations are the most frequent adverse effect, there are many other effects due to tacrine's cholinergic action. For example, 28% of patients will develop nausea or vomiting, 15% will develop diarrhoea and others may experience hypotension or urinary frequency. In clinical trials, approximately 17% of patients stopped tacrine because of adverse effects.

The patient's tolerance of tacrine determines the dose. Treatment begins with 10 mg 4 times a day, gradually increasing at 6 week intervals to a maximum total dose of 160 mg a day, if the patient can tolerate the adverse effects. In the Australian studies, fewer than half the patients were able to tolerate doses greater than 100 mg. Unfortunately, it is as difficult to predict which patients may develop adverse effects as it is to identify patients who may benefit from tacrine.2

Prescribing tacrine will place additional responsibilities on those who care for patients with Alzheimer's disease. Carers will have to ensure the medication is taken, and monitor the patient for adverse effects. They may be the best people to assess the effectiveness of treatment.

In the absence of adverse effects, the manufacturer states that 'the drug may be continued until the decline of the patient has reached a point where therapy is no longer worthwhile'. As few trials have continued beyond 30 weeks, longterm safety is unknown. If treatment fails, tacrine should be withdrawn slowly. Abruptly stopping the drug can cause behavioural disturbances or a further decline in cognitive function.

R E F E R E N C E S
1. Maltby N, Broe GA, Creasey H, Jorm AF, Christensen H, Brooks WS. Efficacy of tacrine and lecithin in mild to moderate Alzheimer's disease: double blind trial. Br Med J 1994;308:879-83.

2. Winker MA. Tacrine for Alzheimer's disease. Which patient, what dose? [editorial]. JAMA 1994;271:1023-4.