New drugs

(Aust Prescr 1994;17:30-2)

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.

Capsular polysaccharide typhoid vaccine

Typhim Vi (Pasteur Merieux)
0.025 mg/0.5 mL in single dose pre-filled syringes
Indication: prevention of typhoid

Travellers to areas where typhoid fever is endemic should be advised to avoid potentially contaminated food and water and be offered vaccination. Immunisation can be achieved with an oral vaccine containing live attenuated bacteria or an injection of heat killed bacteria. The injectable vaccine gives up to 80% protection for approximately 3 years after two doses. However, adverse reactions are common. This new product aims to produce immunity with fewer adverse effects.

The vaccine is made of purified Vi polysaccharide from the capsule of Salmonella typhi. A single intramuscular dose will protect nearly 80% of vaccinees for 3 years.

The most common adverse events are reactions at the injection site. However, systemic reactions including fever, headache, malaise and nausea can occur. This vaccine appears to cause fewer serious adverse events than the whole cell vaccine, but this needs to be confirmed with wider experience after marketing.

The vaccine is not suitable for small children as the polysaccharide antigen does not induce an optimal response in those under 18 months of age.

Flupenthixol decanoate

Fluanxol Depot and Concentrated Depot (Fisons)
depot contains 20 mg/mL in 1 mL and 2 mL ampoules
concentrated depot contains 100 mg/mL in 1 mL ampoules
Indication: schizophrenia

Flupenthixol is an antipsychotic drug of the thioxanthine class. Although the depot preparation has been marketed overseas for many years, in Australia it has only been available through the Special Access Scheme.

The depot formulations release the drug slowly after intramuscular injection with an onset of action of 24-72 hours. Although the effects can last for 2-4 weeks, the drug is not eliminated for up to 3 months. A steady state is probably reached within 6 months.

These products are intended for maintenance therapy of chronic schizophrenia and related psychoses. Shorter-acting antipsychotics should be used in patients with acute symptoms. When changing a patient to a depot formulation of flupenthixol, close supervision is required to establish the correct dose. A test dose is recommended.

Extrapyramidal adverse effects may appear a few days after an injection of flupenthixol. The drug can also cause other reactions in the nervous system, including seizures. As with the other antipsychotics, flupenthixol has other potential adverse effects including tardive dyskinesia and neuroleptic malignant syndrome. As sedation may occur, patients should be cautioned about operating machinery.

Gadodiamide

Omniscan (Winthrop Laboratories)
287 mg/mL in 10 mL, 15 mL and 20 mL vials
Indication: MRI scanning

The value of magnetic resonance imaging may be enhanced by the use of contrast media. A commonly used contrast medium is gadopentetate which is an ionic molecule. Gadodiamide is a gadolinium complex which is non-ionic, but it remains to be seen if this is an advantage.

Gadodiamide is given intravenously to enhance images of intracranial and spinal lesions where there is abnormal vascularity or an abnormal blood-brain barrier. The complex does not cross an intact blood-brain barrier so only accumulates in lesions such as neoplasms and abscesses.

The most frequent adverse effects are nausea, headache and dizziness. It is not known if repeated exposures are safe.

Hexamethylmelamine

Hexalen (David Bull Laboratories)
50 mg capsules
Indication: ovarian cancer

Hexamethylmelamine has been used in clinical trials for many years. It is related to the alkylating agents and can be used in combination with other anticancer drugs to treat stage III and IV ovarian cancer. The precise mechanism of action is unknown.

Absorption is good, but there is extensive first pass metabolism which produces varying plasma concentrations. The half-life is from 4-11 hours and involves the formation of metabolites which are excreted in the urine.

On the basis of the available evidence, hexamethylmelamine has been approved for use in combination with cyclophosphamide, doxorubicin and, if the patient can tolerate it, cisplatin. Hexamethylmelamine is also approved as monotherapy in patients who relapse after first-line therapy, as a response of 18% has been reported.

The patient should have a neurological examination before hexamethylmelamine treatment begins as neurotoxicity is common. This can affect the central nervous system or present as a peripheral neuropathy. Other adverse events include myelosuppression, nausea and vomiting.

Lenograstim

Granocyte (AMRAD Pharmaceuticals)
vials containing 263 micrograms lyophilised powder for injection
Indication: neutropenia

This product is a competitor for filgrastim, a granulocyte colony stimulating factor (G-CSF) which was marketed in 1992 (see `New drugs' Aust Prescr 1992;15:86.) The main difference between the two products is the method of production. Lenograstim is produced in Chinese hamster ovary cells using recombinant technology.

Lenograstim is approved to reduce the duration of neutropenia and the incidence or severity of infections in patients who have had a bone marrow transplant or chemotherapy.

Although there is now competition in the market for G-CSF, lenograstim will probably be an expensive drug. The cost of therapy may be offset by a reduction in the costs of treating febrile neutropenia. However, it is currently unknown if the use of lenograstim improves the patient's chance of survival.

Nafarelin acetate

Synarel Nasal Spray (Syntex)
200 micrograms per actuation in a 10 mL spray pump
Indication: endometriosis

Nafarelin is an analogue of gonadotrophin releasing hormone (GnRH). While a single dose stimulates gonadotrophin release, regular doses gradually reduce gonadotrophin secretion. This results in suppression of ovarian function. The reduced secretion of oestrogens may heal endometriosis.

At the recommended dose, nafarelin is sprayed into one nostril in the morning and into the other in the evening. The drug is rapidly absorbed, but the bioavailability of an intranasal dose averages 3% and can be affected by rhinitis. Nafarelin is metabolised and has a half-life of 3 hours.

Treatment begins at the start (days 2-4) of the menstrual cycle and continues for 6 months. This regimen is as effective as a course of danazol.¹ A higher dose can be considered in patients who have persistent symptoms of endometriosis and do not develop amenorrhoea. If the woman's symptoms recur after therapy, a second course of treatment is not recommended as safety data are lacking.

Nafarelin does not have the same androgenic adverse effects as danazol, but it can cause menopausal symptoms. The most commonly reported symptoms are hot flushes, vaginal dryness, altered libido and headaches. Treatment for 6 months results in a loss of bone density. The vertebral trabecular bone density falls by nearly 9% and may not return to normal after treatment. Nafarelin also has a similar effect to oestrogen deficiency on blood lipids e.g. concentrations of total cholesterol and triglycerides may increase.

As nafarelin is likely to be expensive, it may be reserved for women with endometriosis who do not respond to or cannot tolerate other treatments.

R E F E R E N C E

1. Henzl MR, Corson SL, Moghissi K, Buttram VC, Berqvist C, Jacobson J. Administration of nasal nafarelin as compared with oral danazol for endometriosis. A multicenter double-blind comparative clinical trial. N Engl J Med 1988;318:485-9.

Paroxetine hydrochloride

Aropax 20 (SmithKline Beecham)
20 mg tablets
Indication: depression

Paroxetine is a serotonin re-uptake inhibitor. It is well absorbed from the gut, but undergoes first pass liver metabolism. This first pass metabolism can become partially saturated resulting in non-linear pharmacokinetics in some patients. The lipophilic molecule is extensively distributed through the body with only 1% remaining in the plasma. Excretion occurs by metabolism, with the metabolites being excreted in the faeces and urine. Increased plasma concentrations may occur in patients with renal or hepatic impairment. A lower maximum dose is recommended in elderly patients. Unlike fluoxetine, another serotonin re-uptake inhibitor, the metabolites of paroxetine are relatively inactive. The elimination half-life is approximately 24 hours.

In comparative studies, the drug was more effective than placebo and of similar efficacy to the tricyclic antidepressants. As paroxetine has a low affinity for adrenoceptors and muscarinic cholinergic receptors, cardiovascular and anticholinergic adverse effects are less common than with the tricyclics. The more common adverse effects of paroxetine during clinical trials were nausea, somnolence and sweating.
As paroxetine is metabolised by the liver and inhibits cytochrome P450, practitioners should be aware of potential interactions. There is an interaction with cimetidine, phenytoin and probably warfarin. There are no studies on the concomitant use of paroxetine with neuroleptics or tricyclic antidepressants. A gap of at least two weeks is recommended between paroxetine and monoamine oxidase inhibitor therapy.

Paroxetine has been approved as a once a day treatment for major depressive illness. More data are required to determine the long-term safety and efficacy of paroxetine and whether it is more effective in certain types of depression than in others.

NEW PROPRIETARY BRANDS

Glipizide

Melizide (Alphapharm)
5 mg tablets

Isosorbide dinitrate

Sorbidin (Alphapharm)
10 mg tablets

Dobutamine hydrochloride

Dobutamine Hydrochloride Injection (David Bull Laboratories)
250 mg/20 mL vials

NEW FORMULATIONS

Isotretinoin

Isotrex (Stiefel)
0.05% in 30 g tubes

Ciprofloxacin

Ciloxan (Alcon Australia)
3 mg/mL ophthalmic solution

Ranitidine hydrochloride

Zantac Effervescent Tablets (Glaxo Australia)
150 mg tablets

NEW STRENGTHS

Felodipine

Plendil ER (Astra)
Agon SR (Hoechst)
2.5 mg extended release tablets

Midazolam

Hypnovel (Roche)
50 mg/10 mL ampoules