New drugs

(Aust Prescr 1996;19:108-11)

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.

Alendronate sodium

Fosamax (Merck Sharp & Dohme)
10 mg and 40 mg tablets

Indications: Paget's disease, osteoporosis
The bisphosphonates are effective inhibitors of bone resorption. They can therefore be used in conditions where bone resorption is increased such as Paget's disease and osteoporosis.

Several trials have reported that alendronate increases bone mineral density in postmenopausal women with osteoporosis. A randomised placebo controlled trial of 994 women found that those taking alendronate for 3 years increased their bone density and reduced vertebral fractures. In the final analysis of 881 of the women, 22 (6.2%) of the 355 in the placebo group had at least one new vertebral fracture, compared with 17 (3.2%) of the 526 women who took alendronate.¹ However, the effect on non-vertebral fractures was not significant.

In osteoporosis, the recommended dose is 10 mg a day. A daily dose of 40 mg is recommended for Paget's disease. This higher dose reduces the activity of the disease as judged by significant decreases in alkaline phosphatase concentrations. Treatment is restricted to 6 months' duration.

The bioavailability of alendronate is very low (<1%) so it is important to take the drug at least 30 minutes before food. It should be taken with water as coffee and orange juice reduce the bioavailability by 60%. After absorption, the drug distributes to soft tissues, but is then either excreted or redistributed to bone. Although half of a radiolabelled (intravenous) dose will be excreted within 72 hours, the terminal elimination half-life probably exceeds 10 years.

The adverse effects of alendronate are mainly gastrointestinal and include abdominal pain, oesophageal ulcers and dyspepsia. Some patients will complain of musculoskeletal pain.

Although experience is limited, alendronate appears to have little effect on bone mineralisation. Impairment of bone mineralisation has been a problem with another bisphosphonate, sodium etidronate, resulting in increased fractures.

Alendronate may have an advantage over sodium etidronate, but its exact role is uncertain. Not all patients with Paget's disease require treatment and the clinical outcomes of treatment with alendronate are not clear. The drug is not yet approved for the prevention of osteoporosis. Its use is restricted to postmenopausal women with evidence of an atraumatic fracture or a bone density measurement two or more standard deviations below the mean. It is hoped that the role of the bisphosphonates can be clarified at this year's consensus conference - 'The prevention and management of osteoporosis'.

R E F E R E N C E
1. Liberman UA, Weiss SR, Broll J, Minne HW, Quan H, Bell NH, et al. Effect of oral alendronate on bone mineral density and the incidence of factures in postmenopausal osteoporosis. N Engl J Med 1995;333:1437-43.

Bicalutamide

Cosudex (ICI Pharmaceuticals)
50 mg tablets

Indication: prostate cancer
At present, the best treatment for metastatic prostate cancer is androgen ablation. This may be achieved by orchidectomy, antiandrogens or gonadotrophin releasing hormone agonists.¹

Bicalutamide is an antiandrogen which has been approved for use in combination with a gonadotrophin releasing hormone agonist. If the treatments begin simultaneously, the 'flare' reaction¹ associated with the agonist may be controlled.

One tablet is taken each day. As the drug is metabolised in the liver, no dose adjustment is required if renal function is reduced. In patients with severe liver dysfunction, bicalutamide may accumulate. Accumulation also occurs with routine doses as the half-life of bicalutamide is approximately one week.

Some of the adverse effects of treatment can be expected from the antiandrogen action of bicalutamide e.g. hot flushes and breast symptoms. Other adverse effects include diarrhoea, nausea and vomiting. Liver function should be tested as it may be affected by bicalutamide.

Flutamide is already available for this indication and it is uncertain if bicalutamide offers any significant advantages. An industry sponsored study found no difference in survival between the two treatments.² Although the time to treatment failure was shorter for flutamide, the definition of treatment failure was not restricted to progression of the disease. More patients taking flutamide 'failed treatment' because more of them were withdrawn due to a higher incidence of diarrhoea.

The mortality in patients given a combination of an antiandrogen and a gonadotrophin releasing hormone agonist is 56% after 40 months. As the mortality in castrated patients is 58%, drug treatment does not have a significant advantage and costs more.³

R E F E R E N C E S
1. Boyer M. The management of prostate cancer. Aust Prescr 1996;19:22-4.

2. Schellhammer P, Sharifi R, Block N, Soloway M, Venner P, Patterson AL, et al. A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate cancer. Urology 1995;45:745-52.

3. Prostate Cancer Trialists' Collaborative Group. Maximum androgen blockade in advanced prostate cancer: an overview of 22 randomised trials with 3283 deaths in 5710 patients. Lancet 1995;346:265-9.

Follitropin beta

Puregon (Organon)
ampoules containing 50, 100 and 150 IU

Indication: infertility
Some infertile women require treatment with gonadotrophins to stimulate follicular development. Follitropin is a recombinant human follicle stimulating hormone (FSH) that may supersede the existing products which are derived from urine.

The hormone is produced from genetically engineered Chinese hamster oocytes. It has an amino acid sequence identical to human FSH. Clinical trials suggest that follitropin beta is at least as effective as urinary gonadotrophins.

Follitropin can be used to stimulate follicular development in women with anovulatory infertility. After finding the optimum daily dose, each patient is monitored until pre-ovulatory conditions are reached. Follitropin is then stopped and ovulation induced with human chorionic gonadotrophin (HCG). The hormone can also be used to produce controlled ovarian hyperstimulation. This prepares follicles for retrieval in assisted reproduction programs.

Follitropin beta has also been approved for use in males with deficient spermatogenesis due to hypogonadotrophic hypogonadism. The injections are given 2 or 3 times per week and HCG is given simultaneously. Treatment usually has to continue for at least 3 months before there is an improvement in spermatogenesis.

The main adverse effect in women is unplanned ovarian hyperstimulation. This can result in multiple pregnancies.

Indinavir sulfate

Crixivan (Merck Sharp & Dohme)
200 mg and 400 mg capsules

Indication: HIV infection
The approval of indinavir was based on surrogate end-points, such as CD4 cell counts, as there are no results from controlled clinical trials investigating the effect of indinavir on the progression of HIV infection.

Like saquinavir, indinavir is an inhibitor of HIV protease. While saquinavir is approved for use in combination with other antiretroviral drugs, indinavir can be used as monotherapy if combination therapy is inappropriate.

Indinavir is taken 3 times a day. As absorption is significantly reduced by food, the patient should take the drug with water one hour before or two hours after a meal. Indinavir is mainly metabolised and is rapidly eliminated with a half-life under two hours. This metabolism involves the P450 system so there is the potential for interactions with drugs such as ketoconazole, rifabutin and sertraline. The product information advises that indinavir should not be given concurrently with drugs which are substrates for cytochrome CYP3A4 if there is a potential for serious adverse effects. Competitive inhibition of their metabolism increases the risks of adverse interactions with drugs such as terfenadine, astemizole, alprazolam and triazolam.

The evaluation of indinavir was based on studies lasting up to 24 weeks; other studies are ongoing. A study comparing zidovudine, indinavir and a combination of the two found that surrogate end-points were more favourable with combination therapy. As monotherapy, indinavir appears to be more effective than zidovudine. A combination of indinavir, zidovudine and didanosine was also more favourable than a combination of zidovudine and didanosine.

Approximately 5% of the patients taking indinavir alone in clinical trials stop the drug because of adverse effects. Common adverse reactions include fatigue, nausea, diarrhoea, headache, dry skin, rashes and altered taste. Patients should drink at least 1.5 L of fluid a day to reduce the risk of nephrolithiasis.

Liver function is altered with approximately 10% of patients developing hyperbilirubinaemia.

There are no adequate or well controlled studies of treatment in pregnant women and indinavir has not been approved for use in children under 12 years old. The long-term safety and efficacy of indinavir are unknown.

Lamivudine

3TC (Glaxo Wellcome)
150 mg tablets
10 mg/mL oral solution

Indication: HIV infection
The treatment of HIV infection with a nucleoside analogue, such as zidovudine, is only temporarily effective. There are also the problems of toxicity and the emergence of resistant viral strains. These problems are being addressed by treating patients with combinations of drugs.

Lamivudine, an analogue of cytidine, has been studied in combination with zidovudine. Both drugs act by inhibiting viral reverse transcriptase and lamivudine is active against strains which are resistant to zidovudine. Compared to zidovudine alone, the combination results in a significant increase in CD4 lymphocyte counts. Patients who have been previously treated with zidovudine also benefit.

Patients take lamivudine twice a day. The drug is well absorbed with a bioavailability over 80%. Food delays absorption. Lamivudine is cleared mainly by the kidneys so the dose is adjusted if there is renal impairment. The half-life is 5-7 hours.

Adverse effects are common and similar to those seen in patients treated with zidovudine. The most common complaints are nausea, abdominal discomfort, headache, malaise and fatigue. Abnormal liver function tests and anaemia can occur during treatment. When lamivudine is used alone, resistant viral strains can develop rapidly.

The pivotal efficacy studies in adults only lasted 24 weeks and the outcomes are not clinical end-points. Although the combination of lamivudine and zidovudine is effective, it is unclear when the combination should be used in the course of a HIV infection. For example, should all patients be given the combination when their CD4 counts fall to levels that were studied in the trials?

Raltitrexed

Tomudex (ICI Pharmaceuticals)
vials containing 2 mg as lyophilised powder

Indication: colorectal cancer
Thymidylate synthetase is an enzyme involved in the synthesis of DNA. Anticancer drugs such as methotrexate and fluorouracil (5FU) have an effect on the enzyme, but raltitrexed is a more specific inhibitor. Inhibition of thymidylate synthetase leads to cell death.

Raltitrexed has been studied in patients with advanced colorectal cancer. It is given by infusion every 3 weeks, in the absence of toxicity. Half of a radiolabelled dose will not be recovered, suggesting that some raltitrexed is retained in the tissues. Traces of the radiolabel can still be found in red blood cells 29 days after an infusion. The drug is mainly excreted unchanged in the urine so the dose is modified if renal function is reduced. Serum creatinine should be measured before each treatment.

Many of the patients experience adverse reactions. The most common adverse effects are gastrointestinal, including diarrhoea, anorexia, nausea and vomiting. Blood counts and liver function should be tested before each treatment, because raltitrexed can cause leucopenia, anaemia and increased liver enzyme concentrations. Other adverse effects include asthenia (42% of patients), fever and rashes.

Raltitrexed has been compared with 5FU and leucovorin in patients with previously untreated advanced colorectal cancer.¹ After a mean follow-up of 5 months, over half the patients had died or had disease progression. Of the 222 patients given raltitrexed, 44 had a response, compared with 27 of the 212 patients given the other treatment. There were no significant differences in survival or time to progression of the disease. Adverse effects were similar except fewer patients developed thrombocytopenia or mucositis with raltitrexed. However, increases in liver enzymes were more common.

Although the results of treatment with raltitrexed or 5FU and leucovorin are similar, treatment with raltitrexed requires fewer days in hospital. This may be important to patients with a poor prognosis.

R E F E R E N C E
1. Tomudex Colorectal Cancer Study Group. 'Tomudex' (ZD 1694): Results of a randomised trial in advanced colorectal cancer demonstrate efficacy and reduced mucositis and leucopenia. Eur J Cancer 1995;31A:1945-54.

Saquinavir mesylate

Invirase (Roche Products)
200 mg capsules

Indication: HIV infection
Most of the effective antiviral drugs are analogues of nucleic acids and act in a similar way.¹ Saquinavir interferes with a different stage of the life-cycle by inhibiting the enzyme HIV protease. This reduces viral replication and infectivity.

Saquinavir is taken 3 times a day. Food increases absorption so the dose should be taken within two hours of a meal. Bioavailability is low (4%) because of incomplete absorption and extensive first-pass metabolism. Most of the metabolites are excreted in the faeces. As the metabolism of saquinavir involves the P450 (CYP3A4) system, it has the potential for interaction with several other drugs such as nifedipine, terfenadine and ketoconazole. In theory, it should not interact with drugs metabolised by the CYP2D6 system such as many antidepressants.

The activity and safety of saquinavir has been investigated in relatively short studies using surrogate end-points such as CD4 cell counts. In a 16-week study of previously untreatedHIV positive patients, saquinavir increased cell counts with the maximum increase at around week 4.² This study and other evidence are insufficient to allow the use of saquinavir as monotherapy. It has only been approved for use in combination with other antiretroviral agents. An ongoing study suggests that saquinavir and zalcitabine may be more efficacious than either drug used alone.

Saquinavir is much more active against viral protease than human proteases so it has a reasonable safety profile. The most common adverse effects are asthenia, headache and diarrhoea.

R E F E R E N C E S
1. Locarnini S. Antiviral drugs - mechanisms of action. Aust Prescr 1993;16:78-81.

2. Kitchen VS, Skinner C, Ariyoshi K, Lane EA, Duncan IB, Burckhardt J, et al. Safety and activity of saquinavir in HIV infection. Lancet 1995;345:952-5.

Valaciclovir

Valtrex (Glaxo Wellcome)
500 mg tablets

Indication: herpes zoster
In 1994, the introduction of famciclovir offered a 3 times daily alternative to 5 times a day treatment with acyclovir. The manufacturers of acyclovir have now introduced their own 3 times a day treatment for shingles.

Although valaciclovir is considered to be a new chemical entity, it is an ester of acyclovir. Following absorption, valaciclovir is rapidly converted to acyclovir. Less than 1% of a dose of valaciclovir is recovered unchanged in the urine; it is mainly eliminated as acyclovir and metabolites of acyclovir. As acyclovir is only partially absorbed from the gut, a higher plasma concentration of acyclovir can be obtained by giving valaciclovir.

Like acyclovir, valaciclovir is approved for the treatment of herpes zoster in immunocompetent adults presenting within 72 hours of the rash, and also for ophthalmic zoster. The patients most likely to benefit from treatment are those over 50 years old. In these patients, treatment may shorten the duration of pain by a few days. The preventive effect of valaciclovir for post-herpetic neuralgia is unclear.

The most common adverse effects of treatment with valaciclovir are nausea and headache. Doses should be reduced in patients with renal impairment.

While valaciclovir adds to the choice of therapy, not all patients with herpes zoster require treatment with an antiviral drug.

Answers to self-test questions
1. False	2. False	3. False	4. True
5.True	6. False	7. True	8. False