(Aust Prescr 1998;21:49-55)
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.
Glucobay (Bayer)
50 mg and 100 mg tablets
Indication: diabetes mellitus
At present, non-insulin dependent diabetes can be managed with non-drug treatment, a biguanide or a sulfonylurea. If the blood glucose is not well controlled by these treatments, the patient can now be offered acarbose. Although acarbose has been approved for use in any patient who does not respond to a diet, it will be most useful as an addition to other oral hypoglycaemic drugs or when they are contraindicated or not tolerated.
Acarbose is a saccharide which competes with oligosaccharides for the binding sites on the intestinal glucosidase enzymes such as sucrase and maltase. As acarbose has a high affinity for the binding sites, it acts as a reversible enzyme inhibitor. This results in delayed absorption of dietary carbohydrate and therefore a reduced postprandial rise in blood glucose.
The tablets are taken whole just before a meal or chewed with the first few mouthfuls of food. Acarbose acts in the small intestine and only 1-2% is absorbed. Half of each dose is excreted in the faeces, but there are many metabolites which may be absorbed. (Approximately 35% of a radio-labelled dose will appear in the urine.) Patients with severe renal disease (creatinine clearance <25 mL/minute) should not take acarbose.
In clinical trials, acarbose reduced concentrations of glycosylated haemoglobin (HbA1c) significantly more than placebo. However, in one study of 40 patients who had not responded to diet alone, the difference was not significant.1 Acarbose has also been studied as an addition to treatment with a sulfonylurea. This can lead to further reductions in HbA1c. Although these additional reductions are statistically significant, they are not large. For example, in one study, the mean effect was to reduce HbA1c by 0.54%. Although acarbose has been available overseas for a few years, it is not yet clear if the drug leads to reduced complications or avoids the need to start insulin.
The potential benefits of acarbose are not without the risk of adverse effects. The passage of undigested dietary carbohydrate into the small intestine results in flatulence, diarrhoea and abdominal pain in the majority of patients. These symptoms are dose dependent and may improve with time. If the diarrhoea persists, the dose may have to be reduced or stopped. Acarbose should not be prescribed to patients with chronic intestinal problems such as inflammatory bowel disease or malabsorption.
Acarbose does not induce hypoglycaemia unless it is being used with other hypoglycaemic drugs. Patients who develop acute hypoglycaemia should be given glucose as acarbose will slow the response to sucrose (cane sugar).
Higher doses of acarbose can increase liver transaminases. Patients taking more than 600 mg daily should have monthly liver function tests.
Reference
1. Hotta N, Kakuta H, Sano T, Matsumae H, Yamada H, Kitazawa S, et al. Long-term effect of acarbose on glycaemic control in non-insulin-dependent diabetes mellitus: a placebo-controlled double-blind study. Diabet Med 1993;10:134-8.
Lipitor (Parke Davis)
10 mg, 20 mg and 40 mg tablets
Indication: hypercholesterolaemia
Patients with persistently high concentrations of cholesterol should receive dietary therapy. If this does not reduce the cholesterol, drug treatment should be considered. The choice of drugs includes the HMG CoA reductase inhibitors. Atorvastatin is a new member of this class.
A daily dose of 10 mg will control hypercholesterolaemia in most patients. A response occurs within two weeks and reaches a maximum in one month. The cholesterol concentration is then measured and the dose adjusted accordingly.
Absorption is reduced by food and antacids, but this may not influence the drug's effects. Atorvastatin is metabolised in the liver and first-pass metabolism reduces its bioavailability to 14%. Most of the metabolites are active so its effects last longer than its half-life of 14 hours. Liver function should be tested before treatment and periodically during treatment. As the metabolism involves cytochrome P450 3A4, there is a potential for interactions with other drugs, such as erythromycin, associated with this enzyme system. Atorvastatin is contraindicated in patients with active liver disease, but, as its metabolites are excreted in bile, it can be used in patients with renal insufficiency.
Compared with placebo, atorvastatin reduces total cholesterol, LDL cholesterol and plasma triglycerides. Comparative studies found that after 16 weeks' treatment with atorvastatin, the reductions in LDL cholesterol were greater than for lovastatin, pravastatin and simvastatin.
The adverse effects of atorvastatin resemble those of other HMG CoA reductase inhibitors. Less than 2% of the patients in trials had to withdraw because of adverse effects. The most frequent complaints are constipation, flatulence, dyspepsia and abdominal pain. Other adverse events seen in trials include muscle cramps, myopathy, hepatitis and cholestatic jaundice.
In addition to interactions involving cytochrome P450 3A4, atorvastatin interacts with digoxin, oral contraceptives and cholestyramine.
Although atorvastatin appears to be more potent than other drugs in its class, it should not yet supersede them. The other drugs are accumulating data on clinical end-points, while the effect of atorvastatin on morbidity and mortality is unknown, as is its long-term safety.
The manufacturer has studied atorvastatin in hypertriglyceridaemia.1 Although the study only lasted 4 weeks, total triglycerides were reduced; however, there is currently insufficient evidence to support this indication.
Reference
1.#bakker
Bakker-Arkema R, Davidson MH, Goldstein RJ, Davignon J, Issaacsohn JL,
Weiss SR, et al. Efficacy and safety of a new HMG-CoA reductase
inhibitor, atorvastatin, in patients with hypertriglyceridemia. JAMA
1996;275:128-33.
Cipramil (Lundbeck)
20 mg tabletsIndication: depression
The number of new antidepressants continues to increase. Citalopram adds to the choice of selective serotonin reuptake inhibitors (SSRIs).
The drug is taken as a single daily dose. It is rapidly absorbed with a bioavailability of about 80%. Citalopram is metabolised and produces some active metabolites. The half-life is approximately 36 hours, so a steady state is reached in about one week. Only 12% is excreted unchanged in the urine, so no dose adjustment is needed if there is moderate renal impairment. Low doses should be used if hepatic function is reduced.
Citalopram is more effective than placebo. Some studies have compared citalopram with other antidepressants. No statistically significant differences have been found between citalopram and imipramine, fluoxetine, fluvoxamine and mianserin.
The adverse effects of citalopram resemble those of other SSRIs. Compared with placebo, citalopram is more likely to cause dry mouth, nausea, drowsiness and tremor. As part of the metabolism of citalopram involves cytochrome P450 CYP 2D6, there is a potential for interaction with other drugs metabolised by this system. This potential seems to be less than for fluoxetine or paroxetine. Cimetidine can increase the plasma concentration of citalopram.
Most of the studies of citalopram have lasted for 4-8 weeks. Depression may last much longer and can relapse if not treated for long enough. Citalopram has been available in Europe for a few years, so presumably more information on its long-term effectiveness and safety should become available.
Rescriptor (Pharmacia & Upjohn)
100 mg tablets
Indication: HIV infection
Combination therapy is the currently favoured approach to treating HIV infections. The combinations can include non-nucleoside reverse transcriptase inhibitors. Nevirapine is already available and now delavirdine has been approved for use in combination with nucleoside analogues.
Delavirdine is a selective non-competitive inhibitor of HIV 1 reverse transcriptase. Its effect is to reduce viral replication. Unfortunately, the virus rapidly develops resistance if delavirdine is used as monotherapy.
Approval for marketing is based on two double-blind trials of delavirdine, one of which is still in progress. This trial is comparing the combination of delavirdine and zidovudine with zidovudine alone. The combination appears to be more effective in reducing viral RNA and increasing CD4 lymphocyte counts. The other trial has compared didanosine with a combination of didanosine and delavirdine in patients who have previously taken zidovudine. During the first 8 weeks of treatment, the CD4 lymphocyte count was significantly higher and the reduction in RNA significantly greater in the patients given the combination.
Delavirdine is taken 3 times a day. If didanosine is also being taken, it should not be taken simultaneously. Delavirdine is metabolised by cytochrome P450 3A and possibly P450 2D6, so there is a potential for other interactions. The drugs which interact include rifampicin, rifabutin, phenytoin, carbamazepine, warfarin and calcium channel blockers. Plasma concentrations of delavirdine may also be affected by fluconazole, ketoconazole and saquinavir. Zidovudine and ritonavir have no significant effect on delavirdine concentrations, but delavirdine may increase the concentrations of indinavir. The manufacturers also advise that delavirdine should not be taken with terfenadine, astemizole, triazolam, alprazolam, midazolam or cisapride.
Up to half the patients taking delavirdine will develop a rash. Patients with lower CD4 cell counts are more likely to develop the rash. In most cases, the rash resolves in a few weeks. Other adverse effects include nausea, headache and dizziness.
Overall, delavirdine has a modest benefit. Its efficacy is mainly based on surrogate end-points and in the comparison with didanosine there was no improvement in survival. The role of delavirdine in combination therapy, e.g. with protease inhibitors, will require more trials.
Gonal-F (Serono)
ampoules containing 75 IU or 150 IU as powder for reconstitution
Indication: follicular development
Follitropin alpha is a genetically engineered follicle stimulating hormone. A similar product, follitropin beta is already on the market, but has slightly different indications. Follitropin alpha has been approved for controlled ovarian hyperstimulation in women `undergoing assisted reproductive technologies' and for the treatment of anovulatory infertility in women who have a contraindication or have failed to respond to clomiphene.
Karvea (Sanofi Winthrop)
Avapro ( Bristol-Myers Squibb)
75 mg, 150 mg and 300 mg tablets
Indication: hypertension
Irbesartan is the second angiotensin II receptor antagonist to be registered. (Losartan is already available in Australia.) Blocking the AT1 receptor stops the vasoconstrictive effects of angiotensin.
The usual dose of irbesartan is 150 mg daily. This is reduced if the patient is volume- or salt-depleted e.g. after treatment with diuretics. The tablets have a bioavailability of 60-80% which is unaffected by food. Most of the drug is metabolised by the liver. It has a half-life of 11-15 hours with the metabolites being excreted in faeces and urine.
Clinical trials have compared irbesartan with placebo and found it to have a greater antihypertensive effect. This effect appears within two weeks of starting treatment and peaks within 6 weeks. The mean decreases in systolic/diastolic blood pressure after 6-12 weeks' treatment with 150 mg irbesartan are approximately 7.5-10/4.5-6 mmHg. When the response is inadequate, the dose can be increased to 300 mg once daily. If the blood pressure is still not controlled by this dose, then hydrochlorothiazide can be added.
In clinical trials, 3.3% of the patients taking irbesartan withdrew because of adverse events. More patients withdrew from the placebo group. While headaches, fatigue and muscle pain may be reported, their frequency is not significantly greater than placebo. Cough occurred in 2.8% of the patients taking irbesartan and 2.7% of the placebo group. As sudden deaths have been reported, extra caution is needed when prescribing irbesartan for hypertensive patients who also have heart failure or a history of arrhythmia. Patients with heart failure or impaired renal function should have their serum potassium measured during treatment with irbesartan.
Irbesartan is probably as effective as an ACE inhibitor at lowering the blood pressure; however, there are no data on its long-term effects. Until more data are available, irbesartan will probably be reserved for use in patients who cannot take an ACE inhibitor.
Camptosar (Pharmacia & Upjohn)
20 mg/mL in 2 mL and 5 mL glass vials
Indication: rectal or colonic cancer
The topoisomerases are enzymes involved in many cellular functions including the replication of DNA. Inhibitors of these enzymes have been studied in the treatment of cancer. For example, doxorubicin inhibits topoisomerase II. Irinotecan inhibits topoisomerase I, resulting in breaks in the strands of DNA.
This drug is a semisynthetic derivative of camptothecin which is a plant extract. Irinotecan has been investigated in phase II studies looking mainly at response rates rather than survival. It has been found to have some effect in solid tumours.
As colorectal tumours have higher concentrations of topoisomerase I, they may be more sensitive to enzyme inhibition than the normal cells of the mucosa.
The approval for marketing is mainly based on 3 phase II studies of 304 patients with metastatic colorectal cancer. The patients' cancers had either recurred or progressed after treatments including 5-fluorouracil. These patients were given irinotecan once a week for 4 weeks. They then had a two week rest period. The number of additional courses depended on the patients' responses and their tolerance of the drug.
Patients who were given the recommended starting dose (125 mg/m2) had an overall response rate of 15%. The median duration of this response was approximately 6 months.
The benefits of treatment are offset by the toxicity of irinotecan. Although only 4% of the patients discontinued treatment, 1.6% (5 people) died due to potentially drug-related causes. Nearly 90% of the patients develop diarrhoea. Nausea, vomiting and abdominal pain occur in the majority of patients. More than half the patients develop anaemia, leucopenia or neutropenia. Patients who have received radiotherapy are more likely to develop neutropenia. Other adverse effects include asthenia, fever and alopecia.
Irinotecan forms an active metabolite and liver metabolism seems to be the main route of excretion. However, the drug has not been evaluated in patients with hepatic dysfunction. As a life-threatening pulmonary syndrome was seen in early trials, there have also been few studies of patients with compromised pulmonary function or pleural effusions. Irinotecan has some cholinergic effects so extra caution is needed if it is given to patients with asthma or cardiovascular disease. Intravenous atropine may be needed in patients who develop diarrhoea within 24 hours of treatment.
Although irinotecan may offer some hope, the proportion of patients with metastatic disease who will benefit is unclear. Many will have complications such as ascites which may restrict the use of the drug in practice. As the median number of courses is 3, many of the patient's remaining weeks of life are going to be occupied with receiving and recovering from treatment.
Xalatan (Pharmacia & Upjohn)
2.5 mL in 5 mL bottles
Indication: glaucoma
Latanoprost is a synthetic analogue of prostaglandin F2
. When instilled into the eyes, the drug is absorbed through the cornea and hydrolysed to its active form. The outflow of aqueous humour is increased and therefore intraocular pressure falls.
The peak concentration in the eye is reached two hours after a dose, but the maximum effect occurs after 8-12 hours. As intraocular pressure remains reduced for at least 24 hours, latanoprost only needs to be used once a day. Approximately half of a dose is absorbed systemically and then metabolised in the liver.
Latanoprost has been compared with timolol in randomised double-blind studies. After 6 months, intraocular pressure was reduced by 27-34% in the latanoprost group and by 20-33% in the timolol group.
Adverse events occur in 5-15% of patients. Common complaints are burning, stinging and itching, redness of the eyes and blurred vision. With time, the pigmentation of the iris may change. This alteration in eye colour affected approximately 7% of the 460 patients who took latanoprost during clinical trials.
At present, the long-term effects of latanoprost are unknown. Will treatment prevent loss of vision due to glaucoma? The drug has only been approved for the reduction of elevated intraocular pressure in patients with open-angle glaucoma and ocular hypertension who are intolerant of, or insufficiently responsive to, other drugs. Although this suggests that latanoprost may be added to other treatments, there are limited data on combined therapy.
Lomide (Alcon Laboratories)
0.1% eye drops
Indication: allergic conjunctivitis
Seasonal allergic conjunctivitis and vernal conjunctivitis are two types of allergic conjunctivitis. Lodoxamide is thought to help to improve these conditions by stabilising mast cells.
This inhibits the Type I hypersensitivity reaction in the same way as sodium cromoglycate.
As the eye drops have no vasoconstrictor, anti-inflammatory or histamine effect, they are not good at relieving acute symptoms. They must be given regularly 4 times a day for prevention. The patient will usually notice an improvement within a few days. While continued treatment may be of benefit, there are limited data on long-term use.
Clinical trials suggest that lodoxamide is more effective than sodium cromoglycate eye drops for vernal conjunctivitis. There is also the possibility that lodoxamide may allow a reduction in the use of steroid eye drops by patients with severe vernal conjunctivitis. The evidence suggests that lodoxamide is probably as effective as sodium cromoglycate for seasonal allergic conjunctivitis.
There is little absorption of lodoxamide into the systemic circulation. Most adverse effects occur following instillation e.g. stinging or burning. Patients should be advised not to wear soft contact lenses during treatment.
Posicor (Roche)
50 mg and 100 mg tablets
Indication: angina, hypertension
Calcium channel antagonists block the entry of calcium into cells via the L channels. Mibefradil is believed to also block the T channels.
The effect of mibefradil on vascular smooth muscle results in peripheral vasodilatation. As peripheral vascular resistance is reduced, the blood pressure falls. The heart rate is reduced and there is no reflex tachycardia.
In trials lasting up to 14 weeks, mibefradil was more effective than placebo at reducing blood pressure. A dose of 50 mg reduced systolic blood pressure by a mean of 13 mmHg and diastolic pressure by 9.3 mmHg. There is some evidence to suggest that mibefradil is as effective as amlodipine and possibly more effective than nifedipine and diltiazem at lowering blood pressure.
In patients with chronic stable angina, mibefradil delays the onset of angina during exercise tests. The mean increase in exercise duration, 24 hours after a 100 mg dose, is 77 seconds. Holter monitoring reveals that mibefradil also significantly reduces the number and duration of episodes of silent ischaemia. Compared to amlodipine, mibefradil has a greater effect on exercise tolerance tests, but a similar effect to diltiazem.
The single daily dose is rapidly absorbed. There is first-pass metabolism which can become saturated so the bioavailability at steady state can reach 90% compared to 70% after a single dose. There are two metabolic pathways, one of which involves cytochrome P450. The metabolites are excreted in the bile and urine. After repeat doses, the half-life is 17-35 hours as mibefradil has non-linear kinetics. This can lead to the development of adverse effects if small increases in dose are made at higher doses.
Some of the adverse reactions to mibefradil are due to its vasodilator effect, e.g. swelling of the legs and dizziness. The most common adverse reaction is headache. Some patients will develop heart block on their ECG. Second or third degree block is a contraindication and mibefradil is not recommended for patients with congestive heart failure.
Mibefradil can affect peak concentrations of digoxin. Cytochrome P450 CYP 3A4 and 2D6 are inhibited by mibefradil resulting in potentially serious interactions. For example, co-administration with terfenadine is contraindicated.
Mibefradil is effective in mild to moderate hypertension and chronic stable angina; however, long-term safety data are limited.
Viracept (Roche)
250 mg tablets
50 mg/g oral powder
Indication: HIV infection
Drugs for HIV infection tend to reach the market more rapidly than previously. Nelfinavir is the latest to be approved on the basis of its effects on surrogate end-points. Like the other protease inhibitors (indinavir, ritonavir and saquinavir1), nelfinavir should only be used in combination with other treatments. (Combination helps to reduce the risks of the virus becoming resistant.)
The tablets should be taken with a meal as this will at least double the plasma concentration. Children (over 2 years old) who cannot swallow tablets can mix the oral powder with a small amount of food or fluid. The drug has a half-life of 3-5 hours with most of the dose being metabolised. This metabolism involves many isoforms of cytochrome P450.
In view of potential interactions, nelfinavir should not be given with astemizole, terfenadine, cisapride, midazolam, triazolam, ergot derivatives or rifampicin. Other drugs which interact include oral contraceptives, phenytoin, carbamazepine and rifabutin. There may be other possible interactions due to the potential ability of nelfinavir to inhibit hepatic enzymes. For example, fluvoxamine and fluoxetine have the potential to inhibit cytochrome P450 3A4. Alprazolam is also metabolised by this isoenzyme.
Inhibition of HIV protease prevents the production of mature virus. This results in a fall in viral RNA concentrations. These concentrations can be used to follow the activity of the disease. One study compared zidovudine and lamivudine alone and in combination with nelfinavir. The decrease in viral RNA was significantly greater in the patients who took all 3 drugs. They also had a significantly larger increase in CD4 lymphocytes.
Another study compared stavudine (a nucleoside analogue) and nelfinavir with stavudine alone. Again, the combination therapy had a significantly better effect on the surrogate markers.
Over 1500 patients were involved in the trials of nelfinavir. Diarrhoea was the main adverse reaction they experienced. Patients may also complain of headache, abdominal pain or asthenia. As safety data are limited, the relationship of some adverse events to the drug is unclear. Serious adverse events have included pancreatitis, altered liver function, anaemia, leucopenia, thrombocytopenia and, in patients with haemophilia, an increased bleeding tendency. Some patients develop hyperglycaemia and may require insulin or oral hypoglycaemic drugs.
The marketing approval is based on studies lasting up to24 weeks so there are no long-term clinical outcomes. The pattern of resistance to nelfinavir may differ from those of the other protease inhibitors. More studies are needed to find out if nelfinavir should be used when other protease inhibitors fail or if it should be used first.
Reference
1. Deeks SG, Smith M, Holodniy M, Kahn JO. HIV-1 protease inhibitors. JAMA 1997;277:145-53.
Samarium [Sm 153] lexidronam pentasodium
Quadramet (Australian Nuclear Science and Technology Organisation)
6 GBq/3 mL frozen sterile aqueous solution
Indication: bone metastases
Breast cancer and prostate cancer are two examples of tumours which can spread to bone. Bony metastases can be very painful and palliative treatment is required. Radiotherapy is often used, but has its limitations. This new product aims to deliver a dose of radiation internally.
Samarium lexidronam pentasodium was also known as samarium ethylenediaminetetramethylene phosphoric acid (EDTMP). The EDTMP is a chelating agent that binds to bone and the samarium component is a radioactive metal. Beta and gamma radiation are emitted.
The agent is kept frozen in a lead pot. It should be used within 8 hours of thawing out. The dose is given intravenously over one minute. Samarium is rapidly cleared from the plasma and is taken into bone. The uptake by bone is related to the number of metastatic sites. This delivers a higher dose of radiation to bony metastases than other tissues.
An Australian study1 in the early development of the treatment gave samarium to 23 patients with painful metastases. This produced pain relief in 14 patients with a median duration of 8 weeks. Significant effects are present a week after treatment, but some patients may have increased pain in the first few days after treatment.
The radioactivity affects normal bone so myelosuppression is a problem. The platelet and white blood cell counts reach a nadir 3-5 weeks after treatment. Although most patients in clinical trials will report adverse events, the incidence, apart from myelosuppression, is not very different from that of patients given a placebo.
Samarium 153 is excreted in the urine so the bladder wall is exposed to radiation. Patients are encouraged to drink at least 500 mL of fluid before treatment and to empty the bladder as frequently as possible afterwards. Urinary excretion is complete in approximately 6 hours.
The role of samarium 153 for bony metastases needs to be clarified with respect to other treatments such as strontium 89. It can be considered for pain relief in patients with metastases that appear on radionuclide scans. Caution is needed if there is evidence of an impending problem such as spinal cord compression.
Reference
1. Turner JH, Claringbold PG. A phase II study of treatment of painful multifocal skeletal metastases with single and repeated dose samarium 153 ethylenediaminetetramethylene phosphonate. Eur J Cancer 1991;27:1084-6.
Tasmar (Roche)
100 mg and 200 mg film-coated tablets
Indication: Parkinson's disease
Patients with Parkinson's disease have reduced dopamine concentrations in the substantia nigra. Levodopa is the mainstay of treatment as it can be converted to dopamine after it crosses the blood-brain barrier. To reduce the peripheral effects of dopamine, levodopa is usually given with a decarboxylase inhibitor such as benserazide or carbidopa. Although these combinations are effective, patients still have problems e.g. a `wearing off' effect towards the end of a dose interval. Tolcapone aims to maintain stable plasma concentrations of levodopa by slowing its metabolism. This is achieved by tolcapone reversibly inhibiting catechol-o-methyl transferase, a key enzyme in the metabolism of levodopa.
Tolcapone is given 3 times a day. The drug is rapidly absorbed, but absorption is delayed by food. Tolcapone can cross the blood-brain barrier, but as it is highly protein bound, most of the drug stays in the plasma. Almost all of the dose is metabolised with 60% of the metabolites being excreted in the urine. Clearance can be reduced by cirrhotic liver disease.
When studied in patients experiencing the wearing off of levodopa effects, tolcapone was significantly more effective than placebo. The `off time' was reduced by 20-30%, `on time' was increased and the dose of levodopa could be lowered. Improved motor function was also seen in studies of patients who were not experiencing fluctuations.
As tolcapone increases the availability of levodopa, some adverse effects can be predicted. A reduction in the dose of levodopa may diminish these effects. For patients on higher doses of levodopa, the reduction should be made before starting tolcapone. In the clinical trials, adverse effects included dyskinesia, nausea, disturbed sleep and hallucinations. Approximately 16% of the patients discontinued the drug, the majority (6% of patients) because of diarrhoea. Liver function should be tested before treatment and monthly during the first 6 months.
As tolcapone affects catecholamine metabolism, it can potentially interact with drugs affecting catecholamine concentrations. The drug has been given with selegeline, but there are no data about interactions with monoamine oxidase A inhibitors. There is also a potential to interact with other antidepressants such as venlafaxine and desipramine. It is also possible that tolcapone interacts with warfarin.
Tolcapone is a useful adjunct to levodopa, but it is not yet clear where it fits in with the other treatments for Parkinson's disease.
Navelbine (ASTA Medica)
10 mg/mL in 1 mL and 5 mL vials
Indication: breast cancer and non-small cell lung cancer
Chemotherapy with several drugs has an increasing role in breast cancer.1 Vinorelbine adds to the options available for advanced disease after the failure of other treatments. It is a semi-synthetic alkaloid resembling vinblastine.
Vinorelbine was given to 115 patients with advanced breast cancer which was resistant to chemotherapy with anthracycline. There was a response in approximately 16% of the patients, with a duration of approximately 32 weeks.
The drug is diluted and given by slow injection or infusion once a week. High concentrations occur in the lungs and vinorelbine is highly bound to platelets and lymphocytes. The drug is metabolised by the liver so the dose must be adjusted if liver function is impaired. Vinorelbine has a half-life of 28-43 hours.
As the drug is thought to inhibit mitosis, some of its adverse effects are predictable. Neutropenia occurs in about half the patients. Subsequent doses should be reduced or delayed according to the neutrophil count. Anaemia and thrombocytopenia can also occur. The vinca alkaloids have been associated with peripheral neuropathy, but this may be less pronounced with vinorelbine. Autonomic neuropathy may cause constipation. Although over 25% of patients develop nausea, severe vomiting does not occur often enough to warrant routine use of serotonin receptor antagonists. Injection site reactions are a problem. The vein should be flushed through after vinorelbine is given. Other adverse effects include chest pain, shortness of breath and fatigue.
Although vinorelbine has relatively less toxicity than some other drugs, its role will require further study. For example, how does vinorelbine compare with the taxanes in advanced breast cancer?
Vinorelbine has been studied in other cancers and has been approved for use in non-small cell lung cancer. When vinorelbine is given alone to patients with small cell lung cancer, the response rate is 14%. If the patients are given vinorelbine with cisplatin, the response rate increases to 28-43%, but the combination is likely to be more toxic. Although survival is said to be increased, non-small cell lung cancer has a very poor prognosis. Any increase in life expectancy will be measured in weeks as the median survival time for untreated disease is less than 6 months.
Reference
1. Ackland SP. Drug treatment of breast cancer. Aust Prescr 1998;21:15-9.
NEW STRENGTHS
Augmentin Duo forte (SmithKline Beecham)
tablets containing 875 mg amoxycillin and 125 mg clavulanic acid
Serc (Solvay)
16 mg tablets
Neoral (Novartis)
10 mg capsules
Atrovent Adult uni-dose vials (Boehringer Ingelheim)
500 microgram/mL nebuliser solution (ampoules)
Lucrin Depot-3-Month (Abbott)
22.5 mg powder for injection
NEW FORMULATIONS
Madopar Dispersible
50 mg levodopa/12.5 mg benserazide tablets
100 mg levodopa/25 mg benserazide tablets
Zofran (Glaxo Wellcome)
4 mg/5mL syrup in 50 mL bottles
