Vinorelbine in advanced non-small cell lung cancer. A pharmacoeconomic review.

UNLABELLED: Vinorelbine is a semisynthetic vinca alkaloid that is effective against advanced non-small cell lung cancer (NSCLC). Myelosuppression is the primary dose-limiting toxicity; vinorelbine is otherwise relatively well tolerated. Two studies assessed the cost effectiveness of vinorelbine with or without cisplatin based primarily on data from a phase III comparison with vindesine plus cisplatin. Survival and cost data from this study were supplemented with those from other sources. One model simulated total management costs for the 4986 patients diagnosed with stage IV NSCLC in Canada in 1992. The other applied US cost data to the outcomes from the phase III trial. Using vinorelbine monotherapy or vinorelbine plus cisplatin produced a survival benefit and net cost savings compared with best supportive care according to the Canadian model (and preliminary data from a third analysis, conducted in the US). In the Canadian analysis, incremental cost effectiveness for inpatient or outpatient vinorelbine plus cisplatin ranged from 7450 Canadian dollars ($Can) to $Can30,770 (1993 values) per year of life saved (YLS) compared with outpatient cisplatin plus either etoposide or vinblastine. Cost-effectiveness ratios for vinorelbine plus cisplatin in the US analysis (1994 values) were $US18,000 (vs cisplatin plus etoposide) and $US15,500 (vs cisplatin plus vindesine) per YLS [all inpatient administration]. Detailed pharmacoeconomic comparisons with other current standard regimens (e.g. paclitaxel plus either cisplatin or carboplatin) are not available. Sensitivity analyses suggest that the cost effectiveness of vinorelbine-based therapy is robust to changes in assumptions regarding efficacy and the cost of managing toxicity. Limitations of the available pharmacoeconomic data include the retrospective nature of the analyses, inclusion of data from sources other than the main phase III trial (e.g. those for best supportive care and some chemotherapy regimens), and exclusion of some costs for hospitalisation and/or management of toxicity. CONCLUSIONS: Although some limitations apply, the available data suggest that vinorelbine alone or in combination with cisplatin is cost saving compared with best supportive care for NSCLC, and that vinorelbine plus cisplatin is cost effective compared with some other combination regimens. The pharmacoeconomic placing of vinorelbine in relation to a number of other currently recommended first-line treatments for NSCLC has yet to be resolved, and data from ongoing multicentre phase III trials are awaited with interest. In the meantime, vinorelbine-based chemotherapy appears to be a suitable choice for first-line treatment of advanced NSCLC from both clinical and pharmacoeconomic perspectives.

Mexiletine. A review of its therapeutic use in painful diabetic neuropathy.

UNLABELLED: Mexiletine is an orally active local anaesthetic agent which is structurally related to lidocaine (lignocaine) and has been used for alleviating neuropathic pain of various origins. Mexiletine has been evaluated in several randomised, placebo-controlled trials in patients with painful diabetic neuropathy. The drug decreased mean visual analogue scale (VAS) pain ratings in all studies that used this measure, although in only 2 studies was this effect significantly greater than the often substantial responses seen with placebo. The clinical significance of these decreases is not clear. Statistically significant (vs placebo) reductions in VAS pain ratings were observed in 16 patients receiving mexiletine 10 mg/kg/day for 10 weeks in 1 study and in nocturnal (but not diurnal) pain in 31 patients receiving mexiletine 675 mg/day for 3 weeks in another. Retrospective analysis of another study revealed that mexiletine recipients (225 to 675 mg/day) who described their pain as stabbing, burning or formication on the pain-rating-index-total instrument of the McGill Pain Questionnaire, experienced statistically significant reductions in VAS pain scores after 5 weeks, compared with placebo recipients. Mexiletine generally did not have a significant influence on the quality of sleep in patients with diabetic neuropathy. In Japanese patients, statistically significant reductions in subjective pain ratings were achieved with mexiletine 300 mg/day in 1 study and with 450 mg/day in a further study. In controlled trials, the frequency of adverse events in patients receiving mexiletine for painful diabetic neuropathy ranged from 13.5 to 50%. Gastrointestinal complaints, of which nausea was the most frequent, were the most common adverse events in mexiletine recipients. Central nervous system complaints were uncommon, but included: sleep disturbance, headache, shakiness, dizziness and tiredness. Serious cardiac arrhythmias have not been reported in patients receiving mexiletine for painful diabetic neuropathy; however, transient tachycardia and palpitations have been reported. There are significant differences in the metabolism of mexiletine between people who have cytochrome P450 2D6 [CYP2D6; extensive metabolisers (EMs)] and those who lack this isoenzyme [poor metabolisers (PMs)]. EMs, but not PMs, are susceptible to drug interactions between mexiletine and drugs that inhibit CYP2D6 (e.g. quinidine). Moreover, mexiletine inhibits CYP2D6-mediated metabolism of metoprolol and cytochrome P450 1A2-mediated metabolism of theophylline. Phenytoin and rifampicin (rifampin) induce the metabolism of mexiletine. Clearance of mexiletine is impaired in patients with hepatic, but not renal, dysfunction. Hence, dosage adjustments may be necessary in patients with liver disease. CONCLUSIONS: Tricyclic antidepressants (TCAs) are the agents of choice for painful diabetic neuropathy; however, they are ineffective in approximately 50% of patients and are generally not well tolerated. Mexiletine is an alternative agent for the treatment of painful diabetic neuropathy in patients who have not had a satisfactory response to, or cannot tolerate, TCAs and/or other drugs.

Amphotericin-B colloidal dispersion. A review of its use against systemic fungal infections and visceral leishmaniasis.

UNLABELLED: Formulation of amphotericin B with sodium cholesteryl sulphate alters the pharmacokinetic properties of the drug, particularly reducing its distribution to the kidneys. The antifungal activity in vitro of amphotericin B colloidal dispersion (ABCD) is similar to that of conventional amphotericin B (C-AmB) against true pathogenic organisms including Blastomyces, Coccidioides, Histoplasma and Paracoccidioides species and the opportunistic organisms such as Candida and Cryptococcus species. In animal models, ABCD was generally less effective than an identical dose of C-AmB, but overall was more effective because of its improved therapeutic index. Although ABCD appeared to be more effective than C-AmB in resolving infection and improving survival in patients with proven or probable invasive aspergillosis, the retrospective design of the study and the greater prevalence of neutropenia in patients treated with the conventional formulation necessitate cautious interpretation of the results. ABCD has been effective and seldom caused nephrotoxicity in patients with fungal infection who had previously failed to adequately respond or had developed renal toxicity with C-AmB. Similarly, ABCD was effective in patients with proven or suspected fungal infection after bone marrow transplantation. Preliminary results from a pilot study comparing ABCD and C-AmB in patients with neutropenia and persistent fever reported similar response rates with both formulations. ABCD is an effective treatment for visceral leishmaniasis in immunocompetent patients. In 1 study, about 12% of ABCD recipients discontinued the drug because of adverse events; infusion-related events were the most common cause of discontinuation. The renal tolerability of ABCD is better than that of C-AmB. ABCD appears to be an effective alternative to conventional amphotericin B in patients with invasive aspergillosis or visceral leishmaniasis and in those with proven or suspected systemic fungal infection who are intolerant of the conventional formulation or have pre-existing renal impairment. Preliminary data also suggest that ABCD is an alternative to C-AmB when used empirically in patients with neutropenia and fever. Nevertheless, the efficacy of ABCD compared with that of the conventional formulation has yet to be adequately demonstrated and the role of ABCD relative to that of liposomal and other lipid-based formulations has not been determined. CONCLUSIONS: ABCD, like other lipid-based and liposomal formulations of amphotericin B, has been designed to deliver the active drug to the target site, while reducing renal toxicity. The aim of increasing the therapeutic index compared with C-AmB has been achieved.

Pravastatin. A pharmacoeconomic review of its use in primary and secondary prevention of coronary heart disease.

UNLABELLED: Coronary heart disease (CHD) is a major cause of death and illness in industrialised countries. Like other hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, pravastatin reduces total and low density lipoprotein (LDL)-cholesterol levels and increases high density lipoprotein (HDL)-cholesterol levels. Cholesterol modification with pravastatin in middle-aged hypercholesterolaemic men without CHD (i.e. primary prevention) was shown in the West of Scotland Coronary Prevention Study (WOSCOPS) to reduce the incidence of fatal and nonfatal coronary events. In several other large studies, pravastatin reduced the incidence of CHD events in patients with prior CHD (secondary prevention). Large, long term studies of the relationship between cholesterol modification and CHD event rate have been conducted for some, but not all, other HMG-CoA reductase inhibitors. A UK pharmacoeconomic analysis of the WOSCOPS data indicated that primary prevention with pravastatin was associated with a cost of 20,375 Pounds per year of life gained (YLG) [discounted]. Treatment of men at high risk for CHD resulted in a lower cost estimate (13,995 Pounds/YLG). A US economic analysis based on secondary prevention with pravastatin in large plaque regression studies suggested a net cost of drug therapy of $US7124 to $US12,665 per YLG. A number of projected-risk models have attempted to calculate the cost effectiveness of primary or secondary prevention with pravastatin compared with other lipid-modifying interventions. These comparisons indicated that pravastatin was economically superior to intensive lifestyle counselling without drug therapy. Pravastatin generally appeared to be less cost effective than other HMG-CoA reductase inhibitors, although the relative effectiveness of the various drugs depended on the model considered. Risk-projection economic models are subject to methodological limitations, principally the necessity of estimating clinical effectiveness from epidemiological data (often derived from the Framingham Heart Study). An increased absolute risk of CHD improves the cost effectiveness of lipid-lowering therapy. Thus, the cost per YLG of pravastatin in secondary prevention is, in general, lower than that of primary prevention, reflecting the higher absolute risk of second versus first CHD events. However, it is important to note that individual absolute risk rates may overlap between patients receiving primary and secondary prevention. Similarly, treatment of selected individual patients at high risk for CHD events is associated with a lower cost per YLG than unselected treatment. CONCLUSION: In large clinical studies, pravastatin effectively reduced the risk of primary and secondary CHD events. These benefits come at a substantial economic cost, but one that is in line with accepted costs for other medical interventions. Selective treatment of patients or populations at high risk of CHD events improves the cost effectiveness of pravastatin therapy.

Levonorgestrel subdermal implants. A review of contraceptive efficacy and acceptability.

UNLABELLED: Levonorgestrel 6-capsule subdermal implants (Norplant) are an effective form of reversible contraception. When implanted under the skin of the upper arm, they release drug into the circulation at a relatively constant rate over 5 years. Generally, the cumulative pregnancy rate at the end of 5 years' levonorgestrel implant use is less than 2 per 100 users. The implants provide contraceptive efficacy equivalent to, or better than, that provided by other reversible methods (including oral contraceptives). Younger women are more likely than older women to become pregnant while using levonorgestrel implants. Bodyweight was positively correlated with risk of pregnancy in a number of studies, but may not be a factor with the currently available 6-capsule implant formulation. Limited data suggest that a new 2-rod levonorgestrel subdermal system (Jadelle) is as effective as the more extensively studied 6-capsule system and has a similar tolerability profile. Fertility returns rapidly after the implants are removed. Use of levonorgestrel subdermal implants is compatible with breast-feeding. In several studies, discontinuation rates were 2 to 15% during the first year of use; cumulative 5-year discontinuation rates ranged from 22 to 64 per 100 women. Despite a substantial incidence of adverse events during therapy, levels of user satisfaction are generally high. Menstrual abnormalities (increased or decreased menstrual flow, spotting, irregularity and amenorrhoea) affect most women at some time during therapy and are the most frequent reason for discontinuing levonorgestrel implants before the end of 5 years' treatment (incidence of 4.2 to 30.7 per 100 users). Mood changes and headache also may lead to discontinuation. Other reported adverse events include skin reactions (including acne), dizziness and weight gain. Serious adverse events (such as stroke, thrombotic thrombocytopenia and idiopathic intracranial hypertension) have been reported during levonorgestrel implants therapy, but the population incidence is difficult to calculate and causality is unclear. According to 3 pharmacoeconomic analyses from an institutional or managedcare perspective, all contraceptive interventions result in net cost savings. It is not clear whether levonorgestrel implants provide greater or smaller economic benefits than combined oral contraceptives. CONCLUSION: Levonorgestrel subdermal implants provide effective long term contraception. Despite a high incidence of menstrual adverse events, overall levels of user satisfaction are high, and 1-year continuation rates are better than those for combined oral contraceptives. Levonorgestrel subdermal implants are a good choice of contraceptive method in women who desire effective contraception, but who are unable to, or prefer not to, comply with an oral regimen.

Liposomal amphotericin B. Therapeutic use in the management of fungal infections and visceral leishmaniasis.

Incorporation of amphotericin B into small unilamellar liposomes (AmBisome) alters the pharmacokinetic properties of the drug, but allows it to retain significant in vitro and in vivo activity against fungal species, including Candida, Aspergillus and Cryptococcus, and parasites of the genus Leishmania. Used as prophylaxis against fungal infections in immunocompromised patients, liposomal amphotericin B appeared to reduce the incidence of both fungal colonisation and proven fungal infections, but did not affect overall survival. Empirical therapy with liposomal amphotericin B in immunocompromised adults or children with suspected fungal infections was at least as effective as therapy with conventional amphotericin B. In the largest noncomparative studies, liposomal amphotericin B produced mycological eradication in 40 and 83% of patients with proven Candida infections and 41 and 60% with proven Aspergillus infections; however, these studies included relatively few patients. Mycological eradication rates of 67 to 85% in patients with cryptococcal meningitis have been reported. Liposomal amphotericin B is an effective treatment for visceral leishmaniasis in immunocompetent adults and children, including those with severe or drug-resistant disease. The drug also produces good response rates in immunocompromised patients; however, relapse rates in these patients are high. Liposomal amphotericin B is generally well tolerated. Few patients require discontinuation or dose reduction of the drug because of adverse events. The most frequently reported adverse events are hypokalaemia, nephrotoxicity and infusion-related reactions; however, these occur significantly less often after liposomal amphotericin B than after the conventional formulation of the drug. The acquisition cost of liposomal amphotericin B is higher than that of conventional amphotericin B. Cost-effectiveness analysis did not clearly show an economic benefit for empirical liposomal amphotericin B antifungal therapy in adults; however, one model suggested that initial empirical therapy with the liposomal formulation in children may cost less per cure than initial therapy with the conventional formulation. Liposomal amphotericin B appears to be an effective alternative to conventional amphotericin B in the management of immunocompromised patients with proven or suspected fungal infections. Use of the drug is facilitated by its greatly improved tolerability profile compared with conventional amphotericin B. Because of this, liposomal amphotericin should be preferred to conventional amphotericin B in the management of suspected or proven fungal infections in immunocompromised patients with pre-existing renal dysfunction, amphotericin B-induced toxicity or failure to respond to conventional amphotericin B. Liposomal amphotericin B may also be considered for first- or second-line treatment of immunocompetent patients with visceral leishmaniasis.

Pamidronate. A review of its use in the management of osteolytic bone metastases, tumour-induced hypercalcaemia and Paget's disease of bone.

Pamidronate (APD) is a potent inhibitor of bone resorption that is useful in the management of patients with osteolytic bone metastases from breast cancer or multiple myeloma, tumour-induced hypercalcaemia or Paget's disease of bone. After intravenous administration, the drug is extensively taken up in bone, where it binds with hydroxyapatite crystals in the bone matrix. Matrix-bound pamidronate inhibits osteoclast activity by a variety of mechanisms, the most important of which appears to be prevention of the attachment of osteoclast precursor cells to bone. In patients with osteolytic bone metastases associated with either breast cancer or multiple myeloma, administration of pamidronate together with systemic antitumour therapy reduces and delays skeletal events, including pathological fracture, hypercalcaemia and the requirement for radiation treatment or surgery to bone. Pamidronate generally improves pain control. Quality-of-life and performance status scores in pamidronate recipients were generally as good as, or better than, those in patients who did not receive the drug. Overall survival does not appear to be affected by pamidronate therapy. Tumour-induced hypercalcaemia also responds well to pamidronate therapy: 70 to 100% of patients achieve normocalcaemia, generally 3 to 5 days after treatment. Response durations vary, but are commonly 3 weeks or longer, In comparative studies, pamidronate produced higher rates of normocalcaemia and longer normocalcaemic durations than other available osteoclast inhibitors, including intravenous etidronate, clodronate and plicamycin (mithramycin). In most patients with Paget's disease of bone, intravenous pamidronate reduces bone pain and produces biochemical response. Serum alkaline phosphatase levels generally fall 50 to 70% from baseline 3 to 4 months after pamidronate treatment. Biochemical response may be prolonged. Pamidronate is well tolerated by most patients. Transient febrile reactions, sometimes accompanied by myalgias and lymphopenia, occur commonly after the first infusion of pamidronate. Other reported adverse events include transient neutropenia, mild thrombophlebitis, asymptomatic hypocalcaemia and, rarely, ocular complications (uveitis and scleritis). Pamidronate should be considered for routine use together with systemic hormonal or cytotoxic therapy in patients with breast cancer or multiple myeloma and osteolytic metastases. At present, pamidronate is the drug of choice for first-line use in the management of patients with tumour-induced hypercalcaemia. It is an effective treatment for Paget's disease and is the treatment of choice where oral bisphosphonates are not an option.

Cyclosporin microemulsion (Neoral). A pharmacoeconomic review of its use compared with standard cyclosporin in renal and hepatic transplantation.

UNLABELLED: Cyclosporin microemulsion (Neoral) is a self-emulsifying preconcentrate of cyclosporin which is more rapidly and consistently absorbed than the original oil-based formulation of cyclosporin (standard formulation; Sandimmun, Sandimmune). This superior pharmacokinetic profile suggests that cyclosporin microemulsion may be associated with improved therapeutic and economic outcomes compared with the standard formulation. Clinical studies comparing the 2 formulations of cyclosporin (using the recommended 1:1 dosage conversion factor) in de novo or stable renal and de novo liver transplant patients have demonstrated that cyclosporin microemulsion is as efficacious as the standard formulation. Rates of acute and chronic graft rejection are generally unaffected by the formulation of cyclosporin, although a trend toward fewer rejection episodes in cyclosporin microemulsion recipients was noted in several randomised studies (reaching statistical significance in 4 studies). Most transplant recipients experience adverse events during cyclosporin therapy, and with higher and more reliable maximum blood concentrations achieved by cyclosporin microemulsion, there is a potential risk of more drug-related adverse events. However, most studies have suggested that the frequency of drug-related adverse events (including nephrotoxicity) is not affected by the formulation of cyclosporin. Analyses of healthcare resource utilisation and associated costs in renal and liver transplant patients in Canadian and European studies have suggested that the cost of using cyclosporin microemulsion may be lower than the cost of using the standard formulation. Lower resource consumption among cyclosporin microemulsion recipients in several studies led to slightly (but not statistically significantly) lower overall healthcare costs in this group. The cost of cyclosporin itself was not included in most of these analyses; however, because the 2 formulations of cyclosporin are used in similar dosages and have similar acquisition costs, this was probably not an important factor in determining relative costs. A single cost analysis comparing cyclosporin microemulsion and tacrolimus suggested that the 2 drugs were associated with similar overall costs. The available economic data on the use of cyclosporin microemulsion are subject to a number of important limitations. In particular, only partial results and study methodology have been reported for most analyses. Several studies were based on small patient groups (< 25) and short periods of follow-up (3 months), although some economic studies included larger patient groups receiving treatment for up to 1 year. Moreover, all of the analyses published to date were 'protocol driven' studies, and hence may not reflect resource use in usual clinical practice. CONCLUSION: In de novo and stable renal and de novo liver transplant recipients, cyclosporin microemulsion is as effective and well tolerated as the standard formulation of cyclosporin. Economic analyses comparing the 2 formulations indicate a consistent, although small and not statistically significant, reduction in overall healthcare costs associated with use of cyclosporin microemulsion.

Clopidogrel.

Clopidogrel is a thienopyridine that irreversibly inhibits platelet aggregation by selectively binding to adenylate cyclase-coupled ADP receptors on the platelet surface. In animal models, clopidogrel reduced the formation of both arterial and venous thrombi. After oral administration, clopidogrel is rapidly absorbed and undergoes metabolic activation in the liver. The principal circulating metabolite is SR 26334, an inactive carboxylic acid derivative. The active metabolite is not yet known. Findings of a large, well controlled study of clopidogrel versus aspirin in patients with atherosclerotic vascular disease (CAPRIE study) indicate that clopidogrel has superior efficacy in terms of prevention of ischaemic stroke, myocardial infarction and vascular death. Clopidogrel-treated patients experienced less frequent gastrointestinal upset, abnormal liver function and gastrointestinal haemorrhage than patients who received aspirin, but more frequent rash and diarrhoea. Neutropenia and thrombocytopenia occurred rarely and at similar rates in both groups.

Fosinopril. A review of its pharmacology and clinical efficacy in the management of heart failure.

Fosinopril is the prodrug of the active diacid ACE inhibitor fosinoprilat. In patients with heart failure, fosinopril reduces pulmonary capillary wedge pressure, mean arterial blood pressure, mean right atrial pressure and heart rate, and increases stroke volume index and cardiac index. The drug has compensatory dual elimination routes via renal and hepatic systems and accumulates to a lesser extent than enalapril and lisinopril in patients with chronic renal insufficiency with or without heart failure. Comparative studies of 3 or 6 months' duration with fosinopril 10 to 40 mg/day have demonstrated clinical efficacy significantly superior to that of placebo in patients with heart failure [mostly New York Heart Association (NYHA) functional class II or III]. Fosinopril treatment consistently increased exercise duration and improved heart failure symptoms in these patients. Significantly fewer fosinopril than placebo recipients withdrew or were hospitalised because of worsening heart failure. Additionally, significantly more fosinopril than placebo recipients showed improvement, and fewer patients had deteriorated, in terms of NYHA functional class. Fosinopril and enalapril showed similar clinical efficacy over 6 and 12 months' treatment in patients with NYHA functional class II to IV heart failure. As yet, there are no data showing a mortality benefit with fosinopril. Fosinopril was well tolerated in clinical trials in patients with heart failure. Dizziness (11.9 vs 5.4% for placebo), cough (9.7 vs 5.1%) and hypotension (4.4 vs 0.8%) were the most commonly reported adverse events. In 6- or 12-month comparative studies, fosinopril therapy was associated with a lower incidence of dizziness and hypotension, but a higher incidence of vertigo, than enalapril therapy. 0.8% of patients discontinued the drug because of cough, which occurred to a similar extent with fosinopril and enalapril. Thus, based on available clinical evidence, fosinopril is an effective and well tolerated option for the management of patients with heart failure. Although clinical data are limited, fosinopril may be especially useful in patients with renal or hepatic impairment.

Sumatriptan. A pharmacoeconomic review of its use in migraine.

Migraine is a common illness characterised by severe, often throbbing and/or unilateral headache, which may be accompanied by sensitivity to light or noise. A minority of migraine attacks are preceded by transient visual or sensory disturbances. Migraine is associated with reductions in health-related quality of life both during and between attacks. Despite methodological limitations in cost-of-illness studies, it is clear that the cost of migraine to society is substantial. Indirect costs (primarily workplace productivity losses) make up 75 to 90% of total costs. Direct costs, such as the cost of drug treatment, physician consultation, hospitalisation and emergency room treatment, make up most of the remainder. Sumatriptan is an effective and well tolerated agent in the treatment of migraine. Its main advantage over other agents used in the acute management of migraine appears to be its rapid onset of action. Sumatriptan reduces headache severity within 2 hours of oral administration in 50 to 67% of patients and within 1 hour of subcutaneous administration in 70 to 80% of patients. Headache recurs in approximately 40% of patients who initially respond to oral or subcutaneous sumatriptan; however, a second dose of the drug is effective against the symptoms of recurrence in a majority of patients. Some patients experience relief of non-headache migraine symptoms, including nausea, vomiting, photophobia and phonophobia. Adverse events reported after sumatriptan are generally mild and transient. Data from studies of patients who used their usual therapies and sumatriptan in nonblinded, sequential phases indicate that both workplace and nonworkplace productivity losses were reduced during sumatriptan therapy. A cost-benefit analysis applied to some of these workplace productivity data indicated that, including direct costs and productivity savings, sumatriptan was associated with a net reduction in total cost of migraine. In retrospective cost analyses, sumatriptan was associated with increased prescription costs: the effect of the drug on other direct treatment costs was less clear. A retrospective pharmacoeconomic model suggested that the cost-effectiveness of subcutaneous sumatriptan versus subcutaneous dihydroergotamine depended on which outcome measure was of greatest interest. For measures of rapid relief of migraine, sumatriptan was superior, but the cost of achieving rapid relief was substantial. Sumatriptan improved global quality-of-life scores compared with patients' usual therapy in a randomised crossover trial and appeared to do the same when the drugs were administered in nonblinded, sequential phases in trials which used general and migraine-specific quality-of-life instruments. Thus, sumatriptan is associated with a fast onset of action and improvements in health-related quality of life in patients with migraine. However, the cost of achieving rapid relief of migraine symptoms may be substantial. Compared with patients' usual treatments, sumatriptan appeared to reduce workplace and non-workplace productivity losses. However, few economic data from well controlled prospective comparisons of sumatriptan with other available agents are available to quantify the effect of sumatriptan on the overall cost of migraine.

Epirubicin. An updated review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the management of breast cancer.

Epirubicin, an anthracycline antitumour antibiotic which is structurally related to doxorubicin, is among the most active single agents used in the management of patients with breast cancer. The drug may be administered alone or in combination with other agents both to patients with early breast cancer and to those with metastatic disease. There is a clear relationship between epirubicin dose and tumour response. Dose intensified regimens have produced improved response rates in patients with advanced breast cancer compared with standard dose therapy; however, improved overall survival has not yet been demonstrated. The combination of epirubicin with newer agents such as vinorelbine or paclitaxel shows considerable promise, as does the use of epirubicin in high dose regimens with peripheral blood progenitor cell support. The major adverse effects of epirubicin are acute dose-limiting haematological toxicity and cumulative dose-related cardiac toxicity. These effects are less severe after epirubicin administration than after equimolar doses of doxorubicin. Other major adverse effects of epirubicin administration include mucositis, nausea and vomiting, reversible alopecia and local cutaneous and vesicant reactions. In summary, epirubicin has an established role in the treatment of both early and advanced breast cancer. Incombination with other highly active agents or in dose intensified regimens administered with haemopoietic growth factor and/or peripheral blood progenitor cell support, epirubicin may play a significant role in emerging breast cancer treatment strategies.

Polyethylene glycol-liposomal doxorubicin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the management of AIDS-related Kaposi's sarcoma.

Doxorubicin is an antineoplastic drug which has in vitro and in vivo activity against a number of malignancies including Kaposi's sarcoma. Incorporation of doxorubicin into polyethylene glycol-coated (pegylated) liposomes alters the pharmacokinetics of the drug. Liposomal doxorubicin has a smaller volume of distribution and slower plasma clearance than standard free doxorubicin. The liposomal formulation achieves higher concentrations in the highly vascularised lesions of Kaposi's sarcoma than in normal tissue. Liposomal doxorubicin monotherapy in patients with AIDS-related Kaposi's sarcoma produced overall response rates (complete plus partial) of 43 and 59% in large comparative studies and 67 to 100% in noncomparative studies which included > or = 20 patients. In comparative studies, liposomal doxorubicin was significantly more effective than the combination of standard doxorubicin, bleomycin and vincristine (overall response rates of 43 and 25%, respectively) and bleomycin and vincristine (BV) [overall response rates of 59 and 23%, respectively]. In addition, overall response rates to the liposomal drug were higher in both treatment arms of 2 smaller comparative studies which compared liposomal doxorubicin with BV, but significant between-treatment differences were not detected. Patient numbers in these 2 studies, however, may have been too small to detect significant differences. Liposomal doxorubicin is generally well tolerated. Myelosuppression is the most common dose-limiting adverse effect in patients with AIDS and Kaposi's sarcoma. Neutropenia occurs most often; anaemia and thrombocytopenia occur less frequently, as do nausea and vomiting and stomatitis. Palmar-plantar erythrodysaesthesia occurs in some patients, most commonly after 6 to 8 weeks of chemotherapy. Although symptoms may occasionally be severe, the syndrome usually does not require dosage reduction or treatment delay. Limited data suggest that the incidence of cardiotoxicity may be lower after liposomal doxorubicin than after equivalent doses of standard doxorubicin. Overall, liposomal doxorubicin appears to be one of the most active single agents available for treating patients with AIDS-related Kaposi's sarcoma. The therapeutic potential of liposomal doxorubicin administered in combination with other active agents to patients with Kaposi's sarcoma is, as yet, unknown. However, administered alone, the drug seems to be more effective than the best available combination chemotherapy regimens.