Darbepoetin alfa: new preparation. Just a me-too: no advantage in anaemia of chronic renal failure

(1) Darbepoetin alfa, an epoetin, is slightly more glycosylated than epoetin alfa and beta. (2) The clinical file on anaemic patients with chronic kidney failure shows no advantage of darbepoetin alfa over other epoetins in terms of efficacy or side effects (subcutaneous injections of darbepoetin alfa are more often painful). (3) The dosing schedules of epoetins have not been compared adequately. Dosing schedules should be adapted for each patient.     

Citalopram: new indication. No advantage

(1) Citalopram, a serotonin reuptake inhibitor antidepressant, now has a new licensed indication, in the preventive treatment of panic attacks. In France, clomipramine, a tricyclic antidepressant, and paroxetine, another serotonin reuptake inhibitor, are already approved for this use. (2) In the only available comparative trial the efficacy of citalopram (20-60 mg/day) was similar to that of clomipramine (60-90 mg/day). (3) The safety profile of citalopram is different from that of clomipramine. (4) There are no data clearly comparing citalopram with paroxetine in terms of efficacy, safety, drug interactions, or convenience. (5) Clomipramine is much cheaper than citalopram.     

Darbepoetin alfa: in patients with chemotherapy-related anaemia

Darbepoetin alfa, novel erythropoiesis stimulating protein closely related to human erythropoietin, has been developed for the treatment of chemotherapy-related anaemia in patients with non-myeloid malignancies. In three 12-week, phase II studies in patients with cancer and chemotherapy-related anaemia, subcutaneous darbepoetin alfa, administered in once-weekly or 2-, 3- or 4-weekly regimens, dose-dependently increased the mean haemoglobin levels. In a randomised, double-blind, phase III study in 320 patients with lung cancer and chemotherapy-related anaemia, recipients of subcutaneous darbepoetin alfa 2.25 micro g/kg once weekly, received red blood cell (RBC) transfusion approximate, equals 2-fold less frequently than placebo recipients (p < 0.001). In the same study, patients receiving darbepoetin alfa also received fewer standard units of RBC for transfusion and had greater haematopoietic response rate than placebo recipients (both p < 0.001). Subcutaneous darbepoetin alfa 2.25 micro g/kg once weekly also reduced patient-reported fatigue (assessed by a quality-of-life questionnaire) [p = 0.019 vs placebo]. black triangle Darbepoetin alfa was generally well tolerated in clinical trials. The most frequent darbepoetin alfa-related adverse events were: body oedema, arthralgia and skin rash.     

Epoetin alfa and epoetin beta: new indication. Treatment of anaemia due to cytotoxic chemotherapy

(1) The standard treatment for symptomatic anaemia due to cytotoxic chemotherapy is blood transfusion. (2) The licensing terms for epoetin alfa have been extended to cover the treatment of anaemia induced by all cytotoxic drugs, no longer only by platinum salts. The licensing terms for epoetin beta have been extended to cover some haematological malignancies. (3) The clinical file on epoetin alfa contains data from 8 placebo-controlled double-blind trials in patients with anaemia. Four trials showed a significant reduction (of 12-35%) in the number of patients transfused during the second and third months of treatment with epoetin alfa. (4) Quality of life was mentioned in only two trial reports. In one, the score was significantly better on epoetin alfa than on placebo, but the practical repercussions of this difference are unclear. In the other trial there was no significant difference between the groups. (5) The clinical file on epoetin beta contains data only from unblended dose-finding studies showing a favourable impact on the haemoglobin level and transfusion requirements. (6) The preventive effect of the two epoetins has not been compared with that of alternative treatments. (7) The main known risks of epoetin are arterial hypertension and thrombosis. Stimulation of tumour growth cannot be ruled out. (8) Epoetin beta has a practical advantage, in that it can be stored for a few days at room temperature. (9) In practice, epoetin is the standard treatment of anaemia after chemotherapy, outside emergency situations.     

Etidronic acid and steroid therapy: new indication. No proven impact on fractures

(1) Etidronic acid (disodium etidronate) has a new licensed indication in the prevention of bone loss due to steroid therapy. (2) Three randomised, double-blind placebo-controlled trials have been done in this setting. The benefit of etidronic acid has been shown only on the basis of lumbar bone density (a surrogate end point) and only in women. (3) There is no concrete evidence that etidronic acid is any more effective than a placebo in reducing the risk of fracture in patients on steroid therapy. Similarly, in the absence of comparative trials there is no proof that etidronic acid is any more effective than hormone replacement therapy in postmenopausal women.     

Topotecan: new preparation. No proven benefit

Topotecan does not convincingly alter the grim prognosis of ovarian cancer in failure or relapse after treatment with platinum salts. The only comparative trial has not yet been published; available results suggest that 20% of women had at least a partial response on topotecan, compared to 14% on paclitaxel (no statistically significant difference). The place of paclitaxel in the treatment of ovarian cancer also remains to be determined, especially in combination with other drugs. Like paclitaxel, topotecan has marked haematological and gastrointestinal toxicity: nausea, vomiting, diarrhoea and stomatitis. Topotecan solution does not contain the solvent Cremophor EL degrees , contrary to paclitaxel solution. It does not therefore require preliminary steroid administration, and does not prohibit the use of PVC-based infusion devices.     

Darbepoetin alfa: a review of its use in the treatment of anaemia in patients with cancer receiving chemotherapy

Darbepoetin alfa (Aranesp) is an analogue of recombinant human erythropoietin (rHuEPO) produced using recombinant DNA technology. The high number of sialic acid moieties in darbepoetin alfa results in a prolonged half-life and enhanced in vivo biological activity compared with rHuEPO (as demonstrated in animal studies) and permits a reduction in the frequency of administration.Subcutaneous darbepoetin alfa 2.25 microg/kg once weekly or 500 microg once every 3 weeks (with a provision for dose adjustments) is an effective and well tolerated erythropoietic agent in anaemic patients with cancer receiving chemotherapy. In randomised, controlled clinical trials, the drug increased haemoglobin levels and reduced the need for blood transfusions in patients with various types of nonmyeloid malignancies and also ameliorated anaemia-related fatigue, thereby improving their health-related quality of life (HR-QOL) scores. The once-every-3-weeks dosage regimen provides further convenience by offering the possibility of synchronising its administration with most chemotherapy regimens. Direct comparisons between approved dosages of darbepoetin alfa and other erythropoietic agents have not been conducted. Such comparisons would be very helpful in formulating definitive conclusions about their relative efficacy and cost effectiveness. Darbepoetin alfa provides an effective and well tolerated treatment option for the treatment of anaemia in patients with cancer receiving chemotherapy.     

Caspofungin: new indication. No progress in invasive candidiasis

(1) The reference treatment for invasive candidiasis in patients without neutropenia is standard amphotericin B. If this treatment fails or is too nephrotoxic, second-line alternatives are liposomal amphotericin B and fluconazole. Voriconazole is a third-line option. (2) Caspofungin, an antifungal drug belonging to the echinocandin class, is now approved for use in this indication in France. (3) The clinical evaluation dossier contains no data from comparative trials with fluconazole or voriconazole. It only gives the results of a double-blind trial in 239 patients, designed to show simply that caspofungin was not inferior to standard amphotericin B. Most of the patients did not have neutropenia. About one-third of the patients died. There was no difference in mortality between the two groups. No data are available from trials versus other forms of amphotericin B. (4) In this trial, caspofungin had fewer adverse effects (especially nephrotoxicity) than standard amphotericin B. However, in other trials in other indications, caspofungin had more adverse effects than fluconazole. (5) In France, caspofungin costs nearly 100 times more than standard amphotericin B. (6) In practice, caspofungin has no proven advantages over existing options for the treatment of invasive candidiasis in patients without neutropenia.     

Fluvoxamine: new indication. No progress in obsessive-compulsive disorder

(1) Four drugs are approved in France for patients with obsessive-compulsive disorders, namely clomipramine and three selective serotonin reuptake inhibitors (SSRIs): fluoxetine, paroxetine and sertraline. None of the four has emerged as a reference treatment. For children with obsessive-compulsive disorder, the treatment hierarchy is as follows: psychotherapy; behaviour therapy; clomipramine; sertraline. (2) Fluvoxamine, another SSRI, has now been approved in France for the treatment of obsessive-compulsive disorder in patients aged at least 8 years, after European harmonisation of SPCs for fluvoxamine-based preparations. (3) In adults, two placebo-controlled trials and the six trials versus clomipramine show that fluvoxamine, like clomipramine, is only partially effective (about one-third of patients "respond"). (4) In the only placebo-controlled trial in 120 children and adolescents aged from 8 to 17 years, who were treated for 10 weeks, efficacy was even more modest (response rate 15%, compared to 10% with placebo). (5) The safety profile of fluvoxamine is the same as that of all SSRIs but it has a potential for more drug interactions. (6) In practice, approval of fluvoxamine in adults or children with obsessive-compulsive disorder will have no impact on their management.     

Parecoxib: new preparation. A NSAID for postoperative pain: no proven advantage

(1) Parecoxib is the second nonsteroidal antiinflammatory drug, after ketoprofen, to be marketed in France for the treatment of postoperative pain. (2) Another injectable NSAID, ketorolac, was marketed briefly in the 1990s. It was shown to be no more effective than ketoprofen, but was withdrawn from the French market because it provoked bleeding. (3) The clinical evaluation dossier on parecoxib contains no data from comparative trials with ketoprofen. The three trials versus ketorolac failed to show that parecoxib was more effective. (4) The two trials comparing parecoxib with morphine are biased by the use of a too low dose of morphine (4 mg). Four trials show that adding parecoxib reduces morphine requirements in patients injecting the opiate on demand. There is no evidence that this reduction translates into a lower risk of adverse reactions to opiates. (5) Parecoxib is marketed as "Cox-2-specific inhibitor", but follow-up is too short to show whether this property avoids the severe adverse effects seen with other NSAIDs, such as renal failure, gastrointestinal haemorrhage, and delayed wound healing. Parecoxib, like its principal metabolite valdecoxib, can cause severe hypersensitivity reactions. (6) Parecoxib is 10 times more expensive than injectable ketoprofen in France. (7) In practice, ketoprofen is still the best choice for parenteral NSAID-based pain relief in the postoperative setting.     

Economic evaluation of weekly epoetin alfa versus biweekly darbepoetin alfa for chemotherapy-induced anaemia: evidence from a 16-week randomised trial

INTRODUCTION: A 16-week, open-label, multicentre, randomised trial of weekly epoetin alfa 40 000 units versus biweekly darbepoetin alfa 200microg among 358 patients with solid-tumour cancers and chemotherapy-induced anaemia demonstrated superior haematological outcomes with epoetin alfa. We sought to compare resource use, costs and clinical outcomes between treatment groups and report the results using a cost-consequences framework. METHODS: Pre-specified methods were used to assign costs (US dollars, year 2004-5 values) to medical resources and patient time using a societal perspective. Costs for inpatient care, outpatient care and physician services were based on US Medicare reimbursement rates. Indirect costs assigned to patient time spent receiving study medication were based on the mean hourly wage in the US. In the base-case analysis, the average wholesale price was used to assign costs to medications. Clinical outcomes included all haemoglobin levels and transfusions recorded throughout the trial. Sensitivity analyses were performed to evaluate the impact of different costing methods, cost sources, perspectives and methods to assign haemoglobin values following a blood transfusion. RESULTS: Over a mean follow-up duration of 11.8 weeks, the average cost of study medications and their administration was the single largest component of total costs and was similar between groups (epoetin alfa 5979 US dollars and darbepoetin alfa 5935 US dollars, difference 44 US dollars; 95% CI -590, 692). There were no significant differences in the proportions of patients hospitalised (epoetin alfa 24.6%, darbepoetin alfa 22.0%; p = 0.57). Patients randomised to epoetin alfa experienced more inpatient days, on average, than patients randomised to darbepoetin alfa (2.6 vs 1.6, 95% CI for the difference, 0.07, 2.27). However, with regard to transfusions, patients in the epoetin alfa arm required fewer units of blood than patients in the darbepoetin alfa arm (0.46 vs 0.88, 95% CI for the difference -0.77, -0.08). Mean total costs, comprising costs for study medications and their administration, inpatient care, transfusions, unplanned radiation therapy, haematology and laboratory services, chemotherapy and non-chemotherapy drugs and indirect costs were 14,976 US dollars in the epoetin alfa arm compared with 14,101 US dollars in the darbepoetin alfa arm, a difference of 875 US dollars (95% CI for difference -849, 2607), of which 98% of the difference was attributable to higher inpatient costs in the epoetin alfa arm (2374 US dollars vs 1520 US dollars; 95% CI for difference -33, 1955). Assessments of multiple clinical measures demonstrated improved outcomes with epoetin alfa relative to darbepoetin alfa. CONCLUSION: Most clinical outcome measures suggested greater improvement with epoetin alfa relative to darbepoetin alfa, but most costs for both agents appeared similar. Decision makers must evaluate the differences in costs and efficacy measures that are most relevant from their perspectives.     

Idarubicin oral: new formulation. No proven benefit over 60

(1) Oral idarubicin is marketed in France for the treatment of acute myeloblastic leukaemia in patients over 60 who are ineligible for intensive intravenous treatment. (2) The clinical file on oral idarubicin is limited. (3) In non comparative trials the median survival time after starting treatment with oral idarubicin, alone or combined with other cytotoxic agents, did not exceed 12 months. (4) The only comparative trial of single-agent idarubicin in this indication gave unfavourable results. Another comparative trial tested a combination comprising idarubicin, but the role of idarubicin alone cannot be determined from the results. (5) In the palliative care setting the clinical efficacy of oral idarubicin has not yet been demonstrated. (6) The main adverse events observed during oral idarubicin therapy are neutropenia, thrombocytopenia, nausea and vomiting, diarrhoea and hair loss. Their impact on patients' quality of life has not been adequately assessed.     

Zonisamide: new drug. No advantage in refractory partial epilepsy

(1) The first-line treatment for patients with partial epilepsy is carbamazepine monotherapy. Second-line options include monotherapy with valproic acid, gabapentin, lamotrigine or oxcarbazepine. Other antiepileptics are also available for combination therapy of refractory partial epilepsy. (2) Zonisamide is a sulphonamide derivative that inhibits carbonic anhydrase; it resembles topiramate, a drug already approved for use for this indication in the European Union. (3) The main clinical trial, a double-blind study lasting 36 weeks, compared the addition of zonisamide or placebo to ongoing treatment in 351 patients with refractory partial epilepsy. The "response rate" (the proportion of patients with at least a 50% reduction in the frequency of seizures) was significantly higher with zonisamide plus the previous treatment than with placebo plus the previous treatment (46.6% versus 17.6%). An indirect comparison suggests that this is no better than treatment with a second-line antiepileptic drug. (4) Results of three other placebo-controlled trials of third-line combinations in a total of 499 patients treated for 12 weeks were similar. (5) The main adverse effects of zonisamide are those typically seen with topiramate: neuropsychological disorders and disorders due to carbonic anhydrase inhibition (kidney stones, reduced perspiration, and hyperthermia). There are various other adverse effects, including a risk of severe skin rash. (6) The profile of interactions is complex. There is a risk of pharmacokinetic interactions, and of pharmacodynamic interactions with other carbonic anhydrase inhibitors. (7) In France, treatment with zonisamide costs nearly 20 times more than treatment with carbamazepine or valproic acid. (8) Zonisamide has no therapeutic advantages over other antiepileptics available for combination therapy of partial epilepsy.     

Olanzapine for injection: new formulation. No advantage in agitated patients

(1) The intramuscular neuroleptic of choice for the treatment of agitated schizophrenic patients and patients with acute mania is haloperidol, at a dose of 5 mg. Olanzapine is now marketed in France for hospital use in both these indications. (2) In two comparative trials in patients with schizophrenia, olanzapine 10 mg was shown to be no better than haloperidol 7.5 mg (a high dose). Control of agitation was satisfactory in three-quarters of patients after a single injection of either neuroleptic. (3) Olanzapine has not been compared with other neuroleptics in the treatment of acute mania. In one trial, olanzapine acted faster than lorazepam for injection (used at a rather low dose). (4) In one trial, patients given olanzapine had a lower incidence of acute dystonia and extrapyramidal symptoms (about 1%) than patients given haloperidol (about 6-7%), but the haloperidol dose (7.5 mg) was higher than recommended in the SPC (5 mg). The incidence of postural hypotension was significantly higher among patients given olanzapine (about 12%) compared with haloperidol (about 3%). (5) In practice, haloperidol remains the intramuscular neuroleptic of choice for the treatment of agitated patients with schizophrenia or acute mania.     

Rofecoxib in rheumatoid arthritis: new indication. No better that other NSAIDS

(1) For symptoms of rheumatoid arthritis (pain, joint stiffness), the reference treatment is a nonsteroidal antiinflammatory drug (NSAID) such as diclofenac or ibuprofen. Celecoxib, a coxib NSAID, has no proven advantages over these other NSAIDs. (2) Rofecoxib is the second coxib to be approved in this indication. The clinical evaluation file shows that the optimal daily dose is 25 mg. (3) A comparative trial in more than 8 000 patients, showed that rofecoxib was no more effective than 1 g/day of naproxen. There are no trials comparing rofecoxib with celecoxib, diclofenac or ibuprofen. (4) In clinical trials the overall frequencies of adverse effects and treatment withdrawals for adverse effects were the same for rofecoxib as for other NSAIDs. In one trial, rofecoxib caused fewer gastrointestinal disturbances, particularly serious ones, than naproxen. But rofecoxib caused more gastrointestinal disturbances than placebo. During postmarketing follow up in the United States, a number of deaths due to gastrointestinal complications on rofecoxib were reported. Rofecoxib carries the same renal risk as other NSAIDs. An excess risk of cardiovascular events cannot be ruled out. (5) In practice, the advent of rofecoxib in no way influences the choice of NSAID for symptomatic treatment of rheumatoid arthritis.     

Alendronic acid in primary prevention: new indication. No reduction in fracture risk

(1) Alendronic acid at a dose of 5 mg/day is now licensed in France for primary prevention of postmenopausal fractures. (2) The clinical file is relatively bulky and methodologically adequate, but there are no comparisons with combined hormone replacement therapy or with raloxifen. (3) Three trials have shown that 5 mg/day alendronic acid slows postmenopausal bone loss. However, this effect disappears on treatment cessation, and mineral bone density is only one risk factor for postmenopausal fractures. (4) A placebo-controlled trial of primary prevention involving more than 4,000 patients showed no reduction in the risk of fracture after 4 years of treatment with alendronic acid (5 mg/day for 2 years, then 10 mg/day). (5) Alendronic acid increases the risk of oesophageal ulceration, necessitating strict precautions during ingestion.     

Combined acellular pertussis vaccines: new indication. No tangible benefit in primary vaccination

(1) Two acellular pertussis vaccines included in pentavalent combinations are available in France. Their use was initially restricted to booster injections. This restriction has now been lifted, meaning that the two products can be used for primary vaccination. (2) The initial assessment files, which mainly concerned primary vaccination, showed that the acellular pertussis vaccines had fewer mild side effects than the cellular vaccine, but there was no evidence that they were as effective. (3) Some epidemiological studies with fairly short follow-up (about 2 years), conducted in various countries, suggest that the acellular vaccines confer clinical protection. There are no data comparing the bi- and tri-antigenic acellular vaccines marketed in France. (4) For the time being, the whole-cell pertussis vaccine remains the standard.     

A final analysis from the CHOICE study examining darbepoetin alfa use for chemotherapy-induced anaemia in current European clinical practice

Abstract

Objectives:

The CHOICE study was a prospective, multicentre, observational study designed to assess the level of adherence in current clinical practice to the European product label and the EORTC guidelines for the treatment of chemotherapy-induced anaemia with darbepoetin alfa (DA).