Aripiprazole: new drug. Just another neuroleptic

(1) Neuroleptics are the standard treatment for schizophrenia. The first drugs of this class, such as haloperidol, were marketed nearly 50 years ago, and neuroleptics released over the past 15 last years have provided no major advance. (2) Aripiprazole is a new neuroleptic licensed for the treatment of schizophrenia. (3) Five double-blind placebo-controlled trials lasting 4 to 6 weeks showed that aripiprazole was a little more effective than placebo at daily doses of 10 mg to 30 mg, without a clear dose-response relationship. Based on the least demanding definition of "treatment response" (a 30% reduction in the PANSS global score), less than 50% of patients responded to aripiprazole. (4) In a double-blind trial lasting 6 months, aripiprazole 15 mg/day was more effective than placebo in preventing acute relapses of schizophrenia (34% versus 57%), but the clinical relevance of the combined endpoint used to define relapse is unclear. (5) The only double-blind comparison versus another neuroleptic (haloperidol) involved two trials that were pooled for analysis. Haloperidol was provided at a moderate dose (10 mg/day). These trials were designed to demonstrate the superiority of high-dose aripiprazole (30 mg/day), but failed to do so. The proportion of patients who "responded" during an acute episode, based on the least stringent definition, was about 70% in both groups. In both groups, response persisted in approximately three-quarters of patients. (6) Aripiprazole exhibits the adverse effects classically seen with neuroleptics. In clinical trials, daily doses of aripiprazole, ranging from 15 mg to 30 mg, provoked fewer extrapyramidal disorders than haloperidol 10 mg/day. In contrast, there was no difference in the frequency of extrapyramidal disorders with aripiprazole 20 or 30 mg/day and risperidone (6 mg). Aripiprazole has no proven advantage over haloperidol in terms of the risk of tardive dyskinesia. One trial showed no difference between aripiprazole and olanzapine in the risk of diabetes. Weight gain appears to be comparable with aripiprazole and haloperidol. Aripiprazole provoked postural hypotension and neuroleptic malignant syndrome, but the precise risk relative to other neuroleptics has not been documented. Supra-therapeutic doses of aripiprazole cause dose-dependent QT prolongation. (7) Increased mortality was seen in elderly patients treated with aripiprazole. (8) Animal studies have shown retinal degeneration in rats and biliary lithiasis in monkeys. These adverse effects have not been observed in clinical trials, but they have not been specifically assessed in humans. (9) Animal studies raised the possibility of fetal toxicity and teratogenicity. (10) The aripiprazole dose must be either halved or doubled during co-administration with inhibitors or inducers of cytochrome P450 isoenzymes CYP 3A4 and CYP 2D6. (11) In practice, there are too many unanswered questions to recommend aripiprazole for patients with schizophrenia.     

Rofecoxib: new preparation. A disappointing NSAID analgesic

(1) Rofecoxib, a nonsteroidal antiinflammatory drug, is licensed in France for symptom relief in osteoarthritis. It is promoted by MSD-Chibret as a "specific inhibitor of type 2 cyclooxygenases (COX-2)". (2) The clinical dossier includes trials versus other antiinflammatory drugs, but the reports available are generally vague. Rofecoxib has not been compared with paracetamol. (3) In these trials rofecoxib 12.5-25 mg/day was no more effective than the comparators (ibuprofen or diclofenac) used at maximal recommended doses. (4) Relative to other nonsteroidal antiinflammatory drugs prescribed at high doses to selected patients in the controlled conditions of clinical trials, rofecoxib only moderately reduces the risk of severe gastrointestinal reactions (1.3% versus 1.8% after a year of treatment) and dyspeptic disorders (23.5% versus 25.5%). (5) Questions persist on other adverse effects, especially those potentially affecting the kidneys and heart. (6) Rofecoxib is subject to the same precautions (pregnancy, interactions, etc.) as other nonsteroidal antiinflammatory drugs.     

Valsartan: new preparation. Just a second-line antihypertensive drug

(1) Valsartan is a antihypertensive drug belonging to the family of angiotensin II receptor antagonists. (2) At a dose of 40 mg/day its antihypertensive effect is inconsistent. (3) At 80 mg/day its effect on blood pressure, its adverse effects and its contraindications (mainly pregnancy and renal artery stenosis) are similar to those of angiotensin-converting-enzyme (ACE) inhibitors, except that coughing is rarer with valsartan than with ACE inhibitors. (4) Valsartan has no demonstrated advantage over losartan, another angiotensin II antagonist. (5) Valsartan has not been shown to prevent the complications of arterial hypertension, and its use is therefore less well validated than that of diuretics and betablockers.     

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.     

Zoledronic acid: new preparation. Just a me-too: no advance in hypercalcemia of malignancy

Pamidronic acid is the standard diphosphonate for the treatment of hypercalcemia of malignancy. Zoledronic acid, a more recent drug, was compared with pamidronic acid in two clinical trials, but the results are unconvincing because of the unusually poor performance of pamidronic acid. Safety of zoledronic acid is uncertain, owing to a lack of long-term data.     

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.     

Nabumetone, a new non-steroidal anti-inflammatory drug: a comparison with naproxen

Nabumetone, 500 mg two nocte, was compared with naproxen, 250 mg two nocte and one mane, in the management of 24 patients with rheumatoid arthritis attending an outpatients clinic. Both drugs were generally well tolerated and were of comparable efficacy in the dose employed. Similar numbers incurred side effects while taking either drug, but severe side effects, requiring withdrawal from the trial in two cases, were restricted to those patients taking naproxen. As patients known to be intolerant to naproxen were excluded from the trial, the results could have been expected to favour naproxen in this respect. Nabumetone may have a useful role in the management of patients with poor tolerance of other anti-inflammatory drugs.     

Etanercept: new indication. For ankylosing spondylitis: another option

(1) Nonsteroidal antiinflammatory drugs (NSAIDs) are the standard drug treatments in ankylosing spondylitis. Infliximab, a TNF-alpha antagonist immunosuppressant, is reserved for severely ill patients for whom standard treatment has failed. Infliximab is provided as an infusion and requires close monitoring. (2) Etanercept, another TNF-alpha antagonist immunosuppressant, was recently approved in Europe for the treatment of ankylosing spondylitis. (3) In three double-blind placebo-controlled trials (40 patients treated for 4 months, 277 patients treated for 6 months, 84 patients treated for 3 months), between 60% and 80% of patients on etanercept "responded" to treatment, with at least a 20% improvement in an endpoint combining various symptoms of ankylosing spondylitis. There are no direct comparisons to show whether this short-term effect differs tangibly from that of infliximab. (4) Etanercept has the same adverse effect profile as infliximab. In particular, both immunosuppressants increase the risk of tuberculosis and opportunistic infections. Risks associated with long-term immunosuppression, such as malignancy, are poorly understood: postmarketing follow-up data are only available for 6 years. (5) As of 7 December 2004, no detailed results had been published on randomised trials comparing etanercept with other recently approved immunosuppressants used to treat ankylosing spondylitis. (6) Etanercept is administered subcutaneously twice a week, on an outpatient basis, for the treatment of ankylosing spondylitis as well as psoriatic rheumatism. In contrast, infliximab is infused every 6 to 8 weeks and must be administered in hospital. (7) Etanercept is an alternative to infliximab as a treatment option for patients with ankylosing spondylitis who have failed to respond to standard treatments.     

Atorvastatin + amlodipine: new drug. Just a commercial ploy

No assessment of morbidity or mortality; second-choice component drugs.     

Certolizumab pegol and rheumatoid arthritis. Just another TNF alpha antagonist, no therapeutic advantage

No comparison with other TNF alpha antagonists; possible bleeding risk.     

Penciclovir: new preparation. Slightly effective

(1) A penciclovir skin cream has been approved in France for local treatment of herpes simplex labialis. (2) The clinical file is limited to a single trial versus the excipient. This double-blind trial showed that, even when started immediately after the first manifestations occur, penciclovir cream failed to prevent the emergence of skin lesions. The only effect was a reduction in the duration of the lesions and associated pain by a few hours. In the absence of any specific assessment, there is no evidence that penciclovir improves overall patient satisfaction. (3) Penciclovir has not been compared with aciclovir skin cream.     

Deferiprone: new preparation. Poorly assessed

Deferiprone, an oral iron chelator, has been licensed in Europe for the treatment of iron overload in patients with beta thalassaemia who cannot be treated with deferoxamine because of adverse effects or the difficult administration schedule. (2) The clinical dossier is thin and methodologically mediocre. Even the preclinical assessment dossier is insufficient (there are no studies of carcinogenicity or hepatotoxicity). (3) The only available comparative trial, involving a small number of patients, suggests that deferiprone is less effective than deferoxamine in reducing ferritin levels and hepatic iron stores. (4) A non comparative trial suggests that long-term deferiprone therapy would not only fail, but would also increase the risk of liver fibrosis in some patients. This doubt is not dispelled by the other available non-comparative trials. (5) Deferiprone carries a risk of agranulocytosis in an estimated 1.2% of patients. (6) Deferiprone is teratogenic in two animal species.     

Orlistat: new preparation. No hurry . .

(1) Treatments for obesity are disappointing. None has yet shown an effect on morbidity and mortality. Non drug treatments are poorly assessed. Stable long-term weight loss necessitates long-term management. (2) Orlistat, a gastrointestinal lipase inhibitor, is indicated, in combination with a low-calorie diet, for the management of obesity. (3) The assessment file is rather bulky and methodologically sound, at least in terms of the "weight loss" end point. (4) During medium-term trials (12-24 months), orlistat administered at a dose of 120 mg three times a day and combined with dietary intervention had a moderate positive impact on body weight (-3.5 kg on average). (5) No longer-term trials have been done. (6) It is not known whether this drug affects morbidity and mortality linked to obesity. (7) In clinical trials there was an increase in the frequency of breast cancer among patients treated with orlistat. This potential risk is currently being assessed in a specific trial. (8) Gastrointestinal adverse effects are frequent. (9) Treatment is costly.     

Tamsulosine: new preparation. Capsules: alphablocker

Tamsulosine, an alphablocker, is moderately effective on the symptoms of benign prostatic hyperplasia. Its adverse effects are of the same order as those of other alphablockers already on the market in France (alfuzosine and prazosine); there is notably a risk of postural hypotension. There is no proof that the risk-benefit ratio of tamsulosine is any better than that of other alphablockers or 5-alpha-reductase inhibitors (finasteride).     

Levonorgestrel: new preparation. Emergency contraceptive

(1) The cornerstone of the clinical file on single-agent levonorgestrel (750 mug per tablet) in emergency contraception is a randomised comparative double-blind trial involving nearly 2,000 women. (2) In this trial the efficacy of two levonorgestrel doses (750 mug per dose) was significantly superior to that of two doses of the ethinyloestradiol (100 mug) + levonorgestrel (500 mug) combination: respectively 1.1% and 3.2% of women became pregnant. (3) Nausea and vomiting, dizzy spells and fatigue were half as frequent in the women using single-agent levonorgestrel (750 mug) as in those receiving the combined product. In both groups nearly a third of the women had abnormal periods after treatment.     

Infliximab: new indication. Psoriatic arthritis: just another intravenous me-too drug

Minimal assessment, based on a non comparative prospective cohort study of single-agent therapy.     

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.     

Bambuterol: new preparation. Poorly demonstrated efficacy

(1) Bambuterol is a long-acting metabolic precursor of terbutaline, marketed as an oral preparation. It is approved for long-term treatment of asthma and other reversible obstructive airways diseases. (2) The clinical file on bambuterol is sparse. There is no evidence that bambuterol has any advantages in terms of efficacy relative to oral terbutaline or inhaled salmeterol. (3) The claimed (minimal) advances relative to oral terbutaline, in terms of adverse effects (low level of evidence) and the advantage of once-daily dosing, are in no way decisive.