Tag Archives: adverse effcts


17 August 2014: neil.burman@gmail.com

Sadly, this month’s publication of the biggest-ever trial of Prostate Screening , in 162 000 men across Europe followed  for a mean of 11years, showed no benefit in all-cause mortality, same as was found in  the 5 previous major RCTrials,  or  trials  of xray mammography:.

Lancet. 2014 Aug 6. Schröder FH1 ea  Screening and prostate cancer mortality: results of the western European Randomised Study of Screening for Prostate Cancer (ERSPC) at 13 years of follow-up ie 1.78  million patient years, in some 162 000 men  aged 55 to 69, randomized  to either a screening arm or a control group. If PSA was 3ng/ml or more, they were offered a biopsy. Screening took place on average every four years. Mean follow-up was 11 years.  7408 prostate cancer cases were diagnosed in the intervention group and 6107 cases in the control group. The rate ratio of prostate cancer incidence between the intervention and control groups was  1·66 (1·60-1·73) after 11 years, and 1·57 (1·51-1·62) after 13 years. The rate ratio of prostate cancer mortality was 0·85 (0·70-1·03) after 9 years, 0·78 (0·66-0·91) after 11 years, and 0·79 (0·69-0·91) at 13 years. The absolute risk reduction of death from prostate cancer at 13 years was 0·11 per 1000 person-years or 1·28 per 1000 men randomised, which is equivalent to one prostate cancer death averted per 781 (95% CI 490-1929) men invited for screening or one per 27 (17-66) additional prostate cancer detected. After adjustment for non-participation, the rate ratio of prostate cancer mortality in men screened was 0·73 (95% CI 0·61-0·88). Despite our findings, further quantification of harms and their reduction are still considered a prerequisite for the introduction of populated-based screening.
                                                                                                                   As a 2012 independent analysis on the web says,   Updated data from ERSPC trial still show no impact on all-cause mortality:    A new article in the New England Journal of Medicine this week has updated the prostate cancer-specific and all-cause (overall) mortality data from the European Randomized Study of Screening for Prostate Cancer (ERSPC).       This latest analysis of data by Schröder et al., and based on a randomized comparison of screening (with regularly scheduled PSA tests) as opposed to non-screening, has shown the following results in the predefined, core group of men aged between 55 and 69 years at the time of enrollment:
  • The average (median) follow-up for men in the core group was 11 years.
  • There was no significant difference in all-cause mortality between the groups who were or were not screened for risk of prostate cancer.
  • Reductions in the risk for prostate cancer-specific mortality in men randomized to the screening group as compared to the unscreened group were
    • An absolute reduction of 0.10 prostate cancer deaths per 1,000 person-years
    • An absolute reduction of 1.07 prostate cancer deaths per 1,000 men who underwent screening
    • A relative overall reduction in the risk of prostate cancer deaths in the screening group of 21 percent
    • A relative overall reduction in the risk of prostate cancer deaths in the screening group of 29 percent after adjustment for non-compliance with screening
  • To prevent a single case of prostate cancer-specific mortality
    • 1,055 men would need to be invited to be screened
    • 37 cases of prostate cancer would need to be detected

The authors conclude that this analysis, which adds two additional years of follow-up data to the data originally published in early 2009, shows that “PSA-based screening significantly reduced mortality from prostate cancer but did not affect all-cause mortality.”

‘These new data are unlikely to help to clarify the debate over the value of mass screening for prostate cancer. From one point of view one can use them to argue that screening can prevent between 20 and 30 percent of prostate cancer-specific deaths. From the alternative point of view, one can argue that screening a million men would indeed prevent about 950 prostate cancer-specific deaths, but would also lead to the potential over-treatment of 36 out of every 37 cases of prostate cancer identified, and would have no impact whatsoever on overall mortality’.

Yoon Jae Lee, O.ea.The study was conducted using existing systematic reviews.   Results  In a total of 400 000 men  in 6 included trials from Europe, USA, and Canada, followed for about 10 years,  ie 4million patient-years, Prostate-cancer-specific mortality was not reduced based on similar prior reviews (relative risk [RR] 0.93; P=0.31). The detection rate of stage 1 prostate cancer was not greater, with a RR of 1.67 (95% CI, 0.95-2.94). No difference in all-cause mortality was observed between the screening and control groups (RR, 0.99; 95% CI, 0.98-1.01, P=0.50).
Hayes JH1, Barry MJ2  Harvard Medical School, Boston, Massachusetts  review  evidence from randomized trials and related modeling studies examining the effect of PSA screening vs no screening on prostate cancer-specific mortality and to suggest an approach balancing potential benefits and harms during a longer follow-up (level B evidence).     Available evidence favors clinician discussion of the pros and cons of PSA screening with average-risk men aged 55 to 69 years. Only men who express a definite preference for screening should have PSA testing. Other strategies to mitigate the potential harms of screening include considering biennial screening, a higher PSA threshold for biopsy, and conservative therapy for men receiving a new diagnosis of prostate cancer.


The latest Rimonabant  reports  from USA and UK confirm that there is no place for it for overweight : Rimonabant  produces the same average weight loss as metformin (about 6kg/yr, 0.5kg/month more than placebo) but no study yet shows  that it has the safe benefits of metformin adjusted to tolerated dose (average 2gm/day in Caucasians): halving of new diabetes rates, halving of all deaths and almost halving major common degenerative diseases of aging.
Contrary to the lying blatant adverts promoting it below (still on the internet)  in this  latest  (SERENADE)  trial, serious diverse events  were up to 10fold  more frequent with rimonabant versus placebo: dropout 19.6 vs 10.7%; discontinuation 9.4 vs 2.1%; adverse psychiatric psychiatric event 5.1 vs 0%;  dizziness (10.9% vs. 2.1%), nausea (8.7% vs. 3.6%), anxiety (5.8% vs. 3.6%), depressed mood (5.8% vs. 0.7%), asthenia 3.6 vs 0.7% and paresthesia (2.9% vs.1.4%).    This contrasts with the 80year old plant extract metformin which – in dose simply adjusted to tolerance- has never been shown in dozens of trial for up to 20 years to have any serious adverse effects.  
 So like acarbose, there is no long term evidence that rimonabant is any competition for metformin for either obesity weight loss or type 2 diabetes.
The FDA has for these good reasons  (and no doubt also the fact that it is not a USA- but Italian- developed drug), . declined to licence rimonabant in USA.   In UK ie Europe , where it was not surprisingly  first registered and  – without evidence of longterm safety and benefit as has been so well established for metformin –  is most heavily ie indefensibly used instead of metformin, there have been already 5 associated deaths and 720 adverse reaction reports.  After the endless problems with amphetamines, fenfluramine, glitazones and gliptins, prescribers should be prosecuted for believing implausible advertisements for a new drug instead of staying with the proven metformin. It is firmly established that prescribers and dispensers  (not snakeoil marketeers or bureaucratic regulators) are responsible for their choice and issuing of  appropriate prescription drugs. Thats what doctors and pharmacists undergo arduous training and  onerous registration for.  .
Rimonabant’s  intended mechanism- blockade of cannabinoid receptors- naturally gives it the opposite action to cannabis- ie it causes depression  and dizziness in about 10%;  nausea, anxiety;   and  is  potentially epileptogenic,  and theoretically predisposes to other neurodegenerative diseases as well as hypertension, heart disease, stroke, pain  and cancer.
 Thus rimonabant  perhaps lessens  obesity longterm  , arthritis  and diabetes   (there is as yet no evidence for this) but  shows no prospect of benefit on all-cause morbidity and mortality. 
It’s like statins for mild-moderate hypercholesterolemia, acarbose  for obesity/diabetes, or  kava/black cohosh for menopause symptoms: why prescribe drugs that can cause acute hepatitis or worse when there are safer and more effective longterm preventatives?
“June 4, 2008 ” Acomplia linked to deaths in the U.K.;  While the FDA has been slammed by some drugmakers for its too-conservative approach to drug approval, it may have made the right move with Acomplia. But recent findings by the U.K.’s drug regulator show Sanofi’s weight-loss drug has been linked to five deaths and 720 adverse reactions since the company launched it in Britain two years ago.” http://bcbsma.medscape.com/viewarticle/575640
July 2007 http://www.mhra.gov.uk/Safetyinformation/Safetywarningsalertsandrecalls/Safetywarningsandmessagesformedicines/CON2031809 The European Medicines Agency has recommended that Acomplia (rimonabant), a medicine for the treatment of obesity, must not be used by patients with major depression or those being treated with antidepressants, because of the risk of psychiatric side effects.Questions and answers    How many people have been treated with Acomplia?
Acomplia was granted marketing authorisation in the EU in June 2006.  Currently, rimonabant has been launched in 19 countries, including 13 European countries.  Up to the end of May 2007, it is estimated that about 240,000 patients have been treated with Acomplia worldwide.  Approximately 41,000 patients have been treated with Acomplia in the United Kingdom.
How many people treated with Acomplia might develop psychiatric side effects?
The evidence suggests that one in ten people who take Acomplia may develop psychiatric side effects.  The commonest psychiatric side effects are low mood and depression.  Anxiety, irritability, nervousness and sleep disorders may also occur commonly.  Approximately one patient in every hundred may experience suicidal thoughts.Up to the end of June 2007, the MHRA had received a total of 318 cases, from UK sources, of adverse drug reactions which were suspected to have been caused by Acomplia.  The total number of adverse reactions reported in these cases was 921 because some reports described more than one adverse reaction.  Three hundred and sixty-four (364) psychiatric reactions have been reported.  Amongst these, there have been 48 reports of depression, 16 reports of suicidal thoughts and one report of self-injury.
Nonclinical Overview: CNS Toxicity with Rimonabant        CNS Toxicity. Rimonabant blockade of CB1 receptors appears to influence the anti-convulsant tone of ECS; Rimonabant induced http://www.fda.gov/ohrms/dockets/ac/07/slides/2007-4306s1-09-FDA-Bruno.ppt
Continuing on the theme of unexpected toxicity landmines, I wanted to take a look at a highly anticipated obesity drug from Sanofi. Rimonabant is a small
pipeline.corante.com/archives/2004/07/20/worries_about_rimonabant.php – 55k –

From Wikipedia, the free encyclopedia 19/8/2008

Rimonabant (also known as SR141716, Acomplia,  is an anorectic anti-obesity drug. It is an inverse agonist for the cannabinoid receptor CB1. Its main avenue of effect is reduction in appetite.

Side effects Shortly after market introduction, press reports and independent studies suggest that side effects occur stronger and more commonly than shown by the manufacturer in their clinical studies. Reports of severe depression are frequent. This is deemed to result from the drug being active in the central nervous system, an area of human physiology so complex that the effects of a drug are extremely difficult to predict or anticipate.[5]

Because the drug has the opposite effects of cannabinoid receptor agonists such as tetrahydrocannabinol (THC, one of the substances found in marijuana), which is neuroprotective against excitotoxicity,[6] it can be theorized that Rimonabant promotes the development of neurodegenerative diseases of the central nervous system such as Multiple sclerosis, Alzheimer’s disease, Amyotrophic lateral sclerosis (ALS), Parkinson’s disease, and Huntington’s disease in persons who are susceptible.[7] The reported development of previously clinically silent multiple sclerosis in one patient taking Rimonabant suggests that any patients with an underlying neurological condition should not take Rimonabant, given the neuroprotective role of the endocannabinoid system in many experimental paradigms of neurological disease.

In June 2007[8]  the US FDA  voted not to recommend the drug’s approval because of concerns over suicidality, depression and other related side effects associated with use of the drug.

The risk benefit ratio on the usage of Rimonabant is not yet established. 



Rimonabant and the FDA    By Richard N. Fogoros, M.D., http://heartdisease.about.com/b/2008/04/02/rimonabant-and-the-fda.htm April 2, 2008

Rimonabant, the long-awaited weight-loss and smoking-cessation drug that is available in most Western countries except the U.S., took another blow this week at the American College of Cardiology Scientific Sessions in Chicago, where the results of the STRADIVARIUS trial were presented. In this trial, obese patients randomized to receive rimonabant lost significantly more weight and more inches from their waists than patients on placebo, and in addition they had significantly improved HDL, triglyceride, and CRP levels. But unfortunately, the volume of their atherosclerotic plaques (the primary endpoint of the study) was not significantly improved over the placebo group. Furthermore, patients on rimonabant had a significantly higher incidence of psychiatric effects, mainly depression and suicidal ideation. This study may prove to be the final nail in the coffin for rimonabant in the U.S. American doctors and patients who have been anxious for the approval of rimonabant, and who may wonder why the FDA would refrain from approving a drug that significantly improves weight loss, smoking cessation, and lipid and inflammation profiles, should read this article on rimonabant and the FDA.

See the HRT  and supplement papers  below, and the recommended condition-specific supplement product information.. For specialist  internist consultation on appropriate supplements including HRT for individual circumstances, email your concise health details to info@healthspanlife.com