Preface

Don't take ACTOS !!!

More harmful than NOSCAL that have been banned already!!!
Not only heart failure! If Myocardial Infarction occurs, it may be irreversible!!

　We concluded in February 1998 that Troglitazone (NOSCAL in Japan and REZULINE in the US) should be banned.
And it was finally withdrawn from the US market and subsequently withdrawn also from the Japanese market in March 2000. It was too late but of course an inevitable measure. However where have gone the interest which they earn by selling almost 200 million US dollars in Japan and 700 million US dollars in the US?. Who our cost for insurance would cover? How about the compensation for the victims who suffered from the adverse reaction to Noscal (Rezuline)?
　Troglitazone have been withdrawn, but we become anxious about the safety of ACTOS that was approved in November 1999 and might be used increasingly instead of Noscal (Rezuline).
　So NPOJIP precisely analyzed the data of ACTOS used for the approval. It was found that ACTOS might be as harmful as Noscal (Rezuline).

What will happen when a patient with heart disease become swelled?
What do you think will happen when a patient with heart disease become swelled?

　A patient with heart failure is already swelled. It may be very easy for you to imagine that he or she will be easily become worse even if you were not healthcare professionals.
　 Swelling is a phenomenon in which water is increased outside blood vessels. When water is increased outside blood vessels, water inside of the blood vessels is also increased. A patient with heart failure who has weakened heart cannot circulate blood well and a lot of blood is stay in vein, which causes retention of a lot of water all over the body.
　If the patient swelled more, more water and more blood stay in the body and the heart failure may easily worsen. As one among eight women taking ACTOS become swelled, so they have high risks to become heart failure. Moreover, patient with heart arrhythmia may worsen, and patients with heart attack in the past may experience a new attack again.

ACTOS does not work below the dose that causes toxicity
Such a product is not a drug, nothing but a toxin

　ACTOS was shown to lower blood sugar in rats with artificially induced diabetes mellitus. It is claimed in the colorful pamphlets.
　But the beneficial effects of ACTOS are not shown below 3 mg/kg/day in rats (3 mg per kg body weight every day). This is the same dose that can produce an effective level (actually, area under the curve: AUC) of active ingredients in human. But almost the same dose (3.6 mg/kg/day by mouth) for one year have shown to induce harm effect on the heart and/or bone in the animals. It means that the beneficial effects can be sown first at the dose that harms the animal.

Harmful effects to heart are more serious than to liver

　ACTOS seems less toxic to the liver than Noscal (Rezuline). In the animal toxicity tests, liver toxicity is not so strong. The heart and not the liver is the organ in which toxicity appear at first.

Irreversible cardiomyopathy and lung bleeding

　3.6 mg/kg/day by mouth of ACTOS (the equivalent to the clinical dose for human) induced hypertrophy (enlargement) of the heart, abnormal bone forming and decrease of bone weight (compatible with osteoporosis in human). Higher dose (14.5 mg/kg/day) induced cardiomyopathy with scattered focal necrosis of heart muscles and lung bleeding which may be related to the heart failure.
　These abnormalities (cardiomyopathy and lung bleeding) did not recovered after four month stopping ACTOS. It means those abnormalities are irreversible. Mortality increased related to the dose increased.

Cardiotoxicity is apparent at the human clinical dose

　The lowest effective dose in the animal that is compatible with human clinical dose is definitely harmful to the heart. This dose or more for one year induced cancer in the urinary bladder. So ACTOS may induce cancer.
　So it is substantially probable that diabetic patients treated with ACTOS for many years will have heart disease, fragile bone and/or cancer even if they have no other diseases now.

Heart failure and/or Myocardial infarction were actually reported

　In the clinical trial of ACTOS, rate with anemia, elevation of LDH (indicating cell damage somewhere in the body), CPK (indicating muscle damage), ALT/AST (indicating liver damage) were almost same or higher than that by Noscal (Rezuline). Overall frequency of swelling (edema) was 7 %, but 13 % of women treated with ACTOS experienced swelling (edema)Swelling (edema) is harmful for diabetic patients. Heart failure and/or Myocardial infarction were reported from abroad and in Japan also.
　Diabetic patients tend to have heart complications. Heart diseases are one of the most important complication which diabetes patients wants to prevent. So the agent that induce heart disease or cancer as the first abnormality should be disqualified as a drug for the treatment of diabetes mellitus.

Don't use ACTOS! It should be banned
Emergency letter for the safety of ACTOS

　While we have been warning that it should be banned, emergency doctor letter in which ACTOS should not be administered to the patients with heart failure have been issued on 5th October 2000, since five patients have been reported to get heart failure or the heart failure become worse. It will be easy to understand for you from our explanations that problem is not only for heart failure.
　The final endpoints of the management of diabetes mellitus are to prevent complications in cardiovascular system, kidney and retina (eye) and to prolong comfortable life. But ACTOS will almost definitely increase heart diseases including heart failure, myocardial infarction (heart attack) and/or cardiac arrhythmia. Heart complications are observed frequently not only in the animal study but also in the clinical trials. For example, among patients who were treated with ACTOS for more than half a year, only one myocardial infarction was reported as those classified as severe heart diseases. However among the heart diseases classified as moderate heart diseases, one was revealed actually as myocardial infarction, eight were increased heart-lung ratio (this means almost heart failure), three were abnormal echocardiogram, one had difficult breath on exercise, one had moderate pounding heart, seven had abnormal electrocardiogram including atrial fibrillation (a sort of cardiac arrhythmia), totally 22 patients had any moderate or severe heart complications among 321 patients-year: this means 6.8 patients among 100 patients treated with ACTOS will get moderate or severe heart diseases within one year.
　We surveyed clinical trials of ACTOS and of other drugs for diabetes mellitus. We selected placebo groups of clinical trials of ACTOS and experimental group as well as control group of clinical trials for other drugs for diabetes mellitus as control of ACTOS. Only one myocardial infarction, two patients with asthma or breath difficulty, totally tree was the moderate or severe complication with these treatment for 599 person-year, i.e. 0.6 per 100 person per year. These shows that ACTOS much more easy to induce heart disease (it is expressed as p=5.45×10-8 ).
　Abnormality other than heart was 2.8 per 100 per year for both ACTOS and for control (3.0 for Noscal) with no difference. However if you combine ACTOS and Noscal (Rezuline), incidence of cancer is significantly higher and that of peptic ulcer is tend to be higher for them than for others.
　As these comparisons are not the results obtained by randomized controlled trials (drawing-lots-trials), they are merely one of the information. But in the animal studies, lowest effective dose enlarged heart and reduced bone weight, dose of four times dose of lowest effective dose have induced cardiomyopathy with necrosis of heart muscle and lung bleeding both of that did not recover. Above that dose, mortality increased. So, considering together with the results of the animal toxicity studies, ACTOS should be considered as more dangerous especially for heart.
　Japan Institute of Pharmacovigilance (JIP) has requested the Minister of Health and Welfare to withdraw ACTOS immediately from the market on the 6th October 2000. Subsequently, NPOJIP, TIP and Med Watcher Japan (Yakugai Ombudspersons Committee) as well requested that ACTOS should be banned and should be recalled. on 10th October 2000.

Stop taking ACTOS abruptly will never harm the patients under treatment.

　If the diabetes get worse after stopping ACTOS, insulin may perhaps be necessary for her or for him.
　Noscal (or Rezuline or troglitazone) was withdrawn from the market but the license has never revoked. ACTOS should be withdrawn from the market and the license of Noscal and ACTOS should be revoked.

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