Ban orlistat?

In this article are presented a series of important concepts related with the effects of drugs, characteristics of the orlistat (OR) used for the treatment of overweight and obesity, and some results of the damages taken place in patients under their treatment. The main objective is to point out some important elements so that the reader is able to make a critical decision about the convenience of prohibiting the production and use of OR after almost 20 years on use.

The increment of obesity and overweight at world level force to consider the execution of political and integral measures, because the problem is multifactorial and very complex. Therefore is important to make use of the biggest quantity in available tools to confront it. Some of the possible actions, without being exhaustive, include change in political of health, cities planning, information of appropriate health, readiness of healthy foods, changes of labor habits, of lifestyle. Then to try to limit the actions to the use of medications for the pharmacological treatment or to improve the feeding will be fruitless in most of the cases.

Side effect (SE) is an event that experiences a patient, whether therapeutic or usually adverse, and it is not wanted in general or in the mark of the illness. In opposition the definition of adverse event (AE) is any answer to a drug that is harmful and involuntary and present at therapeutic doses used in the man like prevention, diagnostic or treatment, excluding the non attainment of the wanted purpose.

Adverse event can type being A or B. Those type A (augmented) can be predicted pharmacologically by the well-known activity of the drug, they are habitual, they depend on the dose, in general are not clinically serious and have a very low index of mortality. As they are habitual and prospective reactions, they are usually identified before the medication marketing.

On the contrary the type B reactions (bizarre, strange) are unforeseeable, not very frequent, don´t depend on the dose, can be clinically serious, produce a high mortality and due to hypersensitivity or idiosyncratic mechanism.

In the moment of commercialization, it is probable that they are only known the most common and foregone AE from a pharmacological point of view. After the commercialization, as AE is detected, or that the populations are determined that present a bigger risk of developing secondary effects, this information is added to the technical record of the product, with the purpose that the doctor can prescribe with security or in an extreme case the prohibition of the medication.

Which the approach is for the prohibition of the manufacture and distribution of a medication?

In their press announcement of the FDA about the ban of the use of ephedra like active principle of the constituents of dietary supplements manifest the prevail of a relationship benefits-risk in the consumer´s favor (FDA, P04-106). After carrying out the pertinent research they confirmed that the ephedrine alkaloids elevates blood pressure and alter the circulatory system.

!n 1962, Congress amended the 1938 law to require manufacturers to show that their drug products were effective, as well as safe.  It corresponds the Drug safety Board, integrated (2005) for staff of the FDA and representatives of the National Institute of Health and Veterans Administration to advise the Director of The Center for Drug Evaluation and Research of the FDA about the topics of safety of drugs and works jointly with the agency to communicate the information of safety to the professionals in the health and patients. Over-the-counter OTC and prescription drugs, including generic drugs, are regulated by FDA´s Center for Drug Evaluation and Research (CDER).

OR is an OTC and recently an application is presented to the FDA (April 14) to promote its prohibition. A drug is removed from the market when its risks overweigh its benefits. A medication is taken out of the market due to safety issues that cannot be corrected, it happens this way when is discovered that causes serious unknown side effects to the moment of its approval. If the agency makes the decision, the FDA notifies to the producer that should stop its commercialization. Usually, the manufacturer stops the commercialization voluntarily in front the application of the FDA. If the producer doesn´t agree the agency then she can take legal actions to take out the unsafe product of the market.

OR is a drug used to treat people who are either overweight or obese. Unfortunately it has the potential to damage a number of organs, including the liver, pancreas, and kidneys. It is an inhibitor of lipases, enzymes that break down fat, lipase inhibition therefore stops fats from being broken down and subsequently absorbed in the small intestine. The label points out that the inhibition is reversible, but due to the covalent bond with the enzyme, this inhibition is irreversible. The activation of the enzyme is reestablished after its de novo  synthesis.

From their first launching in 1998 up to 2009 were estimated 40 million patient treatments with OR (prescription and non-prescription medicines). Reports of suspected adverse drugs reactions should be viewed in this context.

In postmarketing surveillance studies smaller adverse events are detected at 1:1,000 but can be relevant still of 1:50,000.

Petition to ban OR

In a petition directed to the Margaret Hamburg, M.D. of the FDA the Sidney M. Wolfe, M. D. of the Public Citizen´s Health Research Group requests the prohibition of OR in its form of prescription drug, Xenical and the OTC drug Alli, because they expose the patients to serious risks that surpass its minimum clinical benefits.

The main arguments to base this request are:   

The safety trials in their preclinical stage revealed evidence of hepatic accumulation of lipids and hepatocellular damage. To increased dose they showed dose-related increases in plasma transaminases, alkaline phosphatase, and bilirrubin. Animals treated with oral OR for two weeks while on high-fat diet were determined to have increases in serum alpha-amylase, which are key indicators of pancreatic injury. In rodents treated for 6 to 9 months with oral OR while feed a high-fat, normal calcium diet, kidney mineralization, pelvic dilation, and progressive nephropaty were commonly observed pathologic lesions on post-mortem histopathology examination. A more recent study demonstrated that the administration of lipase inhibitors resulted in a significant increase in urinary oxalate, elevating the risk of oxalate stone formation.

Clinical results

Severe liver injury, which can lead to liver failure, need for liver transplantation, and death. The FDA medical officer discussed, in her March 2006 review, nine cases associated with hepatic failure or cholestatic hepatitis, two of which resulted in death and one in liver transplantation.

Acute pancreatitis, which frequently results in hospitalization and can lead to death. In her review of the Adverse Event Reporting System (AERS) database, the FDA medical officer found 99 raw cases of pancreatitis, of which 68 were confounded by other factors: gallblader disease (30 cases), dyslipidemia (13 cases), history of pancreatitis/gallstones (9 cases), alcohol use (8 cases) and diabetes (8 cases).

Acute renal failure secondary to acute oxalate nephropathy, and calcium oxalate nephrolithiasis (kidney stones). In phase III studies it was observed a tendency towards increased kidney stone development in the OR group subjects, although no statistically significant. In Public Citizen´s analysis of MedWatch reports they found 73 cases of nephrolithiasis.

Based on the observations about the results obtained in the preclínical phase is it possible to predict the noxious effect of the OR in the human beings?

Are OR adverse reactions predictable? Are secondary effects? Of the total of subjected people to treatment which the proportion of affected people is? Should the FDA to prohibit the manufacture and commercialization of the OR?

1. FDA news release P04-106 (November 23, 2004)(4/16/2011)

2. www.citizen.org/     (FDAsolCitizens1942.pdf)(4/16/2011)

3. http://www.mhra.gov.uk/home/groups/pl-p/documents/websiteresources/con068267.pdf (4/17/2011)