Question: How to insure a full control of the distribution in all Member States MS?
Answer: In the EU, a unique controlled distribution system is not possible in all Member States (MS) given the differences in:Healthcare system, National legislation.
For this reason it is was neccessary to determine a core PPP with key elements to be implemented in all MS.
Then specific implementation details must be defined for each MS after agreement with National Competent Authorities (NCAs).
Question: Who is responsible for collecting and reporting malformations to the authorities and to the public?
Answer: It is the responsibility of prescribers and the pharmaceutical company to report the cases of exposed pregnancy (and not only malformations) to the authorities. The cases will be collected thought the malformation registry in some MS, or thought spontaneous reporting. The public is informed by the EMEA public reports or press releases. In addition, the EMEA will continue to inform patients/victims associations post authorisation.
Question: Who does the Risk Management Plan (RMP) protect?
Answer: Firstly, the RMP should avoid the birth of child with malformations, as the aim of the PPP is to avoid pregnancy exposure. The RMP should protect the Patients 1/ women of childbearing potential from foetal exposure, 2/ all patients from all adverse drug reaction (e.g. neuropathy).
Question: How will the public be informed on the history of thalidomide?
Answer: A paragraph on the history of thalidomide will be included in the European Public Assessment Report (EPAR), the Questions and Answers document (patient friendly information published on the EMEA website a few weeks after the opinion), the Direct Healthcare Professional Communication (sent by the applicant to all healthcare professionals would have been reviewed and adopted by the CHMP), in the educational materials.
12.15.2010 16:56 | Health | back
Thalidomide is a well-known drug, known for its severe birth defects. A derivative of thalidomide, lenalidomide experienced a renaissance now as a possible means to increase the immune competence in old age. rn
The research team discovered that extremely low doses of the drug lenalidomide (Revlimid ®) stimulates the protein production of immunocompetent cells, leading to an improvement in Zytokinaufteilung and production.Cytokines are protein substances that are used in the defense against viruses or bacteria are used. Cytokines are also responsible for the inflammation in the context of infection.
The study, based on these findings, was performed with a comparatively small number of only 13 patients and was aimed to determine the dosage context of such therapy. The data will appear in January in the journal Clinical Immunology.
The identification of a substance that is capable of the immunological decline in old age (so-called immunosenescence) to slow or even neutralize, the result of years of research by Dr. Edward J. Goetzl at UCSF and the National Institute on Aging. Focal point of his work on cytokines, the question of the change of Zytokinniveaus with age, gender differences and their impact on the health of those affected.
"It really speaks today, no one of longevity and life extension. What is rather interesting, a healthy life," said Goetzl, UCSF director of the Allergy and Immunology Research, a specialized department for the development of new diagnostics and therapeutics in allergy and immunology section.
"If the Zytokinlevel with 50 the same as with 25, the probability of disease probably low," said Goetzl. "If they go down but we have to do something about it. Could you take a low dose pill with no side effects, you would not do that, too?"
In 2009, Goetzl, a group of 50 elderly as part of a study by the National Institute on Aging on their cytokine levels for interleukin (IL) -2, IFN-gamma and IL examined-17. He found that really healthy 70-80 year old women the same cytokine levels as healthy had 20 years.
accompanied, on the other side there were older men and women whose levels increased inflammation and decreased immune response from a lower level of IL-2 and IFN-gamma was. This waste, found the researchers, had been in the last section of the middle ages have begun.
Based on this knowledge, they began the search for a substance with which the IL-2 and IFN-gamma levels were raised on, would not that of IL-17 levels significantly affected. IL-2 and IFN-gamma is protective immune modulating substances.
"Based on our studies, we had a profile in humans, which allowed us to begin the search for a suitable active substance," said Goetzl. "Our job was to find not only that, something with which the cytokine levels could be changed in the desired direction, but also that that be possible without the side effects should be."
The research team focused on three different classes of compounds, among whom was lenalidomide, a derivative of the well-known thalidomide. Thalidomide was introduced in the late 50's as a sedative and 1961 in the U.S. withdrawal from the market after the children of mothers who had taken the remedy for nausea during pregnancy, had come to serious birth defects.
In recent years, the derivative lenalidomide has been used more and more as co-therapeutic agent in certain cancers, especially multiple myeloma and renal tumors. Both cancers are considered dependent on IL-2 levels, just the mirror, the Goetzl and his colleagues ascribe an important role in immunosenescence.
In his latest study, researchers tested the compound in healthy seniors. They found that even were able to stimulate small amounts of lenalidomide, the IL-2 production optimally. In the young subjects (21-40 years old) was the IL-2 levels are increased by about a factor of seven. The volunteers over 65 years the increase was even more dramatic, reaching, on average, values for the 120 times the initial values and thus youthful levels. Regarding the needed dose lenalidomide increases the production of IFN-gamma by up to 6-fold, while the production of IL-17 is not affected.
The team led by Dr. Goetzl also found that lenalidomide had additional beneficial properties in the older study participants. It had improved the migration of T cells through the body, strengthened their capacity for knowledge of disease-causing germs and diseased cells and prolonged the life span of cells.
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In 1964 Jacob Sheskin, Professor at the Hebrew University of Jerusalem at Hadassah University Hospital (he was also the chief staff and manager of Hansen Leper Hospital in Jerusalem), administered thalidomide to a critically ill patient with erythema nodosum leprosum (ENL), a painful complication of leprosy, in an attempt to relieve his pain in spite of the ban. The patient slept for hours, and was able to get out of bed without aid upon awakening. The result was followed by more favorable experiences and then by a clinical trial.
He found that patients with erythema nodosum leprosum, a painful skin condition, experienced relief of their pain by taking thalidomide. Further work conducted in 1991 by Dr. Gilla Kaplan at Rockefeller University in New York City showed that thalidomide worked in leprosy by inhibiting tumor necrosis factor alpha. Kaplan partnered with Celgene Corporation to further develop the potential for thalidomide. Subsequent research has shown that thalidomide is effective in the treatment of multiple myeloma, and it was approved for use in the United States by the FDA for use in this malignancy. The FDA has also since approved the drug's use in the treatment of erythema nodosum leprosum. There are studies underway to determine the drug's effects on arachnoiditis and several types of cancers. However, physicians and patients alike must go through a special process to prescribe and receive thalidomide (S.T.E.P.S.) to ensure no more children are born with birth defects traceable to the medication. Celgene Corporation has also developed analogues to thalidomide, such as lenalidomide, that are substantially more powerful and have fewer side effects - except for greater myelosuppression.
On July 16, 1998, the FDA approved the use of thalidomide for the treatment of lesions associated with Erythema Nodosum Leprosum (ENL). Because of thalidomide’s potential for causing birth defects, the distribution of the drug was permitted only under tightly controlled conditions. The FDA required that Celgene Corporation, which planned to market thalidomide under the brand name Thalomid, establish a System for Thalidomide Education and Prescribing Safety (S.T.E.P.S.) oversight program. The conditions required under the program include; limiting prescription and dispensing rights only to authorized prescribers and pharmacies, keeping a registry of all patients prescribed thalidomide, providing extensive patient education about the risks associated with the drug and providing periodic pregnancy tests for women who are prescribed it. On May 26, 2006, the U.S. Food and Drug Administration granted accelerated approval for thalidomide (Thalomid, Celgene Corporation) in combination with dexamethasone for the treatment of newly diagnosed multiple myeloma (MM) patients. The FDA approval came seven years after the first reports of efficacy in the medical literature and Celgene took advantage of "off-label" marketing opportunities to promote the drug in advance of its FDA approval for the myeloma indication. Thalomid, as the drug is commercially known, sold over $300 million per year, while only approved for leprosy.
Thalidomide is available to a number of patients in the UK, generally in specialist cancer treatment centres where research trials are taking place and specialist doctors have experience in its use.
Brazil has the second highest prevalence rate of leprosy in the world and thalidomide has been used by Brazilian physicians as the drug of choice for the treatment of severe ENL since 1965. A study published in 1994 found 61 people born after 1965 whose limb defects and exposure history were compatible with thalidomide embryopathy. In 63.6% of these cases, thalidomide had been prescribed without the physician informing the patient about the drug's teratogenicity. Since then production, dispensing and prescription of thalidomide have been strictly controlled and cases of thalidomide embryopathy are thought to have occurred until today.
The increasing potential therapeutic uses of thalidomide in many medical conditions as well as pressure from medical practitioners and their patients who might benefit from the drug have turned attention to safety and ethical issues. There is considerable debate on which patients thalidomide should be made available to, especially since it is well accepted that controlling access is exceedingly difficult.
The it is speculated that there are many unrecognized cases because the ECLAMC system covers less than 1% of all births in South America and phocomelia may not be specific enough to identify thalidomide embryopathy; that is, many patients might have only craniofacial anomalies. They concluded that there is a need for a birth defect monitoring system in areas where thalidomide is available.
Since ENL, which is the primary indication for thalidomide, has other successful treatment modalities, there is some question about the use of thalidomide to treat this condition (Crawford, ’94a,b). The discussion of thalidomide’s use for any condition, however, continues, with strong advocates on both sides of the debate as to how strict the control should be on the availability and distribution of this drug.
There is no question, however, that great care must be taken if thalidomide is given to a woman of childbearing ages.
Thalidomide has changed from a prototypical teratogen,essentially banned from medical usage to a possible useful therapeutic agent in a wide variety of conditions. In some countries it is still considered an experimental drug, but its availability and use are increasing. In regions where the drug is more difficult to control, infants have been born with the devastating findings of thalidomide embryopathy. Clinicians who desire to use thalidomide must be aware of its teratogenicity and also must appreciate the difficulty of controlling access to at-risk females. It is feared that if thalidomide is available by prescription for a large number of conditions, more cases of thalidomide embryopathy will occur. However, there may be severe cutaneous and systemic diseases for which thalidomide is an effective drug, and physicians and their patients will insist on availability. If this occurs, determining the risks and benefits will be an important challenge for the medical profession.
On 9 July 2001, orphan designation was granted by the European Commission to Laboratoires Laphal, France, for thalidomide for the treatment of multiple myeloma.
The sponsorship was transferred to Pharmion Development in 2004.Pharmion Development changed its name to Pharmion France in 2007 and Celgene 2009.
What is multiple myeloma?
Multiple myeloma is a cancer of a type of white blood cell called a plasma cell. Plasma cells are found in the bone marrow. The bone marrow is the spongy tissue inside the large bones in the body. Normally, the bone marrow makes cells called “blasts” that mature into several different types of blood cells that have specific functions in the body. These include red cells, white cells and platelets. Red blood cells carry oxygen and other materials to all tissues of the body. Platelets make the blood clot, and white blood cells fight infection. In multiple myeloma an excessive number of plasma cells are produced. Normally, the division of cells takes place in a controlled manner but with multiple myeloma, the process gets out of control and abnormal plasma cells multiply, producing many myeloma cells. These fill up the bone marrow and interfere with production of the normal white cells, red cells and platelets. This leads to a number of possible complications, which include anaemia, bone pain and fractures, raised levels of calcium in the blood and kidney disease. Multiple myeloma is life-threatening.
What are the methods of treatment available?
The main treatment of multiple myeloma is chemotherapy (using drugs to kill cancer cells) usually combined with steroids (a group of chemical substances, belonging to a larger class of molecules, the so-called hormones, which have an effect on the activity of certain organs). Several products were authorised for the condition in the Community at the time of submission of the application for orphan drug designation. Radiotherapy (using high-dose x-ray or other high-energy rays to kill cancer cells) can be very useful to treat painful areas and weakened bones. Interferon alpha is a protein normally produced by the body during viral infections, such as flu. Sometimes a combination of interferon and chemotherapy may be used.
Thalidomide could be of potential significant benefit for the treatment of multiple myeloma. The main reason is that it may offer a new way of killing cancer cells and stopping tumour growth in these patients. This assumption will have to be confirmed at the time of marketing authorisation. This will be necessary to maintain the orphan status.
On 24 January 2008 the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion,** recommended to grant a marketing authorisation for the medicinal product Thalidomide Pharmion 50 mg hard capsule, intended for treatment of multiple myeloma. Thalidomide Pharmion was designated as an orphan medicinal product on 20 November 2001.The applicant for this medicinal product is Pharmion Ltd.
The active substance of Thalidomide Pharmion is thalidomide, an immunosuppressive agent (ATC code L04AX02). The precise mechanisms of action of thalidomide are not known but it appears to involve anti-angiogenic and immunomodulatory/anti-inflammatory activity.
The benefit with Thalidomide Pharmion in combination with melphalan and prednisone is an 18-month increase in median survival time in patients with untreated multiple myeloma, = 65 years or ineligible for high-dose chemotherapy, as compared to patients treated with melphalan and prednisone alone. The clinically important side effects are deep vein thrombosis and pulmonary embolism, peripheral neuropathy, severe skin reactions including Stevens Johnson Syndrome and toxic epidermal necrolysis, syncope, bradycardia, and dizziness.
Thalidomide is a potent human teratogen. A pharmacologist have a risk minimization programme called the PPP to prevent pregnancies in women being treated with thalidomide and exposure of unborn children to the medicine, which was implemented as part of the marketing authorisation.
The approved indication was: Thalidomide Pharmion in combination with melphalan and prednisone as first line treatment of patients with untreated multiple myeloma, aged = 65 years or ineligible for high dose chemotherapy. Thalidomide Pharmion is prescribed and dispensed according to the Thalidomide Pharmion Pregnancy Prevention Programme .
Thalidomide treatment must be initiated and monitored under the supervision of physicians with expertise in managing immunomodulatory or chemotherapeutic agents and a full understanding of the risks of thalidomide therapy and monitoring requirements
Detailed recommendations for the use of this product are described in the Summary of Product Characteristics (SPC) which was published in the European Public Assessment Report (EPAR) is available in all official European Union languages by the European Commission.
Prior to starting treatment with Thalidomide Pharmion
All patients should be fully educated regarding the teratogenic effects of thalidomide, advised that thalidomide must not be given to any other person, that they should return unused capsules to the pharmacist, and that they should not donate blood during or up to 1 week after treatment.
All patients should be assessed and categorized into one of the following three categories: women of childbearing potential, women of non-childbearing potential and male patients. These categories define the education and risk minimization measures that should be followed. All female patients or female partners of a male patient should be considered of childbearing potential unless they meet the criteria defined in section 4.4 of the SPC.
All patients should complete a ‘Treatment Initiation Form’ corresponding to their risk category. The prescriber should retain the completed form and provide a copy to the patient.
The European Medicines Agency (EMEA)
European Thalidomide Pharmion (thalidomide)
The European Medicines Agency (EMEA) has recommended the approval of Thalidomide Pharmion (thalidomide) for the treatment of multiple myeloma, a rare cancer of the bone marrow.
on 21-24 January 2008, the Agency’s Committee for Medicinal Products for Human Use (CHMP) concluded that the “benefits of Thalidomide Pharmion in combination with melphalan and prednisone outweigh its risks for the first-line treatment of multiple myeloma for patients over 65 years of age or who cannot be treated with high-dose chemotherapy“. Clinical studies have shown that adding Thalidomide Pharmion to melphalan and prednisone can prolong survival time by about 18 months in newly-diagnosed multiple myeloma patients over 65 years of age, as compared to patients who received conventional chemotherapy.
The CHMP has approved a risk management plan that includes a number of actions intended to prevent pregnancies in women being treated with thalidomide and exposure of unborn children to the medicine. For example, all women of child-bearing potential who are treated with Thalidomide Pharmion must undergo pregnancy tests before, during and after treatment, in addition to using selected and effective contraception.
European Commission has now granted on 16 April 2008, Thalidomide Pharmion a marketing authorisation, as a result of thisThalidomide Pharmion will only be available by prescription, and treatment will be initiated and monitored by a doctor who has experience in the treatment of multiple myeloma.
A clear warning will be printed on the boxes containing the medicine, indicating that Thalidomide Pharmion causes birth defects and foetal death.
Prior to the launch of Thalidomide Pharmion in each Member State, Pharmion Ltd. will provide healthcare professionals and patients with educational materials about the treatment-related risks and the precautions required to ensure the safe use of the product .
What is thalidomide Pharmion?
Thalidomide Pharmion is a medicine containing the active substance thalidomide. It is to be used to treat multiple myeloma in combination with other medicines (melphalan and prednisone ) with multiple myeloma it works by blocking the development of cancer cells, and by stimulating some of the specialised cells of the immune system (the body’s defence mechanism) to attack the cancer cells.
Multiple myeloma is a rare type of bone marrow cancer that usually occurs in older people and that is very difficult to treat.
Clinical studies have shown that adding thalidomide to melphalan and prednisone can prolong survival time in patients with multiple myeloma. Thalidomide Pharmion is to be used in patients who cannot be treated with high-dose chemotherapy (anticancer treatments), or in patients aged over 65 years who have not been treated for multiple myeloma before.
Thalidomide is ‘teratogenic’, meaning that it has a harmful effect on the unborn child.
A USA Company called Celgene now hold all marketing authorisation and in Canada and USA the risk management programme known as the (PPP in Europe) is called the S.T.E.P.s programme
On July 16, 1998, FDA approved the use of thalidomide for the treatment of the debilitating and disfiguring lesions associated with erythema nodosum leprosum (ENL), a complication of Hansen’s Disease, commonly known as leprosy. Because of thalidomide’s potential for causing birth defects, FDA invoked unprecedented regulatory authority to tightly control the marketing of thalidomide in the United States. A System for Thalidomide Education and Prescribing Safety (S.T.E.P.S) oversight program has been initiated that includes limiting authorized prescribers and pharmacies, extensive patient education about the risks associated with thalidomide and a 100% patient registry. This oversight program is designed to help insure a zero tolerance policy for thalidomide exposure during pregnancy.
Celgene Corporation of Warren, NJ, will market thalidomide as Thalomid.
The information presented on this page includes consumer and patient information, thalidomide advisory committee and workshop transcripts, the approved labeling text and the medical review on which the decision to approve this drug was based. Also included are selected links to other web sites containing thalidomide information.
Where is Thalidomide approved ?
Thalidomide is approved in Brazil and Mexico, Canada , Israel, New Zealand, South Korea, Thailand, Turkey, USA, and Australia. Thalidomide Pharmion was approved in Australia earlier this month. It is available in other countries on a named-patient or compassionate-use basis.
Thalidomide is being widely used in Brazil to treat people with leprosy - including women of childbearing age. Government doctors say that the use of the drug is strictly controlled but members of some associations of thalidomide survivors say that many women of childbearing age could be taking the drug, especially in remote areas, where leprosy is most prevalent.
There 228 000 cases of leprosy were recorded in 1992, the last year for which official numbers are available. Of these, 34 000 were new cases - double the number for 1986. The rise is due, to better diagnosis and more primary care. Brazil has the second highest population with leprosy in the world after India, and the Amazon region has the worst rate - 36 cases per 10 000 population.
Brazil has the second highest population with leprosy in the world after India, and the Amazon region has the worst rate - 36 cases per 10 000 population.
Thalidomide, a powerful anti-inflammatory drug, is manufactured in Brazil by one laboratory in Belo Horizonte, and the entire output is sold to the government for distribution to local health services throughout Brazil. We now know that this year it was doubling production to over two million pills. The entire stock was for treating patients with leprosy .
The government have said that 27 cases of people with the thalidomide syndrome have been confirmed. Rosangela Goncalves Nascimento, chairwoman of the Brazilian Association of Thalidomide Victims, claims to have discovered 33 cases, the youngest in a child 2 years old, as a result of "amateur" research. She believes that there could be up to 7000 victims because of the number of women potentially at risk. The association has been distributing posters for use in health posts warning of the dangers of thalidomide and will take part in the international thalidomide survivors congress to be held in Sweden in September.
3. What is thalidomide approved for in the United States?
Celgene markets thalidomide as Thalomid in the U.S. It is approved to treat newly diagnosed for the treatment of multiple myeloma. MM, erythema nodosum leprosum, the painful, disfiguring skin sores associated with leprosy, and to prevent and control the return of these skin sores.