Genetic Trigger Discovered For Most Common Form of Mental Disability and Autism

March 8, 2014

March 08, 1014 – The following article just appeared in PsyBlog and provides highly interesting reading in relation to newly discovered molecular mechanisms in the etiology of (possibly individualized) disease predispositions. Very exciting.

The most common form of intellectual disability is caused by a mechanism which shuts of an associated gene, a new study Gene silencingfinds.Scientists at the Weill Cornell Medical College have also shown that a drug can block the silencing mechanism, thereby preventing the most common form of mental disability: fragile X syndrome (Colak et al., 2014).This points the way towards a therapy for fragile X syndrome — a leading genetic cause of autism — and possibly for about 20 other diseases. Fragile X syndrome causes a wide range of emotional, behavioural and physical problems and occurs mostly in boys. For around twenty years scientists have known that the cause of fragile X syndrome is the excess repetition of a sequence of genetic code. The problem was understanding how this code caused the disease.

Now, in a new study, published in the prestigious journal Science, researchers have discovered that this code halts the production of a protein which is crucial to communication within the brain. To find out how to fix this problem, the researchers used human stem cells from embryos that had tested positive for fragile X syndrome to create brain neurons in the lab.

This gave them a model of how the embryonic brain develops in which to test a new drug developed by Dr. Matthew Disney of the Scripps Research Institute. After adding the drug, they found that the gene continued to produce the vital protein, instead of being deactivated as it is in fragile X syndrome.

This points the way towards a treatment for fragile X syndrome. One of the study’s authors, Dr. Samie Jaffrey, explained: The findings have implications for a range of other diseases because of the biological mechanism that has been discovered. Other diseases including Jacobsen syndrome, an intellectual disorder, and Huntington’s disease, a neurodegenerative disorder, involve similar repetitions of DNA sequences and so may be amenable to similar treatments.


Can We Identify Risk for Drug Toxicity?

October 10, 2013

October 10, 2013 – Very recently, David Kerr, Professor of Cancer Medicine at University of Oxford, in the United Kingdom, and past President of the European Society for Medical Oncology, talked on Medscape (see the video here) about risk-benefit analyses for novel, inventive cancer treatments. See here in italics his statement:

 When we talk about precision medicine and personalized medicine, it occurs to me that most of the discussion has been about benefits and seeing what we can do to better understand the cancer and the molecular biology of the tumor. Through that understanding, we would try to come up with biomarkers that allow us to select patient populations that are likely to receive added benefit.

 As Francis Collins has said, those of us who are in the cancer field are probably standard-bearers for the whole broad field of personalized medicine because of the steps that we have made in terms of linking molecular genotypes to phenotypes and identifying the people who respond better to drugs.

 However, a risk-benefit ratio implies 2 sides of the coin. It seems to me that perhaps we have been missing out in terms of considering the toxicology, the pattern of side effects. These will be determined not by the somatic tumor mutations that we use to identify biomarkers for benefit, but within the germline. How do we metabolize the drug? How do we excrete it? The absorption, distribution, and metabolism components become important. I believe that one way of improving the risk-benefit ratio is to reduce risk. If we had tools, if we had assays, if we had biomarkers to identify patients most at risk for toxicity, most at risk perhaps even for lethal toxicity, then we as an oncology community would adapt our therapy accordingly, possibly even omitting some drugs if the hazard ratio for death or lethality were very high, but more likely modulating the dose of the drug to see if we could obviate the need for inducing life-threatening grade 4 toxicities.

 There is an interesting play here. If we look at most modern, well-designed, phase 3 cancer treatment trials, sometimes including a couple of thousand patients, we are starting to get the statistics that may allow us to do some genome-wide association studies looking for patterns of genetic change in the germline — not in the tumor, but the germline. That may give us an idea about which patients are most at risk for certain adverse effects and tell us, as practicing physicians, to adjust the dose accordingly.

 It is a new science. I am going to call it tox-nostics. There you are. You have heard it here first. I am going to trademark the term. We need to do more concerted research to see if we can improve risk-benefit, but through the portal of reducing risk rather than focusing only on benefit. I think modern, well-designed trials in which germline DNA — ie, blood — has been collected, gives us a way of doing this.

 We know that some tests out there are moderately well used for 5-FU, for irinotecan.[1] I think we can improve on these. I think we can improve test performance, utility, availability. We just need a few clinical champions, a few good tests, to really make the difference.

 Thanks for listening. As always, we will be very happy to take any comments that you may care to make or to post. Medscapers, ahoy! Thank you.

 This is a very notable statement, not only for Medscapers. I would like to comment it on two accounts. First, I am not so sure whether the world has waited for the new term “tox-nostics” and whether a “trade marking” of it will be necessary and would successfully serve its purpose, namely to promote the concepts of targeted efficacy and safety of patient’s therapies. For one, “tox-“ (or any mentioning of toxicity) in the field of drug development and marketing is very negatively looked at and basically considered a “non do”.  Extensive and start-up company terminating (TheraSTrat AG to be precise (you may still search the net for it)) past experience of the author of this Blog would indicate that neither the phamaceutical industry, nor investors and financial markets, nor regulators and patients would like to hear anything near to toxicity in connection with their product and/or therapy.  On the other hand, we (and others), in the early years of the last decade, have coined the term “theragenomics” to embrace the concept of targeted efficacy and safety of patient’s therapies by applying genomic and individualized genetic knowledge to drug therapy.

 Secondly, on a far more positive note, the recently FDA-approved anti-melanoma drug Zelboraf (Vemurafinib) would be one of several good example in case for Prof. Kerr’s proposal/statement. Zelboraf (Vemurafinib) is a kinase inhibitor indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved companion genetic test. Zelboraf (Vemurafinib) is not indicated for treatment of patients with wild-type BRAF melanoma. That means in the clear that before treatment, patients need to be tested for this mutation (i.e. allelic variant of the tumor BRAF gene) by a companion gene test. Only those patients who test positive for the BRAF V600E variant are eligible for and will profit from a  treatment with Zelboraf (Vemurafinib).

 In the “Warnings and Precautions”-section of Zelboraf’s FDA-approved drug label, the following potential serious, if not fatal, adverse effects of Zelboraf are listed: New Primary Cutaneous Malignancies; New Non-Cutaneous Squamous Cell Carcinoma; Other Malignancies; Tumor Promotion in BRAF Wild-Type Melanoma; Serious Hypersensitivity Reactions; Severe Dermatologic Reactions, including Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN); QT Prolongation; Hepatotoxicity; Photosensitivity; Serious Ophthalmologic Reactions; Embryo-Fetal Toxicity. Here (at FDA) and here (at DailyMed), you will find the drug label on Zelboraf (Vemurafinib).

 The other listed severe drug effects not withstanding, at least for “Severe Dermatologic Reactions, including Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)” we know from many other drug which are associated with this adverse effect, that there seems to exist a genetic predisposition of patients to develop SJS and TEN. For example, patients carrying the HLA-B*5701 allele have a very high risk for developing SJS and TEN when treated with Ziagen (Abacavir). Likewise, patients carrying the HLA-B*1501 allele have a very high risk for developing SJS and TEN when treated with Carbamazepine-containing medications such as Tegretol, Equetro, Carbatrol, and generics thereof. For more information on SJS and TEN, you might want to consult the link here to get started.

 Here, with Zelboraf (Vemurafinib) it might be worthwhile to see, if one the HLA-alleles already associated with SJS or TEN also dispose individuals treated with Zelboraf (Vemurafinib) to SJS or TEN or if in this case, genome wide analysis (GWA) would be necessary to identify new (HLA) alleles predisposing according patients to SJS or TEN. In any case, using such procedures, clinicians might in already today be in the position to provide highly effective targeted therapies combined with targeted avoidance of severe, treatments limiting and/or fatal drug toxicities to at least some patients, all of which would be in line with Prof. Kerr’s statement.


EMA: Recommendation to suspend tetrazepam-containing medicines

May 8, 2013

May 09, 2013 – This is from the News and Press Release Archive of the European Medicines Agency (EMA) as of April 29, 2013.  Find here the unedited release in full:

29/04/2013

Recommendation to suspend tetrazepam-containing medicines endorsed by CMDh

Following the recent recommendation by the Pharmacovigilance Risk Assessment Committee (PRAC), the Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) has endorsed by majority the PRAC recommendation to suspend the marketing authorisations of tetrazepam-containing medicines across the European Union (EU). The CMDh, a body representing EU Member States, is responsible for ensuring harmonised safety standards for medicines authorised via national marketing authorisation procedures across the EU.

Tetrazepam, a medicine of the benzodiazepine class, is used in several EU Member States to treat painful contractures (such as in low back pain and neck pain) and spasticity (excessive stiffness of muscles).

The CMDh position will now be sent to the European Commission, which will take a legally binding decision throughout the EU.

The review of tetrazepam was triggered by the French National Agency for the Safety of Medicine and Health ProductsExternal link icon (ANSM), following reports of serious skin reactions with this medicine in France. Having assessed all available data on the risk of skin reactions, including post-marketing data in the EU and the published literature, the PRAC concluded that tetrazepam is associated with a low but increased risk of serious skin reactions (including Stevens-Johnson syndrome, toxic epidermal necrolysis and DRESS syndrome) compared with other benzodiazepines. The Committee also noted that, in the light of the risks identified, the available data on the effectiveness of tetrazepam were not sufficiently robust to support its use in the authorised indications.

The CMDh agreed with the PRAC conclusion that the benefits of these medicines do not outweigh their risks, and adopted a final position that the marketing authorisations should be suspended throughout the EU.

The suspension of the marketing authorisations can be lifted if the companies that market these medicines provide data identifying a specific group of patients for whom the benefits of tetrazepam-containing medicines outweigh the risks.

Information to patients

  • Tetrazepam is a muscle relaxant used in painful conditions such as low back pain and neck pain as well as spasticity (excessive stiffness of muscles).
  • As a result of the risk of unpredictable, serious skin reactions identified, the CMDh position is that tetrazepam-containing medicines should no longer be used in the EU.
  • If you are taking a tetrazepam-containing medicine, you should not suddenly stop taking tetrazepam without your doctor’s advice. You should make an appointment with your treating doctor to discuss your treatment. Your doctor may also consider an appropriate alternative treatment for you.

Information to healthcare professionals

  • In light of the unfavourable benefit-risk balance, doctors should review their patients’ treatment at their next appointment, and may consider an appropriate alternative treatment.
  • Pharmacists should refer patients on a new or repeat prescription for tetrazepam to their treating physician.

The CMDh position is based on the PRAC review of all available data on the risk of skin reactions with tetrazepam, including post-marketing data in the EU and the published literature, and the available information on efficacy in licensed indications:

  • The review found that half of the reported reactions with tetrazepam are skin disorders, which are sometimes serious, life-threatening or fatal. Serious skin reactions include Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), erythema multiforme and drug rash with eosinophilia and systemic symptoms (DRESS) syndrome. They are unpredictable and can occur at any stage during treatment, including after short-term treatment, and at recommended doses.
  • In the pharmacovigilance database of the originator product, Myolastan, a total of 513 cutaneous (or allergic) reactions were identified. 65 cases of SJS and TEN were reported. Although the majority of cases occurred in patients taking concomitant medications, the causal link with tetrazepam was strong in a high number of cases.
  • The risk of skin reaction is higher with tetrazepam than with other benzodiazepines. This is possibly explained by a structural difference between tetrazepam and other benzodiazepines (i.e. the substituted cyclohexenyl ring of tetrazepam).
  • Regarding its efficacy, four studies showed no difference between tetrazepam and other active medicines when used for spasticity. The efficacy of tetrazepam for painful contractures is supported mainly by two small double-blind placebo-controlled clinical trials showing limited efficacy.

In view of the serious, potentially fatal, skin reactions and the limited efficacy of tetrazepam, the benefit-risk balance of tetrazepam-containing medicines is considered no longer favourable.


More about the medicine

Tetrazepam belongs to a group of medicines called benzodiazepines. It is taken by mouth to treat painful contractures (sustained shortening of muscle tissue), and spasticity (excessive stiffness of muscles).

Tetrazepam-containing medicines have been approved since the 1960s via national procedures in several EU Member States (Austria, Belgium, Bulgaria, Czech Republic, France, Germany, Latvia, Lithuania, Luxembourg, Poland, Romania, Slovakia and Spain), and are available on prescription under various trade names, including Epsipam, Miozepam, Musapam, Musaril, Myolastan, Myopam, Panos, Relaxam, Spasmorelax, Tetra-saar, Tetramdura and Tetraratio. The full list is available in Annex I on the EMA website.

Benzodiazepines work by attaching to certain receptors in the brain, thereby increasing the activity of a substance called gamma-amino butyric acid (GABA). GABA decreases the excitability of many brain cells. By increasing GABA activity, benzodiazepines have a calming effect on various functions of the brain. In particular, tetrazepam is used for its muscle relaxant effects.

More about the procedure

The review of tetrazepam-containing medicines was initiated in January 2013 at the request of France, under Article 107i of Directive 2001/83/EC, also known as the urgent Union procedure.

The review was first conducted by the Pharmacovigilance Risk Assessment Committee (PRAC), the Committee responsible for the evaluation of safety issues for human medicines, which made a set of recommendations. As tetrazepam-containing medicines are all authorised nationally, the PRAC recommendations were sent to the Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh), which adopted a final position. The CMDh is composed of representatives of all EU Member States. Its main responsibility is to resolve disagreements between Member States involved in mutual recognition or decentralised procedures, to ensure that patients have the same level of protection, no matter where they are in the EU.

As the CMDh position was adopted by majority vote, the CMDh position will now be sent to the European Commission, which will take an EU-wide legally binding decision.


When you turn blue

May 7, 2013

When you turn blue: Ezogabine [Potiga] Linked To Retinal Abnormalities And Blue Skin Discoloration

May 07, 2013 – The American Food and Drug Administration (FDA) just released a warning to the public that the anti-seizure medication Potiga (Ezogabine) can cause blue skin discoloration and eye abnormalities characterized by pigment changes in the retina. FDA does not currently know if these changes are reversible. FDA is working with the manufacturer to gather and evaluate all available information to better understand these events. FDA will update the public when more information is available.

BACKGROUND: Potiga is approved as adjunctive (added on to other anti-seizure medications) treatment of partial-onset seizures in adult patients 18 years and older. Pigment changes in the retina have the potential to cause serious eye disease with loss of vision. It is not yet known whether the retinal pigment changes caused by Potiga lead to visual impairment, although several patients have been reported to have impaired visual acuity. In some cases, retinal abnormalities have been observed in the absence of skin discoloration. The skin discoloration in the reported cases appeared as blue pigmentation, predominantly on or around the lips or in the nail beds of the fingers or toes, but more widespread involvement of the face and legs has also been reported. Scleral and conjunctival discoloration, on the white of the eye and inside eyelids, has been observed as well. The skin discoloration generally occurred after four years of treatment with Potiga, but has appeared sooner in some patients.

RECOMMENDATION: In light of this new safety information all patients taking Potiga should have a baseline eye exam and periodic eye exams that should include visual acuity testing and dilated fundus photography, and may include fluorescein angiograms (FA), ocular coherence tomography (OCT), perimetry, and electroretinograms (ERG). Potiga should be discontinued if ophthalmic changes are observed unless no other treatment options are available. If a patient develops skin discoloration, serious consideration should be given to changing to an alternate medication. Patients who are taking Potiga and develop any changes in their vision or any discoloration of their skin, including of their lips and nail beds, should contact their health care professional right away.

Patients should not stop taking Potiga without talking to their health care professional. Stopping such treatment suddenly can cause serious and life-threatening medical problems such as recurrence of seizures.

REPORTING: Healthcare professionals and patients are encouraged to report adverse events or side effects related to the use of these products to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program at http://www.fda.gov/MedWatch/report.htm. Download form or call 1-800-332-1088 to request a reporting form, then complete and return to the address on the pre-addressed form, or submit by fax to 1-800-FDA-0178.


FDA has approved Pertuzumab [Perjeta] in combination with Trastuzumab [Herceptin] and docetaxel chemotherapy for the treatment of people with HER2-positive metastatic breast cancer

June 13, 2012

June 11, 2012 – The American Food and Drug Administration (FDA) has approved Pertuzumab [Perjeta].  Pertuzumab [Perjeta] is approved in combination with Trastuzumab [Herceptin]  and docetaxel chemotherapy for the treatment of people with HER2-positive metastatic breast cancer (mBC) who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. This approval is based on data from a Phase III study which showed that people with previously untreated HER2-positive mBC who received the combination of Perjeta, Trastuzumab [Herceptin] and docetaxel chemotherapy lived a median of 6.1 months longer without their cancer getting worse (progression-free survival, or PFS) compared to Trastuzumab [Herceptin] plus docetaxel chemotherapy (median PFS 18.5 vs. 12.4 months). The combination of Pertuzumab [Perjeta], Trastuzumab [Herceptin] and chemotherapy is the only regimen to have shown a significant improvement in PFS compared to Trastuzumab [Herceptin] plus chemotherapy in people with previously untreated HER2-positive mBC.

Pertuzumab [Perjeta] is a personalized medicine that targets the HER2 receptor, a protein found in high quantities on the outside of cells in HER2-positive cancers. Pertuzumab [Perjeta] is believed to work in a way that is complementary to Pertuzumab [Perjeta], as the two medicines target different regions on the HER2 receptor. With the approval by the FDA, Genentech, the maker of Pertuzumab [Perjeta] has agreed to post-marketing commitments related to the manufacturing process for Pertuzumab [Perjeta]. These include FDA review of data from the next several productions of the medicine.  “We expect to meet demand for Pertuzumab [Perjeta] following today’s FDA approval. We recently identified a cell growth issue that might affect our future supply of the medicine,” said Patrick Y. Yang, Ph.D., head, Pharma Global Technical Operations. “We take this very seriously and are working with the FDA to ensure a consistent manufacturing process that maintains drug supply for the people who need it.” Pertuzumab [Perjeta] will be available to people in the United States within two weeks. Genentech is committed to helping people who need Pertuzumab [Perjeta]. Genentech Access Solutions is available to provide doctors and patients coverage and reimbursement support, patient assistance and information resources.

Roche has also submitted a Marketing Authorization Application to the European Medicines Agency (EMA) for Pertuzumab [Perjeta] in combination with Trastuzumab [Herceptin] and docetaxel chemotherapy for the treatment of previously untreated HER2-positive mBC or locally recurrent, unresectable (inoperable) breast cancer, in people who have not received previous treatment or whose disease has returned after treatment in the early-stage setting. This application is currently under review by the EMA.

Pertuzumab [Perjeta] Efficacy in HER2-positive mBC

The FDA approval of Pertuzumab [Perjeta] is based on results from CLEOPATRA (CLinical Evaluation Of Pertuzumab And TRAstuzumab), an international, Phase III, randomized, double-blind, placebo-controlled study. The study evaluated the efficacy and safety profile of Pertuzumab [Perjeta] combined with Trastuzumab [Herceptin] and docetaxel chemotherapy compared to Trastuzumab [Herceptin] and chemotherapy plus placebo in 808 people with previously untreated HER2-positive mBC or that had recurred after prior therapy in the adjuvant or neoadjuvant setting. The study showed people who received Pertuzumab [Perjeta] in combination with Trastuzumab [Herceptin] and chemotherapy experienced a 38 percent reduction in the risk of their disease worsening or death compared to people who received Trastuzumab [Herceptin] and chemotherapy plus placebo (HR=0.62; p-value less than 0.0001, according to independent review). The study demonstrated a 6.1 month improvement in median PFS for people who received Pertuzumab [Perjeta] compared to those who received Trastuzumab [Herceptin] and chemotherapy plus placebo (median PFS 18.5 vs. 12.4 months).

In CLEOPATRA, the most common adverse reactions (rate greater than 30 percent) seen with Pertuzumab [Perjeta] in combination with Trastuzumab [Herceptin] and docetaxel were diarrhea, hair loss, low white blood cell count, nausea, fatigue, rash and peripheral neuropathy (numbness, tingling or burning sensation in the arms or legs). The most common Grade 3-4 adverse reactions (rate greater than 2 percent) were low white blood cell count, low white blood cell count with fever, decrease in a certain type of white blood cell, diarrhea, peripheral neuropathy, decrease in red blood cell count, weakness and fatigue.

More about Pertuzumab [Perjeta]

Pertuzumab [Perjeta] is designed specifically to prevent the HER2 receptor from pairing (or “dimerizing”) with other HER receptors (EGFR/HER1, HER3 and HER4) on the surface of cells, a process that is believed to play a role in tumor growth and survival.Binding of Pertuzumab [Perjeta] to HER2 may also signal the body’s immune system to destroy the cancer cells. The mechanisms of action of Pertuzumab [Perjeta] and Trastuzumab [Herceptin] are believed to complement each other, as both bind to the HER2 receptor, but to different regions. The combination of Pertuzumab [Perjeta], Trastuzumab [Herceptin] and chemotherapy is thought to provide a more comprehensive blockade of HER signaling pathways.

Pertuzumab [Perjeta] Indication Statement

Pertuzumab [Perjeta]is approved for use along with Trastuzumab [Herceptin] and docetaxel (chemotherapy) in people with HER2-positive breast cancer that has spread to different parts of the body (metastatic) and who have not received anti-HER2 therapy or chemotherapy for metastatic breast cancer.

Important Safety Information

  • Pertuzumab [Perjeta] has been shown to work only in people with HER2-positive breast cancer. Patients must have a HER2 test to know if their breast cancer is HER2-positive before receiving an anti-HER2 treatment, such as Pertuzumab [Perjeta]
  • Because side effects from this treatment are common, it is important to know what side effects may happen and what symptoms patients should watch for
  • A patient’s doctor may stop treatment if serious side effects happen. Patients must contact their healthcare team right away if they have questions or are worried about any side effects

Serious Side Effect of Pertuzumab [Perjeta]

Most Serious Side Effect: Receiving Pertuzumab [Perjeta] during pregnancy can result in the death of an unborn baby and birth defects.

  • Birth control should be used while receiving Pertuzumab [Perjeta] and for six months after a patient’s last dose of Pertuzumab [Perjeta]. Patients who are breastfeeding should talk with their doctor about either stopping breastfeeding or stopping Pertuzumab [Perjeta].

Other Possible Side Effects

  • Heart problems: Pertuzumab [Perjeta] can result in heart problems, including those without symptoms (such as reduced heart function) and those with symptoms (such as congestive heart failure). A patient’s doctor may run tests to monitor the patient’s heart function before and during treatment with Pertuzumab [Perjeta]
  • Infusion-related reactions: Pertuzumab [Perjeta] is a medicine that is delivered into a vein through a needle. This process can cause reactions known as infusion-related reactions. The most common infusion-related reactions when receiving Pertuzumab [Perjeta], Trastuzumab [Herceptin], and docetaxel were fatigue, loss of taste, allergic reactions, muscle pain and vomiting
  • Severe allergic reactions: Some people receiving Pertuzumab [Perjeta] may have severe allergic reactions, called hypersensitivity reactions or anaphylaxis. This reaction may be severe, may happen quickly, and may affect many areas of the body

Most Common Side Effects

The most common side effects of Pertuzumab [Perjeta] when given with Trastuzumab [Herceptin] and docetaxel are diarrhea, hair loss, low levels of white blood cells with or without a fever, upset stomach, fatigue, rash and damage to the nerves (numbness, tingling, pain in hands/feet).

Please see also Pertuzumab [Perjeta] Full Prescribing Information including Most Serious Side Effect for additional Important Safety Information.

 About Trastuzumab [Herceptin]

Trastuzumab [Herceptin] is a personalized medicine designed to specifically block the HER2 protein on the surface of some cancer cells. Based on preclinical studies, this biologic antibody is believed to work by attaching to HER2 receptors to stop signals that make the tumor cells grow and divide, and also by signaling the body’s immune system to destroy the cancer cells.

Trastuzumab [Herceptin] has two approved uses in metastatic breast cancer (mBC):

  • Trastuzumab [Herceptin] in combination with the chemotherapy drug paclitaxel is approved for the first-line treatment of HER2-positive mBC.
  • Trastuzumab [Herceptin] alone is approved for the treatment of HER2-positive mBC in patients who have received one or more chemotherapy regimens for metastatic disease.

Important Safety Information on Trastuzumab [Herceptin]

Trastuzumab [Herceptin] treatment can result in heart problems, including for those patients without symptoms (such as reduced heart function) and those patients with symptoms (such as congestive heart failure). One patient died in an adjuvant breast cancer trial from significantly weakened heart muscle. The risk and seriousness of these heart problems were highest in patients who received both Trastuzumab [Herceptin] and a certain type of chemotherapy (anthracycline).

Before taking the first dose of Trastuzumab [Herceptin] and during treatment, a patient’s doctor should check to see if there are any health conditions that may increase the patient’s chance of having serious heart problems. This includes a review of the patient’s health history and tests to see how well the heart muscle is working. These tests may include an echocardiogram or a multigated acquisition (MUGA) scan. Some early-stage breast cancer patients may also need to have a test done after they have finished taking Trastuzumab [Herceptin] to see how well their heart muscle is working.

Some patients have had serious infusion reactions and lung problems; fatal infusion reactions have been reported. These reactions usually occur during or within 24 hours of receiving Trastuzumab [Herceptin].

The patient’s doctor may need to completely stop Trastuzumab [Herceptin] treatment if the patient has a severe allergic reaction, swelling, lung problems, inflammation of the lung or severe shortness of breath.

Trastuzumab [Herceptin] can cause harm to the fetus (unborn baby), and in some cases death to the fetus, when taken by a pregnant woman. Women who could become pregnant need to use effective birth control methods during Trastuzumab [Herceptin] treatment and for at least six months after treatment with Trastuzumab [Herceptin]. Nursing mothers treated with Trastuzumab [Herceptin] should discontinue nursing or discontinue Trastuzumab [Herceptin].

Worsening of low white blood cell counts associated with chemotherapy has also occurred.

Patients must have a HER2 test to determine if their breast cancer is HER2-positive before using Trastuzumab [Herceptin], as benefit has only been shown in patients who are HER2-positive.

The most common side effects associated with Trastuzumab [Herceptin] in patients with breast cancer are fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, shortness of breath, rash, low white and red blood cells and muscle pain.

Because everyone is different, it is not possible to predict what side effects any one patient will have. Patients with questions or concerns about side effects should talk to their doctor.

Patients should read the Trastuzumab [Herceptin] full Prescribing Information including Boxed Warnings.

About Breast Cancer

Breast cancer is the most common cancer among women worldwide. According to the American Cancer Society, approximately 229,000 people will be diagnosed with breast cancer, and 40,000 will die from the disease in 2012. In HER2-positive breast cancer, increased quantities of the Human Epidermal growth factor Receptor 2 (HER2) are present on the surface of the tumor cells. This is known as “HER2 positivity” and affects approximately 25 percent of people with breast cancer.HER2-positive cancer is a particularly aggressive form of breast cancer.

Patients are encouraged to report negative side effects of prescription drugs to the FDA. Visit http://www.fda.gov/medwatch, or call 1-800-FDA-1088.


European Medicines Agency (EMA) starts review of aliskiren-containing medicines

January 17, 2012

January 17, 2012 – Recently, the European Medicines Agency (EMA) has announced that it  is reviewing aliskiren-containing medicines, to assess the impact of data coming from the ALTITUDE study on the balance of benefits and risks of these medicines in their approved indication. Aliskiren-containing medicines are approved for the treatment of essential hypertension. ‘Essential’ means that there is no obvious cause for high blood pressure.

The Agency’s Committee for Medicinal Products for Human Use (CHMP) started the review after it was informed on 19 December 2011 by the marketing authorisation holder of the decision to terminate the ALTITUDE study early. This clinical trial included patients with type 2 diabetes and renal impairment and/or cardiovascular disease. In most patients arterial blood pressure was adequately controlled. The patients included in the trial received aliskiren in addition to either an angiotensin converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB).

Termination of the placebo-controlled phase III trial was recommended by the independent Data Monitoring Committee overseeing the study, because the results showed that there was no benefit with aliskiren and that there were more cases of stroke, renal complications, hyperkalemia and hypotension in patients who received aliskiren compared with patients who received a placebo.

The information available at present is limited. The Committee has asked the company to provide additional analyses to allow the CHMP to assess the impact of the results of the ALTITUDE trial on the overall benefit-risk profile of aliskiren-containing medicines and to determine the need for regulatory action.

Interim advice for doctors and patients

While the review is ongoing the CHMP recommends, as a precautionary measure, that doctors should not prescribe aliskiren-containing medicines to diabetic patients in combination with ACE inhibitors or ARBs.

Doctors should therefore review the treatment of patients taking aliskiren at a routine (non-urgent) appointment, and if patients are diabetic and are also taking ACE inhibitors or ARBs, aliskiren should be stopped and alternative treatments considered.

Patients should not stop any of their treatment before speaking to their doctor, because stopping anti-hypertensive medication without medical supervision can put them at risk. They are advised to discuss their treatment with their doctor at their next scheduled (non-urgent) appointment.

Patients in clinical trials with aliskiren should contact their study site for guidance on their medication.

Further information on the review of aliskiren-containing medicines will be provided when available.

 Additional Notes

  • Eight aliskiren-containing medicines are authorised in the European Union since 2007: Rasilamlo, Rasilez, Rasilez HCT, Rasitrio, Riprazo, Riprazo HCT, Sprimeo, Sprimeo HCT. Some of these medicines (Rasilamlo, Rasilez HCT, Rasitrio, Riprazo HCT and Sprimeo HCT) are combinations of aliskiren with other antihypertensive medicines.
  • The review of aliskiren is conducted in the context of a formal review, initiated at the request of the European Commission under Article 20 of Regulation (EC) No 726/2004.

Bevacizumab [Avastin]: Process for Removal of Breast Cancer Indication Begun Because of Lack of Efficacy

December 19, 2010

December 16, 2010  –  Today, the American Food and Drug Administration notified healthcare professionals and patients that it is recommending removing the breast cancer indication for Bevacizumab [Avastin] because the drug has not been shown to be safe and effective for that use. The drug itself is not being removed from the market and today’s action will not have any immediate impact on its use in treating breast cancer. Today’s action will not affect the approvals for colon, kidney, brain, and lung cancers.

Background:

The Food and Drug Administration (FDA) is making this recommendation after reviewing the results of four clinical studies of Bevacizumab [Avastin] in women with breast cancer and determining that the data indicate that the drug does not prolong overall survival in breast cancer patients or provide a sufficient benefit in slowing disease progression to outweigh the significant risk to patients. None of the studies demonstrated that patients receiving Bevacizumab [Avastin] lived longer and patients receiving Bevacizumab [Avastin] experienced a significant increase in serious side effects. These risks include severe high blood pressure; bleeding and hemorrhage; the development of perforations (or “holes”) in the body, including in the nose, stomach, and intestines; and heart attack or heart failure.

Recommendation:

Oncologists currently treating patients with Bevacizumab [Avastin] for metastatic breast cancer should use their medical judgment when deciding whether a patient should continue treatment with the drug or consider other therapeutic options.

Patients currently receiving Avastin for breast cancer should speak with their oncologists about whether to continue their treatment or explore other treatment options.

More Information:

[12/16/2010 – News Release – FDA]
[12/16/2010 – Questions and Answers about Avastin – FDA]
[12/15/2010 – Avastin Decision Memo (PDF – 125KB) – FDA]

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Gemtuzumab Ozogamicin [Mylotarg]: Market Withdrawal

June 22, 2010

June 21, 2010 –  FDA notified healthcare professionals that results from a recent clinical trial raised new concerns about the product’s safety, and the drug failed to demonstrate clinical benefit to patients enrolled in trials.

Background:

Gemtuzumab Ozogamicin [Mylotarg], indicated for treatment of acute myeloid leukemia (AML), a bone marrow cancer, was approved in May 2000 under the FDA’s accelerated approval program. A confirmatory, post approval clinical trial was begun by Wyeth (now Pfizer) in 2004. The trial was designed to determine whether adding Gemtuzumab Ozogamicin [Mylotarg] to standard chemotherapy demonstrated an improvement in clinical benefit (survival time) to AML patients. The trial was stopped early when no improvement in clinical benefit was observed, and after a greater number of deaths occurred in the group of patients who received Gemtuzumab Ozogamicin [Mylotarg] compared with those receiving chemotherapy alone.

Recommendation:

Gemtuzumab Ozogamicin [Mylotarg] will not be commercially available to new patients. Patients who are currently receiving the drug may complete their therapy following consultation with their health care professional. Health care professionals should inform all patients receiving Gemtuzumab Ozogamicin [Mylotarg] of the product’s potential safety risks. Any future use of Gemtuzumab Ozogamicin [Mylotarg] in the United States will require submission of an investigational new drug application to the FDA.

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FDA, FTC Warn Public of Fraudulent 2009 H1N1 Influenza Products

May 4, 2009

May 03, 2009 – The two antiviral drugs approved by the FDA for treatment and prophylaxis of the 2009 H1N1 influenza virus are Oseltamivir [Tamiflu] and Zanamivir [Relenza].  Tamiflu and Relenza, in addition to their approved labeling, have Emergency Use Authorizations that describe specific authorized uses during this public health emergency.

However, the Food and Drug Administration (FDA) and the Federal Trade Commission (FTC) are urgently alerting the public to be wary of Internet sites and other promotions for products that claim to diagnose, prevent, mitigate, treat or cure the 2009 H1N1 influenza virus.  The agencies are also advising operators of offending web sites that they must take prompt action to correct and/or remove promotions of these fraudulent products or face enforcement action.

“Consumers who purchase products to treat the novel 2009 H1N1 virus that are not approved, cleared or authorized by the FDA for the treatment or prevention of influenza risk their health and the health of their families,” said Michael Chappell, acting FDA Associate Commissioner for Regulatory Affairs. “In conjunction with the Federal Trade Commission, the FDA has developed an aggressive strategy to identify, investigate, and take regulatory or criminal action against individuals or businesses that wrongfully promote purported 2009 H1N1 influenza products in an attempt to take advantage of the current flu public health emergency.”

Products that are offered for sale to the public with claims to diagnose, prevent, mitigate, treat, or cure infections caused by the H1N1 influenza virus that have not  been proven to be safe and effective for these uses must be carefully evaluated. Many of these deceptive products are being sold over the Internet via illegitimate web sites. The operators of these web sites take advantage of the public’s concerns about H1N1 influenza and their desire to protect themselves and their families.  These fraudulent products come in all varieties and could include dietary supplements or other food products, or products purporting to be drugs, devices or vaccines.  Such fraudulent products will not prevent the transmission of the virus or offer effective treatments against infections caused by the H1N1 influenza virus.

More information about FDA-approved antiviral drugs for influenza is available here. More information on CDC recommendations regarding use of antiviral drugs against the current novel 2009 H1N1 influenza is available here. Consumers should also visit FDA’s web site for tips about how to protect themselves when buying medicines online.

View Original Article

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FDA Authorizes Emergency Use of Influenza Medicines, Diagnostic Test in Response to Swine Flu Outbreak in Humans

April 30, 2009

April 27, 2009 – The Food and Drug Administration, in response to requests from the U.S. Centers for Disease Control and Prevention, has issued Emergency Use Authorizations (EUAs) to make available to public health and medical personnel important diagnostic and therapeutic tools to identify and respond to the swine flu virus under certain circumstances. The agency issued these EUAs for the use of certain Relenza and Tamiflu antiviral products, and for the rRT-PCR Swine Flu Panel diagnostic test.

The EUA authority allows the FDA, based on the evaluation of available data, to authorize the use of unapproved or uncleared medical products or unapproved or uncleared uses of approved or cleared medical products following a determination and declaration of emergency, provided certain criteria are met. The authorization will end when the declaration of emergency is terminated or the authorization revoked by the agency.

Current drug label information for Zanamivir [Relenza] and Oseltamivir [Tamiflu] can be found at Drugs@FDA (relenza, tamiflu) and DailyMed (relenza, tamiflu). Relenza is approved to treat acute uncomplicated illnesses due to influenza in adults and children 7 years and older who have been symptomatic for less than two days, and for the prevention of influenza in adults and children 5 years and older.

Tamiflu is approved for the treatment and prevention of influenza in patients 1 year and older. The EUAs allow for Tamiflu also to be used to treat and prevent influenza in children under 1 year, and to provide alternate dosing recommendations for children older than 1 year. In addition, under the EUAs, both medications may be distributed to large segments of the population without complying with the label requirements otherwise applicable to dispensed drugs, and accompanied by written information pertaining to the emergency use. They may also be distributed by a broader range of health care workers, including some public health officials and volunteers, in accordance with applicable state and local laws and/or public health emergency responses.

In authorizing an EUA for the rRT-PCR Swine Flu Panel diagnostic test, the FDA has determined that it may be effective in testing samples from individuals diagnosed with influenza A infections, whose virus subtypes cannot be identified by currently available tests. This EUA allows the CDC to distribute the swine flu test to public health and other qualified laboratories that have the needed equipment and the personnel who are trained to perform and interpret the results.

Please, view the full announcement here.


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