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 limits duration and usage of Tolvaptan (Samsca) due to possible liver injury leading to organ transplant or death

May 2, 2013

April 30, 2013 –   The U.S. Food and Drug Administration (FDA) has determined that the drug Tolvaptan (Samsca) should not be used for longer than 30 days and should not be used in patients with underlying liver disease because it can cause liver injury, potentially requiring liver transplant or death.  Tolvaptan (Samsca) is used to treat low sodium levels in the Tolvapanblood. An increased risk of liver injury was observed in recent large clinical trials evaluating Tolvaptan (Samsca) for a new use in patients with autosomal dominant polycystic kidney disease (ADPKD. FDA has worked with the manufacturer to revise the Tolvaptan (Samsca) drug label to include these new limitations.

The Tolvaptan (Samsca) drug label has been updated to include the following information:

  • Limitation of the duration of Samsca treatment to 30 days. (Dosage and Administration and Warnings and Precautions sections)
  • Removal of the indication for use in patients with cirrhosis, a condition that involves scarring of the liver due to injury or long-term disease.  Use of Samsca in patients with underlying liver disease, including cirrhosis, should be avoided because the ability to recover from liver injury may be impaired. (Indications and Usage and Use in Specific Populations sections)
  • Description of liver injuries seen in clinical trials of patients with autosomal dominant polycystic kidney disease (ADPKD).
  • Recommendation to discontinue Samsca in patients with symptoms of liver injury.

The manufacturer of Tolvaptan (Samsca), Otsuka American Pharmaceutical, Inc., issued a Dear Health Care Provider letter on the potential risk of liver injury on January 22, 2013FDA is reviewing the information from clinical trials of patients with ADPKD and will update the public on the risk of liver injury with Tolvaptan (Samsca) if more information becomes available.


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.


New Breast Cancer HER2 Diagnostic Tests Approved by FDA

June 13, 2012
June 12, 2012 — Two diagnostic tests to identify HER2-positive breast cancer have been approved by the US Food and Drug Administration (FDA) for use as companion diagnostics for the new targeted therapy Pertuzumab [Perjeta].
 
The tests — HercepTest and HER2 FISH pharmDx Kit — are both manufactured by Dako in Glostrup, Denmark. The tests serve as diagnostic tools to identify patients with HER2-positive metastatic breast cancer who might be eligible for treatment with HER2-positive targeted therapies. The latest of these —Pertuzumab [Perjeta]— was approved  just days ago by the American Food and Drug Administration (FDA) for use in combination with Trastuzumab [Herceptin] and chemotherapy in patients with HER2-positivemetastatic breast cancer who have not been treated with either trastuzumab or chemotherapy.
 
“The role of HER2 in diagnosis and clinical decision making continues to evolve with the recent approval of Pertuzumab [Perjeta]”, said David Hicks, MD, director of surgical pathology at the University of Rochester Medical Center in New York. “It is clear that optimal patient care depends now more than ever on the accurate, reliable, and reproducible assessment of HER2 status for the full benefit of pertuzumab to be derived by the appropriate patient population,” he noted in a Dako press release. Dako reported that it had been collaborating with Genentech on a parallel FDA approval process for the 2 tests and the new drug.

Fatal Adverse Events with Pazopanib [Votrient], Sorafenib [Nexavar], and Sunitinib [Sutent]

February 12, 2012

February 12, 2012 – From an article published in Medscape Oncology News on February 9, 2012, we learn the following (article in full, all rights resting with Medscape Oncology News):

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February 9, 2012— New details on the risk for fatal adverse events associated with several targeted cancer drugs have come from a large meta-analysis of clinical trials, which was published online February 6 in the Journal of Clinical Oncology.

The drugs investigated were pazopanib (Votrient, GlaxoSmithKline), which is approved for use in renal cell carcinoma; sorafenib (Nexavar, Bayer & Onyx), which is approved for use in renal cell carcinoma and hepatocellular cancer; and sunitinib (Sutent, Pfizer), which is approved for use in hepatocellular cancer and gastrointestinal stromal tumors. All 3 products are vascular endothelial growth-factor (VEGF) receptor tyrosine kinase inhibitors.

The meta-analysis, which examined data on 4679 patients from 10 clinical trials, found that these 3 drugs were associated with fatal adverse events at a rate that was about twice that seen in the placebo groups. The crude incidence of fatal adverse events was 1.5% in patients taking these drugs, compared with 0.7% in patients in the placebo or control groups (relative risk [RR], 2.23; P = .023).

The most common cause of death was hemorrhage; the second most common was myocardial ischemia. Liver failure and congestive heart failure were also reported.

Senior author Toni Choueiri, MD, from the Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, said that clinicians need to be aware of the risks associated with these drugs.

“There is no doubt that for the average patient, these drugs have benefits,” Dr. Choueiri said in a statement. In fact, these drugs represent a major step forward in the treatment of several malignancies, and they have led to significant improvements in patient outcomes.

However, they are associated with a significant increase in the risk of developing fatal drug-related events, and “practitioners must be aware of the risks associated with their use and must provide rigorous monitoring to continue to improve patient outcomes,” the researchers note.

“While the absolute incidence of these fatal side effects is very small, the relative risks are higher,” Dr. Choueiri noted. In addition, the patients in this meta-analysis were participating in clinical trials and all had adequate organ function at study entry, so the overall incidence and risk for unreported fatal adverse events could be higher in common medical practice.


Ivacaftor [Kalydeco] approved by FDA to treat the rare G551D mutant positive form of cystic fibrosis

February 3, 2012

February 03, 2012 – From a press release by the FDA, we just learn about e new success of the principle of personalized medicine. Please read the original article below:

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The U.S. Food and Drug Administration today approved Kalydeco (ivacaftor) for the treatment of a rare form of cystic fibrosis (CF) in patients ages 6 years and older who have the specific G551D mutation in the Cystic Fibrosis Transmembrane Regulator (CFTR) gene.

CF is a serious genetic disorder affecting the lungs and other organs that ultimately leads to an early death. It is caused by mutations (defects) in a gene that encodes for a protein called CFTR that regulates ion (such as chloride) and water transport in the body. The defect in chloride and water transport results in the formation of thick mucus that builds up in the lungs, digestive tract and other parts of the body leading to severe respiratory and digestive problems, as well as other complications such as infections and diabetes.

CF, which affects about 30,000 people in the United States, is the most common fatal genetic disease in the Caucasian population. About 4 percent of those with CF, or roughly 1,200 people, are believed to have the G551D mutation.

“Kalydeco is an excellent example of the promise of personalized medicine – targeted drugs that treat patients with a specific genetic makeup,” said FDA Commissioner Margaret A. Hamburg, M.D. “The unique and mutually beneficial partnership that led to the approval of Kalydeco serves as a great model for what companies and patient groups can achieve if they collaborate on drug development.”

The FDA reviewed and approved Kalydeco in approximately three months under the agency’s priority review program that is designed to expedite the review of drugs. The priority review program uses a six-month review, instead of the standard 10 months, for drugs that may offer significant advances in treatment over available therapy.

Kalydeco was approved ahead of the drug’s April 18, 2012 prescription user fee goal date and is designated as an orphan drug, which identifies the disease as affecting fewer than 200,000 people in the United States.

In patients with the G551D mutation, Kalydeco, a pill taken two times a day with fat-containing food, helps the protein made by the CFTR gene function better and as a result, improves lung function and other aspects of CF such as increasing weight gain.

“Kalydeco is the first available treatment that targets the defective CFTR protein, which is the underlying cause of cystic fibrosis,” said Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research. “This is a breakthrough therapy for the cystic fibrosis community because current therapies only treat the symptoms of this genetic disease.”

Two 48-week, placebo-controlled clinical studies involving 213 patients, one in patients ages 12 years and older and another in patients ages 6 years to 11 years, were used to evaluate the safety and efficacy of Kalydeco in CF patients with the G551D mutation. In both studies, treatment with Kalydeco resulted in significant and sustained improvement in lung function.

Kalydeco is effective only in patients with CF who have the G551D mutation. It is not effective in CF patients with two copies of the F508 mutation in the CFTR gene, which is the most common mutation that results in CF. If a patient’s mutation status is not known, an FDA-cleared CF mutation test should be used to determine whether the G551D mutation is present.

The most common side effects of Kalydeco include upper respiratory tract infection, headache, stomach ache, rash, diarrhea, and dizziness.


EMA: Public consultation open on concept paper on pharmacogenomics in evaluation of authorised medicines

January 26, 2012

January 26, 2012 – I am relaying the information below by the EMA to the readers of this blog. It might be interessting to dwell into this concept paper (as a scientist, a treating physician, or an informed patient) for informations only or even for commenting.

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 The European Medicines Agency (EMA) has released a concept paper on the development of a guideline on the evaluation of pharmacogenomic methodologies in the evaluation of authorised medicines for public consultation.

The concept paper on key aspects for the use of pharmacogenomic methodologies in the pharmacovigilance evaluation of medicinal products explains that a proportion of the variability in response to medicines is due to genetic differences between individuals. Identifying individuals at risk of side effects, unexpected complications or lack of efficacy may help the development of strategies to optimise the use of medicines.

The concept paper sets out a number of issues that a future guideline could cover. These include the systematic consideration of the effects of genetic variability in safety monitoring of medicines, the use of biomarkers, the timing of the monitoring of genomic data and the information that should be provided in medicines’ product information.

The concept paper is open for comments until 15 March 2012. Comments should be sent to pgwpsecretariat@ema.europa.eu using the form for submission of comments.


Patients on Vemurafenib [Zelboraf] Need Testing for RAS Mutations: Secondary Cancers a Major Concern

January 26, 2012

January 26, 2012 – A January 20, 2012 article in Medscape Medical New illustrates how personalized medicine can be tricky. The case is Vemurafenib [Zelboraf], which was introduced to the market together with an companion genetic test mid 2011 for the treatment of advanced melanoma in suitable BRAF mutation (V600E) positive patients only. In these patients, while melanoma therapy response rates are impressive, a new problem seems to arise, namely secondary tumours. Please read the article published  by Medscape Medical News on this topic.

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Patients with advanced melanoma who are treated with Vemurafenib [Zelboraf ]  should be tested for RAS mutations, according to an editorial published in the January 19 issue of the New England Journal of Medicine.

A study that accompanies the editorial reports that RAS mutations frequently occur in secondary skin tumors that develop in vemurafenib-treated patients.

The testing is necessary because there is “potential for secondary tumor development” that arises from treatment with vemurafenib and other BRAF inhibitors, writes Ashani T. Weeraratna, PhD, from the molecular and cellular oncogenesis program at The Wistar Institute in Philadelphia, Pennsylvania, in her editorial. These secondary skin tumors — namely, cutaneous squamous cell carcinomas and keratoacanthomas — are relatively benign, compared with melanoma, and are no reason to discontinue vemurafenib, said Dr. Weeraratna. However, testing will alert clinicians to which patients have RAS-driven secondary tumors.

The testing is important because patients with RAS mutations could also develop secondary cancers in organs beyond the skin, advised Dr. Weeraratna. “If patients have RAS mutations they should be monitored closely for any development of cutaneous squamous cell carcinomas in all organs,” she told Medscape Medical News.

“Although cutaneous squamous cell carcinomas are not deadly, these lesions can be life-threatening when they occur in other organs,” Dr. Weeraratna writes in her editorial. She discussed other potentially affected organs. “Squamous cell carcinomas can potentially arise in any organ with a squamous epithelium, essentially a layer of flattened epithelial cells that line the basement membranes of organs. A squamous epithelium is found most often in organs where rapid filtration and diffusion is necessary, such as the alveolar lining of the lungs and the glomerulus (kidney). Thus, squamous cell carcinomas can be found in organs such as the lungs, cervix, and esophagus, and also account for a large proportion of head and neck cancers,” Dr. Weeraratna explained.

Importantly, there is no evidence that vemurafenib triggers tumors in other organs. “It is as yet unclear whether the generation of squamous cell carcinomas in these organs, upon BRAF inhibitor therapy, occurs, but these data certainly alert us to that potential risk,” she said.

MEK Inhibitors May Help

In this study of melanoma patients, the investigators sought to characterize the molecular mechanism behind the development of secondary skin cancers in patients treated with vemurafenib.

They admit that a skin cancer drug that causes other skin cancers is unexpected. The development of cutaneous squamous cell carcinomas and keratoacanthomas “is the opposite of what would be expected from a targeted oncogene inhibitor,” write the study authors, led by Fei Su, PhD, from Hoffman-La Roche Pharmaceuticals in Nutley, New Jersey. In their search to understand this toxicity, the investigators analyzed the DNA of a sampling of these tumors and found a high rate of RAS mutations (21 of 35 tumors; 60%). “Mutations in RAS, particularly HRAS, are frequent in cutaneous squamous cell carcinomas and keratoacanthomas that develop in patients treated with vemurafenib,” write the authors.

“This study points out that BRAF inhibitors should only be used in patients who have cancers driven by BRAF mutations, and it raises the concern that cancers driven by RAS mutations (KRAS, HRAS, or NRAS) can be paradoxically activated instead of inhibited with this class of drugs,” said coauthor Antoni Ribas, MD, PhD, in email correspondence with Medscape Medical News. He is from the division of hematology–oncology at the UCLA Medical Center in Los Angeles, California.

Why patients treated with vemurafenib have such a high rate of RAS mutations in these secondary cancers is not known. However, the investigators performed animal-model studies that suggest that the development of RAS-mutation-driven secondary tumors might be prevented with a MEK inhibitor, another class of drugs. There might be “usefulness of combining a BRAF inhibitor with a MEK inhibitor to prevent this toxic effect” of secondary cancers, write the authors.

There has already been clinical investigation of this concept — a phase 2 study of the combination of the MEK inhibitor GSK1120212 and the RAF inhibitor GSK2118436 in metastatic melanoma. That study, which was presented at the 2011 annual meeting of the American Society of Clinical Oncology, and reported at that time by Medscape Medical News, showed that the toxicity of the combination seemed to be lower than that of either agent used alone.

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NEJM: Study

NEJM: Editoral

Medscape Medical News: Article


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.

Drug Safety Communication on Brentuximab Vedotin [Adcetris] – Progressive Multifocal Leukoencephalopathy (PML) and Pulmonary Toxicity

January 17, 2012

January 16, 2012 – The American Food and Drug Administration ( FDA) released on January 13, 2012 the following drug safety communication:

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ISSUE: FDA notified healthcare professionals that two additional cases of progressive multifocal leukoencephalopathy (PML), a rare but serious brain infection that can result in death, have been reported with the lymphoma drug Adcetris (brentuximab vedotin). Due to the serious nature of PML, a new Boxed Warning highlighting this risk has been added to the drug label.

In addition, a new Contraindication warning was added against use of Adcetris with the cancer drug bleomycin due to increased risk of pulmonary (lung) toxicity.

The signs and symptoms of PML may develop over the course of several weeks or months. They may include changes in mood or usual behavior, confusion, thinking problems, loss of memory, changes in vision, speech, or walking, and decreased strength or weakness on one side of the body.

BACKGROUND: Adcetris (brentuximab vedotin) is used to treat Hodgkin lymphoma and a rare lymphoma known as systemic anaplastic large cell lymphoma. At the time of Adcetris’ approval in August 2011, one case of PML was described in the Warnings and Precautions section of the label.

RECOMMENDATION: Patients who develop any signs and symptoms of PML should notify their healthcare professional immediately. Healthcare professionals should hold Adcetris dosing if PML is suspected and discontinue Adcetris if a diagnosis of PML is confirmed. See the Data Summary in the Drug Safety Communication for additional information.

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:

  • Complete and submit the report Online: www.fda.gov/MedWatch/report.htm1
  • Download form2 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

 More Information as of 01/13/2012 – Drug Safety Communication3 – FDA]


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