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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.

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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

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.

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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]

FDA is working to determine whether the reports of bleeding in patients taking Pradaxa are occurring more commonly than would be expected, based on observations in the large clinical trial that supported the approval of Pradaxa.

BACKGROUND: Pradaxa is a blood thinning (anticoagulant) medication used to reduce the risk of stroke in patients with non-valvular atrial fibrillation (AF), the most common type of heart rhythm abnormality.

RECOMMENDATION: At this time, FDA continues to believe that Pradaxa provides an important health benefit when used as directed and recommends that healthcare professionals who prescribe Pradaxa follow the recommendations in the approved drug label.

Patients with AF should not stop taking Pradaxa without talking to their healthcare professional. Stopping use of blood thinning medications can increase their risk of stroke. Strokes can lead to permanent disability and death.

FDA will communicate any new information on the risk of bleeding and Pradaxa when it becomes available.

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 here:  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
• Read more here:  - Drug Safety Communication³ ( FDA)
• And here: FDA Drug Safety Podcast for Healthcare Professionals: Safety review of post-market reports of serious bleeding events with the anticoagulant Pradaxa (dabigatran etexilate mesylate)³

The American Food and Drug Administration (FDA) has now notified healthcare professionals and patients of an update to the drug label for Zoledronic Acid [Reclast] regarding the risk of kidney failure. Cases of acute renal failure requiring dialysis or having a fatal outcome following Zoledronic Acid [Reclast] use have been reported to FDA. The revised label states that Zoledronic Acid [Reclast] is contraindicated in patients with creatinine clearance less than 35 mL/min or in patients with evidence of acute renal impairment. The label also recommends that healthcare professionals screen patients prior to administering Zoledronic Acid [Reclast] in order to identify at-risk patients.

The Zoledronic Acid [Reclast] Medication Guide for patients is being updated to contain information about the risk of severe kidney problems. In addition, the manufacturer of Zoledronic Acid [Reclast] will issue a Dear Healthcare Provider letter to inform healthcare professionals about this risk.

These labeling changes are being made to the Zoledronic Acid [Reclast] label only, although Zoledronic Acid, also sold as  [Zometa], is approved for treatment of cancer-related indications. Renal toxicity is already addressed in the Warnings and Precautions section of the [Zometa] label. Dose reductions for [Zometa] are provided for patients with renal impairment.

Recommendation:

Zoledronic Acid [Reclast] is contraindicated in patients with creatinine clearance less than 35 mL/min, or in patients with evidence of acute renal impairment. Healthcare professionals should screen patients prior to administering Zoledronic Acid [Reclast] in order to identify at-risk patients. Healthcare professionals should also monitor renal function in patients who are receiving Zoledronic Acid [Reclast].

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 by completing and submitting the report online at www.fda.gov/MedWatch/report.htm. Alternatively, download the 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.

Read here the MedWatch safety alert, including links to the Drug Safety Communication, including a Data Summary, and prescribing information.

Healthcare professionals should be aware of the risk of hypersensitivity reactions with Asenapine Maleate [Saphris] and counsel patients who are receiving the drug about how to recognize the signs and symptoms of a serious allergic reaction. Asenapine Maleate [Saphris] should not be used in patients with a known hypersensitivity to the drug.

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 as follows: Complete and submit the report online at www.fda.gov/MedWatch/report.htm. Alternatively, 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. Read here the MedWatch safety alert, including links to the Drug Safety Communication with Data Summary,  and prescribing information.

The abnormal anaplastic lymphoma kinase (ALK) gene causes cancer cell development and growth. About 1 percent to 7 percent of the patients with NSCLC have the ALK gene abnormality. Patients with this form of lung cancer are typically non-smokers. Crizotinib [Xalkori] works by blocking certain proteins called kinases, including the protein produced by the abnormal ALK gene. Xalkori is a pill taken twice a day as a single-agent treatment.

Crizotinib [Xalkori] has been approved together with a companion diagnostic test that will help determine if a patient’s tumor expresses the abnormal ALK gene. This genetic test is called the Vysis ALK Break Apart FISH Probe Kit. The application of this specific test allows the selection of only those  patients for treatment with Crizotinib [Xalkori] who are most likely to respond to the drug. Targeted therapies such as this one invoving Crizotinib [Xalkori] are considered important options for sucessfully treating patients with this disease.

Crizotinib [Xalkori]’s effectiveness was established in two multi-center, single-arm studies enrolling a total of 255 patients with late-stage ALK-positive NSCLC. A sample of a patient’s lung cancer tissue was collected and tested for the ALK gene abnormality prior to study enrollment. The studies were designed to measure objective response rate, the percentage of patients who experienced complete or partial cancer shrinkage. Most patients in the studies had received prior chemotherapy. In one study, the objective response rate was 50 percent with a median response duration of 42 weeks. In another study, the objective response rate was 61 percent with a median response duration of 48 weeks.

Based on these favorable efficacy data, Crizotinib [Xalkori] has been approved under the FDA’s accelerated approval program, which allows the agency to approve a drug to treat a serious  and life-threatening disease based on clinical data showing that the drug has an effect on an endpoint that is reasonably likely to predict a clinical benefit to patients. The program is designed to provide patients with earlier access to promising new drugs, followed by further studies to confirm the drug’s clinical benefit.

The most common side effects reported in patients receiving Crizotinib [Xalkori] included vision disorders, nausea, diarrhea, vomiting, swelling (edema), and constipation. Vision disorders included visual impairment, flashes of light, blurred vision, floaters, double vision, sensitivity to light, and visual field defects. Xalkori use has also been associated with inflammation of the lung tissue (pneumonitis), which can be life-threatening. Patients with treatment-related pneumonitis should permanently stop treatment with Crizotinib [Xalkori]. Moreover, the drug should not be used in pregnant women. In the context of the clinical safety of Crizotinib [Xalkori], we should be aware that the companion test (Vysis ALK Break Apart FISH Probe Kit) does not identify patients with either a predisposition for any of the unwanted drug side effects, or irregularities in drug disposition (e.g., poor or ultrarapid metabolizers). We will also need many more patients treated with Crizotinib [Xalkori] in order to more completely understand the clinical safety profile of Crizotinib [Xalkori].

See the FDA Press Release here.

Vemurafenib [Zelboraf] has been approved with a companion diagnostic test that will help determine whether a patient’s melanoma cells have the BRAF V600E mutation. The first-of-a-kind test is known as the cobas 4800 BRAF V600 Mutation Test (by Roche Molecular Systems).

The approval of Vemurafenib [Zelboraf] and the cobas test is a great example of how companion diagnostics can be developed and used to ensure patients are exposed to highly effective, more personalized therapies in a safe manner,” said Alberto Gutierrez, PhD, director of the Office of In Vitro Diagnostic Device Evaluation and Safety in the FDA’s Center for Devices and Radiological Health. The FDA’s approval of the cobas 4800 BRAF V600 Mutation Test was based on data from the same study that evaluated the safety and effectiveness of Vemurafenib [Zelboraf].

Vemurafenib [Zelboraf] was reviewed under the FDA’s priority review program that provides for an expedited 6-month review of drugs that may offer major advances in treatment or that provide a treatment when no adequate therapy exists, says the agency.

“This has been an important year for patients with late-stage melanoma. Vemurafenib [Zelboraf] is the second new cancer drug approved that demonstrates an improvement in overall survival,” said Richard Pazdur, MD, director of the Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research, in a press statement. “In March, we approved Ipilimumab [Yervoy], another new treatment for late-stage melanoma that also showed patients live longer after receiving the drug.”

View here the  original article