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.


Regulatory Science Update: FDA and International Serious Adverse Events Consortium (SAEC) Complete Third Data Release

February 21, 2010

February 21, 2010 – In the field of pharmaco- and toxicogenetics of serious adverse drug reactions (sADRs) in humans, we learn today from a press release by the US Food and Drug Administration (FDA) of the completion and release by the FDA and the International Serious Adverse Events Consortium (SAEC) of the third data set with  focus on the genetic basis of drug-induced liver injury (DILI) and serious skin reactions (SSRs).

The data focus on the genetics associated with DILI and SSR and may help researchers to better predict an individual’s risk of developing these serious complications.

Drug induced liver injury occurs in a small subset of patients and is often associated with a drug that is an unpredictable liver toxin, and may be the cause of acute liver failure in some patients. Although the exact mechanism behind drug-induced liver injury is unknown, research suggests that a person’s genes contribute to their likelihood of developing this injury.

Drug-induced SSRs, such as Stevens-Johnson, present as allergic-like skin reactions (blistering and peeling of the skin) and are considered serious enough to discontinue treatment with the medication. These reactions can be fatal if the signs and symptoms are not quickly recognized.

The released research data relating to drug-induced liver injury (368 cases) and serious skin reactions (15 cases), complement the already released data from the SAEC’s December, 2008 and May, 2009 data releases.

“FDA is pleased with the Consortium’s progress,” said ShaAvhree Buckman, M.D., Ph.D., director of the Office of Translational Sciences in the FDA’s Center for Drug Evaluation and Research. “The continued accumulation of scientific information on the genetic basis of adverse drug events provides researchers with invaluable tools for understanding why some people respond to medicines differently than others.”

The SAEC is a nonprofit partnership of 10 international pharmaceutical companies, the Wellcome Trust, and academic institutions focused on research relating to the genetics of drug-induced serious adverse events.

Researchers who enter into a data use agreement can obtain free access to the data to generate custom data inquiries and obtain immediate results on the genetic basis of adverse drug events.

For more information on the International Serious Adverse Event Consortium (SAEC), go to http://www.saeconsortium.org

Information on previous SAEC data releases, follow the links below:
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2009/ucm109077.htm, or
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm163067.htm

Blogged with the Flock Browser

Etravirine [Intelence]: Association with fatal cases of Stevens Johnson Syndrome (SJS)

August 28, 2009

August 28, 2009 – As we have learned today, Tibotec Therapeutics and  the American Food and Drug Administration (FDA) notified healthcare professionals of revisions to the WARNINGS AND PRECAUTIONS section of the prescribing information for Etravirine [Intelence].  Etravirine [Intelence] (for chemical structure see graphic provided) is a human immunodeficiency virus type 1 (HIV-1) specific, non-nucleoside 2009 0829 Intelencereverse transcriptase inhibitor (NNRTI) indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-experienced adult patients, who have evidence of viral replication and HIV-1 strains resistant to an NNRTI and other antiretroviral agents.

There have been postmarketing reports of cases of Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme, as well as hypersensitivity reactions characterized by rash, constitutional findings, and sometimes organ dysfunction, including hepatic failure. Etravirine [Intelence] therapy should be immediately discontinued when signs and symptoms of severe skin or hypersensitivity reactions develop.

The new Warnings and Precautions Section (i.e., the Section 5 of that document) of the drug labeling document for Etravirine [Intelence] reads as follows:

5 WARNINGS AND PRECAUTIONS

5.1 Severe Skin and Hypersensitivity Reactions

Severe, potentially life-threatening, and fatal skin reactions have been reported. These include cases of Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme. Hypersensitivity reactions have also been reported and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including hepatic failure. In Phase 3 clinical trials, Grade 3 and 4 rashes were reported in 1.3% of subjects receiving INTELENCE™ compared to 0.2% of placebo subjects. A total of 2% of HIV-1-infected subjects receiving INTELENCE™ discontinued from Phase 3 trials due to rash [see Adverse Reactions (6)]. Rash occurred most commonly during the first 6 weeks of therapy.

Discontinue INTELENCE™ immediately if signs or symptoms of severe skin reactions or hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia). Clinical status including liver transaminases should be monitored and appropriate therapy initiated. Delay in stopping INTELENCE™ treatment after the onset of severe rash may result in a life-threatening reaction.

5.2 Fat Redistribution

Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

5.3 Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including INTELENCE™. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium complex, cytomegalovirus, Pneumocystis jiroveci pneumonia, and tuberculosis), which may necessitate further evaluation and treatment.

Read here the  “Dear Healthcare Professional Letter” sent out by Tibotec Therapeutics in accordance with the FDA.


The HLA-B*5801 Allele as a Genetic Marker in Han Chinese for Severe Cutaneous Adverse Reactions (SCAR) Caused by Allopurinol

May 12, 2009

May 12, 2009 – Drugs that contain the pharmacologically active ingredient allopurinol are commonly prescribed for the treatment of gout, hyperuricemia, and Lesch Nyhan Syndrome. They are frequently the cause of severe cutaneous adverse reactions (SCAR), which include drug hypersensitivity syndromes such as Stevens Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN). So far, these adverse events are unpredictable and they carry significant morbidity and mortality.

In recent years, pharmacogenetic case-control association studies have been carried out in order to identify genetic markers for allopurinol-induced SCAR. For example, in one large study in Han Chinese which enrolled 51 patients with allopuriol-induces SCAR and 228 control individuals (135 allopurinol-tolerant subjects and 93 healthy subjects from the general population), genotyping for 823 single nucleotide polymorphisms (SNPs) in genes related to drug metabolism and immune response was performed. The HLA-B*5801 allele was present in all (100%) of the 51 patients with allopurinol-induced SCAR, but only in 20 (15%) of the 135 allopurinol-tolerant individuals, giving rise to an odds ratio of 580 at the 95% confidence interval level (CI (95%), 34 to 978), and in 19 (20%) of the 93 healthy individuals, giving rise to an odds ratio of 494 (at 95% CI, 23 to 665).

These results indicate that the HLA-B*5801 allele is an important genetic risk factor for allopurinol-induced SCAR, at least in an extended ethnic group such as the Han Chinese. In this study, the HLA alleles A*3303, Cw*0302, and DRB1*0301 were in linkage disequilibrium and formed and extended risk haplotype in combination with the HLA-B*5801 allele.

A strong association of the HLA-B*1502 allele with Stevens Johnson Syndrome (SJS) and Toxic Epidermal Necrosis (TEN), induced by drugs that contain the pharmacologically active ingredient carbamazepine, or by drugs that contain the pharmacologically active ingredients phenytoin or fosphenytoin, has previously been recognized. Moreover, cutaneous hypersensitivity reactions to HIV-combating drugs that contain the active ingredient abacavir, are strongly associated with the HLA-B*5701 allele. Taken together, these data suggest that HLA-B alleles and/or other genetic polymorphisms in the MHC region might play a major role in the pathogenesis of immune-mediated drug-induced SCAR. A specific HLA-B molecule may function as antigenic presentation of certain drugs or their metabolites for HLA-restricted T cell activation.

It is interesting to note that the HLA-B*1502 allele and the HLA-B*5701 allele occur at high frequency in populations of Asian ancestry as does the HLA-B*5801 allele in Han Chinese. This puts patients belonging to these ethnic groups at high risk for the development of SJS and/or TEN when exposed to drugs containing the pharmacologically active ingredients allopurinol, carbamazepine, phenytoin, fosphenytoin, and abacavir. In fact, the American Food and Drug Administration (FDA) recommends that patients be genotyped for the HLA-B*1502 and the HLA-B*5701 allele, respectively, before therapies with carbamazepine and abacavir are initiated, and that carriers of these alleles should not be started on these drug unless the expected benefit clearly outweighs the risks.

A similar recommendation by the FDA for testing for the HLA-B*5801 allele before initiation of therapies with allopurinol-containing drugs has not yet been added to the labels of the according drugs. Nevertheless, it might be wise to discuss with your treating physician the testing for the HLA-B*5801 allele before starting a therapy on allopurinol if you are a patient of Han Chinese ancestry .

In the US, allopurinol-containg drugs are on the market as Allopurinol, Aloprim, Lopurin, and Zyloprim. Please find the newest drug labels for drugs containing allopurinol, carbamazepine, phenytoin, fosphenytoin, or abacavir at Drugs@FDA. Also, read more on the HLA-B*5801 allele.


Erlotinib [Tarceva] Updated Warnings and Precautions

May 9, 2009

May 08, 2009 – Erlotinib [Tarceva] monotherapy is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen. In combination with Gemcitabine [Gemzar], Tarceva is also indicated for the first-line treatment of patients with locally advanced, unresectable, or metastatic pancreatic cancer.

OSI, Genentech and FDA today notified healthcare professionals of new safety information added to the “Warnings” and “Precautions”  sections of the prescribing information for Tarceva. Gastrointestinal perforation (including fatalities), bullous, blistering and exfoliative skin conditions including cases suggestive of Stevens-Johnson Syndrome (SJS) and/or Toxic Epidermal Necrolysis (TEN), in some cases fatal, and ocular disorders, including corneal perforation or ulceration have been reported during use of Tarceva. The new safety information comes from routine pharmacovigilance activities of clinical study and postmarketing reports.

Please read the Dear Health Care Professional Letter and the announcement by FDA. Read also the current drug label information on Erlotinib [Tarceva] and Gemcitabine [Gemzar].


%d bloggers like this: