Wednesday, December 22, 2010

Rivaroxaban

In the recent issue of NEJM results of two studies involving Rivaroxaban have been published. One was an open-label, randomized study that compared oral Rivaroxaban alone (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with subcutaneous Enoxaparin followed by a vitamin K antagonist (either Warfarin or Acenocoumarol) for 3, 6, or 12 months in patients with acute, symptomatic DVT. 

 The second parallel study was a double blind, randomized, event-driven superiority study that compared rivaroxaban alone (20 mg once daily) with placebo for an additional 6 or 12 months in patients who had completed 6 to 12 months of treatment for venous thromboembolism.

The primary efficacy outcome for both studies was recurrent venous thromboembolism. The principal safety outcome was major bleeding or clinically relevant nonmajor bleeding in the initial-treatment study and major bleeding in the continued-treatment study.
The study of rivaroxaban for acute DVT included 3449 patients: 1731 given rivaroxaban and 1718 given enoxaparin plus a vitamin K antagonist. Rivaroxaban had noninferior efficacy with respect to the primary outcome (36 events [2.1%], vs. 51 events with enoxaparin–vitamin K antagonist [3.0%]; hazard ratio, 0.68; 95% confidence interval [CI], 0.44 to 1.04; P<0.001).
The principal safety outcome occurred in 8.1% of the patients in each group. In the continued-treatment study, which included 602 patients in the rivaroxaban group and 594 in the placebo group, rivaroxaban had superior efficacy (8 events [1.3%], vs. 42 with placebo [7.1%]; hazard ratio, 0.18; 95% CI, 0.09 to 0.39; P<0.001).
 Four patients in the rivaroxaban group had nonfatal major bleeding (0.7%), versus none in the placebo group (P=0.11).
The authors have concluded that Rivaroxaban offers a simple, single-drug approach to the short-term and continued treatment of venous thrombosis that may improve the benefit-to-risk profile of anticoagulation.
http://www.nejm.org/doi/full/10.1056/NEJMoa1007903

Friday, December 17, 2010

Anzemet (dolasetron mesylate)

The U.S. Food and Drug Administration (FDA) has informed that the injection form of Anzemet (dolasetron mesylate) should no longer be used to prevent nausea and vomiting associated with cancer chemotherapy (CINV) in pediatric and adult patients.
New data demonstrate that Anzemet injection can increase the risk of developing an abnormal heart rhythm (torsade de pointes), which in some cases can be fatal. Patients at particular risk are those with underlying heart conditions or those who have existing heart rate or rhythm problems. Anzemet causes a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram (ECG).
Anzemet injection may still be used for the prevention and treatment of postoperative nausea and vomiting (PONV) because the lower doses used for PONV are less likely to affect the electrical activity of the heart and result in abnormal heart rhythms. 
Anzemet tablets may still be used to prevent CINV because the risk of developing an abnormal heart rhythm with the oral form of this drug is less than that seen with the injection form.

However, a stronger warning about this potential risk is being added to the Warnings and Precautions sections of the Anzemet tablet label. Anzemet tablets may also still be used for prevention of PONV. 
Nausea and vomiting are common side effects of chemotherapy and general anesthesia used in surgery. Additional highlights:
  • Torsade de pointes, an abnormal heart rhythm, has been reported in some patients receiving Anzemet injection.
  • Anzemet should not be used in patients with congenital long-QT syndrome.
  • Hypokalemia and hypomagnesemia should be corrected before administering Anzemet. These electrolytes should be monitored after administration as clinically indicated.
  • Use electrocardiogram (ECG) monitoring in patients with congestive heart failure, patients with bradycardia, patients with underlying heart disease, the elderly and in patients who are renally impaired who are taking Anzemet.
  • No dose adjustment is necessary for renal-impaired patients, hepatic-impaired patients, or the elderly.
  • Anzemet also causes dose-dependent PR and QRS prolongation. Drugs known to prolong the PR interval (such as verapamil) or QRS interval (such as flecainide or quinidine) should be avoided in patients taking Anzemet.

Avastin (bevacizumab): Process for Removal of Breast Cancer Indication Begun

FDA recommended removing the breast cancer indication for Avastin (bevacizumab) 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.
FDA has made this recommendation after reviewing the results of four clinical studies of Avastin in women with breast cancer and by 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 Avastin lived longer and patients receiving 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.
FDA recommends that the Oncologists currently treating patients with 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. 
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm237172.htm

Wednesday, December 15, 2010

Long-term effect of aspirin on colorectal cancer incidence and mortality

In the November issue of Lancet, a study assessing the effect of aspirin (low doses i.e. 75-300 mg daily) on the incidence and mortality due to colorectal cancer in relation to dose, duration of treatment, and site of tumour was published.
Four randomised trials of aspirin versus control in primary (Thrombosis Prevention Trial, British Doctors Aspirin Trial) and secondary (Swedish Aspirin Low Dose Trial, UK-TIA Aspirin Trial) prevention of vascular events and one trial of different doses of aspirin (Dutch TIA Aspirin Trial) were followed and the effect of aspirin on risk of colorectal cancer over 20 years during and after the trials by analysis of pooled individual patient data was established.
Results
In the four trials of aspirin versus control (mean duration of scheduled treatment 6·0 years), 391 (2·8%) of 14 033 patients had colorectal cancer during a median follow-up of 18·3 years. Allocation to aspirin reduced the 20-year risk of colon cancer (incidence hazard ratio [HR] 0·76, 0·60—0·96, p=0·02; mortality HR 0·65, 0·48—0·88, p=0·005), but not rectal cancer (0·90, 0·63—1·30, p=0·58; 0·80, 0·50—1·28, p=0·35).
 Where subsite data were available, aspirin reduced risk of cancer of the proximal colon (0·45, 0·28—0·74, p=0·001; 0·34, 0·18—0·66, p=0·001), but not the distal colon (1·10, 0·73—1·64, p=0·66; 1·21, 0·66—2·24, p=0·54; for incidence difference p=0·04, for mortality difference p=0·01).
 However, benefit increased with scheduled duration of treatment, such that allocation to aspirin of 5 years or longer reduced risk of proximal colon cancer by about 70% (0·35, 0·20—0·63; 0·24, 0·11—0·52; both p<0·0001) and also reduced risk of rectal cancer (0·58, 0·36—0·92, p=0·02; 0·47, 0·26—0·87, p=0·01).
There was no increase in benefit at doses of aspirin greater than 75 mg daily, with an absolute reduction of 1·76% (0·61—2·91; p=0·001) in 20-year risk of any fatal colorectal cancer after 5-years scheduled treatment with 75—300 mg daily. However, risk of fatal colorectal cancer was higher on 30 mg versus 283 mg daily on long-term follow-up of the Dutch TIA trial (odds ratio 2·02, 0·70—6·05, p=0·15).
The authors concluded that Aspirin taken for several years at doses of at least 75 mg daily reduced long-term incidence and mortality due to colorectal cancer. Benefit was greatest for cancers of the proximal colon, which are not otherwise prevented effectively by screening with sigmoidoscopy or colonoscopy.

Tessalon (benzonatate): Drug Safety Communication - Potential for Accidental Ingestion by Children

The U.S. Food and Drug Administration (FDA) has issued a warning to the public that accidental ingestion of benzonatate (Tessalon)  by children under the age of 10 years can result in death from overdose.
Benzonatate is a prescription drug approved for relief of cough in patients over 10 years of age. The safety and effectiveness of benzonatate in children under 10 years of age have not been established. Benzonatate is sold under the brand-name Tessalon and is also sold in generic preparations. 
Benzonatate may be attractive to children because of the drug's appearance (it is a round-shaped liquid-filled gelatin capsule).
Overdose with benzonatate in children less than 2 years of age has been reported following accidental ingestion of as few as 1 or 2 capsules. Individuals who experience overdose of benzonatate may exhibit restlessness, tremors, convulsions, coma, and cardiac arrest. Signs and symptoms of overdose can occur rapidly after ingestion (within 15-20 minutes). Deaths in children have been reported within hours of the accidental ingestion.  
The FDA has issued guidelines for the healthcare professionals and patients.

Saturday, December 11, 2010

Contrave, a novel combination of naltrexone and bupropion for obesity

Highlights of the document of 7th December, 2010 summarizing the data in support of the approval of Contrave, a novel combination product for the treatment of obesity composed of bupropion and naltrexone developed by Orexigen, Inc. of La Jolla, California.
Proposed Indication: The treatment of obesity and weight management, including weight loss and maintenance of weight loss, used in conjunction with lifestyle modification. Recommended for patients with an initial body mass index 30 kg/m2 or 27 kg/m2 with one or more risk factors (e.g. diabetes, dyslipidemia, or hypertension).
Proposed Dosing: The recommended daily dose of Contrave is two 8 mg naltrexone/90 mg bupropion (8/90) tablets taken twice daily for a total daily dose of 32 mg naltrexone/360 mg bupropion (32/360). Upon initiation, Contrave dosing should be escalated starting with one tablet taken daily for the first week, followed by the addition of another tablet each day during each subsequent week, until the total daily maintenance dose of two tablets twice a day (32/360)is reached at the start of Week 4.
Contrave, a novel combination product for the treatment of obesity, is composed of bupropion (a relatively weak inhibitor of the neuronal uptake of norepinephrine [NE] and dopamine [DA]) combined with naltrexone (a mu-opioid receptor antagonist).
Bupropion has been shown to stimulate hypothalamic proopiomelanocortin (POMC) neurons that release alpha-melanocyte stimulating hormone (α- MSH) which, in turn, binds to melanocortin 4 (MC4) receptors. The binding of α-MSH to MC4 receptors initiates a cascade of actions that results in weight loss via reduced energy intake and increased energy expenditure. When α-MSH is released, POMC neurons simultaneously release β-endorphin, an endogenous agonist of the mu-opioid
receptor that mediates a negative feedback loop on POMC neurons leading to a decrease in
the release of α-MSH. Blocking this inhibitory feedback loop with naltrexone is proposed to facilitate a more potent and longer-lasting activation of POMC neurons, thereby amplifying effects on energy balance. As a result, co-administration of bupropion and naltrexone produces a substantially greater effect on the POMC firing rate than either compound administered
alone, suggesting that the drugs act synergistically.
Adverse events: The observed Contrave safety and tolerability profile was generally comparable to the well-established safety profiles associated with naltrexone and bupropion, each with more
than 20 years of post-marketing experience and approximately 1 million and more than 50 million unique exposures, respectively.  With the exception of nausea and vomiting, the NB combination of naltrexone and bupropion did not appear to be associated with increased adverse events (AEs) relative to the individual components. The adverse events were nausea, constipation, headache, vomiting, dizziness, insomnia, dry mouth and diarrhea.

Friday, December 10, 2010

Somatropin-containing medicines

On 10th December 2010, The European Medicines Agency announced  that it is starting a review of the safety of somatropin-containing medicines authorised centrally or by national procedures in the European Union. The review will look into all available data on somatropin to reassess the benefit-risk balance of these medicines.
This review is being initiated further to information received from the French medicines agency on a long-term epidemiological study in patients treated during childhood with somatropin-containing medicines. The study results suggest an increased risk of mortality with somatropin therapy compared to the general population. The risk appears to be particularly increased when high doses are used (beyond doses as recommended in the Summary of Product Characteristics). The study looked at patients treated during childhood for growth hormone deficiency or short stature of unknown cause. Based on this observational study alone, the risk cannot be associated with certainty to the growth hormone treatment. The results need to be confirmed and complemented with further analyses. The French safety study, “Santé Adulte GH Enfant” (SAGhE), had been initiated in October 2007 and aims at improving the knowledge on recombinant growth hormone and evaluating the health of young adults who have been treated during childhood with recombinant growth hormone. Using the national compulsory France-Hypophyse register, investigators of the SAGhE study identified more than 10,000 young adults who started a recombinant growth hormone treatment between 1985 and 1996. The available analysis covers approximately 7,000 of these patients.
Somatropin is a human growth hormone, manufactured using recombinant DNA technology. It promotes growth during childhood and adolescence, and also affects the way the body handles proteins, fat and carbohydrates.
Somatropin is used to treat a number of conditions associated with a lack of growth hormone and short stature. This includes children who fail to grow due to a lack of growth hormone, Turner syndrome or chronic renal insufficiency.
There are three centrally authorised somatropin medicines in the EU: NutropinAq, Omnitrope and Valtropin. Several other somatropin medicines have been authorised through national procedures throughout the EU.
The Agency will provide further information on this review after the CHMP plenary meeting of 13-16 December 2010. In the meantime, the Agency is reminding prescribers to strictly follow the indications and the approved doses.
http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2010/12/news_detail_001160.jsp&murl=menus/news_and_events/news_and_events.jsp&mid=WC0b01ac058004d5c1

Withdrawal of Thelin (sitaxentan) due to cases of unpredictable serious liver injury

Pfizer has informed The European Medicines Agency about its voluntary decision to withdraw Thelin from the market worldwide because of the new information on two cases of fatal liver injury. Pfizer has also decided to discontinue all ongoing clinical trials.
Thelin, which contains the active substance sitaxentan, has been authorised in the European Union (EU) since 2006 for the treatment of pulmonary arterial hypertension.
Thelin has been known to be associated with liver toxicity and since its initial marketing authorisation has been contra-indicated in patients with mild to severe hepatic impairment (Child-Pugh Class A-C) and elevated aminotransferases prior to initiation of treatment.
At this stage, patients taking Thelin or participating in Thelin studies are advised not to stop treatment and to consult their treating physician to review their treatment at their next scheduled appointment.
The Agency’s scientific Committee for Medicinal Products for Human Use (CHMP) will look at this issue during their plenary meeting on 13–16 December 2010 and will provide detailed advice for patients and prescribers.
What is Thelin?
Thelin is used to treat adults (aged 18 years or over) with pulmonary arterial hypertension (PAH) to improve exercise capacity (the ability to carry out physical activity). PAH is abnormally high blood pressure in the arteries of the lungs. Thelin is used in patients with class III disease. The ‘class’ reflects the seriousness of the disease: ‘class III’ involves marked limitation of physical activity. Thelin has been shown to be effective in PAH with no identified cause and PAH caused by connective tissue disease.
As the number of patients with pulmonary arterial hypertension is low, the disease is considered ‘rare’, and Thelin was designated an ‘orphan medicine’ (a medicine used in rare diseases) on 21 October 2004.

Thursday, December 9, 2010

Management of Stevens Johnsons Syndrome and Toxic Epidermal Necrolysis

Diagnosis
TEN  and SJS are characterized by:
·       Typically, the disease process begins with influenza-like symptoms which are a part of a 1- to 14-day prodrome during which fever, sore throat; chills, headache, and malaise may be present.
·       Mucocutaneous lesions develop abruptly. The rash can begin as macules that develop into papules, vesicles, bullae, or confluent erythema. Characteristic skin lesions are flat, irregular, atypical target lesions or diffuse purpuric macules that frequently have necrotic centers (particularly in TEN) and tend to coalesce over the course of time.
·       In TEN, loss of epidermis is often sheet-like with a frequently positive Nikolsky sign (in which there is lateral displacement of the necrotic epidermis in response to slight pressure). As a result of cell death in the basal layer and stratum spinosum, the epidermis detaches from the dermis, giving rise to flaccid blisters. Although minor presentations may occur, significant involvement of oral, nasal, eye, vaginal, urethral, gastrointestinal, and lower respiratory tract mucous membranes may develop in the course of the illness. Gastrointestinal and respiratory involvement may progress to necrosis.
·       Ocular involvement is seen in many patients with typical manifestations.
The physician is responsible for the early recognition of the reaction and the withdrawal of all potentially responsible drugs, especially those introduced within 1 month from the reaction.
Even if SJS or TEN is primarily diagnosed clinically, the diagnosis should be confirmed through histopathology. Histopathology classically shows widespread keratinocyte apoptosis and full-thickness epidermal necrosis and detachment, whereas the underlying dermis is not greatly altered and the epidermidis is infiltrated by activated lymphocytes, mainly CD8 cells, and macrophage.
The differential diagnosis of SJS or TEN includes a variety of skin reactions such as erythema multiforme (EM) major and atypical EM major, acute generalized erythematous pustulosis, intermediate burns, generalized fixed bullous drug eruption, staphylococcal scalded skin syndrome, edematous erythroderma, bullous pemphigoid, paraneoplastic pemphigus, exfoliative dermatitis, and acute graft-versus-host disease.
Erythema multiforme (EM) presents as initial target-like lesions characterized by an erythematous raised and palpable rim surrounding a gray center, whereas lesions of the SJS/TEN group are flat. In addition to these clinical and etiologic differences, EM and SJS/TEN can be distinguished histologically.
Treatment
No treatment modality has been established as standard for patients with SJS/TEN. Obviously, withdrawal of the suspected offending agent is critically important.
Immunoglobulin: A therapy with intravenous immunoglobulin (IVIG) was adopted on the basis of the identification of the mechanism of keratinocytes apoptosis in SJS/TEN. Nevertheless, at present, there is no strong evidence supporting IVIG administration in these patients.
Corticosteroids: The use of corticosteroids is controversial. A retrospective comparative study reported that combination therapy with corticosteroid and IVIG shows a tendency to reduce the mortality rate in comparison with the administration of corticosteroids alone.
Further studies are needed to determine the true efficacy of other agents such as tumor necrosis factor-α inhibitors, cyclosporine, cyclophosphamide, plasmapheresis and thalidomide.
Treatment, therefore, is primarily supportive and symptomatic and is similar to the therapy for burn patients.
Optimal treatment of SJS/TEN involves a multidisciplinary approach.
·       Fluid replacement must be initiated using macromolecules or saline solutions. Early and continuous enteral nutrition reduces the risk of stress ulcer and enterogenic infection. Total parenteral nutrition should be started in patients with hemodynamic instability or who are unable to take food.
·       Control of infection is crucial in the management of these patients because the high mortality is mostly attributed to bacterial sepsis; however, antibiotic use is generally reserved for the presence of documented infections or signs of sepsis.
·        Given that the majority of patients have ocular involvement, an ophthalmologist often is needed to assess and minimize the risk of infection ocular damage with treatments including topical lubricants-antibiotics and steroid drops.
·       Also, treatment of multiorgan damage, and prevention of further systemic complications. Special attention to airway and hemodynamic stability and pain control.
http://journals.lww.com/drug-monitoring/Fulltext/2010/12000/Stevens_Johnson_Syndrome_and_Toxic_Epidermal.1.aspx?WT.mc_id=EMxj15x20101206xL3 

European Commission Approves Brilique™ (Ticagrelor Tablets)

AstraZeneca announced on 6th December 2010 that the European Commission has granted marketing authorisation to BRILIQUE™ (ticagrelor tablets) for the prevention of atherothrombotic events in adult patients with Acute Coronary Syndromes (ACS). This decision follows the positive opinion from the Committee for Medicinal Products for Human Use on 23rd September and is applicable to the 27 Member States and the 3 European Economic Area countries of the European Union.(1)
BRILIQUE (Ticagrelor) is a direct-acting P2Y12 receptor antagonist in a chemical class called cyclo-pentyl-triazolo-pyrimidines (CPTPs). Ticagrelor is the first reversibly-binding oral ADP receptor antagonist.
BRILIQUE, a prescription oral antiplatelet treatment, co-administered with acetylsalicylic acid (ASA), is indicated for the prevention of atherothrombotic events in adult patients with Acute Coronary Syndromes (unstable angina, NSTEMI, or STEMI), including patients managed medically and those who are managed with percutaneous coronary intervention (PCI) or Coronary Artery Bypass Grafting (CABG).
The majority of launches will occur in the second half of the year due to pricing and reimbursement negotiations.
The marketing authorisation for BRILIQUE is based on a review of the ticagrelor clinical programme, including results from PLATO (A Study of PLATelet Inhibition and Patient Outcomes), which established the superiority of ticagrelor over clopidogrel, and showed that treating 54 ACS patients with ticagrelor instead of clopidogrel for one year prevented one atherothrombotic event and treating 91 patients prevented one cardiovascular death, with no increase in overall major/fatal bleeding over the course of one year of treatment (11.6% for BRILIQUE vs. 11.2% for clopidogrel, p=0.43).
In the PLATO trial (2) the ticagrelor and clopidogrel groups did not differ significantly with regard to the rates of major bleeding as defined in the trial (11.6% and 11.2%, respectively; P = 0.43). There was also no significant difference in the rates of major bleeding according to the Thrombolysis in Myocardial Infarction (TIMI) criteria (7.9% with ticagrelor and 7.7% with clopidogrel, P = 0.57) or fatal or life-threatening bleeding (5.8% in both groups, P = 0.70). The absence of a significant difference in major bleeding according to the trial definition was consistent among all subgroups, without significant heterogeneity, except with regard to the body-mass index (P = 0.05 for interaction). The two treatment groups did not differ significantly in the rates of CABG-related major bleeding or bleeding requiring transfusion of red cells. How-ever, in the ticagrelor group, there was a higher rate of non–CABG-related major bleeding according
to the study criteria (4.5% vs. 3.8%, P = 0.03) and the TIMI criteria (2.8% vs. 2.2%, P = 0.03). With ticagrelor as compared with clopidogrel, there were more episodes of intracranial bleeding (26 [0.3%] vs. 14 [0.2%], P = 0.06), including fatal intracranial bleeding (11 [0.1%] vs. 1 [0.01%], P = 0.02). However, there were fewer episodes of other types of fatal bleeding in the ticagrelor group (9 [0.1%], vs. 21 [0.3%] in the clopidogrel group; P = 0.03). Dyspnea was more common in the ticagrelor group than in the clopidogrel group (in 13.8% of patients vs. 7.8%)
Other uncommonly reported side effects include headache, dizziness, abdominal pain, diarrhea, rash, itching, and upset stomach.