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P T. 2014;39(2): 83, 87-88, 97, 104-107, 110-111, 129

New Drugs/Drug News/New Medical Devices February 2014


Farxiga for Type-2 diabetes

The FDA has approved dapaglifozin (Farxiga, Bristol-Myers Squibb/Astra-Zeneca) tablets to improve glycemic control, along with diet and exercise, in adults with type-2 diabetes.

Dapaglifozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor that blocks the reabsorption of glucose by the kidney, increases glucose excretion, and lowers blood glucose levels. The drug’s safety and efficacy were evaluated in 16 clinical trials involving more than 9,400 patients with type-2 diabetes. These studies showed improvement in hemoglobin A1c, a measure of blood sugar control.

Dapaglifozin has been studied as a stand-alone therapy and in combination with other type-2 diabetes treatments, including metformin, pioglitazone, glimepiride, sitagliptin, and insulin. The drug should not be used to treat people with type-1 diabetes; those who have diabetic ketoacidosis; those with moderate or severe renal impairment or end-stage renal disease; or those on dialysis.

The FDA is requiring six post-marketing studies of dapaglifozin:

  • A cardiovascular outcomes trial (CVOT) to evaluate the cardiovascular risk of dapagliflozin in patients with a high baseline risk of cardiovascular disease
  • A double-blind, randomized, controlled assessment of the risk of bladder cancer in patients enrolled in the CVOT
  • An animal study evaluating the role of dapagliflozin-induced urinary flow/rate and composition changes on bladder tumor promotion in rodents
  • Two clinical trials to assess the pharmacokinetics, efficacy, and safety of dapagliflozin in pediatric patients
  • An enhanced pharmacovigilance program to monitor reports of liver abnormalities and pregnancy outcomes

Source: FDA, January 8, 2014

Tretten for Rare Genetic Clotting Disorder

The FDA has approved coagulation Factor XIII A-subunit (Recombinant) (Tretten, NovoNordisk), the first recombinant product for the routine prevention of bleeding in adults and children who have a rare clotting disorder known as congenital Factor XIII A-subunit deficiency. Factor XIII is a protein that is important for normal clotting. It is composed of two subunits, A and B. Usually there is a deficiency of the A-subunit.

Tretten is a recombinant analogue of the human Factor XIII A-subunit that is produced in yeast cells and is then further purified. A sterile freeze-dried powder, it is designed to be reconstituted with diluent and injected intravenously by a physician or the patient.

This product is also approved as Tretten in Canada and as NovoThirteen in the European Union, Switzerland, and Australia. The FDA granted Tretten an orphan drug designation. More information is available in this month’s Pharmaceutical Approval Update column on page 112.

Source: FDA, December 23, 2013

Orenitram ER for Pulmonary Arterial Hypertension

The FDA has approved treprostinil extended-release tablets (Orenitram, United Therapeutics Corp.) for the treatment of pulmonary arterial hypertension (PAH) in World Health Organization (WHO) group I patients to improve exercise capacity.

A primary efficacy study, FREEDOM-M, demonstrated that patients receiving Orenitram twice daily improved their median six-minute walk distance (6MWD) by 23 meters (P = 0.013) compared with patients given placebo. The benefit of treprostinil, a vasodilator, on exercise is small, and the drug has not been shown to add to other vasodilator therapy. Two other phase 3 studies (FREEDOM-C and FREEDOM-C2) did not demonstrate a benefit in exercise, with median 6MWDs at week 16 of 11 meters (P = 0.072) and 10 meters (P = 0.089), respectively.

The most common side effects reported in clinical studies of treprostinil included headache, nausea, and diarrhea.

Treprostinil is dosed twice a day with food, but the total daily dose can be divided and given three times daily with food. Treprostinil is available in four strengths: 0.125 mg, 0.25 mg, 1.0 mg, and 2.5 mg. The dose of treprostinil should be increased as tolerated to achieve the optimal clinical response. The maximum dose is determined by tolerability.

Treprostinil is also the active ingredient in Remodulin injection and Tyvaso inhalation solution, both marketed by United Therapeutics Corp.

Source: United Therapeutics, December 20, 2013


FEIBA for Hemophilia Patients

The FDA has given the nod to anti-inhibitor coagulant complex (FEIBA, Baxter International Inc.), the first FDA-approved treatment for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in patients with hemophilia A or B who have developed inhibitors (i.e., antibodies produced by the body’s immune system in response to factor-replacement therapy).

Inhibitor development is considered one of the most serious complications associated with the treatment of hemophilia. As many as one-third of previously untreated patients with severe or moderately severe hemophilia A are at risk for developing inhibitors. The presence of an inhibitor makes response to treatment more challenging, and patients with inhibitors have an increased risk of developing complications.

The FDA’s approval is based on data from a pivotal phase 3 study, FEIBA PROOF, in which treatment with a FEIBA prophylactic regimen achieved a 72% reduction in the median annual bleed rate (ABR) compared with treatment with an on-demand regimen. In the intent-to-treat (ITT) analysis, three (18%) of the 17 adult patients in the prophylactic arm reported no bleeding episodes.

The most frequently reported adverse reactions in the prophylaxis trial were anemia, diarrhea, hemarthrosis, hepatitis B surface antibody positive, nausea, and vomiting. The serious adverse reactions seen with FEIBA included hypersensitivity reactions and thromboembolic events, including stroke, pulmonary embolism, and deep vein thrombosis.

FEIBA is an anti-inhibitor coagulant complex indicated for use in patients with hemophilia A and B with inhibitors for the control and prevention of bleeding episodes, for perioperative management, and for routine prophylaxis to prevent or reduce the frequency of bleeding episodes. FEIBA is not indicated for the treatment of bleeding episodes resulting from coagulation factor deficiencies in the absence of inhibitors to coagulation factor VIII or coagulation factor IX.

Source: Baxter, December 19, 2013

Regular FDA Approval For Xalkori

The FDA has granted crizotinib (Xalkori, Pfizer) regular approval for the treatment of patients with metastatic anaplastic lymphoma kinase (ALK)-positive non–small-cell lung cancer (NSCLC), as detected by an FDA-approved test.

Crizotinib was previously granted accelerated approval in August 2011 because of the critical need for new agents for patients with ALK-positive NSCLC.

The FDA’s action was based on data from a pivotal phase 3 confirmatory trial that compared crizotinib with standard chemotherapy in previously treated patients. The results of this study were published in the June 20 issue of the New England Journal of Medicine.

Source: Pfizer, November 21, 2013


Isentress Oral Suspension For Pediatric HIV

The FDA has approved raltegravir (Isentress, Merck) for oral suspension, a new pediatric formulation of the integrase inhibitor. With this approval, raltegravir is now indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency-1 (HIV-1) infection in patients 4 weeks of age and older.

The use of other active agents with raltegravir is associated with a greater likelihood of a treatment response. The oral suspension may be used in patients as young as 4 weeks of age, weighing at least 3 kg to less than 20 kg. The safety and efficacy of Isentress have not been established in infants younger than 4 weeks of age.

Formulations of raltegravir for specific populations now include oral suspension, chewable tablets, and film-coated tablets.

Raltegravir works by inhibiting the insertion of HIV-1 DNA into human DNA by the integrase enzyme. Inhibiting integrase from performing this essential function limits the ability of the virus to replicate and infect new cells.

Source: Merck, January 8, 2013


Tafinlar Termed ‘Breakthrough Therapy’ for Lung Cancer

The FDA has granted a “breakthrough therapy” designation for dabrafenib (Tafinlar, GlaxoSmithKline) for the treatment of patients with metastatic BRAF V600E mutation-positive non–small-cell lung cancer (NSCLC) who have received at least one prior line of platinum-containing chemotherapy. Dabrafenib is not approved for use in this treatment setting.

The new designation was based on interim efficacy and safety results from an ongoing phase 2 study of oral dabrafenib in 25 patients who had NSCLC with the BRAF V600E mutation and who had received at least one course of chemotherapy. The interim results were presented at the 2013 American Society of Clinical Oncology annual meeting.

A “breakthrough therapy” designation is intended to expedite the development and review of drugs to treat serious or life-threatening medical conditions when preliminary clinical evidence demonstrates that the drug may offer substantial improvement on at least one clinically significant endpoint compared with available therapies.

Lung cancer is the second most common cancer in both men and women and is the leading cause of cancer-related death worldwide. Recent advances in the understanding of tumor biology have identified genetic mutations, such as a mutation in the BRAF protein, that can drive malignant cell growth and tumor proliferation in NSCLC. It is estimated that the BRAF V600E mutation targeted by dabrafenib is present in approximately 2% of patients with NSCLC.

Tafinlar (dabrafenib) is currently indicated for the treatment of melanoma.

Source: GlaxoSmithKline, January 13, 2014

Mekinist and Tafinlar Combination for Melanoma

Trametinib (Mekinist) has been approved for use in combination with dabrafenib (Tafinlar) to treat patients with unresectable or metastatic melanoma. These mutations must be detected by an FDA-approved test. Dabrafenib is not indicated for the treatment of patients with wild-type BRAF melanoma. Both Mekinist (previously approved in May 2013) and Tafinlar are marketed by GlaxoSmithKline.

The approval of the combination therapy was based on the demonstration of a response rate and a median duration of response in a phase 1/2 study. Improvement in disease-related symptoms or overall survival has not been demonstrated for Mekinist in combination with Tafinlar.

The combination was approved through the FDA’s accelerated approval program and received a priority review designation. This accelerated approval is contingent on the results of an ongoing phase 3 trial, which is designed to evaluate the clinical benefit of the combination in patients with unresectable or metastatic melanoma.

Trametinib in combination with dabrafenib can cause serious side effects, some of which can be life-threatening, including: new primary cutaneous malignancies, tumor promotion in wild-type BRAF melanoma, hemorrhagic events, venous thromboembolic events, cardiomyopathy, ocular toxicities, interstitial lung disease, serious febrile drug reactions, serious skin toxicity (rash), hyperglycemia, hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, and embryofetal toxicity.

Source: GlaxoSmithKline, January 9, 2014

FDA Limits Acetaminophen In Prescription Products

The FDA is asking manufacturers of prescription combination products that contain acetaminophen to limit the amount of acetaminophen to no more than 325 mg in each tablet or capsule.

The agency also is requiring manufacturers to update labels of all prescription combination acetaminophen products to warn of the potential risk for severe liver injury.

Acetaminophen relieves pain and fever and can be found in both prescription and over-the-counter (OTC) products. It is combined in many prescription products with other ingredients, usually opioids such as codeine (Tylenol with Codeine), oxycodone (Percocet), and hydrocodone (Vicodin). OTC acetaminophen products are not affected by the FDA’s action.

The elimination of higher-dose prescription combination acetaminophen products will be phased in over three years and should not create a shortage of pain medication, the agency says.

Sources: Reuters, January 14, 2014, and FDA, January 13, 2014

Iclusig Marketing Resumes

The FDA has approved revised U.S. prescribing information (USPI) and a risk evaluation and mitigation strategy (REMS) for ponatinib (Iclusig, Ariad Pharmaceuticals), allowing immediate resumption of the drug’s marketing and commercial distribution. The USPI includes a revised indication statement and boxed warning, updated safety information, and recommendations regarding dosing considerations for prescribers.

Ponatinib is indicated for the treatment of adult patients with:

  • T315I-positive chronic myeloid leukemia (CML) (chronic phase, accelerated phase, or blast phase) or T315I-positive Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL)
  • Chronic phase, accelerated phase, or blast phase CML or Ph+ ALL for which no other tyrosine-kinase inhibitor therapy is indicated

The boxed warning for Iclusig has been revised to alert health care professionals and patients to the risk of vascular occlusive events and includes a new warning for heart failure. The starting dose of Iclusig remains 45 mg daily.

Ponatinib is a tyrosine kinase inhibitor (TKI). The drug’s primary target is BCRABL, an abnormal tyrosine kinase that is expressed in CML and Ph+ ALL. Ponatinib was designed to inhibit the activity of BCR-ABL. The drug targets not only native BCR-ABL but also its isoforms, which carry mutations that confer resistance to treatment, including the T315I mutation, a common mutation that has been associated with resistance to other approved TKIs.

Source: Ariad Pharmaceuticals, December 21, 2013


Clinimix and Clinimix E

The FDA has notified health professionals and their medical care organizations of a voluntary recall in the U.S. of two lots of Clinimix (amino acid in dextrose) injection and one lot of Clinimix E (amino acid with electrolytes in dextrose with calcium) injection parenteral nutrition products because of complaints of particulate matter found in the products.

The affected product codes are 2B7729 (lot P287045, expiration date 06/14), 2B7717 (lot P275883, expiration date 10/13), and 2B7709 (lot P28512, expiration date 05/14). The affected lots were distributed to customers between May 2012 and October 2013.

If infused, particulate matter may result in blockages of blood vessels, which can result in stroke, heart attack, or damage to other organs, such as the kidney or liver. There is also the possibility of allergic reactions, local irritation, and inflammation in tissues and organs.

Clinimix and Clinimix E injections are premixed sterile intravenous parenteral nutrition products that come in multichambered containers. Both products are used as a caloric component and as a protein source in a parenteral nutrition program. The products are manufactured by Baxter International.

Baxter has directed customers not to use products from the recalled lots and to locate and remove all affected products from their facilities.

According to the product labeling, parenteral drug products should be inspected visually for particulate matter and discoloration whenever the solution and container permit. The use of a final filter is recommended during the administration of all parenteral solutions, where possible.

Source: FDA, January 6, 2013

Dextrose and Sodium Chloride Solutions

Baxter International has voluntarily recalled one lot of 5% Dextrose Injection, USP, and four lots of 0.9% Sodium Chloride Injection, USP, because of particulate matter found in the solutions.

Injecting a product containing particulate matter may result in blockages of blood vessels, which can result in stroke, heart attack, kidney or liver damage, an allergic reaction, or local tissue or organ irritation and inflammation. There have been no reported adverse events so far, and the root cause of this recall has been identified and resolved.

Dextrose Injection, USP, is a source of water and calories. Sodium Chloride Injection, USP, is a source of water and electrolytes and is used as a priming solution in hemodialysis. These 50-mL and 100-mL containers are primarily used for admixture of medication and as priming solutions. The affected products are as follows:

  • 5% Dextrose Injection, USP, 100 mL, lot P285288
  • 0.9% Sodium Chloride Injection, USP, 50 mL, lot 297283
  • 0.9% Sodium Chloride Injection, USP, 100 mL, lots P292326, P293993, and P293514

The products affected by this recall were packaged in flexible plastic containers with 96 containers per carton and were distributed to the U.S., Puerto Rico, Saudi Arabia, Singapore, and United Arab Emirates.

Customers are being directed not to use product from the recalled lots. The affected lots were distributed to customers between May 2012 and October 2013. Unaffected lot numbers can continue to be used according to the instructions for use.

Source: FDA, December 23, 2013

Abrams Royal Compounding Pharmacy

All non-expired drug products produced and distributed for sterile use by Abrams Royal Compounding Pharmacy in Dallas, Texas, are being recalled voluntarily. The recalled products include injectable medications, intravenous (IV) injections, eye drops, pellet implants, nasal sprays, inhalation solutions, and eye ointments that were distributed between June 17, 2013 and Dec. 17, 2013.

The FDA is aware of one adverse event associated with mineral IV injection produced by Abrams’ lot number 11142013@74. A patient who received this product was admitted to a hospital in California and had blood cultures that tested positive for Stenotrophomonas maltophilia, a gram-negative bacterium that can cause many types of infections. In addition, Abrams identified a similar gram-negative bacterium in the same lot of mineral IV injection.

Source: FDA, December 21, 2013

Orfadin NDA Withdrawn in U.S.

Orphan Biovitrum AB (Sobi), based in Sweden, has withdrawn its new drug application (NDA) for an oral suspension of nitisinone (Orfadin) in the U.S. The FDA wants more information about the usability of the oral suspension and the oral syringe to be included in the package.

Nitisinone is used for the treatment of hereditary tyrosinemia type-1 (HT-1), a rare genetic disorder that can cause liver failure, kidney dysfunction, and neurological problems. This synthetic nitrobenzene derivative acts as a reversible inhibitor of 4-hydroxyphenylpyruvate dioxygenase. It is formulated as capsules for oral administration. Patients with hereditary tyrosinemia type-1 (HT-1) must restrict their dietary intake of tyrosine and phenylalanine. Nitisinone inhibits catabolism of tyrosine by preventing the catabolic intermediates.

The capsules are available in strengths of 2 mg, 5 mg, and 10 mg. Nitisinone is under development for the treatment of alkaptonuria and has also been under development for Parkinson’s disease.

Sobi plans to discuss a resubmission date with the FDA in the first quarter of 2014.

Source: Pharma e-Track, December 27, 2013

FDA to Review Contrave

The FDA considers the recent resubmission of a new drug application (NDA) for naltrexone sustained release (SR)/bupropion SR (Contrave, Orexigen Therapeutics/Takeda) to be a complete response to the agency’s January 31, 2011, action letter.

For the resubmission, the FDA has assigned a Prescription Drug User Fee Act goal date of June 10, 2014. If approved, Contrave is expected to be launched in the second half of 2014.

The NDA for Contrave was resubmitted in December 2013 following an interim analysis of the ongoing Light study—a double-blind, placebo-controlled cardiovascular outcomes trial involving approximately 8,900 patients. This study met prespecified criteria to exclude a hazard ratio of 2.0 for an excess risk of major adverse cardiovascular events in patients treated with Contrave compared with placebo.

Before the start of the Light study, Contrave was evaluated in clinical trials that enrolled more than 4,500 subjects. In these studies, 53% of participants taking Contrave and 21% of those taking placebo lost 5% or more of their body weight over 12 months of treatment.

Source: Orexigen Therapeutics, January 7, 2013

Antidepressants and Teen Suicide

A study of 36,842 children and adolescents found no evidence that the risk of suicide attempts differed significantly when they were treated with one of six commonly prescribed selective serotonin reuptake inhibitors (SSRIs) or serotoninnorepinephrine reuptake inhibitors (SNRIs). This study compared the risk for medically treated suicide attempts among new users of sertraline, paroxetine, citalopram, escitalopram, and venlafaxine to the risk for new users of fluoxetine, the antidepressant the FDA recommends for treatment of depression in this age group.

The retrospective cohort study examined 6-to-18-year-olds enrolled in Tennessee Medicaid between 1995 and 2006. They were defined as “new users” of one of the antidepressants because they had not filled a prescription for antidepressants in the previous 12 months. Common psychiatric diagnoses among the group included major depressive disorder (47.4%), attention-deficit/hyperactivity disorder (about one-fourth), conduct disorder, and anxiety. Their mean age was 14.0 years, and those using different medications had comparable demographics.

Researchers identified 419 medically treated suicide attempts, including four that were completed. The mean age at the time of attempts was 15.4 years. The rate of confirmed suicide attempts for the study drugs ranged from 24.0 per 1,000 person-years to 29.1 per 1,000 person-years. Compared with current users of fluoxetine, the adjusted rate of suicide attempts did not differ significantly among current users of sertraline (adjusted relative risk [RR], 0.97; 95% CI, 0.66–1.45) paroxetine (RR, 0.80; 95% CI, 0.52–1.21), citalopram (RR, 0.92; 95% CI, 0.57–1.50), escitalopram (RR, 0.80; 95% CI, 0.45–1.43), and venlafaxine (RR 0.80; 95% CI, 0.43–1.51). However, children who used multiple antidepressants concomitantly had a higher risk for medically treated suicide attempts (RR, 1.70; 95% CI, 1.10–2.62) than fluoxetine users.

Source: Pediatrics 2014;133:1–7

Green Tea Hampers Nadolol

Green tea consumption may weaken the blood-pressure-lowering effects of the β-blocker drug nadolol, according to a preliminary study published in Clinical Pharmacology & Therapeutics.

Consumption of fruit juices has previously been found to affect how some drugs are processed in the body by inhibiting specific drug transporters, which can alter the level of drug available to exert its intended effect. It is thought that green tea may interact with the same drug transporters; however, it is unclear if this affects medications.

Shingen Misaka of Fukashima Medical University in Japan and colleagues studied 10 healthy volunteers, who were instructed to drink either water or green tea for 14 days, and then given a single 30-mg oral dose of nadolol. The group that consumed green tea showed a 76% reduction in plasma concentrations of nadolol, as well as a smaller reduction in blood pressure levels from the baseline.

Experiments in cell culture suggest that a drug transporter in the organic anion transporting polypeptides (OATP) class called OAPT1A2, present in the intestinal epithelium, is at least partially responsible for transporting nadolol into cells, and that specific components in green tea inhibit the transporter from performing this task. Collectively, the findings indicate that green tea ingestion seems to decrease plasma concentrations of nadolol, in part by inhibiting OATP1A2-mediated intestinal absorption of nadolol.

Studies with larger sample sizes are needed to fully understand interactions between green tea and drugs such as nadolol.

SOURCE: Clin Pharmacol Ther, January 13, 2014, doi:10.1038/clpt.2013.241

Infliximab-Induced Pulmonary Complications

Infliximab (Remicade, Janssen), when used to treat severe psoriasis and other autoimmune diseases, is known to carry pulmonary complications, such as an increased risk of infection from tuberculosis (TB). Interstitial lung disease (ILD) has also been reported as a complication of anti–tumor necrosis factor (TNF)–α. Most published reports are about patients with rheumatoid arthritis and pre-existing ILD.

Researchers from Athens, Greece, report on a case of ILD in a patient with psoriasis and no history of pulmonary disease who was treated with infliximab. A 64-year-old man was admitted to the emergency department (ED) after having general malaise, fever, persistent dry cough, and progressive exertional dyspnea for one week. He had had psoriasis a year earlier and had been treated for depression for two years.

Corticosteroids and cyclosporine were prescribed for the psoriasis, but the patient was switched to two weekly intravenous (IV) doses of methotrexate (MTX). The MTX was discontinued because of ineffectiveness, and infliximab was started. Nine days after the last MTX dose, the patient received the first IV infusion of infliximab 5 mg/kg. A second infusion of the same dose was given two weeks later. One week after that, the patient came to the ED and was admitted to the pulmonary clinic.

On admission the patient had a respiratory rate of 36 breaths per minute; arterial blood gas analysis revealed severe hypoxemia and hypocapnia. A chest examination revealed diffuse, inspiratory fine and coarse rales bilaterally. His blood chemistry was significant for increased inflammatory markers, and there were brightly erythematous psoriatic plaques on his trunk, arms, and lower legs.

Based on the recent infliximab treatment, the low-grade fever, and elevated inflammatory markers, broad-spectrum IV antibiotics, bronchodilators, and furosemide were prescribed. However, treatment failed to relieve the patient’s respiratory condition. The results of an extensive microbiology and immunological workup were negative. A second thoracic computed tomography (CT) scan showed that ILD had progressed; bronchoscopy was performed. Because bronchoalveolar lavage and other testing did not show malignant cells, common pathogens, Pneumocystis carinii, fungi, or TB, the clinical team suspected infliximab-induced ILD.

Oral corticosteroids (prednisone 50 mg/day) rapidly improved the patient’s oxygenation, and his symptoms resolved within days. One week later, a chest x-ray showed marked improvement. He was discharged on a tapering dose of prednisone. (In all four reported cases of infliximab-induced ILD in patients with psoriasis, the patients responded well to corticosteroids.)

The symptoms of infliximab-induced ILD usually appear between six weeks and three months after the drug is started and following the third infusion. However, ILD has been reported even one week after anti–TNF-α therapy in other clinical settings, usually after the second or third infusion. In the Greek case, ILD symptoms appeared only three weeks after the first dose. The patient was a smoker, and the authors say undiagnosed lung disease should not be ruled out. Similarly, they say, MTX might have played a role. Pulmonary toxicity attributed to anti–TNF-α inhibitor usually occurs when the treatment coincides with or follows a course of MTX.

Infliximab is a wonder drug for patients with plaque psoriasis and psoriatic arthritis when symptoms do not respond to traditional regimens. However, some patients are at higher risk for ILD, the authors say. Older age, smoking, systemic disease, and concomitant immunosuppressive therapy are all risk factors (their own patient had three of those factors). When subclinical ILD is suspected, they advise a high-resolution chest CT scan and pulmonary function tests before anti-TNF therapy is begun.

Source: Heart & Lung 2013;42:480–482

Envarsus for Kidney Transplants

A new drug application (NDA) has been submitted to the FDA seeking approval for the marketing and sale of once-daily tacrolimus (Envarsus, Veloxis Pharmaceuticals) for the prevention of organ rejection in kidney transplant recipients. The submission was based on data from 25 clinical studies involving more than 1,000 patients, including two pivotal trials.

In the pivotal studies, Envarsus met the primary endpoint of demonstrating comparable efficacy and safety versus twice-daily tacrolimus (Prograf, Astellas Pharma). In the largest study, Envarsus was shown to have a primary efficacy failure rate of 18.3% compared with 19.6% for Prograf.

Envarsus was granted orphan drug status by the FDA for the prophylaxis of rejection in kidney transplant recipients.

Tacrolimus is a leading immunosuppressive drug used for the prevention of transplant allograft rejection after organ transplantation. Envarsus is an investigational drug that is being developed as a once-daily tablet version of tacrolimus. Transplant patients need to maintain a minimum blood level of tacrolimus for the prevention of transplant allograft rejection.

Source: Veloxis Pharmaceuticals, December 30, 2013

Adherence and Overactive Bladder

More than 50% of patients taking an anticholinergic drug for symptoms of overactive bladder syndrome stop taking their medication permanently, at least half of this group stops therapy within the first six months, and two-thirds of patients never start therapy again, according to researchers from Beaumont Hospital, in Royal Oak, Michigan. The investigators analyzed medical, pharmacy, and other data from the IMS LifeLink Health Plan Claims Database from 103,250 patients with overactive bladder.

Anticholinergic drugs included oxybutynin (Oxytrol, Actavis), tolterodine (Detrol, Pfizer), trospium (Sanctura, Allergan), fesoterodine (Toviaz, Pfizer), and solifenacin (Vesicare, Astellas); 42% of patients received tolterodine ER as their index prescription. To be considered a discontinuation, the patient had to have a gap of at least 45 days in therapy, based on fill dates and days’ supply. The corresponding time to treatment failure was estimated as the number of days between the index date and the date of first medication switch or estimated discontinuation date.

Treatment reinitiation was defined as documentation of a filled prescription for any anticholinergic agent after at least 45 days. The researchers used claims data to avoid the problem of self-reported adherence, which tends to be lower because patients often overstate their adherence to medications.

Initial treatment with the index drug failed in nearly all patients (92%). Of those, only 6% switched drugs. More than half had permanently stopped all anticholinergic drugs at 24 months. Moreover, 33% of patients filled only one prescription, suggesting early failure (within the first 30 days).

The proportion of treatment failures was high across all primary diagnoses, ranging from 89% to 97%. Failure rates were also high regardless of the therapy. For instance, 90% of 43,902 patients receiving extended-release (ER) tolterodine and 96% of 2,246 patients receiving the oxybutynin patch did not meet treatment goals. The researchers then took those numbers and pooled outcomes across all drugs to estimate the overall impact of anticholinergic treatment for these patients. The mean time to treatment failure was 159 days.

Many patients (81%) who switched to a different medication over the 24-month study period also had no luck with the second drug. Treatment also failed for 29% who tried a third drug. Treatment failure did not always stop patients from trying, however; about one-third started treatment again after a gap of at least 45 days, and about one-fifth restarted after one year.

In empirical studies of medications that treat chronic conditions, persistence with drugs for overactive bladder has been very low. In fact, when compared with oral antidiabetes drugs, angiotensin-receptor blockers, statins, bisphosphonates, and prostaglandins, these medications were associated with the lowest persistence rates at six months (32%), compared with 72% for the oral antidiabetes drugs.

In studies of overactive bladder, achieving treatment goals is a strong predictor of satisfaction with therapy, and dissatisfaction with treatment outcomes is the most common reason for stopping therapy. Poor adherence to this class of drugs can have a negative impact on quality of life and may increase the risk of sequelae such as urinary tract infections. Thus, when anticholinergic therapy fails, the researchers say, it is important to give patients options such as botulinum toxin A, sacral neuromodulation, and percutaneous tibial nerve stimulation. Despite the potential for better adherence with some anticholinergic drugs, their findings suggest that the benefits of anticholinergic use in overactive bladder are not being realized, and many patients may end up without any drug therapy at all.

Source: Clin Ther 2013;35:1744–1751

Long-Term Effects of Therapy For Menorrhagia

In most studies of women who have been treated for menorrhagia, patients feel the maximum benefits in quality of life (QoL) come in the first five years. However, these studies have not gone beyond 10 years in follow-up. Finnish researchers who re-interviewed study participants 10 years later found that the effects of treatment had indeed peaked in the first five years, whether the treatment was hysterectomy or a levonorgestrel-releasing intrauterine system (LNG–IUS). Any decline in health-related quality of life (HRQoL) thereafter, they say, was probably a result of aging.

In their study, 236 women with menorrhagia referred to five university hospitals in Finland were randomly assigned to treatment with hysterectomy or LNG– IUS. Follow-up visits took place at six and 12 months and at five and 10 years. The women completed questionnaires at each visit, including the 5-Dimensional Euro-Qol (EQ-5D), which measures morbidity, self-care, usual activities, pain, and mood, and the Finnish version of the RAND 36-Item Health Survey (RAND-36). Other scales measured anxiety, depression, and sexuality-related factors.

The baseline EQ-5D and RAND-36 scores of the study participants were significantly lower than the scores of age-matched Finnish women and, in fact, were similar to the scores of women with chronic illness. Treating their menorrhagia boosted HRQoL and psychosocial well-being scores most strongly in the first year. However, between the fifth and 10th years, HRQoL declined by most measures. Sexual functioning was substantially impaired, for instance. Nevertheless, HRQoL scores were still above or at least at the same level as baseline. The key seems to be that at 10 years after the study, most of the women had entered or passed menopause, although follicle-stimulating hormone values were not measured.

Both treatments improved HRQoL. The researchers suggest, however, that when helping a patient decide whether to have a hysterectomy or a LNG–IUS, their findings show that the LNG–IUS costs 31% less.

Source: Am J Obstet Gynecol 2013;209(6):535.e1–535e14 (December)

Can Perinatal Probiotics Prevent Childhood Asthma?

Prenatal probiotics have been shown to help prevent atopic dermatitis, but are they effective in preventing asthma? Unfortunately, it seems not. Researchers from Canada who analyzed data from randomized controlled trials of pregnant women or healthy infants found no evidence to support a protective association between perinatal probiotics and childhood asthma or wheeze.

In nine trials involving 3,257 children, the incidence of doctor-diagnosed asthma at the final assessment was 11.2% among patients who receive probiotics and 10.2% among those receiving placebo. In nine trials involving 1,949 children, incident wheeze was similar after supplementation with probiotics (35%) versus placebo (31%). Two other trials reported an increased risk of recurrent wheeze after probiotics, and a third reported a lower risk.

However, although inadequately reported, the researchers say, probiotics could be associated with clinically relevant increases in lower respiratory tract infections. Six trials involving 1,364 children with lower respiratory tract infections found an incidence of 14.5% among those who received probiotics, compared with 13.2% among those who received placebo. Notably, four of those trials documented lower respiratory tract infections nonsystematically as adverse events rather than primary or secondary outcomes. When those four trials were excluded, the pooled risk ratio of lower respiratory tract infection associated with probiotics was 1.11.

Subgroup analyses revealed that the effect of probiotics was similar regardless of timing—prenatal versus postnatal, or both—or the person receiving the intervention (mother, infant, or both). The researchers noted, however, that the large variety of strains, combinations, and doses tested made it difficult to assess efficacy.

Future research, the authors say, could help identify infants most likely to benefit from probiotics. They cite research that has shown probiotics were protective against immunoglobulin E–associated allergic disease in caesarean-delivered infants (whose gut microbiota is disrupted) but not in their vaginally delivered counterparts. They suggest that probiotics might play a useful role in other microbiota-disrupting exposures, such as formula feeding and antibiotic treatment. So far, however, the evidence is insufficient to support recommending perinatal probiotics for primary prevention of asthma or childhood wheeze.

Source: BMJ 2013;347

New Test for ‘Superbugs’

BD Diagnostics has received FDA clearance to market the BD MAX MRSA XT assay for use on the BD MAX system. This is the second assay from the company that can detect newly emerging strains of methicillin-resistant Staphylococcus aureus (MRSA) with the mecC gene.

Launched in 2013, the BD MAX StaphSR assay reports results for both S. aureus (SA) and MRSA and was the first commercially available assay in the U.S. to detect mecC strains of MRSA. Both assays can identify a broad range of SA strains, including mecA and mecC dropout mutants, and new strains of MRSA.

MRSA strains with the newly emerging mecC gene account for nearly 3% of all new MRSA cases in some communities but cannot be detected by all assays.

Molecular assays for MRSA are used in active surveillance programs to quickly identify colonized patients. Inaccurate detection may contribute to uncontrolled transmission of MRSA and to inappropriate use of health care resources.

Source: BD Diagnostics, January 13, 2014

Inappropriate ER Antibiotic Use

An analysis of emergency room visits over a 10-year period finds that while inappropriate antibiotic use is decreasing in pediatric settings, it continues to remain a problem in adults, according to an article in Antimicrobial Agents and Chemotherapy.

In the study, the investigators analyzed data from the National Hospital Ambulatory Medical Care Survey for the years 2001–2010. During this period, acute respiratory tract infections accounted for 126 million visits to emergency departments in the U.S. In patients under the age of 19 years, the investigators found a decrease in the use of antibiotics for respiratory infections where they were not indicated. They saw no such reduction in adult patients.

“The observed lack of change in antibiotic utilization for adult acute respiratory tract infection patients, especially those with infections where antibiotics are not indicated, is concerning,” the investigators write in the study. “This may indicate that efforts to curtail inappropriate antibiotic use have not been effective or have not yet been implemented for this subset of patients.”

Complicating the picture, the investigators suggest that the lack of reduction in the use of antibiotics in these cases may reflect, among other things, the difficulty of making definitive diagnoses, and the fact that patients often expect to receive antibiotics and pressure clinicians for them.

Source: American Society for Microbiology, January 9, 2014

Drug Shortages Continue To Affect Patient Care

According to a new survey of pharmacy directors, drug shortages remain a serious problem for patient safety. Nearly half of the responding directors reported adverse events at their facilities due to drug shortages, including patient deaths.

The survey was conducted to better understand how drug shortages affect patient outcomes. The survey asked pharmacy directors from a variety of health care settings to supply information on drug-shortage-related patient complaints, adverse events, medication errors, patient outcomes, demographics, and institutional costs. The survey’s findings were published in the November/December 2013 issue of the Journal of Managed Care Pharmacy.

In general, drug shortages have been known to cause or to contribute to a variety of issues that were represented in the survey responses, including medication errors, increased institutional costs, cancelled care, and delayed treatment.

In addition to the more well-known effects, the survey revealed that nearly 10% of the reported adverse patient outcomes were increased readmissions due to drug-shortage-related treatment failures. Thirty-eight percent of the surveyed pharmacy directors also said their organizations had received at least one patient complaint related to shortages. Of those respondents reporting the actual number of patient complaints, about 20% reported a total of more than 10 complaints.

The authors suggest that the documented occurrence of increased readmission rates and the impact of drug-shortage-related patient complaints could affect health care reimbursements for providers in the future as part of the Patient Protection and Affordable Care Act.

Source: Northwestern Memorial Hospital, January 9, 2014

FDA Lifts Hold on Tosedostat Studies

Cell Therapeutics has announced that it has received notification from the FDA that the partial clinical hold on tosedostat (IND 075503) has been removed and that all studies underway may continue.

The FDA placed the hold after a patient treated with a combination of tosedostat and a chemotherapy drug died of a heart-muscle infection. The agency requested more information on all heart-related events in patients treated with tosedostat.

Tosedostat is a first-in-class selective inhibitor of aminopeptidases, which are required by tumor cells to provide amino acids necessary for growth and tumor cell survival. The drug is under development for the treatment of blood-related cancers. It is being studied in the U.S. and Europe in phase 2 trials in elderly patients with newly diagnosed and relapsed acute myeloid leukemia (AML) or with high-risk myelodysplastic syndrome (MDS).

Sources: Cell Therapeutics, January 2, 2014; and Reuters; January 2, 2014.

Artificial Bone Marrow

Scientists in Germany have developed a prototype of artificial bone marrow. According to their report, published in Biomaterials, the synthetic porous structure possesses the essential properties of natural bone marrow and can be used for the reproduction of hematopoietic stem cells in the laboratory, which might facilitate the treatment of leukemia in the future.

With the help of synthetic polymers, the scientists created a porous structure simulating the sponge-like structure of the bone in the area of blood-forming bone marrow. They also added protein building blocks, similar to those in the matrix of bone marrow, on which blood cells can anchor.

Then the researchers introduced hematopoietic stem cells isolated from cord blood into the artificial bone marrow. After several days, they found that the cells could reproduce in their new environment. Compared with standard cell-cultivation methods, more stem cells retained their specific properties in the artificial bone marrow.

The newly developed artificial marrow, which possesses the major properties of natural bone marrow, can be used by scientists to study the interactions between synthetic materials and stem cells in the laboratory, the researchers say. This will help to determine how the behavior of stem cells can be influenced and controlled by these materials. In turn, this knowledge might lead to the creation of an artificial stem-cell “niche” for the reproduction of stem cells and the treatment of leukemia in 10 to 15 years.

Source: Karlsruhe Institute of Technology, January 10, 2014.



Gel to seal corneal incisions

The FDA has approved ReSure Sealant (Ocular Therapeutix), the first gel sealant for use in stopping fluid from leaking through the incision in a patient’s cornea after cataract surgery with intraocular lens placement in adults. Previously, stitches were the only option for closing a leaking corneal incision after cataract surgery.

During cataract surgery, the surgeon makes a small incision in the cornea through which the patient’s natural lens is removed and the artificial lens is inserted. In many cases the incision is small and self-sealing after the artificial lens is in place. However, if fluid leaks from the incision, the surgeon may need to close the wound.

The ReSure Sealant kit comes as two liquid solutions that the surgeon mixes together just prior to sealing the incision. Using a foam-tipped applicator provided in the kit, the surgeon applies the mixture directly to the incision. Within 20 seconds of applying the liquid to eye tissue, a gel forms that adheres to the eye and seals the incision. The gel gradually breaks down over the course of seven days and is cleared from the body by the eye’s natural tears.

The FDA reviewed several non-clinical and clinical studies, including a randomized clinical study of 471 adult subjects who underwent cataract surgery and experienced leakage from their incision at the time of operation. Of the 471 study participants, 295 received the ReSure sealant to stop leakage and 176 received a suture. The study showed that ReSure was more effective than use of a single suture in preventing incision leakage in the first seven days following cataract surgery. ReSure subjects and suture subjects reported similar rates of eye pain and the sensation of having something in the eye. There were no significant differences in the occurrence of corneal swelling, inflammation, or wound healing among ReSure sealant subjects and suture subjects. Researchers did not report any serious device-related adverse events. One study participant who received ReSure Sealant required sutures to seal a postoperative incision leak.

The device is approved for use in cataract surgeries on patients with clear corneas. The device was not studied on patients with clouded corneas. Ocular Therapeutix will perform a post-approval study evaluating at least 4,857 patients undergoing clear corneal cataract surgery to gather further information on the incidence of adverse events associated with ReSure Sealant.

Source: FDA, January 9, 2014


Marvin M. Goldenberg, PhD, RPH, MS

Name: Harmonic Focus+ Shears with Adaptive Tissue Technology

Manufacturer: Ethicon Endo-Surgery, Inc. (Ethicon), Cincinnati, Ohio

Approval Date: November 12, 2013

Purpose: The Harmonic Focus+ is an ultrasonic device used in open surgical procedures. It is designed for use in general procedures and specialties, including ear, nose, and throat surgery.

Description: The shears are used in transecting, sealing, grasping, and dissection. The lateral thermal spread is 2 mm or less.

Benefit: A slim profile is designed to increase speed and visibility as well as improved dissection. These advantages are accompanied by an easy-to-use ergonomic design that feels like a traditional surgical instrument.


Name: Spectral Breast Density Measurement Application

Manufacturer: Royal Philips, Andover, Mass.

Approval Date: December 19, 2013

Purpose: The device is used with mammography to measure the amount of fibroglandular tissue over the whole breast to determine density. The application is the first spectral breast density measurement tool.

Description: The application is used to determine the glandularity and thickness in each pixel of the image and calculates the total volume and percentage of glandular tissue in the breast. After the calculations are completed, the examination is automatically assigned a MicroDose density score that correlates to the Breast Imaging-Reporting and Data System (BI-RADS), the manual method for determining breast density. The measurement is displayed on the review workstation and is displayed in a structured report.

This first application of non-contrast spectral imaging is made possible by the photon counting technology, which sorts photons into low-energy or high-energy categories, eliminating the need for two exposures. This enables the use of spectral imaging within the routine mammogram.

Benefit: Nearly 50% of women have dense breast tissue, which is a known risk factor for breast cancer. Until now, however, the most frequently used method to determine breast density has been a visual analysis of an image of the breast. This methodology is highly subjective, and several radiologists might allocate a different breast density score for the same image. Rather than estimating density, the new device, obtained during a standard, low-dose MicroDose SI mammogram, allows breast density to be measured objectively.


Name: Axios Stent and Delivery System

Manufacturer: Xlumena, Inc., Mountain View, Calif.

Approval Date: December 23, 2013

Purpose: The stent and delivery system is used to treat pseudocysts that form in the pancreas. This is the first stent designed for drainage of a pancreatic pseudocyst by creating a temporary opening between the pancreas and the gastrointestinal tract.

Pancreatic ducts sometimes become blocked from gallstones or pancreatic injury. This causes the enzymes that normally drain into the small intestine to be released directly into the pancreas, which can cause a pseudocyst to form. Most pseudocysts are small and resolve on their own, but some pseudocysts can become as large as 7 cm (and more than 50 cm wide). They can also become infected with bacteria. Infected pseudocysts are almost always painful and may lead to serious blood infections that can be life-threatening.

Description: The stent and delivery system consists of the catheter-based delivery system and an implantable stent. The stent has two large flanges to hold the tissue layers together and a large diameter for effective drainage. It is fully covered to prevent leakage and to enable removal. The stent creates a translumenal conduit between the wall of the gastrointestinal tract (e.g., stomach or duodenum) and a neighboring fluid-filled cavity.

The Axios Stent is a wire mesh tube with a silicone covering. The stent is tightly compressed and is enclosed within a catheter. The catheter, with the Axios stent, is placed into the stomach through an endoscope that is passed through the patient’s mouth and down into an area of the stomach adjacent to the pseudocyst. After creating a small opening in the wall of the stomach and a small opening in the pseudocyst, the surgeon positions the still-compressed stent across both openings, releases the stent, and removes the delivery system. When the stent is expanded, it allows the contents of the pseudocyst to drain into the stomach. After the pseudocyst has been drained and is smaller, the physician can use standard endoscopic tools to remove the stent.

Benefit: The stent can expand to a diameter exceeding 0.5 inch. Compared with the narrower, plastic stents that are currently on the market, the Axios Stent may be less prone to becoming blocked by solid material inside of the pseudocyst because of its wider diameter. The wider diameter also allows physicians to pass endoscopic tools into the pseudocyst to clean or remove the contents of both the stent and the pseudocyst.

Pancreatic stents currently on the market are placed through the pancreas’ existing ducts, but this does not always provide adequate drainage of a pseudocyst. The Axios Stent provides a less invasive method of treating pseudocysts compared with surgical removal of the pseudocyst.