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P T. 2015;40(10): 622-623, 628-633, 645-648, 696-697

New Drugs/Drug News/New Medical Devices October 2015


Repatha for High Cholesterol

The FDA has approved evolocumab injection (Repatha, Amgen) for some patients who are unable to control their low-density lipoprotein-cholesterol (LDL-C) with current treatment options.

Evolocumab, the second approved pro-protein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, is indicated for use in addition to diet and maximally tolerated statin therapy in adults with heterozygous familial hypercholesterolemia (HeFH), homozygous familial hypercholesterolemia (HoFH), or clinical atherosclerotic cardiovascular disease (ASCVD), such as heart attacks or strokes, who require additional lowering of LDL-C.

The antibody evolocumab targets the PCSK9 protein, which reduces the number of receptors on the liver that remove LDL-C from the blood. Blocking the action of PCSK9 makes more receptors available to rid the blood of LDL-C.

In phase 3 trials, adding evolocumab to lipid-lowering therapy that included statins resulted in intensive reductions in LDL-C levels with favorable effects on other lipid parameters. In patients with clinical ASCVD or HeFH, evolocumab reduced LDL-C by approximately 54% to 77% compared with placebo. In a pivotal phase 3 trial, 90% of clinical ASCVD patients who received evolocumab in addition to maximum doses of statins achieved a LDL-C level of less than 70 mg/dL. In patients with HoFH, evolocumab reduced LDL-C by approximately 30% compared with placebo.

The most common adverse events associated with evolocumab included nasopharyngitis, upper respiratory tract infection, flu, back pain, and injection-site reactions, such as redness, pain, or bruising. Allergic reactions, such as rash and hives, have also been reported.

Repatha is available as a single-use, 140-mg prefilled autoinjector or syringe that patients can self-administer at the recommended adult dose of 140 mg every two weeks or 420 mg once a month. For adults with HoFH, the recommended dosage is 420 mg once a month. The U.S. wholesale acquisition cost of the 140-mg dose is $542, or $14,100 annually for administration every two weeks, but discounts or rebates are expected to lower this price.

Sources: FDA and Amgen, August 27, 2015

Lonsurf for Colorectal Cancer

The FDA has approved trifluridine/tipiracil (Lonsurf, Taiho Oncology), formerly known as TAS-102, for the treatment of metastatic colorectal cancer (mCRC). The drug is indicated for patients who have previously been treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, a biological therapy targeting vascular endothelial growth factor, and (if RAS wild-type) a therapy targeting epidermal growth factor receptor.

The FDA approval is based on results from the global phase 3 RECOURSE trial in 800 patients who had previously been treated for mCRC. Trifluridine/tipiracil provided a statistically significant improvement in overall survival (OS) compared with placebo (hazard ratio, 0.68). Median OS was 7.1 months and 5.3 months for trifluridine/tipiracil and placebo, respectively.

Trifluridine/tipiracil caused severe and life-threatening myelosuppression (grade 3–4) consisting of anemia, neutropenia, thrombocytopenia, and febrile neutropenia. One patient died due to neutropenic infection. Complete blood counts should be obtained prior to and on day 15 of each cycle of trifluridine/tipiracil and more frequently as clinically indicated.

The most common adverse drug reactions or laboratory abnormalities were anemia, neutropenia, asthenia/fatigue, nausea, thrombocytopenia, decreased appetite, diarrhea, vomiting, abdominal pain, and pyrexia. The most common adverse reactions leading to dose reduction were neutropenia, anemia, febrile neutropenia, fatigue, and diarrhea.

Lonsurf was approved in March 2014 in Japan, where it is indicated to treat unresect able advanced or recurrent colorectal cancer. Taiho Oncology is a subsidiary of Taiho Pharmaceutical (Japan).

Source: Taiho Oncology, September 22, 2015

Vraylar for Schizophrenia And Bipolar I Disorder

Cariprazine (Vraylar, Allergan/Gedeon Richter), a second-generation antipsychotic, has received FDA approval for the acute treatment of manic or mixed episodes associated with bipolar I disorder and for the treatment of schizophrenia in adults.

The FDA approval of cariprazine capsules is based on the results of three three-week controlled trials in adults with manic or mixed episodes of bipolar I disorder and three six-week placebo-controlled trials in adults with schizophrenia In these trials, which involved more than 2,700 adults, cariprazine demonstrated improvement compared with placebo as measured by total scores on the Young Mania Rating Scale in patients with bipolar mania and by total scores on the Positive and Negative Syndrome Scale in patients with schizophrenia. Cariprazine also demonstrated efficacy as measured by the Clinical Global Impressions–Severity rating scale.

The most commonly reported adverse reactions associated with the drug in bipolar mania were extrapyramidal symptoms, akathisia, dyspepsia, vomiting, somnolence, and restlessness, while those in schizophrenia were extrapyramidal symptoms and akathisia.

Source: Allergan, September 17, 2015

Nuwiq for Hemophilia A

The FDA has approved intravenous antihemophilic factor, recombinant (Nuwiq, Octapharma) for adults and children with hemophilia A. The approval includes on-demand treatment and control of bleeding episodes; routine prophylaxis to reduce the frequency of bleeding episodes; and perioperative management of bleeding.

Nuwiq is the first B-domain deleted recombinant factor VIII (FVIII) derived from a human cell-line, not chemically modified or fused with another protein, designed for the treatment of patients with hemophilia A.

In tests with a one-stage clotting assay, Nuwiq demonstrated a mean half-life of 17.1 hours in adults, 11.9 hours in children ages 2 to 5, and 13.1 hours in children ages 6 to 12—longer than earlier generations of recombinant FVIII products available in the U.S. Its efficacy and tolerability were evaluated in three prospective, open-label studies involving 135 previously treated patients with severe hemophilia A: 74 adults, three adolescents, and 58 children. They received 16,134 infusions over 15,950 exposure days.

Nuwiq’s prophylactic efficacy for spontaneous bleeds was rated as excellent or good in 92% of patients in a study of 32 adults and in 97% of patients in a study of 59 children. The mean annualized bleeding rates (ABRs) for spontaneous bleeds during prophylaxis were approximately 1.5 in children and 1.2 in adults. For hemophilia A patients receiving Nuwiq prophylaxis compared with on-demand treatment, the ABR was reduced 96% for adults and 93% for children.

Treatment of breakthrough bleeds during Nuwiq prophylaxis was rated as excellent or good for 100% of bleeds in adults and 82% of bleeds in children. For on-demand treatment of bleeds in 22 patients, Nuwiq’s efficacy was excellent or good in 931 of 986 bleeds (94%). Overall efficacy in surgical prophylaxis was rated excellent or good in 32 of 33 procedures (97%) using Nuwiq.

A total of seven adverse events were reported in all clinical studies. Parathesia, headache, injection-site inflammation, injection-site pain, back pain, vertigo, and dry mouth each occurred once—a rate of 0.7% across 135 patients.

Source: Octapharma, September 14, 2015

Varubi for Nausea, Vomiting Related to Chemotherapy

Rolapitant (Varubi, Tesaro, Inc.) has secured FDA approval in combination with other antiemetic agents in adults for the prevention of delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including highly emetogenic chemotherapy (HEC).

Rolapitant is a selective, competitive antagonist of human substance P/neurokinin 1 receptors, with a plasma half-life of approximately seven days. In three phase 3 trials, it significantly reduced episodes of vomiting or the use of rescue medication during the 25 to 120 hours following the administration of moderately emetogenic chemotherapy (MEC) or HEC. Patients who received rolapitant reported experiencing less nausea that interfered with normal daily life and fewer episodes of vomiting or retching during multiple cycles of chemotherapy.

A 180-mg dose of rolapitant is given approximately one to two hours before the administration of chemotherapy in combination with a 5-HT3 receptor antagonist and dexamethasone. No dosage adjustment is required for dexamethasone when administering rolapitant.

The efficacy of rolapitant was established in randomized, controlled, blinded clinical studies that enrolled more than 2,500 patients. Rolapitant, when administered in combination with a 5-HT3 receptor antagonist and dexamethasone, was superior to a 5-HT3 receptor antagonist and dexamethasone in preventing chemotherapy-induced nausea and vomiting (CINV) in patients receiving MEC or HEC.

Two identical phase 3 studies (HEC1 and HEC2) in patients receiving cisplatin-based HEC compared rolapitant 180 mg with active control (a 5-HT3 receptor antagonist plus dexamethasone) in the delayed phase of CINV (25 to 120 hours after chemotherapy). The proportions of patients achieving a complete response (CR) with rolapitant versus active control were 73% and 58%, respectively, in HEC1, and 70% and 62%, respectively, in HEC2. The most common adverse events included neutropenia, hiccups, and abdominal pain.

Another phase 3 study compared rolapitant (180 mg) with active control (5-HT3 receptor antagonist plus dexamethasone) in patients receiving MEC or HEC regimens, including anthracycline/cyclophosphamide combinations, carboplatin, irinotecan, pemetrexed, oxaliplatin, and doxorubicin. In the delayed phase of CINV, the proportions of patients achieving a CR were 71% for rolapitant versus 62% for active control. The most common adverse events included decreased appetite, neutropenia, dizziness, dyspepsia, urinary tract infection, stomatitis, and anemia.

Source: Tesaro, Inc., September 2, 2015

Synjardy for Type-2 Diabetes

A tablet combining empagliflozin and metformin hydrochloride (Synjardy, Boehringer Ingelheim/Eli Lilly) has received FDA approval to treat adults with type-2 diabetes (T2D).

Empagliflozin, a sodium-glucose cotransporter 2 inhibitor, removes excess glucose through the urine by blocking glucose reabsorption in the kidney. Metformin lowers glucose production by the liver and its absorption in the intestine.

Synjardy is indicated as an adjunct to diet and exercise to improve glycemic control in adults with T2D who are not adequately controlled on a regimen containing empagliflozin or metformin, or in patients already being treated with empagliflozin and metformin. The treatment is not intended for patients with type-1 diabetes or diabetic ketoacidosis. The labeling includes a boxed warning regarding the risk of lactic acidosis, which can occur as a result of the accumulation of metformin.

The FDA’s approval was based on results from multiple clinical trials that examined the coadministration of empagliflozin and metformin, alone or in combination with sulfonylurea, in adults with T2D.

Source: Eli Lilly, August 27, 2015

Xuriden for Hereditary Orotic Aciduria

Uridine triacetate (Xuriden, Wellstat Therapeutics Corporation) has become the first FDA-approved treatment for patients with hereditary orotic aciduria, a very rare metabolic disorder in which patients cannot normally synthesize uridine, a necessary component of ribonucleic acid.

Uridine triacetate is administered orally once daily to replace uridine. Its granules can be mixed with food or in milk or infant formula. Xuriden received FDA orphan drug and priority review status.

The safety and effectiveness of uridine triacetate were evaluated in a single-arm, six-week, open-label trial in four patients ranging from 3 to 19 years of age with hereditary orotic aciduria, and in a six-month extension phase of the trial. The study assessed changes in prespecified hematologic parameters. At both the six-week and six-month assessments, uridine triacetate treatment resulted in stability of the hematologic parameters in all four patients. The safety and effectiveness of uridine replacement therapy were further supported by case reports from the published literature.

Source: FDA, September 4, 2015

Generic Approvals

Paliperidone Extended-Release Tablets

The FDA has approved the application of Actavis Laboratories, Inc., to market paliperidone extended-release (ER) tablets in 1.5 mg, 3 mg, 6 mg, and 9 mg strengths. This is the first generic version of Invega ER tablets (Janssen), a second-generation antipsychotic agent indicated for the treatment of schizophrenia and for the treatment of schizoaffective disorder as monotherapy and as an adjunct to mood stabilizers, antidepressants, or both.

Sources: FDA, August 3, 2015, and Invega ER prescribing information

Testosterone Topical Gel 1.62%,

Perrigo Israel Pharmaceuticals Ltd. has received FDA approval to market testosterone topical gel 1.62%, the first generic version of AndroGel (AbbVie). AndroGel 1.62% is indicated for replacement therapy in males for conditions associated with a deficiency or absence of endogenous testosterone, including primary hypogonadism (congenital or acquired) and hypogonadotropic hypogonadism (congenital or acquired).

Sources: FDA, August 4, 2015, and AndroGel 1.62% prescribing information

Testosterone Topical Gel, 10 mg

Testosterone topical gel, 10 mg per pump actuation, can now be marketed by Actavis Laboratories UT, Inc., the FDA has decided. This is the first generic version of Fortesta Gel (Endo Pharmaceuticals). Fortesta is an androgen indicated for replacement therapy in males for conditions associated with a deficiency or absence of endogenous testosterone resulting from primary hypogonadism (congenital or acquired) or from hypogonadotropic hypogonadism (congenital or acquired).

Sources: FDA, August 5, 2015, and Fortesta prescribing information

Tretinoin Gel, 0.05%,

The FDA has approved the marketing of tretinoin gel USP, 0.05%, by Spear Pharmaceuticals — the first generic formulation of Atralin Gel (Dow Pharmaceuticals), a retinoid indicated for topical treatment of acne vulgaris.

Sources: FDA, August 13, 2015, and Atralin Gel prescribing information


Brilinta for Longer Use

The FDA has approved a new 60-mg, twice-daily dosage of ticagrelor (Brilinta, AstraZeneca) for patients with a history of heart attack beyond the first year. With this expanded indication, ticagrelor is now approved to reduce the rate of cardiovascular death, myocardial infarction (MI), and stroke in patients with acute coronary syndrome (ACS) or a history of MI.

Ticagrelor, an oral antiplatelet treatment that works by inhibiting platelet activation, was approved by the FDA in July 2011. It is the only oral antiplatelet agent to demonstrate superior reductions in cardiovascular death compared with clopidogrel (Plavix, Sanofi Aventis). Ticagrelor also reduces the rate of stent thrombosis in patients who have received stents for the treatment of ACS.

In the management of ACS, the recommended maintenance dosage of Brilinta is 90 mg twice daily during the first year after an ACS event. After one year, patients with a history of heart attack can now be treated with 60 mg twice daily. Ticagrelor should be used with a daily maintenance dose of aspirin of 75 to 100 mg.

The expanded indication for ticagrelor was approved under an FDA priority review based on the PEGASUS TIMI-54 study, an outcomes trial involving more than 21,000 patients. The study investigated ticagrelor tablets plus low-dose aspirin, compared with placebo plus low-dose aspirin, for the long-term prevention of cardiovascular death, heart attack, and stroke in patients who had experienced a heart attack one to three years before study enrollment.

Source: AstraZeneca, September 3, 2015

Spiriva Respimat for Asthma

Tiotropium (Spiriva Respimat, Boehringer Ingelheim) has won FDA approval for the long-term, once-daily maintenance treatment of asthma in patients 12 years of age and older.

Pivotal, phase 3 study results showed that tiotropium as an add-on treatment to combined inhaled corticosteroid/long-acting beta agonist maintenance therapy improves asthma symptoms. Tiotropium patients were 68% more likely to improve asthma control, and the number of patients having a severe asthma exacerbation was reduced by 21%.

Spiriva Respimat was previously approved in the United States for the maintenance treatment of chronic obstructive pulmonary disease (COPD) at a once-daily dose of 5 mcg (delivered in two puffs of 2.5 mcg each). For asthma maintenance, the FDA approved a once-daily dose of 2.5 mcg (delivered in two puffs of 1.25 mcg each). Spiriva Respimat is not a treatment for the sudden symptoms of asthma or COPD.

Sources: Boehringer Ingelheim and Medscape, September 16, 2015

Humira for Hidradenitis Suppurativa

The FDA has approved adalimumab (Humira, AbbVie) for the treatment of moderate-to-severe hidradenitis suppurativa (HS), making it the first FDA-approved therapy for adults with this disease.

HS is a chronic inflammatory skin disease characterized by inflamed, painful lesions typically located around the armpits and groin, on the buttocks, and under the breasts. The FDA had granted adalimumab an orphan drug designation for this indication.

This FDA approval of Humira’s ninth indication in the U.S. is based on the results of two pivotal phase 3 studies, PIONEER I and PIONEER II, which included 633 people with moderate-to-severe HS. Patients were randomly assigned to receive either adalimumab or placebo in addition to daily use of topical antiseptic. Both studies showed that more patients given adalimumab had reductions in the total number of abscesses and inflammatory nodules compared with patients given placebo. No new safety risks were identified in these trials.

Source: AbbVie, September 10, 2015

Aptiom as Monotherapy for Partial-Onset Seizures

Eslicarbazepine acetate (Aptiom, Sunovion Pharmaceuticals) has won FDA approval as monotherapy for the treatment of partial-onset seizures in people initiating treatment for the first time or converting from other antiepileptic drugs (AEDs).

Approved in 2013 as adjunctive therapy for partial-onset seizures, eslicarbazepine is the only once-daily non–extended-release AED that can be used alone or in combination with other AEDs in the treatment of partial-onset seizures.

The new approval was supported by data from two identically designed phase 3, dose-blinded, historical-controlled, randomized clinical trials. Both evaluated the safety and efficacy of eslicarbazepine (1,600 mg or 1,200 mg per day) as monotherapy for partial-onset seizures in patients 16 years of age or older whose seizures were not well controlled with other AEDs.

The primary endpoint for both trials was the percentage of patients who withdrew from the studies because of predefined criteria that identified worsening seizure control compared with historical controls from previous, similarly designed trials of epilepsy patients converting to AED monotherapy. The conversion to eslicarbazepine monotherapy was associated with exit rates superior to those of historical controls in patients with partial-onset seizures who were not well controlled by one or two current AEDs.

Eslicarbazepine administered once daily was generally well tolerated in both dose strengths. The most common treatment-related adverse events in the two trials included headache, dizziness, fatigue, somnolence, and nausea.

Source: Sunovion Pharmaceuticals, August 28, 2015

Promacta for Young Children

The FDA has approved eltrombopag (Promacta, Novartis) to treat low platelet counts in patients 1 year of age and older with chronic immune thrombocytopenic purpura (ITP) who have not achieved an appropriate response using other ITP medications or splenectomy.

ITP results in an abnormally low number of platelets; eltrombopag helps increase platelet production. It is available as a tablet taken once daily or as a powder that is mixed with liquid for children 1 to 5 years of age to take orally. It was approved in 2008 to treat adults with ITP.

Eltrombopag, which was designated an orphan drug for this indication, should be used only in ITP patients whose degree of thrombocytopenia and clinical condition increase the risk for bleeding.

Eltrombopag’s efficacy and safety in patients 1 to 17 years of age with chronic ITP were evaluated in two double-blind, placebo-controlled studies involving 159 participants. In a seven-week study, 62% of patients treated with eltrombopag showed an improvement in platelet counts without rescue therapy between weeks 1 and 6, compared with 32% of the placebo group. In a 13-week study, 41% of patients treated with eltrombopag experienced increased platelet counts for at least six out of eight weeks between weeks 5 and 12, compared with 3% of patients receiving placebo.

In both trials, patients using eltrombopag also had less need for other therapies to increase their platelet counts, such as corticosteroids or platelet transfusions. Among patients taking one or more ITP medications at the start of the trials, about half were able to reduce or discontinue their use of these medications, primarily corticosteroids.

The most common adverse effects of eltrombopag treatment in children included infections of the upper respiratory tract or nose and throat (with symptoms that included fever, cough, nasal congestion, runny nose, and sore throat), diarrhea, abdominal pain, rash, and an increase in liver enzymes.

Eltrombopag’s safety and efficacy have not been established in patients younger than 1 year of age with ITP, or in pediatric patients with thrombocytopenia associated with chronic hepatitis C and severe aplastic anemia.

Source: FDA, August 24, 2015

Adcetris for Hodgkin Lymphoma

The FDA has approved brentuximab vedotin (Adcetris, Seattle Genetics, Inc.) for the treatment of patients with classical Hodgkin lymphoma (HL) at high risk of relapse or progression as post-autologous hematopoietic stem-cell transplantation (auto-HSCT) consolidation.

The approval was based on the phase 3 AETHERA trial, which was designed to evaluate up to 16 cycles (approximately one year) of brentuximab therapy administered every three weeks after auto-HSCT in comparison with placebo. Median progression-free survival (PFS) improved significantly among patients who were given brentuximab compared with those given placebo—42.9 months versus 24.1 months. In addition, data from the AETHERA trial converted the FDA’s accelerated approval of the relapsed classical HL indication to regular approval.

Brentuximab vedotin is an antibody–drug conjugate directed to CD30, which is expressed in classical HL and in systemic anaplastic large-cell lymphoma (sALCL), as well as in other lymphoma subtypes.

Brentuximab was granted accelerated approval in August 2011 for two other indications: 1) treatment of HL patients who fail autologous transplant or who fail at least two prior multiagent chemotherapy regimens and are not autologous transplant candidates, and 2) treatment of sALCL patients who fail at least one prior multiagent chemotherapy regimen.

In the AETHERA trial, the most common adverse events in the brentuximab arm included neutropenia, peripheral sensory neuropathy, thrombocytopenia, anemia, upper respiratory tract infection, fatigue, peripheral motor neuropathy, nausea, cough, and diarrhea.

Source: Seattle Genetics, August 17, 2015

OxyContin for Children

The FDA has approved the use of the opioid painkiller oxycodone (OxyContin, Purdue Pharma) in children 11 to 16 years of age who have not benefited from alternative therapies. The long-acting drug, previously approved for adults with around-the-clock pain, has been reformulated over the years to combat rising prescription drug abuse.

Doctors are to prescribe the painkiller only for children who can already tolerate a minimum dose of 20 mg of oxycodone. The warnings and precautions for pediatric patients are the same as those for adults. Purdue Pharma, which had been asked by the FDA to evaluate the drug’s use in children, will also conduct post-marketing studies.

Source: Reuters, August 14, 2015


Durlaza ER Aspirin

The FDA has approved extended-release aspirin capsules (Durlaza, New Haven Pharmaceuticals, Inc.) for the secondary prevention of stroke and acute cardiac events, including myocardial infarction.

The aspirin delivery technology in the 162.5-mg Durlaza capsules extends the release of aspirin to provide a stable anti-platelet effect over the course of the day. Low-dose aspirin has been proven to reduce the risk of secondary cardiovascular events and mortality in high-risk patients with stable cardiovascular disease. This is primarily due to aspirin’s ability to inhibit platelet aggregation. Immediate-release traditional aspirin only stays in the blood for a mean duration of about four to six hours.

Source: New Haven Pharmaceuticals, Inc., September 8, 2015


Breakthrough Therapy

Lenvima for Metastatic Renal Cancer

The FDA has granted breakthrough therapy status to the multiple-receptor tyrosine kinase inhibitor lenvatinib (Lenvima, Eisai Inc.) for investigational use in patients with advanced or metastatic renal-cell carcinoma (RCC) who previously received therapy targeting vascular endothelial growth factor (VEGF). Lenvatinib is currently indicated to treat locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer.

The breakthrough therapy designation was based on results from a phase 2, open-label study of 153 patients who were previously treated with a VEGF-targeted therapy. Patients were randomly assigned to receive lenvatinib and everolimus (LEN/EVE, 18 mg/5 mg once a day), lenvatinib alone (LEN, 24 mg once a day), or everolimus (EVE, 10 mg once a day). Nearly all patients (99%) had received one VEGF-targeted therapy; 1% had received two VEGF-targeted therapies; and 18% had received immunotherapy.

LEN/EVE prolonged median progression-free survival (PFS) compared with EVE (14.6 months versus 5.5 months, respectively). LEN alone also prolonged median PFS compared with EVE (7.4 months versus 5.5 months, respectively). LEN/EVE and LEN alone both improved the overall response rate compared with EVE (25.5% and 18.4% versus 17.5%, respectively). The median duration of response was longest with LEN/EVE (13.1 months) compared with LEN (7.5 months) and EVE (8.5 months).

Lenvatinib inhibits the kinase activities of VEGF receptors 1, 2, and 3. Lenvatinib also inhibits other receptor tyrosine kinases that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions.

Sources: Eisai Inc., July 28, 2015, and American Society of Clinical Oncology, 2015

ACE910 for Hemophilia

The FDA has granted breakthrough therapy status to ACE910 (Roche) for the prophylactic treatment of patients 12 years of age and older with hemophilia A with factor VIII inhibitors.

ACE910 is an investigational humanized bispecific monoclonal antibody engineered to simultaneously bind factors IXa and X. As a result, ACE910 mimics the cofactor function of factor VIII and is designed to promote blood coagulation in hemophilia A patients, regardless of whether they have developed inhibitors to factor VIII. The product is administered subcutaneously once weekly, and since its structure is distinct from that of factor VIII, it is not expected to lead to the formation of inhibitors against factor VIII.

In a phase 1 study, ACE910 showed promising results as a prophylactic treatment administered weekly in subjects with severe hemophilia A with and without inhibitors to factor VIII. The development of inhibitors is a serious complication of hemophilia A treatment regardless of disease severity, making it difficult, if not impossible, to achieve a level of factor VIII sufficient to control bleeding with traditional replacement therapies.

Roche is preparing to initiate a phase 3 trial of ACE910 in patients with hemophilia A with factor VIII inhibitors by the end of 2015, and a phase III trial in patients without inhibitors in 2016. A study in pediatric patients with hemophilia A is also to start in 2016.

Source: Roche, September 4, 2015

Priority Review

Daratumumab for Multiple Myeloma

The FDA has accepted the application for daratumumab (Janssen) with priority review as a treatment for patients with multiple myeloma who are refractory to both a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), or who have received three or more prior lines of therapy, including a PI and an IMiD. This so-called “double refractory” multiple myeloma occurs when a patient’s disease has become resistant to at least two of the most commonly utilized and active classes of antimyeloma agents.

Daratumumab previously received a breakthrough therapy designation for this use. The FDA has assigned a Prescription Drug User Fee Act target date of March 9, 2016, to act on the application.

The regulatory submission is supported by data from the phase 2 MMY2002 (SIRIUS) monotherapy study and by additional data from four other studies. In 2012, Janssen Biotech, Inc., and Genmab A/S entered a worldwide agreement that granted Janssen an exclusive license to develop, manufacture, and commercialize daratumumab.

Daratumumab is an investigational human monoclonal antibody that binds with high affinity to the CD38 molecule, which is highly expressed on the surface of multiple myeloma cells. It is believed to induce rapid tumor cell death through multiple immune-mediated mechanisms, including complement-dependent cytotoxicity, antibody-dependent cellular phagocytosis, and antibody-dependent cellular cytotoxicity, as well as via induction of apoptosis. Five phase 3 clinical studies are ongoing with daratumumab in relapsed and frontline settings.

Source: Janssen, September 4, 2015

Elotuzumab for Multiple Myeloma

The FDA has accepted the application for elotuzumab (Bristol-Myers Squibb/AbbVie) with priority review for the treatment of multiple myeloma as combination therapy in patients who have received one or more prior therapies. The agency previously granted a breakthrough therapy designation to elotuzumab, which has a proposed brand name of Empliciti.

The filing acceptance was primarily supported by the ELOQUENT-2 trial, a phase 3, randomized, open-label study that evaluated elotuzumab in combination with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone. In addition, the filing was supported by a phase 2, randomized, open-label trial that evaluated elotuzumab with bortezomib and dexamethasone versus bortezomib and dexamethasone alone.

Elotuzumab is an investigational immunostimulatory antibody targeted against signaling lymphocyte activation molecule family member 7 (SLAMF7), a cell-surface glycoprotein that is highly and uniformly expressed on myeloma cells and on natural killer cells but is not detected on normal solid tissues or on hematopoietic stem cells.

Source: Bristol-Myers Squibb, September 1, 2015

Alectinib for Some Types of NSCLC

The FDA has granted priority review to the newly accepted application for alectinib (Genentech), an oral investigational anaplastic lymphoma kinase (ALK) inhibitor, for the treatment of patients with ALK-positive, locally advanced or metastatic non–small-cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. The FDA, which previously designated alectinib a breakthrough therapy, is expected to make a decision by March 4, 2016.

The application includes data from two phase 2, single-arm, open-label, multicenter trials evaluating alectinib’s safety and efficacy in patients with ALK-positive NSCLC whose disease progressed on crizotinib.

Assessments by an independent review committee (IRC) showed an objective response rate (ORR) of 47.8% in the NP28761 trial and 50.0% in the NP28673 trial among people treated with alectinib, as measured by Response Evaluation Criteria in Solid Tumors. Among patients whose disease had spread to the brain or other parts of the central nervous system (CNS) at study entry, the IRC found a CNS ORR of 68.8% in NP28761 and 57.1% in NP28673. The most common grade 3 or higher adverse events in NP28761 were increased levels of creatine phosphokinase, alanine aminotransferase, and aspartate aminotransferase, and dyspnea.

Source: Genentech, September 8, 2015

Eteplirsen for Muscular Dystrophy

The newly accepted application for eteplirsen (Sarepta Therapeutics) has received FDA priority review status for the potential treatment of Duchenne muscular dystrophy (DMD) amenable to exon 51 skipping. The Prescription Drug User Fee Act action date for an approval decision is February 26, 2016.

Eteplirsen was designed to address the underlying cause of DMD by enabling the production of a functional dystrophin protein. Data from clinical studies of eteplirsen in DMD patients have demonstrated the restoration of dystrophin protein expression.

Eteplirsen uses phosphorodiamidate morpholino oligomer–based chemistry and proprietary exon-skipping technology to skip exon 51 of the dystrophin gene, thereby enabling the repair of specific genetic mutations that affect approximately 13% of the DMD population. By skipping exon 51, eteplirsen may restore the gene’s ability to make a shorter, but still functional, form of dystrophin from messenger RNA. Promoting the synthesis of a truncated dystrophin protein is intended to stabilize or significantly slow the disease process and to prolong and improve the quality of life for patients with DMD.

Source: Sarepta Therapeutics, August 25, 2015

Orphan Drug Designations

Gilotrif for Advanced Lung Cancer

The FDA has granted an orphan drug designation to the newly filed application for afatinib (Gilotrif, Boehringer Ingelheim) to treat patients with advanced squamous cell carcinoma (SCC) of the lung progressing after treatment with first-line chemotherapy.

The submission was based on the phase 3 LUX-Lung 8 trial, which compared afatinib with erlotinib (Tarceva, Genentech/Astellas Oncology) in patients with advanced SCC of the lung progressing after treatment with first-line platinum-based chemotherapy. Treatment with afatinib resulted in superior progression-free survival, reducing the risk of cancer progression by 19%, and in superior overall survival, reducing the risk of death by 19%, compared with erlotinib.

A higher incidence of severe diarrhea and stomatitis was observed with afatinib compared with erlotinib, while a higher incidence of severe rash/acne was reported with erlotinib compared with afatinib.

Afatinib, an oral, once-daily epidermal growth factor receptor (EGFR)-directed therapy, is indicated in the U.S. for the first-line treatment of patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations, as detected by an FDA-approved test.

Source: Boehringer Ingelheim, August 25, 2015

Fostamatinib for Immune Thrombocytopenic Purpura

The FDA has granted an orphan drug designation to fostamatinib (Rigel Pharmaceuticals, Inc.), an oral spleen tyrosine kinase inhibitor that is in phase 3 clinical studies in patients with chronic immune thrombocytopenic purpura (ITP).

In patients with ITP, the immune system attacks and destroys the body’s blood platelets. ITP patients can experience extraordinary bruising, bleeding, and fatigue as a result. Rigel believes that fostamatinib may address the autoimmune basis of the disease.

Source: Rigel Pharmaceuticals, Inc., September 8, 2015

FDA Expands Warnings About Canagliflozin and Bone Health

The FDA has strengthened its warning about an increased risk of bone fractures for the type-2 diabetes medicine canagliflozin (Invokana and Invokamet, Janssen) and has added information about decreased bone mineral density to the drugs’ labels.

The FDA is continuing to evaluate the risk of bone fractures with other drugs in the sodium-glucose cotransporter 2 (SGLT2) inhibitor class, including dapagliflozin (Farxiga and Xigduo XR, Astra-Zeneca) and empaglifozin (Jardiance and Glyxambi, Boehringer Ingelheim; Synjardy, Boehringer Ingelheim/Eli Lilly), to determine whether additional label changes or studies are needed.

Bone fractures have been seen in patients as early as 12 weeks after they started taking canagliflozin, which has also been linked to decreases in bone mineral density (BMD) at the hip and lower spine.

The new fracture warning is based on pooled data from nine clinical trials with a mean 85 weeks’ exposure to canagliflozin, in which the incidence rates of adjudicated bone fractures were between 1.1 and 1.5 per 100 patient-years of exposure. Data on BMD came from an FDA-mandated post-marketing safety trial involving 714 elderly patients with type-2 diabetes. At two years, patients randomly assigned to canagliflozin 100 mg and 300 mg had placebo-corrected declines in BMD, as measured by dual-energy X-ray absorptiometry, of 0.9% and 1.2%, respectively, at the hip, and of 0.3% and 0.7%, respectively, at the lumbar spine. Health care professionals should consider factors that contribute to fracture risk prior to starting patients on canagliflozin.

Sources: FDA and Medscape, September 10, 2015

Teflaro Labeling Expanded

The FDA has approved an updated label for ceftaroline fosamil (Teflaro, Allergan) for the treatment of adults with acute bacterial skin and skin-structure infections (ABSSSIs) and community-acquired bacterial pneumonia (CABP).

The approved label includes new clinical data from two ABSSSI trials that involved patients with baseline Staphylococcus aureus bacteremia, allowing for use of ceftaroline fosamil in those patients. The updated label also permits ceftaroline fosamil to be administered by intravenous infusion in five to 60 minutes in patients 18 years of age and older.

The approval was based on a subset of data from two identical pivotal trials (CANVAS 1 and 2) that compared ABSSSI patients treated with ceftaroline fosamil monotherapy with patients treated with vancomycin plus aztreonam. Of the 693 patients in the modified intent-to-treat population in the ceftaroline fosamil arm in these trials, 20 had baseline S. aureus bacteremia (nine cases of methicillin-resistant S. aureus [MRSA] and 11 cases of methicillin-susceptible S. aureus). Thirteen of these 20 patients (65%) achieved a clinical response with ceftaroline fosamil at day 3, and 18 of 20 patients (90%) were considered a clinical success at test of cure.

The FDA approved ceftaroline fosamil in October 2010 for the treatment of adults with CABP and ABSSSI due to designated susceptible pathogens. Ceftaroline fosamil is active against both gram-positive and gram-negative pathogens and is the only cephalosporin with activity against MRSA.

Source: Allergan, September 2, 2015

DPP-4 Inhibitors and Joint Pain

The FDA says the type-2 diabetes drugs sitagliptin, saxagliptin, linagliptin, and alogliptin may cause joint pain that can be severe and disabling. The agency has added a new section about this risk to the labels of all of these dipeptidyl peptidase-4 (DPP-4) inhibitors.

Patients should not stop taking the medications, but they should contact their health care professionals right away if they experience severe and persistent joint pain. Health care professionals should consider DPP-4 inhibitors as a possible cause of severe joint pain and discontinue the drugs if appropriate. DPP-4 inhibitors are used with diet and exercise to lower blood sugar in adults with type-2 diabetes. They are available as single-ingredient products and in combination with other diabetes drugs.

The FDA identified cases of severe joint pain associated with the use of DPP-4 inhibitors in a search of the FDA Adverse Event Reporting System (FAERS) database and the medical literature. Patients started having symptoms from one day to years after they started taking a DPP-4 inhibitor. After the patients discontinued the DPP-4 inhibitor, their symptoms were relieved, usually in less than a month. Some patients developed severe joint pain again when they restarted the same or another DPP-4 inhibitor.

The FDA-approved DPP-4 inhibitors are linagliptin/empagliflozin (Glyxambi, Boehringer Ingelheim [BI]), sitagliptin/metformin (Janumet, Merck, Sharp, and Dohme [MSD]), sitagliptin/metformin extended release (Janumet XR, MSD), sitagliptin (Januvia, MSD), linagliptin/metformin (Jentadueto, BI), alogliptin/metformin (Kazano, Takeda Pharmaceuticals [TP]), saxagliptin/metformin extended release (Kombiglyze XR, Astra-Zeneca [AZ]), alogliptin (Nesina, TP), saxagliptin (Onglyza, AZ), alogliptin/pioglitazone (Oseni, TP), and linagliptin (Tradjenta, BI).

Source: FDA, August 28, 2015

Becton-Dickinson Syringes

Compounded or repackaged drugs stored in some lots of Becton-Dickinson (BD) general-use syringes could interact with the syringes’ rubber stoppers and lose potency if not used immediately, the FDA and BD warn. The alert applies to compounded or repackaged drugs stored in 1-mL, 3-mL, 5-mL, 10-mL, 20-mL, and 30-mL BD syringes and BD oral syringes.

The FDA does not know how long drugs can be stored in the syringes before degrading. There is no information to suggest that there is a problem with potency or drug degradation when a medication is administered promptly after the syringes are filled.

The FDA has cleared these syringes for general-purpose fluid aspiration and injection, not for use as a closed-container storage system for drug products. This issue may extend to other general-use syringes made by other manufacturers that were not cleared for use as closed-container storage.

BD says the following drugs in particular can be affected by the stoppers: fentanyl, rocuronium, neostigmine, morphine, midazolam, methadone, atropine, hydromorphone, cisatracurium, and remifentanyl. However, the FDA does not know whether other drugs can be affected. BD has created a webpage ( to help customers determine whether their lots are affected. Hospital pharmacies and staff should not administer compounded or repackaged drugs that have been stored in these syringes unless no suitable alternative is available.

Source: FDA, September 8, 2015

Tramadol Risks in Children

The FDA is investigating the use of the pain medicine tramadol in children 17 years of age and younger because of a rare but serious risk of slowed or difficult breathing. This risk may increase in children treated with tramadol for pain after surgery to remove their tonsils and/or adenoids.

Tramadol is not FDA-approved for use in children, but data show it is being used off-label in this population. Health care professionals should consider prescribing alternative FDA-approved pain medicines for children instead.

In the body, tramadol is converted in the liver to the active form of the opioid, O-desmethyltramadol. Some people have genetic variations that cause tramadol to be converted to the active form of the opioid faster and more completely than usual. These ultrarapid metabolizers are more likely to have higher-than-normal amounts of the active form of the opioid in their blood after taking tramadol, which can result in breathing difficulty that may prove fatal.

Recently, a 5-year-old child in France experienced severely slowed and difficult breathing that required emergency intervention and hospitalization after taking a single prescribed dose of tramadol oral solution for pain relief following surgery to remove his tonsils and adenoids. The child was later found to be an ultrarapid metabolizer and had high levels of O-desmethyltramadol in his body.

Source: FDA, September 21, 2015

ASCO Lung Cancer Guideline

A committee of oncology experts has updated the American Society of Clinical Oncology (ASCO) clinical practice guideline on systemic therapy for patients with stage IV non–small-cell lung cancer (NSCLC). Their recommendations are based on a systematic review of randomized controlled trials conducted from January 2007 to February 2014.

While there is no cure for stage IV NSCLC, various treatment options can help patients control their cancer longer. This guideline will help doctors choose the most appropriate therapies, depending on the tumor’s biology and the patient’s general well-being.

For patients with performance status (PS) 0 to 1 (and appropriate patient cases with PS 2) without an EGFR-sensitizing mutation or ALK gene rearrangement, the guideline recommends cytotoxic chemotherapy, guided by histology, with early concurrent palliative care.

Treatment recommendations for patients in the first-line setting include platinum-doublet therapy for those with PS 0 to 1 (bevacizumab may be added to carboplatin plus paclitaxel if there are no contraindications); combination or single-agent chemotherapy or palliative care alone for those with PS 2; afatinib, erlotinib, or gefitinib for those with sensitizing EGFR mutations; and crizotinib for those with ALK or ROS1 gene rearrangement. Recommended maintenance therapy includes pemetrexed continuation for patients with stable disease or a response to first-line pemetrexed-containing regimens, alternative chemotherapy, or a chemotherapy break.

In the second-line setting, recommended treatments include docetaxel, erlotinib, gefitinib, or pemetrexed for patients with non-squamous cell carcinoma; docetaxel, erlotinib, or gefitinib for those with squamous cell carcinoma; and chemotherapy or ceritinib for those with ALK rearrangement who experience progression after crizotinib.

In the third-line setting, for patients who have not received erlotinib or gefitinib, treatment with erlotinib is recommended. According to the new guidelines, there are insufficient data to recommend routine third-line cytotoxic therapy.

Early palliative care is associated with improved survival of patients with advanced lung cancer. Hospice care also improves patient quality of life and reduces caregiver distress.

Sources: ASCO and the Journal of Clinical Oncology, August 31, 2015

Picato Gel Reactions

The FDA is warning about reports of severe allergic reactions and herpes zoster associated with ingenol mebutate (Picato gel, LEO Pharma Inc.), which is used to treat actinic keratosis.

The agency has also received reports of cases involving severe eye injuries and skin reactions associated with application of the gel. In some cases, the gel was not being used according to the label instructions. The FDA is requiring label changes to warn of these risks and to provide additional instructions on the safe and appropriate application of the product.

Patients should use the gel as prescribed by their health care professionals, and they should not use it on an area of skin larger or for a longer period than instructed in the label. In addition, patients should avoid applying the gel in, near, and around the mouth, lips, and eyes. Accidental transfer of the gel from the hands has occurred even after washing, in some cases through application of make-up and insertion of contact lenses.

Patients who experience a severe allergic reaction should stop using Picato gel and seek immediate medical attention.

Source: FDA, August 21, 2015

Medication Recall

Sterile Products From Medistat RX

An Alabama compounding pharmacy recalled all nonexpired drugs produced for sterile use after inspectors found “significant deficiencies” and warned of possible contamination. The FDA has received reports of adverse events that might be associated with products from Medistat RX, LLC.

Medistat RX serves nine states, more than 5,000 prescribers, and 25,000 patients. The recalled products were distributed between November 1, 2014, and September 3, 2015.

Contaminated drugs put patients at risk of serious infection. Health care professionals should quarantine any Medistat drug products marketed as sterile and should not administer them to patients.

During an ongoing inspection, FDA investigators and Alabama state inspectors found significant deficiencies that raise concerns about Medistat’s ability to assure the sterility of its drug products. Medistat voluntarily ceased sterile compounding operations on September 1. The FDA previously inspected Medistat in September 2014 and issued an FDA Form 483 (which notifies a company’s management of objectionable conditions).

Medistat is registered under section 503B of the federal Food, Drug, and Cosmetic Act as an outsourcing facility.

Sources: FDA, September 9, 2015, and MediStat


Antidepressants, NSAIDs, and Intracranial Hemorrhage Risk

Antidepressants—especially selective serotonin reuptake inhibitors (SSRIs)—and nonsteroidal anti-inflammatory drugs (NSAIDs) have been associated with an increased risk of abnormal bleeding, usually gastrointestinal. Neither drug group has been linked to a higher risk of intracranial hemorrhage (ICH).

However, an analysis of data from nearly 5 million people found that using both antidepressants and NSAIDs increased the 30-day risk of ICH (hazard ratio, 1.6), according to researchers at Seoul National University in South Korea.

The study included patients who began receiving antidepressants without having received a prescription for them during the preceding year. Antidepressants included serotonin-norepinephrine reuptake inhibitors, SSRIs, and tricyclic antidepressants.

Among people who used only anti-depressants, the incidence rate of events was 1.6 per 1,000 person years. Among those who used both antidepressants and NSAIDs, the rate was 5.7. Men had the highest risk for ICH. The combined use did not seem to have a major effect on patients who already had risk factors for ICH, such as advancing age and receiving antithrombotic agents. The researchers also found no statistically meaningful differences in the risk of ICH among the anti depressant drug classes.

Source: BMJ, July 14, 2015

Long-Term Effects Of Cytarabine Combination

Low-dose cytarabine, in combination with valproic acid and all-transretinoic acid (ATRA), is used in stabilizing treatment for patients with acute myeloid leukemia (AML) who are not candidates for intensive therapy. In vivo studies have shown that this triple-drug treatment has immunomodulatory effects. To learn more about the acute and long-term effects of such treatment on the T-cell system, researchers at the University of Bergen in Norway conducted an in vitro study to examine the effects of the combination on activated T cells. They tested cytarabine at concentrations reached during in vivo treatment with high doses, conventional doses, and low doses.

The researchers found that cytarabine—especially when combined with valproic acid and ATRA—can reduce T-cell viability and proliferation, alter the activation-induced expression of membrane molecules, and reduce the release of several cytokines. Cytarabine’s effects on T-cell activation were concentration-dependent: Reduced viability was seen only at the higher concentrations. However, the researchers note that cytarabine had immunoregulatory effects even at lower levels. When cytarabine was combined with valproic acid and ATRA, the researchers observed no or minor effects on T-cell viability.

Only cytarabine 44 μM had both anti-proliferative and proapoptotic effects. The drug reduced AML cell viability only at 0.5 and 0.05 μM, not at the lowest concentration, but it inhibited AML cell proliferation even at 0.01 μM. T-cell proliferation was inhibited only at concentrations of 0.35 μM or more. The researchers conclude that primary AML cells are more susceptible to cytarabine than normal T cells, which suggests a therapeutic window for cytarabine treatment that “makes it possible to achieve antileukemic effects in vivo before severe T-cell toxicity occurs.”

The triple-drug combination’s direct effects on the T cells may be offset by other effects on immunocompetent cells. The researchers say the possible risk of immunosuppression should be further investigated.

Source: BMC Pharmacology and Toxicology, May 2015

Stress Ulcer Prophylaxis

As many as 70% of patients in general wards and intensive care units (ICUs) inappropriately receive drugs for stress ulcer prophylaxis, and the problem is compounded when the drugs are continued upon discharge. Researchers at Banner–University Medical Center in Phoenix note that while acid suppression therapy plays an important role in reducing the risk of stress-related mucosal disease bleeding in ICU patients, the drugs should be used more judiciously in all patients, particularly given the potential adverse clinical outcomes, such as pneumonia. The researchers designed a pharmacist-led program to reduce inappropriate use and save money.

At their 700-bed academic medical center, clinical pharmacists have the prescriptive authority to modify stress ulcer prophylaxis to promote the use of histamine H2 receptor antagonists (H2RAs) in ICU patients with risk factors while discontinuing prophylaxis in patients without indications. Famotidine is the hospital’s preferred agent; pharmacists are authorized to substitute H2RAs for proton pump inhibitors (PPIs) in ICU patients with major risk factors. Per hospital protocol, stress ulcer prophylaxis was considered appropriate for ICU patients with major risk factors for stress-related mucosal disease GI bleeding, including mechanical ventilation or coagulopathy. The researchers analyzed data on 1,134 patients pre-and post-implementation.

The pharmacist program had a “significant impact” on prophylaxis use. The appropriate use of famotidine increased in the post-implementation period from 18% to 89%. The researchers found that the pre-implementation period had a 41% rate of inappropriate prophylaxis days, compared with 7% after the program. The program also cut down on inappropriate prophylaxis among general ward patients and patients being discharged. After implementation, the rate of inappropriate prophylaxis was below 5% among non-ICU patients. The researchers found no differences in clinical outcomes.

The program saved an estimated $200,000 per year in costs associated with medications. The total inpatient costs associated with prophylaxis were $20,052 in the pre-implementation period versus $3,280 in the post-implementation period. The greatest savings were seen in reduced PPI use in both ICU and general ward patients.

Source: American Journal of Medicine, August 2015

Strengthening Aging Muscles

Supplementation with beta-hydroxy-beta-methylbutyrate (HMB) may help prevent muscle atrophy in bedridden older adults, according to researchers at Tianjin Medical University in China.

They reviewed seven randomized controlled trials in which 147 older adults who received HMB were compared with 140 who did not. Participants’ mean age ranged from 67 to 84. Follow-up times ranged from eight weeks to 12 months.

HMB supplementation alone or with other compounds had a beneficial effect on muscle-mass improvement, the researchers say. The studies were small, but all reported absolute changes in fat-free mass or body lean mass and body fat. The meta-analysis of muscle-mass outcome showed increased muscle gain in the intervention groups. The effect seemed to be specific for muscle mass and not for fat mass; researchers found no statistically significant changes in fat mass between the two groups.

While effects on muscle mass were consistent, the researchers note, outcomes for muscle strength and physical performance varied in the reports, perhaps because resistant exercise in combination with HMB is a “potent stimulus for muscle improvement.”

One study they reviewed suggested that HMB can help preserve muscle mass in healthy older adults confined to bed rest. Another study reported that HMB supplementation had a positive impact on muscle atrophy in several pathological conditions, including cancer, AIDS, and sepsis. Because older adults were the main study populations and were limited in their physical activities, which accelerated muscle loss, the researchers hypothesize that HMB could have a role in preventing or reducing muscle atrophy induced by bed rest or other conditions.

Source: Archives of Gerontology and Geriatrics, September-October 2015

Finding Vulvodynia’s Cause

Even light touches in certain areas of the vulva cause severe, prolonged pain for women with vulvodynia. Although as many as 28% of U.S. women have this painful condition, researchers have mostly been in the dark about the cause.

Recently, however, the disease has been linked to immunomodulatory stimulus. And more than 70% of women with localized provoked vulvodynia (LPV), the most common form, report having had frequent vaginal yeast infections—sometimes more than four a year.

To better understand the inflammatory pathways involved, researchers at the University of Rochester in New York used tissue biopsies from women with and without LPV. No participants had used corticosteroids or nonsteroidal anti-inflammatory medications, and none had chronic inflammatory illnesses other than LPV. Pain levels at the vaginal vestibule ranged from 7 to 9 (with 10 being the maximum); pain-free controls scored 0. All of the women had negative yeast cultures at the time of study entry.

Vulvar fibroblast strains produce interleukin (IL)-6 and prostaglandin E2 in response to a challenge with yeast components. The researchers compared the fibroblast responses to zymosan (a mixture of yeast cell wall mannoproteins and β-glucan purified from nonpathogenic Saccharomyces cerevisiae) and Candida albicans.

Upon stimulation with zymosan, vestibular fibroblasts of LPV cases produced as much as five times more IL-6 transcript than vestibular fibroblasts from healthy women. In patients with LPV, vestibular fibroblasts responded strongly to even low infectious doses of C. albicans—as few as 100 colony-forming units (numbers within the normal range). External vulvar cells, not typically associated with pain, responded less, even to higher doses. The results suggest that LPV patients are “exquisitely sensitive” to components of the yeast cell wall, the researchers say, namely β-glucan and mannoprotein.

The researchers pinpointed two possible targets for resolving proinflammatory signaling and pain: the NFκB pathway and dectin-1 mediated signaling.

Source: American Journal of Obstetrics & Gynecology, July 2015

Herpes and Alzheimer’s Risk

Herpes simplex virus (HSV) has been linked to dementia and Alzheimer’s disease for decades. HSV1 has been found in brain tissue from patients with AD and located specifically within amyloid plaques. But as much as 90% of the population has latent HSV1 infection—so why doesn’t everyone get Alzheimer’s? Two studies help clarify possible reasons.

Researchers at Umeå University in Sweden analyzed prospective plasma samples from 360 well-defined AD cases and 360 dementia-free controls. All AD cases were initially examined at the University Hospital Memory Clinic and later reviewed by a specialist in psychogeriatric medicine. Most plasma samples were taken a mean 9.6 years before the AD diagnosis.

The presence of anti-HSV immunoglobulin (Ig) G antibodies doubled the risk of AD among patients whose plasma samples were taken more than six years before the AD diagnosis. The HSV-associated risk for AD appeared to be higher among patients older than 60 at the time of the sampling and among women.

The researchers advise that their findings should be interpreted with caution. Since so many people carry HSV, additional factors must be considered as modifiers of the HSV-associated risk of AD, such as an individual’s humoral immune response to infection. They also point to hypotheses that a weakened immune system in an older person might contribute to HSV reactivation, which could spread to the brain, whereas other non-HSV causes might be more common among younger people.

A second study at Umeå University found a higher risk of AD with reactivated herpes infection. The researchers followed 3,432 adults enrolled in an ongoing longitudinal study. Serum samples were analyzed for anti-HSV antibodies (IgG and IgM); 3,026 subjects (88%) had anti-HSV antibodies at baseline.

During a mean follow-up of 11.3 years, 430 people developed a dementia disorder, including 245 who developed AD. The presence of anti-HSV IgG antibodies did not increase the risk of AD, but anti-HSV IgM antibodies, a sign of reactivated infection, nearly doubled it. The risk for AD did not seem to increase until about eight to 10 years after a positive anti-HSV IgM serum sample, possibly pointing toward HSV reactivation being an early event in the development of AD pathology.

Only a few people were positive for anti-HSV IgM antibodies, and the APOE genotype was not available for all participants. However, anti-HSV IgM antibodies are relatively short-lived and uncommon in the general population. The researchers suggest that a possible explanation for the higher AD risk with HSV reactivation is that a combination of HSV1 and certain host immunological factors that permit reactivation from latency and possibly spread to the central nervous system “constitutes the real risk for AD.”

Source: Alzheimer’s & Dementia, June 2015

Real-World ICD Use

The U.S. is the world’s largest user of implantable cardioverter defibrillators (ICDs), according to researchers at Brigham and Women’s Hospital and Harvard Medical School in Boston. Reviews have shown that real-world ICD recipients are typically older than those in research trials, with more noncardiac comorbidities. Moreover, primary ICD trials were conducted in outpatients with stable, mild-to-moderate heart failure (HF), the researchers note.

But about a third of older patients who get ICDs have undergone the implantation during a hospital admission for exacerbation of HF or other acute comorbidities—and the early post-discharge period for these patients carries a high risk of death, usually from progressive HF.

So, these researchers ask, does the impact of primary ICDs on the prevention of sudden cardiac death translate to overall survival benefits for these patients? They analyzed data from 23,111 HF patients (5,258 with an ICD and 17,853 without). Patients with ICDs were more likely to have ischemic HF. They were younger and more likely to be men, and they had a lower ejection fraction, more previous admissions for cardiac diseases, and more physician visits. They also had a higher prevalence of comorbidities, such as chronic kidney disease and metastatic cancer.

During an average 2.8 years of follow-up, 12,293 patients (53%) died. The crude mortality risk for patients admitted to the hospital was 34% at one year and 56% at three years. The mortality curves for patients with and without ICDs began to diverge immediately after ICD implantation. At one year, crude mortality was lower compared with eligible patients without an ICD (18% versus 39%); at three years, the difference was 40% versus 60%. The researchers note, however, that the crude mortality among hospitalized Medicare patients with an ICD at one year was similar to that seen at three years in trials of ICDs in ambulatory recipients.

The researchers conclude that the benefits of primary ICD therapy previously shown in ambulatory HF patients “do not seem to translate” to the elderly patients in their study group. After adjustment, the remaining apparent impacts of ICD therapy were a 5% reduction in sudden cardiac death and a 9% reduction in all-cause mortality, neither of which was significant. The researchers did find a trend toward benefits for patients who had nonrecent myocardial infarction (more than 40 days prior to the implantation), left bundle branch block, or lower serum B-type natriuretic peptide, although these also did not reach significance. Their study used latency analysis to adjust for healthy candidate bias.

Source: BMJ, July 14, 2015

Medical Device Recalls

OxyTOTE Portable Oxygen Units

Western/Scott Fetzer Company recalled OxyTOTE portable oxygen units after oxygen cylinders ignited and burst on two occasions, causing one death and one injury.

The company said mishandling or dropping the OxyTote may cause the problem. When the injury occurred, the unit was dropped from 4 feet; in the fatality, the victim did not drop the cylinder, but set it down by his side.

The FDA says 161,674 units were distributed in the U.S. from January 1, 2009, to September 30, 2014. Western/Scott Fetzer is scheduling remediation for products affected by the class I recall, which are listed at Customers can contact Western/Scott Fetzer at 1-800-783-7890, extension 2516.

Source: FDA, August 18, 2015

OmniPod Insulin Management System

The Insulet Corporation has recalled 408,460 “pods” used with its OmniPod Insulin Management System (an insulin pump) because some pods may have failure rates that exceed the company’s standards.

The pod is a small adhesive pump that sticks directly to the body. Insulin is delivered through a small port holding a tube that is inserted into the skin. In some recalled units, the pod’s cannula may retract or fail to fully deploy, or the pod may trigger an audible alarm indicating it will no longer deliver insulin. Both situations can interrupt insulin delivery. Insulet has received 90 medical device reports; 13 required medical intervention, but no serious injuries or deaths have been reported.

The pods, packed in boxes of 10, were distributed from December 2013 to March 2015; they will be replaced. A list of lots affected by this class I recall is available at Consumers with questions may contact the company at 1-855-407-3729.

Sources: Insulet Corporation and FDA, August 27, 2015

Dräger Ventilators

Dräger Medical is recalling 2,081 Evita V500 and Babylog VN500 Ventilators because the battery does not last as long as expected. The battery indicator light shows a sufficient charge even when the battery is depleted. When the “battery low” and “battery depleted” alarms sound, the devices do not indicate how much time is left before the ventilator will stop. Dräger’s analysis indicates that the battery should last about 30 minutes.

Dräger told customers it plans to replace all faulty batteries. Meanwhile, customers should not rely on the battery status indicator. If the power alarm sounds, they should provide manual ventilation and immediately connect the ventilator to a main power supply.

The units were distributed from June 1, 2011, to June 30, 2015; this class I recall affects all lots. Customers with questions can contact Dräger Customer Support at 1-800-543-5047: at the prompt, press 1, then 2, then 32349.

Source: FDA, September 2, 2015

CareFusion Alaris Syringe Pump

CareFusion is recalling Alaris Syringe Pumps (model 8110) because an error can trigger an alarm and stop the pump. Even when the user clears the error code (351.6740), the pump does not respond to key presses until it is detached and reattached to the PC unit used to program, monitor, and power the pump.

CareFusion has received 108 reports of the problem that led to this class I recall. The company will schedule repairs. Customers should establish back-up plans in case of a pump failure and should notify the CareFusion Support Center at 1-888-562-6018 if the error code occurs.

Source: FDA, August 27, 2015

Elite Biomedical Pump Frame Membrane

Elite Biomedical Solutions has recalled the Alaris Medley Large Volume Pump Frame Membrane because it can result in over-infusion or under-infusion of fluids. The frame membranes, part of the pump, prevent fluids from leaking into internal components. The 1,502 parts affected by this class I recall were distributed from February 25, 2015, to May 8, 2015; a list of part and lot numbers is available at Users are advised to return the affected products to Elite for replacement. Customers can contact Elite at 1-855-291-6701, Monday through Friday, from 8 a.m. to 5 p.m. Eastern time.

Source: FDA, August 27, 2015

Puritan Bennett 980 Ventilators

Covidien is recalling Puritan Bennett 980 Ventilators because a software error may result in less air being delivered to the patient than the amount programmed by the clinician when the ventilator is in neonatal Volume Control Plus (VC+) mode with active humidification. The units were distributed from March 1, 2014, to June 17, 2015. Covidien plans a software update to correct the error. A list of part and lot numbers involved in the class I recall (and advice for customers awaiting the software update) is available at

Source: FDA, September 2, 2015

Hudson RCI Sheridan Sher-I-Bronch Endobronchial Tube

Teleflex Medical is recalling 62,882 Hudson RCI Sheridan Sher-I-Bronch Endobronchial Tubes after receiving customer complaints that the endobronchial tube’s double swivel connector may break or separate on the tube. If this happens, the device may leak, causing hypoxia or respiratory distress. A complete list of affected lot numbers is available at Customers with questions may call 610-378-0131.

Source: FDA, August 26, 2015


Kunj Gohil, PharmD, RPh

Name: Augment Bone Graft

Manufacturer: Wright Medical, Memphis, Tennessee

Approval Date: September 1, 2015

Purpose: This is a new protein therapeutic for ankle and/or hind-foot fusion procedures.

Description: Augment is a combination of two components: beta-tricalcium phosphate (Beta-TCP) and recombinant human platelet-derived growth factor (rhPDGF). Beta-TCP provides a framework for new bone growth, and rhPDGF stimulates recruitment and proliferation of osteoblasts, which are responsible for the formation of bone.

Benefit: Augment is the first clinically tested therapeutic approved for the orthopedic market in more than 10 years. Traditional procedures require a secondary procedure to harvest autograft tissue, but this new option is a safe alternative that will avoid surgery and site-specific complications.


Name: G5 Mobile Continuous Glucose Monitor (CGM) System

Manufacturer: Dexcom, San Diego, California

Approval Date: August 24, 2015

Purpose: This system is designed to help monitor blood glucose in patients 2 years of age and older

Description: The G5 mobile system is made up of three parts: a small sensor, a transmitter, and a display device. The small sensor is used to measure glucose levels just below the skin. The wireless transmitter is attached to the sensor and sends data to a wireless device. The display device is used to view the readings, which are taken at five-minute intervals; this device can either be a compatible smart device with a mobile application or the Dexcom G5 Mobile Receiver.

Benefit: Dexcom has created a convenient system to take continuous glucose measurements throughout the day. The key is the transmission of information from the sensor to the display device showing readings every five minutes in real time. This will allow patients to view their current glucose levels and trends throughout the day to ensure adequate levels.


Name: Innova Vascular Self-Expanding Stent System

Manufacturer: Boston Scientific, Marlborough, Massachusetts

Approval Date: August 20, 2015

Purpose: This stent is used to treat peripheral artery disease.

Description: Innova is a bare-metal stent, with diameters ranging from 5 mm to 8 mm and lengths of 20 mm to 200 mm, with a triaxial delivery system.

Benefit: This stent provides a safe and effective option for patients requiring stents within the superficial femoral arteries of the thigh and proximal popliteal arteries of the knee. These specific locations can be challenging for stents, but Innova is designed for this anatomy with specific strength and fracture resistance.