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P T. 2015;40(9): 552, 554-560, 582-583

New Drugs / Drug News / New Medical Devices September 2015


Praluent for High Cholesterol

The FDA has approved alirocumab injection (Praluent, Sanofi-Aventis/Regeneron Pharmaceuticals), the first cholesterol-lowering treatment in a new class of drugs called proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors.

Alirocumab is approved for use in addition to diet and maximally tolerated statin therapy in adults with heterozygous familial hypercholesterolemia (HeFH) or in patients with clinical atherosclerotic cardiovascular disease, such as heart attacks or strokes, who require additional lowering of low-density lipoprotein-cholesterol (LDL-C).

Alirocumab is an antibody that targets the PCSK9 protein, which reduces the number of receptors on the liver that remove LDL-C from the blood. Blocking PCSK9’s ability to work leaves more receptors available to remove LDL-C from the blood, thus lowering LDL-C levels.

Alirocumab’s efficacy and safety were evaluated in five placebo-controlled trials involving 2,476 participants exposed to the drug. All had HeFH or were otherwise at a high risk for heart attack or stroke, and all were taking maximally tolerated doses of a statin with or without other lipid-modifying therapies. The subjects receiving alirocumab had average reductions in LDL-C levels ranging from 36% to 59% compared with placebo.

An ongoing trial is investigating the effects on cardiovascular risk reduction when alirocumab is added to statins.

The most common adverse events associated with alirocumab include injection-site itching, swelling, pain, or bruising; nasopharyngitis; and flu. Allergic reactions, such as vasculitis and hypersensitivity reactions requiring hospitalization, have been reported. Patients should stop using alirocumab and get medical help if they experience symptoms of a serious allergic reaction.

Source: FDA, July 24, 2015

Addyi for Sexual Desire Disorder

Flibanserin (Addyi, Sprout Pharmaceuticals) has won FDA approval to treat acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. Addyi is the first agency-approved treatment for sexual desire disorders in either sex.

HSDD is characterized by low sexual desire that causes marked distress or interpersonal difficulty and is not due to a co-existing medical or psychiatric condition, problems within the relationship, or the effects of a medication or other drug. HSDD is acquired when it develops in a patient who previously had no problems with sexual desire. HSDD is generalized when it occurs regardless of the type of sexual activity, the situation, or the sexual partner.

Flibanserin is a serotonin 5HT1A receptor agonist and a 5HT2A receptor antagonist; the mechanism by which it improves sexual desire and related distress is not known. Flibanserin is taken once daily at bedtime to help decrease the risk of adverse events due to possible hypotension, syncope, and central nervous system depression. Patients should discontinue treatment after eight weeks if they do not report an improvement in sexual desire and associated distress.

Developed by Boehringer Ingelheim, flibanserin was rejected by the FDA in 2010 after an advisory panel said its benefits did not outweigh its risks. Sprout acquired the drug, conducted more studies, and resubmitted the application, which the FDA rejected again in 2013. This led to a lobbying campaign by Sprout, aided by women’s groups who accused the FDA of gender bias because it had approved Viagra for men.

A boxed warning highlights flibanserin’s risks of severe hypotension and syncope in patients who drink alcohol during treatment, who also use moderate or strong CYP3A4 inhibitors, and who have liver impairment. Using alcohol is contraindicated while taking flibanserin. Health care professionals must assess the likelihood of the patient reliably abstaining from alcohol before prescribing flibanserin.

Flibanserin was approved with a risk evaluation and mitigation strategy (REMS); prescribers must enroll, complete training, and be certified. They must counsel patients about the increased risk of severe hypotension and syncope and about the importance of not drinking alcohol during flibanserin treatment. The FDA is requiring Sprout to conduct three well-designed studies in women to better understand the known, serious risks of the interaction between flibanserin and alcohol.

Flibanserin’s effectiveness was evaluated in three 24-week, randomized, double-blind, placebo-controlled trials in approximately 2,400 premenopausal women (average age, 36 years) who had acquired, generalized HSDD for an average of about five years. Women counted the number of satisfying sexual events, reported sexual desire over the preceding four weeks, and reported distress related to low sexual desire. On average, flibanserin increased the number of satisfying sexual events by 0.5 to 1.0 additional event per month compared with placebo. Critics say the small benefit is outweighed by the drug’s serious risks.

Sources: FDA and Reuters, August 18, 2015

Daklinza for Genotype 3 HCV

Daclatasvir (Daklinza, Bristol-Myers Squibb) has received FDA approval for use with sofosbuvir (Sovaldi, Gilead Sciences) to treat patients with infections of the genotype 3 hepatitis C virus (GT3 HCV). Daclatasvir is the first drug to demonstrate safety and efficacy in the treatment of GT3 HCV infections without the need for coadministration of interferon or ribavirin. About 10% of the approximately 2.7 million Americans infected with HCV have GT3 HCV.

The safety and efficacy of daclatasvir in combination with sofosbuvir were evaluated in a clinical trial involving 152 treatment-naive and treatment-experienced participants with chronic GT3 HCV infections. The subjects received daclatasvir 60 mg plus sofosbuvir 400 mg once daily for 12 weeks and were monitored for 24 weeks post-treatment.

Ninety-eight percent of the treatment-naive subjects with no cirrhosis of the liver and 58% of the treatment-naive subjects with cirrhosis achieved a sustained virological response (SVR) 12 weeks after finishing treatment. Among treatment-experienced participants, 92% without cirrhosis and 69% with cirrhosis achieved an SVR.

Safety data were available for approximately 1,900 HCV patients treated with the recommended dose of daclatasvir in combination with other anti-HCV drugs in clinical trials. The most common adverse events associated with daclatasvir plus sofosbuvir were fatigue and headache.

The labeling for daclatasvir notes that SVR rates are reduced in GT3 HCV patients with cirrhosis. The labeling also warns that serious symptomatic brady-cardia and cases requiring pacemaker intervention have been reported when amiodarone was coadministered with sofosbuvir in combination with another HCV direct-acting antiviral, including daclatasvir. The coadministration of amiodarone with daclatasvir in combination with sofosbuvir is not recommended.

Daclatasvir received an FDA priority review.

Source: FDA, July 24, 2015

Technivie for Genotype 4 HCV

The FDA has approved ombitasvir/paritaprevir/ritonavir tablets (Technivie, AbbVie) in combination with ribavirin for the treatment of adults with chronic infection by genotype 4 of the hepatitis C virus (GT4 HCV) who do not have cirrhosis. Technivie is the first all-oral, interferon-free, direct-acting antiviral treatment approved in the U.S. for adults with chronic GT4 HCV infection.

The FDA’s approval was based on the PEARL-I trial, which demonstrated a 100% sustained virological response at 12 weeks post-treatment (SVR12) in patients who received Technivie and ribavirin (RBV) for 12 weeks. PEARL-I was an open-label, phase 2b study that evaluated Technivie’s efficacy and safety in chronic GT4 HCV patients without cirrhosis. The study included GT4 patients who were new to therapy (n = 42) or who had failed previous treatment with pegylated interferon and RBV (n = 49).

Ninety-one percent of patients (40 of 44) who were new to therapy achieved SVR12 after being treated with Technivie without RBV. In the treatment-naive group without RBV, on-treatment virological breakthrough was reported in one patient (2%); two patients (5%) experienced post-treatment relapse. There were no virological failures in the other treatment arms.

No discontinuations due to adverse events were reported. The most common treatment-emergent adverse events in patients receiving Technivie alone or with RBV were asthenia, fatigue, nausea, and insomnia. Four patients who received Technivie and RBV experienced anemia, which required RBV dose reductions, but none of these patients required blood transfusions or medication to boost their red blood cell production. All patients treated with Technivie and RBV achieved SVR12.

Technivie is a fixed-dose combination of paritaprevir/ritonavir (150/100 mg) coformulated with ombitasvir (25 mg) taken once daily with a meal. It is coadministered with weight-based RBV (1,000 or 1,200 mg in divided doses, twice daily), taken with food. The two direct-acting antivirals, each with distinct mechanisms of action, target and inhibit specific HCV proteins in the viral replication process.

The FDA granted Technivie priority review and breakthrough therapy designations.

Source: AbbVie, July 24, 2015

Odomzo for Basal Cell Carcinoma

Sonidegib (Odomzo, Novartis) has secured FDA approval for the treatment of patients who have locally advanced basal cell carcinoma (BCC) that has recurred after surgery or radiation therapy or who are not candidates for surgery or radiation therapy. BCC accounts for approximately 80% of nonmelanoma skin cancers.

Sonidegib, a once-daily pill, inhibits the Hedgehog pathway, which is active in BCC. By suppressing this pathway, sonidegib may stop or reduce the growth of cancerous lesions.

The labeling for sonidegib includes a boxed warning that the drug may cause death or severe birth defects in a developing fetus when administered to a pregnant woman. A woman’s pregnancy status should be verified before the start of sonidegib treatment, and both male and female patients should be warned about these risks and advised to use effective contraception.

Sonidegib’s efficacy was established in a multicenter, double-blind trial in which 194 patients with locally advanced BCC were randomly assigned to receive either sonidegib 200 mg daily (n = 66) or 800 mg daily (n = 128). The primary endpoint was the objective response rate (the percentage of patients who experienced partial or complete disappearance of their tumors). Among patients treated with sonidegib 200 mg, 58% had their tumors shrink or disappear. This effect lasted at least 1.9 to as long as 18.6 months, and approximately half of the responding patients’ tumor shrinkage lasted six months or longer. The response rates were similar in patients who received sonidegib 800 mg daily, but adverse effects were more common.

The most common adverse events associated with sonidegib 200 mg daily included muscle spasms, alopecia, dysgeusia, fatigue, nausea, musculoskeletal pain, diarrhea, decreased weight, decreased appetite, myalgia, abdominal pain, headache, pain, vomiting, and pruritus. Sonidegib also has the potential to cause serious musculoskeletal-related adverse events, including increased serum creatine kinase levels (with rare reports of rhabdomyolysis), muscle spasms, and myalgia.

Source: FDA, July 24, 2015

Epiduo Forte for Acne

Antibiotic-free adapalene/benzoyl peroxide gel, 0.3%/2.5% (Epiduo Forte, Galderma Laboratories) has obtained FDA approval for the once-daily topical treatment of acne vulgaris. It is the first combination of 0.3% and 2.5% strengths of adapalene (a retinoid) and benzoyl peroxide, respectively, to be developed for patients with moderate-to-severe acne.

The approval was based on positive data from a pivotal phase 3, 12-week, randomized, double-blind, vehicle-controlled study in which the drug met each of its primary efficacy endpoints compared with vehicle gel in 217 subjects with acne.

The study demonstrated the superiority of Epiduo Forte Gel over vehicle gel in the overall study population (moderate-to-severe acne) at week 12 for the Investigator’s Global Assessment success rate and for changes in inflammatory and noninflammatory lesion counts. Subjects who were “severe” at baseline (50%) were required to go from “severe” to “clear” or “almost clear” within the 12-week trial to be considered a treatment success. Among the study subjects, 50.5% treated with Epiduo Forte gel reported a marked improvement in their severe acne. The most commonly reported adverse events included skin irritation, eczema, atopic dermatitis, and a burning sensation.

Source: Galderma Laboratories, July 16, 2015

Generic Approvals

Bivalirudin for Injection

Hospira, Inc., has obtained FDA approval to sell bivalirudin for injection, a generic version of Angiomax (The Medicines Company). Hospira won a court challenge to The Medicines Company’s patents on Angiomax, which had branded U.S. sales of about $500 million in 2014.

Hospira’s bivalirudin for injection is available in a single-dose flip-top vial, which matches the branded offering. The company also plans a differentiated presentation of the 250-mg bivalirudin for injection in Hospira’s ADD-Vantage vial. Hospira’s bivalirudin for injection is available in a lyophilized format.

Bivalirudin for injection is a direct thrombin inhibitor used as an anticoagulant. It is indicated for patients who have unstable angina and are undergoing percutaneous transluminal coronary angioplasty; who are undergoing percutaneous coronary intervention (PCI) with provisional use of a glycoprotein IIb/IIIa inhibitor; and who have or are at risk of heparin-induced thrombocytopenia or heparin-induced thrombocytopenia and thrombosis syndrome and are undergoing PCI.

Source: Hospira, July 16, 2015

Almotriptan Malate Tablets

The FDA has approved Teva Pharmaceuticals’s almotriptan malate tablets, 6.25 mg and 12.5 mg—the first generic version of Axert tablets (Janssen Pharmaceuticals). Axert is a 5HT1B/1D receptor agonist (triptan) indicated for acute treatment of migraine attacks with or without aura. Axert has annual sales of approximately $31 million in the United States, according to IMS data as of March 2015.

Sources: Teva Pharmaceuticals, July 8, 2015, and Axert prescribing information

Travoprost Ophthalmic Solution

Apotex Inc. has received FDA approval to market the first generic travoprost ophthalmic solution USP (ionic buffered solution), 0.004%. The brand product, Travatan Z (Alcon Pharmaceuticals Ltd.), is a prostaglandin analog indicated for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension.

Sources: FDA, July 10, 2015, and Travatan Z prescribing information

Olopatadine HCl Ophthalmic Solution

Olopatadine hydrochloride ophthalmic solution USP, 0.2%, marketed by Barr Laboratories, Inc., has won FDA approval—the first generic version of Pataday ophthalmic solution (Alcon). Pataday solution is a mast cell stabilizer indicated for the treatment of ocular itching associated with allergic conjunctivitis.

Sources: FDA, July 13, 2015, and Pataday prescribing information

Repaglinide/Metformin HCl Tablets

Lupin Ltd. now has FDA permission to market repaglinide/metformin hydrochloride tablets, 1 mg/500 mg and 2 mg/500 mg. The brand-name product is Prandimet (Novo Nordisk), a meglitinide and biguanide combination product indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus who are already treated with a meglitinide and metformin HCl or who have inadequate glycemic control on a meglitinide alone or metformin HCl alone.

Sources: FDA, July 15, 2015, and Prandimet prescribing information

Linezolid Injection

Linezolid injection in 200 mg/100 mL and 600 mg/300 mL formulations can be marketed by Sandoz, Inc., the FDA has decided. This is the first generic version of Zyvox injection (Pfizer, Inc.), an oxazolidinone-class antibacterial indicated in adults and children for the treatment of specific infections caused by susceptible gram-positive bacteria. Altogether, formulations of Zyvox had U.S. sales of $680 million in 2014, according to Pfizer.

Sources: FDA, July 16, 2015; Pfizer, Inc., January 27, 2015; and Zyvox prescribing information

Ethacrynate Sodium for Injection

Par Pharmaceutical has received FDA approval to market ethacrynate sodium for injection USP, equivalent to ethacrynic acid 50 mg. This is the first generic version of Sodium Edecrin (Aton Pharma), a diuretic used in the treatment of edema. According to IMS Health data, annual U.S. sales of Sodium Edecrin are approximately $40 million.

Source: Par Pharmaceutical, August 4, 2015

Omeprazole Magnesium Delayed-Release Tablets

The FDA has approved Perrigo R&D Company’s application to market over-the-counter omeprazole magnesium delayed-release tablets, 20.6 mg (20 mg base), the generic version of Prilosec OTC delayed-release tablets, 20 mg (AstraZeneca). Prilosec is an acid reducer used to treat frequent heartburn.

Sources: FDA, July 30, 2015, and DailyMed


Zubsolv to Induce Maintenance Therapy in Opioid Dependence

The FDA has approved buprenorphine/naloxone CIII sublingual tablets (Zubsolv, Orexo AB) for the induction of buprenorphine maintenance therapy in patients with opioid dependence. Induction is the process a physician performs when a patient is transitioned from the opioid on which he or she is dependent to Zubsolv for long-term maintenance treatment of opioid dependence.

Approval of the new indication was supported by combined data from two phase 3 studies, the Induction, Stabilization, Adherence, and Retention Trial (ISTART) and Study OX219-007. The studies showed positive results in more than 90% of Zubsolv-treated patients using a formulation with a 30% lower dose of buprenorphine. No significant differences were observed between the safety profiles of Zubsolv and generic buprenorphine. The most common treatment-related adverse events during the induction phase for Zubsolv and generic buprenorphine included nausea and headache.

Zubsolv should be used as part of a comprehensive treatment plan that includes counseling and psychosocial support; treatment should be initiated under the direction of physicians certified under the Drug Addiction Treatment Act of 2000. Zubsolv sublingual tablets can be abused in a manner similar to other opioids. Clinical monitoring appropriate to the patient’s level of stability is essential. Liver function should be monitored before and during treatment. Children who take Zubsolv sublingual tablets can experience severe, possibly fatal respiratory depression.

The combination tablet was originally approved in July 2013.

Source: Orexo AB, August 11, 2015

Keveyis for Primary Periodic Paralysis

Dichlorphenamide (Keveyis, Taro Pharmaceutical Industries Ltd.) has received FDA approval for the treatment of primary hyperkalemic and hypokalemic periodic paralysis. It is the first medicine approved by the FDA for the treatment of primary periodic paralysis, which affects an estimated 5,000 U.S. residents. Taro expects the 50-mg tablets to be available during the third quarter of 2015.

Periodic paralyses are a group of rare hereditary disorders that cause episodes of muscle weakness or paralysis. The disorders are differentiated by criteria that include underlying genetic mutations and changes in blood potassium levels during attacks; both the hypokalemic and hyperkalemic types are common. Keveyis is indicated for the treatment of primary hyperkalemic periodic paralysis, primary hypokalemic periodic paralysis, and related variants.

Dichlorphenamide’s efficacy was evaluated in two clinical studies. In the first, a nine-week, double-blind, placebo-controlled, multicenter study, the 24 hypokalemic periodic paralysis patients treated with dichlorphenamide had 2.2 fewer self-reported attacks of muscle weakness per week over the final eight weeks of the trial than the 20 patients treated with placebo. The 12 hyperkalemic periodic paralysis patients treated with dichlorphenamide had 3.9 fewer attacks per week than the nine patients treated with placebo.

The second study was a 35-week, double-blind, placebo-controlled, multicenter, two-period crossover study that included 31 patients with hyperkalemic periodic paralysis and 42 patients with hypokalemic periodic paralysis. Hyperkalemic periodic paralysis patients treated with dichlorphenamide had 2.3 fewer attacks per week than those on placebo. Acute intolerable worsening necessitating withdrawal was observed in two hypokalemic periodic paralysis patients on dichlorphenamide versus 11 patients on placebo.

The most common side effects of dichlorphenamide were a burning or pricking sensation, difficulty thinking and paying attention, changes in taste, and confusion. Dichlorphenamide may also cause a drop in potassium, excessive acid, or an increased risk of falls.

Dichlorphenamide, an oral carbonic anhydrase inhibitor used to treat glaucoma, received initial U.S. approval in 1958.

Sources: Taro Pharmaceutical Industries Ltd., August 10, 2015, and Keveyis prescribing information

Dysport for Spasticity In the Upper Limbs

AbobotulinumtoxinA (Dysport, Ipsen) is now FDA-approved to treat upper-limb spasticity by decreasing the severity of increased muscle tone in elbow flexors, wrist flexors, and finger flexors.

Clinical improvement may be expected one week after administration of the drug. Most patients in clinical studies were treated for 12 to 16 weeks, and some showed a response for as long as 20 weeks.

Dysport is an injectable form of botulinum toxin type A (BoNT-A), which is isolated and purified from Clostridium BoNT-A bacteria. It is supplied as a lyophilized powder. The drug was previously approved in the U.S. for the treatment of adults with cervical dystonia and adults with moderate-to-severe glabellar lines.

The FDA’s approval was based on studies involving more than 600 patients. In a pivotal, phase 3, double-blind, randomized, placebo-controlled trial, 238 adults with upper-limb spasticity were treated for up to one year. The study compared the efficacy of Dysport (n = 159) with that of placebo (n = 79) in hemiparetic patients after stroke or brain trauma.

Subjects treated with Dysport demonstrated statistically significant improvement in muscle tone in the treated upper limb, as measured by the Modified Ashworth Scale (MAS), and a significantly higher physician-rated clinical benefit, as measured by the Physician Global Assessment score, compared with placebo at week 4. Also at week 4, both doses of Dysport (500 units and 1,000 units) significantly reduced muscle tone, as measured by the MAS, in all primary target muscle groups, including elbow, wrist, and finger muscles. Approximately 75% of patients responded to Dysport.

The most common treatment-associated adverse events included urinary tract infection, nasopharyngitis, muscular weakness, musculoskeletal pain, dizziness, falls, and depression.

Source: Pipeline Review, July 16, 2015

Spritam for Seizures Related to Epilepsy

The FDA has approved levetiracetam (Spritam, Aprecia Pharmaceuticals) for oral use as adjunctive therapy in the treatment of partial-onset seizures, myoclonic seizures, and primary generalized tonic-clonic seizures in adults and children with epilepsy.

The product is manufactured using Aprecia’s ZipDose technology, which employs 3D printing to produce a porous formulation that rapidly disintegrates with a sip of liquid. While 3D printing has been used to make medical devices, this is the first FDA approval for a drug product manufactured with 3D technology.

According to Aprecia, ZipDose technology allows the delivery of a high drug load—up to 1,000 mg in a single dose. Levetiracetam manufactured with Zip-Dose technology is expected to be available in the U.S. in the first quarter of 2016.

Oral levetiracetam is used with other medications to treat primary generalized tonic-clonic seizures in patients 6 years of age and older with certain types of generalized epilepsy; to treat myoclonic seizures in patients 12 years of age and older with juvenile myoclonic epilepsy; and to treat partial-onset seizures in patients 4 years of age and older with epilepsy. It is recommended for use in patients weighing 20 kg (44 pounds) or more.

In clinical trials, the most common adverse events associated with levetiracetam included sleepiness, weakness, dizziness, and infection. In children, the most common adverse events included tiredness, aggression, nasal congestion, decreased appetite, and irritability.

Source: Aprecia Pharmaceuticals, August 3, 2015


Azelaic Acid Foam for Rosacea

The FDA has approved azelaic acid foam, 15% (Finacea, Bayer Healthcare) for the topical treatment of the inflammatory papules and pustules of mild-to-moderate rosacea.

The FDA’s approval was based on two clinical trials that examined the efficacy and safety of azelaic acid compared with the foam vehicle (without azelaic acid) in the topical treatment of papulopustular rosacea, which causes inflammatory lesions (papules and pustules) on the nose, cheeks, chin, and forehead.

The two pivotal, randomized, double-blind, vehicle-controlled, 12-week studies involved 1,362 subjects with papulopustular rosacea, with a mean lesion count of 21.3 (range, 12 to 50) inflammatory papules and pustules. While 681 subjects received active treatment, 681 received vehicle foam. The subjects were 19 to 92 years of age (mean age, 51 years), 96% were Caucasian, and 73% were female. The severity of a subject’s rosacea was assessed using the Investigator’s Global Assessment (IGA) scale and a count of the inflammatory lesions.

In both trials, the subjects were randomly assigned to receive azelaic acid foam, 15%, or its foam vehicle twice daily. Safety and tolerability were evaluated during the full 16-week study course, while efficacy endpoints were assessed at the end of the 12-week treatment period.

Treatment with azelaic acid foam resulted in a greater reduction in the mean nominal change in the inflammatory lesion count from baseline to the end of the 12-week treatment period compared with vehicle (−13.2 versus −10.3 in trial 1 and −13.3 versus −9.5 in trial 2). Azelaic acid foam also led to higher treatment success, defined as a score of “clear” or “minimal” with at least a two-step reduction from baseline on the five-point IGA (32.1% versus 23.4% in trial 1 and 43.4% versus 32.5% in trial 2). The most common adverse events in subjects treated with azelaic acid foam included local application-site pain, pruritus, dryness, and erythema.

Source: Bayer Healthcare, July 31, 2015

Onsolis Buccal Soluble Film

The FDA has approved a new formulation of fentanyl buccal soluble film (Onsolis, BioDelivery Sciences International, Inc.) for the management of breakthrough pain in opioid-tolerant cancer patients. The new formulation, which addresses previously announced appearance-related changes, allows the company to move toward returning Onsolis to the U.S. market, which it may do with an as-yet-unchosen partner as soon as 2016.

Source: BioDelivery Sciences International, Inc., August 13, 2015


Gilenya Tied to Brain Infections

The FDA is warning that a case of definite progressive multifocal leukoencephalopathy (PML) and a case of probable PML have been reported in multiple sclerosis (MS) patients treated with fingolimod (Gilenya, Novartis).

These are the first PML cases reported in patients receiving fingolimod who had not previously been treated with an immunosuppressant drug for MS or any other medical condition. Information about recent cases is being added to the drug label.

Fingolimod is an immunomodulator shown to benefit patients with relapsing forms of MS. Immunomodulators alter the immune system to reduce inflammation. PML is a rare and serious brain infection caused by the John Cunningham (JC) virus. The JC virus is common and harmless in most people but can cause PML in some patients who have weakened immune systems, including those taking immunosuppressants.

In August 2013, the FDA reported that a patient developed PML after receiving fingolimod. PML could not be conclusively linked to fingolimod in this case because prior to fingolimod treatment the patient had been treated with an immunosuppressant that can cause PML. Moreover, during fingolimod therapy the patient had received multiple courses of intravenous corticosteroids, which can weaken the immune system.

Source: FDA, August 3, 2015

Proglycem Lung Issue Probed

The FDA warns that serious pulmonary hypertension has been reported in infants and newborns treated with diazoxide (Proglycem, Merck) for hypoglycemia. In all cases, the disorder resolved or improved after diazoxide was stopped. The FDA is investigating and will determine whether changes are needed in the drug’s prescribing information.

Diazoxide is usually given in the hospital. Health care professionals should closely monitor babies receiving it, especially those with risk factors for pulmonary hypertension, such as meconium aspiration syndrome, respiratory distress syndrome, transient tachypnea of the newborn, pneumonia, sepsis, congenital diaphragmatic hernia, and congenital heart disease. Diazoxide should be stopped if pulmonary hypertension is identified. Caregivers and parents of a child receiving diazoxide should contact a health care professional immediately if they see signs of difficulty breathing.

Diazoxide is used to treat hypoglycemia related to medical conditions that cause the release of too much insulin from the pancreas. Diazoxide works mainly by blocking the pancreas from releasing insulin; this helps to increase blood sugar.

The FDA has identified 11 cases of pulmonary hypertension in infants and newborns treated with diazoxide since the drug’s approval in 1973; additional cases may have gone unreported. In addition to having other serious medical conditions, most of the infants were at high risk for pulmonary hypertension. They developed the condition within a day to a few months after starting diazoxide and were hospitalized or had hospital stays extended because of the condition. All recovered or improved after diazoxide was discontinued.

Source: FDA, July 16, 2015


Self-Screening for Substance Use

A simple, fast screening questionnaire for substance use has been developed and validated by researchers from New York University and Boston Medical Center. The questionnaire could streamline workflow for primary care practitioners and staff while affording patients the privacy to report possibly stigmatizing behavior.

Researchers based their Substance Use Brief Screen (SUBS) on the National Institute on Drug Abuse Quick Screen V1.0, which has not been validated. They tested their screen for reliability in 54 primary care patients and conducted another study to validate it in 586 more.

The questionnaire has four questions: In the past 12 months, how many days did you use tobacco; have four or more alcoholic drinks in a day; use illegal drug(s); or use prescription medication(s) “recreationally.”

The SUBS had high sensitivity and moderate-to-high specificity for detecting unhealthy use of tobacco, alcohol, and other drugs. Sensitivity was lower for prescription drugs alone but increased when they were combined into a single “any drug” category. The researchers say this may reflect drug users’ lack of clarity about what constitutes illicit versus prescription drug misuse.

The test was well accepted among a diverse patient population (although 11% in the reliability study needed help with questions or technical assistance), and easily used on a tablet computer. It compared favorably with other brief substance-use screening tools—all of which are interviewer-administered. A self-administered tool may put patients at greater ease about reporting substance use and thus be more consistently accurate in real-world practice.

Source: American Journal of Medicine, July 2015

Socioeconomics and Warfarin

Age, adherence, monitoring, bleeding history, comorbidity, and drug interactions all influence the risk of hemorrhage during warfarin therapy. Now add socioeconomic level to the list.

Using neighborhood-level income, researchers from the University of Toronto and St. Michael’s Hospital compared hemorrhage-related emergency department (ED) visits and hospitalization in Ontario, Canada, among 166,742 adults taking warfarin for atrial fibrillation. Nearly 10% visited the ED or were hospitalized for hemorrhage during warfarin therapy over a median follow-up of 369 days; 1,802 patients died in the hospital.

The overall rate of hemorrhage was 4.8% per year, but patients in the lowest quintile of income had a risk of 5.3% per person-year, compared with 4.3% among patients at the highest income level. When the researchers stratified the incidence over time, the five-year estimates were 11.5% for the lowest quintile and 9.6% for the highest.

In a secondary analysis, the researchers found a similar association between socioeconomic status and risk of fatal hemorrhage, with the poorest patients 28% more likely to die of warfarin-associated hemorrhage than those in the highest-income quintile. Low socioeconomic status put patients at greater risk for gastrointestinal and other hemorrhage subtypes, but not intracranial hemorrhage; the researchers don’t know why.

Socioeconomic status persisted as a risk factor even after the researchers adjusted for demographic factors, comorbid illness, and exposure to potential interacting medicines.

Their findings contribute to the growing body of literature on how socioeconomic status influences individual health—even in a universal health care system, the researchers say. The disparities may relate to differences in risk factors for cardiovascular and other disease, differences in disease severity, inequitable access to health services, and other determinants. They note that as many as 80% of older patients have inadequate knowledge of warfarin therapy, and lower socioeconomic status impacts health literacy.

Source: American Heart Journal, July 2015

Delirium Common in CICU

As many as one in five cardiac intensive care unit (CICU) patients was diagnosed with delirium in a study by researchers at the University of North Carolina (UNC).

Delirium has long been acknowledged as a problem in general intensive care unit patients. Patients are sicker than ever, with more comorbidities and more critical illness. But less is known about delirium in the CICU.

To help clarify, the researchers analyzed records for patients admitted to the UNC CICU between December 2012 and March 2014. Of 670 patients, 590 had a documented delirium score. Of those, 120 (20%) were diagnosed with delirium, as measured by the Confusion Assessment Method for the ICU (CAM-ICU).

Patients with delirium were more likely to be older, to have a history of end-stage renal disease, and to be more severely ill at baseline. Patients admitted after cardiac arrest or with acute valvular disease or acute respiratory failure were more likely to be CAM-ICU positive.

Patients with delirium in the CICU had longer median ICU stays (five versus two days). The researchers found no significant interaction between disease severity and the CAM-ICU score. Only delirium, history of chronic heart failure, and the APACHE II score were significantly associated with CICU length of stay.

The researchers say delirium was a “robust” predictor of mortality. Patients with delirium were nine times more likely to die in the CICU and more than six times as likely to die in the hospital. If they survived to discharge, they were more likely to transfer to a skilled nursing facility, rehabilitation center, or long-term acute care hospital.

Source: American Heart Journal, July 2015

Gestational Diabetes Rising

Diabetes is one of the most common and fastest-growing comorbidities of pregnancy, according to a study by the Centers for Disease Control and Prevention.

Using Agency for Healthcare Research and Quality databases for 19 states, the researchers found a 56% increase over 10 years in deliveries involving gestational diabetes mellitus (GDM): from 3.71 per 100 deliveries in 2000 to 5.77 per 100 deliveries in 2010. In that period, GDM deliveries increased significantly in all the study states, with relative increases ranging from 36% in Maryland to 88% in Utah.

Overall, the number of GDM deliveries rose by 59%, from 75,212 in 2000 to 119,229 in 2010 in the 19 states studied. In states where ethnicity statistics were analyzed, the highest relative increase was among Hispanic patients. However, overall, non-Hispanic Asians had the highest prevalence of GDM. (Indian Health Services hospitals are not included in the state data; the sample of Native Americans’ deliveries in community hospitals was too small to report.)

Patients with prepregnancy hypertension were also increasingly likely to have a birth complicated by GDM. The greatest relative increase by age was among women 15 to 24 years of age.

In the study period, the proportion of GDM deliveries with comorbidities also rose significantly: Prepregnancy hypertension increased 64%, from 2.5% to 4.1%, and pre-eclampsia increased 12%, from 9.8% to 11.0%.

Not surprisingly, the researchers believe the rise in GDM deliveries can be directly linked to the U.S. rise in obesity. Women who are obese are four to eight times more likely to develop GDM, they note.

Source: American Journal of Preventive Medicine, July 2015

Contraceptive Priorities Surveyed

What do women value most highly in a contraceptive? Safety and effectiveness top the list, say researchers from Washington University in St. Louis, Missouri, who reviewed surveys from 2,590 women enrolled in the Contraceptive CHOICE Project. Other factors weighed more or less heavily according to the individual.

Of the women who completed the survey, 99.6% had used contraceptives, usually oral contraceptives and condoms. When choosing a method, they also considered cost, whether the contraceptive is long-lasting, whether it’s hard to remember to take or use it, and whether it protects against sexually transmitted infections. Health care providers’ recommendations also scored high. The women did not rate the influence of partner, family, friends, or religious community highly.

More than 40% ranked side effects among the three most important factors. The majority had experienced at least one side effect with a contraceptive method, and 60% of those women had discontinued a method because of the side effect.

Tailored counseling about contraceptives is “essential” with women because many attributes are important. Studies that have found personalized contraceptive counseling can improve adherence and satisfaction. However, it’s also important to educate women more fully.

One potential limitation to the study, the researchers say, is that all respondents were participants in the CHOICE Project (a prospective cohort study designed to promote the use of long-acting reversible contraception) and might not be representative of other populations of women. Use of IUDs and implants was much higher among the CHOICE participants than generally in the nation: 75%, compared with 8.5%.

Source: American Journal of Obstetrics & Gynecology, July 2015


FDA Offers Guidance on Duodenoscope Cleaning

The FDA has provided a detailed list of supplemental duodenoscope reprocessing measures that emerged from an agency-led expert panel meeting in May. Facilities that use duodenoscopes can use these steps—in addition to meticulously following manufacturers’ reprocessing instructions—to further reduce the risk of infection.

The complex design of duodenoscopes, which contain many small working parts, presents challenges for effective reprocessing, the FDA says. Proper cleaning and disinfection of the elevator mechanism, with its microscopic, hard-to-reach crevices, is a particular concern. Meticulous adherence to the manufacturer’s reprocessing instructions is labor-intensive and prone to human error. And some bacterial contamination has persisted even with strict adherence to manufacturers’ reprocessing instructions. As a result, the FDA recommends that facilities and staff that reprocess duodenoscopes establish a comprehensive quality-control program.

At the meeting, representatives from health care facilities discussed strategies that have been implemented to reduce the risk of infection transmission in addition to meticulous cleaning as part of strict adherence to the manufacturer’s reprocessing instructions. These have included:

  • Microbiological culturing of samples from duodenoscope channels and the distal end of the scope to identify any bacterial contamination present after reprocessing.
  • Ethylene oxide sterilization following cleaning and high-level disinfection (HLD).
  • Use of a liquid chemical sterilant processing system following cleaning and HLD. The concentration, exposure time, and temperature are crucial.
  • Repeat HLD after the first HLD cycle in their duodenoscope reprocessing procedures.

Source: FDA, August 4, 2015

FDA Pans Symbiq Infusion Pump

The FDA has strongly encouraged health care facilities to discontinue the use of Hospira’s Symbiq infusion pumps because of cybersecurity vulnerabilities.

Hospira and an independent researcher confirmed that the Symbiq infusion system could be accessed remotely through a hospital’s network. This could allow an unauthorized user to control the device and to change the dosage that the pump delivers, which could lead to over- or under-infusion of critical patient therapies. The FDA and Hospira are not aware of any adverse events or unauthorized access of a Symbiq infusion system in a health care setting.

Hospira has stopped making and distributing the system because of unrelated issues and is working with customers to transition to alternative systems. However, because of recent cybersecurity concerns, the FDA strongly encourages health care facilities to begin moving to alternative infusion systems as soon as possible. While the Symbiq infusion system can no longer be purchased through Hospira, it may be available from third parties. The FDA strongly discourages such purchases.

The Symbiq infusion system is a computerized pump designed for the continuous delivery of general infusion therapy for a broad patient population. It is primarily used in hospitals or other acute and nonacute health care facilities, such as nursing homes and outpatient care centers. This infusion system can communicate with a hospital information system via a wired or wireless connection over facility network infrastructures.

While the system is still in use, the FDA says, it should be disconnected from the facility’s computer network (which will require manual updates for each pump).

Source: FDA, July 31, 2015

FDA Warns About LVADs

The FDA has alerted health care providers about serious adverse events associated with left ventricular assist devices (LVADs). Problems include an increased rate of pump thrombosis with the Heart-Mate II Left Ventricular Assist System (Thoratec Corporation) and a high rate of stroke with the HeartWare Ventricular Assist System HVAD (HeartWare, Inc.). Bleeding complications have been associated with both devices.

Implantable LVADs help the left ventricle circulate blood throughout the body in patients with advanced heart failure. The devices consist of a blood pump, power pack, and controller. The pump is implanted inside a patient’s body and attached to the heart’s left ventricle and to the aorta. The power pack and controller are connected to the blood pump and carried by the patient outside the body.

Both the HeartMate II and HeartWare systems (the only FDA-approved LVADs) are indicated to provide circulatory support to patients at risk of imminent death from nonreversible left ventricular heart failure until a donor heart becomes available for a transplant. The HeartMate II is also approved for patients with end-stage left ventricular heart failure who are not candidates for a heart transplant.

HeartMate II patients are experiencing pump thrombosis events more frequently and earlier than observed during clinical trials conducted to support the product’s approvals, the FDA says. And in a recent clinical trial designed to evaluate the safety and effectiveness of the Heart-Ware HVAD in patients not eligible for a heart transplant, 28.7% of HVAD patients experienced one or more strokes over two years, compared with 12.1% among patients implanted with the HeartMate II.

The cause of bleeding complications reported with both devices is not fully understood, but is likely due to many factors. One may be modification of anticoagulation therapy in an attempt to lower the risks of pump thrombosis and embolic stroke.

The FDA believes the benefits of LVADs continue to outweigh the risks; several related studies and investigations continue and the agency is working with both manufacturers. Health care providers should perform a thorough clinical evaluation, assessing the benefit–risk profile of each patient in determining the most appropriate treatment plan and, if necessary, selecting a device.

Source: FDA, August 5, 2015

Device Recall

Cook Medical Angiographic Catheters

Cook Medical recalled 95,167 Beacon Tip Angiographic Catheters based on 26 complaints of tips splitting or separating, resulting in adverse events. The recall includes specific versions and lot numbers of the Torcon NB Advantage Beacon Tip Catheters, Royal Flush Plus Beacon Tip High-Flow Catheters, and Slip-Cath Beacon Tip Catheters, distributed between June 2013 and June 2015.

Product and lot numbers can be found at Those with questions may contact Cook Medical Customer Relations at 1-800-457-4500 or 1-812-339-2235, Monday through Friday, 7:30 a.m. to 5 p.m. Eastern time.

Source: Cook Medical, August 3, 2015


Kunj Gohil, PharmD, RPh

Name: Dentca Denture Base

Manufacturer: Dentca, Los Angeles, California

Approval Date: August 10, 2015

Purpose: The Denta Denture Base is a new resin than can be used to create dentures.

Description: Dentures will be created using the new Dentca denture base and an additive manufacturing process. This process still requires a traditional casting impression in the dentist’s office, but the denture is made using a 3D printer.

Benefit: The approval of the Dentca Denture Base shows the continued advancement of 3D printing and its place in the manufacturing of medical devices. The base was deemed equivalent to the traditional Dentsply Trubyte Denture Base Resin System, with the exception that the new resin utilizes a 3D printing process.


Name: BioPlex 2200 HIV Ag-Ab assay

Manufacturer: Bio-Rad, Hercules, California

Approval Date: July 23, 2015

Purpose: This new assay is designed to aid in the diagnosis of infection with human immunodeficiency virus (HIV)-1 and/or HIV-2, including acute HIV-1 infection

Description: This tool can differentiate between HIV-1 antibodies, HIV-2 antibodies, and HIV-1 p24 antigen in human serum or plasma specimens. When it is used with the BioPlex 2200 system, HIV antigens and antibodies can be detected to provide a timely diagnosis differentiated by type of HIV.

Benefit: More than 1.2 million patients are living with HIV/AIDS in the U.S., and approximately 168,300 are not aware of their infection. Pre-market FDA approval of the BioPlex assay will allow clinicians to quickly make a diagnosis and educate the patient, in turn reducing the risk of transmission. The assay will also be used for organ-donor screening and will help in the diagnosis of infection in pediatric patients.


Name: GC85A Digital Radiography (DR) System

Manufacturer: Samsung, Danvers, Massachusetts

Approval Date: August 6, 2015

Purpose: This digital x-ray system is used for various imaging needs.

Description: The Samsung DR is a ceiling digital x-ray system designed to streamline workflows. It is accompanied by such key features as the S-Vue imaging system for accurate diagnosis in variable conditions, wireless detector and portable grid to display the patients body’s structure without increasing dose, smart control to quickly position the system with control-panel buttons, and S-Share compatibility to allow sharing with other DR systems.

Benefit: This system is designed to provide superior image quality with a more user-friendly experience. With multiple features, the device provides user-and patient-centric imaging required for quick and accurate diagnosis.

Sources: www.fiercemedicaldevices. com,