Ashley N. Lewis PharmD, BCPS

Bloxiverz, manufactured by Éclat Pharmaceuticals, is the first and only FDA-approved neostigmine methylsulfate injection. Bloxiverz is indicated for postoperative reversal of effects produced by nondepolarizing neuromuscular blocking agents (NMBAs) administered for surgical procedures.

 Because neostigmine was first introduced in 1931, its use precedes the 1938 Food, Drug, and Cosmetic Act, which requires premarket approval of all drugs to assure patients and consumers of drug safety and efficacy; therefore, neostigmine has remained on the market as an unapproved, grandfathered drug until the recent introduction of Bloxiverz.

Bloxiverz, a cholinesterase inhibitor, indirectly increases acetylcholine levels in the synaptic cleft by competitively binding to cholinesterases, thus blocking acetylcholine degradation. Acetylcholine, in turn, can then compete with nondepolarizing neuromuscular blocking agents for the same binding site on muscarinic and nicotinic receptors and, hence, reverse neuromuscular blockade after surgery. However, since neostigmine does not readily cross the blood-brain barrier, Bloxiverz does not significantly affect central nervous system cholinergic function.

Bloxiverz onset of action occurs within 1 to 20 minutes, with a duration of action of 1 to 2 hours, and an elimination half-life of 24 to 113 minutes. The volume of distribution ranges between 0.12 and 1.4 L/kg with 15% to 25% protein binding (human serum albumin). Neostigmine undergoes hepatic metabolism with 50% of the drug excreted unchanged in the urine. Total neostigmine clearance is estimated to be between 1.14 and 16.7 mL/kg/min.

Bloxiverz should be administered as an intravenous (IV) injection over at least 1 minute. To achieve a train-of-four (TOF) twitch ratio of 90% (TOF

) within 10 to 20 minutes of administration, a 0.03 to 0.07 mg/kg dose is recommended, and peripheral nerve stimulation devices capable of delivering a TOF stimulus are crucial for treatment initiation as well as for determining possible need for additional Bloxiverz doses. Dosing is highly individualized and is determined based on the half-life of the NMBA being reversed, the extent of recovery that has already occurred prior to administration, and whether there is a need to rapidly reverse the NMBA effects.

The 0.03 mg/kg dose is recommended for reversal of NMBAs with shorter half-lives (eg, rocuronium) and when the first twitch response to TOF stimulus is much greater than 10% of baseline or when a second twitch is present. The 0.07 mg/kg dose is recommended for NMBAs with longer half-lives (eg, vecuronium, pancuronium), when the first twitch response is relatively weak (not substantially greater than 10% of baseline), or if there is need for a more rapid recovery of the neuromuscular blockade. The recommended maximum total dose is 0.07 mg/kg or 5 mg, whichever value is less.

 These dosing guidelines apply for adult and pediatric patients.

Used in practice for over 70 years, the efficacy of neostigmine has been well established; thus, there have not been any studies conducted specifically on the use of Bloxiverz.

 One study utilized a randomized controlled trial to assess neostigmine’s effectiveness, using various low doses, in antagonizing a shallow atracurium block compared with no neostigmine use, with normal saline (NS) as control. Investigators designated the time interval between the intervention (various neostigmine doses as well as NS) and a TOF ratio greater than 0.9 as a primary efficacy end point and neuromuscular recovery after 5 and 10 minutes as a secondary efficacy end point. With these end points in mind, the study demonstrated that, compared with no neostigmine, the time to a TOF ratio greater than 0.9 was shortened and neuromuscular recovery at 5 and 10 minutes was more profound when a neostigmine dose of 10 mcg/kg was administered.

Because Bloxiverz can cause bradycardia, an anticholinergic agent, particularly atropine sulfate or glycopyrrolate, should be administered intravenously prior to Bloxiverz using a separate syringe. In addition to bradycardia, the most common adverse reactions during treatment include nausea, vomiting, and dry mouth.

With a current shortage of neostigmine injection products the recent approval of Bloxiverz has been timely.

 It is supplied as 0.5-mg/mL and 1-mg/mL solutions, and both strengths are available as 10-mL multiple-dose vials in packages of 10. Vials should be stored at room temperature and protected from light.

 The average wholesale price (AWP) of each vial, irrespective of strength, is $15.

Ashley N. Lewis, PharmD, BCPS, is a drug information specialist at University of North Carolina (UNC) Hospitals and a clinical assistant professor at the UNC Eshelman School of Pharmacy.

Sandra Hanna, PharmD Candidate, is a second-year pharmacy student at the UNC Eshelman School of Pharmacy and an intern at the UNC Hospital Drug Information Center in Chapel Hill, North Carolina.

		Bloxiverz [package insert]. Chesterfield, MO: Éclat Pharmaceuticals; May 2013.

		Unapproved drugs: drugs marketed in the United States that do not have required FDA approval. FDA website. www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/EnforcementActivitiesbyFDA/SelectedEnforcementActionsonUnapprovedDrugs/. Published August 22, 2012. Accessed September 13, 2013.

		Neostigmine: drug facts and comparisons. Facts & Comparisons [online database]. St. Louis, MO: Wolters Kluwer Health, Inc; July 2013. Accessed October 7, 2013.

		Fuchs-Buder T, Baumann C, De Guis, J, et al. Low-dose neostigmine to antagonize shallow atracurium neuromuscular block during inhalation anaesthesia: a randomized controlled trial. Eur J Anaesthesiol. 2013; 30:594-598.

		Neostigmine methylsulfate injection drug shortage. American Society of Health-System Pharmacists website. www.ashp.org/DrugShortages/Current/Bulletin.aspx?id=311.Published August 16, 2013. Accessed September 13, 2013.

		Phone conversation with drug representative from Éclat Pharmaceuticals, Chesterfield, MO. September 13, 2013.

Articles

Bloxiverz, manufactured by Ã‰clat Pharmaceuticals, is the first and only FDA-approved neostigmine methylsulfate injection.

Neostigmine Methylsulfate Injection (Bloxiverz)

Elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (Stribild), manufactured by Gilead Sciences, Inc, is a combination antiretroviral agent approved by the FDA as a complete regimen for the treatment of HIV-1 infection in adults who are antiretroviral treatment—naïve. The safety and efficacy of Stribild have not been established in pediatric patients. Stribild is a combination of an integrase inhibitor (elvitegravir), a pharmacokinetic enhancer (cobicistat), and 2 nucleos(t)ide reverse transcriptase inhibitors (emtricitabine/tenofovir).

Elvitegravir inhibits the catalytic activity of integrase, thus preventing integration of the pro-viral gene into human DNA. Cobicistat inhibits enzymes of the CYP3A subfamily and enhances systemic exposure to elvitegravir. Emtricitabine is a cytosine analogue, and tenofovir is an analogue of adenosine 5’-monophosphate. Emtricitabine and tenofovir interfere with HIV viral RNA dependent DNA polymerase activities, resulting in inhibition of viral replication. Time to peak in plasma is about 3 hours with a range of 2 to 4 hours. Protein binding is 99% with elvitegravir, 98% with cobicistat, <4% with emtricitabine, and <1% with tenofovir.

The recommended dose of Stribild is 1 tablet taken by mouth once daily with food. Patients with an estimated creatinine clearance below 70 mL/min should not be started on Stribild. This is due to the inability to decrease the dose of a fixed-dose combination tablet if needed due to renal impairment, which is required for emtricitabine and tenofovir. Treatment should be discontinued if creatinine clearance drops below 50 mL/min during treatment. A dosage adjustment is not required for patients with mild-to-moderate hepatic impairment; however, Stribild is not recommended for use in patients with severe hepatic impairment due to lack of safety data in this population.

The efficacy and safety of Stribild have been evaluated in 2 randomized, double-blind phase 3 studies; 1 comparing Stribild with ritonavir-boosted atazanavir (ATV/RTV) plus emtricitabine/tenofovir (Truvada) and 1 comparing Stribild with efavirenz/emtricitabine/tenofovir (Atripla). Stribild was noninferior in both studies to both of the standard treatment regimens in controlling viral load. In the Stribild versus Atripla trial, 305 of 348 patients (87.6%) on Stribild versus 296 of 352 patients (84.1%) on Atripla had an HIV ribonucleic acid (RNA) concentration of <50 copies/mL at week 48. In the Stribild versus ATV/RTV with Truvada trial, 316 of 353 patients (89.5%) on Stribild versus 308 of 355 patients (86.8%) on Atripla had an HIV RNA concentration of <50 copies/mL at 48 weeks. Additionally, both clinical trials showed a good tolerability profile with Stribild. In the Stribild versus Atripla study, 4% of Stribild patients discontinued treatment due to adverse events compared with 5% of Atripla patients. In the study comparing Stribild with ATV/RTV plus Truvada, 3.7% of patients on Stribild discontinued treatment because of side effects compared with 5.1% on ATV/RTV plus Truvada.

The most commonly observed side effects of Stribild during clinical studies included nausea and diarrhea; however, lactic acidosis and severe hepatomegaly with steatosis have been reported with the use of nucleoside analogues, including tenofovir, which is a component of Stribild. Additionally, severe acute exacerbations of hepatitis B (HBV) have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued emtricitabine or tenofovir, 2 of the components of Stribild. In some patients infected with HBV and treated with Emtriva, exacerbations of HBV were associated with liver decompensation and liver failure. Patients who are coinfected with HIV-1 and HBV should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with Stribild. Stribild can alter the concentration of drugs metabolized by CYP3A or CYP2D6. Drugs that induce CYP3A activity can increase the clearance of elvitegravir and cobicistat, resulting in decreased plasma concentration of cobicistat and elvitegravir, which may lead to development of resistance to Stribild. Significant drug—drug interactions are listed in the package insert.

Stribild is available in bottles of 30 tablets and should be stored at controlled room temperature. The acquisition cost of Stribild is $75 per tablet. More information about Stribild is available at 

		Stribild package insert. Gilead Sciences. Foster City, CA. Updated 8/12.

		Micromedex® 2.0 Online [Intranet]. Truven Health Analytics Inc 2013. www.micromedexsolutions.com. Accessed August 29, 2013.

		DeJesus E, Rockstroh J, Henry K, et al. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate versus ritonavir-boosted atazanavir plus co-formulated emtricitabine and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: a randomized, double-blind, phase 3, non-inferiority trial. 

		Sax P, DeJesus E, Mills A, et al. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3 trial, analysis of results after 48 weeks [correction appears in Lancet. 2012;380:730]. 

Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Fumarate (Stribild)

Ado-trastuzumab emtansine (Kadcyla), manufactured by Genentech, is a human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug conjugate FDA approved for the treatment of patients with HER2-positive, metastatic breast cancer. Prior to receiving ado-trastuzumab emtansine, patients should have previously received treatment with trastuzumab (Herceptin) and a taxane either separately or in combination. Additionally, patients eligible for Kadcyla treatment would have received prior therapy for metastatic disease or developed a disease recurrence within 6 months of completion of adjuvant therapy.

Kadcyla incorporates a monoclonal antibody with antitumor properties (trastuzumab) and a cytotoxic, microtubule-inhibiting agent (DM1). The expression of HER2 is increased in 20% of breast cancers and is associated with a decreased length of survival. The conjugated design of Kadcyla allows intracellular delivery of cytotoxic drug selectively to HER2-overexpressing cells. As a result, the therapeutic effects of Kadcyla are increased while unnecessary side effects associated with exposure of cytotoxic drug to normal tissues are decreased. The pharmacokinetics of Kadcyla were described in a phase 1 study and a pooled analysis of 5 trials in patients with breast cancer. Mean C

 values, observed shortly after the end of infusion, for the trastuzumab and DM1 components were 83.4 μg/mL and 4.61 ng/mL, respectively. The volume of distribution was reported as 3.13 L and a 93% rate of protein binding was observed in vitro. The half-life of Kadycla was approximately 4 days with no accumulation observed with every 3-week administration. Age, race, and renal function have not demonstrated a clinically significant effect on Kadcyla pharmacokinetics.

The recommended dose of Kadcyla is 3.6 mg/kg every 3 weeks as an intravenous infusion. The first infusion should be administered over 90 minutes while the patient is monitored for fever, chills, or an infusion reaction. Subsequent doses can be administered over 30 minutes if the drug is well tolerated. Two stages of dose reduction (3 mg/kg and 2.4 mg/kg) are indicated in the event of increased serum transaminases, thrombocytopenia, hyperbilirubinemia, pulmonary toxicity, left ventricular dysfunction, or peripheral neuropathy.

Kadcyla obtained approval based on results from the EMILIA study. Nine hundred ninety-nine patients with HER2-positive, unresectable, advanced, or metastatic breast cancer previously treated with trastuzumab and a taxane were randomly assigned to treatment with Kadcyla or lapatinib (Tykerb, GlaxoSmithKline) and capecitabine (Xeloda, Genentech). Patients in the lapatinib/capecitabine group self-administered 1250 mg oral lapatinib and 1000 mg/m

 capecitabine every 12 hours on days 1 through 14 of each 21-day cycle. Patients assigned to Kadcyla received 3.6 mg/kg IV every 21 days. Patients continued study treatment until disease progression or side effects became intolerable. The median progression-free survival was 9.6 months with Kadcyla versus 6.4 months with lapatinib/ capecitabine (P <0.001). Additionally, median overall survival was increased, 30.9 months versus 25.1 months (P <0.001), in patients who received Kadcyla.

The most commonly observed side effects of Kadcyla treatment during the EMILIA trial (frequency ≥25%) were fatigue, headache, nausea, constipation, musculoskeletal pain, thrombocytopenia and increased transaminases. Severe hepatoxicity, left ventricular dysfunction, pulmonary toxicities, neurotoxicity, and serious infusion-related reactions were also observed.

On April 17, 2013, the Institute for Safe Medication Practices (ISMP) and the American Society of Health-System Pharmacists (ASHP) activated the National Alert Network (NAN) to warn practitioners of the risk of confusion between the generic names of Kadcyla (ado-trastuzumab emtansine) and Herceptin (trastuzumab). The FDA recommends use of both the brand and nonproprietary name in written, verbal, and electronic communication of Kadcyla. No medication errors have been reported since approval on February 22, 2013, but the FDA notes that medication errors did occur during clinical trials.

Ado-trastuzumab emtansine (Kadcyla) is available as preservative- free powder for injection in a 100- and 160-mg vial. The acquisition cost of Kadcyla is $3328.28 for a 100-mg vial and $5325.25 for a 160-mg vial. More information about Kadcyla is available at 

Ashley N. Lewis, PharmD, BCPS, is a drug information specialist at University of North Carolina (UNC) Hospitals and a clinical assistant professor at the UNC Eshelman School of Pharmacy. Sarah Peters is a 2014 PharmD candidate at the UNC Eshelman School of Pharmacy and an intern at the University of North Carolina (UNC) Hospital Drug Information Center in Chapel Hill, North Carolina.

		Kadcyla [package insert]. South San Francisco, CA: Genentech, Inc; February 2013.

		Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. 

		National Alert Network. Confusion regarding the generic name of the HER2-targeted drug KADCYLA (ado-trastuzumab emtansine). www.ismp.org/nan/files/20130417.pdf. Published April 17, 2013. Accessed May 7, 2013.

		Institute for Safe Medication Practices. Confusion between two HER2-targeted monoclonal antibodies. 

		FDA MedWatch Online. Drug Safety Communication: FDA warns about potential medication errors resulting from confusion regarding nonproprietary name for breast cancer drug Kadcyla (ado-trastuzumab emtansine). www.fda.gov/Drugs/DrugSafety/ucm350733.htm. Published May 6, 2013. Accessed May 7, 2013.

This human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug conjugate is approved for the treatment of patients with HER2-positive, metastatic breast cancer.

Ado-trastuzumab Emtansine (Kadcyla)

Tecfidera (dimethyl fumarate) has been approved by the FDA for the treatment of relapsing forms of multiple sclerosis.

Tecfidera (dimethyl fumarate) is an oral fumaric acid derivative approved by the FDA for the treatment of relapsing forms of multiple sclerosis (MS). The majority of medications available to treat MS are administered parenterally, so the availability of oral agents is desirable for patient convenience and ease of administration. The only other oral agent currently available on the market to treat MS is fingolimod (Gilenya), which is associated with numerous warnings, precautions, and adverse effects including QTc prolongation, AV block, bradycardia, hypertension, infection, and macular edema.

Tecfidera is a fumaric acid derivative that has unknown immunomodulation effects that treat the symptoms of relapsing MS. Tecfidera and its active metabolite monomethyl fumarate (MMF) have been shown to activate the nuclear factor-like 2 (NrF2) pathway, which has a role in cellular response to oxidative stress. MMF also acts as a nicotinic receptor agonist in vitro. Tecfidera displays a linear relationship between dose and corresponding peak plasma concentration (C

) and overall exposure (AUC) within the dose range studied (120-360 mg). The median time to C

 of the active metabolite MMF is 2 to 2.5 hours. Tecfidera is metabolized to MMF prior to reaching systemic circulation by esterase expressed in the gastrointestinal tract, blood, and tissues. Tecfidera is mainly excreted as carbon dioxide via exhalation but also in the urine and feces (1%).

The initial dose of Tecfidera is 120 mg administered orally twice daily for 7 days followed by a maintained dose of 240 mg administered orally twice daily. Dosage adjustments are not needed for renal or hepatic impairment. For patients with serious infections, clinicians should consider withholding treatment until the infection is resolved. Tecfidera may be irritating to mucous membranes and should therefore not be crushed or chewed and the capsule contents should not be sprinkled on food. Tecfidera can be taken with or without food; however, administration with food may reduce the incidence of flushing.

Tecfidera has been shown to reduce relapses and development of brain lesions, as well as to slow disability progression over time, while demonstrating a favorable safety and tolerability profile. Tecfidera was FDA-approved based on data from the DEFINE and CONFIRM clinical trials. In DEFINE, Tecfidera significantly reduced the proportion of patients who relapsed by 49% (p <0.0001), the annualized relapse rate (ARR) by 53% (p <0.0001), and 12-week confirmed disability progression by 38% (p = 0.0050) compared with placebo at 2 years. In CONFIRM, Tecfidera significantly reduced ARR by 44% (p <0.0001) and the proportion of patients who relapsed by 34% (p = 0.0020) compared with placebo at 2 years. Additionally, both studies showed that Tecfidera significantly reduced lesions in the brain compared with placebo, as measured by magnetic resonance imaging; however, the reduction in disability progression seen in the DEFINE study was not seen in the CONFIRM study. The most commonly reported side effects in the Tecfidera group in both studies were flushing, nasopharyngitis, diarrhea, headache, and fatigue.

Contraindications, Warnings, and Precautions

Decreased lymphocyte counts may occur with use of Tecfidera; therefore, a complete blood count should be obtained at least once yearly during use as well as prior to initiation. Flushing may be seen in up to 40% of patients on Tecfidera. Symptoms are worse at initiation of the medication and improved with time. Health care professionals can access more information about Tecfidera, including complete prescribing information, at www.tecfidera.com.

Ashley N. Lewis, PharmD, BCPS, is a drug information specialist at University of North Carolina Hospitals (UNCH). She is currently the pharmacy and therapeutics secretary at UNCH and manages the day-to-day operations of the Drug Information Center and serves as a clinical assistant professor at the UNC Eshelman School of Pharmacy.

		Tecfidera [package insert]. Cambridge, MA: Biogen Idec Inc; May 2013. www.tecfidera.com. 

		Micromedex 2.0 Online [Intranet]. Health Analytics Inc. 2013. www.micromedexsolutions.com.

		Gold R, Kappos L, Arnold DL, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. 

		Fox RJ, Miller DH, Phillips JT, et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. 