PHARMACY PRÉCIS Précis: a concise summary of essential points, statements or facts Volume 32 (Issue 2) July 2014

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1 PHARMACY PRÉCIS Précis: a concise summary of essential points, statements or facts Volume 32 (Issue 2) July 2014 New Molecular Entities of January to June 2014 New molecular entities, biologic agents, and drug formulations/combinations, approved January to June of 2014 (including indication, approval date, and comments) are presented in this issue of Pharmacy Précis. An explanation of the FDA classification of the new drugs also is included. If you need any additional information regarding these agents, please call the Samford University Global Drug Information Service at (205) FDA classification for newly approved drugs is based on chemical classification and is outlined below. CHEMICAL CLASSIFICATION 1. New molecular entity - drug not marketed in U.S. by any manufacturer 2. New salt or active ingredient - active moiety or nonenantiomeric counterpart is marketed in the U.S., but this particular salt, ester, or derivative is not. 3. New formulation - drug marketed in the U.S., but this particular formulation is not 4. New combination - two or more ingredients in combination not marketed in the U.S. 5. New manufacturer - already marketed by another firm; duplicated salt, formulation or combination 6. New indication - already marketed by same firm but used primarily for new indications 7. Marketed without an approved NDA 8. OTC Switch FDA CLASSIFICATIONS THERAPEUTIC CLASSIFICATION S = Standard review - assigned to drugs that appear to have therapeutic qualities similar to drugs already approved P = Priority review - assigned to drugs that appear to have therapeutic gain over drugs currently available O = Orphan designation - Pursuant to Section 526 of the Orphan Drug Act (Public Law as amended). 1. Providing effective therapy or diagnosis for a disease not adequately treated or diagnosed by any marketed drug 2. Providing improved treatment or greater effectiveness or safety 3. Having a modest, but real advantage over convenience, elimination of troublesome adverse-effects, or treatment of a specific sub-population of patients ADDITIONAL CLASSIFICATION AA = AIDS drugs (always classified as P) E = Drugs that treat lifethreatening or severely debilitating diseases F = Possible fraudulently submitted data G = Data from a type F classification is validated N = Nonprescription drug V = Designated orphan drug Editor: Maisha Kelly Freeman, Pharm.D., MS, BCPS, FASCP Associate Editor: Richard Wakefield, Pharm.D., Birmingham, AL Telephone: (205) FAX: (205) Samford University is an Equal Opportunity Institution that complies with applicable law prohibiting discrimination in its educational and employment policies and does not unlawfully discriminate on the basis of race, color, sex, age, disability, or national or ethnic origin.

2 NEW MOLECULAR ENTITIES JANUARY TO JUNE OF 2014 GENERIC NAME (BRAND NAME) SPONSOR CATEGORY APPROVAL DATE Dapagliflozin (Farxiga) AstraZeneca 1S Jan 08, 2014 Tasimelteon (Hetlioz) Vanda Pharms Inc. 1P Jan 31, 2014 Ibrutinib (Imbruvica) Pharmacyclics Inc. 1P Feb 12, 2014 Droxidopa (Northera) Chelsea Theraps Inc. 1P/O Feb 18, 2014 Florbetaben F-18 (Neuraceq) Piramal Imaging 1S Mar 19, 2014 Miltefosine (Impavido) Paladin Therap 1P Mar 19, 2014 Apremilast (Otelzla) Celgene Corp 1S Mar 21, 2014 Ceritinib (Zykadia) Novartis Pharms Corp 1P Apr 29, 2014 Vorapaxar Sulfate (Zontivity) Merck Sharp Dohme 1S May 08, 2014 Dalbavancin HCl (Dalvance) Durata Theraps Intl. 1P May 23, 2014 Dapagliflozin (Farxiga, AstraZeneca) Pharmacology: Sodium-glucose cotransporter 2 (SGLT2) inhibitor. Indication: Adjunct treatment, to diet and exercise, to improve glycemic control in adults with type 2 diabetes mellitus. Adverse Drug Reactions: The most common adverse events reported were female genital mycotic infections, nasopharyngitis, and urinary tract infections. Dose: The recommended starting dose is 5 mg by mouth, once daily, taken in the morning, with or without food. The dose can be increased to 10 mg once daily in patients in need of further glycemic control. In patients that are volume depleted, it is recommended to correct this condition prior to initiation of Dapagliflozin. Dapagliflozin should not be initiated in patients with an egfr < 60 ml/min/1.73m 2 and should also be discontinued if patients have a persistently low egfr < 60 ml/min/1.73m 2. No dosage adjustments are needed for mild renal impairment [egfr > 60 ml/min/1.73m 2 ]. Formulation: 5-mg tablets, 10-mg tablets. Warnings/Contraindications: Dapagliflozin is contraindicated in patients with severe renal impairment, end-stage renal disease (ESRD), and in patients receiving dialysis. Use with caution in patients with impaired renal function, elderly patients, and patients receiving loop diuretics, to help reduce renal and hypotensive adverse events. Use with caution with concomitant use of insulin or insulin secretagogues, to help reduce hypoglycemia. Use with caution in patients with histories of genital mycotic infections. Increases in low-density lipoprotein cholesterol (LDL-C) may occur; monitoring is suggested. Avoid use in patients with active bladder cancer. Consider risks versus benefits of dapagliflozin use in patients with history of bladder cancer. In pregnancy, consider alternative therapies and use only if benefits of treatment outweigh potential harm to the fetus. It is rated pregnancy risk category C. Place in Therapy: Dapagliflozin is the second SGLT2 inhibitor approved for treatment of type 2 diabetes mellitus and can be taken without regard to meals. 1 Clinical studies indicate that reductions in fasting blood glucose can be seen in as early as one week and improvements persist through week Notes: Dapagliflozin is not indicated for treatment of type 1 diabetes mellitus or diabetic ketoacidosis. Safety in children is unknown. Before initiating dapagliflozin, assess the patient s volume status, and monitor signs and symptoms of dehydration and hypotension during therapy. Monitor renal function during therapy as well. Tasimelteon (Hetlioz, Vanda Pharmaceuticals Inc.) Pharmacology: Melatonin receptor agonist. Indication: Non-24-hour sleep-wake disorder. Adverse Drug Reactions: The most common adverse events reported were headache, increased alanine aminotransferase, nightmares or unusual dreams, and upper respiratory or urinary tract infections. Dose: 20 mg by mouth, prior to bedtime, without food, at the same time every night. Formulation: 20-mg capsule. Warnings/Contraindications: Activity prior to going to bed should be limited after patients take Hetlioz; it can impair the performance of activities which require mental alertness. Tasimelteon has not been studied in patients with severe hepatic impairment, so it is recommended to avoid use in these (Back to New Molecular Entities Table) 2

3 Tasimelteon (Hetlioz, Vanda Pharmaceuticals Inc.)(continued) Warnings/Contraindications: patients. Use in pregnancy only if potential benefits outweigh potential harm to the fetus; pregnancy risk category C. Place in Therapy: Tasimelteon is the first agent FDA-approved for non-24-hour sleep-wake disorder. 3 In a clinical study, tasimelteon was associated with an increased in nighttime sleep compared to placebo (50 vs. 22 minutes), and significantly decreased daytime napping (49 vs. 22 minutes). 4 Notes: Avoid use of tasimelteon with rifampin, other CYP3A4 inducers, and with strong CYP1A2 inhibitors. The efficacy of tasimelteon may be reduced in smokers compared to non-smokers, due to CYP1A2 induction caused by smoking. Tasimelteon does not appear to cause physical dependence or withdrawal symptoms following discontinuation. Daily use for several weeks to months may be needed before benefit is observed, due to individual differences in circadian rhythms. Ibrutinib (Imbruvica, Pharmacyclics, Inc.) Pharmacology: Inhibitor of Bruton s tyrosine kinase. Indication: Treatment of mantle cell lymphoma (MCL) or chronic lymphocytic leukemia (CLL) in patients who have received at least one prior therapy. Adverse Drug Reactions: Thrombocytopenia, diarrhea, neutropenia, anemia, fatigue, peripheral edema, upper respiratory infections, nausea, vomiting, bruising, dyspnea, constipation, stomatitis, arthralgias, and anorexia. Subdural hematoma was the most common adverse event resulting in discontinuation. Dose: MCL dosing: 560 mg by mouth once daily; CLL dosing: 420 mg by mouth once daily. Formulation: Available as a 140-mg capsule. Warnings/Contraindications: No contraindications listed. Warnings include increased risk of hemorrhage and bleeding events. Hold 3 7 days prior to and after surgical procedures. Myelosuppression can occur as neutropenia, thrombocytopenia, and anemia. Monitor blood counts monthly, and monitor for fever and infections on a regular basis. Renal toxicity can occur; therefore, creatinine monitoring and hydration maintenance are necessary. In clinical trials, some patients developed secondary primary malignancies such as skin cancers and other carcinomas. Avoid use in hepatic impairment. Place in Therapy: Ibrutinib is an oral once-daily tyrosine kinase inhibitor option for the treatment of MCL. 5 The overall response rate in patients with relapsed or refractory CLL was 71% and 65.8% in patients with MCL. 6 Notes: Do not crush. Retain in original packaging. Significant drug-drug interactions can occur if taken with cytochrome P450 3A4 inhibitors and inducers. Pregnancy category D.. Droxidopa (Northera, Chelsea Therapeutics, Inc.) Pharmacology: Synthetic amino acid analog metabolized directly to norepinephrine. Indication: Treatment of symptomatic neurogenic orthostatic hypotension caused by primary autonomic failure (related to Parkinson s disease (PD), multiple system atrophy, or pure autonomic failure), dopamine beta-hydroxylase deficiency, or non-diabetic autonomic neuropathy. Adverse Drug Reactions: Headache, dizziness, nausea, and hypertension. Dose: Recommended initial dose is 100 mg by mouth three times daily. Titrate to desired symptomatic response, to maximum total daily dosage of 1800 mg. Warnings/Contraindications: No contraindications listed. A boxed warning was issued due to the risk of supine hypertension; if supine hypertension persists after elevation of the head of the bed, reduce dose or discontinue the agent. Administer night time dose at least 3 hours prior to bedtime to reduce risk of supine hypertension. Additional warnings include hyperpyrexia and confusion (especially with concomitant levodopa use) and exacerbation of ischemic heart disease, arrhythmias, and congestive heart failure. Allergic reactions have been reported in relationship to the FD+C Yellow No. 5 dye. Place in Therapy: Droxidopa is an orphan drug approved for the treatment of orthostatic hypotension related to PD and is used to support autonomic integrity in patients with compromised cardiovascular systems. 7 No information is available for efficacy beyond 2 weeks of treatment. 8 Notes: Monitoring of supine hypertension prior to initiation and after dose increases is advised. Notable drug interactions include PD medications and agents that increase blood pressure. Can be taken with or without food, but high fat meals should be avoided with administration. 3

4 Florbetaben (Neuraceq, Piramal Imaging) Pharmacology: Radioactive diagnostic agent. Indication: Positron Emission Tomography (PET) imaging of the brain to detect β-amyloid plaque density in adult patients with cognitive impairment being evaluated for Alzheimer s Disease or alternate causes of cognitive decline. Adverse Drug Reactions: Injection site reactions of erythema, irritation, and pain, Dose: Inject 300 MBq (8.1 mci) as slow single IV bolus (6 sec/ml) in a total volume of 10 mls. Obtain 15 to 20 minute PET images starting from 45 to 130 minutes after IV administration. Formulation: 30 ml multi-dose vial at strength of 50 to 5000 MBq/ml injectable solution. Warnings/Contraindications: Image interpretation errors have occurred (mostly false positives). Determine image results independently of patient s clinical information. Florbetaben contributes to long-term cumulative radiation exposure. Handle safely to protect patients and health care workers from unintentional radiation exposure. Florbetaben has unknown effects on pregnant or lactating women and is a pregnancy category C. Instruct breastfeeding mothers use an alternate source of nutrition for 24 hours after exposure to florbetaben. Place in Therapy: Use of florbetaben with PET imagining allows visualization of plague density in patients with suspected Alzheimer s Disease. 9 Notes: Radiation absorbed dose from a 300 MBq dose of florbetaben is msv in adults. Miltefosine (Impavido, Paladin Therapeutics, Inc) Pharmacology: Antileishmanial. Indication: Visceral leishmaniasis due to Leishmania donovani, cutaneous leishmaniasis due to Leishmania braziliensis, Leishmania guyanensis, and Leishmania panamensis, and mucosal leishmaniasis due to Leishmania braziliensis in children 12 years and older weighing over 30 kg (66 lbs.). Adverse Drug Reactions: Nausea, vomiting, diarrhea, headache, decreased appetite, dizziness, abdominal pain, pruritus, somnolence, elevated transaminases, and elevated creatinine. Dose: Weight-based dosing: 33 to 44 kg: one 50-mg capsule twice daily for 28 consecutive days; 45 kg or greater: one 50-mg capsule three times daily for 28 consecutive days. Formulation: 50-mg oral capsule. Warnings/Contraindications: Contraindications include pregnancy and Sjӧgren-Larsson-Syndrome. Miltefosine causes embryo-fetal toxicity and is a pregnancy category D. It should not be used during breastfeeding, and breastfeeding should be avoided for 5 months after discontinuing miltefosine. One warning for miltefosine includes possible negative reproductive effects due to infertility seen in male and female rats. Other warnings include disrupted absorption of oral contraceptives if gastrointestinal adverse effects occur and thrombocytopenia. Use cautiously in patients with impaired renal or hepatic function. Place in Therapy: Miltefosine provides an option for oral treatment of leishmaniasis. One other FDAapproved agent exists for this indication and is only available parenterally (Amphotericin B). 10 Notes: Due to embryo-fetal toxicity, obtain a urine or serum pregnancy test prior to initiating therapy. Advise use of contraception in females of reproductive age. Administer with food to improve gastrointestinal adverse effects. Do not chew or break the tablet; swallow whole. Consume adequate fluids to prevent dehydration and kidney damage. Monitor platelet count during therapy for visceral leishmaniasis to assess for thrombocytopenia. Apremilast (Otezla, Celgene) Pharmacology: Phosphodiesterase-4 inhibitor. Indication: Active psoriatic arthritis. Adverse Drug Reactions: Diarrhea, nausea, headache, upper respiratory tract infections, vomiting, nasopharyngitis, and upper abdominal pain. Dose: Initiate at 10 mg in the morning and titrate to the recommended dose of 30 mg twice daily using the following schedule. Reduce dose to 30 mg once daily in severe renal impairment (calculated CrCl < 30 ml/min). Initial dose titration in this group should use only the morning doses (skipping the evening doses) of the titration schedule below: Day 1: 10 mg in morning; Day 2: 10 mg in morning and 10 mg in evening; Day 3: 10 mg in morning and 20 mg in evening; Day 4: 20 mg in morning and 20 mg in evening; 4 (Back to New Molecular Entities Table)

5 Apremilast (Otezla, Celgene)(continued) Dose: Day 5: 20 mg in morning and 30 mg in evening; Day 6 and thereafter: 30 mg twice daily. Formulation: 10-mg, 20-mg, and 30-mg oral tablets. Warnings/Contraindications: Warnings include depression, weight decrease, and drug interactions. Monitor patients with depression for suicidal thoughts and behaviors. Monitor weight regularly and consider discontinuation if significant or unexplained weight loss occurs. Strong cytochrome P450 enzyme inducers may interact with apremilast and cause a loss of efficacy to occur. Place in Therapy: Apremilast is the first oral PDE-4 inhibitor indicated for the treatment of psoriatic arthritis. 11 Therapy was associated with significantly more patients achieving the American College of Rheumatology 20 response at week 16 in 3 clinical studies compared to placebo (38%, 32%, and 41% compared with 19%, 19%, and 18%). 12 Notes: Titrate to the recommended dose to reduce risk of gastrointestinal symptoms. Apremilast may be taken with or without food. Tablets should not be crushed, split, or chewed. Ceritinib (Zykadia, Novartis Pharms) Pharmacology: Antineoplastic agent; kinase inhibitor. Indication: Indicated for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who failed therapy with crizotinib. Adverse Drug Reactions: The most common adverse effects experienced in clinical studies were diarrhea, nausea and vomiting, elevated liver enzymes, abdominal pain, fatigue, appetite reduction, and constipation. Dose: Recommended dose is 750 mg by mouth once daily on an empty stomach (separate from meals by 2 hours). Formulation: Ceritinib is available as 150-mg capsules. Warnings/Contraindications: No contraindications currently exist. Dosage reductions may be required in patients who experience intractable GI distress that is not responsive to antiemetics or antidiarrheals. Treatment-induced interstitial lung disease (ILD), QT interval prolongation, bradycardia, hepatotoxicity, and hyperglycemia have been reported. Permanent discontinuation or dose reduction of ceritinib is warranted in patients diagnosed with ILD or other warnings/precautions, respectively. Ceritinib is a pregnancy category D. Place in Therapy: Ceritinib provides another oral therapeutic option for patients with NSCLC who have failed previous treatment. 13 An overall response rate of 43.6% was observed in patients who could not receive crizotinib or at least 2 prior therapies (84%). Complete responses occurred in 2.5% of patients. 14 Notes: Ceritinib is a modest CYP 3A and 2C9 inhibitor/substrate. If possible, avoid concomitant administration of drugs known to utilize these metabolic systems. Vorapaxar Sulfate (Zontivity, Merck Sharpe Dohme) Pharmacology: Cardiovascular agent; protease-activated receptor-1 (PAR-1) receptor antagonist. Indication: Indicated for reduction in thrombotic events or cardiovascular origin in patients with a history of myocardial infarction (MI) and peripheral artery disease (PAD). Adverse Drug Reactions: The most common adverse effect reported was bleeding, which could be lifethreating or fatal. Dose: The recommended dose is one tablet by mouth daily. Formulation: Vorapaxar is available as 2.08-mg tablets. Warnings/Contraindications: Vorapaxar should not be used in patients with active bleeding or history of stroke, transient ischemic attack (TIA), or intracranial hemorrhage. Place in Therapy: Vorapaxar utilizes a unique mechanism of action to reduce cardiovascular events compared with traditional agents. 15 The composite endpoint of cardiovascular death, myocardial infarction, stroke, and urgent coronary revascularization was decreased by 12% at 3 years compared to placebo + standard of care. Similar reductions (17%) were observed in patients who were post-mi or had peripheral artery disease without a history of stroke or TIA. 16 Notes: Vorapaxar may be used in conjunction with clopidogrel (or other antiplatelet agent) and/or aspirin or alone as monotherapy. (Back to New Molecular Entities Table) 5

6 Dalbavancin HCl (Dalvance, Durata Therapeutics) Pharmacology: Anti-infective agent; lipoglycopeptide antibiotic. Indication: Indicated for the treatment of acute bacterial skin and skin structure infections. Adverse Drug Reactions: The most common adverse effects were nausea, headache, and diarrhea. Dose: The recommended dose is 1,000 mg intravenously (over 30 minutes) once followed by an additional 500 mg infusion one week later. Formulation: Available as 500-mg single-use vials containing dalbavancin. Warnings/Contraindications: Patients should not receive dalbavancin if known hypersensitivity is present. Anaphylactic reactions have been known to occur in patients with hypersensitivity to other glycopeptide antibiotics. Dalbavancin may be associated with Clostridium difficile infection (CDI). Elevation of liver enzymes (e.g., ALT) may occur with administration of dalbavancin. Place in Therapy: Dalbavancin provides an additional (lipo)glycopeptide antibiotic to treat infections caused by susceptible gram-positive microorganisms, especially MRSA. 17 The pharmacokinetic profile of dalbavancin allows for once-weekly administration. Notes: Dalbavancin should only be used if culture and sensitivity reports are available and suggest presence of sensitive microorganisms. Dalbavancin should be reconstituted using 25 ml of sterile water and administered only in D5W (1 mg to 5 mg/ml) final concentration. (Back to New Molecular Entities Table) NEW BIOLOGICS JANUARY TO JUNE OF 2014 GENERIC NAME (BRAND NAME) SPONSOR APPROVAL DATE Elosulfase alpha (Vimizim) Biomarin Pharm. Feb 14, 2014 Metreleptin (Myalept) Amylin Pharms LLC Feb 24, 2014 Coagulation Factor IX [Recombinant], Fc Fusion Biogen Idec Inc. Mar 28, 2014 Protein (Alprolix) Abiglutide (Tanzeum) GlaxoSmithKline LLC Apr 15, 2014 Ramucirumab (Cyramza) Eli Lilly and Co. Apr 21, 2014 Siltuximab (Sylvant) Janssen Biotech Apr 22, 2014 Vedolizumab (Entyvio) Takeda Pharms USA May 20, 2014 Elosulfase alfa (Vimizim, BioMarin Pharmaceutical, Inc.) 18 Pharmacology: Hydrolytic lysosomal glycosaminoglycan-specific purified human enzyme. Indication: Mucopolysaccharidosis type IVA (MPS IVA) or Morquio A syndrome. Adverse Drug Reactions: Pyrexia, nausea, vomiting, chills, headache, abdominal pain, and fatigue. Development of neutralizing antibodies was noted during clinical trials, showing a possibility for immunogenicity. Dose: Once weekly 2 mg/kg infused over hours, depending on infusion volume. The vial should be diluted with 0.9% sodium chloride solution to a final volume of 100 ml for patients <25 kg or to a final volume of 250 ml for patients >25 kg. Vials should be gently rotated to mix; do not shake. The concentrated solution contains no preservatives and should be used immediately once diluted, but it may be stored for 24 hours at 2 8 C followed by an additional 24 hours at C, if necessary. Infusion should be performed using a low-protein binding infusion set with a 0.2 micron in-line filter. Infusion rates are based on weight. Formulation: Available as 5 mg/5 ml (1 mg/ml) single-use vials for dilution. Store undiluted vial at 2 8 C; do not freeze. Protect from light. Warnings/Contraindications: No contraindications listed. A boxed warning has been issued due to the risk of anaphylaxis occurring during infusion and up to three hours post-infusion. Pretreatment with antihistamines with or without an antipyretic may be considered. Patients with concomitant MPS IVA and sleep apnea or airway disease should have treatments for these conditions on hand prior to administration in case of exacerbation. Monitor for MPS IVA complications such as spinal and cervical cord compression. Place in Therapy: Elosulfase alpha is currently the only agent FDA-approved for the treatment of Morquio A syndrome. No improvement in symptoms were observed after 24 weeks during a 72-week treatment period. 19 Notes: Safety and efficacy have not been studied in patients under the age of 5 years or over the age of 64 years. 6

7 Metreleptin (Myalept, Amylin Pharmaceuticals, LLC) 20 Pharmacology: Recombinant human leptin analog. Indication: Adjunct treatment to diet for complications of leptin deficiency in patients with congenital or acquired generalized lipodystrophy. Not indicated for patients with HIV-related lipodystrophy, partial lipodystrophy, or liver disease. Adverse Drug Reactions: Headache, hypoglycemia, weight loss, and abdominal pain. Dose: Weight-based dosing according to the following table: Males and Females 40 kg Males > 40 kg Females > 40 kg Starting Daily Dose (injection volume) 0.06 mg/kg (0.012 ml/kg) 2.5 mg (0.5 ml) 5 mg (1 ml) Dose Adjustments (injection volume) 0.02 mg/kg (0.004 ml/kg) 1.25 mg (0.25 ml) to 2.5 mg (0.5 ml) 1.25 mg (0.25 ml) to 2.5 mg (0.5 ml) Maximum Daily Dose (injection volume) 0.13 mg/kg (0.026 ml/kg) 10 mg (2 ml) 10 mg (2 ml) A healthcare provider must train and witness the patient s first self-use of the product. Store the medication in the original carton, protected from light, and in the refrigerator; do not freeze. The reconstituted injection can be administered subcutaneously in the abdomen, thigh, or upper arm; doses exceeding 1 ml can be divided to reduce irritation. See prescribing information for reconstitution instructions. Do not mix with other injections such as insulin. Formulation: Subcutaneous injection supplied as 11.3 mg of metreleptin powder for reconstitution to a final concentration of 5 mg/ml. Warnings/Contraindications: Contraindicated in patients with general obesity unrelated to congenital leptin deficiency and hypersensitivity to metreleptin. Boxed warnings include risk of immunogenicity shown by anti-metreleptin antibodies and possible risk of T-cell lymphoma, although not proven causative. Patients at risk for pancreatitis should discontinue metreleptin. Abrupt cessation is not recommended in this population; taper the dose over 1 week while monitoring triglycerides. Other warnings include hypoglycemia, hypersensitivity, and benzyl alcohol toxicity risks. Notes: Due to the boxed warnings, metreleptin is only available through a restricted Risk Evaluation and Mitigation Strategy (REMS) program. Significant drug-drug interactions include insulin and sulfonylureas due to increased risk for hypoglycemia resulting from increased insulin sensitivity and decreased food intake. Increased monitoring for drugs metabolized by CYP450 (particularly narrow therapeutic index drugs) are warranted and consider back-up birth control methods if using oral contraceptives. Coagulation Factor IX (Recombinant), Fc Fusion Protein (Alprolix, Biogen Idec, Inc) 21 Pharmacology: Recombinant DNA derived, coagulation Factor IX concentrate Indication: Hemophilia B in adult and children for control and prevention of bleeding episodes, perioperative management, and routine prophylaxis to prevent or reduce the frequency of bleeding episodes Adverse Drug Reactions: Headache, oral paresthesia Dose: Dosing depends on the patient s circulating level of Factor IX and severity of bleeding episode. Please see package insert for patient-specific dosing instructions. Estimate required dose: IU/dL (or % of normal) = [Total Dose (IU)/ Body Weight (kg)] x Recovery (IU/dL per IU/kg). For routine prophylaxis administer 50 IU/kg once weekly or 100 IU/kg once every 10 days. Formulation: Lyophilized powder for solution in single use vials containing approximately 500, 1000, 2000, or 3000 IU per vial. Warnings/Contraindications: Warnings for Alprolix include hypersensitivity reactions including anaphylaxis, development of neutralizing antibodies to Alprolix, and development of thromboembolic complications. Alprolix is a pregnancy category C and excretion in human breast milk is unknown. Place in Therapy: Provides an additional recombinant antihemophilic factor product. Notes: For IV administration after reconstitution only. The reconstituted product may be stored for up to 3 hours at room temperature. Each vial of Alprolix will be part of a kit that contains a syringe prefilled with 5 ml of diluent and sealed with a plunger stopper and cap and a sterile vial adapter for reconstituting the powder. One IU of Alprolix per kg body weight increases the circulation level of 7 (Back to New Biologic Approvals Table)

8 Coagulation Factor IX (Recombinant), Fc Fusion Protein (Alprolix, Biogen Idec, Inc) (continued) Notes: Factor IX by 1%. Patients may be trained to self-administer Alprolix after the first dose is administered by a physician. Abiglutide (Tanzeum, GlaxoSmithKline LLC) Pharmacology: Antidiabetic agent; glucagon-like peptide (GLP) 1 receptor antagonist. Indication: Indicated for the treatment of type 2 diabetes mellitus (DM) as add-on therapy to improve glycemic control. Adverse Drug Reactions: The most common adverse effects experienced in clinical studies were diarrhea, nausea, upper respiratory site infections, and injection site reactions. Dose: Recommended starting dose is 30 mg administered subcutaneously in the abdomen, thigh, or upper arm without regard to meals. Dose may be increased to 50 mg once weekly in selected patients. Formulation: Abiglutide is available as a 30- or 50-mg single dose pen. Warnings/Contraindications: Contraindications include: known hypersensitivity to abiglutide or any of its components and family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome. Patients demonstrating signs or symptoms of pancreatitis should not receive abiglutide therapy or therapy should be discontinued in those currently receiving abiglutide. Place in Therapy: Abiglutide grants a once-weekly incretin mimetic option in addition to other marketed agents. 22 Notes: There is no recommended dose adjustment for patients with renal dysfunction. Monitor for adverse drug reactions closely in this population. Nursing mothers should discontinue abiglutide. Ramucirumab (Cyramza, Eli Lilly and Co.) Pharmacology: Antineoplastic agent; human vascular growth factor receptor (VEGFR) 2 receptor antagonist. Indication: Indicated for single agent treatment of advanced gastric cancer or gastro-esophageal junction adenocarcinoma proceeding fluoropyrimidine or platinum-containing chemotherapy. Adverse Drug Reactions: Common adverse effects are hypertension and diarrhea. Dose: Recommended dose is 8 mg/kg administered as an intravenous infusion every 2 weeks. Formulation: Ramucirumab is available as 100-mg/10 ml or 500-mg/10 ml single-dose vials. Warnings/Contraindications: Currently, no contraindications to treatment exist. Discontinue use of ramucirumab for patients experiencing treatment-induced arterial thromboembolism, medically treated, uncontrolled hypertension, prior to surgery, GI perforation, symptomatic cirrhosis, and reversible posterior leukoencephalopathy syndrome. Ramucirumab may cause fetal harm and should be avoided in pregnant patients. Place in Therapy: Ramucirumab prevents binding exclusively by VEGF. It is a fully humanized antibody and provides a therapeutic option to patients with metastatic disease. 23 Significant improvements in overall survival (5.2 vs. 3.8 months) observed in clinical trials. Notes: Nursing mothers should not receive therapy with ramucirumab. Siltuximab (Sylvant, Janssen Biotech) Pharmacology: Immunomodulator/Antineoplastic agent; interleukin-6 (IL-6) antagonist. Indication: Treatment of multicentric Castlemans s disease (MCD) in HIV and herpesvirus-8 negative patients. Adverse Drug Reactions: Common adverse effects are pruritus, weight gain, rash, hyperuricemia, and upper respiratory tract infection. Dose: Recommended dose is 11 mg/kg by intravenous infusion (over 1 hour) every three weeks. Formulation: Siltuximab is available as single-use vials containing 100-mg or 400-mg of lyophilized powder. Warnings/Contraindications: Siltuximab is contraindicated in patients with known hypersensitivity reactions to siltuximab or any ingredients therein. Patients with active infections should not receive siltuximab. GI perforation and life-threatening infusion related reactions may occur with siltuximab. Place in Therapy: Siltuximab is a chimeric, monoclonal antibody and represents the first drug FDAapproved for MCD. 24 Notes: Due to altered immune response associated with siltuximab therapy, live vaccines should not be administered concomitantly while siltuximab is used. (Back to New Biologic Approvals Table) 8

9 Vedolizumab (Entyvio, Takeda Pharms USA) Pharmacology: Gastrointestinal agent; integrin receptor antagonist. Indication: Indicated for the treatment of ulcerative colitis (UC) and Crohn s disease (CD) in adult patients as second- line therapy. Adverse Drug Reactions: The most common adverse effects experienced in clinical studies were diarrhea, nausea, upper respiratory site infections, and injection site reactions. Dose: The recommended dose is 300-mg intravenously infused over 30 minutes once at 0, 2, and 6 weeks. Additional doses should be infused every 8 weeks. Formulation: Available as 300-mg single-use vials containing vedolizumab. Warnings/Contraindications: Patients with known hypersensitivity to vedolizumab or any of its components should not receive treatment with this product. Hypersensitive reactions have known to occur with administration of vedolizumab. Patients receiving vedolizumab are at increased risk for infection and progressive multifocal leukoencephalopathy (PML) and should be monitored for signs and symptoms of infection and declining neurologic status, respectively. Place in Therapy: Vedolizumab provides a therapeutic option for patients with severe UC or CD. 25 Notes: Vedolizumab should be diluted with sterile water and administered in 250 ml of normal saline. NEW DRUG FORMULATIONS / COMBINATIONS JANUARY TO JUNE OF 2014 GENERIC NAME (BRAND NAME) SPONSOR CATEGORY APPROVAL DATE Diclofenac Sodium (Pennsaid) Mallinckrodt Inc. 3S Jan 16, 2014 Diphenhydramine HCl; Naproxen Sodium (Aleve PM) Bayer Healthcare 4S Jan 16, 2014 Decitabine (Decitabine) Sun Pharma Global 5S Jan 23, 2014 Desvenlafaxine Fumarate (Desvenlafaxine Fumarate) Sun Pharma Global 5S Jan 28, 2014 Indomethacin (Tivorbex) Iroko Pharmaceuticals LLC 3S Feb 24, 2014 Testosterone Undecanote (Qudexy) Endo Pharmaceuticals 3S Mar 05, 2014 Oxycodone HCl; APAP (Xartemis XR) Mallinckrodt Inc. 3P Mar 11, 2014 Topiramate (Qudexy XR) Upsher Smith 3S Mar 11, 2014 Docetaxel (Docetaxel) Pfizer Labs 5S Mar 13, 2014 Posaconazole (Noxafil) Merck Sharp Dohme 3P Mar 13, 2014 Propranolol HCl (Hemangeol) Pierre Fabre Derma 5S Mar 14, 2014 Metronidazole (Metronidazole) Valeant Pharm North 5S Mar 24, 2014 Naloxone HCl (Evzio) Kaleo Inc. 3P Apr 03, 2014 Omega-3 Acid Ethyl Esters (Omtryg) Trygg 5S Apr 23, 2014 Mometasone Furoate (Asmanex HFA) Merck Sharp Dohme 2S Apr 25, 2014 Mercaptopurine (Purixan) Nova Labs Ltd. 5S Apr 28, 2014 Umeclidinium Bromide (Incruse Ellipta) Glaxo Grp England 5S Apr 30, 2014 Omega-3 Carboxylic Acids (Epanova) AstraZeneca 5S May 05, 2014 Travoprost (Izba) Alcon Labs Inc. 5S May 15, 2014 Testosterone (Natesto) Trimel Biopharma SRL 5S May 28, 2014 Ketorolac Tromethamine; Phenylephrine HCl (Omidria) Omeros 4S May 30, 2014 Diclofenac Sodium (Pennsaid, Mallinckrodt Inc.) Pharmacology: Non-steroidal anti-inflammatory drug (NSAID). Indication: Treatment of osteoarthritic pain of the knee(s). Dose: Apply 2 pump actuations (40 mg of diclofenac sodium) to clean, dry skin on each knee, twice a day. Wash hands completely after administering product. Wait until the area is dry before covering with clothing or applying other substances. New Formulation: Available in a 2% w/w topical solution. Place in Therapy: Diclofenac sodium topical solution adds another topical alternative for NSAID treatment. 26 (Back to New Biologic Approvals Table) 9

10 Naproxen Sodium and Diphenhydramine Hydrochloride (Aleve-PM, Bayer Healthcare) Pharmacology: Non-steroidal anti-inflammatory drug (NSAID); ethanolamine derivative, histamine H1- receptor antagonist. Indication: Pain relief; Nighttime sleep aid. Dose: For patients 12 years and older it is recommended to take 2 caplets at bedtime with a full glass of water, and do not exceed 2 caplets in 24 hours. Do not take more than directed. New Formulation: Available as 220-mg naproxen sodium and 25-mg diphenhydramine hydrochloride per one caplet. Place in Therapy: Aleve-PM offers the first over-the-counter product with naproxen sodium and diphenhydramine formulated together. Decitabine (Decitabine, Sun Pharma Global) Pharmacology: Nucleoside metabolic inhibitor, analog of the natural nucleoside 2 -deoxycytidine. Indication: Treatment of myelodysplastic syndromes (MDS), including patients with previously treated and untreated, de novo and secondary MDS of all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, excess blasts, or excess blasts in transformation, and chronic myelomonocytic leukemia) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups. Dose: Two treatment regimens; it is recommended that with both regimens patients receive treatment for a minimum of 4 cycles and be pre-medicated with anti-emetics prior to infusions. However, complete or partial response may require more than 4 cycles Treatment Regimen, option 1: o Inject at a dose of 15 mg/m 2 by continuous IV infusion over 3 hours; repeat every 8 hours for 3 days. Repeat cycle every 6 weeks. Treatment Regimen, option 2: o Inject at a dose of 20 mg/m 2 by continuous IV infusion over 1 hour; repeat every 5 days. Repeat cycle every 4 weeks. New Formulation: Available as single-dose vials of 50-mg decitabine and diluent for decitabine injection. Place in Therapy: Decitabine adds a new manufactured formulation to marketed products. 27 Desvenlafaxine Fumarate (Desvenlafaxine Fumarate, Sun Pharma Global) Pharmacology: Serotonin and norepinephrine reuptake inhibitor (SNRI). Indication: Treatment of major depressive disorder (MDD). Dose: Recommend 50 mg by mouth, once daily, with or without food. No evidence exists to show benefit with doses great than 50 mg per day, even though clinical studies have shown doses mg per day to be effective. Upon discontinuation, taper gradually. Do no crush, chew, divide, or dissolve tablets. Moderate renal impairment [CrCl ml/min]: maximum dose is 50 mg per day. Severe renal impairment and end-stage renal disease (ESRD) [CrCl < 30 ml/min]: maximum dose is 50 mg every other day. Moderate to severe hepatic impairment: maximum dose is 100 mg per day. New Formulation: Desvenlafaxine extended-release (ER) tablets available as 50 mg and 100 mg, each tablet containing 72 mg or 144 mg of desvenlafaxine fumarate, equivalent to 50 mg or 100 mg of desvenlafaxine, respectively. Place in Therapy: Provides an additional manufactured formulation of desvenlafaxine fumarate. 28 Indomethacin (Tivorbex, Iroko Pharmaceuticals, LLC) Pharmacology: Non-steroidal anti-inflammatory drug (NSAID). Indication: Treatment of mild to moderate acute pain. Dose: 20 mg by mouth three times daily or 40 mg by mouth three or four times daily. New Formulation: Available as 20-mg and 40-mg capsules. Place in Therapy: Adds a 20 and 40 mg indomethacin dosing option in capsule form. 29 Testosterone Undecanote (Aveed, Endo Pharms) Pharmacology: Androgen. Indication: Primary hypogonadism and hypogonadotropic hypogonadism. Dose: Inject 3 ml(750 mg) intramuscularly at initiation, 4 weeks, and 10 weeks thereafter. (Back to New Drug Formulations/Combinations) Table) 10

11 Testosterone Undecanote (Aveed, Endo Pharms) (continued) New Formulation: 750 mg/3 ml injection. Place in Therapy: Testosterone undecanote provides an additional formulation compared with other marketed testosterone products. 30 Oxycodone Hydrochloride; APAP (Xartemis XR, Mallinckrodt, Inc) Pharmacology: Combination opioid analgesic. Indication: Acute pain unresponsive to alternate treatment. Dose: 2 tablets every 12 hours without regard to food. New Formulation: Available as 7.5 mg/325 mg extended-release tablet. Place in Therapy: The new formulation represents an extended-release oxycodone/apap combination product. 31 Topiramate (Qudexy XR, Upsher Smith Labs) Pharmacology: Antiepileptic. Indication: Partial onset and primary generalized tonic-clonic seizures- initial monotherapy in patients 10 years and older with and adjunctive therapy in patients 2 years and older. Lennox-Gastaut Syndrome (LGS)-adjunctive therapy in patients 2 years and older. Dose: Monotherapy: 50 mg once daily in adults and pediatrics over 10 years of age initially with dose increases of 50 mg weekly for first 4 weeks, then 100 mg for weeks 5 and 6 until recommended dose of 400 mg daily is reached. Adjunctive therapy: 25 mg to 50 mg initially with dose increases of 25 mg to 50 mg weekly to an effective dose or 400 mg in primary generalized seizures and 200 mg to 400 mg in partial seizures. Pediatrics: 25 mg (based on 1mg/kg to 3 mg/kg) at bedtime initially for 7 days with dose increases of 1 mg/kg to 3 mg/kg at 1 to 2 week intervals until recommended dose of 5 mg/kg to 9 mg/kg daily is reached. New Formulation: 25-mg, 50-mg, 100-mg, 150-mg, and 200-mg extended-release capsules. Place in Therapy: Presents an extended-release formulation of topiramate. 32 Docetaxel (Docetaxel, Pfizer) Pharmacology: Antineoplastic agent. Indication: Breast cancer, non-small cell lung cancer, prostate cancer, head and neck cancer, and gastric adenocarcinoma. Dose: 75 mg/m 2 (if in combination with other anti-neoplastic agents) or mg/m 2 every 21 days for treatment of most cancers. New Formulation: 10 mg/ml injection. Place in Therapy: Provides an additional injection strength to already marketed products. 33 Posaconazole (Noxafil, Merck Sharp Dohme) Pharmacology: Azole antifungal. Indication: Prophylaxis of invasive fungal infections (Aspergillus and Candida) in high risk patients (e.g. severely immunocompromised). Dose: Loading dose of 300 mg IV injection twice a day on first day. Maintenance dose of 300 mg IV injection once a day thereafter. New Formulation: 18 mg/ml injection. Place in Therapy: Provides an additional dosage form of posaconazole. 34 Propranolol HCl (Hemangeol, Pierre Fabre) Pharmacology: Non-selective beta-blocker. Indication: Treatment of proliferating infantile hemangioma requiring systemic therapy. Dose: Initiate at 0.15 ml/kg (0.6 mg/kg) twice daily. Increase dose to 0.3 ml/kg (1.1 mg/kg) twice daily after 1 week. Increase to maintenance dose of 0.4 ml/kg (1.7 mg/kg) twice daily after 2 weeks. New Formulation: 4.28 mg/ml oral solution. Place in Therapy: Grants an infant-target dose of propranolol. 35 Metronidazole (Metronidazole, Valeant Pharms) Pharmacology: Nitroimidazole antibiotic. Indication: Bacterial vaginosis in non-pregnant women. Dose: One single-dose, pre-filled disposable applicator intravaginally once at bedtime New Formulation: 1.3% vaginal gel in pre-filled applicator. Place in Therapy: Provides an additional choice to marketed vaginal metronidazole preparations. 36 (Back to New Drug Formulations/Combinations) Table) 11

12 Naloxone HCl (Evzio, Kaleo Inc) Pharmacology: Antidote; mu-opioid receptor antagonist. Indication: Indicated for the reversal of suspected opioid overdose in the emergency setting in conjunction with supportive care. Dose: Administer naloxone pre-filled autoinjectors into the anterolateral aspect of the thigh; administered through clothes, if necessary. Additional doses may be necessary and administered every 2 to 3 minutes. New Formulation: Available as 0.4-mg/0.4 ml autoinjector for intramuscular or subcutaneously use Place in Therapy: Evzio represents an autoinjector technology for naloxone compared with marketed ampules and vials.37 Omega-3 Acid Ethyl Esters (Omtryg, Trygg Pharma Inc) Pharmacology: Antilipemic agent; omega-3 fatty acids. Indication: Indicated for treat of severe hypertriglyceridemia (> 500 mg/dl) in adult patients in addition to diet modifications. Dose: The daily dose is 4 capsules by mouth once daily or 2 capsules by mouth twice daily with meals. Do not chew, crush, or open capsules. New Formulation: Available as 1.2-gram capsules. Place in Therapy: Omtryg adds another FDA-approved formulation of omega-3 fatty acids for treatment of lipid disorders. 38 Mometasone Furoate (Asmanex HFA, Merck Sharp Dohme) Pharmacology: Anti-inflammatory agent; glucocorticoid. Indication: Indicated for the prophylactic treatment of asthma as maintenance therapy in patients 12 years of age or older. Dose: Initial doses are determined based on prior therapy. Patients should inhale 2 sprays by mouth twice daily. New Formulation: Available as HFA-propelled aerosol containing 100 or 200-mcg per spray. Place in Therapy: Asmanex HFA is the hydrofluoroalkane version of the dry powder dosage form of Asmanex. 39 Mercaptopurine (Purixan, Nova Laboratories) Pharmacology: Immunosuppressant/Antineoplastic agent; nucleoside analog. Indication: Indicated for the treatment of acute lymphoblastic leukemia (ALL) in combination with other chemotherapeutic agents. Dose: Absolute neutrophil count (ANC) should provide dosing guidance. Doses range from 1.5 to 2.5 mg/kg administered orally once daily. New Formulation: Available as 2000-mg/100 ml oral suspension. Place in Therapy: Provides an oral solution of mercaptopurine. 40 Umeclidinium Bromide (Incruse Ellipta, Glaxo Grp Ltd) Pharmacology: Respiratory agent; long-acting anticholinergic. Indication: Indicated for maintenance treatment of chronic obstructive pulmonary disease (COPD). Dose: Inhale contents of blister by mouth once daily. New Formulation: Available as blister strips for use with inhaler containing 62.5-mcg of umeclidinium per blister. Place in Therapy: Umeclidinium is available in marketed products in combination with corticosteroids and beta-agonists. Incruse Ellipta introduces umeclidinium apart from other agents. 41 Omega-3 Carboxylic Acids (Epanova, Astra Zeneca) Pharmacology: Antilipemic agent; omega-3 fatty acids. Indication: Indicated for severe hypertriglyceridemia ( 500 mg/dl) adjunctively to diet in adult patients. Dose: The dose of Epanova is 2 to 4 capsules by mouth once daily. New Formulation: Available as 1 gram of gelatin capsules. Place in Therapy: Gives additional formulation of omega-3 fatty acids. 42 Travoprost (Izba, Alcon Labs Inc.) Pharmacology: Ophthalmic agent; prostaglandin analog. Indication: Indicated for the reduction of intraocular pressure in patients with open-angle glaucoma. (Back to New Drug Formulations/Combinations) Table) 12

13 Travoprost (Izba, Alcon Labs Inc.) (continued) Dose: Dose of travoprost is 1 drop in the affected eye once daily in the evening. New Formulation: Available a solution containing 0.03 mg/ml of travoprost. Place in Therapy: Provides an additional therapeutic option for treatment of open-angle glaucoma. 43 Testosterone (Natesto, Trimel Biopharma) Pharmacology: Systemic hormone; androgen. Indication: Indicated for androgen replacement therapy in males with primary hypogonadism or hypogonadotropic hypogonadism. Dose: The recommended dose for indications listed is 2 pumps (i.e., one each nostril) applied intranasally three times daily. New Formulation: Available as a nasal gel metered-dose pump (5.5 mg of testosterone per actuation). Place in Therapy: This formulation of testosterone is administered nasally. 44 Phenylephrine; ketorolac (Omidria, Omeros Corp.) Pharmacology: Ophthalmic agent; alpha-1 receptor agonist, NSAID. Indication: Indicated for maintenance of pupil dilation during surgery and reduction of postoperative ophthalmic pain. Dose: Dilute in 500 ml of ophthalmic irrigating solution and irrigate eye as needed. New Formulation: Available as a sterile solution containing 1% phenylephrine and 0.3% ketorolac in a single-use vial. Place in Therapy: Omidria provides a method to administer drugs to maintain pupil dilation in a noninvasive manner. 45 (Back to New Drug Formulations/Combinations Table) NEW INDICATIONS JANUARY TO JUNE 2014 GENERIC NAME (BRAND NAME) SPONSOR APPROVAL DATE Esomeprazole Magnesium (Nexium 24 HR) AstraZeneca LP Mar 28, 2014 Esomeprazole Magnesium (Nexium 24 HR, AstraZeneca LP) Pharmacology: Proton pump inhibitor. New Indication: Over-the-counter treatment of frequent heartburn. Dose: One 20 mg capsule daily in the morning. Prepared by: Richard A. Wakefield, Pharm.D. Reviewed by: Maisha Kelly Freeman, Pharm.D., MS, BCPS, FASCP 13