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New Drugs of 2013, Part 1

Michael A. Mancano, PharmD
Clinical Professor of Pharmacy Practice
Chair, Department of Pharmacy Practice
Temple University School of Pharmacy
Clinical Consultant Pennsylvania Hospital
Department of Pharmacy
Philadelphia, Pennsylvania

The following contributors have no relevant financial relationships with commercial interests to disclose.

Pharmacy Times Office of Continuing Professional Education
Planning Staff—David Heckard; Maryjo Dixon, RPh; and Steve Lin, PharmD, RPh

Pharmacy Times
Editorial Staff—Kirk McKay

Upon completing this continuing education program, participants should be able to:
  1. Discuss the clinical indications of the new drugs approved by the FDA in 2013.
  2. Explain the various mechanisms of action of the drugs discussed within this program.
  3. Recognize the clinically relevant drug interactions for the drugs reviewed in this program.
  4. Identify the most common adverse reactions of the new drugs approved in 2013.
  5. Explain the approved dosing guidelines and recommended dosage adjustments for the drugs reviewed.
Target audience: Pharmacists
Type of activity: Knowledge
Release date: January 12, 2014
Expiration date: January 12, 2016
Estimated time to complete activity: 2 hours
Fee: Free

Description: Description: Description: Pharmacy Times/Ascend Media Office of Continuing Professional EducationPharmacy Times Office of Continuing Professional Education is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. This activity is approved for 2.0 contact hours (0.2 CEUs) under the ACPE universal activity number 0290-0000-14-003-H04-P. The activity is available for CE credit through January 12, 2016.

During 2013, the FDA approved many unique and important medications, including several biologics, for use in the United States; however, due to constraints in space and the sheer volume of new drug approvals during 2013, 8 new medications spanning 8 different disease states have been selected for in-depth review in the first part of this educational program (Table). The disease states include type 2 diabetes mellitus (T2DM), multiple sclerosis (MS), HIV-1, chronic obstructive pulmonary disease (COPD), pulmonary arterial hypertension (PAH), homozygous familial hypercholesterolemia (HoFH), severe dyspareunia, and major depressive disorder. An additional 8 drug products will be reviewed in the second part of this series, to be published next month.

The drug reviews that comprise this program contain current dosing guidelines, common adverse effects, contraindications to therapy, and the current FDA-approved indication(s) for each medication. This review is designed to focus on the new molecular entities and biologic approvals that may be unique and/or that pharmacists are likely to encounter in practice. Part 2 of this program will include a table of all the new molecular entities approved by the FDA in 2013.

Canagliflozin Tablets (Invokana)
Canagliflozin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with T2DM. Canagliflozin is not recommended for use in patients with type 1 diabetes mellitus, nor for the treatment of diabetic ketoacidosis. Canagliflozin is an inhibitor of sodiumglucose cotransporter 2 (SGLT2), which is expressed in the proximal renal tubules and is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. By inhibiting SGLT2, canagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose, thereby increasing urinary glucose excretion.

The recommended starting dose of canagliflozin is 100 mg once daily by mouth, taken before the first meal of the day. In patients tolerating canagliflozin 100 mg once daily who have an estimated glomerular filtration rate (eGFR) of 60 mL/min/1.73 m2 or greater and require additional glycemic control, the dose may be increased to 300 mg once daily. It is recommended that patients with volume depletion should correct this condition prior to initiating canagliflozin.

No dose adjustment is needed in patients with mild renal impairment (eGFR of 60 mL/min/1.73 m2 or greater); however, the dose of canagliflozin is limited to 100 mg once daily in patients with moderate renal impairment (eGFR of 45 to less than 60 mL/min/1.73 m2), and the medication should not be initiated in patients with an eGFR less than 45 mL/min/1.73 m2. Assessment of renal function is recom-mended prior to initiating therapy with canagliflozin and periodically thereafter, and canagliflozin should be discontinued if eGFR is persistently less than 45 mL/ min/1.73 m2.

If an inducer of uridine diphosphate glucuronosyltransferase (UGT) (eg, rifampin, phenytoin, phenobarbital, ritonavir) is coadministered with cana-gliflozin, the clinician should consider increasing the dosage of canagliflozin to 300 mg once daily in patients currently tolerating canagliflozin 100 mg once daily who have an eGFR of 60 mL/min/1.73 m2 or greater and require additional glycemic control. Another antihyperglycemic agent should be considered for patients with an eGFR of 45 to less than 60 mL/min/1.73 m2 who are receiving concurrent therapy with a UGT inducer.

Canagliflozin can impact the pharmacokinetics of digoxin. When coadministered with canagliflozin 300 mg, there was an increase in the area under the curve (AUC) and mean peak drug concentration (Cmax) of digoxin (20% and 36%, respectively). Therefore, patients taking canagliflozin with concomitant digoxin should have their digoxin level monitored regularly.

The most common adverse reactions associated with canagliflozin (incidence of 5% or greater) are female genital mycotic infections, urinary tract infection (UTI), and increased urination. Canagliflozin may also cause intravascular volume con-traction. Symptomatic hypotension may occur after initiating canagliflozin, par-ticularly in patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2), elderly patients, patients on either diuretics or medications that interfere with the renin-angiotensin-aldosterone sys-tem (eg, angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers), or patients with low systolic blood pres-sure. Before initiating canagliflozin in patients with 1 or more of these charac-teristics, volume status should be assessed and corrected, and signs and symptoms of volume contraction after initiating therapy should be monitored.

Because canagliflozin may lead to hyperkalemia, patients with moderate renal impairment who are taking medications that interfere with potassium excretion (eg, potassium-sparing diuretics) or medications that interfere with the renin-angiotensin-aldosterone system are more likely to develop hyperkalemia. Clinicians are advised to monitor serum potassium levels periodically after initiating canagliflozin in patients with impaired renal function and in patients predisposed to hyperkalemia due to medications or other medical conditions.

Insulin and insulin secretagogues are known to cause hypoglycemia, and canagliflozin may increase the risk of developing hypoglycemia when combined with insulin or an insulin secretagogue. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with canagliflozin.

Canagliflozin also increases the risk of genital mycotic infections, and patients with a history of genital mycotic infections and uncircumcised males are more likely to develop this condition. Patients should be monitored for mycotic infections and treated appropriately while receiving canagliflozin. Hypersensitivity reactions (eg, generalized urticaria), some serious, were reported with canagliflozin treatment, and these reactions generally occurred within hours to days after initiating canagliflozin. If hypersensitivity reactions occur, it is advised to discontinue the use of canagliflozin, to treat per standard of care, and to monitor the patient until signs and symptoms resolve. Dose-related increases in low-density lipoprotein cholesterol (LDL-C) may occur with canagliflozin therapy; therefore, it is essential to monitor LDL-C and to treat per standard of care after initiating canagliflozin.

Canagliflozin is contraindicated in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2), end-stage renal disease, or patients receiv-ing dialysis. Canagliflozin is classified as pregnancy class C, and during pregnancy, clinicians should consider appropriate alternative therapies, especially during the second and third trimesters. Canagliflozin should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus. Canagliflozin is supplied as 100-mg and 300-mg tablets in bottles containing 30, 90, and 500 tablets.

Dimethyl Fumarate Delayed- Release Capsules (Tecfidera)
Biogen Idec
Dimethyl fumarate is indicated for the treatment of patients with relapsing forms of MS, but the mechanism by which dimethyl fumarate exerts its therapeutic effect in MS is unknown. Dimethyl fumarate and the metabolite, monomethyl fumarate (MMF), have been shown to activate the nuclear factor (erythroidderived 2)-like 2 pathway in vitro and in vivo in animal models and in humans, which is involved in the cellular response to oxidative stress. MMF has also been identified as a nicotinic acid receptor agonist in vitro.

The starting dose for dimethyl fumarate is 120 mg orally twice a day, and after 7 days of treatment, the dose should be increased to the maintenance dose of 240 mg orally twice a day. Dimethyl fumarate should be swallowed whole and intact; the medication should not be crushed or chewed, and the capsule contents should not be sprinkled on food. Dimethyl fumarate may be taken with or without food.

P-glycoprotein and in vitro CYP inhibition and induction studies have not identified any potential drug interactions with dimethyl fumarate and MMF. Single doses of interferon beta-1a or glatiramer acetate, or aspirin administered approximately 30 minutes prior to dimethyl fumarate, did not alter the pharmacokinetics of MMF.

The most common adverse reactions (incidence ≥10%) experienced with the use of dimethyl fumarate were flushing, abdominal pain, diarrhea, and nausea. Dimethyl fumarate may also decrease lymphocyte counts, and in placebo-con-trolled trials, the use of dimethyl fuma-rate in patients with MS demonstrated a reduction in mean lymphocyte count of approximately 30% during the first year of treatment with dimethyl fumarate and then remained stable. Four weeks after dimethyl fumarate was stopped, mean lymphocyte counts increased but did not return to baseline. Six percent of dimethyl fumarate patients and <1% of placebo patients experienced lymphocyte counts <0.5 × 109/L (lower limit of normal 0.91 × 109/L). Thus, before initiating treat-ment with dimethyl fumarate, a recent complete blood count (CBC) (ie, within 6 months) should be made available, and a CBC is further recommended annu-ally, as well as when clinically indicated. Withholding treatment should be consid-ered in patients with serious infections until the infection(s) is resolved. It should be noted that dimethyl fumarate has not been studied in patients with preexisting low lymphocyte counts.

Dimethyl fumarate may cause flushing (eg, warmth, redness, itching and/or burning sensation), with clinical trials showing that 40% of patients treated with dimethyl fumarate experienced flushing. Flushing symptoms generally began soon after initiating dimethyl fumarate, and usually improved or resolved over time. Further, in the majority of patients who experienced flushing, it was mild or moderate in severity, but 3% of patients discontinued dimethyl fumarate for flushing and <1% had serious flushing symptoms that were not life threatening but led to hospitalization. Administration of dimethyl fumarate with food may reduce the incidence of flushing.

Dimethyl fumarate is classified as pregnancy category C because there are no adequate and well-controlled studies in pregnant women. In animal models, however, adverse effects on offspring survival, growth, sexual maturation, and neurobehavioral function were observed when dimethyl fumarate was administered during pregnancy and lactation at clinically relevant doses. Dimethyl fumarate should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.

Dimethyl fumarate is supplied as 120-mg and 240-mg delayed-release capsules. Dimethyl fumarate is supplied as 30-day starter packs containing fourteen 120-mg capsules and forty-six 240-mg capsules, as well as bottles containing fourteen 120- mg capsules and bottles containing sixty 240-mg capsules.

Dolutegravir Sodium Tablets (Tivicay)
Dolutegravir is indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and children 12 years and older weighing at least . Dolutegravir is an HIV-1 integrase strand transfer inhibitor (INSTI) which inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral DNA integration, which is essential for the HIV replication cycle.

Prior to initiating treatment with dolutegravir, clinicians should be aware that poor virologic response has been observed in subjects treated with dolutegravir twice daily by mouth with an INSTIresistance Q148 substitution plus 2 or more additional INSTI-resistance substitutions, including L74I/M, E138A/D/K/T, G140A/S, Y143H/R, E157Q, G163E/K/ Q/R/S, or G193E/R.

Patients who are treatment-naïve, as well as treatment-experienced INSTInaïve patients, should receive once daily by mouth, taken with or without food. Patients who are treatmentnaïve or treatment-experienced INSTInaïve, when coadministered with potent UGT1A/CYP3A inducers (ie, efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, or rifampin) should receive twice daily. The safety and efficacy of doses above twice daily by mouth have not been evaluated.

Pediatric patients, 12 years and older and weighing at least , who are treatment-naïve or treatment-experienced INSTI-naïve, should receive dolutegravir once daily by mouth. If efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, or rifampin is coadministered, the recommended dose of dolutegravir is twice daily. The safety and efficacy of dolutegravir have not been established in pediatric patients younger than 12 years or weighing less than , or in pediatric patients who are INSTI-experienced with documented or clinically suspected resistance to other INSTIs (eg, raltegravir, elvitegravir).

Dolutegravir is primarily metabolized via UGT1A1, with some contribution from CYP3A. Dolutegravir is also a substrate of UGT1A3, UGT1A9, BCRP, and P-gp in vitro. Drugs that induce those enzymes and transporters may decrease dolutegravir plasma concentration and reduce the therapeutic effect of the medication. Further, coadministration of dolutegravir and other drugs that inhibit these enzymes may increase dolutegravir plasma concentration. Etravirine significantly reduces plasma concentrations of dolutegravir, but the effect of etravirine is mitigated by the coadministration of lopinavir/ritonavir or darunavir/ritonavir, and is expected to be mitigated by atazanavir/ritonavir. Darunavir/ritonavir, lopinavir/ritonavir, rilpivirine, tenofovir, boceprevir, telaprevir, prednisone, rifabutin, and omeprazole had no clinically significant effect on the pharmacokinetics of dolutegravir. Dolutegravir should be taken 2 hours before or 6 hours after taking cation-containing antacids or laxatives, sucralfate, oral iron supplements, oral calcium supplements, or buffered medications.

The most common adverse reactions of moderate to severe intensity and incidence ≥2% in patients receiving dolutegravir are insomnia and headache. Hypersensitivity reactions have also been reported and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury. The events were reported in 1% or fewer subjects receiving dolutegravir in Phase 3 clinical trials. Dolutegravir and other suspect agents should be discontinued immediately if signs or symptoms of hypersensitivity reactions develop (eg, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters or peeling of the skin, oral blisters or lesions, conjunctivitis, facial edema,hepatitis, eosinophilia, angioedema, difficulty breathing). Clinical status, including liver aminotransferases, should be monitored and appropriate therapy initiated. Delay in stopping treatment with dolutegravir or other suspect agents after the onset of hypersensitivity may result in a life-threatening reaction. Further, dolutegravir should not be used in patients who have experienced a previous hypersensitivity reaction to the drug.

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including dolutegravir. During the initial phase of combination antiretroviral treatment, the immune systems of patients who respond to treatment may develop an inflammatory response to indolent or residual opportunistic infections, such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia, or tuberculosis, which may necessitate further evaluation and treatment. Autoimmune disorders, such as Graves’ disease, polymyositis, and Guillain-Barré syndrome, have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of treatment.

Patients with underlying hepatitis B (HBV) or hepatitis C may be at increased risk for worsening or development of transaminase elevations with use of dolutegravir. In some cases, the elevations in transaminases were consistent with immune reconstitution syndrome or HBV reactivation, particularly when antihepatitis therapy was withdrawn. Appropriate laboratory testing prior to initiating therapy and monitoring for hepatotoxicity during therapy with dolutegravir are recommended in patients with underlying hepatic disease.

The redistribution and/or accumulation of body fat, including central obesity, dorsocervical fat enlargement (ie, buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance,” have also been observed in patients receiving antiretroviral therapy. The mechanisms and long-term consequences of these events are currently unknown, and a causal relationship has not yet been established.

Dolutegravir is classified as pregnancy category B, as there are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, and dolutegravir has been shown to cross the placenta in animal studies, this drug should be used during pregnancy only if clearly needed. Coadministration of dolutegravir with dofetilide is contraindicated due to the potential for increased dofetilide plasma concentrations and the risk for serious and/or life-threatening events. Dolutegravir is supplied as tablets in bottles containing 30 tablets.

Fluticasone Furoate/Vilanterol Inhalation Powder (Breo Ellipta)
The inhalation powder that combines fluticasone furoate, an inhaled corticosteroid, and vilanterol, a long-acting beta2- adrenergic agonist (LABA), is indicated for the long-term maintenance treatment of airflow obstruction and for reducing exacerbations in patients with COPD. It is important to note that fluticasone furoate/vilanterol inhalation powder is not indicated for relief of acute bronchospasm or for treatment of asthma, and that the drug is only for oral inhalation in the maintenance treatment of COPD at a dose of 1 inhalation of 100 mcg fluticasone furoate/25 mcg vilanterol once daily.

After inhalation of fluticasone furoate/ vilanterol inhalation powder, the patient should rinse his/her mouth with water without swallowing to help reduce the risk of developing oropharyngeal candidiasis. Fluticasone furoate/vilanterol inhalation powder should be taken at the same time every day and should not be used more than once every 24 hours. No dosage adjustment is required for geriatric patients, patients with hepatic impairment, or renally impaired patients. However, if fluticasone furoate/vilanterol inhalation powder is administered to patients receiving strong cytochrome P450 3A4 inhibitors (eg, ketoconazole), these types of medications may cause systemic corticosteroid and cardiovascular effects. Clinicians are advised to use fluticasone furoate/vilanterol inhalation powder with extreme caution in patients receiving monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs) because these drugs may potentiate the effect of vilanterol on the vascular system. Fluticasone furoate exposure may increase in patients with moderate or severe hepatic impairment, and patients should be monitored for systemic corticosteroid effects. Concomitant use of beta-blockers should be undertaken cautiously because beta-blockers may inhibit the bronchodilatory effects of beta-agonists and produce severe bronchospasm. Diuretics can cause electrocardiograph changes and/or hypokalemia associated with non–potassium-sparing diuretics, and the beta-agonist component of fluticasone furoate/vilanterol inhalation powder may worsen these conditions.

The most common adverse reactions (incidence ≥3%) encountered during therapy with fluticasone furoate/vilanterol inhalation powder are nasopharyngitis, upper respiratory tract infection, headache, and oral candidiasis. Fluticasone furoate/vilanterol inhalation powder should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of COPD, as the use of fluticasone furoate/vilanterol inhalation powder has not been studied in patients with acutely deteriorating COPD. Consequently, the initiation of fluticasone furoate/vilanterol inhalation powder in this setting is not appropriate. Fluticasone furoate/vilanterol inhalation powder should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medicines containing LABA, as an overdose may result. Notably, patients using Breo Ellipta should not use another medicine containing a LABA (eg, salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.

In clinical trials, the development of localized infections of the mouth and pharynx with Candida albicans has occurred in subjects treated with fluticasone furoate/vilanterol inhalation powder. Clinicians should advise the patient to rinse his/her mouth without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis. When such an infection develops, it should be treated with appropriate local or systemic (ie, oral) antifungal therapy while treatment with fluticasone furoate/vilanterol inhalation powder continues, but at times, therapy with fluticasone furoate/ vilanterol inhalation powder may require interruption. In clinical trials, an increase in the incidence of pneumonia has been observed in subjects with COPD receiving the fluticasone furoate/vilanterol combination, including Breo Ellipta 100 mcg/25 mcg, and there has also been an increased incidence of pneumonias resulting in hospitalization and sometimes death. Health professionals should remain vigilant for the possible development of pneumonia in patients with COPD, as the clinical features of such infections overlap with the symptoms of COPD exacerbations.

Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In such children or adults who have not had these diseases or have not been properly immunized, particular care should be taken to avoid exposure. It is not known how the dose, route, and duration of corticosteroid administration may affect the risk of developing a disseminated infection; the contribution of the underlying disease and/or prior corticosteroid treatment to the risk also remains unknown. If a patient is exposed to chickenpox or measles, prophylaxis with varicella zoster immune globulin or pooled intramuscular immunoglobulin may be indicated, respectively. Further, if chickenpox develops, treatment with antiviral agents may be considered. Inhaled corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infections of the respiratory tract; systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. LABA, such as vilanterol, one of the active ingredients in fluticasone furoate/ vilanterol inhalation powder, may increase the risk of asthma-related death. A placebo-controlled trial with the LABA salmeterol demonstrated an increase in asthma-related deaths in subjects receiving salmeterol. This finding with salmeterol is considered a class effect for all LABAs, including vilanterol, and it should be noted that the safety and efficacy of fluticasone furoate/vilanterol inhalation powder in patients with asthma has not yet been established.

Fluticasone furoate/vilanterol inhalation powder is contraindicated in patients with severe hypersensitivity to milk proteins. Fluticasone furoate/vilanterol inhalation powder is supplied as an inhalation powder with a disposable inhaler containing 2 double-foil blister strips of powder formulation for oral inhalation. One strip contains fluticasone furoate 100 mcg per blister, and the other contains vilanterol 25 mcg per blister.

Macitentan Tablets (Opsumit)
Actelion Pharmaceuticals
Macitentan is an endothelin-receptor antagonist that is indicated for the treatment of pulmonary arterial hypertension (PAH) to delay disease progression. Endothelin (ET)-1 and its receptors (ETA and ETB) mediate a variety of deleterious effects, such as vasoconstriction, fibrosis, proliferation, hypertrophy, and inflammation. In patients with PAH, the local ET system is upregulated and is involved in vascular hypertrophy and in organ damage. Macitentan is an endothelin-receptor antagonist that prevents the binding of ET-1 to both ETA and ETB receptors. Macitentan displays high affinity and sustained occupancy of the ET receptors in human pulmonary arterial smooth muscle cells. One of the metabolites of macitentan is also pharmacologically active at the ET receptors and is estimated to be about 20% as potent as the parent drug in vitro.

The recommended dosage of macitentan is once daily by mouth; higher doses have not been studied in patients with PAH, and are not recommended.

Because strong inducers of CYP3A4 such as rifampin significantly reduce macitentan exposure, concomitant use of macitentan with strong CYP3A4 inducers should be avoided. Concomitant use of strong CYP3A4 inhibitors such as ketoconazole approximately double macitentan exposure, and many HIV drugs such as ritonavir are strong inhibitors of CYP3A4. Clinicians are advised to avoid the concomitant use of macitentan with strong CYP3A4 inhibitors.

The most common adverse reactions associated with the use of macitentan (more frequent than placebo by ≥3%) are anemia, nasopharyngitis/pharyngitis, bronchitis, headache, influenza, and UTI.

Other endothelin receptor antagonists have caused elevations of aminotransferases, hepatotoxicity, and liver failure. Liver enzyme tests should be obtained prior to the initiation of macitentan and repeated during treatment as clinically indicated. Clinicians should advise patients to report symptoms suggesting hepatic injury, such as nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, or itching. If clinically relevant aminotransferase elevations occur in the patient, or if elevations are accompanied by an increase in bilirubin >2× upper limit of normal (ULN) or by clinical symptoms of hepatotoxicity, treatment with macitentan should be discontinued. Reinitiation of macitentan should be considered when hepatic enzyme levels normalize in patients who have not experienced clinical symptoms of hepatotoxicity.

Decreases in hemoglobin and hematocrit have occurred following administration of other endothelin-receptor antagonists and have been observed in clinical studies with macitentan. Decreases in hemoglobin seldom required transfusion, as these decreases occurred early and stabilized thereafter. Initiation of macitentan is not recommended in patients with severe anemia, and hemoglobin should be measured prior to initiation of treatment and repeated during treatment as clinically indicated.

If signs of pulmonary edema occur in patients receiving macitentan, clinicians should consider the possibility of associated pulmonary veno-occlusive disease. If pulmonary veno-occlusive disease is confirmed, macitentan should be discontinued.

Macitentan is classified as pregnancy category X and therefore should not be administered to a pregnant female as it may cause fetal harm. Macitentan was consistently shown to have teratogenic effects when administered to animals. Treatment with macitentan in females of reproductive potential should only be initiated after a negative pregnancy test. Pregnancy tests should be performed monthly during treatment and 1 month after stopping treatment. Pregnancies should be prevented during treatment and for 1 month after stopping treatment by using acceptable methods of contraception. Moreover, for all female patients, macitentan is available only through a restricted program called the macitentan REMS Program, due to the risk of embryo-fetal toxicity. It is not known whether macitentan is present in human milk, but the drug and its metabolites were present in the milk of lactating rats. Because many drugs are present in human milk and because of the potential for serious adverse reactions from macitentan in nursing infants, nursing mothers should also discontinue nursing or discontinue macitentan. In men, other endothelinreceptor antagonists have also caused adverse effects on spermatogenesis; therefore, health professionals should counsel men about the potential effects on fertility.

Macitentan is supplied as tablets in bottles containing 30 tablets.

Mipomersen Sodium Solution for Injection (Kynamro)
Mipomersen is indicated as an adjunct to lipid-lowering medications and diet to reduce LDL-C, apolipoprotein B (apo B), total cholesterol, and non–high-density lipoprotein cholesterol in patients with HoFH. Mipomersen sodium is an oligonucleotide inhibitor of apo B–100 synthesis. Apo B is the principal apolipoprotein of LDL and its metabolic precursor, verylow- density lipoprotein. Mipomersen inhibits synthesis of apo B by sequencespecific binding to its messenger RNA (mRNA), resulting in degradation of the mRNA through enzyme-mediated pathways or disruption of mRNA function through binding alone.

The safety and effectiveness of mipomersen have not been established in patients with hypercholesterolemia who do not have HoFH, and the effects of mipomersen on cardiovascular morbidity and mortality have also not yet been determined. The safety and effectiveness of mipomersen as an adjunct to LDL apheresis have not been established; therefore, the use of mipomersen as an adjunct to LDL apheresis is not recommended.

Mipomersen may cause elevations in transaminases. Therefore, before initiating treatment with mipomersen, clinicians should measure hepatic transaminases (ie, alanine transaminase [ALT], aspartate transaminase [AST]), alkaline phosphatase (ALP), and total bilirubin. Mipomersen is intended for subcutaneous use only and should not be administered intramuscularly or intravenously. The recommended dose of mipomersen is once weekly as a subcutaneous injection, and the injection should be given on the same day every week; if a dose is missed, the injection should be given at least 3 days from the next weekly dose. After initiating mipomersen therapy, lipid levels should be monitored at least every 3 months for the first year. Maximal reduction of LDL-C may be seen with mipomersen therapy after approximately 6 months (based on the time to steady state seen in clinical studies). Health care providers should assess the patient’s LDL-C level after 6 months to determine if the LDL-C reduction achieved with mipomersen is sufficiently robust to warrant the potential risk of liver toxicity.

Each vial or prefilled syringe of mipomersen provides of mipomersen sodium and is intended for single use only. The mipomersen vial or prefilled syringe should be removed from to ( to ) refrigerated storage and allowed to reach room temperature for at least 30 minutes prior to administration. The first injection administered by the patient or caregiver should be performed under the guidance and supervision of an appropriately qualified health care professional. Mipomersen should be injected into the abdomen, thigh region, or outer area of the upper arm, and should not be injected in areas of active skin disease or injury, such as sunburns, skin rashes, inflammation, skin infections, or active areas of psoriasis. Areas of tattooed skin and scarring should also be avoided.

No clinically relevant pharmacokinetic interactions were reported between mipomersen and warfarin, or between mipomersen and simvastatin or ezetimibe. Additionally, coadministration of mipomersen with warfarin did not result in a pharmacodynamic interaction as determined by international normalized ratio (INR), activated partial thromboplastin time, and prothrombin time (PT). No other known reactions with mipomersen have been reported.

The most commonly reported adverse reactions (incidence ≥10% and greater than placebo) are injection site reactions, flu-like symptoms, nausea, headache, and elevations in serum transaminases, specifically ALT. Injection site reactions have been reported in 84% of patients receiving mipomersen therapy, and these local reactions typically consist of one or more of the following: erythema, pain, tenderness, pruritus, and local swelling. Injection site reactions did not occur with all injections but resulted in the discontinuation of therapy in 5% of patients in pooled Phase 3 trials. To minimize the potential for injection site reactions, proper technique for subcutaneous administration should be followed. Furthermore, flu-like symptoms have been reported in 30% of patients receiving mipomersen therapy and include one or more of the following: influenza-like illness, pyrexia, chills, myalgia, arthralgia, malaise, or fatigue. Flu-like symptoms typically occurred within 2 days following an injection and did not occur with all injections. These symptoms did result in the discontinuation of therapy in 3% of patients in pooled Phase 3 trials.

Mipomersen is contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh B or C) or active liver disease, including unexplained persistent elevations of serum transaminases. In the mipomersen clinical trial in patients with HoFH, 12% of patients treated with mipomersen encountered at least 1 elevation in ALT ≥3× ULN. There were no concomitant, clinically meaningful elevations of total bilirubin, INR, or partial thromboplastin time. Mipomersen also increases hepatic fat, with or without concomitant increases in transaminases. In the trials in patients with heterozygous familial hypercholesterolemia and hyperlipidemia, the median absolute increase in hepatic fat was 10% after 26 weeks of treatment, as measured by magnetic resonance imaging. Hepatic steatosis is a risk factor for advanced liver disease, including steatohepatitis and cirrhosis. Clinicians are advised to measure ALT, AST, ALP, and total bilirubin before initiating treatment, then monitor ALT and AST regularly as recommended. During treatment, the dose of mipomersen should be withheld if the ALT or AST is ≥3× ULN, and discontinued for clinically significant liver toxicity.

Mipomersen is supplied in single-use, 2-mL, clear glass vials or single-use, 1-mL, clear prefilled syringes with staked needles. Each single-use vial or prefilled syringe of mipomersen is filled to deliver of mipomersen sodium. Mipomersen is available in cartons containing 1 to 4 vials or prefilled syringes. Mipomersen should be protected from light, stored under refrigeration at to ( to ), and kept in the original carton until time of use. When refrigeration is not available, mipomersen may be stored at or below (), away from heat sources, for up to 14 days. This product contains no preservatives, and any unused drug remaining in vial after extracting 1 mL for injection must be safely discarded. Because of the risk of hepatotoxicosis, only certified health care providers and pharmacies may prescribe and distribute mipomersen under the Kynamro REMS program.

Ospemifene Tablets (Osphena)
Ospemifene is indicated for the treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy, due to menopause. It is an estrogen agonist/antagonist with tissue selective effects. Its biologic actions are mediated through binding to estrogen receptors, resulting in the activation of estrogenic pathways in some tissues (ie, agonism) and blockade of estrogenic pathways in others (ie, antagonism).

The recommended dosage of ospemifene is one tablet taken with food once daily by mouth. Ospemifene should be used for the shortest duration that is consistent with treatment goals and acceptable risks for the individual woman. Postmenopausal women should be reevaluated periodically as clinically appropriate to determine if treatment is still necessary. Ospemifene is an estrogen agonist/antagonist that has agonistic effects on the endometrium. Generally, when a product with estrogen agonistic effects on the endometrium is prescribed for a postmenopausal woman with a uterus, a progestin should be considered to reduce the risk of endometrial cancer; however, a woman without a uterus (eg, through hysterectomy) does not need a progestin. Ospemifene is primarily metabolized by CYP3A4 and CYP2C9, but CYP2C19 and other pathways also contribute to the metabolism of ospemifene. Fluconazole, a moderate CYP3A/strong CYP2C9/ moderate CYP2C19 inhibitor, should not be used with ospemifene. Fluconazole increases the systemic exposure of ospemifene 2.7-fold, and ketoconazole, a strong CYP3A4 inhibitor, increases the systemic exposure of ospemifene 1.4- fold. Coadministration of ospemifene, fluconazole, ketoconazole, or any other drug known to inhibit CYP3A4 and CYP2C9 isoenzymes may increase the risk of ospemifene- related adverse reactions.

Rifampin, a strong CYP3A4/moderate CYP2C9/moderate CYP2C19 inducer, decreases the systemic exposure of ospemifene by 58%. Therefore, coadministration of ospemifene with drugs that induce CYP3A4, CYP2C9, and/or CYP2C19 activity, such as rifampin, would be expected to decrease the systemic exposure of ospemifene, which may decrease its clinical effect.

Repeated administration of ospemifene has demonstrated no effect on the pharmacokinetics of a single dose of warfarin. However, no studies were conducted with multiple doses of warfarin or on clotting time, such as the INR or PT. Because ospemifene is more than 99% bound to serum proteins, it may affect the protein binding of other drugs. As such, the use of ospemifene with other drugs that are highly protein bound may lead to increased exposure of either that drug or ospemifene.

Patients should be counseled that ospemifene may initiate or increase the occurrence of hot flashes in some women. Common adverse reactions (≥1%) associated with the use of ospemifene include hot flush, vaginal discharge, muscle spasms, genital discharge, and hyperhidrosis. Because ospemifene has estrogen agonistic effects in the endometrium, postmenopausal women should be informed of the importance of reporting unusual vaginal bleeding to their health care providers as soon as possible. There is an increased risk of endometrial cancer in women with a uterus who use unopposed estrogens. Adding a progestin to estrogen therapy reduces the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Adequate diagnostic measures, including directed and random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding.

There is a reported increased risk of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) who received daily oral conjugated estrogen-only therapy () over 7.1 years as part of the Women’s Health Initiative. In the clinical trials for ospemifene, with durations of treatment up to 15 months, the incidence rates of thromboembolic and hemorrhagic stroke were 0.72 and 1.45 per 1000 women, respectively, in the ospemifene treatment group, and 1.04 and 0, respectively, in the placebo cohort. The incidence of DVT was 1.45 per 1000 women in the ospemifene treatment group and 1.04 per 1000 women in the placebo group.

Ospemifene is contraindicated in women with (1) undiagnosed abnormal genital bleeding, known or suspected estrogen-dependent neoplasia, active DVT, or pulmonary embolism; (2) a history of these conditions and active arterial thromboembolic disease (eg, stroke and myocardial infarction); or (3) a history of these conditions. Ospemifene is classified as pregnancy category X and is therefore also contraindicated in women who are or may become pregnant, as it may cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if a woman becomes pregnant while taking this drug, she should be apprised of the potential hazard to a fetus. Ospemifene should not be used in women with severe hepatic impairment and should not be used concomitantly with estrogens and estrogen agonists/ antagonists, as the safety of concomitant use of ospemifene with estrogens and estrogen agonists/antagonists has not been studied.

Ospemifene is supplied as tablets in bottles containing 100 tablets.

Vortioxetine Hydrobromide Tablets (Brintellix)
Vortioxetine is indicated for the treatment of major depressive disorder and contains the beta polymorph of vortioxetine hydrobromide, an antidepressant. The mechanism of the antidepressant effect of vortioxetine is not fully understood but is thought to be related to its enhancement of serotonergic activity in the central nervous system through inhibition of the reuptake of serotonin. Vortioxetine is also associated with 5-HT3–receptor antagonism and 5-HT1A–receptor agonism. The efficacy of vortioxetine was established in six 6- to 8-week studies (including 1 study in the elderly) and 1 maintenance study in adults. Vortioxetine has not been evaluated for use in pediatric patients.

The recommended starting dose of vortioxetine is administered orally once daily, without regard to meals. The dose of vortioxetine should then be increased to /day, as tolerated, and /day should be considered for patients who do not tolerate higher doses. Although vortioxetine may be abruptly discontinued, patients in placebo- controlled trials experienced transient adverse reactions such as headache and muscle tension following abrupt discontinuation of vortioxetine /day or /day. To avoid these adverse reactions, it is recommended that the dose be decreased to /day for 1 week before full discontinuation of vortioxetine /day or /day.

At least 14 days should elapse between the discontinuation of an MAOI intended to treat psychiatric disorders and the initiation of therapy with vortioxetine to avoid the risk of developing serotonin syndrome. Similarly, patients should wait at least 21 days after stopping vortioxetine before starting an MAOI intended to treat psychiatric disorders. Due to the increased risk of serotonin syndrome, clinicians should not start vortioxetine in a patient who is currently receiving treatment with linezolid or intravenous methylene blue. In patients who require more urgent treatment of psychiatric conditions, other interventions, including hospitalization, should be considered. The development of potentially lifethreatening serotonin syndrome has also been reported with the use of serotonergic antidepressants, including vortioxetine, when used alone, but more often when used concomitantly with other serotonergic drugs (eg, triptans, TCAs, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort).

Vortioxetine is extensively and primarily metabolized through oxidation via the cytochrome P450 isozymes CYP2D6, CYP3A4/5, CYP2C19, CYP2C9, CYP2A6, CYP2C8, and CYP2B6, followed by glucuronic acid conjugation. CYP2D6 is the primary enzyme that catalyzes the metabolism of vortioxetine to its major, pharmacologically inactive, carboxylic acid metabolite. Poor metabolizers of CYP2D6 have approximately twice the vortioxetine plasma concentration of extensive metabolizers. As such, the maximum recommended dose of vortioxetine is /day in known CYP2D6 poor metabolizers. Reducing the dose of vortioxetine by half is recommended when patients are receiving a CYP2D6 strong inhibitor (eg, bupropion, fluoxetine, paroxetine, quinidine) concomitantly. The dose should be increased to the original level when the CYP2D6 inhibitor is discontinued.

Clinicians should consider increasing the dose of vortioxetine when a strong CYP inducer, such as rifampin, carbamazepine, or phenytoin, is coadministered for more than 14 days. The maximum recommended dose is 3 times the original dose. The dose of vortioxetine should be reduced to the original level within 14 days, when the inducer is discontinued.

The most common adverse reactions in clinical trials with vortioxetine (incidence ≥5% and at least twice the rate of placebo) were nausea, constipation, and vomiting. Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies; however, these studies did not demonstrate an increased risk of suicidal thoughts and behavior with antidepressant use in patients older than 24 years; there was a trend toward reduced risk with antidepressant use in patients 65 years and older. Patients of all ages who are started on antidepressant therapy should be monitored closely for worsening and for the emergence of suicidal thoughts and behaviors. Families and caregivers should be advised of the need for close observation and communication with the prescriber.

The use of drugs that interfere with serotonin reuptake inhibition, including vortioxetine, may increase the risk of bleeding events, and patients should be cautioned about the increased risk of bleeding when vortioxetine is coadministered with nonsteroidal anti-inflammatory drugs, aspirin, or other drugs that may affect coagulation or bleeding. Case reports and epidemiologic studies have demonstrated an association between the use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to drugs that inhibit serotonin reuptake have ranged from ecchymosis, hematoma, epistaxis, and petechiae to lifethreatening hemorrhages.

Symptoms of mania and/or hypomania were reported in <0.1% of patients treated with vortioxetine in premarketing clinical studies. Activation of mania/hypomania has been reported in a small proportion of patients with major affective disorder who were treated with other antidepressants. As with all antidepressants, vortioxetine should be used cautiously in patients with a history or family history of bipolar disorder, mania, or hypomania.

Hyponatremia has also occurred as a result of treatment with serotonergic drugs. In many cases, hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion. One case with serum sodium lower than 110 mmol/L was reported in a subject treated with vortioxetine in a premarketing clinical study. Elderly patients may be at greater risk of developing hyponatremia with a serotonergic antidepressant, as well as patients taking diuretics or those who are otherwise volume depleted. Vortioxetine should be discontinued in patients with symptomatic hyponatremia, and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. More severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.

Vortioxetine is classified as pregnancy category C, and based on animal studies, may cause fetal harm. Vortioxetine should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus, but according to the limited animal data, vortioxetine should be discontinued if a mother is nursing.

Vortioxetine is supplied as , , , and immediaterelease tablets in bottles containing 30, 90, and 500 tablets.

Robust pharmaceutical pipeline activity in 2013 has brought about the FDA approval of numerous important medications, including new molecular entities and biologic drugs, to members of the health care community and various patient populations. In this first part of this 2-part educational series, 8 novel medications that span 8 distinct therapeutic classes are reviewed in detail, and part 2 of this program will delve into another 8. With an armamentarium of pharmacotherapeutic options that continues to expand, health care providers are further empowered to deliver optimal treatment outcomes to their patients.

  1. Breo Ellipta [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2013.
  2. Brintellix [package insert]. Deerfield, IL: Takeda Pharmaceuticals; 2013.
  3. Invokana [package insert]. Titusville, NJ: Janssen Pharmaceuticals; 2013.
  4. Kynamro [package insert]. Cambridge, MA: Genzyme Corporation; 2013.
  5. Opsumit [package insert]. San Francisco, CA: Actelion Pharmaceuticals; 2013.
  6. Osphena [package insert]. Florham Park, NJ: Shionogi Inc; 2013.
  7. Tecfidera [package insert]. Cambridge, MA: Biogen Idec, Inc; 2013.
  8. Tivicay [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2013.

New Drugs of 2013, Part I