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  1. Hussar, Daniel A. PhD

Article Content

THIS ARTICLE FEATURES nine recently approved drugs, including


a bronchodilator for patients with chronic obstructive pulmonary disease administered by oral inhalation once a day, providing a convenient alternative to similar treatments administered twice a day


two drugs indicated to treat pulmonary hypertension


five antineoplastic drugs, including two designated as "breakthrough therapy" by the FDA.


Unless otherwise specified, the information in the following summaries applies to adults, not children. Consult a pharmacist or the package insert for information on drug safety during pregnancy and breastfeeding. Consult a pharmacist, the package insert, or a comprehensive and current drug reference for more details on precautions, drug interactions, and adverse reactions* for all these drugs.



Drug Facts and Comparisons. St. Louis, MO: Facts and Comparisons Inc.; 2014.


Nursing2015 Drug Handbook. Philadelphia, PA: Lippincott Williams & Wilkins; 2014.


Physicians' Desk Reference. 68th ed. Montvale, NJ: Medical Economics; 2014.



Vortioxetine hydrobromide

Multiple actions at serotonin receptors

In 2012, an estimated 16 million American adults experienced at least one episode of major depressive disorder (depression) in the previous year.1 The medications most often prescribed for depression include the selective serotonin reuptake inhibitors (SSRIs) citalopram, escitalopram, fluoxetine, paroxetine, and sertraline; and the serotonin norepinephrine reuptake inhibitors (SNRIs) duloxetine, venlafaxine, desvenlafaxine, and levomilnacipran. Another antidepressant, vilazodone, acts as a serotonin (5-HT) reuptake inhibitor and as a partial agonist at 5-HT1A receptors.


Vortioxetine hydrobromide (Brintellix, Lundbeck; Takeda) is a new drug indicated to treat patients with major depressive disorder. Its primary mechanism of antidepressant action is thought to be inhibition of serotonin reuptake. In addition, it also acts as an agonist at 5-HT1A receptors, a partial agonist at 5-HT1B receptors, and an antagonist at 5-HT3, 5-HT1D, and 5-HT7 receptors. Although it's the only medication with this combination of actions at serotonin receptors, the contribution of any of these additional actions to the drug's antidepressant effect hasn't been established and the clinical relevance is unknown.2


Vortioxetine's effectiveness has been demonstrated in six placebo-controlled, short-term (6- to 8-week) clinical studies, one of which was conducted in older adult patients. In addition, when the new drug was evaluated in a long-term (24- to 64-week) maintenance study, its use resulted in a statistically significant longer time to recurrence of depressive episodes compared with placebo.


Although duloxetine was used as an active comparator in several studies, data are insufficient to compare the effectiveness of vortioxetine and duloxetine, and no data suggest that the new drug is more effective than other antidepressants. However, vortioxetine might be effective for some patients who haven't responded adequately to other antidepressants.


The drug-related problems, warnings, and precautions associated with vortioxetine are generally similar to those for the other serotonin reuptake inhibitors. The labeling for these drugs includes a boxed warning regarding the increased risk of suicidal thinking and behavior in children, adolescents, and young adults (ages 18 to 24). Its safety for pediatric patients is unknown, and this is also noted in a boxed warning.


In clinical trials, treatment was discontinued because of an adverse event in 8% of the patients treated with vortioxetine (20 mg/day), most often because of nausea, compared with 4% of those receiving placebo. Vortioxetine had no significant effect on body weight.


Precautions: (1) Closely monitor patients being treated with vortioxetine or any other antidepressant for clinical worsening, suicidality, or unusual changes in behavior. (2) Contraindicated for use with a monoamine oxidase inhibitor (MAOI) prescribed for depression because of the risk of serotonin syndrome. In addition, an MAOI shouldn't be used within 21 days after treatment with vortioxetine ends, and vortioxetine shouldn't be used within 14 days of stopping treatment with an MAOI. (3) The concurrent use of vortioxetine with an MAOI prescribed for indications other than depression, such as linezolid or I.V. methylene blue, is also contraindicated because of the risk of serotonin syndrome. Because treatment with linezolid or I.V. methylene blue must sometimes be initiated on an urgent basis, vortioxetine should promptly be discontinued; linezolid or methylene blue can then be administered with monitoring for signs and symptoms of serotonin syndrome for 21 days or until 24 hours after the last dose of the MAOI, whichever comes first. (4) The risk of serotonin syndrome is also increased by the concurrent use of vortioxetine and other drugs having serotonergic activity, such as SSRIs, SNRIs, tricyclic antidepressants, triptans, tramadol, tryptophan, fentanyl, lithium, buspirone, and St. John's wort. Closely monitor patients in whom the use of such combinations is clinically warranted. Treatment should be discontinued if patients develop signs and symptoms suggesting serotonin syndrome, such as mental status changes (agitation, hallucinations, delirium, coma), autonomic instability (tachycardia, labile BP, dizziness, diaphoresis, hyperthermia, flushing), neuromuscular effects (tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms (nausea, vomiting, diarrhea). (5) The use of vortioxetine and other serotonergic antidepressants has been associated with the activation of mania/hypomania and the occurrence of hyponatremia and abnormal bleeding. The bleeding risk is increased in patients who are also being treated with an anticoagulant or a nonsteroidal anti-inflammatory drug (NSAID), including aspirin. (6) The concurrent use of a strong CYP2D6 inhibitor (such as bupropion, fluoxetine, paroxetine, or quinidine) may increase vortioxetine's action; reducing the vortioxetine dosage by one-half is recommended. (7) Vortioxetine's action may be reduced by the concomitant use of a strong CYP inducer (such as carbamazepine, phenytoin, or rifampin). Increasing the vortioxetine dosage should be considered, but the increase shouldn't exceed three times the initial dosage.


Adverse reactions:nausea, dizziness, vomiting, constipation, sexual dysfunction


Supplied as: 5 mg, 10 mg, 15 mg, and 20 mg tablets


Dosage: 10 mg/day initially, increase to 20 mg/day as tolerated. 5 mg once a day may be considered in patients who don't tolerate a higher dosage. In patients who are known CYP2D6 poor metabolizers, the maximum recommended dosage is 10 mg/day.


Nursing considerations: (1) Because vortioxetine can cause central nervous system effects such as dizziness, warn patients not to drive or engage in other activities requiring alertness until they determine how the medication affects them. (2) Advise them to avoid alcohol while taking vortioxetine. (3) Warn them that concurrent use of an anticoagulant or an NSAID, including aspirin, may increase their bleeding risk. Tell them to check with their healthcare provider before taking any other medications. (4) Tell patients taking higher dosages (15 to 20 mg/day) not to discontinue the drug abruptly. In clinical trials, some patients taking higher dosages experienced transient adverse reactions such as headache and muscle tension when abruptly stopping the drug. To avoid these possible adverse reactions, the dosage should be reduced to 10 mg/day for 1 week as directed by the healthcare provider. (5) Vortioxetine can be taken without regard to food.



1. National Institutes of Health/National Institute of Mental Health. Major depression among adults. http://www.nimh.nih.gov/statistics/1MDD_ADULT.shtml. [Context Link]


2. Brintellix (vortioxetine) tablets, for oral use. Prescribing information. http://www.us.brintellix.com. [Context Link]



Vilanterol trifenatate/fluticasone furoate

Convenient once-daily dosing is an advantage.

A combination product containing vilanterol trifenatate and fluticasone furoate (BreoEllipta, GlaxoSmithKline), this new product is indicated for use by oral inhalation for long-term, once-daily maintenance treatment of airflow obstruction and for reducing exacerbations in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.1 (Asthma isn't a labeled indication at this time.) Its properties are generally similar to those of salmeterol/fluticasone propionate (Advair) and formoterol fumarate/budesonide (Symbicort). Vilanterol is a new therapeutic agent; the corticosteroid fluticasone has been used for several indications for years.


A long-acting beta2-adrenergic receptor agonist (LABA), vilanterol joins salmeterol, formoterol, arformoterol, and indacaterol in the class of LABA bronchodilators administered by oral inhalation. Unlike the other LABAs, vilanterol isn't available as a single agent and is provided only in combination with fluticasone.


The new combination product was evaluated in studies that included 7,700 patients with COPD. Patients using it showed improved lung function and reduced exacerbations compared with those who received placebo.


Like the other LABAs, vilanterol has a slow onset of action compared with the inhaled short-acting beta2-adrenergic agonists such as albuterol, so vilanterol/fluticasone shouldn't be used to treat acute symptoms such as bronchospasm or acutely deteriorating COPD.


The use of LABAs has been associated with an increased risk of asthma-related death; this is the subject of a boxed warning in the labeling for vilanterol/fluticasone as well as the other products containing a LABA.


The risks associated with the use of corticosteroids apply to this combination product because of its fluticasone component. These include oropharyngeal candidiasis, new infections such as pneumonia or worsening of existing infections, hypercorticism and adrenal suppression, impaired adrenal function when transferring from systemic corticosteroids, development of cataracts and glaucoma, and a reduction in bone mineral density.


The combination product is provided in a disposable plastic inhaler containing two double-foil blister strips, each with 30 blisters. (An institutional pack containing 14 blisters per strip is also available.) Each blister on one strip contains a powder mix that includes micronized vilanterol trifenatate in an amount equivalent to 25 mcg of vilanterol. Each blister on the other strip contains a powder mix that includes 100 mcg of micronized fluticasone furoate. When the inhaler is activated, the powder within both blisters is exposed and available for dispersion into the airstream created by the patient inhaling through the mouthpiece.


The convenient once-daily administration of the new product offers an advantage over other combination formulations of a LABA and inhaled corticosteroid that are administered twice a day.


Precautions: (1) Contraindicated in patients with severe hypersensitivity to milk proteins or any other ingredients. The powder mixes of the two drugs include lactose monohydrate that contains milk proteins. (2) Vilanterol/fluticasone shouldn't be used concurrently with another LABA, which could cause an excessive response. (3) Use with caution in patients being treated with another adrenergic agent (regardless of administration route) because the drugs' sympathomimetic effects may be potentiated. (4) Use with caution in patients with cardiovascular disorders, especially coronary artery disease, cardiac dysrhythmias, and hypertension. Vilanterol may produce clinically significant cardiovascular effects, including increased pulse rate and BP, and prolongation of the corrected QT (QTc) interval. (5) Use with caution in patients with diabetes, seizure disorders, and thyrotoxicosis. Vilanterol, like other beta2-adrenergic agonists, may exacerbate these conditions. (6) Monitor patients for paradoxical bronchospasm, which may be life-threatening. If a patient experiences this response, vilanterol/fluticasone treatment should be immediately discontinued and the patient immediately treated with an inhaled, short-acting bronchodilator such as albuterol. (7) Use caution if vilanterol/fluticasone is used concurrently with an antiarrhythmic drug, tricyclic antidepressant, MAOI, or other drug (such as moxifloxacin) known to prolong the QTc interval because of the increased risk of ventricular dysrhythmias. (8) Corticosteroids and thiazide and loop diuretics may increase vilanterol's hypokalemic effect. (9) Because both vilanterol and fluticasone are primarily metabolized via the CYP3A4 pathway, their actions may be increased by the concurrent use of a strong CYP3A4 inhibitor such as clarithromycin or ketoconazole. Consult the product insert for a complete listing of possible drug interactions.

Table Recently appro... - Click to enlarge in new windowTable Recently approved antineoplastic drugs

Adverse reactions:nasopharyngitis, upper respiratory tract infection, headache, oral candidiasis


Supplied as: a disposable plastic inhaler containing two double-foil blister strips


Dosage: one oral inhalation (25 mcg of vilanterol and 100 mcg of fluticasone furoate) once a day at the same time every day


Nursing considerations: (1) The vilanterol/fluticasone inhalation system is supplied in a moisture-protective foil tray and should only be removed from the tray immediately before initial use. (2) Teach patients to use the inhaler properly and assess their understanding. (3) Tell patients to take the daily dose at the same time each day. (4) After patients take a dose by oral inhalation, they should rinse their mouth with water without swallowing to help reduce the risk of oral candidiasis. (5) Tell patients to discard the inhaler when the dose counter reads "0" after all blisters have been used (after 30 days when used once daily as recommended) or 6 weeks after opening the foil tray, whichever comes first.



1. Breo Elliptia (vilanterol trifenatate and fluticasone furoate). Prescribing information. http://www.mybreo.com. [Context Link]




First drug approved to treat chronic thromboembolic pulmonary hypertension

Pulmonary hypertension (PH) refers to elevated pulmonary arterial pressures and is defined by a mean pulmonary arterial pressure of 25 mm Hg or more at rest (normal, 20 mm Hg or less).1 The resulting increased right ventricular workload can lead to right ventricular hypertrophy and failure. The World Health Organization classifies PH into five groups based on the underlying etiology. PH is a progressive, fatal disease if untreated.1,2


Riociguat (Adempas, Bayer) is one of two new drugs recently approved to treat PH. It's indicated to treat persistent/recurrent chronic thromboembolic PH (CTEPH; Group 4) and pulmonary arterial hypertension (PAH; Group 1) to improve exercise capacity, improve functional class, and delay clinical worsening.3


The primary medical therapy for patients with group 4 PH is anticoagulation, and surgical thromboendarterectomy is indicated for select patients. However, in patients with CTEPH in whom surgery isn't an option or in patients with CTEPH that persists or recurs after surgical treatment, riociguat may be an option. Riociguat is the first drug to be approved for patients with CTEPH.


Riociguat's unique mechanism of action involves stimulation of soluble guanylate cyclase (sGC), an enzyme in the cardiopulmonary system and the receptor for nitric oxide (NO). When NO binds to sGC, the enzyme catalyzes synthesis of the signaling molecule cyclic guanosine monophosphate (cGMP).


Riociguat has a dual mode of action: It sensitizes sGC to endogenous NO by stabilizing the NO-sGC binding, and it directly stimulates sGC via a different binding site, independent of NO. Stimulation of the NO-sGC-cGMP pathway leads to increased generation of cGMP with subsequent vasodilation and improved hemodynamic parameters.


In patients with CTEPH, the effectiveness of riociguat was demonstrated in a study that was designed to measure the change in the distance a patient could walk in 6 minutes (6-minute walking distance). After 16 weeks of treatment, the average improvement in the 6-minute walking distance in patients treated with riociguat was approximately 150 ft (46 m) more than in patients receiving placebo. In patients with PAH treated with riociguat for 12 weeks, the average improvement in the 6-minute walking distance was approximately 118 ft (36 m) more than in patients receiving placebo.


Riociguat may harm the fetus if administered during pregnancy and is classified in Pregnancy Category X, the subject of a boxed warning in its labeling. All female patients, regardless of reproductive potential, must enroll in the Adempas Risk Evaluation and Mitigation Strategy (REMS) program, in which prescribers and pharmacies must also be certified. Male patients are not enrolled in this program.


Precautions: (1) Contraindicated for use during pregnancy, which must be excluded before initiating treatment, monthly during treatment, and 1 month after stopping treatment. (2) Because of the risk of hypotension, riociguat is contraindicated for use with nitrates (such as nitroglycerin) or NO donors (such as amyl nitrite), or phosphodiesterase (PDE) inhibitors, including specific PDE-5 inhibitors (such as sildenafil) and nonspecific PDE inhibitors (such as dipyridamole and theophylline). The potential for symptomatic hypotension is increased in patients with other risk factors, including the concurrent use of antihypertensive medications and medications that may interact with and increase the action of riociguat. Consult the product labeling for details about potential drug interactions and recommended dosage adjustments. (3) Monitor patients for bleeding; in studies, 2.4% of patients experienced serious bleeding events. Immediately report any signs or symptoms of bleeding, such as hemoptysis. (4) Riociguat isn't recommended for patients with pulmonary veno-occlusive disease because it may worsen their cardiovascular status. (5) Riociguat isn't recommended for use in patients with severe hepatic impairment, patients with a creatinine clearance less than 15 mL/minute, or those on dialysis.


Adverse reactions:headache, dyspepsia/gastritis, dizziness, nausea, diarrhea, hypotension, vomiting, anemia, gastroesophageal reflux, constipation


Supplied as: 0.5 mg, 1 mg, 1.5 mg, 2 mg, and 2.5 mg oral tablets


Dosage: Initially, 1 mg three times a day; this may be reduced to 0.5 mg three times a day for patients at risk for hypotension. If systolic BP remains greater than 95 mm Hg and the patient doesn't experience hypotension, the dosage may be titrated upward by 0.5 mg three times a day with increases being made no sooner than 2 weeks apart. The dosage can be increased to the highest tolerated dosage, up to a maximum of 2.5 mg three times a day. If a patient experiences signs or symptoms of hypotension, the dosage may be reduced by 0.5 mg three times a day. Note: The plasma concentrations of riociguat are reduced by 50% to 60% in smokers compared with nonsmokers, so titrating to dosages higher than 2.5 mg three times a day may be considered for patients who smoke. A dosage reduction may be indicated for patients who stop smoking.


Nursing considerations: (1) Warn patients about the drug's potentially teratogenic effects and stress the need to avoid pregnancy. Effective methods of contraception must be used during treatment and for 1 month after stopping treatment. Consult the product labeling for recommended methods of contraception. (2) Tell patients that antacids such as aluminum hydroxide and magnesium hydroxide reduce the absorption of riociguat and shouldn't be administered within 1 hour of taking the new drug. (3) Because of the potential for drug interactions, tell patients to check with their healthcare provider before taking any new drug or over-the-counter products such as St. John's wort, which may reduce the action of riociguat. (4) Teach patients the signs and symptoms of pulmonary edema and actions to take if these develop. (5) Riociguat can be taken without regard to food. Tell patients to take doses 6 to 8 hours apart and warn them not to take more than 7.5 mg/day unless directed by the healthcare provider.



1. Rubin LJ, Hopkins W. Overview of pulmonary hypertension in adults. 2014. http://www.uptodate.com. [Context Link]


2. National Institutes of Health/ National Heart, Lung, & Blood Institute. Types of pulmonary hypertension. 2013. http://www.nhlbi.nih.gov/health/health-topics/topics/pah/types.html. [Context Link]


3. Adempas tablets for oral use. Prescribing information. http://labeling.bayerhealthcare.com/html/products/pi/Adempas_PI.pdf. [Context Link]



Antagonizing a key hormone to ease symptoms

Endothelins (ETs) are a group of peptide hormones that are released by endothelial cells, and certain of these hormones exhibit a potent vasoconstrictor action. ET-1 is the predominant form and is thought to play an important role in the pathogenesis and worsening of PAH. The effects of ET-1 in the vascular smooth muscle and endothelium are mediated by two receptor subtypes, ETA and ETB.


Macitentan (Opsumit, Actelion) is the third endothelin receptor antagonist (ERA) on the market, joining bosentan and ambrisentan. Macitentan prevents ET-1 from binding to both ETA and ETB receptors. It's indicated for the treatment of PAH (WHO Group 1) to delay disease progression, which includes death, initiation of I.V. or subcutaneous prostanoids, or clinical worsening of PAH (decreased 6-minute walking distance, worsened PAH symptoms, and need for additional PAH treatment).1,2


Macitentan's effectiveness was established in a long-term study in patients with PAH with predominantly WHO Functional Class II-III symptoms. Patients were treated with macitentan as monotherapy, or in combination with a PDE-5 inhibitor or inhaled prostanoids. After about 2 years of treatment, 31% of the patients treated with macitentan (10 mg once a day) had experienced a primary endpoint event compared with 46% of those receiving placebo. Macitentan also reduced hospitalization for PAH.


Like the other ERAs and riociguat, macitentan may harm the fetus if administered during pregnancy and is classified in Pregnancy Category X. Specific precautions are the same as those described above for the use of riociguat. All female patients, regardless of reproductive potential, must enroll in the Opsumit REMS program, in which prescribers and pharmacists must also be certified.


Liver failure has been reported with the use of bosentan and the risk of hepatotoxicity is the subject of a boxed warning in its labeling; however, the risk of hepatic adverse reactions appears to be less with ambrisentan and macitentan.


Precautions: (1) Contraindicated for use during pregnancy, which must be excluded before initiating treatment, monthly during treatment, and 1 month after stopping treatment. (2) Not recommended in patients with severe anemia. Patients' hemoglobin and hematocrit concentration should be determined before initiating treatment with macitentan and repeated during treatment as clinically indicated. (3) Like riociguat, macitentan and other ERAs may cause complications, including pulmonary edema, in patients with pulmonary veno-occlusive disease. If pulmonary edema occurs and is confirmed to be associated with this disorder, treatment with macitentan should be discontinued. (4) Liver function tests should be performed before initiating treatment with macitentan and during treatment as clinically indicated because some patients in clinical trials experienced elevations of serum aminotransferases. (5) Avoid concurrent use with a strong CYP3A4 inhibitor such as ketoconazole and ritonavir or a strong CYP3A4 inducer such as rifampin because these may cause clinically significant drug interactions.


Adverse reactions:nasopharyngitis/pharyngitis, headache, anemia, bronchitis, urinary tract infection, influenza


Supplied as: 10 mg tablets


Dosage: 10 mg once a day


Nursing considerations: (1) Warn patients about the drug's potentially teratogenic effects and stress the need to avoid pregnancy. Effective methods of contraception must be used during treatment and for 1 month after stopping treatment. (2) Because of the risk of adverse drug interactions, tell patients to report all medications they take to the healthcare provider, including over-the-counter drugs, vitamins, and herbal supplements. (3) Instruct patients to swallow tablets whole and not to crush, split, or chew them. (4) The ERAs have been reported to inhibit spermatogenesis and reduce sperm counts; advise male patients about the drug's potential effects on fertility. (4) Macitentan can be taken without regard to food.



1. Opsumit (macitentan). Prescribing information. http://opsumit.com/sites/opsumit/files/OPSUMIT-Full-Prescribing-Information.pdf. [Context Link]


2. National Institutes of Health/ National Heart, Lung, & Blood Institute. Types of pulmonary hypertension. 2013. http://www.nhlbi.nih.gov/health/health-topics/topics/pah/types.html. [Context Link]


* Common adverse reactions are italicized throughout this article. [Context Link]