Avanafil (Stendra)

4.0 CONTACT HOURS 4.0 CONTACT HOURS

Abstract: Each year, the FDA approves many pharmaceuticals and products designed to treat or improve a patient’s condition. The following is a sampling of some of the most important drugs approved in 2012 that speciﬁ cally apply to nurse practitioner practice.

By Jennifer M. Belavic, PharmD, BCPS, FASCP

males with diabetes, heart disease, previous radical ▼ Erectile dysfunction prostatectomy, and neurologic conditions. ED is also associated with cardiovascular risk factors, which include Avanafi l (Stendra) hypertension, diabetes, dyslipidemia, chronic kidney Erectile dysfunction (ED) is defi ned as the persistent or disease, and obesity.4,5 recurrent inability to achieve or maintain an erection A series of interrelated mechanisms play a role in suffi cient for satisfactory sexual performance.1,2 ED is the changes in vascular pressure within the cavernosal associated with both impaired psychological health and sinuses that cause penile erection. The main mechanism reduced self-esteem.3 The emotional distress that a man is the nitric oxide/cyclic guanosine monophosphate may experience can impact the patient’s social or marital (NO/cGMP) pathway. Nitric oxide is released during life, which leads to the need for treatment of this condition. sexual arousal or nocturnal tumescence, which causes ED affects 30 million men in the United States and smooth muscle relaxation in the trabeculae and 150 million worldwide. This number is expected to arterioles of the penis.3,6 Cyclic nucleotide phosphodies- increase as the population ages.3 It was found that the terases (PDEs) are a family of hydrolyzing enzymes that prevalence of ED increases with age (40% at 40 years of cleave cAMP or cGMP. The PDE that is the major age, 70% at 70 years of age).4 ED occurs more often in cGMP-hydrolyzing enzyme in the cavernosal tissue is

Keywords: acne, Cushing syndrome, diabetic macular edema, erectile dysfunction, HIV, obesity, overactive bladder, respiratory distress syndrome Illustration © Oksana Pasishnychenko/Istoskphoto

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phosphodiesterase type 5 (PDE5).6 PDE5 plays an ■ Warnings and precautions important role in regulating nitric oxide-mediated There are cardiovascular risks associated with the use of smooth muscle relaxation. PDE5 inhibitors are similar avanafi l during sexual activity in patients with preexist- in structure to cGMP and competitively bind to PDE5. ing cardiovascular disease. Avanafi l should not be used in This binding inhibits the hydrolysis of cGMP, allowing men who have been advised by their healthcare provider for accumulation of cGMP levels, leading to penile to abstain from sexual activity because of their cardiac erection.6 With this effective mechanism of action in history. Avanafi l should not be used in the following mind, the oral PDE5 inhibitor therapy is recommended patient groups10: as first-line treatment for ED. The PDE5 inhibitors have • individuals who have had a myocardial infarction, been shown to restore penile blood flow and erections stroke, life-threatening dysrhythmia, or coronary in response to sexual stimulation.5 revascularization within the last 6 months Despite these options, many men suffering from ED • men with resting hypotension or hypertension fail to respond clinically. Most of these men are patients with severe ED involving diabetes mellitus, severe vascular The recommended dose of avanafi l is insuffi ciency, or postprostatectomy complications. Newer medications in the PDE5-inhibitor class are being studied 100 mg by mouth 30 minutes prior to that have greater effi cacy and lower the adverse reaction sexual activity. profi le.3 Avanafi l is a novel PDE5 inhibitor that was approved by the FDA on April 27, 2012.7,9 This medication has been • men with unstable angina or angina that occurs during shown to have greater selectivity of PDE5 and a higher sexual intercourse selectivity against PDE1 and PDE6.4,8 Vivus, Inc. will • patients with a diagnosed New York Heart Association market the drug under the brand name Stendra.7 (NYHA) class 2 or greater congestive heart failure.10 Avanafi l has systemic vasodilatory properties that can ■ Indication have an effect on antihypertensive medications and Avanafi l is a PDE5 inhibitor approved for the treatment augment the BP-lowering effects. of ED.10 Erections lasting more than 4 hours and priapism have been documented with the use of the other PDE5- ■ Mechanism of action inhibitors.10 Due to this information, patients taking Avanafi l works by inhibiting the effect of PDE5 on degrada- avanafi l need to be educated about this adverse reaction. tion of cGMP. This inhibition leads to penile erection due to Caution needs to be taken if avanafi l is prescribed in the infl ow of blood into the area.10 patients who have an anatomical deformity of the penis or in patients who have other medical conditions that ■ Dosing and administration predispose them to priapism.10 The recommended dose of avanafi l is 100 mg by mouth Avanafi l should be stopped immediately if the patient 30 minutes prior to sexual activity. This medication can be experiences vision loss in one or both eyes. This can be a taken without regards to food. Avanafi l should be taken on sign of permanent vision loss called nonarteritic anterior an as needed basis, but no more than once a day. Based ischemic optic neuropathy (NAION).10 upon effi cacy and tolerability, the dose can be increased to The other PDE5-inhibitors have been documented to a 200 mg maximum dose or decreased to 50 mg. Dosing have a sudden decrease or loss in hearing, which can occur adjustments are not needed in patients with either mild or with tinnitus or dizziness. Patients who experience any of moderate renal or hepatic impairment.10 The drug should these symptoms should stop taking avanafi l immediately.10 not be used in patients with severe renal or hepatic Avanafi l should be used with caution in patients impairment. taking alpha-blockers due to the vasodilating effects of the PDE5-inhibitors. The following must be considered in the ■ Contraindications outlined patient populations: Avanafi l should not be used in combination with any • Men should be on stable alpha-blocker therapy prior to form of organic nitrates. If a nitrate is needed and is seen starting avanafi l. as medically necessary in a life-threatening situation, • Men who are on stable dosing of alpha-blocker 12 hours must have lapsed since a dose of avanafi l was therapy should be started on avanafil at the lowest taken.10 dosage of 50 mg. www.tnpj.com The Nurse Practitioner • February 2013 25

• If an alpha-blocker is indicated and therapy must be • Patients should stop taking avanafi l, and seek medical started on men who are concomitantly taking avanafi l, attention if they experience sudden loss of vision or a the alpha-blocker should be started at the lowest dose decrease or loss of hearing. and continued with a slow titration.10 • A patient who experiences any suspected adverse reactions should contact Vivus at 1-866-330-1871 ■ Adverse reactions or the FDA at 1-800-FDA-1088 or www.fda.gov/ Throughout clinical trial experience, the most com- medwatch.10 monly documented adverse reactions included headache, flushing, nasal congestion, nasopharyngitis, and back pain. These adverse reactions were seen in 2% or REFERENCES more of the patients studied in clinical trials. Other 1. Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA. Oral sildenafi l in the treatment of erectile dysfunction. Sildenafi l Study adverse reactions that occurred in less than 2% of the Group. New Engl J Med. 1998;338(20):1397-1404. patients included the following: upper respiratory 2. Lue TF, Giuliano F, Montorsi F, et al. Summary of the recommendations on sexual dysfunctions in men. J Sex Med. 2004;1(1):6-23. infection (URI), bronchitis, sinusitis, sinus congestion, 3. Limin M, Johnsen N, Hellstrom WJ. Avanafi l, a new rapid-onset phosphodi- infl uenza, hypertension, nausea, dyspepsia, constipation, esterase 5 inhibitor for the treatment of erectile dysfunction. Expert Opin and rash.10 Back pain, dizziness, arthralgia, and diarrhea Investig Drugs. 2010;19(11):1427-1437. 4. Alwaal A, Al-Mannie R, Carrier S. Future prospects in the treatment of were also documented in open-label extension trials. erectile dysfunction: focus on avanafil. Drug Des Devel Ther. 2011;5: 435-443. ■ 5. Hellstrom WJ, Freier MT, Serefoglu EC, Lewis RW, Didonato K, Peterson CA. Drug interactions A phase II, single-blind, randomized, crossover evaluation of the safety and The use of avanafi l in combination with any organic effi cacy of avanafi l using visual sexual stimulation in patients with mild to nitrate is contraindicated. In a life-threatening situation, moderate erectile dysfunction. BJU Int. 2012. [Epub ahead of print.] 6. Palit V, Eardley I. An update on new oral PDE5 inhibitors for the treatment nitrate medication can only be administered at least of erectile dysfunction. Nat Rev Urol. 2010;7:603-609. 12 hours after the last dose of avanafi l was administered.10 7. FDA approves Stendra. www.drugs.com/newdrugs/fda-approves-stendra- Caution must be taken when using avanafi l concomi- erectile-dysfunction-3201.html. 8. Zhao C, Kim SW, Yang DY, et al. Effi cacy and safety of avanafi l for treating tantly with alpha-blocker medications and antihypertensive erectile dysfunction: results of a multicenter, randomized, double-blind, medications. placebo-controlled trial. BJU Int. 2012;110(11):1801-1806. 9. Anon. Stendra (avanafi l): a new oral phosphodiesterase-5 inhibitor indicated The use of alcohol along with avanafi l is not recom- for the treatment of ED. Formulary. 2012. http://license,icopyright.net/used/ mended due to the increased potentiation of BP-lowering viewFreeUse.act?fuid=MYT0NDg3MDg%3D. effects leading to orthostatic hypotension, headache, and 10. Stendra (avanafi l) tablets Prescribing Information. Vivus, Inc. 2012. www. stendra.com. dizziness.10 Because avanafi l is a substrate of CYP3A4, any medication that inhibits CYP3A4 can increase the concentration ▼ HIV-1 infection of avanafi l. Elvitegravir, cobicistat, ■ Pharmacokinetics Avanafi l is administered orally and is rapidly absorbed. A emtricitabine, tenofovir patient can experience a peak concentration in 30 to 45 minutes. Avanafi l is metabolized and cleared by the liver. disoproxil fumarate (Stribild) Its metabolites are excreted in both the feces and urine. AIDS is a global pandemic.1 Antiretroviral medications have The half-life of avanafi l is 5 hours.10 helped tremendously decrease the morbidity and mortality associated with HIV. Since the mid-1990s, ■ Clinical pearls international guidelines recommend initial treatment to • Avanafi l is a pregnancy category C drug. consist of a combination of at least three active agents from • Avanafi l is to be administered 30 minutes prior to sexual two or more classes of antiretroviral drugs.2 The guidelines activity, and is to be used on an as-needed basis, but not recommend that for patients who are treatment-naive to more than once a day. be initially started with two nucleoside/nucleotide reverse • Patients should be educated about the danger of an transcriptase inhibitors (NRTIs) plus a nonnucleoside erection lasting longer than 4 hours or priapism. Patients reverse transcriptase inhibitor (NNRTI), usually efavirenz should know to seek medical attention immediately. (EFV), a ritonavir-boosted protease inhibitor (PI), or the • Avanafi l should not be prescribed for patients with a integrase strand transfer inhibitor raltegravir. The guide- documented cardiovascular disease. lines also mention the use of a fi xed-dose combination

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tablet of emtricitabine (FTC) plus tenofovir disoproxil ■ Indication fumarate (TDF) as a backbone to therapy.3 EVG/COBI/FTC/TDF is FDA approved as a complete The current treatment regimens have successfully regimen for the treatment of HIV-1 infection in adults improved HIV morbidity and mortality, but the regimens who are antiretroviral treatment naive.11 are associated with heavy pill burdens, multiple dosing per day, and unwanted adverse reactions. The pill burden ■ Mechanism of action and dosing regimens affect patient adherence, can lead to EVG/COBI/FTC/TDF is a combination product com- treatment failure, and the need for regimen changes that prised of antiviral medications and a pharmacokinetic can be more costly.4 enhancer. All four medications need to have a full Combination therapy for HIV has been more effective explanation of their mechanisms of action to understand due to the constantly changing genetic material of HIV the combination. mutations. Resistance can occur to all current classes of antiretroviral therapy and can occur easily due to the rapid application of HIV and its turnover.1 Regimens that COBI does not have any antiviral include the ritonavir-boosted PI have shown the ability to activity, so PI resistance is not a concern. decrease the development of drug resistance in comparison to the alternative regimens with NNRTIs. Ritonavir- boosted regimens are well-tolerated but have documented EVG works by inhibiting the strand transfer activity of metabolic complications, including dyslipidemia, lipodys- HIV-1 integrase. HIV-1 integrase is an enzyme that is trophy, insulin resistance, and multiple drug interactions. needed for viral replication. The inhibition achieved by The major limitation of ritonavir is the need for an EVG prevents the integration of HIV-1 DNA into host additional pill to the regimen, leading to tolerability issues genomic DNA, blocking HIV-1 previous formation and and pill burdens.5 propagation of the viral infection.11 Elvitegravir (EVG) is a once-daily HIV integrase COBI is a selective mechanism-based inhibitor of strand transfer inhibitor that demonstrates potent CYP3A. It works by enhancing the exposure of CYP3A antiretroviral activity when given with pharmacokinetic substrates, leading to the enhancement of bioavailability, boosting.2,3 EVG can be given in combination with either and increasing the half-life of medications such as EVG. ritonavir or cobicistat (COBI). COBI has a better adverse- Thus, COBI exhibits booster-like activity. effect proﬁ le in comparison to ritonavir. COBI is a new FTC works by inhibiting the activity of HIV-1 RT by a chemical entity that is used as a pharmaco-enhancer competitive fashion and becomes incorporated into the (booster) to increase the systemic exposure levels of viral DNA, which causes chain termination.11 concomitant medications that are metabolized by CYP3A TDF inhibits the activity of HIV-1 RT by competing enzymes, including EVG and/or HIV PIs that require for incorporation into DNA leading to DNA chain boosting.6 It also has a long elimination half-life, which termination.11 allows once-a-day dosing. COBI does not have any antiviral activity, so there is no concern of the develop- ■ Dosing and administration ment of PI resistance that is usually seen with ritonavir EVG/COBI/FTC/TDF is comprised of the following: combination therapy.7,8 elvitegravir 150 mg, cobicistat 150 mg, emtricitabine A single tablet regimen has been developed and 200 mg, and tenofovir disoproxil fumarate 300 mg. investigated that contains EVG, COBI, emtricitabine EVG/COBI/FTC/TDF is to be taken as one tablet once a (FTC), and TDF. This combination product has been day with food.11 shown to have the same antiretroviral activity as Do not use EVG/COBI/FTC/TDF in patients with EFV/FTC/TDF.2 renal impairment as deﬁ ned with a creatinine clearance On August 27, 2012, the FDA approved elvitegravir below 70 mL/min. Discontinue the drug in patients who (EVG)/cobicistat (COBI)/emtricitabine (FTC)/tenofovir have a drop in their creatinine clearance to less than disoproxil fumarate (TDF), under the brand name Stribild, 50 mL/min.11 which is a combination of two previously approved HIV For patients with mild or moderate hepatic impair- medications FTC and TDF, in addition to two new ment, no dosing adjustments are needed when using medications EVG and COBI.9,10 This regimen is to be used EVG/COBI/FTC/TDF. If a patient develops severe hepatic in treatment-naive adults. EVG/COBI/FTC/TDF will be impairment, EVG/COBI/FTC/TDF should be discontin- made available through Gilead Sciences, Inc.9 ued due to a lack of research in this patient population.11 www.tnpj.com The Nurse Practitioner • February 2013 27

■ Contraindications section, the most commonly observed adverse reactions EVG/COBI/FTC/TDF should not be used in combination include nausea, diarrhea, headache, fatigue, and abnormal with medications that are dependent upon CYP3A for dreams. Other adverse reactions include depression, clearance. When used concomitantly, these medications dyspepsia, back pain, insomnia, and rash.11 can show an increase in plasma concentrations and, in turn, lead to resistance of EVG/COBI/FTC/TDF.11 ■ Drug interactions Since EVG/COBI/FTC/TDF is the complete regimen for ■ Warnings and precautions the treatment of HIV, no other antiretroviral is needed to A Boxed Warning is associated with the use of EVG/COBI/ be administered. Do not give EVG/COBI/FTC/TDF in FTC/TDF. The Boxed Warning covers lactic acidosis/severe combination with other medications indicated for the hepatomegaly with steatosis and posttreatment acute treatment of HIV.11 exacerbation of hepatitis B. Tenofovir is the main drug that As mentioned previously, do not give EVG/COBI/ causes lactic acidosis and severe hepatomegaly with steatosis. FTC/TDF in conjunction with medications that are EVG/COBI/FTC/TDF is not to be used for the treatment of metabolized by CYP3A and CYP2D6. These drug interac- chronic hepatitis B virus infection. Two components of EVG/ tions can lead to altered concentrations of EVG/COBI/ COBI/FTC/TDF, emtricitabine and tenofovir, have been FTC/TDF.11 associated with exacerbations of hepatitis B. It is important to continually monitor hepatic function in these patients.11 ■ Pharmacokinetics EVG/COBI/FTC/TDF is administered orally. Peak plasma concentrations for each of the drug components are EVG As with all antiretroviral medications, (4 hours), COBI (3 hours), FTC (3 hours), and TDF EVG/COBI/FTC/TDF can cause immune (2 hours).11 EVG is metabolized by the CYP3A pathway, and reconstitution syndrome. it also undergoes glucuronidation via UGT1A1/3 enzymes. COBI is metabolized by CYP3A, and to a lesser extent, by CYP2D6. Emtricitabine and tenofovir are not signifi cantly Patients using EVG/COBI/FTC/TDF can develop new metabolized.11 Drug elimination is via feces and urine for or worsening renal impairment. This impairment can EVG and COBI, and via urine for FTC and TDF.11 include acute renal failure and Fanconi syndrome.11 It is important to obtain baseline renal function information ■ Clinical pearls prior to starting EVG/COBI/FTC/TDF in addition to • EVG/COBI/FTC/TDF is a pregnancy category B drug. periodic monitoring throughout treatment. • Both FTC and TDF can be detected in breast milk. In patients who are at risk for experiencing osteoporo- Mothers taking EVG/COBI/FTC/TDF should not sis, bone loss, or a fracture, monitoring of bone mineral breastfeed while on this medication. density is needed.11 EVG/COBI/FTC/TDF has the potential • Patients should understand the signs and symptoms of decreasing bone mineral density.11 associated with the development of lactic acidosis: weak Do not coadminister EVG/COBI/FTC/TDF with any or tired feeling, unusual muscle pain, diffi culty breath- drugs that can contain any of the individual drug compo- ing, and cold extremities. nents of EVG/COBI/FTC/TDF. Do not use EVG/COBI/ • Patients should be instructed to contact their healthcare FTC/TDF in combination with drugs containing emtric- provider if they develop symptoms associated with the itabine or tenofovir, or with drugs containing lamivudine development of liver abnormalities: jaundice, icterus, or adefovir dipivoxil. dark urine, light-colored bowel movements, nausea, As with all antiretroviral medications, EVG/COBI/ and/or loss of appetite. FTC/TDF has the potential to cause immune reconstitu- • EVG/COBI/FTC/TDF is an all-in-one medication for tion syndrome. During the beginning of therapy, patients the treatment of HIV and should be taken once daily may develop an infl ammatory response to opportunistic with food. infections, including Pneumocystis jirovecii pneumonia, • The most common adverse reactions with EVG/ Mycobacterium avium, tuberculosis, and cytomegalovirus.11 COBI/FTC/TDF are nausea and diarrhea. Patients who experience any other suspected adverse reactions ■ Adverse reactions should contact Gilead Sciences, Inc. at 1-800-GILEAD-5 Through clinical trial experience, in addition to the or the FDA at 1-800-FDA-1088 or www.fda.gov/ adverse reactions mentioned in the warnings and precautions medwatch.

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• Gilead’s UC Advancing Access program provides assis- risk factors, decrease the incidence of type 2 diabetes, and tance to patients who do not have insurance or who need reduce pain that is associated with osteoarthritis.3 Weight fi nancial assistance to pay for their medications. Have loss should start with healthy eating, physical activity, patients contact Advancing Access at 1-800-266-2056.9 and behavior modifi cations. The use of medications in • For patients with private insurance, Gilead’s copay coupon the fi ght against obesity can augment the initial weight program provides assistance with out-of-pocket expenses loss options and can also provide additional benefi t for for Gilead’s HIV medications starting at the fi rst dollar.9,11 some patients who did not attain adequate weight loss by lifestyle modifi cations alone. Dexfenfl uramine was the REFERENCES fi rst medication approved for the long-term treatment of 1. Ghosh RK, Ghosh SM, Chawla S. Recent advances in antiretroviral drugs. obesity. Fenfl uramine is the racemic mixture of dexfenfl u- Expert Opin Pharmacother. 2011;12(1):31-46. 2. Sax PE, DeJesus E, Mills A, et al. Co-formulated elvitegravir, cobicistat, ramine and was used as both monotherapy and in emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, combination with phentermine for weight loss. Both of and tonofovir for initial treatment of HIV-1 infection: a randomized, double-blind, phase 3 trial, analysis of results after 48 weeks. Lancet. these medications were removed from the market due to 2012;379(9835):2439-2448. documentation that showed these drugs increased the risk 3. DeJesus E, Rockstroh JK, Henry K, et al. Co-formulated elvitegravir, cobicistat, 6,7 emtricitabine, and tenofovir disoproxil fumarate versus ritonavir-boosted of cardiac valvulopathy and pulmonary hypertension. atazanavir plus co-formulated emtricitabine and tenofovir disoproxil fumarate Both dexfenfl uramine and fenfl uramine worked to for initial treatment of HIV-1 infection: a randomized, double-blind, phase 3, non-inferiority trial. Lancet. 2012;379(9835):2429-2438. suppress the appetite by inhibiting serotonin (5-HT) 4. Cohen C, Elion R, Ruane P, et al. Randomized, phase 2 evaluation of two reuptake and increasing 5-HT release.5 After the removal single-tablet regimens elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate versus efavirenz/emtricitabine/tenofovir disoproxil of these agents from the market, more research was fumarate for the initial treatment of HIV infection. AIDS. 2011;25(6):F7-F12. completed in improving the understanding of the actions 5. Mathias AA, German P, Murray BP, et al. Pharmacokinetics and pharmaco- of the 5-HT receptor subtypes that are involved in dynamics of GS-9350: a novel pharmacokinetic enhancer without anti-HIV activity. Clin Pharmacol Ther. 2010;87(3):322-329. appetite suppression. 6. German P, Warren D, West S, Hui J, Kearney BP. Pharmacokinetics and bioavailability of an integrase and novel pharmacoenhancer-containing single-tablet fi xed-dose combination regimen for the treatment of HIV. Lorcaserin is an agonist of the 5-HT J Acquir Immune Defi c Syndr. 2010;55(3):323-329. 2C 7. Ramanathan S, Mathias AA, German P, Kearney BP. Clinical pharmacoki- receptor that has been designed and netic and pharmacodynamic profi le of the HIV integrase inhibitor elvitegravir. Clin Pharamcokinet. 2011;50(4):229-244. studied for weight loss. 8. Elion R, Cohen C, Gathe J, et al. Phase 2 study of cobicistat versus ritonavir each with once-daily atazanavir and fi xed-dose emtricitabine/tenofovir df in the initial treatment of HIV infection. AIDS. 2011;25(15):1881-1886. 9. Anon. US FDA approved Gilead’s Stribild, a complete once-daily single tablet Serotonin shows its effects through 14 different regimen for treatment-naïve adults with HIV-1 infection. www.gilead.com/ pr_1728981. receptors. The serotonin 5-HT2 receptor contains three 8 10. Anon. FDA approved Stribild. www.drugs.com/newdrugs/fda-approves-new- receptor subtypes: 5-HT2A, 5-HT2B, and 5-HT2C. The cominiation-pill-stribilid-hiv-3455.html. 5-HT2C receptors are found primarily in the central nervous 11. Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate) tablets prescribing information. Gilead Sciences. Inc. 2012. www.stribild. system and are important in controlling mood, cognition, com.content.pdf.stribild_prescribing_information.pdf. and appetite. Activation of the 5-HT2C receptor can increase satiety and decrease hunger, leading to decreased food 9 intake. Through the history of trying to develop 5-HT2C agonists, there has been a lack of selectivity over 5-HT and ▼ Obesity 2A 5-HT2B receptors. When activated, 5-HT2A can cause

hallucinations. Activation of 5-HT2B can lead to the develop- Lorcaserin (Belviq) ment of cardiac valvular insuffi ciency and pulmonary 8 In 2008, it was estimated that 33.9% of adults were obese, hypertension. With research, better selectivity of 5-HT2C, 1,2 and 34.4% were overweight. Obesity is defi ned as an and the development of 5-HT2C receptor agonists, more individual having a body mass index (BMI) of 30 or effi cacious weight loss medications can be developed greater; overweight is a BMI of 25 to 29.9. Excess body without the historical adverse reactions experienced by the weight increases the risk of developing type 2 diabetes, older, nonselective serotonin agonists. Additionally, 5-HT2C hypertension, hyperlipidemia, stroke, heart disease, selective agents can potentially have a role in glucose respiratory problems, sleep apnea, osteoarthritis, depres- tolerance regulation and sensitivity of hepatic insulin.8,9 3-5 sion, and several types of cancer. Lorcaserin is an agonist of the 5-HT2C receptor that Sustained weight loss of 5% to 10% in obese individu- has been designed and studied for weight loss.10 Lorcase- als can have a positive impact on several cardiovascular rin is the fi rst selective 5-HT2C agonist. This medication www.tnpj.com The Nurse Practitioner • February 2013 29

was approved by the FDA on June 27, 2012. Lorcaserin will ■ Warnings and precautions be marketed under the brand name Belviq and will be There are a number of warnings and precautions that the distributed by Eisai, Inc.11 provider should know when prescribing Lorcaserin. Since Lorcaserin is a serotonergic medication, patients ■ Indication taking this drug can be at risk for developing serotonin Lorcaserin is approved as an adjunct therapy to lifestyle syndrome or neuroleptic malignant syndrome (NMS)-like modiﬁ cations, a reduced-calorie diet, and increased symptoms. Serotonin syndrome is associated with chills, physical activity for weight management in patients with tremors, confusional state, disorientation, hyperhidrosis, either a BMI of 30 or greater, a BMI of 27 to 29.9, and a nausea, vomiting, and diarrhea. When serotonin syndrome weight-related, comorbid condition such as type 2 is at its most severe state, it can resemble NMS in which diabetes, hypertension, or dyslipidemia.12 the patient will experience hyperthermia, muscle rigidity, autonomic instability, and mental status changes.12 If, for ■ Mechanism of action some reason, lorcaserin must be used in patients taking a Lorcaserin’s exact mechanism of action is unknown. serotonergic medication, extreme caution and close The proposed mechanism is that it decreases food monitoring are needed.

consumption and promotes satiety through selective As seen with the other 5-HT2 agonists, dexfenﬂ uramine

activation of 5-HT2C receptors. These receptors are and fenﬂ uramine, there is a risk of developing valvular located within the hypothalamus on the anorexigenic heart disease. Symptoms associated with valvular heart proopiomelanocortin (POMC) neurons. POMC is a disease include dyspnea, edema, heart failure, or a cardiac precursor for alpha-melanocortin-4 receptors to murmur that is newly diagnosed. Lorcaserin should not be decrease food intake.12 prescribed to patients with heart failure.12 It has been documented that there is an increase in ■ Dosing and administration risk of developing attention and memory impairments, Lorcaserin is dosed 10 mg by mouth twice daily. The doses confusion, fatigue, and somnolence while taking can be administered without regard to food, and dosing lorcaserin. All patients starting treatment with this adjustments are not needed based upon tolerability.12 medication should be cautioned about the operation of machinery and automobiles until they gain a better understanding of the effects of the medication on their Lorcaserin, like all 5-HT2C receptor functioning.12 agonists, can increase the risk of Patients should be monitored for signs and symptoms developing priapism. of euphoria, hallucinations, and dissociation, in addition to new development or worsening of depression, suicidal thoughts or behavior, or changes in mood or behavior.12 No dosing adjustments are needed in patients with In patients with diabetes that are currently receiving mild renal impairment. Caution should be taken in treatment, the use of lorcaserin can increase the risk of patients with moderate renal impairment. Lorcaserin developing hypoglycemia; therefore, adjustments should should not be used in patients with severe renal impair- be made to the treatment regimens of the antidiabetic ment or end-stage renal disease.12 medications.

For patients with mild-to-moderate hepatic impair- Lorcaserin, like all 5-HT2C receptor agonists, can ment, lorcaserin dosing does not need to be modiﬁ ed. The increase the risk of developing priapism. Lorcaserin drug should not be used in patients with severe hepatic should not be used in men with diagnosed conditions that impairment.12 can cause priapism such as sickle-cell anemia, multiple Therapy should be evaluated at week 12. If a patient myeloma, leukemia, or in men with an anatomical has not lost at least 5% of baseline body weight, lorcaserin deformity of the penis.12 should be stopped, since the patient is not responding and Lorcaserin can cause a decrease in heart rate. Patients will not be able to sustain appropriate weight loss.12 with bradycardia or a history of heart block should be monitored.12 ■ Contraindications Routine lab monitoring is needed while a patient is Lorcaserin is contraindicated in women who are pregnant. taking lorcaserin. Nurse practitioners (NPs) should Therefore, this medication is a pregnancy category X consider monitoring a complete blood count with a focus drug.12 on white blood cell count and prolactin levels. Lorcaserin

30 The Nurse Practitioner • Vol. 38, No. 2 www.tnpj.com

can decrease white blood cell count and increase prolactin medication have not been studied. Weight loss medica- levels.12 tions should not be combined with lorcaserin. Due to the incidence of developing pulmonary • It is important to evaluate patients’ weight loss progress hypertension associated with other serotonin-acting by week 12. If the patient did not lose at least 5% of weight-loss medications (fenfl uramine and dexfenfl ura- baseline body weight at that point, the patient is mine), patients should be monitored for signs and considered a nonresponder, and lorcaserin should be symptoms of developing pulmonary hypertension.12 stopped. Although clinical trials did not show this development, • Lorcaserin is approved for chronic weight management caution is warranted based on history of other medica- in combination with a reduced-calorie diet and exercise. tions that work by similar mechanism of action. • Patients should know the signs and symptoms associated with valvular heart disease such as dyspnea, edema, ■ Adverse reactions dizziness, fatigue, or weakness, and fast or irregular In addition to the adverse reactions outlined in the heartbeat. “Warnings and Precautions” section, clinical trial • Patients should understand the importance of seeking experience shows that the most common documented medical attention in the event of new or worsening adverse reactions include nausea, vomiting, headache, depression, suicidal thoughts, or changes in mood or and dizziness. Other common adverse reactions that behavior. can occur include nasopharyngitis, URI, constipation, • NPs should obtain a full medication list from any dry mouth, fatigue, and back pain.12 Patients who did patient taking lorcaserin, including over-the-counter not have diabetes experienced headache, dizziness, medications, vitamins, and herbal supplements. fatigue, nausea, dry mouth, and constipation more • Patients should report any adverse events to Eisai, Inc. frequently. Patients with diabetes have been shown to at 1-888-274-2378 or the FDA at 1-800-FDA-1088 or experience hypoglycemia, headache, cough, fatigue, and www.fda.gov/medwatch.12 back pain.12 REFERENCES ■ Drug interactions 1. Flegal KM, Carroll MD, Ogden CL, Curtin LR. Prevalence and trends in Lorcaserin can increase exposure of CYP2D6 substrates, so obesity among US adults, 1999-2008. JAMA. 2010;303(3):235-241. 2. National Heart Lung and Blood Institute. Assessing your weight and monitoring is necessary. Due to the potential for develop- health risk. http://www.nhlbi.nih.gov/health/public/heart/obesity/ ing serotonin syndrome, the use of lorcaserin with other lose_wt/risk.htm. medications that can affect the serotonergic neurotrans- 3. Fidler MC, Sanchez M, Raether B, et al. A one-year randomized trial of lorcaserin for weight loss in obese and overweight adults: the BLOSSOM 12 mitter system should be monitored. Refer to the trial. J Clin Endocrinol Metab. 2011;96(10):3067-3077. manufacturer’s prescribing information for a complete 4. Martin CK, Redman LM, Zhang J, et al. Lorcaserin, a 5-HT(2C) receptor agonist, reduces body weight by decreasing energy intake without list of medications that can affect the serotonergic infl uencing energy expenditure. J Endocrinol Metab. 2011;96(3):837-845. neurotransmitter system. 5. Smith SR, Prosser WA, Donahue DJ, Morgan ME, Anderson CM, Shanahan WR; APD356-004 Study Group. Lorcaserin (APD356), a selective 5-HT(2C) agonist, reduces body weight in obese men and women. Obesity (Silver ■ Pharmacokinetics Spring). 2009;17(3):494-503. After oral administration, lorcaserin is absorbed from 6. Centers for Disease Control and Prevention. Cardiac valvulopathy associated with exposure to fenfl uramine or dexfenfl uramine: U.S. the gastrointestinal tract. It reaches a peak plasma Department of Health and Human Services interim public health concentration within 1.5 to 2 hours. Steady state is recommendations, November 1997. MMWR Morb Mortal Wkly Rep. 1997;46(45):1061-1066. reached within 3 days and has a half-life of 11 hours. 7. Sachder M, Miller WC, Ryan T, Jollis JG. Effect of fenfl uramine-derivative Lorcaserin is 70% bound to plasma proteins, and is diet pills on cardiac valves: a meta-analysis of observational studies. Am distributed into the cerebrospinal fl uid and central Heart J. 2002;144(6):1065-1073. 8. Thomsen WJ, Gottick AJ, Menzaghi F, et al. Lorcaserin, a novel selective nervous system. This medication is extensively metabo- human 5-hydroxytryptamine 2C agonist: in vitro and in vivo pharmacological lized in the liver by multiple enzymatic pathways. The characterization. J Pharmacol Exp Ther. 2008;325(2):577-587. 9. O’Neil PM, Smith SR, Weissman NJ, et al. Randomized placebo-controlled major route of elimination for the metabolites is the clinical trial of lorcaserin for weight loss in type 2 diabetes mellitus: the urine with minor elimination in the feces.12 BLOOM-DM study. Obesity. 2012;20(7):1426-1436. 10. Smith SR, Weissman NJ, Anderson CM, et al. Multicenter, placebo- controlled trial of lorcaserin for weight management. New Engl J Med. ■ Clinical pearls 2010;363(3):245-256. • Lorcaserin is a pregnancy category X drug. 11. Anon. FDA approves Belviq. www.drugs.com/newdrugs/fda-approves-belviq- some-overweight-obese-adults-3341. • The safety and effi cacy of combination therapy including 12. Belviq (lorcaserin hydrochloride) tablets Prescribing Information. Eisai, Inc. lorcaserin and any other weight loss prescription 2012. www.us.eisai.com/package_inserts/BelviqPI.pdf. www.tnpj.com The Nurse Practitioner • February 2013 31

Lucinactant is a bioengineered synthetic compound ▼ Respiratory distress syndrome that contains a mixture of phospholipids and a unique peptide that functions as human SP-B. Lucinactant Lucinactant (Surfaxin) (Surfaxin) was approved by the FDA on March 6, 2012, Respiratory distress syndrome (RDS) is the leading cause of and is manufactured and distributed by Discovery morbidity and mortality in preterm infants.1 The incidence Laboratories, Inc., a specialty biotechnology company that of RDA is inversely related to gestational age and results is dedicated to respiratory critical care treatments.5 from morphologic and biochemical immaturity of the lungs. Developmental and biochemical abnormalities are associ- ■ Indication ated with preterm delivery. Morphologically, the lung Lucinactant is indicated for the prevention of RDS that parenchyma has decreased alveoli, leading to a decrease in occurs in premature infants at high risk for developing surface area, which causes a reduction in gas exchange.1 RDS.6 Lucinactant has been shown to reduce the incidence Absent or inadequate production of pulmonary surfactant of RDS at 24 hours and mortality due to RDS.2,4 results in high alveolar surface tension and a tendency toward progressive atelectasis, with alterations in pulmonary ■ Mechanism of action gas exchange and lung mechanics. In addition to a decrease Lucinactant, with the help of the presence of SP-B, works in surfactant levels, these patients experience defi ciencies by lowering the surface tension of the alveolar air-water in antioxidants and anti-infl ammatory modulators that interface.3 This stabilizes the alveoli against collapse at can worsen RDS and lead to the development of chronic resting pulmonary pressures. Lucinactant helps improve lung disease and bronchopulmonary dysplasia (BPD).2 lung compliance and gas exchange in the lungs by being the compensatory agent for the defi ciency of surfactant Surfactant replacement therapy with these patients experience; it also helps restore surface 6 either animal-derived or synthetic activity to the infant’s lungs. surfactants can reduce mortality. ■ Dosing and administration Only healthcare providers experienced in intubation, Pulmonary surfactant is composed of lipids and ventilator management, and general care of premature proteins that work together to form a layer at the air-water infants should use lucinactant.6 The recommended interface of the alveoli in addition to lowering surface starting dose is 5.8 mL/kg birth weight. Within the fi rst tension to prevent alveolar collapse.3 48 hours of life, up to four doses can be given, and this Surfactant replacement therapy with either animal- medication should not be used more than every 6 hours.6 derived or synthetic surfactants can improve oxygenation Refer to the manufacturer’s prescribing information for and reduce mortality.3 Animal-derived surfactants are dosing recommendations and directions for use. obtained by lung lavage or from lung minces from cows or Before administering a dose, the vial should be pigs that are purifi ed and extracted with organic solvents. removed from the refrigerator and warmed for 15 minutes The problems with animal-derived products include the in a dry block heater set at 111.2° F (44° C). After warming following: the amount of surfactant protein (SP)-B differs is completed, the vial must be shaken vigorously until the among the formulations; the compositions can have varying liquid is in a uniform and free-fl owing suspension.6 Sterile protein amounts; carry the risk of transmission of infec- technique must be used to draw up the suspension into a tious agents; evoking immunogenicity to foreign proteins; syringe. After ensuring proper placement of the endotra- and the introduction of proinfl ammatory mediators.1,3,4 cheal tube, the infant should be placed in the right lateral Synthetic surfactants have compositions that can be easily decubitus position with the head and thorax inclined reproduced, are free from the risk of developing immune upward 30 degrees. Each dose of lucinactant must be given reactions or infections, have an identifi ed improvement in four aliquots. The fi rst aliquot is one-fourth of the total outcome, and can be produced in large quantities.4 volume instilled as a bolus while the infant is turned in the Although surfactant replacement therapy has dramati- right lateral decubitus position. The procedure should be cally improved the survival of preterm infants, it has not repeated while the infant is in the left decubitus position, shown to reduce the incidence of BPD. Currently, antenatal followed by the right, then the left to administer all four corticosteroid treatment, surfactant replacement therapy, aliquots. Between each aliquot, the infant’s respiratory and mechanical ventilation are the main treatments for status should be assessed. The infant should be ventilated preterm infants with RDS.4 until stable (oxygen saturation 90% or greater and a heart

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rate 120 beats/minute or greater). After the lucinactant is • Each vial is intended for single use only. instilled completely, the head of the bed is elevated at least • Providers should not suction the infant during the fi rst 10 degrees for 1 to 2 hours.6 hour after dosing unless the infant exhibits signs of signifi cant airway obstruction. ■ Contraindications • Lucinactant needs to be stored in the refrigerator at There are no documented contraindications associated 36° F (2° C) to 46° F (8° C) and protected from light with lucinactant. until ready for administration. • If a patient experiences any suspected adverse reactions, ■ Warnings and precautions providers should contact Discovery laboratories, Inc. at Exogenous surfactants including lucinactant can rapidly 1-877-DURFAXN or the FDA at 1-880-FDA-1088 or change lung compliance and oxygenation. Throughout www.fda.gov/medwatch.6 administration of lucinactant, the infant should be monitored for respiratory changes and have oxygen and REFERENCES ventilator support interventions as needed.6 1. Donn SM. Lucinactant: a novel synthetic surfactant for the treatment of respiratory distress syndrome. Expert Opin Investig Drugs. 2005;14(3):329-354. There are a number of administration-related adverse 2. Maya FR, Gadzinowski J, Bancalari E, et al. A multicenter, randomized, reactions associated with lucinactant. These can include masked, comparison trial of lucinactant, colfosceril palmitate, and beractant for the prevention of respiratory distress syndrome among very preterm bradycardia, oxygen desaturation, refl ux of the drug into infants. Pediatrics. 2005;115(4):1018-1029. 6 the endotracheal tube, and airway obstruction. If any of 3. Moen MD, Perry CM, and Wellington K. Lucinactant: in neonatal respiratory these occur, the dosing of lucinactant should be stopped, distress syndrome. Treat Respir Med. 2005;4(2):139-145. 4. Sinha SK, Lacaze-Masmonteil T, Valls i Soler A, et al. A multicenter, and the patient stabilized. Once the infant is suctioned randomized, controlled trial of lucinactant versus poractant alfa among very and stabilized, dosing can be restarted with increased premature infants at high risk for respiratory distress syndrome. Pediatrics. 2005;115(4):1030-1038. monitoring.6 5. Anon. FDA approved Surfaxin. http://www.drugs.com/newdrugs/ discovery-labs-announces-fda-approval-surfaxin-lucinactant-prevention- ■ Adverse reactions respiratory-distress-syndrome-3144.html. 6. Surfaxin (lucinanctant) Intratracheal Suspension Prescribing Information. In clinical trials, the most common administration-related Discovery Laboratories, Inc. 2012. www.surfaxin.com/prescribinginfo.pdf. adverse reactions associated with lucinactant included pallor, endotracheal tube refl ux, dose interruption, and endotracheal tube obstruction.6 In the continuation of the trials, the following adverse reactions were documented in ▼ Endogenous Cushing syndrome infants 36 weeks postconceptual age: anemia, jaundice, metabolic acidosis, oxygen desaturation, hyperglycemia, Mifepristone (Korlym) pneumonia, hyponatremia, hypotension, respiratory Cushing syndrome results from chronic exposure to acidosis, and bradycardia.6 excessive, endogenous, or exogenous glucocorticoids. If there is an excess, endogenous glucocorticoids are ■ Drug interactions primarily a consequence of excess production and not There are no documented drug interactions associated inadequate destruction of glucocorticoids. This elevation with lucinactant. of glucocorticoid secretion can be caused by two sources: (1) an autonomously functioning adrenal cortex or (2) ■ Pharmacokinetics from an excessive production of adrenocorticotropic The absorption, distribution, metabolism, or elimination hormone (ACTH).1-3 Chronic exposure to excessive of lucinactant has not been studied because it is adminis- corticosteroids can lead to the development of multiple tered directly to the lungs, and the effects occur at the metabolic abnormalities, including glucose intolerance, terminal airways and alveolar surface.6 dyslipidemia, hypertension, osteoporosis, and weight gain.4 The fi rst-line treatment for malignant Cushing ■ Clinical pearls syndrome is surgery–especially in cases of adrenocortical • Lucinactant should only be used by healthcare profes- carcinoma and ectopic ACTH secretion–and chemotherapy sionals experienced in intubation, ventilator manage- and/or radiotherapy for advanced disease.5 Medications ment, and general care of premature infants. that control excessive glucocorticoid secretion include • Lucinactant should not be returned to the refrigerator aminoglutethimide, ketoconazole, metyrapone, and after warming. The vial should be discarded if not used mitotane.6 These drugs are associated with signifi cant within 2 hours of warming. adverse reactions. They all work by decreasing adrenal www.tnpj.com The Nurse Practitioner • February 2013 33

steroid secretion. Another option that works as a glucocor- Each dose adjustment should be based upon tolerability ticoid antagonist is mifepristone. and improvement of symptoms. Early changes in symptom Mifepristone was originally developed in the early response can include changes in glucose control, antidia- 1980s as an antiprogestin but was considered an antigluco- betic medication requirements, changes in insulin levels, corticoid compound. Since it had such strong antiprogestin and improvements in psychiatric symptoms. Symptoms activity, investigators started to research this medication that change later include changes in cushingoid appearance, for use in progesterone-dependent conditions such as hirsutism, acne, and body weight.8 Each of these changes pregnancy.6 Complete abortion is achieved with the will help properly complete the dosing titrations. combination of mifepristone and a prostaglandin. Mifepristone can be used in both renal impairment and mild-to-moderate hepatic impairment at a maximum Mifepristone is recommended for use dose of 600 mg daily. Mifepristone is not recommended to be used in patients with severe hepatic impairment.8 in patients with endogenous Cushing syndrome to control hyperglycemia. ■ Contraindications Mifepristone is not to be used in pregnant women or in women who have a history of unexplained vaginal Mifepristone administration is associated with a bleeding, endometrial hyperplasia, or carcinoma.8 dose-dependent blockade of dexamethasone-induced Mifepristone is not to be used in combination with cortisol suppression. Mifepristone was shown to act as an any medication that is metabolized via the CYP3A, which antiglucocorticoid by antagonizing the negative feedback includes simvastatin, lovastatin, cyclosporine, ergotamine, on the pituitary of endogenous and exogenous glucocorti- fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. coids. With this information, the use of mifepristone in This combination will increase the risk of adverse events.8 patients with glucocorticoid excess was closely studied. Since mifepristone antagonizes glucocorticoids, it On February 17, 2012, mifepristone was approved for should not be used in combination in patients who the treatment of hyperglycemia in adults with endogenous require systemic corticosteroids for other conditions.8 Cushing syndrome. Mifepristone is marketed under the brand name Korlym by Corcept Therapeutics.7 ■ Warnings and precautions There are a number of warnings and precautions associ- ■ Indication ated with mifepristone. Patients taking mifepristone Mifepristone is recommended for use in patients with should be monitored for the development of adrenal endogenous Cushing syndrome to control hyperglycemia. insuffi ciency. Signs and symptoms that can occur include It should only be used in patients with type 2 diabetes or nausea, weakness, fatigue, hypotension, and hypoglycemia. glucose intolerance who have either failed surgery or are Once adrenal insuffi ciency is suspected and diagnosed, not candidates for surgery.8 mifepristone should be stopped, and the patient should be started on glucocorticoids to reverse symptoms.8 ■ Mechanism of action Mifepristone may cause hypokalemia. Potassium levels At higher doses, mifepristone is able to overcome the should be monitored prior to starting therapy and then progesterone receptor antagonism and block the glucocorti- again 1 to 2 weeks after starting therapy or with any dose coid receptor. It has a greater affi nity for the glucocorticoid change. For patients who need replacement, oral or I.V. type II (GR-II) receptor over the GR-I receptor. Mifepris- potassium can be used.8 tone does not have an effect on estrogen, muscarinic, Mifepristone should be used with caution in patients histaminic, or monoamine receptors.8 Mifepristone blocks who have hemorrhagic disorders, since this medication the binding of cortisol to its receptors, which decreases the has the potential to increase vaginal bleeding and cause levels of cortisol, including high blood glucose. endometrial changes.8 Mifepristone produces a dose-dependent change in ■ Dosing and administration the QT interval. Patients may experience QT prolonga- Mifepristone must be started with a dose of 300 mg once tion.8 Periodic monitoring is required. daily taken with food. This medication should be given in a Patients with endogenous Cushing syndrome who are single dose; do not split, crush, or chew the tablet.8 Every 2 to taking mifepristone are also at risk for opportunistic 4 weeks, the dose may be titrated in 300 mg increments to a infections, such as Pneumocystis jiroveci pneumonia, and maximum dose of 1200 mg, without exceeding 20 mg/kg/day.8 should be monitored for signs of infection.

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■ Adverse reactions 2. Bailey MA, Mullin JJ, Kenyon CJ. Mineralocorticoid and glucocorticoid receptors stimulate epithelial sodium channel activity in a mouse model of Through clinical trial experience, the most commonly Cushing syndrome. Hypertension. 2009;54(4):890-896. reported adverse reactions included nausea, vomiting, fatigue, 3. deBruin C, Hofl and LJ, Nieman LK, et al. Mifepristone effects on tumor headache, hypertension, and dizziness. Additionally, patients somatostatin receptor expression in two patients with Cushing’s syndrome due to ectopic adrenocorticotropin secretion. J Clin Endocrinol Metab. 2012;97(2):455-462. could experience hypokalemia, arthralgia, peripheral edema, 4. Chu JW, Matthias DF, Belanoff J, Schatzberg A, Hoffman AR, Feldman D. decreased appetite, and endometrial hypertrophy.8 Successful long-term treatment of refractory Cushing’s disease with high-dose mifepristone (RU 486). J Clin Endocrinol Metab. 2001;86(8):3568-3573. 5. Castinetti F, Fassnacht M, Johanssen S, et al. Merits and pitfalls of mifepris- ■ Drug interactions tone in Cushing’s syndrome. Eur J Endocrinol. 2009;160(6):1003-1010. Mifepristone has a signifi cant effect on the CYP450 isoclass 6. Johanssen S, Allolio B. Mifepristone (RU 486) in Cushing’s syndrome. Eur J Endocrinol. 2007;157(5):561-569. system. Mifepristone is a CYP3A inhibitor, and concomitant use 7. FDA approves Korlym. http://www.drugs.com/news/korlym-approved-cushing- with a medication that relies on CYP3A to be metabolized will s-syndrome-36551.html. cause the medication to have higher plasma concentrations. For 8. Korlym 300mg Tablets Prescribing Information. Corcept Therapeutics Inc. 2012. www.korlym.com/docs/KorlymPrescribingInformation.pdf. drugs that inhibit CYP3A, mifepristone concentrations can be increased, requiring a dose reduction. Avoid coadministration of mifepristone and drugs that are CYP3A inducers, in which a dose reduction of the inducers medication many be needed.8 ▼ Overactive bladder Mifepristone is also an inhibitor of CYP2C8/2C9 and CYP2B6. Concurrent administration of mifepristone with medications Mirabegron (Myrbetriq) that rely on these isoenzymes to be metabolized will cause an About 33 million people in the United States suffer from increase in their plasma levels.8 Mifepristone is a progesterone- overactive bladder. Overactive bladder has symptoms that receptor antagonist and will interfere with hormonal include urinary frequency, urinary urgency, and urge contraceptives. Concurrent use is not recommended.8 urinary incontinence.1 Researchers have recently discovered that beta-1, -2, ■ Pharmacokinetics and -3 adrenoreceptors are in the human urothelium and After oral absorption, the peak plasma concentration of detrusor muscle.2 The urothelium has three layers: an apical mifepristone is reached within 1 to 2 hours. Steady state is cell layer, an intermediate layer, and a basal cell layer.3 When reached in 2 weeks, and it has a half-life of 85 hours. the beta-2 and -3 adrenoreceptors are stimulated, relaxation Mifepristone and its metabolites bind to albumin and are of the detrusor muscles occur, which is due to the activation distributed to the central nervous system and other tissues. of G proteins and adenylyl cyclase. This subsequently leads to Mifepristone is metabolized by CYP3A4 and is excreted increased levels of cyclic adenosine monophosphate. Beta-3 via the fecal route.8 adrenoreceptors relax the detrusor muscle during the storing phase of the micturition cycle, thus, improving the bladder’s ■ Clinical pearls storage capacity without leading to unwanted voiding.3,4 • Mifepristone is a pregnancy category X drug. Mirabegron is a new, selective beta-3 adrenoreceptor • Patients requiring contraception should only use agonist that decreases the frequency of bladder contrac- nonhormonal contraceptives. Mifepristone should not tions that occur during the fi lling phase but does not be used in the treatment of patients with type 2 diabetes suppress bladder during micturition.3 unrelated to Cushing syndrome. On June 28, 2012, mirabegron, an extended-release • Mifepristone should be taken with food to ensure tablet, was approved for the treatment of overactive appropriate plasma levels. bladder in adult patients. Mirabegron, the fi rst beta-3 • Mifepristone is not to be used in patients who are pregnant adrenoreceptor agonist, is marketed under the brand because the medication can terminate the pregnancy. name Myrbetriq by Astellas Pharma US, Inc.1 • A patient who suspects she is pregnant must inform a healthcare provider immediately. ■ Indication • Adverse events should be reported to Corcept Thera- Mirabegron has been approved for the treatment of peutics at 1-855-844-3270 or the FDA at 1-800-FDA- overactive bladder, encompassing the symptoms of urge 1088 or www.fda.gov/medwatch. 8 urinary incontinence, urgency, and urinary frequency.5

REFERENCES ■ Mechanism of action 1. Castinetti F, Conte-Devolx B, Brue T. Medical treatment of Cushing’s Mirabegron works by relaxing the detrusor smooth syndrome: glucocorticoid receptor antagonists and mifepristone. Neuroendo- crinology. 2010;92(suppl 1):125-130. muscle during the storage phase due to the increase in www.tnpj.com The Nurse Practitioner • February 2013 35

bladder capacity. This occurs in the urinary bladder As for warfarin, it has been shown that Mirabegron ﬁ ll-void cycle.5 will increase the S- and R-warfarin maximum concentration and area under the curve. Prothrombin time and the ■ Dosing and administration international normalized ratio need to be monitored. Mirabegron should be started at a daily dose of 25 mg Mirabegron is a CYP2D6 inhibitor. Caution must be taken with or without food. The patient should experience taken when using mirabegron in combination with agents the full effect of mirabegron within 8 weeks of starting that are metabolized by the CYP2D6 enzyme. When these therapy. Based upon the patient’s tolerability and overall two medications are used in combination, mirabegron can effect of the medication, the dose can be increased to cause an increase in exposure of the interacting medication.5 50 mg once daily.5 Patients with either severe renal impairment or moderate hepatic impairment should ■ Pharmacokinetics take only 25 mg daily. Do not prescribe mirabegron for Mirabegron is orally absorbed and will reach a maximum patients who have end-stage renal disease or severe hepatic concentration within 3.5 hours. A patient will reach impairment.5 steady-state concentration within 7 days.5 Mirabegron has a large volume of distribution and is ■ Contraindications plasma protein bound. It is metabolized by a number of Mirabegron has no documented contraindications. pathways including dealkylation, oxidation, glucuronidation, and amide hydrolysis. It is renally eliminated and also ■ Warnings and precautions has a half-life of 50 hours.5 Mirabegron may increase BP. Periodic BP monitoring is recommended, especially for patients with hypertension.5 ■ Clinical pearls The drug is not recommended for use in patients with • Mirabegron is a pregnancy category C drug. severe uncontrolled hypertension (systolic BP of 180 mm • Mirabegron should not be used in patients who have Hg or greater and/or a diastolic BP of 110 mm Hg or severe, uncontrolled hypertension, as this medication greater).5 can increase BP. • Patients should be advised to take mirabegron with water and not to chew, divide, or crush the extended- Mirabegron should be started at a daily release tablet. dose of 25 mg taken with or without food. • Patients should be educated about the importance of informing all of their healthcare providers about all medications they are taking, including over-the-counter Mirabegron should be used with caution in patients medications, vitamins, and herbal supplements. with bladder outlet obstruction, as these patients can • Be sure to inform patients about missed doses of develop urinary retention.5 mirabegron. Instruct the patient to take the dose as soon as it is remembered, but do not double up doses, ■ Adverse reactions and do not take two doses of the drug in the same day. During clinical trials, the most commonly documented • Providers should give patients a list of the most adverse reactions included hypertension, nasopharyngitis, common adverse reactions associated with mirabegron, nausea, diarrhea, constipation, headache, dizziness, and including increased BP, common cold symptoms, tachycardia. Other adverse reactions that occurred in less urinary tract infections, and headache. than 5% of patients included urinary tract infection, • Adverse reactions that may be related to mirabegron abdominal pain, and arthralgia.5 should be reported to Astellus Pharma US, Inc. at 1-800-727-7003 or the FDA at 1-800-FDA-1088 or ■ Drug interactions www.fda.gov/medwatch.5 The major drug interactions associated with the use of mirabegron that require monitoring are digoxin, warfarin, REFERENCES and drugs metabolized by CYP2D6.5 For all patients 1. Anon. FDA approved Myrbetriq. www.drugs.com/newdrugs/fda-approves- mybetriq-overactive-bladder-3344.html. starting a combination of mirabegron and digoxin, the 2. Wyndaele JJ. Modulation of non-voiding activity by the muscarinergic antagonist lowest dose of digoxin should be used and increased as tolterodine and the β(3)-adrenoreceptor agonist mirabegron in conscious rats with partial outﬂ ow obstruction. BJU Int. 2012;110(2 pt 2):E143. needed based on serum digoxin levels.5 Mirabegron 3. Bhide AA, Digesu GA, Fernando R, Khullar V. Use of mirabegron in treating increases serum digoxin levels. overactive bladder. Int Urogynecol J. 2012;23(10):1345-1348.

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4. Khullar V, Cambronero J, Stroberg P, et al. The efﬁ cacy and tolerability of • As an anti-inﬂ ammatory or immunosuppressive agent mirabegron, a potent and selective beta3-adrenoreceptor agonist, compared with placebo and tolterodine slow release in patient with overactive bladder–results that encompasses allergic, dermatologic, gastrointestinal, from a European-Australian phase III trial. Eur Urol Suppl. 2011;10:278-279. ophthalmologic, respiratory, rheumatologic, renal, 5. Myrbetriq (mirabegron) extended-release tablets Prescribing Information. nervous system, and hematologic conditions Astellus Pharma US, Inc. 2012. www.myrbetriq.com/content/pdfs/11G054- MIR-WPI-pdf. • As an immunosuppressive medication in organ transplantation • In the treatment of endocrine conditions ▼ Immunosuppressive therapy • As a palliative agent in neoplastic conditions.6

Prednisone delayed-release ■ Mechanism of action Prednisone delayed-release causes a number of metabolic (Rayos) effects in addition to modifying the body’s immune Glucocorticoids are a major player in the treatment of many response to many stimuli.6 Prednisone delayed-release infl ammatory conditions including rheumatic disorders, possesses all of the properties of corticosteroids. The allergic airway disease, dermatologic diseases, and other local pharmacologic effects include the following6: and systemic disorders.1 The use of these medications in • promotion of gluconeogenesis either high doses or for prolonged periods of time increases • increased deposition of glycogen in the liver the risks of adverse reactions. In order to help reduce the • inhibition of the utilization of glucose risks of adverse reactions, chronotherapy is being studied.2 • anti-insulin activity Chronotherapy coordinates drug administration with the • increased catabolism of protein body’s circadian rhythm to help increase the therapeutic • increased lipolysis effects of the drug and decrease adverse reactions.2 • stimulation of fat synthesis and storage Chronotherapy has been studied in the treatment of • increased glomerular fi ltration rate rheumatoid arthritis (RA) by coordinating glucocorticoid • increased calcium excretion administration with the circadian rhythm. In other condi- • decreased production of eosinophils and lymphocytes tions, such as hypertension, allergic rhinitis, and bronchial • stimulation of leukocytes and erythropoiesis asthma, chronotherapy has shown benefi ts.2 Chronotherapy • inhibition of wound healing. can be benefi cial in the treatment of RA because the symptoms of this disease follow circadian rhythms. These overnight symptoms are due to proinfl ammatory cytokine levels.3 Like all corticosteroids, dosing should RA is a chronic, infl ammatory disease characterized by be based upon the severity of the disease joint swelling and tenderness that causes progressive and and the response achieved. irreversible damage to the synovial-lined joints.4 A new, modifi ed-release prednisone tablet has been developed to optimize chronotherapy. If taken at bedtime ■ Dosing and administration (22:00), prednisone release will occur 4 hours later Like all corticosteroids, dosing should be based upon the (02:00).3 This medication formulation and timing matches severity of the disease and the response achieved. The up to the circadian rhythm. recommended starting dose is 5 to 60 mg daily, depending On July 26, 2012, prednisone delayed-release (Rayos) on the specifi c disease that is being treated. Dosing should was approved by the FDA. Rayos is the fi rst delayed-release be monitored and changed according to response. The formulation of prednisone available on the market. The drug should be taken with food.6 Patients who are cur- drug is marketed and distributed by Horizon Pharma, Inc. rently taking immediate-release prednisone, prednisolone, The drug approval was based on data from the Circadian or methylprednisolone can be switched to prednisone Administration of Prednisone in RA (CAPRA 1 and 2) delayed-release at an equivalent dose based upon potency.6 trials.5 The information provided from these two trials and Prescribers should refer to the manufacturer’s prescribing the pharmacokinetics presented helped this medication information for a corticosteroid comparison chart.6 gain approval for a long list of diseases and treatments. ■ Contraindications ■ Indications Prednisone delayed-release is contraindicated for use in Prednisone delayed-release is a corticosteroid approved for patients with a documented allergy to prednisone or any the following indications: of the medication’s ingredients.6 www.tnpj.com The Nurse Practitioner • February 2013 37

■ Warnings and precautions cyclosporine when they are used together. The combina- Patients taking prednisone delayed-release who have tion of these two medications can increase the risk of hypothalamic-pituitary-adrenal axis suppression, Cushing seizures. Using prednisone delayed-release with nonste- syndrome, and/or hyperglycemia should be monitored. roidal anti-infl ammatory drugs, aspirin, or salicylates can Patients with hypothyroid disorders may experience increase the risk of GI adverse reactions.6 There is also the decreased clearance of prednisone delayed-release, while risk of hypokalemia in patients taking prednisone those with hyperthyroidism may demonstrate increased delayed-release and a potassium-depleting drug. Patients clearance. taking digoxin are at increased for dysrhythmias due to the Prednisone delayed-release may exacerbate infections, risk of hypokalemia.6 increase the risk of disseminated infections, and increase the risk of reactivation or exacerbation of latent infec- ■ Pharmacokinetics tions.6 Prednisone delayed-release can also mask signs Prednisone delayed-release has a unique formulation that of infection, or reduce a patient’s ability to fi ght new allows for modifi ed release of prednisone 4 hours after infections. ingestion.2 Peak plasma concentrations are reached later in Corticosteroids can increase BP and cause sodium time compared to conventional immediate-release and water retention as well as increased excretion of prednisone formulations. It will reach a peak plasma potassium and calcium. Practitioners should monitor BP, concentration at 6 to 6.5 hours compared to 2 hours serum electrolytes, and calcium levels in patients achieved by immediate release.6 receiving prednisone delayed-release.6 Prednisone Prednisone delayed-release is converted to the active delayed-release should be used with caution in patients metabolite prednisolone. It is metabolized by the liver with certain gastrointestinal (GI) disorders, including and excreted in the urine. The half-life of the drug is 2 to abscess, perforation, diverticulitis, or peptic ulcer 3 hours.6 disease. The use of corticosteroids in these patients may increase the risk of GI perforation.6 ■ Clinical pearls Chronic corticosteroid use has been associated with • Prednisone delayed-release is a pregnancy category D decreases in bone density. If prednisone delayed-release is drug. to be used long term, the patient’s bone density levels must • Live, attenuated vaccines must not be used in patients be monitored throughout therapy.6 who are taking prednisone delayed-release in doses used Chronic corticosteroid use has also been associated for immunosuppression. with ophthalmic effects, including cataracts and glaucoma. • For patients taking prednisone delayed-release, the Monitor the intraocular pressure in patients receiving following should be monitored on a routine basis: BP, prednisone delayed-release for more than 6 weeks.6 body weight, lab values of blood glucose and serum potassium, and chest X-ray. ■ Adverse reactions • Patients should be educated about the need to take The most common adverse reactions associated with prednisone delayed-release with food. Patients should prednisone delayed-release include fl uid retention, altered be taught that the tablets cannot be broken, divided, or glucose tolerance, an increase in BP, changes in behavior chewed because doing this will interfere with the and mood, and increased appetite/weight gain.6 The list is delayed release properties of the drug. extensive, so please refer to the prescribing information for • Educate patients about the importance of not discon- a more detailed list. tinuing prednisone delayed-release abruptly or without supervision by a healthcare professional. ■ Drug interactions • Provide patients with the list of most common adverse There are many drug interactions associated with the use reactions associated with prednisone delayed-release: of prednisone delayed-release. Therapeutic effects of fl uid retention, changes in glucose levels, increase in BP, anticoagulant medications can be either increased or changes in mood and behavior, and weight gain/ decreased. Prednisone delayed-release may increase blood increased appetite. glucose concentrations while a patient takes any antidia- • Instruct patients to not double up on doses if one dose betic medication. Dosing adjustments of prednisone of prednisone delayed-release is missed. Patients should delayed-release must be made for patients taking CYP3A4 take the missed dose as soon as possible unless it is time inhibitors or inducers. There is also a reported increase in for the next dose; in that case, patients should take the the activity of both prednisone delayed-release and regular dose at the scheduled time.

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• If the patient experiences a suspected adverse reaction treatment for the management of DME.7 Anti-VEGF has while taking prednisone delayed-release, contact been hypothesized to restore normal retinal anatomy, and Horizon Pharma USA, Inc. at 1-866-479-6742 or the reverse the vision loss from DME. FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Ranibizumab is an antibody that is targeted against If the patient experiences a suspected adverse reaction VEGF-A and has been approved for the treatment of while taking prednisone-delayed release, contact neovascular age-related macular degeneration. Ranibizumab Horizon Pharma USA, Inc. at 1-866-479-6742 or the is an anti-VEGF Fab fragment that is used intravitreally FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.6 and has the ability to reduce macular edema, and improve visual acuity in DME.5 REFERENCES 1. Buttgereit F, Doering G, Schaeffl er A, et al. Effi cacy of modifi ed-release versus standard prednisone to reduce duration of morning stiffness of the joints in rheumatoid arthritis (CAPRA-1): a double-blind, randomised controlled trial. Ranibizumab works by binding to the Lancet. 2008;371(9608):205-214. receptor binding site of VEGF-A. 2. Buttgereit F, Mehta D, Kirwan J, et al. Low-dose prednisone chronotherapy for rheumatoid arthritis: a randomised clinical trial (CAPRA-2). Ann Rheum Dis. 2012. [Epub ahead of print]. 3. Buttgereit F, Doering G, Schaeffl er A, et al. Targeting pathophysiological With that in mind, ranibizumab, under the brand rhythms: prednisone chronotherapy shows sustained effi cacy in rheumatoid arthritis. Ann Rheum Dis. 2010;69(7):1275-1280. name Lucentis, was approved by the FDA on August 10, 4. Aletaha D, Neogi T, Silman AJ, et al. 2010 rheumatoid arthritis classifi cation 2012, for the treatment of DME and will be marketed by criteria: an American College of Rheumatology/European League Against 8 Rheumatism collaborative initiative. Arthritis Rheum. 2010;62(9):2569-2581. Genetech. 5. Anon. Horizon Pharma Announces FDA Approval of Rayos (prednisone) Delayed-Release Tablets for Rheumatoid Arthritis and Multiple Additional Indications. www.equities.com/news/headline-story?dt=2012-07-26&vol= ■ Indication 314500&cat=hcare. Ranibizumab was originally approved in 2006, and over 6. Rayos (prednisone) delayed release tablets prescribing information. Horizon the years, obtained approval for the following conditions: Pharma USA, Inc. 2012. www.rayosrx.com/RAYOS_PI.pdf. neovascular (wet) age-related macular degeneration and macular edema following retinal vein occlusion. The most recent approval was for the treatment of DME.9 ▼ Diabetic mascular edema ■ Mechanism of action Ranibizumab (Lucentis) Ranibizumab works by binding to the receptor binding Diabetic macular edema (DME) is the leading cause of site of VEGF-A. This binding prevents the interaction of blindness in patients with diabetic retinopathy.1 The VEGF-A with its receptors on the surface of endothelial Diabetes Control and Compliance Trail (DCCT) indicated cells, reducing endothelial cell proliferation, vascular that 27% of patients with type 1 diabetes will develop leakage, and new blood vessel formation.9 macular edema within 9 years of diabetes onset.2 It is estimated by the International Diabetes Foundation that ■ Dosing and administration 285 million individuals worldwide have diabetes, and 14% For the treatment of DME, ranibizumab 0.3 mg is given of this group has DME.3 as an ophthalmic intravitreal injection once a month.9 DME is a disease that causes swelling of the central The injection must be completed in a controlled aseptic retina that leads to vision loss. The common pathway environment. The healthcare professional administering that leads to DME is disruption of the blood-retinal the medication must use sterile gloves, a sterile drape, barrier (BRB). Disruption of the BRB is multifactorial and a sterile eyelid speculum. Prior to the injection, a and causes abnormal inflow of fluid in the neurosen- proper anesthetic should be utilized. One vial should be sory retina that exceeds the outflow, resulting in used for the treatment of one eye. Do not use one vial residual fluid accumulation in the intraretinal layers of for both eyes.9 No dosing adjustments are needed for the macula.4,5 special populations. DME pathogenesis includes chronic hyperglycemia and the accumulation of free radicals and proteins that ■ Contraindications lead to the activation of vascular endothelial growth Ranibizumab is contraindicated in two patient groups: factors (VEGFs), primarily VEGF-A, along with the those who have hypersensitivity to reactions to ranibi- increase in vascular permeability.6 VEGF level increase has zumab or patients who are diagnosed with ocular or brought to the forefront the potential for anti-VEGF periocular infections.9 www.tnpj.com The Nurse Practitioner • February 2013 39

■ Warnings and precautions ophthalmologist if they experience reddening of the eye, As with any intravitreal injection, ranibizumab can cause increased sensitivity to light, pain, or changes in vision. endophthalmitis and retinal detachments. Proper sterile • Provide patients with a list of the most common adverse technique must be used during administration of the reactions: conjunctival hemorrhage, eye pain, fl oaters, medication, and the patient must be monitored following and increase in intraocular pressure. the injection for infection.9 • If the patient develops a suspected adverse reaction, Monitor intraocular pressure prior to injection and contact Genetech at 1-888-835-2555 or the FDA at then again postinjection. Ranibizumab has the potential 1-800-FDA-1088 or www.fda.gov/medwatch.9 to cause an increase in intraocular pressure.9 REFERENCES 1. Paulus YM, Gariano RF. Diabetic retinopathy: a growing concern in an aging There are no documented drug interactions population. Geriatrics. 2009;64(2):16-20. 2. White NH, Sun W, Cleary PA, et al; DCCT-EDIC Research Group. Effect of prior intensive therapy in type 1 diabetes on 10-year progression of associated with the use of ranibizumab. retinopathy in the DCCT/EDIC: comparison of adults and adolescents. Diabetes. 2010;59(5):1244-1253. 3. Ho AC, Scott IU, Kim SJ, et al. Anti-vascular endothelial growth factor Due to documented arterial thromboembolic events pharmacotherapy for diabetic macular edema:a report by the American Academy of Ophthalmology. Ophthalmology. 2012;119(10):2179-2188. that occur with the use of VEGF inhibitors, the warning is 4. Bhagat N, Grigorian RA, Tutela A, Zarbin MA. Diabetic macular edema: attached to ranibizumab by association. Arterial thrombo- pathogenesis and treatment. Surv Ophthalmol. 2009;54(1):1-32. embolic events include nonfatal stroke, nonfatal myocar- 5. Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for diabetic macular edema. Results from 2 phase III randomized trials: RISE and RIDE. dial infarction, and vascular death.9 Ophthalmology. 2012;119(4):789-801. 6. Witkin AJ, Brown GC. Update on nonsurgical therapy for diabetic macular edema. Curr Opin Ophthalmol. 2011;22(3):185-189. ■ Adverse reactions 7. Mitchell P, Bandello F, Schmidt-Erfurth U, et al. The RESTORE study: Through clinical trial documentation, the most common ranibizumab monotherapy or combined with laser versus laser monotherapy adverse reactions reported included bleeding of the for diabetic macular edema. Ophthalmology. 2011;118(4):615-625. 8. Anon FDA approves Lucentis to treat diabetic macular edema. www.fda.gov/ conjunctiva, eye pain, fl oaters, and increased intraocular newsevents/Newsroom/PressAnnouncements/ucm315130.htm. pressure. Other adverse reactions include intraocular 9. Lucentis (ranibizumab injection) Intravitreal Injection Prescribing Information. Genetech, Inc. 2012. www.gene.com/gene/products/ infl ammation, cataract formation, increased lacrimation, information/pdf/lucentis-prescribing-pdf. and visual disturbance.9

■ Drug interactions There are no documented drug interactions associated ▼ Acne vulgaris with the use of ranibizumab. Tazarotene (Fabior Foam) ■ Pharmacokinetics Affecting 40 to 50 million Americans, the most com- Pharmacokinetic studies were completed on patients with mon skin problem is acne.1 Acne affects most com- neovascular, age-related, macular degeneration, and that monly adolescents and young adults, but it can occur at information can be related to the patients diagnosed with any age. Breakouts occur due to many different reasons, DME. The maximum serum concentration of ranibizum- but they are mainly due to hormones. Hormones affect ab is reached in 1 day. The maximum concentration has the skin’s sebaceous glands and hair follicles causing been determined to be 1.5 ng/mL. The estimated half-life changes in the skin’s oil, clogging pores, and leading to of this medication is 9 days.9 the development of pimples. Other causes of acne can be due to genetics and heredity, greasy cosmetics, and ■ Clinical pearls adverse reactions of some medications.2 • Ranibizumab is a pregnancy category C drug. The four primary factors in the development of • Sterile technique is used for medication administration, acne are as follows: abnormal desquamation of the and only one vial per dose per eye. follicular epithelial; hyperactivity of the sebaceous • Patients need to be monitored prior to and 30 minutes glands; Propionibacterium acnes proliferation; and following the intravitreal injection of ranibizumab for perifolicular infl ammation.3 Acne can appear as two an increase in intraocular pressure using tonometry. different lesion types: infl ammatory lesions and • Educate patients about the possibility of developing noninfl ammatory lesions. Infl ammatory lesions endophthalmitis. Inform them to contact their consist of papules, pustules, and nodular cystic lesions.

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Noninfl ammatory lesions include open and closed women. Women of child-bearing age should have a comedones.2 negative pregnancy test within two weeks of starting the Tretinoin was the fi rst retinoid to be approved for the drug and must use adequate birth control measures while treatment of acne. As a metabolite of vitamin A, it plays a using this medication.5 role as a mediator of cell differentiation and proliferation. Caution should be taken when using tazarotene foam Topical retinoids work by normalizing the desquamation in patients with a history of local hypersensitivity reac- pattern in sebaceous follicles and decreasing the coherence tions or those with eczema or abraded skin. Some patients of follicular keratinocytes, causing a breakdown of existing can develop redness, burning sensation, or excessive comedones in addition to preventing new ones.3 Retinoids pruritus while using this medication. Also, extreme also play a role in reducing the proliferation of Propioni- weather conditions can increase irritability.5 bacterium acnes.4 Tazarotene was fi rst approved in the treatment of psoriasis. It is now approved in a foam formulation for the Tazarotene foam is to be applied treatment of acne. Having a topical formulation helps topically once a day in the evening. prevent systemic exposure, thus, leading to a better safety profi le.4 On May 11, 2012, the FDA approved Fabior Foam, topical tazarotene foam for the treatment of acne. The use of multiple topical medications can cause an It will be marketed and distributed by Stiefel, a GSK increase in irritation. If the patient develops skin irrita- company.2 tion, the frequency of application might need to be changed or treatment stopped.5 ■ Indication Patients using tazarotene foam have an increased risk Tazarotene foam is approved for the treatment of acne of developing sunburn, both due to natural sunlight or vulgaris in a topical form. It is to be used in patients over artifi cial tanning beds. Advise patients to use sunscreens the age of 12.5,6 and protective clothing while using tazarotene foam. Use tazarotene foam cautiously in patients with a personal or ■ Mechanism of action family history of skin cancer.5 Tazarotene is a retinoid prodrug. Through deesterization, Keep in mind that the propellant in tazarotene foam is this drug is then converted to its active form—tazarotenic fl ammable. Avoid fi re, fl ames, and smoking during and acid. Tazarotenic acid binds to all of the receptors in the after application of the medication.5 retinoic acid receptor family with more selectivity for RAR-beta and RAR-gamma over RAR-alpha; the exact ■ Adverse reactions mechanism by which tazarotene works in acne is unknown, The most commonly experienced adverse reactions but it is speculated to be due to its antiproliferative, associated with the use of tazarotene foam are irritation, normalizing-of-differentiation, and anti-infl ammatory dryness, erythema, and exfoliation at the application site. effects.5 Other adverse reactions include skin discoloration, rash, swelling, dermatitis, and pruritus.5 ■ Dosing and administration Tazarotene foam is to be applied topically once a day in ■ Drug interactions the evening. After washing the face with a mild cleaner, the There are no documented drug interactions associated patient should apply a small amount of foam to cover the with the use of tazarotene foam. To prevent excessive entire affected area. The foam should be massaged in until irritation, avoid the use of other dermatologic medications it completely disappears. Patients should be educated not and cosmetics that have a strong drying effect.5 to get the foam into the eyes, lips, or mucous membranes.5 ■ Pharmacokinetics ■ Contraindications After topical administration of tazarotene foam, the Tazarotene foam is contraindicated in patients who are majority of the medication stays on or in the skin. A small pregnant.6 portion of the medication is absorbed. As mentioned previously, tazarotene is a prodrug that is metabolized in ■ Warnings and precautions the skin to the active form—tazarotenic acid. These are Tazarotene foam has an associated fetal risk. This medica- both then metabolized to sulfoxides, sulfones, and other tion is teratogenic and must not be used in pregnant polar metabolites that are eliminated via urinary and fecal www.tnpj.com The Nurse Practitioner • February 2013 41

routes. The half-life of tazarotene is 8 hours and 21.7 hours tazarotene foam can and to keep the can away from for tazarotenic acid.5 fi re and heat. • Contact Stiefel Laboratories, Inc. at 1-888-784-3335 ■ Clinical pearls (1-888-STIEFEL) or the FDA at 1-800-FDA-1088 or • Tazarotene foam is a pregnancy category X drug. www.fda.gov/medwatch to report any suspected adverse • If the patient experiences irritation, consider reducing reactions.5 the application frequency or stopping therapy completely. Once irritation is resolved, treatment can be REFERENCES 1. American Academy of Dermatology. Acne: who gets and causes. www.aed. restarted. org/sink-conditions/dermatology-ato-z/acne/who-gets-causes/acne-who- • Advise patients to use moisturizers as needed. gets-and-causes. • Advise female patients about the importance of proper 2. Anon. FDA approves Fabior Foam. www.drugs.com/newdrugs/stiefel-receives- us-fda-approval-fabior-foam-0-1-3214.html. contraception during treatment to avoid pregnancy. 3. Shalita AR, Berson DS, Thiboutot DM, et al. Effects of tazarotene 0.1 % cream • Educate the patients about the importance of avoiding in the treatment of facial acne vulgaris: pooled results from two multicenter, double-blind, randomized, vehicle-controlled, parallel-group trials. Clin Ther. exposure to natural or artifi cial sunlight. Sunscreens 2004;26(11):1865-1873. should be used during treatment. 4. Menter A. Pharmacokinetics and safety of tazarotene. J Am Acad Dermatol. • Instruct patients not to get tazarotene foam in the eyes. 2000;43:S31-S35. 5. Fabior (tazarotene) Foam, 0.1% Prescribing Information. Stiefel Laboratories, If this occurs, tell patients to rinse the eyes thoroughly Inc. 2012. www.stiefel.com/content/dam/stiefel/globals/documents/pdf/ with water. US_Fabior.pdf. • Tazarotene foam is not to be used orally, ophthalmically, 6. Kakita L. Tazarotene versus tretinoin or adapalene in the treatment of acne vulgaris. J Am Acad Dermatol. 2000;43(2 pt 3):S51-S54. or intravaginally. • Jennifer M. Belavic is a pharmacy manager at University of Pittsburgh Medical Advise patients that tazarotene foam is fl ammable, Center—Presbyterian Hospital, Pittsburgh, Pa. and tell patients to avoid fi re, an open fl ame, and The author and planners have disclosed no fi nancial relationships related to this smoking during and immediately after application of article. the foam. Also instruct patients not to puncture the DOI-10.1097/01.NPR.0000425824.44694.e8

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