continuing education for pharmacists Volume XXXI, No. 5 New Drugs: Eliquis, Fulyzaq, Sirturo, and Xeljanz

Thomas A. Gossel, R.Ph., Ph.D., Professor Emeritus, Ohio Northern University, Ada, Ohio

Dr. Thomas A. Gossel has no relevant Apixaban (Eliquis) with AF is also very common. The financial relationships to disclose. Warfarin reduces the risk of stroke arrhythmia is a major cardiovas- in patients with atrial fibrillation cular challenge in modern society Goal. The goal of this lesson is to (AF) and is classified as a preferred and its medical, social and eco- provide information on apixaban therapy in practice guidelines. Its nomic aspects are all predicted to (Eliquis®), crofelemer (Fulyzaq™), limitations, however, have con- intensify over the coming decades. bedaquiline (Sirturo™) and tofaci- tributed to its underuse in clinical Fortunately, a number of valuable tinib (Xeljanz®). practice. These limitations have led treatments have been devised in to development of several new oral recent years that may offer some Objectives. At the completion of anticoagulants, including direct solution to this problem. this activity, the participant will be thrombin inhibitors and blood Since its discovery in the able to: clotting factor Xa inhibitors, for early 1920s, warfarin has been the 1. identify the new drugs by patients with AF. One of the new major therapeutic agent for reduc- generic name, trade name and drugs is Eliquis. tion of thromboembolic events in chemical name when relevant; Indications and Use. Eliquis patients with AF. Its benefits are 2. select the indication(s), is a factor Xa inhibitor anticoagu- well documented and include a 64 pharmacologic action(s) and clinical lant indicated to reduce the risk of percent relative risk reduction in applications for each drug; stroke and systemic embolism in stroke compared with placebo and 3. recognize important thera- patients with nonvalvular AF. a 37 percent risk reduction com- peutic uses for the drugs and their Stroke and systemic embo- pared with antiplatelet therapy. applications in specified patholo- lism in atrial fibrillation. AF is However, various drug and diet gies; and an abnormal, irregular, and rapid interactions can lead to an unpre- 4. demonstrate an understand- beating of the heart such that the dictable dose response that can ing of adverse effects and toxicity, atria do not contract in synchrony reduce its clinical effectiveness or significant drug-drug interactions, with the ventricles. This may lead increase its toxicity, sometimes and patient counseling information to intra-atrial formation of thrombi with catastrophic results. More- for these drugs. that can break loose and circulate over, its need for regular laboratory as emboli to the brain or elsewhere monitoring, perhaps weekly, makes Drugs discussed within this lesson in the body. Anti-clotting drugs it an unattractive choice for many are new-molecular entity drugs for lower the risk of stroke by helping patients. As a result, use of warfa- oral administration that are indi- prevent thrombi from forming. rin in patients with AF is often not cated to treat a variety of patholo- AF is the most common cardiac ideal, especially to those at highest gies (Table 1). The lesson provides arrhythmia, currently estimated to risk for thromboembolic events. a brief introduction to the new be 1.5 to 2 percent of the general However, warfarin is safe when the drugs and is not intended to extend population worldwide. The average patient’s international normalized beyond an overview of the topic. age of patients with AF is steadily ratio (INR) is maintained within The reader is, therefore, urged to rising, now averaging between 75 the therapeutic range. Complica- consult the products’ full Prescrib- and 85 years. The arrhythmia is tions usually occur when it is not ing Information leaflet (package associated with a five-fold increase in range – i.e., bleeding can occur insert), Medication Guide when in risk of stroke, a three-fold when the INR is high and the risk available, and other published ref- increase in incidence of congestive for ischemic stroke is increased erence sources for detailed descrip- heart failure, and higher mortal- when the INR is low. tions. ity. Hospitalization of patients Oral anticoagulants that pro- Table 1 Selected new drugs

Generic Applicant/Sponsor/ Indication Dose* Dosage Most Common Medication (Proprietary Distributor Form Adverse Guide± Name) Reactions

Apixaban Bristol-Myers Squibb Anticoagulant 5 mg 2.5, 5 mg Incidence >1%: Yes (Eliquis) Company, & Pfizer for patients with twice daily tablets bleeding reactions atrial fibrillation

Bedaquiline Janssen Therapeutics Pulmonary multi- 400 mg/day 100 mg Incidence ≥10%: Yes (Sirturo) drug resistant TB for 2 weeks, tablets nausea, arthralgia, then 200 mg headache 3 times a week for 22 weeks

Crofelemer Salix Antidiarrheal for 125 mg 125 mg Incidence ≥3%: No (Fulyzaq) Pharmaceuticals, patients with twice daily delayed- URT§ infections Inc. HIV/AIDS release bronchitis, cough, tablets flatulence, increased bilirubin

Tofacitinib Pfizer Moderate to severe 5 mg 5 mg Incidence ≥2%: Yes (Xeljanz) rheumatoid twice daily tablets URT§ infections, arthritis headache, diarrhea, nasopharyngitis

*Recommended dose for most patients §URT – Upper respiratory tract ±At the time of lesson publication

vide stable, predictable anticoagu- development. As a result of factor patient-years). In AVERROES, the lation without the need for moni- Xa inhibition, the drug prolongs mean duration of exposure was toring have long been of interest. clotting tests such as prothrombin approximately 59 weeks (>3000 Agents such as apixaban and oth- time (PT), INR, and activated par- patient-years). ers have the potential to address tial thromboplastin time (aPTT). The most common reason some of the limitations of warfa- Changes in these clotting tests (Table 1) for discontinuation of rin. In general, they have fewer with therapeutic drug doses, how- treatment in both studies was drug and food interactions and a ever, are small, subject to a high bleeding-related events; in ARIS- more predictable anticoagulant degree of variability, and not useful TOTLE this occurred in 1.7 percent effect, thus allowing fixed dosing in monitoring the anticoagulation and 2.5 percent of patients treated without the need for careful labo- effect of apixaban. with Eliquis and warfarin, respec- ratory monitoring. Furthermore, Safety. Evidence for the safety tively, and in AVERROES, in 1.5 their shorter half-life compared to of Eliquis was derived from the percent and 1.3 percent on Eliquis warfarin may provide additional ARISTOTLE (Apixaban for Reduc- and aspirin, respectively. advantages, e.g., if temporary in- tion In STroke and Other Throm- Warnings, Precautions and terruption is required for a surgical boemboLic Events in atrial fibril- Contraindications. The following procedure in the case of a hemor- lation) and AVERROES (Apixaban warnings and precautions are rhagic complication. VErsus acetylsalicylic acid (ASA) to listed: Mechanism of Action. Apixa- Reduce the Rate Of Embolic Stroke • Serious and potentially fatal ban is a reversible and selective in atrial fibrillation) trials. These bleeding: signs and symptoms of inhibitor of coagulation factor Xa. studies included 11,284 patients blood loss should be evaluated It inhibits free and clot-bound fac- receiving Eliquis 5 mg twice daily promptly. tor Xa, and prothrombinase activ- and 602 patients taking doses of • Prosthetic heart valves: be- ity. Apixaban has no direct effect 2.5 mg twice daily. The duration cause the use of Eliquis for patients on platelet aggregation, but indi- of drug exposure in the two trials with prosthetic heart valves has rectly inhibits platelet aggregation was ≥12 months for 9375 patients not been studied, its use in these induced by thrombin. By inhibit- and ≥24 months for 3369 patients. patients is not recommended. ing factor Xa, apixaban decreases In ARISTOTLE, the mean duration • A Boxed Warning advises thrombin generation and thrombus of exposure was 89 weeks (>15,000 that patients are at an increased stances across biological mem- to Mycobacterium tuberculosis or Table 2 branes). Strong dual inhibitors of drug-sensitive TB has yet to be Patient counseling CYP3A4 and P-gp (e.g., ketocon- established. Likewise, there are no information for Eliquis azole, itraconazole, ritonavir, clar- data to support treatment with Sir- ithromycin) increase blood levels turo for extra-pulmonary TB (e.g., Patients should be advised: of apixaban and increase the risk central nervous system); therefore, • Do not discontinue Eliquis without first talking to their physician. of bleeding. Eliquis dosage should use of the drug in these conditions • It might take longer than usual be reduced to 2.5 mg with concomi- is not recommended. for bleeding to stop, and bruising tant drug use. Simultaneous use Sirturo should only be used in or bleeding may occur more easily of strong inducers of CYP3A4 and combination with at least three when treated with Eliquis. Advise P-gp (e.g., rifampin, carbamaze- other drugs to which the patient’s patients how to recognize bleeding or pine, phenytoin, St. John’s wort) MDR-TB isolate has been shown symptoms of hypovolemia and of the decrease exposure to apixaban and, to be susceptible in vitro. If in vitro urgent need to report any unusual thus, increase the risk of stroke. testing results are unavailable, bleeding to the physician. Concomitant use should be avoid- treatment may be initiated with • Tell their physician and dentist that they are taking Eliquis, and/ ed. Sirturo in combination with at or any other product known to affect Coadministration of aspirin least four other drugs to which the bleeding (including OTC products and other antiplatelet agents, other patient’s MDR-TB isolate is likely such as aspirin or NSAIDs); before anticoagulants, heparin, thrombo- to be susceptible. any surgery or medical or dental pro- lytic agents, selective serotonin Tuberculosis. TB, a term that cedure is scheduled; and before any reuptake inhibitors, serotonin- describes a broad range of clinical new drug is taken. norepinephrine reuptake inhibitors illnesses caused primarily by M. • Tell their physician if they are and nonsteroidal anti-inflamma- tuberculosis, was identified as far pregnant or plan to become preg- tory drugs (NSAIDs) may increase back as ancient Egyptian times. It nant, or are breastfeeding or intend to breastfeed during treatment with the risk of bleeding. is one of the world’s deadliest dis- Eliquis. Patient Counseling Infor- eases. TB did not emerge as a ma- • Take a missed dose as soon as mation. An FDA-approved Medi- jor health problem until the advent possible on the same day; twice daily cation Guide must be dispensed of the industrialized revolution, administration should be resumed. with Eliquis. Specific points for which led to crowded living and Doses should not be doubled to make counseling are summarized in working conditions that favored up for a missed dose. Table 2. its spread. It is spread through • A Medication Guide is dispensed the air when an infected person with this prescription. Be sure to coughs, sneezes, speaks or sings. read the information before taking Bedaquiline (Sirturo) Eliquis. The number of multi-drug resis- The pathogen can remain airborne tant tuberculosis (MDR-TB) cases for several hours. TB usually af- reported to the World Health Or- fects the lungs but can also affect ganization (WHO) increased from other parts of the body such as the risk of thrombotic events following 29,000 to 53,000 between 2008 and brain, spine and kidneys. Humans Eliquis discontinuation. 2010. According to the U.S. Centers are the only known reservoir for M. Contraindications for Eliquis for Disease Control and Prevention tuberculosis, an aerobic, non-spore- include active pathological bleed- (CDC), nearly nine million people forming, nonmotile bacillus. The ing, and severe hypersensitivity to around the world and 10,528 emerging threat is development of the drug. people in this country became sick extensively drug-resistant TB, first Eliquis should be discontinued with TB in 2011. Sirturo is the reported in 2005. A WHO Emer- at least 24 hours prior to elective first FDA-approved agent to treat gency Global Task Force defines surgery or invasive procedures as- MDR-TB. MDR-TB as TB that is resistant sociated with a low risk of bleeding Indications and Use. Sir- to at least isoniazid and rifampin or where the bleeding would be turo is an antimycobacterial drug (among the first-line antimycobac- non-critical in location and easily indicated as part of combination terial agents), to any fluoroquino- controlled. Eliquis should be dis- therapy in adults ≥18 years of age lone antibiotic, and to at least one continued at least 48 hours prior to with pulmonary MDR-TB. The second-line injectable drug (amika- elective surgery or invasive proce- drug should be reserved for use cin, capreomycin or kanamycin). dures that have a moderate or high when an effective treatment regi- Mechanism of Action. Be- risk of unacceptable or clinically men cannot otherwise be provided. daquiline inhibits mycobacterial significant bleeding. The drug is not indicated for treat- ATP (adenosine 5’-triphosphate) Drug Interactions. Apixaban ment of latent, extra-pulmonary synthase, an enzyme essential for is a substrate of both CYP3A4 and or drug-sensitive tuberculosis. cellular generation of energy in M. P-glycoprotein (P-gp; a transporter Safety and efficacy of Sirturo for tuberculosis. The drug is primarily that regulates movement of sub- treatment of latent infection due subjected to oxidative metabolism pared to the parent compound. M2 tive QT prolongation. Table 3 concentrations appear to correlate • Hepatic-related adverse drug Patient counseling with QT prolongation. reactions: liver-related laboratory information for Sirturo Safety. Adverse drug reac- tests should be monitored carefully. tions for Sirturo (Table 1) were • Non-adherence to the pre- Patients should be advised: identified from the pooled safety scribed treatment regimen: this can • Tuberculosis is a serious disease data from 335 bedaquiline-exposed result in drug failure or M. tuber- that can be fatal; some patients with resistant TB may have limited treat- patients who received the drug for culosis resistance. ment options. eight weeks (Study 2) and 24 weeks • A Boxed Warning alerts • Serious side effects can occur: (Studies 1 and 3) at the proposed health care professionals and death, heart rhythm abnormalities, dose. In both treatment groups, pa- patients that QT prolongation and/or hepatitis. tients received Sirturo or placebo in can occur with Sirturo, and that • Patients should also be advised combination with other drugs used increased risk of death can occur about other potential side effects with to treat MDR-TB. Study 3 is an on- with the drug. Sirturo: nausea, joint pain, headache, going, open-label, noncomparative There are no contraindica- hemoptysis (coughing up of blood or study with Sirturo administered tions listed. blood-stained sputum), chest pain, anorexia, and/or rash. Additional as part of an individualized pulmo- Drug Interactions. Use of testing may be needed to monitor nary MDR-TB treatment regimen systemic potent CYP3A4 inducers or reduce the likelihood of adverse to previously treated patients. should be avoided. Sirturo should effects. Patients in Study 1 had a not be used for more than 14 • Take Sirturo in combination with statistically significant increased consecutive days along with strong other antimycobacterial drugs as mortality risk by Week 120 in the CYP3A4 inhibitors unless benefit prescribed. Stay fully compliant with Sirturo treatment group compared outweighs risk. Appropriate clini- the full course of therapy. Skip- to the placebo group. Five of the cal monitoring for Sirturo-related ping doses or not completing the Sirturo-group deaths and the two adverse reactions is recommended. full course of therapy may decrease the effectiveness of the treatment placebo-group deaths were TB- Patient Counseling Infor- and increase the likelihood that the related. One death occurred dur- mation. An FDA-approved Medi- infection may develop resistance and ing the 24-week Sirturo treatment cation Guide must be dispensed the disease will not be treatable by period. The median time to death with Sirturo. Specific points for Sirturo or other antibacterial drugs for the remaining eight subjects in counseling are summarized in in the future. the Sirturo treatment group was Table 3. • If a dose is missed during the first 329 days after their last intake of two weeks of treatment, patients Sirturo. This imbalance in deaths Crofelemer (Fulyzaq) should not make up the missed dose is unexplained; no discernible pat- Diarrhea is a common and often but should continue the usual dosing schedule. From Week 3 onward, if tern between death and sputum inadequately treated complication a 200 mg dose is missed, patients conversion, relapse, sensitivity to in patients with HIV infection. It is should take the missed dose as soon other drugs used to treat TB, HIV also a common reason why patients as possible, and then resume the status, and severity of disease was discontinue or switch their antiret- three times a week regimen. observed. roviral therapies. It is estimated • Take the drug with food. Swallow Warnings, Precautions and that 50 to 60 percent of patients the tablets whole with water. Contraindications. The follow- with AIDS experience diarrhea at • Abstain from alcohol, hepatotoxic ing warnings and precautions some point during their illness. medications or herbal products. include: Although the CDC defines chronic • Discuss with their physician the other medications they are taking • QT prolongation: patients’ diarrhea as an average of ≥2 loose and other medical conditions before ECGs should be monitored fre- or watery stools per day for one starting treatment with Sirturo. quently. Sirturo should be discon- month or longer, various other • Consult with their physician if they tinued if significant ventricular definitions are used in the litera- have a personal or family history of arrhythmias or QT prolongation ture. Before Fulyzaq was approved, congenital QT prolongation or heart develops. Use with other QT- there were no FDA-approved thera- failure. prolonging drugs (e.g., fluoroqui- pies for HIV-associated diarrhea. nolones, macrolide antibacterials, The new drug is a proantho- clofazimine) or in persons with cyanidin oligomer that has been leading to formation of the metabo- a history of Torsade de Pointes, isolated and purified from the latex lite N-monodesmethyl (M2). M2 congenital long QT syndrome, of Croton lechleri (family Euphorbi- is not believed to contribute sig- hypothyroidism and bradyarrhyth- aceae). This plant is widely distrib- nificantly to clinical efficacy given mias, uncompensated heart failure, uted throughout Western Amazoni- its low average exposure (23 to 31 or serum calcium, magnesium or an South America. The red, viscous percent) and four- to six-fold lower potassium levels below the lower latex from this plant is widely antimycobacterial activity com- limits of normal may cause addi- known for its medicinal properties, including relief of diarrhea. Ac- sons: diarrhea can be attributed to cording to ethnobotanists who have infectious agents, gastrointestinal Table 4 interviewed indigenous populations malignancies, HIV enteropathy, Patient counseling using this plant product, adverse idiopathic etiology or medications. information for Fulyzaq effects are minimal after routine Mechanism of Action. oral use. Although its mechanism of action Patients should be advised: Indications and Use. Fulyzaq remains to be fully elucidated, it is • Tablets should not be crushed or is an antidiarrheal indicated for generally believed that crofelemer chewed; they must be swallowed symptomatic relief of non-infec- acts by blocking chloride secretion whole. • Tablets may be taken with or with- tious diarrhea in adult patients into the bowel and accompanying out food. with HIV/AIDS who are taking high volume water loss in diarrhea, antiretroviral therapy. thus normalizing the flow of chlo- Diarrhea in patients with ride and water in the GI tract. HIV/AIDS. Although the in- Safety. The safety profile of Patient Counseling Infor- cidence of pathogen-associated Fulyzaq was similar in patients mation. Specific points for coun- diarrhea may be decreasing since with baseline CD4 cell count less seling are summarized in Table 4. introduction of highly active than 404 cells/µL (lower limit of antiretroviral therapy (HAART), normal range) (N=388) and pa- Tofacitinib (Xeljanz) many patients with HIV continue tients with baseline CD4 cell count The natural history of rheuma- to have chronic diarrhea with no greater than or equal to 404 cells/ toid arthritis (RA) has changed identifiable pathogen despite an µL (N=289), The drug’s safety dramatically since the 1980s with extensive evaluation. Regardless profile was also similar in patients introduction of methotrexate into of the cause, diarrhea can result with baseline HIV viral loads less its therapy. Methotrexate changed in decreased quality of life and than 400 copies/mL (N=412) and the course of the disease, slowing significantly greater economic costs patients with baseline HIV viral or even preventing development of for affected patients with HIV loads greater than or equal to 400 bone erosions, thus becoming the infection when compared to those copies/mL (N=278). Therefore, no first-line choice disease modifying without diarrhea. Patients with dose modifications are recommend- antirheumatic drug (DMARD). In adverse GI symptoms are likely to ed with respect to CD4 cell count the 1990s, significant work on the be less adherent to their medica- and HIV viral load, based on the pathophysiology of RA led to devel- tion regimen, especially if they findings in subgroups of patients opment of specific DMARDs using attribute the symptoms directly defined by CD4 cell count and HIV monoclonal antibodies and receptor to their medications. Medication viral load. decoys, which made them a main- nonadherence can potentially lead Warnings, Precautions and stay of treatment with or without to treatment failures and increased Contraindications. The following methotrexate. However, these bio- rates of resistant strains of virus. warning is listed: logic treatments need to be injected Therefore, evaluation of effective • Infectious etiologies of diar- parenterally, are expensive, and treatments for diarrhea in patients rhea: these should be ruled out have significant adverse effects. with AIDS is important for qual- before starting Fulyzaq. If infec- Moreover, a significant proportion ity of life issues as well as other tious etiologies are not considered of patients treated with biologics concerns. and treatment is initiated based on and/or methotrexate fail to respond Diarrhea can also cause a a presumptive diagnosis, there is a or lose their response to the treat- number of other important clini- risk that patients with such etiolo- ment. Therefore, oral, relatively cal ramifications. Chronic diarrhea gies will not receive the appropri- inexpensive, small molecules that contributes to malnutrition and ate therapy and their disease may target specific pathways could rep- weight loss. Along with thrush, worsen. resent a valuable addition to the weight loss, fever and night sweats, There are no contraindica- current DMARD armamentarium. chronic diarrhea has emerged as tions listed. Xeljanz provides a new treatment a clinical indicator of progression Drug Interactions. In vitro option for adults suffering from of immunodeficiency. Patients studies have shown that crofele- debilitating RA. with AIDS and chronic diarrhea mer has the potential to inhibit Indications and Uses. Xel- are more likely to have increased CYP3A4 at drug concentrations janz is indicated for treatment of weight loss and immunosuppres- expected in the gut. Due to the adult patients with moderately to sion than patients without diar- minimal absorption of crofelemer, severely active RA who have had rhea, regardless of etiology. Sur- it is unlikely to inhibit CYP450 an inadequate response or intoler- vival is also known to be impacted isoenzymes 1A2, 2A6, 2B6, 2C9, ance to methotrexate. It may be by acute or chronic diarrhea. 2C19, 2D6, 2E1 and CYP3A4 sys- used as monotherapy or in combi- Determining the cause of diarrhea temically. nation with methotrexate or other is important for therapeutic rea- nonbiologic DMARDs. The drug in turn, modulate intracellular nancies: these have been reported Table 5 activity including gene expression. in patients treated with Xeljanz. Patient counseling Tofacitinib modulates the signal- • Gastrointestinal perfora- information for Xeljanz ing pathway at the point of JAKs, tions: the drug should be used with preventing phosphorylation and caution in patients who may be at Patients should be advised: • A Medication Guide is dispensed activation. increased risk (e.g., persons with a with this prescription. Be sure to Safety. Safety of Xeljanz was history of diverticulitis). Patients read the information before taking evaluated in seven clinical trials in presenting with new-onset abdomi- Xeljanz. adult patients with moderately to nal symptoms should be evaluated • Use Xeljanz only as prescribed. severely active RA. The new drug promptly for early identification of was associated with an increased gastrointestinal perforations. should not be used in combination risk of serious infections, including • Laboratory monitoring: close with biologic DMARDs or potent opportunistic infections (ones that monitoring is recommended due to immunosuppressants such as aza- occur primarily when the immune potential changes in lymphocytes, thioprine and cyclosporine. system is suppressed), TB, cancers neutrophils, hemoglobin, liver en- Rheumatoid Arthritis. RA, a and lymphoma. The drug was also zymes and lipids. chronic autoimmune disease of the associated with increases in lipids • Immunizations: live vaccines musculoskeletal system estimated and liver enzymes and decreases should not be given concurrently to affect 1.5 million people in the in blood counts and hemoglobin. As with Xeljanz. United States, is characterized by noted in Table 1, the most com- • Severe hepatic impairment: infiltration of inflammatory cells mon adverse reactions in all seven Xeljanz use is not recommended. into the synovium, a structure clinical trials were upper respira- • A Boxed Warning emphasizes that lines the joints. The thickened tory tract infections, headache, the importance of these warnings synovium forms an abnormal layer diarrhea, and inflammation of the and precautions. of fibrovascular or granulation nasal passages and the upper areas There are no contraindica- tissue called pannus that slowly de- of the pharynx. The proportion of tions listed. stroys cartilage and bone adjacent patients who discontinued treat- Drug Interactions. With to the joint. Both the small joints of ment due to any adverse reaction potent inhibitors of CYP3A4 (e.g., the hands and feet, and the larger during exposure in the double- ketoconazole), the dose of Xeljanz joints such as the knees and wrists, blind, placebo-controlled trials should be reduced to 5 mg once dai- are damaged in RA, ultimately was 4 percent for patients taking ly. With one or more concomitant leading to serious functional im- Xeljanz and 3 percent for those tak- medications that result in both pairment. More aggressive forms ing a placebo. moderate inhibition of CYP3A4 and of RA also involve extra-articular To study the long-term effects potent inhibition of CYP2C19 (e.g., tissues to cause lung inflammation, of Xeljanz on heart disease, cancer, fluconazole), Xeljanz dose should be splenomegaly with cytopenias (re- and serious infections, FDA is re- reduced to 5 mg once daily. Potent duced number of blood cells), skin quiring a postmarketing study that CYP inducers (e.g., rifampin): may nodules, and vasculitis. The disease will evaluate two doses of Xeljanz result in loss of or reduced clinical is associated with considerable and include a group of patients on response. morbidity, premature mortality, an alternate approved treatment to Patient Counseling Infor- disability and diminished quality serve as a comparison. mation. An FDA-approved Medi- of life, and imposes a substantial Warnings, Precautions and cation Guide must be dispensed economic burden on patients and Contraindications. The following with Xeljanz. Specific points for society. Treatment aims at termi- warnings and precautions are counseling are summarized in nating the inflammatory response listed: Table 5. before permanent damage occurs. • Serious infections: serious Mechanism of Action. To- and sometimes fatal infections Overview and Summary facitinib is a novel small molecule due to bacterial, mycobacterial, Four unrelated human pathologies Janus kinase (JAK) inhibitor. invasive fungal, viral or other op- that represent significant thera- JAKs are intracellular enzymes portunistic pathogens have been peutic challenges are profiled in that transmit signals arising from reported in persons with RA who this lesson. While each disorder is cytokine or growth factor-receptor are receiving Xeljanz. Patients associated with a variety of signs interactions on the cellular mem- should not receive Xeljanz during and symptoms that are indepen- brane to influence cellular pro- an active infection, including local- dent of those characteristic of the cesses of hematopoiesis (formation ized infections. If a serious infec- other conditions, there is one com- and development of blood cells) and tion develops, Xeljanz administra- mon element that is shared by all immune cell function. Within the tion should be interrupted until the four pathologies: each can now be signaling pathway, JAKs phosphor- problem is controlled. treated with a new drug recently ylate and activate receptors which, • Lymphomas and other malig- approved for its therapy. The author, the Ohio Pharmacists Founda- tion and the Ohio Pharmacists Association disclaim any liability to you or your patients resulting from reliance solely upon the infor- mation contained herein. Bibliography for additional reading and inquiry is available upon request.

This lesson is a knowledge-based CE activ- ity and is targeted to pharmacists in all practice settings.

Program 0129-0000-13-005-H01-P Release date: 5-15-13 Expiration date: 5-15-16 CE Hours: 1.5 (0.15 CEU) The Ohio Pharmacists Foundation Inc. is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Please print. Program 0129-0000-13-005-H01-P 0.15 CEU continuing education quiz Name______New Drugs: Eliquis, Fulyzaq, Sirturo, and Xeljanz Address______City, State, Zip______1. All of the following are true about atrial fibrillation EXCEPT: Email______a. it is the most common cardiac arrhythmia. b. it occurs in 15 to 20 percent of the general population. NABP e-Profile ID*______*Obtain NABP e-Profile number at www.MyCPEmonitor.net. c. it is associated with a 5-fold increased risk of stroke. d. hospitalization of patients with AF is very common. Birthdate______(MMDD) Return quiz and payment (check or money order) to 2. All of the following are true about apixaban EXCEPT: Correspondence Course, OPA, a. it is a clotting factor Xa inhibitor. 2674 Federated Blvd, Columbus, OH 43235-4990 b. it indirectly inhibits platelet aggregation. 8. Counseling information for Situro includes all of the fol- c. it has a longer half-life than warfarin. lowing EXCEPT: d. weekly INR monitoring is not needed. a. take with other antimycobacterial drugs as directed. b. swallow the tablets whole with water. 3. The most common reason for discontinuation of apixaban c. take with food and abstain from alcohol. in pre-marketing clinical trials was: d. missed doses during the first two weeks of treatment a. bleeding-related events. should be made up. b. the large number of drug interactions. c. intense nausea with vomiting. 9. Which of the following drugs is a proanthocyanidin

oligomer isolated and purified from a plant growing in South 4. Which of the following drugs is reported to increase blood America? levels of apixaban? a. Apixaban c. Crofelemer a. Rifampin c. Ketoconazole b. Bedaquiline d. Tofacitinib b. Phenytoin d. St. John’s Wort 10. Fulyzaq was approved to treat diarrhea associated with 5. For patients whose multi-drug resistant TB isolate is which of the following? susceptible in vitro, Sirturo should only be used in com- a. HIV/AIDS c. Influenza bination with at least how many other antimycobacterial b. Tuberculosis d. Filariasis drugs? a. One c. Three 11. All of the following are true about RA EXCEPT: b. Two d. Four a. it is a chronic autoimmune disease. b. the pannus destroys bone adjacent to the joint. 6. Which of the following is inhibited by bedaquiline? c. the joints of the hands, feet, knees and wrists are dam- a. Janus kinase c. Chlorine transportase aged. b. ATP synthase d. Endodeoxyribonuclease d. aggressive disease is confined to articular tissue.

7. A Boxed Warning with Situro alerts about: 12. Janus kinases are enzymes that: a. possible QT prolongation. a. destroy intra-articular membranes that protect joint b. lymphoma. capsules. c. increased liver enzymes and lipids. b. influence cellular processes of hematopoiesis and im- mune cell function. c. block phosphorylation and activation of receptors in Completely fill in the lettered box corresponding to the signaling pathway. your answer. 1. [a] [b] [c] [d] 6. [a] [b] [c] [d] 11. [a] [b] [c] [d] 13. Xeljanz may be used concurrently with which of the fol- 2. [a] [b] [c] [d] 7. [a] [b] [c] 12. [a] [b] [c] lowing drugs? 3. [a] [b] [c] 8. [a] [b] [c] [d] 13. [a] [b] [c] [d] a. Azathioprine c. Cyclosporine 4. [a] [b] [c] [d] 9. [a] [b] [c] [d] 14. [a] [b] [c] [d] b. Methotrexate d. A biologic DMARD 5. [a] [b] [c] [d] 10. [a] [b] [c] [d] 15. [a] [b] [c] [d] 14. Which of the following drugs has a contraindication  I am enclosing $10 (member); $15 (nonmember) for listed in its label? this month’s quiz made payable to: Ohio Pharmacists a. Eliquis c. Fulyzaq Association. b. Sirturo d. Xeljanz

1. Rate this lesson: (Excellent) 5 4 3 2 1 (Poor) 15. An FDA-approved Medication Guide must be dispensed 2. Did it meet each of its objectives?  yes  no with all of the following EXCEPT? If no, list any unmet______a. Eliquis c. Xeljanz 3. Was the content balanced and without commercial bias? b. Sirturo d. Fulyzaq  yes  no 4. Did the program meet your educational/practice needs? To receive CE credit, your quiz must be received no later than May 15,  yes  no 2016. A passing grade of 80% must be attained. All quizzes received 5. How long did it take you to read this lesson and complete the after July 1, 2012 will be uploaded to the CPE Monitor and a state- quiz? ______ment of credit will not be mailed. Send inquiries to 6. Comments/future topics welcome. [email protected]. may 2013