The Medical Letter ® on Drugs and Therapeutics Objective Drug Reviews Since 1959 Volume 57 ISSUE ISSUE No 1433 1467 Volume 56 April 27, 2015 IN THIS ISSUE Carbidopa/Levodopa Extended-Release Capsules (Rytary) p 59 Netupitant/Palonosetron (Akynzeo) for Chemotherapy-Induced Nausea and Vomiting p 61 Umeclidinium (Incruse Ellipta) for COPD p 63 Glyxambi — A New Combination for Type Diabetes p 65 Addendum: Diet, Drugs, and Surgery for Weight Loss p 66 Important Copyright Message FORWARDING OR COPYING IS A VIOLATION OF U.S AND INTERNATIONAL COPYRIGHT LAWS The Medical Letter, Inc publications are protected by U.S and international copyright laws Forwarding, copying or any distribution of this material is prohibited Sharing a password with a non-subscriber or otherwise making the contents of this site available to third parties is strictly prohibited By accessing and reading the attached content I agree to comply with U.S and international copyright laws and these terms and conditions of The Medical Letter, Inc For further information click: Subscriptions, Site Licenses, Reprints or call customer service at: 800-211-2769 Published by The Medical Letter, Inc • A Nonprofit Organization The Medical Letter publications are protected by US and international copyright laws Forwarding, copying or any other distribution of this material is strictly prohibited For further information call: 800-211-2769 The Medical Letter ® on Drugs and Therapeutics Objective Drug Reviews Since 1959 Volume 57 ISSUE ISSUE No 1433 1467 Volume 56 ▶ April 27, 2015 Take CME Exams ALSO IN THIS ISSUE Netupitant/Palonosetron (Akynzeo) for Chemotherapy-Induced Nausea and Vomiting p 61 Umeclidinium (Incruse Ellipta) for COPD .p 63 Glyxambi — A New Combination for Type Diabetes p 65 Addendum: Diet, Drugs, and Surgery for Weight Loss p 66 Carbidopa/Levodopa ExtendedRelease Capsules (Rytary) The FDA has approved a new formulation of carbidopa/ levodopa (Rytary – Impax) in extended-release capsules for treatment of Parkinson’s disease (PD) Pronunciation Key Carbidopa: kar" bi doe' pa Rytary: rye tar' ee Levodopa: lee" voe doe' pa CARBIDOPA/LEVODOPA — The combination of levodopa and carbidopa is still the most effective pharmacologic treatment for symptomatic relief of PD.1 It has been available for many years as immediate- and sustained-release tablets (Sinemet, Sinemet CR, and generics), orally disintegrating tablets, and in combination with the COMT inhibitor entacapone (Stalevo, and generics) Sustainedrelease tablets have a slower and less predictable onset of action than immediate-release tablets Many patients must take a half or a whole immediate-release tablet concomitantly with sustained-release tablets, particularly with the first dose of the day Some small studies in patients with PD fluctuations have found no significant difference in "off" time between sustainedrelease and immediate-release formulations.2 A PHARMACOKINETIC STUDY — Rytary capsules contain a combination of immediate- and extendedrelease beads In an open-label pharmacokinetic study, levodopa plasma concentrations increased at a similar rate following administration of a single dose of either immediate-release carbidopa/levodopa or the new extended-release capsules Serum Table Pharmacology of Rytary Carbidopa Levodopa Class Decarboxylase inhibitor Dopamine precursor Metabolism Glucuronidation Decarboxylation, O-methylation Tmax hours hour Excretion 30% unchanged in urine Urine as metabolites, 6% unchanged Half-life (terminal) ~2 hours ~2 hours concentrations remained higher than 50% of levodopa Cmax significantly longer with the extended-release formulation (4.0 vs 1.4 hours).3 CLINICAL STUDIES — FDA approval of Rytary was based on two clinical trials The first, a 30-week trial, found that extended-release carbidopa/levodopa capsules were significantly more effective than placebo in treating levodopa-naive patients with PD.4 The second was a 22-week comparison of extendedand immediate-release carbidopa/levodopa in patients with advanced PD and motor fluctuations; the extended-release capsules produced a greater reduction in “off” time as a percentage of waking hours (-13.06% vs -6.21%), a greater reduction in daily “off” time (-2.18 vs -1.01 hours), and about one more hour of “on” time with no or non-troublesome dyskinesia (11.8 vs 10.9 hours), all significant differences, with fewer daily doses (mean 3.6 vs 5.0).5 In a third trial in patients with advanced PD, those taking extended-release carbidopa/levodopa capsules had a lower percentage of “off” time than those taking immediate-release carbidopa/levodopa plus entacapone (24.0% vs 32.5%).6 59 Published by The Medical Letter, Inc • A Nonprofit Organization The Medical Letter Vol 57 (1467) ® April 27, 2015 Table Some Carbidopa/Levodopa Combinations for Parkinson’s Disease Drug Some Available Formulations Usual Daily Dosage Cost1 23.75/95, 36.25/145 48.75/195, 61.25/245 mg caps2 285-1170 mg levodopa, divided3 $207.00 immediate-release – generic Sinemet (Merck) 10/100, 25/100, 25/250 mg tabs 300-1500 mg levodopa, divided 25.20 87.00 orally disintegrating – generic 10/100, 25/100, 25/250 mg tabs 300-1500 mg levodopa, divided 70.00 sustained-release – generic4 Sinemet CR (Merck) 25/100, 50/200 mg tabs 400-1600 mg levodopa, divided 60.50 141.00 12.5/50/200, 18.75/75/200, 25/100/200, 31.25/125/200, 37.5/150/200, 50/200/200 mg tabs 300-1500 mg levodopa, divided 272.10 497.90 Carbidopa/levodopa extended-release – Rytary (Impax) Carbidopa/levodopa/entacapone – generic Stalevo (Orion) Approximate WAC for 30 days’ treatment with the lowest recommended dosage WAC = wholesaler acquisition cost or manufacturer’s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price Source: AnalySource® Monthly April 5, 2015 Reprinted with permission by First Databank, Inc All rights reserved ©2015 www.fdbhealth.com/policies/drug-pricing-policy Capsules may be opened, and the contents sprinkled on 1-2 tablespoons of applesauce and taken immediately Dosages of Rytary are not interchangeable with those of other carbidopa/levodopa products See Table Generic sustained-release tablets are bioequivalent to Sinemet CR sustained-release tablets, but they are called "carbidopa and levodopa extended-release tablets" in their package inserts ADVERSE EFFECTS — The tolerability of the new extended-release capsules appears to be similar to that of other carbidopa/levodopa formulations The most common adverse effects reported in clinical trials were nausea, dizziness, and headache should first be converted to the appropriate Rytary dose using the conversion table below If patients are converting from carbidopa/levodopa plus entacapone (or another COMT inhibitor), the starting dosage may need to be higher DOSAGE AND ADMINISTRATION — Rytary capsules are not interchangeable with immediate-release or sustained-release formulations of carbidopa/ levodopa; the strengths were intentionally made different by the manufacturer to avoid confusion with other available products In levodopa-naive patients, the recommended starting dosage of the new formulation is 23.75/95 mg three times daily for the first three days, which can be increased to 36.25/145 mg three times daily starting on day and then, if needed, increased to 97.5/390 mg three times daily The dosing frequency may then be increased to five times daily if necessary The total daily dose of Rytary should not exceed 612.5/2450 mg The capsules should be swallowed whole and can be taken with or without food For patients who have difficulty swallowing, the contents of the capsules can be sprinkled on 1-2 tablespoons of applesauce and taken immediately To switch patients from immediate-release carbidopa/ levodopa to Rytary, the daily immediate-release dose Table Conversion from IR Carbidopa/Levodopa to Rytary1 Total Daily IR Levodopa Dose Total Daily Rytary Levodopa Dose Rytary Starting Dosage 400-549 mg 855 mg caps of 23.75/95 mg TID 550-749 mg 1140 mg caps of 23.75/95 mg TID 750-949 mg 1305 mg caps of 36.25/145 mg TID 950-1249 mg 1755 mg caps of 48.75/195 mg TID 2205 mg or 2340 mg caps of 61.25/245 mg TID or caps of 48.75/195 mg TID ≥1250 mg RA Hauser 2015 How to dose Rytary (carbidopa and levodopa extendedrelease) [White paper] National Parkinson Foundation Available at www parkinson.org Accessed April 15, 2015 60 CONCLUSION — Extended-release carbidopa/levodopa capsules (Rytary) can decrease “off” time and dosing frequency compared to immediate-release tablets Dosages of Rytary are not interchangeable with those of other carbidopa/levidopa products ■ Drugs for Parkinson’s disease Med Lett Drugs Ther 2013; 11:101 R Pahwa et al Practice Parameter: treatment of Parkinson disease with motor fluctuations and dyskinesia (an evidencebased review): report of the Quality Standards Subcommittee of the American Academy of Neurology Neurology 2006; 66:983 RA Hauser et al Crossover comparison of IPX066 and a standard levodopa formulation in advanced Parkinson’s disease Mov Disord 2011; 26:2246 R Pahwa et al Randomized trial of IPX066, carbidopa/ levodopa extended release, in early Parkinson’s disease Parkinsonism Relat Disord 2014; 20:142 RA Hauser et al Extended-release carbidopa-levodopa (IPX066) compared with immediate-release carbidopalevodopa in patients with Parkinson’s disease and motor fluctuations: a phase randomised, double-blind trial Lancet Neurol 2013; 12:346 F Stocchi et al Comparison of IPX066 with carbidopalevodopa plus entacapone in advanced PD patients Parkinsonism Relat Disord 2014; 20:1335 The Medical Letter ▶ ® Netupitant/Palonosetron (Akynzeo) for Chemotherapy-Induced Nausea and Vomiting The FDA has approved Akynzeo (Helsinn/Eisai), an oral fixed-dose combination of the substance P/neurokinin (NK1) receptor antagonist netupitant and the serotonin-3 (5-HT3) receptor antagonist palonosetron, for prevention of acute and delayed nausea and vomiting associated with cancer chemotherapy in adults Akynzeo is the first product to combine drugs from these two classes Palonosetron (Aloxi) is also available as a single agent for prevention of chemotherapy-induced and postoperative nausea and vomiting.1 Netupitant is the second substance P/NK1 receptor antagonist to be approved in the US; aprepitant (Emend) was the first.2 Pronunciation Key Netupitant: ne tue' pi tant Akynzeo: a kin' zee oh Palonosetron: pal" oh noe' se tron STANDARD TREATMENT — Current guidelines recommend that patients undergoing highly emetogenic chemotherapy receive a 3-drug regimen consisting of aprepitant, a 5-HT3 receptor antagonist, and dexamethasone for prevention of acute and delayed nausea and vomiting.3,4 Palonosetron administered in combination with dexamethasone is recommended for patients receiving moderately emetogenic chemotherapy Granisetron or ondansetron (Zofran, and generics) may be substituted if palonosetron is not available Table Pharmacology of Akynzeo Class Netupitant Palonosetron Substance P/NK1 receptor antagonist 5-HT3 receptor antagonist Metabolism Primarily by CYP3A4, and to a lesser extent by CYP2C9 and 2D6 Primarily by CYP2D6, and to a lesser extent by CYP3A4 and 1A2 Tmax hours hours Excretion Feces (~71% in 14 days); urine (~4% in 14 days) Urine (85%-93%); feces (5%-8%) Half-life 96 hrs (healthy subjects); 44 hrs (healthy subjects); ~ 80 hrs (cancer patients) ~ 48 hrs (cancer patients) MECHANISM OF ACTION — Palonosetron has a higher affinity for 5-HT3 receptors than other available 5-HT3 receptor antagonists Netupitant selectively inhibits NK1 receptors and blocks the action of substance P, a neuropeptide that binds to NK1 receptors in the gut, brainstem, and area postrema, all of which are involved in the emetic response The combination of Vol 57 (1467) April 27, 2015 palonosetron and netupitant may block the action of substance P synergistically.5 CLINICAL STUDIES — FDA approval of netupitant/ palonosetron was based on two double-blind controlled trials The first was a dose-ranging trial that randomized 694 chemotherapy-naive patients undergoing highly emetogenic (cisplatin-based) chemotherapy to a single oral dose of netupitant 100, 200, or 300 mg plus palonosetron 0.5 mg, or to a single oral dose of palonosetron 0.5 mg alone Oral aprepitant for days plus IV ondansetron on day was included as an “exploratory arm” that was only to be compared to palonosetron All groups also received oral dexamethasone on days 1-4.6 The second trial randomized 1455 chemotherapynaive patients undergoing moderately emetogenic (anthracycline-cyclophosphamide) chemotherapy to a single oral dose of netupitant 300 mg plus palonosetron 0.5 mg or a single oral dose of palonosetron 0.5 mg alone Both groups also received oral dexamethasone on day 1.7 Table Netupitant/Palonosetron Clinical Trials Netupitant/ Palonosetron1 Palonosetron2 Aprepitant + Ondansetron3 Highly Emetogenic Chemotherapy Trial4 (n=694) Complete Response5 Acute Phase 98.5% (0-24 h) Delayed Phase 90.4% (25-120 h) Overall Phase 89.6% (0-120 h) 89.7% 94.8% 80.1% 88.8% 76.5% 86.6% Moderately Emetogenic Chemotherapy Trial6 (n=1455) Complete Response5 Acute Phase 88.4% (0-24 h) Delayed Phase 76.9% (25-120 h) Overall Phase 74.3% (0-120 h) 85.0% — 69.5% — 66.6% — The dosage of netupitant/palonosetron was 300 mg/0.5 mg once Patients in the highly emetogenic chemotherapy trial also received oral dexamethasone 12 mg once on day and mg twice daily on days 2-4 Patients in the moderately emetogenic chemotherapy trial received oral dexamethasone 20 mg on day Palonosetron was administered as a single oral 0.5-mg dose Patients in the highly emetogenic chemotherapy trial received oral dexamethasone 20 mg on days and mg twice daily on days 2-4 Patients in the moderately emetogenic chemotherapy trial received oral dexamethasone 20 mg on day Administered as oral aprepitant 125 mg, IV ondansetron 32 mg, and oral dexamethasone 12 mg on day 1, followed by oral aprepitant 80 mg once daily and oral dexamethasone mg twice daily on days 2-3, then oral dexamethasone mg twice daily on day 4 Patients undergoing cisplatin-based chemotherapy (PJ Hesketh et al Ann Oncol 2014; 25:1340) Defined as no emesis and no use of rescue medication Patients undergoing chemotherapy containing cyclophosphamide and an anthracycline; this combination is now classified as highly emetogenic (M Aapro et al Ann Oncol 2014; 25:1328) 61 The Medical Letter Vol 57 (1467) ® April 27, 2015 Table Some Drugs for Chemotherapy-Induced Nausea and Vomiting Some Available Formulations Usual Adult Dosage for Highly Emetogenic Chemotherapy1 Dolasetron – Anzemet (Sanofi) 50, 100 mg tabs PO : 100 mg once $95.50 Granisetron – generic mg tabs; mg/mL,3 mg/4 mL vials; 0.1 mg/mL preservative-free vials 52 cm2 patch5 PO : mg once IV : mg or 0.01 mg/kg once patch 24 hours before chemotherapy6 31.20 19.704 435.50 4, 8, 16, 24 mg tabs; mg/5 mL oral soln; mg/mL vials3; mg/2 mL syringes 4, 8, 24 mg tabs; mg/5 mL oral soln; mg/mL vials3 PO : 24 mg once or mg twice/d x day IV : mg or 0.15 mg/kg once PO : 24 mg once or mg twice/d x day IV : mg or 0.15 mg/kg once 3.607 4, mg tabs ODT: 24 mg once 4, mg oral films 24 mg 30 minutes before chemotherapy 0.075 mg/1.5 mL, 0.25 mg/5 mL single-use vials IV : 0.25 mg once 411.00 Aprepitant – Emend (Merck) 40, 80, 125 mg caps PO : 125 mg on day 1, then 80 mg on days 2-3 495.109 Fosaprepitant – Emend (Merck) 150 mg vials (lyophilized powder) IV : 150 mg once 257.00 PO : 300 mg/0.5 mg once 499.80 Drug Cost2 5-HT3 Receptor Antagonists transdermal patch – Sancuso (Prostrakan) Ondansetron – generic Zofran (GSK) orally disintegrating tablet – generic Zofran ODT (GSK) oral soluble film – Zuplenz (Galena) Palonosetron – Aloxi (Helsinn/Eisai) 2.008 110.607 42.708 5.80 104.40 75.20 Substance P/NK1 Receptor Antagonists Substance P/NK1 Receptor Antagonist and 5-HT3 Receptor Antagonist Combination Netupitant/palonosetron – Akynzeo (Helsinn/Eisai) 300 mg/0.5 mg caps ODT = orally disintegrating tablet For single-day chemotherapy Approximate WAC for one dose WAC = wholesaler acquisition cost or manufacturer’s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price Source: AnalySource® Monthly April 5, 2015 Reprinted with permission by First Databank, Inc All rights reserved ©2015 www.fdbhealth.com/policies/drug-pricing-policy Also available as preservative-free solution Cost for mg Each patch contains 34.3 mg of granisetron and releases 3.1 mg of granisetron per 24 hours for up to days Remove the patch a minimum of 24 hours after chemotherapy It may be worn for up to days Cost for three 8-mg tablets Cost for mg Cost for one 125-mg capsule and two 80-mg capsules In both trials, complete response rates (no emesis and no use of rescue medication) were significantly higher with netupitant plus palonosetron than with palonosetron alone (see Table 2) Another study in 413 patients undergoing moderately or highly emetogenic chemotherapy found that complete response rates with netupitant/palonosetron were maintained over multiple cycles of chemotherapy and appeared to be similar to those achieved with aprepitant/palonosetron.8 ADVERSE EFFECTS — The most common adverse effects of netupitant/palonosetron (occurring in ≥3% of patients) were headache, asthenia, dyspepsia, fatigue, constipation, and erythema Serotonin syndrome has been reported with use of 5-HT3 receptor antagonists Elevations in liver enzymes and total bilirubin have occurred rarely PREGNANCY – Akynzeo is classified as category C (embryofetal toxicity in animals; no adequate studies in women) for use during pregnancy 62 DRUG INTERACTIONS — Netupitant is a moderate inhibitor of CYP3A4 and can increase serum concentrations of drugs that are substrates of CYP3A4, such as dexamethasone, midazolam, and some chemotherapy agents As with aprepitant, a lower dose of dexamethasone should be used in combination with netupitant/palonosetron Netupitant is a substrate of CYP3A4; concurrent use with CYP3A4 inducers, such as rifampin, should be avoided.9 Serotonin syndrome has been reported with concurrent use of 5-HT3 receptor antagonists and other serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) DOSAGE AND ADMINISTRATION — The recommended dosage of Akynzeo is one capsule (netupitant 300 mg/palonosetron 0.5 mg) approximately hour before the start of chemotherapy Patients receiving highly emetogenic chemotherapy should also take oral dexamethasone 12 mg 30 minutes before chemo- The Medical Letter ® Table Emetogenicity of Some IV Chemotherapy Drugs1,2 Highly Emetogenic Drugs Carmustine (BiCNU) Cisplatin (Platinol)3 Cyclophosphamide4 (Cytoxan)3 Dacarbazine (DTIC-Dome)3 Moderately Emetogenic Drugs Azacitidine (Vidaza)3 Alemtuzumab (Campath) Bendamustine (Treanda) Carboplatin (Paraplatin)3 Clofarabine (Clolar) Cyclophosphamide4 (Cytoxan)3 Cytarabine6 (Cytosar-U)3 Dactinomycin (Cosmegen)3 Mechlorethamine (Mustargen) Streptozocin (Zanosar) Daunorubicin5 (Cerubidine)3 Doxorubicin5 (Adriamycin)3 Epirubicin5 (Ellence)3 Idarubicin5 (Idamycin)3 Ifosfamide (Ifex)3 Irinotecan (Camptosar)3 Oxaliplatin (Eloxatin)3 Mildly Emetogenic Drugs Bortezomib (Velcade) Cabazitaxel (Jevtana Kit) Cytarabine6 (Cytosar-U)3 Docetaxel (Taxotere)3 Doxorubicin, liposomal (Doxil)3 Etoposide (Vepesid)3 Fluorouracil (Adrucil)3 Gemcitabine (Gemzar)3 Ixabepilone (Ixempra Kit) Methotrexate (Folex)3 Mitomycin (Mutamycin)3 Mitoxantrone (Novantrone)3 Paclitaxel (Taxol)3 Panitumumab (Vectibix) Pemetrexed (Alimta) Temsirolimus (Torisel) Topotecan (Hycamtin)3 Trastuzumab (Herceptin) E Basch et al J Clin Oncol 2011; 29:4189; F Roila et al Ann Oncol 2010; 21:v232 Antineoplastics are often given in combination Dose, route, and schedule of administration also affect the incidence and intensity of nausea and vomiting Available generically Doses of cyclophosphamide ≥1500 mg/m2 are classified as highly emetogenic and doses 1000 mg/m2 are classified as moderately emetogenic and doses ≤1000 mg/m2 are classified as mildly emetogenic therapy on day and mg once daily on days 2-4 Patients receiving moderately emetogenic chemotherapy should take oral dexamethasone 12 mg 30 minutes before chemotherapy on day CONCLUSION — The oral fixed-dose combination of netupitant and palonosetron (Akynzeo) is more effective than oral palonosetron alone and appears to be similar to the currently recommended regimen of aprepitant plus a 5-HT3 receptor antagonist for prevention of acute and delayed nausea and vomiting in adult patients undergoing highly and moderately emetogenic chemotherapy ■ Palonosetron (Aloxi) for prevention of nausea and vomiting due to cancer chemotherapy Med Lett Drugs Ther 2004; 46:27 Aprepitant (Emend) for prevention of nausea and vomiting due to cancer chemotherapy Med Lett Drugs Ther 2003; 45:62 E Basch et al Antiemetics: American Society of Clinical Oncology clinical practice guideline update J Clin Oncol 2011; 29:4189 F Roila et al Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting: results of the Perugia consensus conference Ann Oncol 2010; 21 (suppl 5):v232 C Rojas et al Molecular mechanisms of 5-HT3 and NK1 receptor antagonists in prevention of emesis Eur J Pharmacol 2014; 722:26 PJ Hesketh et al Efficacy and safety of NEPA, an oral Vol 57 (1467) April 27, 2015 combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy: a randomized dose-ranging pivotal study Ann Oncol 2014; 25:1340 M Aapro et al A randomized phase III study evaluating the efficacy and safety of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapyinduced nausea and vomiting following moderately emetogenic chemotherapy Ann Oncol 2014; 25:1328 RJ Gralla et al A phase III study evaluating the safety and efficacy of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting over repeated cycles of chemotherapy Ann Oncol 2014; 25:1333 Inhibitors and inducers of CYP enzymes and P-glycoprotein Med Lett Drugs Ther 2013; 55:e44 ▶ Umeclidinium (Incruse Ellipta) for COPD The FDA has approved Incruse Ellipta (GSK), a single-agent inhaler containing the long-acting anticholinergic umeclidinium, for once-daily maintenance treatment of chronic obstructive pulmonary disease (COPD) Umeclidinium was initially approved in combination with the long-acting beta2-adrenergic agonist vilanterol as Anoro Ellipta.1 Pronunciation Key Umeclidinium: ue mek" li din' ee um Incruse Ellipta: in' cruise ee lip' ta MAINTENANCE TREATMENT — In patients with moderate to severe COPD, regular treatment with an inhaled long-acting bronchodilator (a beta2agonist or an anticholinergic) can relieve symptoms, improve lung function, and reduce the frequency of exacerbations A combination of a beta2-agonist and an anticholinergic can be used for patients inadequately controlled on a single agent.2 CLINICAL STUDIES — In a 12-week, double-blind trial, 206 patients with moderate to very severe COPD were randomized to receive once-daily umeclidinium 62.5 mcg or 125 mcg, or placebo After 12 weeks, the mean improvement in trough forced expiratory volume in second (FEV1) from baseline was Table Pharmacology Class Anticholinergic Formulation Dry powder inhaler containing 30 doses Route Oral inhalation Tmax 5-15 minutes Metabolism Primarily by CYP2D6 Elimination 92% (feces),