New Medications:
Recent Releases, Updates,
and Coming Attractions
Sunny Linnebur, Pharm.D., FCCP, BCPS, CGP Associate Professor
Joseph P. Vande Griend, PharmD, BCPS, CGP Assistant Professor
Department of Clinical Pharmacy University of Colorado
Skaggs School of Pharmacy and Pharmaceutical Sciences
Objectives
1. Identify new medications approved in the last year that may be useful in the clinical care of older adults
2. Identify characteristics, such as dosing,
pharmacokinetics, side effects, and monitoring that may require special attention in older adults 3. Recognize patients who may be candidates for
these medications, taking into consideration other patient characteristics
4. Describe indication updates to medications already on the market
New Drugs
• Rivaroxaban (Xarelto®) – VTE treatment • Mirabegron (Myrbetriq®) 9Overactive bladder • Tafluprost (Zioptan®) 9Glaucoma • Avanafil (Stendra®) 9Erectile dysfunction • Aclidinium bromide (Tudorza Pressair®) 9COPD • Apixaban (Eliquis®) 9Non-Valvular A-Fib • Quick update on Combivent® and Cymbalta®Rivaroxaban (Xarelto®)
Rivaroxaban (Xarelto®)
• FDA-approved for treatment of acute VTE
and reduction in the risk of recurrence of
VTE (11/2/12)
– Previous approvals: DVT ppx with knee & hip replacement (7/11) and atrial fibrillation (11/11)
• Manufacturer
– Janssen Pharmaceuticals
• Mechanism of Action
– Orally bioavailable factor Xa inhibitor that selectively blocks the active site of factor Xa
Rivaroxaban (Xarelto®)
• Approved dosing for VTE tx
– Acute treatment:
• 15mg BID with food for the first 21 days, then • 20mg daily with food for remaining treatment
– Long-term treatment:
• 20mg daily with food
• Avoid use in patients with a CrCl <30 mL/min
– No renal dosing recommended
– Afib renal dosing for CrCl 15-50 mL/min = 15mg daily
Rivaroxaban (Xarelto®)
• Antidote
– No reversal agent available – Potential for prothrombin
complex concentrate – Absorption maxed at 50mg
• Monitoring
– Bleeding, renal function
• Black Box Warning
– Discontinuation in A-fib – Spinal/epidural hematoma
• Side effects
– Bleeding• Drug interactions
– CYP3A4 inducers/inhibitors• Cost
– Currently covered under several formularies
– $270 monthly
Rivaroxaban (Xarelto®)
Clinical Trials: EINSTEIN studies (DVT/PE)
• Open label, noninferiority trials for 3-12 months– Rivaroxaban 15mg BID X3wks, then 20mg daily – OR Enoxaparin 1mg/kg BID + vit K antagonist
• Goal INR = 2-3 (in range ≈60%)
• Inclusion/exclusion
– DVT study: Acute proximal DVT without PE – PE study: Acute PE with/without DVT – Excluded: those receiving >48 hrs of
heparin/LMWH or >1 dose of warfarin; CrCl< 30 ml/min, liver dz, treatment with CYP3A4
inhibitor/inducer, others
Rivaroxaban (Xarelto®)
Clinical Trials: EINSTEIN studies (DVT/PE)
DVT study • 3449 pts
– Mean age 56 yrs – Cause: unprovoked 61% – Hx previous VTE: 19% – CrCl 30-49: 7%
PE study • 4562 pts
– Mean age 58 yrs – Cause: unprovoked 64% – Hx previous VTE: 19% – CrCl 30-49: 8%
NEJM 2010;363:2499-510 (DVT/Extension); NEJM 2012;366:1287-97 (PE)
1° Efficacy endpoint: Symptomatic recurrent VTE
1° Safety endpoint: Clinically relevant bleeding (major or clinically relevant non-major bleeding)
2° endpoint: Net clinical benefit (1° outcome or major bleeding)
Rivaroxaban (Xarelto®)
Clinical Trials: EINSTEIN studies (DVT)
NEJM 2010;363:2499-510 (DVT/Extension); NEJM 2012;366:1287-97 (PE)
HR: 0.68 (CI: 0.44-1.04; p <0.001 for non-inferiority)
Rivaroxaban (Xarelto®)
Clinical Trials: EINSTEIN studies (DVT)
Outcome Rivaroxaban Warfarin Hazard ratio
(95% CI) P-value Events (n) Event rate (%) Events (n) Event rate (%) 1º Outcome 36 2.1 51 3.0 0.68 (0.44-1.04) <0.001 1º Safety 139 8.1 138 8.1 0.97 (0.76-1.22) 0.77 Major bleeding 14 0.8 20 1.2 0.65 (0.33-1.30) 0.21 Clinically relevant non-major 126 7.3 119 7.0
Net Clinical Benefit 51 2.9 73 4.2 0.67 (0.47-0.95) 0.03
NEJM 2010;363:2499-510 (DVT/Extension); NEJM 2012;366:1287-97 (PE) Treatment duration: 3mo (12%), 6mo (63%), 12mo (25%)
Rivaroxaban (Xarelto®)
Clinical Trials: EINSTEIN studies (PE)
NEJM 2010;363:2499-510 (DVT/Extension); NEJM 2012;366:1287-97 (PE)
Rivaroxaban (Xarelto®)
Clinical Trials: EINSTEIN studies (PE)
Outcome Rivaroxaban Warfarin Hazard ratio
(95% CI) P-value Events (n) Event rate (%) Events (n) Event rate (%) 1º Outcome 50 2.1 44 1.8 1.12 (0.75-1.68) 0.003 1º Safety 249 10.3 274 11.4 0.90 (0.76-1.07) 0.23 Major bleeding 26 1.1 52 2.2 0.49 (0.31-0.79) 0.003 Intracranial 3 <0.1 12 0.4 Clinically relevant non-major 228 9.5 235 9.8
Net Clinical Benefit 83 3.4 96 4.0 0.85 (0.63-1.14) 0.28
NEJM 2010;363:2499-510 (DVT/Extension); NEJM 2012;366:1287-97 (PE) Treatment duration: 3mo (5%), 6mo (57%), 12mo (37%)
Rivaroxaban (Xarelto®)
Clinical Trial: EINSTEIN-Extension
• Double-blind, superiority trial for 6-12 months – Rivaroxaban 20mg daily
– OR Placebo • Inclusion/exclusion
– History of symptomatic DVT or PE
– Completed 6-12 mo treatment for acute event
• Vit K antagonist or rivaroxaban
– Excluded: CrCl < 30 ml/min, liver dz, treatment with CYP3A4 inhibitor/inducer, others
NEJM 2010;363:2499-510 (DVT/Extension)
Rivaroxaban (Xarelto®)
Clinical Trial: EINSTEIN-Extension
• 1197 patients– Mean age 58 yrs
– Initial diagnosis: DVT 64%, PE 36%--mainly unprovoked – Time since sx onset: median 6.8 months
– Previous VTE: 18% – CrCl 30-49 mL/min: 6%
• 1° Efficacy endpoint: Symptomatic recurrent VTE • 2° endpoint: Net clinical benefit (1° outcome or
major bleeding)
NEJM 2010;363:2499-510 (DVT/Extension)
Rivaroxaban (Xarelto®)
Clinical Trial: EINSTEIN-Extension
NEJM 2010;363:2499-510 (DVT/Extension)
Rivaroxaban (Xarelto®)
Clinical Trial: EINSTEIN-Extension
NEJM 2010;363:2499-510 (DVT/Extension)
Outcome Rivaroxaban Placebo Hazard ratio
(95% CI) P-value Events (n) Event rate (%) Events (n) Event rate (%) 1º Outcome 8 1.3 42 7.1 0.18 (0.09-0.39) <0.001 1º Safety 36 6 7 1.2 5.19 (2.3-11.7) <0.001 Major bleeding 4 0.7 0 0 NA 0.11 Clinically relevant non-major 32 5.4 7 1.2
Treatment duration: 6mo (60%), 12mo (40%)
Where does Xarelto® fit for VTE tx?
• Only alternative to warfarin for VTE tx – Oral, effective, no monitoring, expensive – Similar bleeding to warfarin – no reversal
– Unable to compare long-term therapy to warfarin – Tx of recurrent events not really studied
• Rivaroxaban in older adults – Likely good alternative for:
• Those unable to take warfarin due to inability to comply with INR monitoring
• Before considering IVC filter
– Limited to those with CrCl >30mL/min
– No renal dosing for those with CrCl 30-50 mL/min – Consider patient’s insurance coverage—may be
cheaper than getting INRs
Mirabegron (Myrbetriq®)
Mirabegron (Myrbetriq®)
• FDA-approved for treatment of OAB with
symptoms of urge UI, urgency, & urinary
frequency (6/28/12)
• Manufacturer: Astellas Pharma
• Mechanism of action
–Β3 adrenergic activation relaxes the detrusor muscle during the storage phase to increase bladder capacity
Mirabegron (Myrbetriq®)
• Approved dosing
– Initial dose: 25 mg once daily – Can be increased to 50 mg/d
– Dose adjustment: max 25 mg/d if CrCl 15-29 mL/min or moderate hepatic impairment – Not recommended in ESRD or severe hepatic
impairment
• Pharmacokinetics
– Metabolism: multiple pathways
– 6-12% of unchanged drug renally eliminated – t ½ ≈ 50 hours
Mirabegron (Myrbetriq®)
• Warnings and Precautions – BP increase: B-1
adrenergic activity occurs at 200mg • ≈3 pt↑ in SBP w/50mg – Potential worsening of urinary retention • Patients with BPH or taking antimuscarinics • Side effects: HTN (11%), UTI (4%), HA (3%), nasopharyngitis (4%) • Cost: $ 244/mo • Drug interactions – Moderate inhibitor of CYP2D6
– Dose adjustment may be necessary for narrow therapeutic index drugs that rely on CYP2D6 (e.g. thioridazine, flecanide, propafenone) – Digoxin: use lowest
dose of digoxin and monitor serum concentrations
Mirabegron (Myrbetriq®)
• Three 12-week, DB, PBO-controlled studies
– 2736 patients
• Mean age 59 yrs (range 18-95)
– Studied 25mg, 50mg, and 100mg once daily
• Most took 50mg daily
– Modest, but significant reductions in
incontinence episodes per 24h, micturitions per 24h, volume voided compared to PBO
– No differences in older adults
Mirabegron (Myrbetriq®)
• Head-to-head data: 12 wk DB, RCT
– 4 treatment arms: • Mirabegron 50mg • Mirabegron 100mg • Tolterodine ER 4mg/d • Placebo – 1987 patients• Mean age 59 yrs • ≥65 yrs: 37% • ≥75 yrs: 9%
Mirabegron (Myrbetriq®)
Adjusted Mean
Δ
in Incontinence/24h
Eur Urol 2013;63:283-295
Mirabegron (Myrbetriq®)
Adjusted Mean
Δ
in Micturitions/24h
Eur Urol 2013;63:283-295
Where does Myrbetriq® fit for OAB?
• Alternative to traditional antimuscarinic tx
– Similar efficacy– Different side effect profile
• Mirabegron in older adults
– Likely well tolerated unless uncontrolled BP/HR – Renal dosing: max 25 mg/d
– Consider patient’s insurance coverage
Tafluprost (Zioptan®)
• FDA-approved 2/10/12
• Tafluprost 0.0015%
• Indicated for ocular HTN or POAG
– Same MOA as other PG analogs – Dose: one drop each evening
• Benefit over other products
– Preservative-free formulation – Potentially less dryness/irritation – Single use containers—pkg #30 or #90
• Storage: in refrigerator until the foil pack is
opened, then good for 28 days
Avanafil (Stendra®)
• FDA-approved 4/27/12
• Indicated for erectile dysfunction
– PDE-5 inhibitor
– Starting dose: 100mg PRN
• Available in 50mg, 100mg, 200mg
• No advantage over other PDE-5 inhibitors
– Same PK as sildenafil/vardenafil – Similar DIs/CIs, except:
• Nitrates CI within 48 hours
• >3 EtOH drinks increases hypotension risk
• Label contains warnings about use in patients with CVD
Aclidinium bromide
(Tudorza Pressair™)
Aclidinium (Tudorza Pressair™)
• FDA-approved for the long-term maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. (July 23, 2012) • Manufacturer
– Forest Pharmaceuticals, Inc.
• Mechanism of Action
– Long-acting anti-muscarinic agent with similar affinity to the M1 to M5 subtypes of muscarinic receptors
– In the airways, it exhibits pharmacological effects through inhibition of M3 receptor
Aclidinium (Tudorza Pressair™)
• Approved dosing
– COPD:
• 400mcg inhaled twice daily ÆNo dosage adjustments • Inhalation powder: the multi-dose device is a dry
powder inhaler metering 400 mcg of aclidinium bromide per actuation
Warnings and Precautions
• Contraindications:None• Warnings and Precautions
– Potential worsening of narrow angle glaucoma – Potential worsening of urinary retention
• Absolute bioavailability of ~ 6% in healthy adults
• Use as indicated by guidelines; educate patients and monitor, especially in BPH/LUTS
• Drug interactions
– Limited potential for CYP450 Interactions Æno studies
• Side effects:
• Cost: currently covered under Tricare
Administration via Pressair™
• Breathe in until you hear a “click” sound. Keep breathing in, even after you have heard the inhaler “click” to be sure you get the full dose.
Aclidinium (Tudorza™)
Clinical Trials
• Change in trough FEV1from baseline
Eur Respir J 2012; 40: 830–836.
# p < 0.001 vs. placebo
Aclidinium (Tudorza™)
Aclidinium vs. Placebo vs. Tiotropium
• Double-blind, placebo- and active-controlled crossover clinical study with three 15-day treatment periods, separated by a 9- to 15-day washout
– Aclidinium 400 mcg BID vs. Tiotropium 18 mcg daily
• Inclusion (n = 27 patients completed) – Moderate-Severe COPD
• Clinical diagnosis of COPD, aged 40 years or older, FEV1/FVC ratio of < 70% with FEV1of 30%-80% predicted, current or ex-smokers
Aclidinium (Tudorza™)
Aclidinium vs. Placebo vs. Tiotropium
CHEST. 2012; 141(3):745–752
• Statistically different between Aclidinium/Tiotropium vs. Placebo • No clinical differences (e.g. rescue med use) between Aclidinium
and Tiotropium
Where does Tudorza™ fit?
• Alternative to tiotropium
• Limited clinical evidence, no head-to-head clinical comparison to other long-acting bronchodilators
• At this point, Aclidinium (Tudorza™) would only be preferred if cost was substantially less
Apixaban (Eliquis™)
• FDA-approved to reduce the risk of stroke and systemic embolism in non-valvular atrial fibrillation (December 28, 2012)
• Manufacturer
– Bristol-Myers Squibb
• Mechanism of Action
– Oral, reversible, and selective active site inhibitor of factor Xa
Apixaban (Eliquis™)
• Approved dosing for non-valvular a-fib
–
5mg orally twice daily
–
2.5mg orally twice daily
for patients with at
least 2 of the following characteristics:
• Age > 80 years • Body weight < 60 kg
Apixaban (Eliquis™)
• Approved dosing for non-valvular a-fib
–2.5mg orally twice dailyfor patients who are
taking strong dual inhibitorsof CYP3A4 and P-gp
• e.g. ketoconazole, itraconazole, ritonavir, clarithromycin
• Do not use with these drugs if already on 2.5mg twice daily because of age, weight, or renal function
–Avoidapixaban with strong dual inducersof
CYP3A4 and P-gp due to reduced drug exposure
• e.g. rifampin, CBZ, PHT, St. John’s Wort
Apixaban (Eliquis™)
• Antidote
– No reversal agent available
• Monitoring
– Weight, bleeding, renal function
• Black Box Warning
– Discontinuing in patientswithout adequate
continuous anticoagulation increases the risk of stroke
• Side effects
– Bleeding• Warnings/Precaution
– Use not recommended inpatients with heart valves
• Cost
Apixaban (Eliquis™)
Clinical Trials: Aristotle
• Noninferiority trial for median of 1.8 years
– 5mg twice daily or 2.5mg twice daily for those with 2 of the following: age > 80; weight < 60kg; SrCr > 1.5 mg/dL – Warfarin adjusted to INR 2-3 (TTR = 62%)
• Inclusion/exclusion
– Non-valvular a-fib with intermediate risk (mean CHADS2= 2.1)
• One of the following: age > 75 yrs, previous stroke/TIA, systemic embolism, LVEF < 35%, heart failure, diabetes, or HTN requiring treatment – Excluded: conditions requiring warfarin (e.g. prostetic
heart valve, aspirin > 165 mg/d, SrCr > 2.5 mg/dL, or calculated CrCl < 25 mL/min
NEJM. 2011; 365: 883-890
Apixaban (Eliquis™)
Clinical Trials: Aristotle
• 18,201 patients
– Median age 70 yrs (IQR: 63-76 yrs)
– CHADS2score: 1 (34%); 2 (36%); > 3 (30%) – 20% had previous TIA/stroke/systemic embolism – 31% were using aspirin at baseline
• 1° Efficacy endpoint:
Stroke and systemic embolism• 1° Safety endpoint:
major bleedingApixaban (Eliquis™)
Clinical Trials: Aristotle
NEJM. 2011; 365: 981-992 p < 0.001 for non-inferiority
p = 0.01 for superiority
p < 0.001
Newer anticoagulants vs. Warfarin
Study Dose 1º outcome (% per year)
Major
bleeding All stroke
Hemorrhagic stroke RE-LY (dabigatran) 110mg BID 1.53 vs. 1.69 3.75 vs. 4.13 1.44 vs. 1.57 0.12 vs. 0.38 150mg BID 1.11 vs. 1.69 3.64 vs. 4.13 1.01 vs. 1.57 0.10 vs. 0.38 ROCKET-AF (rivaroxaban) 15 or 20mg daily 1.7 vs. 2.20 3.6 vs. 3.4 2.61 vs. 3.12 0.5 vs. 0.7 ARISTOTLE (apixaban) 2.5 or 5mg BID 1.27 vs. 1.6 2.13 vs. 3.09 1.19 vs. 1.51 0.24 vs. 0.47
Yellow: statistical non-inferiority
Green: statistical superiority
Orange: statistically significant
• Compared to warfarin, overall similar or lower rates in both ischemic stroke and major bleeding, lack of need for monitoring, small reduction in ICH, and less susceptibility to dietary and drug interactions.
NEJM. 2009; 361: 1139-1151. NEJM. 2011; 365: 883-890. NEJM. 2011; 365: 981-992.
Newer Anticoagulant Comparison
Apixaban Rivaroxaban Dabigatran* Mechanism Factor Xa inhibitor Factor Xa inhibitor Direct Thrombin Inhibitor
Approved
indications Non-valvular a-fib
1) Non-valvular a-fib 2) DVT/PE treatment
3) DVT prophylaxis
Non-valvular a-fib
Dosing 2.5 or 5mg BID 10, 15, or 20mg daily 110 or 150mg BID
Elimination 25% renal 33% Renal, 66% Hepatic Renal
Drug interactions
Strong CYP3A4/P-gp inhibitors/inducers
Strong and weak CYP3A4/P-gp inhibitors/inducers
N/A
CHADS2
studied 2.1 3.5 2.1
*Listed on the 2012 Beers list to use caution in those > 75 years or if CrCl < 30 mL/min
Where does Eliquis™ fit?
• Alternative to warfarin, rivaroxaban, and dabigatran for non-valvular a-fib
• Will likely be chosen after rivaroxaban and dabigatran until clinical experience increases • Twice daily dosing with similar drug interactions
and features to rivaroxaban, so minimal advantage over rivaroxaban
Other Tidbits for Your Practice
• Duloxetine (Cymbalta®) FDA-approved forchronic musculoskeletal pain, in addition to all of the other indications
•
Combivent
reformulated to remove CFCs
– New version Combivent Respimat® – Old version gone 7/13
– Brand name only – No propellent
Conclusions
• Rivaroxaban (Xarelto®)
9Only alternative to warfarin for VTE
• Mirabegron (Myrbetriq®)
9New MOA, different SEs
• Apixaban (Eliquis®)
• Tafluprost (Zioptan®)
9Brand, but no preservative
• Avanafil (Stendra®)
9Another option