New Drug Update - Weart ppt.ppt · New Drug Update 2012‐2013 C. Wayne Weart, Pharm D, FASHP, FAPhA, BCPS ... South Carolina College of Pharmacy Professor of Family Medicine Medical

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New Drug Update 2012‐2013

C. Wayne Weart, Pharm D, FASHP, FAPhA, BCPS

Professor of Clinical Pharmacy and Outcome Sciences

South Carolina College of Pharmacy

Professor of Family Medicine

Medical University of South Carolina

Charleston, South Carolina

[email protected]

Faculty Disclaimer

• I am a consultant for Merck in the area of outcomes research.

• I served on a formulary advisory board for BMS and Pfizer for apixabanBMS and Pfizer for apixaban.

Objectives1. Discuss the FDA Warnings and label changes that relate

to medication safety and how this information should be applied in the selection and monitoring of evidence-based pharmacotherapy to achieve better patient related outcomes.

2 Describe the current information concerning newly FDA2. Describe the current information concerning newly FDA approved medications (pharmacology, pharmacokinetics, efficacy and safety data, drug interactions, dosing, monitoring and cost) in the selection of evidence-based pharmacotherapy.

3. Compare and contrast these selected newer agents to the existing therapies and be able to recommend an appropriate medication regimen for a specific patient.

Immunization Update• At its October 2012 meeting, the ACIP voted to recommend

that healthcare personnel administer a dose of Tdap vaccine to pregnant women during each pregnancy—ideally at between 27 and 36 weeks’ gestation—regardless of the woman’s prior history of receiving Tdap.– Reported cases of pertussis have spikedp p p

– Youngest infants are the most vulnerable

– Vaccinating the mother during pregnancy can protect the youngest infants.

– Tdap given at one pregnancy provides insufficient protection for subsequent pregnancies

– Data support the safety of Tdap for pregnant women and their infants

The CDC is expected to publish these recommendations in MMWR 2‐22‐2013

FDA Okays Pneumococcal Vaccine for Older Adults

• December 20, 2011 The FDA approved the pneumococcal 13‐valent conjugate vaccine (manufactured by Wyeth Pharmaceuticals, marketed by Pfizer Inc) for adults aged 50 years and older for the prevention of pneumonia and invasive disease caused by the 13 Streptococcus pneumoniaecaused by the 13 Streptococcus pneumoniaeserotypes contained in the vaccine.

• The move comes on the heels of the November 16, 2011, meeting of the FDA's Vaccines and Related Biologics Advisory Committee, in which the committee voted 14 to 1 in favor of expanding the indication for Prevnar 13 to adults.

FDA Okays Pneumococcal Vaccine for Older Adults

• Until now, Pneumovax 23 from Merck was the only pneumococcal vaccine licensed in the United States for use in adults aged 50 years and older.

• In studies conducted among adults 50 and older in the United States and Europe, Prevnar 13 induced antibody levels that were similar to or higher than the levels induced by Pneumovax 23, the FDA notes.

• The safety of Prevnar 13 was evaluated in about 6,000 people ages 50 and older who received Prevnar 13 and who had and had not previouslyolder who received Prevnar 13 and who had and had not previously received Pneumovax 23. Common adverse reactions reported with Prevnar 13 were pain, redness, and swelling at the injection site, limitation of movement of the injected arm, fatigue, headache, chills, decreased appetite, generalized muscle pain, and joint pain. Similar reactions were observed in those who received Pneumovax 23

• The FDA says an additional trial in 85,000 people aged 65 years and older with no history of receiving Pneumovax 23 is underway to confirm the clinical benefit of Prevnar 13 in the prevention of pneumococcal pneumonia. ACIP is waiting for this data before they review this new FDA approved indication.

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CDC Recommends Immunocompromised Adults Get Prevnar 13 Vaccine

• June 21, 2012 the Centers for Disease Control and Prevention's Advisory Committee on Vaccine Practices voted 14 to 0 that adults "with AIDS, cancer, organ transplants, advanced kidney disease and other immune weakeningdisease and other immune‐weakening conditions" should be given pneumococcal vaccine Prevnar 13, including those "who've already had Pneumovax 23" The panel has not yet decided if "all adults 50 years old and older should get Prevnar 13."

ACIP Recommendations for PCV13 and PPSV23 Use

• Adults with specified immunocompromising conditions who are eligible for pneumococcal vaccine should be vaccinated with PCV13 during their next pneumococcal vaccination opportunity.

• Pneumococcal vaccine‐naïve persons. ACIP recommends that adults aged ≥19 years with immunocompromising conditions, functional or anatomic asplenia, CSF leaks, or cochlear implants, and who have not previously received PCV13 or PPSV23, should receive a dose of PCV13 first, followed by a dose of PPSV23 at least 8 weeks later. Subsequent doses of PPSV23 should follow current PPSV23 recommendations for adults at high risk. Specifically, a second PPSV23 dose is recommended 5 years after the first PPSV23 dose for persons aged 19–64 years with functional or anatomic asplenia and for persons with immunocompromising conditions. Additionally, those who received PPSV23 before age 65 years for any indication should receive another dose of the vaccine at age 65 years, or later if at least 5 years have elapsed since their previous PPSV23 dose.

– MMWR October 12, 2012 / 61(40);816‐819

ACIP Recommendations for PCV13 and PPSV23 Use

• Previous vaccination with PPSV23. Adults aged ≥19 years with immunocompromising conditions, functional or anatomic asplenia, CSF leaks, or cochlear implants, who previously have received ≥1 doses of PPSV23 should be given a PCV13 dose ≥1 year after the last PPSV23 dose was received. For those who require additional doses of PPSV23, the first such dose should be given no sooner than 8 weeks after PCV13 and at least 5 years after the most recent dose of PPSV23. – MMWR October 12, 2012 / 61(40);816‐819

Immunization Update

• For children age 6 through 18yrs with functional or anatomic asplenia (including sickle cell disease), HIV infection or other immunocompromising condition, cochlear i l CSF l k id i i 1 d fimplant, or CSF leak, consider giving 1 dose of PCV13 regardless of previous history of PCV7 or PPSV.

• The FDA has approved PCV 13 for children ages 6‐17 (12/2012)

Influenza Vaccine in Patients with Egg Allergy?

• The American College of Allergy, Asthma and Immunology "The very low risk of reacting to the injection is greatly outweighed by the risks associated with the flu."

• ACAAI recommends that those with a previous history of egg allergy get the injectable vaccine in a medical facility whereallergy get the injectable vaccine in a medical facility where any allergic emergencies can be recognized and treated if they occur. For those who have had serious reactions after eating eggs, the vaccine should be administered in an allergist's office.

• In the past, there was concern that because the flu vaccine is grown in eggs, residual protein could trigger a reaction in those with allergies.

Influenza Vaccine in Patients with Egg Allergy?

• June 21, 2012 The ACIP meeting marked the 1‐year anniversary of a change in recommendations that removed egg allergy as a contraindication to influenza vaccinationa contraindication to influenza vaccination, and it does not appear that the modification affected the rate of allergic reactions, according to data from the Vaccine Adverse Event Reporting System (VAERS).

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Influenza Vaccines for 2013‐14• Influenza formulation changes for the 2013‐2014 vaccine have been announced. Trivalent vaccine (IIV3) will cover: – A/California/7/2009 (H1N1)‐like virus; (H3N2) virus antigenically like the cell‐propagatedvirus antigenically like the cell propagated prototype virus A/Victoria/361/2011; and B/Massachusetts/2/2012‐like virus.

• Quadrivalent vaccine (IIV4) will also include additional B virus coverage: – B/Brisbane/60/2008‐like virus– Note that the FDA must first approve any changes before they can be made

Recently‐FDA approved Influenza Vaccines for 2013‐14 Season

• Quadrivalent Live‐attenuated Influenza Vaccine (LAIV4)—Flumist Quadrivalent (MedImmune) age 2‐49 (2 influenza A and 2 influenza B strains)

• Quadrivalent Inactivated Influenza Vaccine (IIV4)—Fluarix Quadrivalent (GSK) age 3 and older and Fluzone Quadrivalent (Sanofi) age 6 mo and older both have (2 influenza A and 2 influenza B strains)

• Cell‐culture based inactivated influenza vaccine (ccIIV3)—Flucelvax (Novartis) age 18 and older

• Recombinant hemagglutinin vaccine (RIV3)—FluBlok (Protein Sciences) age 18‐49

Existing Influenza Vaccines for 2013‐14?

• Fluvirin – II3/TIV by Novartis age 4 yrs and up

• FluLavel – II3/TIV by GSK age 18 yrs and up

• Afluria – II3/TIV by Merck age 9 yrs and up

/• Fluzone High Dose – II3/TIV by Sanofi age 65 and older

• Fluzone Interdermal – II3/TIV by Sanofi age 18 to 64 yrs

FDA approves Flucelvax by Novartis• November 20, 2012 The U.S. Food and Drug Administration

announced today the approval of Flucelvax, the first seasonal influenza vaccine licensed in the United States produced using cultured animal cells, instead of fertilized chicken eggs. Flucelvax is approved to prevent seasonal influenza in people ages 18 years and older.

• The manufacturing process for Flucelvax is similar to the egg‐based production method, the virus strains included in the vaccine are grown in animal cells of mammalian origin instead of in eggs. Cell culture technology has already been in use for several decades to produce other U.S. licensed vaccines (polio, rubella and hepatitis A).

• A “subunit” influenza virus vaccine prepared from virus propagated in Madin Darby Canine Kidney (MDCK) cells.

Flublok by Protein Sciences Corporation• Flublok (Influenza Vaccine) Sterile Solution for Intramuscular

Injection contains purified HA proteins produced in a continuous insect cell line (expresSF+®) that is derived from Sf9 cells of the fall armyworm, Spodoptera frugiperda, and grown in serum‐free medium composed of chemically‐defined lipids, vitamins, amino acids, and mineral salts.p

• Flublok is approved for use in persons 18 through 49 years of age.– For the 2012 ‐ 2013 influenza season it is formulated to contain 135

mcg HA per 0.5 mL dose, with 45 mcg HA of each of the following 3 influenza virus strains: A/California/7/2009 (H1N1), A/Victoria/361/2011 (H3N2), and B/Wisconsin/1/2010. FDA approval 12‐21‐2012

Acetaminophen UpdateJanuary 13, 2011 FDA Drug Safety Communication: Prescription Acetaminophen Products to be Limited to 325 mg Per Dosage Unit ‐ The FDA is asking drug manufacturers to limit the strength of acetaminophen in prescription drug products, which are predominantly combinations of acetaminophen and opioids. This action will limit the amount of acetaminophen in these products to 325 mg per tablet, capsule, or other dosage unit, making these products safer for patients.

• Drug companies will have three years from the date of publication of the Federal Register Notice (January 14, 2011) to limit the amount of acetaminophen in their oral prescription drug products to 325 mg per dosage unit (see the Federal Register Notice2 Docket number FDA‐2011‐N‐0021‐0001).

• In addition, a Boxed Warning highlighting the potential for severe liver injury and a Warning highlighting the potential for allergic reactions (e.g., swelling of the face, mouth, and throat, difficulty breathing, itching, or rash) are being added to the label of all prescription drug products that contain acetaminophen.

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Abbott Announces New Reformulated Vicodin (hydrocodone/acetaminophen)

• May 29, 2012 Abbott is discontinuing manufacturing and distribution of current formulations of Vicodin– Vicodin (hydrocodone bitartrate 5mg /– Vicodin (hydrocodone bitartrate 5mg / acetaminophen 500mg) will be 5mg/300mg

– Vicodin ES (hydrocodone bitartrate 7.5mg / acetaminophen 750mg) will be 7.5mg/300mg

– Vicodin HP (hydrocodone bitartrate 10mg / acetaminophen 660mg) will be 10mg/300mg

New controlled‐release OxyContin• FDA announced April 16, 2013 that it will not approve any

generic versions of the original OxyContin formulation, as the benefits no longer outweigh its risks. The original OxyContin was withdrawn from sale for reasons of safety, as it could be easily misused and abused by crushing and snorting. The original formulation was approved in 1995.

• FDA approved updated labeling for reformulated• FDA approved updated labeling for reformulated oxycodone hydrochloride controlled‐release (OxyContin, Purdue Pharma) tablets. The new labeling indicates that the product has physical and chemical properties that are expected to make misuse and abuse via injection difficult and to reduce abuse via the intranasal route.

• The reformulated product has abuse‐deterrent properties, making it more difficult to crush, break, or dissolve. It also forms a viscous hydrogel and cannot be easily prepared for injection.

Top 10 Meds by PrescriptionsDrug 2008 2009 2010 2011 2012

Hydrocodone/aceta 125.5 129.4 132.1 136.7 135.3

Levothyroxine 98.8 100.2 103.2 104.7 107.5

Lisinopril 77.2 83.0 87.6 88,8 90.8

Simvastatin 68.0 84.1 94.4 96.8 86.1

Metoprolol 79.7 76.9 76.6 76.3 78.1

Amlodipine 46.0 52.1 57.8 62.5 66.0

Omeprazole 35.8 45.6 53.5 59.4 65.5

Metformin 51.6 53.8 57.0 59.1 61.6

Albuterol 50.1 54.5 55.1 56.9 61.5

Atorvastatin 58.5 51.7 45.3 43.3 54.9

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# of Rx’s (30 and 90 day supply) in millions March 22, 2013 by IMS

Aliskiren‐containing Medications: Drug Safety Communication ‐ New Warning and

Contraindication• 4/20/2012 RECOMMENDATION: Concomitant use of aliskiren with ARBs or ACEIs in patients with diabetes is contraindicated because of the risk of renal impairment, hypotension, and hyperkalemia. Avoid use of aliskiren with ARBs or ACEIs in patients with renal impairment where GFR < 60 mL/min. Patients should not stop taking aliskiren without talking to your healthcare professional. Stopping aliskiren suddenly can cause problems if your high blood pressure (hypertension) is not treated.

Dual RAS Inhibition?• A systematic review and meta‐analysis: 33 randomized controlled trials with 68,405 patients (mean age 61 years, 71% men) and mean duration of 52 weeks

• Dual blockade of the renin‐angiotensin system was not associated with any significant benefit for all cause mortality (relative risk 0.97, 95% CI 0.89 to 1.06) and cardiovascular mortality (0.96, 0.88 to 1.05) compared with monotherapy.– BMJ 2013;346:f360

Dual RAS Inhibition?• Compared with monotherapy, dual therapy was associated with an 18% reduction in admissions to hospital for heart failure (0.82, 0.74 to 0.92). However, compared with monotherapy, dual therapy was associated with a 55% increase in the risk of hyperkalaemia (P < 0.001), a 66% increase in the risk of hypotension (P < 0.001), a 41% increase in the risk of renal failure (P = 0.01), and a 27% increase in the risk of withdrawal owing to adverse events (P < 0.001). – BMJ 2013;346:f360

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FDA Safety Update ‐ Zolpidem• Jan 10, 2013 FDA is requiring the manufacturers of certain

immediate‐release zolpidem products (Ambien, Edluar, and Zolpimist) to lower the recommended dose. FDA has informed manufacturers that:

• The recommended initial dose for women should be lowered from 10 mg to 5 mg, immediately before bedtime.

• The drug labeling should recommend that health care professionals consider prescribing a lower dose of 5 mg for men. In many men, the 5 mg dose provides sufficient efficacy.

• The drug labeling should include a statement that, for both men and women, the 5 mg dose could be increased to 10 mg if needed, but the higher dose is more likely to impair next‐morning driving and other activities that require full alertness.

New FDA Approved Label (4/2013)

• “Use the lowest effective dose for the patient. The recommended initial dose is 5 mg for women and either 5 or 10 mg for men, taken only once per night immediately before bedtime with at least 7‐8 hours remaining before the planned time of awakening. If the 5 mg dose is not effective, the dose can be increased to 10 mg. In some patients, the higher morning blood levels following use of the 10 mg dose increase the risk of next day impairment of driving and other activities that require full alertness.”

New FDA Approved Label for Ambien CR (5‐14‐2013)

• “FDA is also warning that patients who take the sleep medication zolpidem extended‐release (Ambien CR)―either 6.25 mg or 12.5 mg―should not drive or engage in othermg should not drive or engage in other activities that require complete mental alertness the day after taking the drug because zolpidem levels can remain high enough the next day to impair these activities.”

Anticholinergic Medications and Mild Cognitive Impairment?

• Older adults using anticholinergic (AC) medications for just 2 months to manage sleep problems, urinary incontinence, and other ailments could be at increased risk of developing mild cognitive impairment (MCI), a new study suggests.

• The association between AC medication use and cognition appears to depend not only on the length of exposure but also on the strength of the p y g p gmedication burden. The study showed that the risk for cognitive impairment was increased by 50% in adults receiving at least 3 mild ACs for more than 90 days and by 100% in those receiving 1 or more severe ACs for more than 60 days.

• The results highlight the importance of limiting prescriptions for ACs in older adults and helps fill some research gaps, said study author Malaz Boustani, MD, associate director, Indiana University Center for Aging Research, Indiana University School of Medicine,

– Alzheimer's & Dementia: The Journal of the Alzheimer's Association published on‐line 11‐26‐2012

FDA Approves Doxylamine and Pyridoxine (Diclegis)

• April 8, 2013 The U.S. Food and Drug Administration today approved Diclegis (doxylamine succinate 10mg and pyridoxine hydrochloride 10mg/tab) to treat pregnant women experiencing nausea and vomiting.

• Diclegis is a delayed‐release tablet intended for women who have not adequately responded to conservative management of nausea and vomiting during pregnancy, such as dietary and lifestyle modifications. These modifications include eating several small meals instead of three large meals, eating bland foods that are low in fat and easy to digest and avoiding smells that can trigger nausea.

• “Diclegis is now the only FDA‐approved treatment for nausea and vomiting due to pregnancy, providing a therapeutic option for pregnant women seeking relief from these symptoms.

Doxylamine and Pyridoxine‐Diclegis• 261 women were randomly assigned to receive two weeks of

treatment with Diclegis or a placebo.

• The primary efficacy endpoint was the change from baseline at Day 15 in the Pregnancy Unique‐Quantification of Emesis (PUQE) score. The PUQE score incorporates the number of daily vomiting episodes, number of daily heaves, and length of daily nausea in hours, for an overall score of symptoms rated from 3 (no symptoms) to 15 (most severe).

– At baseline, the mean PUQE score was 9.0 in the DICLEGIS arm and 8.8 in the placebo arm. There was a 0.7 (95% confidence interval 0.2 to 1.2 with p‐value 0.006) mean decrease (improvement in nausea and vomiting symptoms) from baseline in PUQE score at Day 15 with DICLEGIS compared to placebo

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Doxylamine and Pyridoxine‐Diclegis

• Tablets must be taken whole on an empty stomach. The recommended starting dose is two tablets taken at bedtime. If

t t d t lsymptoms are not adequately controlled, the dose can be increased to a maximum recommended dose of four tablets daily (one in the morning, one mid‐afternoon and two at bedtime).

The cost is $475.00 WACper 100 tablets

Doxylamine and Pyridoxine‐Diclegis• Pregnancy Category A. Doxylamine/pyridoxine is intended for

use in pregnant women.

• The combination of doxylamine succinate and pyridoxine hydrochloride has been the subject of many epidemiological studies (cohort, case control and meta‐analyses) designed to detect possible teratogenicity A meta analysis of 16 cohortdetect possible teratogenicity. A meta‐analysis of 16 cohort and 11 case‐control studies published between 1963 and 1991 reported no increased risk for malformations from first trimester exposures to doxylamine succinate and pyridoxine hydrochloride, with or without dicyclomine hydrochloride. A second meta‐analysis of 12 cohort and 5 case‐control studies published between 1963 and 1985 reported similar results.

Prothrombin Complex Conc. (human) – Kcentra by Behring

• FDA Approved 4‐29‐2013 for reversal of acute bleeding in patients on warfarin

• Contains lyophilized human factors II,VII,IX and X as well as Protein C and S along with 8‐40 U of heparin per 500 units of factor IX per vial

• IV infusion based upon INR and patient weight with dosage based upon factor IX 25‐50 units/Kg

• Also needs to be given with vitamin K to maintain effect to increase the INR

• No data in patients with a history of thromboembolic event(s) in the previous 3 months

Prothrombin Complex Conc. (human) – Kcentra

• May cause arterial or venous thrombosis

• More predictable than fresh frozen plasma, faster onset and does not require blood typing prior to use or thawing of the fresh frozen plasma

• Reverses increased INR within 30 minutes and maintained for at least 24 hours

• May need up to 10 x 500 unit vials as the maximum dose is 5,000 units based upon an INR >6 and a patient who weighs 100 Kg or more

• Cost $818.40/500 unit vial WAC

Rivaroxaban – Xarelto by Bayer HealthCare AG and Janssen Pharmaceuticals

Rivaroxaban exhibits a linear pharmacokinetic relationship with a rapid onset of action, resulting in maximal factor Xa inhibition in approximately 3 hours. Maintenance of the anti–factor Xa effect lasted 8 to 12 hours, depending on the dose of rivaroxaban.

Terminal half‐life of rivaroxaban is approximately 9 hours in adults and 12 hours in elderly patients (older than 65 years of age). Elimination of rivaroxaban occurs by multiple routes: renal (one‐third is excreted unchanged), biliary/fecal, and hepatic (through CYP‐450 3A4). Renal function impairment may influence elevated plasma concentrations and increased anti‐Xa activity; therefore, dose adjustments may be required

Rivaroxaban ‐ Xarelto• July 5, 2011 The FDA approved rivaroxaban a factor Xa

inhibitor indicated for the prophylaxis of deep vein thrombosis (DVT) which may lead to pulmonary embolism (PE) in patients undergoing knee or hip replacement.

• The recommended dose of is 10 mg taken orally once daily with or without food. The initial dose should be taken at leastwith or without food. The initial dose should be taken at least 6 to 10 hours after surgery once hemostasis has been established.

– For patients undergoing hip replacement surgery, treatment duration of 35 days is recommended.

– For patients undergoing knee replacement surgery, treatment duration of 12 days is recommended.

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ROCKET‐AF Trial • The ROCKET AF study was a multicenter, double‐blind, randomized trial of once‐daily oral rivaroxaban 20 mg or 15 mg daily in patients with a creatinine clearance of 30 to 49 ml per minute) compared with dose‐adjusted warfarin (INR 2‐3) in moderate‐to‐high risk patients with nonvalvular AF The authorshigh‐risk patients with nonvalvular AF. The authors hypothesized that rivaroxaban is noninferior to warfarin at preventing the composite of stroke (ischemic and hemorrhagic) and systemic embolism. The 14,264 enrolled patients (median age, 73; 40% women) had a mean CHADS2 score of 3.5; about half had a CHADS2 score of 4.– N Engl J Med 2011;365:883‐91.

ROCKET‐AF Trial Outcome

Rivaroxaban(n=7081)

Warfarin(n=7090)

Hazard ratio(95% CI) p

Primary end point,noninferiority

1.71 2.16 0.79 (0.66‐0.96)NNT 222

<0.001

Primary end point, ontreatment superiority

1.70 2.15 0.79 (0.65‐0.95) 0.015

Primary end point,i i

2.12 2.42 0.88 (0.74‐1.03) 0.117

N Egl J Med 2011;365:883‐91.

intention‐to‐treat superiority

Vascular death, stroke, embolism

3.11 3.63 0.86 (0.74‐0.99)NNT 193

0.034

Hemorrhagic stroke 0.26 0.44 0.59 (0.37‐0.93)NNT 556

0.024

Ischemic stroke 1.34 1.42 0.94 (0.75‐1.17) 0.581

Unknown stroke 0.06 0.10 0.65 (0.25‐1.67) 0.366

ROCKET‐AF Trial Outcome

Rivaroxaban(n=7081)

Warfarin(n=7090)

Hazard ratio(95% CI) p

Major and nonmajorbleeding

14.91 14.52 1.03 (0.96‐1.11) 0.442

Major bleeding 3.60 3.45 1.04 (0.90‐1.20) 0.576

>2 g/dL hemoglobin d

2.77 2.26 1.22 (1.03‐1.44)NNH 197

0.019

N Engl J Med 2011;365:883‐91.

drop NNH 197

Transfusion 1.65 1.32 1.25 (1.01‐1.55)NNH 304

0.044

Critical organbleeding

0.82 1.18 0.69 (0.53‐0.91)NNT 278

0.007

Bleeding causingdeath

0.24 0.48 0.50 (0.31‐0.79)NNT 455

0.003

Intracranial hemorrhage

0.49 0.74 0.67 (0.47‐0.94)NNT 400

0.019

Rivaroxaban ‐ Xarelto• Nonvalvular Atrial Fibrillation:

– For patients with CrCl >50 mL/min: 20 mg orally, once daily with the evening meal

– For patients with CrCl 15 ‐ 50 mL/min: 15 mg orally, once daily with the evening mealy, y g

– Avoid use in patients with CrCl <15 mL/min• The absolute bioavailability of rivaroxaban at a dose of 20 mg in the fasted state is approximately 66%. Coadministration of XARELTO with food increases the bioavailability of the 20 mg dose (mean AUC and Cmax increasing by 39% and 76% respectively with food). XARELTO 15 mg and 20 mg tablets should be taken with the evening meal

Rivaroxaban ‐ Xarelto• Box Warning: “Discontinuing XARELTO places patients at an increased risk of thrombotic events. An increased rate of stroke was observed following XARELTO discontinuation in clinical trials in atrial fibrillation patients. If anticoagulation with XARELTO must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant”– Rocket AF did not have a protocol for what to do after the trial ended and the results were not good

Switching Anticoagulants?

• Switching to XARELTO® from warfarin– Discontinue warfarin and start XARELTO® as soon as the INR is below 3.0 to avoid periods of inadequate anticoagulation

• Switching from XARELTO® to warfarin– No clinical trial data are available to guide converting patients from XARELTO® to warfarin. XARELTO® affects INR, so INR measurements made during coadministration with warfarin may not be useful for determining the appropriate dose of warfarin. One approach is to discontinue XARELTO® and begin both a parenteral anticoagulant and warfarin at the time the next dose of XARELTO® would have been taken

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Rivaroxaban ‐ Xarelto

• AHA/ASA advisory on stroke prevention in atrial fibrillation (Stroke 2012; DOI:10.1161/STR.0b013e318266722a. Available at: http://stroke.ahajournals.org)– In patients with nonvalvular AF who are at moderate to high risk of

stroke (prior history of transient ischemic attack [TIA], stroke, or systemic embolization or more than two additional risk factors)systemic embolization or more than two additional risk factors), rivaroxaban 20 mg/day "is reasonable" as an alternative to warfarin.

– In patients with renal impairment and nonvalvular AF who are at moderate to high risk of stroke (prior history of TIA, stroke, or systemic embolization or more than two additional risk factors), with a CrCl of 15 to 50 mL/min, 15 mg of rivaroxaban daily may be considered, but its safety and efficacy have not been established. Rivaroxaban should not be used if the CrCl is <15 mL/min.

* Intent to treat population N Engl J Med 2010;363:2499‐510.

EINSTEIN DVT TrialEndpoint Xarelto

N=1731 (%)Enox + WarfN=1718 (%)

HR (95% CI)

Primary composite (DVT or nonfatal or fatal pulmonary embolism

36 (2.1%) 51 (3.0%) 0.68 (0.44‐1.04)

Death (PE) 1 (<0.1%) 0 (0%)( ) ( ) ( )

Death (PE can not be excluded) 3 (0.2%) 6 (0.3%)

Symptomatic recurrent PE + DVT 1 (<0.1%) 0 (0%)

Symptomatic recurrent PE only 20 (1.2%) 18 (1.0%)

Symptomatic recurrent DVT only 14 (0.8%) 28 (1.6%)

Intent to treat populationN Engl J Med 2010;363:2499‐510.

Rivaroxaban for Symptomatic VenousThromboembolism: Einstein DVT

• In parallel, we carried out a double‐blind, randomized, event‐driven superiority study that compared rivaroxaban alone (20 mg once daily) with placebo for an additional 6 or 12 months in patients who had completed 6 to 12 months of treatment for venous thromboembolismthromboembolism.

• In the continued‐treatment study, which included 602 patients in the rivaroxaban group and 594 in the placebo group, rivaroxaban had superior efficacy (8 events [1.3%], vs. 42 with placebo [7.1%]; hazard ratio, 0.18; 95% CI, 0.09 to 0.39; P<0.001). Extended prophylaxis may be appropriate?

N Engl J Med 2010;363:2499‐510

EINSTEIN PE TrialEndpoint Xarelto

N=2419 (%)Enox + WarfN=2413 (%)

HR (95% CI)

Primary composite endpoint 50 (2.1%) 44 (1.8%) 1.12 (0.75‐1.68)

Death (PE) 3 (0.1%) 1 (<0.1%)

Death (PE cannot be excluded) 8 (0 3%) 6 (0 2%)Death (PE cannot be excluded) 8 (0.3%) 6 (0.2%)

Symptomatic recurrent PE + DVT

0 (0%) 2 (<0.1%)

Symptomatic recurrent PE only 23 (1.0%) 20 (0.8%)

Symptomatic recurrent DVT only

18 (0.7%) 17 (0.7%)

Intent to treat population

N Engl J Med 2012; 366:1287‐1297N Engl J Med 2012; 366:1287‐129

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Rivaroxaban ‐ Xarelto

• Nov 2, 2012 FDA approval for treatment of DVT and PE based upon EINSTIEN Trials non‐inferior to warfarin (INR 2‐3) and no difference in bleeding rates

• Treatment of DVT PE and Reduction in the Risk ofTreatment of DVT, PE, and Reduction in the Risk of Recurrence of DVT and of PE: 15 mg orally twice daily with food for the first 21 days for the initial treatment of acute DVT or PE. After the initial treatment period, 20 mg orally once daily with food for the remaining treatment and the long‐term reduction in the risk of recurrence of DVT and of PE

Apixaban – Eliquis by BMS/Pfizer• Apixaban is a factor Xa inhibitor anticoagulant indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.– 1‐P priority FDA approval 12‐28‐2012p y pp

– Available as a 2.5 and 5 mg tablet

– ($240.00/60 tabs WAC)

– The recommended dose is 5 mg orally twice daily. In patients with at least 2 of the following characteristics: age > 80 years, body weight <60 kg, or serum creatinine >1.5 mg/dL, the recommended dose is 2.5 mg orally twice daily

– Patients with a serum creatinine of greater than 2.5 mg were excluded in the trials

Apixaban‐Eliquis• Box Warning:”DISCONTINUING ELIQUIS IN PATIENTS WITHOUT ADEQUATE CONTINUOUS ANTICOAGULATION INCREASES RISK OF STROKE”

• Drug Interactions– Strong dual inhibitors of CYP3A4 and P‐gp increase bl d l l f b d b dblood levels of apixaban: Reduce apixaban dose to 2.5 mg or avoid concomitant use

– Simultaneous use of strong inducers of CYP3A4 and P‐gp reduces blood levels of apixaban: Avoid concomitant use

Apixaban ‐ Eliquis• Switching from warfarin to Apixaban: Warfarin should be discontinued and apixaban started when the international normalized ratio (INR) is below 2.0.

• Switching from Apixaban to warfarin: Apixabanaffects INR, so that INR measurements during coadministration with warfarin may not be useful forcoadministration with warfarin may not be useful for determining the appropriate dose of warfarin. If continuous anticoagulation is necessary, discontinue apixaban and begin both a parenteral anticoagulant and warfarin at the time the next dose of apixaban would have been taken, discontinuing the parenteral anticoagulant when INR reaches an acceptable range.

Apixaban 5 mg oral twice dailyApixaban 5 mg oral twice daily

RandomizeRandomizedouble blind, double blind,

double dummydouble dummy(n = 18,201)(n = 18,201)

Inclusion risk factorsInclusion risk factorsAge ≥ 75 years Age ≥ 75 years Prior stroke, TIA or SEPrior stroke, TIA or SEHF or LVEF ≤ 40%HF or LVEF ≤ 40%Diabetes mellitusDiabetes mellitusHypertensionHypertensionMean CHADS 2 Score 2.1Mean CHADS 2 Score 2.1

Inclusion risk factorsInclusion risk factorsAge ≥ 75 years Age ≥ 75 years Prior stroke, TIA or SEPrior stroke, TIA or SEHF or LVEF ≤ 40%HF or LVEF ≤ 40%Diabetes mellitusDiabetes mellitusHypertensionHypertensionMean CHADS 2 Score 2.1Mean CHADS 2 Score 2.1

ExclusionExclusionMechanical prosthetic valveMechanical prosthetic valveSevere renal insufficiencySevere renal insufficiencyNeed for aspirin plus Need for aspirin plus thienopyridinethienopyridine

ExclusionExclusionMechanical prosthetic valveMechanical prosthetic valveSevere renal insufficiencySevere renal insufficiencyNeed for aspirin plus Need for aspirin plus thienopyridinethienopyridine

Atrial Fibrillation with at Least One Additional Risk Factor for Stroke

Warfarin Warfarin (target INR 2(target INR 2--3)3)

Apixaban 5 mg oral twice dailyApixaban 5 mg oral twice daily(2.5 mg BID in selected patients IE. ≥ 80 (2.5 mg BID in selected patients IE. ≥ 80

years, body weight ≤ 60 kg, serum creatinine years, body weight ≤ 60 kg, serum creatinine ≥ 1.5 mg/dL )≥ 1.5 mg/dL )

Primary outcome: stroke or systemic embolismPrimary outcome: stroke or systemic embolism

Hierarchical testing: nonHierarchical testing: non--inferiority for primary outcome, superiority for inferiority for primary outcome, superiority for primary outcome, major bleeding, death primary outcome, major bleeding, death

Warfarin/warfarin placebo adjusted by INR/sham INR based on encrypted point-of-care testing device

N Engl J Med 2011;365:981-92.

Apixaban and Warfarin Dosing

• Apixaban (or matching placebo) was dosed at 5 mg twice daily, or 2.5 mg twice daily for a subset of patients with 2 or more of the following criteria: age ≥ 80 years, body weight ≤ 60 kg, serum creatinine ≥ 1.5 mg/dL (133 µmol/L).

• Warfarin (or matching placebo) was dosed guided by blinded encrypted INR point-of-care device, with target INR of 2.0–3.0.

N Engl J Med 2011;365:981-92

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ARISTOTLE Main Trial Results (Mean 1.8 yrs)

21%21% 31%31%

ISTH major bleedingInternational Society of Thrombosis and Hemostasis

Stroke or systemic embolism

21% 21% RRRRRR

31% 31% RRRRRR

Median TTR 66%

Apixaban 212 patients, 1.27% per year Warfarin 265 patients, 1.60% per yearHR 0.79 (95% CI, 0.66–0.95); P=0.011ARR 0.33% NNT 303

Apixaban 327 patients, 2.13% per year Warfarin 462 patients, 3.09% per yearHR 0.69 (95% CI, 0.60–0.80); P<0.001ARR 0.96% NNT 105

N Engl J Med 2011;365:981-92.

Summary

Treatment with apixaban as compared to warfarin in patients with AF and at least one additional risk factor for stroke:

• Reduces stroke and systemic embolism by 21% (p=0.01) ARR 0.33%/NNT 303

• Reduces major bleeding by 31% (p<0.001) ARR 0.96%/NNT 105

• Reduces mortality by 11% (p=0.047) ARR 0.42%/NNT 238

with consistent effects across all major subgroups and with fewer study drug discontinuations on apixaban than on warfarin, consistent with good tolerability.

N Engl J Med 2011;365:981-92

Apixaban‐Eliquis• AHA/ASA advisory on stroke prevention in atrial fibrillation

(Stroke 2012; DOI:10.1161/STR.0b013e318266722a. Available at: http://stroke.ahajournals.org)– Apixaban 5 mg twice daily is a "relatively safe and efficacious

alternative" to warfarin in patients with nonvalvular AF deemed appropriate for vitamin‐K‐antagonist therapy who have at least one pp p g pyadditional risk factor and no more than one of the following characteristics: age >80 years, weight <60 kg, or serum creatinine >1.5 mg/dL.

– Although its safety and efficacy have not been established, apixaban 2.5 mg twice daily may be considered as an alternative to warfarin in patients with nonvalvular AF deemed appropriate for vitamin‐K‐antagonist therapy who have at least one additional risk factor and more than two of the following criteria: age >80 years, weight <60 kg, or serum creatinine >1.5 mg/dL. Apixaban should not be used if the CrCl is <25 mL/min.

Is the patient a good candidate for a new anticoagulant? (CRABI)

• C => Good prescription coverage?• R => Normal renal function?• A => Are you an early adopter willing to take a new drug with one large trial in AF?new drug with one large trial in AF?

• B => No history of GI bleeding?• I => For patients on warfarin, has there been INR instability requiring frequent dose changes?– Seth D Bilazarian MD, Private practice blog on theheart.org (9/2012)

Ticagrelor – Brilinta by Astra Zeneca

• Indicated to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS) (unstable angina, non‐ST elevation myocardial infarction, or ST elevation myocardial infarction)elevation myocardial infarction).– Shown to reduce the rate of a combined endpoint of cardiovascular death, myocardial infarction, or stroke compared to clopidogrel. The difference between treatments was driven by CV death and MI with no difference in stroke.

– In patients treated with PCI, it also reduces the rate of stent thrombosis.

Mean inhibition of platelet aggregation (±SE) following single oral doses of placebo, 180 mg ticagrelor, or 600

mg clopidogrel

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Ticagrelor ‐ BrilintaEffects of Other Drugs on Ticagrelor• CYP3A4 is the major enzyme responsible for ticagrelor

metabolism and the formation of its major active metabolite.– Strong CYP3A inhibitors (e.g., atazanavir, clarithromycin,

indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole)ritonavir, saquinavir, telithromycin and voriconazole) substantially increase ticagrelor exposure and are not recommended

– Moderate CYP3A inhibitors have lesser effects (e.g., diltiazem and verapamil) and do not require a dosage adjustment

– CYP3A inducers (e.g., rifampin, dexamethasone, phenytoin, carbamazepine, and phenobarbital) substantially reduce ticagrelor blood levels and are not recommended

Ticagrelor – BrilintaN Engl J Med 2009;361:1045‐57

• PLATO Trial, a randomized double‐blind study comparing ticagrelor (180 mg LD then 90 mg BID)(N=9333) to clopidogrel (300mg LD then 75 mg QD) (N=9291), both given in combination with aspirin (75‐100 mg QD but higher doses were allowed per investigator) and other standard therapy, in patients with acute coronary syndromes (ACS) Patients were treated for at least 6syndromes (ACS). Patients were treated for at least 6 months and for up to 12 months.– Patients were predominantly male (72%) and Caucasian (92%).

About 43% of patients were >65 years and 15% were >75 years.– Primary endpoint was the composite of first occurrence of

cardiovascular death, non‐fatal MI (excluding silent MI), or non‐fatal stroke. The components were assessed as secondary endpoints

– Median exposure to study drug was 277 days

Ticagrelor – BrilintaN Engl J Med 2009;361:1045‐57

Endpoint TicagrelorN=9333

Clopidogrel N=9291

Hazard Ratio (95% CI)

P‐value ARR/NNT

Primary Composite (CV death, MI, CVA)

9.8% 11.7% 0.84 (0.77‐0.92)

0.0003 1.9%/53

Secondary Endpoints

CV death 4 0% 5 1% 0 79 0 0013 1 1%/91CV death 4.0% 5.1% 0.79(0.69‐0.91)

0.0013 1.1%/91

MI 5.8% 6.9% 0.84(0.75‐0.95)

0.0045 1.1%/91

Stroke 1.5% 1.3% 1.17(0.91‐1.52)

0.22

All cause mortality 4.5% 5.9% 0.78 (0.69‐0.89)

0.0003 1.4%/72

In‐stent thrombosis (11,289 pts with PCI/stenting)

1.3% 1.9% 0.67(0.50‐0.91)

0.0091 0.6%/167

Ticagrelor – BrilintaN Engl J Med 2009;361:1045‐57.

• No significant difference in the rates of major bleeding was found between the ticagrelor and clopidogrel groups (11.6% and 11.2%, respectively; P = 0.43)

• Ticagrelor was associated with a higher rate of major bleeding not related to coronary‐artery bypass grafting (4 % 3 8% 0 03 A I 0 % NNH 143)(4.5% vs. 3.8%, P = 0.03, ARI = 0.7%, NNH = 143) including more instances of fatal intracranial bleeding and fewer of fatal bleeding of other types.

• In a genetic substudy of PLATO (n=10,285), the effects of ticagrelor compared to clopidogrel on thrombotic events and bleeding were not significantly affected by CYP2C19 genotype.

PLATO: CV Death, MI, Stroke by maintenance aspirin dose in the US and

outside the USTicagrelor – Brilinta

• Dyspnea was usually mild to moderate in intensity and often resolved during continued treatment. If a patient develops new, prolonged, or worsened dyspnea during treatment with ticagrelor, exclude underlying diseases that may require treatment. If dyspnea is determined to be related to ticagrelor, no specific treatment is required; continue ticagrelor without interruption.

• Although the mechanism of dyspnea remains unknown, it appears to be related to adenosine‐mediated stimulation of pulmonary C fibers. We do know that ticagrelor inhibits adenosine uptake by erythrocytes.

• Given the frequency of dyspnea as a side effect, with reports ranging from 6% to 38.6%, it may affect long‐term compliance if the agent is to be used routinely. For clinicians, it could be problematic during the recovery phase of ACS, because the presence of dyspnea could be confused with an angina equivalent, leading to further testing to exclude ischemia only to ascertain that it is produced by the administration of ticagrelor.

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Ticagrelor – BrilintaDOSAGE AND ADMINISTRATION:

• Initiate ticagrelor treatment with a 180 mg (two 90 mg tablets) loading dose and continue treatment with 90 mg twice daily with or without food

• After the initial loading dose of aspirin (usually 325 mg), use ticagrelor with a daily maintenance dose of aspirin of 75‐100 mg (typically 81mg)

COST: $7.24 per day or $217.20 per month WAC

AT‐9 Chest GuidelinesFor patients in the first year after an ACS who have not undergone percutaneous coronary intervention (PCI):• We recommend dual antiplatelet therapy (ticagrelor 90 mg twice daily plus low‐dose aspirin 75 100 mg daily or clopidogrel 75 mg dailyaspirin 75‐100 mg daily or clopidogrel 75 mg daily plus low‐dose aspirin 75‐100 mg daily) over single antiplatelet therapy (Grade 1B).

• We suggest ticagrelor 90 mg daily plus low dose aspirin over clopidogrel 75 mg daily plus low‐dose aspirin (Grade 2B) .– Chest AT‐9 Feb 2012

AT‐9 Chest GuidelinesFor patients in the first year after an ACS who have undergone PCI with stent placement:• We recommend dual antiplatelet therapy (ticagrelor 90 mg

twice daily plus low‐dose aspirin 75‐100 mg daily, clopidogrel 75 mg daily plus low‐dose aspirin, or prasugrel10 mg daily plus low‐dose aspirin over single antiplatelet therapy) (Grade 1B)therapy) (Grade 1B).

• We suggest ticagrelor 90 mg twice daily plus low‐dose aspirin over clopidogrel 75 mg daily plus low‐dose aspirin (Grade 2B). – Evidence suggests that prasugrel results in no benefit or net

harm in patients with a body weight of , <60 kg, age . >75 years, or with a previous stroke/transient ischemic attack.

– Chest AT‐9 Feb 2012

• June 27, 2012 the FDA has approved lorcaserin – Belviq (bel‐veek) by Arena Pharmaceuticals for the treatment of obesity as an adjunct to diet and exercise in patients with a BMI >/= 30 and with a BMI >/= 27 in patients with comorbidities. It will be promoted by Eisai

• Lorcaserin appears to work by stimulating the serotonin 2 C receptor in the hypothalamus and resulting in a feeling of fullness sooner than without the drug.

• The safety and efficacy of lorcaserin were evaluated in three randomized, placebo‐controlled trials that included nearly 8,000 obese and overweight

Lorcaserin – Belviq (C‐IV)

placebo controlled trials that included nearly 8,000 obese and overweight patients, with and without type 2 diabetes, treated for 52 to 104 weeks. All participants received lifestyle modification that consisted of a reduced calorie diet and exercise counseling. Compared with placebo, treatment with lorcaserin for up to one year was associated with average weight loss ranging from 3 percent to 3.7 percent or 5‐6 Kg

• The approved labeling for lorcaserin recommends that the drug be discontinued in patients who fail to lose 5 percent of their body weight after 12 weeks of treatment, as these patients are unlikely to achieve clinically meaningful weight loss with continued treatment.

• Dose 10 mg BID Cost $191.40/60 WAC

Lorcaserin ‐ Belviq Lorcaserin ‐ Belviq• At the approved dose of 10 milligrams twice a day, lorcaserin does not

appear to activate the serotonin 2B receptor and to date has not been associated with heart valve defects.

• The most common side effects of lorcaserin in non‐diabetic patients are headache, dizziness, fatigue, nausea, dry mouth, and constipation, and in diabetic patients are low blood sugar (hypoglycemia), headache, back pain, cough, and fatigue.

• The manufacturer will be required to conduct six post marketing studies, l d l d l l h ffincluding a long‐term cardiovascular outcomes trial to assess the effect

of lorcaserin on the risk for major adverse cardiac events such as heart attack and stroke as well as several trials in pediatric patients.

• The Drug Enforcement Administration has made a final scheduling decision. (C‐IV)– In a human abuse potential study in recreational drug abusers,

supratherapeutic oral doses of lorcaserin (40 and 60 mg) produced up to two‐ to six‐fold increases on measures of “High”, “Good Drug Effects”, “Hallucinations” and “Sedation” compared to placebo. These responses were similar to those produced by oral administration of the positive control drugs, zolpidem (15 and 30 mg). 19% with locaserin vs. 13‐16% with zolpidem.

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Phentermine/Topiramate extended‐release – Qsymia (C‐IV)

• July 17, 2012 the FDA approved the newest weight loss medication Qsymia (Kyoo sim ee’ uh)by Vivus as an addition to a reduced‐calorie diet and exercise for chronic weight management. (Phentermine is indicated for short‐term weight loss in overweight or obese adults who are exercising and eating a reduced calorie diet)exercising and eating a reduced calorie diet)

• The drug is approved for use in adults with a body mass index (BMI) of 30 or greater (obese) or adults with a BMI of 27 or greater (overweight) who have at least one weight‐related condition such as high blood pressure (hypertension), type 2 diabetes, or high cholesterol (dyslipidemia).

• Available as *3.75/23 mg; 7.5/46 mg; *11.25/69 mg and 15/92 mg (phentermine/topiramate) extended release capsules * (these doses are only for titration purposes)

Phentermine/Topiramate extended‐release ‐ Qsymia

Contraindications:• Pregnancy category X ‐ a fetus exposed to topiramate, a

component of Qsymia, in the first trimester of pregnancy has an increased risk of oral clefts (cleft lip with or without cleft palate). Females of reproductive potential must not be pregnant when starting Qsymia therapy or become p g g Q y pypregnant while taking Qsymia. Females of reproductive potential should have a negative pregnancy test before starting Qsymia and every month while using the drug and should use effective contraception consistently while taking Qsymia.

• Glaucoma• Hyperthyroidism• MAO inhibitors in the last 2 weeks



Adverse Effects: (at the target dose 15/92 mg)• Increased heart rate ‐ >10 BPM 56% of patients and > 20 BPM in

20% of patients• Paresthesia (tingling of face, hands and feet) 20% of patients vs.

1.9% on placebo• Metallic taste 9.4% vs. 1.1% on placebop• Mood/sleep disorder 20.6% vs.10.3% on placebo• Anxiety 7.9% vs. 2.6% on placebo• Impaired cognition 7.6% vs. 1.5% on placebo• Metabolic acidosis ‐ reduced bicarbonate (<21 mEq/L) 12.8% vs.

2.1%• Hypokalemia (< 3.5 mEq/L) 4.9% vs. 1.1%• Elevated serum creatinine (monitor baseline and periodically)• Nephrolithiasis 1.1% vs. 0.3% on placebo

Icosapent ethyl ‐ Vascepa by Amarin

• There are 3 omega‐3 fatty acids: alpha‐linolenic acid, EPA, and DHA. Only 2 of these omega‐3 fatty acids, EPA and DHA, are found in fish oils.

• Icosapent ethyl is an ethyl ester of the omega‐3 fatty acid EPA. EPA is thought to inhibit hepatic very‐low‐density lipoprotein (VLDL) TG synthesis and/or secretion and enhance the clearance of TGs from circulating VLDLenhance the clearance of TGs from circulating VLDL particles.

• The pharmacologic effects of EPA and DHA on lipids appear to be different. From studies using rats, it was thought that EPA was primarily responsible for the TG‐lowering effects of fish oil. However, clinical trials in humans have shown that both EPA and DHA are able to decrease serum TGs when used as monotherapy. Additionally, DHA increased serum high‐density lipoprotein cholesterol (HDL‐C) concentrations and increased LDL‐C particle size.

Icosapent ethyl ‐ Vascepa

• FDA approved 7/26/2012: Icosapent ethyl is indicated as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe hypertriglyceridemia (500 mg/dL orsevere hypertriglyceridemia (500 mg/dL or more).– The effect of VASCEPA on cardiovascular mortality and morbidity and on the risk for pancreatitis, in patients with severe hypertryglyceridemia has not been determined.

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Icosapent ethyl ‐ Vascepa• The effects of VASCEPA 4 grams per day were assessed in a randomized, placebo controlled, double‐blind, parallel‐group study of adult patients (76 on VASCEPA, 75 on placebo) with severe hypertriglyceridemia. Patients whose baseline TG levels were between 500 and 2 000 mg/dL were enrolled in this study for 12and 2,000 mg/dL were enrolled in this study for 12 weeks. – The median baseline TG and LDL‐C levels in these patients were 684 mg/dL and 86 mg/dL, respectively.

– Median baseline HDL‐C level was 27 mg/dL. – The randomized population in this study was mostly Caucasian (88%) and male (76%).

– The mean age was 53 years and the mean body mass index was 31 kg/m2


Results at 12 weeks in 151 patients with mean TG of 684 mg/dl:• Triglycerides ‐33% vs. placebo (p<0.001)• LDL‐C ‐2% vs placeboLDL C 2% vs. placebo• Non HDL‐C ‐18% vs. placebo• HDL‐C ‐4% vs. placebo• VLDL‐C ‐29% vs. placebo (p<0.05)• Apo B ‐9% vs. placebo (p<0.05)

Icosapent ethyl ‐ VascepaDosage:• The daily dose of VASCEPA

is 4 grams per day taken as 2 capsules twice daily with food.

• Patients should be advised to swallow VASCEPA capsules whole. Do not break open, crush, dissolve, or chew VASCEPA

• Cost: $184.00 for 1 Gm/120 caps WAC


• Currently, it is not known if use of oral EPA therapy alone carries any long‐term benefits or disadvantage compared with using products that contain a combination of DHAproducts that contain a combination of DHA and EPA.– LOVAZA is a combination of ethyl esters of omega 3 fatty acids, principally EPA and DHA

– Cost: $189.00 1 Gm/120 caps WAC

Icosapent ethyl ‐ Vascepa• The REDUCE‐IT (Reduction of Cardiovascular Events Outcomes trial): A multi‐center, prospective, randomized, double‐blind, placebo‐controlled, parallel‐group study to evaluate the effectiveness of Vascepa as an add‐on to statin therapy, in reducingVascepa as an add on to statin therapy, in reducing the first major cardiovascular event in an high‐risk patient population compared to statin therapy alone. Patients enrolled in the study have elevated triglyceride levels (>150 mg/dL) and at least one other defined cardiovascular risk factor. The control arm of the study is comprised of patients on optimized statin therapy.

JELIS Trial Methods:JELIS Trial Methods:

• 18,645 patients with a total cholesterol of 6.5 mmol/L or greater were randomly assigned to receive either 1800 mg of EPA daily with statin (EPA group; n = 9326) or statin only (controls; n = 9319) with a 5-year follow-up.

• Primary endpoint: Any major coronary event

Including sudden cardiac death fatal and non fatal– Including sudden cardiac death, fatal and non-fatal myocardial infarction, and other nonfatal events including unstable angina pectoris, angioplasty, stenting, or coronary artery bypass grafting.

• Analysis was by intention-to-treat.

• Patients were on very low doses of statins (IE pravastatin 10 mg or simvastatin 5 mg/day)

Yokoyama M et al. Lancet . 2007;369:1090–98.

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KaplanKaplan--Meier Estimates of Coronary EventsMeier Estimates of Coronary Events

Total Study Population

Primary Prevention Arm

Secondary Prevention Arm

Es (%

)

4

3

2

2.0

1.5

1.0

12.0

8.0

ControlEPA

Slide Source:Lipids Online Slide Librarywww.lipidsonline.org

MC

E

1

0

0.5

0

4.0

00 1 2 3 4 50 1 2 3 4 5 0 1 2 3 4 5

Years Years Years

HR: 0.81 (0.69-0.95)P = 0.011

HR: 0.82 (0.63-1.06)P = 0.132

HR: 0.81 (0.66-0.99)P = 0.048

Numbers at RiskControl Group 9319 8931 8671 8433 8192 7958 7478 7204 7103 6841 6678 6508 1841 1727 1658 1592 1514 1450Treat. Group 9326 8929 8658 8389 8153 7924 7503 7210 7020 6823 6649 6482 1823 1719 1638 1566 1504 1442


Percentage Changes Percentage Changes From Baseline in Serum Lipid ProfileFrom Baseline in Serum Lipid Profile

Rat

es (%

)

10

0

-10

ControlEPA All Patients

Patients with ≥ 1.7 mmol/L

at registration


Cha

nge

-20

-30

-40 TC LDL-C HDL-C Triglycerides Triglycerides

TC=total cholesterol. LDL C=low-density lipoprotein cholesterol. HDL C=high-density lipoprotein cholesterol.


Total Total mortalitymortalityreduced reduced by by 28%28%(p=0.027)(p=0.027)

GISSI-Prevenzione: Time Course of Clinical Events

>11,300 post>11,300 post--MI patients were given usual care MI patients were given usual care with or without with or without 850850 mg EPA+DHA for 3.5 yearsmg EPA+DHA for 3.5 years

Probab

ility

n-3 PUFAControl

0.59 (0.36–0.97)p=0.037

0.72 (0.54–0.96)p=0.0270.96

0.97

0.98

0.99

1.00


Sudden Sudden deathdeathreduced reduced by by 47%47%(p=0.0136)(p=0.0136)

Marchioli R et al. Circulation 2002;105:1897-1903.

Days 0 30 60 90 120 150 180 210 240 270 300 330 360

Probab

ility

0 30 60 90 120 150 180 210 240 270 300 330 360

n-3 PUFAControl

Days

0.47 (0.22–0.99)p=0.048

0.53 (0.32–0.88)p=0.0136

0.95

0.95

0.96

0.97

0.98

0.99

1.00

mg/d

L

mg/d

L

GISSI-Prevenzione: Effects of 850 mg/d of EPA+DHA on Serum Lipids

Total Cholesterol LDL Cholesterol

n-3Control

n-3Control

200205210215220225230

125130135140145150155


Months1 2 3 4 5 6

mg/d

L

Months1 2 3 4 5 6

mg/d

L

HDL Cholesterol Triglycerides

n-3Control

n-3Control

38404244464850

140145150155160165170

Marchioli R et al. Circulation 2002;105:1897-1903.

Omega-3 Acid Ethyl Esters in Lovaza 1 Gm

≥90% Omega≥90% Omega--33

Other Omega-3 60 mg

DHA 375 mgEPA

465 mg


Omega-6 80 mg

Omega-7 and -9 80 mg

Other FA 10 mg

Omega‐3 Fatty Acids and CV Events

• A meta‐analysis of 14 randomized, double‐blind, placebo‐controlled trials (involving 20 485 patients with a history of CVD) were included in the final analyses. Supplementation with omega‐3 fatty acids did not reduce the risk of overall cardiovascular events (relative risk, 0.99; 95% CI, 0.89‐1.09), all‐cause mortality, sudden cardiac death, myocardial infarction, congestive heart failure, or transient ischemic attack and stroke.– Arch Intern Med. 2012;172(9):686‐694.

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Omega‐3 Fatty Acids and CV Events

• A meta‐analysis of 20 studies of 68,680 patients were included, reporting 7044 deaths, 3993 cardiac deaths, 1150 sudden deaths, 1837 myocardial infarctions, and 1490 strokes. No statistically significant association was observed y gwith all‐cause mortality (RR, 0.96; 95% CI, 0.91 to 1.02; cardiac death (RR, 0.91; 95% CI, 0.85 to 0.98; sudden death (RR, 0.87; 95% CI, 0.75 to 1.01; myocardial infarction (RR, 0.89; 95% CI, 0.76 to 1.04; and stroke (RR, 1.05; 95% CI, 0.93 to 1.18); when all supplement studies were considered.– JAMA. 2012;308(10):1024‐1033

Risk and Prevention Study Collaborative Group

• The GISSI Group enrolled 12 513 patients, including 6244 randomly assigned to 1 g of n‐3 fatty acids (EPA/DHA) and 6269 patients randomized to placebo (olive oil).

• After a median follow‐up of five years, the primary end point curves were virtually superimposable. The primary end point occurred in 11.7% of patients who received the fish oil and 11.9% who received the placebo. The rates of the secondary end points were also similar in both treatment groups.– N Engl J Med 2013; 368: 1800‐1808.

Atorvastatin/Ezetimibe‐Liptruzet by Merck

• May 3. 2013 The FDA has approved this combination product with 10 mg of ezetimibe combined with 10, 20, 40 and 80 mg of atorvastatin.

• The approved indications include:

– For the reduction of elevated total‐C, LDL‐C, Apo B, , , p ,TG, and non‐HDL‐C, and to increase HDL‐C in patients with primary (heterozygous familial and non‐familial) hyperlipidemia or mixed hyperlipidemia.

– For the reduction of elevated total‐C and LDL‐C in patients with homozygous familial hypercholesterolemia, as an adjunct to other lipid‐lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable.

Atorvastatin/Ezetimibe‐Liptruzet

– Limitations of Use:• No incremental benefit of atorvastatin/ezetimibe combination on cardiovascular morbidity and mortality over and above that demonstrated for atorvastatin has been established.

• It has not been studied in Fredrickson type I III IV• It has not been studied in Fredrickson type I, III, IV, and V dyslipidemias.

– Patients with primary hyperlipidemia the added benefit with the 10/80 combination with ezetimibe over atorvastatin 80 mg/day were:

• Total‐C 6% LDL‐C 7% Apo B 4%

• HDL‐C 4% TG 9% Non‐HDL‐C 7%

Atorvastatin/Ezetimibe‐LiptruzetHomozygous Familial Hypercholesterolemia (HoFH):

• A double‐blind, randomized, 12‐week study was performed in patients with a clinical and/or genotypic diagnosis of HoFH. Data were analyzed from a subgroup of patients (n=36) receiving atorvastatin 40 mg at baseline. Increasing the dose of atorvastatinmg at baseline. Increasing the dose of atorvastatin from 40 to 80 mg (n=12) produced a reduction of LDL‐C of 2% from baseline on atorvastatin 40 mg. Coadministered ezetimibe and atorvastatin (10/40 and 10/80 pooled, n=24), produced a reduction of LDL‐C of 19% from baseline on atorvastatin 40 mg. In those patients coadministered ezetimibe and atorvastatin (10/80, n=12), a reduction of LDL‐C of 25% from baseline on atorvastatin 40 mg was produced.

Atorvastatin/Ezetimibe‐Liptruzet

• This is the third time that Merck has tried to have this combination approved and it may have benefit in those patients with homozygous familial hypercholesterolemia (HoFH) as these patients are at very high risk of CV events and the current therapies y g pare not able to achieve desirable levels of cholesterol.

• Outcome data is not available for any therapies for patients with HoFH and we await the IMPROVE‐IT Trial which will be the real test for a combination of a statin with ezetimibe vs. a statin alone in patients with ACS not HoFH.

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Indacaterol – Arcapta Neohalerby Novartis

$195.84/30 capsules AWP

Indacaterol – Arcapta Neohaler• A long acting beta 2 agonist that increases cyclic AMP levels

which causes relaxation of bronchial smooth muscle. FDA approved for the long term, once‐daily maintenance bronchodilator treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema

• Not indicated to treat acute deteriorations of chronic obstructive pulmonary disease– In vitro studies have shown that indacaterol has more than 24‐fold

greater agonist activity at beta 2‐receptors compared to beta 1‐receptors and 20‐fold greater agonist activity compared to beta 3‐receptors. This selectivity profile is similar to formoterol.

– The effective half‐life, calculated from the accumulation of indacaterol after repeated dosing with once daily doses between 75 mcg and 600 mcg ranged from 40 to 56 hours which is consistent with the observed time‐to‐steady state of approximately 12‐15 days.

Indacaterol – Arcapta NeohalerBOX WARNING: ASTHMA‐RELATED DEATH• Long‐acting beta2‐adrenergic agonists (LABA) increase the

risk of asthma‐related death. Data from a large placebo‐controlled US study that compared the safety of another long‐acting beta2‐adrenergic agonist (salmeterol) or placebo added to usual asthma therapy showed an increase in asthma‐to usual asthma therapy showed an increase in asthma‐related deaths in patients receiving salmeterol. This finding with salmeterol is considered a class effect of LABA, including indacaterol, the active ingredient in ARCAPTA NEOHALER. The safety and efficacy of ARCAPTA NEOHALER in patients with asthma have not been established. ARCAPTA NEOHALER is not indicated for the treatment of asthma.

Indacaterol – Arcapta NeohalerTable 2. Pharmacokinetic Parameters for Inhaled Long-Acting

Beta-2 Agonists Administered Using a Portable Inhaler

Pharmacokinetic Parameter

Formoterol Indacaterol Salmeterol

Cmax ≈ 5 min ≈ 15 min 20 min

Half-life 7 to 10 h 30 h 5.5 h

Exchanged in the urine

2% to 18% < 1% NS

The recommended dosage of ARCAPTA NEOHALER is the once-daily inhalation of the contents of one 75 mcg capsule using the NEOHALER inhaler. The dose should be administered once daily every day at the same time of the day by the orally inhaled route only. If a dose is missed, the next dose should be taken as soon as it is remembered. Do not use ARCAPTA NEOHALER more than one time every 24 hours.ARCAPTA capsules must always be stored in the blister, and only removed IMMEDIATELY BEFORE USE

Indacaterol – Arcapta Neohaler Fluticasone furoate /Vilanterol inhalation powder –Breo Ellipta

• May 10, 2013 The Food and Drug Administration today approved Breo Ellipta (fluticasone furoateand vilanterol inhalation powder) for the long‐term, once‐daily, maintenance treatment of airflow obstruction in patients with chronicairflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. It is also approved to reduce exacerbations of COPD in patients with a history of exacerbations. – Developed by GlaxoSmithKline, in collaboration with Theravance.

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Fluticasone furoate /Vilanterol inhalation powder –Breo Ellipta

• Maintenance treatment of COPD: 1 inhalation of Breo Ellipta 100 mcg/25 mcg (fluticasone furoate /vilanterol inhalation powder) once dailydaily.

• The plasma half‐life of the components is ~ 24 hours and 21 hours respectively

• FDA Box Warning as with all other LABA containing medications Asthma Related Deaths but NOT indicated for patients with asthma



Be careful, every time you move the cover you move to the next dose!

Aclidinium bromide ‐ Tudorza Pressair by Forest

• Aclidinium bromide is a long‐acting antimuscarinic antagonist (also referred to as an anticholinergic) selective for the M3 receptor. Human lungs contain all 3 muscarinic receptor types. The M1 and M3 receptors are responsible for promotion of mucusreceptors are responsible for promotion of mucus secretion from the mucosal glands. The M3 receptor is localized in airway smooth muscle and produces a bronchoconstrictive response.

• July 23, 2012 FDA approved for long‐term maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.

Aclidinium bromide ‐ Tudorza Pressair Aclidinium bromide ‐ Tudorza Pressair

• The TUDORZA PRESSAIR inhaler has a dose indicator to show you how many doses are left in your inhaler. Each TUDORZA PRESSAIR inhaler has 60 doses of medicine.

• You do not need to clean yourYou do not need to clean your TUDORZA PRESSAIR inhaler. If you wish to clean it, wipe the outside of the mouthpiece with a dry tissue or paper towel. Do not use water to clean your TUDORZA PRESSAIR inhaler, as this may damage your medicine.

• Cost $208.67/60 doses WAC

• Spiriva $249.58/30 WAC

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Aclidinium bromide ‐ Tudorza Pressair

• Tiotropium was a definite improvement over ipratropium for the treatment of patients with COPD. Aclidinium bromide inhalation powder is a twice‐daily inhaled muscarinic receptor antagonist and provides health care providers with anotherprovides health care providers with another treatment option for COPD. In clinical trials that compared aclidinium 400 mcg taken twice daily to tiotropium 18 mcg, their efficacy was shown to be similar; however, aclidinium bromide inhalation powder provided improved symptom control over tiotropium when assessed at bedtime and in the morning before the next dose.

COMBIVENT® (ipratropium bromide and albuterol sulfate) Inhalation

• As of July 2013, COMBIVENT RESPIMAT will be the only inhaler available for COMBIVENT. COMBIVENT RESPIMAT is an inhaler that delivers the same medicine in a slow‐moving, soft mist.

• Under the Clean Air Act, the FDA made a rule that products containing certain propellants, including COMBIVENT MDI, be removed from the market.

• Delivers 20 mcg ipratropium bromide (monohydrate) and 100 mcg albuterol (equivalent to 120 mcg albuterol sulfate) from the mouthpiece


• Dose of COMBIVENT RESPIMAT is one inhalation four times a day, not to exceed 6 doses in 24 hours.

• Prior to first use, the COMBIVENT RESPIMAT cartridge is inserted into the COMBIVENT RESPIMAT inhaler and the unit is primed. When using the unit for the first time, patients are to actuate the inhaler toward the ground until an aerosol cloud is visible and then repeat the process three more times. The unit is then considered primed and ready for use. If not used for more than 3 days, patients are to actuate the inhaler once to prepare the inhaler for use. If not used for more than 21 days, patients are to actuate the inhaler until an aerosol cloud is visible and then repeat the process three more times to prepare the inhaler for use.


• COMBIVENT RESPIMAT (20/100 mcg) was shown to be non‐inferior to CFC‐propelled COMBIVENT Inhalation Aerosol (36/206 mcg) in terms of mean FEV 1 AUC 0‐6hin terms of mean FEV 1 AUC 0 6h.

• The COMBIVENT RESPIMAT inhaler contains 120 puffs, equal to 120 doses.

• The new formulation does not contain peanut oil like the original MDI.


• The dose indicator shows approximately how much medicine is left. When the pointer enters the red area of the scale, there is enough medicine for 7 gdays. This is when you need to refill your prescription

• Once the dose indicator has reached the end of the scale, all 120 puffs have been used and the COMBIVENT RESPIMAT inhaler locks automatically. At this point, the base cannot be turned any further.

Comparison Of Long ActingBronchodilators

POET-COPD Trial (Prevention Of Exacerbations with Tiotropium in COPD)

• R, DB trial of tiotropium (18 mcg QD) vs salmeterol (50 mcg BID) in 7376 patients with moderate-to-very-severe COPD X 1 year

• 50% receiving inhaled steroids, using PRN beta-agonists PRNg , g g• Results: Tiotropium was superior:

• Increased time to first exacerbation - 187 days vs 145 days (p< 0.001)

• Reduced number of moderate or severe exacerbations – 0.64 vs 0.72 (p=0.002) Requiring oral steroids or antibiotics

• Reduced number of severe exacerbations – 0.09 vs 0.13 (p< 0.001) Requiring hospitalization

• No difference in serious adverse events

NEJM 2011;364(12):1093-1103.

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Inhaled Bronchodilators - Summary

Stick with the guidelines• Use short-acting bronchodilators as needed for

symptoms (LOE: A)• When regular use is needed, long-acting

bronchodilators are more effective and convenientbronchodilators are more effective and convenient (LOE: A)

• Long-acting anticholinergic may be more effective than LABA (LOE: A)

• Encourage smoking cessation MOST IMPORTANT

COPD Treatment and CV Events?

• A nested case‐control analysis of a retrospective cohort study in Ontario compared the risk of events between older COPD patients newly prescribed inhaled long acting beta agonists (LABA) and long actingacting beta‐agonists (LABA) and long acting anticholinergics (LAMA), after matching and adjusting for prognostic factors

• Main Outcome and Measures: An emergency department visit or a hospitalization for a cardiovascular event.– JAMA Intern Med. Published online May 20, 2013

COPD Treatment and CV Events?• Results: Of 191 005 eligible patients, 53 532 (28.0%) had a hospitalization or an emergency department visit for a cardiovascular event.

• Patients newly prescribed a LABA and/or a LAMA were found to have a greater risk of an event compared with nonuse of those medications (respective adjusted odds ratios, 1.31 [95% CI, 1.12‐1.52; P<.001] and 1.14 [1.01‐1.28; P=.03]).– No significant difference in events between the 2 medications (adjusted odds ratio of long‐acting inhaled beta‐agonists compared with anticholinergics, 1.15 [95% CI,0.95‐1.38; P=.16]).

• JAMA Intern Med. Published online May 20, 2013

COPD Treatment and CV Events?• "These results along with the previous data support the need for close monitoring of all patients with COPD who require long‐acting bronchodilators, regardless of drug class," study author Gershon and colleagues state.

• That conclusion however sits ill with Woodruff who• That conclusion, however, sits ill with Woodruff who points out in the accompanying Editorial that “without a firm recommendation as to what exactly this monitoring should consist of, monitoring remains the same as it has always been—the responsibility of the treating physician”.– HeartWire Clinical Cardiology May 20, 2013

Mirabegron – Myrbetriq by Astellas• Myrbetriq (meer‐BEH‐trick) ‐mirabegron 25 and 50 mg extended‐release tablets

• A beta‐3 adrenergic agonist (not an anticholinergic) indicated for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinaryurinary incontinence, urgency, and urinary frequency.– Mirabegron relaxes the detrusor smooth muscle during the storage phase of the urinary bladder fill‐void cycle by activation of beta‐3 AR which increases bladder capacity.

– The terminal elimination half‐life (t1/2) is approximately 50 hours.

Mirabegron – Myrbetriq

Table 2. Mean Number of Incontinence Episodes Per 24 Hours (Coprimary End Point From Pooled Analysis of Three 12 Week Pivotal Trials [178-CL-046, 178-CL-047, 178-CL-074])

Placebo (n = 878) Mirabegron 25 mg (n = 254)

Mirabegron 50 mg (n = 862)


Baseline

Mean 2.73 2.65 2.71 2.79

Fi l i itFinal visit

Mean 1.64 1.21 1.23 1.25

Change from baseline

Mean −1.09 −1.36 −1.48 −1.54

Adjusted difference vs placebo

Mean −0.4 −0.4 −0.41

95% CIa −0.58, −0.21 −0.62, −0.19

P value 0.005 < 0.001 < 0.001

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Mirabegron – Myrbetriq

Table 3. Mean Number of Micturitions Per 24 Hours (Coprimary End Point From Pooled Analysis of Three 12-Week Pivotal Trials [178-CL-046, 178-CL-047, 178-CL-074])

Placebo (n = 1,328) Mirabegron 25 mg (n = 415)

Mirabegron 50 mg (n = 1,324)


Baseline

Mean 11.58 11.68 11.7 11.58

Final visit

Mean 10.39 10.02 9.93 9.83

Change from baseline

Mean −1.18 −1.66 −1.77 −1.75

Adjusted difference vs placebo

Mean −0.47 −0.55 −0.54

95% CI −0.75, −0.36 −0.77, −0.31

P value 0.007 < 0.001 < 0.001

Mirabegron – Myrbetriq• 1,978 patients were randomized in Europe and Australia to: Mirabegron

50 or 100 mg, tolterodine ER 4 mg, or placebo once daily for 12 weeks.

Table 6. Primary and Secondary Efficacy End Points for 12‐Week Pivotal Trials (178‐CL‐046)

Mirabegron50 mg

Mirabegron 100 mg

Tolterodine ER Placebo

Coprimary end points

Change from baseline to final visit in mean number of incontinence/24 h

Number of incontinence/24 h

−1.57 −1.46 −1.27 −1.17

Adjusted mean difference vs placebo

−0.41 (P = 0.003)

−0.29 (P = 0.01)

−0.1 (P = 0.11)

Change from baseline to final visit in mean number of micturitions/24 h

Number of micturitions/24 h

−1.93 −1.77 −1.59 −1.34

Adjusted mean difference vs placebo

−0.6 (P < 0.001)

−0.44 (P = 0.005)

−0.25 (P = 0.11)

Mirabegron – MyrbetriqTable 7. Patients From Studies 1, 2, and 3 Treated With Mirabegron 25 or 50 mg or Placebo for

≤ 12 Weeks With Adverse Reactions Exceeding the Placebo Rate and Reported by ≥ 1%

Adverse Reactions Mirabegron 25 mg (n = 432)

Mirabegron 50 mg (n = 1,375)

Placebo (n = 1,380)

Hypertension 11.3% 7.5% 7.6%

Nasopharyngitis 3.5% 3.9% 2.5%

Headache 2.1% 3.2% 3%

UTI 4.2% 2.9% 1.8%

Constipation 1.6% 1.6% 1.4%

Diarrhea 1.2% 1.5% 1.3%

Upper respiratory tract infection

2.1% 1.5% 1.7%

Arthralgia 1.6% 1.3% 1.1%

Fatigue 1.4% 1.2% 1%

Tachycardia 1.6% 1.2% 0.6%

Abdominal pain 1.4% 0.6% 0.7%

Mirabegron – MyrbetriqDosing:• Recommended starting dose is 25 mg once daily, with or without food. After 8 weeks on the 25 mg dose and based on individual efficacy and tolerability, the dose may increase to 50 mg once daily.

• Cost 25 and 50 mg $200.04/30 tabs WAC• Swallow whole with water, do not chew, divide or crush the extended release tablets.

• Monitor BP periodically• Manufacturer must evaluate the incidence of serious cardiovascular outcomes and the incidence of new malignant events in patients treated with mirabegron

Mirabegron – Myrbetriq• CONCLUSION: Mirabegron is the first beta‐3 adrenoceptor agonist

intended for the treatment of OAB. Most drugs approved for the treatment of OAB are anticholinergic agents. Mirabegron may be useful for patients who are unable to tolerate the side effects associated with anticholinergic agents or patients for whom anticholinergic‐induced mydriasis may increase IOP (eg, uncontrolled narrow‐angle glaucoma).

• When dosed at 50 mg once daily, mirabegron therapy is generally well tolerated and associated with a decrease in micturitions per 24 hours bytolerated and associated with a decrease in micturitions per 24 hours by 0.55, a decreased number of incontinence episodes per 24 hours by 0.4, and an increased mean volume voided by 11.9 ml.

• Some of the studies included an active comparator (eg, tolterodine), mainly for safety assessment. Both drugs were effective, and mirabegrontherapy was associated with fewer anticholinergic‐like adverse effects

Linaclotide – Linzess by Forest Labs/Ironwood Pharmaceuticals

• FDA approved for the treatment of adults with irritable bowel syndrome with constipation (IBS‐C) or chronic idiopathic constipation (CIC).

• Linaclotide is a 14‐amino acid peptide that is metabolized within the gastrointestinal tract to an active metabolite It is awithin the gastrointestinal tract to an active metabolite. It is a guanylate cyclase‐C (GC‐C) agonist and both it and its metabolite bind to GC‐C and act locally on the luminal surface of the intestinal epithelium. Activation of GC‐C results in an increase in both intracellular and extracellular concentrations of cyclic guanosine monophosphate (cGMP). Elevation in intracellular cGMP stimulates secretion of chloride and bicarbonate into the intestinal lumen, resulting in increased intestinal fluid and accelerated transit.

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Linaclotide – Linzess• The effectiveness of linaclotide was demonstrated in placebo controlled studies. In patients with IBS‐C, the drug 290 mcg QD was more effective than placebo in increasing the number of complete spontaneous bowel movements (CSBM) and in reducing abdominal painreducing abdominal pain.

• In patients with CIC, patients receiving linaclotide 145 mcg QD experienced more CSBM than those taking placebo.

• The higher dosage (290 mcg once a day) was not approved for the treatment of CIC because it was no more effective than the 145 mcg once a day dosage in the clinical studies.

Linaclotide – Linzess• SIGNIFICANT RESPONDER RATES IN ABDOMINAL PAIN vs PLACEBO IBS‐C

– Responder rates for 9 of 12 weeks ‐ Responder rates for 6 of 12 weeks

Linaclotide – Linzess

• SIGNIFICANT RESPONDER RATES IN CSBM (Complete spontaneous bowel movement) in CIC

– Responder rates for 9 of 12 weeks ‐ Responder rates for 6 of 12 weeks


ADVERSE EFFECTS:

• In IBS‐C clinical trials, the most common adverse reactions in LINZESS‐treated patients with 290 mcg doses (incidence ≥2% andwith 290 mcg doses (incidence ≥2% and greater than placebo) were diarrhea (20% vs3% placebo), abdominal pain (7% vs 5%), flatulence (4% vs 2%), headache (4% vs 3%), viral gastroenteritis (3% vs 1%) and abdominal distension (2% vs 1%).


• In CIC clinical trials, the most common adverse reactions in LINZESS‐treated patients with the 145 mcg doses (incidence ≥2% and greater than placebo) were diarrhea (16% vsgreater than placebo) were diarrhea (16% vs 5% placebo), abdominal pain (7% vs 6%), flatulence (6% vs 5%), upper respiratory tract infection (5% vs 4%), sinusitis (3% vs 2%) and abdominal distension (3% vs 2%).

Linaclotide – Linzess• Risk of toxicity in children (REMS boxed warning; contraindicated in pediatric patients up to 6 years of age, and use should be avoided in pediatric patients 6 through 17 years of age); contraindicated in patients with known or suspected mechanicalin patients with known or suspected mechanical gastrointestinal obstruction; severe diarrhea.– In studies in young juvenile mice, deaths occurred within 24 hours following administration of one or two daily oral doses. Although there were no deaths in older juvenile mice, the lack of safety data in pediatric patients contraindicates its use in children up to 6 years of age.

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REMS: Post marketing studies are required to determine the mechanism of death in neonatal and juvenile mice treated with linaclotide (due April 2014), a safety and efficacy evaluation in pediatric patients with chronic idiopathic constipation ages 7 months up to 17 years (due December 2023), and a safety and ffi l i i di i i i h IBS C 7efficacy evaluation in pediatric patients with IBS‐C ages 7 years up to 17 years (due December 2023). The manufacturer is also required to determine if linaclotide is excreted in the breast milk of healthy lactating but non–breast‐feeding female volunteers, develop and validate sensitive and precise assays for the detection of antilinaclotide antibodies, and develop a clinical trial in adults to assess the development of antilinaclotide antibodies during treatment with linaclotide.

Linaclotide – LinzessDOSAGE AND ADMINISTRATION:

• Irritable Bowel Syndrome with Constipation – The recommended dose of LINZESS is 290 mcg taken orally once daily on an empty stomach, at least 30 minutes prior to the first meal of the day.

Ch i Idi hi C i i• Chronic Idiopathic Constipation – The recommended dose of LINZESS is 145 mcg taken orally once daily on an empty stomach, at least 30 minutes prior to the first meal of the day.

• Swallow capsules whole; do not break or chew.

Linaclotide – Linzess• Linzess has not been directly compared with lubiprostone – Amitiza a locally acting chloride channel activator, actively transporting chloride ions into the lumen. Sodium ions and fluids passively follow and increase intestinal fluid secretion.– AMITIZA (lubiprostone) 24 mcg twice daily is approved to treat Chronic Idiopathic Constipation in adults. AMITIZA 8 mcg twice daily is approved to treat Irritable Bowel Syndrome with Constipation (IBS‐C) in women 18 years of age and older.

• Cost: Linzess 145 and 290 mcg tabs $204.36 WAC/30 tabs

Amitiza 8 and 24 mcg tabs $249,93 WAC/60 tabs

What’s New in Type 2 Daibetes?

Recommendations: Recommendations: Hypertension/Blood Pressure ControlHypertension/Blood Pressure Control

Goals:People with diabetes and hypertension should

be treated to a systolic blood pressure goal of <140 mmHg. (B)

Lower systolic targets, such as <130 mmHg, may be appropriate for certain individuals, such as younger patients if it can be such as younger patients, if it can be achieved without undue treatment burden. (C)

c Patients with diabetes should be treated to a diastolic blood pressure <80 mmHg. (B)

Diabetes Care 2013; 36 (suppl1) S-6

.

Aggressive Blood Pressure Control Increases Coronary Heart Disease Risk Among Diabetic Patients

Diabetes Care 2013 published online May 20, 2013

• LSU Healthcare Services reports the results of a prospective cohort study (2000–2009) on diabetic patients including 17,536 African American and 12 618 white Cox proportional hazards regression12,618 white. Cox proportional hazards regression models were used to estimate the association of blood pressure with CHD risk.

• During a mean follow‐up of 6.0 years, 7,260 CHD incident cases were identified

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BP levels Achieved and Risk of CHD Events in Patients with Diabetes

Patients BP <110/65 mm Hg

110‐119/65‐69 mm Hg

120‐129/70‐80 mm Hg

130‐139/80‐90 mm Hg

140‐159/90‐100 mm Hg

>/=160/100 mm Hg

Hg

African American

1.73 1.16 1.04 1.00Reference

1.06 1.11

White 1.60 1.27 1.08 1.00 Reference

0.95 0.99

Diabetes Care 2013 published online May 20, 2013

Aggressive Blood Pressure Control Increases Coronary Heart Disease Risk Among Diabetic PatientsDiabetes Care 2013 published online May 20, 2013

CONCLUSIONS:

• “Our study suggests that there is a U‐shaped or inverse association between blood pressure and the risk of CHD and aggressive bloodand the risk of CHD, and aggressive blood pressure control (blood pressure <120/70 mmHg) is associated with an increased risk of CHD among both African American and white patients with diabetes.”

Aggressive Blood Pressure Control Increases Coronary Heart Disease Risk Among Diabetic PatientsDiabetes Care 2013 published online May 20, 2013

• “For the elder group, the harm is even higher. Since there is currently no robust evidence available for lowering the blood pressure <130/80 mmHg in people with diabetes it<130/80 mmHg in people with diabetes, it might be advisable to maintain blood pressure between 130–139 and 80–89 mmHg and to recommend less intense goals to elderly patients than to younger ones.”

ADA 2012 Clinical Practice Recommendations (Diabetes Care 2012;35: S11-S63)

• “Growing evidence suggests that there is an association between increase in sleep-time blood pressure and incidence of CVD events. A recent RCT of 448 participants with type 2 diabetes and hypertensionwith type 2 diabetes and hypertension demonstrated reduced cardiovascular events and mortality with median follow-up of 5.4 years if at least one antihypertensive medication was given at bedtime.”

• “Administer one or more antihypertensive medications at bedtime. (A)”

Influence of Time of Day of Blood Pressure–Lowering Treatment onCardiovascular Risk in Hypertensive Patients with Type 2 Diabetes

Diabetes Care 2011; 34:1270-76

• A prospective, randomized, single study center in Spain, open-label, blinded end point trial on 448 hypertensive patients with type 2 diabetes, 255 men/193 women, mean age 62.5 years, randomized to ingest all their prescribed hypertension medications

k i 1 f th t b dtiupon awakening or 1 or more of them at bedtime. • Ambulatory blood pressure was measured for 48 hrs

at baseline and again annually or even more frequently (quarterly) after adjustments in treatment.

• The mean follow-up was 5.4 years.• This was a subset of the original MAPEC Trial in 2156

hypertensive subjects from Spain (Chronobiology International 2010; 27(8): 1629–1651)

Influence of Time of Day of Blood Pressure–Lowering Treatment onCardiovascular Risk in Hypertensive Patients with Type 2 Diabetes

(Diabetes Care 2011; 34:1270-76)

• Results: patients ingesting one or more hypertension medications at bedtime showed a significantly lower cardiovascular risk (adjusted by age and sex) than subjects ingesting all medications upon awakening (hazard ratio 0.33 [95% CI 0 21 0 54] P 0 001)[95% CI 0.21–0.54]; P , 0.001).

• The difference between groups in the adjusted risk of major events (cardiovascular death, myocardial infarction, and stroke) was also statistically significant (0.25 [0.10–0.61]; P = 0.003).

• There was a significant 12% cardiovascular risk reduction per each 5 mmHg decrease in asleep systolic blood pressure during follow-up (P , 0.001).

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HOPE Study: DesignHOPE Study: Design

Inclusion Inclusion Criteria:Criteria:Age Age ≥55 years, ≥55 years, history: CHD, history: CHD, stroke, or PVD stroke, or PVD OR diabetes + OR diabetes + ≥≥11

Exclusion Exclusion Criteria: Criteria: CHF; known EF CHF; known EF <0.40; MI or <0.40; MI or stroke within 4 stroke within 4 weeks; current weeks; current ACE inhibitorACE inhibitor

267 267 Centers:Centers:

US, Europe, US, Europe, Canada, Canada, Central Central AmericaAmerica

CV risk factorCV risk factor ACE inhibitor, ACE inhibitor, vitamin Evitamin E

AmericaAmerica

RamiprilRamipril10 mg HS10 mg HSN = 4645N = 4645

PlaceboPlaceboN = 4652N = 4652

Patients Patients Randomized Randomized

N = 9297N = 9297

Yusef S, et al. N Engl J Med. 2000;342:145-53.

CHD = coronary heart diseasePVD = peripheral vascular diseaseCHF = congestive heart failure.

CV Risk Reduction Even Greater in CV Risk Reduction Even Greater in Patients With DiabetesPatients With Diabetes

00NonfatalNonfatal

MIMI StrokeStroke CV DeathCV Death AllAll--CauseCauseMortality*Mortality*

onon

Effects Beyond Baseline TherapyEffects Beyond Baseline Therapy•• Aspirin and other antiplateletsAspirin and other antiplatelets•• BetaBeta--blockersblockers•• LipidLipid--lowering agentslowering agents

•• DiureticsDiuretics•• Calcium channel blockersCalcium channel blockers

Yusef S, et al. N Engl J Med. 2000;342:145-53. HOPE Study Investigators. Lancet. 2000;355:253-9.

--3030--3535--4040

--2525--2020--1515--1010--55

HOPE HOPE MICROMICRO--HOPEHOPE

20%20%22%22%

32%32% 33%33%

26%26%

37%37%

16%16%

24%24%

% R

elat

ive

Ris

k R

educ

tio%

Rel

ativ

e R

isk

Red

uctio

P P = .01= .01

P P = .0001= .0001

P P = .0074= .0074

P P = .004= .004

P P = .0003= .0003P P = .005= .005

P P = .0002= .0002

P P = .0002= .0002

*Secondary end point*Secondary end point

2013 AACE Guidelines for BP2013 AACE Guidelines for BP

Goal BP ~130/80 mm HgInitial therapy with either an ACEI or an ARBIf not at goal add either a thiazide diuretic, a CCB or a beta blockerIf BP >150/100 mm Hg start with dual therapy– Endocrine Practice 2013; 19 (No 2)

Recommendations:Recommendations:Dyslipidemia/Lipid ManagementDyslipidemia/Lipid Management

Treatment recommendations and goals (2)• Statin therapy should be added to lifestyle

therapy, regardless of baseline lipid levels – with overt CVD (A)– without CVD >40 years of age who have one or more other without CVD 40 years of age who have one or more other

CVD risk factors (A)

• For patients at lower risk (e.g., without overt CVD, <40 years of age) (E)– Consider statin therapy in addition to lifestyle therapy if LDL

cholesterol remains >100 mg/dL– In those with multiple CVD risk factors

ADA. VI. Prevention, Management of Complications. Diabetes Care 2012;35(suppl 1):S30-31.

ADA Recommendations:ADA Recommendations:Dyslipidemia/Lipid ManagementDyslipidemia/Lipid Management

Treatment recommendations and goals (5)• If targets are not reached on maximally tolerated

doses of statins (E)• Combination therapy has been shown not to

provide additional cardiovascular benefit above statin therapy alone and is not generally recommended. (A) (added in 2013)

• Statin therapy is contraindicated in pregnancy (B)

ADA. VI. Prevention, Management of Complications. Diabetes Care 2013;36(suppl 1):S7. Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

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UK Prospective Diabetes StudyGlucose Interventional Trial

Outcome at 10 years Diet/Met Diet/Sulf/Insulin

Diet RRR/ARR/NNT (Diet/Met vs. Diet)

Any DM related endpoint

28.7% 36.8% 38.9% 26.2%/10.2%/10

Diabetes related death 8.2% 10.8% 13.4% 38.8%/5.2%/19

All cause mortality 14.6% 20% 21.7% 32.7%/7.1%/14

MI 11.4% 14.6% 17.8% 36%/6.4%/16

Stroke 3.5% 6.3% 5.6% 44.4%/2.8$/36

Micro-vascular events 7.0% 7.8% 9.2% N/S

Lancet, 1998;352: 854 - 865

LongLong--term Effects of Metformin on Metabolismterm Effects of Metformin on Metabolismand Microvascular and Macrovascular Diseaseand Microvascular and Macrovascular Diseasein Patients With Type 2 Diabetes Mellitus Treated in Patients With Type 2 Diabetes Mellitus Treated with with Insulin Insulin Arch Intern Med. 2009;169(6):616Arch Intern Med. 2009;169(6):616--625625

Results: Metformin treatment prevented weight gain (mean weight gain, −3.07 kg [range, −3.85 to −2.28 kg]; P.001), Improved glycemic control (mean reduction in HbA1c level, 0.4% percentage point [95% CI, 0.55-0.25]; P.001), despite the aim of similar glycemic control in both groups, Reduced insulin requirements (mean reduction 19 63 IU/d [95% Reduced insulin requirements (mean reduction, 19.63 IU/d [95% CI, 24.91-14.36 IU/d]; P.001).Metformin was not associated with an improvement in the primary end point.It was, however, associated with an improvement in the secondary, macrovascular end point (hazard ratio, 0.61 (95% CI, 0.40-0.94; P=.02), which was partly explained by the difference in weight.The number needed to treat to prevent 1 macrovascular end point was 16.1 (95% CI, 9.2-66.6).These sustained beneficial effects support the policy to continue metformin treatment after the introduction of insulin in any patient with DM2, unless contraindicated.

Proposed Proposed Recommendations Recommendations for for Use Use of of Metformin Based Metformin Based on on ee--GFRGFRDiabetes Care 2011;34:1435Diabetes Care 2011;34:1435

eGFR (ml/min per 1.73m2)

Action

>60 No renal contraindication to metformin

>45 Continue useIncrease monitoring of renal function (every 3–6 months)

<45 and >30 Prescribe metformin with cautionUse lower dose (e.g., 50%, or half-maximal dose)Closely monitor renal function (every 3-6months) Do not start new patients on metformin

<30 Stop metformin

consistent with the National Institute for Health and Clinical Excellence guidelines in the U.K. and those endorsed by the Canadian Diabetes Association and the Australian Diabetes Society NOT FDA APPROVED!

CanagliflozinCanagliflozinCanagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.The FDA has asked for five postmarketing studies for the drug including a cardiovascular outcomes trial, an enhanced pharmacovigilance program, a bone safety study and two pediatric studiesAvailable as 100 mg and 300 mg tablets

Cost: ~ $9.00/dose

CanagliflozinCanagliflozinMechanism of Action

Sodium-glucose co-transporter 2 (SGLT2), expressed in the proximal renal tubules, is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. Canagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2 canagliflozin reduces reabsorption of SGLT2, canagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose (RTG), and thereby increases urinary glucose excretion.Maximal suppression of mean RTG over the 24-hour period was seen with the 300 mg daily dose to approximately 70 to 90 mg/dL in patients with type 2 diabetes in Phase 1 studies.

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CanagliflozinCanagliflozinWarnings and Precautions

Hypotension - canagliflozin causes intravascular volume contraction. Symptomatic hypotension can occur after initiating csanagliflozin particularly in patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2), elderly patients, patients on either diuretics or

di ti th t i t f ith th i i t imedications that interfere with the renin-angiotensin-aldosterone system (e.g., angiotensin-converting-enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs]), or patients with low systolic blood pressure.Before initiating canagliflozin in patients with one or more of these characteristics, volume status should be assessed and corrected.Monitor for signs and symptoms after initiating therapy. Keep up with fluids/hydration.

CanagliflozinCanagliflozinPatients with Renal Impairment

Canagliflozin increases serum creatinine and decreases eGFR.

Patients with hypovolemia may be more susceptible to these changes.No dose adjustment is needed in patients with mild renal impairment ( GFR f 60 L/ i /1 73 2 )(eGFR of 60 mL/min/1.73 m2 or greater).The dose of canagliflozin is limited to 100 mg once daily in patients with moderate renal impairment with an eGFR of 45 to less than 60 mL/min/1.73 m2.Canagliflozin should be discontinued or not be initiated in patients with an eGFR less than 45 mL/min/1.73 m2.Assessment of renal function is recommended prior to initiation of canagliflozin therapy and periodically thereafter.

CanagliflozinCanagliflozin

Genital Mycotic Infections:Canagliflozin increases the risk of genital mycoticinfections. Patients with a history of genital mycotic infections and uncircumcised males were more likely to develop genital mycotic infections more likely to develop genital mycotic infections. (10-12% in women and 3-4% in men).

Urinary Tract Infections:4-6% of patients

Increased Urination/Polyuria:4-6% of patients


Canagliflozin can lead to hyperkalemia. Patients with moderate renal impairment who are taking medications that interfere with potassium excretion, such as p ,potassium-sparing diuretics, or medications that interfere with the renin-angiotensin-aldosterone system are more likely to develop hyperkalemia.Monitor serum potassium levels periodically.


Lipid Effects:Mean changes (percent changes) from baseline in LDL-C relative to placebo were 4.4 mg/dL (4.5%) and 8.2 mg/dL (8.0%) with g ( ) g ( )canagliflozin 100 mg and 300 mg, respectively.Cardiovascular outcomes have not been assessed to date.


Results from 26-Week Placebo-Controlled Clinical Study with canagliflozinmonotherapy:

584 atients (mean: a e 55; eGFR 87; 44% 584 patients (mean: age 55; eGFR 87; 44% men; A1c ~8.0%; weight ~86 Kg)Results: (all placebo subtracted)

A1c (%) -.91(100mg) and -1.18 (300mg)FBS (mg/dl) – 36 (100mg) -43 (300mg)Weight (Kg) – 2.2 (100mg) -3.3 (300mg)

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Results from 26-Week Placebo-Controlled Clinical Study of Canagliflozin in Combination with Metformin

1009 patients (>/= 2.0 Gms metformin/day; p ( y;mean age 55; eGFR 89; 47% men; A1c ~8.0; and weight 85-88 Kg)Results (all placebo subtracted)

A1c (%) – 0.62 (100mg) -0.77 (300mg)FBS (mg/dl) -30 (100mg) -40 (300mg)Weight (Kg) -2.5 (100mg) -2.9 (300mg)


Results from 52−Week Clinical Study Comparing Canagliflozin to Glimepiride in Combination with Metformin

1450 patients(mean: age 56; eGFR 90; 52% men; A1c (%) ~7.8; weight (Kg) ~87)A1c (%) 7.8; weight (Kg) 87)Results:

A1c (%) -0.82 (100mg); 0.93(300mg); -0.81 (glimepiride)FBS (mg/dl) -24 (100mg);-28 (300mg); -18 (glimepiride)Weight (Kg) -4.2 (100mg); -4.7 (300mg); +1.0 (glimepiride)


Results from 18−Week Placebo-Controlled Clinical Study of Canagloflozin in Combination with Insulin ≥ 30 Units/Day (With or Without Other Oral Antihyperglycemic Agents)

1718 patients (mean: age 63; eGFR 75; 66% men; 70% b l/b l i li A1 (%) 8 2 8 3 ~70% on basal/bolus insulin; A1c(%) ~8.2-8.3;

weight(Kg) ~97)Results:

A1c (%) -0.63 (100mg); -0.72 (300mg); +0.01 (placebo)FBS (mg/dl) -19 (100mg); -25(300mg); +4.0 (placebo)Weight (Kg) -1.8 (100mg);-2.3 (300mg); +0.1 (placebo)


Results from 52−Week Clinical Study Comparing Canagliflozin to Sitagliptin (100mg) in Combination with Metformin and Sulfonylureay755 patients (mean: age 57; eGFR 88; 56% men; A1c~8.1; Weight (Kg) ~88-90)Results:

A1c(%) -1.03 (300mg) -0.66 (sitagliptin)FBS(mg/dl) -30 (300mg) -6.0 (sitagliptin)Weight (Kg) -2.5 (300mg) +0.3 (sitagliptin)

CanagliflozinCanagliflozinRecommended Dosage

The recommended starting dose of canagliflozinis 100 mg once daily, taken before the first meal of the day. In patients tolerating 100 mg once daily who have an eGFR of 60 mL/min/1 73 m2 or greater have an eGFR of 60 mL/min/1.73 m2 or greater and require additional glycemic control, the dose can be increased to 300 mg once daily.The dose is limited to 100 mg once daily in patients with moderate renal impairment with an eGFR of 45 to less than 60 mL/min/1.73 m2.Canagliflozin should not be initiated in patients with an eGFR less than 45 mL/min/1.73 m2.

Documents

New Drug Update - Weart ppt.ppt · New Drug Update 2012‐2013 C. Wayne Weart, Pharm D, FASHP, FAPhA, BCPS ... South Carolina College of Pharmacy Professor of Family Medicine Medical