Tom Frank, Pharm.D., BCPS Discloses that he is on the speaker’s bureau of Pfizer, Novartis and Amgen
1 Dabigatran
• Oral anticoagulant indicated to reduce the risk of stroke and systemic embolism • Non-valvular atrial fibrillation • Direct thrombin (factor IIa) inhibitor • Inhibition of thrombin decreases the conversion of fibrinogen to fibrin • Also inhibits free thrombin, fibrin bound thrombin and thrombin induced platelet aggregation
2 Dabigatran Pharmacokinetics
• Hydrolyzed to active moiety • Metabolized to four glucuronides, all are active • Bioavailability 3-7% (do not crush or open capsule) • Peak concentration in one hour • Protein binding 35% • Eliminated primarily in urine • Half life 12-17 hours • Adjust dose for diminished renal function
Dabigatran Pharmacokinetics
• Drug interactions: • Rifampin (reduced dabigatran levels) • No changes other than Cmax or AUC seen when used with ketoconazole, verapamil, amiodarone, quinidine, clarithromycin • No changes in coagulation when given with given clopidogrel or enoxaparin • No change in dabigatran levels when given with digoxin, H2 blockers or PPI’s • Pharmacodynamics: median aPTT 2x control onset of therapeutic effect between 30 min and 2 hours
3 Dabigatran Clinical Trials
• Dabigatran 110mg or 150mg twice daily compared to warfarin (INR 2-3) • Patients with atrial fibrillation and risk factors for stroke • Primary end point: rate of stroke or systemic embolism • Primary safety outcome: rate of major hemorrhage • Low dose aspirin or other anti-platelet allowed • Primary end point: dabigatran 110mg 1.53%/yr; 150mg 1.11%/yr and 1.69%/yr for warfarin • Primary safety end point: dabigatran 110mg 0.12%/yr, 150mg 0.10%/yr and 0.38%/yr for warfarin
Dabigatran Adverse Effects
• Dyspepsia • Intracranial hemorrhage • Life threatening bleed • Major bleeding • Major GI bleeding • Rates of MI from RE-LY: 0.82% for 110mg, 0.81% for 150mg and 0.64% for warfarin
4 Dabigatran Dosing
• 150mg p.o. twice daily • 75mg p.o. twice daily if CrCl 15-30ml/min • If switching from warfarin, stop warfarin and start dabigatran when the INR < 2 • If switching from parenteral anticoagulant, start dabigatran less than 2 hours before next injection would have been given OR at the time IV heparin is discontinued • Discontinue 1-2 days prior to elective surgery; check ECT or aPTT if emergent surgery
5 Denosumab
• Human monoclonal antibody indicated for the treatment of postmenopausal women with osteoporosis at a high risk for fracture • Denosumab binds to the RANK ligand and inhibits maturation of osteoclasts • Denosumab mimics the effects of osteoprotegerin
6 7 Denosumab Pharmacokinetics
• Bioavailability 100% • Levels detectable within one hour • Half life 25 days • Metabolized by RES • Drug interactions: not studied
Denosumab Clinical Trials
• Placebo controlled trial evaluating denosumab 60mg SQ every 6 months • Female patients with low T-score at hip or spine • End point: new vertebral fracture at 36 months • Secondary end points: time to first non-vertebral fracture and time to hip fracture • End point reached in 7.2% on placebo and 2.3% on denosumab • Non-vertebral fractures: 8% vs 6.5%; hip fracture rate 1.2% vs 0.7%
8 Denosumab Clinical Trials
• Randomized, double blind, placebo controlled trial evaluated denosumab 60mg every six months in men on androgen deprivation therapy for prostate cancer • End point: BMD change after 24 months • Denosumab group improved by 5.6%, placebo group decreased by 1% • New vertebral fractures: 1.5% vs 3.9%
Denosumab Adverse Effects
• Hypocalcemia • Non-fatal serious infections • New malignancies • Dermatologic reaction • Osteonecrosis of the jaw • Pancreatitis
9 Denosumab Dosing
• 60mg subcutaneously every 6 months • Inject into upper arm, thigh or abdomen • Should be administered by healthcare professional • Patient should be taking calcium and vitamin D
10 Belimumab
• Human monoclonal antibody indicated for patients with active SLE who are receiving standard therapy • B-lymphocyte stimulator (BLyS) protein inhibitor • Blocks binding of BLyS to receptors on B-cells • Inhibited B-cell survival and reduced differentiation of B-cells
Belimumab Pharmacokinetics
• Half life 19.4 days • No changes based on age, gender race or renal impairment • Drug interactions: steroids and ACEI produce increased clearance but no clinical impact; no impact with used with mycophenolate, azathioprine, methotrexate, antimalarials, NSAID’s, aspirin and HMGCoA reductase inhibitors
11 Belimumab Clinical Trials
• Randomized double-blind, placebo-controlled trials in patients with active SLE disease (76 weeks and 52 weeks duration) • Stratified based on SELENA-SLEDAI score, proteinuria and race • >70% were on 2 or more SLE drugs • Patients with severe lupus nephritis or CNS lupus excluded • Assigned to 1mg/kg/day or 10mg/kg/day or placebo • Doses given on day 0, 14, 28 then every 28 days
Belimumab Clinical Trials
• SLE Responder Index end point reached in 41%, 43% and 43% respectively in 76 week trial • End point reached in 51%, 58% and 44% respectively in 52 week trial • Subgroup analysis: response rate in black/African American patients less than placebo in one study and similar response to other patients in second study
12 Belimumab Adverse Effects
• Nausea • Diarrhea • Pyrexia • Death • Serious infections • Malignancy • Hypersensitivity reactions • Infusion reactions • Depression
Belimumab Dosing
• 10mg/kg at two weeks intervals for first three doses and four week intervals after that • IV infusion given over one hour • Can pre-medicate for infusion reactions
13 Ulipristal
• Progesterone agonist/antagonist indicated for emergency contraception • Selective progesterone receptor modulator • Binds to progesterone, glucocorticoid and androgen receptors • Primary mechanism of action is inhibition or delay of ovulation
14 Ulipristal Pharmacokinetics
• Highly protein bound • Peak concentration in one hour • Presence of food does not require dose adjustment • Metabolized by CYP 3A4 • Half life 32 hours • Drug interactions: CYP 3A4 inducers (barbiturates, carbamazepine, felbamate, rifampin, St. John’s wort, topiramate)
Ulipristal Clinical Trials
• Open-label trial; ulipristal 30mg in women who presented for emergency contraception within 48-120 hours after unprotected intercourse; 27 pregnancies (observed rate 2.2%, expected rate 5.5%) • Ulipristal 30mg compared to levonorgestrel 1.5mg in single blind trial • Stratified according to time since unprotected intercourse • Taken with 72 hours: pregnancy rates were ulipristal 1.8% and levonorgestrel 2.6% • Between 72-120 hours: ulipristal no pregnancies, levonorgestrel 3% pregnancy rate
15 Ulipristal Adverse Effects
• Headache • Abdominal pain • Nausea • Dysmenorrhea • Fatigue • Dizziness • Rapid return of fertility likely • Cycle length increased by mean of 2.5 days
Ulipristal Dosing
• Take one tablet orally as soon as possible within 120 hours after unprotected intercourse or a known or suspected contraceptive failure
16 Dienogest/estradiol valerate
• Indicated for preventing pregnancy in women with BMI < 30kg/m2 • Estradiol inhibits ovulation • Dienogest potent progestin with anti- androgenic activity- thicken cervical mucus and changes in endometrium • Packaged in four-phase dose configuration
17 Dienogest/ethinyl estradiol Pharmacokinetics
• Peak estrogen level in 3 hours, peak progestin levels in 1.5 hours • Estradiol 2-3% circulates free, dienogest 10% circulates free • Metabolism by CYP 3A4 • Half life: estradiol 14 hours, dienogest 11 hours • Drug interactions: drugs that induce CYP 3A4 (decrease efficacy/BTB); do not use with strong CYP 3A4 inducers; strong CYP 3A4 inhibitors increase hormone concentrations; protease inhibitors
Dienogest/estradiol valerate Clinical Trials
• Open-label, single-arm study • Treated for up to 28 cycles • 3,969 exposure cycles • 5 pregnancies identified in 13 cycle window • Pearl Index of 1.64 • Contraceptive failure rate after a year of 0.016 on Kaplan Meier curve
18 Dienogest/estradiol valerate Clinical Trials
• Dienogest/estradiol compared to levonorgestrel/EE over seven cycles to compare withdrawal bleeding patterns • Withdrawal bleeding on schedule: dienogest/estradiol- 77-83% compared to levonorgestrel/EE 89-93% of the time • Duration of withdrawal bleeding: dienogest/estradiol- 4.1-4.7 days; levonorgestrel/EE- 5.0-5.2 days • Breakthrough bleeding rates 14% vs 12%
Dienogest/estradiol valerate Adverse Effects
• Headache • Metrorrhagia and irregular menstruation • Breast pain • Nausea or vomiting • Acne • Increased weight
19 3.5
3
2.5
2
yellow = 1.5 Estradiol green= 1 Dienogest
0.5
0 Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day 1 3 5 7 9 11 13 15 17 19 21 23 25 27 28
Dienogest/estradiol valerate Dosing
• One tablet once a day (note different tablet colors associated with varying content) • Response to missed pills depends on which pill was missed • Start on first day of menses
20 The time to onset of therapeutic effect (aPTT > 2x control) for dabigatran is 1 hour 6 hours 2-3 days One week
21 Ceftaroline
• “Next generation” cephalosporin indicated for treatment of acute bacterial skin and skin structure infections and community acquired pneumonia • Unique binding properties among cephalosporins for PBP2a • Good activity for MRSA and streptococci including multi-drug resistant Streptococcus pneumoniae • Lacks enterococcus coverage, limited gram negative spectrum
Ceftaroline Pharmacokinetics
• Low protein binding • Converted to active form by phosphatase enzyme • Half life 2.6 hours • Primarily renal elimination • Reduce dose in moderate to severe renal dysfunction • Drug interactions: no studies conducted
22 Ceftaroline Clinical Trials
• Non-inferiority trials comparing ceftaroline 600mg IV q12h to vancomycin plus azetreonam • Acute bacterial skin and skin structure infections • Responder rates on day three: ceftaroline 74%, vanc/aztreonam 64-68% • Clinical cure rates: ceftaroline 85-86%, vanc/aztreonam 85%
Ceftaroline Clinical Trials
• Randomized, double-blind non-inferiority trials comparing ceftaroline 600mg IV q12h to ceftriaxone 1gm IV once daily for 5-7 days • Patients with community acquired bacterial pneumonia • Known or suspected MRSA patients were excluded • Responder rates based on new FDA criteria on day 4 (confirmed bacterial pathogen): ceftaroline 69%, ceftriaxone 58-61% • Clinical cure rates 8-15 days after therapy: ceftaroline 81-83%, ceftriaxone 75-77%
23 Ceftaroline Adverse Effects
• Diarrhea • Nausea • Constipation • Vomiting • Rash • Positive direct Coombs test
Ceftaroline Dosing
• 600mg IV q12h over one hour (adults >/= 18 y/o) • Reduce dose for decreased renal function • For ESRD or dialysis 200mg IV q12h
24 Fingolimod
• Sphingosine 1-phosphate receptor modulator indicated to decrease the frequency of exacerbations and delay physical disability progression in adults with relapsing-remitting multiple sclerosis • Diminishes capacity of antigen activated lymphocytes to come out of lymph nodes • Decreases lymphocyte migration into CNS • Reduces number of lymphocytes in peripheral blood
25 Fingolimod Pharmacokinetics
• Bioavailability 93% • Peak concentration in 12-16 hours • Highly protein bound • Metabolized primarily by cytochrome P450 oxidation • Half life 6-9 days • No dose adjustment necessary for patients with renal or hepatic dysfunction • Exposure doubled in patients with severe hepatic dysfunction
26 Fingolimod Pharmacokinetics
• Drug interactions: • Class Ia and class III antiarrhythmics (decreased heart rate, potential for torsades) • Ketoconazole (increased fingolimod levels) • Vaccines (avoid live attenuated vaccines) • Immunosuppressives (increased risk of immunosuppression) • Beta blockers, diltiazem (additional heart rate reduction)
Fingolimod Clinical Trials
• Double blind trial in RRMS patients comparing fingolimod 0.5mg, 1.25mg and placebo over 24 months • Primary efficacy end point: annualized relapse rate • No additional benefit of 1.25mg over 0.5mg • Fingolimod 0.18 relapses/yr.; placebo 0.40 relapses/yr • Fingolimod 70% had no relapses, placebo 46% had no relapses • Number of new lesions on MRI: fingolimod 2.5; placebo 9.8
27 Fingolimod Clinical Trials
• Double-blind, double-dummy 12 month trial in patients with RRMS • Comparing fingolimod 0.5mg, 1.25mg and interferon beta-1a • Primary efficacy end point: annualized relapse rate • No advantage to 1.25mg dose vs. 0.5mg dose • Relapse rate: fingolimod 0.16 relapses/yr.; interferon 0.33 relapses/yr • Fingolimod 83% had no relapses; interferon 70% had no relapses • Mean number of new lesions: fingolimod 1.6 lesions; interferon 2.6 lesions
Fingolimod Adverse Effects
• Headache • Elevated AST/ALT • Influenza • Diarrhea • Back pain • Bradycardia • Heart block • Macular edema
28 Fingolimod Dosing
• 0.5mg daily with or without food • Observe for six hours after first dose for signs and symptoms of bradycardia • Check EKG, CBC, ophthalmologic exam, PFT’s, liver functions, VZV status and contraception • Monitor blood pressure for possible elevation
29 Lurasidone
• Atypical antipsychotic agent indicated for treatment of schizophrenia • Blocks serotonin type 2 (5HT2a) and dopamine type 2 (D2) receptors • Blocks serotonin type 7 (5HT7), serotonin type 1a (5HT1a) and alpha 2c adrenergic receptors with greater affinity than others in class • Low affinity for binding to alpha-1 adrenergic histamine-1 and cholinergic M1
Lurasidone Pharmacokinetics
• Bioavailability 9-19% • Highly protein bound • Reaches peak concentration in 1-3 hours • Increased peak and AUC when taken with food • Excreted primarily in feces • Half life 18 hours • Drug interactions: strong CYP 3A4 inhibitors- do not use; moderate CYP 3A4 inhibitors- limit to 40mg dose; rifampin (do not use); lithium (no lurasidone dose adjustment needed)
30 Lurasidone Clinical Trials
• Randomized trial comparing lurasidone 40mg, 80mg and 120mg/d and placebo over 6 weeks in patients with schizophrenia • Primary end point: difference from placebo in change in PANSS from baseline • Efficacy end points: -2.1 (40mg), -6.4 (80mg) and -3.5 (120mg) • Responder rates: placebo- 38%, 80mg- 52% and 120mg- 50%
Lurasidone Clinical Trials
• 6 week, active-controlled trial in patients with schizophrenia • Compared placebo, lurasidone 40mg, 120mg and olanzapine 15mg/d • Difference from placebo in change from baseline PANSS score primary end point • Lurasidone 40mg -9.7 points, 120mg -7.5 points; olanzapine -12.6 points
31 Lurasidone Adverse Effects
• Somnolence • Akathisia • Parkinsonism • Nausea • Dystonic reactions • Insomnia
Lurasidone Dosing
• 40mg once daily • 80mg once daily maximum recommended dose • Take with food
32 Spinosad
• Pediculocide indicated for topical treatment of head lice in patients four years of age and older • Excites neurons in the CNS • Produces contractions and tremors and insects become paralyzed from neuromuscular fatigue • Not thought to be due to direct effects on neuromuscular system
33 Spinosad Pharmacokinetics
• Plasma levels undetectable after 10 minute topical application
Spinosad Clinical Trials
• Spinosad compared to permethrin in two investigator-blind trials • Patients treated on day 0, returned on day 7 and retreated if live lice were present • If retreated, patients returned on days 14 and 21 • Lice free rates 14 days after final treatment: 84- 86% with spinosad, 42-44% with permethrin
34 Spinosad Adverse Effects
• Eye redness • Application site erythema • Application site irritation
Spinosad Dosing
• On dry hair, apply to scalp and hair enough to cover • Rinse off with warm water after 10 minutes • Repeat treatment if live lice are seen 7 days after first treatment
35 The natural chemical origin of fingolimod involves which combination Rotted meat and wood Corn and fermentation Cicadas and fungi Orchid nectar and birds
36 Roflumilast
• Oral phophodiesterase-4 inhibitor • Indicated for reduction in risk of COPD exacerbations in patients with severe COPD • Produces increases in cyclic AMP in inflammatory and structural cells • Suppresses cytokine release and inhibits lung infiltration with neutrophils
Roflumilast Pharmacokinetics
• Bioavailability 80% • Peak concentration in 1 hour • Protein binding 99% • Extensive hepatic metabolism by CYP 3A4 and CYP 1A2 to active metabolites • Half life 17 hours (parent cd.); 30 hours (metabolite) • Avoid use inpatient with moderate or sever hepatic impairment • Drug interactions: erythromycin, ketoconazole, fluvoxamine, cimetidine (increased roflumilast levels)
37 Roflumilast Clinical Trials
• Roflumilast 250mcg and 500mcg daily compared to placebo • Patients with moderate-severe COPD • End points: post-bronchodilator FEV1 and change in the SGRQ • FEV1 changes: +74ml, +97ml and -45ml • Improvements in SGRQ in all three groups, unique distinction not seen
Roflumilast Clinical Trials
• Pooled trials comparing roflumilast and placebo regarding COPD exacerbations • Salmeterol added to both groups in one study and tiotropium added to both groups in the other study • Roflumilast groups FEV1 improved 33-46ml, placebo improved 8-25ml • Rate of exacerbation: combo groups not different than the single drug treatment groups
38 Roflumilast Adverse Effects
• Diarrhea • Weight loss • Nausea • Insomnia, anxiety, depression, suicidal thoughts • Patients with CHF not studied in clinical trials
Roflumilast Dosing
• Take one tablet orally daily with or without food
39 Azilsartan
• Angiotensin receptor blocker indicated for the treatment of hypertension • Can be used alone or in combination with other antihypertensive agents • Selectively blocks the binding of angiotensin-2
with the AT1 receptor • Blocks vasoconstriction and aldosterone secreting effects
40 Azlisartan Pharmacokinetics
• Bioavailability 60% • Peak concentration 1.5-3 hours • 99% protein bound • Metabolized primarily by CYP 2C9 • Half life 11 hours • No dose adjustment based on age, race, gender, renal or hepatic impairment • Drug interactions: NSAID’s
Azlisartan Clinical Trials
• Randomized, double-blind trials comparing azlisartan 40mg, 80mg, placebo, olmesartan 40mg and valsartan 320mg daily • End points: trough blood pressure measurement and 24 hour ambulatory blood pressure monitoring • Trough blood pressures reductions: azlisartan 80mg 12-14/6-8mmHg, olmesartan 11-12/5-7mmHg, valsartan 9-10/4-7mmHg • Mean ambulatory blood pressure reductions: azilsartan 80mg 13-15/7-9mmHg, olmesartan 11- 12/7mmHg, valsartan 10/7mmHg
41 Azlisartan Adverse Effects
• Diarrhea
Azlisartan Dosing
• 80mg once daily • Consider 40mg daily starting dose for patients treated with higher doses of diuretics
42 Vilazodone
• Antidepressant indicated for major depressive disorder in adults • Potent SSRI activity plus partial agonist activity at 5HT1a • No affinity for norepinephrine or dopamine reuptake
43 Vilazodone Pharmacokinetics
• Bioavailability 72% when taken with food • Peak concentration in 4-5 hours • 96-99% protein bound • Extensively metabolized by CYP 3A4 and non- CYP pathways • Half life 25 hours • Drug interactions: MAOI’s; serotonin syndrome risk with usual suspects; drugs that interfere with hemostasis; inhibitors off CYP 3A4; inducers of CYP 3A4
Vilazodone Clinical Trials
• Two, randomized, double-blind, placebo- controlled trials over 8 weeks • Regimen: vilzazodone 10mg daily for 7 days then 20mg daily for 7 days then 40mg daily ongoing • Vilazodone superior to placebo as measured by MADRS total score • Difference from placebo in change from baseline was -3.2 points in one study and -2.5 points in the other study
44 Vilazodone Adverse Effects
• Diarrhea • Nausea • Dizziness • Insomnia • Vomiting • Abnormal dreams • Decreased libido • Abnormal orgasm
Vilazodone Dosing
• Initial dose 10mg once daily for 7 day then 20mg once daily for 7 days followed by 40mg once daily • Should be taken with food • Gradual dose reduction recommended when discontinuing
45 Linagliptin
• Indicated to improve glycemic control in adults with type 2 diabetes • Inhibits DPP-4 enzyme that normally degrades GLP-1 and GIP • Enhanced incretin effect
46 Linagliptin Pharmacokinetics
• Bioavailability 30% • Protein binding 70-80% • 10% metabolized to inactive metabolite, remainder excreted unchanged primarily by enterohepatic system • Half life 12 hours • No dosing adjustment necessary for patients with renal, hepatic impairment, age, gender weight or race • Drug interactions: rifampin
Linagliptin Clinical Trials
• Linagliptin 5mg daily compared to placebo • Baseline HgbA1c 8-8.1% • Difference form placebo at end of trial -0.6% and -0.7% • HgbA1c <7%: 28% and 25% (placebo group 15% and 12%) • FBS change from placebo: -20mg/dl and -23mg/dl
47 Linagliptin Clinical Trials
• Linagliptin 5mg daily or placebo added to metformin in 24 week randomized, double-blind trial • Baseline HgbA1c 8-8.1% • Change from baseline HgbA1c: -0.5% in combination group and +0.15% in the metformin/placebo group • HgbA1c < 7%: 28.3% in combination group and 11.4% in the metformin/placebo group • FBS difference between groups -21.1mg/dl • 2hrPPG -48.9mg/dl in combination group and +18.3mg/dl in metformin/placebo group
Linagliptin Adverse Effects
• Hypoglycemia • Nasopharyngitis • Increased uric acid • Pancreatitis •
48 Linagliptin Dosing
• 5mg once daily • Can be given with or without food
The impact of drugs that improve incretin function is primarily reflected in which of the following lab values? Fasting glucose Post-prandial glucose Triglycerides Lipase
49 The major monoclonal antibody drug for osteoporosis introduced in 2010 is: Panitumumab Nimotuzumab Denosumab Igovomab
Want to learn more?
• www.prescribersletter.com • www.wsj.com • The Pink Sheet • www.fda.gov • www.internetdrugnews.com • package inserts
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