Mease Countryside Hospital

Mease Countryside Hospital
2018 Medications Update Lairyn Kenney, PharmD Morton Plant Hospital Kevin Deemer, PharmD Mease Countryside Hospital

Speakers have no disclosures to report

Objectives Introduce medications FDA approved in 2018
Explain indication, mechanism of action, side effects, warning and precautions of newly approved medications Review pertinent clinical trial data leading to drug approval Provide clinical pearls

2018 Medication Approvals: 59
Circulatory Takhzyro Dermatology Seysara Rheumatology Olumiant Crysvita Ilumya Women’s Health Annovera Orilissa Infectious Disease Trogarzo Krintafel Moxidectin Revcovi Biktarvy Tpoxx Xofluza Zemdri Aemcolo Nuzyra Pifeltro Xerava Genetics Palynziq Galafold Takhzyro Neurology Epidiolex Aimovig Ajovy Emgality Diacomit Tegsedi Onpattrov GI/Urology/Nephrology Motegrity Lokelma Ophthalmology Oxervate Pain Lucemyra Pediatrics Omegaven Gilenya Pulmonology Symdeko Yupelri Lonhala Magnair Heme/Onc Akynzeo Asparlas Braftovi Crysvita Copiktra Daurismo Doptelet Elzonris Erleada Firdapse Gamifant Libtayo Lokelma Lorbrena Lumoxiti Lutathera Mektovi Mulpleta Palynziq Poteligeo Talzenna Tavalisse Tibsovo Xospata Ultomiris Vitrakvi Vizimpro

Infectious Disease

Complicated intra-abdominal infections
Indication Complicated intra-abdominal infections Class Synthetic fluorocycline; related to tetracycline Mechanism Inhibits protein synthesis by binding to bacterial 30S ribosomal unit Antimicrobial activity Gram-positive (Bacteriostatic) Gram-negative (Demonstrated bactericidal against certain strains of E. coli and K. pneumoniae in vitro) Anaerobes *Exception: No Pseudomonas coverage Drug Interactions May require lower dose of anticoagulation medications Strong 3A4 inducers may decrease efficacy of Xerava Not indicated for the treatment of complicated urinary tract infection Tigecycline is typically used for rapid growing mycobacterium This will not replace Tigecycline because unsure of for atypicals Xerava (eravacycline) [prescribing information]. Watertown, MA: Tetraphase Pharmaceuticals Inc; August 2018. Zhanel G, Cheung D, Adam H et al. Review of Eravacycline, a Novel Fluorocycline Antibacterial Agent. Drugs. 2016;76(5): doi: /s

1 mg/kg IV every 12 hours for 4-14 days
Dose 1 mg/kg IV every 12 hours for 4-14 days Child-Pugh Class C: 1 mg/kg IV every 12 hours on day 1, then every 24 hours for 4-14 days Administer over 60 minutes Warnings/ Contraindications Warnings: Hypersensitivity reactions Tooth discoloration during tooth development and/or inhibition of bone growth during late stage pregnancy, infants, children up to 8 years old Clostridium difficile-associated diarrhea CI: Known hypersensitivity to Xerava or tetracyclines Adverse Effects Infusion site reactions, N/V/D, hypotension, wound dehiscence At 1.5 mg/kg (higher than the recommended dose of 1 mg/kg), no QTc prolongation was experienced Poor oral bioavailability- 28% Xerava (eravacycline) [prescribing information]. Watertown, MA: Tetraphase Pharmaceuticals Inc; August 2018.

*Comparators include ertapenem and meropenem
Xerava (eravacycline) [prescribing information]. Watertown, MA: Tetraphase Pharmaceuticals Inc; August 2018.

Place in Therapy Multi-Drug Resistant Acinetobacter species Cost $175 per day of therapy

Neurology

Lennox-Gastaut Syndrome Dravet Syndrome
Indication Lennox-Gastaut Syndrome Dravet Syndrome Class Cannabinoid; Class V Dose Initiation: Recommended starting dose is 2.5 mg/kg twice daily by mouth May be increased after one week to 5 mg/kg twice daily for maintenance dosage Maximum maintenance dose can be of 10 mg/kg twice daily by mouth Hepatic adjustment: Adjust dose in patients with moderate-severe hepatic impairment (Child-Pugh B-C). May need to titrate doses slower than in patients with adequate hepatic function. Hepatic adjustment by reducing the dose in half Epidiolex (cannabidiol) [prescribing information]. Carlsbad, CA: Greenwich Biosciences, Inc; September 2018.

Warnings/ Contraindications
Mechanism Unknown Warnings/ Contraindications Warnings: May cause CNS depression, suicidal ideation (pooled analysis of antiepileptics) CI: Hypersensitivity to cannabidiol Adverse Effects Decreased weight (16%), decreased hemoglobin and hematocrit (30%), increased serum creatinine (reversible), transaminase elevations Drug Interactions Strong inhibitors of 3A4 and 2C19 will increase cannabidiol concentrations Co-administration with clobazam resulted in 3x increase in the active-metabolite of clobazam Warnings: standard to the anticonvulsants Epidiolex (cannabidiol) [prescribing information]. Carlsbad, CA: Greenwich Biosciences, Inc; September 2018.

Lennox Gastaut Syndrome Dravet Syndrome
Patients who saw ≥75% reduction in drop seizures Epidiolex 10 mg/kg/day: 11% 20 mg/kg/day: 25% VS. Placebo: 3% Dravet Syndrome Reduction in monthly seizures Epidiolex 20 mg/kg/day: 39% Vs. Placebo: 13% Monthly reduction of drop seizures: Epidiolex 10 mg/kg/day: 37% 20 mg/kg/day: 42% VS. Placebo: 17% Epidiolex (cannabidiol) [prescribing information]. Carlsbad, CA: Greenwich Biosciences, Inc; September 2018.

$14.82 per mL of 100 mg/mL solution $32,500 per year
Place in Therapy Lennox Gastaut: Adjunctive therapy to first and second line treatment options Dravet Syndrome: Though not included in 2016 expert treatment consensus, Epidiolex is a reasonable first line agent Palatability/Taste Cost $14.82 per mL of 100 mg/mL solution $32,500 per year Dominguez N. What is Dravet Syndrome?. Dravet Syndrome Foundation. Published Accessed February 28, 2019 Lgsfoundation.org. Published Accessed February 28, 2019.

Women’s Health

Gonadotropin-releasing hormone (GnRH) receptor antagonist
Class Gonadotropin-releasing hormone (GnRH) receptor antagonist Indication Management of moderate to severe pain associated with endometriosis Mechanism Inhibits GnRH, thereby suppressing luteinizing hormone and follicle-stimulating hormone, which decreases serum concentrations of estradiol and progesterone. Pharmacodynamics Orilissa caused dose-dependent reduction in median estradiol concentrations 150 mg PO daily: Ovulation rate of ~50%; median estradiol concentration of 42 pg/mL 200 mg PO twice daily: Ovulation rate of ~32%; median estradiol concentration of 12 pg/mL Class: This is in contrast compared to typical gonadotropin releasing hormone AGONISTS that are used in practice today, which cease production of estrogen. ORILISSA is a GnRH receptor antagonist that inhibits endogenous GnRH signaling by binding competitively to GnRH receptors in the pituitary gland. Administration of ORILISSA results in dose-dependent suppression of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), leading to decreased blood concentrations of the ovarian sex hormones, estradiol and progesterone. In a 3-menstrual cycle study in healthy women, ORILISSA 150 mg once daily and 200 mg twice daily resulted in an ovulation rate of approximately 50% and 32%, respectively. In the Phase 3 trials in women with endometriosis, ORILISSA caused a dose-dependent reduction in median estradiol concentrations to approximately 42 pg/mL for 150 mg once daily regimen and 12 pg/mL for the 200 mg twice daily regimen. Orilissa (elagolix) [product monograph]. St-Laurent, Quebec, Canada: AbbVie Corporation; October 2018

Maximum Treatment Duration
Dosing Regimen Maximum Treatment Duration Coexisting Condition Initiate treatment with ORILISSA 150 mg once daily 24 months None Consider initiating treatment with ORILISSA 200 mg twice daily 6 months Dyspareunia Initiate treatment with ORILISSA 150 mg once daily. Use of 200 mg twice daily is not recommended. Moderate hepatic impairment (Child-Pugh Class B) Dyspareunia- pain with intercourse Limited duration due to concern for bone loss Orilissa (elagolix) [product monograph]. St-Laurent, Quebec, Canada: AbbVie Corporation; October 2018

CI: Pregnancy, known osteoporosis, severe hepatic impairment, strong OAT-1B1 inhibitors Warnings: Bone loss, reduced ability to recognize pregnancy, suicidal ideation and mood disorders, elevated hepatic enzymes, potential for reduced efficacy with estrogen-containing contraceptives Adverse Effects Hot flashes, night sweats, nausea, headache, insomnia, mood swings, anxiety, arthralgia, amenorrhea Cost $ per month OAT-1B1: Cyclosporine, gemfibrozil, statins Bone loss is not reversible One completed suicide while on Orilissa Cost representative of without insurance Zoladex: $640/month Lupron: $1,600 Orilissa (elagolix) [product monograph]. St-Laurent, Quebec, Canada: AbbVie Corporation; October 2018

Add transition ORILISSA® (elagolix) 150 mg or 200 mg Tablets. ORILISSA.COM. Published Accessed March 1, 2019.

Pediatrics

Omegaven® (fish oil triglycerides)
Indication Source of calories and fatty acids in pediatric patients with parenteral nutrition-associated cholestasis (PNAC) Class Fish oil triglyceride Dose Recommended daily dose (and maximum dosage) 1 mg/kg Age Energy expenditure Clinical status Body weight Tolerance Ability to metabolize Consideration of additional energy sources given to the patient. Adverse Effects Vomiting, agitation, bradycardia, apnea and viral infections Omegaven® is NOT indicated for the prevention of PNALD. Parenteral nutrition (PN) is life saving for many preterm infants and other neonates with severe illness, but prolonged use of PN can lead to intrahepatic cholestasis, referred to as parenteral nutrition–associated cholestasis (PNAC). It is defined as direct bilirubin greater than 2.0 mg/dL persistent for at least 2 consecutive tests duringthe administration of PN, not associated with other known causes of cholestasis Limitations of use: Omegaven is not indicated for the prevention of PNAC. It has not been demonstrated that Omegaven prevents PNAC in parenteral nutrition (PN)-dependent patients. It has not been demonstrated that the clinical outcomes observed in patients treated with Omegaven are a result of the omega-6:omega-3 fatty acid ratio of the product. (1) Omegaven (fish oil triglycerides) [prescribing information]. Graz, Austria: Fresenius Kabi; July 2018.

Administration Infused via central or peripheral line, either directly from the vial, or admixed into TPN Administer Omegaven until direct or conjugated bilirubin are less than 2 mg/dL, or until the patient no longer requires parenteral nutrition Warnings/ Contraindications CI: Known hypersensitivity to egg or fish protein, severe hemorrhagic disorder, or severe hyperlipidemia or disorders of lipid metabolism with serum triglycerides > 1,000 mg/dL Warnings: Risk of death due to Pulmonary Lipid Accumulation Risk of infection, refeeding syndrome, fat overload syndrome and hypertriglyceridemia Aluminum toxicity Pulmonary Lipid Accumulation Risk of Death in Preterm Infants due to Pulmonary Lipid Accumulation: Deaths in preterm infants after infusion of intravenous soybean oil-based lipid emulsions have been reported in literature, and autopsy findings included intravascular fat accumulation in the lungs. Risk with Omegaven is unknown. Monitor for signs and symptoms of pleural or pericardial effusion. Omegaven (fish oil triglycerides) [prescribing information]. Graz, Austria: Fresenius Kabi; July 2018.

Clinical Trials Pair matched (2:1) in both Study 1 and Study 2 90% patients in Omegaven group were pre-term, vs. 83% in the comparator group Median chronological age: 9 weeks in Omegaven group vs. 7 weeks in comparator group Nutritional efficacy was assessed by biomarkers of lipid metabolism, growth indices (body weight, length/height and head circumference), and/or mean changes in fatty acid parameters Findings In the combined analysis from Study 1 and Study 2, the number of Omegaven and historical control patients who achieved full enteral feeding by the end of the study was 52 (63%) patients and 24 (59%) patients, respectively. The median time to full enteral feeding was approximately 15 weeks for both groups. Historical patients who received soybean oil lipid emulsion at 3 g/kg/day as a comparator Although Study 1 and Study 2 were not adequately designed to demonstrate noninferiority or superiority of Omegaven to the soybean oil-based lipid emulsion comparator, the data from these studies support Omegaven as a source of calories in pediatric patients with PNAC Study 1 enrolled patients less than 2 years of age and Study 2 enrolled patients less than 5 years of age. The median (range) of the duration of treatment was 2.7 months (5 days to 8 years) for the Omegaven group and 3.6 months (16 days to 2 years) for the historical control group. Omegaven (fish oil triglycerides) [prescribing information]. Graz, Austria: Fresenius Kabi; July 2018.

Cost: $535 per 500 mL Added to BayCare Formulary with restrictions: Pediatric patients on TPN > 7 days Pediatric patients who have received Smoflipids for minimum of 7 days Patients with direct bilirubin ≥ 2 mg/dL Although Study 1 and Study 2 were not adequately designed to demonstrate noninferiority or superiority of Omegaven to the soybean oil-based lipid emulsion comparator, the data from these studies support Omegaven as a source of calories in pediatric patients with PNAC Historical patients who received soybean oil lipid emulsion at 3 g/kg/day as a comparator Study 1 enrolled patients less than 2 years of age and Study 2 enrolled patients less than 5 years of age. The median (range) of the duration of treatment was 2.7 months (5 days to 8 years) for the Omegaven group and 3.6 months (16 days to 2 years) for the historical control group. In the combined analysis from Study 1 and Study 2, the number of Omegaven and historical control patients who achieved full enteral feeding by the end of the study was 52 (63%) patients and 24 (59%) patients, respectively. The median time to full enteral feeding was approximately 15 weeks for both groups. Omegaven (fish oil triglycerides) [prescribing information]. Graz, Austria: Fresenius Kabi; July 2018.

Infectious Disease

For antiretroviral (ARV) naive patients
Indication For antiretroviral (ARV) naive patients To replace current ARV therapy in virologically suppressed patients (HIV-1 RNA < 50 copies per mL) who: Are on a stable ARV regimen for 3 months No history of treatment failure No history of resistance to the individual components of BIKTARVY Mechanism 2 Nucleoside Reverse Transcriptase Inhibitors + Integrase Inhibitor Descovy + Integrase Inhibitor Similar to Triumeq (dolutegravir, abacavir, lamivudine) WARNING: POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing emtricitabine (FTC) and/or tenofovir disoproxil fumarate (TDF), and may occur with discontinuation of BIKTARVY. Closely monitor hepatic function with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue BIKTARVY. If appropriate, anti-hepatitis B therapy may be warranted [see Warnings and Precautions (5.1)]. Biktarvy (bictegravir, emtricitabine, tenofovir alafenamide) [prescribing information]. Foster City, CA; Gilead Sciences: February 2018.

50 mg/200 mg/25 mg 1 tablet by mouth once daily
Dose 50 mg/200 mg/25 mg 1 tablet by mouth once daily Warnings/ Contraindications Post treatment HBV acute exacerbation → liver decompensation and/or failure Not recommended in CrCl < 30 mL/min Drug Interactions Do not administer with dofetilide or rifampin No food-drug requirements Adverse Effects Immune reconstitution syndrome Declining renal function Lactic acidosis, severe hepatomegaly with steatosis Increases effects of dofetilide Side effects are similar across the board; less incidence of nausea 17% with Triumeq vs. 5% Biktarvy Cost: Triumeq: $3,366 (AWP) Biktarvy (bictegravir, emtricitabine, tenofovir alafenamide) [prescribing information]. Foster City, CA; Gilead Sciences: February 2018.

Treatment naïve patients: Triumeq vs. Descovy + Dolutegravir
Virological suppression in treatment naïve patients is was helped get this medication to be added as first line therapy Virologically suppressed patients: Incidence of adverse effects was also lower in the bictegravir groups than in the comparator arm and no individual in either study developed treatment-emergent resistance to any of the study drugs. Biktarvy (bictegravir, emtricitabine, tenofovir alafenamide) [prescribing information]. Foster City, CA; Gilead Sciences: February 2018 Gallant J, Lazzarin A, Mills A, et al. Bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir, abacavir, and lamivudine for initial treatment of HIV-1 infection (GS-US ): a double-blind, multicentre, phase 3, randomised controlled non-inferiority trial. Lancet. 2017;390(10107): Molina JM, Ward, D, Brar I, et al. Switching to fixed-dose bictegravir, emtricitabine, and tenofovir alafenamide from dolutegravir plus abacavir and lamivudine in virologically suppressed adults with HIV-1: 48 week results of a randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial. Lancet HIV. 2018;5(7):e357-e365

Now a recommended initial treatment regimen for most people with HIV
Place in Therapy Now a recommended initial treatment regimen for most people with HIV High resistance barrier- no treatment resistance in treatment naive patients through week 96, or in virologically suppressed patients through week 48 Cost $3,084 per 30 tablets (AWP) Cost of Triumeq: $2900

Infectious Disease

Treatment experienced adult patients with multidrug resistant HIV-1 infection failing their current regimen Class Monoclonal antibody Mechanism Binds to CD-4, interfering with post-attachment mechanisms of viral entry Dose 2,000 mg once, then 800 mg IV every 2 weeks in addition to oral HAART regimen Warnings/ Contraindications Immune reconstitution syndrome (IRIS) reported in 1 patient Adverse Effects Diarrhea, Nausea, Dizziness, Rash Trogarzo (ibalizumab-uiyk) [package insert]. Quebec, Canada; Theratechnologies, Inc.; May

HIV-1 worldwide resistance prevalence (1996 to 2016)
12% for protease inhibitors (PIs) 21% for nucleoside reverse transcriptase inhibitors (NRTIs) 22% for non-nucleoside reverse transcriptase inhibitors (NNRTIs) Resistance was measured using Stanford’s HIVdb program (genotypic screening, not measuring treatment failure in this case) Integrase inhibitor resistance was not assayed in this study INTEGRASE INHIBITOR RESISTANCE DATA Zazzi et al. PeerJ. 2018;6:e4848. Published 2018 May 25. doi: /peerj.4848

CD4 binding with GP120 prior to viral entry

Phase 3 Clinical Trial (Emu et al.) 40 patients enrolled Inclusion:
HIV-1 infection Treatment experienced w/ ‘triple resistance’ Viral load >1,000 copies/mL Intervention: Control period with current therapy from days 1 to 6 Ibalizumab loading dose 2000 mg IV day 7 Optimized oral regimen mg maintenance ibalizumab started day 14 Study conducted for 25 weeks Triple resistance referred to resistance to at least one agent in at least three classes Virologic failure was defined as two consecutive measurements after day 14 that showed a reduction from baseline in viral load of less than 0.5 log10 copies per milliliter. Viral rebound was defined as an increase of at least 1.0 log10 copies per milliliter in viral load from the nadir value. patients with less than 50 cells/mcL baseline count possessed far less change in CD4 count than patients with >50 cells /mcL (about 1/5th) Emu et al. Phase 3 Study of Ibalizumab for Multidrug-Resistant HIV-1. N Engl J Med. 2018;379(7):

31 patients in ITT analysis
9 patients dropped out 4 died 1 discontinued due to immune reconstitution syndrome Day 14 Viral response: 24 (60%) had >1 log10 change (10% of original) 33 (83%) had >0.5 log10 change (30% of original) Including first group Mean log10 change was Week 25 Viral response: 22 (55%) had >1 log10 change 25 (63%) had >0.5 log10 change Includes first group Mean log10 change was CD4 Response Mean increase of 62 cells/mcL Smart art w/ arrows for time progression

Designated as an orphan drug
Conclusion: ibalizumab produces antiretroviral and immunologic response in small subset of treatment refractory patients Place in therapy Designated as an orphan drug Disease population <200,000 American citizens Annual wholesale acquisition cost by OptumRx = $118,000 200mg/1.33mL vial 10 vials for loading dose 4 vials for maintenance dose OptumRx. Trogarzo™ (ibalizumab-uiyk) – New orphan drug approval. Accessed at:

Infectious Disease

Complicated Urinary Tract Infection With or Without Pyelonephritis
Indication Complicated Urinary Tract Infection With or Without Pyelonephritis Class Neoglycoside Antibiotic Mechanism Inhibition of 30S subunit of bacterial ribosome Dose CrCL > 90 mL/min: 15mg/kg IV q24h CrCL 60 to < 90 mL/min: 10mg/kg IV q24h CrCL 15 to <30 mL/min: 10mg/kg IV q48h Zemdri (plazomicin) [prescribing information]. South San Francisco, CA: Achaogen, Inc; June 2018.

Shared with aminoglycoside class:
Black Box Warnings Shared with aminoglycoside class: Nephrotoxicity: therapeutic drug monitoring required; higher prevalence in elderly and those receiving concomitant nephrotoxic medications Ototoxicity: may be irreversible and may not present until after completion of therapy Neuromuscular blockade: close monitoring for high risk patients Fetal Harm: crosses placental barrier; avoid use in pregnant population Therapeutic Drug Monitoring Target trough: < 3 mcg/mL Adjustment: increase interval x1.5-fold when trough high (i.e. 24 → 36h, 48 → 72h) Zemdri (plazomicin) [prescribing information]. South San Francisco, CA: Achaogen, Inc; June 2018.

Spectrum of activity Retains activity vs Enterobacteriaceae possessing aminoglycoside-modifying enzymes (AMEs) Susceptible pathogens E. coli, Klebsiella spp., Enterobacter spp., S. marascens, Citrobacter spp, M. morganii, Providencia spp., Proteus spp. Higher MICs with M morganii, Providencia spp., Proteus spp. Variable activity vs P. aeruginosa (comparable to poorer than traditional aminoglycosides) No activity vs A. baumanii Zemdri (plazomicin) [prescribing information]. South San Francisco, CA: Achaogen, Inc; June 2018.

Comparison of MIC of ACHN-490 (plazomicin) to classic aminoglycosides in bacteria with known aminoglycoside modifying enzymes Briefly explain MICs and aminoglycoside modifying enzymes We don’t have CLSI breakpoints yet on plazomicin, but compare roughly to amikacin (MIC for Enterobacteriaceae is 16) Aggen et al. Antimicrob Agents Chemother. 2010;54(11):

The difference in day 17 composite clinical cure rates was significant
Zemdri ® official website. Accessed at Cloutier DJ et al. Open Forum Infectious Diseases, Volume 4, Issue suppl_1, , pp S532,

Plazomicin within Baycare
Only 4 cUTI cases in 2018 were resistant to carbapenems and all current formulary aminoglycosides Of these 4, 3 were susceptible to ceftazidime/avibactam (1 not tested) Recommended not to adopted to formulary at this time due to narrow indication Based on Data from the CARE trial (or lack thereof) the FDA denied the indication for bloodstream infections, but there are certainly implications for potential use off-label for this indication

Neurology

70 mg or 140 mg subcutaneously once per month
Indication Migraine prevention Class Monoclonal antibody Mechanism Binds with high affinity to CGRP receptors, prevents CGRP-mediated vasodilation Dose 70 mg or 140 mg subcutaneously once per month Warnings/ Contraindications None Adverse Effects Injection site reactions (all other major reactions recorded were not statistically significant vs placebo) Aimovig (erenemab-aooe) [package insert]. Thousand Oaks, CA. Amgen, Inc; 2018 May.

Calcitonin Gene-related Peptide
Highly potent microvasodilator ~10 times more potent than any prostaglandin Subjects with chronic migraine have significantly higher plasma levels of CGRP 2 Patients displaying favorable outcomes to erenumab in trials displayed hypersensitivity to CGRP infusion 3 Image: modified from figure 5 of Russell et al.1 Russell et al. Physiol Rev. 2014;94(4): Cernuda-morollón et al. . Neurology. 2013;81(14):1191-6 Christensen et al. J Headache Pain. 2018;19(1):105

STRIVE trial (phase III)
Intervention groups Erenumab 140 mg SQ monthly Erenumab 70 mg SQ monthly Placebo SQ monthly Duration = 6 months Recreated from table 2 of Goadsby et al. Erenumab 140 mg Erenumab 70 mg Placebo Change in migraine days per month -3.7 ( + 0.2) -3.2 ( + 0.2) -1.8 ( + 0.2) >50% reduction from baseline migraine days per month 159 / 318 (50%) 135 / 312 (43.3%) 84 / 316 (26.6%) In the published article, outcomes so far only consist of data collected during treatment phase (24 weeks of treatment), not reported were active treatment phase (where all patients were re-randomized to receive 70 or 140mg [i.e. no placebo group], and the safety follow-up phase (12 weeks). Goadsby et al. N Engl J Med. 2017;377(22):

Adverse Events Event Pooled event rate (%) RR (95% CI) P value
Injection site pain Erenumab - 49/1413 (3.5) Placebo - 23/1014 (2.3) 1.69 ( ) 0.047 Hypertension Erenumab - 5/633 (0.8) Placebo - 8/319 (2.5) 0.36 ( ) 0.079 Any Adverse Event Erenumab - 786/1519 (51.7) Placebo /1167 (53) 0.95 ( ) 0.166 Any Serious Adverse Event Erenumab - 28/1519 (1.8) Placebo - 20/1167 (1.7) 0.96 ( ) 0.893 Adverse Event Leading to Discontinuation Erenumab - 24/1519 (1.6) Placebo - 14/1167 (1.2) 1.12 ( ) 0.744 This adverse event is from a recent metanalysis that looked at 5 clinical studies of Aimovig (including the STRIVE trial). These are a smaller selection of total events selected either for p significance or for clinical relevance and potential popular interest, note that only one outcome was found to be significant with an alpha of 0.05. Surprisingly, we see a lower rate of hypertension (though most accurately it is insignificant) for erenumab vs placebo Lattanzi et al. Drugs doi: /s

No cardiovascular adverse events reported during trials
Conclusions: No cardiovascular adverse events reported during trials Long term health outcomes are still being followed No drug-drug interactions identified during treatment Annual estimated cost of $6900 Per ICER, average discount of 27% - down to $5000 Same price for 70 mg and 140 mg dose strengths CGRP in research (as it is a vasodilator) has documented effects with implications in hypertension, pulmonary hypertension, heart failure, sepsis, kidney disease and more ICER: institute for clinical and economic review – institution that evaluates drugs and their cost effectiveness ICER official website. Accessed at

Neurology

Treatment of acute opioid withdrawal symptoms
Indication Treatment of acute opioid withdrawal symptoms Class Alpha-2 agonist Mechanism Bind with increased affinity to alpha 2a and 2c receptor subtypes; increased central effects, less hypotensive effects (attributed to alpha 2b) Warnings/ Contraindications Hypotension, Bradycardia, QT prolongation, CNS depression, Increased risk of relapse-related mortality, Discontinuation symptoms Adverse Effects Hypotension, Orthostasis, Bradycardia, Somnolence, Sedation, Xerostomia, Dizziness Opioid withdrawal (DSM-V) - at least 3 of the following symptoms after cessation or reduction of opioid use: dysphoric mood, nausea/vomiting, muscle aches, lacrimation/rhinorrhea, pupillary dilation, piloerection, diarrhea, yawning, fever, and insomnia. Lucemyra (lofexidine) tablets package insert. Louisville, KY: US WorldMeds, LLC; 2018 May.

Max dose = 4 tabs 4xdaily (16 tabs)
Initially:3 tablets (0.54 mg) PO every hours for 14 days (dose adjust as needed) Max dose = 4 tabs 4xdaily (16 tabs) Renal Impairment: CrCL 30 to < 90 mL/min: 2 tablets (0.36 mg) PO 4 times daily CrCL < 30 mL/min: 1 tablet (0.18 mg) PO 4 times daily Hepatic Impairment: Childs-Pugh B - 2 tablets (0.36 mg) PO 4 times daily Childs-Pugh C - 1 tablet (0.18) PO 4 times daily Lucemyra (lofexidine) tablets package insert. Louisville, KY: US WorldMeds, LLC; 2018 May.

Approved in UK since 1992 for treatment of opioid withdrawal
Recommendations in NICE guidelines Structurally similar to clonidine Noradrenaline upregulated during withdrawal Allodynia Vasomotor symptoms Restlessness Nausea/Vomiting National Collaborating Centre for Mental Health (UK). Leicester (UK): British Psychological Society; (NICE Clinical Guidelines, No. 52.) Available from:

Phase III Clinical Trial
Intervention: Lofexidine 0.8 mg or placebo PO 4x daily; days 1 - 5 All patients given placebo on days 6 and 7 no meds given on day 8 Primary Outcome: Subjective Opioid Withdrawal Scale - (Gossop) 0 - 3 for each item Results: Day 3 SOWS-G score 2.4 points lower vs placebo 71/134 (53%) completion per protocol vs 45/130 (34.6%) in placebo SOWS - Gossop Scale Each condition rated from 0 (none) to 3 (severe) Note: Lofexidine 0.18 mg PO as the American product is equivalent to 0.2 mg of lofexidine (1 tab) as marketed in UK Gorodetzky et al. Drug Alcohol Depend. 2017;176:79-88.

Comparison with Clonidine
Kahn A. et al. Drug and Alcohol Dependence (1). 57–61.doi: /s (96)

Clinical Pearls Place in therapy: setting where BP is not being monitored Example: elderly patients weaning off of high-dose opioids in ambulatory setting GoodRx price with coupon (as of February 2019): $ $2058 for 96 tablets (8 day supply at labeled dosing) Compared to ~$7 - $10 for clonidine 90 tablets (0.2 mg)

Respiratory

Lonhala Magnair Indication
Long-term chronic obstructive pulmonary disease (COPD) treatment Class Long acting muscarinic antagonist (LAMA) Mechanism Inhibits M3 cholinergic receptors in the lungs, causing bronchodilation Dose 1 vial (25 mcg) or 2 vials (50mcg) via nebulizer twice daily Warnings/ Contraindications Known hypersensitivity to glycopyrrolate Adverse Effects Adverse events with 2% higher incidence than placebo: Urinary tract infection Dyspnea

Lonhala = drug (glycopyrrolate)
Magnair = delivery device (detailed instructions for assembly/operation in package insert) Sylatron (peginterferon alfa-2b) [package insert]. Whitehouse Station, NJ: Merck Sharp & Dohme Corp; 2011. Lonhala Magnair (glycopyrrolate) [package insert]. Marlborough, MA: Sunovion Pharmaceuticals, Inc.

Clinical Trials Experience
Analysis Population Outcomes Pooled analysis of GOLDEN 3 and GOLDEN 4 Intervention: Placebo, glycopyrrolate 25mg, or glycopyrrolate 50mg Twice daily via nebulizer for 12 weeks 1,111 patients separated according to multiple criteria: Age: <65, >65, >75 years FEV1,% predicted: <50%, >50% Change in FEV1 from baseline: Glycopyrrolate 25 mg BID: L Glycopyrrolate 50mg BID: L p<0.001 in both Saint George’s Respiratory Questionnaire: Glycopyrrolate 25 mg BID: -3.71 Glycopyrrolate 50mg BID: Placebo: Continuation of background existing LABA/ICS therapy was granted in ~30% of the patients in these analyses SGRQ: St george’s respiratory questionnaire: subjective assessment that elucidates how severe a patient’s symptoms are at the particular time of administration (i.e. subjective scale good for trending and heavily validated). Max score is 60 and corresponds with worse symptoms Ohar et al. Int J Chron Obstruct Pulmon Dis. 2018;14: Dec 18. doi: /COPD.S184808

Right: FEV1 response separated into age groups
Left: graph depicing the FEV response in patients separated into baseline FEV1 groups Right: FEV1 response separated into age groups Ohar et al. Int J Chron Obstruct Pulmon Dis. 2018;14: Dec 18. doi: /COPD.S184808

Ohar et al. Int J Chron Obstruct Pulmon Dis. 2018;14:27-37. Dec 18
Ohar et al. Int J Chron Obstruct Pulmon Dis. 2018;14: Dec 18. doi: /COPD.S184808

Explain groups C and D briefly
Starting with the 2017 algorithm (restated in 2018), LAMAs became the first line agents in groups C and D for their reduction in exacerbations coupled with their mild side effect profile (quaternary ammonium compounds are very poorly absorbed by design) GOLD. Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) ( Accessed July 17, 2018); 2018

Place in Therapy First FDA approved LAMA for nebulizer Implications for in-patients with poor inspiratory capacity Dry powder inhalers require sharp inhalation Cost $1, per 60 unit-dose vial (30d supply) (AWP)

2018 Medication Approvals: First in class
Circulatory Takhzyro Dermatology Seysara Rheumatology Olumiant Crysvita Ilumya Women’s Health Annovera Orilissa Infectious Disease Trogarzo Krintafel Moxidectin Revcovi Biktarvy Tpoxx Xofluza Zemdri Aemcolo Nuzyra Pifeltro Xerava Genetics Palynziq Galafold Takhzyro Neurology Epidiolex Aimovig Ajovy Emgality Diacomit Tegsedi Onpattro GI/Urology/Nephrology Motegrity Lokelma Ophthalmology Oxervate Pain Lucemyra Pediatrics Omegaven Gilenya Pulmonology Symdeko Yupelri Lohnala Magnair Heme/Onc Akynzeo Asparlas Braftovi Crysvita Copiktra Daurismo Doptelet Elzonris Erleada Firdapse Gamifant Libtayo Lokelma Lorbrena Lumoxiti Lutathera Mektovi Mulpleta Palynziq Poteligeo Talzenna Tavalisse Tibsovo Xospata Ultomiris Vitrakvi Vizimpro 19 first in class drugs

2018 Medication Approvals: Rare “orphan” disease
Circulatory Takhzyro Dermatology Seysara Rheumatology Olumiant Crysvita Ilumya Women’s Health Annovera Orilissa Infectious Disease Trogarzo Krintafel Moxidectin Revcovi Biktarvy Tpoxx Xofluza Zemdri Aemcolo Nuzyra Pifeltro Xerava Genetics Palynziq Galafold Takhzyro Neurology Epidiolex Aimovig Ajovy Emgality Diacomit Tegsedi Onpattro GI/Urology/Nephrology Motegrity Lokelma Ophthalmology Oxervate Pain Lucemyra Pediatrics Omegaven Gilenya Pulmonology Symdeko Yupelri Lonhala Magnair Heme/Onc Akynzeo Asparlas Braftovi Crysvita Copiktra Daurismo Doptelet Elzonris Erleada Firdapse Gamifant Libtayo Lokelma Lorbrena Lumoxiti Lutathera Mektovi Mulpleta Palynziq Poteligeo Talzenna Tavalisse Tibsovo Xospata Ultomiris Vitrakvi Vizimpro 34 novel approvals for rare diseases

Acknowledgements Christine Price, PharmD Kerry Marr, PharmD, BCPS
Lynne Krop, PharmD, BCPS, AQ-ID

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