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New Drug Update 2015 Jess Monitz, PharmD PGY-1 Pharmacy Resident Disclosure The presenter has no disclosures or conflicts of interest Outline Introduction New Medications to Market Review/Questions Objectives 1. Match the medications to their appropriate indication 2. Identify therapy limiting side effects of the medications 3. Explain correct storage and preparation directions for each medication 2015: A Year in Review 2015: A Year in Review Impact Novel Drug Orphan Drug Standard Drug 18% 47% Approval Priority Accelerated Standard 35% Fast Track Breakthrough Standard 32% 14% Designation 47% 31% 54% 22% Medications to Review Entresto®: Sacubitiril/valsartan Praxbind®: Idarucizumab Ibrance®: Palbociclib Bridion®: Sugammadex Avycaz®: Ceftazidime/Avibactam Corlanor®: Ivabradine Sacubitiril/Valsartan Indications Heart failure Reduces blood pressure Mechanism of Action Angiotensin receptor neprilysin inhibitor (ARNI) Sacubitril: Prodrug that inhibits neprilysin leading to increased levels of natriuretic peptides Valsartan: Direct antagonism of angiotensin II receptors inducing vasoconstriction through aldosterone, catecholamine, arginine vasopressin release Medication Properties Sacubitril is a prodrug converted to its active metabolite by esterases in the blood Use of an ACE inhibitor with sacubitril is contraindicated; allow a 36 hour washout period when switching from or to an ACE inhibitor Medication Dosing Patients previously taking >10 mg/day of enalapril or >160 mg/day of valsartan (or equivalent dose of another ACE inhibitor or ARB): Sacubitril 49 mg and valsartan 51 mg twice daily Patients previously taking low doses of an ACE inhibitor (≤10 mg/day of enalapril or ≤160 mg/day of valsartan (or equivalent dose of another ACE inhibitor or ARB): Sacubitril 24 mg and valsartan 26 mg twice daily Patients not currently taking an ACE inhibitor or an ARB: Sacubitril 24 mg and valsartan 26 mg twice daily Double the dose as tolerated after 2 to 4 weeks to the target maintenance dose of sacubitril 97 mg and valsartan 103 mg twice daily Storage, Preparation, and Administration Administer with or without food Store in a cool, dry place Precautions Side Effects • Hypotension • Hyperkalemia • Increase serum creatinine • Angioedema • Cough Contraindications • History of angioedema with previous ACE or ARB therapy • Use of ACE inhibitors within 36 hours of dose • Use with aliskirin • Pregnancy Clinical Trials Paradigm-HF Review Idarucizumab Indications Reversal of dabigatran (Pradaxa®) Indicated for emergent surgery or lifethreatening/uncontrolled bleeding Mechanism of Action Humanized monoclonal antibodies Binds to dabigatran and its metabolites Neutralizes the anticoagulation affect in minutes Medication Properties Effect on bleeding is observed within minutes and normal blood function is restored in approximately 12 hours Medication effect lasts for up to 24 hours Medication Dosing Administer 5 g as 2 separate, 2.5 mg doses 15 minutes apart No dosing adjustments are necessary May redose 5 g if patient continues to have elevated labs or needs emergent surgery Storage, Preparation, and Administration Medication is administered undiluted as an IV bolus Infusion of each vial should take no longer than 5-10 minutes If placed in a bag, medication expires in 1 hour Refrigerate medication in original packaging (protect from light) Vial is good for 48 hours at room temperature or 6 hours if exposed to light Precautions Side Effects •Hypersensitivity •Risk of clotting •Fever •Headache •Hypokalemia Contraindications •No contraindications to a rescue medication Clinical Trials Re-VERSE AD Review Palbociclib Indications Estrogen receptor (ER) positive, human epidermal growth factor (HER@) negative advanced breast cancer in combination with letrozole in post-menopausal women as initial endocrine based therapy in metastatic disease Mechanism of Action Palbociclib Inhibits cyclin-dependent kinase (CDK) 4 and 6 CDK 4 and 6 are downstream signaling pathways that lead to cell multiplication. Inhibiting this pathways prevents cells from moving for G1 into S phase of the cell cycle Medication Properties Must be administered with high-fat, high calorie meal because absorption increases drastically Medication is metabolized by the liver, leading to many drug-drug interactions Medication must be handled like a hazardous substance Medication Dosing 125 mg once daily with food for 21 days, then 7 days off Given in combination with letrozole 2.5 mg once daily In combination with Cyp3A4 inhibitors (azole antifungals, verapamil, etc.) dose should be reduced to 75 mg once daily Storage, Preparation, and Administration Must be administered with a high-fat meal at approximately the same time each day Capsules must be swallowed whole, cannot be opened Precautions Side Effects • Fatigue • Peripheral neuropathy • Alopecia • Nausea/vomiting (low) • Neutropenia • Infection Warnings • Neutropenia median onset of 15 days and duration of 7 days • Pulmonary embolism was observed in trials Clinical Trials Paloma-1/Trio-18 Paloma3 Review Sugammadex Indications Reversal of neuromuscular blockade from rocuronium or vecuronium Immediate reversal of neuromuscular blockade at 3 minutes after administration of rocuronium (intubation) Mechanism of Action Selectively binds free molecules of nondepolarizing neuromuscular blocking agents rocuronium or vecuronium Bridion Mechanism of Action Does not affect neuromuscular blocker already bound to receptors Rocuronium or vecuronium Though nondepolarizing neuromuscular blockers, pancuronium, ciastracurium and mivacurium fit poorly or not at all in the complex Bridion Inactive complex Medication Properties Onset of effect is less than 3 minutes Half-life is increased with renal impairment Medication is excreted in the urine unchanged Medication Dosing Routine reversal of rocuronium or vecuronium-induced blockade Deep block: 4 mg/kg as a single dose Moderate block: 2 mg/kg as a single dose Immediate reversal of rocuronium-induced blockade (intubation) 16 mg/kg as a single dose administered soon (~3 minutes) after administration of a single dose of 1.2 mg/kg of rocuronium This dose has not been evaluated following administration of vecuronium Storage, Preparation, and Administration Rapid IV push over 10 seconds Compatible with NS, D5W, LR, D5NS Store at 25°C Protect from light Product is only good for 5 days if not protected from light Precautions Side Effects •Hypotension •Headache •Nausea •Vomiting •Pain at injection site Warnings/Precautions •Sugammadex has a high affinity for bone and tooth enamel which may cause deposits of the medication •Bradycardia can occur within minutes after administration and can be treated with atropine if necessary •Recurrence of neuromuscular blockade usually due to suboptimal dosing •Only indicated to surgical reversal of neuromuscular blockers, use in the intensive care unit has not been evaluated Contraindications •Hypersensitivity was documented in studies •CrCl <30 mL/min or dialysis Clinical Trials Aurora Trial Review Ceftazidime/Avibactam Indications Complicated intra-abdominal infections Complicated urinary tract infections including pyelonephritis Coverage of gram positive and gram negative organisms, especially those resistant to carbapenems (e.g. meropenem) Mechanism of Action Ceftazidime: Inhibits bacterial cell wall synthesis causing the bacteria to lyse Avibactam: Inactivates betalactamases and protects ceftazidime from degradation Avycaz Medication Properties Avycaz 2.5 g contains 2 g ceftazidime and 0.5 g avibactam Eliminated in the urine Medication Dosing 2.5 g IV every 8 hours for 5-14 days Dose is reduced for patients with renal impairment Storage, Preparation, and Administration Store at room temperature and protect from light Supplied as a powder that is reconstituted with 10 mLs NS Store vials at room temperature and protect from light Mixed solutions are good for 12 hour at room temperature or 24 hours refrigerated Precautions Side Effects • Constipation • Abdominal pain • Anxiety • Renal impairment • Dizziness • C.diff Contraindications • Allergy to penicillins or cephalosporins • Previous neurotoxicity Clinical Trials Urinary tract: Recapture 1 and 2 Intra-abdominal: Reclaim 1 and 2 Review Ivabradine Indications Stable systolic heart failure Ejection fraction of <35 Heart rate >70 Used a beta blocker at the highest tolerated dose Inappropriate sinus tachycardia (off-label) Mechanism of Action Funny Channel Antagonist Works only on channels that are hyperpolarized No effects on repolarization or heart contractility Medication Properties Metabolized in the liver by Cyp3A4 causing lots of drug interactions Azole antifungals, HIV medications, diltiazem, verapamil, digoxin, amiodarone Must be taken with food, availability of the medication is doubled Medication Dosing Recommended starting dose is 5 mg twice daily with meals Dose can be increased to 7.5 mg twice daily after two weeks to achieve a resting heart rate of 50-60 beats per minute Heart rate >60 bpm: Increase by 2.5 mg twice daily Heart rate <50 or symptoms of bradycardia: Decrease by 2.5 mg twice daily Patients with a history of conduction defects, bradycardia, hemodynamic compromise, or they elderly may want to initiate therapy at 2.5 mg BID Storage, Preparation, and Administration Administer with meals Store in a cool, dry place Precautions Side Effects • Luminous phenomena • Increased uncorrected Qt interval with heart rate slowing • New onset atrial fibrillation • Bradycardia • Conduction disturbances • Risk of fetal toxicity Contraindications • Acute decompensate heart failure • Blood pressure less than 90/50 mmHg • Sick sinus syndrome, sinoatrial block, or 3rd degree AV block • Resting heart rate less than 60 bpm prior to treatment • Severe hepatic impairment • Pacemaker dependence Clinical Trials Systolic Heart Failure: SHIFT Trial Stable Coronary Heart Disease: Beautiful and Signify Trials Inappropriate Sinus Tachycardia Review Questions 1. Choose the correct match between the drug and its indication a. Ceftazidime/avibactam = heart failure c. Ivabradine d. Sugammadex b. Idarucizumab = breast cancer c. Palbociclib = reversal of dabigatran d. Sugammadex = Reversal of roncuronium e. Ivabradine = intra-abdominal infections 2. Which side effect limits the use of ivabradine? a. Bradycardia (slow heart rate) b. Nausea c. Skin rash d. Headache 4. Which medication is classified as a hazardous drug and appropriate precautions should be followed a. Idarucizumab b. Sacubitiril/valsartan c. Ceftazidime/avibactam d. Palbociclib 5. Which medication causes therapy limiting hypotension (low blood pressure)? a. Ivabradine b. Sugammadex 3. Which medication is dispensed as 2 vials that are drawn into 1 syringe and administered as a bolus? a. Palbociclib b. Idarucizumab c. Sacubitiril/valsartan d. Ceftazidime/avibactam
