The P&T Committee Lisinopril (Qbrelis )

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1 Situation Background Assessment The P&T Committee Lisinopril (Qbrelis ) Qbrelis, 1 mg/ml lisinopril oral solution, has recently become an FDA- approved formulation. Current practice at UK Chandler Medical Center is to compound a lisinopril 1 mg/ml solution for patients requiring dosages unavailable in tablet formulations. Under the FD&C Act section 503A, there are restrictions on making drugs that are essentially copies of available formulations. These restrictions are put in place to decrease the public health risk of exposing patients to drug products that have not been shown to be safe and effective. Lisinopril was originally approved as an oral tablet by the FDA in 1987 for the treatment of HTN in adults and pediatric patients 6 years of age and older, adjunct therapy for heart failure, and treatment of acute myocardial infarction. Qbrelis was approved and found to be bioequivalent to lisinopril tablets by the FDA in July of The expected release date of this product is currently unknown. According to the FD&C Act in Section 503A (See Appendix I), A compounded drug product is not eligible for the exemptions in section 503A if it is both 1) essentially a copy of a commercially available drug product, and it is 2) compounded regularly or in inordinate amounts. The FDA considers a compounded drug product to be essentially a copy of a commercially available drug product if: The compounded drug product has the same active pharmaceutical ingredient(s) (API) as the commercially available drug product; The API(s) have the same, similar, or an easily substitutable dosage strength; and the commercially available drug product can be used by the same route of administration as prescribed for the compounded drug. Current practice at UK Chandler Medical Center is to compound a 1 mg/ml lisinopril solution using commercially available lisinopril 10 mg tablets, Ora- Plus and Ora- Sweet. Between August 2015 and September 2016, UK Chandler Medical Center used a lisinopril solution for dosing in 34 patients (approximately 650 ml needed). This compounding formulation contains the same API, the same dosage strength and same route of administration as the newly approved Qbrelis. Although not being compounded on a routine schedule, it can be anticipated that pediatric patients requiring lisinopril at lower dosages will be using the oral solution formulation. The cost of Qbrelis (150mL) is currently $592.80, while the UK compounded formulation is < $100 per 120 ml. Recommendation Recommendation to continue following Qbrelis for anticipated availability and addition to inpatient and outpatient formulary once available. Although there will be significant cost increase to provide patients with lisinopril oral solution, the regulations of the FD&C Act will require UK Chandler Medical Center to add Qbrelis to the inpatient and outpatient formulary if it wishes to abide by FDA regulations. Submitted By Hannah Underwood, PharmD Candidate 2017

2 Formulary Addition Request Lisinopril (Qbrelis ) REQUESTOR: Kentucky Children s Hospital Pediatric Satellite Pharmacy GENERIC NAME: Lisinopril PROPRIETARY NAME: Qbrelis MANUFACTURER: Silvergate Pharmaceuticals, Inc. THERAPEUTIC CLASS: Angiotensin- converting enzyme inhibitor OTHER AVAILABLE DOSAGE FORMS: Tablets, oral: 2.5 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg SERVICE OR PERSONS AFFECTED: UK Chandler Medical Center Pharmacies REQUEST RATIONALE: Current practice at UK Chandler Medical Center uses a compounding formula to make a 1 mg/ml lisinopril solution for doses less than available tablets. Information requested to determine if this newly approved lisinopril 1 mg/ml solution should be added to inpatient formulary to replace current compounding practice. HISTORY Lisinopril is an angiotensin converting enzyme (ACE) inhibitor that received its initial approval in 1987 for the treatment of HTN in adults and pediatric patients 6 years of age and older, adjunct therapy for heart failure, and treatment of acute myocardial infarction. INDICATIONS: Treatment of hypertension in adults and pediatric patients 6 years of age and older Adjunct therapy for heart failure Treatment of Acute Myocardial Infarction DOSING: Hypertension: Initial adult dose is 10 mg once daily. Titrate up to 40 mg daily based on blood pressure response. Initiate patients on diuretics at 5 mg once daily. Pediatric patients with glomerular filtration rate >30 ml/min/1.73m2: Initial dose in patients 6 years of age and older is 0.07 mg per kg (up to 5 mg total) once daily. Heart Failure: Initiate with 5 mg once daily. Increase dose as tolerated to 40 mg daily. Acute Myocardial Infarction (MI): Give 5 mg within 24 hours of MI followed by 5 mg after 24 hours, then 10 mg once daily. Renal Impairment: For patients with creatinine clearance 10 ml/min and 30 ml/min, halve usual initial dose. For patients with creatinine clearance <10 ml/min or on hemodialysis, the recommended initial dose is 2.5 mg. ADMINISTRATION: Oral administration DOSAGE ADJUSTMENTS: Children 6 years and Adolescents: o Manufacturer's labeling: GFR >30 ml/minute/1.73 m2: No dosage adjustment necessary. GFR <30 ml/minute/1.73 m2: Use is not recommended. o In addition, the following dosage adjustments have been recommended (Aronoff 2007): GFR >50 ml/minute/1.73 m2: No dosage adjustment necessary. GFR 10 to 50 ml/minute/1.73 m2: Administer 50% of usual dose.

3 GFR <10 ml/minute/1.73 m2: Administer 25% of usual dose. Intermittent hemodialysis: Administer 25% of usual dose Peritoneal dialysis (PD): Administer 25% of usual dose. Continuous renal replacement therapy (CRRT): Administer 50% of usual dose. AVAILABILITY/STORAGE: Qbrelis (lisinopril), 1 mg/ml, is supplied as 150 ml Store at controlled room temperature 20 C- 25 C in a tightly closed container. CLINICAL PHARMACOLOGY: Mechanism of Action o Lisinopril inhibits angiotensin- converting enzyme (ACE) in human subjects and animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. The beneficial effects of lisinopril in hypertension and heart failure appear to result primarily from suppression of the renin- angiotensin- aldosterone system. Inhibition of ACE results in decreased plasma angiotensin II which leads to decreased vasopressor activity and to decreased aldosterone secretion. PHARMACOKINETICS: The pharmacokinetics of lisinopril were studied in 29 pediatric hypertensive patients between 6 years and 16 years with glomerular filtration rate > 30 ml/min/1.73 m2. After doses of 0.1 to 0.2 mg per kg, steady state peak plasma concentrations of lisinopril occurred within 6 hours and the extent of absorption based on urinary recovery was about 28%. These values are similar to those obtained previously in adults. The typical value of lisinopril oral clearance (systemic clearance/absolute bioavailability) in a child weighing 30 kg is 10 L/h, which increases in proportion to renal function. CONTRAINDICATIONS: A history of angioedema or hypersensitivity related to previous treatment with an angiotensin converting enzyme inhibitor Hereditary or idiopathic angioedema Co- administration with aliskiren in patients with diabetes WARNINGS AND PRECAUTIONS: Fetal Toxicity: Use of drugs that act on the renin- angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. When pregnancy is detected, discontinue QBRELIS as soon as possible. Angioedema o Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis and/or larynx, including some fatal reactions, have occurred in patients treated with angiotensin converting enzyme inhibitors, including lisinopril, at any time during treatment. QBRELIS should be promptly discontinued and appropriate therapy and monitoring should be provided until complete and sustained resolution of signs and symptoms of angioedema has occurred.

4 o Intestinal Angioedema Intestinal angioedema has occurred in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C- 1 esterase levels were normal. Impaired Renal Function o Monitor renal function periodically in patients treated with QBRELIS. Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin- angiotensin system. Patients whose renal function may depend in part on the activity of the renin- angiotensin system (e.g., patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, post- myocardial infarction or volume depletion) may be at particular risk of developing acute renal failure on QBRELIS. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on QBRELIS Hypotension o QBRELIS can cause symptomatic hypotension, sometimes complicated by oliguria, progressive azotemia, acute renal failure or death. Patients at risk of excessive hypotension include those with the following conditions or characteristics: heart failure with systolic blood pressure below 100 mmhg, ischemic heart disease, cerebrovascular disease, hyponatremia, high dose diuretic therapy, renal dialysis, or severe volume and/or salt depletion of any etiology. o In these patients, QBRELIS should be started under very close medical supervision and such patients should be followed closely for the first two weeks of treatment and whenever the dose of QBRELIS and/or diuretic is increased. Avoid use of QBRELIS in patients who are hemodynamically unstable after acute MI. o Symptomatic hypotension is also possible in patients with severe aortic stenosis or hypertrophic cardiomyopathy. o Surgery/Anesthesia In patients undergoing major surgery or during anesthesia with agents that produce hypotension, QBRELIS may block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion. Hyperkalemia o Serum potassium should be monitored periodically in patients receiving QBRELIS. Drugs that inhibit the renin- angiotensin system can cause hyperkalemia. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium- sparing diuretics, potassium supplements and/or potassium- containing salt substitutes Hepatic Failure o ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice or hepatitis and progresses to fulminant hepatic necrosis and sometimes death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical treatment.

5 ADVERSE REACTIONS: Common adverse reactions (2% greater than placebo): o Hypertension: headache, dizziness and cough o Heart failure: hypotension and chest pain o Acute Myocardial Infarction: hypotension DRUG INTERACTIONS: Diuretics o Initiation of QBRELIS in patients on diuretics may result in excessive reduction of blood pressure. o QBRELIS attenuates potassium loss caused by thiazide- type diuretics. Therefore, if concomitant use of such agents is indicated, monitor the patient s serum potassium frequently. Antidiabetics o Concomitant administration of QBRELIS and antidiabetic medicines (insulins, oral hypoglycemic agents) may cause an increased blood- glucose- lowering effect with risk of hypoglycemia. NSAIDs o The antihypertensive effect of ACE inhibitors, including lisinopril, may be attenuated by NSAIDs. Dual Blockade of the Renin- Angiotensin System (RAS) o Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. mtor Inhibitors o Patients taking concomitant mtor inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema RECOMMENDED MONITORING: Blood pressure Heart rate BUN, Serum creatinine Potassium Consider baseline LFTs (if preexisting hepatic impairment)- monitor for jaundice or signs of hepatic failure Patient should be monitored for angioedema that may potentially affect airway or intestine, hypovolemia, postural hypotension, and anaphylactic reaction following first dose, any increase in dose, and regularly during therapy COST: Qbrelis: 1mg/mL (150 ml) = $ UK HealthCare Compounding formula: 1 mg/ml (120 ml) = $17.32 From August 2015 to September 2016 o 650 ml of lisinopril 1 mg/ml solution dispensed o Qbrelis: $2964 o UK HealthCare compounding formula: ~$100

6 References: 1. Qbrelis [package insert]. Greenwood Village, CO. Silvergate Pharmaceuticals, Inc. July Compounded Drug Products. Federal Food, Drug, and Cosmetic Act. Section 503A. July 2016