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Pharmaceutical Approval Update December 2016
Lisinopril Oral Solution (Qbrelis)
Manufacturer: Silvergate Pharmaceuticals, Inc., Greenwood Village, Colorado
Date of Approval: July 29, 2016
Indication: Lisinopril oral solution is indicated for the treatment of hypertension (HTN) in patients 6 years of age and older. It is also approved as adjunctive therapy for heart failure and to treat acute myocardial infarction (MI).
Drug Class: Angiotensin-converting enzyme inhibitor (ACEI)
Uniqueness of Drug: Many pediatric patients require ACEI treatment for HTN. Until the approval of Qbrelis, there was no commercially available ACEI preparation to treat this age group, although a number of ACEIs were extemporaneously compounded to prepare pediatric doses. Qbrelis is the first and only ACEI oral solution approved by the Food and Drug Administration. It is bioequivalent to lisinopril tablets under fasted and fed conditions.
Warnings and Precautions:
Boxed warning: fetal toxicity. Lisinopril should be discontinued immediately in a pregnant patient. Fetal injury and death may occur during the second and third trimesters of pregnancy. These drugs reduce fetal renal function and increase fetal and neonatal morbidity and death. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death.
Head and neck angioedema/intestinal angioedema. Angioedema of the face, extremities, lips, tongue, glottis, and/or larynx, including some fatal reactions, has occurred in ACEI-treated patients; intestinal angioedema has also occurred. Patients with tongue, glottis, or laryngeal involvement are likely to experience airway obstruction, especially those with a history of airway surgery. Lisinopril should be discontinued promptly and appropriate therapy and monitoring should be provided until complete and sustained resolution of angioedema has occurred. Patients with a history of angioedema unrelated to ACEI therapy may be at increased risk while receiving an ACEI. Coadministration of ACEIs and mammalian target of rapamycin inhibitors (e.g., temsirolimus, sirolimus, everolimus) may increase the risk for angioedema.
Anaphylactoid reactions. Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACEIs had life-threatening anaphylactoid reactions. Sudden and potentially life-threatening anaphylactoid reactions have occurred in some patients dialyzed with high-flux membranes while being concomitantly treated with an ACEI. Dialysis must be immediately stopped in these patients, and aggressive therapy must be initiated. Antihistamines did not relieve the symptoms in these situations. Therefore, consideration should be given to using a different type of dialysis membrane or a different antihypertensive class. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption.
Impaired renal function. Renal function should be periodically monitored in patients treated with lisinopril because acute renal failure may occur. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function.
Hypotension. Lisinopril can cause symptomatic hypotension, sometimes complicated by oliguria, progressive azotemia, or acute renal failure, which can be fatal. Patients at risk for excessive hypotension include those with heart failure with systolic blood pressure less than 100 mm Hg, ischemic heart disease, cerebrovascular disease, hyponatremia, or severe volume and/or salt depletion of any etiology, and those undergoing high-dose diuretic therapy or renal dialysis. In these patients, lisinopril should be started under close medical supervision and should be followed closely during the first two weeks of treatment and whenever the dose is increased and/or the diuretic dose is increased. Lisinopril should be avoided in patients who are hemodynamically unstable after acute MI. Symptomatic hypotension is also possible in patients with severe aortic stenosis or hypertrophic cardiomyopathy.
Hyperkalemia. During lisinopril treatment, serum potassium should be periodically monitored because ACEIs can cause hyperkalemia. Risk factors for developing hyperkalemia include renal insufficiency, diabetes mellitus, and concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt substitutes.
Hepatic failure. ACEIs have been associated with chole-static jaundice or hepatitis progressing to fulminant hepatic necrosis and sometimes death (mechanism unknown). Patients receiving ACEIs who develop jaundice or marked hepatic enzyme elevations should immediately discontinue the ACEI and receive appropriate medical treatment.
Dosage and Administration: Qbrelis is available in a 150-mL bottle containing 1 mg/mL of lisinopril oral solution.
In adults with HTN, begin treatment with 10 mg once daily. Adjust the dose to the blood pressure response. Doses up to 80 mg per day have been used, but do not appear to give greater effect. In combination with diuretics, the starting dose is 5 mg daily.
In patients with heart failure, initiate treatment with 5 mg once daily, and increase the dose as tolerated to 40 mg daily.
Acute MI patients should be administered 5 mg within 24 hours of the MI followed by 5 mg after 24 hours, then 10 mg once daily.
For pediatric HTN patients over the age of 6 years with a glomerular filtration rate greater than 30 mL/min/1.73 m2, start lisinopril oral solution at 0.07 mg per kg (up to 5 mg total) taken once daily. The dosage should be adjusted according to blood pressure response up to a maximum of 0.61 mg per kg (up to 40 mg) once daily. Doses above 0.61 mg per kg (or in excess of 40 mg) have not been studied in pediatric patients.
For patients with creatinine clearance greater than or equal to 10 mL/min and less than or equal to 30 mL/min, begin treatment with half the usual initial dose. For patients with creatinine clearance less than 10 mL/min or on hemodialysis, the recommended initial dose is 2.5 mg.
Commentary: The safety and efficacy of lisinopril were established in multiple studies treating adults with HTN, heart failure, and MI; however, it demonstrated less antihypertensive effect in black patients than in non-black patients.
In a clinical study of 115 hypertensive pediatric patients 6 to 16 years of age, the patients were divided into six treatment groups: those weighing less than 50 kg received 0.625 mg, 2.5 mg, or 20 mg of lisinopril once daily and those weighing 50 kg or more received 1.25 mg, 5 mg, or 40 mg of lisinopril once daily. Lisinopril was administered as tablets to patients tolerant of swallowing pills or in a suspension for those children who could not or who required a lower dose than was available in tablet form. After two weeks, lisinopril lowered trough blood pressure in a dose-dependent manner, with antihypertensive efficacy demonstrated at doses greater than 1.25 mg (0.02 mg per kg). This effect was confirmed in a randomized withdrawal phase, where the diastolic pressure rose by about 9 mm Hg more in patients randomized to placebo compared with patients who remained on the middle and high doses of lisinopril. This effect was consistent across several demographic subgroups (e.g., age, Tanner stage, gender, and race).
Sources: Silvergate Pharmaceuticals, Qbrelis prescribing information, Food and Drug Administration
Manufacturer: Sandoz, Princeton, New Jersey
Date of Approval: August 30, 2016
Indication: Etanercept-szzs is indicated for the treatment of moderately to severely active rheumatoid arthritis (RA), poly-articular juvenile idiopathic arthritis (JIA) in patients 2years of age and older, psoriatic arthritis (PsA), ankylosing spondylitis (AS), and plaque psoriasis (PsO).
Drug Class: Tumor necrosis factor-alfa (TNF-α) inhibitor biosimilar
Uniqueness of Drug: Erelzi is the first biosimilar for the blockbuster reference product Enbrel (etanercept, Amgen/Immunex). It is the first subcutaneously administered anti-TNF-α biosimilar to receive Food and Drug Administration approval.
Warnings and Precautions:
Boxed warning: malignancies.
- Lymphoma. Lymphoma cases have been observed in patients receiving TNF-α inhibitors. During the controlled portions of clinical trials in adults with RA, AS, and PsA, two lymphomas were observed among 3,306 etanercept-treated patients compared with none among 1,521 control patients. In other controlled and uncontrolled portions of etanercept clinical trials enrolling 6,543 adult patients with RA, AS, and PsA, the observed lymphoma rate was 0.10 cases per 100 patient-years (12,845 total patient-years of therapy). This rate was threefold higher than the rate expected in the general U.S. population based on the Surveillance, Epidemiology, and End Results Database (SEER).
- Leukemia. Post-marketing data have reported both acute and chronic leukemia cases associated with TNF inhibitors. Compared with the general population, RA patients may already have an approximate twofold higher risk of developing leukemia. During controlled portions of etanercept’s trials, two cases of leukemia occurred among 5,445 etanercept-treated patients compared with zero among 2,890 control patients (duration of treatment up to 48 months).
- Melanoma and nonmelanoma skin cancer. Melanoma and nonmelanoma skin cancer have been reported in TNF-α inhibitor-treated patients, including etanercept products. Periodic skin examinations should be considered for all patients at increased skin cancer risk.
Boxed warning: serious infections. Increased risk of serious infections leading to hospitalization or death, including tuberculosis (TB), bacterial sepsis, invasive fungal infections (such as histoplasmosis), and infections due to other opportunistic pathogens, have occurred.
Etanercept-szzs should not be started if a patient has an active infection. If one develops, patients should be carefully monitored, and etanercept-szzs should be stopped. Consider empiric antifungal therapy for patients at risk for invasive fungal infections who develop a severe systemic illness while receiving etanercept-szzs. All patients should be monitored for active TB during treatment, even if the initial latent TB test is negative.
Demyelinating disease. Etanercept and other TNF-α inhibitors have been associated with rare cases (less than 0.1%) of new-onset or exacerbated central nervous system demyelinating disorders, some presenting with mental status changes, permanent disability, and peripheral nervous system demyelinating disorders. Prescribers should use caution when considering etanercept-szzs for patients with pre-existing or recent-onset central or peripheral nervous system demyelinating disorders; etanercept products and TNF-α inhibitors have been associated with rare cases of new-onset multiple sclerosis, Guillain-Barré syndrome, seizure disorders, optic neuritis, and other related disorders.
Congestive heart failure. Worsening or new-onset congestive heart failure may occur. Physicians should exercise caution when using etanercept-szzs in patients who also have heart failure.
Hematological events. Rare reports (less than 0.1%) of pancytopenia, including very rare reports of aplastic anemia, some with fatal outcomes, have been reported in etanercept-treated patients. If pancytopenia or aplastic anemia symptoms develop, patients should immediately seek medical attention and consider stopping etanercept-szzs.
Hepatitis B reactivation. Monitor patients previously infected with hepatitis B virus during and several months following etanercept-szzs therapy. If reactivation of the virus occurs, consider stopping etanercept-szzs and beginning antiviral therapy.
Autoimmunity. Treatment with etanercept-szzs may result in autoantibody formation. If lupus-like syndrome or autoimmune hepatitis occurs, discontinue etanercept-szzs.
Drug interactions. Live vaccines should not be given concurrently with etanercept-szzs. Pediatric patients should be brought up to date with all immunizations before initiating therapy. Etanercept-szzs should not be administered with anakinra or abatacept due to an increased risk of developing serious infections. It should not be administered with cyclophosphamide due to a potentially higher incidence of developing noncutaneous solid malignancies.
Dosage and Administration: The recommended dosage for RA, AS, and PsA patients 18 years of age or older is 50 mg weekly. Adults with RA or PsA may also receive methotrexate if warranted. Adult PsO patients should begin on 50 mg twice weekly for three months, followed by maintenance doses of 50 mg once weekly. JIA patients weighing more than 63 kg should receive a 50-mg dose weekly.
Commentary: A biosimilar is a biological product that must demonstrate that it is highly similar to an already-approved biological product and has no clinically meaningful differences in terms of safety and effectiveness when compared with that reference product. The approval of Erelzi was based on review of evidence that included structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamic data, clinical immunogenicity data, and other clinical safety and effectiveness data that demonstrated its biosimilarity to the reference product Enbrel.
Sources: Sandoz, Erelzi-szzs prescribing information
Lumacaftor 100 mg/Ivacaftor 125 mg (Orkambi)
Manufacturer: Vertex Pharmaceuticals, Inc., Boston, Massachusetts
Date of Approval: September 30, 2016
Indication: Orkambi is indicated for the treatment of cystic fibrosis (CF) in patients 6 years of age and older who are homozygous for the F508del mutation on the CFTR gene. If the patient’s genotype is unknown, a Food and Drug Administration-cleared CF mutation test should be used to detect the presence of the F508del mutation on both alleles of the CFTR gene.
Drug Class: Cystic fibrosis transmembrane conductance regulator (CFTR) potentiator
Uniqueness of Drug: CF is a disease of exocrine gland function that involves multiple organ systems, predominantly the lungs, which results in chronic respiratory infections, pancreatic enzyme insufficiency, and associated complications if left untreated. Ninety percent of patients who survive the neonatal period have pulmonary involvement. End-stage lung disease is the principal cause of death. Previously, Orkambi tablets (lumacaftor 200 mg/ivacaftor 125 mg) were only approved for patients 12 years of age and older who are homozygous for the F508del-CFTR mutation. This new approval makes a lower-dosage tablet available (lumacaftor 100 mg/ivacaftor 125 mg), which expands the indication to include children 6 to 11 years of age with CF who are homozygous for the F508del-CFTR mutation.
Warnings and Precautions:
Hepatic injury. Liver-related events, such as elevated alanine transaminase (ALT) and aspartate transaminase (AST), have been observed in some cases associated with elevated bilirubin in Orkambi-treated patients. Serum transaminase and bilirubin levels should be measured before initiating Orkambi and should also be obtained every three months during the first year of treatment and annually thereafter. For patients with a history of ALT, AST, or bilirubin elevations, more frequent monitoring should be considered. Dosing should be interrupted in patients with ALT or AST levels greater than five times the upper limit of normal (ULN), or ALT or AST levels greater than three times the ULN with bilirubin levels greater than twice the ULN. Following resolution, consider the benefits and risks of resuming treatment.
Respiratory events. Chest discomfort, dyspnea, and abnormal respiration were observed more commonly during initiation of Orkambi. Clinical experience in patients with a percent-predicted forced expiratory volume in one second of less than 40 is limited, and additional monitoring of these patients is recommended during therapy initiation.
Blood pressure. Increased blood pressure has been observed in some patients; therefore, blood pressure should be periodically measured in all patients.
Cataracts. Noncongenital lens opacities/cataracts have been reported in pediatric patients treated with Orkambi and with ivacaftor monotherapy. Baseline ophthalmological examinations and follow-ups are recommended for pediatric patients.
Drug interactions. Use with sensitive cytochrome P4503A (CYP3A) substrates or CYP3A substrates with a narrow therapeutic index may decrease systemic exposure of the medicinal products, and coadministration is not recommended. Hormonal contraceptives should not be relied upon as an effective method of contraception. Use with strong CYP3A inducers may diminish exposure to ivacaftor, which may lessen its effectiveness; therefore, coadministration is not recommended.
Adverse reactions. The most common adverse reactions that occurred in 5% or more of patients were dyspnea, nasopharyngitis, nausea, diarrhea, upper respiratory tract infection, fatigue, abnormal respiration, increase in blood creatine phosphokinase, rash, flatulence, rhinorrhea, and influenza.
Dosage and Administration: The recommended dosage for patients 12 years of age and older is two tablets (each containing lumacaftor 200 mg/ivacaftor 125 mg) taken orally every 12 hours. The recommended dosage for children 6 to 11 years old is two tablets (each containing lumacaftor 100 mg/ivacaftor 125 mg) taken orally every 12 hours. Note that the recommended dose for this age group contains a lower dose of lumacaftor. When commencing treatment in patients taking strong CYP3A inhibitors, reduce the Orkambi dose for the first treatment week.
Commentary: The mean lumacaftor area under the curve at steady state (AUCss) following administration of Orkambi in 6- to 11-year-old patients dosed every 12 hours was comparable to the mean AUCss in patients 12 years of age and older. The mean ivacaftor AUCss was also comparable to the mean AUCss in patients 12 years of age and older. The safety profile of Orkambi in 6- to 11-year-old patients and in patients older than 12 years is similar. The safety and efficacy of Orkambi in CF patients younger than 6 years old have not been established.
Sources: Vertex, Orkambi prescribing information; Medscape eMedicine