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Insulin degludec, Lixisenatide, and Patiromer sorbitex calcium
DEPARTMENTS Journal of the American Pharmacists Association 56 (2016) 691e694
Contents lists available at ScienceDirect
Journal of the American Pharmacists Association journal homepage: www.japha.org
NEW DRUGS
Insulin degludec, Lixisenatide, and Patiromer sorbitex calcium Daniel A. Hussar, Melissa N. White
Antidiabetic agents Insulin degludec (TresibaeNovo Nordisk) is the third long-acting human insulin analogue, joining insulin glargine (Lantus) and insulin detemir (Levemir). It is prepared with the use of recombinant DNA technology and, following subcutaneous administration, forms multihexamers that result in a depot of the drug and delayed absorption from the subcutaneous tissues. Its duration of action is approximately 42 hours and it is administered once a day. The duration of action of insulin glargine (Lantus) is approximately 24 hours and it is administered once a day, and the duration of action of insulin detemir is somewhat less than 24 hours and it is administered once or twice a day. A new formulation of insulin glargine (Toujeo) has a duration of action that is slightly more than 24 hours. Insulin glargine (both Lantus and Toujeo) and insulin detemir should be administered at the same time each day, whereas insulin degludec may be administered at any time of the day. Insulin degludec is indicated to improve glycemic control in adults with type 1 or 2 diabetes mellitus. The indication for the Toujeo formulation of insulin glargine also limits use to adult patients, whereas the indications for the Lantus formulation of insulin glargine and insulin detemir include pediatric patients with type 1 diabetes as young as 6 years and 2 years, respectively. Insulin degludec and the other longacting insulins should not be used for the treatment of patients with diabetic ketoacidosis, for which the intravenous administration of a rapid-acting or short-acting insulin would usually be indicated.
The effectiveness of insulin degludec was evaluated in multiple clinical studies in which it was demonstrated to be noninferior to insulin glargine and insulin detemir in lowering glycosylated hemoglobin (HbA1c) concentrations. In some studies, the frequency of nocturnal hypoglycemia with insulin degludec was lower than with the other insulin analogs. In another study, insulin degludec was determined to be more effective than sitagliptin (Januvia) in lowering HbA1c concentrations, but it was also more likely to cause hypoglycemia. All insulins may cause hypoglycemia, and this is the most important concern with their use. The use of insulin degludec is contraindicated during episodes of hypoglycemia, and patients should be more closely monitored regarding this risk when changes are made in insulin dosage, coadministration of other glucose-lowering medications, meal patterns, and/or physical activity. Caution should also be exercised in patients with hepatic or renal impairment. The risk of hypoglycemia may be increased not only by the concurrent use of other antidiabetic agents, but also by medications such as angiotensin-converting enzyme inhibitors (ACEIs; e.g., lisinopril) and angiotensin II receptor blockers (ARBs; e.g., valsartan). Conversely, the blood glucoseelowering effect may be reduced by the concurrent use of medications
such as thiazide diuretics and corticosteroids. The activity of insulin degludec may also be altered by the consumption of alcoholic beverages or the concurrent use of a beta-blocker. Beta-blockers and other anti-adrenergic drugs, such as clonidine, may also blunt the signs and symptoms of hypoglycemia and delay the recognition of a developing problem. In addition to hypoglycemia, other commonly occurring adverse events in the clinical studies include nasopharyngitis (reported in 13% of patients with type 2 diabetes), headache (9%), upper respiratory tract infection (8%), and diarrhea (6%). Patients with type 2 diabetes treated with insulin degludec for 1 year experienced weight gain of an average 3 kg. Some patients have experienced hypersensitivity reactions, injection site reactions, rash, lipodystrophy, edema, and hypokalemia. Potassium concentrations should be monitored in patients at risk for hypokalemia. The thiazolidinedione antidiabetic agents (e.g., pioglitazone) may also cause edema and, when used concurrently with insulin degludec or other insulins, fluid retention and heart failure have occurred in some patients. If heart failure occurs, dosage reduction or discontinuation of treatment should be considered. Insulin degludec is classified in Pregnancy Category C and should be used during pregnancy only if the anticipated
The New Drugs column informs readers about new chemical and biologic entities approved for marketing by the US Food and Drug Administration. The column is written by Contributing Editor Daniel A. Hussar, PhD, Remington Professor of Pharmacy, Philadelphia College of Pharmacy, University of the Sciences in Philadelphia, PA.
http://dx.doi.org/10.1016/j.japh.2016.10.002 1544-3191/© 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.
DEPARTMENTS D.A. Hussar, M.N. White / Journal of the American Pharmacists Association 56 (2016) 691e694
benefit justifies the risk to the unborn child. The effectiveness and safety of the drug in patients younger than 18 years of age have not been established. Insulin degludec is administered subcutaneously into the thigh, upper arm, or abdomen once a day at any time of the day. However, to encourage compliance in administering the daily doses, it is recommended that the drug be administered at approximately the same time each day. Injection sites should be rotated to reduce the risk of lipodystrophy. The dosage of insulin degludec must be individualized based on the patient’s metabolic needs, blood glucose monitoring results, and the glycemic control goal. The starting dose is determined, and the recommended interval between dosage increases is 3 to 4 days. In insulinnaïve patients with type 1 diabetes, the recommended starting dose is approximately one-third to one-half of the total daily insulin dose. The remainder of the total daily insulin dose should be administered as a short-acting insulin and divided between each daily meal. As a general rule, 0.2 to 0.4 units of insulin per kilogram of bodyweight can be used to calculate the initial total daily insulin dose. In insulin-naïve patients with type 2 diabetes, the recommended starting dose is 10 units once a day. For patients with type 1 or type 2 diabetes who are already on insulin therapy, insulin degludec should be started at the same dose in units as the total daily long- or intermediate-acting insulin dose in units. Patients who miss a dose should inject their daily dose during waking hours when they recognize that a dose has been missed. At least 8 hours should separate the administration of consecutive doses. Insulin degludec is supplied in prefilled pens (Flextouch) containing 100 units/mL (U-100; 3 mL) and 200 units/mL (U-200; 3 mL). The pens enable, respectively, maximum doses of 80 units and 160 units per single injection. The dose window for both the U-100 and U-200 pens shows the number of insulin units to be delivered, and dose conversion is not needed. Before use, the insulin degludec pens should be stored in a refrigerator, but once “in use,” the pens should not be refrigerated and may be kept at room temperature for up to 8 weeks.
692
At the same time that it approved insulin degludec, the FDA also approved a combination formulation (Ryzodeg 70/30) of insulin degludec with insulin aspart, a rapid-acting human insulin analogue. However, this product is not currently available, and marketing plans are indefinite. More recently, the FDA has approved a “follow-on” version of insulin glargine (Basaglar) that is similar in activity to Lantus. GLP-1 agonists Glucagon-like peptide 1 (GLP-1) is a peptide hormone that is released soon after eating a meal. It has been shown to suppress glucagon secretion from pancreatic alpha cells and stimulate glucose-dependent insulin secretion by pancreatic beta cells. Lixisenatide (AdlyxineSanofi [marketed under the trade name Lyxumia in many other countries]) is the fifth GLP-1 receptor agonist to be marketed in the United States, joining exenatide (Byetta), extended-release exenatide (Bydureon), liraglutide (Victoza), albiglutide (Tanzeum), and dulaglutide (Trulicity). Like the other agents, lixisenatide is administered subcutaneously and is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. As with liraglutide, lixisenatide is administered once a day, whereas the Byetta formulation of exenatide is administered twice a day, and albiglutide, dulaglutide, and the extended-release formulation of exenatide are administered once a week. The effectiveness of lixisenatide was evaluated in 10 clinical trials that enrolled 5400 patients with type 2 diabetes. The new agent was studied as monotherapy and in combination with other antidiabetic agents, including metformin, sulfonylureas, pioglitazone, and a basal insulin. Lixisenatide provided reductions in HbA1c and fasting plasma glucose concentrations. In a 12-week placebo-controlled study, patients treated with lixisenatide (20mcg daily) experienced a reduction in HbA1c concentrations of 0.83% compared with a reduction of 0.18% in patients receiving placebo, representing a difference from placebo of 0.65%. As with the other GLP-1 agonists, lixisenatide is not recommended as firstline therapy for patients whose diabetes
is inadequately controlled with diet and exercise. Metformin is the usual initial treatment of choice in patients with type 2 diabetes who do not have risk factors that would preclude its use. Many patients with diabetes, however, do not experience adequate glycemic control with the use of metformin alone, and a GLP-1 agonist is among the options available for addition to the regimen. In an active-controlled study in patients with type 2 diabetes inadequately controlled with diet, exercise, and metformin, patients were treated with lixisenatide (20 mcg once a day) or exenatide (10 mcg twice a day). The new drug met the prespecified noninferiority margin of 0.4% for the difference in HbA1c reduction from baseline. However, lixisenatide provided less of an HbA1c reduction ( 0.73%) than exenatide ( 0.90%), and the difference was statistically significant. Lixisenatide has also been evaluated in a placebo-controlled cardiovascular outcomes trial in more than 6000 patients with type 2 diabetes after a recent acute coronary syndrome event. The primary composite end point was the time to the first occurrence of a major adverse cardiovascular event, and the use of lixisenatide did not increase the risk of such events. Although lixisenatide did not increase or decrease cardiovascular risks, the results of a recent study with liraglutide indicate a reduction in the risk of cardiac death of 22% and a reduction of overall heart risks of 13%. However, liraglutide and lixisenatide have not been directly compared in clinical studies of cardiovascular outcomes. The limitations of use with lixisenatide are generally similar to those for the other GLP-1 agonists. It is not indicated for the treatment of patients with type 1 diabetes or patients with diabetic ketoacidosis. It has not been studied in patients with gastroparesis, and use is not recommended in those patients. Acute pancreatitis has been infrequently reported with the GLP-1 agonists, including lixisenatide, and treatment should be promptly discontinued if pancreatitis is suspected. Other antidiabetic agents should be considered for patients with a history of pancreatitis. Lixisenatide has not been studied in combination with short-acting insulin. Certain of the GLP-1 agonists have been reported to cause thyroid C-cell tumors in rodents. Although it is not
DEPARTMENTS D.A. Hussar, M.N. White / Journal of the American Pharmacists Association 56 (2016) 691e694
known whether these agents cause these tumors, including medullary thyroid carcinoma (MTC), in humans, the labeling for extended-release exenatide, liraglutide, albiglutide, and dulaglutide includes a boxed warning about this possibility and contraindications for use in patients with a personal or family history of MTC or patients with multiple endocrine neoplasia syndrome type 2. However, the labeling for lixisenatide does not include warnings or contraindications regarding this potential risk. The most commonly experienced adverse events in the clinical studies of lixisenatide include nausea (25%), vomiting (10%), headache (9%), diarrhea (8%), and dizziness (7%). Serious hypersensitivity reactions, including anaphylaxis, have been infrequently experienced. It is not known if individuals who have experienced such a reaction with another GLP-1 agonist are predisposed to those events with lixisenatide, and the use of the new drug in these patients must be closely monitored. Acute kidney injury and worsening of chronic renal failure have occurred in a small number of patients treated with a GLP-1 agonist. Most of these events have been reported in patients who have experienced severe gastrointestinal (GI) adverse events. Renal function should be monitored when initiating treatment or increasing the dosage of lixisenatide in patients with renal impairment and in patients with serious GI reactions. The use of lixisenatide is not recommended in patients with end-stage renal disease. Patients may develop antibodies to lixisenatide; in a pooled analysis of studies, 70% of patients were antibody positive at week 24, although information is not available regarding the presence of neutralizing antibodies. A higher incidence of allergic reactions and injection site reactions has been reported in antibody-positive patients, and an attenuated glycemic response has been observed in patients with the highest antibody concentrations. Many patients with diabetes are overweight, and some antidiabetic agents (e.g., insulin, sulfonylureas) have been associated with weight gain during treatment. Numerous patients treated with a GLP-1 agonist have experienced weight loss and, in most of the studies of lixisenatide, patients experienced a small loss in weight.
Lixisenatide should be used during pregnancy only if the anticipated benefit justifies the risk to the unborn child. The effectiveness and safety of the new agent in patients younger than 18 years of age have not been established. Lixisenatide and the other GLP-1 agonists are not likely to cause hypoglycemia. However, there is an increased risk of this response if it is used in combination with insulin or an insulin secretagogue (e.g., a sulfonylurea), and a reduction in dosage of the latter agent may be necessary. The GLP-1 agonists delay gastric emptying, which may reduce the rate of absorption of orally administered medications. The use of oral medications that have a narrow therapeutic index or otherwise require close monitoring must be used with additional caution in patients treated with lixisenatide. If one of these oral medications should be administered with food, patients should be advised to take it with a meal or snack other than the first meal of the day that is preceded by lixisenatide administration. Oral medications such as antibiotics, that depend on threshold concentrations for efficacy, as well as medications such as acetaminophen, for which a delay in the onset of action is undesirable, should be administered at least 1 hour before lixisenatide. Women taking oral contraceptives should be advised to take them at least 1 hour before or at least 11 hours after administration of lixisenatide. Following subcutaneous administration of lixisenatide, the median time to maximum concentration is 1 to 3.5 hours. Its metabolism and elimination are thought to occur via proteolytic degradation and glomerular filtration. Plasma concentrations are increased in patients with impaired renal function. Dosage adjustment is not necessary in patients with mild or moderate renal impairment, although patients should be monitored for changes in renal function and the occurrence of GI adverse events. There is only limited experience with lixisenatide in patients with severe renal impairment, and treatment must be closely monitored. The activity of lixisenatide is not likely to be changed in patients with hepatic impairment. Lixisenatide is administered by subcutaneous injection in the abdomen, thigh, or upper arm. Treatment is initiated with a dosage of 10 mcg once a day within 1 hour before the first meal of the
day, for 14 days. On day 15, the dosage should be increased to 20 mcg once a day. If a dose is missed, the drug should be administered within 1 hour before the next meal. Lixisenatide injection is supplied in single patient-use pens containing 3 mL of solution. The pen used for initiating treatment contains the drug in a concentration of 50 mcg/mL and delivers 14 doses of 10 mcg. The pen to be used for maintenance treatment contains lixisenatide in a concentration of 100 mcg/mL, and delivers 14 doses of 20 mcg. The products should be stored in a refrigerator before the first use. When use of the pen is initiated, it may be stored at room temperature and protected from light. A pen should be discarded 14 days after first use. Agent for hyperkalemia Hyperkalemia is characterized by a serum potassium concentration greater than 5.0mEq/L, and may be associated with complications such as cardiac arrhythmias. It is most often experienced by patients with kidney disease, heart failure, or diabetes, particularly in those who are taking medications that inhibit the renin-angiotensin-aldosterone system (RAAS), such as ACEIs (e.g., lisinopril), ARBs (e.g., valsartan), the direct renin inhibitor aliskiren (Tekturna), and aldosterone antagonists (e.g., spironolactone, eplerenone). The management of hyperkalemia has involved a reduction in dosage or use of therapeutic alternatives to medications that increase serum potassium concentrations, restriction of foods and beverages with a high potassium content, and the use of diuretics that promote the excretion of potassium as well as sodium. The cation-exchange resin sodium polystyrene sulfonate (e.g., Kayexalate) has been used orally or as an enema in the treatment of hyperkalemia. However, it may cause serious GI adverse events and sodium and fluid retention. Patiromer sorbitex calcium (VeltassaeRelypsa) consists of the active moiety, patiromer, a nonabsorbed potassiumbinding polymer, and a calcium-sorbitol counterion. When administered orally, the calcium-sorbitol counterion is exchanged for potassium that binds with patiromer in the lumen of the GI tract. This exchange results in reduced potassium absorption and increased
693
DEPARTMENTS D.A. Hussar, M.N. White / Journal of the American Pharmacists Association 56 (2016) 691e694
fecal potassium excretion, thereby reducing serum potassium concentrations. Patiromer is indicated for the treatment of hyperkalemia and is the first drug to be approved for this condition in more than 50 years. Because patiromer has a delayed onset of action, it should not be used as an emergency treatment for life-threatening hyperkalemia. The effectiveness of patiromer was evaluated in hyperkalemic patients with chronic kidney disease who were on stable doses of at least one RAAS inhibitor. After 4 weeks of treatment, 76% of patients experienced a reduction in serum potassium concentrations to the target range of 3.8 mEq/L to less than 5.1 mEq/L. In a study in hyperkalemic patients with chronic kidney disease and type 2 diabetes on RAAS inhibitor therapy, the effectiveness of patiromer in reducing serum potassium concentrations was maintained during continued therapy for up to 52 weeks. The availability of the new drug provides the opportunity to reduce the risk of hyperkalemia for patients with chronic diseases (e.g., kidney disease, heart failure, diabetes) for whom the continued use of an RAAS inhibitor is beneficial notwithstanding their tendency to increase serum potassium concentrations. The adverse events most often experienced by patients in the clinical studies of patiromer include constipation (7%), diarrhea (5%), nausea (2%), abdominal discomfort (2%), and flatulence (2%). The use of patiromer should be avoided in patients with severe constipation or bowel obstruction or impaction, including abnormal postoperative bowel
694
motility disorders, because the drug may be ineffective and may worsen GI conditions. Hypokalemia (serum potassium less than 3.5 mEq/L) was reported in 5% of the patients. In addition to binding to potassium, patiromer also binds to magnesium in the colon, and approximately 9% of patients in the clinical studies developed hypomagnesemia (serum magnesium less than 1.4 mg/dL). Serum magnesium concentrations should be monitored and the use of a magnesium supplement considered for patients who experience low magnesium concentrations. Patiromer binds to many orally administered medications, which may reduce their absorption and effectiveness. This is the subject of a boxed warning in the labeling for the new drug, and other oral medications should be administered at least 6 hours before or 6 hours after patiromer. If it is not possible to separate the administration of the medications by at least 6 hours, a decision should be made to administer either patiromer or the other oral medication. Patiromer is not absorbed and is not expected to present a risk if it is used during pregnancy or by a nursing mother. The effectiveness and safety of the new drug in pediatric patients have not been established. Patiromer sorbitex calcium is a powder that is insoluble in water. Each gram of patiromer, the active moiety, is equivalent to a nominal amount of 2 g of patiromer sorbitex calcium. The inactive ingredient is xanthan gum. The medication is packaged in single-use packets containing 8.4 g, 16.8 g, and 25.2 g of
patiromer powder for oral suspension. The product should be stored in a refrigerator and should not be heated when it is prepared for administration. If it is stored at room temperature, it must be used within 3 months of being taken out of the refrigerator. Patiromer should be administered with food but should not be added to heated foods or liquids. The recommended starting dosage is 8.4 g once a day. Serum potassium concentrations should be monitored and the dosage adjusted based on the potassium concentration and the desired target range. The dosage may be increased at 1-week or longer intervals, in increments of 8.4 g, up to the maximum dosage of 25.2 g once a day. Each dose of patiromer should be prepared immediately before administration. The contents of a packet should be emptied into a glass or cup containing about 1 ounce of water. The mixture should be stirred thoroughly and an additional 2 ounces of water should be added and thoroughly mixed. The powder does not dissolve and the mixture is cloudy, and patients should be instructed to drink the mixture immediately. If some powder remains in the glass after drinking, more water should be added and stirred, with this process repeated as needed until the entire dose is administered.
Daniel A. Hussar, PhD, Remington Professor of Pharmacy, Philadelphia College of Pharmacy, University of the Sciences, Philadelphia, PA Melissa N. White, Student Pharmacist, Philadelphia College of Pharmacy, University of the Sciences, Philadelphia, PA
Contents lists available at ScienceDirect
Journal of the American Pharmacists Association journal homepage: www.japha.org
NEW DRUGS
Insulin degludec, Lixisenatide, and Patiromer sorbitex calcium Daniel A. Hussar, Melissa N. White
Antidiabetic agents Insulin degludec (TresibaeNovo Nordisk) is the third long-acting human insulin analogue, joining insulin glargine (Lantus) and insulin detemir (Levemir). It is prepared with the use of recombinant DNA technology and, following subcutaneous administration, forms multihexamers that result in a depot of the drug and delayed absorption from the subcutaneous tissues. Its duration of action is approximately 42 hours and it is administered once a day. The duration of action of insulin glargine (Lantus) is approximately 24 hours and it is administered once a day, and the duration of action of insulin detemir is somewhat less than 24 hours and it is administered once or twice a day. A new formulation of insulin glargine (Toujeo) has a duration of action that is slightly more than 24 hours. Insulin glargine (both Lantus and Toujeo) and insulin detemir should be administered at the same time each day, whereas insulin degludec may be administered at any time of the day. Insulin degludec is indicated to improve glycemic control in adults with type 1 or 2 diabetes mellitus. The indication for the Toujeo formulation of insulin glargine also limits use to adult patients, whereas the indications for the Lantus formulation of insulin glargine and insulin detemir include pediatric patients with type 1 diabetes as young as 6 years and 2 years, respectively. Insulin degludec and the other longacting insulins should not be used for the treatment of patients with diabetic ketoacidosis, for which the intravenous administration of a rapid-acting or short-acting insulin would usually be indicated.
The effectiveness of insulin degludec was evaluated in multiple clinical studies in which it was demonstrated to be noninferior to insulin glargine and insulin detemir in lowering glycosylated hemoglobin (HbA1c) concentrations. In some studies, the frequency of nocturnal hypoglycemia with insulin degludec was lower than with the other insulin analogs. In another study, insulin degludec was determined to be more effective than sitagliptin (Januvia) in lowering HbA1c concentrations, but it was also more likely to cause hypoglycemia. All insulins may cause hypoglycemia, and this is the most important concern with their use. The use of insulin degludec is contraindicated during episodes of hypoglycemia, and patients should be more closely monitored regarding this risk when changes are made in insulin dosage, coadministration of other glucose-lowering medications, meal patterns, and/or physical activity. Caution should also be exercised in patients with hepatic or renal impairment. The risk of hypoglycemia may be increased not only by the concurrent use of other antidiabetic agents, but also by medications such as angiotensin-converting enzyme inhibitors (ACEIs; e.g., lisinopril) and angiotensin II receptor blockers (ARBs; e.g., valsartan). Conversely, the blood glucoseelowering effect may be reduced by the concurrent use of medications
such as thiazide diuretics and corticosteroids. The activity of insulin degludec may also be altered by the consumption of alcoholic beverages or the concurrent use of a beta-blocker. Beta-blockers and other anti-adrenergic drugs, such as clonidine, may also blunt the signs and symptoms of hypoglycemia and delay the recognition of a developing problem. In addition to hypoglycemia, other commonly occurring adverse events in the clinical studies include nasopharyngitis (reported in 13% of patients with type 2 diabetes), headache (9%), upper respiratory tract infection (8%), and diarrhea (6%). Patients with type 2 diabetes treated with insulin degludec for 1 year experienced weight gain of an average 3 kg. Some patients have experienced hypersensitivity reactions, injection site reactions, rash, lipodystrophy, edema, and hypokalemia. Potassium concentrations should be monitored in patients at risk for hypokalemia. The thiazolidinedione antidiabetic agents (e.g., pioglitazone) may also cause edema and, when used concurrently with insulin degludec or other insulins, fluid retention and heart failure have occurred in some patients. If heart failure occurs, dosage reduction or discontinuation of treatment should be considered. Insulin degludec is classified in Pregnancy Category C and should be used during pregnancy only if the anticipated
The New Drugs column informs readers about new chemical and biologic entities approved for marketing by the US Food and Drug Administration. The column is written by Contributing Editor Daniel A. Hussar, PhD, Remington Professor of Pharmacy, Philadelphia College of Pharmacy, University of the Sciences in Philadelphia, PA.
http://dx.doi.org/10.1016/j.japh.2016.10.002 1544-3191/© 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.
DEPARTMENTS D.A. Hussar, M.N. White / Journal of the American Pharmacists Association 56 (2016) 691e694
benefit justifies the risk to the unborn child. The effectiveness and safety of the drug in patients younger than 18 years of age have not been established. Insulin degludec is administered subcutaneously into the thigh, upper arm, or abdomen once a day at any time of the day. However, to encourage compliance in administering the daily doses, it is recommended that the drug be administered at approximately the same time each day. Injection sites should be rotated to reduce the risk of lipodystrophy. The dosage of insulin degludec must be individualized based on the patient’s metabolic needs, blood glucose monitoring results, and the glycemic control goal. The starting dose is determined, and the recommended interval between dosage increases is 3 to 4 days. In insulinnaïve patients with type 1 diabetes, the recommended starting dose is approximately one-third to one-half of the total daily insulin dose. The remainder of the total daily insulin dose should be administered as a short-acting insulin and divided between each daily meal. As a general rule, 0.2 to 0.4 units of insulin per kilogram of bodyweight can be used to calculate the initial total daily insulin dose. In insulin-naïve patients with type 2 diabetes, the recommended starting dose is 10 units once a day. For patients with type 1 or type 2 diabetes who are already on insulin therapy, insulin degludec should be started at the same dose in units as the total daily long- or intermediate-acting insulin dose in units. Patients who miss a dose should inject their daily dose during waking hours when they recognize that a dose has been missed. At least 8 hours should separate the administration of consecutive doses. Insulin degludec is supplied in prefilled pens (Flextouch) containing 100 units/mL (U-100; 3 mL) and 200 units/mL (U-200; 3 mL). The pens enable, respectively, maximum doses of 80 units and 160 units per single injection. The dose window for both the U-100 and U-200 pens shows the number of insulin units to be delivered, and dose conversion is not needed. Before use, the insulin degludec pens should be stored in a refrigerator, but once “in use,” the pens should not be refrigerated and may be kept at room temperature for up to 8 weeks.
692
At the same time that it approved insulin degludec, the FDA also approved a combination formulation (Ryzodeg 70/30) of insulin degludec with insulin aspart, a rapid-acting human insulin analogue. However, this product is not currently available, and marketing plans are indefinite. More recently, the FDA has approved a “follow-on” version of insulin glargine (Basaglar) that is similar in activity to Lantus. GLP-1 agonists Glucagon-like peptide 1 (GLP-1) is a peptide hormone that is released soon after eating a meal. It has been shown to suppress glucagon secretion from pancreatic alpha cells and stimulate glucose-dependent insulin secretion by pancreatic beta cells. Lixisenatide (AdlyxineSanofi [marketed under the trade name Lyxumia in many other countries]) is the fifth GLP-1 receptor agonist to be marketed in the United States, joining exenatide (Byetta), extended-release exenatide (Bydureon), liraglutide (Victoza), albiglutide (Tanzeum), and dulaglutide (Trulicity). Like the other agents, lixisenatide is administered subcutaneously and is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. As with liraglutide, lixisenatide is administered once a day, whereas the Byetta formulation of exenatide is administered twice a day, and albiglutide, dulaglutide, and the extended-release formulation of exenatide are administered once a week. The effectiveness of lixisenatide was evaluated in 10 clinical trials that enrolled 5400 patients with type 2 diabetes. The new agent was studied as monotherapy and in combination with other antidiabetic agents, including metformin, sulfonylureas, pioglitazone, and a basal insulin. Lixisenatide provided reductions in HbA1c and fasting plasma glucose concentrations. In a 12-week placebo-controlled study, patients treated with lixisenatide (20mcg daily) experienced a reduction in HbA1c concentrations of 0.83% compared with a reduction of 0.18% in patients receiving placebo, representing a difference from placebo of 0.65%. As with the other GLP-1 agonists, lixisenatide is not recommended as firstline therapy for patients whose diabetes
is inadequately controlled with diet and exercise. Metformin is the usual initial treatment of choice in patients with type 2 diabetes who do not have risk factors that would preclude its use. Many patients with diabetes, however, do not experience adequate glycemic control with the use of metformin alone, and a GLP-1 agonist is among the options available for addition to the regimen. In an active-controlled study in patients with type 2 diabetes inadequately controlled with diet, exercise, and metformin, patients were treated with lixisenatide (20 mcg once a day) or exenatide (10 mcg twice a day). The new drug met the prespecified noninferiority margin of 0.4% for the difference in HbA1c reduction from baseline. However, lixisenatide provided less of an HbA1c reduction ( 0.73%) than exenatide ( 0.90%), and the difference was statistically significant. Lixisenatide has also been evaluated in a placebo-controlled cardiovascular outcomes trial in more than 6000 patients with type 2 diabetes after a recent acute coronary syndrome event. The primary composite end point was the time to the first occurrence of a major adverse cardiovascular event, and the use of lixisenatide did not increase the risk of such events. Although lixisenatide did not increase or decrease cardiovascular risks, the results of a recent study with liraglutide indicate a reduction in the risk of cardiac death of 22% and a reduction of overall heart risks of 13%. However, liraglutide and lixisenatide have not been directly compared in clinical studies of cardiovascular outcomes. The limitations of use with lixisenatide are generally similar to those for the other GLP-1 agonists. It is not indicated for the treatment of patients with type 1 diabetes or patients with diabetic ketoacidosis. It has not been studied in patients with gastroparesis, and use is not recommended in those patients. Acute pancreatitis has been infrequently reported with the GLP-1 agonists, including lixisenatide, and treatment should be promptly discontinued if pancreatitis is suspected. Other antidiabetic agents should be considered for patients with a history of pancreatitis. Lixisenatide has not been studied in combination with short-acting insulin. Certain of the GLP-1 agonists have been reported to cause thyroid C-cell tumors in rodents. Although it is not
DEPARTMENTS D.A. Hussar, M.N. White / Journal of the American Pharmacists Association 56 (2016) 691e694
known whether these agents cause these tumors, including medullary thyroid carcinoma (MTC), in humans, the labeling for extended-release exenatide, liraglutide, albiglutide, and dulaglutide includes a boxed warning about this possibility and contraindications for use in patients with a personal or family history of MTC or patients with multiple endocrine neoplasia syndrome type 2. However, the labeling for lixisenatide does not include warnings or contraindications regarding this potential risk. The most commonly experienced adverse events in the clinical studies of lixisenatide include nausea (25%), vomiting (10%), headache (9%), diarrhea (8%), and dizziness (7%). Serious hypersensitivity reactions, including anaphylaxis, have been infrequently experienced. It is not known if individuals who have experienced such a reaction with another GLP-1 agonist are predisposed to those events with lixisenatide, and the use of the new drug in these patients must be closely monitored. Acute kidney injury and worsening of chronic renal failure have occurred in a small number of patients treated with a GLP-1 agonist. Most of these events have been reported in patients who have experienced severe gastrointestinal (GI) adverse events. Renal function should be monitored when initiating treatment or increasing the dosage of lixisenatide in patients with renal impairment and in patients with serious GI reactions. The use of lixisenatide is not recommended in patients with end-stage renal disease. Patients may develop antibodies to lixisenatide; in a pooled analysis of studies, 70% of patients were antibody positive at week 24, although information is not available regarding the presence of neutralizing antibodies. A higher incidence of allergic reactions and injection site reactions has been reported in antibody-positive patients, and an attenuated glycemic response has been observed in patients with the highest antibody concentrations. Many patients with diabetes are overweight, and some antidiabetic agents (e.g., insulin, sulfonylureas) have been associated with weight gain during treatment. Numerous patients treated with a GLP-1 agonist have experienced weight loss and, in most of the studies of lixisenatide, patients experienced a small loss in weight.
Lixisenatide should be used during pregnancy only if the anticipated benefit justifies the risk to the unborn child. The effectiveness and safety of the new agent in patients younger than 18 years of age have not been established. Lixisenatide and the other GLP-1 agonists are not likely to cause hypoglycemia. However, there is an increased risk of this response if it is used in combination with insulin or an insulin secretagogue (e.g., a sulfonylurea), and a reduction in dosage of the latter agent may be necessary. The GLP-1 agonists delay gastric emptying, which may reduce the rate of absorption of orally administered medications. The use of oral medications that have a narrow therapeutic index or otherwise require close monitoring must be used with additional caution in patients treated with lixisenatide. If one of these oral medications should be administered with food, patients should be advised to take it with a meal or snack other than the first meal of the day that is preceded by lixisenatide administration. Oral medications such as antibiotics, that depend on threshold concentrations for efficacy, as well as medications such as acetaminophen, for which a delay in the onset of action is undesirable, should be administered at least 1 hour before lixisenatide. Women taking oral contraceptives should be advised to take them at least 1 hour before or at least 11 hours after administration of lixisenatide. Following subcutaneous administration of lixisenatide, the median time to maximum concentration is 1 to 3.5 hours. Its metabolism and elimination are thought to occur via proteolytic degradation and glomerular filtration. Plasma concentrations are increased in patients with impaired renal function. Dosage adjustment is not necessary in patients with mild or moderate renal impairment, although patients should be monitored for changes in renal function and the occurrence of GI adverse events. There is only limited experience with lixisenatide in patients with severe renal impairment, and treatment must be closely monitored. The activity of lixisenatide is not likely to be changed in patients with hepatic impairment. Lixisenatide is administered by subcutaneous injection in the abdomen, thigh, or upper arm. Treatment is initiated with a dosage of 10 mcg once a day within 1 hour before the first meal of the
day, for 14 days. On day 15, the dosage should be increased to 20 mcg once a day. If a dose is missed, the drug should be administered within 1 hour before the next meal. Lixisenatide injection is supplied in single patient-use pens containing 3 mL of solution. The pen used for initiating treatment contains the drug in a concentration of 50 mcg/mL and delivers 14 doses of 10 mcg. The pen to be used for maintenance treatment contains lixisenatide in a concentration of 100 mcg/mL, and delivers 14 doses of 20 mcg. The products should be stored in a refrigerator before the first use. When use of the pen is initiated, it may be stored at room temperature and protected from light. A pen should be discarded 14 days after first use. Agent for hyperkalemia Hyperkalemia is characterized by a serum potassium concentration greater than 5.0mEq/L, and may be associated with complications such as cardiac arrhythmias. It is most often experienced by patients with kidney disease, heart failure, or diabetes, particularly in those who are taking medications that inhibit the renin-angiotensin-aldosterone system (RAAS), such as ACEIs (e.g., lisinopril), ARBs (e.g., valsartan), the direct renin inhibitor aliskiren (Tekturna), and aldosterone antagonists (e.g., spironolactone, eplerenone). The management of hyperkalemia has involved a reduction in dosage or use of therapeutic alternatives to medications that increase serum potassium concentrations, restriction of foods and beverages with a high potassium content, and the use of diuretics that promote the excretion of potassium as well as sodium. The cation-exchange resin sodium polystyrene sulfonate (e.g., Kayexalate) has been used orally or as an enema in the treatment of hyperkalemia. However, it may cause serious GI adverse events and sodium and fluid retention. Patiromer sorbitex calcium (VeltassaeRelypsa) consists of the active moiety, patiromer, a nonabsorbed potassiumbinding polymer, and a calcium-sorbitol counterion. When administered orally, the calcium-sorbitol counterion is exchanged for potassium that binds with patiromer in the lumen of the GI tract. This exchange results in reduced potassium absorption and increased
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fecal potassium excretion, thereby reducing serum potassium concentrations. Patiromer is indicated for the treatment of hyperkalemia and is the first drug to be approved for this condition in more than 50 years. Because patiromer has a delayed onset of action, it should not be used as an emergency treatment for life-threatening hyperkalemia. The effectiveness of patiromer was evaluated in hyperkalemic patients with chronic kidney disease who were on stable doses of at least one RAAS inhibitor. After 4 weeks of treatment, 76% of patients experienced a reduction in serum potassium concentrations to the target range of 3.8 mEq/L to less than 5.1 mEq/L. In a study in hyperkalemic patients with chronic kidney disease and type 2 diabetes on RAAS inhibitor therapy, the effectiveness of patiromer in reducing serum potassium concentrations was maintained during continued therapy for up to 52 weeks. The availability of the new drug provides the opportunity to reduce the risk of hyperkalemia for patients with chronic diseases (e.g., kidney disease, heart failure, diabetes) for whom the continued use of an RAAS inhibitor is beneficial notwithstanding their tendency to increase serum potassium concentrations. The adverse events most often experienced by patients in the clinical studies of patiromer include constipation (7%), diarrhea (5%), nausea (2%), abdominal discomfort (2%), and flatulence (2%). The use of patiromer should be avoided in patients with severe constipation or bowel obstruction or impaction, including abnormal postoperative bowel
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motility disorders, because the drug may be ineffective and may worsen GI conditions. Hypokalemia (serum potassium less than 3.5 mEq/L) was reported in 5% of the patients. In addition to binding to potassium, patiromer also binds to magnesium in the colon, and approximately 9% of patients in the clinical studies developed hypomagnesemia (serum magnesium less than 1.4 mg/dL). Serum magnesium concentrations should be monitored and the use of a magnesium supplement considered for patients who experience low magnesium concentrations. Patiromer binds to many orally administered medications, which may reduce their absorption and effectiveness. This is the subject of a boxed warning in the labeling for the new drug, and other oral medications should be administered at least 6 hours before or 6 hours after patiromer. If it is not possible to separate the administration of the medications by at least 6 hours, a decision should be made to administer either patiromer or the other oral medication. Patiromer is not absorbed and is not expected to present a risk if it is used during pregnancy or by a nursing mother. The effectiveness and safety of the new drug in pediatric patients have not been established. Patiromer sorbitex calcium is a powder that is insoluble in water. Each gram of patiromer, the active moiety, is equivalent to a nominal amount of 2 g of patiromer sorbitex calcium. The inactive ingredient is xanthan gum. The medication is packaged in single-use packets containing 8.4 g, 16.8 g, and 25.2 g of
patiromer powder for oral suspension. The product should be stored in a refrigerator and should not be heated when it is prepared for administration. If it is stored at room temperature, it must be used within 3 months of being taken out of the refrigerator. Patiromer should be administered with food but should not be added to heated foods or liquids. The recommended starting dosage is 8.4 g once a day. Serum potassium concentrations should be monitored and the dosage adjusted based on the potassium concentration and the desired target range. The dosage may be increased at 1-week or longer intervals, in increments of 8.4 g, up to the maximum dosage of 25.2 g once a day. Each dose of patiromer should be prepared immediately before administration. The contents of a packet should be emptied into a glass or cup containing about 1 ounce of water. The mixture should be stirred thoroughly and an additional 2 ounces of water should be added and thoroughly mixed. The powder does not dissolve and the mixture is cloudy, and patients should be instructed to drink the mixture immediately. If some powder remains in the glass after drinking, more water should be added and stirred, with this process repeated as needed until the entire dose is administered.
Daniel A. Hussar, PhD, Remington Professor of Pharmacy, Philadelphia College of Pharmacy, University of the Sciences, Philadelphia, PA Melissa N. White, Student Pharmacist, Philadelphia College of Pharmacy, University of the Sciences, Philadelphia, PA