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Pharmaceutical Approval Update December 2019
Manufacturer: Kyowa Kirin Inc., Bedminster, New Jersey
Date of Approval: August 27, 2019
Indication: Istradefylline is an adenosine receptor antagonist indicated as adjunctive treatment to levodopa/carbidopa in adult patients with Parkinson’s disease (PD) experiencing “off” episodes.
Drug Class: Adenosine A2A receptor antagonists
Uniqueness of Drug: Patients taking drugs such as levodopa or carbidopa to top up dopamine levels often experience “off” episodes when their symptoms, such as tremor and difficulty walking, become worse. Istradefylline is a novel nondopaminergic pharmacological approach to treating “off” episodes for patients living with PD.
Warnings and Precautions:
Dyskinesia. Monitor patients for dyskinesia or exacerbation of existing dyskinesia.
Hallucinations/psychotic behavior. Because of the potential risk of exacerbating psychosis, patients with a major psychotic disorder should not be treated with istradefylline. Consider dosage reduction or discontinuation if a patient develops hallucinations or psychotic behaviors while taking istradefylline.
Impulse control/compulsive behaviors. Patients treated with istradefylline and one or more medications for the treatment of PD (including levodopa) may experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge or compulsive eating, and/or other intense urges, as well as the inability to control these urges. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending, binge or compulsive eating, or other urges while being treated with istradefylline. Consider dose reduction or discontinuation if a patient develops such urges while taking the drug.
Dosage and Administration:
- The recommended dosage is 20 mg orally once daily. The dosage may be increased to a maximum of 40 mg once daily.
- Istradefylline may be taken with or without food.
- The maximum recommended dosage of istradefylline with concomitant use of strong CYP3A4 inhibitors is 20 mg once daily.
- Avoid use of istradefylline with strong CYP3A4 inducers.
- The maximum recommended dosage of istradefylline in patients with moderate hepatic impairment (Child-Pugh class B) is 20 mg once daily. Closely monitor patients with moderate hepatic impairment for adverse reactions when on istradefylline treatment. Avoid use of istradefylline in patients with severe hepatic impairment (Child-Pugh class C).
- The recommended dosage of istradefylline in patients who use tobacco in amounts of 20 or more cigarettes per day (or the equivalent of another tobacco product) is 40 mg once daily.
Commentary: The Food and Drug Administration (FDA) approval was based on four randomized, multicenter, double-blind, 12-week, placebo-controlled clinical studies that included 1,143 patients with PD. Patients took istradefylline and a stable dose of levodopa/carbidopa with or without other PD medications. They experienced a statistically significant decrease from baseline in daily “off” time compared with patients receiving a placebo. The most common adverse reactions (at least 5%) were dyskinesia, dizziness, constipation, nausea, hallucination, and insomnia.
Sources: Kyowa Kirin Inc.; Nourianz prescribing information
Manufacturer: Ardelyx, Inc., Fremont, California
Date of Approval: September 12, 2019
Indication: Tenapanor is a sodium/hydrogen exchanger 3 (NHE3) inhibitor indicated for treatment of irritable bowel syndrome with constipation (IBS-C) in adults.
Drug Class: IBS agents, NHE3 inhibitors
Uniqueness of Drug: Tenapanor has a novel mechanism and is an innovative approach to managing IBS-C. The minimally absorbed small molecule acts locally in the gastrointestinal tract to inhibit NHE3, resulting in an increase in bowel movements and a decrease in abdominal pain for IBS-C patients.
Warnings and Precautions:
- Tenapanor is contraindicated in patients younger than 6 years of age. In nonclinical studies in young juvenile rats, administration of tenapanor caused deaths presumed to be due to dehydration.
- Avoid use of tenapanor in patients 6 years to less than 12 years of age.
- The safety and effectiveness of tenapanor have not been established in pediatric patients less than 18 years of age.
Diarrhea. Diarrhea was the most common adverse reaction in two randomized, double-blind, placebo-controlled trials of IBS-C. Severe diarrhea was reported in 2.5% of tenapanor-treated patients. If severe diarrhea occurs, suspend dosing and rehydrate the patient.
Dosage and Administration: The recommended dosage of tenapanor in adults is 50 mg orally twice daily.
- Take tenapanor immediately prior to breakfast or the first meal of the day and immediately prior to dinner.
- If a dose is missed, skip the missed dose and take the next dose at the regular time. Do not take two doses at the same time.
Commentary: The FDA approval of tenapanor is based on data from two phase 3, randomized, double-blind, placebo-controlled trials. The primary endpoint for both trials was the proportion of patients who saw at least a 30% reduction in the weekly average abdominal pain score compared with baseline and an increase of at least one complete spontaneous bowel movement in weekly average from baseline, in the same week, for at least six of the first 12 weeks of treatment. In both phase 3 trials, the drug met the primary endpoint as compared to the treatment group that received only placebo (Trial 1: 37% versus 24%, tenapanor versus placebo, respectively. Trial 2: 27% versus 19%, tenapanor versus placebo, respectively). The most common adverse reactions (2% or more) are diarrhea, abdominal distension, flatulence, and dizziness.
Sources: Ardelyx, Inc.; Ibsrela prescribing information
Manufacturer: Novo Nordisk A/S, Bagsvaerd, Denmark
Date of Approval: September 20, 2019
Indication: Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type-2 diabetes mellitus.
Limitations of use:
- It is not recommended as first-line therapy for patients inadequately controlled on diet and exercise.
- It has not been studied in patients with a history of pancreatitis.
- It is not indicated for use in patients with type-1 diabetes mellitus or treatment of diabetic ketoacidosis.
Drug Class: Antidiabetics, GLP-1 agonists
Uniqueness of Drug: Semaglutide is the first oral (pill) GLP-1 agonist for type-2 diabetes. The FDA approval provides more options for patients with type-2 diabetes to access the significant benefits of GLP-1 agonists, namely lowering HbA1c and prompting weight loss.
Warnings and Precautions:
- In rodents, semaglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures. It is unknown whether semaglutide causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans because the human relevance of semaglutide-induced rodent thyroid C-cell tumors has not been determined.
- Semaglutide is contraindicated in patients with a personal or family history of MTC or in patients with multiple endocrine neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk for MTC with the use of semaglutide and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with semaglutide.
Pancreatitis. After initiation of semaglutide, observe patients carefully for signs and symptoms of pancreatitis (including persistent, severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting). If pancreatitis is suspected, semaglutide should be discontinued and appropriate management initiated. If pancreatitis is confirmed, semaglutide should not be restarted.
Diabetic retinopathy complications. Rapid improvement in glucose control has been associated with a temporary worsening of diabetic retinopathy. The effect of long-term glycemic control with semaglutide on diabetic retinopathy complications has not been studied. Patients with a history of diabetic retinopathy should be monitored for progression of diabetic retinopathy.
Hypoglycemia. The risk of hypoglycemia is increased when semaglutide is used in combination with insulin secretagogues (e.g., sulfonylureas) or insulin. Patients may require a lower dose of the secretagogue or insulin to reduce the risk of hypoglycemia in this setting.
Acute kidney injury. There have been post-marketing reports of acute kidney injury and worsening of chronic renal failure, which may sometimes require hemodialysis, in patients treated with GLP-1 receptor agonists, including semaglutide. Some of these events have been reported in patients without known underlying renal disease. A majority of the reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration. Monitor renal function when initiating or escalating doses of semaglutide in patients reporting severe adverse gastrointestinal reactions.
Hypersensitivity reactions. Anaphylaxis and angioedema have been reported with GLP-1 receptor agonists. Use caution in a patient with a history of angioedema or anaphylaxis with another GLP-1 receptor agonist because it is unknown whether such patients will be predisposed to anaphylaxis with semaglutide.
Dosage and Administration:
- Instruct patients to take semaglutide at least 30 minutes before the first food, beverage, or other oral medications of the day with no more than 4 ounces of plain water only. Waiting less than 30 minutes, or taking with food, beverages (other than plain water), or other oral medications will lessen the effect of semaglutide. Waiting more than 30 minutes to eat may increase the absorption of semaglutide.
- Swallow tablets whole. Do not cut, crush, or chew tablets.
- Start semaglutide with 3 mg once daily for 30 days. The 3-mg dose is intended for treatment initiation and is not effective for glycemic control.
- After 30 days on the 3-mg dose, increase the dose to 7 mg once daily.
- The dose may be increased to 14 mg once daily if additional glycemic control is needed after at least 30 days on the 7-mg dose.
- Taking two 7-mg semaglutide tablets to achieve a 14-mg dose is not recommended.
- If a dose is missed, the missed dose should be skipped, and the next dose should be taken the following day.
- Switching patients between Ozempic (injectable semaglutide) and Rybelsus (oral semaglutide):
- Patients treated with Rybelsus 14 mg daily can be transitioned to Ozempic subcutaneous injection 0.5 mg once weekly. Patients can start Ozempic the day after their last dose of Rybelsus.
- Patients treated with once-weekly Ozempic 0.5 mg subcutaneous injection can be transitioned to Rybelsus 7 mg or 14 mg. Patients can start Rybelsus up to seven days after their last injection of Ozempic. There is no equivalent dose of Rybelsus for Ozempic 1 mg.
Commentary: The FDA approval of semaglutide is based on results from 10 PIONEER clinical trials, which enrolled 9,543 participants and included head-to-head studies of semaglutide versus sitagliptin, empagliflozin, and liraglutide 1.8 mg. In the trials, semaglutide reduced HbA1c and, as a secondary endpoint, showed reductions in body weight. The most common adverse reactions, reported in at least 5% of patients treated with semaglutide, are nausea, abdominal pain, diarrhea, decreased appetite, vomiting, and constipation.
Sources: Novo Nordisk A/S, Rybelsus prescribing information