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Pharmaceutical Approval Update August 2018
Lofexidine hydrochloride (Lucemyra)
Manufacturer: US WorldMeds LLC, Louisville, Kentucky
Date of Approval: May 16, 2018
Indication: Lofexidine is a central alpha-2 adrenergic agonist indicated for the mitigation of withdrawal symptoms to facilitate abrupt discontinuation of opioids in adults.
Drug Class: Psychiatry agents
Uniqueness of Drug: The Food and Drug Administration approved lofexidine as the first non-opioid treatment for the management of opioid withdrawal symptoms, so it provides a new option for patients. The FDA granted this application Priority Review and Fast Track designations.
Warnings and Precautions
Risk of hypotension, bradycardia, and syncope. Lofexidine may cause a decrease in blood pressure, a decrease in pulse, and syncope. Monitor vital signs before dosing and advise patients on how to minimize the risk of these cardiovascular effects and manage symptoms, should they occur. Monitor symptoms related to bradycardia and orthostasis. When using lofexidine in an outpatient setting, ensure that patients are capable of self-monitoring signs and symptoms. Avoid use in patients with severe coronary insufficiency, recent myocardial infarction, cerebrovascular disease, chronic renal failure, or marked bradycardia.
Risk of QT prolongation. Lofexidine prolongs the QT interval, so avoid using the drug in patients with congenital long QT syndrome. Monitor ECG in patients with electrolyte abnormalities, congestive heart failure, bradyarrhythmias, hepatic or renal impairment. Patients taking other medications that lead to QT prolongation should also be monitored.
Increased risk of CNS depression with concomitant use of CNS depressant drugs. Lofexidine potentiates the CNS depressant effects of benzodiazepines and may potentiate the CNS depressant effects of alcohol, barbiturates, and other sedating drugs.
Increased Risk of Opioid Overdose after Opioid Discontinuation. Patients who complete opioid discontinuation are at an increased risk of fatal overdose should they resume opioid use. Use in conjunction with comprehensive management program for treatment of opioid use disorder and inform patients and caregivers of the increased risk of a fatal overdose if they start using opioids again.
Risk of Discontinuation Symptoms. Tell patients not to discontinue therapy without consulting their health care provider. When discontinuing therapy, taper dose gradually.
Dosage and Administration: The usual starting dosage is three, 0.18-mg tablets taken orally 4 times daily during the period of peak withdrawal symptoms (generally the first 5 to 7 days following last use of opioid) with dosing guided by symptoms and side effects. There should be 5 to 6 hours between each dose. The total daily dosage should not exceed 2.88 mg (16 tablets) and no single dose should exceed 0.72 mg (4 tablets).
Treatment may be continued for up to 14 days with dosing guided by symptoms.
Discontinue lofexidine with a gradual dose reduction over a 2-to 4-day period to mitigate withdrawal symptoms (for example, reduce the dose by 1 tablet every 1 to 2 days). The dose should be reduced, held, or discontinued for individuals who demonstrate a greater sensitivity to side effects. Lower doses may be appropriate as opioid withdrawal symptoms wane.
Note that the recommendation for dosage adjustment is based on the degree of hepatic or renal impairment.
Commentary: The safety of lofexidine was supported by three randomized, double-blind, placebo-controlled clinical trials, an open-label study, and clinical pharmacology studies with concomitant administration of either methadone, buprenorphine, or naltrexone. Data show that compared to placebo, participants treated with lofexidine experienced less severe withdrawal symptoms and were significantly more likely to complete a seven-day opioid discontinuation treatment. The most common adverse reactions (≥10% and notably more frequent than placebo) are orthostatic hypotension, bradycardia, hypotension, somnolence, sedation, and dry mouth. Lofexidine is marketed in other countries, and the most frequently reported postmarketing adverse event has been hypotension. The efficacy of lofexidine was supported by two randomized, double-blind, placebo-controlled trials.
Sources: US WorldMeds LLC, Lucemyra prescribing information
Manufacturer: Amgen Inc., Thousand Oaks, California
Date of Approval: May 17, 2018
Indication: Erenumab-aooe is a calcitonin gene–related peptide receptor antagonist indicated for the preventive treatment of migraine in adults.
Drug Class: Antimigraine agents, CGRP Monoclonal Antibodies
Uniqueness of Drug: Erenumab-aooe is the first preventive agent approved by the Food and Drug Administration in a new class of drugs that work by blocking the activity of calcitonin gene–related peptide, a molecule that is involved in creating migraine attacks.
Dosage and Administration: The recommended dosage of erenumab-aooe is 70 mg injected subcutaneously once a month. Some patients may benefit from a dosage of 140 mg injected subcutaneously also at an interval of once a month. This higher dose is administered as two consecutive subcutaneous injections of 70 mg each.
If a dose of erenumab-aooe is missed, administer as soon as possible. Thereafter, erenumab-aooe can be scheduled monthly from the date of the last dose.
Erenumab-aooe is intended for patient self-administration. Prior to use, provide proper training to patients, their caregivers, or both, on how to prepare and administer the drug—including aseptic technique—using the single-dose prefilled autoinjector or single-dose prefilled syringe.
The needle shield within the white cap of the prefilled autoinjector and the gray needle cap of the prefilled syringe contain dry natural rubber (a derivative of latex), which may cause allergic reactions in individuals sensitive to latex.
The subcutaneous injections are administered in the abdomen, thigh, or upper arm.
Commentary: The efficacy of erenumab-aooe for the preventive treatment of migraine was evaluated in three clinical trials. The first study included 955 participants with a history of episodic migraine and compared the medication to placebo. Over the course of six months, erenumab-aooe-treated patients experienced, on average, one to two fewer monthly migraine days than those on placebo.
The second study included 577 patients with a history of episodic migraine and compared erenumab-aooe to placebo. Over the course of three months, erenumab-aooe-treated patients experienced, on average, one fewer migraine day per month than those on placebo.
The third study enrolled 667 patients with a history of chronic migraine and compared erenumab-aooe to placebo. In that study, over the course of three months, patients treated with erenumab-aooe experienced, on average, two and a half fewer monthly migraine days than those receiving placebo.
The most common adverse reactions in clinical studies (occurring in at least 3% of treated patients and more often than placebo) were injection-site reactions and constipation.
Sources: Amgen Inc., Aimovig prescribing information
Sodium zirconium cyclosilicate (Lokelma)
Manufacturer: AstraZeneca Pharmaceuticals LP, Wilmington, Delaware
Date of Approval: May 18, 2018
Indication: Sodium zirconium cyclosilicate is a potassium binder indicated for the treatment of hyperkalemia in adults. However, it should not be used as an emergency treatment for life-threatening hyperkalemia because of its delayed onset of action.
Drug Class: Potassium binders
Uniqueness of Drug: Sodium zirconium cyclosilicate is a highly selective, oral potassium-removing agent. The consequences of hyperkalemia can be serious, even life-threatening, and it commonly occurs in patients with chronic kidney disease and heart failure. Until recently, patients had few options for treatment.
Warnings and Precautions
Gastrointestinal adverse events in patients with motility disorders. Avoid use of sodium zirconium cyclosilicate in patients with severe constipation, bowel obstruction or impaction, including abnormal postoperative bowel motility disorders, because it has not been studied in patients with these conditions. It may be ineffective and could worsen gastrointestinal conditions.
Edema. Each 5-g dose of sodium zirconium cyclosilicate contains approximately 400 mg of sodium. In clinical trials, edema was generally mild to moderate in severity and was more commonly seen in patients treated with 15 g once daily. Patients should be monitored for signs of edema, particularly those who should restrict their sodium intake or who are prone to fluid overload (e.g., heart failure or renal disease). Advise patients to adjust dietary sodium, if appropriate. Diuretic dosages may need to be increased.
Dosage and Administration
Sodium zirconium cyclosilicate comes in doses of 5 g and 10 g in foil-lined packets. It is administered orally as a suspension in water. Instruct patients to empty the entire contents of the packet(s) into a drinking glass containing approximately 3 tablespoons of water—or more—if desired. Stir well and drink immediately. If powder remains in the drinking glass, patients should add more water, stir, and drink immediately. They should repeat this until no powder remains to ensure they are getting the entire dose.
For initial treatment of hyperkalemia, the recommended dose is 10 g administered three times a day for up to 48 hours.
For continued treatment, the recommended dose is 10 g once daily.
Monitor serum potassium and adjust the dose of sodium zirconium cyclosilicate based on the serum potassium level and desired target range. During maintenance treatment, the dose may be increased based on the serum potassium level at intervals of one week or longer and in increments of 5 g. The dose should be decreased or discontinued if the serum potassium is below the desired target range. The recommended maintenance dose range is from 5 g every other day to 15 g daily.
In general, other oral medications should be administered at least two hours before or two hours after sodium zirconium cyclosilicate.
Commentary: The approval of sodium zirconium cyclosilicate was based on three studies, one of which was extended by 11 months. Most (92%) patients reached normal potassium levels within 48 hours from baseline. The treatment effect was maintained for up to 12 months. Sodium zirconium cyclosilicate was found to be effective at lowering potassium levels in patients with chronic kidney disease, heart failure, diabetes, and those taking renin-angiotensin-aldosterone system inhibitors. The most common adverse reaction with sodium zirconium cyclosilicate was mild to moderate edema.
Sources: AstraZeneca Pharmaceuticals LP, Lokelma prescribing information