THIS ARTICLE reviews seven drugs recently approved by the FDA, including:
> two drugs indicated to treat heart failure.
> a peripherally acting mu-opioid receptor antagonist for treating opioid-induced constipation.
> a human monoclonal antibody for adults with severe plaque psoriasis.
Unless otherwise specified, the information in the following summaries applies to adults, not children. Consult a pharmacist or the package insert for information on drug safety during pregnancy and breastfeeding. Consult a pharmacist, the package insert, or a current and comprehensive drug reference for more details on precautions, drug interactions, and adverse reactions for all these drugs.
SELECTED REFERENCES
Drug Facts and Comparisons. St. Louis, MO: Facts and Comparisons, Inc.; 2016.
Nursing2016 Drug Handbook. Philadelphia, PA: Lippincott Williams & Wilkins; 2016.
Physician's Desk Reference. 69th ed. Montvale, NJ: Medical Economics; 2016.
DRUGS FOR HEART FAILURE
Sacubitril/valsartan
Effective new first-line option for HF
Sacubitril/valsartan (Entresto, Novartis) is indicated to reduce the risk of cardiovascular death and hospitalization for heart failure (HF) in patients with chronic HF (NYHA Class II-IV) and reduced ejection fraction. It's usually administered in conjunction with other HF therapies in place of an angiotensin-converting enzyme (ACE) inhibitor or other angiotensin receptor blocker (ARB).
In a clinical study comparing the new combination with enalapril, sacubitril/valsartan was found to be superior in reducing the risk of the combined endpoint of cardiovascular death or hospitalization for HF (21.8% for the new product versus 26.5% with enalapril). Compared with enalapril, the new agent was associated with significantly reduced rates of cardiovascular death, hospitalizations related to HF, and all-cause mortality. The greater effectiveness of sacubitril/valsartan is a significant advantage that will result in its first-line use as an alternative to an ACE inhibitor or ARB in regimens for treating HF.
Sacubitril/valsartan is a combination of sacubitril, a neprilysin inhibitor, and valsartan, an angiotensin II receptor blocker (ARB). Neprilysin is a neutral endopeptidase that degrades certain vasoactive peptides such as natriuretic peptides and bradykinin.
Sacubitril, the new agent, is a prodrug that's rapidly converted by esterases to LBQ657, its active metabolite with a unique mechanism of action as a neprilysin inhibitor. By inhibiting neprilysin, sacubitril/LBQ657 increases concentrations of these peptides, thereby reducing vasoconstriction and sodium retention. Valsartan contributes to the cardiovascular and renal benefits of the new combination in patients with HF by inhibiting the actions of angiotensin II by selectively blocking AT1 receptors.
Sacubitril has been evaluated and is supplied as part of a combination formulation with valsartan; it's not available as a single agent.
In the clinical study, 0.5% of the patients treated with sacubitril/valsartan and 0.2% of patients treated with enalapril experienced angioedema. The incidence of angioedema was higher in Black patients (2.4%) than in non-Black patients.
Precautions: (1) Contraindicated in patients with a history of angioedema related to previous treatment with an ACE inhibitor or ARB. (2) Contraindicated for concurrent use with an ACE inhibitor because of the increased risk of angioedema; the new agent shouldn't be administered within 36 hours of switching from or to an ACE inhibitor. (3) The concurrent use of sacubitril/valsartan with the direct renin inhibitor aliskiren is contraindicated in patients with diabetes; concurrent use should also be avoided in patients with renal impairment (estimated glomerular filtration rate [eGFR] less than 60 mL/minute/1.73 m2). Use of an ARB (including sacubitril/valsartan) may reduce renal function in susceptible patients as a consequence of inhibiting the renin-angiotensin-aldosterone system. (4) Avoid concurrent use of the new formulation with another ARB. (5) Sacubitril/valsartan isn't recommended for patients with severe hepatic impairment. (6) Patients being treated with high doses of diuretics are at greater risk of hypotension; volume or salt depletion should be corrected before treatment with sacubitril/valsartan starts, or treatment should be initiated with a lower dosage. (7) In older adults and those who are volume-depleted or have compromised renal function, the concurrent use of a nonsteroidal anti-inflammatory drug with sacubitril/valsartan may result in a worsening of renal function, and this risk should be periodically monitored. (8) Increased serum lithium concentrations and lithium toxicity have been reported in some patients treated concurrently with an ARB; serum lithium concentrations should be monitored in patients also being treated with sacubitril/valsartan.
Adverse reactions: hypotension, hyperkalemia, cough, dizziness, renal failure
Supplied as: film-coated tablets in 24 mg/26 mg (sacubitril/valsartan), 49 mg/51 mg, and 97 mg/103 mg potencies
Dosage: Initially, 49 mg/51 mg twice a day. After 2 to 4 weeks of treatment, the dosage should be increased to the target maintenance dosage of 97 mg/103 mg twice a day, as tolerated. A reduced initial dosage of 24 mg/26 mg twice a day is recommended in patients with moderate hepatic impairment or severe renal impairment (eGFR less than 30 mL/minute/1.73 m2), and in patients not currently taking an ACE inhibitor or ARB or who were previously being treated with a low dosage of one of these agents. See the product labeling for full dosage recommendations for patients with severe renal impairment or moderate hepatic impairment.
Nursing considerations: (1) Tell patients that the drug can be taken without regard to food. (2) Periodically monitor serum potassium concentrations, especially in patients with risk factors for hyperkalemia such as severe renal impairment, diabetes, hypoaldosteronism, a high potassium diet, or the concurrent use of a potassium-sparing diuretic (such as spironolactone), potassium supplement, or a salt substitute containing potassium. (3) Monitor renal function in patients with renal artery stenosis and in those who develop a clinically significant decrease in renal function. (4) Inform women of childbearing potential that ACE inhibitors and ARBs may harm an unborn child if taken during pregnancy, with the risk of harm being greater during the second and third trimesters. Advise them to use effective contraception. If a patient becomes pregnant, treatment should be discontinued as soon as possible and a safer alternative treatment initiated.
REFERENCE
Entresto (sacubitril/valsartan) tablets. Prescribing information. http://www.entrestohcp.com.
Ivabradine hydrochloride
Reducing the sinus node's pacemaker activity
Also indicated to treat patients with HF, ivabradine hydrochloride (Corlanor, Amgen) causes a dose-dependent reduction in heart rate by blocking the hyperpolarization-activated cyclic nucleotide-gated channel responsible for the cardiac pacemaker If current, which regulates heart rate. The selective inhibition of the If current reduces the sinus node's pacemaker activity, reducing heart rate. Its use hasn't been associated with changes in ventricular repolarization or myocardial contractility.
Ivabradine is specifically indicated to reduce the risk of hospitalization for worsening HF in patients with stable, symptomatic chronic HF with a left ventricular ejection fraction of 35% or lower who are in sinus rhythm with resting heart rate of at least 70 beats/minute and either are on maximally tolerated doses of beta-blockers or have a contraindication to beta-blocker use.
The effectiveness of ivabradine was evaluated in several large placebo-controlled studies. The study that provided the strongest support for its approval included patients with stable NYHA Class II-IV HF who were receiving an optimized and stable clinical regimen that included maximally tolerated doses of beta-blockers and, in most cases, an ACE inhibitor or ARB, spironolactone, and diuretics. The primary endpoint was a composite of the first occurrence of either hospitalization for worsening HF or cardiovascular death. Although ivabradine reduced the risk of the combined endpoint (25% versus 29% of patients taking placebo), the benefit of the medication reflected only a reduction in the risk of hospitalization; a favorable effect on the mortality component of the primary endpoint wasn't found. In two other studies with a similar primary composite endpoint, ivabradine didn't significantly affect the endpoint and provide benefit.
In clinical trials, approximately 3% of patients experienced luminous phenomena, also called phosphenes, which are characterized by a transiently enhanced brightness in a limited area of the visual field and effects such as halos, kaleidoscopic effects, colored bright lights, or multiple images. The retinal current Ih is involved in reducing retinal responses to bright light stimuli; ivabradine's action may inhibit this current, causing phosphenes. The onset of visual disturbances is generally within the first 2 months of treatment, after which they may occur repeatedly.
Precautions: (1) Contraindicated in patients with acute decompensated HF, BP less than 90/50 mm Hg, resting heart rate less than 60 beats/minute prior to treatment, and pacemaker dependence (heart rate maintained exclusively by the pacemaker). (2) Contraindicated in patients with sick sinus syndrome, sinoatrial block, or 3rd degree atrioventricular (AV) block unless a functioning demand pacemaker is present. (3) Avoid use in patients with 2nd degree AV block unless a functioning demand pacemaker is present. However, ivabradine isn't recommended for use in patients with demand pacemakers set to a rate of 60 beats/minute or higher. (4) Contraindicated in patients with severe hepatic impairment. (5) Contraindicated for concurrent use with strong CYP3A4 inhibitors such as clarithromycin and itraconazole, which may increase the concentration of ivabradine and raise the risk of bradycardia and conduction disturbances. (6) Avoid the concurrent use of ivabradine and a moderate CYP3A4 inhibitor such as diltiazem, verapamil, and grapefruit juice. Besides increasing ivabradine exposure, diltiazem and verapamil may also contribute to reduction of heart rate. (7) Avoid concurrent use with CYP3A4 inducers such as carbamazepine, rifampin, and St. John's wort, which may reduce the action of ivabradine. (8) Closely monitor patients who also take any other drugs that slow heart rate such as digoxin, amiodarone, and beta-blockers; concurrent use with ivabradine increases the risk of bradycardia. (Although beta-blockers slow heart rate, their benefits in patients with HF result in their use in most patients who are candidates for the addition of ivabradine to the treatment regimen.)
Adverse reactions: bradycardia, hypertension, atrial fibrillation, luminous phenomena
Supplied as: film-coated 5 mg and 7.5 mg tablets
Dosage: 5 mg twice a day with meals. After 2 weeks, the dosage should be adjusted to achieve a resting heart rate between 50 and 60 beats/minute. Then the dosage should be adjusted based on resting heart rate and tolerability. Maximum dosage: 7.5 mg twice a day. See the full prescribing information for dosage recommendations for patients with a history of conduction defects or bradycardia that may lead to hemodynamic compromise.
Nursing considerations: (1) Tell patients to report significant decreases in heart rate or signs and symptoms such as dizziness, fatigue, or hypotension, as well as symptoms of atrial fibrillation such as palpitations or shortness of breath. (2) Instruct patients to take each dose with food. (3) Warn patients to avoid grapefruit products. (4) Ivabradine may harm a fetus if used during pregnancy; tell women of childbearing potential to use effective contraception.
REFERENCE
Corlanor (ivabradine hydrochloride). Prescribing information. http://www.corlanorhcp.com.
DRUG FOR CONSTIPATION
Naloxegol oxalate
Relief from a common adverse reaction to opioid analgesics
Opioid analgesics such as morphine, hydrocodone, and oxycodone have unique value in the treatment of pain because of their ability to bind to mu-receptors in the central nervous system (CNS). However, opioids also bind to mu-receptors in the gastrointestinal (GI) tract, reducing GI motility. This causes opioid-induced constipation (OIC), a common adverse reaction to opioids. Laxatives and stool softeners help prevent or reduce OIC in many patients treated with an opioid, but some patients don't respond adequately.
Naloxegol oxalate (Movantik, AstraZeneca) is indicated to treat OIC in adults with chronic noncancer pain. Naloxegol, a pegylated derivative of naloxone, is a peripherally acting mu-opioid receptor antagonist that's effective following oral administration. The CNS penetration of naloxegol is thought to be negligible at the recommended dosage, so the new drug shouldn't interfere with centrally mediated opioid analgesia.
The effectiveness of naloxegol was demonstrated in two placebo-controlled studies in patients with OIC and noncancer-related pain (such as back pain) in patients who'd taken an opioid for at least 4 weeks. The primary endpoint was response defined as 3 or more spontaneous bowel movements (SBMs) per week and a change from baseline of 1 or more SBM per week for at least 9 out of the 12 study weeks and 3 out of the last 4 weeks. In the first clinical trial, 44% of the patients receiving naloxegol in a dosage of 25 mg/day and 41% of those receiving the drug in a dosage of 12.5 mg/day experienced an increase in the number of SBMs per week, compared with 29% of those receiving placebo. Similar results were reported in the second trial.
Maintenance laxative therapy should be discontinued before initiating treatment with naloxegol. However, if response to naloxegol is suboptimal after 3 days, laxatives can be used as needed. If treatment with the opioid analgesic is discontinued, naloxegol should also be discontinued.
Precautions: (1) Contraindicated in patients with known or suspected GI obstruction and patients at increased risk for recurrent obstruction because of the potential for GI perforation. (2) Use naloxegol with caution in patients who have or may have impaired integrity of the GI tract wall, as with peptic ulcer disease or Crohn disease. (3) Contraindicated for concurrent use with a strong CYP3A4 inhibitor such as clarithromycin or itraconazole; avoid concurrent use with a moderate CYP3A4 inhibitor such as diltiazem or verapamil whenever possible. The consumption of grapefruit products should also be avoided during treatment. The concentration and activity of naloxegol are increased by the concurrent use of a CYP3A4 inhibitor. (4) The concurrent use of a strong CYP3A4 inducer such as carbamazepine, rifampin, or St. John's wort isn't recommended. The concentration and activity of naloxegol are reduced by the concurrent use of a CYP3A4 inducer. (5) Avoid concurrent use of naloxegol with another opioid antagonist because of the increased risk of opioid withdrawal. (6) Avoid use in patients with severe hepatic impairment. (7) A dosage reduction is recommended for patients with significant renal impairment. (8) Although naloxegol is unlikely to cross the blood-brain barrier, patients with disruptions of the blood-brain barrier may be at increased risk for opioid withdrawal or reduced analgesia. (9) Because the blood-brain barrier hasn't fully matured in an unborn child, naloxegol could precipitate opioid withdrawal in the fetus.
Adverse reactions: abdominal pain, diarrhea, nausea, flatulence, headache, vomiting; rarely, symptoms related to opioid withdrawal, such as hyperhidrosis and chills
Supplied as: 12.5 mg and 25 mg tablets
Dosage: 25 mg once a day in the morning at least 1 hour before the first meal of the day or 2 hours after the meal. Reduce the dosage to 12.5 mg once a day in patients with moderate, severe, or end-stage renal impairment, and in patients in whom the concurrent use of a moderate CYP3A4 inhibitor is unavoidable.
Nursing considerations: (1) Tell patients to take each dose on an empty stomach as directed, and to swallow tablets whole. (2) Instruct patients not to consume grapefruit products while taking naloxegol. (3) Tell patients to stop taking laxatives as directed before starting therapy with naloxegol. The healthcare provider may recommend resuming use of a laxative if naloxegol isn't effective after 3 days. (4) Instruct patients to discontinue naloxegol if they stop taking an opioid analgesic.
REFERENCE
Moventik (naloxegol) tablets, for oral use. Prescribing information. http://www.azpicentral.com/movantik/movantik.pdf#page=1.
ANTICOAGULANT
Edoxaban tosylate monohydrate
New factor Xa inhibitor reduces risk of stroke
Edoxaban tosylate monohydrate (Savaysa, Daiichi-Sankyo) is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, and for treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) following 5 to 10 days of initial therapy with a parenteral anticoagulant. Like rivaroxaban and apixaban, it's a factor Xa inhibitor anticoagulant.
In patients with nonvalvular atrial fibrillation, edoxaban was evaluated and compared with warfarin in a study of more than 21,000 participants. Edoxaban was determined to be noninferior to warfarin for the primary efficacy endpoint of reducing the occurrence of stroke and systemic embolism (1.2% occurrence [with the 60 mg daily dosage] compared with 1.5% for warfarin). Statistical superiority wasn't established, although there was a favorable trend.
For treatment of DVT and PE, edoxaban was evaluated in more than 8,000 patients and determined to be noninferior to warfarin for the primary endpoint of recurrent venous thromboembolic events (3.2% compared with 3.5% for warfarin). Like the other new oral anticoagulants, edoxaban hasn't been studied in patients with mechanical heart valves or moderate to severe mitral stenosis, so it's not recommended for these patients.
As with other anticoagulants, bleeding is the most important concern with the use of edoxaban. However, in the clinical studies, the incidence of major bleeding (such as intracranial hemorrhage) was less with edoxaban compared with warfarin (3.1% compared with 3.7% in patients with nonvalvular atrial fibrillation). The risk of bleeding is increased by the concurrent use of other medications that affect hemostasis, including aspirin and other antiplatelet agents, other antithrombotic agents, thrombolytic therapy, and chronic use of nonsteroidal anti-inflammatory drugs.
As with rivaroxaban and apixaban, no specific antidote is available to reverse excessive anticoagulation from edoxaban. This represents a disadvantage for these drugs compared with warfarin, for which vitamin K is a specific antidote.
Unlike therapy with rivaroxaban and apixaban, use of edoxaban to treat DVT and PE must be initiated with parenteral anticoagulation. Consult the prescribing information for specific dosage recommendations for transitions between edoxaban to or from another anticoagulant.
Precautions: (1) Contraindicated in patients with active pathologic bleeding. Edoxaban should be discontinued at least 24 hours before invasive procedures or surgery because of the risk of bleeding. (2) Not recommended for patients with mechanical heart valves or moderate to severe mitral stenosis. (3) Epidural or spinal hematomas may occur in patients treated with anticoagulants, including edoxaban, who are receiving neuraxial anesthesia or undergoing spinal puncture; this is the subject of a boxed warning in the labeling. These hematomas may result in paralysis, so appropriate precautions must be observed. (4) Not recommended in patients with moderate or severe hepatic impairment because these patients may have intrinsic coagulation abnormalities. (5) Edoxaban is less effective in patients with nonvalvular atrial fibrillation with a creatinine clearance greater than 95 mL/minute; this is the subject of a boxed warning in its labeling. Renal function should be evaluated using the Cockcroft-Gault equation (provided in the labeling) prior to initiating treatment. Edoxaban shouldn't be used in patients with a creatinine clearance greater than 95 mL/minute because of increased risk for ischemic stroke compared with warfarin. (6) Edoxaban is a substrate of the permeability glycoprotein (P-gp) transporter and its use with the P-gp inducer rifampin should be avoided.
Adverse reactions:In patients treated for nonvalvular atrial fibrillation: bleeding, anemia. In patients treated for DVT or PE: bleeding, rash, anemia, abnormal liver function tests
Supplied as: 15 mg, 30 mg, and 60 mg tablets
Dosage:In patients treated for nonvalvular atrial fibrillation: 60 mg once a day. The dosage should be reduced to 30 mg once a day in patients with a creatinine clearance of 15 to 50 mL/minute. In patients treated for DVT and PE: 60 mg once a day following 5 to 10 days of therapy with a parenteral anticoagulant. The dosage should be reduced to 30 mg once a day in patients with a creatinine clearance of 15 to 50 mL/minute, in patients who weigh less than or equal to 60 kg (132 lb), or patients who are taking certain concomitant P-gp inhibitors. Consult the product labeling for detailed dosage recommendations.
Nursing considerations: (1) Monitor patients undergoing spinal procedures for signs and symptoms of spinal or epidural hematoma, such as back pain, lower extremity paresthesias, muscle weakness, and incontinence. (2) Warn patients that abruptly discontinuing edoxaban increases the risk of thrombotic events such as stroke. They should discontinue the drug only as directed by the healthcare provider, who may prescribe alternative anticoagulation. (3) Tell patients they can take edoxaban without regard to food. (4) Patients who miss a dose of edoxaban should take it as soon as possible on the same day. However, they shouldn't double the next day's dose to make up for the missed dose. (5) Warn patients that concurrent use with certain other drugs and products may affect edoxaban's safety and effectiveness. Instruct them to consult the healthcare provider before taking other drugs, including over-the-counter medications, herbal products, vitamins, or dietary supplements.
REFERENCE
Savaysa (edoxaban) tablets for oral use. Prescribing information. http://www.savaysahcp.com.
DRUG FOR PSORIASIS
Secukinumab
Human monoclonal antibody inhibits release of proinflammatory substances.
Psoriasis is a chronic immune-mediated inflammatory disease that affects an estimated 6.7 million Americans.1 It's characterized by thick and extensive skin lesions (plaques) that can cause itching, scaling, and pain.2 Mild and limited lesions can often be effectively treated with topical medications; options for treating more widespread and/or severe lesions and lesions that don't respond adequately to topical treatment include phototherapy with UV light, or systemic therapy with an oral or parenteral medication.
Secukinumab (Cosentyx, Novartis) is a human monoclonal antibody that selectively binds to the interleukin-17A (IL-17A) cytokine and inhibits its interaction with the IL-17 receptor, inhibiting the release of proinflammatory cytokines and chemokines. A naturally occurring cytokine, IL-17A is involved in normal inflammatory and immune responses and is present in elevated concentrations in psoriatic plaques.
Administered subcutaneously, secukinumab is indicated for treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy, adults with active psoriatic arthritis, and adults with active ankylosing spondylitis. Its effectiveness was demonstrated in four placebo-controlled trials that included more than 2,400 participants.3
As with other medications that suppress immune function, secukinumab increases the risk of infection, with nasopharyngitis, upper respiratory tract infection, and mucocutaneous infections with Candida reported most often and more frequently than in patients receiving placebo.
Patients treated with secukinumab shouldn't receive live vaccines. Non-live vaccinations administered during a course of treatment may not elicit an immune response sufficient to prevent disease.
Precautions: (1) Patients should be evaluated for tuberculosis infection before starting treatment with secukinumab. In patients with a history of latent or active tuberculosis in whom an adequate course of antitubercular therapy can't be confirmed, such treatment should be considered before initiating treatment with the new drug. (2) Use caution in patients with chronic or recurring infections. If a serious infection develops, discontinue secukinumab until the infection resolves. (3) Closely monitor patients with inflammatory bowel disease for exacerbations, which were experienced by some patients in the clinical trials. (4) Contraindicated in patients who are allergic to secukinumab or its components. Serious hypersensitivity reactions, including anaphylaxis, have been reported infrequently.
Adverse reactions: nasopharyngitis, diarrhea, upper respiratory tract infection
Supplied as: a solution containing a 150 mg/mL concentration of the drug in a single-use pen and in a single-use prefilled syringe. Another formulation for injection contains 150 mg of the drug as a lyophilized powder that requires reconstitution in a single-use vial. This formulation should be prepared and reconstituted by a healthcare provider.
Dosage:For plaque psoriasis: 300 mg at weeks 0, 1, 2, 3, and 4 followed by 300 mg every 4 weeks, administered by subcutaneous injection in the abdomen, thighs, or upper arms. Each 300 mg dose is given as two subcutaneous injections of 150 mg. For active psoriatic arthritis and active ankylosing spondylitis: Consult the prescribing information for protocols.
Nursing considerations: (1) Store the drug in a refrigerator. Remove the prefilled syringe or pen from the refrigerator and allow it to stand for 15 to 30 minutes to reach room temperature. Administer it within 1 hour after removal from the refrigerator. Don't shake the drug. Consult the product labeling for details about the preparation and administration of the formulation that requires reconstitution. (2) The prefilled syringes and the pen device's removable cap contain natural rubber latex. Warn latex-sensitive patients not to handle these devices. (3) Teach patients using either the prefilled pen or the prefilled syringe at home how to prepare and use the device and how to clean and rotate injection sites. The product labeling includes a Medication Guide and illustrated instructions for patients. (4) Teach patients to store the drug in the refrigerator and to keep it in the original carton to protect it from light. (5) Tell patients to avoid vaccinations unless recommended by the healthcare provider. (6) Tell patients to contact the healthcare provider immediately if they develop signs and symptoms of an infection. (7) Teach patients to recognize signs and symptoms of a hypersensitivity reaction. If an anaphylactic reaction or other serious allergic reaction occurs, instruct them to stop taking the drug and to call 911 immediately.
REFERENCES
1. Helmick CG, Lee-Han H, Hirsch SC, Baird TL, Bartlett CL. Prevalence of psoriasis among adults in the U.S.: 2003-2006 and 2009-2010 National Health and Nutrition Examination Surveys. Am J Prev Med. 2014;47(1):37-45. [Context Link]
2. National Psoriasis Foundation. About psoriasis. https://www.psoriasis.org/about-psoriasis. [Context Link]
3. Cosentyx (secukinumab) injection for subcutaneous use. Prescribing information. http://www.pharma.us.novartis.com/product/pi/pdf/cosentyx.pdf. [Context Link]
HYPNOTIC
Suvorexant
Treating insomnia by suppressing the wake drive
Insomnia is most often characterized by difficulties in falling asleep (sleep onset) and/or sleep maintenance. Medications approved to treat insomnia include benzodiazepines, nonbenzodiazepine sedatives, melatonin agonists, antidepressants, and orexin antagonists.1 The characteristics of the insomnia and the properties of the pharmacologic agents, particularly the onset of action and/or duration of action, are important factors in the choice of drug therapy.
Suvorexant (Belsomra, Merck) is an orexin receptor antagonist. The orexins are naturally occurring neuropeptides that act in a signaling system as a central promoter of wakefulness. This wake-promoting action results, at least in part, from the binding of orexin A and orexin B to OX1R and OX2R receptors. By blocking the binding of orexins to their receptors, suvorexant is thought to suppress the wake drive. It's the first medication with this mechanism of action.
Suvorexant has been approved to treat insomnia characterized by difficulties with sleep onset and/or sleep maintenance.2 Eszopiclone, a nonbenzodiazepine hypnotic, and the extended-release formulation of zolpidem are other hypnotics that have labeled indications for difficulties with both sleep onset and sleep maintenance.
The effectiveness of suvorexant was evaluated in three placebo-controlled trials that included more than 500 participants. The new drug was determined to be superior to placebo in reducing the time to sleep onset and in increasing total sleep time. Suvorexant hasn't been directly compared with other hypnotics in clinical studies.
The antagonism of orexin receptors may underlie potential adverse reactions such as signs and symptoms of narcolepsy/cataplexy. Symptoms similar to those of mild cataplexy, including periods of leg weakness lasting seconds to minutes, have been reported with suvorexant, with the risk increasing as the dosage is increased. Sleep paralysis (an inability to move or speak for several minutes during sleep-wake transitions) and hallucinations have also been infrequently reported.
In some patients, the use of hypnotics including suvorexant has been associated with cognitive and behavioral changes such as amnesia, anxiety, and hallucinations. "Sleep-driving" (driving while not fully awake after taking a hypnotic), and other complex behaviors (such as preparing and eating food, making phone calls, and having sex) with amnesia for the event have been experienced by some patients treated with hypnotics. The use of other CNS depressants including alcohol may increase the risk of such behaviors.
Worsening of depression and suicidal ideation have been associated with the use of hypnotics. Appropriate precautions must be observed in evaluating, treating, and monitoring patients taking suvorexant. Because intentional overdose is more common in primarily depressed patients treated with sedative-hypnotics, the lowest number of tablets that is effective should be prescribed for a patient at any one time.
Suvorexant is associated with a risk of abuse and is classified as a Schedule IV controlled substance. Abuse is likely to increase the occurrence of somnolence, daytime sleepiness, and impaired driving skills. However, no evidence for physical dependence with the prolonged use of the drug was found in the clinical studies, and no withdrawal symptoms were reported after discontinuation of treatment.
Precautions: (1) Contraindicated in patients with narcolepsy. (2) Impairment of daytime wakefulness and driving skills may occur even with the use of suvorexant at the recommended dosage. CNS depressant effects and related risks increase with dosage and the concurrent use of other CNS depressants, including alcohol. (3) Worsening of depression or suicidal thinking may occur. Risk increases with dose. Immediately evaluate any new behavioral changes. (4) Use caution in patients with severe obstructive sleep apnea or severe chronic obstructive pulmonary disease because suvorexant may compromise respiratory function. (5) Not recommended for patients with severe hepatic impairment. (6) The serum concentration of suvorexant is higher in females than in males and in obese females compared with nonobese females. The higher drug concentration in obese females should be considered before increasing the drug dosage. (7) Not recommended in patients taking a strong CYP3A inhibitor (such as clarithromycin or itraconazole) and the suvorexant dosage should be reduced in patients taking a moderate CYP3A inhibitor (such as diltiazem, verapamil, and grapefruit juice). The concentration and action of suvorexant may be increased by the concurrent use of a CYP3A inhibitor. The action of suvorexant will be reduced by the concurrent use of a strong CYP3A inducer (such as carbamazepine, rifampin, or St. John's wort). (8) Suvorexant may increase digoxin concentrations, which should be monitored during concurrent use.
Adverse reaction: somnolence
Supplied as: 5 mg, 10 mg, 15 mg, and 20 mg film-coated tablets
Dosage: 10 mg once a night within 30 minutes of bedtime, with at least 7 hours remaining before the planned time of awakening. The dose may be increased as needed to a maximum recommended dosage of 20 mg/day. If a patient takes a moderate CYP3A inhibitor concurrently, the recommended initial dosage is 5 mg once a night, and the dosage should generally not exceed 10 mg daily. A dosage reduction may also be necessary in patients taking other CNS depressants and in obese female patients.
Nursing considerations: (1) Advise patients that the drug can be taken without regard to meals, but that the onset of action may be delayed if it's taken with or soon after a meal. (2) Warn patients about the risk of cognitive and behavioral changes, including amnesia, anxiety, hallucinations, and complex behaviors such as sleep-driving. Inform them that taking suvorexant with another CNS depressant, including alcohol, increases the risk of adverse reactions. Tell patients and families to inform the healthcare provider immediately if such behaviors occur. (3) Advise patients not to drive or engage in other activities requiring alertness within 8 hours of taking suvorexant. Those taking the maximum recommended dosage (20 mg/day) should avoid driving and other activities requiring alertness the following day. (4) Tell patients and families to immediately report any signs and symptoms of worsening depression or suicidal ideation. (5) Tell patients to inform the healthcare provider if the prescribed dosage seems ineffective. Warn them not to increase the dosage unless directed to do so by the healthcare provider.
REFERENCES
1. Bonnet MH, Arand DL. Treatment of insomnia. UpToDate. http://www.uptodate.com. [Context Link]
2. Belsomra (suvorexant) tablets, for oral use, C-IV. Prescribing information. http://www.merck.com/product/usa/pi_circulars/b/belsomra/belsomra_pi.pdf. [Context Link]
ANTIBACTERIAL DRUG
Ceftazidime pentahydrate/avibactam sodium
I.V. therapy for certain complicated infections
Joining ceftolozane/tazobactam, ceftazidime pentahydrate/avibactam sodium (Avycaz, Actavis) is the second combination of a cephalosporin and beta-lactamase inhibitor to be marketed. Ceftazidime is a cephalosporin antibacterial drug that's been available as a single agent for years. Avibactam is a new beta-lactamase inhibitor that protects ceftazidime against inactivation by beta-lactamase enzymes, thereby increasing antibacterial activity against Gram-negative bacteria. Avibactam is a non-beta-lactam and may inhibit certain bacteria-produced beta-lactamases that aren't inhibited by other beta-lactamase inhibitors such as tazobactam and sulbactam. Of particular importance is the activity of the new combination against Gram-negative bacteria that produce Klebsiella pneumoniae carbapenemase.
Like ceftolozane/tazobactam, ceftazidime/avibactam is administered by I.V. infusion for treatment of complicated intra-abdominal infections (cIAI) and complicated urinary tract infections (cUTI), although there are some differences in the specific bacteria that have been demonstrated to be susceptible to the two combination formulations.
Ceftazidime/avibactam is used in a regimen that also includes metronidazole to treat adults with cIAI caused by Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Providencia stuartii, Enterobacter cloacae, Klebsiella oxytoca, and Pseudomonas aeruginosa. It's also indicated to treat adults with cUTI including pyelonephritis caused by Escherichia coli, Klebsiella pneumoniae, Citrobacter koseri, Enterobacter aerogenes, Enterobacter cloacae, Citrobacter freundii, Proteus species, and Pseudomonas aeruginosa. Because the efficacy and safety data for ceftazidime/avibactam are limited, the use of the combination should be reserved for patients who have limited or no alternative treatment options.
The contribution of avibactam to the combination product was based on data from in vitro studies and animal models of infection. The effectiveness of the new combination plus metronidazole was evaluated in a study of patients with cIAI, in which it was compared with meropenem. Both treatments provided a favorable microbiological response in more than 90% of patients. In patients with cUTI, ceftazidime/avibactam was compared with imipenem/cilastatin, and both treatments provided a favorable microbiological response in approximately 70% of patients.
Like other cephalosporins and the other classes of beta-lactam antibacterial agents such as penicillins and carbapenems, ceftazidime is associated with a risk of hypersensitivity and anaphylactic reactions. In addition, almost all systemic antibacterial drugs including ceftazidime can cause Clostridium difficile-associated diarrhea (CDAD) that ranges in severity from mild diarrhea to fatal colitis. CDAD should be considered in all patients who experience diarrhea following use of an antibacterial agent, including the period of time following completion of treatment; CDAD has been reported to occur more than 2 months after the administration of antibacterial agents.
Neuromuscular excitability, seizures, and other CNS reactions have been infrequently reported in patients treated with ceftazidime, particularly in patients with renal impairment.
Precautions: (1) Contraindicated in patients with known serious hypersensitivity to ceftazidime, another cephalosporin, or avibactam. (2) Use caution if ceftazidime/avibactam is used in a patient known to be allergic to any of the beta-lactam agents because of the potential for cross-sensitivity with other beta-lactam antibacterial drugs. (3) Monitor renal function and reduce the dosage as directed in patients with moderate to severe renal impairment or end-stage renal disease. (4) Not recommended for concurrent use with probenecid, which may reduce elimination of avibactam.
Adverse reactions: vomiting, nausea, constipation, anxiety, abdominal pain, dizziness
Supplied as: a powder in single-use vials in quantities equivalent to 2 g of ceftazidime and 0.5 g of avibactam
Dosage: 2 g/0.5 g every 8 hours by I.V. infusion over 2 hours for 5 to 14 days to treat cIAI and for 7 to 14 days to treat cUTI. Metronidazole should be included in the treatment regimen for cIAI. See the prescribing information for dosage recommendations for patients with impaired renal function.
Nursing considerations: (1) In patients with changing renal function, creatinine clearance should be monitored at least daily and the dosage should be appropriately adjusted. (2) When preparing ceftazidime/avibactam for administration, reconstitute the contents of a vial with 10 mL of Sterile Water for Injection, 0.9% Sodium Chloride Injection, 5% Dextrose Injection, Lactated Ringer's Injection, or any concentration of Dextrose Injection and Sodium Chloride Injection containing up to 2.5% dextrose and 0.45% sodium chloride. With the same diluents used for the constitution of the powder (except Sterile Water for Injection), the constituted solution should be diluted to achieve a total volume between 50 mL and 250 mL. (3) Administer the diluted solution in the infusion bag within 12 hours when stored at room temperature. The diluted solution may be stored under refrigeration for up to 24 hours following dilution and administered within 12 hours of subsequent storage at room temperature. (4) Assess patients for prior hypersensitivity reactions to beta-lactams and other allergens. Advise them to seek immediate medical attention for serious hypersensitivity reactions. (5) Teach patients to recognize CDAD and tell them to report severe or watery diarrhea to the healthcare provider immediately. Inform them that the risk may continue for several weeks after treatment ends. (6) Patients who monitor their glucose levels should use tests based on enzymatic glucose oxidase reactions because ceftazidime may cause a false-positive reaction with certain urine glucose tests.
REFERENCE
Avycaz (ceftazidime pentahydrate/avibactam sodium) for injection, for intravenous use. Prescribing information. http://pi.actavis.com/data_stream.asp?product_group=1957&p=pi&language=E.