IN THIS ARTICLE, you'll learn about 14 recently approved drugs, including
the first in a new class of antidiabetic agents.
an anticoagulant that proved superior to warfarin for certain indications.
new antineoplastic drugs indicated for multiple myeloma, unresectable or metastatic melanoma, and thyroid cancer.
Unless otherwise specified, the information in the following summaries applies to adults, not children. Consult a pharmacist or the package insert for information about each drug's safety during pregnancy and breastfeeding. Consult a pharmacist, the package insert, or a comprehensive and current drug reference for more details on precautions, drug interactions, and adverse reactions* for all these drugs.
Drug Facts and Comparisons. St. Louis, MO: Facts and Comparisons, Inc.; 2014.
Nursing 2014 Drug Handbook. Ambler, PA: Lippincott Williams & Wilkins; 2014.
Physicians' Desk Reference. 68th ed. Montvale, NJ: Medical Economics; 2014.
Several significant advantages over warfarin
Apixaban (Eliquis, Bristol-Myers Squibb; Pfizer), a factor Xa inhibitor anticoagulant, is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Evaluated and compared with warfarin in a multinational study of more than 18,000 patients, apixaban was determined to be superior to warfarin for the primary study endpoint of reducing the risk of stroke and systemic embolism. Superiority to warfarin was primarily attributable to a reduction in hemorrhagic and ischemic strokes with hemorrhagic conversion compared to warfarin. Purely ischemic strokes occurred with similar rates with both drugs.
Treatment with apixaban resulted in a significantly lower rate of all-cause death than did treatment with warfarin, primarily because of a reduction in cardiovascular death, particularly stroke deaths.
As with other anticoagulants, bleeding is the most important concern with apixaban. In clinical trials, however, significantly fewer major bleeding events (such as intracranial and gastrointestinal [GI] bleeding) occurred in patients treated with apixaban than in those treated with warfarin. The rate of major bleeding events was 2.13% per year with apixaban, compared with 3.09% with warfarin. Deaths attributable to bleeding events including hemorrhagic stroke occurred in 0.06% and 0.24% of patients per year, respectively. The bleeding risk increases when other medications that affect hemostasis are used concurrently.
Apixaban should be discontinued at least 48 hours before elective surgery or invasive procedures with a moderate or high risk of unacceptable or clinically significant bleeding. It should be discontinued at least 24 hours before elective surgery or invasive procedures in which the risk of bleeding is low or bleeding can be easily controlled.
Apixaban doesn't require routine international normalized ratio (INR) monitoring, an advantage over warfarin. However, no specific antidote reverses an excessive anticoagulant action of apixaban. This represents a disadvantage for the new drug compared with warfarin, for which vitamin K is a specific antidote. A procoagulant reversal agent such as prothrombin complex concentrate may be considered, but this option hasn't been evaluated in clinical studies.
Discontinuation of apixaban in the absence of adequate alternative anticoagulation increases the risk of thrombotic events such as strokes, the subject of a boxed warning in the labeling. If treatment with apixaban must be discontinued for a reason other than pathologic bleeding, coverage with another anticoagulant should be strongly considered.
Precautions: (1) Contraindicated in patients with active pathologic bleeding. (2) Use cautiously in patients taking other drugs that affect hemostasis, such as other anticoagulants, fibrinolytic agents, aspirin and other antiplatelet drugs, nonsteroidal anti-inflammatory drugs, selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, and serotonin-norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine. (3) Not recommended for patients with prosthetic heart valves. (4) Not recommended for patients with severe hepatic impairment. (5) Apixaban is a substrate of P-glycoprotein (P-gp), as well as CYP3A4. The concurrent use of a strong dual inhibitor of CYP3A4 and P-gp (such as ketoconazole or clarithromycin) increases the concentration of apixaban and the dosage of the anticoagulant should be reduced or its use avoided. (6) Avoid concurrent use with strong dual inducers of CYP3A4 and P-gp (such as carbamazepine, rifampin, and St. John's wort), which reduce exposure to apixaban.
Adverse reactions: bleeding, hypersensitivity reactions such as skin rash
Supplied as: 2.5 mg and 5 mg film-coated tablets
Dosage: 5 mg twice a day. A lower dosage of 2.5 mg twice a day is recommended in patients with any two of the following characteristics: age 80 years or older; body weight of 60 kg or less; serum creatinine of 1.5 mg/dL or higher. If a patient is also taking a strong dual inhibitor of CYP3A4 and P-gp, the recommended dosage is 2.5 mg twice a day. Avoid concurrent use of a strong dual inhibitor of CYP3A4 and P-gp in patients already being treated with a dosage of 2.5 mg twice a day.
Nursing considerations: (1) Teach patients to take the medication as prescribed and to recognize and report signs and symptoms of bleeding. (2) Tell patients that if they miss taking a dose at the scheduled time, they should take it as soon as possible on the same day and resume twice-daily administration. Warn them not to double the dose to make up for a missed dose. (3) Discontinue apixaban as prescribed before invasive procedures. (4) If a patient is switching from warfarin to apixaban treatment, discontinue warfarin and start apixaban when the INR is below 2, as prescribed. Switching a patient from apixaban to warfarin treatment is a challenge; apixaban affects the INR, so determining the appropriate warfarin dosage is difficult. Consult the product labeling for detailed recommendations on discontinuing apixaban or switching therapy from apixaban to another anticoagulant.
Prescribing information. Eliquis (apixaban) tablets for oral use. http://packageinserts.bms.com/pi/pi_eliquis.pdf.
Lomitapide mesylate Mipomersen sodium
Two drugs newly approved for a rare genetic disorder
Homozygous familial hypercholesterolemia (HoFH) is a rare inherited disorder caused by defects in the low-density lipoprotein (LDL) receptor gene. These defects are associated with changes in vascular endothelial function that result in very high serum concentrations of LDL cholesterol. Approximately one in 1 million individuals in the United States (about 300 people) experiences HoFH. These patients are at risk for cardiovascular disorders and death at an early age, even during childhood.
Two new drugs were marketed in 2013 specifically to treat HoFH. Although approved for the same indication, they'll be discussed separately because they have different mechanisms of action and administration routes.
1. FDA approves new orphan drug for rare cholesterol disorder. FDA news release. December 26, 2012.
Lomitapide mesylate (Juxtapid, Aegerion) is indicated to treat patients with HoFH as an adjunct to a low-fat diet and other lipid-lowering treatments, including LDL apheresis where available, to reduce LDL-cholesterol (LDL-C), total cholesterol (TC), apolipoprotein B (apoB), and non-high-density lipoprotein cholesterol (non-HDL-C). Its effectiveness was demonstrated in a clinical study involving 29 patients, 23 of whom completed the study over 78 weeks. The effect of lomitapide on cardiovascular morbidity and mortality wasn't determined, and its effectiveness hasn't been established in patients with hypercholesterolemia who don't have HoFH.
The risk of hepatotoxicity is the subject of a boxed warning in its labeling and is the reason the drug is available only through a restricted distribution program. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, and total bilirubin should be determined before the start of treatment, and at least ALT and AST should be determined before each dosage increase or monthly, whichever comes first, during the first year. After the first year, these tests should be performed at least every 3 months and before any dosage increase.
Lomitapide increases hepatic fat (hepatic steatosis), which is also a subject of the boxed warning. This may occur with or without elevations in ALT and AST, and may be a risk factor for progressive liver disease, including steatohepatitis and cirrhosis.
In clinical trials, most patients (93%) experienced GI adverse reactions; 14% experienced GI reactions so severe that treatment was discontinued early. To reduce the risk of GI adverse reactions, the dosage of lomitapide should be increased gradually and patients should adhere to a low-fat diet. The administration of lomitapide with food may increase the risk of GI adverse reactions, so it should be administered apart from food.
Because it primarily acts in the small intestine, lomitapide may reduce the absorption of fat-soluble nutrients. The risk of nutritional deficiencies may be increased in patients with chronic bowel or pancreatic diseases that predispose them to malabsorption. Consult the product insert for details about daily dietary supplements recommended for patients taking lomitapide.
Lomitapide is classified in Pregnancy Category X and is contraindicated in pregnant women.
Precautions: (1) Contraindicated in patients with moderate or severe hepatic impairment or active liver disease. (2) Patients treated with lomitapide should avoid alcohol or consume no more than one alcoholic drink per day. Alcohol may increase concentrations of hepatic fat and induce or exacerbate liver injury. (3) Use with caution in patients who are also being treated with other medications that are associated with a risk of hepatotoxicity, such as amiodarone or methotrexate. (4) Avoid use of lomitapide in patients with rare hereditary problems such as galactose intolerance or glucose-galactose malabsorption because of the increased possibility of diarrhea and malabsorption. (5) Lomitapide exposure is increased by about 50% in patients with end-stage renal disease receiving dialysis or mild hepatic impairment; the dosage shouldn't exceed 40 mg daily for these patients. (6) Lomitapide is extensively metabolized in the liver via the CYP3A4 pathway and is contraindicated for concurrent use with strong CYP3A4 inhibitors, such as ketoconazole and clarithromycin, or moderate CYP3A4 inhibitors such as diltiazem and verapamil. (7) Lomitapide is associated with many potential drug interactions. Consult the product insert for comprehensive warnings and recommended dosage adjustments.
Adverse reactions: diarrhea, nausea, dyspepsia, vomiting, abdominal pain
Supplied as: 5 mg, 10 mg, and 20 mg capsules
Dosage: Initially 5 mg/day, increased gradually based on patient tolerance to the maximum recommended dosage of 60 mg once a day. Consult the product insert for detailed recommendations, including monitoring parameters and dosage adjustments for certain patient populations.
Nursing considerations: (1) Women of reproductive potential should have a negative pregnancy test before starting treatment and use reliable contraception during therapy. (2) Because of the risk of nutritional deficiencies, teach patients the importance of taking dietary supplements as prescribed. (3) Tell patients on warfarin therapy to get regular INR testing as directed by their healthcare provider. Lomitapide has been reported to increase the plasma concentration of warfarin by about 30% and the INR by 30%. (4) Warn patients that taking lomitapide with food may exacerbate GI problems. Tell them to take each dose with a glass of water at least 2 hours after the evening meal. (5) Instruct patients to avoid grapefruit juice, which is a CYP3A4 inhibitor. (6) Remind patients to swallow capsules whole without opening, crushing, dissolving, or chewing them.
Prescribing information. Juxtapid (lomitapide) capsules for oral use. http://juxtapid.com/sites/default/files/downloads/Prescribing_Information.pdf.
The primary goal of treatment of patients with HoFH is to reduce the greatly elevated concentrations of LDL-C. Mipomersen sodium (Kynamro, Genzyme) is an oligonucleotide inhibitor of apoB-100 synthesis. ApoB-100 is the principal apolipoprotein of LDL. Administered via subcutaneous injection, this drug has been approved as an adjunct to lipid-lowering medications and diet to reduce LDL-C, apoB, TC, and non-HDL-C in patients with HoFH. It hasn't been evaluated as an adjunct to LDL apheresis and isn't recommended for use in patients receiving this treatment.
The effectiveness of mipomersen was demonstrated in a placebo-controlled study in 51 patients. An average reduction in LDL-C concentrations of approximately 25% was found during the first 26 weeks of therapy. As with lomitapide, its effect on cardiovascular morbidity and mortality hasn't been determined, and its effectiveness hasn't been established in patients with hypercholesterolemia who don't have HoFH.
As with lomitapide, the risk of hepatotoxicity is the most important concern for patients taking mipomersen, and the contraindications and warnings in the product labeling for the two drugs are almost exactly the same. The risk of hepatotoxicity is the subject of a boxed warning for both drugs and is the reason they're available only through a restricted distribution program. The risk of increased hepatic fat is also a subject of the boxed warning.
Before a patient starts treatment, ALT, AST, alkaline phosphatase, and total bilirubin should be determined, and at least ALT and AST should be determined monthly during the first year of treatment. After the first year, these tests should be performed at least every 3 months.
Precautions: (1) Mipomersen is contraindicated in patients with moderate or severe hepatic impairment or active liver disease. (2) Avoid concurrent use with other medications that can increase hepatic fat. (3) Patients taking mipomersen should avoid alcohol or consume no more than one alcoholic drink a day. (4) Not recommended for patients with severe renal impairment or clinically significant proteinuria, or for those on renal dialysis.
Adverse reactions: injection site reactions (pain, pruritus, inflammation), flu-like symptoms (pyrexia, chills, myalgia, fatigue), nausea, headache, elevated ALT
Supplied as: single-use vials and prefilled syringes providing 200 mg/mL
Dosage: 200 mg once a week, on the same day every week. Consult the product labeling for recommended dosage adjustments in patients who experience elevations of transaminases.
Nursing considerations: (1) For patients who will self-administer the drug at home, the first injection should be supervised by an appropriately qualified healthcare professional. Teach patients how to administer mipomersen subcutaneously into the abdomen, thigh region, or outer area of the upper arm. Instruct them to avoid areas of active skin disease or injury such as sunburns, skin infections, or areas of tattooed skin and scarring, and to alternate injection sites. (2) If patients miss a dose, tell them to take it if at least 3 days remain until the next scheduled weekly dose. (3) Tell patients to refrigerate vials and syringes, keep them in their original cartons until time of use, and protect them from light. Before administration, the drug should be removed from refrigeration for at least 30 minutes so it can warm to room temperature.
Prescribing information. Kynamro (miposmersen sodium) Injection. http://www.kynamro.com/~/media/Kynamro/Files/KYNAMRO-PI.pdf.
First in its class
Designated as a sodium-glucose cotransporter 2 (SGLT2) inhibitor, canagliflozin (Invokana, Janssen) is the first drug approved in this new class of antidiabetic drugs. SGLT2 is expressed in the proximal renal tubules and is responsible for the reabsorption of most glucose filtered by the kidney. By inhibiting SGLT2, canagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose, thereby increasing urinary glucose excretion and lowering blood glucose concentrations.
Canagliflozin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Its effectiveness has been demonstrated in studies in which it was used as monotherapy, in combination with metformin, a sulfonylurea, metformin and a sulfonylurea, metformin and pioglitazone, and in combination with insulin (with or without other antihyperglycemic agents). It's also been compared with sitagliptin and glimepiride in clinical studies. The use of canagliflozin resulted in reductions in A1C concentrations and fasting plasma glucose concentrations, and, in many patients, weight reduction. Hypersensitivity reactions, including erythema, rash, pruritus, and angioedema, were experienced by 4% of patients in the clinical studies of canagliflozin, with a small number of patients experiencing serious reactions.
Canagliflozin increases serum creatinine concentrations and decreases estimated glomerular filtration rate (eGFR); patients with hypovolemia may be more susceptible to these changes. Assessment of renal function is recommended before treatment starts and periodically thereafter. Treatment shouldn't be initiated in patients with an eGFR less than 45 mL/minute/1.73 m2. More frequent renal function monitoring is recommended in patients with an eGFR below 60 mL/minute/1.73 m2. The drug should be discontinued if the eGFR is persistently less than 45 mL/minute/1.73 m2.
Canagliflozin causes an osmotic diuresis that may reduce intravascular volume and cause symptomatic hypotension, particularly in patients with impaired renal function (eGFR less than 60 mL/minute/1.73 m2) or low systolic BP, older adults, or patients treated with diuretics or medications that interfere with the renin-angiotensin-aldosterone system, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs).
Although canagliflozin isn't likely to cause hypoglycemia, it can increase the risk of hypoglycemia when used in combination with insulin or an insulin secretagogue such as a sulfonylurea. Dosage reductions for these agents may be warranted for patients on a combination regimen that includes canagliflozin. The concurrent use of drugs such as rifampin, ritonavir, phenytoin, and phenobarbital may require a higher dosage of the new drug because these drugs may decrease canagliflozin's action.
In clinical studies, the incidence of pancreatitis and bone fracture was higher in patients treated with canagliflozin than with comparator agents. The FDA is requiring postmarketing studies that will monitor for these events, as well as malignancies, severe hypersensitivity reactions, photosensitivity reactions, liver abnormalities, adverse pregnancy outcomes, and cardiovascular outcomes.
Precautions: (1) Contraindicated in patients with a history of a serious hypersensitivity reaction. (2) Contraindicated in patients with severe renal impairment (eGFR less than 30 mL/minute/1.73 m2) and end-stage renal disease, and in patients on dialysis. (3) Periodically monitor serum potassium concentrations for hyperkalemia in patients with impaired renal function and in those who are being treated with an ACE inhibitor, ARB, or potassium-sparing diuretic. (4) Closely monitor patients on digoxin therapy because canagliflozin may increase digoxin's concentration and action.
Adverse reactions: female genital mycotic infections such as vulvovaginal candidiasis, urinary tract infections, increased urination, and male genital mycotic infections such as balanitis, hyperkalemia, increased LDL cholesterol, hypermagnesemia, and hyperphosphatemia
Supplied as: 100 mg and 300 mg film-coated tablets
Dosage: Initially, 100 mg once a day, taken before the first meal of the day. Dosage may be increased to 300 mg/day in certain patients; consult the product insert for dosage adjustment guidelines.
Nursing considerations: (1) Teach patients to take canagliflozin before the first meal of the day. This recommendation is based on its potential to reduce postprandial plasma glucose excursions due to delayed intestinal glucose absorption. (2) Teach female patients to recognize and report signs and symptoms of a vaginal yeast infection, such as white or yellowing discharge that may resemble cottage cheese and vaginal itching. (3) Teach male patients to report signs and symptoms of yeast infections affecting skin around the penis, such as redness, itching, or swelling of the penis and pain in the skin around the penis. (4) Educate all patients about signs and symptoms of hypoglycemia, such as headache, drowsiness, irritability, hunger, rapid heart beat, sweating, and feeling jittery. (5) Encourage patients to maintain the prescribed diet and exercise program and to regularly monitor their serum glucose levels as directed.
Prescribing information. Invokana (canagliflozin) tablets, for oral use. http://www.invokanahcp.com/prescribing-information.pdf.
New addition to an established drug class
The fourth dipeptidyl peptidase-4 (DPP-4) inhibitor to be approved, alogliptin benzoate (Nesina, Takeda) joins the class of drugs that includes sitagliptin, saxagliptin, and linagliptin. Its properties are very similar to those of its predecessors: By inhibiting the inactivation of incretins, the DPP-4 inhibitors increase and prolong their activity in increasing insulin biosynthesis and secretion.
Like the other DPP-4 inhibitors, alogliptin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. It's not indicated to treat patients with type 1 diabetes or those with diabetic ketoacidosis.
The effectiveness of alogliptin was demonstrated in placebo-controlled studies in which it was evaluated as monotherapy, and in combination with metformin, glyburide, pioglitazone (either alone or in combination with metformin or a sulfonylurea), and insulin (either alone or in combination with metformin). It hasn't been directly compared with other DPP-4 inhibitors in clinical studies.
Like its predecessors, alogliptin is well tolerated by most patients; however, rare but serious hypersensitivity reactions to DPP-4 inhibitors have been reported. In addition, some patients treated with a DPP-4 inhibitor, including alogliptin, have experienced acute pancreatitis.
The labeling for alogliptin includes a warning regarding hepatic failure. Conducting liver function tests before initiating treatment is recommended.
The DPP-4 inhibitors don't cause hypoglycemia and aren't likely to cause hypoglycemia when used in combination with metformin. However, their concurrent use with insulin or insulin secretagogues such as the sulfonylureas may cause hypoglycemia.
Precautions: (1) Contraindicated in patients with a history of a serious hypersensitivity reaction to any drug in this class, such as anaphylaxis, angioedema, and severe cutaneous reactions. (2) Treatment with alogliptin should be promptly discontinued and the patient treated appropriately if pancreatitis is suspected. (3) Treatment with alogliptin should be interrupted if the patient experiences signs and symptoms that may indicate liver injury and/or if liver enzyme concentrations are significantly elevated. Treatment shouldn't resume unless another explanation for liver test abnormalities is found. (4) Closely monitor patients taking alogliptin with insulin or an insulin secretagogue. If indicated, reduce the dosage of insulin or the insulin secretagogue as prescribed. (5) Reduce the dosage as prescribed in patients with moderate or severe renal impairment or end-stage renal disease.
Adverse reactions: nasopharyngitis, headache, upper respiratory tract infection
Supplied as: 25 mg, 12.5 mg, and 6.25 mg film-coated tablets. Alogliptin is also available in a combination formulation with metformin and in a combination formulation with pioglitazone.
Dosage: 25 mg once a day. Consult the product insert for recommended dosage reductions for patients with impaired renal function.
Nursing considerations: (1) Assess renal function tests before patients begin therapy and periodically thereafter as prescribed. (2) Tell patients that alogliptin can be taken without regard to food. (3) Educate patients about the risk of acute pancreatitis and tell them to discontinue the drug and contact their healthcare provider immediately if they experience persistent, severe abdominal pain. (4) Warn patients about the risk of hypersensitivity reactions. Tell them to discontinue the drug and seek medical attention immediately if they experience signs of an allergic reaction such as skin rash or hives; swelling of the lips, tongue, or throat; and difficulty breathing. (5) If patients miss a dose, they should skip that dose and take the next one on schedule rather than doubling a dose.
Nesina (alogliptin) tablets. https://www.takedadiabetes.com.
DRUG FOR DYSPAREUNIA
Pain relief in a convenient oral formulation
The reduction in estrogen concentration associated with menopause may make vaginal tissues thinner, drier, and more fragile, resulting in dyspareunia (pain during sexual intercourse). These symptoms of vaginal and vulvar atrophy are among those most frequently reported by postmenopausal women. Ospemifene (Osphena, Shionogi) is an estrogen agonist/antagonist with actions that are mediated through binding to estrogen receptors. It acts like estrogen on vaginal tissues, making them thicker and less fragile. Also designated as a selective estrogen receptor modulator, ospemifene has properties that are most similar to those of raloxifene, a drug used primarily for treatment and prevention of osteoporosis in postmenopausal women.
Ospemifene is indicated for moderate-to-severe dyspareunia, a symptom of vulvar and vaginal atrophy, due to menopause. It's the first orally administered drug with estrogenic activity to be approved for this indication.
The new drug exhibits estrogen agonistic effects in the endometrium; an increased risk of endometrial cancer in women with a uterus who use unopposed estrogens is the subject of a boxed warning in the labeling. Although adding a progestin to postmenopausal estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer, increased risks such as breast cancer are associated with use of progestins. An increased risk of cardiovascular disorders such as stroke and deep vein thrombosis (DVT) is also the subject of a boxed warning in the labeling.
Precautions: (1) Ospemifene is classified in Pregnancy Category X and is contraindicated in women who are or may become pregnant. (2) Contraindicated in women with known or suspected estrogen-dependent neoplasia. Appropriate diagnostic measures should be taken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. (3) Contraindicated in women with known or suspected breast cancer or a history of breast cancer. (4) Contraindicated in women with active DVT, pulmonary embolism, active arterial thromboembolic disease such as stroke or myocardial infarction, or a history of these disorders. (5) Discontinuing ospemifene is recommended at least 4 weeks before any surgery associated with an increased risk of thromboembolism and during prolonged periods of immobilization. (6) Ospemifene shouldn't be used concurrently with an estrogen agonist/antagonist. (7) Not recommended for use in patients with severe hepatic impairment. (8) Ospemifene shouldn't be used concurrently with fluconazole, which inhibits the pathways involved in the metabolism of ospemifene and increases the exposure of the new drug by 2.7-fold. Ketoconazole may also increase exposure of the new drug, but to a lesser extent. Conversely, rifampin induces these metabolic pathways and decreases the exposure of ospemifene by 58%, which is likely to reduce its clinical effect. (9) To reduce the risk of serious adverse reactions that may be associated with long-term use, the drug should be prescribed for the shortest duration that's consistent with treatment goals.
Adverse reactions: hot flush, vaginal discharge, muscle spasms, hyperhidrosis, genital discharge
Supplied as: 60 mg film-coated tablets
Dosage: 60 mg once a day
Nursing considerations: (1) Warn patients that ospemifene is likely to cause fetal harm and must not be used by women who are or may become pregnant. (2) Tell patients to take each dose with food, which increases the drug's bioavailability. (3) Teach patients to immediately report unusual vaginal bleeding, changes in vision or speech, sudden new or severe headaches, and severe pain in the chest or legs, with or without shortness of breath, weakness, and fatigue.
Prescribing information. Osphena (ospemifene) tablets, for oral use. http://www.shionogi.com/pdf/PI/Osphena-PI.pdf.
First prescription weight-loss drug in years
Lorcaserin (Belviq, Arena; Eisai), a new molecular entity, represents the first new prescription weight-loss drug approved by the FDA in 13 years. (Another new weight-loss product, Qsymia [Vivus], is a combination of two older medications, the anorexiant phentermine and the antiepileptic drug topiramate.) A serotonin 2C receptor agonist, lorcaserin is thought to reduce food consumption and promote satiety by selectively activating serotonin 2C receptors on anorexigenic proopiomelanocortin neurons in the hypothalamus. When used in the recommended dosage, the new drug doesn't appear to activate serotonin 2B receptors, the action associated with the heart valve damage that prompted withdrawal of fenfluramine and dexfenfluramine from the market.
Lorcaserin is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index of 30 or greater (obese), or 27 or greater (overweight) in the presence of at least one weight-related comorbid condition, such as hypertension, dyslipidemia, or type 2 diabetes mellitus. In placebo-controlled studies, about 50% of patients who didn't have type 2 diabetes lost at least 5% of their baseline body weight compared with approximately 25% of those receiving placebo. In patients with type 2 diabetes, approximately 38% of patients treated with lorcaserin and 16% of those receiving placebo lost at least 5% of their body weight. Improved glycemic control was also associated with the use of lorcaserin in patients with diabetes.
Because lorcaserin is a serotonergic drug, its use is associated with a risk of life-threatening serotonin syndrome or neuroleptic malignant syndrome-like reactions. The risk of serotonin syndrome is increased by the concurrent use of other drugs with serotonergic activity, including selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, serotonin-norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine, tricyclic antidepressants, monoamine oxidase inhibitors, lithium, triptans such as sumatriptan, tramadol, tryptophan, bupropion, dextromethorphan, and St. John's wort. The concurrent use of lorcaserin with any of these is best avoided, but if such therapies are clinically warranted, patients should be monitored even more closely for signs and symptoms of serotonin syndrome, such as mental status changes (agitation, hallucinations), autonomic instability (tachycardia, labile BP, hyperthermia), neuromuscular changes (hyperreflexia, incoordination), and GI effects (nausea, vomiting, diarrhea).
The use of serotonergic anorexiants with serotonin 2B receptor agonist activity such as dexfenfluramine has been associated with a risk of heart valve damage. Because lorcaserin is a selective serotonin 2C receptor agonist, it appears less likely to cause such problems and the infrequent reports of valvular effects were at an incidence (approximately 2%) that was similar to that with placebo. However, lorcaserin was not studied in patients with congestive heart failure and it must be used with caution in patients with this condition.
Approximately 2% of the patients treated with lorcaserin for at least 1 year in the clinical studies reported impairment of attention and memory, compared with 0.5% of those receiving placebo. Other cognitive adverse events included confusion, somnolence, and fatigue.
Lorcaserin has been classified in Schedule IV under the provisions of the Controlled Substances Act because at larger than recommended dosages, it may cause euphoria, hallucination, and dissociation in some patients.
Precautions: (1) Contraindicated during pregnancy; lorcaserin is classified in Pregnancy Category X. (2) Monitor patients for signs and symptoms of serotonin syndrome, particularly those taking lorcaserin and another drug with serotonergic activity concurrently. (3) Contraindicated for concurrent use with serotonergic and dopaminergic drugs that are potent serotonin 2B receptor agonists and are known to increase the risk of cardiac valvulopathy, such as cabergoline. (4) Monitor patients for depression and/or suicidal ideation, a potential risk with lorcaserin and other centrally acting drugs. Treatment should be discontinued in patients who experience suicidal thoughts or behaviors. (5) Activation of serotonin 2C receptors may increase the possibility of priapism, so lorcaserin should be used with caution in men with conditions that may predispose them to priapism, such as sickle cell anemia or leukemia, and in men using drugs to treat erectile dysfunction, such as sildenafil. (6) Closely monitor patients with risk factors for these potential problems: decreased heart rate, decreased red and white blood cell counts (periodic monitoring of complete blood cell [CBC] counts may be indicated), increased prolactin concentrations, hypoglycemia in patients with type 2 diabetes treated with insulin and/or insulin secretagogues such as sulfonylureas, and pulmonary hypertension. (7) Use caution in patients with moderate renal impairment or severe hepatic impairment. Lorcaserin isn't recommended for patients with severe renal impairment or end-stage renal disease.
Adverse reactions: In patients who don't have diabetes mellitus: headache, dizziness, nausea, fatigue, constipation, dry mouth. In patients with diabetes: hypoglycemia, headache, back pain, cough, fatigue.
Supplied as: 10 mg film-coated tablets
Dosage: 10 mg twice a day.
Nursing considerations: (1) Lorcaserin can be taken without regard to food. (2) Reinforce the importance of diet and exercise in any weight-loss program. (3) Because of the drug's potential cognitive adverse effects, caution patients to avoid driving and other hazardous activities requiring alertness until they determine how the medication affects them. (4) Warn women of childbearing potential that the drug is likely to harm a fetus and tell them to use reliable contraception throughout therapy. (5) Warn men about the potential for priapism. If appropriate, tell them to discuss concurrent use of medications for erectile dysfunction with their healthcare provider. (6) The patient's response to treatment should be evaluated by week 12. If the patient hasn't lost at least 5% of baseline body weight, treatment may be discontinued because it's unlikely that the patient will achieve meaningful weight loss with continued treatment.
Prescribing information. Belviq (lorcaserin). http://www.belviq.com/documents/Belviq_Prescribing_information.pdf.
DRUG FOR MULTIPLE SCLEROSIS
Another option for patients with relapsing forms of MS
Dimethyl fumarate (Tecfidera, Biogen Idec) is the third oral drug to be marketed in the last 3 years to treat patients with relapsing forms of multiple sclerosis (MS), joining fingolimod and teriflunomide. The effectiveness and safety of dimethyl fumarate (DMF) was evaluated in two placebo-controlled studies. The primary endpoint of one study was the proportion of patients who experienced relapse within 2 years. Only 27% of patients treated with DMF experienced relapse, compared with 46% of those receiving placebo. The drug was also more effective in attaining additional endpoints, including annualized relapse rate and time to confirmed disability progression. In the second study, the primary endpoint was the annualized relapse rate at 2 years, at which time these rates were 0.224 for DMF and 0.401 for placebo. In both studies the drug had a significant effect on the magnetic resonance imaging endpoints, such as a lower number of new or newly enlarging lesions.
Precautions: (1) Because DMF decreases mean lymphocyte counts, patients taking it may have an increased infection risk. A CBC count within 6 months of starting therapy is recommended to identify patients with a preexisting lymphopenia. A CBC count is recommended annually during treatment or more often as indicated. (2) Treatment should be interrupted and the patient treated if a serious infection develops.
Adverse reactions: flushing (warmth, redness, itching, and/or burning sensation), abdominal pain, diarrhea, nausea
Supplied as: 120 mg and 240 mg delayed release capsules. A 30-day starter pack is available that includes a 7-day bottle with 120 mg capsules and a 23-day bottle with 240 mg capsules. A 30-day bottle containing 60 of the 240-mg capsules is available for maintenance treatment.
Dosage: Initially, 120 mg twice a day. After 7 days, the dosage is increased to the maintenance dosage of 240 mg twice a day.
Nursing considerations: (1) Instruct patients to swallow capsules whole, without crushing or chewing them. (2) Patients are more likely to experience flushing as an adverse reaction soon after starting treatment. Tell them that this usually resolves over time. GI adverse reactions, which are less common, usually resolve over time as well. (3) Although the drug may be taken without regard to food, advise patients that taking it with food may reduce the incidence of flushing. (4) Teach patients to recognize signs and symptoms of infection and report them to the healthcare provider. (5) Tell patients to store capsules in the original container. Once opened, bottles of DMF should be discarded after 90 days.
Prescribing information. Tecfidera (dimethyl fumarate) delayed release capsules, for oral use. http://www.tecfidera.com/pdfs/full-prescribing-information.pdf.
Effective therapy for multidrug-resistant TB
Tuberculous (TB) is relatively rare in the United States, but worldwide it's estimated to affect 9 million people. The CDC reports that 10,528 people in the United States became ill with TB in 2011.
Combination regimens of antitubercular drugs that include isoniazid, rifampin, and often other drugs have been the standard of treatment and are usually effective. However, strains of Mycobacterium tuberculosis resistant to isoniazid and rifampin are being reported with increasing frequency.
Bedaquiline fumarate (Sirturo, Janssen) is the first antitubercular drug to be approved to treat MDR-TB. Classified as a diarylquinoline antimycobacterial drug, it inhibits mycobacterial adenosine 5'-triphosphate synthase, an enzyme essential for the generation of energy and replication of M. tuberculosis.
Bedaquiline is indicated as part of combination therapy in adults with pulmonary MDR-TB. It must be used in combination with at least three other drugs to which the patient's MDR-TB isolate is susceptible based on lab testing. If test results are unavailable, treatment may be initiated with bedaquiline in combination with at least four other drugs to which the patient's MDR-TB isolate is likely to be susceptible. Bedaquiline should be reserved for use in patients for whom an effective treatment regimen can't otherwise be provided.
The approval of bedaquiline was based on the analysis of time to sputum culture conversion from two clinical studies in patients with pulmonary MDR-TB. Its effectiveness and safety have not been established in patients with extrapulmonary TB, latent infection due to M. tuberculosis, or drug-sensitive TB.
In one of the clinical studies, a higher incidence of death was found in patients receiving bedaquiline (9/79; 11.4%), compared with those receiving placebo (2/81; 2.5%); this is the subject of a boxed warning in its labeling. Because a reason for the imbalance in deaths hasn't been identified, bedaquiline should be used only when another effective treatment regimen can't be provided.
Bedaquiline has been reported to prolong the QT interval. Its concurrent use with other medications that prolong the QT interval (such as antiarrhythmic agents, certain fluoroquinolone and macrolide antibacterial drugs, and the antimycobacterial clofazimine) can result in additive QT prolongation and an increased risk of ventricular dysrhythmias. This is the subject of a boxed warning in its labeling. The risk of QT prolongation and subsequent complications is higher in patients with a history of torsade de pointes, hypothyroidism and bradydysrhythmias, uncompensated heart failure, congenital long QT syndrome, or reduced calcium, magnesium, or potassium concentrations.
Bedaquiline should be administered by directly observed therapy. Failure to adhere to the prescribed treatment regimen may result in increased antibiotic resistance and treatment failure.
Precautions: (1) Because of the risk of ventricular dysrhythmias, an ECG should be obtained before treatment starts and at least 2, 12, and 24 weeks thereafter. Serum potassium, calcium, and magnesium should be determined at baseline and corrected if abnormal. Follow-up monitoring of electrolytes should be performed if QT prolongation is detected. (2) Treatment should be discontinued if the patient develops a clinically significant ventricular dysrhythmia or a heart rate corrected QT interval greater than 500 ms. (3) Because of the risk of hepatic adverse reactions, patients should avoid the concurrent use of alcohol and other hepatotoxic agents. New or worsening hepatic dysfunction (elevated liver function tests and signs and symptoms such as fatigue, anorexia, nausea, jaundice, and dark urine) should be promptly evaluated. Consult the product insert for detailed recommendations about hepatic function monitoring and guidelines for modification or discontinuation of treatment. (4) Use caution in patients with severe hepatic or renal impairment because the drug hasn't been evaluated in these patients. (Dosage adjustment isn't necessary in patients with mild-to-moderate hepatic or renal impairment.) (5) Bedaquiline is metabolized via the CYP3A4 pathway. Avoid concurrent administration with rifampin or another strong CYP3A4 inducer, which significantly reduces exposure to bedaquiline. (6) Avoid concurrent use of ketoconazole, a strong CYP3A4 inhibitor, for more than 14 consecutive days unless the benefit outweighs the risk. Ketoconazole increases exposure to bedaquiline, increasing the risk of adverse reactions.
Adverse reactions: nausea, arthralgia, headache, hemoptysis, chest pain, increased serum transaminases
Supplied as: 100 mg tablets
Dosage: Initially, 400 mg (four tablets) once a day with food for 2 weeks. For weeks 3 to 24, the dosage is 200 mg three times a week with food (for example, Monday, Wednesday, and Friday with at least 48 hours between doses) for a total dosage of 600 mg/week. The total duration of treatment is 24 weeks.
Nursing considerations: (1) Educate patients about the importance of adhering to the treatment regimen. (2) Tell patients to take each dose with food, and to swallow tablets whole with water. (3) If a dose is missed during the first 2 weeks of treatment, patients shouldn't make up the missed dose but should continue the prescribed dosing schedule. If patients miss a dose during subsequent weeks of treatment, they should take the missed dose as soon as possible, then resume the three-times-a-week regimen. (4) Bedaquiline tablets should be dispensed in the original container. Tablets dispensed outside the original container should be stored in a tight light-resistant container with an expiration date not to exceed 3 months.
FDA news release. December 31, 2012.
Prescribing information. Sirturo (bedaquiline fumarate) tablets. http://www.sirturo.com/sites/default/files/pdf/sirturo-pi.pdf.
First drug approved to manage diarrhea in patients with HIV/AIDS
Many patients with HIV/AIDS who are treated with antiretroviral agents experience diarrhea, and some don't respond adequately to conventional antidiarrheal drugs such as loperamide or bismuth subsalicylate. Persistent or severe diarrhea leads some patients to become nonadherent to their antiretroviral regimen.
Crofelemer (Fulyzaq, Salix) is a botanical substance derived from the red sap of Croton lechleri, a tree that grows in Central and South America. Administered orally, crofelemer is indicated for symptomatic relief of noninfectious diarrhea in adult patients with HIV/AIDS on antiretroviral therapy. It's the first drug to be approved to treat diarrhea in patients with HIV/AIDS.
The secretion of chloride and fluid by intestinal epithelial cells is regulated by the cyclic adenosine monophosphate-stimulated cystic fibrosis transmembrane conductance regulator chloride ion channel, as well as the calcium-activated chloride channels. Crofelemer inhibits both of these channels. By blocking chloride secretion and accompanying high-volume water loss in diarrhea, it normalizes the flow of chloride and water in the GI tract.
The drug's effectiveness was established in a clinical study of 374 HIV-positive patients on stable antiretroviral therapy with a history of diarrhea lasting at least 1 month. The desired clinical response was achieved by 18% of patients taking crofelemer, compared with 8% of those on placebo. The antidiarrheal effect persisted in some patients for 20 weeks.
Patients were excluded from the clinical trial if there was evidence that the diarrhea was associated with an infectious cause or if they had a history of a GI disease associated with diarrhea, such as ulcerative colitis or Crohn disease. Crofelemer is being evaluated in patients with conditions such as traveler's diarrhea and irritable bowel syndrome associated with diarrhea, but these aren't labeled indications at present.
Following oral administration, crofelemer is absorbed to only a limited extent, so patients aren't likely to experience adverse reactions or drug interactions.
Precaution: Infectious causes of diarrhea should be ruled out before therapy with crofelemer begins.
Adverse reactions: upper respiratory tract infection, bronchitis, cough, flatulence, increased bilirubin
Supplied as: 125 mg enteric-coated delayed-release tablets
Dosage: 125 mg twice a day
Nursing considerations: (1) Tell patients that crofelemer can be taken without regard to food. (2) Instruct patients to swallow the tablets whole, without chewing or crushing them.
Prescribing information. Fulyzaq (crofelemer) delayed release tablets, for oral use. http://cdn.salix.com/shared/pi/fulyzaq-pi.pdf.