CE Activities
Pharmacist Feedback
Poll 4
The patient is prescribed naloxegol and returns one week later with a prescription for ketoconazole. What do you do?
Poll 3
After assessing that your patient was adherent to her bowel regimen, you call her prescriber. The prescriber is interested in targeted therapy for OIC. Which drug do you recommend?
Poll 2
After recommending an over-the-counter bowel regimen, the patient presents three months later with another prescription for oxycodone 5 mg every 6 hours. She complains of uncontrolled pain and troubling constipation associated with her opioid therapy. What do you recommend?
Poll 1
A patient presents a prescription for a 30-day supply of oxycodone 10 mg every 6 hours as needed. How do you proceed?

New Drugs of 2013, Part 2

 
Michael A. Mancano, PharmD
Clinical Professor of Pharmacy Practice
Chair, Department of Pharmacy Practice
Temple University
School of Pharmacy
Clinical Consultant
Pennsylvania Hospital, Department of Pharmacy
Philadelphia, Pennsylvania
 
Disclosures
The following contributors have no relevant financial relationships with commercial interests to disclose.
 
Faculty
Michael A. Mancano, PharmD
 
Pharmacy Times Office of Continuing Professional Education
Planning Staff—David Heckard; Maryjo Dixon, RPh; and Steve Lin, PharmD, RPh
 
Pharmacy Times
Editorial Staff—Kirk McKay
 
Educational Objectives
After completing this continuing education program, participants will be able to:
  1. Discuss the clinical indications of the new drugs approved by the FDA in 2013.
  2. Explain the various mechanisms of action of the drugs discussed within this program.
  3. Recognize the clinically relevant drug interactions for the drugs reviewed in this program.
  4. Identify the most common adverse reactions for the new drug approvals in 2013.
  5. Explain the approved dosing guidelines and recommended dosage adjustments for the drugs reviewed.
Target audience: Pharmacists
Type of activity: Knowledge
Release date: February 12, 2014
Expiration date: February 12, 2016
Estimated time to complete activity: 2 hours
Fee: Free

Description: Pharmacy Times/Ascend Media Office of Continuing Professional EducationPharmacy Times Office of Continuing Professional Education is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. This activity is approved for 2.0 contact hours (0.2 CEUs) under the ACPE universal activity number 0290-0000-14-003-H04-P. The activity is available for CE credit through February 12, 2016.

Introduction
The first installment of this 2-part educational series reviewed 8 new molecular entities and biologic drugs approved by the US FDA in 2013. Part 2 of this continuing education program reviews an additional 8 new medications approved in 2013 that account for the following disease states: type 2 diabetes mellitus (T2DM), menopause symptoms and postmenopausal osteoporosis, melanoma, seizures, various fungal infections, chronic lymphocytic leukemia, chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension, and hepatitis C virus (HCV).

The drug reviews contained in this program comprise the current dosing guidelines, common adverse effects, contraindications to therapy, and the current FDA-approved indication(s) for each medication. This program is designed to focus on the new molecular entities and biologic approvals that may be unique and/or that pharmacists are likely to encounter in practice. A table containing a complete list of the new molecular entities and biologics approved in 2013 can be found at the end of this article.
 
Alogliptin Tablets (Nesina)
Takeda Pharmaceuticals
Alogliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with T2DM, but alogliptin is not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis, as it would not be effective in those settings.

Increased concentrations of the incretin hormones, such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released into the bloodstream from the small intestine in response to meals. These hormones cause insulin release from the pancreatic beta cells in a glucose-dependent manner, but are often inactivated by the DPP-4 enzyme within minutes. GLP-1 normally lowers glucagon secretion from pancreatic alpha cells, which reduces hepatic glucose production. However, in patients with T2DM, concentrations of GLP-1 are reduced while the insulin response to GLP-1 is preserved. Alogliptin is a DPP-4 inhibitor that slows the inactivation of incretin hormones, thereby increasing bloodstream concentrations and reducing fasting and postprandial glucose concentrations in a glucose-dependent manner. Alogliptin selectively binds to and inhibits DPP-4 but does not inhibit DPP-8 or DPP-9 activity in vitro at therapeutic concentrations.

The recommended dose of alogliptin in patients with normal renal function or mild renal impairment is 25 mg by mouth daily, with or without food. Patients with moderate renal impairment (creatinine clearance [CrCl] ≥30 to <60 mL/min) are advised to take alogliptin 12.5 mg once daily, and those with severe renal impairment (CrCl ≥15 to <30 mL/min) or end-stage renal disease (CrCl <15 mL/min or requiring hemodialysis) are advised to take 6.25 mg once daily. It should be noted that alogliptin may be administered without regard to the timing of dialysis.

Alogliptin is primarily renally excreted, and metabolism via cytochrome (CYP) P450 enzymes is negligible. No significant drug–drug interactions have been observed with the CYP-substrates or inhibitors tested or with renally excreted drugs.

Common adverse reactions reported among ≥4% of patients treated with alogliptin 25 mg and more frequently than in patients who received placebo are nasopharyngitis, headache, and upper respiratory tract infection.

Postmarketing reports have noted acute pancreatitis in patients taking alogliptin; as such, after initiating alogliptin, patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, alogliptin should be discontinued promptly and appropriate management should be initiated by the clinician. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of the condition while using alogliptin.

There have also been postmarketing reports of serious hypersensitivity reactions in patients treated with alogliptin; these reactions include anaphylaxis, angioedema, and severe cutaneous adverse reactions (eg, Stevens-Johnson syndrome). If a serious hypersensitivity reaction is suspected in the patient, clinicians are advised to discontinue alogliptin, assess for other potential causes of the event, and institute alternative treatment for diabetes. Caution should be used in patients with a history of angioedema with another DPP-4 inhibitor, as it is unknown whether such patients will be predisposed to developing angioedema with alogliptin.

Further, postmarketing reports have noted fatal and nonfatal hepatic failure in patients taking alogliptin, although some of the reports contain insufficient information to establish probable cause. In randomized controlled studies, serum alanine aminotransferase  elevations that were greater than 3 times the upper limit of normal (ULN) were observed among 1.3% of alogliptin-treated patients and 1.5% of comparator-treated patients. Patients with T2DM may have fatty liver disease, which may cause liver test abnormalities. These patients may also have other forms of liver disease. Therefore, obtaining a liver test panel and assessing the patient before initiating alogliptin therapy are recommended. In patients with abnormal liver tests, alogliptin should be initiated with caution by the clinician.

It is important to measure liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice. If the patient is found to have clinically significant liver enzyme elevations, and if liver test results continue to be abnormal or to worsen, clinicians are advised to interrupt alogliptin therapy and investigate to establish the probable cause. Alogliptin should not be restarted in these types of patients without an explanation for the abnormal liver test results.

Insulin and insulin secretagogues, such as sulfonylureas, are known to cause hypoglycemia. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia in patients during combination use with alogliptin.

Alogliptin is classified as pregnancy category B, as no adequate or well-controlled studies in pregnant women have been conducted with alogliptin, and based on animal data, alogliptin is not predicted to increase the risk of fetal developmental abnormalities. Because animal reproduction studies are not always predictive of human risk and exposure, alogliptin should be used during pregnancy only if clearly indicated.

Alogliptin is supplied as 6.25, 12.5, and 25 mg tablets in bottles of 30, 90, and 500 tablets.
 
 
Bazedoxifene/Conjugated Estrogens Tablets (Duavee)
Pfizer
The combination of conjugated estrogens with bazedoxifene, an estrogen agonist/antagonist, is indicated in women with a uterus for the treatment of moderate to severe vasomotor symptoms that are associated with menopause, as well as for the prevention of postmenopausal osteoporosis. The efficacy and safety of bazedoxifene/conjugated estrogens tablets have not been established for use in premenopausal women; therefore, this combination product is not recommended for use in this population. Bazedoxifene/conjugated estrogens tablets should be used for the shortest duration that is consistent with treatment goals and appropriate risks for the patient. Postmenopausal women should be re-evaluated periodically to determine if continued treatment is necessary. When bazedoxifene/conjugated estrogens tablets are prescribed solely for the prevention of postmenopausal osteoporosis, therapy should be considered only for female patients who are at significant risk of osteoporosis, and nonestrogen medications should be carefully considered by the clinician.

Bazedoxifene/conjugated estrogens tablets function by binding to and activating estrogen receptors (ERs) α and β, which vary in proportion from tissue to tissue among patients. Conjugated estrogens are composed of multiple estrogens and are agonists of the α and β ERs. Bazedoxifene is an estrogen agonist/antagonist that acts as an agonist in some estrogen-sensitive tissues and as an antagonist in others (eg, the uterus). The pairing of conjugated estrogens with bazedoxifene produces a composite effect that is specific to each target tissue in the patient. Bazedoxifene also reduces the risk of endometrial hyperplasia, which can occur with the use of conjugated estrogens alone.

The recommended dose of bazedoxifene/conjugated estrogens tablets is 1 tablet by mouth once daily, without regard to meals, and the tablets should be swallowed whole. If a dose is missed, patients are instructed to take it as soon as they remember, unless it is almost time for the next scheduled dose; however, patients are advised not to take 2 doses at the same time. Women taking bazedoxifene/conjugated estrogens tablets for the prevention of postmenopausal osteoporosis should also add supplemental calcium and/or vitamin D to their diets if daily intake is inadequate. Women taking bazedoxifene/conjugated estrogens tablets are recommended not to take progestins, additional estrogens, or additional estrogen agonist/antagonists.

No drug interaction studies were conducted with bazedoxifene/conjugated estrogens tablets; however, because the medication contains estrogens, which are metabolized partially by CYP3A4, the concomitant use of bazedoxifene/conjugated estrogens tablets with CYP3A4 inhibitors may increase the exposure of conjugated estrogens, thereby increasing the risk of endometrial hyperplasia.

In 4 prospective, randomized, placebo-controlled trials, common adverse reactions (incidence ≥5%) seen with the use of bazedoxifene/conjugated estrogens tablets included muscle spasms, nausea, diarrhea, dyspepsia, abdominal pain upper, oropharyngeal pain, dizziness, and neck pain. The use of estrogens has been associated with a 2- to 4-fold increase in the risk of gallbladder disease that requires surgery in postmenopausal women. Retinal vascular thrombosis has also been reported in patients receiving estrogens. Clinicians are advised to discontinue the use of bazedoxifene/conjugated estrogens tablets pending an examination if the patient experiences a sudden, partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. If the examination reveals papilledema or retinal vascular lesions, the bazedoxifene/conjugated estrogens tablets should be permanently discontinued. The use of estrogen may also increase blood pressure and serum triglyceride levels.

Estrogen administration may also lead to increased thyroid-binding globulin (TBG) levels. Women with normal thyroid function may compensate for the increased TBG by producing more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. However, women who are dependent on thyroid hormone replacement therapy and are also receiving estrogens may require increased doses of their thyroid replacement therapy. These types of patients should have their thyroid function monitored to maintain free thyroid hormone levels in an appropriate range.

Estrogens may cause fluid retention, so careful observation is warranted for patients who have relevant conditions, such as cardiac dysfunction or renal impairment, when estrogens are prescribed. The use of bazedoxifene/conjugated estrogens tablets in patients with renal impairment is not recommended. Estrogen therapy should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur. Estrogens may also cause exacerbations of asthma, diabetes mellitus, epilepsy, migraine or porphyria, systemic lupus erythematosus, and hepatic hemangiomas, and should therefore be used with caution in women with those conditions.

There is an increased risk of developing endometrial cancer in a woman with a uterus who uses unopposed estrogens, but bazedoxifene/conjugated estrogens tablets have been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding.

The Women’s Health Initiative (WHI) estrogen-alone sub-study reported increased risks of stroke and deep venous thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral conjugated estrogens (0.625 mg) alone, relative to placebo. The WHI Memory Study—an estrogen-alone ancillary study—reported an increased risk of probable dementia in postmenopausal women 65 years of age and older during 5.2 years of treatment with daily conjugated estrogens (0.625 mg) alone, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women. It should be noted that estrogen therapy should not be used for the prevention of cardiovascular disease or dementia.

The pharmacokinetics of bazedoxifene/conjugated estrogens tablets have not been evaluated in patients with renal impairment; their use in patients with renal impairment is not recommended. Similarly, bazedoxifene/conjugated estrogens tablets have not been studied in women older than 75 years; therefore, their use in women older than 75 years is not recommended.

Bazedoxifene/conjugated estrogens tablets are contraindicated in women with any of the following conditions: undiagnosed abnormal uterine bleeding; known, suspected, or past history of breast cancer; known or suspected estrogen-dependent neoplasia; active DVT, pulmonary embolism, or history of these conditions; active arterial thromboembolic disease (eg, stroke, myocardial infarction) or history of these conditions; hypersensitivity (eg, anaphylaxis, angioedema) to estrogens, bazedoxifene, or any the drug’s ingredients; known hepatic impairment or disease; known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders. The use of bazedoxifene/conjugated estrogens tablets is contraindicated in women who are pregnant, women who may become pregnant, and nursing mothers, as the medication may cause fetal harm when given to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

Bazedoxifene/conjugated estrogens tablets contain 0.45 mg conjugated estrogens and 20 mg bazedoxifene, and are supplied as 2 blisters containing 15 tablets each. Bazedoxifene/conjugated estrogens tablets should be dispensed in the original package and should not be removed from blisters until immediately before use. After the foil pouch is opened, bazedoxifene/conjugated estrogens tablets must be used within 60 days.
 
 
Dabrafenib Capsules (Tafinlar)
GlaxoSmithKline
Dabrafenib is a kinase inhibitor indicated for the treatment of patients with unresectable or metastatic melanoma with the BRAF V600E mutation, as detected by an FDA-approved test. The presence of BRAF V600E mutation in tumor specimens must be confirmed prior to initiating treatment with dabrafenib, as the drug is not indicated for use in patients with wild-type BRAF melanoma.

Dabrafenib is an inhibitor of several mutated forms of BRAF kinases (ie, BRAF V600E, BRAF V600K, BRAF V600D enzymes). Dabrafenib also inhibits wild-type BRAF and CRAF kinases, and other kinases, such as SIK1, NEK11, and LIMK1, at higher concentrations. Some mutations in the BRAF gene, including those that result in BRAF V600E, may result in constitutively activated BRAF kinases that may stimulate tumor cell growth. Dabrafenib works by inhibiting BRAF V600 mutation-positive melanoma cell growth.

The recommended dose for dabrafenib is 150 mg orally taken twice daily, approximately 12 hours apart, until disease progression or unacceptable toxicity occurs. Dabrafenib should be taken at least 1 hour before or at least 2 hours after a meal, and a missed dose can be taken up to 6 hours prior to the next dose. Further, dabrafenib capsules should not be opened, crushed, or broken prior to administration. Product labeling should be consulted for additional detailed dose modifications based on severe adverse reactions.

Dabrafenib is primarily metabolized by CYP2C8 and CYP3A4. Therefore, strong inhibitors or inducers of CYP3A4 or CYP2C8 may increase or decrease concentrations of dabrafenib, respectively. Substitution of strong inhibitors or strong inducers of CYP3A4 or CYP2C8 is recommended during treatment with dabrafenib. If concomitant use of strong inhibitors (eg, ketoconazole, nefazodone, clarithromycin, gemfibrozil) or strong inducers (eg, rifampin, phenytoin, carbamazepine, phenobarbital, St. John’s wort) of CYP3A4 or CYP2C8 is unavoidable, patients should be monitored closely for adverse reactions when taking strong inhibitors or for loss of efficacy when taking strong inducers.

Medications that alter the pH of the upper gastrointestinal tract (eg, proton pump inhibitors, histamine2-receptor antagonists, antacids) may also alter the solubility of dabrafenib and reduce its bioavailability. However, no formal clinical trials have been conducted to evaluate the effect of gastric pH-altering agents on the systemic exposure of dabrafenib. When dabrafenib is coadministered with a proton pump inhibitor, histamine2-receptor antagonist, or antacid, systemic exposure of dabrafenib may be decreased, but the effect on its efficacy is unknown.

Dabrafenib induces CYP3A4 and may induce other enzymes (eg, CYP2B6, CYP2C8, CYP2C9, CYP2C19, UDP glucuronosyltransferases) and transporters. Dabrafenib decreases the maximum concentration (Cmax) and area under the curve of midazolam (a substrate of CYP3A4) by 61% and 74%, respectively. Coadministration of dabrafenib with other substrates of these enzymes (eg, warfarin, dexamethasone, hormonal contraceptives) can result in decreased concentrations of dabrafenib and loss of efficacy. It is recommended that these medications be substituted or that patients be monitored for the loss of treatment efficacy if the use of these medications is unavoidable.

The most common adverse reactions (≥20%) encountered with dabrafenib therapy are hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, and palmar-plantar erythrodysesthesia syndrome.

Dabrafenib results in an increased incidence of cutaneous squamous cell carcinoma, keratoacanthoma, and melanoma. Dermatologic evaluations are recommended prior to initiating dabrafenib, every 2 months while on therapy, and for up to 6 months following discontinuation of dabrafenib. In vitro experiments have demonstrated paradoxical activation of mitogen-activated protein kinase signaling and increased cell proliferation in BRAF wild-type cells that have been exposed to BRAF inhibitors. Evidence of BRAF V600E mutation status should be confirmed by the clinician prior to initiating treatment with dabrafenib.

Serious febrile drug reactions—defined as serious cases of fever or fever of any severity accompanied by hypotension, rigors or chills, dehydration, or renal failure in the absence of another identifiable cause (eg, infection)—occurred in 3.7% (7/187) of patients treated with dabrafenib. It is recommended that clinicians withhold dabrafenib for patients with fever of 101.3ºF or higher, or with any serious febrile drug reaction, and evaluate for signs and symptoms of infection. Clinicians should be advised to consult the product labeling for the recommended dose modifications to account for adverse reactions. Prophylaxis with antipyretics may be required when resuming dabrafenib.

Hyperglycemia that requires an initiation or increase in the dose of insulin or oral hypoglycemic therapy may occur with dabrafenib. Serum glucose levels should be monitored as clinically appropriate during treatment with dabrafenib in patients with preexisting diabetes or hyperglycemia. Patients are advised to report symptoms of severe hyperglycemia, such as excessive thirst or any increase in the volume or frequency of urination.

Uveitis (including iritis) occurred in 1% of patients treated with dabrafenib. Symptomatic treatment in clinical trials included steroid and mydriatic ophthalmic drops. Clinicians should monitor patients for visual signs and symptoms of uveitis (eg, change in vision, photophobia, eye pain).

Dabrafenib contains a sulfonamide moiety and confers a potential risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. As such, patients with G6PD deficiency should be closely observed for signs of hemolytic anemia.

Dabrafenib is classified as pregnancy category D based on its mechanism of action, and can cause fetal harm when administered to a pregnant woman. If dabrafenib is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Female patients of reproductive potential should be advised to use a highly effective, nonhormonal method of contraception during treatment and for 4 weeks after treatment because dabrafenib may render hormonal contraceptives ineffective. Patients are further advised to contact their health care provider if they become pregnant or if pregnancy is suspected while taking dabrafenib.

Negative effects on spermatogenesis have also been observed in animals receiving dabrafenib. Clinicians should advise male patients of the potential risk for impaired spermatogenesis and to seek counseling on fertility and family planning options prior to starting treatment with dabrafenib.

Dabrafenib is supplied as 50- and 75-mg capsules in bottles containing 120 capsules.
 
Eslicarbazepine Acetate Tablets (Aptiom)
Sunovion Pharmaceuticals
Eslicarbazepine acetate is indicated as an adjunct treatment for partial-onset seizures. Eslicarbazepine acetate is extensively converted to eslicarbazepine, which is considered to be responsible for its therapeutic effects in humans. The precise mechanism(s) by which eslicarbazepine exerts its anticonvulsant activity is unknown but is thought to involve inhibition of voltage-gated sodium channels.

Treatment should be initiated with eslicarbazepine acetate at 400 mg orally once daily. After 1 week, the dosage should be increased to 800 mg once daily, which is the recommended maintenance dosage. Some patients may benefit from the maximum recommended maintenance dosage of 1200 mg once daily, although this dosage is associated with an increase in adverse reactions. A maximum dose of 1200 mg daily should only be initiated after the patient has tolerated 800 mg daily for at least 1 week. For some patients, treatment may be initiated at 800 mg once daily if the need for additional seizure reduction outweighs the increased risk of adverse reactions during treatment initiation.

Eslicarbazepine acetate should not be taken as an adjunct to oxcarbazepine, and some adverse reactions occur more frequently with concomitant use of these agents. While eslicarbazepine acetate and carbamazepine may be taken together, carbamazepine reduces the plasma concentration of eslicarbazepine. When eslicarbazepine acetate and carbamazepine are taken concomitantly, the dose of eslicarbazepine acetate or carbamazepine may require adjustment based on efficacy and tolerability. Several antiepileptic drugs (AEDs) (eg, carbamazepine, phenobarbital, phenytoin, primidone) may induce enzymes that metabolize eslicarbazepine acetate, causing decreased plasma concentrations of the drug.

Eslicarbazepine acetate may inhibit CYP2C19, causing increased plasma concentrations of drugs that are metabolized by this isoenzyme (eg, phenytoin, clobazam, omeprazole). In vivo studies suggest that eslicarbazepine acetate may also induce CYP3A4, thereby decreasing plasma concentrations of drugs that are metabolized by this isoenzyme (eg, simvastatin).

A dose reduction is recommended in patients with moderate or severe renal impairment (creatinine clearance <50 mL/min). Treatment should be initiated at 200 mg orally once daily, and after 2 weeks, the dosage should be increased to 400 mg once daily, the recommended maintenance dosage. Some patients may benefit from the maximum recommended maintenance dosage of 600 mg once daily. Dose adjustments are not required in patients with mild to moderate hepatic impairment. The use of eslicarbazepine acetate in patients with severe hepatic impairment has not been studied and is therefore not recommended.

When discontinuing eslicarbazepine acetate, clinicians are advised to reduce the dosage gradually and to avoid abrupt discontinuation to minimize the risk of increased seizure frequency and status epilepticus.

The most common adverse reactions in patients receiving eslicarbazepine acetate (≥4% and ≥2% greater than placebo) are dizziness, somnolence, nausea, headache, diplopia, vomiting, fatigue, vertigo, ataxia, blurred vision, and tremor.

AEDs such as eslicarbazepine acetate increase the risk of suicidal thoughts or behavior. As such, patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Serious dermatologic reactions, including Stevens-Johnson syndrome (SJS), have also been reported in association with the use of eslicarbazepine acetate. Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis and SJS, have been reported in patients using oxcarbazepine or carbamazepine, which are chemically related to eslicarbazepine acetate. If a patient develops a dermatologic reaction while taking eslicarbazepine acetate, the use of eslicarbazepine acetate should be discontinued, unless the reaction is clearly not drug related. Patients with a prior dermatologic reaction to either oxcarbazepine or eslicarbazepine acetate should not be treated with eslicarbazepine acetate.

Drug reaction with eosinophilia and systemic symptoms (DRESS), also known as multi-organ hypersensitivity, has been reported in patients taking eslicarbazepine acetate and may be fatal or life threatening. Although not exclusively, DRESS typically presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, eosinophilia, or myositis sometimes resembling an acute viral infection. Because this disorder varies in its expression, other organ systems may also be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident; if such signs or symptoms are present, the patient should be evaluated immediately. Eslicarbazepine acetate should be discontinued and not be resumed if an alternative etiology for the signs or symptoms cannot be established. Patients with a prior DRESS reaction to oxcarbazepine or eslicarbazepine acetate should not be treated with eslicarbazepine acetate.

Rare cases of anaphylaxis and angioedema have been reported in patients taking eslicarbazepine acetate. Anaphylaxis and angioedema associated with laryngeal edema can be fatal. If a patient develops any of these reactions after treatment with eslicarbazepine acetate, the drug should be discontinued. Patients with a prior anaphylactic-type reaction with either oxcarbazepine or eslicarbazepine acetate also should not be treated with eslicarbazepine acetate.

Clinically significant hyponatremia (sodium <125 mEq/L) may develop in patients taking eslicarbazepine acetate. These effects are dose related and generally appear within the first 8 weeks of treatment, and as early as after 3 days. Serious, life-threatening complications have been reported with eslicarbazepine acetate–associated hyponatremia (as low as 112 mEq/L), including seizures, severe nausea/vomiting leading to dehydration, severe gait instability, and injury. Some patients required hospitalization and discontinuation of eslicarbazepine acetate. Concurrent hypochloremia may also be present in patients with hyponatremia. Depending on the severity of hyponatremia, the dose of eslicarbazepine acetate may require reduction or discontinuation. Measurement of serum sodium and chloride levels should be considered during maintenance treatment with eslicarbazepine acetate, particularly if the patient is receiving other medications known to decrease serum sodium levels, and these measurements should be performed if symptoms of hyponatremia develop (eg, nausea/vomiting, malaise, headache, lethargy, confusion, irritability, muscle weakness/spasms, obtundation, increase in seizure frequency or severity).

Eslicarbazepine acetate causes dose-related increases in adverse reactions related to dizziness and disturbance in gait and coordination (eg, dizziness, ataxia, vertigo, balance disorder, gait disturbance, nystagmus, abnormal coordination). There is an increased risk of these adverse reactions during the titration period (compared with the maintenance period), and there may also be an increased risk of these adverse reactions in patients who are 60 years and older compared with younger adults. Nausea and vomiting may also occur with these events. Eslicarbazepine acetate causes dose-dependent increases in somnolence and fatigue-related adverse reactions (eg, fatigue, asthenia, malaise, hypersomnia, sedation, lethargy). Eslicarbazepine acetate also causes dose-dependent increases in cognitive dysfunction–related events (eg, memory impairment, disturbance in attention, amnesia, confusional state, aphasia, speech disorder, slowness of thought, disorientation, psychomotor retardation).

Eslicarbazepine acetate causes dose-dependent increases in events related to visual changes, including diplopia, blurred vision, and impaired vision. There is an increased risk of these adverse reactions during the titration period (compared with the maintenance period) and also in patients 60 years and older compared with younger adults. The incidence of diplopia is greater with the concomitant use of eslicarbazepine acetate and carbamazepine compared with the use of eslicarbazepine acetate alone. Clinicians are advised to counsel patients against engaging in hazardous activities that require mental alertness, such as operating motor vehicles or dangerous machinery, until the effects of eslicarbazepine acetate are known.

Hepatic effects, ranging from mild to moderate elevations in transaminases (>3× the ULN) to rare cases with concomitant elevations of total bilirubin (>2× the ULN) have been reported with eslicarbazepine acetate use. Baseline evaluations of liver laboratory tests are recommended. The combination of elevated transaminase and bilirubin levels without evidence of obstruction is generally recognized as an important predictor of severe liver injury. Eslicarbazepine acetate should be discontinued in patients with jaundice or other evidence of significant liver injury.

Eslicarbazepine acetate is contraindicated in patients with a hypersensitivity to eslicarbazepine acetate or oxcarbazepine.

Eslicarbazepine acetate is classified as pregnancy category C because no adequate and well-controlled studies have been conducted in pregnant women. Eslicarbazepine acetate should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus. Because concomitant use of eslicarbazepine acetate and ethinylestradiol/levonorgestrel is associated with lower plasma levels of those hormones, females of reproductive potential should use additional or alternative nonhormonal birth control.

Eslicarbazepine acetate is supplied as 200-, 400-, 600-, and 800-mg tablets.
 
 
Luliconazole Cream (Luzu)
Medicis
Luliconazole cream 1% is an azole antifungal indicated for the topical treatment of interdigital tinea pedis, tinea cruris, and tinea corporis caused by the organisms Trichophyton rubrum and Epidermophyton floccosum, in patients 18 years and older. When interdigital tinea pedis is treated, a thin layer of luliconazole cream 1% should be applied to the affected area and approximately 1 inch of the immediate surrounding area(s) once daily for 2 weeks. When tinea cruris or tinea corporis is treated, luliconazole cream 1% should be applied to the affected area and approximately 1 inch of the immediate surrounding area(s) once daily for 1 week. Luliconazole cream is for topical use only and not for ophthalmic, oral, or intravaginal use.

Luliconazole is an antifungal that belongs to the azole class, and although the exact mechanism of action against dermatophytes is unknown, luliconazole appears to inhibit ergosterol synthesis by inhibiting the enzyme lanosterol demethylase. Inhibition of this enzyme’s activity by azoles results in a decreased amount of ergosterol, a constituent of fungal cell membranes, and decreased accumulation of lanosterol. To date, a mechanism of resistance to luliconazole has not been described.

The potential for luliconazole to inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 was evaluated in vitro. At therapeutic doses, luliconazole was found, particularly in patients with moderate to severe tinea cruris, to inhibit the activity of CYP2C19 and CYP3A4. However, no in vivo drug interaction trials have been conducted to evaluate the effects of luliconazole on other drugs that are substrates of CYP2C19 and CYP3A4.

The most common adverse reactions observed in clinical trials were application site reactions, which occurred in less than 1% of subjects.

Luliconazole cream is classified as pregnancy category C because no adequate and well controlled studies of luliconazole cream 1% have been conducted in pregnant women. Luliconazole cream 1% should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.

Luliconazole is supplied as a 1% cream in 30- and 60-g tubes.
 
Obinutuzumab Injection (Gazyva)
Genentech, Inc
Obinutuzumab is indicated, in combination with chlorambucil, for the treatment of patients with previously untreated chronic lymphocytic leukemia. Obinutuzumab is a monoclonal antibody that targets the CD20 antigen expressed on the surface of pre B and mature Blymphocytes. Upon binding to CD20, obinutuzumab mediates B-cell lysis through the engagement of immune effector cells by directly activating intracellular death, signaling pathways and/or activation of the complement cascade. The immune effector cell mechanisms include antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis.

The recommended dosage of obinutuzumab is 1000 mg, administered intravenously, for 6 cycles, with the exception of the first set of infusions during cycle 1, which are administered on day 1 (100 mg) and day 2 (900 mg). Patients should be premedicated before each infusion with a glucocorticoid, acetaminophen, and an antihistamine. Obinutuzumab should be administered only as an intravenous infusion through a dedicated line and should not be administered as an intravenous push or bolus. Blood counts should be monitored at regular intervals during obinutuzumab therapy.

The most common adverse reactions (incidence ≥10%) that were noted with obinutuzumab therapy were infusion reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, and musculoskeletal disorders.

Obinutuzumab may cause severe and life threatening infusion reactions. Two-thirds of patients experienced a reaction to the first 1000 mg of obinutuzumab, but infusion reactions may also occur with subsequent infusions. In addition, infusion reactions may occur within 24 hours of receiving obinutuzumab. Symptoms may include hypotension, tachycardia, dyspnea, and respiratory symptoms (eg, bronchospasm, larynx and throat irritation, wheezing, laryngeal edema). Other common symptoms include nausea, vomiting, diarrhea, hypertension, flushing, headache, pyrexia, and chills. Clinicians are advised to institute medical management (eg, glucocorticoids, epinephrine, bronchodilators, and/or oxygen) for infusion reactions, as needed, and to closely monitor patients during the entire infusion.

Patients with preexisting cardiac or pulmonary conditions should be monitored more frequently throughout the infusion and postinfusion periods, as these patients may be at greater risk of experiencing more severe reactions. Hypotension may occur as part of the obinutuzumab infusion reaction, so it is recommended to withhold antihypertensive treatments for 12 hours prior to and during each obinutuzumab infusion, as well as for the first hour after administration, until blood pressure is stable. For patients at increased risk of hypertensive crisis, clinicians should consider the benefits versus the risks of withholding the patient’s hypertensive medication.

Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, and/or hyperphosphatemia from tumor lysis syndrome (TLS) may occur within 12 to 24 hours following the first infusion. Patients with high tumor burden and/or high circulating lymphocyte count (>25 × 109/L) are at greater risk for TLS and should receive appropriate tumor lysis prophylaxis with an antihyperuricemic (eg, allopurinol) and hydration, starting at 12 to 24 hours prior to the infusion of obinutuzumab.

Serious bacterial, fungal, and new or reactivated viral infections may occur during and following obinutuzumab therapy. Clinicians should not administer obinutuzumab to patients with an active infection, and patients with a history of recurring or chronic infections may be at increased risk of infection. The safety and efficacy of immunization with live or attenuated viral vaccines during or following obinutuzumab therapy has not been studied; therefore, immunization with live virus vaccines is not recommended during treatment and until B-cell recovery.

Obinutuzumab used in combination with chlorambucil caused grade 3 or 4 neutropenia in 34% of patients in a clinical trial. As such, patients with grade 3 or 4 neutropenia should be monitored frequently with regular laboratory testing until resolution. Clinicians should anticipate, evaluate, and treat any signs or symptoms of developing infection. Neutropenia may also have a late onset (ie, occurring more than 28 days after completion of treatment) and/or be prolonged (ie, lasting longer than 28 days). It is strongly recommended that patients with neutropenia receive antimicrobial prophylaxis throughout the treatment period, and antiviral and antifungal prophylaxis should be considered as well.

Obinutuzumab used in combination with chlorambucil caused grade 3 or 4 thrombocytopenia in 12% of patients in a clinical trial. In 5% of patients, obinutuzumab caused acute thrombocytopenia that occurred within 24 hours after the obinutuzumab infusion. Patients with grade 3 or 4 thrombocytopenia should have their platelet counts monitored more frequently until resolution. Transfusion of blood products (ie, platelet transfusion) may also be necessary.

JC virus infection resulting in progressive multifocal leukoencephalopathy (PML), which can be fatal, has been observed in patients treated with obinutuzumab. It is recommended that clinicians consider the diagnosis of PML in any patient who presents with new onset of, or changes to preexisting, neurologic manifestations. An evaluation of PML includes consultation with a neurologist, brain magnetic resonance imaging, and lumbar puncture. Obinutuzumab therapy should be discontinued in patients who develop PML, and discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy should also be considered.

Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, may occur in patients treated with anti-CD20 antibodies, such as obinutuzumab. HBV reactivation is defined as an abrupt increase in HBV replication, manifesting as a rapid increase in serum HBV DNA level or detection of hepatitis B surface antigen (HBsAg) in a person who was previously HBsAg negative and hepatitis B core antibody (anti-HBc) positive. HBV reactivation has been reported in patients who are HBsAg positive, and also in patients who are HBsAg negative but are anti-HBc positive. Reactivation has also occurred in patients who appear to have resolved hepatitis B infection (ie, HBsAg negative, anti-HBc positive, and hepatitis B surface antibody [anti-HBs] positive). Reactivation of HBV replication is often followed by hepatitis (eg, increase in transaminase levels) and, in severe cases, an increased bilirubin level, liver failure, and death.

All patients should be screened for HBV infection by measurement of HBsAg and anti-HBc before treatment with obinutuzumab. For patients who show evidence of HBV infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), physicians with expertise in managing hepatitis B should be consulted regarding appropriate monitoring and consideration for HBV antiviral therapy. Clinicians are advised to monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following treatment with obinutuzumab. HBV reactivation has been reported for other CD20-directed cytolytic antibodies following the completion of therapy.

Patients who develop reactivation of HBV while receiving obinutuzumab should immediately discontinue obinutuzumab and any concomitant chemotherapy, and appropriate treatment should be instituted. Resuming treatment with obinutuzumab in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing HBV. However, insufficient data exist regarding the safety of resuming obinutuzumab in patients who develop HBV reactivation.

Obinutuzumab is classified as pregnancy category C because there are no adequate and well-controlled studies of obinutuzumab in pregnant women. Women of childbearing potential should use effective contraception while receiving obinutuzumab, and for 12 months following treatment. Obinutuzumab should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.

Obinutuzumab is supplied as a 1000-mg/40 mL (25-mg/mL) single-use vial. Obinutuzumab is stable at 2°C to 8°C (36°F to 46°F) and should not be frozen or shaken. Obinutuzumab vials should be protected from light.
 
 
Riociguat Tablets (Adempas)
Bayer Healthcare
Riociguat is indicated for the treatment of adults with (1) persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) (World Health Organization [WHO] Group 4) following surgical treatment; (2) inoperable CTEPH to improve exercise capacity and WHO functional class; and (3) patients with pulmonary arterial hypertension (WHO Group 1) to improve exercise capacity, improve WHO functional class, and delay clinical worsening.

Riociguat is a stimulator of soluble guanylate cyclase (sGC), an enzyme in the cardiopulmonary system, and the receptor for nitric oxide (NO). When NO binds to sGC, the enzyme catalyzes the synthesis of cyclic guanosine monophosphate (cGMP), a signaling molecule. Intracellular cGMP plays an important role in regulating processes that influence vascular tone, proliferation, fibrosis, and inflammation. Pulmonary hypertension is associated with endothelial dysfunction, impaired synthesis of NO, and insufficient stimulation of the NO-sGC-cGMP pathway. Riociguat has a dual mode of action: it sensitizes sGC to endogenous NO by stabilizing the NO-sGC binding, and also directly stimulates sGC via a different binding site, independently of NO. By stimulating the NO-sGC-cGMP pathway, riociguat leads to increased generation of cGMP, with subsequent vasodilation.

The recommended starting dosage of riociguat is 1 mg orally 3 times a day. Patients who may not tolerate the hypotensive effect of riociguat should consider a starting dose of 0.5 mg 3 times a day. If systolic blood pressure remains greater than 95 mm Hg, and the patient has no signs or symptoms of hypotension, the dose may be up-titrated by 0.5 mg to be taken 3 times a day. Dose titration should occur in 2 week intervals. The dose may be increased to the highest tolerated dosage, which is a maximum of 2.5 mg 3 times a day. If at any time the patient experiences symptoms of hypotension, the dosage should be reduced to 0.5 mg 3 times a day. If a dose is missed, patients are advised to continue with the next regularly scheduled dose. In case riociguat is interrupted for 3 days or more, it will be necessary to retitrate riociguat.

Riociguat is not recommended in patients with creatinine clearance <15 mL/min or in patients receiving dialysis. Further, riociguat is not recommended in patients with severe (Child-Pugh class C) hepatic impairment.

Plasma concentrations in smokers are reduced by 50% to 60% compared with nonsmokers. Based on pharmacokinetic modeling, for patients who are smokers, doses higher than 2.5 mg orally 3 times a day may be needed to achieve the exposure seen in nonsmoking patients. Safety and effectiveness of riociguat in doses higher than 2.5 mg 3 times a day have not been established. A dose reduction should be considered in patients who stop smoking.

Concomitant use of riociguat with strong cytochrome CYP inhibitors and Pgp/BCRP inhibitors, such as azole antimycotics (eg, ketoconazole, itraconazole) or HIV protease inhibitors (eg, ritonavir), increases riociguat exposure and may result in hypotension. Clinicians should consider a starting dose of 0.5 mg orally 3 times a day when initiating riociguat in patients who are receiving strong CYP and P-glycoprotein (P-gp)/BCRP inhibitors. Patients should be monitored for signs and symptoms of hypotension during the initiation of, and treatment with, strong CYP and P-gp/BCRP inhibitors. A dose reduction should be considered in patients who may not be able to tolerate the hypotensive effect of riociguat.

Strong inducers of CYP3A (eg, rifampin, phenytoin, carbamazepine, phenobarbital, St. John’s Wort) may significantly reduce riociguat exposure. Data are not available to guide dosing of riociguat when strong CYP3A inducers are coadministered. Antacids such as aluminum hydroxide/magnesium hydroxide decrease riociguat absorption and should not be taken within 1 hour of riociguat administration.

Coadministration of riociguat with nitrates or NO donors (eg, amyl nitrite) in any form is contraindicated due to hypotension. Coadministration of riociguat with phosphodiesterase (PDE) inhibitors,
including specific PDE-5 inhibitors (eg, sildenafil, tadalafil, vardenafil) and nonspecific PDE inhibitors (eg, dipyridamole, theophylline), is also contraindicated due to hypotension.

Adverse reactions occurring more frequently (≥3%) with riociguat compared with placebo include headache, dizziness, dyspepsia/gastritis, nausea, diarrhea, hypotension, vomiting, anemia, gastroesophageal reflux, and constipation.

As riociguat reduces blood pressure, clinicians should consider the potential for symptomatic hypotension or ischemia in patients with hypovolemia, severe left ventricular outflow obstruction, resting hypotension, autonomic dysfunction, or concomitant treatment with antihypertensives or strong CYP and P-gp/BCRP inhibitors. A dose reduction should be considered if the patient develops signs or symptoms of hypotension.

In the placebo controlled clinical trials program, serious bleeding occurred in 2.4% of patients taking riociguat compared with 0% of patients taking placebo. Serious hemoptysis (including 1 fatal event) occurred in 1% of patients taking riociguat compared with 0% of patients taking placebo. Serious hemorrhagic events included vaginal hemorrhage (2 patients), catheter site hemorrhage (2 patients), and subdural hematoma, hematemesis, and intra-abdominal hemorrhage (1 patient each).

Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Therefore, administration of riociguat to such patients is not recommended. If signs of pulmonary edema occur, the possibility of associated PVOD should be considered, and if confirmed, treatment with riociguat should be discontinued.

Riociguat is classified as pregnancy category X and may cause fetal harm when administered to a pregnant woman; therefore, riociguat is contraindicated in females who are pregnant. Riociguat has consistently been shown to have teratogenic effects when administered to animals. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. It is recommended that female patients obtain pregnancy tests prior to initiating treatment and monthly during therapy with riociguat.

It is not known if riociguat is present in human milk; however, riociguat or its metabolites were present in the milk of rats. Because many drugs are present in human milk and due to the potential for serious adverse reactions in nursing infants, either nursing or riociguat should be discontinued.

Riociguat is supplied as 0.5-, 1-, 1.5-, 2-, and 2.5-mg tablets in bottles containing 90 tablets or in blister packs of 42 tablets. Females may only receive riociguat through the Adempas REMS Program, a restricted distribution program.
 
 
Simeprevir Capsules (Olysio)
Janssen Therapeutics
Simeprevir is indicated for the treatment of chronic hepatitis C (CHC) infection as a component of a combination antiviral treatment regimen. Simeprevir is an inhibitor of the HCV NS3/4A protease, which is essential for viral replication. In a biochemical assay, simeprevir inhibited the proteolytic activity of recombinant genotype 1a and 1b HCV NS3/4A proteases. The efficacy of simeprevir has been established when used in combination with peginterferon alfa and ribavirin in HCV genotype 1 infected patients with compensated liver disease (including cirrhosis).

The following points should be considered when initiating simeprevir for treatment of chronic HCV infection: (1) simeprevir must not be used as monotherapy; (2) its efficacy in combination with peginterferon alfa and ribavirin is substantially reduced in patients who are infected with HCV genotype 1a with an NS3 Q80K polymorphism at baseline; thus, screening patients with HCV genotype 1a infection for the presence of virus with the NS3 Q80K polymorphism at baseline is strongly recommended, and alternative therapy should be considered for patients infected with HCV genotype 1a containing the Q80K polymorphism; and (3) the efficacy of simeprevir has not been studied in patients who have previously failed a treatment regimen that includes simeprevir or other HCV protease inhibitors.

The recommended dose of simeprevir is one 150-mg capsule orally once daily with food; the type of food does not affect systemic exposure to the medication. The capsule should be swallowed whole. For all patients, the recommended duration of treatment with simeprevir is 12 weeks, initiated in combination with peginterferon alfa and ribavirin. All treatment naïve and prior relapse patients, including those with cirrhosis, should receive an additional 12 weeks of peginterferon alfa and ribavirin therapy after completing 12 weeks of treatment with simeprevir, peginterferon alfa, and ribavirin, for a total treatment duration of 24 weeks. All prior nonresponder patients, including partial responders, null responders, and those with cirrhosis, should receive an additional 36 weeks of peginterferon alfa and ribavirin after completing 12 weeks of treatment with simeprevir, peginterferon alfa, and ribavirin, for a total treatment duration of 48 weeks.

HCV RNA levels should be monitored as clinically indicated. The use of a sensitive assay with a lower limit of quantification of at least 25 IU/mL for monitoring HCV RNA levels during treatment is recommended. It is unlikely that patients with inadequate on-treatment virologic response will achieve a sustained virologic response; therefore, discontinuation of treatment is recommended in these patients. The HCV RNA threshold that triggers the discontinuation of treatment is a week 4 HCV RNA that is greater than or equal to 25 IU/mL. If peginterferon alfa or ribavirin is discontinued for any reason, simeprevir must also be discontinued. To prevent treatment failure, the dose of simeprevir must not be reduced or interrupted, and if treatment with simeprevir is discontinued due to adverse reactions or inadequate on-treatment virologic response, treatment with simeprevir must not be reinitiated.

There are no dose recommendations for patients with moderate or severe hepatic impairment (Child-Pugh class B or C) due to higher simeprevir exposures. In clinical trials, higher simeprevir exposures have been associated with an increased frequency of adverse reactions, including rash and photosensitivity. The safety and efficacy of simeprevir have not been studied in HCV-infected patients with moderate or severe hepatic impairment (Child-Pugh class B or C). The combination of peginterferon alfa and ribavirin is contraindicated in patients with decompensated cirrhosis (moderate or severe hepatic impairment). As such, the potential risks and benefits of simeprevir should be carefully considered prior to its use in patients with moderate or severe hepatic impairment.

Patients of East Asian ancestry exhibit higher simeprevir exposures, and in clinical trials, higher simeprevir exposures have been associated with increased frequency of adverse reactions. There are insufficient safety data to recommend an appropriate dose for patients of East Asian ancestry; therefore, the potential risks and benefits of treatment with simeprevir should be carefully considered prior to use in such patients.

Coadministration of simeprevir with substances that are moderate/strong inducers or inhibitors of CYP3A is not recommended, as this may significantly reduce or increase simeprevir exposure, respectively. Simeprevir mildly inhibits CYP1A2 activity and intestinal CYP3A4 activity, but it does not affect hepatic CYP3A4 activity. Coadministration of simeprevir with drugs that are primarily metabolized by CYP3A4 may result in increased plasma concentrations of such agents. Simeprevir does not affect CYP2C9, CYP2C19, or CYP2D6 in vivo, but it does inhibit OATP1B1/3 and P-gp transporters. Coadministration of simeprevir with drugs that are substrates for OATP1B1/3 and P-gp transport may result in increased plasma concentrations of these drugs. The simeprevir product labeling should be consulted for a more detailed list of established and potentially significant drug interactions.

The most common reported adverse reactions (greater than 20% of subjects) in subjects receiving the combination of simeprevir, peginterferon, and ribavirin—and occurring with at least 3% higher frequency compared with subjects receiving placebo in combination with peginterferon alfa and ribavirin during the first 12 weeks of treatment—were rash (including photosensitivity), pruritus, and nausea.

Photosensitivity reactions have been observed with simeprevir when used in combination with peginterferon alfa and ribavirin and have included serious reactions that resulted in hospitalization. Photosensitivity reactions with this drug combination occur most frequently in the first 4 weeks of treatment but can occur at any time during therapy. Photosensitivity may present as an exaggerated sunburn reaction, usually affecting areas that are exposed to light (ie, face, “V” area of the neck, extensor surfaces of the forearms, dorsa of the hands). Manifestations may include burning, erythema, exudation, blistering, and edema. Patients are advised to use sun-protective measures, limit their sun exposure, and avoid the use of tanning devices during treatment with combined simeprevir, peginterferon alfa, and ribavirin. Discontinuation of simeprevir should be considered if a photosensitivity reaction occurs, and patients should be monitored until the reaction has resolved.

Rash has been observed in subjects receiving simeprevir in combination with peginterferon alfa and ribavirin. While it occurred most frequently in the first 4 weeks of treatment with the drug regimen, it may occur at any time during therapy. Severe rash and rash requiring discontinuation of simeprevir have been reported, but most of the rash events in simeprevir-treated patients were of mild or moderate severity. Patients with mild to moderate rashes should be followed for the possible progression of rash, including the development of mucosal signs (eg, oral lesions, conjunctivitis) or systemic symptoms. If the rash becomes severe, simeprevir therapy should be discontinued. Patients should be monitored until the rash has resolved.

Simeprevir contains a sulfonamide moiety. Although no increased incidence of rash or photosensitivity reactions has been observed in subjects with a history of sulfa allergy, there are insufficient data to exclude an association between sulfa allergy and the frequency or severity of adverse reactions observed with the use of simeprevir.

The use of simeprevir in combination with peginterferon alfa and ribavirin is contraindicated in pregnant women and in men whose female partners are pregnant, due to the risks for birth defects and fetal death associated with ribavirin, and the abortifacient effects seen with the use of interferons in animal studies. Simeprevir is pregnancy category C; however, because simeprevir must be dosed with ribavirin, which is pregnancy category X, the CHC regimen is considered pregnancy category X. Therefore, extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Ribavirin therapy should not be started unless a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Female patients of childbearing potential and their male partners, as well as male patients and their female partners, must use 2 effective contraceptive methods during treatment and for 6 months after completion of treatment. Routine monthly pregnancy tests must be performed during this time.

Simeprevir is supplied as 150-mg capsules in bottles containing 28 capsules and in emergency supply bottles containing 7 capsules.


Table: New Molecular Entities and Biologics Approved in 2013

Generic Name
(Dosage Form)
Brand Name Company Approved Indication
Ado-trastuzumab emtansine
(IV infusion)
Kadcyla Genentech Treatment of patients with HER2-positive, metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination
Afatinib dimaleate
(oral tablets)
Gilotrif Boehringer
Ingelheim
Treatment of metastatic non–small cell lung cancer whose tumors have epidermal growth factor receptor exon 19 deletions or exon 21 (L858R) substitution mutations
Alogliptin benzoate/pioglitazone HCl
(oral tablets)
Oseni Takeda Adjunct to diet and exercise to improve glycemic control in adults with T2DM
Alogliptin benzoate
(oral tablets)
Nesina Takeda Adjunct to diet and exercise to improve glycemic control in adults with T2DM
Alogliptin benzoate/ metformin HCl
(oral tablets)
Kazano Takeda Adjunct to diet and exercise to improve glycemic control in adults with T2DM
Botulism antitoxin heptavalent
(A, B, C, D, E, F, G) (equine)
(IV infusion)
BAT Cangene Treatment of symptomatic botulism
Canagliflozin
(oral tablets)
Invokana Janssen Adjunct to diet and exercise to improve glycemic control in adults with T2DM
Coagulation factor IX (recombinant)
(IV injection)
Rixubis Baxter To prevent or control bleeding in patients with hemophilia B
Bazedoxifene/ conjugated estrogens
(oral tablets)
Duavee Pfizer Treatment of moderate to severe vasomotor symptoms associated with menopause and prevention of postmenopausal osteoporosis
Dabrafenib mesylate
(oral capsules)
Tafinlar GlaxoSmithKline Treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation
Dimethyl fumarate
(oral capsules)
Tecfidera Biogen Idec Treatment of patients with relapsing forms of multiple sclerosis
Dolutegravir sodium
(oral tablets)
Tivicay GlaxoSmithKline Indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and children
Eslicarbazepine acetate
(oral tablets)
Aptiom Sunovion
Pharmaceuticals
Adjunctive therapy in the treatment of partial-onset seizures in patients with epilepsy
Flutemetamol F18
(IV injection)
Vizamyl GE Healthcare A radioactive diagnostic agent indicated for PET imaging of the brain to estimate β amyloid neuritic plaque density in adult patients with cognitive impairment who are being evaluated for Alzheimer’ s disease
Fluticasone furoate/vilanterol
(Oral inhalation)
Breo Ellipta GlaxoSmithKline Long-term, once-daily maintenance treatment of airflow obstruction and for reducing exacerbations in patients with chronic obstructive pulmonary disease
Gadoterate meglumine
(IV injection)
Dotarem Guerbet Contrast agent indicated for intravenous administration for magnetic resonance imaging in brain, spine, and associated tissues in adult and pediatric patients to detect and visualize areas with disruption of the blood-brain barrier and/or abnormal vascularity
Glycerol phenylbutyrate
(oral liquid)
Ravicti Hyperion
Therapeutics
A nitrogen-binding agent for chronic management of adult and pediatric patients ≥2 years of age with urea cycle disorders that cannot be managed by dietary protein restriction and/or amino acid supplementation alone
Golimumab
(IV infusion)
Simponi Aria Janssen
Biotech
Treatment of rheumatoid arthritis in combination with methotrexate
Ibrutinib
(oral capsules)
Imbruvica Pharmacyclics Treatment of mantle cell lymphoma in patients who have received at least 1 prior therapy
Influenza A (H5N1) monovalent vaccine, adjuvanted
(IM injection)
N/A GlaxoSmithKline Vaccine for active immunization in persons 18 years and older to prevent disease caused by the influenza A virus H5N1 subtype
Influenza vaccine
(IM injection)
Flublok Protein
Sciences
Vaccine for prevention of influenza which is prepared by cell culture
Luliconazole
cream, 1%
(topical cream)
Luzu Medicis Topical treatment of interdigital tinea pedis, tinea cruris, and tinea corporis caused by the organisms Trichophyton rubrum and Epidermophyton floccosum
Macitentan
(oral tablets)
Opsumit Actelion
Pharmaceuticals
Treatment of pulmonary arterial hypertension
Mipomersen sodium
(SC injection)
Kynamro Genzyme Adjunct to lipid-lowering medications and diet to reduce low-density lipoprotein cholesterol, apo-B, total cholesterol, and non–high density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia
Obinutuzumab
(IV infusion)
Gazyva Genentech Administered in combination with chlorambucil for treating patients with previously untreated chronic lymphocytic leukemia
Ospemifene
(oral tablets)
Osphena Shionogi Treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy, due to menopause
Pomalidomide
(oral capsules)
Pomalyst Celgene Treatment of patients with multiple myeloma who have received at least two prior therapies, including lenalidomide and bortezomib, and have demonstrated disease progression on or within 60 days of completion of the last therapy
Prothrombin complex concentrate (human)
(IV injection; lyophilized powder for reconstitution)
Kcentra CSL Behring Urgent reversal of acquired coagulation factor deficiency induced by vitamin K antagonist therapy in adults with acute major bleeding
Radium Ra223 dichloride
(IV injection)
Xofigo Bayer
HealthCare
Treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases, and no known visceral metastatic disease
Riociguat
(oral tablets)
Adempas Bayer
HealthCare
Treatment of adults with persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) after surgical treatment, with inoperable CTEPH, or with
pulmonary arterial hypertension
Simeprevir
(oral capsules)
Olysio Janssen Treatment of chronic hepatitis C infection as a component of a combination antiviral treatment regimen
Sofosbuvir
(oral tablets)
Sovaldi Gilead Sciences Treatment of chronic hepatitis C infection as a component of a combination antiviral treatment regimen
Technetium Tc 99m tilmanocept
(SC, intradermal, or peritumoral injection)
Lymphoseek Navidea
Biopharm
Radioactive diagnostic agent indicated for lymphatic mapping with a handheld gamma counter to assist in the localization of lymph nodes draining a primary tumor site in patients with breast cancer or melanoma
Trametinib dimethyl sulfoxide
(oral tablets)
Mekinist GlaxoSmithKline Treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations
Umeclidinium and vilanterol
(oral inhalation)
Anoro Ellipta GlaxoSmithKline Long-term, once-daily maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease, including chronic bronchitis and/or emphysema
Vortioxetine hydrobromide
(oral tablets)
Brintellix Takeda Treatment of major depressive disorder
 
T2DM = type 2 diabetes mellitus.

References for Product Approvals
  1. FDA/Center for Biologics Evaluation and Research. 2013 Biological License Application Approvals. www.fda.gov/BiologicsBloodVaccines/DevelopmentApprovalProcess/BiologicalApprovalsbyYear/ucm338256.htm. Accessed December 31, 2013.
  2. FDA/Center for Drug Evaluation and Research, Drugs@ FDA Database. www.accessdata.fda.gov/scripts/cder/drugsatfda. Accessed December 31, 2013.
References for Drugs 
  1. Adempas [package insert]. Whippany, NJ: Bayer Healthcare; October 2013.
  2. Aptiom [package insert]. Marlborough, MA: Sunovion Pharmaceuticals; November 2013.
  3. Duavee [package insert]. Philadelphia, PA: Pfizer, Wyeth Pharmaceuticals; October 2013.
  4. Gazyva [package insert]. South San Francisco, CA: Genentech, Inc; November 2013.
  5. Luzu [package insert]. Bridgewater, NJ: Medicis;  November 2013.
  6. Nesina [package insert]. Deerfield, NJ: Takeda Pharmaceuticals; January 2013.
  7. Olysio [package insert]. Titusville, NJ: Janssen Therapeutics; November 2013.
  8. Tafinlar [package insert]. Research Triangle Park, NC: GlaxoSmithKline; May 2013.
 
New Drugs of 2013, Part 2
Expires
02-12-2016
Credits
2.00
UAN
0290-0000-14-003-H04-P