New Drugs of 2007 by Amy P

continuing education

New Drugs of 2007 By Amy P. Witte, PharmD; Jodie V. Mahlhotra, PharmD; and Trevor McKibbin, PharmD, MSc, BCPS

pon successful completion of this There have been no reported contraindications with article, the pharmacist should be the use of retapamulin. A thin layer should be applied to able to: the affected area (up to 100 cm2 in total area in adults or 1. Identify the new molecular entities 2 percent total body surface area in pediatric patients) approved by the Food and Drug twice daily for five days. Administration (FDA) in 2007. The most common adverse effect seen with re- U2. Review approved indications, mechanism of tapamulin use was application site irritation. Patients action, and pharmacokinetic profile for each should discontinue the use of retapamulin in the event agent. of severe local irritation or sensitization. It is not intend- 3. List the available dosage forms and ed for ingestion or for intraoral, intranasal, ophthalmic, strengths, dosing schedules, and routes of or intravaginal use. Patients should also be aware of administration for the new agents. the potential for microbial overgrowth while using reta- 4. Describe the potential adverse effects, drug pamulin. If a superinfection is suspected during treat- interactions, precautions, and contraindica- ment, the patient should contact their physician. The tions associated with routine use. effect of retapamulin in combination with other topical 5. Identify medications that have been with- agents to the same area of skin has not been studied. drawn from the market in 2007. Retapamulin is a pregnancy category B agent. How- ever, it is not known whether retapamulin is excreted In 2007, the FDA approved 15 new molecular in breast milk. Dosage adjustments are unnecessary entities (13 of which are discussed in this article) as when co-administered with a CYP3A4 inhibitor, such well as numerous new dosage forms (see Tables 2 as ketoconazole, due to the low incidence of systemic and 4, pages 37 and 39). While this is not a com- exposure to retapamulin. prehensive review of the new drugs, it highlights Retapamulin is available by prescription as an oint- important information on agents approved in 2007. ment. It is supplied in a 5 gram, 10 gram, or 15 gram Additionally, six medications were withdrawn from tube. Patients should only use retapamulin as directed the market (see Table 3, page 38 ). by a physician. Both patients and caregivers should wash their hands after each application. The patient ALTABAX™ (RETAPAMULIN) should notify their physician if there is no improvement Manufactured by GlaxoSmithKline, retapamu- in symptoms within three to four days after starting use lin 1 percent is first in a new class of topical of retapamulin. antibacterials used for the treatment of impetigo due to Staphylococcus aureus (methicil- BYSTOLIC™ (NEBIVOLOL) lin-susceptible) or Streptococcus pyogenes in Bystolic, manufactured by Forest Pharmaceuticals, is patients nine months of age or older. It works by an orally active inhibitor of beta ß adrenergic receptors. selectively inhibiting bacterial protein synthesis. Nebivolol is primary a ß1 selective inhibitor, however Retapamulin demonstrates both bacteriostatic at higher doses it inhibits both ß1 and ß2 adrenergic and bactericidal activity. receptors. This new drug is indicated for the treatment of

www.americaspharmacist.net June 2008 | america’s Pharmacist 35 Table 1: Lisdexamfetamine Drug Interactions

Drug/Class Interaction

Urinary acidifying agents Decrease serum amphetamine level

Adrenergic blockers Inhibited by amphetamine

Tricyclic antidepressants Enhanced activity of both agents

MAO inhibitors Slowed amphetamine metabolism

Antihistamines Blocked sedative effects of antihistamines

Antihypertensives Antagonism of antihypertensive

Chlorpromazine, haloperidol, lithium carbonate Inhibition of stimulant effects

Ethosuximide Delayed intestinal absorption of ethosuximide

Meperidine Potentiation of analgesic effects of meperidine

Methenamine therapy Increased urinary excretion of stimulant

Norepinephrine Enhanced adrenergic effects of norepinephrine

Phenobarbital Delayed intestinal absorption of Phenobarbital

Phenytoin Delayed intestinal absorption of phenytoin

Veratrum alkaloids Inhibition of hypotensive effects of veratrum alkaloid

hypertension. It may be used alone or in combination with bradycardia. Nebivolol should be used with other antihypertensive agents. caution when myocardial depressants, inhibi- Nebivolol is contraindicated in patients with se- tors of AV conduction, or antiarrhythmic agents vere bradycardia, heart block greater than first degree, are used concurrently. It is metabolized by gluc- cardiogenic shock, decompensated cardiac failure, uronidation and hydroxylation by CYP2D6 and sick sinus syndrome (unless a permanent pacemaker should be used with caution when co-adminis- is in place), or severe hepatic impairment (Child-Pugh tered with CYP2D6 inhibitors such as quinidine, >B), and in patients who are hypersensitive to any fluoxetine, or paroxetine. component of this product. Caution should be advised The recommended starting dose is 5 mg in patients with diabetes, cardiac failure, peripheral vas- orally once daily with or without food. For cular disease, and in patients concomitantly treated with those patients requiring further reduction in a non-dihydropyridine calcium channel blocker, such blood pressure, the dose can be increased at as diltiazem. Nebivolol has not been studied in patients two week intervals to a maximum dose of 40 with angina pectoris or who had a recent myocardial mg. In patients with severe renal or moderate infarction. In addition, patients with bronchospastic dis- hepatic impairment, the recommended dose eases should not receive beta blockers. is 2.5 mg once daily. Nebivolol is available Nebivolol is a pregnancy category C agent. However, by prescription as 2.5 mg, 5 mg, or 10 mg it is not known whether this drug had been excreted in tablets. All three strengths are supplied as a human breast milk. Nebivolol should be used with caution 30 or 100 bottle. in patients with severe renal impairment and moderate hepatic impairment. Furthermore, it has not been studied DORIBAX™ (DORIPENEM) in patients receiving dialysis. Doribax is manufactured by Shionogi & Co., The most common adverse reactions reported with and distributed by Ortho-McNeil Pharma- nebivolol use were headache, dizziness, nausea, and ceuticals. It is indicated as a single agent for

36 america’s Pharmacist | June 2008 www.americaspharmacist.net Table 2: New Drug Approvals of 2007

Brand Name Generic Name Manufacturer Approved Indication

Altabax Retapamulin GlaxoSmithKline Topical treatment of impetigo

Bystolic Nebivolol Forest/Mylan Treatment of hypertension Treatment of complicated intra-abdominal infections (cIAI)† and Doribax Doripenem Ortho-McNeil complicated urinary tract infections Isentress Raltegravir Merck Treatment of HIV-1 infection Bristol-Meyers Ixempra Ixabepilone Treatment of metastatic or locally advanced breast cancer Squibb

Kuvan Sapropterin BioMarin Treatment of phenylketonuria (PKU)

Letairis Ambrisentan Gilead Sciences Treatment of pulmonary arterial hypertension

Treatment of the signs and symptoms of early-stage idiopathic Neupro Rotigotine Schwarz Pharma Parkinson’s disease

Selzentry Maraviroc Pfizer Treatment of HIV-1 infection

Somatuline Lanreotide Beaufour Ipsen Treatment of acromegaly

Tasigna Nilotinib Novartis Treatment of chronic myelogenous leukemia (CML)

Tekturna Aliskiren Novartis Treatment of hypertension

Torisel Temsirolimus Wyeth Treatment of advanced renal cell carcinoma

Treatment of advanced or metastatic breast cancer in combination Tykerb Lapatinib GlaxoSmithKline with capecitabine

Vyvanse Lisdexamfetamine Shire Treatment of attention-deficit/hyperactivity disorder (ADHD)

the treatment of complicated intra-abdomi- other drugs in the carbapenem class. Use of doripenem nal infections and complicated urinary tract is also contraindicated in patients who have demonstrat- infections (including pyelonephritis) that are ed anaphylactic reactions to beta-lactams. Doripenem is caused by designated susceptible bacteria. a pregnancy category B. It is not know whether doripe- Doripenem belongs to the carbapenem class nem is excreted in human milk, so it should be used with of antimicrobials. It works by inhibiting bacte- caution in nursing women. rial cell wall biosynthesis. The most common adverse effects (≥5%) associ- The recommended dose of doripenem for ated with doripenem are headache, nausea, diarrhea, patients 18 or older is 500 mg every eight hours rash, and phlebitis. Additionally, Clostridium difficile- administered by intravenous infusion over an associated diarrhea has been associated with nearly hour. For patients with moderately impaired re- all antibacterial agents. Only two drug interactions nal function (estimated creatinine clearance ≥30 have been reported with doripenem use. Carbapen- ml/min to ≤50 ml/min) the recommended dose ems may reduce the serum valproic acid concentra- is 250 mg intravenously (over an hour) every tions, resulting in a loss of seizure control. Frequent eight hours. For patients with severely impaired monitoring of serum valproic acid concentrations renal function (estimated creatinine clearance is recommended following initiation of doripenem >10 ml/min to <30 ml/min), the recommended therapy. Probenicid has been shown to reduce the dose is 250 mg intravenously (over an hour) renal clearance of doripenem, which results in in- every 12 hours. creased concentrations of doripenem. Therefore, co- Doripenem is contraindicated in patients administration of probenecid and doripenem is with a known hypersensitivity to doripenem or not recommended.

www.americaspharmacist.net June 2008 | america’s Pharmacist 37 Table 3: Drugs Withdrawn in 2007

Brand Name Generic Name Manufacturer Reason

Ethomozine Moricizine Shire Marketing decision

Exubera Insulin human Pfizer Poor product acceptance

Permax Pergolide Valeant, Par, Teva Risk of heart valve damage

Sporanox Injection Itraconazole Other Biotech Marketing decision

Trasylol Aprotinin Bayer Possible increased risk for death

Zelnorm Tegaserod Novartis Increased risk of cardiovascular adverse effects

Doripenem is available by prescription as a single- develop opportunistic infections which will re- use 500 mg vial and should be stored at 25 degrees quire further evaluation and treatment. Patients Celsius (77 degrees Fahrenheit). Constitution of doripe- should be advised to inform their physician of nem (250 mg or 500 mg) is done using 10 mL of sterile any sign or symptom of infection. The pharma- water for injection or 0.9 percent sodium chloride injec- cokinetics of raltegravir in patients with severe tion (normal saline). The constituted suspension is not for hepatic impairment has not been studied. direct injection. Once constituted, the suspension should Furthermore, the safety and efficacy of ralte- be withdrawn using a 21 gauge needle and added to 100 gravir in pediatric patients less than 16 years mL of normal saline or 5 percent dextrose. The infusion of age has not been evaluated. Raltegravir bag should be gently shaken until clear. For the 250 mg has not been clinically studied in patients over dose, remove 55 mL of the final solution from the infu- 65; therefore it should be used with caution in sion bag and discard. The final infusion solution con- elderly patients until further studies are concentration, for both 250 mg and 500 mg, is 4.5 mg/mL. ducted. Raltegravir is a pregnancy category Upon constitution, doripenem suspension is stable for C agent. Breast feeding is not recommended one hour in the vial. Following dilution with normal saline, while taking raltegravir. doripenem is stable for eight hours at room temperature The most common adverse effects re- (24 hours at 2 degrees to 8 degrees C). If the suspension ported with the use of raltegravir were diar- is diluted with 5 percent dextrose, doripenem is stable for rhea, nausea, and headache. Patients should four hours at room temperature (24 hours at 2 degrees to inform their physician immediately if they 8 degrees C). experience unexplained muscle pain, tender- ness, or weakness while taking raltegravir. ISENTRESS™ (RALTEGRAVIR POTASSIUM) Caution should be used when raltegravir is Isentress, manufactured by Merck and Co., is a human co-administered with strong inducers such as immunodeficiency virus integrase strand transfer inhibi- rifampin. Raltegravir is available by prescrip- tor (HIV-1 INSTI) indicated in combination with other tion as a 400 mg tablet. The recommended antiretroviral agents for the treatment of HIV-1 infection. It dose is 400 mg orally twice daily with or works by inhibiting the activity of HIV-1 integrase, which without food. If a patient misses a dose, they is an HIV-1 enzyme that is required for viral replica- should take it as soon as they remember. If tion. When used in combination with other antiretroviral it is time for the next dose, they should skip agents, raltegravir may reduce the viral load and also the missed dose and go back to their regular increase the number of CD4 (T) cells, also known as schedule. No dosage adjustment is neces- white blood cells. sary in patients with mild-moderate hepatic There have been no reported contraindications with impairment or renal impairment. the use of raltegravir. Patients taking raltegravir may still Raltegravir is supplied as a pink, oval-

38 america’s Pharmacist | June 2008 www.americaspharmacist.net Table 4: Important New Dosage Forms Approved in 2007

Generic Name Brand Name Description Amlodipine/olmesartan Azor Combination calcium channel blocker / angiotensin receptor blocker

Amlodipine/valsartan Exforge Combination calcium channel blocker / angiotensin receptor blocker

Armodafinil Nuvigil The R-enantiomer of modafinil Azithromycin AzaSite Opthalmic drops Brimonidine/timolol Combigan Combination ophthalmic to reduce intraocular pressure Cyclobenzaprine Amrix Extended release, once-daily product Diclofenac Flector Diclofenac patch Diclofenac Voltaren Topical diclofenac gel Estradiol Divigel Topical hormone replacement gel Estradiol Evamist Transdermal spray Ethinyl estradiol/ levonorgestrel Lybrel Continuous use contraceptive Fluticasone Furoate Veramyst Once daily nasal spray Formeterol fumarate Perforomist Long acting beta-2 agonist Influenza vaccine, live FluMist Refrigerated formulation Ketoconazole Extina 2% topical foam Levocetirizine Xyzal Enantiomer of cetirizine Lidocane Zingo Powder for intradermal injection Mesalamine Lialda Once-daily tablets Orlistat Alli Over-the-counter formulation Pantoprazole Protonix Oral suspension Risedronate Actonel 75 mg tablet Rivastigmine Exelon Transdermal formulation Sevelamer Renvela Carbonate salt of Renagel Sitagliptan/metformin Janumet Combination antihyperglycemic Terbinafine Lamisil Oral granule formulation Tropsium Sanctura XR Extended-release formulation Zileutin Zyflo CR Extended-release formulation Zoledronic acid Reclast New 5 mg infusion

shaped, film-coated tablet and should be IXEMPRA™ (IXABEPILONE) stored at room temperature. Patients should Ixempra is manufactured by Baxter and distributed by be informed that raltegravir is not a cure for Bristol-Myers Squibb. It is indicated as monotherapy HIV infection or AIDS, and does not reduce the for the treatment of metastasized or locally advanced chance of passing HIV to others through sexual breast cancer after failure of an anthracycline, taxane, contact, sharing needles, or being exposed to and capecitabine. It is also indicated, in combination blood. Patients should be advised to continue with capecitabine, for the treatment of metastasized or to practice safe sex and to use latex or poly- locally advanced breast cancer in patients after failure urethane condoms or other barrier methods. of an anthracycline and a taxane. The recommended Further studies are needed to determine the dose of ixabepilone is 40 mg/m2 infused intravenously long-term effects of raltegravir. over three hours every three weeks. Dose reductions

www.americaspharmacist.net June 2008 | america’s Pharmacist 39 are required in patients with elevations in alanine ami- should be refrigerated (2 degrees to 8 degrees notransferase (ALT), aspartate aminotransferase (AST), C) and protected from light until ready for use. or bilirubin, and for patients experiencing significant Prior to reconstitution the product should be adverse events. allowed to stand at room temperature for 30 To minimize the chance of a hypersensitivity reaction, minutes. After removal from refrigeration, a patients should be premedicated with an H1 antagonist white precipitate in the vial may be noticed in (diphenhydramine 50 mg orally or equivalent) and an H2 the supplied diluent vial, this should dissolve to antagonist (ranitidine 150–300 mg orally or equivalent) form a clear solution as the vial warms to room one hour prior to treatment. Patients who experience a temperature. Ixabepilone is then reconstituted hypersensitivity reaction to ixabepilone require premedi- with the supplied diluent and further diluted in cation with a corticosteroid (dexamethasone 20 mg oral Lactated Ringers for injection to a concentra- or intravenously) prior to administration. tion of 0.2 mg/mL to 0.6 mg/mL. Once diluted Ixabepilone is a pregnancy category D. It is with Lactated Ringers, Ixabepilone is stable for contraindicated in patients with a hypersensitivity to six hours at room temperature and light, and Cremophor® EL, a baseline neutrophil count of less should be administered within this time period. than 1500 cells/mm3, or a platelet count lower than 100,000 cells/mm3. The combination of capecitabine LETAIRIS™ (AMBRISENTAN) and ixabepilone is contraindicated in patients with an Manufactured by Gilead Sciences, Letairis is AST or ALT greater than 2.5 times the upper limit of an endothelin receptor antagonist indicated normal, or a bilirubin greater than the upper limit of for the treatment of pulmonary arterial hy- normal. Dosage reductions are recommended if ixa- pertension (WHO Group 1) in patients with bepilone is to be used as monotherapy in patients with WHO class II or III symptoms to improve hepatic impairment. exercise capacity and delay clinical worsen- Ixabepilone works by binding to ß-tubulin subunits ing. Ambrisentan is an endothelin receptor on microtubules. This suppresses the microtubule dy- antagonist that is selective for the endothelin namics needed for normal cellular division. As a result, type-A (ETA ) receptor. Endothelin type-A is ixabepilone disrupts the mitotic phase of cell division, responsible for causing vasoconstriction and leading to cell death. Ixabepilone is extensively metabo- cell proliferation. lized in the liver, primarily by CYP3A4, with a terminal Use is contraindicated in pregnancy elimination half-life of approximately 52 hours. Inhibitors (pregnancy category X). Prior to initiation of of CYP3A4 may increase the plasma concentration of therapy, women of childbearing potential must ixabepilone and should be avoided. If co-administered have a confirmed negative pregnancy test and with a strong CYP3A4 inhibitor, the dose of ixabepilone be using two reliable methods of contracep- should be decreased. tion. No other form of contraception is needed The most common adverse events reported are pe- if the patient has had a tubal sterilization or ripheral sensory neuropathy, fatigue, myalgia/arthral- Copper T 380A IUD or LNg 20 IUD inserted. gia, alopecia, nausea, vomiting, mucositis, diarrhea, Pregnancy tests should be obtained monthly and musculoskeletal pain. Hematologic abnormalities in women of childbearing potential taking are common and include neutropenia, leukopenia, ambrisentan. Because of the serious risks of anemia, and thrombocytopenia. Further, palmar-plan- fetal harm and birth defects, ambrisentan is tar erythrodysesthesia (hand-foot syndrome), anorexia, only available through a restricted distribution abdominal pain, nail disorders, and constipation have program called the Letairis Education and Ac- been received. Specific guidelines for dosing ixabepi- cess Program (LEAP). lone in patients experiencing toxicity are available in Ambrisentan may only be distributed and the prescribing information. prescribed by pharmacists and prescribers Ixabepilone is supplied in 15 mg and 45 mg vials and who are registered with LEAP. In addition, it

40 america’s Pharmacist | June 2008 www.americaspharmacist.net may only be dispensed to patients who are NEUPRO® (ROTIGOTINE TRANSDERMAL enrolled in and meet all the conditions of SYSTEM) the LEAP program. Ambrisentan contains Neupro is manufactured by Schwarz Pharma. Rotigotine the following warnings: potential liver injury, is indicated for the treatment of the signs and symp- decreases in hemoglobin, and mild to mod- toms of early-stage idiopathic Parkinson’s disease. It is erate peripheral edema. Elevations of liver a transdermal delivery system that provides rotigotine, a aminotransferases (ALT and AST) to at least non-ergoline D3/D2/D1 dopamine agonist, continuously three times the upper limit of normal (ULN) over a 24 hour period. The precise mechanism of action have been reported with ambrisentan use. is unknown but is thought to be related to its ability to Ambrisentan should be avoided in patients stimulate dopamine D2 receptors in the caudate-puta- with moderate or severe hepatic impairment. men in the brain. It should be used with caution in patients with mild hepatic impairment. Once therapy Concomitant Medications Maraviroc Dose is initiated, liver aminotransferases should be monitored monthly. Ambrisentan should be CYP3A in hibitors (with or discontinued if the liver aminotransferases without a CYP3A inducer) including: are >5 x ULN or if elevations are accompa- • protease inhibitors (except nied by bilirubin >2 x ULN or by signs and tipranavir/ritonavir) symptoms of liver dysfunction. Decreases • delavirdine 150 mg orally twice daily • ketoconazole, itraconazole, in hemoglobin have been observed during clarithromycin, the first few weeks of treatment. Hemoglo- • other strong CYP3A inhibitors (e.g., nefazadone, bin should be measured prior to initiation of telithromycin) therapy and at one month and periodically thereafter. Other concomitant medications, including tipranavir/ritonavir, 300 mg orally twice daily The most common adverse effects seen nevirapine, all NRTIs and with ambrisentan use are peripheral edema, na- enfuvirtide sal congestion, sinusitis, flushing, palpitations, CYP3A inducers (without abdominal pain, and constipation. Ambrisentan a strong CYP3A inhibitor) including: is metabolized by the CYP3A4 and CYP2C19. • efavirenz 600 mg orally twice daily Caution should be used when co-administered • rifampin • carbamazepine, with cyclosporine and with strong CYP3A4 in- phenobarbital, and phenytoin hibitors, such as ketoconazole, and with strong CYP2C19 inhibitors, such as omeprazole. There has been no documented interaction with war- The recommended initial dose of rotigotine trans- farin or sildenafil. dermal is 2 mg/24 hours. Based on individual response The initial treatment dose is 5 mg orally and tolerability, the dosage may be increased weekly once daily with or without food. The dose can by 2 mg/24 hours for additional therapeutic effects. The be increased to 10 mg once daily if the 5mg lowest effective dose was 4 mg/24 hours, and the highest dose is tolerated. There are no dosage ad- recommended dose is 6 mg/24 hours. Discontinuation of justments necessary in patients with mild or therapy should be gradually by reducing the daily dose moderate renal impairment. The safety and by 2 mg/24 hours every other day until complete with- efficacy of ambrisentan has not been evaluated drawal. No dosage adjustments are required for patients in pediatric patients. Ambrisentan is available who have moderate impairment of hepatic function or by prescription as 5 mg and 10 mg film-coated, mild to severe impairment of renal function. unscored tablets. Both strengths are supplied The rotigotine transdermal system is applied once as a bottle of either 30 or 100 count. daily, preferably at the same every day. The adhesive

www.americaspharmacist.net June 2008 | america’s Pharmacist 41 side of the transdermal system should be applied to Maraviroc can be taken with or without clean, dry, intact healthy skin on the abdomen, thigh, hip, food. Concomitant use of maraviroc and St. flank, shoulder, or upper arm. Application site should be John’s wort (hypericum perforatum) is not changed daily and should not be used more than once recommended due to substantial decreases every 14 days. in the concentration of maraviroc. The use of Rotigotine transdermal is contraindicated in patients maraviroc is not recommended in patients with a known hypersensitivity to rotigotine transdermal or under 16 due to a lack of safety and efficacy the components of the transdermal system. Rotigotine data. Maraviroc has not been clinically stud- transdermal is a pregnancy category C. It decreases ied in patients over 65; therefore it should be prolactin secretion in humans and could potentially inhibit used with caution in elderly patients. lactation. It is not known if rotigotine transdermal is ex- The safety and efficacy of maraviroc has not creted in human breast milk. been specifically studied in patients with renal There have been reports of patients that are treated impairment, and therefore should be used with with rotigotine transdermal falling asleep during activities caution in this population. Patients with a cre- of daily living, including operating motor vehicles. Roti- atinine clearance of less than 50 mL/min who gotine transdermal contains sodium metabisulfite, which are receiving maraviroc and a CYP3A inhibitor may cause allergic-type reactions including anaphylactic are at an increased risk of adverse effects due symptoms and life threatening asthmatic episodes in to increased maraviroc concentrations. The susceptible individuals. pharmacokinetics of maraviroc have not been The most common adverse effects associated with studied sufficiently in patients with hepatic rotigotine transdermal are nausea, application site reac- impairment. However, maraviroc concentrations tion, somnolence, dizziness, headache, vomiting, and will likely be increased in these patients due to insomnia. Only one potential drug interaction has been liver metabolism. reported with rotigotine transdermal. It is possible that The most common adverse effects (>8%) dopamine antagonists may diminish the effectiveness of associated with maraviroc are cough, pyrexia, rotigotine transdermal. upper respiratory tract infections, rash, mus- Rotigotine transdermal is available in three strengths: 2 culoskeletal symptoms, abdominal pain, and mg/24 hours (4.5 mg/system), 4 mg/24 hours (9 mg/system), dizziness. There have been no reported contra- and 6 mg/24 hours (13.5 mg/system). Each transdermal indications with the use of maraviroc. However, system is individually packaged in a separate pouch and there is a black box warning regarding hepa- available in cartons of seven and 30 transdermal systems. totoxicity with maraviroc. There has been one case of possible maraviroc-induced hepatotox- SELZENTRY™ (MARAVIROC) icity with allergic features. Hepatotoxicity may Selzentry is manufactured by Pfizer Labs. Maraviroc be preceded by evidence of a systemic aller- is a CCR5 co-receptor antagonist that is indicated for gic reaction. Therapy discontinuation should combination antiretroviral treatment of adults infected be considered in any patient with signs and with only CCR5-tropic HIV-1 detectable, who have symptoms of hepatitis, or with increased liver evidence of viral replication and HIV-1 strains resistant transaminases in combination with rash or other to multiple antiretroviral agents. There is no evidence systemic symptoms. demonstrating the effect of maraviroc on clinical pro- Maraviroc should be used with caution in gression of HIV-1. patients with pre-existing liver dysfunction or Maraviroc must be administered in combination with who are co-infected with viral hepatitis B or other antiretroviral medications. It is available by prescrip- C. Caution should be used when administer- tion as 150 mg and 300 mg film coated tablet. The rec- ing maraviroc to patients with an increased ommended dose for maraviroc is based on concomitant risk for cardiovascular events or a history of medications due to drug interactions. postural hypotension or on concomitant med-

42 america’s Pharmacist | June 2008 www.americaspharmacist.net ications to lower blood pressure. Maraviroc more information about medications associated with is a pregnancy category B, but should only QT prolongation. be used in pregnant women if the potential The most frequently reported adverse events re- benefit justifies the potential risk to the fetus. ported with nilotinib are rash, pruritis, nausea, fatigue, Breast feeding is not recommended while headache, constipation, diarrhea, and vomiting. Seri- taking maraviroc. ous adverse reactions include neutropenia, thrombocytopenia, pneumonia, febrile neutropenia, leukopenia, TASIGNA® (NILOTINIB) elevated lipase, intracranial hemorrhage, Tasigna, manufactured by Novartis, is an and pyrexia. inhibitor of the Bcr-Abl kinase. It is indicated Nilotinib is a pregnancy category D. Women should for the treatment of chronic and accelerated use effective contraception and should not breast feed phase Philadelphia chromosome positive during treatment with nilotinib. Metabolism of nilotinib chronic myelogenous leukemia (CML) in is mainly via hepatic oxidation and hydroxylation. Nilo- adult patients resistant to or intolerant to tinib is a competitive inhibitor of the CYP3A4 enzyme. prior therapy that included imatinib. The Increases in nilotinib concentrations have been noted dose of nilotinib is 400 mg orally twice daily, when administered in combination with CYP3A4 inhibi- approximately 12 hours apart. Nilotinib is tors and decreased concentrations with CYP3A4 induc- supplied as 200 mg capsules that should ers. Accordingly, administration of nilotinib in combina- be swallowed whole with water. Food may tion with strong CYP3A4 inhibitors and inducers should increase blood levels of the medication, so be avoided. Because nilotinib is primarily eliminated food should not be consumed for at least hepatically, caution should be used in patients with he- two hours before the or one hour after the patic impairment and these patients should be closely dose is taken. Dose adjustments may be monitored for QT prolongation. Patients with an AST required for drug interactions, hematologic or ALT of 2.5 times the upper limit of normal or greater, and non-hematologic toxicities. or a bilirubin of 1.5 times the upper limit of normal or Nilotinib may cause myelosuppression greater have been excluded from previous clinical trials resulting in neutropenia, thrombocytopenia of nilotinib. and anemia. A complete blood count (CBC) should be monitored at least every two weeks TEKTURNA® (ALISKIREN) for the first two months, then monthly there- Tekturna, manufactured by Novartis Pharmaceuticals, after. A back box warning for QT interval is indicated for the treatment of hypertension. It may be prolongation by nilotinib is included in the used as monotherapy or in combination with other antihy- prescribing information. Other medications pertensive medications. Aliskiren is only the novel agent known to prolong the QT interval and sub- in its class known as the direct renin inhibitors. It works stances known to inhibit CYP3A4 should be by decreasing plasma renin activity (PRA) and inhibiting avoided, including grape fruit juice. If present, the conversion of angiotensinogen to angiotensin (Ang I) hypokalemia and hypomagnesemia should be in the renin-angiotensin-aldosterone-system (RAAS). It is corrected prior to administration and elec- not known whether aliskiren affects other RAAS compo- trolytes should be monitored at baseline and nents such as angiotensin-converting enzyme (ACE) or periodically thereafter. Electrocardiograms non-ACE pathways. are recommended at baseline, seven days There have been no reported contraindications after initiation, and periodically thereafter. As with the use of aliskiren. However, it should be used well, dosing recommendations based on QT with caution in pregnant women, pregnancy category prolongation and other toxicities can be found C (first trimester) and D (second and third trimes- in the prescribing information. Clinicians may ters), in patients with impaired renal function (serum find the Web site www.qtdrugs.org useful for creatinine 1.7 mg/dL for women and 2.0 mg/dL for

www.americaspharmacist.net June 2008 | america’s Pharmacist 43 men and/or estimated glomerular filtration rate (GFR) Pretreatment with an antihistamine is rec- <30 mL/min), and patients with hyperkalemia (serum ommended prior to each dose of temsirolimus potassium >5.5 meq/L) which is more commonly seen because of the potential for hypersensitivity in combination with an ACE inhibitor. There is currently reactions. If hypersensitivity should occur, the no data available on the use of aliskiren in patients infusion should be stopped and appropriate with renal artery stenosis. management initiated depending on the sever- Common adverse effects include hypotension, ity of the reaction (see prescribing information diarrhea, cough, and rash. More serious, but rare ad- for more detail). verse effect which can occur is angioedema (swelling The most common adverse reactions in- of face, extremities, eyes, lips, tongue, and difficulty clude rash, mucositis, nausea, edema, anorex- in swallowing or breathing). Only two drug interac- ia, and asthenia. Laboratory abnormalities fol- tions have been reported with aliskiren use. Aliskiren lowing treatment with temsirolimus are common concomitantly administered with furosemide results in and include hyperglycemia, hyperlipidemia, a significant reduction in furosemide blood concentra- elevated serum creatinine, hypophosphatemia, tions. Therefore, the effect of furosemide could be di- lymphopenia, thrombocytopenia, and elevated minished after starting aliskiren therapy. When aliskiren alkaline phosphatase. The hyperglycemia and was administered with cyclosporine, the blood con- hyperlipidemia may require additional treatment centrations of aliskiren significantly increased. with antidiabetic and antilipidemic medications. The concomitant use of aliskiren with cyclosporine is Other potentially severe adverse reactions not recommended. include infection resulting from immunosup- Aliskiren is available by prescription as 150 mg and pression, interstitial lung disease, renal failure 300 mg tablets. The usual dose is 150 mg administered and bowel perforation. Because temsirolimus orally once daily with or without food. The dose may be may lead to abnormal wound healing, caution increased to 300 mg daily in those patients whose blood should used be if prescribed in a periopera- pressure is not adequately controlled. Aliskiren can be tive period. The use of live vaccines and close used in combination with other antihypertensive agents. contact with those who have recently received a However, the use of aliskiren has not been studied with live vaccine should be avoided during treatment maximum doses of ACE inhibitors. No dosage adjust- with temsirolimus. ment is required in elderly patients, in patients with mild- Temsirolimus is primarily metabolized by the severe renal impairment, or in patients with mild-moder- CYP3A4 enzyme. Concomitant administration ate hepatic insufficiency. Aliskiren is supplied as a light with strong inducers or inhibitors of CYP3A4 pink (150 mg) and light red (300 mg) unscored tablet. should be avoided. If patients need to be Both strengths are packaged in bottles and unit-dose co-administered a strong CYP3A4 inhibitor blister packages (10 strips of 10 tablets) and are stored at with temsirolimus, a dose reduction to 12.5 room temperature. mg should be considered. Also, if a strong CYP3A4 inducer must be administered with TORISEL™ (TEMSIROLIMUS) temsirolimus, a dose increase to 50 mg should Manufactured by Wyeth Pharmaceuticals, Torisel is indi- be considered. If dose adjustments are made, cated for the treatment of advanced renal cell carcinoma. care should be taken to confirm continued co- Temsirolimus inhibits tumor growth by inhibiting mTOR, the administration and patient compliance with the mammalian target of rapamycin. An intracellular protein, interacting medication(s) prior to each adminis- mTOR is involved in regulating cellular growth, motility, tration of temsirolimus. survival, and protein synthesis. The recommended dose Temsirolimus may leach plasticizer from of temsirolimus is 25 mg infused intravenously over 30 to PVC infusion bags and sets. To avoid this, 60 minutes once weekly. Treatment is often continued until temsirolimus should be stored in bottles (glass, disease progression or unacceptable toxicity occurs. polypropylene) or bags (polypropylene, poly-

44 america’s Pharmacist | June 2008 www.americaspharmacist.net olefin) and administered through polyethylene- Severe diarrhea in patients taking lapatinib has lined infusion sets. been reported. Management with anti-diarrheal agents, Temsirolimus is supplied in a 25 mg/mL hydration, and electrolytes may be required. Because vial with a separate vial containing 1.8 mL of lapatinib may also prolong the QT interval, electrolyte diluent and should be refrigerated (2 degrees monitoring and electrocardiogram monitoring may also to 8 degrees C) and protected from light until be recommended. The most common adverse events ready for use. Once mixed with the supplied reported include diarrhea, nausea, vomiting, rash, pal- diluent, the required amount of temsirolimus mar-plantar erythrodysesthesia (hand-foot syndrome), is further diluted by addition to a 250 mL and fatigue. Lapatinib has also been associated with in- container (glass, polypropylene, polyolefin) terstitial lung disease and patients should be monitored of 0.9 percent sodium chloride injection. An for pulmonary symptoms. Lapatinib is a pregnancy cat- inline polyethersulfone filter with a pore size egory D and women should be advised not to become not greater than five microns is recommended pregnant when taking lapatinib. for administration. Lapatinib is extensively metabolized, primarily by CYP3A4 and CYP3A5, with minor contributions TYKERB® (LAPATINIB) from CYP2C19 and CYP2D8 and eliminated via the Lapatinib is manufactured by GlaxoSmith- liver. Systemic exposure to lapatinib is increased Kline. It is indicated, in combination with when administered with food, administered in di- capecitabine, for the treatment of patients vided daily doses (twice daily), when co-administered with advanced or metastasized breast can- with CYP3A4 inhibitors, or with P-glycoprotein (Pgp, cer whose tumors over express HER2 and ABCB1) inhibitors. Co-administration with CYP3A4 who have received prior therapy including an inducers decreases systemic exposure to lapatinib. anthracycline, a taxane, and trastuzumab. Co-administration of lapatinib with strong CYP3A4 The recommended dose of lapatinib is 1,250 inducers or inhibitors should be avoided, if necessary, mg (five tablets) given orally ONCE daily on dose adjustments should be considered and care- days 1–21 continuously in combination with ful monitoring is required. Dosage reductions may capecitabine 2,000 mg/m2/day on days 1–14 also be required for patients with hepatic impairment. in a repeating 21-day cycle. Although clinical data are currently lacking, in patients The capecitabine component is adminis- with severe hepatic impairment (Child-Pugh Class C) tered orally in two divided doses, approximately a dose reduction to 750 mg/day is predicted to adjust 12 hours apart. Lapatinib should be taken once the area under the curve to the normal range. Careful daily at least one hour before or one hour after and frequent monitoring for adverse events is recom- a meal. However, capecitabine should be taken mended in this population. with food or within 30 minutes after food. Dose modification may be needed for cardiac and VYVANSE™ (LISDEXAMFETAMINE DIMESYLATE) other toxicities, severe hepatic impairment, and Vyvanse is manufactured by New River Pharmaceu- CYP3A4 drug interactions. ticals and distributed by Shire. It is indicated for the Decreases in left ventricular ejection frac- treatment of Attention-Deficit/Hyperactivity Disorder tion (LVEF) have been reported with lapatinib. (ADHD). Lisdexamfetamine is a prodrug of dextroam- A normal LVEF should be confirmed prior to phetamine. Amphetamines are non-catecholamine starting the medication. Patients with decreases sympathomimetic amines with CNS stimulant activity. in LVEF while taking lapatinib may need to have Although the exact mechanism of action is unknown, the medication discontinued. A reduced dose they are thought to block the reuptake of norepineph- (1,000 mg/day) may be restarted after a mini- rine and dopamine into the presynaptic neuron and mum of two weeks if the LVEF returns to normal increase the release of these monoamines into the and the patient is asymptomatic. extraneuronal space.

www.americaspharmacist.net June 2008 | america’s Pharmacist 45 The recommended initial dose of lisdexamfetamine for children 6–12 years of age is 30 mg orally, once Amy P. Witte, PharmD, and Jodie V. Mahlhotra, PharmD, daily in the morning with or without food. Dosage may are assistant professors of pharmacy practice at the Uni- be increased by 20 mg/day at approximately weekly versity of the Incarnate Word, Feik School of Pharmacy, intervals. The maximum dose for children is 70 mg/ San Antonio. Trevor McKibbin, PharmD, MSc, BCPS, is an day. Lisdexamfetamine has not been studied in indi- assistant professor of clinical pharmacy at the University of viduals under 6 years of age or over 12. Lisdexamfet- Tennessee College of Pharmacy, Memphis, Tennessee. amine is available in 30 mg, 50 mg, and 70 mg capsules. Doses may be taken with or without food and should be taken either as a whole capsule or opened Editor’s Note: To obtain the complete list of refer- and the entire contents dissolved in a glass of water. ences used in the article, contact Chris Linville No dosage adjustments are required for at NCPA (703-838-2680), or at chris.linville@ lisdexamfetamine ncpanet.org. Lisdexamfetamine is contraindicated in patients with advanced arteriosclerosis, symptomatic cardiovascular disease, moderate to severe hypertension, hyperthyroidism, known hypersensitivity or idiosyn- crasy to sympathomimetic amines, or glaucoma. CONTINUING EDUCATION QUIZ It is also contraindicated in patients currently in an Select the correct answer. agitated state or a history of drug abuse. Lisdexamfet- 1. All of the following agents are pregnancy amine is also contraindicated during or within 14 days category B or C except? following the administration of monoamine oxidase a. Nebivolol inhibitors due to the risk of hypertensive crisis. Lisdex- b. Aliskiren amfetamine is a pregnancy category C and should c. Ambrisentan only be used during pregnancy if the potential d. Raltegravir benefit justifies the potential risk to the fetus. Amphet- amines are excreted in human milk, therefore mothers 2. Retapamulin is indicated for the treatment of: taking lisdexamfetamine should be advised to refrain a. Hypertension from nursing. b. Impetigo Lisdexamfetamine is a stimulant medication and is c. HIV-1 infection associated with several potentially serious side effects. d. ADHD Table 1 (page 36) shows potential drug interactions with lisdexamfetamine. Stimulant therapy has been reported 3. Which of the following medications are me- to result in sudden death in patients who have heart tabolized primarily by CYP2D6? problems or heart defects, stroke and heart attacks in a. Aliskiren adults, and increased blood pressure and heart rate. b. Raltegravir There have also been reports of new or worsening mental c. Nebivolol health problems such as behavior and thought problems, d. Retapamulin bipolar disorder, aggression, or psychotic symptoms. Other serious side effects associated with lisdexamfe- 4. Which of the following is considered a novel tamine are slowing of growth in children, seizures, and agent in its class known as the direct renin eyesight changes or blurred vision. The most common inhibitors? adverse effects (≥5%) associated with lisdexamfetamine a. Aliskiren are upper abdominal pain, decreased appetite, dizziness, b. Doripenem dry mouth, irritability, insomnia, nausea, vomiting, and c. Maraviroc decreased weight. d. Nilotinib

46 america’s Pharmacist | June 2008 www.americaspharmacist.net

5. Common side effects of raltegravir therapy 11. Which of the following medications should be taken include: on an empty stomach? a. Abdominal pain a. Nilotinib b. Dizziness b. Lapatinib c. Edema c. Temsirolimus d. Headache d. Both A and B

6. The recommended dose of Isentress™ 12. Which of the following is an adverse event frequently (raltegravir) for most patients is? associated with ixabepilone? a. 400 mg orally daily a. QT prolongation b. 400 mg orally twice a day b. Peripheral neuropathy c. 800 mg orally daily c. Interstitial lung disease d. 800 mg orally twice a day d. Hyperglycemia and hyperlipidemia

7. Which one of the following tests should be 13. Temsirolimus is indicated for which of the following? performed prior to initiating treatment with a. Advanced breast cancer Tasigna(r) (nilotinib)? b. Chronic myelogenous leukemia a. Electrocardiogram (ECG) c. Hypertension b. Pulmonary function test d. Advanced renal cell carcinoma c. Magnetic resonance imaging (MRI) d. Chest X-ray 14. Following dilution with 100 ml of normal saline in an IV infusion bag, how long is doripenem stable at room 8. The recommended dose of Torisel™ temperature? (temsirolimus) for most patients is? a. Two hours a. 40 mg/m2 every 3 weeks b. Four hours b. 400 mg/day c. Six hours c. 1,250 mg/day d. Eight hours d. 25 mg weekly 15. What is the recommended dose for maraviroc when 9. Which of the following medications is associ- used in combination with ketoconazole? ated with QT interval prolongation? a. 150 mg twice a day a. Nilotinib b. 300 mg twice a day b. Lapatinib c. 600 mg twice a day c. Both of the above d. None of the above d. None of the above 16. How many milligrams of rotigotine are in a 4 mg/24 10. Lapatinib, ixabepilone, nilotinib and temsiro- hour transdermal patch? limus are primarily eliminated via which mecha- a. 4 mg nism? b. 4.5 mg a. All are primarily eliminated renally. c. 6 mg b. All are primarily eliminated renally with the d. 9 mg exception of ixabepilone which is eliminated hepatically via CYP3A4. c. All are primarily eliminated hepatically via CYP2C19. d. All are primarily eliminated hepatically via CYP3A4.

www.americaspharmacist.net June 2008 | america’s Pharmacist 47

17. Which of the following medications is contra- New Drugs of 2007 indicated during or within 14 days following the June 1, 2008 (expires June 1, 2011) administration of an MAO inhibitor? FREE ONLINE C.E. Pharmacists now have online access to NCPA’s a. Doripenem CE programs through Powered by CECity. By taking this test online— b. Lisdexamfetamine go to the Continuing Education section of the NCPA Web site (www. ncpanet.org) by clicking on “Professional Development” under the c. Nilotinib Education heading you will receive immediate online test results and d. Temsirolimus certificates of completion at no charge.

To earn continuing education credit: ACPE Program 207-000-08-006-H04-P 18. Lisdexamfetamine is indicated for which of A score of 70 percent is required to successfully complete the CE quiz. the following? If a passing score is not achieved, one free reexamination is permitted. a. Attention-Deficit/Hyperactivity Disorder Statements of credit for mail-in exams will be available online for you to print out approximately three weeks after the date of the program b. Hypertension (transcript Web site: www.cecerts.ORG). If you do not have access to a c. Parkinson’s disease computer, check this box and we will make other arrangements to send d. Urinary tract infections you a statement of credit: q

Record your quiz answers and the following information on this form. 19. Maraviroc is metabolized by q NCPA Member License NCPA Member No. ______State ______No. ______a. CYP1A2 q Nonmember State ______No. ______b. CYP2D6 All fields below are required. Mail this form and $7 for manual processing to: c. CYP2C19 NCPA CE Processing Ctr.; 405 Glenn Drive, Suite 4; Sterling, VA. 20164 d. CYP3A4 ______Last 4 digits of SSN MM-DD of birth ______Name 20. Which of the following is associated with ______interstitial lung disease? Pharmacy name ______a. Aliskiren Address ______b. Doripenem City State ZIP ______c. Lapatinib Phone number (store or home) d. Maraviroc ______Store e-mail (if avail.) Date quiz taken

Quiz: Shade in your choice a b c d e a b c d e 1. q q q q q 11. q q q q q 2. q q q q q 12. q q q q q 3. q q q q q 13. q q q q q 4. q q q q q 14. q q q q q 5. q q q q q 15. q q q q q

6. q q q q q 16. q q q q q 7. q q q q q 17. q q q q q 8. q q q q q 18. q q q q q 9. q q q q q 19. q q q q q 10. q q q q q 20. q q q q q

Quiz: Circle your choice 21. Is this program used to meet your mandatory C.E. requirements? a. yes b. no 22. Type of pharmacist: a. owner b. manager c. employee 23. Age group: a. 21–30 b. 31–40 c. 41–50 d. 51–60 e. Over 60 24. Did this article achieve its stated objectives? a. yes b. no 25. How much of this program can you apply in practice? a. all b. some c. very little d. none

How long did it take you to complete both the reading and the quiz? ______minutes

NCPA® is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. NCPA has assigned two contact hours (0.2 CEU) of continuing education credit to this article. Eligibility to receive continuing education credit for this article expires three years from the month published.