Current FDA-Related Drug Information - Approvals, Submission, and Important Labeling Changes for US Marketed Pharmaceuticals

Hosp Pharm 2012;47(2):139–1442012 � Thomas Land Publishers, Inc.www.thomasland.comdoi: 10.1310/hpj4702-139

Current FDA-Related Drug Information

Approvals, Submission, and Important Labeling Changesfor US Marketed Pharmaceuticals

Danial E. Baker, PharmD, FASHP, FASCPp

This monthly feature will help readers keep current on new drugs, new indications, dosage forms,and safety-related changes in labeling or use. Efforts have been made to ensure the accuracy of thisinformation; however, if there are any questions, please let me know at [email protected].

Table 1. New drugs approved by the US Food and Drug Administration (FDA): November 17, 2011 throughDecember 15, 2011Aflibercept – Eylea (Regeneron Pharmaceuticals)

Comparative agents: Ranibizumab

Indication: Treatment of patients with neovascular (wet) age-related macular degeneration

Mechanism of action: Soluble decoy receptor that binds vascular endothelial growthfactor-A and placental growth factor and prevents the activation of thecognate vascular endothelial growth factor receptors

Common adverse effects: Conjunctival hemorrhage, eye pain, cataract, vitreous detachment, vitreous floaters,and increased intraocular pressure

Dosage form & strength: Injection; 40 mg/mL single-use vial

Product labeling: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125387lbl.pdf

Asparaginase Erwinia chrysanthemi – Erwinaze (EUSA)

Comparative agents: Pegaspargase

Indication: Component of a multiagent chemotherapeutic regimen for the treatment of patientswith acute lymphoblastic leukemia (ALL) who have developed hypersensitivity toEscherichia coli-derived asparaginase

Mechanism of action: Reduction in circulating levels of asparagine by catalyzing the deamidation ofasparagine to aspartic acid and ammonia

Common adverse effects: Serious hypersensitivity reactions, including anaphylaxis, pancreatitis, abnormaltransaminases, coagulation abnormalities including thrombosis and hemorrhage,nausea and vomiting, and hyperglycemia

Dosage form & strength: Injection; 10,000 IU lyophilized powder per vial

Product labeling: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125359lbl.pdf

*Director, Drug Information Center, College of Pharmacy, Washington State University Spokane, PO Box 1495, Spokane, WA99210-1495.

Hospital Pharmacy 139

Table 2. Agents pending FDA approval: November 17, 2011 through December 15, 2011

Generic name Brand name(Company)

Indication and comments

Recommended for approval byan FDA advisory panel

Axitinib Inlyta(Pfizer Oncology)

Treatment of advanced renal cell carcinoma after failureof first-line therapy

Peginesatide (Affymax /TakedaPharmaceuticals)

Treatment of dialysis patients with anemia due to chronickidney disease

Staccato loxapine Adasuve(Alexza Pharmaceuticals)

Inhaled formulation intended for the treatment of agitationassociated with schizophrenia or bipolar disorder in adults.Vote for approval was 9:8 and 1 abstention.

FDA revoked approvals

Bevacizumab Avastin(Genentech)

Approval for the use in the treatment of breast cancerwas revoked. The drug is still approved for the treatmentof other types of cancer.

Fluocinolone acetonide Iluvien(Alimera)

Insufficient data regarding safety and efficacy in the treatmentof diabetic macular edema.

Table 3. New drug / biologics license applications filed by manufacturer: November 17, 2011 throughDecember 15, 2011

Generic nameBrand name(Company)

Comparativeagents

Indication Mechanismof action

Common adverseeffects

Dosageform orroute

Comments

Alogliptin/metformin(Takeda/FuriexPharmaceuticals)

Linagliptin,saxagliptin,sitagliptin

Type 2diabetesmellitus

Selectivedipeptidylpeptidase IVinhibitor;reduction ofglucoseproductionby the liver

Upper respiratorytract infection,nasopharyngitis,creatinine renalclearance decreased,diarrhea, headache,hypertension, andurinary tract infection

Oral

Aripiprazole depot(OtsukaPharmaceuticals)

Aripiprazole Maintenancetreatment ofadult patientswithschizophrenia

DopamineD2 partialagonist

Same as aripiprazole Injection Once monthlydepotformulation

TeduglutideGattex(NPSPharmaceuticals)

– Short bowelsyndrome

Recombinantanalog ofhumanglucagon-likepeptide

Abdominal pain,nausea,gastrointestinal stomacomplications, andabdominal distension

Injection

140 Volume 47, February 2012


Table 4. Significant labeling changes or “Dear Health Professional” letters related to safetya


Warning

Aliskiren/amlodipineTekamlo

Amlodipine/aliskiren/hydrochlorothiazideAmturnide(Novartis)

WARNINGS AND PRECAUTIONS:Drug Interactions With Amlodipine: 77% increase in exposure to simvastatincompared to simvastatin alone. Limit the dose of simvastatin in patientson amlodipine to 20 mg daily.Drug Interactions With Cyclosporine or Itraconazole: Blood concentrations ofaliskiren are significantly increased.Avoid concomitant use of aliskiren with cyclosporine or itraconazole.ADVERSE REACTIONS:Postmarketing Experience: Hypersensitivity: Angioedema requiring airwaymanagement and hospitalization; peripheral edema; and increased blood creatinineconcentrationshttp://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm279774.htmhttp://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm250259.htm

Ambenonium chlorideMytelase(sanofi-aventis)

CONTRAINDICATIONS: Should not be administered to patients with a knownhypersensitivity to ambenonium chloride or any other ingredients.PRECAUTIONS: Use with caution in patients with Parkinson disease.ADVERSE REACTIONS: Nausea, increase in bronchial and lachrymal secretionsand vomiting, and nicotinic effects (ie, muscle cramps, fasciculation of voluntarymuscles, and rarely generalized malaise with anxiety and vertigo)http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm283120.htm

Amlodipine/aliskiren/hydrochlorothiazideAmturnide(Novartis)

Cyclosporine and itraconazole therapies can increase the blood concentration ofaliskiren; concomitant use should be avoided.Angioedema, peripheral edema, and increased blood creatinine levels wereadded to the adverse reaction section.http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm279774.htm

Antiretrovirals(Various)

Class labeling change:WARNINGS AND PRECAUTIONS: Immune Reconstitution Syndrome:Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barresyndrome) have also been reported to occur in the setting of immune reconstitution,however, the time to onset is more variable and can occur many months afterinitiation of treatment.http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm283152.htm

Baclofen intrathecalLioresal(Medtronic)

WARNINGS: Overdose has generally been related to inadvertentsubcutaneous injection.PRECAUTIONS: Inadvertent injection into the subcutaneous tissue canoccur if the reservoir refill septum is not properly accessed. Subcutaneousinjection may result in symptoms of a systemic overdose or early depletionof the reservoir.http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm250616.htm

Estradiol transdermal sprayEvamist(KV Pharm)

Changes in the Boxed Warning, Warnings & Precautions, and PatientCounseling sections regarding the risk of breast budding, breast masses, andgynecomastia in children with unintentional secondary exposureshttp://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm279996.htm

Ezetimibe/simvastatinVytorin(Schering)

Drug should be discontinued if markedly elevated CPK levels occuror myopathy is diagnosed or suspected.Rare postmarketing reports of fatal and nonfatal hepatic failure; cognitiveimpairment (eg, memory loss, forgetfulness, amnesia, memory impairment, confusion)http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm208609.htm

(continued)



Table 4. Significant labeling changes or “Dear Health Professional” letters related to safetya (CONT.)


Warning

Fosphenytoin sodiumCerebyx(Pfizer)

Phenytoin(Various)

BOXED WARNING: Cardiovascular Risk Associated With Rapid Infusion Rates:The rate of intravenous administration should not exceed 150 mg phenytoin sodiumequivalents per minute because of the risk of severe hypotension andcardiac arrhythmias.WARNINGS: Serious Dermatologic Reactions: If a rash occurs, the patient shouldbe evaluated for signs and symptoms of drug reaction with eosinophilia and systemicsymptoms (DRESS). The risk may be higher in patients of Chinese ancestry and thepresence of HLA-B*1502 in patients using carbamazepine.DRESS/multiorgan hypersensitivity, also known as multiorgan hypersensitivity,has been reported in patients taking antiepileptic drugs, including phenytoin.CONTRAINDICATION: Contraindicated with delavirdine due to potential forloss of virologic response and possible resistance to delavirdine or to the class ofnon-nucleoside reverse transcriptase inhibitorsPRECAUTIONS: Local toxicity characterized by edema, discoloration, and paindistal to the site of injection (‘‘purple glove syndrome’’) has also been reportedfollowing peripheral intravenous injection. This reaction may or may not beassociated with extravasation and may occur several days after injection.DRUG INTERACTION: Fluorouracil may increase phenytoin concentrations.http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm283239.htmhttp://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm243476.htm

Lithium (Various) Risk of unmasking of Brugada syndrome added to Warnings, Precautions, andAdverse Reactions sections.http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm279930.htm

MaravirocSelzentry(ViiV Healthcare)

Changes in the Boxed Warning and Warnings & Precautions sections regardingthe risk of hepatotoxicity.http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm215506.htm

Methotrexate injection(Various)

WARNINGS: Use caution when administering high-dose methotrexate to patientsreceiving proton pump inhibitor (PPI) therapy. Case reports and publishedpopulation pharmacokinetic studies suggest that concomitant use of PPIs withmethotrexate (primarily at high dose) may elevate and prolong serum levels ofmethotrexate and/or its metabolite hydroxymethotrexate, possibly leading tomethotrexate toxicities.http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm283114.htm

Naproxen/esomeprazolemagnesiumVimovo(AstraZeneca)

WARNINGS AND PRECAUTIONS: Bone Fracture: Observational studiessuggest that PPI therapy may be associated with an increased risk forosteoporosis-related fractures of the hip, wrist, or spine. The risk of fracturewas increased in patients who received high-dose, defined as multiple daily doses,and long-term PPI therapy (a year or longer).ADVERSE REACTIONS: Postmarketing Experience: Bone fracturehttp://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm262248.htm

PazopanibVotrient(GlaxoSmithKline)

Hypertension, including hypertensive crisis, has been reported. If hypertensivecrisis or if hypertension is severe and persistent despite antihypertensive therapyand dose reduction. then therapy should be discontinued.Serious adverse reactions associated with pazopanib include hepatotoxicity,QT prolongation and torsades de pointes, hemorrhagic events, arterialthrombotic events, gastrointestinal perforation, fistula, and hypertensive crisis.http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm279961.htm

(continued)





Warning

Phenytoin(Various)

CONTRAINDICATION: Contraindicated with delavirdine due to potential forloss of virologic response and possible resistance to delavirdine or to the class ofnon-nucleoside reverse transcriptase inhibitorsWARNINGS: DRESS/multiorgan hypersensitivity, also known as multiorganhypersensitivity, has been reported in patients taking antiepileptic drugs, includingphenytoin. Chronic use is associated with decreased bone mineral density(osteopenia, osteoporosis, and osteomalacia) and bone fractures.DRUG INTERACTION: Phenytoin is extensively bound to serum plasma proteinsand is prone to competitive displacement. Phenytoin is metabolized by hepaticcytochrome P450 enzymes and inhibition of metabolism may produce significantincreases in circulating phenytoin concentrations and enhance the risk of drugtoxicity. Phenytoin is also a potent inducer of hepatic drug-metabolizing enzymes.Drugs that should not be used concurrently with phenytoin: delavirdine.Drugs that may increase phenytoin serum levels include fluvoxamine, fluorouracil,omeprazole, sertraline, and warfarin.Drugs that may decrease plasma phenytoin concentrations includenelfinavir, ritonavir.Drugs whose efficacy is impaired by phenytoin include azoles (ketoconazole,itraconazole, voriconazole), sertraline, teniposide, irinotecan,paclitaxel, and warfarin.Phenytoin decreases plasma concentrations of certain HIV antivirals(amprenavir, efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir,saquinavir) and anti-epileptic agents (felbamate, topiramate, oxcarbazepine,quetiapine). Addition or withdrawal of phenytoin during concomitant therapywith these agents may require adjustment of the dose of these agents.http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm283237.htm

Quinolone antibiotics(Various)

Class labeling added to the Warnings and Precautions section of variousquinolone antibiotics regarding the risk of convulsions and increased intracranialpressure (including pseudotumor cerebri). Updated information and changes in thelanguage related to the risk of tendinitis and tendon rupture added to theBoxed Warning and Warnings and Precaution sections.http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm279844.htmhttp://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm279846.htmhttp://www.fda.gov/Safety/MedWatch/SafetyInformation/Safety-RelatedDrugLabelingChanges/ucm161806.htmhttp://www.fda.gov/Safety/MedWatch/SafetyInformation/Safety-RelatedDrugLabelingChanges/ucm121615.htmhttp://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm275724.htm

SaxagliptinOnglyza(Bristol-Myers Squibb)

Saxagliptin/metforminKombiglyze XR(Bristol-MyersSquibb, AstraZeneca)

CONTRAINDICATIONS: History of a serious hypersensitivity reaction toKombiglyze XR or saxagliptin (ie, anaphylaxis, angioedema, or exfoliativeskin conditions).WARNINGS AND PRECAUTIONS:Pancreatitis: Postmarketing reports of acute pancreatitis. If pancreatitis is suspected,promptly discontinue and initiate appropriate management.Hypersensitivity Reactions: Reports of serious hypersensitivity reactions inpatients treated with saxagliptin.Use caution in a patient with a history of angioedema to another dipeptidylpeptidase-4 (DPP4) inhibitor, because it is unknown whether such patientswill be predisposed to angioedema with this drug.ADVERSE REACTIONS: Hypersensitivity Reactions: Hypersensitivity-relatedevents, such as urticaria and facial edema, were reported in 1.5%, 1.5%, and0.4% of patients who received saxagliptin 2.5 mg, saxagliptin 5 mg,and placebo, respectively.http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm283038.htm

(continued)





Warning

SimvastatinZocor(Merck)

Drug should be discontinued if markedly elevated CPK levels occur or myopathyis diagnosed or suspected.Amiodarone added to the list of potential drugs associated with increased riskof myopathy/rhabdomyolysisRare postmarketing reports of fatal and nonfatal hepatic failure, cognitiveimpairment (eg, memory loss, forgetfulness, amnesia, memory impairment,confusion), and increases in HbA1C and fasting serum glucose.http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm208610.htm

SorafenibNexavar(Bayer)

Increased mortality observed with sorafenib administered in combination withcarboplatin/paclitaxel and gemcitabine/cisplatin in squamous cell lung canceradded to the Warnings and Precautions section. The risk of QT/QTc intervalprolongation and subsequent arrhythmias added to the Warnings and Precautionssection. Rifampicin and neomycin may lower the plasma concentrations of sorafenib.http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm280363.htm

TeniposideVumon(Bristol-Myers Squibb)

Metabolic acidosis and hypersensitivity reactions added to the Warningssection. New adverse reactions include neurotoxicity, sepsis, headache,confusion, asthenia, and effects on male fertility.http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm279934.htm

TopotecanHycamtin(GlaxoSmithKline)

Severe bone marrow depression added as a contraindication. Informationregarding the risk of interstitial lung disease added to the Warnings andPrecautions section.http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm279915.htm

aPractitioners are encouraged to check the FDA’s MEDWATCH Web site (http://www.fda.gov/medwatch/safety.htm) for updated information.



Documents

Current FDA-Related Drug Information - Approvals, Submission, and Important Labeling Changes for US Marketed Pharmaceuticals