Approvals,Submission,and Important LabelingChanges for US Marketed Pharmaceuticals

FDA published two Federal Register notices to formally withdraw the applications for all prescription combination drug products that contain more than 325 mg of acetaminophen per tablet, capsule, or other dosage unit.

http://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm390509.htm

Recommended for approval to improve glycemic control in adults with type 1 diabetes (13 to 1) and type 2 diabetes (14 to 0).

Prescription Drug User Fee Act (PDUFA) date changed to July 15, 2014.

WARNINGS

…added paragraphs:

Anagrelide increases the QTc interval of the electrocardiogram and increases the heart rate in healthy volunteers. Anagrelide should not be used in patients with known risk factors for QT interval prolongation, such as congenital long QT syndrome, a known history of acquired QTc prolongation, medicinal products that can prolong QTc interval, and hypokalemia.

In patients with heart failure, bradyarrhythmias, or electrolyte abnormalities, consider periodic monitoring with electrocardiograms.

In patients with cardiac disease, use Agrylin only when the benefits outweigh the risks.

PRECAUTIONS

Hypotension: In 9 subjects receiving a single 5 mg dose of anagrelide, standing blood pressure fell an average of 22/15 mm Hg, usually accompanied by dizziness. Only minimal changes in blood pressure were observed following a dose of 2 mg.

http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm175918.htm

WARNINGS AND PRECAUTIONS

Hypersensitivity Reactions

Grade 3 and 4 hypersensitivity reactions after the use of Erwinaze have occurred in 5% of patients in clinical trials.

Anaphylaxis after the use of Erwinaze has occurred in 0.8% of patients in clinical trials.

Glucose Intolerance

Glucose intolerance has been reported with Erwinaze therapy in 4% of patients in clinical trials.

http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm392222.htm

WARNINGS

Serious Infections - Progressive Multifocal Leukoencephalopathy.

Cases of JC virus-associated infection resulting in progressive multifocal leukoencephalopathy (PML), sometimes fatal, have been reported in patients treated with immunosuppressants, including Imuran. Risk factors for PML include treatment with immunosuppressant therapies and impairment of immune function. Consider the diagnosis of PML in any patient presenting with new-onset neurological manifestations and consider consultation with a neurologist as clinically indicated. Consider reducing the amount of immunosuppression in patients who develop PML. In transplant patients, consider the risk that the reduced immunosuppression represents to the graft.

http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm258794.htm

WARNINGS AND PRECAUTIONS

Pancytopenia (Use with Ribavirin and Peginterferon Alfa)

Serious cases of pancytopenia have been reported postmarketing in patients receiving Victrelis in combination with peginterferon alfa and ribavirin. Complete blood counts (with white blood cell differential counts) should be obtained at pretreatment, and at treatment weeks 2, 4, 8, and 12, and should be monitored closely at other time points, as clinically appropriate. Refer to the Package Inserts for ribavirin and peginterferon alfa for guidelines for discontinuation of therapy based on laboratory parameters.

ADVERSE REACTIONS

Postmarketing Experience

Blood and Lymphatic System Disorders: agranulocytosis, pancytopenia, thrombocytopenia

Infections and Infestations: pneumonia, sepsis

PATIENT COUNSELING INFORMATION

Pancytopenia

Patients should be informed that serious cases of pancytopenia have been reported during postmarketing when Victrelis was administered with peginterferon alfa and ribavirin. Patients should be advised that laboratory evaluations are required prior to starting therapy and periodically thereafter

http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm303600.htm

WARNINGS AND PRECAUTIONS

Gastrointestinal Disorders

Gastrointestinal (GI) hemorrhage and perforation, ileus, enterocolitis, neutropenic enterocolitis, including fatal outcome, have been reported in patients treated with Jevtana. Risk may be increased with neutropenia, age, steroid use, concomitant use of NSAIDs, anti-platelet therapy, or anti-coagulants, and patients with a prior history of pelvic radiotherapy, adhesions, ulceration, and GI bleeding. Abdominal pain and tenderness, fever, persistent constipation, diarrhea, with or without neutropenia, may be early manifestations of serious GI toxicity and should be evaluated and treated promptly. Jevtana treatment delay or discontinuation may be necessary.

http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm392358.htm

Information from a meta-analysis of 21 randomized, controlled studies was added to the Warnings and Precaution and Adverse Reactions sections regarding the increased risk of malignancies with calcitonin-salmon therapy.

http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm190771.htm

WARNINGS

The addition of Lodosyn with carbidopa-levodopa reduces the peripheral effects (nausea, vomiting) due to decarboxylation of levodopa; however, Lodosyn does not decrease the adverse reactions due to the central effects of levodopa. Because Lodosyn permits more levodopa to reach the brain and more dopamine to be formed, certain adverse central nervous system (CNS) effects, eg, dyskinesias (involuntary movements), may occur at lower dosages and sooner with levodopa in combination with Lodosyn than with levodopa alone.

Falling Asleep During Activities of Daily Living and Somnolence

Neuroleptic Malignant Syndrome (NMS) section revised into Hyperpyrexia and Confusion

PRECAUTIONS

Sections added:

Impulse Control/Compulsive Behaviors; Hallucinations/Psychotic Like Behavior; Dyskinesia; Depression; Melanoma Information for Patients

DRUG INTERACTIONS

Lodosyn and iron salts or multivitamins containing iron salts should be coadministered with caution. Iron salts can form chelates with levodopa and carbidopa and consequently reduce the bioavailability of carbidopa and levodopa.

http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm388773.htm

BOXED WARNING

WARNING: RISK FOR HEPATIC DECOMPENSATION IN PATIENTS WITH CHRONIC HEPATITIS C

In patients with chronic hepatitis C, Promacta in combination with interferon and ribavirin may increase the risk of hepatic decompensation.

WARNINGS AND PRECAUTIONS

Hepatic Decompensation in Patients With Chronic Hepatitis C

Revised to include the risk of hepatic decompensation.

Hepatotoxicity

Promacta can cause liver enzyme elevations. Measure serum ALT, AST, and bilirubin prior to initiation of Promacta, every 2 weeks during the dose adjustment phase, and monthly following establishment of a stable dose. Promacta inhibits UGT1A1 and OATP1B1, which may lead to indirect hyperbilirubinemia.

Bone Marrow Reticulin Formulation …section removed.

Laboratory Monitoring…section removed.

ADVERSE REACTIONS

Hepatic Decompensation in Patients With Chronic Hepatitis C

PATIENT COUNSELING INFORMATION

Confusion

Swelling of the stomach area (abdomen)

http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm207394.htm

CONTRAINDICATIONS

Known anaphylactic reaction or angioedema

Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders

WARNINGS AND PRECAUTIONS

Hereditary Angioedema

Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema.

ADVERSE REACTIONS

Postmarketing Experiences

Skin: Nipple and areola discoloration, usually on the same side of the body as the inner forearm on which Evamist is applied, rash, pruritus, alopecia, urticaria, dry skin, skin discoloration, chloasma

http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm279996.htm

WARNINGS AND PRECAUTIONS

Impaired Wound Healing

Everolimus delays wound healing and increases the occurrence of wound-related complications like wound dehiscence, wound infection, incisional hernia, lymphocele, and seroma. These wound-related complications may require surgical intervention. Exercise caution with the use of Afinitor in the peri-surgical period.

Embryo-fetal Toxicity

Based on the mechanism of action, Afinitor can cause fetal harm. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures. 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. Advise female patients of reproductive potential to avoid becoming pregnant and to use highly effective contraception while using Afinitor and for up to 8 weeks after ending treatment.

ADVERSE REACTIONS

Clinical Study Experience in Advanced Pancreatic Neuroendocrine Tumors: irregular menstruation…percentage increased … occurred in 5 of 46 (11%)

http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm258494.htm

CONTRAINDICATIONS

Added…cobicistat-containing products

WARNINGS AND PRECAUTIONS

Myopathy/Rhabdomyolysis

Drug Interactions… paragraph added

DRUG INTERACTIONS

Added… cobicistat-containing products to the existing list of strong CYP3A4 inhibitors

http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm208609.htm

CONTRAINDICATIONS

Coadministration of other drugs known to prolong the QT interval and which are metabolized via the enzyme CYP3A4 such as erythromycin are contraindicated in patients receiving fluconazole.

WARNINGS

Patients with deep seated fungal infections who develop rashes during treatment with Diflucan should be monitored closely and the drug discontinued if lesions progress. Fluconazole should be discontinued in patients treated for superficial fungal infection who develop a rash that may be attributed to fluconazole.

PRECAUTIONS

Drug Interactions

Cyclosporine: Diflucan significantly increases cyclosporine levels in renal transplant patients with or without renal impairment. Careful monitoring of cyclosporine concentrations and serum creatinine is recommended in patients receiving Diflucan and cyclosporine. This combination may be used by reducing the dosage of cyclosporine depending on cyclosporine concentration.

Quinidine: Although not studied in vitro or in vivo, concomitant administration of fluconazole with quinidine may result in inhibition of quinidine metabolism. Use of quinidine has been associated with QT prolongation and rare occurrences of torsades de pointes. Coadministration of fluconazole and quinidine is contraindicated.

http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm262570.htm

WARNINGS AND PRECAUTIONS

Serious Infections - Tuberculosis

Cases of active tuberculosis have occurred in patients treated with the subcutaneous formulation of golimumab during and after treatment for latent tuberculosis. Monitor patients for the development of signs and symptoms of tuberculosis including patients who tested negative for latent tuberculosis infection prior to initiating therapy, patients who are on treatment for latent tuberculosis, or patients who were previously treated for tuberculosis infection.

Vaccinations/Therapeutic Infectious Agents

Live Vaccines

Patients treated with Simponi Aria may receive vaccinations, except for live vaccines. In patients receiving anti-TNF therapy, limited data are available on the response to live vaccination, or on the secondary transmission of infection by live vaccines. Use of live vaccines could result in clinical infections, including disseminated infections.

Therapeutic Infectious Agents

Other uses of therapeutic infectious agents such as live attenuated bacteria (eg, BCG bladder instillation for the treatment of cancer) could result in clinical infections, including disseminated infections. It is recommended that therapeutic infectious agents not be given concurrently with Simponi Aria.

http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm388774.htm

BOXED WARNING

Addition of contraindicated medications…methadone, disopyramide, dronedarone, ranolazine.

WARNINGS

QT Prolongation and Drug Interaction Leading to QT Prolongation

Addition of contraindicated medications…methadone, disopyramide, dronedarone, ranolazine.

PRECAUTIONS

Drug Interactions …entire section revised

http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm364157.htm

CONTRAINDICATIONS

Added…cobicistat-containing products

WARNINGS

Strong inhibitors of CYP3A4:

Added…cobicistat-containing products

PRECAUTIONS

CYP3A4 Interactions

Added…cobicistat-containing products

http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm389714.htm

WARNINGS AND PRECAUTIONS

Cardiovascular Events

Caution should be used when administering Selzentry in patients with a history of or risk factors for postural hypotension, cardiovascular comorbidities, or on concomitant medication known to lower blood pressure. Patients with cardiovascular comorbidities could be at increased risk of cardiovascular adverse events triggered by postural hypotension.

http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm215506.htm

CONTRAINDICATIONS

Pregnancy: May cause fetal harm when administered to a pregnant woman; is contraindicated in women who are pregnant. If this drug is used during pregnancy, or if the woman becomes pregnant while taking this drug, the woman should be apprised of the potential hazard to a fetus.

WARNINGS AND PRECAUTIONS: Sections updated

Ovarian Hyperstimulation Syndrome (OHSS)

Pulmonary and Vascular Complications

Ovarian Torsion

Multi-fetal Gestation and Birth

Congenital Malformations

Ectopic Pregnancy

Spontaneous Abortion

Ovarian Neoplasms

http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm389227.htm

WARNINGS AND PRECAUTIONS

Renal Effects

Patients at greatest risk of this reaction are those with impaired renal function, hypovolemia, heart failure, liver dysfunction, salt depletion; those taking diuretics, ACE inhibitors, or angiotensin II receptor antagonists; and the elderly.

Laboratory Tests

Health care providers should temporarily stop esomeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (eg, for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.

http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm262248.htm

WARNINGS AND PRECAUTIONS

Hypersensitivity reactions, including anaphylaxis, have been reported with or without known hypersensitivity to other 5-HT3 receptor antagonists.

http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm388768.htm

WARNINGS AND PRECAUTIONS

Concomitant use with P-glycoprotein Inhibitors

Concomitant administration of drugs that are P-glycoprotein inhibitors with rifaximin can substantially increase the systemic exposure to rifaximin. Caution should be exercised when concomitant use of rifaximin and a P-glycoprotein inhibitor such as cyclosporine is needed. In patients with hepatic impairment, a potential additive effect of reduced metabolism and concomitant P-glycoprotein inhibitors may further increase the systemic exposure to rifaximin.

DRUG INTERACTIONS

Concomitant P-glycoprotein inhibitors

An in vitro study suggested that rifaximin is a substrate of P-glycoprotein. Co-administration of cyclosporine, a potent P-glycoprotein inhibitor, with rifaximin resulted in 83-fold and 124-fold increases in rifaximin mean Cmax and AUC in healthy subjects. The clinical significance of this increase in systemic exposure is unknown.

http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm392729.htm

BOXED WARNING

Optimal timing between the administration of Xarelto and neuraxial procedures is not known.

WARNINGS AND PRECAUTIONS

Spinal/Epidural Anesthesia or Puncture

To reduce the potential risk of bleeding associated with the concurrent use of rivaroxaban and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of rivaroxaban. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of rivaroxaban is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known.

Should the physician decide to administer anticoagulation in the context of epidural or spinal anesthesia/analgesia or lumbar puncture, monitor frequently to detect any signs or symptoms of neurological impairment, such as midline back pain, sensory and motor deficits (numbness, tingling, or weakness in lower limbs), bowel and/or bladder dysfunction. Instruct patients to immediately report if they experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though such treatment may not prevent or reverse neurological sequelae.

http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm367392.htm

WARNINGS

Reports of QT prolongation, associated with torsade de pointes (in exceptional cases, fatal), have been received. Caution should be exercised when administering sevoflurane to susceptible patients (eg, patients with congenital long QT syndrome or patients taking drugs that can prolong the QT interval).

http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm319035.htm

WARNINGS AND PRECAUTIONS

Effects on the Eye

Based on published literature, the annual incidence of non-arteritic anterior ischemic optic neuropathy (NAION) is 2.5-11.8 cases per 100,000 in males aged ≥ 50. An observational study evaluated whether recent use of PDE5 inhibitors, as a class, was associated with acute onset of NAION. The results suggest an approximate 2-fold increase in the risk of NAION within 5 half-lives of PDE5 inhibitor use.

http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm319416.htm

http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm200593.htm

CONTRAINDICATIONS

Added…cobicistat-containing products

WARNINGS AND PRECAUTIONS

Myopathy/Rhabdomyolysis - Drug Interactions… paragraph added

DRUG INTERACTIONS

Added… cobicistat-containing products to the existing list of strong CYP3A4 inhibitors

http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm208610.htm

CONTRAINDICATIONS

Added…cobicistat-containing products

WARNINGS AND PRECAUTIONS

Myopathy/Rhabdomyolysis

Drug Interactions… paragraph added

DRUG INTERACTIONS

Added… cobicistat-containing products to the existing list of strong CYP3A4 inhibitors

http://www.fda.gov/Safety/MedWatch/SafetyInformation/Safety-RelatedDrugLabelingChanges/ucm323856.htm

CONTRAINDICATIONS

Breastfeeding

ADVERSE REACTIONS

The following adverse reactions have been reported with doses of sodium iodide I-131 used in the treatment of benign disease, such as hyperthyroidism:

Sialadenitis, iododerma, hypothyroidism, hyperthyroidism, thyrotoxic crisis, hypoparathyroidism, and local [sic]

The following adverse reactions have been reported with doses of sodium iodide I-131 used in the treatment of malignant disease:

Solid cancers, nausea, vomiting, and congenital hypothyroidism

http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm296271.htm

WARNINGS

Serious infections, including fatal sepsis and pneumonia, have been reported. Some infections were associated with agranulocytosis, neutropenia, or myelosuppression. Discontinue Azulfidine if a patient develops a serious infection. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with Azulfidine. For a patient who develops a new infection during treatment with Azulfidine, perform a prompt and complete diagnostic workup for infection and myelosuppression. Caution should be exercised when considering the use of sulfasalazine in patients with a history of recurring or chronic infections or with underlying conditions or concomitant drugs which may predispose patients to infections.

Severe hypersensitivity reactions may include internal organ involvement, such as hepatitis, nephritis, myocarditis, mononucleosis-like syndrome (ie, pseudomononucleosis), hematological abnormalities (including hematophagic histiocytosis), and/or pneumonitis including eosinophilic infiltration.

PRECAUTIONS

Drug/Laboratory Test Interactions

Several reports of possible interference with measurements, by liquid chromatography, of urinary normetanephrine causing a false-positive test result have been observed in patients exposed to sulfasalazine or its metabolite, mesalamine/mesalazine.

ADVERSE REACTIONS

Postmarketing Reports

Blood dyscrasias: pseudomononucleosis; Cardiac disorders: myocarditis; Metabolism and nutrition system disorders: folate deficiency; Renal and urinary disorders: nephrolithiasis; Respiratory, thoracic, and mediastinal disorders: oropharyngeal pain

http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm335424.htm

WARNINGS AND PRECAUTIONS

Use with CYP3A4 Inhibitors and Inducers

QT Prolongation …added section

Gastrointestinal Perforation …added section

ADVERSE REACTIONS

Added bullet point…Gastrointestinal Perforation

DRUG INTERACTIONS

Dose adjustments may be needed along with frequent monitoring of tacrolimus whole blood trough concentrations when Astagraf XL is administered with CYP3A inhibitors or inducers. In addition, patients should be monitored for adverse reactions including changes in renal function and QT prolongation.

http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm388770.htm

WARNINGS AND PRECAUTIONS

Non-Melanoma Skin Cancer

Non-melanoma skin cancers (NMSCs) have been reported in patients treated with Xeljanz. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.

http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm392730.htm

CONTRAINDICATIONS

Hypersensitivity…section added

ADVERSE REACTIONS

Postmarketing Experience

Immune System Disorders: Hypersensitivity reactions including anaphylactic shock and rash generalized.

http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm294226.htm

WARNINGS AND PRECAUTIONS

Cardiomyopathy

Results from two studies were added to this section.

http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm392225.htm

CONTRAINDICATIONS

Pregnancy…may cause fetal harm when administered to a pregnant woman; is contraindicated in women who are pregnant. If this drug is used during pregnancy, or if the woman becomes pregnant while taking this drug, the woman should be apprised of the potential hazard to a fetus.

WARNINGS AND PRECAUTIONS: Sections updated

Ovarian Hyperstimulation Syndrome (OHSS)

Pulmonary and Vascular Complications

Ovarian Torsion

Multi-fetal Gestation and Birth

Congenital Malformations

Ectopic Pregnancy

Spontaneous Abortion

Ovarian Neoplasms

http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm389226.htm

BOXED WARNING

Life-Threatening Adverse Reactions: Hepatotoxicity

Hepatic failure resulting in fatalities has occurred in patients receiving valproic acid and its derivatives. These incidents usually have occurred during the first 6 months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Serum liver tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first 6 months.

Populations at increased risk include: children under the age of 2 years are at a considerably increased risk of developing fatal hepatotoxicity, especially those on multiple anticonvulsants, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease; incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups; and patients with mitochondrial disease (patients with hereditary neurometabolic syndromes caused by DNA mutations of the mitochondrial DNA Polymerase γ [POLG] gene [eg, Alpers Huttenlocher Syndrome]).

WARNINGS AND PRECAUTIONS

Hepatotoxicity: General Information on Hepatotoxicity; Patients with Known or Suspected Mitochondrial Disease

http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm360495.htm

WARNINGS AND PRECAUTIONS

Hypersensitivity Reactions - addition of DRESS Syndrome

ADVERSE REACTIONS

addition of Hypersensitivity Reactions

Postmarketing Experience

addition of… progression of a pre-existing chronic myelomonocytic leukemia with NRAS mutation.

http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm364374.htm