MedWatch - July 2008 Safety-Related Drug Labeling Changes

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Detailed View: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER) -- July 2008

The detailed view includes drug products with safety labeling changes to the BOXED WARNING, CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, ADVERSE REACTIONS, or PATIENT PACKAGE INSERT/MEDICATION GUIDE sections. Deletions or editorial revisions made to these sections are not included in this summary. Read about the new physician labeling format.

Summary View

Brand (Generic) Name	Sections Modified	Summary of Changes to Contraindications and Warnings
Baraclude (entecavir) Tablets and Oral Solution Prescribing Information (in new labeling format)	BOXED WARNING WARNINGS: SEVERE ACUTE EXACERBATIONS OF HEPATITIS B, PATIENTS CO-INFECTED WITH HIV AND HBV, and LACTIC ACIDOSIS AND HEPATOMEGALY WARNINGS AND PRECAUTIONS Severe Acute Exacerbations of Hepatitis B (new header) Patients Co-infected with HIV and HBV (new header) Lactic Acidosis and Severe Hepatomegaly with Steatosis (new subsection) ADVERSE REACTIONS Clinical Trial Experience The most common adverse reactions of any severity (>3%) with at least a possible relation to study drug for Baraclude-treated subjects were headache, fatigue, dizziness, and nausea... Postmarketing Experience Immune system disorders Anaphylactoid reaction USE IN SPECIFIC POPULATIONS Pregnancy Nursing Mothers PATIENT COUNSELING INFORMATION Information about Treatment Patients using the oral solution should be instructed to hold the dosing spoon in a vertical position and fill it gradually to the mark corresponding to the prescribed dose. Rinsing of the dosing spoon with water is recommended after each daily dose.	BOXED WARNING (the following headed added) WARNINGS: SEVERE ACUTE EXACERBATIONS OF HEPATITIS B, PATIENTS CO-INFECTED WITH HIV AND HBV, and LACTIC ACIDOSIS AND HEPATOMEGALY WARNINGS AND PRECAUTIONS Lactic Acidosis and Severe Hepatomegaly with Steatosis (new subsection) Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination with antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogues to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with Baraclude should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

Exforge (amlodipine and valsartan) Tablets Prescribing Information (in new labeling format) Patient Package Insert	BOXED WARNING WARNING: AVOID USE IN PREGNANCY WARNINGS AND PRECAUTIONS Fetal/Neonatal Morbidity and Mortality Hypotension Impaired Renal Function - Hypertension DRUG INTERACTIONS Drug/Food Interactions Studies with Exforge The bioavailabilities of amlodipine and valsartan are not altered by the co-administration of food. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D Nursing Mothers ...Valsartan was excreted into the milk of lactating rats; however, animal breast milk drug levels may not accurately reflect human breast milk levels... Geriatric Use Initial Paragraph Amlodipine Valsartan PATIENT PACKAGE INSERT What is the most important information I should know about Exforge? What is Exforge? What should I tell my doctor before taking Exforge? How should I take Exforge? What are the possible side effects of Exforge? Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. What is high blood pressure (hypertension)?	BOXED WARNING WARNING: AVOID USE IN PREGNANCY When pregnancy is detected, discontinue Exforge as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus. [See Warnings and Precautions (5.1)] WARNINGS AND PRECAUTIONS Fetal/Neonatal Morbidity and Mortality Exforge can cause fetal harm when administered 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 the fetus. Drugs that act on the renin angiotensin system can cause fetal and neonatal morbidity and mortality when used in pregnancy. In several dozen published cases, ACE inhibitor use during the second and third trimesters of pregnancy was associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death [see Use in Specific Populations (8.1)]. Hypotension ...Volume depletion should be corrected prior to administration of Exforge. Treatment with Exforge should start under close medical supervision... Impaired Renal Function - Hypertension ...As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may occur particularly in volume depleted patients...

Strattera (atomoxetine hydrochloride) Capsules Prescribing Information (in new labeling format) Medication Guide	BOXED WARNING WARNING: SUICIDAL IDEATION IN CHILDREN AND ADOLESCENTS WARNINGS AND PRECAUTIONS Suicidal Ideation Effects on Blood Pressure and Heart Rate ADVERSE REACTIONS Clinical Trials Experience Initial Paragraph Child and Adolescent Clinical Trials Reasons for discontinuation of treatment due to adverse reactions in child and adolescent clinical trials abdominal pain (0.2%, N=4) Adult Clinical Trials Male and female sexual dysfunction USE IN SPECIFIC POPULATIONS Patients with Concomitant Illness Anxiety in patients with ADHD and comorbid Anxiety Disorders (new subsection) MEDICATION GUIDE Other information for children, teenagers, and adults... ...Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.	BOXED WARNING WARNING: SUICIDAL IDEATION IN CHILDREN AND ADOLESCENTS ...Co-morbidities occurring with ADHD may be associated with an increase in the risk of suicidal ideation and/or behavior... WARNINGS AND PRECAUTIONS Suicidal Ideation All pediatric patients being treated with Strattera should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. Effects on Blood Pressure and Heart Rate Strattera-treated adult subjects experienced mean increases in systolic (about 2.0 mm Hg) and diastolic (about 1.0 mm Hg) blood pressures compared with placebo. At the final study visit before drug discontinuation, 2.2% (11/510) of Strattera-treated adult subjects had systolic blood pressure measurements >150 mm Hg compared with 1.0% (4/393) of placebo subjects. At the final study visit before drug discontinuation, 0.4% (2/510) of Strattera-treated adult subjects had diastolic blood pressure measurements >100 mm Hg compared with 0.5% (2/393) of placebo subjects. No adult subject had a high systolic or diastolic blood pressure detected on more than one occasion.

Tykerb (lapatinib) Tablets Prescribing Information (in new labeling format) Patient Package Insert	BOXED WARNING WARNING: HEPATOTOXICITY WARNINGS AND PRECAUTIONS Hepatotoxicity Patients with Severe Hepatic Impairment ADVERSE REACTIONS Clinical Trials Experience Hepatotoxicity USE IN SPECIFIC POPULATIONS Hepatic Impairment PATIENT PACKAGE INSERT Before you start taking Tykerb, tell your doctor about all of your medical conditions, including if you... have liver problems. You may need a lower dose of Tykerb. What are the possible side effects of Tykerb? Serious side effects include... liver problems, which may cause itching, yellow eyes or skin, dark urine, or pain or discomfort in the right upper area of the belly. Your doctor should do blood tests to check your liver before you start taking Tykerb and during treatment.	BOXED WARNING WARNING: HEPATOTOXICITY Hepatotoxicity has been observed in clinical trials and postmarketing experience. The hepatotoxicity may be severe and deaths have been reported. Causality of the deaths is uncertain. [See Warnings and Precautions (5.2).] WARNINGS AND PRECAUTIONS Hepatotoxicity Hepatotoxicity (ALT or AST >3 times the upper limit of normal and total bilirubin >1.5 times the upper limit of normal) has been observed in clinical trials (<1% of patients) and postmarketing experience. The hepatotoxicity may be severe and deaths have been reported. Causality of the deaths is uncertain. The hepatotoxicity may occur days to several months after initiation of treatment. Liver function tests (transaminases, bilirubin, and alkaline phosphatase) should be monitored before initiation of treatment, every 4 to 6 weeks during treatment, and as clinically indicated. If changes in liver function are severe, therapy with Tykerb should be discontinued and patients should not be retreated with Tykerb [see Adverse Reactions (6.1)]. Patients with Severe Hepatic Impairment ...In patients who develop severe hepatotoxicity while on therapy, Tykerb should be discontinued and patients should not be retreated with Tykerb [see Warnings and Precautions (5.2)]

Ziagen (abacavir sulfate) Tablets and Oral Solution Prescribing Information (in new labeling format) Medication Guide See MedWatch Safety Alert posted 07/24/2008 for additional safety-related information on Ziagen or Abacavir-containing medications.	BOXED WARNING WARNING: RISK OF HYPERSENSITIVITY REACTIONS, LACTIC ACIDOSIS, AND SEVERE HEPATOMEGALY CONTRAINDICATIONS WARNINGS AND PRECAUTIONS Hypersensitivity Reaction Clinical Management of Hypersensitivity Risk Factor: HLA-B5701 Allele Myocardial Infarction ADVERSE REACTIONS* Postmarketing Experience Cardiovascular Myocardial infarction PATIENT COUNSELING INFORMATION Information About Therapy With Ziagen Hypersensitivity Reaction - Inform patients: that if they develop symptoms consistent with a hypersensitivity reaction they should call their doctor right away to determine if they should stop taking Ziagen... The following three section headers were added: Lactic Acidosis/Hepatomegaly Redistribution/Accumulation of Body Fat Information About HIV Infection MEDICATION GUIDE What is the most important information I should know about Ziagen? Serious Allergic Reaction to Abacavir: ...Your risk of this allergic reaction is much higher if you have a gene variation called HLA-B5701 than if you do not... Before starting Ziagen, tell your doctor about all of your medical conditions, including if you: have been tested and know whether or not you have a particular gene variation called HLA-B5701. have heart problems, smoke, or suffer from diseases that increase your risk of heart disease such as high blood pressure, high cholesterol, or diabetes. What are the possible side effects of Ziagen? Some HIV medicines including Ziagen may increase your risk of heart attack... ...Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.	BOXED WARNING WARNING: RISK OF HYPERSENSITIVITY REACTIONS, LACTIC ACIDOSIS, AND SEVERE HEPATOMEGALY Patients who carry the HLA-B5701 allele are at high risk for experiencing a hypersensitivity reaction to abacavir. Prior to initiating therapy with abacavir, screening for the HLA-B5701 allele is recommended; this approach has been found to decrease the risk of hypersensitivity reaction. Screening is also recommended prior to reinitiation of abacavir in patients of unknown HLA-B5701 status who have previously tolerated abacavir. HLA-B5701-negative patients may develop a suspected hypersensitivity reaction to abacavir; however, this occurs significantly less frequently than in HLA-B5701-positive patients. Regardless of HLA-B5701 status, permanently discontinue Ziagen if hypersensitivity cannot be ruled out, even when other diagnoses are possible. CONTRAINDICATIONS ...NEVER restart Ziagen or any other abacavir-containing product following a hypersensitivity reaction to abacavir, regardless of HLA-B5701 status [see Warnings and Precautions (5.1), Adverse Reactions (6)]... WARNINGS AND PRECAUTIONS* Hypersensitivity Reaction ...Patients who carry the HLA-B5701 allele are at high risk for experiencing a hypersensitivity reaction to abacavir. Prior to initiating therapy with abacavir, screening for the HLA-B5701 allele is recommended; this approach has been found to decrease the risk of a hypersensitivity reaction. Screening is also recommended prior to reinitiation of abacavir in patients of unknown HLA-B5701 status who have previously tolerated abacavir. For HLA-B5701-positive patients, treatment with an abacavir-containing regimen is not recommended and should be considered only with close medical supervision and under exceptional circumstances when the potential benefit outweighs the risk. HLA-B5701-negative patients may develop a hypersensitivity reaction to abacavir; however, this occurs significantly less frequently than in HLA-B5701-positive patients. Regardless of HLA-B5701 status, permanently discontinue Ziagen if hypersensitivity cannot be ruled out, even when other diagnoses are possible... Clinical Management of Hypersensitivity* ...If the patient is of unknown HLA-B5701 status, screening for the allele is recommended prior to reinitiation of Ziagen... ...Even in the absence of the HLA-B5701 allele, it is important to permanently discontinue abacavir and not rechallenge with abacavir if a hypersensitivity reaction cannot be ruled out on clinical grounds, due to the potential for a severe or even fatal reaction... *Risk Factor: HLA-B5701 Allele** (new section) Studies have shown that carriage of the HLA-B5701 allele is associated with a significantly increased risk of a hypersensitivity reaction to abacavir... ...Screening for carriage of the HLA-B5701 allele is recommended prior to initiating treatment with abacavir. Screening is also recommended prior to reinitiation of abacavir in patients of unknown HLA-B5701 status who have previously tolerated abacavir... Myocardial Infarction* (new section) In a published prospective, observational, epidemiological study designed to investigate the rate of myocardial infarction in patients on combination antiretroviral therapy, the use of abacavir within the previous 6 months was correlated with an increased risk of myocardial infarction (MI)...

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Brand (Generic) Name	Sections Modified	Summary of Changes to Contraindications and Warnings
Advair HFA (fluticasone propionate and salmeterol) Inhalation Aerosol for Oral Inhalation Only Prescribing Information Medication Guide	WARNINGS The following additional WARNINGS about Advair HFA should be noted: Pneumonia MEDICATION GUIDE Who should not use Advair HFA? Do not use Advair HFA: • to treat sudden severe symptoms of asthma • if you are allergic to any of the ingredients in Advair HFA... What are the possible side effects with Advair HFA? Pneumonia... (added) Common side effects of Advair HFA include upper respiratory tract infection and headache. How should I store Advair HFA? Keep Advair HFA and all medicines out of the reach of children. What are the ingredients in Advair HFA?	WARNINGS: Pneumonia Lower respiratory tract infections, including pneumonia, have been reported in patients with COPD following the inhaled administration of corticosteroids, including fluticasone propionate and Advair Diskus. In 2 replicate 12-month studies of 1,579 patients with COPD, there was a higher incidence of pneumonia reported in patients receiving Advair Diskus 250/50 (7%) than in those receiving salmeterol 50 mcg (3%). The incidence of pneumonia in the patients treated with Advair Diskus was higher in patients over 65 years of age (9%) compared with the incidence in patients less than 65 years of age (4%). In a 3-year study of 6,184 patients with COPD, there was a higher incidence of pneumonia reported in patients receiving Advair Diskus 500/50 compared with placebo (16% with Advair Diskus 500/50, 14% with fluticasone propionate 500 mcg, 11% with salmeterol 50 mcg, and 9% with placebo). Similar to what was seen in the 1-year studies with Advair Diskus 250/50, the incidence of pneumonia was higher in patients over 65 years of age (18% with Advair Diskus 500/50 versus 10% with placebo) compared with patients less than 65 years of age (14% with Advair Diskus 500/50 versus 8% with placebo.

Avandia (rosiglitazone maleate) Tablets Prescribing Information (in new labeling format)	WARNINGS AND PRECAUTIONS Cardiac Failure Myocardial Ischemia Myocardial Ischemic Events in Large Long-Term Prospective Randomized Controlled Trials of Avandia Congestive Heart Failure and Myocardial Ischemia During Coadministration of Avandia With Insulin Weight Gain ADVERSE REACTIONS Clinical Trial Experience Adult In clinical trials, approximately 9,900 patients with type 2 diabetes have been treated with Avandia... Short-Term Trials of Avandia as Monotherapy and in Combination With Other Hypoglycemic Agents (see Table 4) Long-Term Trial of Avandia as Monotherapy: A 4- to 6-year study (ADOPT) compared the use of Avandia (n = 1,456), glyburide (n = 1,441), and metformin (n = 1,454) as monotherapy in patients recently diagnosed with type 2 diabetes who were not previously treated with antidiabetic medication... (new) In ADOPT, fractures were reported in a greater number of women treated with Avandia... (new) Table 5 (new) Laboratory Abnormalities Serum Transaminase Levels Postmarketing Experience ...There are postmarketing reports with Avandia of hepatitis, hepatic enzyme elevations to 3 or more times the upper limit of normal, and hepatic failure with and without fatal outcome...	WARNINGS AND PRECAUTIONS Cardiac Failure ...Although no treatment difference in change from baseline of ejection fractions was observed, more cardiovascular adverse events were observed following treatment with Avandia compared to placebo during the 52-week study. (See Table 1.) Myocardial Ischemia: Myocardial Ischemic Events in Large Long-Term Prospective Randomized Controlled Trials of Avandia ...For these 3 trials, analyses were performed using a composite of major adverse cardiovascular events (myocardial infarction, cardiovascular death, or stroke), referred to hereafter as MACE... Congestive Heart Failure and Myocardial Ischemia During Coadministration of Avandia With Insulin ...The total number of patients with emergent congestive heart failure was 21 (2.4%) and 7 (1.1%) in the Avandia plus insulin and insulin groups, respectively... Weight Gain (see text after Table 3) In a 4- to 6-year, monotherapy, comparative trial (ADOPT) in patients recently diagnosed with type 2 diabetes not previously treated with antidiabetic medication [see Clinical Studies (14.1)], the median weight change (25th, 75th percentiles) from baseline at 4 years was 3.5 kg (0.0, 8.1) for Avandia, 2.0 kg (-1.0, 4.8) for glyburide, and -2.4 kg (-5.4, 0.5) for metformin.

Diovan HCT (valsartan and hydrochlorothiazide USP) Tablets Prescribing Information (in new labeling format) Patient Package Insert	WARNINGS AND PRECAUTIONS Fetal/Neonatal Morbidity and Mortality ADVERSE REACTIONS Clinical Trials Experience Initial Therapy - Hypertension USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D Nursing Mothers PATIENT COUNSELING INFORMATION Information for Patients Pregnancy PATIENT PACKAGE INSERT What is Diovan HCT? Diovan HCT may be used to lower high blood pressure (hypertension) in adults... ...as the first medicine to lower high blood pressure if your doctor decides you are likely to need more than one medicine. What is high blood pressure (hypertension)? ...High blood pressure makes the heart work harder to pump blood throughout the body...	WARNINGS AND PRECAUTIONS Fetal/Neonatal Morbidity and Mortality Diovan HCT can cause fetal harm when administered 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 the fetus. Drugs that act on the renin-angiotensin system can cause fetal and neonatal morbidity and mortality when used in pregnancy. In several dozen published cases, ACE inhibitor use during the second and third trimesters of pregnancy was associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death [See Use in Specific Populations (8.1)]...

FazaClo (clozapine, USP) Orally Disintegrating Tablets For current prescribing information, contact Azur Pharma, Inc. at 1-877-329-2256.	WARNINGS Tardive Dyskinesia ADVERSE REACTIONS Extrapyramidal Symptoms Dystonia Class Effect Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. Clozapine, an atypical antipsychotic, is associated with a low incidence of dystonia [See Warnings, Tardive Dyskinesia].	WARNINGS Tardive Dyskinesia There are several reasons for predicting that FazaClo may be different from other antipsychotic drugs in its potential for inducing tardive dyskinesia, including the preclinical finding that it has a relatively weak dopamine-blocking effect and the clinical finding of a low incidence of certain acute extrapyramidal symptoms, e.g., dystonia.

Januvia (sitagliptin) Tablets Prescribing Information (in new labeling format)	WARNINGS AND PRECAUTIONS Macrovascular Outcomes	WARNINGS AND PRECAUTIONS Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Januvia or any other anti-diabetic drug.

Lopressor (metoprolol tartrate) Tablets Lopressor (metoprolol tartrate) Injection, Solution Prescribing Information	WARNINGS Hypertension and Angina Bronchospastic Diseases Major Surgery Myocardial Infarction Bronchospastic Diseases ADVERSE REACTIONS Postmarketing Experience (section added)	WARNINGS Hypertension and Angina Bronchospastic Diseases PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD, IN GENERAL, NOT RECEIVE BETA BLOCKERS, including Lopressor... Major Surgery The necessity or desirability of withdrawing beta-blocking therapy, including Lopressor, prior to major surgery is controversial; the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures... Myocardial Infarction/Bronchospastic Diseases PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD, IN GENERAL, NOT RECEIVE BETA BLOCKERS, including Lopressor...

Lopressor HCT (metoprolol tartrate USP and hydrochlorothiazide USP) Tablets Prescribing Information	WARNINGS Lopressor Bronchospastic Diseases Major Surgery Diabetes and Hypoglycemia ADVERSE REACTIONS Postmarketing Experience (section added)	WARNINGS: Lopressor Bronchospastic Diseases PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD, IN GENERAL, NOT RECEIVE BETA BLOCKERS, including Lopressor HCT... Major Surgery The necessity or desirability of withdrawing beta-blocking therapy, including Lopressor HCT, prior to major surgery is controversial; the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures... Diabetes and Hypoglycemia ...Beta blockers, including Lopressor HCT, may mask tachycardia occurring with hypoglycemia, but other manifestations such as dizziness and sweating may not be significantly affected...

Lovenox (enoxaparin sodium injection) for Subcutaneous and Intravenous Use Prescribing Information (in new labeling format)	WARNINGS AND PRECAUTIONS Use of Lovenox with Concomitant Medical Conditions ADVERSE REACTIONS Postmarketing Experience ...Skin necrosis (occurring at either the injection site or distant from the injection site)... ...Cases of hyperkalemia have been reported. Most of these reports occurred in patients who also had conditions that tend toward the development of hyperkalemia (e.g., renal dysfunction, concomitant potassium-sparing drugs, administration of potassium, hematoma in body tissues)... USE IN SPECIFIC POPULATIONS Renal Impairment ...In patients with renal failure, treatment with enoxaparin has been associated with the development of hyperkalemia [see Adverse Reactions (6.2)].	WARNINGS AND PRECAUTIONS Use of Lovenox with Concomitant Medical Conditions Lovenox should be used with care in patients with a bleeding diathesis, uncontrolled arterial hypertension or a history of recent gastrointestinal ulceration, diabetic retinopathy, renal dysfunction and hemorrhage.

Mirena (levonorgestrel-releasing intrauterine system) Prescribing Information Patient Package Insert	WARNINGS Intrauterine Pregnancy Long-term effects and congenital anomalies Embedment Perforation Expulsion Ovarian Cysts Breast Cancer PRECAUTIONS Patient Counseling Information Patient Evaluation and Clinical Considerations A physical examination should include... Irregular bleeding may mask symptoms and signs of endometrial polys or cancer... ...If involution is substantially delayed, consider waiting 12 weeks postpartum... Mirena should be used with caution in patients who have: migraine, focal migraine with asymmetrical visual loss or other symptoms indicating transient cerebral ischemia exceptionally severe headache marked increase of blood pressure severe arterial disease such as stroke or myocardial infarction Insertion Precautions Observe strict asepsis during insertion... Fundal positioning of Mirena is important to prevent expulsion... If the patient develops decreased pulse, perspiration, or pallor, have her remain supine until these signs resolve. Insertion may be associated with some pain and/or bleeding... Continuation and Removal Re-examine and evaluate patients 4 to 12 weeks after insertion and once a year thereafter... If the threads are not visible, they may have retracted into the uterus or broken, or Mirena may have broken... Promptly examine users with complaints of pain, odorous discharge... Consider the possibility of ectopic pregnancy... Removal may be associated with pain and/or bleeding or neurovascular episodes. ADVERSE REACTIONS ...Very common adverse reactions (>1/10 users) include uterine/vaginal bleeding (including spotting, irregular bleeding, heavy bleeding, oligomenorrhea and amenorrhea) and ovarian cysts... PATIENT PACKAGE INSERT Who should not use Mirena? Do not use Mirena if you... have or suspect you might have cancer of the uterus or cervix have breast cancer now or in the past or suspect you have breast cancer Tell your healthcare provider if you have high blood pressure How is Mirena placed? Should I check that Mirena is in the proper position? How soon after placement of Mirena should I return to my healthcare provider? What are the possible side effects of using Mirena? The following are serious but uncommon side effects of Mirena: Embedment... Perforation... Common side effects of Mirena include: Discomfort during placement... Cyst on the ovary... ...You may report side effects to... PATIENT CHECKLIST (updated) Do you have any of these conditions (the following conditions have been added): Severe headache Stroke High blood pressure	WARNINGS Intrauterine Pregnancy If pregnancy should occur with Mirena in place, Mirena should be removed. Removal or manipulation of Mirena may result in pregnancy loss... Long-term effects and congenital anomalies ...Some observational data support a small increased risk of masculinization of the external genitalia of the female fetus following exposure to progestins at doses greater than those currently used for oral contraception. Whether these data apply to Mirena is unknown. Embedment ...Embedment may decrease contraceptive effectiveness and result in pregnancy (see WARNINGS, Ectopic Pregnancy and Intrauterine Pregnancy). An embedded Mirena should be removed. Embedment can result in difficult removal and, in some cases surgical removal may be necessary. Perforation ...If perforation occurs, pregnancy may result (see WARNINGS, Ectopic Pregnancy and Intrauterine Pregnancy). Mirena must be located and removed; surgery may be required. Delayed detection of perforation may result in migration outside the uterine cavity, adhesions... The risk of perforation may be increased in lactating women, in women with fixed retroverted uteri, and during the postpartum period. To decrease the risk of perforation postpartum, Mirena insertion should be delayed a minimum of 6 weeks after delivery or until uterine involution is complete. If involution is substantially delayed, consider waiting until 12 weeks postpartum... Expulsion Partial or complete expulsion of Mirena may occur (see PRECAUTIONS, Continuation and Removal). Symptoms of the partial or complete expulsion of any lUD may include bleeding or pain. However, the system can be expelled from the uterine cavity without the woman noticing it. Partial expulsion may decrease the effectiveness of Mirena. As menstrual flow typically decreases after the first 3 to 6 months of Mirena use, an increase of menstrual flow may be indicative of an expulsion. If expulsion has occurred, Mirena may be replaced within 7 days of a menstrual period after pregnancy has been ruled out. Ovarian Cysts ...Most of these follicles are asymptomatic, although some may be accompanied by pelvic pain or dyspareunia. In most cases the enlarged follicles disappear spontaneously during two to three months observation. Persistent enlarged follicles should be evaluated... Breast Cancer Women who currently have or have had breast cancer, or have a suspicion of breast cancer, should not use hormonal contraception because breast cancer is a hormone sensitive tumor...

Primaquine (primaquine phosphate tablets, USP) Prescribing Information	WARNINGS	WARNINGS Hemolytic reactions (moderate to severe) may occur in individuals with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency and in individuals with a family or personal history of favism. Areas of high prevalence of G-6-PD deficiency are Africa, Southern Europe, Mediterranean region, Middle East, South-East Asia, and Oceania. People from these regions have a greater tendency to develop hemolytic anemia (due to a congenital deficiency of erythrocytic glucose-6-phosphate dehydrogenase) while receiving Primaquine and related drugs.

Tekturna HCT (aliskiren and hydrochlorothiazide) Tablets Prescribing Information (in new labeling format) Patient Package Insert	WARNINGS AND PRECAUTIONS Serum Electrolyte Abnormalities Tekturna HCT Renal Artery Stenosis Cyclosporine Aliskiren DRUG INTERACTIONS Aliskiren Effects of Other Drugs on Aliskiren P-glycoprotein Effects Ketoconazole Cyclosporine PATIENT PACKAGE INSERT Tell your doctor about all the medicines you take... cyclosporine (a medicine used to suppress the immune system) potassium-containing medicines, potassium supplements, or salt substitutes containing potassium	WARNINGS AND PRECAUTIONS Serum Electrolyte Abnormalities Tekturna HCT ...Based on experience with the use of other substances that affect the renin-angiotensin system (RAS), concomitant use of Tekturna HCT with potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, or other drugs that increase potassium levels may lead to increases in serum potassium. If concomitant use is considered necessary, caution should be exercised. Renal Artery Stenosis (added) No data are available on the use of Tekturna HCT in patients with unilateral or bilateral renal artery stenosis or stenosis of the artery to a solitary kidney. Cyclosporine: Aliskiren (added) When aliskiren was given with cyclosporine, the blood concentrations of aliskiren were significantly increased. Concomitant use of aliskiren with cyclosporine is not recommended [see Drug Interactions (7)].

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Brand (Generic) Name	Sections Modified
Cancidas (caspofungin acetate) for Injection (Intravenous Use Only) Prescribing Information (in new labeling format)	USE IN SPECIFIC POPULATIONS Pregnancy ...In offspring born to pregnant rats treated with caspofungin at doses comparable to the human dose based on body surface area comparisons, there was incomplete ossification of the skull and torso and increased incidences of cervical rib. Pediatric Use ADVERSE REACTIONS Clinical Trials Experience in Pediatric Patients (3 months to 17 years of age) Table 5

Capastat Sulfate (capreomycin for injection, USP) for Intramuscular and Intravenous Infusion Only Prescribing Information	PRECAUTIONS Laboratory Tests ...Since hypokalemia, hypomagnesemia and hypocalcemia may occur during therapy, these serum electrolyte levels should be determined frequently. ADVERSE REACTIONS Nephrotoxicity ...Electrolyte disturbances including hypokalemia, hypomagnesemia and hypocalcemia, sometimes serious in nature, have been reported.

Colazal (balsalazide disodium) Capsules Prescribing Information (in new labeling format)	USE IN SPECIFIC POPULATIONS Pediatric Use ADVERSE REACTIONS Postmarketing Experience Hepatic

Coreg (carvedilol) Tablets Prescribing Information (in new labeling format)	DRUG INTERACTIONS Digitalis Glycosides Both digitalis glycosides and β-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. Digoxin concentrations are increased by about 15% when digoxin and carvedilol are administered concomitantly...

Duac Topical Gel (clindamycin, 1% - benzoyl peroxide, 5%) Prescribing Information	PRECAUTIONS Information for Patients ...Patients who develop allergic symptoms such as severe swelling or shortness of breath should discontinue use and contact their physician immediately. ADVERSE REACTIONS ...Anaphylaxis, as well as allergic reactions leading to hospitalization, has been reported in postmarketing use with Duac Topical Gel...

Flovent HFA (fluticasone propionate) Inhalation Aerosol for Oral Inhalation Only Prescribing Information Patient Package Insert	PRECAUTIONS Pediatric Use Children Less Than 4 Years of Age: Pharmacokinetics Pharmacodynamics Safety In Vitro Testing of Dose Delivery With Holding Chambers Table 1 (and text following Table 1) PATIENT PACKAGE INSERT Who should not use Flovent HFA? What should I tell my doctor before taking Flovent HFA? How should I use Flovent HFA? What are the possible side effects of Flovent HFA? What are the ingredients in Flovent HFA? Using Your Flovent HFA... Priming the Inhaler

Fortamet (metformin hydrochloride) Extended-Release Tablets Prescribing Information	PRECAUTIONS General Microvascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Fortamet or any other anti-diabetic drug.

Levoxyl (levothyroxine sodium) Tablets Prescribing Information	PRECAUTIONS Drug Interactions Table 2 Drugs that may decrease T4 absorption, which may result in hypothyroidism Orlistat Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.

Natacyn (natamycin ophthalmic suspension) 5% Prescribing Information	PRECAUTIONS General Use only if the container is undamaged. Information for Patients ...Patients should be advised not to wear contact lenses if they have signs and symptoms of fungal blepharitis, conjunctivitis, and keratitis. ADVERSE REACTIONS The following events have been identified during postmarketing use of Natacyn in clinical practice...

Prandin (repaglinide) Tablets Prescribing Information	PRECAUTIONS Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Prandin or any other anti-diabetic drug.

Starlix (nateglinide) Tablets Prescribing Information	PRECAUTIONS Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Starlix or any other anti-diabetic drug.

Symbicort (budesonide and formoterol fumarate dihydrate) Inhalation Aerosol for Oral Inhalation Only Prescribing Information Medication Guide	PRECAUTIONS Information for Patients ...Patients should be instructed about the differences between Symbicort and their other inhaled medications including the differences in intended use and physical appearance. MEDICATION GUIDE How do I use Symbicort? ...Note the differences between Symbicort and your other inhaled medications, including the differences in prescribed use and physical appearance. General Information about Symbicort ...Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088...

Synthroid (levothyroxine sodium tablets, USP) Prescribing Information	PRECAUTIONS Drug Interactions Table 2 Drugs that may decrease T4 absorption, which may result in hypothyroidism Orlistat Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.

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Brand (Generic) Name	Sections Modified
Abraxane for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) [albumin-bound] Prescribing Information	ADVERSE REACTIONS Adverse Event Experiences by Body System Hypersensitivity Reactions (HSRs) ...During postmarketing surveillance, rare occurrences of severe hypersensitivity reactions have been reported with Abraxane. The use of Abraxane in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied. Patients who experience a severe hypersensitivity reaction to Abraxane should not be rechallenged with the drug.

Imuran (azathioprine) 50 mg Tablets and 100 mg (as the sodium salt) for Intravenous Injection Prescribing Information	ADVERSE REACTIONS Others ...hepatosplenic T-cell lymphoma (added)

Simcor (simvastatin/niacin extended-release) Tablet, Film Coated, Extended Release for Oral Use Prescribing Information (in new labeling format)	ADVERSE REACTIONS Overview In a controlled clinical study, 14% of patients randomized to Simcor discontinued therapy due to an adverse event...

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Brand (Generic) Name	Sections Modified
EC-Naprosyn (naproxen delayed-release tablets) Naprosyn (naproxen tablets) Anaprox/Anaprox DS (naproxen sodium tablets) Naprosyn (naproxen suspension) Medication Guide [for Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)]	MEDICATION GUIDE ...Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or Roche at 1-800-526-6367.

Enbrel (etanercept) for Subcutaneous Injection Medication Guide	MEDICATION GUIDE (new)

Vicoprofen (hydrocodone bitartrate/ibuprofen) Tablets Medication Guide [for Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)]	MEDICATION GUIDE ...Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

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