SILICEA arged prostate gland • glaucoma (Nighttime only) Ask a doctor or pharmacist before use if you are • taking sedatives or tranquilizers (Nighttime only) • taking the blood thinning drug warfarin When using these products • do not use more than directed In addition, when using Nighttime: • excitability may occur, especially in children • may cause marked drowsiness • avoid alcoholic drinks • be careful when driving a motor vehicle or operating machinery • alcohol, sedatives, and tranquilizers may increase drowsiness Stop use and ask a doctor if • you get nervous, dizzy or sleepless (Daytime only) • redness or swelling is present • fever gets worse or lasts more than 3 days • new symptoms occur • pain, nasal congestion or cough gets worse or lasts more than 7 days • cough comes back or occurs with rash or headache that lasts. These could be signs of a serious condition. If pregnant or breast-feeding, ask a health professional before use. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away. (1-800-222-1222) Quick medical attention is critical for adults as well as for children even if you do not notice any signs or symptoms. get medical help or contact a Poison Control Center right away. (1-800-222-1222) Quick medical attention is critical for adults as well as for children even if you do not notice any signs or symptoms. Directions • take only as directed - see Liver warning • take Nighttime OR Daytime Nighttime Softgels • do not exceed 8 softgels per 24 hrs adults & children 12 yrs & over 2 softgels with water every 6 hrs children 4 to under 12 yrs ask a doctor children under 4 yrs do not use Daytime Softgels • do not exceed 8 softgels per 24 hrs adults & children 12 yrs & over 2 softgels with water every 4 hrs children 4 to under 12 yrs ask a doctor children under 4 yrs do not use • when using other Daytime or Nighttime products, carefully read each label to insure correct dosing Ask a doctor before use if you have • liver disease • heart disease (Daytime only) • thyroid disease (Daytime only) • diabetes (Daytime only) • high blood pressure (Daytime only) • cough that occurs with too much phlegm (mucus) • a breathing problem such as emphysema or chronic bronchitis (Nighttime only) • persistent or chronic cough as occurs with smoking, asthma, or emphysema • trouble urinating due to an enlarged prosta • a breathing problem such as emphysema or chronic bronchitis (Nighttime only) • persistent or chronic cough as occurs with smoking, asthma, or emphysema • trouble urinating due to an enlarged prostate gland • glaucoma (Nighttime only) Stop use and ask a doctor if • you get nervous, dizzy or sleepless (Daytime only) • redness or swelling is present • fever gets worse or lasts more than 3 days • new symptoms occur • pain, nasal congestion or cough gets worse or lasts more than 7 days • cough comes back or occurs with rash or headache that lasts. These could be signs of a serious condition. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away. (1-800-222-1222) Quick medical attention is critical for adults as well as for children even if you do not notice any signs or symptoms. Use helps prevent recurrence of scalp flaking and itching associated with dandruff Purpose Anti-dandruff Warnings For external use only. When using this product avoid contact with eyes. If contact occurs rinse eyes thoroughly with water. Stop use and ask a doctor if condition worsens or does not improve after regular use of this product as directed. Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center right away. Directions wet hair, massage shampoo into scalp. rinse off and repeat if desired. for best results, use at least twice a week or as directed by a doctor. Stop use and ask a doctor if condition worsens or does not improve after regular use of this product as directed. Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center right away. INDICATIONS AND USAGE Tretinoin Capsules are indicated for the induction of remission in patients with acute promyelocytic leukemia (APL), French-American-British (FAB) classification M3 (including the M3 variant), characterized by the presence of the t(15;17) translocation and/or the presence of the PML/RARα gene who are refractory to, or who have relapsed from, anthracycline chemotherapy, or for whom anthracycline based chemotherapy is contraindicated. Tretinoin is for the induction of remission only. The optimal consolidation or maintenance regimens have not been defined, but all patients should receive an accepted form of remission consolidation and/or maintenance therapy for APL after completion of induction therapy with tretinoin. WARNINGS Pregnancy Category D See boxed WARNINGS Tretinoin has teratogenic and embryotoxic effects in mice, rats, hamsters, rabbits and pigtail monkeys, and may be expected to cause fetal harm when administered to a pregnant woman. Tretinoin causes fetal resorptions and a decrease in live fetuses in all animals studied. Gross external, soft tissue and skeletal alterations occurred at doses higher than 0.7 mg/kg/day in mice, 2 mg/kg/day in rats, 7 mg l resorptions and a decrease in live fetuses in all animals studied. Gross external, soft tissue and skeletal alterations occurred at doses higher than 0.7 mg/kg/day in mice, 2 mg/kg/day in rats, 7 mg/kg/day in hamsters, and at a dose of 10 mg/kg/day, the only dose tested, in pigtail monkeys (about 1/20, 1/4, and 1/2 and 4 times the human dose, respectively, on a mg/m 2 basis). There are no adequate and well-controlled studies in pregnant women. Although experience with humans administered tretinoin is extremely limited, increased spontaneous abortions and major human fetal abnormalities related to the use of other retinoids have been documented in humans. Reported defects include abnormalities of the CNS, musculoskeletal system, external ear, eye, thymus and great vessels; and facial dysmorphia, cleft palate, and parathyroid hormone deficiency. Some of these abnormalities were fatal. Cases of IQ scores less than 85, with or without obvious CNS abnormalities, have also been reported. All fetuses exposed during pregnancy can be affected and at the present time there is no antepartum means of determining which fetuses are and are not affected. Effective contraception must be used by ll fetuses exposed during pregnancy can be affected and at the present time there is no antepartum means of determining which fetuses are and are not affected. Effective contraception must be used by all females during tretinoin therapy and for 1 month following discontinuation of therapy. Contraception must be used even when there is a history of infertility or menopause, unless a hysterectomy has been performed. Whenever contraception is required, it is recommended that two reliable forms of contraception be used simultaneously, unless abstinence is the chosen method. If pregnancy does occur during treatment, the physician and patient should discuss the desirability of continuing or terminating the pregnancy. Patients Without the t(15;17) Translocation Initiation of therapy with tretinoin may be based on the morphological diagnosis of acute promyelocytic leukemia. Confirmation of the diagnosis of APL should be sought by detection of the t(15;17) genetic marker by cytogenetic studies. If these are negative, PML/RARα fusion should be sought using molecular diagnostic techniques. The response rate of other AML subtypes to tretinoin has not been demonstrated; therefore, patients who If these are negative, PML/RARα fusion should be sought using molecular diagnostic techniques. The response rate of other AML subtypes to tretinoin has not been demonstrated; therefore, patients who lack the genetic marker should be considered for alternative treatment. Retinoic Acid-APL (RA-APL) Syndrome In up to 25% of patients with APL treated with tretinoin, a syndrome occurs which can be fatal (see boxed WARNINGS and ADVERSE REACTIONS ). Leukocytosis at Presentation and Rapidly Evolving Leukocytosis During Tretinoin Treatment See boxed WARNINGS . Pseudotumor Cerebri Retinoids, including tretinoin, have been associated with pseudotumor cerebri (benign intracranial hypertension), especially in pediatric patients. The concomitant use of other agents known to cause pseudotumor cerebri/intracranial hypertension, such as tetracyclines, might increase the risk of this condition (see PRECAUTIONS, Drug Interactions ). 2 Early signs and symptoms of pseudotumor cerebri include papilledema, headache, nausea and vomiting, and visual disturbances. Patients with these symptoms should be evaluated for pseudotumor cerebri, and, if present, appropriate care should be instituted in concert with headache, nausea and vomiting, and visual disturbances. Patients with these symptoms should be evaluated for pseudotumor cerebri, and, if present, appropriate care should be instituted in concert with neurological assessment. Lipids Up to 60% of patients experienced hypercholesterolemia and/or hypertriglyceridemia, which were reversible upon completion of treatment. The clinical consequences of temporary elevation of triglycerides and cholesterol are unknown, but venous thrombosis and myocardial infarction have been reported in patients who ordinarily are at low risk for such complications. Elevated Liver Function Test Results Elevated liver function test results occur in 50% to 60% of patients during treatment. Liver function test results should be carefully monitored during treatment and consideration be given to a temporary withdrawal of tretinoin if test results reach > 5 times the upper limit of normal values. However, the majority of these abnormalities resolve without interruption of tretinoin or after completion of treatment. DOSAGE AND ADMINISTRATION The recommended dose is 45 mg/m 2 /day administered as two evenly divided doses until complete remission is documented. Ther on of tretinoin or after completion of treatment. DOSAGE AND ADMINISTRATION The recommended dose is 45 mg/m 2 /day administered as two evenly divided doses until complete remission is documented. Therapy should be discontinued 30 days after achievement of complete remission or after 90 days of treatment, whichever occurs first. If after initiation of treatment of tretinoin the presence of the t(15;17) translocation is not confirmed by cytogenetics and/or by polymerase chain reaction studies and the patient has not responded to tretinoin, alternative therapy appropriate for acute myelogenous leukemia should be considered. Tretinoin is for the induction of remission only. Optimal consolidation or maintenance regimens have not been determined. All patients should, therefore, receive a standard consolidation and/or maintenance chemotherapy regimen for APL after induction therapy with tretinoin, unless otherwise contraindicated. ADVERSE REACTIONS Virtually all patients experience some drug related toxicity, especially headache, fever, weakness, and fatigue. These adverse effects are seldom permanent or irreversible nor do they usually require interruption of therapy. Some of the adverse related toxicity, especially headache, fever, weakness, and fatigue. These adverse effects are seldom permanent or irreversible nor do they usually require interruption of therapy. Some of the adverse events are common in patients with APL, including hemorrhage, infections, gastrointestinal hemorrhage, disseminated intravascular coagulation, pneumonia, septicemia, and cerebral hemorrhage. The following describes the adverse events, regardless of drug relationship, that were observed in patients treated with tretinoin. Typical Retinoid Toxicity The most frequently reported adverse events were similar to those described in patients taking high doses of vitamin A and included headache (86%), fever (83%), skin/mucous membrane dryness (77%), bone pain (77%), nausea/vomiting (57%), rash (54%), mucositis (26%), pruritus (20%), increased sweating (20%), visual disturbances (17%), ocular disorders (17%), alopecia (14%), skin changes (14%), changed visual acuity (6%), bone inflammation (3%), visual field defects (3%). RA-APL Syndrome APL patients treated with tretinoin have experienced a potentially fatal syndrome characterized by fever, dyspnea, acute respiratory distress, weight gain, radi ual field defects (3%). RA-APL Syndrome APL patients treated with tretinoin have experienced a potentially fatal syndrome characterized by fever, dyspnea, acute respiratory distress, weight gain, radiographic pulmonary infiltrates, pleural and pericardial effusions, edema, and hepatic, renal, and multi-organ failure. This syndrome has occasionally been accompanied by impaired myocardial contractility and episodic hypotension and has been observed with or without concomitant leukocytosis. Some patients have expired due to progressive hypoxemia and multi-organ failure. The syndrome generally occurs during the first month of treatment, with some cases reported following the first dose of tretinoin. The management of the syndrome has not been defined rigorously, but high dose steroids given at the first signs of the syndrome appear to reduce morbidity and mortality. Treatment with dexamethasone, 10 mg intravenously administered every 12 hours for 3 days or until resolution of symptoms, should be initiated without delay at the first suspicion of symptoms (one or more of the following: fever, dyspnea, weight gain, abnormal chest auscultatory findings or radiographic abnormalities). Sixty uld be initiated without delay at the first suspicion of symptoms (one or more of the following: fever, dyspnea, weight gain, abnormal chest auscultatory findings or radiographic abnormalities). Sixty percent or more of patients treated with tretinoin may require high dose steroids because of these symptoms. The majority of patients do not require termination of tretinoin therapy during treatment of the syndrome. Body as a Whole General disorders related to tretinoin administration and/or associated with APL included malaise (66%), shivering (63%), hemorrhage (60%), infections (58%), peripheral edema (52%), pain (37%), chest discomfort (32%), edema (29%), disseminated intravascular coagulation (26%), weight increase (23%), injection site reactions (17%), anorexia (17%), weight decrease (17%), myalgia (14%), flank pain (9%), cellulitis (8%), face edema (6%), fluid imbalance (6%), pallor (6%), lymph disorders (6%), acidosis (3%), hypothermia (3%), ascites (3%). Respiratory System Disorders Respiratory system disorders were commonly reported in APL patients administered tretinoin. The majority of these events are symptoms of the RA-APL syndrome (see boxed WARNINGS ). Respiratory syste rs Respiratory system disorders were commonly reported in APL patients administered tretinoin. The majority of these events are symptoms of the RA-APL syndrome (see boxed WARNINGS ). Respiratory system adverse events included upper respiratory tract disorders (63%), dyspnea (60%), respiratory insufficiency (26%), pleural effusion (20%), pneumonia (14%), rales (14%), expiratory wheezing (14%), lower respiratory tract disorders (9%), pulmonary infiltration (6%), bronchial asthma (3%), pulmonary edema (3%), larynx edema (3%), unspecified pulmonary disease (3%). Ear Disorders Ear disorders were consistently reported, with earache or feeling of fullness in the ears reported by 23% of the patients. Hearing loss and other unspecified auricular disorders were observed in 6% of patients, with infrequent (< 1%) reports of irreversible hearing loss. Gastrointestinal Disorders GI disorders included GI hemorrhage (34%), abdominal pain (31%), other gastrointestinal disorders (26%), diarrhea (23%), constipation (17%), dyspepsia (14%), abdominal distention (11%), hepatosplenomegaly (9%), hepatitis (3%), ulcer (3%), unspecified liver disorder (3%). Cardiovascular and Heart Rate and Rhythm Disorders onstipation (17%), dyspepsia (14%), abdominal distention (11%), hepatosplenomegaly (9%), hepatitis (3%), ulcer (3%), unspecified liver disorder (3%). Cardiovascular and Heart Rate and Rhythm Disorders Arrhythmias (23%), flushing (23%), hypotension (14%), hypertension (11%), phlebitis (11%), cardiac failure (6%) and for 3% of patients: cardiac arrest, myocardial infarction, enlarged heart, heart murmur, ischemia, stroke, myocarditis, pericarditis, pulmonary hypertension, secondary cardiomyopathy. Central and Peripheral Nervous System Disorders and Psychiatric Dizziness (20%), paresthesias (17%), anxiety (17%), insomnia (14%), depression (14%), confusion (11%), cerebral hemorrhage (9%), intracranial hypertension (9%), agitation (9%), hallucination (6%) and for 3% of patients: abnormal gait, agnosia, aphasia, asterixis, cerebellar edema, cerebellar disorders, convulsions, coma, CNS depression, dysarthria, encephalopathy, facial paralysis, hemiplegia, hyporeflexia, hypotaxia, no light reflex, neurologic reaction, spinal cord disorder, tremor, leg weakness, unconsciousness, dementia, forgetfulness, somnolence, slow speech. Urinary System Disorders Renal insufficiency (11%), dysuria (9%) ex, neurologic reaction, spinal cord disorder, tremor, leg weakness, unconsciousness, dementia, forgetfulness, somnolence, slow speech. Urinary System Disorders Renal insufficiency (11%), dysuria (9%), acute renal failure (3%), micturition frequency (3%), renal tubular necrosis (3%), enlarged prostate (3%). Miscellaneous Adverse Events Isolated cases of erythema nodosum, basophilia and hyperhistaminemia, Sweet's syndrome, organomegaly, hypercalcemia, pancreatitis and myositis have been reported. Additional Adverse Reactions Reported With Tretinoin Cardiovascular Cases of thrombosis (both venous and arterial) involving various sites (e.g., cerebrovascular accident, myocardial infarction, renal infarct) have been reported rarely (see PRECAUTIONS, General ). Hematologic Rare cases of thrombocytosis have been reported. 6 Skin Genital ulceration. 7 Miscellaneous Adverse Events Rare cases of vasculitis, predominantly involving the skin, have been reported. 8 Uses Uses: Helps protect against cavities PURPOSE Purpose: Anticavity WARNINGS Warnings: Keep out of the reach of children under 6 years of age. If more than used for brushing is accidentally swallowed, get medical help or contact a Poison Control Center right away. Directions Directions: Adults and children 2 years of age and older: Brush teeth thoroughly, preferably after each meal or at least twice a day, or as directed by a dentist or physician Children 2 to 6 years: Use only a pea sized amount and supervise child's brushing and rinsing (to minimize swallowing) Children under 2 years: Ask a dentist or physician KEEP OUT OF REACH OF CHILDREN Keep out of the reach of children under 6 years of age. 1 INDICATIONS AND USAGE Simvastatin tablets USP are indicated: To reduce the risk of total mortality by reducing risk of coronary heart disease death, non-fatal myocardial infarction and stroke, and the need for coronary and non-coronary revascularization procedures in adults with established coronary heart disease, cerebrovascular disease, peripheral vascular disease, and/or diabetes, who are at high risk of coronary heart disease events. As an adjunct to diet to reduce low-density lipoprotein cholesterol (LDL-C): In adults with primary hyperlipidemia. In adults and pediatric patients aged 10 years and older with heterozygous familial hypercholesterolemia (HeFH). As an adjunct to other LDL-C-lowering therapies to reduce LDL-C in adults with homozygous familial hypercholesterolemia (HoFH). As an adjunct to diet for the treatment of adults with: Primary dysbetalipoproteinemia. Hypertriglyceridemia. Simvastatin tablets USP are an HMG-CoA reductase inhibitor indicated: To reduce the risk of total mortality by reducing risk of coronary heart disease death, non-fatal myocardial infarction and stroke, and the need for coronary and non-coronary revascularization procedures in adults with of total mortality by reducing risk of coronary heart disease death, non-fatal myocardial infarction and stroke, and the need for coronary and non-coronary revascularization procedures in adults with established coronary heart disease, cerebrovascular disease, peripheral vascular disease, and/or diabetes, who are at high risk of coronary heart disease events. As an adjunct to diet to reduce low-density lipoprotein cholesterol (LDL-C): In adults with primary hyperlipidemia. In adults and pediatric patients aged 10 years and older with heterozygous familial hypercholesterolemia (HeFH). As an adjunct to other LDL-C-lowering therapies to reduce LDL-C in adults with homozygous familial hypercholesterolemia (HoFH). As an adjunct to diet for the treatment of adults with: Primary dysbetalipoproteinemia. Hypertriglyceridemia. 2 DOSAGE AND ADMINISTRATION Important Dosage and Administration Information : ( 1 ) Take simvastatin tablets USP orally once daily in the evening. Maximum recommended dosage is simvastatin tablets USP 40 mg once daily. An 80 mg daily dosage of simvastatin tablets USP is restricted to patients who have been taking simvastatin tablets USP 80 mg daily chronically (e.g., f ge is simvastatin tablets USP 40 mg once daily. An 80 mg daily dosage of simvastatin tablets USP is restricted to patients who have been taking simvastatin tablets USP 80 mg daily chronically (e.g., for 12 months or more) without evidence of muscle toxicity. For patients that require a high-intensity statin or are unable to achieve their LDL-C goal receiving simvastatin tablets USP 40 mg daily, prescribe alternative LDL-C lowering treatment. Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating, and adjust the dosage if necessary. Adults : Recommended dosage is 20 mg to 40 mg once daily. ( 2.2 ) Pediatric Patients Aged 10 Years and Older with HeFH : Recommended dosage is 10 mg to 40 mg once daily. ( 2.3 ) Patients with Severe Renal Impairment : Recommended starting dosage is simvastatin 5 mg once daily. ( 2.4 , 8.6 ) See full prescribing information for simvastatin tablets USP dosage modifications due to drug interactions. ( 2.5 ) 2.1 Important Dosage and Administration Information Take simvastatin tablets USP orally once daily in the evening. The maximum recommended dosage is simvastatin tablets USP 40 mg once daily [see DOSAGE AND ADMINISTRATION ( 2.2 , 2 istration Information Take simvastatin tablets USP orally once daily in the evening. The maximum recommended dosage is simvastatin tablets USP 40 mg once daily [see DOSAGE AND ADMINISTRATION ( 2.2 , 2.3 )]. An 80 mg daily dosage of simvastatin tablets USP is restricted to patients who have been taking simvastatin tablets USP 80 mg daily chronically (e.g., for 12 months or more) without evidence of muscle toxicity [see WARNINGS AND PRECAUTIONS ( 5.1 )]. If as dose is missed, take the missed dose as soon as possible. Do not double the next dose. For patients that require a high-intensity statin or are unable to achieve their LDL-C goal receiving simvastatin tablets USP 40 mg daily, prescribe alternative LDL-C-lowering treatment. Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating simvastatin tablets USP, and adjust the dosage if necessary. 2.2 Recommended Dosage in Adult Patients The recommended dosage range of simvastatin tablets USP is 20 mg to 40 mg once daily 2.3 Recommended Dosage in Pediatric Patients 10 Years of Age and Older with HeFH The recommended dosage range of simvastatin tablets USP is 10 mg to 40 mg daily. 2.4 Recommended Dosage in Patients ly 2.3 Recommended Dosage in Pediatric Patients 10 Years of Age and Older with HeFH The recommended dosage range of simvastatin tablets USP is 10 mg to 40 mg daily. 2.4 Recommended Dosage in Patients with Renal Impairment For patients with severe renal impairment [creatinine clearance (CLcr) 15 – 29 mL/min], the recommended starting dosage of simvastatin is 5 mg once daily [see WARNINGS AND PRECAUTIONS ( 5.1 ) AND USE IN SPECIFIC POPULATIONS ( 8.6 )]. Use another simvastatin product to initiate dosing in such patients [see DOSAGE AND ADMINISTRATION ( 2.1 )]. There are no dosage adjustment recommendations for patients with mild or moderate renal impairment. 2.5 Dosage Modifications Due to Drug Interactions Concomitant use of simvastatin tablets USP with the following drugs requires dosage modification of simvastatin tablets USP [see WARNINGS AND PRECAUTIONS ( 5.1 ) AND DRUG INTERACTIONS ( 7.1 )]. Patients taking Lomitapide Reduce the dosage of simvastatin tablets USP by 50%. Do not exceed simvastatin tablets USP 20 mg once daily (or 40 mg once daily for patients who have previously taken an 80 mg daily dosage of simvastatin tablets USP chronically while taking lomitapide) [see DOSAG ed simvastatin tablets USP 20 mg once daily (or 40 mg once daily for patients who have previously taken an 80 mg daily dosage of simvastatin tablets USP chronically while taking lomitapide) [see DOSAGE AND ADMINISTRATION (2.1)]. Patients taking Verapamil, Diltiazem, or Dronedarone Do not exceed simvastatin tablets USP 10 mg once daily. Patients taking Amiodarone, Amlodipine, or Ranolazine Do not exceed simvastatin tablets USP 20 mg once daily. 6 ADVERSE REACTIONS The following important adverse reactions are described below and elsewhere in the labeling: Myopathy and Rhabdomyolysis [see WARNINGS AND PRECAUTIONS ( 5.1 )] Immune-Mediated Necrotizing Myopathy [see WARNINGS AND PRECAUTIONS ( 5.2 )] Hepatic Dysfunction [see WARNINGS AND PRECAUTIONS ( 5.3 )] Increases in HbA1c and Fasting Serum Glucose Levels [see WARNINGS AND PRECAUTIONS ( 5.4 )] Most common adverse reactions (incidence ≥5%) are: upper respiratory infection, headache, abdominal pain, constipation, and nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical studies are co ort SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. In clinical studies, 2,423 adult patients were exposed to simvastatin with a median duration of follow-up of approximately 18 months. The most commonly reported adverse reactions (incidence ≥5%) in these simvastatin clinical studies were: upper respiratory infections (9%), headache (7%), abdominal pain (7%), constipation (7%), and nausea (5%). Overall, 1.4% of patients discontinued simvastatin due to adverse reactions. The most common adverse reactions that led to discontinuation were: gastrointestinal disorders (0.5%), myalgia (0.1%), and arthralgia (0.1%). In a Cardiovascular Outcomes Study (the Scandinavian Simvastatin Survival Study [Study 4S]), adult patients (age range 35-71 years, 19% women, 100% Caucasians) were treated with 20-40 mg per day of s In a Cardiovascular Outcomes Study (the Scandinavian Simvastatin Survival Study [Study 4S]), adult patients (age range 35-71 years, 19% women, 100% Caucasians) were treated with 20-40 mg per day of simvastatin or placebo over a median of 5.4 years [see CLINICAL STUDIES ( 14 )] ; adverse reactions reported in ≥2% of patients and at a rate greater than placebo are shown in Table 1. Table 1 : Adverse Reactions Reported ≥2% of Patients Treated with Simvastatin and Greater than Placebo in Study 4S % Placebo (N = 2,223) % Simvastatin (N = 2,221) Bronchitis 6.3 6.6 Abdominal pain 5.8 5.9 Atrial fibrillation 5.1 5.7 Gastritis 3.9 4.9 Eczema 3.0 4.5 Vertigo 4.2 4.5 Diabetes mellitus 3.6 4.2 Insomnia 3.8 4.0 Myalgia 3.2 3.7 Urinary tract infection 3.1 3.2 Edema/swelling 2.3 2.7 Headache 2.1 2.5 Sinusitis 1.8 2.3 Constipation 1.6 2.2 Myopathy/Rhabdomyolysis In clinical studies with a median follow-up of at least 4 years, in which 24,747 patients received simvastatin, the incidence of myopathy (defined as unexplained muscle weakness, pain, or tenderness accompanied by CK increases greater than 10xULN) was approximately 0.03%, 0.08%, and 0.61% for the simvastatin 20 mg, 40 mg, and 80 mg daily efined as unexplained muscle weakness, pain, or tenderness accompanied by CK increases greater than 10xULN) was approximately 0.03%, 0.08%, and 0.61% for the simvastatin 20 mg, 40 mg, and 80 mg daily groups, respectively. In a clinical outcomes study in which 12,064 adult patients with a history of myocardial infarction were treated with simvastatin (mean follow-up 6.7 years), the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum CK >10x [1200 U/L] ULN) in patients taking simvastatin 20 mg and 80 mg daily was approximately 0.02% and 0.9%, respectively. The incidence of rhabdomyolysis (defined as myopathy with a CK >40xULN) in patients on simvastatin 20 mg and 80 mg daily was approximately 0% and 0.4%, respectively. The incidence of myopathy and rhabdomyolysis were highest during the first year and then decreased during the subsequent years of treatment. In another clinical outcomes study in which 10,269 adult patients were treated with simvastatin 40 mg per day (mean follow-up of 5 years), the incidence of myopathy/rhabdomyolysis was <0.1% in patients treated with simvastatin. Elevations in Liver Enzyme Tests Moderate (less than 3xULN) elevations of per day (mean follow-up of 5 years), the incidence of myopathy/rhabdomyolysis was <0.1% in patients treated with simvastatin. Elevations in Liver Enzyme Tests Moderate (less than 3xULN) elevations of serum transaminases have been reported with use of simvastatin. Persistent increases to more than 3xULN in serum transaminases have occurred in approximately 1% of patients receiving simvastatin in clinical studies. Marked persistent increases of hepatic transaminases have occurred with simvastatin. Elevated alkaline phosphatase and γ-glutamyl transpeptidase have also been reported. In Study 4S, with a median follow-up of 5.4 years, 1,986 adult patients were treated with simvastatin 20 mg once daily, of whom 37% titrated to 40 mg once daily. The percentage of patients with one or more occurrences of transaminase elevations to >3xULN was 0.7% in patients taking simvastatin compared with 0.6% in patients taking placebo. Elevated transaminases leading to discontinuation of study treatment occurred in 0.4% of patients taking simvastatin and 0.2% of patients taking placebo. The majority of elevated transaminases leading to treatment discontinuation occurred within in the first year. Advers curred in 0.4% of patients taking simvastatin and 0.2% of patients taking placebo. The majority of elevated transaminases leading to treatment discontinuation occurred within in the first year. Adverse Reactions in Pediatric Patients with Heterozygous Familial Hypercholesterolemia In a 48-week clinical study in pediatric patients 10 years of age and older (43% female, 97.7% Caucasians, 1.7% Hispanics, 0.6% Multiracial) with HeFH (n=175), treated with placebo or simvastatin (10 - 40 mg daily), the most common adverse reactions were upper respiratory infection, headache, abdominal pain, and nausea [see USE IN SPECIFIC POPULATIONS (8.4) AND CLINICAL STUDIES ( 14 )] . 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of simvastatin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as whole fever, chills, malaise, asthenia Blood and Lymphatic System Disorders anemia, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia Gastrointestinal Diso dy as whole fever, chills, malaise, asthenia Blood and Lymphatic System Disorders anemia, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia Gastrointestinal Disorders pancreatitis, vomiting Hepatic and Pancreatic Disorders hepatitis/jaundice, fatal and non-fatal hepatic failure Immune System Disorders hypersensitivity syndrome including: anaphylaxis, angioedema, lupus erythematous-like syndrome, dermatomyositis, vasculitis Musculoskeletal and Connective Tissue Disorders muscle cramps, immune-mediated necrotizing myopathy, polymyalgia rheumatica, arthritis Nervous System Disorders dizziness, depression, paresthesia, peripheral neuropathy. Rare reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. Cognitive impairment was generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks). There have been rare reports of new-onset or exacerbation of myasthenia gravis, including ocular myasthenia, and reports of recurrence when the same or a different statin was administered of 3 weeks). There have been rare reports of new-onset or exacerbation of myasthenia gravis, including ocular myasthenia, and reports of recurrence when the same or a different statin was administered. Skin and Subcutaneous Tissue Disorders pruritus, alopecia, a variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails), purpura, lichen planus, urticaria, photosensitivity, flushing, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome Respiratory and Thoracic interstitial lung disease, dyspnea Reproductive System Disorders erectile dysfunction