SILICEA ion of amoxicillin in this age group, the recommended upper dose of amoxicillin is 30 mg/kg/day divided every 12 hours. There are currently no dosing recommendations for pediatric patients with impaired renal function. 2.3 Dosing for H. pylori Infection Triple therapy: The recommended adult oral dose is 1 gram amoxicillin, 500 mg clarithromycin, and 30 mg lansoprazole, all given twice daily (every 12 hours) for 14 days. Dual therapy: The recommended adult oral dose is 1 gram amoxicillin and 30 mg lansoprazole, each given three times daily (every 8 hours) for 14 days. Please refer to clarithromycin and lansoprazole full prescribing information. 2.4 Dosing in Renal Impairment Patients with impaired renal function do not generally require a reduction in dose unless the impairment is severe. Severely impaired patients with a glomerular filtration rate of < 30 mL/min. should not receive a 875-mg dose. Patients with a glomerular filtration rate of 10 to 30 mL/min should receive 500 mg or 250 mg every 12 hours, depending on the severity of the infection. Patients with a glomerular filtration rate less than 10 mL/min should receive 500 mg or 250 mg every 24 hours, depending on severity of mg every 12 hours, depending on the severity of the infection. Patients with a glomerular filtration rate less than 10 mL/min should receive 500 mg or 250 mg every 24 hours, depending on severity of the infection. Hemodialysis patients should receive 500 mg or 250 mg every 24 hours, depending on severity of the infection. They should receive an additional dose both during and at the end of dialysis. 2.5 Directions for Mixing Oral Suspension Tap bottle until all powder flows freely. Add approximately 1/3 of the total amount of water for reconstitution (see Table 2) and shake vigorously to wet powder. Add remainder of the water and again shake vigorously. Table 2. Amount of Water for Mixing Oral Suspension Strength Bottle Size Amount of Water Required for Reconstitution Oral Suspension 125 mg/5 mL 80 mL 55 mL 100 mL 68 mL 150 mL 102 mL Oral Suspension 200 mg/5 mL 50 mL 34 mL 75 mL 51 mL 100 mL 68 mL Oral Suspension 250 mg/5 mL 80 mL 55 mL 100 mL 68 mL 150 mL 102 mL Oral Suspension 400 mg/5 mL 50 mL 34 mL 75 mL 51 mL 100 mL 68 mL After reconstitution, the required amount of suspension should be placed directly on the child’s tongue for swallowing. Alternate means of administration ar g/5 mL 50 mL 34 mL 75 mL 51 mL 100 mL 68 mL After reconstitution, the required amount of suspension should be placed directly on the child’s tongue for swallowing. Alternate means of administration are to add the required amount of suspension to formula, milk, fruit juice, water, ginger ale, or cold drinks. These preparations should then be taken immediately. NOTE: SHAKE ORAL SUSPENSION WELL BEFORE USING. Keep bottle tightly closed. Any unused portion of the reconstituted suspension must be discarded after 14 days. Refrigeration is preferable, but not required. 6 ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Anaphylactic reactions [see Warnings and Precautions ( 5.1 )] CDAD [see Warnings and Precautions ( 5.2 )] The most common adverse reactions (> 1%) observed in clinical trials of amoxicillin capsules, tablets or oral suspension were diarrhea, rash, vomiting, and nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates obser c. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most common adverse reactions (> 1%) observed in clinical trials of amoxicillin capsules, tablets or oral suspension were diarrhea, rash, vomiting, and nausea. Triple therapy : The most frequently reported adverse events for patients who received triple therapy (amoxicillin/clarithromycin/ lansoprazole) were diarrhea (7%), headache (6%), and taste perversion (5%). Dual therapy : The most frequently reported adverse events for patients who received double therapy amoxicillin/lansoprazole were diarrhea (8%) and headache (7%). For more information on adverse reactions with clarithromycin or lansoprazole, refer to the Adverse Reactions section of their package inserts. 6.2 Post-Marketing or Other Experience In addition to adverse events reported from clinical trials, the following events have been identified during post-mar eactions section of their package inserts. 6.2 Post-Marketing or Other Experience In addition to adverse events reported from clinical trials, the following events have been identified during post-marketing use of penicillins. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to amoxicillin. Infections and Infestations: Mucocutaneous candidiasis. Gastrointestinal: Black hairy tongue, and hemorrhagic/pseudomembranous colitis. Onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment [see Warnings and Precautions ( 5.2 )] . Hypersensitivity Reactions: Anaphylaxis [see Warnings and Precautions ( 5.1 )] . Serum sickness–like reactions, erythematous maculopapular rashes, erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, hypersensitivity vasculitis, and urticaria have been reported. Liver: A moderate rise in AST and/or ALT has been noted, but the significance of necrolysis, acute generalized exanthematous pustulosis, hypersensitivity vasculitis, and urticaria have been reported. Liver: A moderate rise in AST and/or ALT has been noted, but the significance of this finding is unknown. Hepatic dysfunction including cholestatic jaundice, hepatic cholestasis and acute cytolytic hepatitis have been reported. Renal: Crystalluria has been reported [see Overdosage ( 10 )] . Hemic and Lymphatic Systems: Anemia, including hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia, and agranulocytosis have been reported. These reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena. Central Nervous System: Reversible hyperactivity, agitation, anxiety, insomnia, confusion, convulsions, behavioral changes, and/or dizziness have been reported. Miscellaneous: Tooth discoloration (brown, yellow, or gray staining) has been reported. Most reports occurred in pediatric patients. Discoloration was reduced or eliminated with brushing or dental cleaning in most cases. 1 INDICATIONS AND USAGE Ketorolac tromethamine ophthalmic solution is indicated for the temporary relief of ocular itching due to seasonal allergic conjunctivitis. Ketorolac tromethamine ophthalmic solution is also indicated for the treatment of postoperative inflammation in patients who have undergone cataract extraction. Ketorolac tromethamine ophthalmic solution is a nonsteroidal, anti-inflammatory indicated for: The treatment of inflammation following cataract surgery. (1) The temporary relief of ocular itching due to seasonal allergic conjunctivitis. (1) 2 DOSAGE AND ADMINISTRATION One drop of ketorolac tromethamine ophthalmic solution should be applied to the affected eye(s) four times a day for relief of ocular itching due to seasonal allergic conjunctivitis. For the treatment of postoperative inflammation in patients who have undergone cataract extraction, one drop of ketorolac tromethamine ophthalmic solution should be applied to the affected eye four times daily beginning 24 hours after cataract surgery and continuing through the first 2 weeks of the postoperative period. (2.1) 2.1 Recommended Dosing Patient Dosing The recommended dose of ketorolac tromethamine ophthalmic hours after cataract surgery and continuing through the first 2 weeks of the postoperative period. (2.1) 2.1 Recommended Dosing Patient Dosing The recommended dose of ketorolac tromethamine ophthalmic solution is one drop four times a day to the affected eye(s) for relief of ocular itching due to seasonal allergic conjunctivitis. For the treatment of postoperative inflammation in patients who have undergone cataract extraction, one drop of ketorolac tromethamine ophthalmic solution should be applied to the affected eye four times daily beginning 24 hours after cataract surgery and continuing through the first 2 weeks of the postoperative period. 2.2 Use with Other Topical Ophthalmic Medications Ketorolac tromethamine ophthalmic solution has been safely administered in conjunction with other ophthalmic medications such as antibiotics, alpha-agonists, beta blockers, carbonic anhydrase inhibitors, cycloplegics, and mydriatics. Drops should be administered at least 5 minutes apart. 6 ADVERSE REACTIONS The most frequent adverse reactions reported by up to 40% of patients participating in clinical trials have been transient stinging and burning on instillation. (6.1) To report SUSPECTED SE REACTIONS The most frequent adverse reactions reported by up to 40% of patients participating in clinical trials have been transient stinging and burning on instillation. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies 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 the rates in the clinical studies of another drug and may not reflect the rates observed in practice. The most frequent adverse reactions reported with the use of ketorolac tromethamine ophthalmic solutions have been transient stinging and burning on instillation. These reactions were reported by up to 40% of patients participating in clinical trials. Other adverse reactions occurring approximately 1 to 10% of the time during treatment with ketorolac tromethamine ophthalmic solutions included allergic reactions, corneal edema, iritis, ocular inflammation, ocular irritation, superficial keratitis, and superficial ocular infections. Other adverse reactions reported rarel c solutions included allergic reactions, corneal edema, iritis, ocular inflammation, ocular irritation, superficial keratitis, and superficial ocular infections. Other adverse reactions reported rarely with the use of ketorolac tromethamine ophthalmic solutions included: corneal infiltrates, corneal ulcer, eye dryness, headaches, and visual disturbance (blurry vision). 6.2 Postmarketing Experience The following adverse reactions have been identified during post-marketing use of ketorolac tromethamine ophthalmic solution 0.5% in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. The reactions, which have been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection to topical ketorolac tromethamine ophthalmic solution 0.5% or a combination of these factors, include bronchospasm or exacerbation of asthma, corneal erosion, corneal perforation, corneal thinning, and epithelial breakdown [see Warnings and Precautions (5.2 , 5.4) ] . 1 INDICATIONS AND USAGE Entecavir tablets are indicated for the treatment of chronic hepatitis B virus infection in adults and pediatric patients 2 years of age and older with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease. Entecavir tablets are a hepatitis B virus nucleoside analogue reverse transcriptase inhibitor indicated for the treatment of chronic hepatitis B virus infection in adults and children at least 2 years of age with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease. ( 1 ) 2 DOSAGE AND ADMINISTRATION Nucleoside-inhibitor-treatment-naïve with compensated liver disease (greater than or equal to 16 years old): 0.5 mg once daily. ( 2.2 ) Nucleoside-inhibitor-treatment-naïve and lamivudine-experienced pediatric patients at least 2 years of age and weighing at least 10 kg: dosing is based on weight. ( 2.3 ) Lamivudine-refractory or known lamivudine or telbivudine resistance substitutions (greater than or equal to 16 years old): 1 mg once daily. ( 2.2 ) Decompensa 10 kg: dosing is based on weight. ( 2.3 ) Lamivudine-refractory or known lamivudine or telbivudine resistance substitutions (greater than or equal to 16 years old): 1 mg once daily. ( 2.2 ) Decompensated liver disease (adults): 1 mg once daily. ( 2.2 ) Renal impairment: Dosage adjustment is recommended if creatinine clearance is less than 50 mL/min. ( 2.4 ) Entecavir tablets should be administered on an empty stomach. ( 2.1 ) 2.1 Timing of Administration Entecavir tablets should be administered on an empty stomach (at least 2 hours after a meal and 2 hours before the next meal). 2.2 Recommended Dosage in Adults Compensated Liver Disease The recommended dose of entecavir tablets for chronic hepatitis B virus infection in nucleoside-inhibitor-treatment-naïve adults and adolescents 16 years of age and older is 0.5 mg once daily. The recommended dose of entecavir tablets in adults and adolescents (at least 16 years of age) with a history of hepatitis B viremia while receiving lamivudine or known lamivudine or telbivudine resistance substitutions rtM204I/V with or without rtL180M, rtL80I/V, or rtV173L is 1 mg once daily. Decompensated Liver Disease The recommended dose of entecavir tabl known lamivudine or telbivudine resistance substitutions rtM204I/V with or without rtL180M, rtL80I/V, or rtV173L is 1 mg once daily. Decompensated Liver Disease The recommended dose of entecavir tablets for chronic hepatitis B virus infection in adults with decompensated liver disease is 1 mg once daily. 2.3 Recommended Dosage in Pediatric Patients Table 1 describes the recommended dose of entecavir tablets for pediatric patients 2 years of age or older and weighing at least 10 kg. The oral solution should be used for patients with body weight up to 30 kg. Table 1: Dosing Schedule for Pediatric Patients Recommended Once-Daily Dose of Oral Solution (mL) Body Weight (kg) Treatment-Naïve Patients a Lamivudine-Experienced Patients b 10 to 11 3 6 greater than 11 to 14 4 8 greater than 14 to 17 5 10 greater than 17 to 20 6 12 greater than 20 to 23 7 14 greater than 23 to 26 8 16 greater than 26 to 30 9 18 greater than 30 10 20 a Children with body weight greater than 30 kg should receive 10 mL (0.5 mg) of oral solution or one 0.5 mg tablet once daily. b Children with body weight greater than 30 kg should receive 20 mL (1 mg) of oral solution or one 1 mg tablet once daily. 2.4 Renal Impa mL (0.5 mg) of oral solution or one 0.5 mg tablet once daily. b Children with body weight greater than 30 kg should receive 20 mL (1 mg) of oral solution or one 1 mg tablet once daily. 2.4 Renal Impairment In adult subjects with renal impairment, the apparent oral clearance of entecavir decreased as creatinine clearance decreased [see Clinical Pharmacology (12.3) ] . Dosage adjustment is recommended for patients with creatinine clearance less than 50 mL/min, including patients on hemodialysis or continuous ambulatory peritoneal dialysis (CAPD), as shown in Table 2. The once-daily dosing regimens are preferred. Table 2: Recommended Dosage of Entecavir Tablets in Adult Patients with Renal Impairment Creatinine Clearance (mL/min) Usual Dose (0.5 mg) Lamivudine-Refractory or Decompensated Liver Disease (1 mg) 50 or greater 0.5 mg once daily 1 mg once daily 30 to less than 50 0.5 mg every 48 hours 0.5 mg once daily OR 1 mg every 48 hours 10 to less than 30 0.5 mg every 72 hours 1 mg every 72 hours Less than 10 Hemodialysis * or CAPD 0.5 mg every 7 days 1 mg every 7 days * If administered on a hemodialysis day, administer entecavir tablets after the hemodialysis session. Although there 72 hours Less than 10 Hemodialysis * or CAPD 0.5 mg every 7 days 1 mg every 7 days * If administered on a hemodialysis day, administer entecavir tablets after the hemodialysis session. Although there are insufficient data to recommend a specific dose adjustment of entecavir tablets in pediatric patients with renal impairment, a reduction in the dose or an increase in the dosing interval similar to adjustments for adults should be considered. 2.5 Hepatic Impairment No dosage adjustment is necessary for patients with hepatic impairment. 2.6 Duration of Therapy The optimal duration of treatment with entecavir tablets for patients with chronic hepatitis B virus infection and the relationship between treatment and long-term outcomes such as cirrhosis and hepatocellular carcinoma are unknown. 6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: Exacerbations of hepatitis after discontinuation of treatment [see Boxed Warning , Warnings and Precautions (5.1) ] . Lactic acidosis and severe hepatomegaly with steatosis [see Boxed Warning , Warnings and Precautions (5.3) ] . In adults, the most common adverse reactions (≥3%, all severity grades) utions (5.1) ] . Lactic acidosis and severe hepatomegaly with steatosis [see Boxed Warning , Warnings and Precautions (5.3) ] . In adults, the most common adverse reactions (≥3%, all severity grades) are headache, fatigue, dizziness, and nausea. The adverse reactions observed in pediatric patients were consistent with those observed in adults. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trial Experience in Adults Compensated Liver Disease Assessment of adverse reactions is based on four studies (AI463014, AI463022, AI463026, and AI463027) in which 1,720 subjects with chronic hepatitis B virus infection and compensated liver disease received double-blind treatment with entecavir 0.5 mg/day (n=679), entecavir 1 mg/day (n=183), or lamivudine (n=858) for up to 2 years. Median duration of virus infection and compensated liver disease received double-blind treatment with entecavir 0.5 mg/day (n=679), entecavir 1 mg/day (n=183), or lamivudine (n=858) for up to 2 years. Median duration of therapy was 69 weeks for entecavir-treated subjects and 63 weeks for lamivudine-treated subjects in Studies AI463022 and AI463027 and 73 weeks for entecavir-treated subjects and 51 weeks for lamivudine-treated subjects in Studies AI463026 and AI463014. The safety profiles of entecavir and lamivudine were comparable in these studies. The most common adverse reactions of any severity (≥3%) with at least a possible relation to study drug for entecavir-treated subjects were headache, fatigue, dizziness, and nausea. The most common adverse reactions among lamivudine-treated subjects were headache, fatigue, and dizziness. One percent of entecavir-treated subjects in these four studies compared with 4% of lamivudine-treated subjects discontinued for adverse events or abnormal laboratory test results. Clinical adverse reactions of moderate-severe intensity and considered at least possibly related to treatment occurring during therapy in four clinical studies in which entecavir was compared wi ults. Clinical adverse reactions of moderate-severe intensity and considered at least possibly related to treatment occurring during therapy in four clinical studies in which entecavir was compared with lamivudine are presented in Table 3. Table 3: Clinical Adverse Reactions a of Moderate-Severe Intensity (Grades 2 to 4) Reported in Four Entecavir Clinical Trials Through 2 Years Nucleoside-Inhibitor-Naïve b Lamivudine-Refractory c Entecavir Lamivudine Entecavir Lamivudine Body System/ Adverse Reaction 0.5 mg 100 mg 1 mg 100 mg n=679 n=668 n=183 n=190 Any Grade 2 to 4 adverse reaction a 15% 18% 22% 23% Gastrointestinal Diarrhea <1% 0 1% 0 Dyspepsia <1% <1% 1% 0 Nausea <1% <1% <1% 2% Vomiting <1% <1% <1% 0 General Fatigue 1% 1% 3% 3% Nervous System Headache 2% 2% 4% 1% Dizziness <1% <1% 0 1% Somnolence <1% <1% 0 0 Psychiatric Insomnia <1% <1% 0 <1% a Includes events of possible, probable, certain, or unknown relationship to treatment regimen. b Studies AI463022 and AI463027. c Includes Study AI463026 and the entecavir 1 mg and lamivudine treatment arms of Study AI463014, a Phase 2 multinational, randomized, double-blind study of three doses of entecavir (0.1, 0.5, and 1 mg) once dail tudy AI463026 and the entecavir 1 mg and lamivudine treatment arms of Study AI463014, a Phase 2 multinational, randomized, double-blind study of three doses of entecavir (0.1, 0.5, and 1 mg) once daily versus continued lamivudine 100 mg once daily for up to 52 weeks in subjects who experienced recurrent viremia on lamivudine therapy. Laboratory Abnormalities Frequencies of selected treatment-emergent laboratory abnormalities reported during therapy in four clinical trials of entecavir compared with lamivudine are listed in Table 4. Table 4: Selected Treatment-Emergent a Laboratory Abnormalities Reported in Four Entecavir Clinical Trials Through 2 Years Nucleoside-Inhibitor-Naïve b Lamivudine-Refractory c Entecavir Lamivudine Entecavir Lamivudine 0.5 mg 100 mg 1 mg 100 mg Test n=679 n=668 n=183 n=190 Any Grade 3 to 4 laboratory abnormality d 35% 36% 37% 45% ALT >10 x ULN and >2 x baseline 2% 4% 2% 11% ALT >5 x ULN 11% 16% 12% 24% Albumin <2.5 g/dL <1% <1% 0 2% Total bilirubin >2.5 x ULN 2% 2% 3% 2% Lipase ≥2.1 x ULN 7% 6% 7% 7% Creatinine >3 x ULN 0 0 0 0 Confirmed creatinine increase ≥0.5 mg/dL 1% 1% 2% 1% Hyperglycemia, fasting >250 mg/dL 2% 1% 3% 1% Glycosuria e 4% 3% 4% 6% Hemat 2% 2% 3% 2% Lipase ≥2.1 x ULN 7% 6% 7% 7% Creatinine >3 x ULN 0 0 0 0 Confirmed creatinine increase ≥0.5 mg/dL 1% 1% 2% 1% Hyperglycemia, fasting >250 mg/dL 2% 1% 3% 1% Glycosuria e 4% 3% 4% 6% Hematuria f 9% 10% 9% 6% Platelets <50,000/mm 3 <1% <1% <1% <1% a On-treatment value worsened from baseline to Grade 3 or Grade 4 for all parameters except albumin (any on-treatment value <2.5 g/dL), confirmed creatinine increase ≥0.5 mg/dL, and ALT >10 x ULN and >2 x baseline. b Studies AI463022 and AI463027. c Includes Study AI463026 and the entecavir 1 mg and lamivudine treatment arms of Study AI463014, a Phase 2 multinational, randomized, double-blind study of three doses of entecavir (0.1, 0.5, and 1 mg) once daily versus continued lamivudine 100 mg once daily for up to 52 weeks in subjects who experienced recurrent viremia on lamivudine therapy. d Includes hematology, routine chemistries, renal and liver function tests, pancreatic enzymes, and urinalysis. e Grade 3 = 3+, large, ≥500 mg/dL; Grade 4 = 4+, marked, severe. f Grade 3 = 3+, large; Grade 4 = ≥4+, marked, severe, many. ULN=upper limit of normal. Among entecavir-treated subjects in these studies, on-treatment ALT elevations gr ; Grade 4 = 4+, marked, severe. f Grade 3 = 3+, large; Grade 4 = ≥4+, marked, severe, many. ULN=upper limit of normal. Among entecavir-treated subjects in these studies, on-treatment ALT elevations greater than 10 times the upper limit of normal (ULN) and greater than 2 times baseline generally resolved with continued treatment. A majority of these exacerbations were associated with a ≥2 log 10 /mL reduction in viral load that preceded or coincided with the ALT elevation. Periodic monitoring of hepatic function is recommended during treatment. Exacerbations of Hepatitis After Discontinuation of Treatment An exacerbation of hepatitis or ALT flare was defined as ALT greater than 10 times ULN and greater than 2 times the subject’s reference level (minimum of the baseline or last measurement at end of dosing). For all subjects who discontinued treatment (regardless of reason), Table 5 presents the proportion of subjects in each study who experienced post-treatment ALT flares. In these studies, a subset of subjects was allowed to discontinue treatment at or after 52 weeks if they achieved a protocol-defined response to therapy. If entecavir is discontinued without regard to treatment re ies, a subset of subjects was allowed to discontinue treatment at or after 52 weeks if they achieved a protocol-defined response to therapy. If entecavir is discontinued without regard to treatment response, the rate of post-treatment flares could be higher [see Warnings and Precautions (5.1) ] . Table 5: Exacerbations of Hepatitis During Off-Treatment Follow-up, Subjects in Studies AI463022, AI463027, and AI463026 Subjects with ALT Elevations >10 x ULN and >2 x Reference a Entecavir Lamivudine Nucleoside-inhibitor-naïve HBeAg-positive 4/174 (2%) 13/147 (9%) HBeAg-negative 24/302 (8%) 30/270 (11%) Lamivudine-refractory 6/52 (12%) 0/16 a Reference is the minimum of the baseline or last measurement at end of dosing. Median time to off-treatment exacerbation was 23 weeks for entecavir-treated subjects and 10 weeks for lamivudine-treated subjects. Decompensated Liver Disease Study AI463048 was a randomized, open-label study of entecavir 1 mg once daily versus adefovir dipivoxil 10 mg once daily given for up to 48 weeks in adult subjects with chronic HBV infection and evidence of hepatic decompensation, defined as a Child-Turcotte-Pugh (CTP) score of 7 or higher [see Clinical Studies (1 daily given for up to 48 weeks in adult subjects with chronic HBV infection and evidence of hepatic decompensation, defined as a Child-Turcotte-Pugh (CTP) score of 7 or higher [see Clinical Studies (14.1) ] . Among the 102 subjects receiving entecavir, the most common treatment-emergent adverse events of any severity, regardless of causality, occurring through Week 48 were peripheral edema (16%), ascites (15%), pyrexia (14%), hepatic encephalopathy (10%), and upper respiratory infection (10%). Clinical adverse reactions not listed in Table 3 that were observed through Week 48 include blood bicarbonate decreased (2%) and renal failure (<1%). Eighteen of 102 (18%) subjects treated with entecavir, and 18/89 (20%) subjects treated with adefovir dipivoxil died during the first 48 weeks of therapy. The majority of deaths (11 in the entecavir group and 16 in the adefovir dipivoxil group) were due to liver-related causes such as hepatic failure, hepatic encephalopathy, hepatorenal syndrome, and upper gastrointestinal hemorrhage. The rate of hepatocellular carcinoma (HCC) through Week 48 was 6% (6/102) for subjects treated with entecavir and 8% (7/89) for subjects treated with adefovir dipi d upper gastrointestinal hemorrhage. The rate of hepatocellular carcinoma (HCC) through Week 48 was 6% (6/102) for subjects treated with entecavir and 8% (7/89) for subjects treated with adefovir dipivoxil. Five percent of subjects in either treatment arm discontinued therapy due to an adverse event through Week 48. No subject in either treatment arm experienced an on-treatment hepatic flare (ALT >2 x baseline and >10 x ULN) through Week 48. Eleven of 102 (11%) subjects treated with entecavir and 11/89 (13%) subjects treated with adefovir dipivoxil had a confirmed increase in serum creatinine of 0.5 mg/dL through Week 48. HIV/HBV Co-infected The safety profile of entecavir 1 mg (n=51) in HIV/HBV co-infected subjects enrolled in Study AI463038 was similar to that of placebo (n=17) through 24 weeks of blinded treatment and similar to that seen in non-HIV infected subjects [see Warnings and Precautions (5.2) ] . Liver Transplant Recipients Among 65 subjects receiving entecavir in an open-label, post-liver transplant trial [see Use in Specific Populations (8.8) ] , the frequency and nature of adverse events were consistent with those expected in patients who have received a liver trans label, post-liver transplant trial [see Use in Specific Populations (8.8) ] , the frequency and nature of adverse events were consistent with those expected in patients who have received a liver transplant and the known safety profile of entecavir. Clinical Trial Experience in Pediatric Subjects The safety of entecavir in pediatric subjects 2 to less than 18 years of age is based on two clinical trials in subjects with chronic HBV infection (one Phase 2 pharmacokinetic trial [AI463028] and one Phase 3 trial [AI463189]). These trials provided experience in 168 HBeAg-positive subjects treated with entecavir for a median duration of 72 weeks. The adverse reactions observed in pediatric subjects who received treatment with entecavir were consistent with those observed in clinical trials of entecavir in adults. Adverse drug reactions reported in greater than 1% of pediatric subjects included abdominal pain, rash events, poor palatability (“product taste abnormal”), nausea, diarrhea, and vomiting. 6.2 Postmarketing Experience Data from Long-Term Observational Study Study AI463080 was a randomized, global, observational, open-label Phase 4 study to assess long-­term risks and benefits of iting. 6.2 Postmarketing Experience Data from Long-Term Observational Study Study AI463080 was a randomized, global, observational, open-label Phase 4 study to assess long-­term risks and benefits of entecavir (0.5 mg/day or 1 mg/day) treatment as compared to other standard-of-care HBV nucleos(t)ide analogues in subjects with chronic HBV infection. A total of 12,378 patients were treated with entecavir (n=6,216) or other HBV nucleos(t)ide treatment [non-entecavir (ETV)] (n=6,162). Patients were evaluated at baseline and subsequently every 6 months for up to 10 years. The principal clinical outcome events assessed during the study were overall malignant neoplasms, liver-related HBV disease progression, HCC, non-HCC malignant neoplasms, and death. The study showed that entecavir was not significantly associated with an increased risk of malignant neoplasms compared to other standard-of-care HBV nucleos(t)ides, as assessed by either the composite endpoint of overall malignant neoplasms or the individual endpoint of non-HCC malignant neoplasms. The most commonly reported malignancy in both the entecavir and non-ETV groups was HCC followed by gastrointestinal malignancies. The data also the individual endpoint of non-HCC malignant neoplasms. The most commonly reported malignancy in both the entecavir and non-ETV groups was HCC followed by gastrointestinal malignancies. The data also showed that long-term entecavir use was not associated with a lower occurrence of HBV disease progression or a lower rate of death overall compared to other HBV nucleos(t)ides. The principal clinical outcome event assessments are shown in Table 6. Table 6: Principal Analyses of Time to Adjudicated Events - Randomized Treated Subjects Endpoint c Number of Subjects with Events Entecavir N=6,216 Non-ETV N=6,162 Hazard Ratio [Entecavir:Non-ETV] (CI a ) Primary Endpoints Overall malignant neoplasm 331 337 0.93 (0.800, 1.084) Liver-related HBV disease progression 350 375 0.89 (0.769, 1.030) Death 238 264 0.85 (0.713, 1.012) Secondary Endpoints Non-HCC malignant neoplasm 95 81 1.10 (0.817, 1.478) HCC 240b 263 0.87 (0.727, 1.032) Analyses were stratified by geographic region and prior HBV nucleos(t)ide experience. a 95.03% CI for overall malignant neoplasm, death, and liver-related HBV disease progression; 95% CI for non-HCC malignant neoplasm and HCC. b One subject had a pre-treatment HCC ev (t)ide experience. a 95.03% CI for overall malignant neoplasm, death, and liver-related HBV disease progression; 95% CI for non-HCC malignant neoplasm and HCC. b One subject had a pre-treatment HCC event and was excluded from the analysis. c Overall malignant neoplasm is a composite event of HCC or non-HCC malignant neoplasm. Liver-related HBV disease progression is a composite event of liver-related death, HCC, or non-HCC HBV disease progression. CI = confidence interval; N = total number of subjects. Limitations of the study included population changes over the long-term follow-up period and more frequent post-randomization treatment changes in the non-ETV group. In addition, the study was underpowered to demonstrate a difference in the non-HCC malignancy rate because of the lower than expected background rate. Adverse Reactions from Postmarketing Spontaneous Reports The following adverse reactions have been reported during postmarketing use of entecavir. Because these reactions were reported voluntarily from a population of unknown size, it is not possible to reliably estimate their frequency or establish a causal relationship to entecavir exposure. Immune system disorders: Anap reported voluntarily from a population of unknown size, it is not possible to reliably estimate their frequency or establish a causal relationship to entecavir exposure. Immune system disorders: Anaphylactoid reaction. Metabolism and nutrition disorders: Lactic acidosis. Hepatobiliary disorders: Increased transaminases. Skin and subcutaneous tissue disorders: Alopecia, rash. 1 INDICATIONS & USAGE Calcium Acetate Capsules are a phosphate binder indicated to reduce serum phosphorus in patients with end stage renal disease (ESRD). Calcium Acetate Capsules are a phosphate binder indicated for the reduction of serum phosphorus in patients with end stage renal disease. ( 1 ) 2 DOSAGE & ADMINISTRATION The recommended initial dose of Calcium Acetate Capsules for the adult dialysis patient is 2 capsules with each meal. Increase the dose gradually to lower serum phosphorus levels to the target range, as long as hypercalcemia does not develop. Most patients require 3-4 capsules with each meal. Starting dose is 2 capsules with each meal. ( 2 ) Titrate the dose every 2-3 weeks until acceptable serum phosphorus level is reached. Most patients require 3-4 capsules with each meal. ( 2 ) 6 ADVERSE REACTIONS Hypercalcemia is discussed elsewhere [see Warnings and Precautions (5.1)] . The most common (>10%) adverse reactions are hypercalcemia, nausea, and vomiting. ( 6.1 ). In clinical studies, patients have occasionally experienced nausea during calcium acetate therapy. ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Nostrum Laboratories Inc. at quality@nostrumphar n clinical studies, patients have occasionally experienced nausea during calcium acetate therapy. ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Nostrum Laboratories Inc. at quality@nostrumpharma.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In clinical studies, calcium acetate has been generally well tolerated. Calcium Acetate Capsules were studied in a 3-month, open-label, non-randomized study of 98 enrolled ESRD hemodialysis patients and in a two week double-blind, placebo-controlled, cross-over study with 69 enrolled ESRD hemodialysis patients. Adverse reactions (>2% on treatment) from these trials are presented in Table 1. Table 1: Adverse Reactions in Patients with End-Stage Renal Disease Undergoing Hemodialysis Preferred Term Total adverse reactions reported for calcium acetate n = 167 n (%) 3-mo, open-label study of calcium acetate n = 98 n (%) Double-blind, placebo-con Renal Disease Undergoing Hemodialysis Preferred Term Total adverse reactions reported for calcium acetate n = 167 n (%) 3-mo, open-label study of calcium acetate n = 98 n (%) Double-blind, placebo-controlled, cross-over study of calcium acetate n = 69 Calcium acetate n (%) Placebo n (%) Nausea 6 (3.6) 6 (6.1) 0 (0.0) 0 (0.0) Vomiting 4 (2.4) 4 (4.1) 0 (0.0) 0 (0.0) Hypercalcemia 21 (12.6) 16 (16.3) 5 (7.2) 0 (0.0) Mild hypercalcemia may be asymptomatic or manifest itself as constipation, anorexia, neusea, and vomiting. More severe hypercalcemia is associated with confusion, delirium, stupor, and coma. Decreasing dialysate calcium concentration could reduce the incidence and severity of Calcium Acetate Capsules induced hypercalcemia. Isolated cases of pruritus have been reported, which may represent allergic reactions. 6.2 Postmarketing Experience Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or to establish a causal relationship to drug exposure. The following additional adverse reactions have been identified during post-approval of calcium acetate: dizziness, edema, and weakness. 1 INDICATIONS AND USAGE MAXALT ® and MAXALT-MLT ® are indicated for the acute treatment of migraine with or without aura in adults and in pediatric patients 6 to 17 years old. Limitations of Use MAXALT should only be used where a clear diagnosis of migraine has been established. If a patient has no response for the first migraine attack treated with MAXALT, the diagnosis of migraine should be reconsidered before MAXALT is administered to treat any subsequent attacks. MAXALT is not indicated for use in the management of hemiplegic or basilar migraine [see Contraindications (4) ] . MAXALT is not indicated for the prevention of migraine attacks. Safety and effectiveness of MAXALT have not been established for cluster headache. MAXALT is a serotonin (5-HT) 1B/1D receptor agonist (triptan) indicated for the acute treatment of migraine with or without aura in adults and in pediatric patients 6 to 17 years of age ( 1 ) Limitations of Use : Use only after clear diagnosis of migraine has been established ( 1 ) Not indicated for the prophylactic therapy of migraine ( 1 ) Not indicated for the treatment of cluster headache ( 1 ) 2 DOSAGE AND ADMINISTRATION Although rizatriptan benzoate 5 mg t stablished ( 1 ) Not indicated for the prophylactic therapy of migraine ( 1 ) Not indicated for the treatment of cluster headache ( 1 ) 2 DOSAGE AND ADMINISTRATION Although rizatriptan benzoate 5 mg tablets and orally disintegrating tablets are available in the marketplace, MAXALT Tablets and MAXALT-MLT Orally Disintegrating Tablets are no longer marketed in the 5 mg strength. Adults: 5 or 10 mg single dose; separate repeat doses by at least two hours; maximum dose in a 24-hour period: 30 mg ( 2.1 ) Pediatric patients 6 to 17 years: 5 mg single dose in patients less than 40 kg (88 lb); 10 mg single dose in patients 40 kg (88 lb) or more ( 2.2 ) Adjust dose if co-administered with propranolol ( 2.4 ) 2.1 Dosing Information in Adults The recommended starting dose of rizatriptan benzoate is either 5 mg or 10 mg for the acute treatment of migraines in adults. The 10-mg dose may provide a greater effect than the 5-mg dose, but may have a greater risk of adverse reactions [see Clinical Studies (14.1) ] . Redosing in Adults Although the effectiveness of a second dose or subsequent doses has not been established in placebo-controlled trials, if the migraine headache returns, a second dose es (14.1) ] . Redosing in Adults Although the effectiveness of a second dose or subsequent doses has not been established in placebo-controlled trials, if the migraine headache returns, a second dose may be administered 2 hours after the first dose. The maximum daily dose should not exceed 30 mg in any 24-hour period. The safety of treating, on average, more than four headaches in a 30-day period has not been established. 2.2 Dosing Information in Pediatric Patients (Age 6 to 17 Years) Dosing in pediatric patients is based on the patient's body weight. The recommended dose of rizatriptan benzoate is 5 mg in patients weighing less than 40 kg (88 lb), and 10 mg in patients weighing 40 kg (88 lb) or more. The efficacy and safety of treatment with more than one dose of rizatriptan benzoate within 24 hours in pediatric patients 6 to 17 years of age have not been established. 2.3 Administration of MAXALT-MLT Orally Disintegrating Tablets For MAXALT-MLT Orally Disintegrating Tablets, administration with liquid is not necessary. Orally disintegrating tablets are packaged in a blister within an outer aluminum pouch and patients should not remove the blister from the outer pouch until just p ration with liquid is not necessary. Orally disintegrating tablets are packaged in a blister within an outer aluminum pouch and patients should not remove the blister from the outer pouch until just prior to dosing. The blister pack should then be peeled open with dry hands and the orally disintegrating tablet placed on the tongue, where it will dissolve and be swallowed with the saliva. 2.4 Dosage Adjustment for Patients on Propranolol Adult Patients In adult patients taking propranolol, only the 5-mg dose of rizatriptan benzoate is recommended, up to a maximum of 3 doses in any 24-hour period (15 mg) [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ]. Pediatric Patients For pediatric patients weighing 40 kg (88 lb) or more, taking propranolol, only a single 5-mg dose of rizatriptan benzoate is recommended (maximum dose of 5 mg in a 24-hour period). Rizatriptan benzoate should not be prescribed to propranolol-treated pediatric patients who weigh less than 40 kg (88 lb) [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ]. 6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: Myocardial Ischemia, ee Drug Interactions (7.1) and Clinical Pharmacology (12.3) ]. 6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: Myocardial Ischemia, Myocardial Infarction, and Prinzmetal's Angina [see Warnings and Precautions (5.1) ] . Arrhythmias [see Warnings and Precautions (5.2) ]. Chest, Throat, Neck and/or Jaw Pain/Tightness/Pressure [see Warnings and Precautions (5.3) ] . Cerebrovascular Events [see Warnings and Precautions (5.4) ] . Other Vasospasm Reactions [see Warnings and Precautions (5.5) ] . Medication Overuse Headache [see Warnings and Precautions (5.6) ] . Serotonin Syndrome [see Warnings and Precautions (5.7) ] . Increase in Blood Pressure [see Warnings and Precautions (5.8) ] . The most common adverse reactions in adults were (incidence ≥5% and greater than placebo): asthenia/fatigue, somnolence, pain/pressure sensation and dizziness ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Organon LLC, a subsidiary of Organon & Co., at 1-844-674-3200 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 reacti rganon & Co., at 1-844-674-3200 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. Adults Incidence in Controlled Clinical Trials Adverse reactions to MAXALT were assessed in controlled clinical trials that included over 3700 adult patients who received single or multiple doses of MAXALT Tablets. The most common adverse reactions during treatment with MAXALT (≥5% in either treatment group and greater than placebo) were asthenia/fatigue, somnolence, pain/pressure sensation and dizziness. These adverse reactions appeared to be dose related. Table 1 lists the adverse reactions (incidence ≥2% and greater than placebo) after a single dose of MAXALT in adults. Table 1: Incidence (≥2% and Greater than Placebo) of Adverse Reactions After a Single Dose of MAXALT Tablets or Placebo in Adults % of Patients Adverse Reactions MAXALT 5 mg (N=977) MAXALT 10 mg (N=1167) Placebo (N=627) Atypical Sensations n Placebo) of Adverse Reactions After a Single Dose of MAXALT Tablets or Placebo in Adults % of Patients Adverse Reactions MAXALT 5 mg (N=977) MAXALT 10 mg (N=1167) Placebo (N=627) Atypical Sensations 4 5 4 Paresthesia 3 4 <2 Pain and other Pressure Sensations 6 9 3 Chest Pain: tightness/pressure and/or heaviness <2 3 1 Neck/throat/jaw: pain/tightness/pressure <2 2 1 Regional Pain: tightness/pressure and/or heaviness <1 2 0 Pain, location unspecified 3 3 <2 Digestive 9 13 8 Dry Mouth 3 3 1 Nausea 4 6 4 Neurological 14 20 11 Dizziness 4 9 5 Headache <2 2 <1 Somnolence 4 8 4 Other Asthenia/fatigue 4 7 2 The frequencies of adverse reactions in clinical trials did not increase when up to three doses were taken within 24 hours. Adverse reaction frequencies were also unchanged by concomitant use of drugs commonly taken for migraine prophylaxis (including propranolol), oral contraceptives, or analgesics. The incidences of adverse reactions were not affected by age or gender. There were insufficient data to assess the impact of race on the incidence of adverse reactions. Other Events Observed in Association with the Administration of MAXALT in Adults In the following section, the frequenci icient data to assess the impact of race on the incidence of adverse reactions. Other Events Observed in Association with the Administration of MAXALT in Adults In the following section, the frequencies of less commonly reported adverse events are presented that were not reported in other sections of the labeling. Because the reports include events observed in open studies, the role of MAXALT in their causation cannot be reliably determined. Furthermore, variability associated with adverse event reporting, the terminology used to describe adverse events, limit the value of the quantitative frequency estimates provided. Event frequencies are calculated as the number of patients who used MAXALT and reported an event divided by the total number of patients exposed to MAXALT (N=3716). All reported events occurred at an incidence ≥1%, or are believed to be reasonably associated with the use of the drug. Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are those defined as those occurring in at least (>)1/100 patients; infrequent adverse experiences are those occurring in 1 ecreasing frequency using the following definitions: frequent adverse events are those defined as those occurring in at least (>)1/100 patients; infrequent adverse experiences are those occurring in 1/100 to 1/1000 patients; and rare adverse experiences are those occurring in fewer than 1/1000 patients. General: Infrequent was facial edema. Rare were syncope and edema/swelling. Atypical Sensations: Frequent were warm sensations. Cardiovascular: Frequent was palpitation. Infrequent were tachycardia, cold extremities, and bradycardia. Digestive: Frequent were diarrhea and vomiting. Infrequent were dyspepsia, tongue edema and abdominal distention. Musculoskeletal: Infrequent were muscle weakness, stiffness, myalgia and muscle cramp/spasm. Neurological/Psychiatric: Frequent were hypoesthesia, euphoria and tremor. Infrequent were vertigo, insomnia, confusion/disorientation, gait abnormality, memory impairment, and agitation. Respiratory: Frequent was dyspnea. Infrequent was pharyngeal edema. Special Senses: Infrequent were blurred vision and tinnitus. Rare was eye swelling. Skin and Skin Appendage: Frequent was flushing. Infrequent were sweating, pruritus, rash, and urticaria. Rare was . Special Senses: Infrequent were blurred vision and tinnitus. Rare was eye swelling. Skin and Skin Appendage: Frequent was flushing. Infrequent were sweating, pruritus, rash, and urticaria. Rare was erythema, hot flashes. The adverse reaction profile seen with MAXALT-MLT Orally Disintegrating Tablets was similar to that seen with MAXALT Tablets. Pediatric Patients 6 to 17 Years of Age Incidence in Controlled Clinical Trials in Pediatric Patients Adverse reactions to MAXALT-MLT were assessed in a controlled clinical trial in the acute treatment of migraines (Study 7) that included a total of 1382 pediatric patients 6-17 years of age, of which 977 (72%) administered at least one dose of study treatment (MAXALT-MLT and/or placebo) [see Clinical Studies (14.2) ]. The incidence of adverse reactions reported for pediatric patients in the acute clinical trial was similar in patients who received MAXALT to those who received placebo. The adverse reaction pattern in pediatric patients is expected to be similar to that in adults. Other Events Observed in Association with the Administration of MAXALT-MLT in Pediatric Patients In the following section, the frequencies of less commonly reporte ted to be similar to that in adults. Other Events Observed in Association with the Administration of MAXALT-MLT in Pediatric Patients In the following section, the frequencies of less commonly reported adverse events are presented. Because the reports include events observed in open studies, the role of MAXALT-MLT in their causation cannot be reliably determined. Furthermore, variability associated with adverse event reporting, the terminology used to describe adverse events, limit the value of the quantitative frequency estimates provided. Event frequencies are calculated as the number of pediatric patients 6 to 17 years of age who used MAXALT-MLT and reported an event divided by the total number of patients exposed to MAXALT-MLT (N=1068). All reported events occurred at an incidence ≥1%, or are believed to be reasonably associated with the use of the drug. Events are further classified within system organ class and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are those occurring in (>)1/100 pediatric patients; infrequent adverse experiences are those occurring in 1/100 to 1/1000 pediatric patients; and rare adverse experienc itions: frequent adverse events are those occurring in (>)1/100 pediatric patients; infrequent adverse experiences are those occurring in 1/100 to 1/1000 pediatric patients; and rare adverse experiences are those occurring in fewer than 1/1000 patients. General: Frequent was fatigue. Ear and labyrinth disorders: Infrequent was hypoacusis. Gastrointestinal disorders: Frequent was abdominal discomfort. Nervous system disorders: Infrequent were coordination abnormal, disturbance in attention, and presyncope. Psychiatric disorders: Infrequent was hallucination. 6.2 Postmarketing Experience The following section enumerates potentially important adverse events that have occurred in clinical practice and which have been reported spontaneously to various surveillance systems. The events enumerated include all except those already listed in other sections of the labeling or those too general to be informative. Because the reports cite events reported spontaneously from worldwide postmarketing experience, frequency of events and the role of MAXALT in their causation cannot be reliably determined. Neurological/Psychiatric: Seizure. General: Allergic conditions including anaphylaxis/anaphylact xperience, frequency of events and the role of MAXALT in their causation cannot be reliably determined. Neurological/Psychiatric: Seizure. General: Allergic conditions including anaphylaxis/anaphylactoid reaction, angioedema, wheezing, and toxic epidermal necrolysis [see Contraindications (4) ]. Special Senses: Dysgeusia. INDICATIONS AND USAGE Kepivance is indicated to decrease the incidence and duration of severe oral mucositis in patients with hematologic malignancies receiving myelotoxic therapy requiring hematopoietic stem cell support. The safety and efficacy of Kepivance have not been established in patients with non-hematologic malignancies (see PRECAUTIONS ). DOSAGE AND ADMINISTRATION The recommended dosage of Kepivance is 60 mcg/kg/day, administered as an IV bolus injection for 3 consecutive days before and 3 consecutive days after myelotoxic therapy for a total of 6 doses. Pre-myelotoxic therapy: The first 3 doses should be administered prior to myelotoxic therapy, with the third dose 24 to 48 hours before myelotoxic therapy (see PRECAUTIONS: Drug Interactions ). Post-myelotoxic therapy: The last 3 doses should be administered post-myelotoxic therapy; the first of these doses should be administered after, but on the same day of hematopoietic stem cell infusion and at least 4 days after the most recent administration of Kepivance (see PRECAUTIONS: Drug Interactions ). No dose adjustment is recommended for patients with renal impairment (see CLINICAL PHARMACOLOGY: Special Populations ). Prep t recent administration of Kepivance (see PRECAUTIONS: Drug Interactions ). No dose adjustment is recommended for patients with renal impairment (see CLINICAL PHARMACOLOGY: Special Populations ). Preparation of Kepivance Do not use Kepivance beyond the date stamped on the vial label. Kepivance lyophilized powder should only be reconstituted with Sterile Water for Injection, USP (not supplied). Kepivance should be reconstituted aseptically by slowly injecting 1.2 mL of Sterile Water for Injection, USP (not supplied) to yield a final concentration of 5 mg/mL. The contents should be swirled gently during dissolution. Do not shake or vigorously agitate the vial . Generally, dissolution of Kepivance takes less than 3 minutes. PROTECT FROM LIGHT The reconstituted solution contains no preservatives and is intended for single use only. Following reconstitution, it is recommended that the product be used immediately. If not used immediately, the reconstituted solution of Kepivance may be stored refrigerated in its carton at 2° to 8°C (36° to 46°F) for up to 24 hours. Prior to injection‚ Kepivance may be allowed to reach room temperature for a maximum of 1 hour but should be protected from l refrigerated in its carton at 2° to 8°C (36° to 46°F) for up to 24 hours. Prior to injection‚ Kepivance may be allowed to reach room temperature for a maximum of 1 hour but should be protected from light. Discard Kepivance left at room temperature for more than 1 hour. Do not freeze the reconstituted solution. The reconstituted solution should be clear and colorless. Visually inspect the solution for discoloration and particulate matter before administration. Kepivance should not be administered if discoloration or particulates are observed. DO NOT FILTER the reconstituted solution during preparation or administration. Administration of Kepivance Kepivance should be administered by intravenous bolus injection. If heparin is used to maintain an IV line, saline should be used to rinse the line prior to and after Kepivance administration (see PRECAUTIONS: Drug Interactions ). ADVERSE REACTIONS Please refer to the PRECAUTIONS: Potential for Stimulation of Tumor Growth and CLINICAL PHARMACOLOGY: Mechanism of Action sections regarding the potential for tumor stimulatory effects in KGF receptor-expressing tumors. Clinical Trial Experience Because clinical trials are conducted under widel OLOGY: Mechanism of Action sections regarding the potential for tumor stimulatory effects in KGF receptor-expressing tumors. Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. Safety data are based upon 409 patients with hematologic malignancies (NHL, Hodgkin's disease, AML, ALL, CML, CLL, or multiple myeloma) who received Kepivance and 241 patients who received placebo in 3 randomized, placebo-controlled clinical studies and a pharmacokinetic study. Patients received Kepivance either before, or before and after, regimens of myelotoxic chemotherapy, with or without TBI, followed by PBPC support. The patients were predominantly between the ages of 41 and 60 years (median 48 yrs), male (62%), white (83%). NHL was the most common malignancy followed by Hodgkin's dise I, followed by PBPC support. The patients were predominantly between the ages of 41 and 60 years (median 48 yrs), male (62%), white (83%). NHL was the most common malignancy followed by Hodgkin's disease, multiple myeloma, and leukemia. The most common serious adverse reaction attributed to Kepivance was skin rash, which was reported in less than 1% (3/409) of patients treated with Kepivance. Grade 3 skin rashes occurred in 14 patients, 9 of 409 (3%) receiving Kepivance and 5 of 241 (2%) receiving placebo. In seven patients (5 Kepivance, 2 placebo), study drug was discontinued due to skin rash. Other serious adverse reactions occurred at a similar rate in patients who received Kepivance (20%) or placebo (21%). The most frequently reported serious adverse events in Kepivance and placebo-treated patients were fever, gastrointestinal events, and respiratory events. The most common adverse reactions attributed to Kepivance were skin toxicities (rash, erythema, edema, pruritus), oral toxicities (dysesthesia, tongue discoloration, tongue thickening, alteration of taste), pain arthralgias, and dysesthesia. The median time to onset of cutaneous toxicity was 6 days following the first of 3 ties (dysesthesia, tongue discoloration, tongue thickening, alteration of taste), pain arthralgias, and dysesthesia. The median time to onset of cutaneous toxicity was 6 days following the first of 3 consecutive daily doses of Kepivance, with a median duration of 5 days. In patients receiving Kepivance, dysesthesia (including hyperesthesia, hypoesthesia, and paresthesia) was usually localized to the perioral region, whereas in patients receiving placebo dysesthesias were more likely to occur in extremities. Adverse events occurring more frequently in Kepivance-treated patients as compared to placebo-treated patients (a higher incidence of ≥ 5%) are listed in Table 2. Table 2. Adverse Events Occurring With ≥ 5% Higher Incidence in Kepivance vs. Placebo BODY SYSTEM Adverse Event Kepivance (n = 409) Placebo (n = 241) BODY AS A WHOLE Edema 28% 21% Pain 16% 11% Fever 39% 34% GASTROINTESTINAL Mouth/Tongue Thickness or Discoloration 17% 8% MUSCULOSKELETAL Arthralgia 10% 5% SKIN AND APPENDAGES Rash 62% 50% Pruritus 35% 24% Erythema 32% 22% SPECIAL SENSES Taste Altered 16% 8% CNS/PNS Dysesthesia – Hyperesthesia / hypoesthesia / paresthesia 12% 7% METABOLIC Elevated serum lipase (Grade 3/4) Rash 62% 50% Pruritus 35% 24% Erythema 32% 22% SPECIAL SENSES Taste Altered 16% 8% CNS/PNS Dysesthesia – Hyperesthesia / hypoesthesia / paresthesia 12% 7% METABOLIC Elevated serum lipase (Grade 3/4) 28% (11%) 23% (5%) Elevated serum amylase (Grade 3/4) 62% (38%) 54% (31%) Hypertension: In a phase 1 placebo-controlled study in patients undergoing hematopoietic transplantation and receiving Kepivance (3 doses pre-myelotoxic therapy and 3 doses post-transplant), the proportion of Kepivance-treated patients reporting an adverse event of hypertension in the 60- and 80-mcg/kg/day Kepivance cohorts was greater than in the placebo group (2/15 patients [13%], 2/14 [14%], and 2/23 [9%], respectively). These events were transient and did not require treatment discontinuation in any patient. In an integrated analysis of adverse events across Kepivance studies in the hematology transplant setting, hypertensive events were reported in 30/409 Kepivance (7%) patients and 13/241 placebo (5%) patients. Proteinuria: In a placebo-controlled study conducted in 145 patients with metastatic colorectal cancer receiving multi-cycle chemotherapy (5-FU/leucovorin), serial urine specimens were collected for Proteinuria: In a placebo-controlled study conducted in 145 patients with metastatic colorectal cancer receiving multi-cycle chemotherapy (5-FU/leucovorin), serial urine specimens were collected for 27 placebo-treated and 54 Kepivance-treated patients. Among the 54 Kepivance-treated patients, 9 patients with a baseline urinalysis negative for protein subsequently developed 2+ or greater proteinuria after treatment with Kepivance. Among the 27 placebo-treated patients evaluated, none developed 2+ or greater proteinuria. Because of the study design, the number of cycles with urine analysis data collected was higher in the Kepivance- treated patients. In addition, for the 9 patients with proteinuria, underlying medical conditions known to be associated with proteinuria were present at baseline. A causal relationship between Kepivance and proteinuria has not been established. Laboratory Values: Reversible elevations in serum lipase and amylase, which did not require treatment intervention, are shown in Table 2. In general, peak increases were observed during the period of cytotoxic therapy and returned to baseline by the day of PBPC infusion. Fractionation of amylase revealed it to be , are shown in Table 2. In general, peak increases were observed during the period of cytotoxic therapy and returned to baseline by the day of PBPC infusion. Fractionation of amylase revealed it to be predominantly salivary in origin. Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The clinical significance of antibodies to Kepivance is unknown but may include lessened activity and/or cross reactivity with other members of the FGF family of growth factors. A sensitive electrochemiluminescence-based binding assay was performed on post-treatment sera from 645 patients treated with Kepivance in clinical studies. Twelve (2%) of these 645 patients tested positive for antibodies to Kepivance following treatment. None of the samples had evidence of neutralizing activity in a cell-based assay. The incidence of antibody positivity is highly dependent on the specific assay and its sensitivity. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of the incidence o n an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of the incidence of antibodies to Kepivance with the incidence of antibodies to other products may be misleading. Postmarketing Experience The following adverse reactions have been identified during postapproval of Kepivance. 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. The following adverse reactions have been identified during postmarketing use of Kepivance in the stem cell transplant setting: tongue disorder (e.g. redness, bumps, edema); face edema and mouth edema; vaginal edema and erythema; transient hyperpigmentation of the skin; Palmar-plantar Erythrodysaesthesia Syndrome (dysaesthesia, erythema, edema on the palms and soles) and anaphylactic / allergic reactions. Use decrease bacteria on skin Purpose Antibacterial Warnings For external use only Directions adults and children 2 years and over apply to hands allow skin to dry without wiping children under 2 years ask a doctor before use Stop use and ask a doctor if irritation or rash develops and continues for more than 72 hours Keep out of reach of children If swallowed, get medical help or contact a Poison Control Center right away. 1 INDICATIONS AND USAGE Tramadol hydrochloride tablets are indicated in adults for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. Limitations of Use Because of the risks of addiction, abuse, and misuse, overdose, and death opioids, which can occur at any dosage or duration and persist over the course of therapy, reserve opioid analgesics, including tramadol hydrochloride for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Tramadol hydrochloride tablets are opioid agonist indicated in adults for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate ( 1 ). Limitations of Use ( 1 ) Because of the risks of addiction, abuse, misuse overdose, and death which can occur at any dosage or duration ( 5.1 ), and persist over the course of therapy reserve opioids analgesics, including tramadol hydrochloride for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide suffi eserve opioids analgesics, including tramadol hydrochloride for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. 2 DOSAGE AND ADMINISTRATION Periodically reassess patients receiving tramadol hydrochloride tablets to evaluate the continued need for opioid analgesics to maintain pain control, for the signs or symptoms of adverse reactions, and for the development of addiction, abuse, or misuse. ( 2.4 ). Tramadol hydrochloride tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. ( 2.1 ) Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals ( 2.1 ). Reserve titration to higher doses of tramadol hydrochloride tablets for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. ( 2.1 , 5 ) Initiate the dosing regimen for each patient individually, taking into account the patient's severity of pain, patient response, prior a dose opioid clearly outweigh the substantial risks. ( 2.1 , 5 ) Initiate the dosing regimen for each patient individually, taking into account the patient's severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse ( 2.1 ). Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available. ( 2.1 ) Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse. ( 2.1 , 5.1 ) Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with tramadol hydrochloride tablets. Consider this risk when selecting an initial dose and when making dose adjustments. ( 2.1 , 5.2 ) Start at 25 mg/day and titrate in 25 mg increments as separate doses every 3 days to reach 100 mg/day (25 mg four times a day). There ng an initial dose and when making dose adjustments. ( 2.1 , 5.2 ) Start at 25 mg/day and titrate in 25 mg increments as separate doses every 3 days to reach 100 mg/day (25 mg four times a day). Thereafter the total daily dose may be increased by 50 mg as tolerated every 3 days to reach 200 mg/day (50 mg four times a day). After titration, tramadol hydrochloride, tablets 50 mg to 100 mg can be administered as needed for pain relief every 4 to 6 hours not to exceed 400 mg/day ( 2.3 , 2.4 ). Severe Renal Impairment: increase the tramadol hydrochloride tablets, dosing interval to 12 hours, and limit maximum daily dose to 200 mg ( 2.3 ). Severe hepatic impairment: Recommended dose is 50 mg every 12 hours. Do not rapidly reduce or abruptly discontinue tramadol hydrochloride in a physically-dependent patient because rapid reduction or abrupt discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide ( 2.3 ). Discuss opioid overdose reversal agents and options for acquiring them with the patient and/or caregiver, both when initiating and renewing treatment with tramadol hydrochloride tablets, especially if the patient has additional ri al agents and options for acquiring them with the patient and/or caregiver, both when initiating and renewing treatment with tramadol hydrochloride tablets, especially if the patient has additional risk factors for overdose, or close contacts at risk for exposure and overdose. ( 2.2 , 5.1 , 5.2 , 5.3 ) 2.1 Important Dosage and Administration Instructions Do not use tramadol hydrochloride tablets concomitantly with other tramadol-containing products. Do not administer tramadol hydrochloride tablets at a dose exceeding 400 mg per day. Tramadol hydrochloride tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals [see Warnings and Precautions ( 5 )] . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of tramadol hydrochloride tablets for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. Many acute pain conditions (e.g. s for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available. There is variability in the opioid analgesic dose and duration needed to adequately manage pain due both to the cause of pain and to individual patient factors. Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions ( 5.1 )] . Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with tramadol hydrochloride tablets. Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings and Precautions ( 5 )] . 2.2 Patient Access an Opioid Overdose Reversal Agent ol hydrochloride tablets. Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings and Precautions ( 5 )] . 2.2 Patient Access an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose Inform patients and caregivers about opioid overdose reversal agents (e.g.,naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. The presence of risk factors for overdose should not prevent the management of pain in any patient [see Warnings and Precautions ( 5.1 , 5.2 , 5.3 )] . Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program) [see Warnings and Precautions ( 5.2 )] . There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient ag ased program) [see Warnings and Precautions ( 5.2 )] . There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent. 2.3 Initial Dosage Initiating Treatment with tramadol hydrochloride tablets Initiate treatment with tramadol hydrochloride tablets in a dosing range of 50 mg to 100 mg every 4 to 6 hours as needed for pain, and at the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient's response to their initial dose of tramadol hydrochloride tablets. For patients not requiring rapid onset of analgesic effect, the tolerability of tramadol hydrochloride tablets can be improved by initiating therapy with the following titration regimen: Start tramadol hydrochloride tablets at 25 mg/day and titrate in 25 mg increments as separate doses every 3 days to reach 100 mg/day (25 mg four times a day). Thereafter the total daily dose may be increased by 50 mg as tolerated every 3 days to r ay and titrate in 25 mg increments as separate doses every 3 days to reach 100 mg/day (25 mg four times a day). Thereafter the total daily dose may be increased by 50 mg as tolerated every 3 days to reach 200 mg/day (50 mg four times a day). After titration, tramadol hydrochloride tablets 50 to 100 mg can be administered as needed for pain relief every 4 to 6 hours not to exceed 400 mg/day. For the subset of patients for whom rapid onset of analgesic effect is required and for whom the benefits outweigh the risk of discontinuation due to adverse events associated with higher initial doses, tramadol hydrochloride tablets 50 mg to 100 mg can be administered as needed for pain relief every four to six hours, not to exceed 400 mg per day. Conversion from Tramadol to Extended-Release Tramadol The relative bioavailability of tramadol compared to extended-release tramadol is unknown, so conversion to extended-release formulations may lead to increased risk of excessive sedation and respiratory depression. Dosage Modification in Patients with Hepatic Impairment The recommended dose for adult patients with severe hepatic impairment is 50 mg every 12 hours. Dosage Modification in Patients wi y depression. Dosage Modification in Patients with Hepatic Impairment The recommended dose for adult patients with severe hepatic impairment is 50 mg every 12 hours. Dosage Modification in Patients with Renal Impairment In all patients with creatinine clearance less than 30 mL/min, it is recommended that the dosing interval of tramadol hydrochloride tablets be increased to 12 hours, with a maximum daily dose of 200 mg. Since only 7% of an administered dose is removed by hemodialysis, dialysis patients can receive their regular dose on the day of dialysis. Dosage Modification in Geriatric Patients Do not exceed a total dose of 300 mg/day in patients over 75 years old. 2.4 Titration and Maintenance of Therapy Individually titrate tramadol hydrochloride tablets to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving tramadol hydrochloride tablets to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions, as well as to reassess for the development of addiction, abuse, or misuse [see Warnings and Precautions (5.1) and Withdrawal (5.18) ] . Frequent communication is importa , and other adverse reactions, as well as to reassess for the development of addiction, abuse, or misuse [see Warnings and Precautions (5.1) and Withdrawal (5.18) ] . Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the tramadol hydrochloride tablets dosage. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after dosage increase), consider reducing the dosage [see Warnings and Precautions (5) ] . Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions. 2.5 Safe Reduction or Discontinuation of tramadol hydrochloride Do not rapidly reduce or abruptly discontinue tramadol hydrochloride in patients who may be physically dependent on opioids. Rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal sy drochloride in patients who may be physically dependent on opioids. Rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances. When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking tramadol hydrochloride tablets, there are a variety of factors that should be considered, including the total daily dose of opioid (including tramadol hydrochloride tablets) the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discont of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with comorbid pain and substance use disorders may benefit from referral to a specialist. There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on tramadol hydrochloride tablets who are physically opioid-dependent, initiate the taper by a small enough increment, (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper. It may be necessary to provide the patient with a lower d ering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper. It may be necessary to provide the patient with a lower dosage strength to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances. When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time, and/or with high doses for chronic pain, ensure that a multimoda r substances. When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time, and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [see Warnings and Precautions (5. 17 ), Drug Abuse and Dependence ( 9.3 )] . 6 ADVERSE REACTIONS The following serious adverse reactions are described, or described in greater detail, in other sections: Addiction, Abuse, and Misuse [see Warnings and Precautions ( 5.1 )] Life-Threatening Respiratory Depression [see Warnings and Precautions ( 5.3 )] Ultra-Rapid Metabolism of Tramadol and Other Risk Factors for Life-threatening Respiratory Depression in Children [see Warnings and Precautions ( 5.6 )] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions ( 5.4 )] Interactions with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions ( 5.3 )] Serotonin Syndrome [see Warnings al Opioid Withdrawal Syndrome [see Warnings and Precautions ( 5.4 )] Interactions with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions ( 5.3 )] Serotonin Syndrome [see Warnings and Precautions ( 5.9 )] Seizures [see Warnings and Precautions ( 5.10 )] Suicide [see Warnings and Precautions ( 5.11 )] Adrenal Insufficiency [see Warnings and Precautions ( 5.13 )] Severe Hypotension [see Warnings and Precautions ( 5.14 )] Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.16 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.17 )] Withdrawal [see Warnings and Precautions ( 5.18 )] Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions ( 5.8 ) The most common incidence of treatment-emergent adverse events (≥15.0%) in patients from clinical trials were dizziness/vertigo, nausea, constipation, headache, somnolence, vomiting and pruritus. To report SUSPECTED ADVERSE REACTIONS, contact Unichem Pharmaceuticals (USA) Inc. at 1-866-562-4616 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in th 66-562-4616 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Tramadol hydrochloride tablets were administered to 550 patients during the double-blind or open-label extension periods in U.S. studies of chronic nonmalignant pain. Of these patients, 375 were 65 years old or older. Table 1 reports the cumulative incidence rate of adverse reactions by 7, 30 and 90 days for the most frequent reactions (5% or more by 7 days). The most frequently reported events were in the central nervous system and gastrointestinal system. Although the reactions listed in the table are felt to be probably related to tramadol hydrochloride tablets administration, the reported rates also include some events that may have been due to underlying disease or concomitant medication. The overall incidence rates of adverse experiences in these trials were similar for tramadol hydrochloride tablets and the active control gro been due to underlying disease or concomitant medication. The overall incidence rates of adverse experiences in these trials were similar for tramadol hydrochloride tablets and the active control groups, TYLENOL with Codeine #3 (acetaminophen 300 mg with codeine phosphate 30 mg), and aspirin 325 mg with codeine phosphate 30 mg, however, the rates of withdrawals due to adverse events appeared to be higher in the tramadol hydrochloride tablets groups. Table 1: Cumulative Incidence of Adverse Reactions for tramadol hydrochloride tablets in Chronic Trials of Nonmalignant Pain (N=427) Up to 7 days Up to 30 days Up to 90 days Dizziness/Vertigo 26% 31% 33% Nausea 24% 34% 40% Constipation 24% 38% 46% Headache 18% 26% 32% Somnolence 16% 23% 25% Vomiting 9% 13% 17% Pruritus 8% 10% 11% "CNS Stimulation" 1 7% 11% 14% Asthenia 6% 11% 12% Sweating 6% 7% 9% Dyspepsia 5% 9% 13% Dry Mouth 5% 9% 10% Diarrhea 5% 6% 10% 1 "CNS Stimulation" is a composite of nervousness, anxiety, agitation, tremor, spasticity, euphoria, emotional lability and hallucinations Incidence 1% to Less than 5% Possibly Causally Related The following lists adverse reactions that occurred with an incidence of 1% to less than 5% city, euphoria, emotional lability and hallucinations Incidence 1% to Less than 5% Possibly Causally Related The following lists adverse reactions that occurred with an incidence of 1% to less than 5% in clinical trials, and for which the possibility of a causal relationship with tramadol hydrochloride tablets exists. Body as a Whole : Malaise. Cardiovascular : Vasodilation. Central Nervous System : Anxiety, Confusion, Coordination disturbance, Euphoria, Miosis, Nervousness, Sleep disorder. Gastrointestinal : Abdominal pain, Anorexia, Flatulence. Musculoskeletal : Hypertonia. Skin : Rash. Special Senses : Visual disturbance. Urogenital : Menopausal symptoms, Urinary frequency, Urinary retention. Incidence Less than 1%, Possibly Causally Related The following lists adverse reactions that occurred with an incidence of less than 1% in clinical trials of tramadol and/or reported in post-marketing experience with tramadol-containing products. Body as a Whole : Accidental injury, Allergic reaction, Anaphylaxis, Death, Suicidal tendency, Weight loss, Serotonin syndrome (mental status change, hyperreflexia, fever, shivering, tremor, agitation, diaphoresis, seizures and coma). Cardiovascula action, Anaphylaxis, Death, Suicidal tendency, Weight loss, Serotonin syndrome (mental status change, hyperreflexia, fever, shivering, tremor, agitation, diaphoresis, seizures and coma). Cardiovascular : Orthostatic hypotension, Syncope, Tachycardia. Central Nervous System : Abnormal gait, Amnesia, Cognitive dysfunction, Depression, Difficulty in concentration, Hallucinations, Paresthesia, Seizure, Tremor. Respiratory : Dyspnea. Skin : Stevens-Johnson syndrome/Toxic epidermal necrolysis, Urticaria, Vesicles. Special Senses : Dysgeusia. Urogenital : Dysuria, Menstrual disorder. Other Adverse Experiences, Causal Relationship Unknown A variety of other adverse events were reported infrequently in patients taking tramadol hydrochloride tablets during clinical trials and/or reported in post-marketing experience. A causal relationship between tramadol hydrochloride tablets and these events has not been determined. However, the most significant events are listed below as alerting information to the physician. Cardiovascular : Abnormal ECG, Hypertension, Hypotension, Myocardial ischemia, Palpitations, Pulmonary edema, Pulmonary embolism. Central Nervous System : Migraine. Gastrointestinal to the physician. Cardiovascular : Abnormal ECG, Hypertension, Hypotension, Myocardial ischemia, Palpitations, Pulmonary edema, Pulmonary embolism. Central Nervous System : Migraine. Gastrointestinal : Gastrointestinal bleeding, Hepatitis, Stomatitis, Liver failure. Laboratory Abnormalities : Creatinine increase, Elevated liver enzymes, Hemoglobin decrease, Proteinuria. Sensory : Cataracts, Deafness, Tinnitus. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of tramadol hydrochloride tablets. 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. Serotonin syndrome : Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Adrenal insufficiency : Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Androgen deficiency : Cases of androgen deficiency have occurred with use of opioids for an extended period of time [see Clinical d with opioid use, more often following greater than one month of use. Androgen deficiency : Cases of androgen deficiency have occurred with use of opioids for an extended period of time [see Clinical Pharmacology (12.2) ] . Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions ( 5.8 )] QT prolongation/torsade de pointes : Cases of QT prolongation and/or torsade de pointes have been reported with tramadol use. Many of these cases were reported in patients taking another drug labeled for QT prolongation, in patients with a risk factor for QT prolongation (e.g., hypokalemia), or in the overdose setting. Eye disorders – mydriasis Metabolism and nutrition disorders – Hyponatremia: Cases of severe hyponatremia and/or SIADH have been reported in patients taking tramadol, most often in females over the age of 65, and within the first week of therapy [see Warnings and Precautions ( 5.19 )] . Hypoglycemia: Cases of hypoglycemia have been reported in patients taking tramadol. Most reports were in patients with predisposing risk factors, including diabetes or renal insufficiency, or in elderly patie emia: Cases of hypoglycemia have been reported in patients taking tramadol. Most reports were in patients with predisposing risk factors, including diabetes or renal insufficiency, or in elderly patients [see Warnings and Precautions ( 5.20 )] . Nervous system disorders – movement disorder, speech disorder Psychiatric disorders – delirium Opioid-induced esophageal dysfunction (OIED): Cases of OIED have been reported in patients taking opioids, and may occur more frequently in patients taking higher doses of opioid, and/or in patients taking opioids longer term [see Warnings and Precautions ( 5.16 )] . Adverse Reactions from Observational Studies A prospective, observational cohort study estimated the risks of addiction, abuse, and misuse in patients initiating long-term use of Schedule II opioid analgesics between 2017 and 2021. Study participants included in one or more analyses had been enrolled in selected insurance plans or health systems for at least one year, were free of at least one outcome at baseline, completed a minimum number of follow-up assessments, and either: 1) filled multiple extended-release/long-acting opioid analgesic prescriptions during a 90 day period (n=978 t one outcome at baseline, completed a minimum number of follow-up assessments, and either: 1) filled multiple extended-release/long-acting opioid analgesic prescriptions during a 90 day period (n=978); or 2) filled any Schedule II opioid analgesic for at least 70 of 90 days (n=1,244). Those included also had no dispensing of the qualifying opioids in the previous 6 months. Over 12 months: approximately 1% to 6% of participants across the two cohorts newly met criteria for addiction, as assessed with two validated interviewbased measures of moderate-to-severe opioid use disorder based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, and approximately 9% and 22% of participants across the two cohorts newly met criteria for prescription opioid abuse and misuse [defined in Drug Abuse and Dependence ( 9.2 )] , respectively, as measured with a validated self-reported instrument. A retrospective, observational cohort study estimated the risk of opioid involved overdose or opioid overdose-related death in patients with new long-term use of Schedule II opioid analgesics from 2006 through 2016 (n=220,249). Included patients had been enrolled in eithe involved overdose or opioid overdose-related death in patients with new long-term use of Schedule II opioid analgesics from 2006 through 2016 (n=220,249). Included patients had been enrolled in either one of two commercial insurance programs, one managed care program, or one Medicaid program for at least 9 months. New long-term use was defined as having Schedule II opioid analgesic prescriptions covering at least 70 days' supply over the 3 months prior to study entry and none during the preceding 6 months. Patients were excluded if they had an opioid-involved overdose in the 9 months prior to study entry. Overdose was measured using a validated medical code-based algorithm with linkage to the National Death Index database. The 5-year cumulative incidence estimates for opioid-involved overdose or opioid overdose-related death ranged from approximately 1.5% to 4% across study sites, counting only the first event during follow-up. Approximately 17% of first opioid overdoses observed over the entire study period (5-11 years, depending on the study site) were fatal. Higher baseline opioid dose was the strongest and most consistent predictor of opioid-involved overdose or opioid overdos the entire study period (5-11 years, depending on the study site) were fatal. Higher baseline opioid dose was the strongest and most consistent predictor of opioid-involved overdose or opioid overdose-related death. Study exclusion criteria may have selected patients at lower risk of overdose, and substantial loss to follow-up (approximately 80%) also may have biased estimates. The risk estimates from the studies described above may not be generalizable to all patients receiving opioid analgesics, such as those with exposures shorter or longer than the duration evaluated in the studies associated with NSAID use. The concurrent use of aspirin and an NSAID, such as etodolac, increases the risk of serious gastrointestinal (GI) events (see WARNINGS ). Status Post Coronary Artery Bypass Graft (CABG) Surgery Two-large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG (see CONTRAINDICATIONS ). Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of etodolac in pat r NSAIDs. Fatal reactions have been reported in such patients (see CONTRAINDICATIONS and PRECAUTIONS , General , Pre-existing Asthma ). Emergency help should be sought in cases where an anaphylactoid reaction occurs. Serious Skin Reactions NSAIDs, including etodolac, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of etodolac tablets at the first appearance of skin rash or any other sign of hypersensitivity. Etodolac tablet is contraindicated in patients with previous serious skin reactions to NSAIDs (see CONTRAINDICATIONS ). Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as Etodolac. Some of these events have been fatal or l ilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as Etodolac. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue etodolac and evaluate the patient immediately. Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs, including etodolac, in pregnant women at about 30 weeks gestation and later. NSAIDs including etodolac, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Ol lac, in pregnant women at about 30 weeks gestation and later. NSAIDs including etodolac, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment: Use of NSAIDs, including etodolac, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit etodolac use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if etodolac treatment extends beyond 20 weeks and 30 weeks gestation, limit etodolac use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if etodolac treatment extends beyond 48 hours. Discontinue etodolac if oligohydramnios occurs and follow up according to clinical practice [see PRECAUTIONS ; Pregnancy ] . DOSAGE AND ADMINISTRATION Carefully consider the potential benefits and risks of etodolac and other treatment options before deciding to use etodolac. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS ). After observing the response to the initial therapy with etodolac, the dose and frequency should be adjusted to suit an individual patient's needs. Dosage adjustment of etodolac is generally not required in patients with mild to moderate renal impairment. Etodolac should be used with caution in such patients, because, as with other NSAIDs, it may further decrease renal function in some patients with impaired renal function (see WARNINGS, Renal Effects ). Analgesia The recommended total daily dose of etodolac for acute pain is up to 1,000 mg, given as 200 to 400 mg every 6 to 8 hours. atients with impaired renal function (see WARNINGS, Renal Effects ). Analgesia The recommended total daily dose of etodolac for acute pain is up to 1,000 mg, given as 200 to 400 mg every 6 to 8 hours. Doses of etodolac greater than 1,000 mg/day have not been adequately evaluated in well-controlled clinical trials. Osteoarthritis and Rheumatoid Arthritis The recommended starting dose of etodolac for the management of the signs and symptoms of osteoarthritis or rheumatoid arthritis is: 300 mg b.i.d., t.i.d., or 400 mg b.i.d., or 500 mg b.i.d. A lower dose of 600 mg/day may suffice for long-term administration. Physicians should be aware that doses above 1,000 mg/day have not been adequately evaluated in well-controlled clinical trials. In chronic conditions, a therapeutic response to therapy with etodolac is sometimes seen within one week of therapy, but most often is observed by two weeks. After a satisfactory response has been achieved, the patient's dose should be reviewed and adjusted as required. ADVERSE REACTIONS In patients taking etodolac or other NSAIDs, the most frequently reported adverse experiences occurring in approximately 1 to 10% of patients are: Gastrointestinal exp d as required. ADVERSE REACTIONS In patients taking etodolac or other NSAIDs, the most frequently reported adverse experiences occurring in approximately 1 to 10% of patients are: Gastrointestinal experiences including : abdominal pain, constipation, diarrhea, dyspepsia, flatulence, gross bleeding/perforation, heartburn, nausea, GI ulcers (gastric/duodenal), vomiting. Other events including : abnormal renal function, anemia, dizziness, edema, elevated liver enzymes, headaches, increased bleeding time, pruritis, rashes, tinnitus. Adverse-reaction information for etodolac was derived from 2,629 arthritic patients treated with etodolac in double-blind and open-label clinical trials of 4 to 320 weeks in duration and worldwide postmarketing surveillance studies. In clinical trials, most adverse reactions were mild and transient. The discontinuation rate in controlled clinical trials, because of adverse events, was up to 10% for patients treated with etodolac. New patient complaints (with an incidence greater than or equal to 1%) are listed below by body system. The incidences were determined from clinical trials involving 465 patients with osteoarthritis treated with 300 to 500 mg of et incidence greater than or equal to 1%) are listed below by body system. The incidences were determined from clinical trials involving 465 patients with osteoarthritis treated with 300 to 500 mg of etodolac b.i.d. (i.e., 600 to 1,000 mg/day). Incidence Greater Than Or Equal To 1% - Probably Causally Related Body as a whole - Chills and fever. Digestive system - Dyspepsia (10%), abdominal pain*, diarrhea*, flatulence*, nausea*, constipation, gastritis, melena, vomiting. Nervous system - Asthenia/malaise*, dizziness*, depression, nervousness. Skin and appendages - Pruritus, rash. Special senses - Blurred vision, tinnitus. Urogenital system - Dysuria, urinary frequency. * Drug-related patient complaints occurring in 3 to 9% of patients treated with etodolac. Drug-related patient-complaints occurring in fewer than 3%, but more than 1%, are unmarked. Incidence Less Than 1% - Probably Causally Related (Adverse reactions reported only in worldwide postmarketing experience, not seen in clinical trials, are considered rarer and are italicized.) Body as a whole - Allergic reaction, anaphylactic/anaphylactoid reactions (including shock). Cardiovascular system - Hypertension, congestive heart l trials, are considered rarer and are italicized.) Body as a whole - Allergic reaction, anaphylactic/anaphylactoid reactions (including shock). Cardiovascular system - Hypertension, congestive heart failure, flushing, palpitations, syncope, vasculitis (including necrotizing and allergic). Digestive system - Thirst, dry mouth, ulcerative stomatitis, anorexia, eructation, elevated liver enzymes, cholestatic hepatitis, hepatitis, cholestatic jaundice, duodenitis, jaundice, hepatic failure, liver necrosis, peptic ulcer with or without bleeding and/or perforation , intestinal ulceration, pancreatitis. Hemic and lymphatic system - Ecchymosis, anemia, thrombocytopenia, bleeding time increased, agranulocytosis, hemolytic anemia, leukopenia, neutropenia, pancytopenia. Metabolic and nutritional - Edema, serum creatinine increase, hyperglycemia in previously controlled diabetic patients. Nervous system - Insomnia, somnolence. Respiratory system - Asthma, pulmonary infiltration with eosinophilia. Skin and appendages - Angioedema, sweating, urticaria, exfoliative dermatitis, vesiculobullous rash, cutaneous vasculitis with purpura, Stevens-Johnson Syndrome, toxic epidermal necrolysis, fixed dru Skin and appendages - Angioedema, sweating, urticaria, exfoliative dermatitis, vesiculobullous rash, cutaneous vasculitis with purpura, Stevens-Johnson Syndrome, toxic epidermal necrolysis, fixed drug eruption (FDE), leukocytoclastic vasculitis, hyperpigmentation, erythema multiforme. Special senses - Photophobia, transient visual disturbances. Urogenital system - Elevated BUN, renal failure, renal insufficiency, renal papillary necrosis. Incidence Less Than 1% - Causal Relationship Unknown (Medical events occurring under circumstances where causal relationship to etodolac is uncertain. These reactions are listed as alerting information for physicians.) Body as a whole - Infection, headache. Cardiovascular system - Arrhythmias, myocardial infarction, cerebrovascular accident. Digestive system - Esophagitis with or without stricture or cardiospasm, colitis. Metabolic and nutritional - Change in weight. Nervous system - Paresthesia, confusion. Respiratory system - Bronchitis, dyspnea, pharyngitis, rhinitis, sinusitis. Skin and appendages - Alopecia, maculopapular rash, photosensitivity, skin peeling. Special senses - Conjunctivitis, deafness, taste perversion. Urogenital system - Cy haryngitis, rhinitis, sinusitis. Skin and appendages - Alopecia, maculopapular rash, photosensitivity, skin peeling. Special senses - Conjunctivitis, deafness, taste perversion. Urogenital system - Cystitis, hematuria, leukorrhea, renal calculus, interstitial nephritis, uterine bleeding irregularities. Additional Adverse Reactions Reported with NSAIDS Body as a whole - Sepsis, death Cardiovascular system - Tachycardia Digestive system - Gastric ulcers, gastritis, gastrointestinal bleeding, glossitis, hematemesis Hemic and lymphatic system - Lymphadenopathy Nervous system - Anxiety, dream abnormalities, convulsions, coma, hallucinations, meningitis, tremors, vertigo Respiratory system - Respiratory depression, pneumonia Urogenital system - Oliguria/polyuria, proteinuria INDICATIONS Indications: CROCUS SATIVUS Fatigue USES To relieve the symptoms of Fatigue. STOP USE AND ASK DOCTOR If symptoms persist/worsen or if pregnant/nursing, stop use and consult your practitioner. DIRECTIONS Adults: Dissolve 3 to 5 under the tongue three times a day or as directed by Lic. Practitioner. Take at greater intervals as condition subsides. Children: Dissolve 3 to 5 under the tongue three times a day or as directed by Lic. Practitioner. Take at greater intervals as condition subsides. KEEP OUT OF REACH OF CHILDREN Keep this and all medicines out of reach of children. INDICATIONS Indications: GUATTERIA GAUMERI Indigestion USES To relieve the symptoms of indigestion. STOP USE AND ASK DOCTOR If symptoms persist/worsen or if pregnant/nursing, stop use and consult your practitioner. DIRECTIONS Adults: Dissolve 3 to 5 under the tongue three times a day or as directed by Lic. Practitioner. Take at greater intervals as condition subsides. Children: Dissolve 3 to 5 under the tongue three times a day or as directed by Lic. Practitioner. Take at greater intervals as condition subsides. KEEP OUT OF REACH OF CHILDREN Keep this and all medicines out of reach of children. 1 INDICATIONS AND USAGE Capecitabine tablets is a nucleoside metabolic inhibitor indicated for: Colorectal Cancer • adjuvant treatment of patients with Stage III colon cancer as a single agent or as a component of a combination chemotherapy regimen. ( 1.1 ) • perioperative treatment of adults with locally advanced rectal cancer as a component of chemoradiotherapy. ( 1.1 ) • treatment of patients with unresectable or metastatic colorectal cancer as a single agent or as a component of a combination chemotherapy regimen. ( 1.1 ) Breast Cancer • treatment of patients with advanced or metastatic breast cancer as a single agent if an anthracycline-or taxane-containing chemotherapy is not indicated. ( 1.2 ) • treatment of patients with advanced or metastatic breast cancer in combination with docetaxel after disease progression on prior anthracycline-containing chemotherapy. ( 1.2 ) Gastric, Esophageal, or Gastroesophageal Junction Cancer • treatment of adults with unresectable or metastatic gastric, esophageal, or gastroesophageal junction cancer as a component of a combination chemotherapy regimen. ( 1.3 ) • treatment of adults with HER2-overexpressing metastatic gastric or gastroesophag astric, esophageal, or gastroesophageal junction cancer as a component of a combination chemotherapy regimen. ( 1.3 ) • treatment of adults with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic disease as a component of a combination regimen. ( 1.3 ) Pancreatic Cancer • adjuvant treatment of adults with pancreatic adenocarcinoma as a component of a combination chemotherapy regimen. ( 1.4 ) 1.1 Colorectal Cancer Capecitabine tablets are indicated for the: adjuvant treatment of patients with Stage III colon cancer as a single agent or as a component of a combination chemotherapy regimen. perioperative treatment of adults with locally advanced rectal cancer as a component of chemoradiotherapy. treatment of patients with unresectable or metastatic colorectal cancer as a single agent or as a component of a combination chemotherapy regimen. 1.2 Breast Cancer Capecitabine tablets are indicated for the: • treatment of patients with advanced or metastatic breast cancer as a single agent if an anthracycline- or taxanecontaining chemotherapy is not indicated. • treatment of patients with advanced or metasta eatment of patients with advanced or metastatic breast cancer as a single agent if an anthracycline- or taxanecontaining chemotherapy is not indicated. • treatment of patients with advanced or metastatic breast cancer in combination with docetaxel after disease progression on prior anthracycline-containing chemotherapy. 1.3 Gastric, Esophageal, or Gastroesophageal Junction Cancer Capecitabine tablets are indicated for the: • treatment of adults with unresectable or metastatic gastric, esophageal, or gastroesophageal junction cancer as a component of a combination chemotherapy regimen. • treatment of adults with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic disease as a component of a combination regimen. 1.4 Pancreatic Cancer Capecitabine tablets are indicated for the adjuvant treatment of adults with pancreatic adenocarcinoma as a component of a combination chemotherapy regimen. 2 DOSAGE AND ADMINISTRATION Adjuvant Treatment of Colon Cancer • Single agent: 1,250 mg/m 2 twice daily orally for the first 14 days of each 21-day cycle for a maximum of 8 cycles. ( 2.1 ) In combination with Oxalipla NISTRATION Adjuvant Treatment of Colon Cancer • Single agent: 1,250 mg/m 2 twice daily orally for the first 14 days of each 21-day cycle for a maximum of 8 cycles. ( 2.1 ) In combination with Oxaliplatin-Containing Regimens: 1,000 mg/m 2 orally twice daily for the first 14 days of each 21-day cycle for a maximum of 8 cycles in combination with oxaliplatin 130 mg/m 2 administered intravenously on day 1 of each cycle. ( 2.1 ) Perioperative Treatment of Rectal Cancer • With Concomitant Radiation Therapy: 825 mg/m 2 orally twice daily ( 2.1 ) • Without Radiation Therapy: 1,250 mg/m 2 orally twice daily ( 2.1 ) Unresectable or Metastatic Colorectal Cancer: • Single agent: 1,250 mg/m 2 twice daily orally for the first 14 days of each 21-day cycle until disease progression or unacceptable toxicity. ( 2.1 ) • In Combination with Oxaliplatin: 1,000 mg/m 2 orally twice daily for the first 14 days of each 21-day cycle until disease progression or unacceptable toxicity in combination with oxaliplatin 130 mg/m 2 administered intravenously on day 1 of each cycle. ( 2.1 ) Advanced or Metastatic Breast Cancer: • Single agent: 1,000 mg/m 2 or 1,250 mg/m 2 twice daily orally for the first 14 days of tin 130 mg/m 2 administered intravenously on day 1 of each cycle. ( 2.1 ) Advanced or Metastatic Breast Cancer: • Single agent: 1,000 mg/m 2 or 1,250 mg/m 2 twice daily orally for the first 14 days of each 21-day cycle until disease progression or unacceptable toxicity. ( 2.2 ) • In combination with docetaxel: 1,000 mg/m 2 or 1,250 mg/m 2 orally twice daily for the first 14 days of a 21-day cycle, until disease progression or unacceptable toxicity in combination with docetaxel at 75 mg/m 2 administered intravenously on day 1 of each cycle ( 2.2 ) Unresectable or Metastatic Gastric, Esophageal, or Gastroesophageal Junction Cancer • 625 mg/m 2 orally twice daily on days 1 to 21 of each 21-day cycle for a maximum of 8 cycles in combination with platinum-containing chemotherapy. ( 2.3 ) OR • 850 mg/m 2 or 1,000 mg/m 2 orally twice daily for the first 14 days of each 21-day cycle until disease progression or unacceptable toxicity in combination with oxaliplatin 130 mg/m 2 administered intravenously on day 1 of each cycle. ( 2.3 ) HER2-overexpressing metastatic adenocarcinoma of the gastroesophageal junction or stomach • 1,000 mg/m 2 orally twice daily for the first 14 days of each 21-da venously on day 1 of each cycle. ( 2.3 ) HER2-overexpressing metastatic adenocarcinoma of the gastroesophageal junction or stomach • 1,000 mg/m 2 orally twice daily for the first 14 days of each 21-day cycle until disease progression or unacceptable toxicity in combination with cisplatin and trastuzumab. ( 2.3 ) Pancreatic cancer • 830 mg/m 2 orally twice daily for the first 21 days of each 28-day cycle for maximum of 6 cycles in combination with gemcitabine 1,000 mg/m 2 administered intravenously on days 1, 8, and 15 of each cycle. ( 2.4 ) Refer to Sections 2.5 and 2.6 for information related to dosage modifications for adverse reactions and renal impairment ( 2.5 and 2.6 ). 2.1 Recommended Dosage for Colorectal Cancer Adjuvant Treatment of Colon Cancer Single Agent The recommended dosage of capecitabine tablets is 1,250 mg/m 2 orally twice daily for the first 14 days of each 21-day cycle for a maximum of 8 cycles. In Combination with Oxaliplatin-Containing Regimens The recommended dosage of capecitabine tablets is 1,000 mg/m 2 orally twice daily for the first 14 days of each 21-day cycle for a maximum of 8 cycles in combination with oxaliplatin 130 mg/m 2 administered intravenous sage of capecitabine tablets is 1,000 mg/m 2 orally twice daily for the first 14 days of each 21-day cycle for a maximum of 8 cycles in combination with oxaliplatin 130 mg/m 2 administered intravenously on day 1 of each cycle. Refer to the oxaliplatin prescribing information for additional dosing information as appropriate. Perioperative Treatment of Rectal Cancer The recommended dosage of capecitabine is 825 mg/m 2 orally twice daily when administered with concomitant radiation therapy and 1,250 mg/m 2 orally twice daily when administered without radiation therapy as part of a peri-operative combination regimen. Unresectable or Metastatic Colorectal Cancer Single Agent The recommended dosage of capecitabine tablets is 1,250 mg/m 2 orally twice daily for the first 14 days of a 21-day cycle until disease progression or unacceptable toxicity. In Combination with Oxaliplatin The recommended dosage of capecitabine tablets is 1,000 mg/m 2 orally twice daily for the first 14 days of each 21-day cycle until disease progression or unacceptable toxicity in combination with oxaliplatin 130 mg/m 2 administered intravenously on day 1 of each cycle. Refer to the Prescribing Information for oxal day cycle until disease progression or unacceptable toxicity in combination with oxaliplatin 130 mg/m 2 administered intravenously on day 1 of each cycle. Refer to the Prescribing Information for oxaliplatin for additional dosing information as appropriate. 2.2 Recommended Dosage for Breast Cancer Advanced or Metastatic Breast Cancer Single Agent The recommended dosage of capecitabine tablets is 1,000 mg/m 2 or 1,250 mg/m 2 orally twice daily for the first 14 days of a 21-day cycle until disease progression or unacceptable toxicity. Individualize the dose and dosing schedule of capecitabine tablets based on patient risk factors and adverse reaction In Combination with Docetaxel The recommended dosage of capecitabine tablets is 1,000 mg/m 2 or 1,250 mg/m 2 orally twice daily for the first 14 days of a 21-day cycle until disease progression or unacceptable toxicity in combination with docetaxel 75 mg/m 2 administered intravenously on day 1 of each cycle. Refer to the Prescribing Information for docetaxel for additional dosing information as appropriate. 2.3 Recommended Dosage for Gastric, Esophageal, or Gastroesophageal Junction Cancer The recommended dosage of capecitabine tablets f ion for docetaxel for additional dosing information as appropriate. 2.3 Recommended Dosage for Gastric, Esophageal, or Gastroesophageal Junction Cancer The recommended dosage of capecitabine tablets for unresectable or metastatic gastric, esophageal, or gastroesophageal junction cancer is: • 625 mg/m 2 orally twice daily on days 1 to 21 of each 21-day cycle for a maximum of 8 cycles in combination with platinum-containing chemotherapy. OR • 850 mg/m 2 or 1,000 mg/m 2 orally twice daily for the first 14 days of each 21-day cycle until disease progression or unacceptable toxicity in combination with oxaliplatin 130 mg/m 2 administered intravenously on day 1 of each cycle. Individualize the dose and dosing schedule of capecitabine tablets based on patient risk factors and adverse reactions. The recommended dosage of capecitabine tablets for HER2- overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma is 1,000 mg/m 2 orally twice daily for the first 14 days of each 21-day cycle until disease progression or unacceptable toxicity in combination with cisplatin and trastuzumab. Refer to the Prescribing Information for agents used in combination for additional dosing 1-day cycle until disease progression or unacceptable toxicity in combination with cisplatin and trastuzumab. Refer to the Prescribing Information for agents used in combination for additional dosing information as appropriate. 2.4 Recommended Dosage for Pancreatic Cancer The recommended dosage of capecitabine tablets is 830 mg/m 2 orally twice daily for the first 21 days of each 28-day cycle until disease progression, unacceptable toxicity, or for a maximum 6 cycles in combination with gemcitabine 1,000 mg/m 2 administered intravenously on days 1, 8, and 15 of each cycle. Refer to Prescribing Information for gemcitabine for additional dosing information as appropriate. 2.5 Dosage Modifications for Adverse Reactions Monitor patients for adverse reactions and modify dosages of capecitabine tablets as described in Table 1. Do not replace missed doses of capecitabine tablets; instead resume capecitabine tablets with the next planned dosage. When capecitabine tablets is administered with docetaxel, withhold capecitabine tablets and docetaxel until the requirements for resuming both capecitabine tablets and docetaxel are met. Refer to the Prescribing Information for docetaxel for additi ocetaxel, withhold capecitabine tablets and docetaxel until the requirements for resuming both capecitabine tablets and docetaxel are met. Refer to the Prescribing Information for docetaxel for additional dosing information as appropriate. Table 1 Recommended Dosage Modifications for Adverse Reactions Severity Dosage Modification Resume at Sameor Reduced Dose (Percentof Current Dose) Grade 2 1st appearance Withhold until resolved to grade 0-1. 100% 2nd appearance 75% 3rd appearance 50% 4th appearance Permanently discontinue. - Grade 3 1st appearance Withholduntil resolved to grade 0-1. 75% 2nd appearance 50% 3rd appearance Permanently discontinue. - Grade 4 1st appearance Permanently discontinue OR Withhold until resolved to grade 0-1. 50% Hyperbilirubinemia Patients with Grade 3-4 hyperbilirubinemia may resume treatment once the event is Grade 2 or less (less than three times the upper limit of normal), using the percent of current dose as shown in column 3 of Table 1 [see Warnings and Precautions ( 5.10 )]. 2.6 Dosage Modification For Renal Impairment Reduce the dose of capecitabine tablets by 25% for patients with creatinine clearance (CLcr) of 30 to 50 mL/min as determined by C d Precautions ( 5.10 )]. 2.6 Dosage Modification For Renal Impairment Reduce the dose of capecitabine tablets by 25% for patients with creatinine clearance (CLcr) of 30 to 50 mL/min as determined by Cockcroft-Gault equation. A dosage has not been established in patients with severe renal impairment (CLcr <30 mL/min) [see Use in Specific Populations (8.6) ]. 2.7 Administration Round the recommended dosage for patients to the nearest 150 mg dose to provide whole capecitabine tablets. Swallow capecitabine tablets whole with water within 30 minutes after a meal. Do not chew, cut, or crush capecitabine tablets [see Warnings and Precautions ( 5.12 )]. Take capecitabine tablets at the same time each day approximately 12 hours apart. Do not take an additional dose after vomiting and continue with the next scheduled dose. Do not take a missed dose and continue with the next scheduled dose. Capecitabine tablet is a hazardous drug. Follow applicable special handling and disposal procedures. 6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Cardiotoxicity [see Warnings and Precautions ( 5.3 )] Diarrhea [see Warnings and Precauti ERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Cardiotoxicity [see Warnings and Precautions ( 5.3 )] Diarrhea [see Warnings and Precautions ( 5.4 )] Dehydration [see Warnings and Precautions ( 5.5 )] Renal Toxicity [see Warnings and Precautions ( 5.6 )] Serious Skin Toxicities [see Warnings and Precautions ( 5.7 )] Palmar-Plantar Erythrodysesthesia Syndrome [see Warnings and Precautions ( 5.8 )] Myelosuppression [see Warnings and Precautions ( 5.9 )] Hyperbilirubinemia [see Warnings and Precautions ( 5.10 )] • Most common adverse reactions in patients who received capecitabine tablets as a single agent for the adjuvant treatment for colon cancer (>30%) were palmar-plantar erythrodysesthesia syndrome, diarrhea, and nausea. ( 6.1 ) • Most common adverse reactions (>30%) in patients with metastatic colorectal cancer who received capecitabine tablets as a single agent were anemia, diarrhea, palmar-plantar erythrodysesthesia syndrome, hyperbilirubinemia, nausea, fatigue, and abdominal pain. ( 6.1 ) • Most common adverse reactions (>30%) in patients with metastatic breast cancer who received capecitabine tablets with docetax ndrome, hyperbilirubinemia, nausea, fatigue, and abdominal pain. ( 6.1 ) • Most common adverse reactions (>30%) in patients with metastatic breast cancer who received capecitabine tablets with docetaxel were diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome, nausea, alopecia, vomiting, edema, and abdominal pain. ( 6.1 ) • Most common adverse reactions (>30%) in patients with metastatic breast cancer who received capecitabine tablets as a single agent were lymphopenia, anemia, diarrhea, handand- foot syndrome, nausea, fatigue, vomiting, and dermatitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy’s Laboratories Inc., at 1-888-375-3784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adjuvant Treatment of Colon Cancer Single Agent The safety of capecitabine tablets as a single agent was evaluated in patients with Stage III colon cancer in X-ACT [see Clinical observed in practice. Adjuvant Treatment of Colon Cancer Single Agent The safety of capecitabine tablets as a single agent was evaluated in patients with Stage III colon cancer in X-ACT [see Clinical Studies (14.1)]. Patients receivedcapecitabine tablets 1,250 mg/m 2 orally twice daily for the first 14 days of a 21-day cycle (N=995) or leucovorin 20 mg/m 2 intravenously followed by fluorouracil 425 mg/m 2 as an intravenous bolus on days 1 to 5 of each 28-day cycle (N=974). Among patients who received capecitabine tablets, the median duration of treatment was 5.4 months. Deaths due to all causes occurred in 0.8% of patients who received capecitabine tablets on study or within 28 days of receiving study drug. Permanent discontinuation due to an adverse reaction occurred in 11% of patients who received capecitabine tablets. Most common adverse reactions (>30%) were palmar-plantar erythrodysesthesia syndrome, diarrhea, and nausea. Tables 2 and 3 summarize the adverse reactions and laboratory abnormalities in X-ACT. Table 2 Adverse Reactions (>10%) in Patients Who Received Capecitabine Tablets for Adjuvant Treatment of Colon Cancer in X-ACT Adverse Reaction C apecitabine Tablets (N=995) ry abnormalities in X-ACT. Table 2 Adverse Reactions (>10%) in Patients Who Received Capecitabine Tablets for Adjuvant Treatment of Colon Cancer in X-ACT Adverse Reaction C apecitabine Tablets (N=995) Fluorouracil + Leucovorin (N=974) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Skin and Subcutaneous Tissue Palmar-plantar erythrodysesthesiasyndrome 60 17 9 <1 Gastrointestinal Diarrhea 47 12 65 14 Nausea 34 2 47 2 Stomatitis 22 2 60 14 Vomiting 15 2 21 2 Abdominal pain 14 3 16 2 General Fatigue 16 <1 16 1 Asthenia 10 <1 10 1 Lethargy 10 <1 9 <1 Clinically relevant adverse reactions in <10% of patients are presented below: Eye: conjunctivitis Gastrointestinal: constipation, upper abdominal pain, dyspepsia General: pyrexia Metabolism and Nutrition : anorexia Nervous System:d izziness, dysgeusia, headache Skin & Subcutaneous Tissue: rash, alopecia, erythema Table 3 Grade 3 or 4 Laboratory Abnormalities (>1%) in Patients Who Received Capecitabine Tablets as a Single Agent for Adjuvant Treatment of Colon Cancer in X- ACT Laboratory Abnormality C apecitabine Tablets (N=995) Fluorouracil + Leucovorin (N=974) Grade 3 or 4 (%) Grade 3 or 4 (%) Bilirubin increased 20 6 Lymp for Adjuvant Treatment of Colon Cancer in X- ACT Laboratory Abnormality C apecitabine Tablets (N=995) Fluorouracil + Leucovorin (N=974) Grade 3 or 4 (%) Grade 3 or 4 (%) Bilirubin increased 20 6 Lymphocytes decreased 13 13 Neutrophils/granulocytes decreased 2.4 26 Calcium decreased 2.3 2.2 Neutrophils decreased 2.2 26 ALT increased 1.6 0.6 Calcium increased 1.1 0.7 Hemoglobin decreased 1 1.2 Platelets decreased 1 0.7 In Combination with Oxaliplatin-Containing Regimens The safety of capecitabine tablets for the perioperative treatment of adults with Stage III colon cancer as a component of a combination chemotherapy regimen was derived from published literature [see Clinical Studies ( 14.1 )]. The safety of capecitabine tablets for the adjuvant treatment of patients with Stage III colon cancer as a component of a combination chemotherapy regimen was similar to those in patients treated with capecitabine tablets as a single agent, with the exception of an increased incidence of neurosensory toxicity. Perioperative Treatment of RectalCancer The safety of capecitabine tablets for the perioperative treatment of adults with locally advanced rectal cancer as a component of chemoradiother sory toxicity. Perioperative Treatment of RectalCancer The safety of capecitabine tablets for the perioperative treatment of adults with locally advanced rectal cancer as a component of chemoradiotherapy was derived from published literature [see Clinical Studies ( 14.1 )]. The safety of capecitabine tablets for the perioperative treatment of adults with locally advanced rectal cancer as a component of chemoradiotherapy was similar to those in patients treated with capecitabine tablets as a single agent, with the exception of an increased incidence of diarrhea. Metastatic Colorectal Cancer Single Agent The safety of capecitabine tablets as a single agent was evaluated in a pooled metastatic colorectal cancer population (Study SO14695 and Study SO14796)[see Clinical Studies ( 14.1 )]. Patients received capecitabine tablets 1,250 mg/m 2 orally twice a day for the first 14 days of a 21-day cycle (N=596) or leucovorin 20 mg/m 2 intravenously followed by fluorouracil 425 mg/m 2 as an intravenous bolus on days 1 to 5 of each 28-day cycle (N=593). Among the patients who received capecitabine tablets, the median duration of treatment was 4.6 months. Deaths due to all causes occurred in 8% enous bolus on days 1 to 5 of each 28-day cycle (N=593). Among the patients who received capecitabine tablets, the median duration of treatment was 4.6 months. Deaths due to all causes occurred in 8% of patients who received capecitabine tablets on study or within 28 days of receiving study drug. Permanent discontinuation due to an adverse reaction or intercurrent illness occurred in 13% of patients who received capecitabine tablets. Most common adverse reactions (>30%) were anemia, diarrhea, palmar-plantar erythrodysesthesia syndrome, hyperbilirubinemia, nausea, fatigue, and abdominal pain. Table 4 shows the adverse reactions occurring in this pooled colorectal cancer population. Table 4 Adverse Reactions (>10%) in Patients Who Received Capecitabine Tablets in Pooled Metastatic Colorectal Cancer Population (Study SO14695 and Study SO14796) Adverse Reaction C apecitabine Tablets (N=596) Fluorouracil + Leucovorin (N=593) All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) Blood and Lymphatic System Anemia 80 2 <1 79 1 <1 Neutropenia 13 1 2 46 8 13 Gastrointestinal Diarrhea 55 13 2 61 10 2 Nausea 43 4 – 51 3 <1 Abdominal pain 35 9 <1 31 5 – Vomiting 27 4 <1 Grade 4 (%) Blood and Lymphatic System Anemia 80 2 <1 79 1 <1 Neutropenia 13 1 2 46 8 13 Gastrointestinal Diarrhea 55 13 2 61 10 2 Nausea 43 4 – 51 3 <1 Abdominal pain 35 9 <1 31 5 – Vomiting 27 4 <1 30 4 <1 Stomatitis 25 2 <1 62 14 1 Constipation 14 1 <1 17 1 – Gastrointestinal motility disorder 10 <1 – 7 <1 – Oral discomfort 10 – – 10 – – Skin and Subcutaneous Tissue Palmar-plantar erythrodysesthesia syndrome 54 17 NA 6 1 NA Dermatitis 27 1 – 26 1 – Hepatobiliary Hyperbilirubinemia 48 18 5 17 3 3 General Fatigue* 42 4 – 46 4 – Pyrexia 18 1 – 21 2 – Edema 15 1 – 9 1 – Pain 12 1 – 10 1 – Metabolism and Nutrition Decreased appetite 26 3 <1 31 2 <1 Respiratory Thoracic and Mediastinal Dyspnea 14 1 – 10 <1 1 Eye Eye irritation 13 – – 10 <1 – Nervous System Peripheral sensory neuropathy 10 – – 4 – – Headache 10 1 – 7 – – Musculoskeletal Back pain 10 2 – 9 <1 – – Not observed* Includes weakness NA = Not Applicable Clinically relevant adverse reactions in <10% of patients are presented below: Eye: abnormal vision Gastrointestinal: upper gastrointestinal tract inflammatory disorders, gastrointestinal hemorrhage, ileus General: chest pain Infections: viral Metabolism and Nutrition: dehydra : Eye: abnormal vision Gastrointestinal: upper gastrointestinal tract inflammatory disorders, gastrointestinal hemorrhage, ileus General: chest pain Infections: viral Metabolism and Nutrition: dehydration Musculoskeletal: arthralgia Nervous System:dizziness (excluding vertigo), insomnia, taste disturbance Psychiatric: mood alteration, depression Respiratory, Thoracic, and Mediastinal:cough, pharyngeal disorder Skin and Subcutaneous Tissue: skin discoloration, alopecia Vascular: venous thrombosis In Combination with Oxaliplatin The safety of capecitabine tablets for the treatment of patients with unresectable or metastatic colorectal cancer as a component of a combination chemotherapy regimen was derived from published literature [see Clinical Studies ( 14.1 )]. The safety of capecitabine tablets for the treatment of patients with unresectable or metastatic colorectal cancer as a component of a combination chemotherapy regimen was similar to those in patients treated with capecitabine tablets as a single agent, with the exception of an increased incidence of peripheral neuropathy. Metastatic Breast Cancer In Combination with Docetaxel The safety of capecitabine tablets in combinatio ablets as a single agent, with the exception of an increased incidence of peripheral neuropathy. Metastatic Breast Cancer In Combination with Docetaxel The safety of capecitabine tablets in combination with docetaxel was evaluated in patients with metastatic breast cancer in Study SO14999 [see Clinical Studies ( 14.2 )].Patients received capecitabine tablets 1,250 mg/m 2 orally twice daily for the first 14 days of a 21-day cycle with docetaxel 75 mg/m 2 as 1- hour intravenous infusion on day 1 of each 21-day cycle for at least 6 weeks or docetaxel 100 mg/m 2 as a 1-hour intravenous infusion on day 1 of each 21-day cycle for at least 6 weeks. Among patients who received capecitabine tablets, the mean duration of treatment was 4.2 months. Permanent discontinuation due to an adverse reaction occurred in 26% of patients who received capecitabine tablets. Dosage interruptions due to an adverse reaction occurred in 79% of patients who received capecitabine tablets and dosage reductions due to an adverse reaction occurred in 65%. Most common adverse reactions (>30%) were diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome, nausea, alopecia, vomiting, edema, and abdominal pain o an adverse reaction occurred in 65%. Most common adverse reactions (>30%) were diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome, nausea, alopecia, vomiting, edema, and abdominal pain. Table 5 summarizes the adverse reactions in Study SO14999. Table 5 Adverse Reactions (≥10%) in Patients Who Received Capecitabine Tablets with Docetaxel for Metastatic Breast Cancer in Study SO14999 Adverse Reaction C apecitabine Tablets with Docetaxel (N=251) Docetaxel (N=255) All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) Gastrointestinal Diarrhea 67 14 <1 48 5 <1 Stomatitis 67 17 <1 43 5 – Nausea 45 7 – 36 2 – Vomiting 35 4 1 24 2 – Abdominal pain 30 3 <1 24 2 – Constipation 20 2 – 18 – – Dyspepsia 14 – – 8 1 – Skin and Subcutaneous Tissue Palmar-plantar erythrodysesthesia syndrome 63 24 NA 8 1 NA Alopecia 41 6 – 42 7 – Nail disorder 14 2 – 15 – – Cardiac Edema 33 <2 – 34 <3 1 General Pyrexia 28 2 – 34 2 – Asthenia 26 4 <1 25 6 – Fatigue 22 4 – 27 6 – Weakness 16 2 – 11 2 – Pain in Limb 13 <1 – 13 2 – Blood and Lymphatic System Neutropenic fever 16 3 13 21 5 16 Nervous System Taste disturbance 16 <1 – 14 <1 – Headache 15 3 – 15 2 – Paresthesia 12 <1 akness 16 2 – 11 2 – Pain in Limb 13 <1 – 13 2 – Blood and Lymphatic System Neutropenic fever 16 3 13 21 5 16 Nervous System Taste disturbance 16 <1 – 14 <1 – Headache 15 3 – 15 2 – Paresthesia 12 <1 – 16 1 – Dizziness 12 – – 8 <1 – Musculoskeletal and Connective Tissue Arthralgia 15 2 – 24 3 – Myalgia 15 2 – 25 2 – Back Pain 12 <1 – 11 3 – Respiratory, Thoracic and Mediastinal Dyspnea 14 2 <1 16 2 – Cough 13 1 – 22 <1 – Sore Throat 12 2 – 11 <1 – Metabolism and Nutrition Anorexia 13 <1 – 11 <1 – Appetite decreased 10 – – 5 – – Dehydration 10 2 – 7 <1 <1 Eye Lacrimation increased 12 – – 7 <1 – – Not observed NA = Not Applicable Clinically relevant adverse reactions in <10% of patients are presented below: Blood and Lymphatic System: agranulocytosis, prothrombin decreased Cardiac: supraventricular tachycardia Eye: conjunctivitis, eye irritation Gastrointestinal: ileus, necrotizing enterocolitis, esophageal ulcer, hemorrhagic diarrhea, dry mouth General: chest pain (non-cardiac), lethargy, pain, influenza-like illness Hepatobiliary: jaundice, abnormal liver function tests, hepatic failure, hepatic coma, hepatotoxicity Immune System: hypersensitivity Infection: hypoesthesia, neutropen y, pain, influenza-like illness Hepatobiliary: jaundice, abnormal liver function tests, hepatic failure, hepatic coma, hepatotoxicity Immune System: hypersensitivity Infection: hypoesthesia, neutropenic sepsis, sepsis, bronchopneumonia, oral candidiasis, urinary tract infection Metabolism and Nutrition: weight decreased Musculoskeletal and Connective Tissue:bone pain Nervous System: insomnia, peripheral neuropathy, ataxia, syncope, taste loss, polyneuropathy, migraine Psychiatric: depression Renal and Urinary: renal failure Respiratory, Thoracic and Mediastinal: upper respiratory tract infection, pleural effusion, epistaxis, rhinorrhea Skin and Subcutaneous Tissue: pruritis, rash erythematous, dermatitis, nail discoloration, onycholysis Vascular: lymphedema, hypotension, venous phlebitis and thrombophlebitis, postural hypotension, flushing Table 6 summarizes the laboratory abnormalities in this trial. Table 6 Laboratory Abnormalities (≥20%) in Patients Who Received Capecitabine Tablets with Docetaxel for Metastatic Breast Cancer in Study SO14999 Laboratory Abnormality C apecitabine Tablets with Docetaxel (N=251) Docetaxel (N=255) All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (% with Docetaxel for Metastatic Breast Cancer in Study SO14999 Laboratory Abnormality C apecitabine Tablets with Docetaxel (N=251) Docetaxel (N=255) All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) Hematologic Lymphocytopenia 99 48 41 98 44 40 Leukopenia 91 37 24 88 42 33 Neutropenia 86 20 49 87 10 66 Anemia 80 7 3 83 5 <1 Thrombocytopenia 41 2 1 23 1 2 Hepatobiliary Hyperbilirubinemia 20 7 2 6 2 2 Single Agent The safety of capecitabine tablets as a single agent was evaluated in patients with metastatic breast cancer in Study SO14697 [see Clinical Studies ( 14.2 )]. Patients received capecitabine tablets 1,250 mg/m 2 orally twice daily for the first 14 days of a 21-day cycle. The mean duration of treatment was 3.7 months. Permanent discontinuation due to an adverse reaction or intercurrent illness occurred in 8% of patients. Most common adverse reactions (>30%) were lymphopenia, anemia, diarrhea, hand-and-foot syndrome, nausea, fatigue, vomiting, and dermatitis. Table 7 summarizes the adverse reactions in Study SO14697. Table 7 Adverse Reactions (>10%) in Patients Who Received Capecitabine Tablets for Metastatic Breast Cancer in Study SO14697 Adverse Re itis. Table 7 summarizes the adverse reactions in Study SO14697. Table 7 Adverse Reactions (>10%) in Patients Who Received Capecitabine Tablets for Metastatic Breast Cancer in Study SO14697 Adverse Reaction C apecitabine Tablets (n=162) All Grades (%) Grade 3 (%) Grade 4 (%) Blood and Lymphatic System Lymphopenia 94 44 15 Anemia 72 3 1 Neutropenia 26 2 2 Thrombocytopenia 24 3 1 Gastrointestinal Diarrhea 57 12 3 Nausea 53 4 – Vomiting 37 4 – Stomatitis 24 7 – Abdominal pain 20 4 – Constipation 15 1 – Skin and Subcutaneous Tissue Hand-and-foot syndrome 57 11 NA Dermatitis 37 1 – General Fatigue 41 8 – Pyrexia 12 1 – Metabolism and Nutrition Anorexia 23 3 – Hepatobiliary Hyperbilirubinemia 22 9 2 Nervous System Paresthesia 21 1 – Eye Eye irritation 15 – – – = Not observed NA = Not Applicable Pooled SafetyPopulation Clinically relevant adverse reactions in <10% of patients who received capecitabine tablets as a single agent are presented below. Blood & Lymphatic System: leukopenia, coagulation disorder, bone marrow depression, pancytopenia Cardiac: tachycardia, bradycardia, atrial fibrillation, myocarditis, edema Ear: vertigo Eye: conjunctivitis Gastrointestinal: abdominal distension, tion disorder, bone marrow depression, pancytopenia Cardiac: tachycardia, bradycardia, atrial fibrillation, myocarditis, edema Ear: vertigo Eye: conjunctivitis Gastrointestinal: abdominal distension, dysphagia, proctalgia, gastric ulcer, ileus, gastroenteritis, dyspepsia General: chest pain, influenza-like illness, hot flushes, pain, thirst, fibrosis, hemorrhage, edema, pain in limb Hepatobiliary: hepatic fibrosis, hepatitis, cholestatic hepatitis, abnormal liver function tests Immune System:drug hypersensitivity Infections: bronchitis, pneumonia, keratoconjunctivitis, sepsis, fungal infections Metabolism and Nutrition: cachexia, hypertriglyceridemia, hypokalemia, hypomagnesemia, dehydration Musculoskeletal and Connective Tissue:myalgia, arthritis, muscleweakness Nervous System: insomnia, ataxia, tremor, dysphasia, encephalopathy, dysarthria, impaired balance, headache, dizziness Psychiatric: depression, confusion Renal and Urinary: renal impairment Respiratory, Mediastinal and Thoracic: cough, epistaxis, respiratory distress, dyspnea Skin and Subcutaneous Tissue:nail disorder, sweating increased, photosensitivity reaction, skin ulceration, pruritus, radiation recall syndrome Vascu c: cough, epistaxis, respiratory distress, dyspnea Skin and Subcutaneous Tissue:nail disorder, sweating increased, photosensitivity reaction, skin ulceration, pruritus, radiation recall syndrome Vascular: hypotension, hypertension, lymphedema, pulmonary embolism Unresectable or Metastatic Gastric, Esophageal, or Gastroesophageal Junction Cancer The safety of capecitabine tablets for the treatment of adults with unresectable or metastatic gastric, esophageal, or gastroesophageal junction cancer as a component of a combination chemotherapy regimen was derived from published literature [see Clinical Studies ( 14.3 )]. The safety of capecitabine tablets for the treatment of adults with unresectable or metastatic gastric, esophageal, or gastroesophageal junction cancer as a component of a combination chemotherapy regimen was consistent with the known safety profile of capecitabine tablets. The safety of capecitabine tablets for the treatment of patients with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic disease as a component of a combination regimen was derived from the published literature [see C astric or gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic disease as a component of a combination regimen was derived from the published literature [see Clinical Studies ( 14.3 )]. The safety of capecitabine tablets for the treatment of patients with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma was consistent with the known safety profile of capecitabine tablets. Pancreatic Cancer The safety of capecitabine tablets for the adjuvant treatment of adults with pancreatic adenocarcinoma as a component of a combination chemotherapy regimen was derived from the published literature [see Clinical Studies ( 14.4 )]. The safety of capecitabine tablets for the adjuvant treatment of adults with pancreatic adenocarcinoma as a component of a combination chemotherapy regimen was consistent with the known safety profile of capecitabine tablets. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of capecitabine tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their freq tified during post-approval use of capecitabine tablets. 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. Eye: lacrimal duct stenosis, corneal disorders including keratitis Hepatobiliary: hepatic failure Immune System Disorders: angioedema Nervous System: toxic leukoencephalopathy Renal & Urinary: acute renal failure secondary to dehydration including fatal outcome Skin & Subcutaneous Tissue: cutaneous lupus erythematosus, severe skin reactions such as Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis (TEN), persistent or severe PPES can eventually lead to loss of fingerprints 1 INDICATIONS AND USAGE Trazodone is a selective serotonin reuptake inhibitor indicated for the treatment of major depressive disorder (MDD) ( 1 ). Trazodone hydrochloride tablets are indicated for the treatment of major depressive disorder (MDD) in adults. 2 DOSAGE AND ADMINISTRATION Starting dose: 150 mg in divided doses daily. May be increased by 50 mg per day every three to four days. Maximum dose: 400 mg per day in divided doses ( 2 ). Trazodone hydrochloride tablets should be taken shortly after a meal or light snack ( 2 ). Tablets should be swallowed whole or broken in half along the score line, and should not be chewed or crushed ( 2 ). When discontinued, gradual dose reduction is recommended ( 2 ). 2.1 Dose Selection An initial dose of 150 mg/day in divided doses is suggested. The dosage should be initiated at a low-dose and increased gradually, noting the clinical response and any evidence of intolerance. Occurrence of drowsiness may require the administration of a major portion of the daily dose at bedtime or a reduction of dosage. The dose may be increased by 50 mg/day every 3 to 4 days. The maximum dose for outpatients usually should not exceed 400 mg/day in divided do ion of the daily dose at bedtime or a reduction of dosage. The dose may be increased by 50 mg/day every 3 to 4 days. The maximum dose for outpatients usually should not exceed 400 mg/day in divided doses. Inpatients (i.e., more severely depressed patients) may be given up to but not in excess of 600 mg/day in divided doses. Once an adequate response has been achieved, dosage may be gradually reduced, with subsequent adjustment depending on therapeutic response. 2.2 Improtant Administration Instructions Trazodone hydrochloride tablets can be swallowed whole or administered as a half tablet by breaking the tablet along the score line. Trazodone hydrochloride tablets should be taken shortly after a meal or light snack. 2.3 Screen for Bipolar Disorder Prior to Starting Trazodone Prior to initiating treatment with trazodone hydrochloride tablets or another antidepressant, screen patients for a personal or family history of bipolar disorder, mania, or hypomania [see Warnings and Precautions ( 5.7 )]. 2.4 Switchning to or from Monoamine Oxidase Inhibitor Antidepressant At least 14 days must elapse between discontinuation of a monoamine oxidase inhibitor (MAOI) antidepressant and initiatio ( 5.7 )]. 2.4 Switchning to or from Monoamine Oxidase Inhibitor Antidepressant At least 14 days must elapse between discontinuation of a monoamine oxidase inhibitor (MAOI) antidepressant and initiation of trazodone hydrochloride tablets. In addition, at least 14 days must elapse after stopping trazodone hydrochloride tablets before starting an MAOI antidepressant [see Contraindications ( 4 ), Warnings and Precautions ( 5.2 )]. 2.5 Dosage Recommendations for Concomitant Use with Strong CYP3A4 Inhibitors or Inducers Coadministration with Strong CYP3A4 Inhibitors Consider reducing trazodone dose based on tolerability when trazodone is coadministered with a strong CYP3A4 inhibitor [see Drug Interactions ( 7.1 )]. Coadministration with Strong CYP3A4 Inducers Consider increasing trazodone dose based on therapeutic response when trazodone is coadministered with a strong CYP3A4 inducer [see Drug Interactions ( 7.1 )]. 2.6 Discontinuation of Treatment with Trazodone Adverse reactions may occur upon discontinuation of trazodone [See Warnings and Precautions ( 5.8 )]. Gradually reduce the dosage rather than stopping trazodone abruptly whenever possible. 6 ADVERSE REACTIONS Most common adverse upon discontinuation of trazodone [See Warnings and Precautions ( 5.8 )]. Gradually reduce the dosage rather than stopping trazodone abruptly whenever possible. 6 ADVERSE REACTIONS Most common adverse reactions (incidence ≥ 5% and twice that of placebo) are: edema, blurred vision, syncope, drowsiness, fatigue, diarrhea, nasal congestion, weight loss ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The following serious adverse reactions are described elsewhere in the labeling: Suicidal Thoughts and Behavior in Children, Adolescents and Young Adults [see Boxed Warning and Warnings and Precautions ( 5.1 )] Serotonin Syndrome [see Warnings and Precautions ( 5.2 )] Cardiac Arrythmias ( see Warnings and Precautions ( 5.3 )] Orthostatic Hypotension and Syncope [see Warnings and Precautions ( 5.4 )] Increased Risk of Bleeding [see Warnings and Precautions ( 5.5 )] Priapism [see Warnings and Precautions ( 5.6 )] Activation of Mania or Hypomania [see Warnings and Precautions ( 5.7 )] Discontinuation Syndrome [see Warnings and Precautions ( 5.8 )] Potential for Cognitive and Motor Impair nd Precautions ( 5.6 )] Activation of Mania or Hypomania [see Warnings and Precautions ( 5.7 )] Discontinuation Syndrome [see Warnings and Precautions ( 5.8 )] Potential for Cognitive and Motor Impairment [see Warnings and Precautions ( 5.9 )] Angle-Closure Glaucoma [see Warnings and Precautions ( 5.10 )] Hyponatremia [see Warnings and Precautions ( 5.11 )] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Table 2 Common Adverse Reactions Occurring in ≥ 2% of Trazodone-treated Patients and Greater than the Rate of Placebo-Treated Patients as Observed in Controlled Clinical Studies Inpatients Outpatients Trazodone Placebo Trazodone Placebo N=142 N=95 N=157 N=158 Allergic Skin Condition/Edema 3% 1% 7% 1% Autonomic Blurred Vision 6% 4% 15% 4% Constipation 7% 4% 8% 6% Dry Mouth 15% 8% 34% 20% Cardiovascular Hypertension 20% 1% 1% * Hypotension 7% 1% 4% 0 Syncope 3% 2% 5% 1% CNS Confusion 5% 0 6% 8% Decreased Concentration 3% 2% 1% 0 Disorientati ipation 7% 4% 8% 6% Dry Mouth 15% 8% 34% 20% Cardiovascular Hypertension 20% 1% 1% * Hypotension 7% 1% 4% 0 Syncope 3% 2% 5% 1% CNS Confusion 5% 0 6% 8% Decreased Concentration 3% 2% 1% 0 Disorientation 2% 0 * 0 Dizziness/Light-Headedness 20% 5% 28% 15% Drowsiness 24% 6% 41% 20% Fatigue 11% 4% 6% 3% Headache 10% 5% 20% 16% Nervousness 15% 11% 6% 8% Gastrointestinal Abdominal/Gastric Disorder 4% 4% 6% 4% Diarrhea 0 1% 5% 1% Nausea/Vomiting 10% 1% 13% 10% Musculoskeletal Aches/Pains 6% 3% 5% 3% Neurological Incoordination 5% 0 2% * Tremors 3% 1% 5% 4% Other Eyes Red/Tired/Itching 3% 0 0 0 Head Full-Heavy 3% 0 0 0 Malaise 3% 0 0 0 Nasal/Sinus Congestion 3% 0 6% 3% Weight Gain 1% 0 5% 2% Weight Loss * 3% 6% 3% Other adverse reactions occurring at an incidence of <2% with the use of trazodone hydrochloride in the controlled clinical studies: akathisia, allergic reaction, anemia, chest pain, delayed urine flow, early menses, flatulence, hallucinations/delusions, hematuria, hypersalivation, hypomania, impaired memory, impaired speech, impotence, increased appetite, increased libido, increased urinary frequency, missed periods, muscle twitches, numbness, paresthesia, retrograde ejaculation ypomania, impaired memory, impaired speech, impotence, increased appetite, increased libido, increased urinary frequency, missed periods, muscle twitches, numbness, paresthesia, retrograde ejaculation, shortness of breath, and tachycardia/palpitations. Occasional sinus bradycardia has occurred in long-term studies. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of trazodone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure: Blood and lymphatic system disorders: hemolytic anemia, leukocytosis Cardiac disorders: cardiospasm, congestive heart failure, conduction block, orthostatic hypotension and syncope, palpitations, bradycardia, atrial fibrillation, myocardial infarction, cardiac arrest, arrhythmia, ventricular ectopic activity, including ventricular tachycardia and QT prolongation. Prolonged QT interval, torsade de pointes, and ventricular tachycardia have been reported at doses of 100 mg per day or less [see Warnings and Precautions ( 5.3 )]. Endocrine disorders: inappropriate ADH longed QT interval, torsade de pointes, and ventricular tachycardia have been reported at doses of 100 mg per day or less [see Warnings and Precautions ( 5.3 )]. Endocrine disorders: inappropriate ADH syndrome Eye disorders: diplopia Gastrointestinal disorders: increased salivation, nausea/vomiting General disorders and administration site conditions: chills, edema, unexplained death, weakness Hepatobiliary disorders: cholestasis, jaundice, hyperbilirubinemia, liver enzyme alterations Investigations: increased amylase Metabolism and nutrition disorders: methemoglobinemia Nervous system disorders: aphasia, ataxia, cerebrovascular accident, extrapyramidal symptoms, grand mal seizures, paresthesia, tardive dyskinesia, vertigo Psychiatric disorders: abnormal dreams, agitation, anxiety, hallucinations, insomnia, paranoid reaction, psychosis, stupor Renal and urinary disorders: urinary incontinence, urinary retention Reproductive system and breast disorders: breast enlargement or engorgement, clitorism, lactation, priapism [see Warnings and Precautions ( 5.6 )] Respiratory, thoracic and mediastinal disorders: apnea Skin and subcutaneous tissue disorders: alopecia, hirsutism, leukonychia, , clitorism, lactation, priapism [see Warnings and Precautions ( 5.6 )] Respiratory, thoracic and mediastinal disorders: apnea Skin and subcutaneous tissue disorders: alopecia, hirsutism, leukonychia, pruritus, psoriasis, rash, urticaria Vascular disorders: vasodilation INDICATIONS AND USAGE POLOCAINE (Mepivacaine HCl Injection, USP), is indicated for production of local or regional analgesia and anesthesia by local infiltration, peripheral nerve block techniques, and central neural techniques including epidural and caudal blocks. The routes of administration and indicated concentrations for mepivacaine are: local infiltration 0.5% (via dilution) or 1% peripheral nerve blocks 1% and 2% epidural block 1%, 1.5%, 2% caudal block 1%, 1.5%, 2% See DOSAGE AND ADMINISTRATION for additional information. Standard textbooks should be consulted to determine the accepted procedures and techniques for the administration of mepivacaine. WARNINGS LOCAL ANESTHETICS SHOULD ONLY BE EMPLOYED BY CLINICIANS WHO ARE WELL VERSED IN DIAGNOSIS AND MANAGEMENT OF DOSE-RELATED TOXICITY AND OTHER ACUTE EMERGENCIES WHICH MIGHT ARISE FROM THE BLOCK TO BE EMPLOYED, AND THEN ONLY AFTER INSURING THE IMMEDIATE AVAILABILITY OF OXYGEN, OTHER RESUSCITATIVE DRUGS, CARDIOPULMONARY RESUSCITATIVE EQUIPMENT, AND THE PERSONNEL RESOURCES NEEDED FOR PROPER MANAGEMENT OF TOXIC REACTIONS AND RELATED EMERGENCIES. (See also ADVERSE REACTIONS and PRECAUTIONS .) DELAY IN PROPER MANAGEMENT OF DOSE-R TIVE EQUIPMENT, AND THE PERSONNEL RESOURCES NEEDED FOR PROPER MANAGEMENT OF TOXIC REACTIONS AND RELATED EMERGENCIES. (See also ADVERSE REACTIONS and PRECAUTIONS .) DELAY IN PROPER MANAGEMENT OF DOSE-RELATED TOXICITY, UNDERVENTILATION FROM ANY CAUSE, AND/OR ALTERED SENSITIVITY MAY LEAD TO THE DEVELOPMENT OF ACIDOSIS, CARDIAC ARREST AND, POSSIBLY, DEATH. Local anesthetic solutions containing antimicrobial preservatives (ie, those supplied in multiple-dose vials) should not be used for epidural or caudal anesthesia because safety has not been established with regard to intrathecal injection, either intentionally or inadvertently, of such preservatives. It is essential that aspiration for blood or cerebrospinal fluid (where applicable) be done prior to injecting any local anesthetic, both the original dose and all subsequent doses, to avoid intravascular or subarachnoid injection. However, a negative aspiration does not ensure against an intravascular or subarachnoid injection. Reactions resulting in fatality have occurred on rare occasions with the use of local anesthetics. Mepivacaine with epinephrine or other vasopressors should not be used concomitantly with ergot-type oxytocic dru esulting in fatality have occurred on rare occasions with the use of local anesthetics. Mepivacaine with epinephrine or other vasopressors should not be used concomitantly with ergot-type oxytocic drugs, because a severe persistent hypertension may occur. Likewise, solutions of mepivacaine containing a vasoconstrictor, such as epinephrine, should be used with extreme caution in patients receiving monoamine oxidase inhibitors (MAOI) or antidepressants of the triptyline or imipramine types, because severe prolonged hypertension may result. Local anesthetic procedures should be used with caution when there is inflammation and/or sepsis in the region of the proposed injection. Mixing or the prior or intercurrent use of any local anesthetic with mepivacaine cannot be recommended because of insufficient data on the clinical use of such mixtures DOSAGE AND ADMINISTRATION The dose of any local anesthetic administered varies with the anesthetic procedure, the area to be anesthetized, the vascularity of the tissues, the number of neuronal segments to be blocked, the depth of anesthesia and degree of muscle relaxation required, the duration of anesthesia desired, individual tolerance and the arity of the tissues, the number of neuronal segments to be blocked, the depth of anesthesia and degree of muscle relaxation required, the duration of anesthesia desired, individual tolerance and the physical condition of the patient. The smallest dose and concentration required to produce the desired result should be administered. Dosages of mepivacaine hydrochloride should be reduced for elderly and debilitated patients and patients with cardiac and/or liver disease. The rapid injection of a large volume of local anesthetic solution should be avoided and fractional doses should be used when feasible. For specific techniques and procedures, refer to standard textbooks. The recommended single adult dose (or the total of a series of doses given in one procedure) of mepivacaine hydrochloride for unsedated, healthy, normal-sized individuals should not usually exceed 400 mg. The recommended dosage is based on requirements for the average adult and should be reduced for elderly or debilitated patients. While maximum doses of 7 mg/kg (550 mg) have been administered without adverse effect, these are not recommended, except in exceptional circumstances and under no circumstances should the ed patients. While maximum doses of 7 mg/kg (550 mg) have been administered without adverse effect, these are not recommended, except in exceptional circumstances and under no circumstances should the administration be repeated at intervals of less than 1 1 / 2 hours. The total dose for any 24-hour period should not exceed 1,000 mg because of a slow accumulation of the anesthetic or its derivatives or slower than normal metabolic degradation or detoxification with repeat administration. (See CLINICAL PHARMACOLOGY and PRECAUTIONS ). Pediatric patients tolerate the local anesthetic as well as adults. However, the pediatric dose should be carefully measured as a percentage of the total adult dose based on weight , and should not exceed 5 mg/kg to 6 mg/kg (2.5 mg/lb to 3 mg/lb) in pediatric patients, especially those weighing less than 30 lbs. In pediatric patients under 3 years of age or weighing less than 30 lbs concentrations less than 2% (eg, 0.5% to 1.5%) should be employed. Unused portions of solutions not containing preservatives, ie, those supplied in single-dose vials, should be discarded following initial use. This product should be inspected visually for particulate matter a rtions of solutions not containing preservatives, ie, those supplied in single-dose vials, should be discarded following initial use. This product should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Solutions which are discolored or which contain particulate matter should not be administered. Recommended Concentrations and Doses of Mepivacaine Hydrochloride Procedure Concentration Total Dose Comments mL mg Cervical, brachial, intercostal, 1% 5−40 50−400 Pudendal block: one half of total dose injected each side. pudendal nerve block 2% 5−20 100−400 Transvaginal block (paracervical plus pudendal) 1% up to 30 (both sides) up to 300 (both sides) One half of total dose injected each side. See PRECAUTIONS . Paracervical block 1% up to 20 (both sides) up to 200 (both sides) One half of total dose injected each side. This is maximum recommended dose per 90-minute period in obstetrical and non-obstetrical patients. Inject slowly, 5 minutes between sides. See PRECAUTIONS . Caudal and Epidural block 1% 1.5% 15−30 10−25 150−300 150−375 Dosage forms listed as POLOCAINE-MPF (Mepivacaine HCl injection, USP) are sing . Inject slowly, 5 minutes between sides. See PRECAUTIONS . Caudal and Epidural block 1% 1.5% 15−30 10−25 150−300 150−375 Dosage forms listed as POLOCAINE-MPF (Mepivacaine HCl injection, USP) are single-dose solutions which do not contain a preservative. Use only single-dose vials which do not contain a preservative. 2% 10−20 200−400 Infiltration 1% up to 40 up to 400 An equivalent amount of a 0.5% solution (prepared by diluting the 1% solution with Sodium Chloride Injection, USP) may be used for large areas. Therapeutic block (pain management) 1% 2% 1−5 1−5 10−50 20−100 Unused portions of solutions not containing preservatives should be discarded. ADVERSE REACTIONS Reactions to mepivacaine are characteristic of those associated with other amide-type local anesthetics. A major cause of adverse reactions to this group of drugs is excessive plasma levels, which may be due to overdosage, inadvertent intravascular injection, or slow metabolic degradation. Systemic The most commonly encountered acute adverse experiences which demand immediate countermeasures are related to the central nervous system and the cardiovascular system. These adverse experiences are generally dose related and ered acute adverse experiences which demand immediate countermeasures are related to the central nervous system and the cardiovascular system. These adverse experiences are generally dose related and due to high plasma levels which may result from overdosage, rapid absorption from the injection site, diminished tolerance, or from unintentional intravascular injection of the local anesthetic solution. In addition to systemic dose-related toxicity, unintentional subarachnoid injection of drug during the intended performance of caudal or lumbar epidural block or nerve blocks near the vertebral column (especially in the head and neck region) may result in underventilation or apnea (“Total or High Spinal”). Also, hypotension due to loss of sympathetic tone and respiratory paralysis or underventilation due to cephalad extension of the motor level of anesthesia may occur. This may lead to secondary cardiac arrest if untreated. Factors influencing plasma protein binding, such as acidosis, systemic diseases which alter protein production, or competition of other drugs for protein binding sites, may diminish individual tolerance. Central Nervous System Reactions These are characterized by ex emic diseases which alter protein production, or competition of other drugs for protein binding sites, may diminish individual tolerance. Central Nervous System Reactions These are characterized by excitation and/or depression. Restlessness, anxiety, dizziness, tinnitus, blurred vision, or tremors may occur, possibly proceeding to convulsions. However, excitement may be transient or absent, with depression being the first manifestation of an adverse reaction. This may quickly be followed by drowsiness merging into unconsciousness and respiratory arrest. Other central nervous system effects may be nausea, vomiting, chills, and constriction of the pupils. The incidence of convulsions associated with the use of local anesthetics varies with the procedure used and the total dose administered. In a survey of studies of epidural anesthesia, overt toxicity progressing to convulsions occurred in approximately 0.1% of local anesthetic administrations. Cardiovascular Reactions High doses or, inadvertent intravascular injection, may lead to high plasma levels and related depression of the myocardium, decreased cardiac output, heart block, hypotension (or sometimes hypertension), bradycardia, dvertent intravascular injection, may lead to high plasma levels and related depression of the myocardium, decreased cardiac output, heart block, hypotension (or sometimes hypertension), bradycardia, ventricular arrhythmias, and possibly cardiac arrest. (See WARNINGS , PRECAUTIONS , and OVERDOSAGE sections.) Allergic Allergic-type reactions are rare and may occur as a result of sensitivity to the local anesthetic or to other formulation ingredients, such as the antimicrobial preservative methylparaben, contained in multiple-dose vials. These reactions are characterized by signs such as urticaria, pruritus, erythema, angioneurotic edema (including laryngeal edema), tachycardia, sneezing, nausea, vomiting, dizziness, syncope, excessive sweating, elevated temperature, and possibly, anaphylactoid-like symptomatology (including severe hypotension). Cross sensitivity among members of the amide-type local anesthetic group has been reported. The usefulness of screening for sensitivity has not been definitely established. Neurologic The incidences of adverse neurologic reactions associated with the use of local anesthetics may be related to the total dose of local anesthetic administered an been definitely established. Neurologic The incidences of adverse neurologic reactions associated with the use of local anesthetics may be related to the total dose of local anesthetic administered and are also dependent upon the particular drug used, the route of administration, and the physical status of the patient. Many of these effects may be related to local anesthetic techniques, with or without a contribution from the drug. In the practice of caudal or lumbar epidural block, occasional unintentional penetration of the subarachnoid space by the catheter or needle may occur. Subsequent adverse effects may depend partially on the amount of drug administered intrathecally and the physiological and physical effects of a dural puncture. A high spinal is characterized by paralysis of the legs, loss of consciousness, respiratory paralysis, and bradycardia. Neurologic effects following epidural or caudal anesthesia may include spinal block of varying magnitude (including high or total spinal block); hypotension secondary to spinal block; urinary retention; fecal and urinary incontinence; loss of perineal sensation and sexual function; persistent anesthesia, paresthesia, weakness, pa pinal block); hypotension secondary to spinal block; urinary retention; fecal and urinary incontinence; loss of perineal sensation and sexual function; persistent anesthesia, paresthesia, weakness, paralysis of the lower extremities, and loss of sphincter control all of which may have slow, incomplete, or no recovery; headache; backache; septic meningitis; meningismus; slowing of labor; increased incidence of forceps delivery; cranial nerve palsies due to traction on nerves from loss of cerebrospinal fluid. Neurologic effects following other procedures or routes of administration may include persistent anesthesia, paresthesia, weakness, paralysis, all of which may have slow, incomplete or no recovery. INDICATIONS: For temporary relief of minor symptoms of sore, overexerted muscles. INDICATIONS: For temporary relief of minor symptoms of sore, overexerted muscles. WARNINGS: For external use only. If pregnant or breast-feeding, ask a health professional before use. Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center right away. When using this product - do not get into eyes. Stop use and ask a doctor if - Conditions worsens - Symptoms last more than 7 days. DIRECTIONS: Apply at least 3 times daily over the affected area. KEEP OUT OF REACH OF CHILDREN. If swallowed, get medical help or contact a Poison Control Center right away. 1 INDICATIONS AND USAGE Bupropion hydrochloride tablets are indicated for the treatment of major depressive disorder (MDD), as defined by the Diagnostic and Statistical Manual (DSM). The efficacy of bupropion in the treatment of a major depressive episode was established in two 4-week controlled inpatient trials and one 6-week controlled outpatient trial of adult subjects with MDD [see Clinical Studies (14) ] . Bupropion hydrochloride is an aminoketone antidepressant, indicated for the treatment of major depressive disorder (MDD). ( 1 ) 2 DOSAGE AND ADMINISTRATION Starting Dose: 200 mg/day given as 100 mg twice daily ( 2.1 ) General: Increase dose gradually to reduce seizure risk. ( 2.1 , 5.3 ) After 3 days, may increase the dose to 300 mg/day, given as 100 mg 3 times daily at an interval of at least 6 hours between doses. ( 2.1 ) Usual target dose: 300 mg/day as 100 mg 3 times daily. ( 2.1 ) Maximum dose: 450 mg/day given as 150 mg 3 times daily. ( 2.1 ) Periodically reassess the dose and need for maintenance treatment. ( 2.1 ) Moderate to severe hepatic impairment: 75 mg once daily. ( 2.2 , 8.7 ) Mild hepatic impairment: Consider reducing the dose and/or frequency of dosing. ( 2. and need for maintenance treatment. ( 2.1 ) Moderate to severe hepatic impairment: 75 mg once daily. ( 2.2 , 8.7 ) Mild hepatic impairment: Consider reducing the dose and/or frequency of dosing. ( 2.2 , 8.7 ) Renal Impairment: Consider reducing the dose and/or frequency. ( 2.3 , 8.6 ) 2.1 General Instructions for Use To minimize the risk of seizure, increase the dose gradually [see Warnings and Precautions (5.3) ] . Increases in dose should not exceed 100 mg/day in a 3-day period. Bupropion hydrochloride tablets should be swallowed whole and not crushed, divided, or chewed. Bupropion hydrochloride tablets may be taken with or without food. The recommended starting dose is 200 mg/day, given as 100 mg twice daily. After 3 days of dosing, the dose may be increased to 300 mg/day, given as 100 mg 3 times daily, with at least 6 hours between successive doses. Dosing above 300 mg/day may be accomplished using the 75 mg or 100 mg tablets. A maximum of 450 mg/day, given in divided doses of not more than 150 mg each, may be considered for patients who show no clinical improvement after several weeks of treatment at 300 mg/day. Administer the 100 mg tablet 4 times daily to not exceed the lim more than 150 mg each, may be considered for patients who show no clinical improvement after several weeks of treatment at 300 mg/day. Administer the 100 mg tablet 4 times daily to not exceed the limit of 150 mg in a single dose. It is generally agreed that acute episodes of depression require several months or longer of antidepressant drug treatment beyond the response in the acute episode. It is unknown whether the dose of bupropion hydrochloride tablets needed for maintenance treatment is identical to the dose that provided an initial response. Periodically reassess the need for maintenance treatment and the appropriate dose for such treatment. 2.2 Dose Adjustment in Patients with Hepatic Impairment In patients with moderate to severe hepatic impairment (Child-Pugh score: 7 to 15), the maximum dose of bupropion hydrochloride tablets is 75 mg/day. In patients with mild hepatic impairment (Child-Pugh score: 5 to 6), consider reducing the dose and/or frequency of dosing [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ] . 2.3 Dose Adjustment in Patients with Renal Impairment Consider reducing the dose and/or frequency of bupropion hydrochloride tablets in pa ecific Populations (8.7) and Clinical Pharmacology (12.3) ] . 2.3 Dose Adjustment in Patients with Renal Impairment Consider reducing the dose and/or frequency of bupropion hydrochloride tablets in patients with renal impairment (Glomerular Filtration Rate < 90 mL/min) [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ] . 2.4 Switching a Patient to or from a Monoamine Oxidase Inhibitor (MAOI) Antidepressant At least 14 days should elapse between discontinuation of an MAOI intended to treat depression and initiation of therapy with bupropion hydrochloride tablets. Conversely, at least 14 days should be allowed after stopping bupropion hydrochloride tablets before starting an MAOI antidepressant [see Contraindications (4) and Drug Interactions (7.6) ] . 2.5 Use of Bupropion Hydrochloride Tablets with Reversible MAOIs such as Linezolid or Methylene Blue Do not start bupropion hydrochloride tablets in a patient who is being treated with a reversible MAOI such as linezolid or intravenous methylene blue. Drug interactions can increase the risk of hypertensive reactions. In a patient who requires more urgent treatment of a psychiatric condition, non-pharmacological i olid or intravenous methylene blue. Drug interactions can increase the risk of hypertensive reactions. In a patient who requires more urgent treatment of a psychiatric condition, non-pharmacological interventions, including hospitalization, should be considered [see Contraindications (4) and Drug Interactions (7.6) ] . In some cases, a patient already receiving therapy with bupropion hydrochloride tablets may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of hypertensive reactions in a particular patient, bupropion hydrochloride tablets should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with bupropion hydrochloride tablets may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue. The risk of administering methylene blue by non chever comes first. Therapy with bupropion hydrochloride tablets may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue. The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with bupropion hydrochloride tablets is unclear. The clinician should, nevertheless, be aware of the possibility of a drug interaction with such use [see Contraindications (4) and Drug Interactions (7.6) ] . 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Suicidal thoughts and behaviors in adolescents and young adults [see Boxed Warning and Warnings and Precautions (5.1) ] Neuropsychiatric symptoms and suicide risk in smoking cessation treatment [see Boxed Warning and Warnings and Precautions (5.2) ] Seizure [see Warnings and Precautions (5.3) ] Hypertension [see Warnings and Precautions (5.4) ] Activation of mania or hypomania [see Warnings and Precautions (5.5) ] Psychosis and other neuropsychiatric reactions [see Warnings and Precautions (5.6) ] Hypersensitivity reactions [see Warnings and Precautions mania or hypomania [see Warnings and Precautions (5.5) ] Psychosis and other neuropsychiatric reactions [see Warnings and Precautions (5.6) ] Hypersensitivity reactions [see Warnings and Precautions (5.7) ] Most common adverse reactions (incidence ≥ 5% and ≥ 1% more than placebo rate) are: agitation, dry mouth, constipation, headache/migraine, nausea/vomiting, dizziness, excessive sweating, tremor, insomnia, blurred vision, tachycardia, confusion, rash, hostility, cardiac arrhythmias, and auditory disturbance. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuticals Inc. toll free at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Adverse Reactions Leading to Discontinuation of Treatment Adverse reactions were sufficiently troublesome to cause discontinuation of treatment with bupropion in approximately 10% of the 2,400 subjec Adverse Reactions Leading to Discontinuation of Treatment Adverse reactions were sufficiently troublesome to cause discontinuation of treatment with bupropion in approximately 10% of the 2,400 subjects and healthy volunteers who participated in clinical trials during the product’s initial development. The more common events causing discontinuation include neuropsychiatric disturbances (3%), primarily agitation and abnormalities in mental status; gastrointestinal disturbances (2.1%), primarily nausea and vomiting; neurological disturbances (1.7%), primarily seizures, headaches, and sleep disturbances; and dermatologic problems (1.4%), primarily rashes. It is important to note, however, that many of these events occurred at doses that exceed the recommended daily dose. Commonly Observed Adverse Reactions Adverse reactions commonly encountered in subjects treated with bupropion are agitation, dry mouth, insomnia, headache/migraine, nausea/vomiting, constipation, tremor, dizziness, excessive sweating, blurred vision, tachycardia, confusion, rash, hostility, cardiac arrhythmia, and auditory disturbance. Table 2 summarizes the adverse reactions that occurred in placebo-controlled trials ive sweating, blurred vision, tachycardia, confusion, rash, hostility, cardiac arrhythmia, and auditory disturbance. Table 2 summarizes the adverse reactions that occurred in placebo-controlled trials at an incidence of at least 1% of subjects receiving bupropion and more frequently in these subjects than in the placebo group. Table 2. Adverse Reactions Reported by at Least 1% of Subjects and at a Greater Frequency than Placebo in Controlled Clinical Trials Adverse Reaction Bupropion Patients (n = 323) % Placebo (n = 185) % Cardiovascular Cardiac arrhythmias Dizziness Hypertension Hypotension Palpitations Syncope Tachycardia 5.3 22.3 4.3 2.5 3.7 1.2 10.8 4.3 16.2 1.6 2.2 2.2 0.5 8.6 Dermatologic Pruritus Rash 2.2 8 0 6.5 Gastrointestinal Appetite increase Constipation Dyspepsia Nausea/vomiting 3.7 26 3.1 22.9 2.2 17.3 2.2 18.9 Genitourinary Impotence Menstrual complaints Urinary frequency 3.4 4.7 2.5 3.1 1.1 2.2 Musculoskeletal Arthritis 3.1 2.7 Neurological Akathisia Cutaneous temperature disturbance Dry mouth Excessive sweating Headache/migraine Impaired sleep quality Insomnia Sedation Sensory disturbance Tremor 1.5 1.9 27.6 22.3 25.7 4 18.6 19.8 4 21.1 1.1 1.6 18.4 14.6 22.2 1.6 ture disturbance Dry mouth Excessive sweating Headache/migraine Impaired sleep quality Insomnia Sedation Sensory disturbance Tremor 1.5 1.9 27.6 22.3 25.7 4 18.6 19.8 4 21.1 1.1 1.6 18.4 14.6 22.2 1.6 15.7 19.5 3.2 7.6 Neuropsychiatric Agitation Anxiety Confusion Decreased libido Delusions Euphoria Hostility 31.9 3.1 8.4 3.1 1.2 1.2 5.6 22.2 1.1 4.9 1.6 1.1 0.5 3.8 Nonspecific Fever/chills 1.2 0.5 Special Senses Auditory disturbance Blurred vision Gustatory disturbance 5.3 14.6 3.1 3.2 10.3 1.1 Other Adverse Reactions Observed During the Clinical Development of Bupropion The conditions and duration of exposure to bupropion varied greatly, and a substantial proportion of the experience was gained in open and uncontrolled clinical settings. During this experience, numerous adverse events were reported; however, without appropriate controls, it is impossible to determine with certainty which events were or were not caused by bupropion. The following enumeration is organized by organ system and describes events in terms of their relative frequency of reporting in the database. The following definitions of frequency are used: Frequent adverse reactions are defined as those occurring in m and describes events in terms of their relative frequency of reporting in the database. The following definitions of frequency are used: Frequent adverse reactions are defined as those occurring in at least 1/100 subjects. Infrequent adverse reactions are those occurring in 1/100 to 1/1,000 subjects, while rare events are those occurring in less than 1/1,000 subjects. Cardiovascular: Frequent was edema; infrequent were chest pain, electrocardiogram (ECG) abnormalities (premature beats and nonspecific ST-T changes), and shortness of breath/dyspnea; rare were flushing, and myocardial infarction. Dermatologic : Infrequent was alopecia. Endocrine : Infrequent was gynecomastia; rare was glycosuria. Gastrointestinal : Infrequent were dysphagia, thirst disturbance, and liver damage/jaundice; rare was intestinal perforation. Genitourinary : Frequent was nocturia; infrequent were vaginal irritation, testicular swelling, urinary tract infection, painful erection, and retarded ejaculation; rare were enuresis, and urinary incontinence. Neurological : Frequent were ataxia/incoordination, seizure, myoclonus, dyskinesia, and dystonia; infrequent were mydriasis, vertigo, and dysarthria; rare wer were enuresis, and urinary incontinence. Neurological : Frequent were ataxia/incoordination, seizure, myoclonus, dyskinesia, and dystonia; infrequent were mydriasis, vertigo, and dysarthria; rare were electroencephalogram (EEG) abnormality, and impaired attention. Neuropsychiatric : Frequent were mania/hypomania, increased libido, hallucinations, decrease in sexual function, and depression; infrequent were memory impairment, depersonalization, psychosis, dysphoria, mood instability, paranoia, formal thought disorder, and frigidity; rare was suicidal ideation. Oral Complaints : Frequent was stomatitis; infrequent were toothache, bruxism, gum irritation, and oral edema. Respiratory : Infrequent were bronchitis and shortness of breath/dyspnea; rare was pulmonary embolism. Special Senses: Infrequent was visual disturbance; rare was diplopia. Nonspecific : Frequent were flu-like symptoms; infrequent was nonspecific pain; rare was overdose. Altered Appetite and Weight A weight loss of greater than 5 lbs occurred in 28% of subjects receiving bupropion. This incidence is approximately double that seen in comparable subjects treated with tricyclics or placebo. Furthermore, while 35% of sub er than 5 lbs occurred in 28% of subjects receiving bupropion. This incidence is approximately double that seen in comparable subjects treated with tricyclics or placebo. Furthermore, while 35% of subjects receiving tricyclic antidepressants gained weight, only 9.4% of subjects treated with bupropion did. Consequently, if weight loss is a major presenting sign of a patient’s depressive illness, the anorectic and/or weight reducing potential of bupropion should be considered. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of bupropion and are not described elsewhere in the label. 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 (General): Arthralgia, myalgia, and fever with rash and other symptoms suggestive of delayed hypersensitivity. These symptoms may resemble serum sickness. Cardiovascular: Hypertension (in some cases severe), orthostatic hypotension, third degree heart block. Endocrine: Syndrome of inappropriate antidiuretic hormone secretion, hyperglycemia, hypo ckness. Cardiovascular: Hypertension (in some cases severe), orthostatic hypotension, third degree heart block. Endocrine: Syndrome of inappropriate antidiuretic hormone secretion, hyperglycemia, hypoglycemia. Gastrointestinal: Esophagitis, hepatitis. Hemic and Lymphatic: Ecchymosis, leukocytosis, leukopenia, thrombocytopenia. Altered PT and/or INR, infrequently associated with hemorrhagic or thrombotic complications, were observed when bupropion was coadministered with warfarin. Musculoskeletal: Muscle rigidity/fever/rhabdomyolysis, muscle weakness. Nervous System: Aggression, coma, completed suicide, delirium, dream abnormalities, paranoid ideation, paresthesia, restlessness, suicide attempt, unmasking of tardive dyskinesia. Skin and Appendages: Stevens-Johnson syndrome, angioedema, exfoliative dermatitis, urticaria. Special Senses: Tinnitus, increased intraocular pressure. Uses • temporarily relieves nasal congestion due to: • common cold • hay fever • upper respiratory allergies • shrinks swollen nasal membranes so you can breathe more freely Purpose Nasal decongestant Warnings Ask a doctor before use if you have • heart disease • thyroid disease • high blood pressure • diabetes • trouble urinating due to an enlarged prostate gland When using this product • do not use more than directed • do not use for more than 3 days. Use only as directed. Frequent or prolonged use may cause nasal congestion to recur or worsen. • temporary discomfort such as burning, stinging, sneezing or an increase in nasal discharge may occur • use of this container by more than one person may spread infection Stop use and ask a doctor if symptoms persist If pregnant or breast-feeding, ask a health professional before use. Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center right away. Directions • adults and children 6 to under 12 years of age (with adult supervision): 2 or 3 sprays in each nostril not more often than every 10 to 12 hours. Do not exceed 2 doses in any 24-hour period. • children under 6 years of age: ask a doctor To s of age (with adult supervision): 2 or 3 sprays in each nostril not more often than every 10 to 12 hours. Do not exceed 2 doses in any 24-hour period. • children under 6 years of age: ask a doctor To spray, squeeze bottle quickly and firmly. Do not tilt head backward while spraying. Wipe nozzle clean after use. Ask a doctor before use if you have • heart disease • thyroid disease • high blood pressure • diabetes • trouble urinating due to an enlarged prostate gland Stop use and ask a doctor if symptoms persist Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center right away. 1. INDICATIONS AND USAGE Levetiracetam tablets USP are antiepileptic drugs indicated for adjunctive therapy in the treatment of: Partial onset seizures in patients 4 years of age and older with epilepsy ( ) 1.1 Myoclonic seizures in patients 12 years of age and older with juvenile myoclonic epilepsy ( ) 1.2 Primary generalized tonic-clonic seizures in patients 6 years of age and older with idiopathic generalized epilepsy ( ) 1.3 1.1 Partial Onset Seizures Levetiracetam tablets USP are indicated as adjunctive therapy in the treatment of partial onset seizures in adults and children 4 years of age and older with epilepsy. Information describing the use of levetiracetam in pediatric patients less than 4 years of age as adjunctive therapy in the treatment of partial onset seizures is approved for UCB, Inc.'s levetiracetam tablets. However, due to UCB, Inc.'s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 1.2 Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy Levetiracetam tablets USP are indicated as adjunctive therapy in the treatment of myoclonic seizures in adults and adolescents 12 years of age and older with juvenile my th Juvenile Myoclonic Epilepsy Levetiracetam tablets USP are indicated as adjunctive therapy in the treatment of myoclonic seizures in adults and adolescents 12 years of age and older with juvenile myoclonic epilepsy. 1.3 Primary Generalized Tonic-Clonic Seizures Levetiracetam tablets USP are indicated as adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in adults and children 6 years of age and older with idiopathic generalized epilepsy. 2. DOSAGE AND ADMINISTRATION Use the oral solution for pediatric patients with body weight ≤ 20 kg ( ). 2.1 For pediatric patients, use weight-based dosing for the oral solution with a calibrated measuring device (not a household teaspoon or tablespoon) ( ) 2.1 Partial Onset Seizures : 10 mg/kg twice daily, increase in increments of 10 mg/kg twice daily every 2 weeks to recommended dose of 30 mg/kg twice daily ( ) 4 Years to < 16 Years 2.2 : 500 mg twice daily, increase as needed and tolerated in increments of 500 mg twice daily every 2 weeks to a maximum recommended dose of 1500 mg twice daily ( ) Adults 16 Years and Older 2.2 Myoclonic Seizures in Adults and Pediatric Patients 12 Years and Older 500 mg twice daily, ce daily every 2 weeks to a maximum recommended dose of 1500 mg twice daily ( ) Adults 16 Years and Older 2.2 Myoclonic Seizures in Adults and Pediatric Patients 12 Years and Older 500 mg twice daily, increase by 500 mg twice daily every 2 weeks to recommended dose of 1500 mg twice daily ( ) 2.3 Primary Generalized Tonic-Clonic Seizures : 10 mg/kg twice daily, increase in increments of 10 mg/kg twice daily every 2 weeks to recommended dose of 30 mg/kg twice daily ( ) 6 Years To < 16 Years 2.4 : 500 mg twice daily, increase by 500 mg twice daily every 2 weeks to recommended dose of 1500 mg twice daily ( ) Adults 16 Years and Older 2.4 Adult Patients with Impaired Renal Function Dose adjustment is recommended, based on the patient's estimated creatinine clearance ( , ) 2.5 8.6 2.1 Important Administration Instructions Levetiracetam tablets are given orally with or without food. The levetiracetam dosing regimen depends on the indication, age group, dosage form (tablets or oral solution), and renal function. Prescribe the oral solution for pediatric patients with body weight ≤ 20 kg. Prescribe the oral solution or tablets for pediatric patients with body weight above 20 kg. Levetiracet and renal function. Prescribe the oral solution for pediatric patients with body weight ≤ 20 kg. Prescribe the oral solution or tablets for pediatric patients with body weight above 20 kg. Levetiracetam tablets should be swallowed whole. Levetiracetam tablets should not be chewed or crushed. 2.2 Partial Onset Seizures Adults 16 Years and Older In clinical trials, daily doses of 1000 mg, 2000 mg, and 3000 mg, given as twice-daily dosing were shown to be effective. Although in some studies there was a tendency toward greater response with higher dose , a consistent increase in response with increased dose has not been shown. [see CLINICAL STUDIES ( )] 14.1 Treatment should be initiated with a daily dose of 1000 mg/day, given as twice-daily dosing (500 mg twice daily). Additional dosing increments may be given (1000 mg/day additional every 2 weeks) to a maximum recommended daily dose of 3000 mg. Doses greater than 3000 mg/day have been used in open-label studies for periods of 6 months and longer. There is no evidence that doses greater than 3000 mg/day confer additional benefit. Pediatric Patients Dosing information in pediatric patients less than 4 years of age as adjunctive therapy d longer. There is no evidence that doses greater than 3000 mg/day confer additional benefit. Pediatric Patients Dosing information in pediatric patients less than 4 years of age as adjunctive therapy in the treatment of partial onset seizures is approved for UCB, Inc.'s levetiracetam tablets. However, due to UCB, Inc.'s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 4 Years to < 16 Years: Treatment should be initiated with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg twice daily). The daily dose should be increased every 2 weeks by increments of 20 mg/kg to the recommended daily dose of 60 mg/kg (30 mg/kg twice daily). If a patient cannot tolerate a daily dose of 60 mg/kg, the daily dose may be reduced. In the clinical efficacy trial, the mean daily dose was 44 mg/kg. The maximum daily dose was 3000 mg/day. For levetiracetam tablet dosing in pediatric patients weighing 20 to 40 kg, treatment should be initiated with a daily dose of 500 mg given as twice daily dosing (250 mg twice daily). The daily dose should be increased every 2 weeks by increments of 500 mg to a maximum recommended daily dose of 1500 mg (750 mg twice dail e of 500 mg given as twice daily dosing (250 mg twice daily). The daily dose should be increased every 2 weeks by increments of 500 mg to a maximum recommended daily dose of 1500 mg (750 mg twice daily). For levetiracetam tablet dosing in pediatric patients weighing more than 40 kg, treatment should be initiated with a daily dose of 1000 mg/day given as twice daily dosing (500 mg twice daily). The daily dose should be increased every 2 weeks by increments of 1000 mg/day to a maximum recommended daily dose of 3000 mg (1500 mg twice daily). Levetiracetam Oral Solution Weight-Based Dosing Calculation For Pediatric Patients The following calculation should be used to determine the appropriate daily dose of oral solution for pediatric patients: 2.3 Myoclonic Seizures in Patients 12 Years of Age and Older with Juvenile Myoclonic Epilepsy Treatment should be initiated with a dose of 1000 mg/day, given as twice-daily dosing (500 mg twice daily). Dosage should be increased by 1000 mg/day every 2 weeks to the recommended daily dose of 3000 mg. The effectiveness of doses lower than 3000 mg/day has not been studied. 2.4 Primary Generalized Tonic-Clonic Seizures Adults 16 Years and Older Treatm 2 weeks to the recommended daily dose of 3000 mg. The effectiveness of doses lower than 3000 mg/day has not been studied. 2.4 Primary Generalized Tonic-Clonic Seizures Adults 16 Years and Older Treatment should be initiated with a dose of 1000 mg/day, given as twice-daily dosing (500 mg twice daily). Dosage should be increased by 1000 mg/day every 2 weeks to the recommended daily dose of 3000 mg. The effectiveness of doses lower than 3000 mg/day has not been adequately studied. Pediatric Patients Ages 6 to <16 Years Treatment should be initiated with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg twice daily). The daily dose should be increased every 2 weeks by increments of 20 mg/kg to the recommended daily dose of 60 mg/kg (30 mg/kg twice daily). The effectiveness of doses lower than 60 mg/kg/day has not been adequately studied. Patients with body weight ≤ 20 kg should be dosed with oral solution. Patients with body weight above 20 kg can be dosed with either tablets or oral solution . Only whole tablets should be administered. [see DOSAGE AND ADMINISTRATION ( )] 2.1 2.5 Adult Patients with Impaired Renal Function Levetiracetam tablets dosing must be individualized accordi olution . Only whole tablets should be administered. [see DOSAGE AND ADMINISTRATION ( )] 2.1 2.5 Adult Patients with Impaired Renal Function Levetiracetam tablets dosing must be individualized according to the patient's renal function status. Recommended doses and adjustment for dose for adults are shown in Table 1. In order to calculate the dose recommended for patients with renal impairment, creatinine clearance adjusted for body surface area must be calculated. To do this an estimate of the patient's creatinine clearance (CL ) in mL/min must first be calculated using the following formula: cr Table 1: Dosing Adjustment Regimen for Adult Patients with Impaired Renal Function Group Creatinine Clearance ( mL / min / 1 . 73 m 2 ) Dosage ( mg ) Frequency Normal >80 500 to 1,500 Every 12 hours Mild 50 to 80 500 to 1,000 Every 12 hours Moderate 30 to 50 250 to 750 Every 12 hours Severe <30 250 to 500 Every 12 hours ESRD patients using dialysis ----- 500 to 1000 Following dialysis, a 250 to 500 mg supplemental dose is recommended. Every 24 hours Image 0 Image 1 6. ADVERSE REACTIONS Most common adverse reactions (incidence in levetiracetam -treated patients is ≥5% more than in placebo-tr 500 mg supplemental dose is recommended. Every 24 hours Image 0 Image 1 6. ADVERSE REACTIONS Most common adverse reactions (incidence in levetiracetam -treated patients is ≥5% more than in placebo-treated patients) include: Adult patients: somnolence, asthenia, infection and dizziness ( ) 6.1 Pediatric patients: fatigue, aggression, nasal congestion, decreased appetite, and irritability ( ) 6.1 To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceutical Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or . www.fda.gov/medwatch The following adverse reactions are discussed in more details in other sections of labeling: Psychiatric Symptoms [see WARNINGS AND PRECAUTIONS ( )] 5.1 Suicidal Behavior and Ideation [see WARNINGS AND PRECAUTIONS ( )] 5.2 Somnolence and Fatigue [see WARNINGS AND PRECAUTIONS ( )] 5.3 Serious Dermatological Reactions [see WARNINGS AND PRECAUTIONS ( )] 5.4 Coordination Difficulties [see WARNINGS AND PRECAUTIONS ( )] 5.5 Withdrawal Seizures [see WARNINGS AND PRECAUTIONS ( )] 5.6 Hematologic Abnormalities [see WARNINGS AND PRECAUTIONS ( )] 5.7 Blood Pressure Increases [see WARNINGS AND PRECAUTIONS ( )] 5.8 Seizure Control During Pregnancy [see WARNINGS AN