SILICEA bital, Primidone, or Valproate to Monotherapy with Lamotrigine Orally Disintegrating Tablets No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine orally disintegrating tablets with AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate. 2.4 Bipolar Disorder The goal of maintenance treatment with lamotrigine orally disintegrating tablet is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy [see Indications and Usage (1.2) ] . Patients taking lamotrigine orally disintegrating tablets for more than 16 weeks should be periodically reassessed to determine the need for maintenance treatment. Adults The target dose of lamotrigine orally disintegrating tablet is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitor lopinavir/ritonavir that increase the apparent clearance of lamotrigine). I taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitor lopinavir/ritonavir that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2) ] . Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine orally disintegrating tablets are introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine orally disintegrating tablets should be adjusted. In patients discontinuing valproate, the dose of lamotrigine orally disintegrating tablets should be doubled over a 2-week period in equal weekly increments (see Table 6). In patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation, the dose of lamotrigine orally disintegrating tablets shoul her drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation, the dose of lamotrigine orally disintegrating tablets should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 6). The dose of lamotrigine orally disintegrating tablets may then be further adjusted to the target dose (200 mg) as clinically indicated. If other drugs are subsequently introduced, the dose of lamotrigine orally disintegrating tablets may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine orally disintegrating tablets [see Drug Interactions (7) , Clinical Pharmacology (12.3) ]. To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine orally disintegrating tablets should not be exceeded [see Boxed Warning ]. Table 5. Escalation Regimen for Lamotrigine Orally Disintegrating Tablets in Adults with Bipolar Disorder In Patients TAKING Valproate a In Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone, b or Valproate a In Pat otrigine Orally Disintegrating Tablets in Adults with Bipolar Disorder In Patients TAKING Valproate a In Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone, b or Valproate a In Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone b and NOT TAKING Valproate a Weeks 1 and 2 25 mg every other day 25 mg daily 50 mg daily Weeks 3 and 4 25 mg daily 50 mg daily 100 mg daily, in divided doses Week 5 50 mg daily 100 mg daily 200 mg daily, in divided doses Week 6 100 mg daily 200 mg daily 300 mg daily, in divided doses Week 7 100 mg daily 200 mg daily up to 400 mg daily, in divided doses a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7) , Clinical Pharmacology (12.3) ] . b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Adm vir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1) ] . Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1) , Drug Interactions (7) , Clinical Pharmacology (12.3) ]. Table 6. Dosage Adjustments to Lamotrigine Orally Disintegrating Tablets in Adults with Bipolar Disorder following Discontinuation of Psychotropic Medications Discontinuation of Psychotropic Drugs (excluding Valproate, a Carbamazepine, Phenytoin, Phenobarbital, or Primidone b ) After Discontinuation of Valproate a After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital, or Primidone b Current Dose of Lamotrigine Orally Disintegrating Tablets (mg/day) 100 Current Dose of Lamotrigine Orally Disintegrating Tablets(mg/day) 400 Week 1 Maintain current dose of lamotrigine orally disintegrating tablets 150 400 Week 2 Maintain current dose of lamotrigine orally dis t Dose of Lamotrigine Orally Disintegrating Tablets(mg/day) 400 Week 1 Maintain current dose of lamotrigine orally disintegrating tablets 150 400 Week 2 Maintain current dose of lamotrigine orally disintegrating tablets 200 300 Week 3 onward Maintain current dose of lamotrigine orally disintegrating tablets 200 200 a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7) , Clinical Pharmacology (12.3) ]. b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1) ] . Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1) , Drug Interactions (7) , Clinical Pha e same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1) , Drug Interactions (7) , Clinical Pharmacology (12.3) ]. 2.6 Administration of Lamotrigine Orally Disintegrating Tablets Lamotrigine orally disintegrating tablets should be placed onto the tongue and moved around in the mouth. The tablet will disintegrate rapidly, can be swallowed with or without water, and can be taken with or without food. 6 ADVERSE REACTIONS The following serious adverse reactions are described in more detail in the Warnings and Precautions section of the labeling: Serious Skin Rashes [see Warnings and Precautions (5.1) ] Hemophagocytic Lymphohistiocytosis [see Warnings and Precautions (5.2) ] Multiorgan Hypersensitivity Reactions and Organ Failure [see Warnings and Precautions (5.3) ] Cardiac Rhythm and Conduction Abnormalities [see Warnings and Precautions (5.4) ] Blood Dyscrasias [see Warnings and Precautions (5.5) ] Suicidal Behavior and Ideation [see Warnings and Precautions (5.6) ] Aseptic Meningitis [see Warnings and Precautions (5.7) ] Withdrawal Seizures [see Warnings and Precautions (5.10) ] utions (5.5) ] Suicidal Behavior and Ideation [see Warnings and Precautions (5.6) ] Aseptic Meningitis [see Warnings and Precautions (5.7) ] Withdrawal Seizures [see Warnings and Precautions (5.10) ] Status Epilepticus [see Warnings and Precautions (5.11) ] Sudden Unexplained Death in Epilepsy [see Warnings and Precautions (5.12) ] Epilepsy : Most common adverse reactions (incidence ≥10%) in adults were dizziness, headache, diplopia, ataxia, nausea, blurred vision, somnolence, rhinitis, pharyngitis, and rash. Additional adverse reactions (incidence ≥10%) reported in children included vomiting, infection, fever, accidental injury, diarrhea, abdominal pain, and tremor. ( 6.1 ) Bipolar disorder : Most common adverse reactions (incidence >5%) in adults were nausea, insomnia, somnolence, back pain, fatigue, rash, rhinitis, abdominal pain, and xerostomia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Endo at 1-800-828-9393 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 with rates in th al 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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Epilepsy Most Common Adverse Reactions in All Clinical Trials : Adjunctive Therapy in Adults w ith Epilepsy: The most commonly observed (≥5% for lamotrigine and more common on drug than placebo) adverse reactions seen in association with lamotrigine during adjunctive therapy in adults and not seen at an equivalent frequency among placebo-treated patients were: dizziness, ataxia, somnolence, headache, diplopia, blurred vision, nausea, vomiting, and rash. Dizziness, diplopia, ataxia, blurred vision, nausea, and vomiting were dose-related. Dizziness, diplopia, ataxia, and blurred vision occurred more commonly in patients receiving carbamazepine with lamotrigine than in patients receiving other AEDs with lamotrigine. Clinical data suggest a higher incidence of rash, including serious rash, in patients receiving concomitant valproate than in patients not receiving valproate [see Warnings and Precautions (5 trigine. Clinical data suggest a higher incidence of rash, including serious rash, in patients receiving concomitant valproate than in patients not receiving valproate [see Warnings and Precautions (5.1) ]. Approximately 11% of the 3,378 adult patients who received lamotrigine as adjunctive therapy in premarketing clinical trials discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated with discontinuation were rash (3%), dizziness (2.8%), and headache (2.5%). In a dose-response trial in adults, the rate of discontinuation of lamotrigine for dizziness, ataxia, diplopia, blurred vision, nausea, and vomiting was dose related. Monotherapy in Adults w ith Epilepsy: The most commonly observed (≥5% for lamotrigine and more common on drug than placebo) adverse reactions seen in association with the use of lamotrigine during the monotherapy phase of the controlled trial in adults not seen at an equivalent rate in the control group were vomiting, coordination abnormality, dyspepsia, nausea, dizziness, rhinitis, anxiety, insomnia, infection, pain, weight decrease, chest pain, and dysmenorrhea. The most commonly observed (≥5% for lamotrigine and mo rdination abnormality, dyspepsia, nausea, dizziness, rhinitis, anxiety, insomnia, infection, pain, weight decrease, chest pain, and dysmenorrhea. The most commonly observed (≥5% for lamotrigine and more common on drug than placebo) adverse reactions associated with the use of lamotrigine during the conversion to monotherapy (add-on) period, not seen at an equivalent frequency among low-dose valproate-treated patients, were dizziness, headache, nausea, asthenia, coordination abnormality, vomiting, rash, somnolence, diplopia, ataxia, accidental injury, tremor, blurred vision, insomnia, nystagmus, diarrhea, lymphadenopathy, pruritus, and sinusitis. Approximately 10% of the 420 adult patients who received lamotrigine as monotherapy in premarketing clinical trials discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated with discontinuation were rash (4.5%), headache (3.1%), and asthenia (2.4%). Adjunctive Therapy in Pediatric Patients w ith Epilepsy: The most commonly observed (≥5% for lamotrigine and more common on drug than placebo) adverse reactions seen in association with the use of lamotrigine as adjunctive treatment in pediatric patie epsy: The most commonly observed (≥5% for lamotrigine and more common on drug than placebo) adverse reactions seen in association with the use of lamotrigine as adjunctive treatment in pediatric patients aged 2 to 16 years and not seen at an equivalent rate in the control group were infection, vomiting, rash, fever, somnolence, accidental injury, dizziness, diarrhea, abdominal pain, nausea, ataxia, tremor, asthenia, bronchitis, flu syndrome, and diplopia. In 339 patients aged 2 to 16 years with partial-onset seizures or generalized seizures of Lennox-Gastaut syndrome, 4.2% of patients on lamotrigine and 2.9% of patients on placebo discontinued due to adverse reactions. The most commonly reported adverse reaction that led to discontinuation of lamotrigine was rash. Approximately 11.5% of the 1,081 pediatric patients aged 2 to 16 years who received lamotrigine as adjunctive therapy in premarketing clinical trials discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated with discontinuation were rash (4.4%), reaction aggravated (1.7%), and ataxia (0.6%). Controlled Adjunctive Clinical Trials in Adults w ith Epilepsy: Table 8 lists adverse r s most commonly associated with discontinuation were rash (4.4%), reaction aggravated (1.7%), and ataxia (0.6%). Controlled Adjunctive Clinical Trials in Adults w ith Epilepsy: Table 8 lists adverse reactions that occurred in adult patients with epilepsy treated with lamotrigine in placebo-controlled trials. In these trials, either lamotrigine or placebo was added to the patient’s current AED therapy. Table 8. Adverse Reactions in Pooled, Placebo-Controlled Adjunctive Trials in Adult Patients with Epilepsy a,b Body System/ Adverse Reaction Percent of Patients Receiving Adjunctive Lamotrigine (n = 711) Percent of Patients Receiving Adjunctive Placebo (n = 419) Body as a whole Headache 29 19 Flu syndrome 7 6 Fever 6 4 Abdominal pain 5 4 Neck pain 2 1 Reaction aggravated (seizure exacerbation) 2 1 Digestive Nausea 19 10 Vomiting 9 4 Diarrhea 6 4 Dyspepsia 5 2 Constipation 4 3 Anorexia 2 1 Musculoskeletal Arthralgia 2 0 Nervous Dizziness 38 13 Ataxia 22 6 Somnolence 14 7 Incoordination 6 2 Insomnia 6 2 Tremor 4 1 Depression 4 3 Anxiety 4 3 Convulsion 3 1 Irritability 3 2 Speech disorder 3 0 Concentration disturbance 2 1 Respiratory Rhinitis 14 9 Pharyngitis 10 9 Cough increased 8 6 Ski Insomnia 6 2 Tremor 4 1 Depression 4 3 Anxiety 4 3 Convulsion 3 1 Irritability 3 2 Speech disorder 3 0 Concentration disturbance 2 1 Respiratory Rhinitis 14 9 Pharyngitis 10 9 Cough increased 8 6 Skin and appendages Rash 10 5 Pruritus 3 2 Special senses Diplopia 28 7 Blurred vision 16 5 Vision abnormality 3 1 Urogenital Female patients only (n = 365) (n = 207) Dysmenorrhea 7 6 Vaginitis 4 1 Amenorrhea 2 1 a Adverse reactions that occurred in at least 2% of patients treated with lamotrigine and at a greater incidence than placebo. b Patients in these adjunctive trials were receiving 1 to 3 of the concomitant antiepileptic drugs carbamazepine, phenytoin, phenobarbital, or primidone in addition to lamotrigine or placebo. Patients may have reported multiple adverse reactions during the trial or at discontinuation; thus, patients may be included in more than 1 category. In a randomized, parallel trial comparing placebo with 300 and 500 mg/day of lamotrigine, some of the more common drug-related adverse reactions were dose related (see Table 9). Table 9. Dose-Related Adverse Reactions from a Randomized, Placebo-Controlled, Adjunctive Trial in Adults with Epilepsy Adverse Reaction Percen lated adverse reactions were dose related (see Table 9). Table 9. Dose-Related Adverse Reactions from a Randomized, Placebo-Controlled, Adjunctive Trial in Adults with Epilepsy Adverse Reaction Percent of Patients Experiencing Adverse Reactions Placebo (n = 73) Lamotrigine 300 mg (n = 71) Lamotrigine 500 mg (n = 72) Ataxia 10 10 28 a,b Blurred vision 10 11 25 a,b Diplopia 8 24 a 49 a,b Dizziness 27 31 54 a,b Nausea 11 18 25 a Vomiting 4 11 18 a a Significantly greater than placebo group ( P <0.05). b Significantly greater than group receiving lamotrigine 300 mg ( P <0.05). The overall adverse reaction profile for lamotrigine was similar between females and males and was independent of age. Because the largest non-Caucasian racial subgroup was only 6% of patients exposed to lamotrigine in placebo-controlled trials, there are insufficient data to support a statement regarding the distribution of adverse reaction reports by race. Generally, females receiving either lamotrigine as adjunctive therapy or placebo were more likely to report adverse reactions than males. The only adverse reaction for which the reports on lamotrigine were > 10% more frequent in females than males (without a ve therapy or placebo were more likely to report adverse reactions than males. The only adverse reaction for which the reports on lamotrigine were > 10% more frequent in females than males (without a corresponding difference by gender on placebo) was dizziness (difference = 16.5%). There was little difference between females and males in the rates of discontinuation of lamotrigine for individual adverse reactions. Controlled Monotherapy Trial in Adults w ith Partial-Onset Seizures: Table 10 lists adverse reactions that occurred in patients with epilepsy treated with monotherapy with lamotrigine in a double-blind trial following discontinuation of either concomitant carbamazepine or phenytoin not seen at an equivalent frequency in the control group. Table 10. Adverse Reactions in a Controlled Monotherapy Trial in Adult Patients With Partial-Onset Seizures a,b Body System/ Adverse Reaction Percent of Patients Receiving Lamotrigine c as Monotherapy (n = 43) Percent of Patients Receiving Low-Dose Valproate d Monotherapy (n = 44) Body as a whole Pain 5 0 Infection 5 2 Chest pain 5 2 Digestive Vomiting 9 0 Dyspepsia 7 2 Nausea 7 2 Metabolic and nutritional Weight decrease 5 2 Nervous Coo ow-Dose Valproate d Monotherapy (n = 44) Body as a whole Pain 5 0 Infection 5 2 Chest pain 5 2 Digestive Vomiting 9 0 Dyspepsia 7 2 Nausea 7 2 Metabolic and nutritional Weight decrease 5 2 Nervous Coordination abnormality 7 0 Dizziness 7 0 Anxiety 5 0 Insomnia 5 2 Respiratory Rhinitis 7 2 Urogenital (female patients only) (n = 21) (n = 28) Dysmenorrhea 5 0 a Adverse reactions that occurred in at least 5% of patients treated with lamotrigine and at a greater incidence than valproate-treated patients. b Patients in this trial were converted to lamotrigine or valproate monotherapy from adjunctive therapy with carbamazepine or phenytoin. Patients may have reported multiple adverse reactions during the trial; thus, patients may be included in more than 1 category. c Up to 500 mg/day. d 1,000 mg/day. Adverse reactions that occurred with a frequency of < 5% and > 2% of patients receiving lamotrigine and numerically more frequent than placebo were: Body as a Whole: Asthenia, fever. Digestive: Anorexia, dry mouth, rectal hemorrhage, peptic ulcer. Metabolic and Nutritional: Peripheral edema. Nervous System: Amnesia, ataxia, depression, hypesthesia, libido increase, decreased reflexes, increa Anorexia, dry mouth, rectal hemorrhage, peptic ulcer. Metabolic and Nutritional: Peripheral edema. Nervous System: Amnesia, ataxia, depression, hypesthesia, libido increase, decreased reflexes, increased reflexes, nystagmus, irritability, suicidal ideation. Respiratory: Epistaxis, bronchitis, dyspnea. Skin and Appendages: Contact dermatitis, dry skin, sweating. Special Senses: Vision abnormality. Incidence in Controlled Adjunctive Trials in Pediatric Patients w ith Epilepsy: Table 11 lists adverse reactions that occurred in 339 pediatric patients with partial-onset seizures or generalized seizures of Lennox-Gastaut syndrome who received lamotrigine up to 15 mg/kg/day or a maximum of 750 mg/day. Table 11. Adverse Reactions in Pooled, Placebo-Controlled Adjunctive Trials in Pediatric Patients with Epilepsy a Body System/ Adverse Reaction Percent of Patients Receiving Lamotrigine (n = 168) Percent of Patients Receiving Placebo (n = 171) Body as a whole Infection 20 17 Fever 15 14 Accidental injury 14 12 Abdominal pain 10 5 Asthenia 8 4 Flu syndrome 7 6 Pain 5 4 Facial edema 2 1 Photosensitivity 2 0 Cardiovascular Hemorrhage 2 1 Digestive Vomiting 20 16 Diarrhea 11 9 Nausea 10 2 Consti al injury 14 12 Abdominal pain 10 5 Asthenia 8 4 Flu syndrome 7 6 Pain 5 4 Facial edema 2 1 Photosensitivity 2 0 Cardiovascular Hemorrhage 2 1 Digestive Vomiting 20 16 Diarrhea 11 9 Nausea 10 2 Constipation 4 2 Dyspepsia 2 1 Hemic and lymphatic Lymphadenopathy 2 1 Metabolic and nutritional Edema 2 0 Nervous system Somnolence 17 15 Dizziness 14 4 Ataxia 11 3 Tremor 10 1 Emotional lability 4 2 Gait abnormality 4 2 Thinking abnormality 3 2 Convulsions 2 1 Nervousness 2 1 Vertigo 2 1 Respiratory Pharyngitis 14 11 Bronchitis 7 5 Increased cough 7 6 Sinusitis 2 1 Bronchospasm 2 1 Skin Rash 14 12 Eczema 2 1 Pruritus 2 1 Special senses Diplopia 5 1 Blurred vision 4 1 Visual abnormality 2 0 Urogenital Male and female patients Urinary tract infection 3 0 a Adverse reactions that occurred in at least 2% of patients treated with lamotrigine and at a greater incidence than placebo. Bipolar Disorder in Adults The most common adverse reactions seen in association with the use of lamotrigine as monotherapy (100 to 400 mg/day) in adult patients (aged 18 to 82 years) with bipolar disorder in the 2 double-blind, placebo-controlled trials of 18 months’ duration are included in Table 12. Adverse reacti erapy (100 to 400 mg/day) in adult patients (aged 18 to 82 years) with bipolar disorder in the 2 double-blind, placebo-controlled trials of 18 months’ duration are included in Table 12. Adverse reactions that occurred in at least 5% of patients and were numerically more frequent during the dose-escalation phase of lamotrigine in these trials (when patients may have been receiving concomitant medications) compared with the monotherapy phase were: headache (25%), rash (11%), dizziness (10%), diarrhea (8%), dream abnormality (6%), and pruritus (6%). During the monotherapy phase of the double-blind, placebo-controlled trials of 18 months’ duration, 13% of 227 patients who received lamotrigine (100 to 400 mg/day), 16% of 190 patients who received placebo, and 23% of 166 patients who received lithium discontinued therapy because of an adverse reaction. The adverse reactions that most commonly led to discontinuation of lamotrigine were rash (3%) and mania/hypomania/mixed mood adverse reactions (2%). Approximately 16% of 2,401 patients who received lamotrigine (50 to 500 mg/day) for bipolar disorder in premarketing trials discontinued therapy because of an adverse reaction, most commonly d s (2%). Approximately 16% of 2,401 patients who received lamotrigine (50 to 500 mg/day) for bipolar disorder in premarketing trials discontinued therapy because of an adverse reaction, most commonly due to rash (5%) and mania/hypomania/mixed mood adverse reactions (2%). The overall adverse reaction profile for lamotrigine was similar between females and males, between elderly and nonelderly patients, and among racial groups. Table 12. Adverse Reactions in 2 Placebo-Controlled Trials in Adult Patients with Bipolar I Disorder a,b Body System/ Adverse Reaction Percent of Patients Receiving Lamotrigine (n = 227) Percent of Patients Receiving Placebo (n = 190) General Back pain 8 6 Fatigue 8 5 Abdominal pain 6 3 Digestive Nausea 14 11 Constipation 5 2 Vomiting 5 2 Nervous System Insomnia 10 6 Somnolence 9 7 Xerostomia (dry mouth) 6 4 Respiratory Rhinitis 7 4 Exacerbation of cough 5 3 Pharyngitis 5 4 Skin Rash (nonserious) c 7 5 a Adverse reactions that occurred in at least 5% of patients treated with lamotrigine and at a greater incidence than placebo. b Patients in these trials were converted to lamotrigine (100 to 400 mg/day) or placebo monotherapy from add-on therapy with other psych eated with lamotrigine and at a greater incidence than placebo. b Patients in these trials were converted to lamotrigine (100 to 400 mg/day) or placebo monotherapy from add-on therapy with other psychotropic medications. Patients may have reported multiple adverse reactions during the trial; thus, patients may be included in more than 1 category. c In the overall bipolar and other mood disorders clinical trials, the rate of serious rash was 0.08% (1 of 1,233) of adult patients who received lamotrigine as initial monotherapy and 0.13% (2 of 1,538) of adult patients who received lamotrigine as adjunctive therapy [see Warnings and Precautions (5.1) ]. Other reactions that occurred in 5% or more patients but equally or more frequently in the placebo group included: dizziness, mania, headache, infection, influenza, pain, accidental injury, diarrhea, and dyspepsia. Adverse reactions that occurred with a frequency of < 5% and > 1% of patients receiving lamotrigine and numerically more frequent than placebo were: General: Fever, neck pain. Cardiovascular: Migraine. Digestive: Flatulence. Metabolic and Nutritional: Weight gain, edema. Musculoskeletal: Arthralgia, myalgia. Nervous System: Am t than placebo were: General: Fever, neck pain. Cardiovascular: Migraine. Digestive: Flatulence. Metabolic and Nutritional: Weight gain, edema. Musculoskeletal: Arthralgia, myalgia. Nervous System: Amnesia, depression, agitation, emotional lability, dyspraxia, abnormal thoughts, dream abnormality, hypoesthesia. Respiratory: Sinusitis. Urogenital: Urinary frequency. Adverse Reactions following Abrupt Discontinuation : In the 2 controlled clinical trials, there was no increase in the incidence, severity, or type of adverse reactions in patients with bipolar disorder after abruptly terminating therapy with lamotrigine. In the clinical development program in adults with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine [see Warnings and Precautions (5.10)] . Mania/Hypomania/Mixed Episodes: During the double-blind placebo-controlled clinical trials in bipolar I disorder in which adults were converted to monotherapy with lamotrigine (100 to 400 mg/day) from other psychotropic medications and followed for up to 18 months, the rates of manic or hypomanic or mixed mood episodes reported as adverse reactions were 5% for patients treated with lam mg/day) from other psychotropic medications and followed for up to 18 months, the rates of manic or hypomanic or mixed mood episodes reported as adverse reactions were 5% for patients treated with lamotrigine (n = 227), 4% for patients treated with lithium (n = 166), and 7% for patients treated with placebo (n = 190). In all bipolar controlled trials combined, adverse reactions of mania (including hypomania and mixed mood episodes) were reported in 5% of patients treated with lamotrigine (n = 956), 3% of patients treated with lithium (n = 280), and 4% of patients treated with placebo (n = 803). 6.2 Other Adverse Reactions Observed in All Clinical Trials Lamotrigine has been administered to 6,694 individuals for whom complete adverse reaction data was captured during all clinical trials, only some of which were placebo controlled. During these trials, all adverse reactions were recorded by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having adverse reactions, similar types of adverse reactions were grouped into a smaller number of standardized categories using modified COSTART dictionary termino te of the proportion of individuals having adverse reactions, similar types of adverse reactions were grouped into a smaller number of standardized categories using modified COSTART dictionary terminology. The frequencies presented represent the proportion of the 6,694 individuals exposed to lamotrigine who experienced an event of the type cited on at least 1 occasion while receiving lamotrigine. All reported adverse reactions are included except those already listed in the previous tables or elsewhere in the labeling, those too general to be informative, and those not reasonably associated with the use of the drug. Adverse reactions are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse reactions are defined as those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1,000 patients; rare adverse reactions are those occurring in fewer than 1/1,000 patients. Body as a Whole Infrequent : Allergic reaction, chills, malaise. Cardiovascular System Infrequent : Flushing, hot flashes, hypertension, palpitations, postural hypotension, syncope, ta 1,000 patients. Body as a Whole Infrequent : Allergic reaction, chills, malaise. Cardiovascular System Infrequent : Flushing, hot flashes, hypertension, palpitations, postural hypotension, syncope, tachycardia, vasodilation. Dermatological Infrequent : Acne, alopecia, hirsutism, maculopapular rash, skin discoloration, urticaria. Rare : Angioedema, erythema, exfoliative dermatitis, fungal dermatitis, herpes zoster, leukoderma, multiforme erythema, petechial rash, pustular rash, Stevens-Johnson syndrome, vesiculobullous rash. Digestive System Infrequent : Dysphagia, eructation, gastritis, gingivitis, increased appetite, increased salivation, liver function tests abnormal, mouth ulceration. Rare : Gastrointestinal hemorrhage, glossitis, gum hemorrhage, gum hyperplasia, hematemesis, hemorrhagic colitis, hepatitis, melena, stomach ulcer, stomatitis, tongue edema. Endocrine System Rare : Goiter, hypothyroidism. Hematologic and Lymphatic System Infrequent : Ecchymosis, leukopenia. Rare : Anemia, eosinophilia, fibrin decrease, fibrinogen decrease, iron deficiency anemia, leukocytosis, lymphocytosis, macrocytic anemia, petechia, thrombocytopenia. Metabolic and Nutritional Disorders Infreque ia, eosinophilia, fibrin decrease, fibrinogen decrease, iron deficiency anemia, leukocytosis, lymphocytosis, macrocytic anemia, petechia, thrombocytopenia. Metabolic and Nutritional Disorders Infrequent : Aspartate transaminase increased. Rare : Alcohol intolerance, alkaline phosphatase increase, alanine transaminase increase, bilirubinemia, general edema, gamma glutamyl transpeptidase increase, hyperglycemia. Musculoskeletal System Infrequent : Arthritis, leg cramps, myasthenia, twitching. Rare : Bursitis, muscle atrophy, pathological fracture, tendinous contracture. Nervous System Frequent : Confusion, paresthesia. Infrequent : Akathisia, apathy, aphasia, central nervous system depression, depersonalization, dysarthria, dyskinesia, euphoria, hallucinations, hostility, hyperkinesia, hypertonia, libido decreased, memory decrease, mind racing, movement disorder, myoclonus, panic attack, paranoid reaction, personality disorder, psychosis, sleep disorder, stupor, suicidal ideation. Rare : Choreoathetosis, delirium, delusions, dysphoria, dystonia, extrapyramidal syndrome, faintness, grand mal convulsions, hemiplegia, hyperalgesia, hyperesthesia, hypokinesia, hypotonia, manic depression Choreoathetosis, delirium, delusions, dysphoria, dystonia, extrapyramidal syndrome, faintness, grand mal convulsions, hemiplegia, hyperalgesia, hyperesthesia, hypokinesia, hypotonia, manic depression reaction, muscle spasm, neuralgia, neurosis, paralysis, peripheral neuritis. Respiratory System Infrequent : Yawn. Rare : Hiccup, hyperventilation. Special Senses Frequent : Amblyopia. Infrequent : Abnormality of accommodation, conjunctivitis, dry eyes, ear pain, photophobia, taste perversion, tinnitus. Rare : Deafness, lacrimation disorder, oscillopsia, parosmia, ptosis, strabismus, taste loss, uveitis, visual field defect. Urogenital System Infrequent : Abnormal ejaculation, hematuria, impotence, menorrhagia, polyuria, urinary incontinence. Rare : Acute kidney failure, anorgasmia, breast abscess, breast neoplasm, creatinine increase, cystitis, dysuria, epididymitis, female lactation, kidney failure, kidney pain, nocturia, urinary retention, urinary urgency. 6.3 Postmarketing Experience The following adverse reactions have been identified during postapproval use of lamotrigine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always poss The following adverse reactions have been identified during postapproval use of lamotrigine. 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. Blood and Lymphatic Agranulocytosis, hemolytic anemia, lymphadenopathy not associated with hypersensitivity disorder. Gastrointestinal Esophagitis. Hepatobiliary Tract and Pancreas Pancreatitis. Immunologic Hypogammaglobulinemia, lupus-like reaction, vasculitis. Lower Respiratory Apnea. Musculoskeletal Rhabdomyolysis has been observed in patients experiencing hypersensitivity reactions. Nervous System Aggression, exacerbation of Parkinsonian symptoms in patients with pre-existing Parkinson’s disease, tics. Non-site Specific Progressive immunosuppression. Renal and Urinary Disorders Tubulointerstitial nephritis (has been reported alone and in association with uveitis). Use reduces the symptoms of dandruff Purpose Anti-dandruff Warnings For external use only. When using this product avoid contact with eyes. If contact occurs, rinse eyes thoroughly with water. Stop use and ask a doctor if condition worsens or does not improve after regular use of this product as directed. Keep this and all drugs out of reach of children. If swallowed, get medical help or contact a Poison Control Center right away. Directions shake before use. apply to affected areas one to four times daily or as directed by a doctor. squeeze product directly onto exposed scalp and massage in slowly. Do not rinse Stop use and ask a doctor if condition worsens or does not improve after regular use of this product as directed. Keep this and all drugs out of reach of children. If swallowed, get medical help or contact a Poison Control Center right away. Indicated for the gradual bleaching of hyperpigmented skin conditions such as chloasma, melasma, freckles, senile lentigines, and other unwanted areas of hyperpigmentation. WARNINGS Keep out of reach of children. Contains Sodium Metabisulfite, a sulfite that may cause serious allergic-type reactions including anaphylactic symptoms (e.g. hives, itching), and life threatening or less severe asthmatic episodes in certain susceptible persons. For external use only. Avoid contact with the eyes. Some users may experience a mild skin irritation. If skin irritation becomes severe, stop use and consult a physician. Do not use on children under 12 years of age unless directed by a physician. If swallowed, get medical help or contact a poison control center right away. DOSAGE AND ADMINISTRATION Apply 2 pumps (1 g) to affected areas twice a day or as directed by a physician. Always use sunscreen protection. (See enclosed package insert for full prescribing information.) Uses • when applied to chest and throat, temporarily relieves cough due to minor throat and bronchial irritation associated with the common cold • when applied to muscles and joints, temporarily relieves minor aches and pains of muscles and joints Active ingredients Purpose Cough suppressant & topical analgesic Cough suppressant Cough suppressant & topical analgesic Warnings For external use only; avoid contact with eyes. Directions • see important warnings under “When using this product” • adults and children 2 years and over: • for cough suppression • rub a thick layer on throat & chest • cover with a warm, dry cloth if desired • keep clothing loose about throat and chest to help vapors reach the nose and mouth • use up to three times daily or as directed by doctor • for muscle / joint minor aches and pains apply to affected area not more than 3 to 4 times daily • children under 2 years: do not use Ask a doctor before use if you have • cough that occurs with too much phlegm (mucus) • persistent or chronic cough such as occurs with smoking, asthma or emphysema Stop use and ask a doctor if • muscle aches and pains worsen or persist for more than 7 days or clear up and occur again w persistent or chronic cough such as occurs with smoking, asthma or emphysema Stop use and ask a doctor if • muscle aches and pains worsen or persist for more than 7 days or clear up and occur again within a few days. • cough persists for more than 1 week, tends to recur, or is accompanied by fever, rash, or persistent headache. A persistent cough may be a sign of a serious condition. Keep out of reach of children. Uses For the treatment of acne. Helps keep skin clear of new acne pimples, blackheads and/or whiteheads Purpose Acne Cleanser Uses For the treatment of acne. Helps keep skin clear of new acne pimples, blackheads and/or whiteheads Warnings: When using this product,avoid unnecessary sun exposure and use a sunscreen. ____________________________________________________________________________ For external use only. ____________________________________________________________________________ Using other topical acne drugs at the same time or immediately following the sue of this product may increase dryness or irritation of the skin. If this occurs, only one drug should be sued unless directed by a physician. _________________________________________________________________________________________ Do not use in or near the eyes. Keep out of reach of children If swallowed, get medical help or contact Poison Control Center immediately. Directions: Apply a small amount of cleanser to damp skin with fingertips and massage into a light foaming lather. Wash in a gentle circular motion. Rinse with warm (not hot) water and pat dry. Start with one treatment daily or as directed by a physician. n with fingertips and massage into a light foaming lather. Wash in a gentle circular motion. Rinse with warm (not hot) water and pat dry. Start with one treatment daily or as directed by a physician. Keep out of reach of children If swallowed, get medical help or contact Poison Control Center immediately. Indications To minimize adverse acute and chronic vaccination stress reactions. To minimize adverse acute and chronic vaccination stress reactions. Warning If symptoms persist, contact a licensed practitioner. If you are pregnant or nursing a baby, seek the advice of a health care professional before use. Keep out of the reach of children. Dosage Unless otherwise prescribed, adults take 5 drops orally in liquid, 1 time per day. Children take 3 drops orally in liquid, 1 time per day. If symptoms persist, contact a licensed practitioner. Keep out of the reach of children. INDICATIONS AND USAGE Metaxalone is indicated as an adjunct to rest, physical therapy, and other measures for the relief of discomforts associated with acute, painful musculoskeletal conditions. The mode of action of this drug has not been clearly identified, but may be related to its sedative properties. Metaxalone does not directly relax tense skeletal muscles in man. WARNINGS Metaxalone may enhance the effects of alcohol and other CNS depressants. DOSAGE AND ADMINISTRATION The recommended dose for adults and children over 12 years of age is one 800 mg tablet three to four times a day. ADVERSE REACTIONS The most frequent reactions to metaxalone include: CNS: drowsiness, dizziness, headache, and nervousness or “irritability”; Digestive: nausea, vomiting, gastrointestinal upset. Other adverse reactions are: Immune System: hypersensitivity reaction, rash with or without pruritus; Hematologic: leukopenia; hemolytic anemia; Hepatobiliary: jaundice. Though rare, anaphylactoid reactions have been reported with metaxalone. Use(s) For the temporary relief of pain and itching associated with: • Sunburn • Minor burns • Insect bites • Cuts • Scrapes Purpose Topical Analgesic Purpose Topical Antiseptic Warnings For External Use Only. Do not use • In the eyes • Over large areas of the body or on deep puncture wounds, animal bites, or serious burns • In large quantities, particularly over raw surfaces or blistered areas Stop use and ask a doctor if • The condition gets worse • Condition clears up and recurs within a few days • Condition persists for more than 7 days If pregnant or breast feeding Ask a health care professional before use. Keep out of reach of children If swallowed, get medical help or contact a Poison Control Center (1-800-222-1222) right away. Directions Adults and children 2 years and over: • Clean the affected area • Apply a small amount of this product on the area 3 to 4 times daily • May be covered with a sterile bandage Children under 2 years: • Consult a doctor Stop use and ask a doctor if • The condition gets worse • Condition clears up and recurs within a few days • Condition persists for more than 7 days Keep out of reach of children If swallowed, get medical help or contact a Pois f • The condition gets worse • Condition clears up and recurs within a few days • Condition persists for more than 7 days Keep out of reach of children If swallowed, get medical help or contact a Poison Control Center (1-800-222-1222) right away. Uses relieves occasional constipation (irregularity) generally produces bowel movement in 6-12 hours Purpose Stool softener Laxative Warnings Do not use if you are now taking mineral oil, unless directed by a doctor laxative products for longer than 1 week unless directed by a doctor Ask a doctor before use if you have stomach pain nausea vomiting noticed a sudden change in bowel habits that continues over a period of 2 weeks Stop use and ask a doctor if you have rectal bleeding or fail to have a bowel movement after use of a laxative. These may indicate a serious condition. If pregnant or breast-feeding, ask a health professional before use. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away. Directions take preferably at bedtime or as directed by a doctor age starting dosage maximum dosage adults and children 12 years of age or over 2 tablets once a day 4 tablets twice a day children 6 to under 12 years 1 tablet once a day 2 tablets twice a day children 2 to under 6 years 1/2 tablet once a day 1 tablet twice a day children under 2 years ask a doctor ask a doctor Ask a doctor before use if you have stomach pain nausea ay 2 tablets twice a day children 2 to under 6 years 1/2 tablet once a day 1 tablet twice a day children under 2 years ask a doctor ask a doctor Ask a doctor before use if you have stomach pain nausea vomiting noticed a sudden change in bowel habits that continues over a period of 2 weeks Stop use and ask a doctor if you have rectal bleeding or fail to have a bowel movement after use of a laxative. These may indicate a serious condition. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away. Uses • treats vaginal yeast infections • relieves external itching and irritation due to a vaginal yeast infection Purpose Vaginal antifungal Warnings For vaginal use only Do not use if you have never had a vaginal yeast infection diagnosed by a doctor Ask a doctor before use if you have • vaginal itching and discomfort for the first time • lower abdominal, back or shoulder pain, fever, chills, nausea, vomiting, or foul-smelling vaginal discharge. You may have a more serious condition. • vaginal yeast infections often (such as once a month or 3 in 6 months). You could be pregnant or have a serious underlying medical cause for your symptoms, including diabetes or a weakened immune system. • been exposed to the human immunodeficiency virus (HIV) that causes AIDS Ask a doctor or pharmacist before use if you are taking a prescription blood thinning medicine, such as warfarin, because bleeding or bruising may occur When using this product • do not use tampons, douches, spermicides or other vaginal products. Condoms and diaphragms may be damaged and fail to prevent pregnancy or sexually transmitted diseases (STDs). • do not have vaginal intercourse • mild increase in vaginal burning, itc vaginal products. Condoms and diaphragms may be damaged and fail to prevent pregnancy or sexually transmitted diseases (STDs). • do not have vaginal intercourse • mild increase in vaginal burning, itching or irritation may occur Stop use and ask a doctor if • symptoms do not get better in 3 days • symptoms last more than 7 days • you get a rash or hives, abdominal pain, fever, chills, nausea, vomiting, or foul-smelling vaginal discharge 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. (1-800-222-1222) Directions • before using this product, read the enclosed consumer information leaflet for complete directions and information • adults and children 12 years of age and over: • applicators: insert 1 applicatorful into the vagina at bedtime for 3 nights in a row. Throw applicator away after use. • external cream: squeeze a small amount of cream onto your fingertip. Apply the cream onto the itchy, irritated skin outside the vagina. Use 2 times daily for up to 7 days, as needed. • children under 12 years of age: ask a doctor Ask a doctor before use if you have p. Apply the cream onto the itchy, irritated skin outside the vagina. Use 2 times daily for up to 7 days, as needed. • children under 12 years of age: ask a doctor Ask a doctor before use if you have • vaginal itching and discomfort for the first time • lower abdominal, back or shoulder pain, fever, chills, nausea, vomiting, or foul-smelling vaginal discharge. You may have a more serious condition. • vaginal yeast infections often (such as once a month or 3 in 6 months). You could be pregnant or have a serious underlying medical cause for your symptoms, including diabetes or a weakened immune system. • been exposed to the human immunodeficiency virus (HIV) that causes AIDS Stop use and ask a doctor if • symptoms do not get better in 3 days • symptoms last more than 7 days • you get a rash or hives, abdominal pain, fever, chills, nausea, vomiting, or foul-smelling vaginal discharge Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center right away. (1-800-222-1222) INDICATIONS & USAGE Cyclobenzaprine hydrochloride tablets are indicated as an adjunct to rest and physical therapy for relief of muscle spasm associated with acute, painful musculoskeletal conditions. Improvement is manifested by relief of muscle spasm and its associated signs and symptoms, namely, pain, tenderness, limitation of motion, and restriction in activities of daily living. Cyclobenzaprine hydrochloride tablets should be used only for short periods (up to two or three weeks) because adequate evidence of effectiveness for more prolonged use is not available and because muscle spasm associated with acute, painful musculoskeletal conditions is generally of short duration and specific therapy for longer periods is seldom warranted. Cyclobenzaprine hydrochloride tablets have not been found effective in the treatment of spasticity associated with cerebral or spinal cord disease, or in children with cerebral palsy. WARNINGS Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome has been reported with Cyclobenzaprine Hydrochloride when used in combination with other drugs, such as selective serotonin reuptake inhibitors (SSRIs), serotonin norepine reatening serotonin syndrome has been reported with Cyclobenzaprine Hydrochloride when used in combination with other drugs, such as selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tramadol, bupropion, meperidine, verapamil, or (MAO) inhibitors. The concomitant use of Cyclobenzaprine Hydrochloride with MAO inhibitors is contraindicated (see CONTRAINDICATIONS). Serotonin syndrome symptoms may include mental status changes (e.g., confusion, agitation, hallucinations), autonomic instability (e.g., diaphoresis, tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g., tremor, ataxia, hyperreflexia, clonus, muscle rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Treatment with Cyclobenzaprine Hydrochloride and any concomitant serotonergic agents should be discontinued immediately if the above reactions occur and supportive symptomatic treatment should be initiated. If concomitant treatment with Cyclobenzaprine Hydrochloride and other serotonergic drugs is clinically warranted, careful observation is advised, particularly during treatment ini should be initiated. If concomitant treatment with Cyclobenzaprine Hydrochloride and other serotonergic drugs is clinically warranted, careful observation is advised, particularly during treatment initiation or dose increases (see PRECAUTIONS, Drug Interactions). Cyclobenzaprine is closely related to the tricyclic antidepressants, e.g., amitriptyline and imipramine. In short term studies for indications other than muscle spasm associated with acute musculoskeletal conditions, and usually at doses somewhat greater than those recommended for skeletal muscle spasm, some of the more serious central nervous system reactions noted with the tricyclic antidepressants have occurred (see WARNINGS, below, and ADVERSE REACTIONS). Tricyclic antidepressants have been reported to produce arrhythmias, sinus tachycardia, prolongation of the conduction time leading to myocardial infarction and stroke. Cyclobenzaprine may enhance the effects of alcohol, barbiturates, and other CNS depressants. DOSAGE & ADMINISTRATION For most patients, the recommended dose of cyclobenzaprine hydrochloride tablets is 5 mg three times a day. Based on individual patient response, the dose may be increased to 10 mg three DMINISTRATION For most patients, the recommended dose of cyclobenzaprine hydrochloride tablets is 5 mg three times a day. Based on individual patient response, the dose may be increased to 10 mg three times a day. Use of cyclobenzaprine hydrochloride tablets for periods longer than two or three weeks is not recommended (see INDICATIONS AND USAGE). Less frequent dosing should be considered for hepatically impaired or elderly patients (see PRECAUTIONS, Impaired Hepatic Function, and Use in the Elderly). ADVERSE REACTIONS PLEASE REVIEW THE DRUG MANUFACTURER'S COMPLETE INFORMATION ON ADVERSE REACTIONS AT THE FDA SITE HERE: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6ecd47d4-c618-48b1-a38d-1d558d54fd09 INDICATIONS AND USAGE Cisplatin Injection is indicated as therapy to be employed as follows: Metastatic Testicular Tumors In established combination therapy with other approved chemotherapeutic agents in patients with metastatic testicular tumors who have already received appropriate surgical and/or radio therapeutic procedures. Metastatic Ovarian Tumors In established combination therapy with other approved chemotherapeutic agents in patients with metastatic ovarian tumors who have already received appropriate surgical and/or radiotherapeutic procedures. An established combination consists of cisplatin and cyclophosphamide. Cisplatin Injection, as a single agent, is indicated as secondary therapy in patients with metastatic ovarian tumors refractory to standard chemotherapy who have not previously received Cisplatin Injection therapy. Advanced Bladder Cancer Cisplatin Injection is indicated as a single agent for patients with transitional cell bladder cancer which is no longer amenable to local treatments, such as surgery and/or radiotherapy. WARNINGS Cisplatin produces cumulative nephrotoxicity which is potentiated by aminoglycoside antibiotics. The serum creatinine, blood urea n e to local treatments, such as surgery and/or radiotherapy. WARNINGS Cisplatin produces cumulative nephrotoxicity which is potentiated by aminoglycoside antibiotics. The serum creatinine, blood urea nitrogen (BUN), creatinine clearance, and magnesium, sodium, potassium, and calcium levels should be measured prior to initiating therapy, and prior to each subsequent course. At the recommended dosage, cisplatin should not be given more frequently than once every 3 to 4 weeks (see ADVERSE REACTIONS ). Elderly patients may be more susceptible to nephrotoxicity (see PRECAUTIONS, Geriatric Use ). There are reports of severe neuropathies in patients in whom regimens are employed using higher doses of cisplatin or greater dose frequencies than those recommended. These neuropathies may be irreversible and are seen as paresthesias in a stocking-glove distribution, areflexia, and loss of proprioception and vibratory sensation. Elderly patients may be more susceptible to peripheral neuropathy (see PRECAUTIONS, Geriatric Use ). Loss of motor function has also been reported. Anaphylactic-like reactions to cisplatin have been reported. These reactions have occurred within minutes of administration PRECAUTIONS, Geriatric Use ). Loss of motor function has also been reported. Anaphylactic-like reactions to cisplatin have been reported. These reactions have occurred within minutes of administration to patients with prior exposure to cisplatin, and have been alleviated by administration of epinephrine, corticosteroids, and antihistamines. Cisplatin can commonly cause ototoxicity which is cumulative and may be severe. Audiometric testing should be performed prior to initiating therapy and prior to each subsequent dose of drug (see ADVERSE REACTIONS ). All pediatric patients receiving cisplatin should have audiometric testing at baseline, prior to each subsequent dose of drug and for several years post therapy. Cisplatin can cause fetal harm when administered to a pregnant woman. Cisplatin is mutagenic in bacteria and produces chromosome aberrations in animal cells in tissue culture. In mice cisplatin is teratogenic and embryotoxic. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Patients should be advised to avoid becoming pregnant. The carcinogenic effect of cispl nt becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Patients should be advised to avoid becoming pregnant. The carcinogenic effect of cisplatin was studied in BD IX rats. Cisplatin was administered intraperitoneally (i.p.) to 50 BD IX rats for 3 weeks, 3 x 1 mg/kg body weight per week. Four hundred and fifty-five days after the first application, 33 animals died, 13 of them related to malignancies: 12 leukemias and 1 renal fibrosarcoma. The development of acute leukemia coincident with the use of cisplatin has been reported. In these reports, cisplatin was generally given in combination with other leukemogenic agents. Injection site reactions may occur during the administration of cisplatin (see ADVERSE REACTIONS ). Given the possibility of extravasation, it is recommended to closely monitor the infusion site for possible infiltration during drug administration. A specific treatment for extravasation reactions is unknown at this time. DOSAGE AND ADMINISTRATION Cisplatin is administered by slow intravenous infusion. CISPLATIN SHOULD NOT BE GIVEN BY RAPID INTRAVENOUS INJECTION. Note: Needles or intravenous sets containing a his time. DOSAGE AND ADMINISTRATION Cisplatin is administered by slow intravenous infusion. CISPLATIN SHOULD NOT BE GIVEN BY RAPID INTRAVENOUS INJECTION. Note: Needles or intravenous sets containing aluminum parts that may come in contact with cisplatin should not be used for preparation or administration. Aluminum reacts with cisplatin, causing precipitate formation and a loss of potency. Metastatic Testicular Tumors The usual cisplatin dose for the treatment of testicular cancer in combination with other approved chemotherapeutic agents is 20 mg/m 2 IV daily for 5 days per cycle. Metastatic Ovarian Tumors The usual cisplatin dose for the treatment of metastatic ovarian tumors in combination with cyclophosphamide is 75 to 100 mg/m 2 IV per cycle once every 4 weeks (DAY 1). The dose of cyclophosphamide when used in combination with cisplatin is 600 mg/m 2 IV once every 4 weeks (DAY 1). For directions for the administration of cyclophosphamide, refer to the cyclophosphamide package insert. In combination therapy, cisplatin and cyclophosphamide are administered sequentially. As a single agent, cisplatin should be administered at a dose of 100 mg/m 2 IV per cycle once every 4 weeks. A rt. In combination therapy, cisplatin and cyclophosphamide are administered sequentially. As a single agent, cisplatin should be administered at a dose of 100 mg/m 2 IV per cycle once every 4 weeks. Advanced Bladder Cancer Cisplatin should be administered as a single agent at a dose of 50 to 70 mg/m 2 IV per cycle once every 3 to 4 weeks depending on the extent of prior exposure to radiation therapy and/or prior chemotherapy. For heavily pretreated patients an initial dose of 50 mg/m 2 per cycle repeated every 4 weeks is recommended. All Patients Pretreatment hydration with 1 to 2 liters of fluid infused for 8 to 12 hours prior to a cisplatin dose is recommended. The drug is then diluted in 2 liters of 5% Dextrose in 1/2 or 1/3 normal saline containing 37.5 g of mannitol, and infused over a 6 hour to 8 hour period. If diluted solution is not to be used within 6 hours, protect solution from light. Do not dilute cisplatin in just 5% Dextrose Injection. Adequate hydration and urinary output must be maintained during the following 24 hours. A repeat course of cisplatin should not be given until the serum creatinine is below 1.5 mg/100 mL, and/or the BUN is below 25 mg/100 mL. A repeat ut must be maintained during the following 24 hours. A repeat course of cisplatin should not be given until the serum creatinine is below 1.5 mg/100 mL, and/or the BUN is below 25 mg/100 mL. A repeat course should not be given until circulating blood elements are at an acceptable level (platelets ≥ 100,000/mm 3 , WBC ≥ 4,000/mm 3 ). Subsequent doses of cisplatin should not be given until an audiometric analysis indicates that auditory acuity is within normal limits. ADVERSE REACTIONS Nephrotoxicity Dose-related and cumulative renal insufficiency, including acute renal failure, is the major dose-limiting toxicity of cisplatin. Renal toxicity has been noted in 28% to 36% of patients treated with a single dose of 50 mg/m 2 . It is first noted during the second week after a dose and is manifested by elevations in BUN and creatinine, serum uric acid and/or a decrease in creatinine clearance. Renal toxicity becomes more prolonged and severe with repeated courses of the drug. Renal function must return to normal before another dose of cisplatin can be given. Elderly patients may be more susceptible to nephrotoxicity (see PRECAUTIONS, Geriatric Use ). Impairment of renal function has been ust return to normal before another dose of cisplatin can be given. Elderly patients may be more susceptible to nephrotoxicity (see PRECAUTIONS, Geriatric Use ). Impairment of renal function has been associated with renal tubular damage. The administration of cisplatin using a 6 hour to 8 hour infusion with intravenous hydration, and mannitol has been used to reduce nephrotoxicity. However, renal toxicity still can occur after utilization of these procedures. Ototoxicity Ototoxicity has been observed in up to 31% of patients treated with a single dose of cisplatin 50 mg/m 2 , and is manifested by tinnitus and/or hearing loss in the high frequency range (4,000 to 8,000 Hz). The prevalence of hearing loss in children is particularly high and is estimated to be 40 to 60%. Decreased ability to hear normal conversational tones may occur. Deafness after the initial dose of cisplatin has been reported. Ototoxic effects may be more severe in children receiving cisplatin. Hearing loss can be unilateral or bilateral and tends to become more frequent and severe with repeated cisplatin doses. It is unclear whether cisplatin-induced ototoxicity is reversible. Vestibular toxicity has also been r ilateral or bilateral and tends to become more frequent and severe with repeated cisplatin doses. It is unclear whether cisplatin-induced ototoxicity is reversible. Vestibular toxicity has also been reported. Ototoxic effects may be related to the peak plasma concentration of cisplatin. Ototoxicity can occur during treatment or be delayed. Audiometric monitoring should be performed prior to initiation of therapy, prior to each subsequent dose, and for several years post therapy. The risk of ototoxicity may be increased by prior or simultaneous cranial irradiation, and may be more severe in patients less than 5 years of age, patients being treated with other ototoxic drugs (e.g., aminoglycosides and vancomycin), and in patients with renal impairment. Genetic factors (e.g., variants in the thiopurine S-methyltransferase [TPMT] gene) may contribute to cisplatin-induced ototoxicity; although this association has not been consistent across populations and study designs. Hematologic Myelosuppression occurs in 25% to 30% of patients treated with cisplatin. The nadirs in circulating platelets and leukocytes occur between days 18 to 23 (range 7.5 to 45) with most patients recovering by day pression occurs in 25% to 30% of patients treated with cisplatin. The nadirs in circulating platelets and leukocytes occur between days 18 to 23 (range 7.5 to 45) with most patients recovering by day 39 (range 13 to 62). Leukopenia and thrombocytopenia are more pronounced at higher doses (>50 mg/m 2 ). Anemia (decrease of 2 g hemoglobin/100 mL) occurs at approximately the same frequency and with the same timing as leukopenia and thrombocytopenia. Fever and infection have also been reported in patients with neutropenia. Potential fatalities due to infection (secondary to myelosuppression) have been reported. Elderly patients may be more susceptible to myelosuppression (see PRECAUTIONS, Geriatric Use ). In addition to anemia secondary to myelosuppression, a Coombs' positive hemolytic anemia has been reported. In the presence of cisplatin hemolytic anemia, a further course of treatment may be accompanied by increased hemolysis and this risk should be weighed by the treating physician. The development of acute leukemia coincident with the use of cisplatin has been reported. In these reports, cisplatin was generally given in combination with other leukemogenic agents. Gastrointestinal M development of acute leukemia coincident with the use of cisplatin has been reported. In these reports, cisplatin was generally given in combination with other leukemogenic agents. Gastrointestinal Marked nausea and vomiting occur in almost all patients treated with cisplatin, and may be so severe that the drug must be discontinued. Nausea and vomiting may begin within 1 hour to 4 hours after treatment and last up to 24 hours. Various degrees of vomiting, nausea and/or anorexia may persist for up to 1 week after treatment. Delayed nausea and vomiting (begins or persists 24 hours or more after chemotherapy) has occurred in patients attaining complete emetic control on the day of cisplatin therapy. Diarrhea has also been reported. To report SUSPECTED ADVERSE REACTIONS, contact Sagent Pharmaceuticals at 1-866-625-1618 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . Uses for the temporary relief of minor aches and pains or as recommended by your doctor. Because of its delayed action, this product will not provide fast relief of headaches or other symptoms needing immediate relief. ask your doctor about other uses for safety coated 81 mg aspirin Purpose Pain reliever Warnings Reye's syndrome : Children and teenagers who have or are recovering from chicken pox or flu-like symptoms should not use this product. When using this product, if changes in behavior with nausea and vomiting occur, consult a doctor because these symptoms could be an early sign of Reye's syndrome, a rare but serious illness. Allergy alert : Aspirin may cause a severe allergic reaction, which may include: hives facial swelling shock asthma (wheezing) Stomach bleeding warning: This product contains an NSAID, which may cause severe stomach bleeding. The chance is higher if you: are age 60 or older have had stomach ulcers or bleeding problems take a blood thinning (anticoagulant) or steroid drug take other drugs containing prescription or nonprescription NSAIDs [aspirin, ibuprofen, naproxen, or others] have 3 or more alcoholic drinks every day while using this product take more r steroid drug take other drugs containing prescription or nonprescription NSAIDs [aspirin, ibuprofen, naproxen, or others] have 3 or more alcoholic drinks every day while using this product take more or for a longer time than directed Do not use if you are allergic to aspirin or any other pain reliever/fever reducer. if you have ever had an allergic reaction to this product or any of its ingredients Ask a doctor before use if stomach bleeding warning applies to you you have a history of stomach problems, such as heartburn you have high blood pressure, heart disease, liver cirrhosis or kidney disease you have asthma you are taking a diuretic Ask a doctor or pharmacist before use if you are taking a prescription drug for gout diabetes arthritis Stop use and ask a doctor if an allergic reaction occurs. Seek medical help right away. you experience any of the following signs of stomach bleeding: feel faint have bloody or black stools vomit blood have stomach pain that does not get better pain gets worse or lasts more than 10 days fever gets worse or lasts more than 3 days redness or swelling is present ringing in the ears or loss of hearing occurs new symptoms occur These could be sign ain gets worse or lasts more than 10 days fever gets worse or lasts more than 3 days redness or swelling is present ringing in the ears or loss of hearing occurs new symptoms occur These could be signs of a serious condition. If pregnant or breast-feeding, ask a health professional before use. It is especially important not to use aspirin during the last 3 months of pregnancy unless definitely directed to do so by a doctor because it may cause problems in the unborn child or complications during delivery. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center (1-800-222-1222) right away. Directions drink a full glass of water with each dose adults and children 12 years and over: take 4 to 8 tablets every 4 hours not to exceed 48 tablets in 24 hours unless directed by a doctor children under 12 years: consult a doctor Ask a doctor before use if stomach bleeding warning applies to you you have a history of stomach problems, such as heartburn you have high blood pressure, heart disease, liver cirrhosis or kidney disease you have asthma you are taking a diuretic Stop use and ask a doctor if an allergic reaction occurs. Seek medical help rn you have high blood pressure, heart disease, liver cirrhosis or kidney disease you have asthma you are taking a diuretic Stop use and ask a doctor if an allergic reaction occurs. Seek medical help right away. you experience any of the following signs of stomach bleeding: feel faint have bloody or black stools vomit blood have stomach pain that does not get better pain gets worse or lasts more than 10 days fever gets worse or lasts more than 3 days redness or swelling is present ringing in the ears or loss of hearing occurs new symptoms occur These could be signs of a serious condition. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center (1-800-222-1222) right away. Uses Helps prevent sunburn Purpose Sunscreen Warnings For external use only Do not use on broken or damaged skin When using this product keep out of eyes. Rinse with water to remove. Stop use and ask a doctor if rash occurs Keep out of reach of children. If product is swallowed, get medical help or contact a Poison Control Center right away. Directions For suncreen use Apply liberally 15 minutes before sun exposure Use a water resistant sunscreen if swimming or sweating or washing Reapply at least every 2 hours Spending time in the sun increases your risk of skin cancer and early skin aging. Sun Protection Measures. To decrease this risk, regularly use a sunscreen with a broad spectrum SPF of 15 or higher and other sun protection measures including: limit time in the sun, especially from 10 a.m. – 2 p.m. wear long-sleeve shirts, pants, hats, and sunglasses Children under 6 months: ask a doctor Stop use and ask a doctor if rash occurs Keep out of reach of children. If product is swallowed, get medical help or contact a Poison Control Center right away. INDICATIONS AND USAGE DIFLUCAN (fluconazole) is indicated for the treatment of: Vaginal candidiasis (vaginal yeast infections due to ). Candida Oropharyngeal and esophageal candidiasis. In open noncomparative studies of relatively small numbers of patients, DIFLUCAN was also effective for the treatment of urinary tract infections, peritonitis, and systemic infections including candidemia, disseminated candidiasis, and pneumonia. Candida Candida Cryptococcal meningitis. Before prescribing DIFLUCAN (fluconazole) for AIDS patients with cryptococcal meningitis, please see section. Studies comparing DIFLUCAN to amphotericin B in non-HIV infected patients have not been conducted. CLINICAL STUDIES Prophylaxis. DIFLUCAN is also indicated to decrease the incidence of candidiasis in patients undergoing bone marrow transplantation who receive cytotoxic chemotherapy and/or radiation therapy. Specimens for fungal culture and other relevant laboratory studies (serology, histopathology) should be obtained prior to therapy to isolate and identify causative organisms. Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results bec ained prior to therapy to isolate and identify causative organisms. Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, anti-infective therapy should be adjusted accordingly. WARNINGS (1) Hepatic injury: DIFLUCAN should be administered with caution to patients with liver dysfunction. DIFLUCAN has been associated with rare cases of serious hepatic toxicity, including fatalities primarily in patients with serious underlying medical conditions. In cases of DIFLUCAN-associated hepatotoxicity, no obvious relationship to total daily dose, duration of therapy, sex, or age of the patient has been observed. DIFLUCAN hepatotoxicity has usually, but not always, been reversible on discontinuation of therapy. Patients who develop abnormal liver function tests during DIFLUCAN therapy should be monitored for the development of more severe hepatic injury. DIFLUCAN should be discontinued if clinical signs and symptoms consistent with liver disease develop that may be attributable to DIFLUCAN. (2) Anaphylaxis: In rare cases, anaphylaxis has been reported. (3) Dermatologic: Exfoliative skin disorders during symptoms consistent with liver disease develop that may be attributable to DIFLUCAN. (2) Anaphylaxis: In rare cases, anaphylaxis has been reported. (3) Dermatologic: Exfoliative skin disorders during treatment with DIFLUCAN have been reported. Fatal outcomes have been reported in patients with serious underlying diseases. Patients with deep seated fungal infections who develop rashes during treatment with DIFLUCAN should be monitored closely and the drug discontinued if lesions progress. Fluconazole should be discontinued in patients treated for superficial fungal infection who develop a rash that may be attributed to fluconazole. (4) Use in Pregnancy: There are no adequate and well-controlled studies of DIFLUCAN in pregnant women. Available human data do not suggest an increased risk of congenital anomalies following a single maternal dose of 150 mg. A few published case reports describe a rare pattern of distinct congenital anomalies in infants exposed to high dose maternal fluconazole (400–800 mg/day) during most or all of the first trimester. These reported anomalies are similar to those seen in animal studies. If this drug is used during pregnancy or if the patient becomes pr ole (400–800 mg/day) during most or all of the first trimester. These reported anomalies are similar to those seen in animal studies. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be informed of the potential hazard to the fetus (See .) in utero PRECAUTIONS, Pregnancy DOSAGE AND ADMINISTRATION Dosage and Administration in Adults Single Dose Vaginal candidiasis The recommended dosage of DIFLUCAN for vaginal candidiasis is 150 mg as a single oral dose. Multiple Dose SINCE ORAL ABSORPTION IS RAPID AND ALMOST COMPLETE, THE DAILY DOSE OF DIFLUCAN (FLUCONAZOLE) IS THE SAME FOR ORAL (TABLETS AND SUSPENSION) AND INTRAVENOUS ADMINISTRATION. In general, a loading dose of twice the daily dose is recommended on the first day of therapy to result in plasma concentrations close to steady-state by the second day of therapy. The daily dose of DIFLUCAN for the treatment of infections other than vaginal candidiasis should be based on the infecting organism and the patient's response to therapy. Treatment should be continued until clinical parameters or laboratory tests indicate that active fungal infection has subsided. An inadequa he infecting organism and the patient's response to therapy. Treatment should be continued until clinical parameters or laboratory tests indicate that active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of active infection. Patients with AIDS and cryptococcal meningitis or recurrent oropharyngeal candidiasis usually require maintenance therapy to prevent relapse. Oropharyngeal candidiasis The recommended dosage of DIFLUCAN for oropharyngeal candidiasis is 200 mg on the first day, followed by 100 mg once daily. Clinical evidence of oropharyngeal candidiasis generally resolves within several days, but treatment should be continued for at least 2 weeks to decrease the likelihood of relapse. Esophageal candidiasis The recommended dosage of DIFLUCAN for esophageal candidiasis is 200 mg on the first day, followed by 100 mg once daily. Doses up to 400 mg/day may be used, based on medical judgment of the patient's response to therapy. Patients with esophageal candidiasis should be treated for a minimum of three weeks and for at least two weeks following resolution of symptoms. Systemic Candida infections For systemic infections including candidemi ophageal candidiasis should be treated for a minimum of three weeks and for at least two weeks following resolution of symptoms. Systemic Candida infections For systemic infections including candidemia, disseminated candidiasis, and pneumonia, optimal therapeutic dosage and duration of therapy have not been established. In open, noncomparative studies of small numbers of patients, doses of up to 400 mg daily have been used. Candida Urinary tract infections and peritonitis For the treatment of urinary tract infections and peritonitis, daily doses of 50–200 mg have been used in open, noncomparative studies of small numbers of patients. Candida Cryptococcal meningitis The recommended dosage for treatment of acute cryptococcal meningitis is 400 mg on the first day, followed by 200 mg once daily. A dosage of 400 mg once daily may be used, based on medical judgment of the patient's response to therapy. The recommended duration of treatment for initial therapy of cryptococcal meningitis is 10–12 weeks after the cerebrospinal fluid becomes culture negative. The recommended dosage of DIFLUCAN for suppression of relapse of cryptococcal meningitis in patients with AIDS is 200 mg once daily. P –12 weeks after the cerebrospinal fluid becomes culture negative. The recommended dosage of DIFLUCAN for suppression of relapse of cryptococcal meningitis in patients with AIDS is 200 mg once daily. Prophylaxis in patients undergoing bone marrow transplantation The recommended DIFLUCAN daily dosage for the prevention of candidiasis in patients undergoing bone marrow transplantation is 400 mg, once daily. Patients who are anticipated to have severe granulocytopenia (less than 500 neutrophils per cu mm) should start DIFLUCAN prophylaxis several days before the anticipated onset of neutropenia, and continue for 7 days after the neutrophil count rises above 1000 cells per cu mm. Dosage and Administration in Children The following dose equivalency scheme should generally provide equivalent exposure in pediatric and adult patients: Pediatric Patients Adults 3 mg/kg 100 mg 6 mg/kg 200 mg 12 mg/kg Some older children may have clearances similar to that of adults. Absolute doses exceeding 600 mg/day are not recommended. 400 mg Experience with DIFLUCAN in neonates is limited to pharmacokinetic studies in premature newborns. (See .) Based on the prolonged half-life seen in premature newborns g/day are not recommended. 400 mg Experience with DIFLUCAN in neonates is limited to pharmacokinetic studies in premature newborns. (See .) Based on the prolonged half-life seen in premature newborns (gestational age 26 to 29 weeks), these children, in the first two weeks of life, should receive the same dosage (mg/kg) as in older children, but administered every 72 hours. After the first two weeks, these children should be dosed once daily. No information regarding DIFLUCAN pharmacokinetics in full-term newborns is available. CLINICAL PHARMACOLOGY Oropharyngeal candidiasis The recommended dosage of DIFLUCAN for oropharyngeal candidiasis in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Treatment should be administered for at least 2 weeks to decrease the likelihood of relapse. Esophageal candidiasis For the treatment of esophageal candidiasis, the recommended dosage of DIFLUCAN in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Doses up to 12 mg/kg/day may be used, based on medical judgment of the patient's response to therapy. Patients with esophageal candidiasis should be treated for a minimum of three weeks and for at least 2 weeks f 12 mg/kg/day may be used, based on medical judgment of the patient's response to therapy. Patients with esophageal candidiasis should be treated for a minimum of three weeks and for at least 2 weeks following the resolution of symptoms. Systemic Candida infections For the treatment of candidemia and disseminated infections, daily doses of 6–12 mg/kg/day have been used in an open, noncomparative study of a small number of children. Candida Cryptococcal meningitis For the treatment of acute cryptococcal meningitis, the recommended dosage is 12 mg/kg on the first day, followed by 6 mg/kg once daily. A dosage of 12 mg/kg once daily may be used, based on medical judgment of the patient's response to therapy. The recommended duration of treatment for initial therapy of cryptococcal meningitis is 10–12 weeks after the cerebrospinal fluid becomes culture negative. For suppression of relapse of cryptococcal meningitis in children with AIDS, the recommended dose of DIFLUCAN is 6 mg/kg once daily. Dosage In Patients With Impaired Renal Function Fluconazole is cleared primarily by renal excretion as unchanged drug. There is no need to adjust single dose therapy for vaginal candidiasis because . Dosage In Patients With Impaired Renal Function Fluconazole is cleared primarily by renal excretion as unchanged drug. There is no need to adjust single dose therapy for vaginal candidiasis because of impaired renal function. In patients with impaired renal function who will receive multiple doses of DIFLUCAN, an initial loading dose of 50 to 400 mg should be given. After the loading dose, the daily dose (according to indication) should be based on the following table: Creatinine Clearance (mL/min) Percent of Recommended Dose >50 100% ≤50 (no dialysis) 50% Regular dialysis 100% after each dialysis Patients on regular dialysis should receive 100% of the recommended dose after each dialysis; on non-dialysis days, patients should receive a reduced dose according to their creatinine clearance. These are suggested dose adjustments based on pharmacokinetics following administration of multiple doses. Further adjustment may be needed depending upon clinical condition. When serum creatinine is the only measure of renal function available, the following formula (based on sex, weight, and age of the patient) should be used to estimate the creatinine clearance in adults: Males: 72 × serum c is the only measure of renal function available, the following formula (based on sex, weight, and age of the patient) should be used to estimate the creatinine clearance in adults: Males: 72 × serum creatinine (mg/100 mL) Weight (kg) × (140 – age) Females: 0.85 × above value Although the pharmacokinetics of fluconazole has not been studied in children with renal insufficiency, dosage reduction in children with renal insufficiency should parallel that recommended for adults. The following formula may be used to estimate creatinine clearance in children: K × serum creatinine (mg/100 mL) linear length or height (cm) (Where K=0.55 for children older than 1 year and 0.45 for infants.) Administration DIFLUCAN is administered orally. DIFLUCAN can be taken with or without food. Directions for Mixing the Oral Suspension Prepare a suspension at time of dispensing as follows: tap bottle until all the powder flows freely. To reconstitute, add 24 mL of distilled water or Purified Water (USP) to fluconazole bottle and shake vigorously to suspend powder. Each bottle will deliver 35 mL of suspension. The concentrations of the reconstituted suspensions are as follows: Fluconazole Content per Bottle conazole bottle and shake vigorously to suspend powder. Each bottle will deliver 35 mL of suspension. The concentrations of the reconstituted suspensions are as follows: Fluconazole Content per Bottle Concentration of Reconstituted Suspension 350 mg 10 mg/mL 1400 mg 40 mg/mL Note: Shake oral suspension well before using. Store reconstituted suspension between 86°F (30°C) and 41°F (5°C) and discard unused portion after 2 weeks. Protect from freezing. ADVERSE REACTIONS DIFLUCAN is generally well tolerated. In some patients, particularly those with serious underlying diseases such as AIDS and cancer, changes in renal and hematological function test results and hepatic abnormalities have been observed during treatment with fluconazole and comparative agents, but the clinical significance and relationship to treatment is uncertain. In Patients Receiving a Single Dose for Vaginal Candidiasis During comparative clinical studies conducted in the United States, 448 patients with vaginal candidiasis were treated with DIFLUCAN, 150 mg single dose. The overall incidence of side effects possibly related to DIFLUCAN was 26%. In 422 patients receiving active comparative agents, the incidence was asis were treated with DIFLUCAN, 150 mg single dose. The overall incidence of side effects possibly related to DIFLUCAN was 26%. In 422 patients receiving active comparative agents, the incidence was 16%. The most common treatment-related adverse events reported in the patients who received 150 mg single dose fluconazole for vaginitis were headache (13%), nausea (7%), and abdominal pain (6%). Other side effects reported with an incidence equal to or greater than 1% included diarrhea (3%), dyspepsia (1%), dizziness (1%), and taste perversion (1%). Most of the reported side effects were mild to moderate in severity. Rarely, angioedema and anaphylactic reaction have been reported in marketing experience. In Patients Receiving Multiple Doses for Other Infections Sixteen percent of over 4000 patients treated with DIFLUCAN (fluconazole) in clinical trials of 7 days or more experienced adverse events. Treatment was discontinued in 1.5% of patients due to adverse clinical events and in 1.3% of patients due to laboratory test abnormalities. Clinical adverse events were reported more frequently in HIV infected patients (21%) than in non-HIV infected patients (13%); however, the patterns in H patients due to laboratory test abnormalities. Clinical adverse events were reported more frequently in HIV infected patients (21%) than in non-HIV infected patients (13%); however, the patterns in HIV infected and non-HIV infected patients were similar. The proportions of patients discontinuing therapy due to clinical adverse events were similar in the two groups (1.5%). The following treatment-related clinical adverse events occurred at an incidence of 1% or greater in 4048 patients receiving DIFLUCAN for 7 or more days in clinical trials: nausea 3.7%, headache 1.9%, skin rash 1.8%, vomiting 1.7%, abdominal pain 1.7%, and diarrhea 1.5%. Hepatobiliary In combined clinical trials and marketing experience, there have been rare cases of serious hepatic reactions during treatment with DIFLUCAN. (See .) The spectrum of these hepatic reactions has ranged from mild transient elevations in transaminases to clinical hepatitis, cholestasis and fulminant hepatic failure, including fatalities. Instances of fatal hepatic reactions were noted to occur primarily in patients with serious underlying medical conditions (predominantly AIDS or malignancy) and often while taking multiple concomitant nstances of fatal hepatic reactions were noted to occur primarily in patients with serious underlying medical conditions (predominantly AIDS or malignancy) and often while taking multiple concomitant medications. Transient hepatic reactions, including hepatitis and jaundice, have occurred among patients with no other identifiable risk factors. In each of these cases, liver function returned to baseline on discontinuation of DIFLUCAN. WARNINGS In two comparative trials evaluating the efficacy of DIFLUCAN for the suppression of relapse of cryptococcal meningitis, a statistically significant increase was observed in median AST (SGOT) levels from a baseline value of 30 IU/L to 41 IU/L in one trial and 34 IU/L to 66 IU/L in the other. The overall rate of serum transaminase elevations of more than 8 times the upper limit of normal was approximately 1% in fluconazole-treated patients in clinical trials. These elevations occurred in patients with severe underlying disease, predominantly AIDS or malignancies, most of whom were receiving multiple concomitant medications, including many known to be hepatotoxic. The incidence of abnormally elevated serum transaminases was greater in patients t r malignancies, most of whom were receiving multiple concomitant medications, including many known to be hepatotoxic. The incidence of abnormally elevated serum transaminases was greater in patients taking DIFLUCAN concomitantly with one or more of the following medications: rifampin, phenytoin, isoniazid, valproic acid, or oral sulfonylurea hypoglycemic agents. Post-Marketing Experience In addition, the following adverse events have occurred during post-marketing experience. In rare cases, anaphylaxis (including angioedema, face edema and pruritus) has been reported. Immunologic: : Asthenia, fatigue, fever, malaise. Body as a Whole QT prolongation, torsade de pointes. (See .) Cardiovascular: PRECAUTIONS Seizures, dizziness. Central Nervous System: and Leukopenia, including neutropenia and agranulocytosis, thrombocytopenia. Hematopoietic Lymphatic: Hypercholesterolemia, hypertriglyceridemia, hypokalemia. Metabolic: : Cholestasis, dry mouth, hepatocellular damage, dyspepsia, vomiting. Gastrointestinal : Taste perversion. Other Senses myalgia. Musculoskeletal System: Insomnia, paresthesia, somnolence, tremor, vertigo. Nervous System: : Acute generalized exanthematous-pustulosis, drug astrointestinal : Taste perversion. Other Senses myalgia. Musculoskeletal System: Insomnia, paresthesia, somnolence, tremor, vertigo. Nervous System: : Acute generalized exanthematous-pustulosis, drug eruption, increased sweating, exfoliative skin disorders including Stevens-Johnson syndrome and toxic epidermal necrolysis (see ), alopecia. Skin and Appendages WARNINGS Adverse Reactions in Children The pattern and incidence of adverse events and laboratory abnormalities recorded during pediatric clinical trials are comparable to those seen in adults. In Phase II/III clinical trials conducted in the United States and in Europe, 577 pediatric patients, ages 1 day to 17 years were treated with DIFLUCAN at doses up to 15 mg/kg/day for up to 1,616 days. Thirteen percent of children experienced treatment-related adverse events. The most commonly reported events were vomiting (5%), abdominal pain (3%), nausea (2%), and diarrhea (2%). Treatment was discontinued in 2.3% of patients due to adverse clinical events and in 1.4% of patients due to laboratory test abnormalities. The majority of treatment-related laboratory abnormalities were elevations of transaminases or alkaline phosphatase. Per e clinical events and in 1.4% of patients due to laboratory test abnormalities. The majority of treatment-related laboratory abnormalities were elevations of transaminases or alkaline phosphatase. Percentage of Patients With Treatment-Related Side Effects Fluconazole (N=577) Comparative Agents (N=451) With any side effect 13.0 9.3 Vomiting 5.4 5.1 Abdominal pain 2.8 1.6 Nausea 2.3 1.6 Diarrhea 2.1 2.2 INDICATIONS AND USAGE Hydrocodone bitartrate and acetaminophen tablets, USP are indicated 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, with opioids, even at recommended doses [see WARNINGS ], reserve hydrocodone bitartrate and acetaminophen tablets, USP for use in patients for whom alternative treatment options (e.g., non-opioid analgesics): have not been tolerated, or are not expected to be tolerated, have not provided adequate analgesia, or are not expected to provide adequate analgesia WARNINGS Addiction, Abuse, and Misuse Hydrocodone bitartrate and acetaminophen tablets contain hydrocodone, a Schedule II controlled substance. As an opioid, hydrocodone bitartrate and acetaminophen tablets expose users to the risks of addiction, abuse, and misuse [see DRUG ABUSE AND DEPENDENCE ]. Although the risk of addiction in any individual is unknown, it can occur in patient’s appropriately prescribed hydrocodone bitartrate and acetaminophen tablets. Addiction can occur at recommended dosages and if the drug is misused or abused. Assess each known, it can occur in patient’s appropriately prescribed hydrocodone bitartrate and acetaminophen tablets. Addiction can occur at recommended dosages and if the drug is misused or abused. Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing hydrocodone bitartrate and acetaminophen tablets, and monitor all patients receiving hydrocodone bitartrate and acetaminophen tablets for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as hydrocodone bitartrate and acetaminophen tablets, but use in such patients necessitates intensive counseling about the risks and proper use of hydrocodone bitartrate and acetaminophen tablets along with intensive monitoring for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose [see WARNINGS , Life-Threatening Respirator lets along with intensive monitoring for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose [see WARNINGS , Life-Threatening Respiratory Depression; DOSAGE AND ADMINISTRATION , Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose ]. Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing hydrocodone bitartrate and acetaminophen tablets. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [see PRECAUTIONS; Information for Patients ]. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product. Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Unde s of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following: Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain. Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG . Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them. Consider using hasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them. Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient- prescriber responsibilities. To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 800-503-0784, or log on to www.opioidanalgesicrems.com . The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint . Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see OVERDOSAGE ]. Carbon dioxide (CO 2 ) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, l pending on the patient’s clinical status [see OVERDOSAGE ]. Carbon dioxide (CO 2 ) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of hydrocodone bitartrate and acetaminophen tablets, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with and following dosage increases of hydrocodone bitartrate and acetaminophen tablets. To reduce the risk of respiratory depression, proper dosing and titration of hydrocodone bitartrate and acetaminophen tablets are essential [see DOSAGE AND ADMINISTRATION ]. Overestimating the hydrocodone bitartrate and acetaminophen tablets dosage when converting patients from another opioid product can result in a fatal overdose. Accidental ingestion of even one dose of hydrocodone bitartrate and acetaminophen tablets, especially by children, can result in respiratory depression and death due to an overdose of hydrocodone bitartrate and acetaminophen tablets. Edu of hydrocodone bitartrate and acetaminophen tablets, especially by children, can result in respiratory depression and death due to an overdose of hydrocodone bitartrate and acetaminophen tablets. Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see PRECAUTIONS, Information for Patients/Caregivers ]. Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see DOSAGE AND ADMINISTRATION ]. Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with hydrocodone bitartrate and acetaminophen tablets. Inform patients and caregivers about the various ways to obtain nal tial need for access to naloxone, both when initiating and renewing treatment with hydrocodone bitartrate and acetaminophen tablets. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered [see PRECAUTIONS, Information for Patients/Caregivers ]. Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of other CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone [see usehold members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone [see WARNINGS, Addiction, Abuse, and Misuse, Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants; PRECAUTIONS, Information for Patients/Caregivers ]. Neonatal Opioid Withdrawal Syndrome Prolonged use of hydrocodone bitartrate and acetaminophen tablets during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see PRECAUTIONS; Information for Patients , Pregnancy ]. Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers Concomitant use of hydrocodone bitartrate and acet [see PRECAUTIONS; Information for Patients , Pregnancy ]. Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers Concomitant use of hydrocodone bitartrate and acetaminophen tablets with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of hydrocodone bitartrate and acetaminophen tablets and prolong opioid adverse reactions, and which may cause potentially fatal respiratory depression [see WARNINGS ], particularly when an inhibitor is added after a stable dose of hydrocodone bitartrate and acetaminophen tablets is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in hydrocodone bitartrate and acetaminophen tablets-treated patients may increase hydrocodone plasma concentrations and prolong opoid adverse reactions. When adding CYP3A4 inhibitors or discontinuing CYP3A4 inducers in hydrocodone bitartrate and acetaminophen tablets-treated patients, follow patients at frequent intervals and consider dosage reduction of hydrocodone bitartrate and acetamin tinuing CYP3A4 inducers in hydrocodone bitartrate and acetaminophen tablets-treated patients, follow patients at frequent intervals and consider dosage reduction of hydrocodone bitartrate and acetaminophen tablets until stable drug effects are achieved [see PRECAUTIONS; Drug Interactions ]. Concomitant use of hydrocodone bitartrate and acetaminophen tablets with CYP3A4 inducers or discontinuation of an CYP3A4 inhibitor could decrease hydrocodone plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to hydrocodone. When using hydrocodone bitartrate and acetaminophen tablets with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, follow patients at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur [see PRECAUTIONS; Drug Interactions ]. Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Profound sedation, respiratory depression, coma, and death may result from the concomitant use of hydrocodone bitartrate and acetaminophen tablets with benzodiazepines or other CNS depressants (e.g., Profound sedation, respiratory depression, coma, and death may result from the concomitant use of hydrocodone bitartrate and acetaminophen tablets with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see PRECAUTIONS; Drug Interactions ]. If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or othe lgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation. If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see WARNINGS, Life-Threatening Respiratory Depression; DOSAGE AND ADMINISTRATION, Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose ]. Advise both patients and caregivers about the risks of respiratory depression and sedation when hydrocodone bitartrate and acetaminophen tablets are used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the b lets are used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see PRECAUTIONS; Drug Interactions , Information for Patients ]. Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of hydrocodone bitartrate and acetaminophen tablets in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated. Patients with Chronic Pulmonary Disease : Hydrocodone bitartrate and acetaminophen tablet-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at inc ignificant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of hydrocodone bitartrate and acetaminophen tablets [see WARNINGS; Life-Threatening Respiratory Depression ]. Elderly, Cachectic, or Debilitated Patients : Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see WARNINGS; Life-Threatening Respiratory Depression ]. Follow such patients closely, particularly when initiating and titrating hydrocodone bitartrate and acetaminophen tablets and when hydrocodone bitartrate and acetaminophen tablets is given concomitantly with other drugs that depress respiration [see WARNINGS; Life-Threatening Respiratory Depression ]. Alternatively, consider the use of non-opioid analgesics in these patients. Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often spiratory Depression ]. Alternatively, consider the use of non-opioid analgesics in these patients. Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency. Severe Hypotension Hydrocodone bitartrate and acetaminophen tablets may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increa al insufficiency. Severe Hypotension Hydrocodone bitartrate and acetaminophen tablets may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see PRECAUTIONS; Drug Interactions ]. Follow these patients for signs of hypotension after initiating or titrating the dosage of hydrocodone bitartrate and acetaminophen tablets. In patients with circulatory shock hydrocodone bitartrate and acetaminophen tablets may cause vasodilatation that can further reduce cardiac output and blood pressure. Avoid the use of hydrocodone bitartrate and acetaminophen tablets with circulatory shock. Hepatotoxicity Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4,000 milligrams per day, and often involve more than one acetaminophen-containing product. The excessiv of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4,000 milligrams per day, and often involve more than one acetaminophen-containing product. The excessive intake of acetaminophen may be intentional to cause self-harm or unintentional as patients attempt to obtain more pain relief or unknowingly take other acetaminophen-containing products. The risk of acute liver failure is higher in individuals with underlying liver disease and in individuals who ingest alcohol while taking acetaminophen. Instruct patients to look for acetaminophen or APAP on package labels and not to use more than one product that contains acetaminophen. Instruct patients to seek medical attention immediately upon ingestion of more than 4,000 milligrams of acetaminophen per day, even if they feel well. Serious Skin Reactions Rarely, acetaminophen may cause serious skin reactions such as acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. Patients should be informed about the signs of serious skin reactions, and use of the drug should be discontinued at the first appearance of ski d toxic epidermal necrolysis (TEN), which can be fatal. Patients should be informed about the signs of serious skin reactions, and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity. Hypersensitivity/Anaphylaxis There have been post-marketing reports of hypersensitivity and anaphylaxis associated with the use of acetaminophen. Clinical signs included swelling of the face, mouth, and throat, respiratory distress, urticaria, rash, pruritus, and vomiting. There were infrequent reports of life-threatening anaphylaxis requiring emergency medical attention. Instruct patients to discontinue hydrocodone bitartrate and acetaminophen tablets immediately and seek medical care if they experience these symptoms. Do not prescribe hydrocodone bitartrate and acetaminophen tablets for patients with acetaminophen allergy [see PRECAUTIONS; Information for Patients/Caregivers . Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness In patients who may be susceptible to the intracranial effects of CO 2 retention (e.g., those with evidence of increased intracranial pressure or brai in Tumors, Head Injury, or Impaired Consciousness In patients who may be susceptible to the intracranial effects of CO 2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), hydrocodone bitartrate and acetaminophen tablets may reduce respiratory drive, and the resultant CO 2 retention can further increase intracranial pressure. Follow such patients for signs of sedation and respiratory depression, particularly when initiating therapy with hydrocodone bitartrate and acetaminophen tablets. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of hydrocodone bitartrate and acetaminophen tablets in patients with impaired consciousness or coma. Risks of Use in Patients with Gastrointestinal Conditions Hydrocodone bitartrate and acetaminophen tablets are contraindicated in patients with gastrointestinal obstruction, including paralytic ileus. The administration of hydrocodone bitartrate and acetaminophen tablets or other opioids may obscure the diagnosis or clinical course in patients with acute abdominal conditions. Hydrocodone may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase her opioids may obscure the diagnosis or clinical course in patients with acute abdominal conditions. Hydrocodone may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. Increased Risk of Seizures in Patients with Seizure Disorders The hydrocodone in hydrocodone bitartrate and acetaminophen tablets may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Follow patients with a history of seizure disorders for worsened seizure control during hydrocodone bitartrate and acetaminophen tablet therapy. Withdrawal Do not abruptly discontinue hydrocodone bitartrate and acetaminophen tablets in a patient physically dependent on opioids. When discontinuing hydrocodone bitartrate and acetaminophen tablets in a physically dependent patient, gradually taper the dosage. Rapid tapering of hydrocodone bitartrate and acetaminophen tablets in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [see DOSAGE AND AD aper the dosage. Rapid tapering of hydrocodone bitartrate and acetaminophen tablets in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [see DOSAGE AND ADMINISTRATION, DRUG ABUSE AND DEPENDENCE ]. Additionally, avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including hydrocodone bitartrate and acetaminophen tablets. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms [see PRECAUTIONS; Drug Interactions ]. DOSAGE AND ADMINISTRATION Important Dosage and Administration Instructions Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see WARNINGS ]. 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 [see WARNINGS ]. Follow patients closely for respiratory depression, espec s severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse [see WARNINGS ]. Follow patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy and following dosage increases with hydrocodone bitartrate and acetaminophen tablets and adjust the dosage accordingly [see WARNINGS ]. Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with hydrocodone bitartrate and acetaminophen tablets [see WARNINGS, Life-Threatening Respiratory Depression; PRECAUTIONS, Information for Patients/Caregivers ]. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing regulations (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Consider prescribing naloxone, based on the patients risk factors for overdose, such as concomitant use of CNS ., by prescription, directly from a pharmacist, or as part of a community-based program). Consider prescribing naloxone, based on the patients risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient [see WARNINGS, Addiction, Abuse, and Misuse, Life-Threatening Respiratory Depression, Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants ]. Consider prescribing naloxone when the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose . Initial Dosage Initiating Treatment with Hydrocodone Bitartrate and Acetaminophen Tablets 2.5 mg/325 mg The usual adult dosage is one or two tablets every four to six hours as needed for pain. The total daily dosage should not exceed 8 tablets. 5 mg/325 mg The usual adult dosage is one or two tablets every four to six hours as needed for pain. The total daily dosage should not exceed 8 tablets. 7.5 mg/325 mg, 10 mg/325 mg The usual adult dosage is one tablet every four to six hours as n wo tablets every four to six hours as needed for pain. The total daily dosage should not exceed 8 tablets. 7.5 mg/325 mg, 10 mg/325 mg The usual adult dosage is one tablet every four to six hours as needed for pain. The total daily dosage should not exceed 6 tablets. Conversion from Other Opioids to Hydrocodone Bitartrate and Acetaminophen Tablets There is inter-patient variability in the potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dosage of hydrocodone bitartrate and acetaminophen tablets. It is safer to underestimate a patient’s 24-hour hydrocodone bitartrate and acetaminophen tablets dosage than to overestimate the 24-hour hydrocodone bitartrate and acetaminophen tablets dosage and manage an adverse reaction due to overdose. Conversion from Hydrocodone Bitartrate and Acetaminophen Tablets to Extended-Release Hydrocodone The relative bioavailability of hydrocodone from hydrocodone bitartrate and acetaminophen tablets compared to extended-release hydrocodone products is unknown, so conversion to extended-release products must be accompanied by close observation for signs of excessive sedation and r minophen tablets compared to extended-release hydrocodone products is unknown, so conversion to extended-release products must be accompanied by close observation for signs of excessive sedation and respiratory depression. Titration and Maintenance of Therapy Individually titrate hydrocodone bitartrate and acetaminophen tablets to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving hydrocodone bitartrate and acetaminophen tablets to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse [see WARNINGS ]. 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 hydrocodone bitartrate and acetaminophen tablets dosage. If unacceptable opioid-related adverse reactions are observed, consider reducing the dosage. Adjust the dosage to obtain before increasing the hydrocodone bitartrate and acetaminophen tablets dosage. If unacceptable opioid-related adverse reactions are observed, consider reducing the dosage. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions. Safe Reduction or Discontinuation of Hydrocodone Bitartrate and Acetaminophen Tablets Do not abruptly discontinue hydrocodone bitartrate and acetaminophen tablets 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 hydrocodone bitartrate and acetaminophen tablets, there are a variety of factors that should be considered, including the do rease the dose or discontinue therapy in an opioid-dependent patient taking hydrocodone bitartrate and acetaminophen tablets, there are a variety of factors that should be considered, including the dose of hydrocodone bitartrate and acetaminophen 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 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 co-morbid 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. F o 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 hydrocodone bitartrate and acetaminophen 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 lower dosage strengths 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 xiety, 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, monitor 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 a long duration 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/ Withdrawal, DRUG ABUSE AND DEPENDENCE ]. ADVERSE REACTIONS The following adverse reactions have been identified during post approval use of hydrocodone and acetaminophen tablets. Because these reactions are reported voluntarily from a population SE REACTIONS The following adverse reactions have been identified during post approval use of hydrocodone and acetaminophen 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. The most frequently reported adverse reactions are light-headedness, dizziness, sedation, nausea and vomiting. Other adverse reactions include: Central Nervous System: Drowsiness, mental clouding, lethargy, impairment of mental and physical performance, anxiety, fear, dysphoria, psychological dependence, mood changes. Gastrointestinal System: Constipation. Genitourinary System: Ureteral spasm, spasm of vesical sphincters, and urinary retention. Special Senses: Cases of hearing impairment or permanent loss have been reported predominately in patients with chronic overdose. Dermatological: Skin rash, pruritus, Stevens-Johnson syndrome, toxic epidermal necrolysis, allergic reactions. Hematological: Thrombocytopenia, agranulocytosis. Serotonin syndrome : Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomi sis, allergic reactions. Hematological: Thrombocytopenia, agranulocytosis. 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. Anaphylaxis : Anaphylaxis has been reported with ingredients contained in hydrocodone bitartrate and acetaminophen tablets. Androgen deficiency : Cases of androgen deficiency have occurred with chronic use of opioids [see CLINICAL PHARMACOLOGY ]. INDICATIONS AND USAGE Mirtazapine tablets, USP are indicated for the treatment of major depressive disorder. The efficacy of mirtazapine in the treatment of major depressive disorder was established in 6 - week controlled trials of outpatients whose diagnoses corresponded most closely to the Diagnostic and Statistical Manual of Mental Disorders -3 rd edition (DSM-III) category of major depressive disorder (see CLINICAL PHARMACOLOGY ). A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning, and includes at least 5 of the following 9 symptoms: depressed mood, loss of interest in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt, or suicidal ideation. The effectiveness of mirtazapine in hospitalized depressed patients has not been adequately studied. The efficacy of mirtazapine, USP in maintaining a response in patients with major depressive disorder for u ctiveness of mirtazapine in hospitalized depressed patients has not been adequately studied. The efficacy of mirtazapine, USP in maintaining a response in patients with major depressive disorder for up to 40 weeks following 8 to 12 weeks of initial open-label treatment was demonstrated in a placebo-controlled trial. Nevertheless, the physician who elects to use mirtazapine, USP for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see CLINICAL PHARMACOLOGY ). WARNINGS Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emerge e disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 sho of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1. Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18 - 24 5 additional cases Decreases Compared to Placebo 25 - 64 1 fewer case ≥ 65 6 fewer cases No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not suf nal cases Decreases Compared to Placebo 25 - 64 1 fewer case ≥ 65 6 fewer cases No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, bot ychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediatel ients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Mirtazapine tablets, USP should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family histo nts with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Mirtazapine tablets, USP are not approved for use in treating bipolar depression. Agranulocytosis In premarketing clinical trials, 2 (1 with Sjögren's Syndrome) out of 2796 patients treated with Mirtazapine tablets, USP developed agranulocytosis [absolute neutrophil count (ANC) < 500/mm 3 with associated signs and symptoms, e.g., fever, infection, etc.] and a third patient developed severe neutropenia (ANC < 500/mm 3 without any associated symptoms). For these 3 patients, onset of severe neutropenia was detected on days 61, 9, and 14 of treatment, respectively. All 3 patients recovered after mirtazapine was stopped. These 3 cases yield a crude incidence of severe neutropenia (with or without associated infection) of approximately 1.1 per thousand patients exposed, with a very wide 95% confidence interval, i.e., 2.2 cases per 10,000 to 3.1 cases per 1000. If a patient develops a sore throat, fever, stomatitis, or o pproximately 1.1 per thousand patients exposed, with a very wide 95% confidence interval, i.e., 2.2 cases per 10,000 to 3.1 cases per 1000. If a patient develops a sore throat, fever, stomatitis, or other signs of infection, along with a low WBC count, treatment with mirtazapine should be discontinued and the patient should be closely monitored. Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including mirtazapine, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's wort), and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordin ), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome. The concomitant use of mirtazapine with MAOIs intended to treat psychiatric disorders is contraindicated. Mirtazapine tablets, USP should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking Mirtazapine tablets, USP. Mirtazapine tablets, USP should be discontinued before initiating treatment with the MAOI (see CONTRAINDICA uch as linezolid or intravenous methylene blue in a patient taking Mirtazapine tablets, USP. Mirtazapine tablets, USP should be discontinued before initiating treatment with the MAOI (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION ). If concomitant use of mirtazapine with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John's wort, is clinically warranted, be aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. Treatment with mirtazapine and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. Angle-Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs including Mirtazapine tablets, USP may trigger an angle-closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. QT Prolongation and Torsades de Pointes The effect of Mirtazapine on QTc interval was assessed in a clinical randomized trial with placebo and positive (moxifloxacin) controls involving nt iridectomy. QT Prolongation and Torsades de Pointes The effect of Mirtazapine on QTc interval was assessed in a clinical randomized trial with placebo and positive (moxifloxacin) controls involving 54 healthy volunteers using exposure response analysis. This trial showed a positive relationship between mirtazapine concentrations and prolongation of the QTc interval. However, the degree of QT prolongation observed with both 45 mg (therapeutic) and 75 mg (supratherapeutic) doses of mirtazapine was not at a level generally considered to be clinically meaningful. During the postmarketing use of mirtazapine, cases of QT prolongation, Torsades de Pointes, ventricular tachycardia, and sudden death, have been reported (see ADVERSE REACTIONS ). The majority of reports occurred in association with overdose or in patients with other risk factors for QT prolongation, including concomitant use of QTc-prolonging medicines (see PRECAUTIONS , Drug Interactions and OVERDOSAGE sections). Caution should be exercised when Mirtazapine is prescribed in patients with known cardiovascular disease or family history of QT prolongation, and in concomitant use with other medicinal products thought to prolo ld be exercised when Mirtazapine is prescribed in patients with known cardiovascular disease or family history of QT prolongation, and in concomitant use with other medicinal products thought to prolong the QTc interval. DOSAGE AND ADMINISTRATION Initial Treatment The recommended starting dose for Mirtazapine tablets, USP is 15 mg/day, administered in a single dose, preferably in the evening prior to sleep. In the controlled clinical trials establishing the efficacy of mirtazapine in the treatment of major depressive disorder, the effective dose range was generally 15 to 45 mg/day. While the relationship between dose and satisfactory response in the treatment of major depressive disorder for mirtazapine has not been adequately explored, patients not responding to the initial 15-mg dose may benefit from dose increases up to a maximum of 45 mg/day. Mirtazapine has an elimination half-life of approximately 20 to 40 hours; therefore, dose changes should not be made at intervals of less than 1 to 2 weeks in order to allow sufficient time for evaluation of the therapeutic response to a given dose. Elderly and Patients with Renal or Hepatic Impairment The clearance of mirtazapine is reduc n 1 to 2 weeks in order to allow sufficient time for evaluation of the therapeutic response to a given dose. Elderly and Patients with Renal or Hepatic Impairment The clearance of mirtazapine is reduced in elderly patients and in patients with moderate to severe renal or hepatic impairment. Consequently, the prescriber should be aware that plasma mirtazapine levels may be increased in these patient groups, compared to levels observed in younger adults without renal or hepatic impairment (see PRECAUTIONS and CLINICAL PHARMACOLOGY ). Maintenance/Extended Treatment It is generally agreed that acute episodes of depression require several months or longer of sustained pharmacological therapy beyond response to the acute episode. Systematic evaluation of Mirtazapine tablets, USP has demonstrated that its efficacy in major depressive disorder is maintained for periods of up to 40 weeks following 8 to 12 weeks of initial treatment at a dose of 15 to 45 mg/day (see CLINICAL PHARMACOLOGY ). Based on these limited data, it is unknown whether or not the dose of mirtazapine needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be period d on these limited data, it is unknown whether or not the dose of mirtazapine needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment. Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with Mirtazapine tablets, USP. Conversely, at least 14 days should be allowed after stopping mirtazapine before starting an MAOI intended to treat psychiatric disorders (see CONTRAINDICATIONS ). Use of Mirtazapine With Other MAOIs, Such as Linezolid or Methylene Blue Do not start mirtazapine in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered (see CONTRAINDICATIONS ). In some cases, a patient already receiving thera quires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered (see CONTRAINDICATIONS ). In some cases, a patient already receiving therapy with mirtazapine 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 serotonin syndrome in a particular patient, mirtazapine should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with mirtazapine may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue (see WARNINGS ). 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 mirtazapine is unclear. The clinician should, nevertheless, be a hylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with mirtazapine is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use (see WARNINGS ). Discontinuation of Mirtazapine Treatment Symptoms associated with the discontinuation or dose reduction of Mirtazapine tablets, USP have been reported. Patients should be monitored for these and other symptoms when discontinuing treatment or during dosage reduction. A gradual reduction in the dose over several weeks, rather than abrupt cessation, is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, dose titration should be managed on the basis of the patient's clinical response (see PRECAUTIONS and ADVERSE REACTIONS ). Information for Patients Patients should be advised that taking mirtazapine can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle-closure glaucoma, when diag llary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle-closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible. ADVERSE REACTIONS Associated with Discontinuation of Treatment Approximately 16% of the 453 patients who received Mirtazapine tablets, USP in US 6-week controlled clinical trials discontinued treatment due to an adverse experience, compared to 7% of the 361 placebo-treated patients in those studies. The most common events (≥1%) associated with discontinuation and considered to be drug related (i.e., those events associated with dropout at a rate at least twice that of placebo) are included in Table 2. Table 2: Common Adverse Events Associated with Discontinuation of Treatment in 6-Week US Mirtazapine Trials Percentage of Patients Discontinuing with Adverse Event Adverse Event Mirtazapine (n=453) Pl Table 2: Common Adverse Events Associated with Discontinuation of Treatment in 6-Week US Mirtazapine Trials Percentage of Patients Discontinuing with Adverse Event Adverse Event Mirtazapine (n=453) Placebo (n=361) Somnolence 10.4% 2.2% Nausea 1.5% 0% Commonly Observed Adverse Events in US Controlled Clinical Trials The most commonly observed adverse events associated with the use of Mirtazapine tablets, USP (incidence of 5% or greater) and not observed at an equivalent incidence among placebo-treated patients (mirtazapine incidence at least twice that for placebo) are listed in Table 3. Table 3: Common Treatment-Emergent Adverse Events Associated With the Use of Mirtazapine in 6 ‑ Week US Trials Percentage of Patients Reporting Adverse Event Adverse Event Mirtazapine (n=453) Placebo (n=361) Somnolence 54% 18% Increased Appetite 17% 2% Weight Gain 12% 2% Dizziness 7% 3% Adverse Events Occurring at an Incidence of 1% or More Among Mirtazapine-Treated Patients Table 4 enumerates adverse events that occurred at an incidence of 1% or more, and were more frequent than in the placebo group, among Mirtazapine tablets, USP-treated patients who participated in short-term US placebo-controlle vents that occurred at an incidence of 1% or more, and were more frequent than in the placebo group, among Mirtazapine tablets, USP-treated patients who participated in short-term US placebo-controlled trials in which patients were dosed in a range of 5 to 60 mg/day. This table shows the percentage of patients in each group who had at least 1 episode of an event at some time during their treatment. Reported adverse events were classified using a standard COSTART-based dictionary terminology. The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side-effect incidence rate in the population studied. Table 4: Incidence of Adverse Clinical Experiences * ( ≥1%) in Short-Term US Contro g the relative contribution of drug and nondrug factors to the side-effect incidence rate in the population studied. Table 4: Incidence of Adverse Clinical Experiences * ( ≥1%) in Short-Term US Controlled Studies Body System Adverse Clinical Experience MIRTAZAPINE (n=453) Placebo (n=361) Body as a Whole Asthenia 8% 5% Flu Syndrome 5% 3% Back Pain 2% 1% Digestive System Dry Mouth 25% 15% Increased Appetite 17% 2% Constipation 13% 7% Metabolic and Nutritional Disorders Weight Gain 12% 2% Peripheral Edema 2% 1% Edema 1% 0% Musculoskeletal System Myalgia 2% 1% Nervous System Somnolence 54% 18% Dizziness 7% 3% AbnormalDreams 4% 1% Thinking Abnormal 3% 1% Tremor 2% 1% Confusion 2% 0% Respiratory System Dyspnea 1% 0% Urogenital System Urinary Frequency 2% 1% * Events reported by at least 1% of patients treated with mirtazapine are included, except the following events, which had an incidence on placebo greater than or equal to mirtazapine: headache, infection, pain, chest pain, palpitation, tachycardia, postural hypotension, nausea, dyspepsia, diarrhea, flatulence, insomnia, nervousness, libido decreased, hypertonia, pharyngitis, rhinitis, sweating, amblyopia, tinnitus, taste perversion. achycardia, postural hypotension, nausea, dyspepsia, diarrhea, flatulence, insomnia, nervousness, libido decreased, hypertonia, pharyngitis, rhinitis, sweating, amblyopia, tinnitus, taste perversion. ECG Changes The electrocardiograms for 338 patients who received Mirtazapine tablets, USP and 261 patients who received placebo in 6-week, placebo-controlled trials were analyzed. Prolongation in QTc ≥ 500 msec was not observed among mirtazapine-treated patients; mean change in QTc was +1.6 msec for mirtazapine and -3.1 msec for placebo. Mirtazapine was associated with a mean increase in heart rate of 3.4 bpm, compared to 0.8 bpm for placebo. The clinical significance of these changes is unknown. The effect of mirtazapine on QTc interval was assessed in a clinical randomized trial with placebo and positive (moxifloxacin) controls involving 54 healthy volunteers using exposure response analysis. This trial showed a positive relationship between mirtazapine concentrations and prolongation of the QTc interval. However, the degree of QT prolongation observed with both 45 mg (therapeutic) and 75 mg (supratherapeutic) doses of mirtazapine was not at a level generally considered to be clinica the QTc interval. However, the degree of QT prolongation observed with both 45 mg (therapeutic) and 75 mg (supratherapeutic) doses of mirtazapine was not at a level generally considered to be clinically meaningful. Other Adverse Events Observed During the Premarketing Evaluation of Mirtazapine During its premarketing assessment, multiple doses of Mirtazapine tablets, USP were administered to 2796 patients in clinical studies. The conditions and duration of exposure to mirtazapine varied greatly, and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, fixed-dose and titration studies. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories. In the tabulations that follow, reported adverse events were classified using a standard COSTART-based dictionary terminology. The frequencies presented, t ler number of standardized event categories. In the tabulations that follow, reported adverse events were classified using a standard COSTART-based dictionary terminology. The frequencies presented, therefore, represent the proportion of the 2796 patients exposed to multiple doses of mirtazapine who experienced an event of the type cited on at least 1 occasion while receiving mirtazapine. All reported events are included except those already listed in Table 4, those adverse experiences subsumed under COSTART terms that are either overly general or excessively specific so as to be uninformative, and those events for which a drug cause was very remote. It is important to emphasize that, although the events reported occurred during treatment with mirtazapine, they were not necessarily caused by it. Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring on 1 or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Only those events not already ons in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Only those events not already listed in Table 4 appear in this listing. Events of major clinical importance are also described in the WARNINGS and PRECAUTIONS sections. Body as a Whole : frequent: malaise, abdominal pain, abdominal syndrome acute; infrequent: chills, fever, face edema, ulcer, photosensitivity reaction, neck rigidity, neck pain, abdomen enlarged; rare: cellulitis, chest pain substernal. Cardiovascular System : frequent: hypertension, vasodilatation; infrequent: angina pectoris, myocardial infarction, bradycardia, ventricular extrasystoles, syncope, migraine, hypotension; rare: atrial arrhythmia, bigeminy, vascular headache, pulmonary embolus, cerebral ischemia, cardiomegaly, phlebitis, left heart failure. Digestive System : frequent: vomiting, anorexia; infrequent: eructation, glossitis, cholecystitis, nausea and vomiting, gum hemorrhage, stomatitis, colitis, liver function tests abnormal; rare: tongue discoloration, ulcerative stomatitis, salivary gland enlargement, increased salivation, intestinal nausea and vomiting, gum hemorrhage, stomatitis, colitis, liver function tests abnormal; rare: tongue discoloration, ulcerative stomatitis, salivary gland enlargement, increased salivation, intestinal obstruction, pancreatitis, aphthous stomatitis, cirrhosis of liver, gastritis, gastroenteritis, oral moniliasis, tongue edema. Endocrine System : rare: goiter, hypothyroidism. Hemic and Lymphatic System : rare: lymphadenopathy, leukopenia, petechia, anemia, thrombocytopenia, lymphocytosis, pancytopenia. Metabolic and Nutritional Disorders : frequent: thirst; infrequent: dehydration, weight loss; rare: gout, SGOT increased, healing abnormal, acid phosphatase increased, SGPT increased, diabetes mellitus, hyponatremia. Musculoskeletal System : frequent: myasthenia, arthralgia; infrequent: arthritis, tenosynovitis; rare: pathologic fracture, osteoporosis fracture, bone pain, myositis, tendon rupture, arthrosis, bursitis. Nervous System : frequent: hypesthesia, apathy, depression, hypokinesia, vertigo, twitching, agitation, anxiety, amnesia, hyperkinesia, paresthesia; infrequent: ataxia, delirium, delusions, depersonalization, dyskinesia, extrapyramidal syndrome, libido increased, coordina vertigo, twitching, agitation, anxiety, amnesia, hyperkinesia, paresthesia; infrequent: ataxia, delirium, delusions, depersonalization, dyskinesia, extrapyramidal syndrome, libido increased, coordination abnormal, dysarthria, hallucinations, manic reaction, neurosis, dystonia, hostility, reflexes increased, emotional lability, euphoria, paranoid reaction; rare: aphasia, nystagmus, akathisia (psychomotor restlessness), stupor, dementia, diplopia, drug dependence, paralysis, grand mal convulsion, hypotonia, myoclonus, psychotic depression, withdrawal syndrome, serotonin syndrome. Respiratory System : frequent: cough increased, sinusitis; infrequent: epistaxis, bronchitis, asthma, pneumonia; rare: asphyxia, laryngitis, pneumothorax, hiccup. Skin and Appendages : frequent: pruritus, rash; infrequent: acne, exfoliative dermatitis, dry skin, herpes simplex, alopecia; rare: urticaria, herpes zoster, skin hypertrophy, seborrhea, skin ulcer. Special Senses : infrequent: eye pain, abnormality of accommodation, conjunctivitis, deafness, keratoconjunctivitis, lacrimation disorder, angle-closure glaucoma, hyperacusis, ear pain; rare: blepharitis, partial transitory deafness, otitis media, tast f accommodation, conjunctivitis, deafness, keratoconjunctivitis, lacrimation disorder, angle-closure glaucoma, hyperacusis, ear pain; rare: blepharitis, partial transitory deafness, otitis media, taste loss, parosmia. Urogenital System : frequent: urinary tract infection; infrequent: kidney calculus, cystitis, dysuria, urinary incontinence, urinary retention, vaginitis, hematuria, breast pain, amenorrhea, dysmenorrhea, leukorrhea, impotence; rare: polyuria, urethritis, metrorrhagia, menorrhagia, abnormal ejaculation, breast engorgement, breast enlargement, urinary urgency. Other Adverse Events Observed During Postmarketing Evaluation of Mirtazapine Adverse events reported since market introduction, which were temporally (but not necessarily causally) related to mirtazapine therapy, include cases of the ventricular arrhythmia Torsades de Pointes. In the majority of these cases, however, concomitant drugs were implicated. Cases of severe skin reactions, including Stevens-Johnson syndrome, bullous dermatitis, erythema multiforme and toxic epidermal necrolysis have also been reported. Increased creatine kinase blood levels and rhabdomyolysis have also been reported. Hyperprolactinemia , bullous dermatitis, erythema multiforme and toxic epidermal necrolysis have also been reported. Increased creatine kinase blood levels and rhabdomyolysis have also been reported. Hyperprolactinemia (and related symptoms, e.g., galactorrhea and gynecomastia) has been reported. Somnambulism (ambulation and other complex behaviors out of bed) has been reported. Uses for the relief of: heartburn, acid indigestion, and sour stomach when accompanied with headache or body aches and pains upset stomach with headache from overindulgence in food or drink headache, body aches, and pain alone Purpose Acetylsalicylic Acid 500 mg Analgesic Phenylephrine Bitartrate 8 mg Decongestant Chlorpheniramine maleate 2 mg Antihistamine Warnings Reye's syndrome: Children and teenagers should not use this medicine for chicken pox or flu symptoms before a doctor is consulted about Reye's syndrome, a rare but serious illness reported to be associated with aspirin. Allergy alert: Aspirin may cause a severe allergic reaction which may include: hives asthma (wheezing) Alcohol warning: If you consume 3 or more alcoholic drinks every day, ask your doctor whether you should take aspirin or other pain relievers/fever reducers. Aspirin may cause stomach bleeding. Directions fully dissolve 2 tablets in 4 ounces of water before taking adults and children 12 years and over: 2 tablets every 4 hours, or as directed by a doctor do not exceed 8 tablets in 24 hours adults 60 years and over 2 tablets every 4 hours, or as directed by a doctor do not exceed 4 tablets in 24 hours chi blets every 4 hours, or as directed by a doctor do not exceed 8 tablets in 24 hours adults 60 years and over 2 tablets every 4 hours, or as directed by a doctor do not exceed 4 tablets in 24 hours children under 12 years consult a doctor Other information each tablet contains: sodium 567 mg store at room temperature. Avoid excessive heat. Tabcin 500 in water contains principally the antacid sodium citrate and the analgesic sodium acetylsalicylate Keep out of reach of children In case of overdose, get medical help or contact a Poison Control Center right away. Uses temporarily relieves: cough as may occur with a cold occasional minor irritation and sore throat Purpose Cough suppressant / Oral anesthetic Warnings Sore throat warning: if sore throat is severe, persists for more than 2 days, is accompanied or followed by fever, headache, rash, swelling, nausea, or vomiting, consult a doctor promptly. If sore mouth symptoms do not improve in 7 days, see your dentist or doctor promptly. These symptoms may be serious. Directions adults and children 5 years and over - dissolve 1 lozenge slowly in mouth. Repeat every 2 hours as needed or as directed by a doctor. children under 5 years - ask a doctor Ask a doctor before use if you have persistent or chronic cough such as occurs with smoking, asthma, or emphysema cough accompanied by excessive phlegm (mucus) Stop use and consult doctor if cough persists for more than 7 days, tends to recur, or is accompanied by fever, reash, or persistent headache. These could be signs of a serious condition. sore throat is severe, or irritation, pain or redness lasts or worsens sore mouth does not improve in 7 days Keep out of reach of children. Uses relieves occasional constipation (irregularity) generally produces bowel movement in 1/2 to 6 hours Purpose Saline laxative Warnings Ask a doctor before use if you have kidney disease a magnesium-restricted diet stomach pain, nausea, or vomiting a sudden change in bowel habits that lasts over 14 days ​ Ask a doctor or pharmacist before use if you are presently taking a prescription drug. This product may interact with certain prescription drugs. Stop use and ask a doctor if you have rectal bleeding or no bowel movement after using this product. These could be signs of a serious condition. you need to use a laxative for more than 1 week If pregnant or breast-feeding, ask a health professional before use. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center (1-800-222-1222) right away. Directions shake well before use do not exceed the maximum recommended daily dose in a 24 hour period dose may be taken once a day preferably at bedtime, in divided doses, or as directed by a doctor drink a full glass (8 oz) of liquid with each dose for accurate dosing, only use the dosing cup provided mL = milliliter age dose adults and children ime, in divided doses, or as directed by a doctor drink a full glass (8 oz) of liquid with each dose for accurate dosing, only use the dosing cup provided mL = milliliter age dose adults and children 12 years and over 30 mL to 60 mL children 6 to 11 years 15 mL to 30 mL children under 6 years ask a doctor Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center (1-800-222-1222) right away. Uses Aids in the prevention of dental cavities Helps prevent and reduce plaque and gingivitis Helps control plaque bacteria that contribute to the development of gingivitis and bleeding gums Purpose Antigingivitis/antiplaque Anticavity Ask a dentist if symptoms persist or condition worsens after regular use. Directions Adults and children 6 years of age and older Use once a day after brushing your teeth with a toothpaste Remove cap Pour 10 milliliters into a cap (10 mL mark on inside of cap); do not fill above 10 mL mark Vigorously swish 10 milliliters of rinse between your teeth for 1 minute and then spit out Do not swallow the rinse Do not eat or drink for 30 minutes after rinsing Instruct children 12 years under age in good rinsing habits (to minimize swallowing) Supervise children as necessary until capable of using without supervision Children under 6 years of age Consult a dentist or doctor Warnings Keep out of reach of children. If more than used for rinsing is accidentally swallowed, get medical help or contact a Poison Control Center right away. Uses • temporarily relieves these symptoms associated with hay fever or other upper respiratory allergies, and the common cold: • headache • sinus congestion and pressure • nasal congestion • minor aches and pains • helps decongest sinus openings and passages • promotes sinus drainage • helps clear nasal passages • temporarily reduces fever Purpose Pain reliever/fever reducer Nasal decongestant Warnings Liver warning: This product contains acetaminophen. Severe liver damage may occur if you take • more than 4,000 mg of acetaminophen in 24 hours • with other drugs containing acetaminophen • 3 or more alcoholic drinks every day while using this product Allergy alert: Acetaminophen may cause severe skin reactions. Symptoms may include: • skin reddening • blisters • rash If a skin reaction occurs, stop use and seek medical help right away. Do not use • with any other drug containing acetaminophen (prescription or nonprescription). If you are not sure whether a drug contains acetaminophen, ask a doctor or pharmacist. • if you are now taking a prescription monoamine oxidase inhibitor (MAOI) (certain drugs for depression, psychiatric, or emotional conditions, or Parkinson’s disease), or f ask a doctor or pharmacist. • if you are now taking a prescription monoamine oxidase inhibitor (MAOI) (certain drugs for depression, psychiatric, or emotional conditions, or Parkinson’s disease), or for 2 weeks after stopping the MAOI drug. If you do not know if your prescription drug contains an MAOI, ask a doctor or pharmacist before taking this product. • if you have ever had an allergic reaction to this product or any of its ingredients Ask a doctor before use if you have • liver disease • heart disease • high blood pressure • thyroid disease • diabetes • trouble urinating due to an enlarged prostate gland Ask a doctor or pharmacist before use if you are taking the blood thinning drug warfarin When using this product do not exceed recommended dosage Stop use and ask a doctor if • nervousness, dizziness, or sleeplessness occur • pain or nasal congestion gets worse or lasts more than 7 days • fever gets worse or lasts more than 3 days • redness or swelling is present • new symptoms occur These could be signs of a serious condition. If pregnant or breast-feeding, ask a health professional before use. Keep out of reach of children. Overdose warning: In case of overdose, get medical ccur These could be signs of a serious condition. If pregnant or breast-feeding, ask a health professional before use. Keep out of reach of children. Overdose warning: In case of overdose, get medical help or contact a Poison Control Center right away (1-800-222-1222). Quick medical attention is critical for adults as well as for children even if you do not notice any signs or symptoms. Directions • do not take more than directed (see overdose warning) adults and children 12 years and over • take 2 caplets every 4 hours • swallow whole – do not crush, chew or dissolve • do not take more than 10 caplets in 24 hours children under 12 years ask a doctor Ask a doctor before use if you have • liver disease • heart disease • high blood pressure • thyroid disease • diabetes • trouble urinating due to an enlarged prostate gland Stop use and ask a doctor if • nervousness, dizziness, or sleeplessness occur • pain or nasal congestion gets worse or lasts more than 7 days • fever gets worse or lasts more than 3 days • redness or swelling is present • new symptoms occur These could be signs of a serious condition. Keep out of reach of children. Overdose warning: In case of overdose, get medical s more than 3 days • redness or swelling is present • new symptoms occur These could be signs of a serious condition. Keep out of reach of children. Overdose warning: In case of overdose, get medical help or contact a Poison Control Center right away (1-800-222-1222). Quick medical attention is critical for adults as well as for children even if you do not notice any signs or symptoms. INDICATIONS & USAGE Major Depressive Disorder: Bupropion hydrochloride extended-release tablets (XL) are indicated for the treatment of major depressive disorder. The efficacy of bupropion in the treatment of a major depressive episode was established in two 4-week controlled trials of inpatients and in one 6-week controlled trial of outpatients whose diagnoses corresponded most closely to the Major Depression category of the APA Diagnostic and Statistical Manual (DSM) (see CLINICAL TRIALS ). A major depressive episode (DSM-IV) implies the presence of 1) depressed mood or 2) loss of interest or pleasure; in addition, at least 5 of the following symptoms have been present during the same 2-week period and represent a change from previous functioning: depressed mood, markedly diminished interest or pleasure in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt, or suicidal ideation. The efficacy of bupropion in maintaining an antidepressant response for up to 44 weeks following 8 weeks of acute , slowed thinking or impaired concentration, a suicide attempt, or suicidal ideation. The efficacy of bupropion in maintaining an antidepressant response for up to 44 weeks following 8 weeks of acute treatment was demonstrated in a placebo-controlled trial with the sustained-release formulation of bupropion (see CLINICAL TRIALS ). Nevertheless, the physician who elects to use bupropion hydrochloride extended-release tablets (XL) for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient. Seasonal Affective Disorder: Bupropion hydrochloride extended-release tablets (XL) are indicated for the prevention of seasonal major depressive episodes in patients with a diagnosis of seasonal affective disorder. The efficacy of bupropion hydrochloride extended-release tablets (XL) for the prevention of seasonal major depressive episodes was established in 3 controlled trials of adult outpatients with a history of major depressive disorder with an autumn-winter seasonal pattern as defined by Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria (see CLINICAL TRIALS ). Seasonal affective disorder is characteriz an autumn-winter seasonal pattern as defined by Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria (see CLINICAL TRIALS ). Seasonal affective disorder is characterized by recurrent major depressive episodes, most commonly occurring during the autumn and/or winter months. Episodes may last up to 6 months in duration, typically beginning in the autumn and remitting in the springtime. Although patients with seasonal affective disorder may have depressive episodes during other times of the year, the diagnosis of seasonal affective disorder requires that the number of seasonal episodes substantially outnumber the number of non-seasonal episodes during the individual's lifetime. WARNINGS DOSAGE & ADMINISTRATION General Dosing Considerations: It is particularly important to administer bupropion hydrochloride extended-release tablets (XL) in a manner most likely to minimize the risk of seizure (see WARNINGS ). Gradual escalation in dosage is also important if agitation, motor restlessness, and insomnia, often seen during the initial days of treatment, are to be minimized. If necessary, these effects may be managed by temporary reduction of dose or the sho agitation, motor restlessness, and insomnia, often seen during the initial days of treatment, are to be minimized. If necessary, these effects may be managed by temporary reduction of dose or the short-term administration of an intermediate to long-acting sedative hypnotic. A sedative hypnotic usually is not required beyond the first week of treatment. Insomnia may also be minimized by avoiding bedtime doses. If distressing, untoward effects supervene, dose escalation should be stopped. Bupropion hydrochloride extended-release tablets (XL) should be swallowed whole and not crushed, divided, or chewed. Bupropion hydrochloride extended-release tablets (XL) may be taken without regard to meals. Major Depressive Disorder:Initial Treatment: The usual adult target dose for bupropion hydrochloride extended-release tablets (XL) is 300 mg/day, given once daily in the morning. Dosing with bupropion hydrochloride extended-release tablets (XL) should begin at 150 mg/day given as a single daily dose in the morning. If the 150-mg initial dose is adequately tolerated, an increase to the 300-mg/day target dose, given as once daily, may be made as early as day 4 of dosing, as this may lead to an i se in the morning. If the 150-mg initial dose is adequately tolerated, an increase to the 300-mg/day target dose, given as once daily, may be made as early as day 4 of dosing, as this may lead to an increased risk of adverse effects including seizures. There should be an interval of at least 24 hours between successive doses. Increasing the Dosage Above 300 mg/day: As with other antidepressants, the full antidepressant effect of bupropion hydrochloride extended-release tablets (XL) may not be evident until 4 weeks of treatment or longer. An increase in dosage to the maximum of 450 mg/day, given as a single dose, may be considered for patients in whom no clinical improvement is noted after several weeks of treatment at 300 mg/day. Maintenance Treatment: It is generally agreed that acute episodes of depression require several months or longer of sustained pharmacological therapy beyond response to the acute episode. It is unknown whether or not the dose of bupropion hydrochloride extended-release tablets (XL) needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to determine the need for maintenance d-release tablets (XL) needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment. Seasonal Affective Disorder: For the prevention of seasonal major depressive episodes associated with seasonal affective disorder, bupropion hydrochloride extended-release tablets (XL) should generally be initiated in the autumn prior to the onset of depressive symptoms. Treatment should continue through the winter season and should be tapered and discontinued in early spring. The timing of initiation and duration of treatment should be individualized based on the patient's historical pattern of seasonal major depressive episodes. Patients whose seasonal depressive episodes are infrequent or not associated with significant impairment should not generally be treated prophylactically. Dosing with bupropion hydrochloride extended-release tablets (XL) should begin at 150 mg/day given as a single daily dose in the morning. If the 150-mg initial dose is adequately tolerated, the dose of bupropion hydrochloride extended-release tablets ( tablets (XL) should begin at 150 mg/day given as a single daily dose in the morning. If the 150-mg initial dose is adequately tolerated, the dose of bupropion hydrochloride extended-release tablets (XL) should be increased to the 300-mg/day dose after 1 week. If the 300-mg dose is not adequately tolerated, the dose can be reduced to 150 mg/day. The usual adult target dose for bupropion hydrochloride extended-release tablets (XL) is 300 mg/day, given once daily in the morning. For patients taking 300 mg/day during the autumn-winter season, the dose should be tapered to 150 mg/day for 2 weeks prior to discontinuation. Doses of bupropion hydrochloride extended-release tablets (XL) above 300 mg/day have not been studied for the prevention of seasonal major depressive episodes. Switching Patients from WELLBUTRINTablets or from WELLBUTRIN SRSustained-Release Tablets: When switching patients from WELLBUTRINTablets to bupropion hydrochloride extended-release tablets (XL) or from WELLBUTRIN SRSustained-Release Tablets to bupropion hydrochloride extended-release tablets (XL), give the same total daily dose when possible. Patients who are currently being treated with WELLBUTRINTablets at 300 Sustained-Release Tablets to bupropion hydrochloride extended-release tablets (XL), give the same total daily dose when possible. Patients who are currently being treated with WELLBUTRINTablets at 300 mg/day (for example, 100 mg 3 times a day) may be switched to bupropion hydrochloride extended-release tablets (XL) 300 mg once daily. Patients who are currently being treated with WELLBUTRIN SRSustained-Release Tablets at 300 mg/day (for example, 150 mg twice daily) may be switched to bupropion hydrochloride extended-release tablets (XL) 300 mg once daily Dosage Adjustment for Patients with Impaired Hepatic Function: Bupropion hydrochloride extended-release tablets (XL) should be used with extreme caution in patients with severe hepatic cirrhosis. The dose should not exceed 150 mg every other day in these patients. bupropion hydrochloride extended-release tablets (XL) should be used with caution in patients with hepatic impairment (including mild-to-moderate hepatic cirrhosis) and a reduced frequency and/or dose should be considered in patients with mild-to-moderate hepatic cirrhosis (see CLINICAL PHARMACOLOGY , WARNINGS , and PRECAUTIONS ). Dosage Adjustment for Patients with Impair ced frequency and/or dose should be considered in patients with mild-to-moderate hepatic cirrhosis (see CLINICAL PHARMACOLOGY , WARNINGS , and PRECAUTIONS ). Dosage Adjustment for Patients with Impaired Renal Function: Bupropion hydrochloride extended-release tablets (XL) should be used with caution in patients with renal impairment and a reduced frequency and/or dose should be considered (see CLINICAL PHARMACOLOGY and PRECAUTIONS ). ADVERSE REACTIONS (See also WARNINGS and PRECAUTIONS .) Major Depressive Disorder: Bupropion hydrochloride extended-release tablets (XL) has been demonstrated to have similar bioavailability both to the immediate-release formulation of bupropion and to the sustained-release formulation of bupropion (see CLINICAL PHARMACOLOGY ). The information included under this subsection is based primarily on data from controlled clinical trials with WELLBUTRIN SRthe sustained-release formulation of bupropion. Adverse Events Leading to Discontinuation of Treatment With WELLBUTRINor WELLBUTRIN SR In placebo-controlled clinical trials, 9% and 11% of patients treated with 300 and 400 mg/day, respectively, of the sustained-release formulation of bupropion and 4% of pati WELLBUTRINor WELLBUTRIN SR In placebo-controlled clinical trials, 9% and 11% of patients treated with 300 and 400 mg/day, respectively, of the sustained-release formulation of bupropion and 4% of patients treated with placebo discontinued treatment due to adverse events. The specific adverse events in these trials that led to discontinuation in at least 1% of patients treated with either 300 mg/day or 400 mg/day of WELLBUTRIN SRthe sustained-release formulation of bupropion, and at a rate at least twice the placebo rate are listed in Table 6. Table 6. Treatment Discontinuations Due to Adverse Events in Placebo-Controlled Trials for Major Depressive Disorder WELLBUTRIN SRWELLBUTRIN SR300 mg/day400 mg/dayPlaceboAdverse Event Term(n = 376)(n = 114)(n = 385)Rash2.4%0.9%0.0%Nausea0.8%1.8%0.3%Agitation0.3%1.8%0.3%Migraine0.0%1.8%0.3%In clinical trials with the immediate-release formulation of bupropion, 10% of patients and volunteers discontinued due to an adverse event. Events resulting in discontinuation, in addition to those listed above for the sustained-release formulation of bupropion, include vomiting, seizures, and sleep disturbances. Adverse Events Occurring at an Incidence of 1 discontinuation, in addition to those listed above for the sustained-release formulation of bupropion, include vomiting, seizures, and sleep disturbances. Adverse Events Occurring at an Incidence of 1% or More Among Patients Treated With WELLBUTRIN or WELLBUTRIN SRTable 7 enumerates treatment-emergent adverse events that occurred among patients treated with 300 and 400 mg/day of the sustained-release formulation of bupropion and with placebo in controlled trials. Events that occurred in either the 300- or 400-mg/day group at an incidence of 1% or more and were more frequent than in the placebo group are included. Reported adverse events were classified using a COSTART-based Dictionary. Accurate estimates of the incidence of adverse events associated with the use of any drug are difficult to obtain. Estimates are influenced by drug dose, detection technique, setting, physician judgments, etc. The figures cited cannot be used to predict precisely the incidence of untoward events in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. These incidence figures also cannot be compared with those obta ourse of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. These incidence figures also cannot be compared with those obtained from other clinical studies involving related drug products as each group of drug trials is conducted under a different set of conditions. Finally, it is important to emphasize that the tabulation does not reflect the relative severity and/or clinical importance of the events. A better perspective on the serious adverse events associated with the use of bupropion is provided in the WARNINGS and PRECAUTIONS sections. Table 7. Treatment-Emergent Adverse Events in Placebo-Controlled Trials*for Major Depressive Disorder WELLBUTRIN SRWELLBUTRIN SRBody System/300 mg/day400 mg/dayPlaceboAdverse Event(n = 376)(n = 114)(n = 385)* Adverse events that occurred in at least 1% of patients treated with either 300 or 400 mg/day of the sustained-release formulation of bupropion, but equally or more frequently in the placebo group, were: abnormal dreams, accidental injury, acne, appetite increased, back pain, bronchitis, dysmenorrhea, dyspepsia, flatulence, flu syndrome, hypertension, neck pain, r requently in the placebo group, were: abnormal dreams, accidental injury, acne, appetite increased, back pain, bronchitis, dysmenorrhea, dyspepsia, flatulence, flu syndrome, hypertension, neck pain, respiratory disorder, rhinitis, and tooth disorder.Incidence based on the number of female patients.Hyphen denotes adverse events occurring in greater than 0 but less than 0.5% of patients.Body (General)Headache26%25%23%Infection8%9%6%Abdominal pain3%9%2%Asthenia2%4%2%Chest pain3%4%1%Pain2%3%2%Fever1%2%CardiovascularPalpitation2%6%2%Flushing1%4%Migraine1%4%1%Hot flashes1%3%1%DigestiveDry mouth17%24%7%Nausea13%18%8%Constipation10%5%7%Diarrhea5%7%6%Anorexia5%3%2%Vomiting4%2%2%Dysphagia0%2%0%MusculoskeletalMyalgia2%6%3%Arthralgia1%4%1%Arthritis0%2%0%Twitch1%2%Nervous systemInsomnia11%16%6%Dizziness7%11%5%Agitation3%9%2%Anxiety5%6%3%Tremor6%3%1%Nervousness5%3%3%Somnolence2%3%2%Irritability3%2%2%Memory decreased3%1%Paresthesia1%2%1%Central nervous2%1%1%system stimulationRespiratoryPharyngitis3%11%2%Sinusitis3%1%2%Increased cough1%2%1%SkinSweating6%5%2%Rash5%4%1%Pruritus2%4%2%Urticaria2%1%0%Special sensesTinnitus6%6%2%Taste perversion2%4%Blurred vision or diplopia3%2%2%UrogenitalUrinary frequ 1%2%Sinusitis3%1%2%Increased cough1%2%1%SkinSweating6%5%2%Rash5%4%1%Pruritus2%4%2%Urticaria2%1%0%Special sensesTinnitus6%6%2%Taste perversion2%4%Blurred vision or diplopia3%2%2%UrogenitalUrinary frequency2%5%2%Urinary urgency2%0%Vaginal hemorrhage0%2%Urinary tract infection1%0%Additional events to those listed in Table 7 that occurred at an incidence of at least 1% in controlled clinical trials of the immediate-release formulation of bupropion (300 to 600 mg/day) and that were numerically more frequent than placebo were: cardiac arrhythmias (5% vs 4%), hypertension (4% vs 2%), hypotension (3% vs 2%), tachycardia (11% vs 9%), appetite increase (4% vs 2%), dyspepsia (3% vs 2%), menstrual complaints (5% vs 1%), akathisia (2% vs 1%), impaired sleep quality (4% vs 2%), sensory disturbance (4% vs 3%), confusion (8% vs 5%), decreased libido (3% vs 2%), hostility (6% vs 4%), auditory disturbance (5% vs 3%), and gustatory disturbance (3% vs 1%). Incidence of Commonly Observed Adverse Events in Controlled Clinical Trials: Adverse events from Table 7 occurring in at least 5% of patients treated with the sustained-release formulation of bupropion and at a rate at least twice the placebo rate a Controlled Clinical Trials: Adverse events from Table 7 occurring in at least 5% of patients treated with the sustained-release formulation of bupropion and at a rate at least twice the placebo rate are listed below for the 300- and 400-mg/day dose groups. 300 mg/day of WELLBUTRIN SR Anorexia, dry mouth, rash, sweating, tinnitus, and tremor. 400 mg/day of WELLBUTRIN SR Abdominal pain, agitation, anxiety, dizziness, dry mouth, insomnia, myalgia, nausea, palpitation, pharyngitis, sweating, tinnitus, and urinary frequency. Seasonal Affective Disorder: Adverse Events Leading to Discontinuation of Treatment With Bupropion Hydrochloride Extended-Release Tablets (XL): In placebo-controlled clinical trials, 9% of patients treated with bupropion hydrochloride extended-release tablets (XL) and 5% of patients treated with placebo discontinued treatment due to adverse events. The adverse events in these trials that led to discontinuation in at least 1% of patients treated with bupropion hydrochloride extended-release tablets (XL) and at a rate numerically greater than the placebo rate are insomnia (2% vs <1%) and headache (1% vs <1%). Adverse Events Occurring at an Incidence of 2% or More Amon ide extended-release tablets (XL) and at a rate numerically greater than the placebo rate are insomnia (2% vs <1%) and headache (1% vs <1%). Adverse Events Occurring at an Incidence of 2% or More Among Patients Treated With Bupropion Hydrochloride Extended-Release Tablets (XL) : Table 8 enumerates treatment-emergent adverse events that occurred among patients treated with bupropion hydrochloride extended-release tablets (XL) for up to approximately 6 months in 3 placebo-controlled trials. Events that occurred at an incidence of 2% or more and were more frequent than in the placebo group are included. Reported adverse events were classified using a MedDRA-based Dictionary. Accurate estimates of the incidence of adverse events associated with the use of any drug are difficult to obtain. Estimates are influenced by drug dose, detection technique, setting, physician judgments, etc. The figures cited cannot be used to predict precisely the incidence of untoward events in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. These incidence figures also cannot be compared with those obtained from othe medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. These incidence figures also cannot be compared with those obtained from other clinical studies involving related drug products as each group of drug trials is conducted under a different set of conditions; e.g., different patient populations, different treatment durations. Finally, it is important to emphasize that the tabulation does not reflect the relative severity and/or clinical importance of the events. A better perspective on the serious adverse events associated with the use of bupropion is provided in the WARNINGS and PRECAUTIONS sections. Table 8. Treatment-Emergent Adverse Events* in Placebo-Controlled Trials of Seasonal Affective Disorder BupropionHydrochlorideExtended-ReleaseSystem Organ Class/Tablets (XL)PlaceboPreferred Term(n = 537)(n = 511)* Adverse events that occurred in at least 2% of patients treated with bupropion hydrochloride extended-release tablets (XL) , but equally or more frequently in the placebo group, were: abdominal pain upper, arthralgia, back pain, diarrhea, dyspepsia, fatigue, gastroenteritis viral, hyperhidrosis, influenza, se tablets (XL) , but equally or more frequently in the placebo group, were: abdominal pain upper, arthralgia, back pain, diarrhea, dyspepsia, fatigue, gastroenteritis viral, hyperhidrosis, influenza, irritability, migraine, nasal congestion, neck pain, palpitations, pharyngolaryngeal pain, sinus congestion.Gastrointestinal DisorderDry Mouth26%15%Nausea13%8%Constipation9%2%Flatulence6%3%Abdominal pain2%<1%Nervous System DisordersHeadache34%26%Dizziness6%5%Tremor3%<1%Infections and InfestationsNasopharyngitis13%12%Upper respiratory tract infection9%8%Sinusitis5%4%Psychiatric DisordersInsomnia20%13%Anxiety7%5%Abnormal dreams3%2%Agitation2%<1%Musculoskeletal and Connective Tissue DisordersMyalgia3%2%Pain in extremity3%2%Respiratory, Thoracic and Mediastinal DisordersCough4%3%General Disorders and Administration Site ConditionsFeeling jittery3%2%Skin and Subcutaneous Tissue DisordersRash3%2%Metabolism and Nutrition DisordersDecreased appetite4%1%Reproductive System and Breast DisordersDysmenorrhea2%<1%Ear and Labyrinth DisordersTinnitus3%<1%Vascular DisordersHypertension2%0% Incidence of Commonly Observed Adverse Events in Controlled Clinical Trials: Adverse events from Table 8 that oc enorrhea2%<1%Ear and Labyrinth DisordersTinnitus3%<1%Vascular DisordersHypertension2%0% Incidence of Commonly Observed Adverse Events in Controlled Clinical Trials: Adverse events from Table 8 that occurred in at least 5% of patients treated with bupropion hydrochloride extended-release tablets (XL) and at a rate at least twice the placebo rate were constipation and flatulence. Adverse Events During Taper or Following Discontinuation of Bupropion Hydrochloride Extended-Release Tablets (XL): Adverse events with onset during the 2 weeks following down-titration of bupropion hydrochloride extended-release tablets (XL) from 300 mg/day to 150 mg/day were reported by 14% of patients compared to 18% of patients who continued on placebo. Adverse events with onset during the 2 weeks following discontinuation of bupropion hydrochloride extended-release tablets (XL) were reported by 9% of patients compared with 12% of patients following discontinuation of placebo. Other Events Observed During the Clinical Development and Postmarketing Experience of Bupropion: In addition to the adverse events noted above, the following events have been reported in clinical trials and postmarketing experience Clinical Development and Postmarketing Experience of Bupropion: In addition to the adverse events noted above, the following events have been reported in clinical trials and postmarketing experience with the sustained-release formulation of bupropion in depressed patients and in nondepressed smokers, as well as in clinical trials and postmarketing clinical experience with the immediate-release formulation of bupropion. Adverse events for which frequencies are provided below occurred in clinical trials with the sustained-release formulation of bupropion. The frequencies represent the proportion of patients who experienced a treatment-emergent adverse event on at least one occasion in placebo-controlled studies for depression (n = 987) or smoking cessation (n = 1,013), or patients who experienced an adverse event requiring discontinuation of treatment in an open-label surveillance study with the sustained-release formulation of bupropion (n = 3,100). All treatment-emergent adverse events are included except those listed in Tables 2 through 8, those events listed in other safety-related sections, those adverse events subsumed under COSTART terms that are either overly general or exce s are included except those listed in Tables 2 through 8, those events listed in other safety-related sections, those adverse events subsumed under COSTART terms that are either overly general or excessively specific so as to be uninformative, those events not reasonably associated with the use of the drug, and those events that were not serious and occurred in fewer than 2 patients. Events of major clinical importance are described in the WARNINGS and PRECAUTIONS sections of the labeling. Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions of frequency: Frequent adverse events are defined as those occurring in at least 1/100 patients. Infrequent adverse events are those occurring in 1/100 to 1/1,000 patients, while rare events are those occurring in less than 1/1,000 patients. Adverse events for which frequencies are not provided occurred in clinical trials or postmarketing experience with bupropion. Only those adverse events not previously listed for sustained-release bupropion are included. The extent to which these events may be associated with bupropion hydrochloride extended-release tablets (XL) is u se adverse events not previously listed for sustained-release bupropion are included. The extent to which these events may be associated with bupropion hydrochloride extended-release tablets (XL) is unknown. Body (General): Infrequent were chills, facial edema, musculoskeletal chest pain, and photosensitivity. Rare was malaise. Also observed were arthralgia, myalgia, and fever with rash and other symptoms suggestive of delayed hypersensitivity. These symptoms may resemble serum sickness (see PRECAUTIONS ). Cardiovascular: Infrequent were postural hypotension, stroke, tachycardia, and vasodilation. Rare was syncope. Also observed were complete atrioventricular block, extrasystoles, hypotension, hypertension (in some cases severe, see PRECAUTIONS ), myocardial infarction, phlebitis, and pulmonary embolism. Digestive: Infrequent were abnormal liver function, bruxism, gastric reflux, gingivitis, glossitis, increased salivation, jaundice, mouth ulcers, stomatitis, and thirst. Rare was edema of tongue. Also observed were colitis, esophagitis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, intestinal perforation, liver damage, pancreatitis, and stomach ulcer. Endocrine: Also obse