SILICEA s more than 5 X ULN, hepatitis/jaundice, fatal and non-fatal hepatic failure Immune System Disorders: hypersensitivity syndrome including: anaphylaxis, angioedema, lupus erythematous-like syndrome, dermatomyositis, vasculitis Musculoskeletal and Connective Tissue Disorders: muscle cramps, immune-mediated necrotizing myopathy, rhabdomyolysis, myalgia, arthralgia, polymyalgia rheumatica, arthritis, elevated creatine phosphokinase Nervous System Disorders: dizziness, depression, paresthesia, peripheral neuropathy, rare reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. Cognitive impairment was generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks). There have been rare reports of new-onset or exacerbation of myasthenia gravis, including ocular myasthenia, and reports of recurrence when the same or a different statin was administered. Skin and Subcutaneous Tissue Disorders: rash, pruritus, alopecia, a variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous membranes, changes t ifferent statin was administered. Skin and Subcutaneous Tissue Disorders: rash, pruritus, alopecia, a variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails), purpura, lichen planus, urticaria, photosensitivity, flushing, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome. Respiratory and Thoracic: interstitial lung disease, dyspnea Reproductive System Disorders: erectile dysfunction INDICATIONS: For temporary relief of symptoms due to cough and upper respiratory infection. INDICATIONS: For temporary relief of symptoms due to cough and upper respiratory infections. WARNINGS: If pregnant or breast-feeding, ask a health care professional before use. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away. Do not use if tamper evident seal is broken or missing. Store in a cool, dry place. DIRECTIONS: 10 drops orally, 3 times a day. Consult physician for use in children under 12 years of age. KEEP OUT OF REACH OF CHILDREN. In case of overdose, get medical help or contact a Poison Control Center right away. Uses temporarily relieves these common cold and flu symptoms: cough nasal congestion minor aches and pains sore throat headache runny nose sneezing temporarily reduces fever controls cough to help your child get to sleep Active ingredients (in each 10 mL) Purposes Acetaminophen 325 mg Pain reliever/fever reducer Diphenhydramine HCl 12.5 mg Antihistamine/cough suppressant Phenylephrine HCl 5 mg Nasal decongestant Warnings Liver warning This product contains acetaminophen. Severe liver damage may occur if your child takes: more than 5 doses in 24 hours, which is the maximum daily amount with other drugs containing acetaminophen 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. Sore throat warning I f sore throat is severe, persists for more than 2 days, is accompanied or followed by fever, headache, rash, nausea, or vomiting, consult a doctor promptly. 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. to make a child sleepy with t 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. to make a child sleepy with any other product containing diphenhydramine, even one used on the skin in a child who is 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 child's prescription drug contains an MAOI, ask a doctor or pharmacist before giving this product. Ask a doctor before use if the child has liver disease heart disease diabetes high blood pressure thyroid disease glaucoma a breathing problem such as chronic bronchitis persistent or chronic cough such as occurs with asthma cough that occurs with too much phlegm (mucus) Ask a doctor or pharmacist before use if the child is taking the blood thinning drug warfarin taking sedatives or tranquilizers When using this product do not use more than directed (see Overdose warning ) excitability may occur, especially in children marked drowsiness may occur sedatives and tranquilizers may in ranquilizers When using this product do not use more than directed (see Overdose warning ) excitability may occur, especially in children marked drowsiness may occur sedatives and tranquilizers may increase drowsiness Stop use and ask a doctor if nervousness, dizziness, or sleeplessness occur pain, nasal congestion, or cough gets worse or lasts more than 5 days fever gets worse or lasts more than 3 days redness or swelling is present new symptoms occur cough comes back, or occurs with fever, rash, or headache that lasts. These could be signs of a serious condition. Keep out of reach of children. Overdose warning Taking more than the recommended dose (overdose) may cause liver damage. I n case of overdose, get medical help or contact a Poison Control Center right away. Quick medical attention is critical even if you do not notice any signs or symptoms. Directions this product does not contain directions or complete warnings for adult use do not give more than directed (see Overdose warning ) measure only with dosing cup provided do not use dosing cup with other products dose as follows or as directed by a doctor children 6 to under 12 years of age: 10 mL in dosing cup provided every ing ) measure only with dosing cup provided do not use dosing cup with other products dose as follows or as directed by a doctor children 6 to under 12 years of age: 10 mL in dosing cup provided every 4 hours while symptoms last; do not give more than 5 doses in any 24-hour period children under 6 years of age: do not use Ask a doctor before use if the child has liver disease heart disease diabetes high blood pressure thyroid disease glaucoma a breathing problem such as chronic bronchitis persistent or chronic cough such as occurs with asthma cough that occurs with too much phlegm (mucus) Stop use and ask a doctor if nervousness, dizziness, or sleeplessness occur pain, nasal congestion, or cough gets worse or lasts more than 5 days fever gets worse or lasts more than 3 days redness or swelling is present new symptoms occur cough comes back, or occurs with fever, rash, or headache that lasts. These could be signs of a serious condition. Keep out of reach of children. Uses first aid to help prevent the risk of infection in minor cuts, scrapes and burns • aids in the removal of phlegm, mucus, or other secretions associated with occasional sore mouth Purpose first aid antiseptic/oral debriding agent Warnings For external use only. Directions first aid antiseptic: • clean affected area • apply small amount of product on affected area 1-3 times a day • may be covered with a sterile bandage • if bandaged, let dry first oral debriding agent (oral rinse): • adults and children 2 years of age and over: • mix with an equal amount of water • swish around in the mouth over affected area for at least 1 minute and then spit out • use up to 4 times daily after meals and at bedtime or as directed by a dentist or doctor children under 12 years should be supervised in the use of this product • children under 2 years of age; consult a dentist or doctor Ask a doctor before use if you have deep or puncture wounds, animal bites or serious burns Stop use and ask a doctor if the condition persists or gets worse sore mouth symptoms do not improve in 7 days irritation, pain or redness persists or worsens swelling, rash or fever develops Keep this and all drugs out of th if the condition persists or gets worse sore mouth symptoms do not improve in 7 days irritation, pain or redness persists or worsens swelling, rash or fever develops Keep this and all drugs out of the reach of children. If swallowed, seek professional assistance or contact a Poison Control Center immediately. Uses Hand Sanitizer to decrease bacteria on the skin. Recommended for repeat use. Purpose Antimicrobial Warnings • For external use only: Hands Do not use on irritated or broken skin When using this product Avoid contact with eyes In case of eye contact, flush with water Keep out of reach of children. If swallowed, get medical help. Discontinue use If skin irritation or redness develops Directions Apply liberally to hands, and massage into skin. Reapply as necessary For children under 6, use only under adult supervision. Keep out of reach of children. If swallowed, get medical help. Discontinue use If skin irritation or redness develops Uses helps loosen phlegm (mucus) and thin bronchial secretions to rid the bronchial passageways of bothersome mucus and make coughs more productive temporarily relieves: cough due to minor throat and bronchial irritation as may occur with the common cold or inhaled irritants the intensity of coughing the impulse to cough to help you get to sleep nasal congestion due to a cold Purposes Cough suppressant Expectorant Nasal Decongestant Warnings Do not use 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. for children under 12 years of age Ask a doctor before use if you have heart disease thyroid disease diabetes high blood pressure trouble urinating due to an enlarged prostate gland persistent or chronic cough such as occurs with smoking, asthma, chronic bronchitis or emphysema cough that occurs with too much phlegm (mucus) When using this product, do not use more than directed. Stop use and ask a doctor if nerv as occurs with smoking, asthma, chronic bronchitis or emphysema cough that occurs with too much phlegm (mucus) When using this product, do not use more than directed. Stop use and ask a doctor if nervousness, dizziness or sleeplessness occur symptoms do not get better within 7 days or occur with a fever cough comes back, or occurs with fever, rash or headache that lasts These could be signs of a serious condition. If pregnant or breast-feeding, ask a health professional before use. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center (1-800-222-1222) right away. Directions do not take more than 6 doses in a 24-hour period measure only with dosing cup provided Do not use any other dosing device. keep dosing cup with product mL=milliliter shake well before using adults and children 12 years of age and older : 20 mL in dosing cup provided every 4 hours children under 12 years of age: do not use Ask a doctor before use if you have heart disease thyroid disease diabetes high blood pressure trouble urinating due to an enlarged prostate gland persistent or chronic cough such as occurs with smoking, asthma, chronic bronchitis or emphysema sease thyroid disease diabetes high blood pressure trouble urinating due to an enlarged prostate gland persistent or chronic cough such as occurs with smoking, asthma, chronic bronchitis or emphysema cough that occurs with too much phlegm (mucus) Stop use and ask a doctor if nervousness, dizziness or sleeplessness occur symptoms do not get better within 7 days or occur with a fever cough comes back, or occurs with fever, rash or headache that lasts These could be signs of a serious condition. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center (1-800-222-1222) right away. use helps control plaque that leads to gingivitis Purtpose Antigingivitis, Antiplaque Warnings for this product Do not use if you have painful or swollen gums, pus from the gum line, loose teeth or increased spacing between the teeth. See you dentist immediately. These may be signs of periodontitis, a serious form of gum disease Stop use and ask a dentst if gingivitis, bleeding, or redness persists for more than 2 weeks 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. Directions adults and children 12 years of age and older - vigorously swish 20 mL (2/3 FL OZ or 4 teaspoonfuls) between teeth for 30 seconds then spit out; do not swallow children under 12 years of age - consult a dentist or doctor • this rinse is not intended to replace brushing of flossing Adverse Reactions Another Quality Product Distributed by McKesson One Post Street San Francisco , CA 94104 Money Back Guarantee Please visit us at www.sunmarkbrand.com Stop use and ask a dentst if gingivitis, bleeding, or redness persists for more than 2 weeks Keep out of reach of children If more than used for rinsing is accident se visit us at www.sunmarkbrand.com Stop use and ask a dentst if gingivitis, bleeding, or redness persists for more than 2 weeks 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. Use helps prevent recurrence of flaking and itching associated with dandruff. Purpose Anti-dandruff Warnings For external use only When using this product ♦ avoid contact with the eyes. If contact occurs, rinse eyes thoroughly with water Stop use and ask a doctor if ♦ condition worsens or does not improve after regular use of this product as directed Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center right away Directions ♦ shake well ♦ wet hair ♦ massage onto scalp ♦ rinse ♦ repeat if desired ♦ for best results use at least twice a week or as directed by a doctor ♦ for maximum dandruff control, use every time you shampoo Stop use and ask a doctor if ♦ condition worsens or does not improve after regular use of this product as directed Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center right away INDICATIONS AND USAGE Symptomatic Trichomoniasis. Metronidazole tablets are indicated for the treatment of T. vaginalis infection in females and males when the presence of the trichomonad has been confirmed by appropriate laboratory procedures (wet smears and/or cultures). Asymptomatic Trichomoniasis. Metronidazole tablets are indicated in the treatment of asymptomatic T. vaginalis infection in females when the organism is associated with endocervicitis, cervicitis, or cervical erosion. Since there is evidence that presence of the trichomonad can interfere with accurate assessment of abnormal cytological smears, additional smears should be performed after eradication of the parasite. Treatment of Asymptomatic Sexual Partners. T. vaginalis infection is a venereal disease. Therefore, asymptomatic sexual partners of treated patients should be treated simultaneously if the organism has been found to be present, in order to prevent reinfection of the partner. The decision as to whether to treat an asymptomatic male partner who has a negative culture or one for whom no culture has been attempted is an individual one. In making this decision, it should be noted that there is evidence that reat an asymptomatic male partner who has a negative culture or one for whom no culture has been attempted is an individual one. In making this decision, it should be noted that there is evidence that a woman may become reinfected if her sexual partner is not treated. Also, since there can be considerable difficulty in isolating the organism from the asymptomatic male carrier, negative smears and cultures cannot be relied upon in this regard. In any event, the sexual partner should be treated with metronidazole tablets in cases of reinfection. Amebiasis. Metronidazole tablets are indicated in the treatment of acute intestinal amebiasis (amebic dysentery) and amebic liver abscess. In amebic liver abscess, metronidazole tablets therapy does not obviate the need for aspiration or drainage of pus. Anaerobic Bacterial Infections. Metronidazole tablets are indicated in the treatment of serious infections caused by susceptible anaerobic bacteria. Indicated surgical procedures should be performed in conjunction with metronidazole tablets therapy. In a mixed aerobic and anaerobic infection, antimicrobials appropriate for the treatment of the aerobic infection should be used in addition to m med in conjunction with metronidazole tablets therapy. In a mixed aerobic and anaerobic infection, antimicrobials appropriate for the treatment of the aerobic infection should be used in addition to metronidazole tablets. INTRA-ABDOMINAL INFECTIONS, including peritonitis, intra-abdominal abscess, and liver abscess, caused by Bacteroides species including the B. fragilis group ( B. fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron, B. vulgatus ), Clostridium species, Eubacterium species, Peptococcus species, and Peptostreptococcus species. SKIN AND SKIN STRUCTURE INFECTIONS caused by Bacteroides species including the B. fragilis group, Clostridium species, Peptococcus species, Peptostreptococcus species, and Fusobacterium species. GYNECOLOGIC INFECTIONS, including endometritis, endomyometritis, tubo-ovarian abscess, and postsurgical vaginal cuff infection, caused by Bacteroides species including the B. fragilis group, Clostridium species, Peptococcus species, Peptostreptococcus species, and Fusobacterium species. BACTERIAL SEPTICEMIA caused by Bacteroides species including the B. fragilis group and Clostridium species. BONE AND JOINT INFECTIONS, (as adjunctive therapy), caused ecies, and Fusobacterium species. BACTERIAL SEPTICEMIA caused by Bacteroides species including the B. fragilis group and Clostridium species. BONE AND JOINT INFECTIONS, (as adjunctive therapy), caused by Bacteroides species including the B. fragilis group. CENTRAL NERVOUS SYSTEM (CNS) INFECTIONS, including meningitis and brain abscess, caused by Bacteroides species including the B. fragilis group. LOWER RESPIRATORY TRACT INFECTIONS, including pneumonia, empyema, and lung abscess, caused by Bacteroides species including the B. fragilis group. ENDOCARDITIS caused by Bacteroides species including the B. fragilis group. To reduce the development of drug-resistant bacteria and maintain the effectiveness of metronidazole tablets and other antibacterial drugs, metronidazole tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. WARNINGS Hypersensitivity selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. WARNINGS Hypersensitivity Reactions Hypersensitivity reactions including severe cutaneous adverse reactions (SCARs) can be serious and potentially life threatening (see ADVERSE REACTIONS ). Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions (SCARs) including toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported with the use of metronidazole. Symptoms can be serious and potentially life threatening. If symptoms or signs of SCARs develop, discontinue metronidazole tablets immediately and institute appropriate therapy. Central and Peripheral Nervous System Effects Encephalopathy and peripheral neuropathy: Cases of encephalopathy and peripheral neuropathy (including optic neuropathy) have been reported with metronidazole. Encephalopathy has been reported in association with cerebellar toxicity characterized by ataxia, dizziness, and dysarthria. CNS l y (including optic neuropathy) have been reported with metronidazole. Encephalopathy has been reported in association with cerebellar toxicity characterized by ataxia, dizziness, and dysarthria. CNS lesions seen on MRI have been described in reports of encephalopathy. CNS symptoms are generally reversible within days to weeks upon discontinuation of metronidazole. CNS lesions seen on MRI have also been described as reversible. Peripheral neuropathy, mainly of sensory type has been reported and is characterized by numbness or paresthesia of an extremity. Convulsive seizures have been reported in patients treated with metronidazole. Aseptic meningitis: Cases of aseptic meningitis have been reported with metronidazole. Symptoms can occur within hours of dose administration and generally resolve after metronidazole therapy is discontinued. The appearance of abnormal neurologic signs and symptoms demands the prompt evaluation of the benefit/risk ratio of the continuation of therapy (see ADVERSE REACTIONS ). DOSAGE AND ADMINISTRATION Trichomoniasis: In the Female: One-day treatment − two grams of metronidazole tablets, given either as a single dose or in two divided doses of one gram eac ERSE REACTIONS ). DOSAGE AND ADMINISTRATION Trichomoniasis: In the Female: One-day treatment − two grams of metronidazole tablets, given either as a single dose or in two divided doses of one gram each, given in the same day. Seven-day course of treatment − 250 mg three times daily for seven consecutive days. There is some indication from controlled comparative studies that cure rates as determined by vaginal smears and signs and symptoms, may be higher after a seven-day course of treatment than after a one-day treatment regimen. The dosage regimen should be individualized. Single-dose treatment can assure compliance, especially if administered under supervision, in those patients who cannot be relied on to continue the seven-day regimen. A seven-day course of treatment may minimize reinfection by protecting the patient long enough for the sexual contacts to obtain appropriate treatment. Further, some patients may tolerate one treatment regimen better than the other. Pregnant patients should not be treated during the first trimester (see CONTRAINDICATIONS ). In pregnant patients for whom alternative treatment has been inadequate, the one-day course of therapy should not be used, as should not be treated during the first trimester (see CONTRAINDICATIONS ). In pregnant patients for whom alternative treatment has been inadequate, the one-day course of therapy should not be used, as it results in higher serum levels which can reach the fetal circulation (see PRECAUTIONS, Pregnancy ). When repeat courses of the drug are required, it is recommended that an interval of four to six weeks elapse between courses and that the presence of the trichomonad be reconfirmed by appropriate laboratory measures. Total and differential leukocyte counts should be made before and after re-treatment. In the Male: Treatment should be individualized as it is for the female. Amebiasis Adults: For acute intestinal amebiasis (acute amebic dysentery): 750 mg orally three times daily for 5 to 10 days. For amebic liver abscess: 500 mg or 750 mg orally three times daily for 5 to 10 days. Pediatric patients: 35 to 50 mg/kg/24 hours, divided into three doses, orally for 10 days. Anaerobic Bacterial Infections In the treatment of most serious anaerobic infections, intravenous metronidazole is usually administered initially. The usual adult oral dosage is 7.5 mg/kg every six hours (approx. 500 m l Infections In the treatment of most serious anaerobic infections, intravenous metronidazole is usually administered initially. The usual adult oral dosage is 7.5 mg/kg every six hours (approx. 500 mg for a 70 kg adult). A maximum of 4 g should not be exceeded during a 24-hour period. The usual duration of therapy is 7 to 10 days; however, infections of the bone and joint, lower respiratory tract, and endocardium may require longer treatment. Dosage Adjustments Patients with Severe Hepatic Impairment For patients with severe hepatic impairment (Child-Pugh C), the dose of metronidazole tablets should be reduced by 50% (see CLINICAL PHARMACOLOGY and PRECAUTIONS ). Patients Undergoing Hemodialysis Hemodialysis removes significant amounts of metronidazole and its metabolites from systemic circulation. The clearance of metronidazole will depend on the type of dialysis membrane used, the duration of the dialysis session, and other factors. If the administration of metronidazole cannot be separated from the hemodialysis session, supplementation of metronidazole dosage following the hemodialysis session should be considered, depending on the patient’s clinical situation (see CLINICAL PHAR parated from the hemodialysis session, supplementation of metronidazole dosage following the hemodialysis session should be considered, depending on the patient’s clinical situation (see CLINICAL PHARMACOLOGY ). ADVERSE REACTIONS The following reactions have been reported during treatment with metronidazole: Central Nervous System: The most serious adverse reactions reported in patients treated with metronidazole have been convulsive seizures, encephalopathy, aseptic meningitis, optic and peripheral neuropathy, the latter characterized mainly by numbness or paresthesia of an extremity. Since persistent peripheral neuropathy has been reported in some patients receiving prolonged administration of metronidazole, patients should be specifically warned about these reactions and should be told to stop the drug and report immediately to their physicians if any neurologic symptoms occur. In addition, patients have reported headache, syncope, dizziness, vertigo, incoordination, ataxia, tinnitus, hearing impairment, hearing loss, confusion, dysarthria, irritability, depression, weakness, and insomnia (see WARNINGS ). Gastrointestinal: The most common adverse reactions reported have been ref s, hearing impairment, hearing loss, confusion, dysarthria, irritability, depression, weakness, and insomnia (see WARNINGS ). Gastrointestinal: The most common adverse reactions reported have been referable to the gastrointestinal tract, particularly nausea, sometimes accompanied by headache, anorexia, and occasionally vomiting; diarrhea; epigastric distress; and abdominal cramping and constipation. Mouth : A sharp, unpleasant metallic taste is not unusual. Furry tongue, glossitis, and stomatitis have occurred; these may be associated with a sudden overgrowth of Candida which may occur during therapy. Dermatologic : Dermatitis bullous, fixed drug eruption, erythematous rash and pruritus. Hematopoietic : Reversible neutropenia (leukopenia); rarely, reversible thrombocytopenia. Cardiovascular : QT prolongation has been reported, particularly when metronidazole was administered with drugs with the potential for prolonging the QT interval. Flattening of the T-wave may be seen in electrocardiographic tracings. Hypersensitivity : Toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous diographic tracings. Hypersensitivity : Toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP) (see WARNINGS ), urticaria, erythematous rash, flushing, nasal congestion, dryness of the mouth (or vagina or vulva), and fever. Renal : Dysuria, cystitis, polyuria, incontinence, and a sense of pelvic pressure. Instances of darkened urine have been reported by approximately one patient in 100,000. Although the pigment which is probably responsible for this phenomenon has not been positively identified, it is almost certainly a metabolite of metronidazole and seems to have no clinical significance. Hepatic: Cases of severe irreversible hepatotoxicity/acute liver failure, including cases with fatal outcomes with very rapid onset after initiation of systemic use of metronidazole, have been reported in patients with Cockayne syndrome (latency from drug start to signs of liver failure as short as 2 days) (see CONTRAINDICATIONS ). Other : Proliferation of Candida in the vagina, dyspareunia, decrease of libido, proctitis, and fleeting joint pains sometimes resembling “seru er failure as short as 2 days) (see CONTRAINDICATIONS ). Other : Proliferation of Candida in the vagina, dyspareunia, decrease of libido, proctitis, and fleeting joint pains sometimes resembling “serum sickness.” Rare cases of pancreatitis, which generally abated on withdrawal of the drug, have been reported. Patients with Crohn’s disease are known to have an increased incidence of gastrointestinal and certain extraintestinal cancers. There have been some reports in the medical literature of breast and colon cancer in Crohn’s disease patients who have been treated with metronidazole at high doses for extended periods of time. A cause and effect relationship has not been established. Crohn’s disease is not an approved indication for metronidazole tablets. 1 INDICATIONS AND USAGE Pramipexole dihydrochloride extended-release tablets are indicated for the treatment of Parkinson's disease. Pramipexole dihydrochloride extended-release tablet is a non-ergot dopamine agonist indicated for the treatment of Parkinson’s disease (PD) (1) 2 DOSAGE AND ADMINISTRATION Pramipexole dihydrochloride extended-release tablets are taken once daily, with or without food (2.1) Tablets must be swallowed whole and must not be chewed, crushed, or divided (2.1) Starting dose is 0.375 mg given once daily (2.2) Dose may be increased gradually, not more frequently than every 5 to 7 days, first to 0.75 mg per day and then by 0.75 mg increments up to a maximum recommended dose of 4.5 mg per day. Assess therapeutic response and tolerability at a minimal interval of 5 days or longer after each dose increment. (2.2) Patients may be switched overnight from immediate-release pramipexole tablets to extended-release pramipexole tablets at the same daily dose. Dose adjustment may be needed in some patients (2.3) Pramipexole dihydrochloride extended-release tablets should be discontinued gradually. (2.2) 2.1 General Dosing Considerations Pramipexole dihydrochloride extende may be needed in some patients (2.3) Pramipexole dihydrochloride extended-release tablets should be discontinued gradually. (2.2) 2.1 General Dosing Considerations Pramipexole dihydrochloride extended-release tablets are taken orally once daily, with or without food. Pramipexole dihydrochloride extended-release tablets must be swallowed whole and must not be chewed, crushed, or divided. If a significant interruption in therapy with pramipexole dihydrochloride extended-release tablets has occurred, re-titration of therapy may be warranted. 2.2 Recommended Dosage The starting dose is 0.375 mg given once per day. Based on efficacy and tolerability, dosages may be increased gradually, not more frequently than every 5 to 7 days, first to 0.75 mg per day and then by 0.75 mg increments up to a maximum recommended dose of 4.5 mg per day. In clinical trials, dosage was initiated at 0.375 mg/day and gradually titrated based on individual therapeutic response and tolerability. Doses greater than 4.5 mg/day have not been studied in clinical trials. Patients should be assessed for therapeutic response and tolerability at a minimal interval of 5 days or longer after each dose increment [see Cli 4.5 mg/day have not been studied in clinical trials. Patients should be assessed for therapeutic response and tolerability at a minimal interval of 5 days or longer after each dose increment [see Clinical Studies ( 14) ]. Due to the flexible dose design used in clinical trials, specific dose-response information could not be determined [see Clinical Studies ( 14 ) ]. Pramipexole dihydrochloride extended-release tablets may be tapered off at a rate of 0.75 mg per day until the daily dose has been reduced to 0.75 mg. Thereafter, the dose may be reduced by 0.375 mg per day [see Warnings and Precautions ( 5.10 , 5.11 )]. Recommended Dosage in Patients with Renal Impairment: In patients with moderate renal impairment (creatinine clearance between 30 and 50 mL/min), pramipexole dihydrochloride extended-release tablets should initially be taken every other day. Caution should be exercised and careful assessment of therapeutic response and tolerability should be made before increasing to daily dosing after one week, and before any additional titration in 0.375 mg increments up to 2.25 mg per day. Dose adjustment should occur no more frequently than at weekly intervals. Pramipexole dihydro y dosing after one week, and before any additional titration in 0.375 mg increments up to 2.25 mg per day. Dose adjustment should occur no more frequently than at weekly intervals. Pramipexole dihydrochloride extended-release tablets have not been studied in patients with severe renal impairment (creatinine clearance <30 mL/min) or patients on hemodialysis, and are not recommended in these patients. 2.3 Switching from Immediate-Release Pramipexole Tablets to Extended-Release Pramipexole Tablets Patients with Parkinson’s disease may be switched overnight from immediate-release pramipexole tablets to extended-release pramipexole tablets at the same daily dose. When switching between immediate-release pramipexole tablets and extended-release pramipexole tablets, patients should be monitored to determine if dosage adjustment is necessary. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Falling Asleep During Activities of Daily Living and Somnolence [see Warnings and Precautions (5.1) ] Symptomatic Orthostatic Hypotension [see Warnings and Precautions (5.2) ] Impulse Control / Compulsive Behaviors [see Warnings and P f Daily Living and Somnolence [see Warnings and Precautions (5.1) ] Symptomatic Orthostatic Hypotension [see Warnings and Precautions (5.2) ] Impulse Control / Compulsive Behaviors [see Warnings and Precautions (5.3) ] Hallucinations and Psychotic-like Behavior [see Warnings and Precautions (5.4) ] Dyskinesia [see Warnings and Precautions (5.5) ] Postural Deformity [see Warnings and Precautions ( 5.6 ) ] Rhabdomyolysis [see Warnings and Precautions (5.8) ] Retinal Pathology [see Warnings and Precautions (5.9) ] Events Reported with Dopaminergic Therapy [see Warnings and Precautions (5.10) ] Withdrawal Symptoms [see Warnings and Precautions ( 5.11 )] Most common adverse reactions (incidence ≥5% and greater than placebo) : Early PD without levodopa: somnolence, nausea, constipation, dizziness, fatigue, hallucinations, dry mouth, muscle spasms, and peripheral edema (6.1) Advanced PD with levodopa: dyskinesia, nausea, constipation, hallucinations, headache, and anorexia (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy’s Laboratories, Inc. at 1-888-375-3784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducte PECTED ADVERSE REACTIONS, contact Dr. Reddy’s Laboratories, Inc. at 1-888-375-3784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug (or of another development program of a different formulation of the same drug) and may not reflect the rates observed in practice. During the premarketing development of pramipexole dihydrochloride extended-release tablets, patients with early Parkinson's disease were treated with pramipexole dihydrochloride extended-release tablets, placebo, or immediate-release pramipexole tablets. In addition, a randomized, double-blind, parallel group trial was conducted in 156 early Parkinson’s disease patients (Hoehn & Yahr Stages I-III) to assess overnight switching of immediate-release pramipexole tablets to extended-release pramipexole tablets. In this latter study, concomitant treatment with stable doses of levodopa, monoamine oxidase B inhibitor (MAOB-I) drugs, anticholinergics, or amantadine, individually or in combi pramipexole tablets. In this latter study, concomitant treatment with stable doses of levodopa, monoamine oxidase B inhibitor (MAOB-I) drugs, anticholinergics, or amantadine, individually or in combination, was allowed. In a third trial, advanced Parkinson’s disease patients received pramipexole extended-release tablets, placebo, or immediate-release pramipexole tablets as adjunctive therapy to levodopa. Early Parkinson's Disease The most common adverse reactions (≥5% and more frequent than placebo) after 33 weeks of treatment with pramipexole dihydrochloride extended-release tablets in the trial of early Parkinson’s disease patients were somnolence, nausea, constipation, dizziness, fatigue, hallucinations, dry mouth, muscle spasms, and peripheral edema. Twenty four of 223 (11%) patients treated with pramipexole dihydrochloride extended-release tablets for 33 weeks discontinued treatment due to adverse reactions compared to 4 of 103 (4%) patients who received placebo and approximately 20 of 213 (9%) patients who received immediate-release pramipexole tablets. The adverse reaction most commonly causing discontinuation of treatment with pramipexole dihydrochloride extended-release t 20 of 213 (9%) patients who received immediate-release pramipexole tablets. The adverse reaction most commonly causing discontinuation of treatment with pramipexole dihydrochloride extended-release tablets was nausea (2%). Table 1 lists adverse reactions that occurred with a frequency of at least 2% with pramipexole dihydrochloride extended-release and were more frequent than with placebo during 33 weeks of treatment in a double-blind, placebo-controlled study in early Parkinson's disease. In this study, patients did not receive concomitant levodopa; however, levodopa was permitted as rescue medication. Table 1 Adverse-Reactions in a 33-Week Double-Blind, Placebo-Controlled Trial with Pramipexole Dihydrochloride Extended-Release in Early Parkinson’s Disease Body System / Adverse Reaction Placebo Extended-Release Pramipexole Immediate Release Pramipexole (n=103) (n=223) (n=213) % % % Nervous system disorders Somnolence 15 36 33 Dizziness 7 12 12 Tremor 1 3 3 Balance disorder 1 2 0 Gastrointestinal disorders Nausea 9 22 24 Constipation 2 14 12 Dry mouth 1 5 4 Vomiting 0 4 4 Upper abdominal pain 1 3 4 Dyspepsia 2 3 3 Abdominal discomfort 0 2 1 Psychiatric disorders Hallucinations, in rointestinal disorders Nausea 9 22 24 Constipation 2 14 12 Dry mouth 1 5 4 Vomiting 0 4 4 Upper abdominal pain 1 3 4 Dyspepsia 2 3 3 Abdominal discomfort 0 2 1 Psychiatric disorders Hallucinations, including visual, auditory and mixed 1 5 6 Insomnia 3 4 4 Sleep attacks or sudden onset of sleep 1 3 6 Sleep disorder 1 2 3 Depression 0 2 0 General disorders and administration site conditions Fatigue 4 6 6 Peripheral edema 4 5 8 Asthenia 2 3 1 Musculoskeletal and connective tissue disorders Muscle spasms 3 5 3 Injury, poisoning and procedural complications Fall 1 4 4 Ear and labyrinth disorders Vertigo 1 4 2 Respiratory, thoracic and mediastinal disorders Cough 1 3 3 Metabolism and nutrition disorders Increased appetite 1 3 2 Vascular disorders Orthostatic hypotension 1 3 0 Because this study used a flexible dose titration design, it was not possible to assess the effects of dose on the incidence of adverse reactions. Adverse reactions can initially occur in either the titration or maintenance phase. Some adverse reactions developed in pramipexole dihydrochloride extended-release-treated patients during the titration phase and persisted (≥7 days) into the maintenance phase (i.e., prami ance phase. Some adverse reactions developed in pramipexole dihydrochloride extended-release-treated patients during the titration phase and persisted (≥7 days) into the maintenance phase (i.e., pramipexole dihydrochloride extended-release % - placebo % = treatment difference ≥2%); persistent adverse reactions were somnolence, nausea, constipation, fatigue, and dry mouth. A double-blind, randomized, parallel group trial evaluated the tolerability of an overnight switch from immediate-release pramipexole tablets to extended-release pramipexole tablets at the same daily dose in 156 early Parkinson’s disease patients with or without levodopa. One of 104 patients switched from immediate-release pramipexole tablets to extended-release pramipexole tablets discontinued due to adverse reactions (vertigo and nausea). Advanced Parkinson's Disease The most common adverse reactions (≥5% and greater frequency than in placebo) during 18 weeks of treatment with pramipexole dihydrochloride extended-release tablets in the trial of advanced Parkinson’s disease patients with concomitant levodopa were dyskinesia, nausea, constipation, hallucinations, headache, and anorexia. Eight of 164 (5%) patients lease tablets in the trial of advanced Parkinson’s disease patients with concomitant levodopa were dyskinesia, nausea, constipation, hallucinations, headache, and anorexia. Eight of 164 (5%) patients treated with pramipexole dihydrochloride extended-release tablets for 18 weeks discontinued treatment due to adverse reactions compared to 7 of 178 (4%) patients who received placebo and 8 of 175 (5%) patients who received immediate-release pramipexole tablets. The most common adverse reactions leading to discontinuation of treatment with pramipexole dihydrochloride extended-release tablets were nausea (1%) and hallucination (1%). Table 2 lists adverse reactions that occurred with a frequency of at least 2% with pramipexole dihydrochloride extended-release and were more frequent than with placebo during 18 weeks of treatment in patients with advanced Parkinson’s disease treated with pramipexole dihydrochloride extended-release tablets. In this study, pramipexole dihydrochloride extended-release tablets, immediate-release pramipexole tablets, or placebo was administered to patients who were also receiving concomitant levodopa. Table 2 Adverse-Reactions in an 18-Week Double-Blind, Placeb lease tablets, immediate-release pramipexole tablets, or placebo was administered to patients who were also receiving concomitant levodopa. Table 2 Adverse-Reactions in an 18-Week Double-Blind, Placebo-Controlled Trial with Pramipexole Dihydrochloride Extended-Release in Advanced Parkinson’s Disease Body System/Adverse Reaction Placebo Extended-Release Pramipexole Immediate-Release Pramipexole n = 178 n = 164 n = 175 % % % Nervous system disorders Dyskinesia 8 17 18 Headache 3 7 4 Dizziness (postural) 1 2 3 Gastrointestinal disorders Nausea 10 11 11 Constipation 5 7 6 Salivary hypersecretion 0 2 0 Diarrhea 1 2 1 Psychiatric disorders Hallucinations, including visual, auditory and mixed 2 9 7 Insomnia 2 4 4 Metabolism and nutrition disorders Anorexia 2 5 1 Musculoskeletal and connective tissue disorders Back pain 1 2 3 Because this flexible dose study used a titration design, it was not possible to assess the effects of dose on the incidence of adverse reactions. Adverse reactions can initially occur in either the titration or maintenance phase. Some adverse reactions developed in pramipexole dihydrochloride extended-release-treated patients during the titration phase and persisted nitially occur in either the titration or maintenance phase. Some adverse reactions developed in pramipexole dihydrochloride extended-release-treated patients during the titration phase and persisted (≥7 days) into the maintenance phase (i.e., pramipexole dihydrochloride extended-release % - placebo % = treatment difference ≥2%); persistent adverse reactions were dyskinesia and insomnia. Laboratory Testing During the development of pramipexole dihydrochloride extended-release tablets, no systematic abnormalities on routine laboratory testing were noted. Other adverse reactions observed during clinical trials of pramipexole dihydrochloride immediate-release tablets or pramipexole dihydrochloride extended-release tablets inearly and advanced Parkinson’s disease Other adverse reactions in clinical studies involving pramipexole dihydrochloride immediate-release tablets or pramipexole dihydrochloride extended-release tablets include abnormal dreams, akathisia, amnesia, decreased libido, decreased weight, dyspnea, pneumonia, and vision abnormalities. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of pramipexole dihydrochloride i reased weight, dyspnea, pneumonia, and vision abnormalities. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of pramipexole dihydrochloride immediate-release tablets or pramipexole dihydrochloride extended-release tablets, primarily in Parkinson’s diseasepatients. 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. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of thereaction, (2) frequency of reporting, or (3) strength of causal connection to pramipexole tablets. Cardiac Disorders: cardiac failure Gastrointestinal Disorders : vomiting General Disorders and Administration Site Conditions: withdrawal symptoms [see Warnings and Precautions ( 5.11 )] Metabolism and Nutrition Disorders : syndrome of inappropriate antidiuretic hormone secretion (SIADH), weight increase Musculoskeletal and Connective Tissue Disorders: postural deformity [see Warnings and Precautions (5.6)] Nervous System Disorders: syncop priate antidiuretic hormone secretion (SIADH), weight increase Musculoskeletal and Connective Tissue Disorders: postural deformity [see Warnings and Precautions (5.6)] Nervous System Disorders: syncope Reproductive System and Breast Disorders: priapism Skin and Subcutaneous Tissue Disorders: skin reactions (including erythema, rash, pruritus, urticaria) There are postmarketing reports of patients noticing tablet residue in their stool that resembles a swollen pramipexole dihydrochloride extended-release whole tablet or swollen pieces of the tablet. Some patients have reported worsening of their Parkinson’s disease symptoms when tablet residue was observed. If a patient reports tablet residue with worsening of their Parkinson’s symptoms, prescribers may need to re-evaluate their medications. Use Relief for Molluscum Contagiosum symptoms, such as itch, bumps, and lesions. Purpose Molluscum Symptom Relief Warnings Directions Wash and dry the affected area. Apply the liquid to the bumps 3-4 times a day and let it dry. Continue the treatment daily until molluscum contagiosum disappears. Ask Doctor If you are allergic to this product. If symptoms persist for over 7 days or worsen, consult your physician. If you are pregnant or breast-feeding You become pregnant or are planning to become pregnant while using this product Stop Use If you are allergic to this product. If symptoms persist for over 7 days or worsen, consult your physician. If you are pregnant or breast-feeding You become pregnant or are planning to become pregnant while using this product Keep Out Of Reach Of Children Keep out of reach of children.In case of ingestion, call Poison Control Center hotline immediately or seek medical help. Uses • temporarily relieves cough due to minor throat and bronchial irritation as may occur with a cold • helps loosen phlegm (mucus) and thin bronchial secretions to drain bronchial tubes Purposes Cough suppressant Expectorant Warnings Do not use 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. Ask a doctor before use if you have • cough that occurs with too much phlegm (mucus) • cough that lasts or is chronic such as occurs with smoking, asthma, chronic bronchitis or emphysema Stop use and ask a doctor if cough lasts for more than 7 days, comes back, or is accompanied by fever, rash, or persistent headache. A persistent cough may be a sign of a serious condition. If pregnant or breast-feeding, ask a health professional before use. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away (1-800-222-1222). Directions • do not take more than 6 doses i ofessional before use. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away (1-800-222-1222). Directions • do not take more than 6 doses in any 24-hour period • measure only with dosing cup provided • keep dosing cup with product • mL = milliliter • this adult product is not intended for use in children under 12 years of age age dose adults and children 12 years and over 10 mL every 4 hours children under 12 years do not use Ask a doctor before use if you have • cough that occurs with too much phlegm (mucus) • cough that lasts or is chronic such as occurs with smoking, asthma, chronic bronchitis or emphysema Stop use and ask a doctor if cough lasts for more than 7 days, comes back, 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. In case of overdose, get medical help or contact a Poison Control Center right away (1-800-222-1222). Use • relieves occasional constipation (irregularity) • generally produces a bowel movement in 1 to 3 days Purpose Osmotic Laxative Warnings Allergy alert: Do not use if you are allergic to polyethylene glycol Do not use if you have kidney disease, except under the advice and supervision of a doctor Ask a doctor before use if you have • nausea, vomiting or abdominal pain • a sudden change in bowel habits that lasts over 2 weeks • irritable bowel syndrome Ask a doctor or pharmacist before use if you are taking a prescription drug When using this product you may have loose, watery, more frequent stools Stop use and ask a doctor if • you have rectal bleeding or your nausea, bloating, cramping or abdominal pain gets worse. These may be signs of a serious condition. • you get diarrhea • you need to use a laxative for longer 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 right away (1-800-222-1222). Directions • do not take more than directed unless advised by your doctor • the bottle top is a measuring cap marked to contain 17 grams of powder when fil Control Center right away (1-800-222-1222). Directions • do not take more than directed unless advised by your doctor • the bottle top is a measuring cap marked to contain 17 grams of powder when filled to the indicated line (white section in cap) • adults and children 17 years of age and older: • use once a day • fill to top of white section in cap which is marked to indicate correct dose (17 g) • stir and dissolve in any 4 to 8 ounces of beverage (cold, hot or room temperature) then drink • do not combine with starch-based thickeners used for difficulty swallowing • ensure that powder is fully dissolved before drinking • do no drink if there are any clumps • do not use no more than 7 days • children 16 years of age or under: ask a doctor Ask a doctor before use if you have • nausea, vomiting or abdominal pain • a sudden change in bowel habits that lasts over 2 weeks • irritable bowel syndrome Stop use and ask a doctor if • you have rectal bleeding or your nausea, bloating, cramping or abdominal pain gets worse. These may be signs of a serious condition. • you get diarrhea • you need to use a laxative for longer than 1 week Keep out of reach of children. In case of overdose, get or abdominal pain gets worse. These may be signs of a serious condition. • you get diarrhea • you need to use a laxative for longer than 1 week Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away (1-800-222-1222). Uses • temporarily relieves minor aches and pains due to: • headache • muscular aches • minor pain of arthritis • toothache • backache • the common cold • menstrual cramps • temporarily reduces fever Purposes Pain reliever/fever reducer Warnings Allergy alert: Ibuprofen may cause a severe allergic reaction, especially in people allergic to aspirin. Symptoms may include: • hives • facial swelling • asthma (wheezing) • shock • skin reddening • rash • blisters If an allergic reaction occurs, stop use and seek medical help right away. 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 or for a longer time than directed Heart attack and stroke warning: NSAIDs, except aspirin, increase the risk of heart attack, heart failure, and stroke. These can be fatal. The risk is higher if you use more than direc e than directed Heart attack and stroke warning: NSAIDs, except aspirin, increase the risk of heart attack, heart failure, and stroke. These can be fatal. The risk is higher if you use more than directed or for longer than directed. Do not use • if you have ever had an allergic reaction to ibuprofen or any other pain reliever/fever reducer • right before or after heart surgery Ask a doctor before use if • you have problems or serious side effects from taking pain relievers or fever reducers • the 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, kidney disease, asthma, or had a stroke • you are taking a diuretic Ask a doctor or pharmacist before use if you are • taking aspirin for heart attack or stroke, because ibuprofen may decrease this benefit of aspirin • under a doctor’s care for any serious condition • taking any other drug When using this product • take with food or milk if stomach upset occurs Stop use and ask a doctor if • you experience any of the following signs of stomach bleeding: • feel faint • vomit blood • have bloody or black stools • have stomach pain milk if stomach upset occurs Stop use and ask a doctor if • you experience any of the following signs of stomach bleeding: • feel faint • vomit blood • have bloody or black stools • have stomach pain that does not get better • you have symptoms of heart problems or stroke: • chest pain • trouble breathing • weakness in one part or side of body • slurred speech • leg swelling • pain gets worse or lasts more than 10 days • fever gets worse or lasts more than 3 days • redness or swelling is present in the painful area • any new symptoms appear If pregnant or breast-feeding, ask a health professional before use. It is especially important not to use ibuprofen at 20 weeks or later in 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 right away (1-800-222-1222). Directions • do not take more than directed • the smallest effective dose should be used adults and children 12 years and older • take 1 tablet every 4 to 6 hours while symptoms persist • if pain or fever does not respond to 1 tablet, 2 irected • the smallest effective dose should be used adults and children 12 years and older • take 1 tablet every 4 to 6 hours while symptoms persist • if pain or fever does not respond to 1 tablet, 2 tablets may be used • do not exceed 6 tablets in 24 hours, unless directed by a doctor children under 12 years • ask a doctor Ask a doctor before use if • you have problems or serious side effects from taking pain relievers or fever reducers • the 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, kidney disease, asthma, or had a stroke • you are taking a diuretic Stop use and ask a doctor if • you experience any of the following signs of stomach bleeding: • feel faint • vomit blood • have bloody or black stools • have stomach pain that does not get better • you have symptoms of heart problems or stroke: • chest pain • trouble breathing • weakness in one part or side of body • slurred speech • leg swelling • pain gets worse or lasts more than 10 days • fever gets worse or lasts more than 3 days • redness or swelling is present in the painful area • any new symptoms appear K slurred speech • leg swelling • pain gets worse or lasts more than 10 days • fever gets worse or lasts more than 3 days • redness or swelling is present in the painful area • any new symptoms appear Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away (1-800-222-1222). 1 INDICATIONS & USAGE Metformin hydrochloride tablets is indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients 10 years of age and older with type 2 diabetes mellitus. Metformin hydrochloride extended-release tablets is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Metformin is a biguanide indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients 10 years of age and older with type 2 diabetes mellitus. (1) Metformin is a biguanide indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. (1) 2 DOSAGE & ADMINISTRATION Adult Dosage for Metformin Hydrochloride Tablets: Starting dose: 500 mg orally twice a day or 850 mg once a day, with meals (2.1) Increase the dose in increments of 500 mg weekly or 850 mg every 2 weeks, up to a maximum dose of 2550 mg per day, given in divided doses (2.1) Doses above 2000 mg may be better tolerated given 3 times a day with meals (2.1) Adult Dosage for Metformin Hydrochloride Extented-Release Tablets: Swallow metformin hydrochloride divided doses (2.1) Doses above 2000 mg may be better tolerated given 3 times a day with meals (2.1) Adult Dosage for Metformin Hydrochloride Extented-Release Tablets: Swallow metformin hydrochloride extended-release tablets whole and never crush, cut or chew (2.1) Starting dose: 500 mg orally once daily with the evening meal (2.1) Increase the dose in increments of 500 mg weekly, up to a maximum of 2000 mg once daily with the evening meal (2.1) Patients receiving metformin hydrochloride tablets may be switched to metformin hydrochloride extended-release tablets once daily at the same total daily dose, up to 2000 mg once daily (2.1) Pediatric Dosage for Metformin Hydrochloride Tablets: Starting dose: 500 mg orally twice a day, with meals (2.2) Increase dosage in increments of 500 mg weekly up to a maximum of 2000 mg per day, given in divided doses twice daily (2.2) Renal Impairment: • Prior to initiation, assess renal function with estimated glomerular filtration rate (eGFR) (2.3) Do not use in patients with eGFR below 30 mL/minute/1.73 m 2 (2.3) Initiation is not recommended in patients with eGFR between 30-45 mL/minute/1.73 m 2 (2.3) Asses risk/benefit of continuing if eGFR fall not use in patients with eGFR below 30 mL/minute/1.73 m 2 (2.3) Initiation is not recommended in patients with eGFR between 30-45 mL/minute/1.73 m 2 (2.3) Asses risk/benefit of continuing if eGFR falls below 45 mL/minute/1.73 m 2 (2.3) Discontinue if eGFR falls below 30 mL/minute/1.73 m 2 (2.3) Discontinuation for Iodinated Contrast Imaging Procedures: • Metformin hydrochloride tablets and metformin hydrochloride extended-release tablets may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures (2.4) 2.1 Adult Dosage Metformin Hydrochloride Tablets The recommended starting dose of metformin hydrochloride tablets is 500 mg orally twice a day or 850 mg once a day, given with meals. Increase the dose in increments of 500 mg weekly or 850 mg every 2 weeks on the basis of glycemic control and tolerability, up to a maximum dose of 2550 mg per day, given in divided doses. Doses above 2000 mg may be better tolerated given 3 times a day with meals. Metformin Hydrochloride Extended-Release Tablets Swallow metformin hydrochloride extended-release tablets whole and never crush, cut or chew. The recommended starting dose of metformin hydrochloride extended-relea rochloride Extended-Release Tablets Swallow metformin hydrochloride extended-release tablets whole and never crush, cut or chew. The recommended starting dose of metformin hydrochloride extended-release tablets is 500 mg orally once daily with the evening meal. Increase the dose in increments of 500 mg weekly on the basis of glycemic control and tolerability, up to a maximum of 2000 mg once daily with the evening meal. If glycemic control is not achieved with metformin hydrochloride extended-release tablets 2000 mg once daily, consider a trial of metformin hydrochloride extended-release tablets 1000 mg twice daily. If higher doses are required, switch to metformin hydrochloride tablets at total daily doses up to 2550 mg administered in divided daily doses, as described above. Patients receiving metformin hydrochloride tablets may be switched to metformin hydrochloride extended-release tablets once daily at the same total daily dose, up to 2000 mg once daily. 2.2 Pediatric Dosage for metformin hydrochloride tablets The recommended starting dose of metformin hydrochloride tablets for pediatric patients 10 years of age and older is 500 mg orally twice a day, given with meals. Increase tformin hydrochloride tablets The recommended starting dose of metformin hydrochloride tablets for pediatric patients 10 years of age and older is 500 mg orally twice a day, given with meals. Increase dosage in increments of 500 mg weekly on the basis of glycemic control and tolerability, up to a maximum of 2000 mg per day, given in divided doses twice daily. 2.3 Recommendations for Use in Renal Impairment Assess renal function prior to initiation of metformin hydrochloride tablets and metformin hydrochloride extended-release tablets and periodically thereafter. Metformin hydrochloride tablets and metformin hydrochloride extended-release tablets is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/minute/1.73 m 2 . Initiation of metformin hydrochloride tablets and metformin hydrochloride extended-release tablets in patients with an eGFR between 30 – 45 mL/minute/1.73 m 2 is not recommended. In patients taking metformin hydrochloride tablets and metformin hydrochloride extended-release tablets whose eGFR later falls below 45 mL/min/1.73 m 2 , assess the benefit risk of continuing therapy. Discontinue metformin hydrochloride tablets and metfo metformin hydrochloride extended-release tablets whose eGFR later falls below 45 mL/min/1.73 m 2 , assess the benefit risk of continuing therapy. Discontinue metformin hydrochloride tablets and metformin hydrochloride extended-release tablets if the patient’s eGFR later falls below 30 mL/minute/1.73 m 2 [see Warnings and Precautions ( 5.1 ) ]. 2.4 Discontinuation for Iodinated Contrast Imaging Procedures Discontinue metformin hydrochloride tablets and metformin hydrochloride extended-release tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m 2 ; in patients with a history of liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart metformin hydrochloride tablets and metformin hydrochloride extended-release tablets if renal function is stable. 6 ADVERSE REACTIONS The following adverse reactions are also discussed elsewhere in the labeling: Lactic Acidosis [see Boxed Warning and Warnings and Precautions ( 5.1 )] Vitamin B 12 Deficiency [see Warnings and Precautions ( 5.2 )] Hyp erse reactions are also discussed elsewhere in the labeling: Lactic Acidosis [see Boxed Warning and Warnings and Precautions ( 5.1 )] Vitamin B 12 Deficiency [see Warnings and Precautions ( 5.2 )] Hypoglycemia [see Warnings and Precautions ( 5.3 )] For metformin hydrochloride tablets and metformin hydrochloride extended-release tablets, the most common adverse reactions (>5.0%) are diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Ascend Laboratories, LLC at 1-877-ASCRX01 (877-272-7901) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Metformin Hydrochloride Tablets In a U.S. clinical trial of metformin hydrochloride tablets in patients with type 2 diabetes mellitus, a total of 141 patients received metformin hydrochloride tablets up to 2,550 mg per day. Adverse reactions reported in greater tformin hydrochloride tablets in patients with type 2 diabetes mellitus, a total of 141 patients received metformin hydrochloride tablets up to 2,550 mg per day. Adverse reactions reported in greater than 5% of metformin hydrochloride tablets treated patients and that were more common than in placebo-treated patients, are listed in Table 1. Table 1: Adverse Reactions from a Clinical Trial of Metformin Hydrochloride Tablets Occurring >5% and More Common than Placebo in Patients with Type 2 Diabetes Mellitus Metformin Hydrochloride Tablets (n=141) Placebo (n=145) Diarrhea 53% 12% Nausea/Vomiting 26% 8% Flatulence 12% 6% Asthenia 9% 6% Indigestion 7% 4% Abdominal Discomfort 6% 5% Headache 6% 5% Diarrhea led to discontinuation of metformin hydrochloride tablets in 6% of patients. Additionally, the following adverse reactions were reported in ≥1% to ≤5% of metformin hydrochloride tablets treated patients and were more commonly reported with metformin hydrochloride tablets than placebo: abnormal stools, hypoglycemia, myalgia, lightheaded, dyspnea, nail disorder, rash, sweating increased, taste disorder, chest discomfort, chills, flu syndrome, flushing, palpitation. In metformin hydrochlo rmal stools, hypoglycemia, myalgia, lightheaded, dyspnea, nail disorder, rash, sweating increased, taste disorder, chest discomfort, chills, flu syndrome, flushing, palpitation. In metformin hydrochloride tablets clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels was observed in approximately 7% of patients. Pediatric Patients In clinical trials with metformin hydrochloride tablets in pediatric patients with type 2 diabetes mellitus, the profile of adverse reactions was similar to that observed in adults. Metformin Hydrochloride Extended-Release Tablets In placebo-controlled trials, 781 patients were administered metformin hydrochloride extended-release tablets. Adverse reactions reported in greater than 5% of the metformin hydrochloride extended-release tablets patients, and that were more common in metformin hydrochloride extended-release tablets- than placebo-treated patients, are listed in Table 2. Table 2: Adverse Reactions from Clinical Trials of Metformin Hydrochloride Extended-Release Tablets Occurring >5% and More Common than Placebo in Patients with Type 2 Diabetes Mellitus Metformin Hydrochloride Extended-Re ctions from Clinical Trials of Metformin Hydrochloride Extended-Release Tablets Occurring >5% and More Common than Placebo in Patients with Type 2 Diabetes Mellitus Metformin Hydrochloride Extended-Release Tablets Placebo (n=781) (n=195) Diarrhea 10% 3% Nausea/Vomiting 7% 2% Diarrhea led to discontinuation of metformin hydrochloride extended-release tablets in 0.6% of patients. Additionally, the following adverse reactions were reported in ≥1.0% to ≤5.0% of metformin hydrochloride extended-release tablets patients and were more commonly reported with metformin hydrochloride extended-release tablets than placebo: abdominal pain, constipation, distention abdomen, dyspepsia/heartburn, flatulence, dizziness, headache, upper respiratory infection, taste disturbance. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of metformin. 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. Cholestatic, hepatocellular, and mixed hepatocellular liver injury have been reported with postmarketing ible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cholestatic, hepatocellular, and mixed hepatocellular liver injury have been reported with postmarketing use of metformin. 1 INDICATIONS AND USAGE Zoledronic Acid Injection is a bisphosphonate indicated for the treatment of: Hypercalcemia of malignancy ( 1.1 ) Patients with multiple myeloma and patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy ( 1.2 ) Important limitation of use: The safety and efficacy of Zoledronic Acid Injection has not been established for use in hyperparathyroidism or nontumor-related hypercalcemia ( 1.3 ) 1.1 Hypercalcemia of Malignancy Zoledronic Acid Injection is indicated for the treatment of hypercalcemia of malignancy defined as an albumin-corrected calcium (cCa) of greater than or equal to 12 mg/dL [3.0 mmol/L] using the formula: cCa in mg/dL=Ca in mg/dL + 0.8 (4.0 g/dL - patient albumin (g/dL)). 1.2 Multiple Myeloma and Bone Metastases of Solid Tumors Zoledronic Acid Injection is indicated for the treatment of patients with multiple myeloma and patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least ltiple myeloma and patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy. 1.3 Important Limitation of Use The safety and efficacy of Zoledronic Acid Injection in the treatment of hypercalcemia associated with hyperparathyroidism or with other nontumor-related conditions have not been established. 2 DOSAGE AND ADMINISTRATION Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Hypercalcemia of malignancy ( 2.1 ) 4 mg as a single-use intravenous infusion over no less than 15 minutes. 4 mg as retreatment after a minimum of 7 days. Multiple myeloma and bone metastasis from solid tumors. ( 2.2 ) 4 mg as a single-use intravenous infusion over no less than 15 minutes every 3-4 weeks for patients with creatinine clearance of greater than 60 mL/min Reduce the dose for patients with renal impairment. Coadminister oral calcium supplements of 500 mg and a multiple vitamin containing 400 IU of Vitamin D daily. Administer through a separate ven L/min Reduce the dose for patients with renal impairment. Coadminister oral calcium supplements of 500 mg and a multiple vitamin containing 400 IU of Vitamin D daily. Administer through a separate vented infusion line and do not allow to come in contact with any calcium or divalent cation-containing solutions. ( 2.3 ) 2.1 Hypercalcemia of Malignancy The maximum recommended dose of Zoledronic Acid Injection in hypercalcemia of malignancy (albumin-corrected serum calcium greater than or equal to 12 mg/dL [3.0 mmol/L]) is 4 mg. The 4-mg dose must be given as a single-dose intravenous infusion over no less than 15 minutes . Patients who receive Zoledronic Acid Injection should have serum creatinine assessed prior to each treatment. Dose adjustments of Zoledronic Acid Injection are not necessary in treating patients for hypercalcemia of malignancy presenting with mild-to-moderate renal impairment prior to initiation of therapy (serum creatinine less than 400 μmol/L or less than 4.5 mg/dL). Patients should be adequately rehydrated prior to administration of Zoledronic Acid Injection [ see Warnings and Precautions ( 5.2 ) ]. Consideration should be given to the severity of, as well as the Patients should be adequately rehydrated prior to administration of Zoledronic Acid Injection [ see Warnings and Precautions ( 5.2 ) ]. Consideration should be given to the severity of, as well as the symptoms of, tumor-induced hypercalcemia when considering use of Zoledronic Acid Injection. Vigorous saline hydration, an integral part of hypercalcemia therapy, should be initiated promptly and an attempt should be made to restore the urine output to about 2 L/day throughout treatment. Mild or asymptomatic hypercalcemia may be treated with conservative measures (i.e., saline hydration, with or without loop diuretics). Patients should be hydrated adequately throughout the treatment, but overhydration, especially in those patients who have cardiac failure, must be avoided. Diuretic therapy should not be employed prior to correction of hypovolemia. Retreatment with Zoledronic Acid Injection 4 mg may be considered if serum calcium does not return to normal or remain normal after initial treatment. It is recommended that a minimum of 7 days elapse before retreatment, to allow for full response to the initial dose. Renal function must be carefully monitored in all patients receiving Zoledr tment. It is recommended that a minimum of 7 days elapse before retreatment, to allow for full response to the initial dose. Renal function must be carefully monitored in all patients receiving Zoledronic Acid Injection and serum creatinine must be assessed prior to retreatment with Zoledronic Acid Injection [ see Warnings and Precautions ( 5.2 ) ]. 2.2 Multiple Myeloma and Metastatic Bone Lesions of Solid Tumors The recommended dose of Zoledronic Acid Injection in patients with multiple myeloma and metastatic bone lesions from solid tumors for patients with creatinine clearance greater than 60 mL/min is 4 mg infused over no less than 15 minutes every 3-4 weeks. The optimal duration of therapy is not known. Upon treatment initiation, the recommended Zoledronic Acid Injection doses for patients with reduced renal function (mild and moderate renal impairment) are listed in Table 1 . These doses are calculated to achieve the same AUC as that achieved in patients with creatinine clearance of 75 mL/min. Creatinine clearance (CrCl) is calculated using the Cockcroft-Gault formula [ see Warnings and Precautions ( 5.2 ) ]. Table 1: Reduced Doses for Patients with Baseline CrCl less than or of 75 mL/min. Creatinine clearance (CrCl) is calculated using the Cockcroft-Gault formula [ see Warnings and Precautions ( 5.2 ) ]. Table 1: Reduced Doses for Patients with Baseline CrCl less than or equal to 60 mL/min Baseline Creatinine Clearance (mL/min) Zoledronic Acid Injection Recommended Dose* *Doses calculated assuming target AUC of 0.66(mg•hr/L) (CrCl = 75mL/min) greater than 60 4 mg 50 – 60 3.5 mg 40 – 49 3.3 mg 30 – 39 3 mg During treatment, serum creatinine should be measured before each Zoledronic Acid Injection dose and treatment should be withheld for renal deterioration. In the clinical studies, renal deterioration was defined as follows: For patients with normal baseline creatinine, increase of 0.5 mg/dL For patients with abnormal baseline creatinine, increase of 1.0 mg/dL In the clinical studies, Zoledronic Acid Injection treatment was resumed only when the creatinine returned to within 10% of the baseline value. Zoledronic Acid Injection should be reinitiated at the same dose as that prior to treatment interruption. Patients should also be administered an oral calcium supplement of 500 mg and a multiple vitamin containing 400 IU of Vitamin D daily. 2.3 Preparatio same dose as that prior to treatment interruption. Patients should also be administered an oral calcium supplement of 500 mg and a multiple vitamin containing 400 IU of Vitamin D daily. 2.3 Preparation of Solution Zoledronic Acid Injection must not be mixed with calcium or other divalent cation-containing infusion solutions, such as Lactated Ringer's solution, and should be administered as a single intravenous solution in a line separate from all other drugs. 4 mg/5 mL Single-Use Vial Vials of Zoledronic Acid Injection concentrate for infusion contain overfill allowing for the withdrawal of 5 mL of concentrate (equivalent to 4 mg zoledronic acid). This concentrate should immediately be diluted in 100 mL of sterile 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP, following proper aseptic technique, and administered to the patient by infusion. Do not store undiluted concentrate in a syringe, to avoid inadvertent injection. To prepare reduced doses for patients with baseline CrCl less than or equal to 60 mL/min, withdraw the specified volume of the Zoledronic Acid Injection concentrate from the vial for the dose required (see Table 2 ). Table 2: Preparation of Reduced Doses – less than or equal to 60 mL/min, withdraw the specified volume of the Zoledronic Acid Injection concentrate from the vial for the dose required (see Table 2 ). Table 2: Preparation of Reduced Doses – Zoledronic Acid Injection concentrate Remove and Use Zoledronic Acid Injection Volume (mL) Dose (mg) 4.4 3.5 4.1 3.3 3.8 3.0 The withdrawn concentrate must be diluted in 100 mL of sterile 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP. If not used immediately after dilution with infusion media, for microbiological integrity, the solution should be refrigerated at 2°C-8°C (36°F-46°F). The refrigerated solution should then be equilibrated to room temperature prior to administration. The total time between dilution, storage in the refrigerator, and end of administration must not exceed 24 hours. 2.4 Method of Administration Due to the risk of clinically significant deterioration in renal function, which may progress to renal failure, single doses of Zoledronic Acid Injection should not exceed 4 mg and the duration of infusion should be no less than 15 minutes [ see Warnings And Precautions ( 5.2 ) ]. In the trials and in postmarketing experience, renal deterioration, progressio not exceed 4 mg and the duration of infusion should be no less than 15 minutes [ see Warnings And Precautions ( 5.2 ) ]. In the trials and in postmarketing experience, renal deterioration, progression to renal failure and dialysis, have occurred in patients, including those treated with the approved dose of 4 mg infused over 15 minutes. There have been instances of this occurring after the initial Zoledronic Acid Injection dose. 6 ADVERSE REACTIONS The most common adverse events (greater than 25%) were nausea, fatigue, anemia, bone pain, constipation, fever, vomiting, and dyspnea ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pharmaceutics International, Incorporated (Pii) at 410-584-0001 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Hypercalcemia of Malignancy The safety of Zoledronic Acid Injection was studied in 185 patients with hypercalcemia of malignancy (HCM) who receive g and may not reflect the rates observed in practice. Hypercalcemia of Malignancy The safety of Zoledronic Acid Injection was studied in 185 patients with hypercalcemia of malignancy (HCM) who received either Zoledronic Acid Injection 4 mg given as a 5 - minute intravenous infusion (n=86) or pamidronate 90 mg given as a 2 - hour intravenous infusion (n=103). The population was aged 33 - 84 years, 60% male and 81% Caucasian, with breast, lung, head and neck, and renal cancer as the most common forms of malignancy. NOTE: pamidronate 90 mg was given as a 2 - hour intravenous infusion. The relative safety of pamidronate 90 mg given as a 2 - hour intravenous infusion compared to the same dose given as a 24 - hour intravenous infusion has not been adequately studied in controlled clinical trials. Renal Toxicity Administration of Zoledronic Acid Injection 4 mg given as a 5 - minute intravenous infusion has been shown to result in an increased risk of renal toxicity, as measured by increases in serum creatinine, which can progress to renal failure. The incidence of renal toxicity and renal failure has been shown to be reduced when Zoledronic Acid Injection 4 mg is given as a 15 - minute in n serum creatinine, which can progress to renal failure. The incidence of renal toxicity and renal failure has been shown to be reduced when Zoledronic Acid Injection 4 mg is given as a 15 - minute intravenous infusion. Zoledronic Acid Injection should be administered by intravenous infusion over no less than 15 minutes [ see Warnings and Precautions ( 5 ) and Dosage and Administration ( 2 ) ]. The most frequently observed adverse events were fever, nausea, constipation, anemia and dyspnea. (see Table 3 ). Table 3 provides adverse events that were reported by 10% or more of the 189 patients treated with Zoledronic Acid Injection 4 mg or Pamidronate 90 mg from the two HCM trials. Adverse events are listed regardless of presumed causality to study drug. Table 3: Percentage of Patients with Adverse Events ≥10% Reported in Hypercalcemia of Malignancy Clinical Trials by Body System Zoledronic Acid Injection 4 mg n (%) Pamidronate 90 mg n (%) Patients Studied Total No. of Patients Studied 86 (100) 103 (100) Total No. of Patients with any AE 81 (94) 95 (92) Body as a Whole Fever 38 (44) 34 (33) Progression of Cancer 14 (16) 21 (20) Cardiovascular Hypotension 9 (11) 2 (2) Digestive Nausea (100) 103 (100) Total No. of Patients with any AE 81 (94) 95 (92) Body as a Whole Fever 38 (44) 34 (33) Progression of Cancer 14 (16) 21 (20) Cardiovascular Hypotension 9 (11) 2 (2) Digestive Nausea 25 (29) 28 (27) Constipation 23 (27) 13 (13) Diarrhea 15 (17) 17 (17) Abdominal pain 14 (16) 13 (13) Vomiting 12 (14) 17 (17) Anorexia 8 (9) 14 (14) Hemic and Lymphatic System Anemia 19 (22) 18 (18) Infections Moniliasis 10 (12) 4 (4) Laboratory Abnormalities Hypophosphatemia 11 (13) 2 (2) Hypokalemia 10 (12) 16 (16) Hypomagnesemia 9 (11) 5 (5) Musculoskeletal Skeletal Pain 10 (12) 10 (10) Nervous Insomnia 13 (15) 10 (10) Anxiety 12 (14) 8 (8) Confusion 11 (13) 13 (13) Agitation 11 (13) 8 (8) Respiratory Dyspnea 19 (22) 20 (19) Coughing 10 (12) 12 (12) Urogenital Urinary Tract Infection 12 (14) 15 (15) The following adverse events from the two controlled multicenter HCM trials (n=189) were reported by a greater percentage of patients treated with Zoledronic Acid Injection 4 mg than with pamidronate 90 mg and occurred with a frequency of greater than or equal to 5% but less than 10%. Adverse events are listed regardless of presumed causality to study drug: Asthenia, chest pain, leg edem midronate 90 mg and occurred with a frequency of greater than or equal to 5% but less than 10%. Adverse events are listed regardless of presumed causality to study drug: Asthenia, chest pain, leg edema, mucositis, dysphagia, granulocytopenia, thrombocytopenia, pancytopenia, nonspecific infection, hypocalcemia, dehydration, arthralgias, headache and somnolence. Rare cases of rash, pruritus, and chest pain have been reported following treatment with Zoledronic Acid Injection. Acute Phase Reaction Within three days after Zoledronic Acid Injection administration, an acute phase reaction has been reported in patients, with symptoms including pyrexia, fatigue, bone pain and/or arthralgias, myalgias, chills, and influenza-like illness; these symptoms usually resolve within a few days. Pyrexia has been the most commonly associated symptom, occurring in 44% of patients. Mineral and Electrolyte Abnormalities Electrolyte abnormalities, most commonly hypocalcemia, hypophosphatemia and hypomagnesemia, can occur with bisphosphonate use. Grade 3 and Grade 4 laboratory abnormalities for serum creatinine, serum calcium, serum phosphorus, and serum magnesium observed in two clinical trials of Zoledr ia, can occur with bisphosphonate use. Grade 3 and Grade 4 laboratory abnormalities for serum creatinine, serum calcium, serum phosphorus, and serum magnesium observed in two clinical trials of Zoledronic Acid Injection in patients with HCM are shown in Table 4 and 5 . Table 4: Grade 3 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Two Clinical Trials in Patients with HCM Grade 3 Laboratory Parameter Zoledronic Acid Injection 4 mg Pamidronate 90 mg n/N (%) n/N (%) Serum Creatinine 1 2/86 (2%) 3/100 (3%) Hypocalcemia 2 1/86 (1%) 2/100 (2%) Hypophosphatemia 3 36/70 (51%) 27/81 (33%) Hypomagnesemia 4 0/71 - 0/84 - Table 5: Grade 4 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Two Clinical Trials in Patients with HCM 1 Grade 3 (greater than 3x Upper Limit of Normal); Grade 4 (greater than 6x Upper Limit of Normal) 2 Grade 3 (less than 7 mg/dL); Grade 4 (less than 6 mg/dL) 3 Grade 3 (less than 2 mg/dL); Grade 4 (less than 1 mg/dL) 4 Grade 3 (less than 0.8 mEq/L); Grade 4 (less than 0.5 mEq/L) Grade 4 Laboratory Parameter Zoledronic Acid Injection 4 mg Pamidronate 90 mg n/N (% e 3 (less than 2 mg/dL); Grade 4 (less than 1 mg/dL) 4 Grade 3 (less than 0.8 mEq/L); Grade 4 (less than 0.5 mEq/L) Grade 4 Laboratory Parameter Zoledronic Acid Injection 4 mg Pamidronate 90 mg n/N (%) n/N (%) Serum Creatinine 1 0/86 - 1/100 (1%) Hypocalcemia 2 0/86 - 0/100 - Hypophosphatemia 3 1/70 (1%) 4/81 (5%) Hypomagnesemia 4 0/71 - 1/84 (1%) Injection Site Reactions Local reactions at the infusion site, such as redness or swelling, were observed infrequently. In most cases, no specific treatment is required and the symptoms subside after 24 - 48 hours. Ocular Adverse Events Ocular inflammation such as uveitis and scleritis can occur with bisphosphonate use, including Zoledronic Acid Injection. No cases of iritis, scleritis or uveitis were reported during these clinical trials. However, cases have been seen in postmarketing use [ see Adverse Reactions ( 6.2 )]. Multiple Myeloma and Bone Metastases of Solid Tumors The safety analysis includes patients treated in the core and extension phases of the trials. The analysis includes the 2,042 patients treated with Zoledronic Acid Injection 4 mg, pamidronate 90 mg or placebo in the three controlled multicenter bone metastases trials, ion phases of the trials. The analysis includes the 2,042 patients treated with Zoledronic Acid Injection 4 mg, pamidronate 90 mg or placebo in the three controlled multicenter bone metastases trials, including 969 patients completing the efficacy phase of the trial, and 619 patients that continued in the safety extension phase. Only 347 patients completed the extension phases and were followed for 2 years (or 21 months for the other solid tumor patients). The median duration of exposure for safety analysis for Zoledronic Acid Injection 4 mg (core plus extension phases) was 12.8 months for breast cancer and multiple myeloma, 10.8 months for prostate cancer, and 4.0 months for other solid tumors. Table 6 describes adverse events that were reported by 10% or more of patients. Adverse events are listed regardless of presumed causality to study drug. Table 6: Percentage of Patients with Adverse Events ≥10% Reported in Three Bone Metastases Clinical Trials by Body System Zoledronic Acid Injection 4 mg Pamidronate 90 mg Placebo n (%) n (%) n (%) Patients Studied Total No. of Patients 1031 (100) 556 (100) 455 (100) Total No. of Patients with any AE 1015 (98) 548 (99) 445 (98) Blood and Ly ection 4 mg Pamidronate 90 mg Placebo n (%) n (%) n (%) Patients Studied Total No. of Patients 1031 (100) 556 (100) 455 (100) Total No. of Patients with any AE 1015 (98) 548 (99) 445 (98) Blood and Lymphatic Anemia 344 (33) 175 (32) 128 (28) Neutropenia 124 (12) 83 (15) 35 (8) Thrombocytopenia 102 (10) 53 (10) 20 (4) Gastrointestinal Nausea 476 (46) 266 (48) 171 (38) Vomiting 333 (32) 183 (33) 122 (27) Constipation 320 (31) 162 (29) 174 (38) Diarrhea 249 (24) 162 (29) 83 (18) Abdominal Pain 143 (14) 81 (15) 48 (11) Dyspepsia 105 (10) 74 (13) 31 (7) Stomatitis 86 (8) 65 (12) 14 (3) Sore Throat 82 (8) 61 (11) 17 (4) General Disorders and Administration Site Fatigue 398 (39) 240 (43) 130 (29) Pyrexia 328 (32) 172 (31) 89 (20) Weakness 252 (24) 108 (19) 114 (25) Edema Lower Limb 215 (21) 126 (23) 84 (19) Rigors 112 (11) 62 (11) 28 (6) Infections Urinary Tract Infection 124 (12) 50 (9) 41 (9) Upper Respiratory Tract Infection 101 (10) 82 (15) 30 (7) Metabolism Anorexia 231 (22) 81 (15) 105 (23) Weight Decreased 164 (16) 50 (9) 61 (13) Dehydration 145 (14) 60 (11) 59 (13) Appetite Decreased 130 (13) 48 (9) 45 (10) Musculoskeletal Bone Pain 569 (55) 316 (57) 284 (62) Myalgia 239 (23) 143 (23) Weight Decreased 164 (16) 50 (9) 61 (13) Dehydration 145 (14) 60 (11) 59 (13) Appetite Decreased 130 (13) 48 (9) 45 (10) Musculoskeletal Bone Pain 569 (55) 316 (57) 284 (62) Myalgia 239 (23) 143 (26) 74 (16) Arthralgia 216 (21) 131 (24) 73 (16) Back Pain 156 (15) 106 (19) 40 (9) Pain in Limb 143 (14) 84 (15) 52 (11) Neoplasms Malignant Neoplasm Aggravated 205 (20) 97 (17) 89 (20) Nervous Headache 191 (19) 149 (27) 50 (11) Dizziness (excluding vertigo) 180 (18) 91 (16) 58 (13) Insomnia 166 (16) 111 (20) 73 (16) Paresthesia 149 (15) 85 (15) 35 (8) Hypoesthesia 127 (12) 65 (12) 43 (10) Psychiatric Depression 146 (14) 95 (17) 49 (11) Anxiety 112 (11) 73 (13) 37 (8) Confusion 74 (7) 39 (7) 47 (10) Respiratory Dyspnea 282 (27) 155 (28) 107 (24) Cough 224 (22) 129 (23) 65 (14) Skin Alopecia 125 (12) 80 (14) 36 (8) Dermatitis 114 (11) 74 (13) 38 (8) Grade 3 and Grade 4 laboratory abnormalities for serum creatinine, serum calcium, serum phosphorus, and serum magnesium observed in three clinical trials of Zoledronic Acid Injection in patients with bone metastases are shown in Tables 7 and 8 . Table 7: Grade 3 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus nical trials of Zoledronic Acid Injection in patients with bone metastases are shown in Tables 7 and 8 . Table 7: Grade 3 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Three Clinical Trials in Patients with Bone Metastases 1 Grade 3 (greater than 3x Upper Limit of Normal); Grade 4 (greater than 6x Upper Limit of Normal) * Serum creatinine data for all patients randomized after the 15-minute infusion amendment 2 Grade 3 (less than 7 mg/dL); Grade 4 (less than 6 mg/dL) 3 Grade 3 (less than 2 mg/dL); Grade 4 (less than 1 mg/dL) 4 Grade 3 (greater than 3 mEq/L); Grade 4 (greater than 8 mEq/L) 5 Grade 3 (less than 0.9 mEq/L); Grade 4 (less than 0.7 mEq/L) Grade 3 Laboratory Parameter Zoledronic Acid Injection 4 mg Pamidronate 90 mg Placebo n/N (%) n/N (%) n/N (%) Serum Creatinine 1* 7/529 (1%) 4/268 (2%) 4/241 (2%) Hypocalcemia 2 6/973 (<1%) 4/536 (<1%) 0/415 - Hypophosphatemia 3 115/973 (12%) 38/537 (7%) 14/415 (3%) Hypermagnesemia 4 19/971 (2%) 2/535 (<1%) 8/415 (2%) Hypomagnesemia 5 1/971 (<1%) 0/535 - 1/415 (<1%) Table 8: Grade 4 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesiu 19/971 (2%) 2/535 (<1%) 8/415 (2%) Hypomagnesemia 5 1/971 (<1%) 0/535 - 1/415 (<1%) Table 8: Grade 4 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Three Clinical Trials in Patients with Bone Metastases 1 Grade 3 (greater than 3x Upper Limit of Normal); Grade 4 (greater than 6x Upper Limit of Normal) * Serum creatinine data for all patients randomized after the 15-minute infusion amendment 2 Grade 3 (less than 7 mg/dL); Grade 4 (less than 6 mg/dL) 3 Grade 3 (less than 2 mg/dL); Grade 4 (less than 1 mg/dL) 4 Grade 3 (greater than 3 mEq/L); Grade 4 (greater than 8 mEq/L) 5 Grade 3 (less than 0.9 mEq/L); Grade 4 (less than 0.7 mEq/L) Grade 4 Laboratory Parameter Zoledronic Acid Injection 4 mg Pamidronate 90 mg Placebo n/N (%) n/N (%) n/N (%) Serum Creatinine 1* 2/529 (<1%) 1/268 (<1%) 0/241 -- Hypocalcemia 2 7/973 (<1%) 3/536 (<1%) 2/415 (<1%) Hypophosphatemia 3 5/973 (<1%) 0/537 -- 1/415 (<1%) Hypermagnesemia 4 0/971 -- 0/535 -- 2/415 (<1%) Hypomagnesemia 5 2/971 (<1%) 1/535 (<1%) 0/415 -- Among the less frequently occurring adverse events (less than 15% of patients), rigors, hypokalemia, influenza-like illness, and hypocalcemi 415 (<1%) Hypomagnesemia 5 2/971 (<1%) 1/535 (<1%) 0/415 -- Among the less frequently occurring adverse events (less than 15% of patients), rigors, hypokalemia, influenza-like illness, and hypocalcemia showed a trend for more events with bisphosphonate administration (Zoledronic Acid Injection 4 mg and pamidronate groups) compared to the placebo group. Less common adverse events reported more often with Zoledronic Acid Injection 4 mg than pamidronate included decreased weight, which was reported in 16% of patients in the Zoledronic Acid Injection 4 mg group compared with 9% in the pamidronate group. Decreased appetite was reported in slightly more patients in the Zoledronic Acid Injection 4 mg group (13%) compared with the Pamidronate (9%) and placebo (10%) groups, but the clinical significance of these small differences is not clear. Renal Toxicity In the bone metastases trials, renal deterioration was defined as an increase of 0.5 mg/dL for patients with normal baseline creatinine (less than 1.4 mg/dL) or an increase of 1.0 mg /dL for patients with an abnormal baseline creatinine (greater than or equal to 1.4 mg/dL). The following are data on the incidence of renal deterioration ess than 1.4 mg/dL) or an increase of 1.0 mg /dL for patients with an abnormal baseline creatinine (greater than or equal to 1.4 mg/dL). The following are data on the incidence of renal deterioration in patients receiving Zoledronic Acid Injection 4 mg over 15 minutes in these trials (see Table 9 ). Table 9: Percentage of Patients with Treatment Emergent Renal Function Deterioration by Baseline Serum Creatinine* *Table includes only patients who were randomized to the trial after a protocol amendment that lengthened the infusion duration of Zoledronic Acid Injection to 15 minutes. Patient Population/Baseline Creatinine Multiple Myeloma and Breast Cancer Zoledronic Acid Injection 4 mg Pamidronate 90 mg n/N (%) n/N % Normal 27/246 (11%) 23/246 (9%) Abnormal 2/26 (8%) 2/22 (9%) Total 29/272 (11%) 25/268 (9%) Solid Tumors Zoledronic Acid Injection 4 mg Placebo n/N (%) n/N (%) Normal 17/154 (11%) 10/143 (7%) Abnormal 1/11 (9%) 1/20 (5%) Total 18/165 (11%) 11/163 (7%) Prostate Cancer Zoledronic Acid Injection 4 mg Placebo n/N (%) n/N (%) Normal 12/82 (15%) 8/68 (12%) Abnormal 4/10 (40%) 2/10 (20%) Total 16/92 (17%) 10/78 (13%) The risk of deterioration in renal function appeared to be re nic Acid Injection 4 mg Placebo n/N (%) n/N (%) Normal 12/82 (15%) 8/68 (12%) Abnormal 4/10 (40%) 2/10 (20%) Total 16/92 (17%) 10/78 (13%) The risk of deterioration in renal function appeared to be related to time on study, whether patients were receiving Zoledronic Acid Injection (4 mg over 15 minutes), placebo, or pamidronate. In the trials and in postmarketing experience, renal deterioration, progression to renal failure and dialysis have occurred in patients with normal and abnormal baseline renal function, including patients treated with 4 mg infused over a 15 - minute period. There have been instances of this occurring after the initial Zoledronic Acid Injection dose. 6.2 Postmarketing Experience The following adverse reactions have been reported during postapproval use of Zoledronic Acid Injection. Because these reports are from a population of uncertain size and are subject to confounding factors, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Osteonecrosis of the Jaw Cases of osteonecrosis (primarily involving the jaws) have been reported predominantly in cancer patients treated with intravenous bisphosphonates ationship to drug exposure. Osteonecrosis of the Jaw Cases of osteonecrosis (primarily involving the jaws) have been reported predominantly in cancer patients treated with intravenous bisphosphonates including Zoledronic Acid Injection. Many of these patients were also receiving chemotherapy and corticosteroids which may be a risk factor for ONJ. Data suggests a greater frequency of reports of ONJ in certain cancers, such as advanced breast cancer and multiple myeloma. The majority of the reported cases are in cancer patients following invasive dental procedures, such as tooth extraction. It is therefore prudent to avoid invasive dental procedures as recovery may be prolonged [ see Warnings and Precautions ( 5 ) ]. Acute Phase Reaction- Within three days after Zoledronic Acid Injection administration, an acute phase reaction has been reported, with symptoms including pyrexia, fatigue, bone pain and/or arthralgias, myalgias, chills, and influenza-like illness; these symptoms usually resolve within three days of onset, but resolution could take up to 7 to 14 days. However, some of these symptoms have been reported to persist for a longer duration. Musculoskeletal Pain Severe and occa olve within three days of onset, but resolution could take up to 7 to 14 days. However, some of these symptoms have been reported to persist for a longer duration. Musculoskeletal Pain Severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported with bisphosphonate use [ see Warnings and Precautions ( 5 )]. Atypical subtrochanteric and diaphyseal femoral fractures Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate therapy, including Zoledronic Acid Injection [ see Warnings and Precautions ( 5.6 ) ]. Ocular Adverse Events Cases of uveitis, scleritis, episcleritis, conjunctivitis, iritis, and orbital inflammation including orbital edema have been reported during postmarketing use. In some cases, symptoms resolved with topical steroids. Hypersensitivity Reactions There have been rare reports of allergic reaction with intravenous zoledronic acid including angioedema, and bronchoconstriction. Very rare cases of anaphylactic reaction /shock have also been reported. Additional adverse reactions reported in postmarketing use include: CNS : taste disturbance, hyperesthesia, tremor; Special Senses : blurred vision; Gas lactic reaction /shock have also been reported. Additional adverse reactions reported in postmarketing use include: CNS : taste disturbance, hyperesthesia, tremor; Special Senses : blurred vision; Gastrointestinal : dry mouth; Skin : Increased sweating; Musculoskeletal : muscle cramps; Cardiovascular : hypertension, bradycardia, hypotension (associated with syncope or circulatory collapse primarily in patients with underlying risk factors); Respiratory : bronchospasms, interstitial lung disease (ILD) with positive re-challenge; Renal : hematuria, proteinuria; General Disorders and Administration Site : weight increase, influenza-like illness (pyrexia, asthenia, fatigue or malaise) persisting for greater than 30 days; Laboratory Abnormalities : hyperkalemia, hypernatremia. 1 INDICATIONS AND USAGE Leflunomide Tablets, USP are indicated for the treatment of adults with active rheumatoid arthritis (RA). Leflunomide tablets are a pyrimidine synthesis inhibitor indicated for the treatment of adults with active rheumatoid arthritis. ( 1 ) 2 DOSAGE AND ADMINISTRATION Loading dosage for patients at low risk for leflunomide -associated hepatotoxicity and leflunomide -associated myelosuppression: 100 mg daily for 3 days. ( 2.1 ) Maintenance dosage: 20 mg daily. ( 2.1 ) Maximum recommended daily dosage: 20 mg once daily. ( 2.1 ) If 20 mg once daily is not tolerated, may decrease dosage to 10 mg once daily. ( 2.1 ) Screen patients for active and latent tuberculosis, pregnancy test (females), blood pressure, and laboratory tests before starting leflunomide tablets.( 2.2 ) 2.1 Recommended Dosage The recommended dosage of Leflunomide is 20 mg once daily. Treatment may be initiated with or without a loading dose, depending upon the patient's risk of leflunomide -associated hepatotoxicity and leflunomide associated myelosuppression. The loading dosage provides steady-state concentrations more rapidly. For patients who are at low risk for leflunomide-associated hepato ted hepatotoxicity and leflunomide associated myelosuppression. The loading dosage provides steady-state concentrations more rapidly. For patients who are at low risk for leflunomide-associated hepatotoxicity and leflunomide-associated myelosuppression the recommended leflunomide loading dosage is 100 mg once daily for 3 days. Subsequently administer 20 mg once daily. For patients at high risk for leflunomide-associated hepatotoxicity (e.g., those taking concomitant methotrexate) or leflunomide-associated myelosuppression (e.g., patients taking concomitant immunosuppressants), the recommended leflunomide dosage is 20 mg once daily without a loading dose [see Warnings and Precautions ( 5.2 , 5.4 )]. The maximum recommended daily dosage is 20 mg once per day. Consider dosage reduction to 10 mg once daily for patients who are not able to tolerate 20 mg daily (i.e., for patients who experience any adverse events listed in Table 1). Monitor patients carefully after dosage reduction and after stopping therapy with leflunomide, since the active metabolite of leflunomide, teriflunomide, is slowly eliminated from the plasma [see Clinical Pharmacology (12.3) ]. After stopping leflunomide tre r stopping therapy with leflunomide, since the active metabolite of leflunomide, teriflunomide, is slowly eliminated from the plasma [see Clinical Pharmacology (12.3) ]. After stopping leflunomide treatment, an accelerated drug elimination procedure is recommended to reduce the plasma concentrations of the active metabolite, teriflunomide [see Warnings and Precautions (5.3) ]. Without use of an accelerated drug elimination procedure, it may take up to 2 years to reach undetectable plasma teriflunomide concentrations after stopping leflunomide [see Clinical Pharmacology (12.3) ]. 2.2 Evaluation and Testing Prior to Starting leflunomide tablets Prior to starting leflunomide treatment the following evaluations and tests are recommended: Evaluate patients for active tuberculosis and screen patients for latent tuberculosis infection [see Warnings and Precautions (5.4) ] Laboratory tests including serum alanine aminotransferase (ALT); and white blood cell, hemoglobin or hematocrit, and platelet counts [see Warnings and Precautions ( 5.2 , 5.4 )] For females of reproductive potential, pregnancy testing [see Warnings and Precautions (5.1) ] Check blood pressure [see Warnings and Precaution let counts [see Warnings and Precautions ( 5.2 , 5.4 )] For females of reproductive potential, pregnancy testing [see Warnings and Precautions (5.1) ] Check blood pressure [see Warnings and Precautions (5.10) ] 6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: Hepatotoxicity [see Warnings and Precautions (5.2) ] Immunosuppression [see Warnings and Precautions (5.4) ] Bone marrow suppression [see Warnings and Precautions (5.4) ] Stevens-Johnson syndrome and toxic epidermal necrolysis [see Warnings and Precautions (5.5) ] Peripheral neuropathy [see Warnings and Precautions (5.7) ] Interstitial lung disease [see Warnings and Precautions (5.8) ] The most commonly reported adverse reactions (≥10%) regardless of relation to leflunomide treatment were diarrhea, respiratory infection, nausea, headache, rash, abnormal liver enzymes, dyspepsia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Chartwell RX, LLC. at 1-845-232-1683 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. In clinical studies (Trials 1, 2, and 3), 1,865 patients were treated with leflunomide administered as either monotherapy or in combination with methotrexate or sulfasalazine. Patients ranged in age from 19 to 85 years, with an overall median age of 58 years. The mean duration of RA was 6 years ranging from 0 to 45 years. Elevation of Liver Enzymes Treatment with leflunomide was associated with elevations of liver enzymes, primarily ALT and AST, in a significant number of patients; these effects were generally reversible. Most transaminase elevations were mild (≤ 2-fold ULN) and usually resolved while continuing treatment. Marked elevations (>3-fold ULN) occurred infrequently and reversed with dose reduction or discontinuation of treatment. Table 1 shows liver enzyme elevations seen with monthly monitoring in clinical trials Trial 1 and Trial 2. It wa occurred infrequently and reversed with dose reduction or discontinuation of treatment. Table 1 shows liver enzyme elevations seen with monthly monitoring in clinical trials Trial 1 and Trial 2. It was notable that the absence of folate use in Trial 3 was associated with a considerably greater incidence of liver enzyme elevation on methotrexate. Table 1. Liver Enzyme Elevations >3-fold Upper Limits of Normal (ULN) in Patients with RA in Trials 1, 2, and 3** Trial 1 Trial 2 Trial 3* LEF 20 mg/day (n=182) PL (n=118) MTX 7.5-15 mg/wk (n=182) LEF 20mg/day (n=133) PL (n=92) SSZ 2.0 g/day LEF 20 mg/day (n=501) MTX 7.5-15 mg/wk (n=498) ALT(SGPT)>3-fold ULN (n%) 8(4.4) 3(2.5) 5(2.7) 2(1.5) 1(1.1) 2(1.5) 13(2.6) 83(16.7) Reversed to ≤ 2-fold ULN: 8 3 5 2 1 2 12 82 Timing of Elevation 0 - 3 Months 4 - 6 Months 7 - 9 Months 10 - 12 Months 6 1 1 - 1 1 1 - 1 3 1 - 2 - - - 1 - - - 2 - - - 7 1 - 5 27 34 16 6 LEF = leflunomide, MTX = methotrexate, PL = placebo, SSZ = sulfasalazine, ULN = Upper limit of normal *Only 10% of patients in Trial 3 received folate. All patients in Trial 1 received folate. In a 6 month study of 263 patients with persistent active rheumatoid arthritis despite methotrexate f normal *Only 10% of patients in Trial 3 received folate. All patients in Trial 1 received folate. In a 6 month study of 263 patients with persistent active rheumatoid arthritis despite methotrexate therapy, and with normal LFTs, leflunomide was administered to a group of 130 patients starting at 10 mg per day and increased to 20 mg as needed. An increase in ALT greater than or equal to three times the ULN was observed in 3.8% of patients compared to 0.8% in 133 patients continued on methotrexate with placebo. Most Common Adverse Reactions The most common adverse reactions in leflunomide-treated patients with RA include diarrhea, elevated liver enzymes (ALT and AST), alopecia and rash. Table 2 displays the most common adverse reactions in the controlled studies in patients with RA at one year (≥5% in any leflunomide treatment group). Table 2. Percentage of Patients with Adverse Events ≥ 5% In Any Leflunomide Treated Group in all RA Studies in Patients with RA Placebo-Controlled Trials Active-Controlled Trials All RA Studies Trial 1 and 2 Trial 3 1 LEF 20 mg/day (N=315) PL (N=210) SSZ 2.0g/day (N=133) MTX 7.5-15 mg/wk (N=182) LEF 20 mg/day (N=501) MTX 7.5–15 mg/wk (N=498) LEF (N=13 Active-Controlled Trials All RA Studies Trial 1 and 2 Trial 3 1 LEF 20 mg/day (N=315) PL (N=210) SSZ 2.0g/day (N=133) MTX 7.5-15 mg/wk (N=182) LEF 20 mg/day (N=501) MTX 7.5–15 mg/wk (N=498) LEF (N=1339) 2 Diarrhea 27% 12% 10% 20% 22% 10% 17% Headache 13% 11% 12% 21% 10% 8% 7% Nausea 13% 11% 19% 18% 13% 18% 9% Rash 12% 7% 11% 9% 11% 10% 10% Abnormal Liver Enzymes 10% 2% 4% 10% 6% 17% 5% Alopecia 9% 1% 6% 6% 17% 10% 10% Hypertension 3 9% 4% 4% 3% 10% 4% 10% Asthenia 6% 4% 5% 6% 3% 3% 3% Back Pain 6% 3% 4% 9% 8% 7% 5% GI/Abdominal Pain 6% 4% 7% 8% 8% 8% 5% Abdominal Pain 5% 4% 4% 8% 6% 4% 6% Allergic Reaction 5% 2% 0% 6% 1% 2% 2% Bronchitis 5% 2% 4% 7% 8% 7% 7% Dizziness 5% 3% 6% 5% 7% 6% 4% Mouth Ulcer 5% 4% 3% 10% 3% 6% 3% Pruritus 5% 2% 3% 2% 6% 2% 4% Rhinitis 5% 2% 4% 3% 2% 2% 2% Vomiting 5% 4% 4% 3% 3% 3% 3% Tenosynovitis 2% 0% 1% 2% 5% 1% 3% LEF = leflunomide, MTX = methotrexate, PL = placebo, SSZ = sulfasalazine 1 Only 10% of patients in Trial3 received folate. All patients in Trial 1 received folate; none in Trial 2 received folate. 2 Includes all controlled and uncontrolled trials with leflunomide (duration up to 12 3 Hypertension as a preexisting condition was overrepresent al 1 received folate; none in Trial 2 received folate. 2 Includes all controlled and uncontrolled trials with leflunomide (duration up to 12 3 Hypertension as a preexisting condition was overrepresented in all leflunomide treatment groups in phase III trials. Adverse events during a second year of treatment with leflunomide in clinical trials were consistent with those observed during the first year of treatment and occurred at a similar or lower incidence. Less Common Adverse Reactions In addition, in controlled clinical trials, the following adverse events in the leflunomide treatment group occurred at a higher incidence than in the placebo group. These adverse events were deemed possibly related to the study drug. Blood and Lymphatic System: leukocytosis, thrombocytopenia; Cardiovascular: chest pain, palpitation, thrombophlebitis of the leg, varicose vein; Eye: blurred vision, eye disorder, papilledema, retinal disorder, retinal hemorrhage; Gastrointestinal: alkaline phosphatase increased, anorexia, bilirubinemia, flatulence, gamma- GT increased, salivary gland enlarged, sore throat, vomiting, dry mouth; General Disorders: malaise; Immune System: anaphylactic reaction; Infection reased, anorexia, bilirubinemia, flatulence, gamma- GT increased, salivary gland enlarged, sore throat, vomiting, dry mouth; General Disorders: malaise; Immune System: anaphylactic reaction; Infection: abscess, flu syndrome, vaginal moniliasis; Nervous System: dizziness, headache, somnolence; Respiratory System: dyspnea; 6.2 Post Marketing Experience The following additional adverse reactions have been identified during postapproval use of leflunomide. 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 System: agranulocytosis, leukopenia, neutropenia, pancytopenia; Infection: opportunistic infections, severe infections including sepsis; Gastrointestinal: acute hepatic necrosis, colitis, including microscpic colitis, hepatitis, jaundice/cholestasis, pancreatitis; severe liver injury such as hepatic failure Immune System: angioedema; Nervous system: peripheral neuropathy; Respiratory: interstitial lung disease, including interstitial pneumonitis and pulmonary fibrosis, which may be fatal; pulmonary hypertension; Ski m: angioedema; Nervous system: peripheral neuropathy; Respiratory: interstitial lung disease, including interstitial pneumonitis and pulmonary fibrosis, which may be fatal; pulmonary hypertension; Skin and Appendages: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, vasculitis including cutaneous necrotizing vasculitis, cutaneous lupus erythematosus, pustular psoriasis or worsening psoriasis. 1 INDICATIONS AND USAGE Lubiprostone is a chloride channel activator indicated for the treatment of: chronic idiopathic constipation (CIC) in adults. ( 1.1 ) opioid-induced constipation (OIC) in adult patients with chronic, non-cancer pain, including patients with chronic pain related to prior cancer or its treatment who do not require frequent (e.g., weekly) opioid dosage escalation. ( 1.2 ) Limitations of Use: Effectiveness of lubiprostone in the treatment of OIC in patients taking diphenylheptane opioids (e.g., methadone) has not been established. ( 1.2 , 7.1 ) irritable bowel syndrome with constipation (IBS-C) in women ≥ 18 years old. ( 1.3 ) 1.1 Chronic Idiopathic Constipation in Adults Lubiprostone is indicated for the treatment of chronic idiopathic constipation (CIC) in adults. 1.2 Opioid-Induced Constipation in Adult Patients with Chronic Non-Cancer Pain Lubiprostone is indicated for the treatment of opioid-induced constipation (OIC) in adult patients with chronic non-cancer pain, including patients with chronic pain related to prior cancer or its treatment who do not require frequent (e.g., weekly) opioid dosage escalation. Limitations of Use: Effectiveness of lubiproston ain, including patients with chronic pain related to prior cancer or its treatment who do not require frequent (e.g., weekly) opioid dosage escalation. Limitations of Use: Effectiveness of lubiprostone in the treatment of opioid-induced constipation in patients taking diphenylheptane opioids (e.g., methadone) has not been established. [see Clinical Studies (14.2) ] 1.3 Irritable Bowel Syndrome with Constipation Lubiprostone is indicated for the treatment of irritable bowel syndrome with constipation (IBS-C) in women at least 18 years old. 2 DOSAGE AND ADMINISTRATION Recommended Dosage ( 2.1 ) CIC and OIC: 24 mcg twice daily. IBS-C: 8 mcg twice daily. See full prescribing information for dosage adjustment by indication and degree of hepatic impairment. Administration Instructions ( 2.2 ) Swallow capsules whole and do not break apart or chew, Take capsules with food and water, Assess periodically the need for continuous therapy. 2.1 Recommended Dosage The recommended oral dosage of lubiprostone by indication and adjustments for patients with moderate (Child Pugh Class B) and severe (Child Pugh Class C) hepatic impairment are shown in Table 1. Table 1. Recommended Dosage Regimen CIC a rostone by indication and adjustments for patients with moderate (Child Pugh Class B) and severe (Child Pugh Class C) hepatic impairment are shown in Table 1. Table 1. Recommended Dosage Regimen CIC and OIC IBS-C Recommended Adult Dosage Regimen 24 mcg twice daily 8 mcg twice daily Dosage Adjustment for Hepatic Impairment [see Use in Specific Populations (8.6) ] Moderate Impairment (Child-Pugh Class B) : 16 mcg twice daily If the dose is tolerated and an adequate response has not been obtained after an appropriate interval, doses can then be escalated to full dosing with appropriate monitoring of patient response. Moderate Impairment (Child-Pugh Class B) : No adjustment necessary Severe Impairment (Child-Pugh Class C) : 8 mcg twice daily Severe Impairment (Child-Pugh Class C) : 8 mcg once daily 2.2 Administration Instructions Take lubiprostone orally with food and water. Swallow capsules whole and do not break apart or chew. Physicians and patients should periodically assess the need for continued therapy. 6 ADVERSE REACTIONS The following adverse reactions are described below and elsewhere in labeling: Nausea [see Warnings and Precautions (5.1) ] Diarrhea [see Warnings and Precaut or continued therapy. 6 ADVERSE REACTIONS The following adverse reactions are described below and elsewhere in labeling: Nausea [see Warnings and Precautions (5.1) ] Diarrhea [see Warnings and Precautions (5.2) ] Syncope and Hypotension [see Warnings and Precautions (5.3) ] Dyspnea [see Warnings and Precautions (5.4) ] Most common adverse reactions (> 4%) are: CIC: nausea, diarrhea, headache, abdominal pain, abdominal distension, and flatulence. ( 6.1 ) OIC: nausea and diarrhea. ( 6.1 ) IBS-C: nausea, diarrhea, and abdominal pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy's Laboratories Inc. at 1-888-375-3784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. During clinical development of lubiprostone for CIC, OIC, and IBS-C, 1648 patients were treated with lubiprostone for 6 months and 710 patients were treated for 1 year (not mutually exclusive). Chronic Idiopathi ical development of lubiprostone for CIC, OIC, and IBS-C, 1648 patients were treated with lubiprostone for 6 months and 710 patients were treated for 1 year (not mutually exclusive). Chronic Idiopathic Constipation Adverse reactions in adult dose-finding, efficacy, and long-term clinical studies: The data described below reflect exposure to lubiprostone 24 mcg twice daily in 1113 patients with CIC over 3- or 4-week, 6-month, and 12-month treatment periods; and from 316 patients receiving placebo over short-term exposure (≤4 weeks). The placebo population (N = 316) had a mean age of 48 (range 21 to 81) years; was 87% female; 81% Caucasian, 10% African American, 7% Hispanic, 1% Asian, and 12% elderly (≥65 years of age). Of those patients treated with lubiprostone 24 mcg twice daily (N=1113), the mean age was 50 (range 19-86) years; 87% were female; 86% Caucasian, 8% African American, 5% Hispanic, 1% Asian, and 17% elderly (≥65 years of age). The most common adverse reactions (>4%) in CIC were nausea, diarrhea, headache, abdominal pain, abdominal distension, and flatulence. Table 2 presents data for the adverse reactions that occurred in at least 1% of patients and that occurred more were nausea, diarrhea, headache, abdominal pain, abdominal distension, and flatulence. Table 2 presents data for the adverse reactions that occurred in at least 1% of patients and that occurred more frequently with lubiprostone than placebo. Table 2. Adverse Reactions Reported in at least 1% of patients treated with lubiprostone and greater than placebo in Clinical Trials of Adults with CIC System/Adverse Reaction Placebo lubiprostone 24 mcg Twice Daily N = 316 % N = 1113 % Nausea 3 29 Diarrhea 1 12 Headache 5 11 Abdominal pain 3 8 Abdominal distension 2 6 Flatulence 2 6 Vomiting 0 3 Loose stools 0 3 Edema <1 3 Abdominal discomfort This term combines "abdominal tenderness," "abdominal rigidity," "gastrointestinal discomfort," "stomach discomfort", and "abdominal discomfort." 1 3 Dizziness 1 3 Chest discomfort/pain 0 2 Dyspnea 0 2 Dyspepsia <1 2 Fatigue 1 2 Dry mouth <1 1 Nausea: Approximately 29% of patients who received lubiprostone experienced nausea; 4% of patients had severe nausea and 9% of patients discontinued treatment due to nausea. The rate of nausea was lower among male (8%) and elderly (19%) patients. No patients in the clinical studies were hospitalized due to nausea. a and 9% of patients discontinued treatment due to nausea. The rate of nausea was lower among male (8%) and elderly (19%) patients. No patients in the clinical studies were hospitalized due to nausea. Diarrhea: Approximately 12% of patients who received lubiprostone experienced diarrhea; 2% of patients had severe diarrhea and 2% of patients discontinued treatment due to diarrhea. Electrolytes: No serious adverse reactions of electrolyte imbalance were reported in clinical studies, and no clinically significant changes were seen in serum electrolyte levels in patients receiving lubiprostone. Less common adverse reactions (<1%): fecal incontinence, muscle cramp, defecation urgency, frequent bowel movements, hyperhidrosis, pharyngolaryngeal pain, intestinal functional disorder, anxiety, cold sweat, constipation, cough, dysgeusia, eructation, influenza, joint swelling, myalgia, pain, syncope, tremor, decreased appetite. Opioid-Induced Constipation Adverse reactions in adult efficacy and long-term clinical studies: The data described below reflect exposure to lubiprostone 24 mcg twice daily in 860 patients with OIC for up to 12 months and from 632 patients receiving placebo twice daily ng-term clinical studies: The data described below reflect exposure to lubiprostone 24 mcg twice daily in 860 patients with OIC for up to 12 months and from 632 patients receiving placebo twice daily for up to 12 weeks. The total population (N = 1492) had a mean age of 50 (range 20–89) years; was 63% female; 83% Caucasian, 14% African American, 1% American Indian/Alaska Native, 1% Asian; 5% were of Hispanic ethnicity, and 9% were elderly (≥65 years of age). The most common adverse reactions (>4%) in OIC were nausea and diarrhea. Table 3 presents data for the adverse reactions that occurred in at least 1% of patients and that occurred more frequently with study drug than placebo. Table 3. Adverse Reactions Reported in at least 1% of patients treated with lubiprostone and greater than placebo in Clinical Trials of Adults with OIC System/Adverse Reaction Placebo lubiprostone 24 mcg Twice Daily N = 632 % N = 860 % Nausea 5 11 Diarrhea 2 8 Abdominal pain 1 4 Flatulence 3 4 Abdominal distension 2 3 Vomiting 2 3 Headache 1 2 Peripheral edema <1 1 Abdominal discomfort This term combines "abdominal tenderness," "abdominal rigidity," "gastrointestinal discomfort," "stomach discomfort", and " ion 2 3 Vomiting 2 3 Headache 1 2 Peripheral edema <1 1 Abdominal discomfort This term combines "abdominal tenderness," "abdominal rigidity," "gastrointestinal discomfort," "stomach discomfort", and "abdominal discomfort." 1 1 Nausea: Approximately 11% of patients who received lubiprostone experienced nausea; 1% of patients had severe nausea and 2% of patients discontinued treatment due to nausea. Diarrhea: Approximately 8% of patients who received lubiprostone experienced diarrhea; 2% of patients had severe diarrhea and 1% of patients discontinued treatment due to diarrhea. Less common adverse reactions (<1%): fecal incontinence, blood potassium decreased. Irritable Bowel Syndrome with Constipation Adverse reactions in adult dose-finding, efficacy, and long-term clinical studies: The data described below reflect exposure to lubiprostone 8 mcg twice daily in 1011 patients with IBS-C for up to 12 months and from 435 patients receiving placebo twice daily for up to 16 weeks. The total population (N = 1267) had a mean age of 47 (range 18–85) years; was 92% female; 78% Caucasian, 13% African American, 9% Hispanic, 0.4% Asian, and 8% elderly (≥65 years of age). The most common adverse r pulation (N = 1267) had a mean age of 47 (range 18–85) years; was 92% female; 78% Caucasian, 13% African American, 9% Hispanic, 0.4% Asian, and 8% elderly (≥65 years of age). The most common adverse reactions (>4%) in IBS-C were nausea, diarrhea, and abdominal pain. Table 4 presents data for the adverse reactions that occurred in at least 1% of patients and that occurred more frequently with study drug than placebo. Table 4. Adverse Reactions Reported in at least 1% of patients treated with lubiprostone and greater than placebo in Clinical Trials of Adults with IBS-C System/Adverse Reaction Placebo lubiprostone 8 mcg Twice Daily N = 435 % N = 1011 % Nausea 4 8 Diarrhea 4 7 Abdominal pain 5 5 Abdominal distension 2 3 Nausea: Approximately 8% of patients who received lubiprostone 8 mcg twice daily experienced nausea; 1% of patients had severe nausea and 1% of patients discontinued treatment due to nausea. Diarrhea: Approximately 7% of patients who received lubiprostone 8 mcg twice daily experienced diarrhea; <1% of patients had severe diarrhea and <1% of patients discontinued treatment due to diarrhea. Less common adverse reactions (<1%): dyspepsia, loose stools, vomiting, fatigue, d experienced diarrhea; <1% of patients had severe diarrhea and <1% of patients discontinued treatment due to diarrhea. Less common adverse reactions (<1%): dyspepsia, loose stools, vomiting, fatigue, dry mouth, edema, increased alanine aminotransferase, increased aspartate aminotransferase, constipation, eructation, gastroesophageal reflux disease, dyspnea, erythema, gastritis, increased weight, palpitations, urinary tract infection, anorexia, anxiety, depression, fecal incontinence, fibromyalgia, hard feces, lethargy, rectal hemorrhage, pollakiuria. 6.2 Postmarketing Experience The following additional adverse reactions have been identified during post-approval use of lubiprostone. 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. Cardiovascular: syncope and/or hypotension [see Warnings and Precautions (5.3) ] , tachycardia Gastrointestinal: ischemic colitis General: asthenia Immune System: hypersensitivity reactions including rash, swelling, and throat tightness malaise Muscoskeletal: muscle cramps or muscle spasms. Directions: FOR ORAL USE ONLY. Use: Temporary relief of flu symptoms. Warnings: Claims based on traditional homeopathic practice, not accepted medical evidence. Not FDA evaluated. Do not use if allergic to any ingredient. Consult a doctor before use for serious conditions or if conditions worsen or persist. If pregnant or nursing, consult a doctor before use. Do not use if safety seal is broken or missing. REFRIGERATE AFTER OPENING. BEST WHEN USED WITHIN 90 DAYS OF OPENING. Take 3-4 times daily. Ages 12 and older: 10 drops. Ages 2-11: 5 drops. Under age 2: Consult a doctor. KEEP OUT OF REACH OF CHILDREN. INDICATIONS AND USAGE Carefully consider the potential benefits and risks of sulindac tablets and other treatment options before deciding to use sulindac tablets. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see ). WARNINGS Sulindac tablets are indicated for acute or long-term use in the relief of signs and symptoms of the following: Osteoarthritis Rheumatoid arthritis The safety and effectiveness of sulindac tablets have not been established in rheumatoid arthritis patients who are designated in the American Rheumatism Association classification as Functional Class IV (incapacitated, largely or wholly bedridden, or confined to wheelchair; little or no self-care). Ankylosing spondylitis Acute painful shoulder (Acute subacromial bursitis/supraspinatus tendinitis) Acute gouty arthritis WARNINGS CARDIOVASCULAR EFFECTS Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselect hree years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events (see ). GI WARNINGS Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see ). CONT olled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see ). CONTRAINDICATIONS Hypertension NSAIDs, including sulindac tablets, can lead to onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including sulindac tablets, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy. Congestive Heart Failure and Edema Fluid retention and edema have been observed in some patients taking NSAIDs. Sulindac tablets should be used with caution in patients with fluid retention or heart failure. Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation NSAIDs, including sulindac tablets, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, sm n, Bleeding, and Perforation NSAIDs, including sulindac tablets, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3–6 months, and in about 2–4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk. NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding with a who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population. prior history of peptic ulcer disease and/or gastrointestinal bleeding To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be conside t is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered. Hepatic Effects In addition to hypersensitivity reactions involving the liver, in some patients the findings are consistent with those of cholestatic hepatitis (see ). As with other non-steroidal anti-inflammatory drugs, borderline elevations of one or more liver tests without any other signs and symptoms may occur in up to 15% of patients taking NSAIDs including sulindac tablets. These laboratory abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. The SGPT (ALT) test is probably the most sensitive indicator of liver dysfunction. Meaningful (3 times the upper limit of normal) elevations of SGPT or SGOT (AST) occurred in controlled clinical trials in less than 1% of patients. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fat more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported. WARNINGS, Hypersensitivity A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with sulindac tablets. Although such reactions as described above are rare, if abnormal liver tests persist or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), sulindac tablets should be discontinued. In clinical trials with sulindac tablets, the use of doses of 600 mg/day has been associated with an increased incidence of mild liver test abnormalities (see for maximum dosage recommendation). DOSAGE AND ADMINISTRATION Renal Effects Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal t normalities (see for maximum dosage recommendation). DOSAGE AND ADMINISTRATION Renal Effects Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a non-steroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, patients who are volume-depleted, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. Advanced Renal Disease No information is available from controlled clinical studies regarding the use of sulindac tablets in patients with advanced renal disease. Therefore, treatment with sulindac tablets is not recommended in these patients with advanced renal disease. If sulindac tablets therapy must be initiated, close monitoring th advanced renal disease. Therefore, treatment with sulindac tablets is not recommended in these patients with advanced renal disease. If sulindac tablets therapy must be initiated, close monitoring of the patient's renal function is advisable. Anaphylactic/Anaphylactoid Reactions As with other NSAIDs, anaphylactic/anaphylactoid reactions may occur in patients without known prior exposure to sulindac tablets. Sulindac tablets should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see and ). Emergency help should be sought in cases where an anaphylactic/anaphylactoid reaction occurs. CONTRAINDICATIONS PRECAUTIONS – Preexisting Asthma Skin Reactions NSAIDs, including sulindac tablets, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and , and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity. Hypersensitivity Rarely, fever and other evidence of hypersensitivity (see ) including abnormalities in one or more liver function tests and severe skin reactions have occurred during therapy with sulindac tablets. Fatalities have occurred in these patients. Hepatitis, jaundice, or both, with or without fever, may occur usually within the first one to three months of therapy. Determinations of liver function should be considered whenever a patient on therapy with sulindac tablets develops unexplained fever, rash or other dermatologic reactions or constitutional symptoms. If unexplained fever or other evidence of hypersensitivity occurs, therapy with sulindac tablets should be discontinued. The elevated temperature and abnormalities in liver function caused by sulindac tablets characteristically have reverted to normal after discontinuation of therapy. Administration of sul discontinued. The elevated temperature and abnormalities in liver function caused by sulindac tablets characteristically have reverted to normal after discontinuation of therapy. Administration of sulindac tablets should not be reinstituted in such patients. ADVERSE REACTIONS Pregnancy In late pregnancy, as with other NSAIDs, sulindac tablets should be avoided because it may cause premature closure of the ductus arteriosus. DOSAGE AND ADMINISTRATION Carefully consider the potential benefits and risks of sulindac tablets and other treatment options before deciding to use sulindac tablets. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see ). WARNINGS After observing the response to initial therapy with sulindac tablets, the dose and frequency should be adjusted to suit an individual patient's needs. Sulindac tablets should be administered orally twice a day with food. The maximum dosage is 400 mg per day. Dosages above 400 mg per day are not recommended. In osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis, the recommended starting dosage is 150 mg twice a day. The dosage may be lowered or raised depending o per day are not recommended. In osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis, the recommended starting dosage is 150 mg twice a day. The dosage may be lowered or raised depending on the response. A prompt response (within one week) can be expected in about one-half of patients with osteoarthritis, ankylosing spondylitis, and rheumatoid arthritis. Others may require longer to respond. In acute painful shoulder (acute subacromial bursitis/supraspinatus tendinitis) and acute gouty arthritis, the recommended dosage is 200 mg twice a day. After a satisfactory response has been achieved, the dosage may be reduced according to the response. In acute painful shoulder, therapy for 7–14 days is usually adequate. In acute gouty arthritis, therapy for 7 days is usually adequate. ADVERSE REACTIONS The following adverse reactions were reported in clinical trials or have been reported since the drug was marketed. The probability exists of a causal relationship between sulindac tablets and these adverse reactions. The adverse reactions which have been observed in clinical trials encompass observations in 1,865 patients, including 232 observed for at least 48 weeks. Incidence Gr lets and these adverse reactions. The adverse reactions which have been observed in clinical trials encompass observations in 1,865 patients, including 232 observed for at least 48 weeks. Incidence Greater Than 1% Gastrointestinal The most frequent types of adverse reactions occurring with sulindac tablets are gastrointestinal; these include gastrointestinal pain (10%), dyspepsia , nausea with or without vomiting, diarrhea , constipation , flatulence, anorexia and gastrointestinal cramps. Incidence between 3% and 9%. Those reactions occurring in 1% to 3% of patients are not marked with an asterisk. Dermatologic Rash , pruritus. Central Nervous System Dizziness , headache , nervousness. Special Senses Tinnitus. Miscellaneous Edema (see ). WARNINGS Incidence Less Than 1 in 100 Gastrointestinal Gastritis, gastroenteritis or colitis. Peptic ulcer and gastrointestinal bleeding have been reported. GI perforation and intestinal strictures (diaphragms) have been reported rarely. Liver function abnormalities; jaundice, sometimes with fever; cholestasis; hepatitis; hepatic failure. There have been rare reports of sulindac metabolites in common bile duct "sludge" and in biliary calculi in pat abnormalities; jaundice, sometimes with fever; cholestasis; hepatitis; hepatic failure. There have been rare reports of sulindac metabolites in common bile duct "sludge" and in biliary calculi in patients with symptoms of cholecystitis who underwent a cholecystectomy. Pancreatitis (see ). PRECAUTIONS Ageusia; glossitis. Dermatologic Stomatitis, sore or dry mucous membranes, alopecia, photosensitivity. Erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, and exfoliative dermatitis have been reported. Cardiovascular Congestive heart failure, especially in patients with marginal cardiac function; palpitation; hypertension. Hematologic Thrombocytopenia; ecchymosis; purpura; leukopenia; agranulocytosis; neutropenia; bone marrow depression, including aplastic anemia; hemolytic anemia; increased prothrombin time in patients on oral anticoagulants (see ). PRECAUTIONS Genitourinary Urine discoloration; dysuria; vaginal bleeding; hematuria; proteinuria; crystalluria; renal impairment, including renal failure; interstitial nephritis; nephrotic syndrome. Renal calculi containing sulindac metabolites have been observed rarely. Metabolic Hyperkalemia. Musculoskeletal Muscl impairment, including renal failure; interstitial nephritis; nephrotic syndrome. Renal calculi containing sulindac metabolites have been observed rarely. Metabolic Hyperkalemia. Musculoskeletal Muscle weakness. Psychiatric Depression; psychic disturbances including acute psychosis. Nervous System Vertigo; insomnia; somnolence; paresthesia; convulsions; syncope; aseptic meningitis (especially in patients with systemic lupus erythematosus (SLE) and mixed connective tissue disease, see ). PRECAUTIONS Special Senses Blurred vision; visual disturbances; decreased hearing; metallic or bitter taste. Respiratory Epistaxis. Hypersensitivity Reactions Anaphylaxis; angioneurotic edema; urticaria; bronchial spasm; dyspnea. Hypersensitivity vasculitis. A potentially fatal apparent hypersensitivity syndrome has been reported. This syndrome may include constitutional symptoms (fever, chills, diaphoresis, flushing), cutaneous findings (rash or other dermatologic reactions — see above), conjunctivitis, involvement of major organs (changes in liver function including hepatic failure, jaundice, pancreatitis, pneumonitis with or without pleural effusion, leukopenia, leukocytosis, eosinophilia, dissem , involvement of major organs (changes in liver function including hepatic failure, jaundice, pancreatitis, pneumonitis with or without pleural effusion, leukopenia, leukocytosis, eosinophilia, disseminated intravascular coagulation, anemia, renal impairment, including renal failure), and other less specific findings (adenitis, arthralgia, arthritis, myalgia, fatigue, malaise, hypotension, chest pain, tachycardia). Causal Relationship Unknown A rare occurrence of fulminant necrotizing fasciitis, particularly in association with Group A β-hemolytic streptococcus, has been described in persons treated with non-steroidal anti-inflammatory agents, sometimes with fatal outcome (see also ). PRECAUTIONS, General Other reactions have been reported in clinical trials or since the drug was marketed, but occurred under circumstances where a causal relationship could not be established. However, in these rarely reported events, that possibility cannot be excluded. Therefore, these observations are listed to serve as alerting information to physicians. Cardiovascular Arrhythmia. Metabolic Hyperglycemia. Nervous System Neuritis. Special Senses Disturbances of the retina and its vasculature. Misc listed to serve as alerting information to physicians. Cardiovascular Arrhythmia. Metabolic Hyperglycemia. Nervous System Neuritis. Special Senses Disturbances of the retina and its vasculature. Miscellaneous Gynecomastia. Uses • temporarily relieves these symptoms due to a cold: • minor aches and pains • minor sore throat pain • headache • nasal and sinus congestion • runny nose • sneezing • itchy nose or throat • itchy, watery eyes due to hay fever • cough due to minor throat and bronchial irritation • temporarily reduces fever Purposes Pain reliever/fever reducer Antihistamine/cough suppressant 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. Sore throat warning: If sore throat is severe, persists for more than 2 days, is accompanied or followed by fever, headache, rash, nausea, or vomiting consult a doctor promptly. Do not use • in a child under 12 years of age • if you are allergic to acetaminophen • with any other drug containing acetaminophen (prescription or nonprescription). If y g consult a doctor promptly. Do not use • in a child under 12 years of age • if you are allergic to acetaminophen • with any other drug containing acetaminophen (prescription or nonprescription). If you are not sure whether a drug contains acetaminophen, ask a doctor or pharmacist. • with any other product containing diphenhydramine, even one used on the skin • 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. Ask a doctor before use if you have • liver disease • heart disease • high blood pressure • thyroid disease • diabetes • glaucoma • trouble urinating due to an enlarged prostate gland • a breathing problem such as emphysema or chronic bronchitis • cough that occurs with too much phlegm (mucus) • cough that lasts or is chronic such as occurs with smoking, asthma or emphysema Ask a doctor or pharmacist before use if you are • taking sedatives or tranquilizers • taking the blood thinning drug warfarin Whe lasts or is chronic such as occurs with smoking, asthma or emphysema Ask a doctor or pharmacist before use if you are • taking sedatives or tranquilizers • taking the blood thinning drug warfarin When using this product • do not exceed recommended dosage • avoid alcoholic drinks • marked drowsiness may occur • alcohol, sedatives and tranquilizers may increase drowsiness • be careful when driving a motor vehicle or operating machinery • excitability may occur, especially in children Stop use and ask a doctor if • nervousness, dizziness, or sleeplessness occurs • fever gets worse or lasts more than 3 days • redness or swelling is present • new symptoms occur • pain, cough or nasal congestion gets worse or lasts more than 7 days • cough comes back or occurs with rash or headache that lasts. These could be signs of a serious condition. If pregnant or breast-feeding, ask a health professional before use. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away. Prompt medical attention is critical for adults as well as for children even if you do not notice any signs or symptoms. Directions • do not use more than directed • meas on Control Center right away. Prompt medical attention is critical for adults as well as for children even if you do not notice any signs or symptoms. Directions • do not use more than directed • measure the dose correctly using the enclosed dosing cup • take every 4 hours in dosing cup provided, while symptoms persist • do not take more than 5 doses (150 mL) in 24 hours unless directed by a doctor Age Dose adults and children 12 years of age and over 30 mL children under 12 years of age do not use Ask a doctor before use if you have • liver disease • heart disease • high blood pressure • thyroid disease • diabetes • glaucoma • trouble urinating due to an enlarged prostate gland • a breathing problem such as emphysema or chronic bronchitis • cough that occurs with too much phlegm (mucus) • cough that lasts or is chronic such as occurs with smoking, asthma or emphysema Stop use and ask a doctor if • nervousness, dizziness, or sleeplessness occurs • fever gets worse or lasts more than 3 days • redness or swelling is present • new symptoms occur • pain, cough or nasal congestion gets worse or lasts more than 7 days • cough comes back or occurs with rash or headache that lasts. These c days • redness or swelling is present • new symptoms occur • pain, cough or nasal congestion gets worse or lasts more than 7 days • cough comes back or occurs with rash or headache that lasts. These could be signs of a serious condition. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away. Prompt medical attention is critical for adults as well as for children even if you do not notice any signs or symptoms. 1 INDICATIONS AND USAGE Ziprasidone capsules are indicated for the treatment of schizophrenia, as monotherapy for the acute treatment of bipolar manic or mixed episodes, and as an adjunct to lithium or valproate for the maintenance treatment of bipolar disorder. When deciding among the alternative treatments available for the condition needing treatment, the prescriber should consider the finding of ziprasidone’s greater capacity to prolong the QT/QTc interval compared to several other antipsychotic drugs [see Warnings and Precautions (5.3)]. Prolongation of the QTc interval is associated in some other drugs with the ability to cause torsade de pointes-type arrhythmia, a potentially fatal polymorphic ventricular tachycardia, and sudden death. In many cases this would lead to the conclusion that other drugs should be tried first. Whether ziprasidone will cause torsade de pointes or increase the rate of sudden death is not yet known [see Warnings and Precautions ( 5.3 )]. Schizophrenia Ziprasidone is indicated for the treatment of schizophrenia in adults [see Clinical Studies ( 14.1 )]. Bipolar I Disorder (Acute Mixed or Manic Episodes and Maintenance Treatment as an Adjunct to Lithi iprasidone is indicated for the treatment of schizophrenia in adults [see Clinical Studies ( 14.1 )]. Bipolar I Disorder (Acute Mixed or Manic Episodes and Maintenance Treatment as an Adjunct to Lithium or Valproate) Ziprasidone is indicated as monotherapy for the acute treatment of adults with manic or mixed episodes associated with bipolar I disorder [see Clinical Studies ( 14.2 )]. Ziprasidone is indicated as an adjunct to lithium or valproate for the maintenance treatment of bipolar I disorder in adults [see Clinical Studies ( 14.2 )]. Ziprasidone is an atypical antipsychotic. In choosing among treatments, prescribers should be aware of the capacity of ziprasidone to prolong the QT interval and may consider the use of other drugs first ( 5.3 ) Ziprasidone is indicated as an oral formulation for the: Treatment of schizophrenia. ( 1 ) Acute treatment as monotherapy of manic or mixed episodes associated with bipolar I disorder. ( 1 ) Maintenance treatment of bipolar I disorder as an adjunct to lithium or valproate. ( 1 ) 2 DOSAGE AND ADMINISTRATION Give oral doses with food. Schizophrenia: Initiate at 20 mg twice daily. Daily dosage may be adjusted up to 80 mg twice daily. Dose ad djunct to lithium or valproate. ( 1 ) 2 DOSAGE AND ADMINISTRATION Give oral doses with food. Schizophrenia: Initiate at 20 mg twice daily. Daily dosage may be adjusted up to 80 mg twice daily. Dose adjustments should occur at intervals of not less than 2 days. Safety and efficacy has been demonstrated in doses up to 100 mg twice daily. The lowest effective dose should be used. ( 2.1 ) Acute treatment of manic/mixed episodes of bipolar I disorder: Initiate at 40 mg twice daily. Increase to 60 mg or 80 mg twice daily on day 2 of treatment. Subsequent dose adjustments should be based on tolerability and efficacy within the range of 40 mg to 80 mg twice daily. ( 2.2 ) Maintenance treatment of bipolar I disorder as an adjunct to lithium or valproate: Continue treatment at the same dose on which the patient was initially stabilized, within the range of 40 mg to 80 mg twice daily. ( 2.2 ) 2.1 Schizophrenia Dose Selection Ziprasidone capsules should be administered at an initial daily dose of 20 mg twice daily with food. In some patients, daily dosage may subsequently be adjusted on the basis of individual clinical status up to 80 mg twice daily. Dosage adjustments, if indicated, should ge 20 mg twice daily with food. In some patients, daily dosage may subsequently be adjusted on the basis of individual clinical status up to 80 mg twice daily. Dosage adjustments, if indicated, should generally occur at intervals of not less than 2 days, as steady-state is achieved within 1 to 3 days. In order to ensure use of the lowest effective dose, patients should ordinarily be observed for improvement for several weeks before upward dosage adjustment. Efficacy in schizophrenia was demonstrated in a dose range of 20 mg to 100 mg twice daily in short-term, placebo-controlled clinical trials. There were trends toward dose response within the range of 20 mg to 80 mg twice daily, but results were not consistent. An increase to a dose greater than 80 mg twice daily is not generally recommended. The safety of doses above 100 mg twice daily has not been systematically evaluated in clinical trials [see Clinical Studies ( 14.1 )]. Maintenance Treatment While there is no body of evidence available to answer the question of how long a patient treated with ziprasidone should remain on it, a maintenance study in patients who had been symptomatically stable and then randomized to continue zipr able to answer the question of how long a patient treated with ziprasidone should remain on it, a maintenance study in patients who had been symptomatically stable and then randomized to continue ziprasidone or switch to placebo demonstrated a delay in time to relapse for patients receiving ziprasidone capsules [see Clinical Studies ( 14.1 )]. No additional benefit was demonstrated for doses above 20 mg twice daily. Patients should be periodically reassessed to determine the need for maintenance treatment. 2.2 Bipolar I Disorder (Acute Mixed or Manic Episodes and Maintenance Treatment as an Adjunct to Lithium or Valproate) Acute Treatment of Manic or Mixed Episodes Dose Selection-Oral ziprasidone should be administered at an initial daily dose of 40 mg twice daily with food. The dose may then be increased to 60 mg or 80 mg twice daily on the second day of treatment and subsequently adjusted on the basis of tolerance and efficacy within the range 40 mg to 80 mg twice daily. In the flexible-dose clinical trials, the mean daily dose administered was approximately 120 mg [see Clinical Studies ( 14.2 )]. Maintenance Treatment (as an adjunct to lithium or valproate) Continue treatment at ble-dose clinical trials, the mean daily dose administered was approximately 120 mg [see Clinical Studies ( 14.2 )]. Maintenance Treatment (as an adjunct to lithium or valproate) Continue treatment at the same dose on which the patient was initially stabilized, within the range of 40 mg to 80 mg twice daily with food. Patients should be periodically reassessed to determine the need for maintenance treatment [see Clinical Studies ( 14.2 )]. 6 ADVERSE REACTIONS Commonly observed adverse reactions (incidence ≥5% and at least twice the incidence for placebo) were: Schizophrenia: Somnolence, respiratory tract infection. ( 6.1 ) Manic and Mixed Episodes Associated with Bipolar Disorder: Somnolence, extrapyramidal symptoms, dizziness, akathisia, abnormal vision, asthenia, vomiting. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates obser ely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical trials for oral ziprasidone included approximately 5,700 patients and/or normal subjects exposed to one or more doses of ziprasidone. Of these 5,700, over 4,800 were patients who participated in multiple-dose effectiveness trials, and their experience corresponded to approximately 1,831 patient-years. These patients include: (1) 4,331 patients who participated in multiple-dose trials, predominantly in schizophrenia, representing approximately 1,698 patient-years of exposure as of February 5, 2000, and (2) 472 patients who participated in bipolar mania trials representing approximately 133 patient-years of exposure. An additional 127 patients with bipolar disorder participated in a long-term maintenance treatment study representing approximately 74.7 patient-years of exposure to ziprasidone. The conditions and duration of treatment with ziprasidone included open-label and double-blind studies, inpatient and outpatient studies, and short-term and longer-term exp of exposure to ziprasidone. The conditions and duration of treatment with ziprasidone included open-label and double-blind studies, inpatient and outpatient studies, and short-term and longer-term exposure. Adverse reactions during exposure were obtained by collecting voluntarily reported adverse experiences, as well as results of physical examinations, vital signs, weights, laboratory analyses, ECGs, and results of ophthalmologic examinations. The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. Adverse Findings Observed in Short-Term, Placebo-Controlled Trials with Oral Ziprasidone The following findings are based on the short-term placebo-controlled premarketing trials for schizophrenia (a pool of two 6-week, and two 4-week fixed-dose trials) and bipolar mania (a pool of two 3-week flexible-dose trials) in which ziprasidone was administered in doses ranging from 10 to 200 mg/day. Commonly Observed Adverse Reactions i eek fixed-dose trials) and bipolar mania (a pool of two 3-week flexible-dose trials) in which ziprasidone was administered in doses ranging from 10 to 200 mg/day. Commonly Observed Adverse Reactions in Short Term-Placebo-Controlled Trials The following adverse reactions were the most commonly observed adverse reactions associated with the use of ziprasidone (incidence of 5% or greater) and not observed at an equivalent incidence among placebo-treated patients (ziprasidone incidence at least twice that for placebo): Schizophrenia trials (see Table 11 ) Somnolence Respiratory Tract Infection Bipolar trials (see Table 12 ) Somnolence Extrapyramidal Symptoms which includes the following adverse reaction terms: extrapyramidal syndrome, hypertonia, dystonia, dyskinesia, hypokinesia, tremor, paralysis and twitching. None of these adverse reactions occurred individually at an incidence greater than 10% in bipolar mania trials. Dizziness which includes the adverse reaction terms dizziness and lightheadedness. Akathisia Abnormal Vision Asthenia Vomiting SCHIZOPHRENIA Adverse Reactions Associated with Discontinuation of Treatment in Short-Term, Placebo-Controlled Trials of Oral Ziprasidone Ap ightheadedness. Akathisia Abnormal Vision Asthenia Vomiting SCHIZOPHRENIA Adverse Reactions Associated with Discontinuation of Treatment in Short-Term, Placebo-Controlled Trials of Oral Ziprasidone Approximately 4.1% (29/702) of ziprasidone-treated patients in short-term, placebo-controlled studies discontinued treatment due to an adverse reaction, compared with about 2.2% (6/273) on placebo. The most common reaction associated with dropout was rash, including 7 dropouts for rash among ziprasidone patients (1%) compared to no placebo patients [see Warnings and Precautions ( 5.8 )]. Adverse Reactions Occurring at an Incidence of 2% or More Among Ziprasidone-Treated Patients in Short-Term, Oral, Placebo-Controlled Trials Table 11 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred during acute therapy (up to 6 weeks) in predominantly patients with schizophrenia, including only those reactions that occurred in 2% or more of patients treated with ziprasidone and for which the incidence in patients treated with ziprasidone was greater than the incidence in placebo-treated patients. Table 11 Treatment-Emergent Adverse Reaction I nts treated with ziprasidone and for which the incidence in patients treated with ziprasidone was greater than the incidence in placebo-treated patients. Table 11 Treatment-Emergent Adverse Reaction Incidence in Short-Term Oral Placebo-Controlled Trials - Schizophrenia Percentage of Patients Reporting Reaction Body System/Adverse Reaction Ziprasidone (N=702) Placebo (N=273) Body as a Whole Asthenia 5 3 Accidental Injury 4 2 Chest Pain 3 2 Cardiovascular Tachycardia 2 1 Digestive Nausea 10 7 Constipation 9 8 Dyspepsia 8 7 Diarrhea 5 4 Dry Mouth 4 2 Anorexia 2 1 Nervous Extrapyramidal Symptoms Extrapyramidal Symptoms includes the following adverse reaction terms: extrapyramidal syndrome, hypertonia, dystonia, dyskinesia, hypokinesia, tremor, paralysis and twitching. None of these adverse reactions occurred individually at an incidence greater than 5% in schizophrenia trials. 14 8 Somnolence 14 7 Akathisia 8 7 Dizziness Dizziness includes the adverse reaction terms dizziness and lightheadedness. 8 6 Respiratory Respiratory Tract Infection 8 3 Rhinitis 4 2 Cough Increased 3 1 Skin and Appendages Rash 4 3 Fungal Dermatitis 2 1 Special Senses Abnormal Vision 3 2 Dose Dependency of Advers edness. 8 6 Respiratory Respiratory Tract Infection 8 3 Rhinitis 4 2 Cough Increased 3 1 Skin and Appendages Rash 4 3 Fungal Dermatitis 2 1 Special Senses Abnormal Vision 3 2 Dose Dependency of Adverse Reactions in Short-Term, Fixed-Dose, Placebo-Controlled Trials An analysis for dose response in the schizophrenia 4-study pool revealed an apparent relation of adverse reaction to dose for the following reactions: asthenia, postural hypotension, anorexia, dry mouth, increased salivation, arthralgia, anxiety, dizziness, dystonia, hypertonia, somnolence, tremor, rhinitis, rash, and abnormal vision. Extrapyramidal Symptoms (EPS) The incidence of reported EPS (which included the adverse reaction terms extrapyramidal syndrome, hypertonia, dystonia, dyskinesia, hypokinesia, tremor, paralysis and twitching) for ziprasidone-treated patients in the short-term, placebo-controlled schizophrenia trials was 14% vs. 8% for placebo. Objectively collected data from those trials on the Simpson-Angus Rating Scale (for EPS) and the Barnes Akathisia Scale (for akathisia) did not generally show a difference between ziprasidone and placebo. Dystonia Class Effect: Symptoms of dystonia, prolonged abnormal c ng Scale (for EPS) and the Barnes Akathisia Scale (for akathisia) did not generally show a difference between ziprasidone and placebo. Dystonia Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. Vital Sign Changes Ziprasidone is associated with orthostatic hypotension [see Warnings and Precautions ( 5.9 )]. ECG Changes Ziprasidone is associated with an increase in the QTc interval [see Warnings and Precautions (5.3)]. In the schizophrenia trials, ziprasidone was associated with a mean increase in heart rate of 1.4 beats per minute compared to a 0.2 beats per minute decrease among placebo patients. Other Adverse Reactions Observed During the , ziprasidone was associated with a mean increase in heart rate of 1.4 beats per minute compared to a 0.2 beats per minute decrease among placebo patients. Other Adverse Reactions Observed During the Premarketing Evaluation of Oral Ziprasidone Following is a list of COSTART terms that reflect treatment-emergent adverse reactions as defined in the introduction to the ADVERSE REACTIONS section reported by patients treated with ziprasidone in schizophrenia trials at multiple doses >4 mg/day within the database of 3,834 patients. All reported reactions are included except those already listed in Table 11 or elsewhere in labeling, those reaction terms that were so general as to be uninformative, reactions reported only once and that did not have a substantial probability of being acutely life-threatening, reactions that are part of the illness being treated or are otherwise common as background reactions, and reactions considered unlikely to be drug-related. It is important to emphasize that, although the reactions reported occurred during treatment with ziprasidone, they were not necessarily caused by it. Adverse reactions are further categorized by body system and listed in order of d t, although the reactions reported occurred during treatment with ziprasidone, they were not necessarily caused by it. Adverse reactions are further categorized by body system and listed in order of decreasing frequency according to the following definitions: Frequent - adverse reactions occurring in at least 1/100 patients (≥1% of patients) (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); Infrequent - adverse reactions occurring in 1/100 to 1/1000 patients (in 0.1 to 1% of patients) Rare - adverse reactions occurring in fewer than 1/1000 patients (<0.1% of patients). Body as a Whole Frequent - abdominal pain, flu syndrome, fever, accidental fall, face edema, chills, photosensitivity reaction, flank pain, hypothermia, motor vehicle accident Cardiovascular System Frequent - tachycardia, hypertension, postural hypotension Infrequent - bradycardia, angina pectoris, atrial fibrillation Rare - first degree AV block, bundle branch block, phlebitis, pulmonary embolus, cardiomegaly, cerebral infarct, cerebrovascular accident, deep thrombophlebitis, myocarditis, thrombophlebitis Digestive System Frequent - anorexia, vomiting Inf h block, phlebitis, pulmonary embolus, cardiomegaly, cerebral infarct, cerebrovascular accident, deep thrombophlebitis, myocarditis, thrombophlebitis Digestive System Frequent - anorexia, vomiting Infrequent - rectal hemorrhage, dysphagia, tongue edema Rare - gum hemorrhage, jaundice, fecal impaction, gamma glutamyl transpeptidase increased, hematemesis, cholestatic jaundice, hepatitis, hepatomegaly, leukoplakia of mouth, fatty liver deposit, melena Endocrine Rare - hypothyroidism, hyperthyroidism, thyroiditis Hemic and Lymphatic System Infrequent - anemia, ecchymosis, leukocytosis, leukopenia, eosinophilia, lymphadenopathy Rare - thrombocytopenia, hypochromic anemia, lymphocytosis, monocytosis, basophilia, lymphedema, polycythemia, thrombocythemia Metabolic and Nutritional Disorders Infrequent - thirst, transaminase increased, peripheral edema, hyperglycemia, creatine phosphokinase increased, alkaline phosphatase increased, hypercholesteremia, dehydration, lactic dehydrogenase increased, albuminuria, hypokalemia Rare - BUN increased, creatinine increased, hyperlipemia, hypocholesteremia, hyperkalemia, hypochloremia, hypoglycemia, hyponatremia, hypoproteinemia, glucose tolerance de ed, albuminuria, hypokalemia Rare - BUN increased, creatinine increased, hyperlipemia, hypocholesteremia, hyperkalemia, hypochloremia, hypoglycemia, hyponatremia, hypoproteinemia, glucose tolerance decreased, gout, hyperchloremia, hyperuricemia, hypocalcemia, hypoglycemic reaction, hypomagnesemia, ketosis, respiratory alkalosis Musculoskeletal System Frequent - myalgia Infrequent - tenosynovitis Rare - myopathy Nervous System Frequent - agitation, extrapyramidal syndrome, tremor, dystonia, hypertonia, dyskinesia, hostility, twitching, paresthesia, confusion, vertigo, hypokinesia, hyperkinesia, abnormal gait, oculogyric crisis, hypesthesia, ataxia, amnesia, cogwheel rigidity, delirium, hypotonia, akinesia, dysarthria, withdrawal syndrome, buccoglossal syndrome, choreoathetosis, diplopia, incoordination, neuropathy Infrequent - paralysis Rare - myoclonus, nystagmus, torticollis, circumoral paresthesia, opisthotonos, reflexes increased, trismus Respiratory System Frequent - dyspnea Infrequent - pneumonia, epistaxis Rare - hemoptysis, laryngismus Skin and Appendages Infrequent - maculopapular rash, urticaria, alopecia, eczema, exfoliative dermatitis, contact dermatitis, vesiculobullous uent - pneumonia, epistaxis Rare - hemoptysis, laryngismus Skin and Appendages Infrequent - maculopapular rash, urticaria, alopecia, eczema, exfoliative dermatitis, contact dermatitis, vesiculobullous rash Special Senses Frequent - fungal dermatitis Infrequent - conjunctivitis, dry eyes, tinnitus, blepharitis, cataract, photophobia Rare - eye hemorrhage, visual field defect, keratitis, keratoconjunctivitis Urogenital System Infrequent - impotence, abnormal ejaculation, amenorrhea, hematuria, menorrhagia, female lactation, polyuria, urinary retention metrorrhagia, male sexual dysfunction, anorgasmia, glycosuria Rare - gynecomastia, vaginal hemorrhage, nocturia, oliguria, female sexual dysfunction, uterine hemorrhage BIPOLAR DISORDER Acute Treatment of Manic or Mixed Episodes Adverse Reactions Associated with Discontinuation of Treatment in Short Term, Placebo-Controlled Trials Approximately 6.5% (18/279) of ziprasidone-treated patients in short-term, placebo-controlled studies discontinued treatment due to an adverse reaction, compared with about 3.7% (5/136) on placebo. The most common reactions associated with dropout in the ziprasidone-treated patients were akathisia, anxiety, de ued treatment due to an adverse reaction, compared with about 3.7% (5/136) on placebo. The most common reactions associated with dropout in the ziprasidone-treated patients were akathisia, anxiety, depression, dizziness, dystonia, rash and vomiting, with 2 dropouts for each of these reactions among ziprasidone patients (1%) compared to one placebo patient each for dystonia and rash (1%) and no placebo patients for the remaining adverse reactions. Adverse Reactions Occurring at an Incidence of 2% or More Among Ziprasidone-Treated Patients in Short-Term, Oral, Placebo-Controlled Trials Table 12 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred during acute therapy (up to 3 weeks) in patients with bipolar mania, including only those reactions that occurred in 2% or more of patients treated with ziprasidone and for which the incidence in patients treated with ziprasidone was greater than the incidence in placebo-treated patients. Table 12: Treatment-Emergent Adverse Reactions Incidence in Short-Term Oral Placebo-Controlled Trials – Manic and Mixed Episodes Associated with Bipolar Disorder Body System/Adverse Reaction Percent . Table 12: Treatment-Emergent Adverse Reactions Incidence in Short-Term Oral Placebo-Controlled Trials – Manic and Mixed Episodes Associated with Bipolar Disorder Body System/Adverse Reaction Percentage of Patients Reporting Reaction Ziprasidone (N=279) Placebo (N=136) Body as a Whole Headache 18 17 Asthenia 6 2 Accidental Injury 4 1 Cardiovascular Hypertension 3 2 Digestive Nausea 10 7 Diarrhea 5 4 Dry Mouth 5 4 Vomiting 5 2 Increased Salivation 4 0 Tongue Edema 3 1 Dysphagia 2 0 Musculoskeletal Myalgia 2 0 Nervous Somnolence 31 12 Extrapyramidal Symptoms* 31 12 Dizziness** 16 7 Akathisia 10 5 Anxiety 5 4 Hypesthesia 2 1 Speech Disorder 2 0 Respiratory Pharyngitis 3 1 Dyspnea 2 1 Skin and Appendages Fungal Dermatitis 2 1 Special Senses Abnormal Vision 6 3 *Extrapyramidal Symptoms includes the following adverse reaction terms: extrapyramidal syndrome, hypertonia, dystonia, dyskinesia, hypokinesia, tremor, paralysis and twitching. None of these adverse reactions occurred individually at an incidence greater than 10% in bipolar mania trials. **Dizziness includes the adverse reaction terms dizziness and lightheadedness. Explorations for interactions on the basis of gender did not rev t an incidence greater than 10% in bipolar mania trials. **Dizziness includes the adverse reaction terms dizziness and lightheadedness. Explorations for interactions on the basis of gender did not reveal any clinically meaningful differences in the adverse reaction occurrence on the basis of this demographic factor. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of ziprasidone hydrochloride. 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. Adverse reaction reports not listed above that have been received since market introduction include rare occurrences of the following : Cardiac Disorders: Tachycardia, torsade de pointes (in the presence of multiple confounding factors), [see Warnings and Precautions ( 5.3 )]; Digestive System Disorders: Swollen Tongue; Reproductive System and Breast Disorders: Galactorrhea, priapism; Nervous System Disorders: Facial Droop, neuroleptic malignant syndrome, serotonin syndrome (alone or in combination with serotonergic medicinal products), nd Breast Disorders: Galactorrhea, priapism; Nervous System Disorders: Facial Droop, neuroleptic malignant syndrome, serotonin syndrome (alone or in combination with serotonergic medicinal products), tardive dyskinesia; Psychiatric Disorders: Insomnia, mania/hypomania; Skin and subcutaneous Tissue Disorders: Allergic reaction (such as allergic dermatitis, angioedema, orofacial edema, urticaria), rash, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS); Urogenital System Disorders: Enuresis, urinary incontinence; Vascular Disorders: Postural hypotension, syncope. INDICATIONS AND USAGE Verapamil Hydrochloride Tablets are indicated for the treatment of the following: Angina 1. Angina at rest including: – Vasospastic (Prinzmetal’s variant) angina – Unstable (crescendo, pre-infarction) angina 2. Chronic stable angina (classic effort-associated angina) Arrhythmias 1. In association with digitalis for the control of ventricular rate at rest and during stress in patients with chronic atrial flutter and/or atrial fibrillation (see WARNINGS; Accessory bypass tract ) 2. Prophylaxis of repetitive paroxysmal supraventricular tachycardia Essential hypertension: Verapamil is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes, including this drug. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many p t of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute oke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy. WARNINGS Heart failure: Verapamil has a negative inotropic effect, which in most patients is compensated by its afterload reduction (decreased systemic vascular resistance) uide selection of therapy. WARNINGS Heart failure: Verapamil has a negative inotropic effect, which in most patients is compensated by its afterload reduction (decreased systemic vascular resistance) properties without a net impairment of ventricular performance. In clinical experience with 4,954 patients, 87 (1.8%) developed congestive heart failure or pulmonary edema. Verapamil should be avoided in patients with severe left ventricular dysfunction (e.g., ejection fraction less than 30%) or moderate to severe symptoms of cardiac failure and in patients with any degree of ventricular dysfunction if they are receiving a beta-adrenergic blocker (see PRECAUTIONS, Drug Interactions ). Patients with milder ventricular dysfunction should, if possible, be controlled with optimum doses of digitalis and/or diuretics before verapamil treatment. ( Note interactions with digoxin under PRECAUTIONS .) Hypotension: Occasionally, the pharmacologic action of verapamil may produce a decrease in blood pressure below normal levels, which may result in dizziness or symptomatic hypotension. The incidence of hypotension observed in 4,954 patients enrolled in clinical trials was 2.5%. In hypertensive pati essure below normal levels, which may result in dizziness or symptomatic hypotension. The incidence of hypotension observed in 4,954 patients enrolled in clinical trials was 2.5%. In hypertensive patients, decreases in blood pressure below normal are unusual. Tilt-table testing (60 degrees) was not able to induce orthostatic hypotension. Elevated liver enzymes: Elevations of transaminases with and without concomitant elevations in alkaline phosphatase and bilirubin have been reported. Such elevations have sometimes been transient and may disappear even with continued verapamil treatment. Several cases of hepatocellular injury related to verapamil have been proven by rechallenge; half of these had clinical symptoms (malaise, fever, and/or right upper quadrant pain), in addition to elevation of SGOT, SGPT, and alkaline phosphatase. Periodic monitoring of liver function in patients receiving verapamil is therefore prudent. Accessory bypass tract (Wolff-Parkinson-White or Lown-Ganong-Levine): Some patients with paroxysmal and/or chronic atrial fibrillation or atrial flutter and a coexisting accessory AV pathway have developed increased antegrade conduction across the accessory pathway e): Some patients with paroxysmal and/or chronic atrial fibrillation or atrial flutter and a coexisting accessory AV pathway have developed increased antegrade conduction across the accessory pathway bypassing the AV node, producing a very rapid ventricular response or ventricular fibrillation after receiving intravenous verapamil (or digitalis). Although a risk of this occurring with oral verapamil has not been established, such patients receiving oral verapamil may be at risk and its use in these patients is contraindicated (see CONTRAINDICATIONS ). Treatment is usually DC-cardioversion. Cardioversion has been used safely and effectively after oral verapamil hydrochloride. Atrioventricular block: The effect of verapamil on AV conduction and the SA node may cause asymptomatic first-degree AV block and transient bradycardia, sometimes accompanied by nodal escape rhythms. PR-interval prolongation is correlated with verapamil plasma concentrations especially during the early titration phase of therapy. Higher degrees of AV block, however, were infrequently (0.8%) observed. Marked first-degree block or progressive development to second-or third-degree AV block requires a reduction in ase of therapy. Higher degrees of AV block, however, were infrequently (0.8%) observed. Marked first-degree block or progressive development to second-or third-degree AV block requires a reduction in dosage or, in rare instances, discontinuation of verapamil hydrochloride and institution of appropriate therapy, depending on the clinical situation. Patients with hypertrophic cardiomyopathy (IHSS): In 120 patients with hypertrophic cardiomyopathy (most of them refractory or intolerant to propranolol) who received therapy with verapamil at doses up to 720 mg/day, a variety of serious adverse effects were seen. Three patients died in pulmonary edema; all had severe left ventricular outflow obstruction and a past history of left ventricular dysfunction. Eight other patients had pulmonary edema and/or severe hypotension; abnormally high (greater than 20 mm Hg) pulmonary wedge pressure and a marked left ventricular outflow obstruction were present in most of these patients. Concomitant administration of quinidine (see PRECAUTIONS, Drug interactions ) preceded the severe hypotension in 3 of the 8 patients (2 of whom developed pulmonary edema). Sinus bradycardia occurred in 11% of the patie stration of quinidine (see PRECAUTIONS, Drug interactions ) preceded the severe hypotension in 3 of the 8 patients (2 of whom developed pulmonary edema). Sinus bradycardia occurred in 11% of the patients, second-degree AV block in 4%, and sinus arrest in 2%. It must be appreciated that this group of patients had a serious disease with a high mortality rate. Most adverse effects responded well to dose reduction, and only rarely did verapamil use have to be discontinued. DOSAGE AND ADMINISTRATION The dose of verapamil must be individualized by titration. The usefulness and safety of dosages exceeding 480 mg/day have not been established; therefore, this daily dosage should not be exceeded. Since the half-life of verapamil increases during chronic dosing, maximum response may be delayed. Angina: Clinical trials show that the usual dose is 80 mg to 120 mg three times a day. However, 40 mg three times a day may be warranted in patients who may have an increased response to verapamil (e.g., decreased hepatic function, elderly, etc.). Upward titration should be based on therapeutic efficacy and safety evaluated approximately eight hours after dosing. Dosage may be increased at daily (e.g. decreased hepatic function, elderly, etc.). Upward titration should be based on therapeutic efficacy and safety evaluated approximately eight hours after dosing. Dosage may be increased at daily (e.g., patients with unstable angina) or weekly intervals until optimum clinical response is obtained. Arrhythmias: The dosage in digitalized patients with chronic atrial fibrillation (see PRECAUTIONS ) ranges from 240 to 320 mg/day in divided (three times a day or four times a day) doses. The dosage for prophylaxis of PSVT (non-digitalized patients) ranges from 240 to 480 mg/day in divided (three times a day or four times a day) doses. In general, maximum effects for any given dosage will be apparent during the first 48 hours of therapy. Essential hypertension: Dose should be individualized by titration. The usual initial monotherapy dose in clinical trials was 80 mg three times a day (240 mg/day). Daily dosages of 360 and 480 mg have been used but there is no evidence that dosages beyond 360 mg provided added effect. Consideration should be given to beginning titration at 40 mg three times per day in patients who might respond to lower doses, such as the elderly or people of small stature mg provided added effect. Consideration should be given to beginning titration at 40 mg three times per day in patients who might respond to lower doses, such as the elderly or people of small stature. The antihypertensive effects of verapamil are evident within the first week of therapy. Upward titration should be based on therapeutic efficacy, assessed at the end of the dosing interval. ADVERSE REACTIONS Serious adverse reactions are uncommon when verapamil hydrochloride therapy is initiated with upward dose titration within the recommended single and total daily dose. See WARNINGS for discussion of heart failure, hypotension, elevated liver enzymes, AV block, and rapid ventricular response. Reversible (upon discontinuation of verapamil) non-obstructive, paralytic ileus has been infrequently reported in association with the use of verapamil. The following reactions to orally administered verapamil occurred at rates greater than 1% or occurred at lower rates but appeared clearly drug-related in clinical trials in 4,954 patients: Constipation 7.3% Dyspnea 1.4% Dizziness 3.3% Bradycardia (HR<50/min) 1.4% Nausea 2.7% AV block total (1°, 2°, 3°) 1.2 % 1.2% Hypotension 2.5% 2° and 3° 0 related in clinical trials in 4,954 patients: Constipation 7.3% Dyspnea 1.4% Dizziness 3.3% Bradycardia (HR<50/min) 1.4% Nausea 2.7% AV block total (1°, 2°, 3°) 1.2 % 1.2% Hypotension 2.5% 2° and 3° 0.8% Headache 2.2% Rash 1.2% Edema 1.9% Flushing 0.6% CHF,Pulmonary edema 1.8% Fatigue 1.7% Elevated liver enzymes (see WARNINGS ) In clinical trials related to the control of ventricular response in digitalized patients who had atrial fibrillation or flutter, ventricular rates below 50 at rest occurred in 15% of patients and asymptomatic hypotension occurred in 5% of patients. The following reactions, reported in 1% or less of patients, occurred under conditions (open trials, marketing experience) where a causal relationship is uncertain; they are listed to alert the physician to a possible relationship: Cardiovascular: angina pectoris, atrioventricular dissociation, chest pain, claudication, myocardial infarction, palpitations, purpura (vasculitis), syncope. Digestive system: diarrhea, dry mouth, gastrointestinal distress, gingival hyperplasia. Hemic and lymphatic: ecchymosis or bruising. Nervous system: cerebrovascular accident, confusion, equilibrium disorders, insomnia, muscle cram y mouth, gastrointestinal distress, gingival hyperplasia. Hemic and lymphatic: ecchymosis or bruising. Nervous system: cerebrovascular accident, confusion, equilibrium disorders, insomnia, muscle cramps, paresthesia, psychotic symptoms, shakiness, somnolence, extrapyramidal symptoms. Skin: arthralgia and rash, exanthema, hair loss, hyperkeratosis, macules, sweating, urticaria, Stevens-Johnson syndrome, erythema multiforme. Special senses: blurred vision, tinnitus. Urogenital: gynecomastia, galactorrhea/hyperprolactinemia, increased urination, spotty menstruation, impotence. Treatment of acute cardiovascular adverse reactions: The frequency of cardiovascular adverse reactions that require therapy is rare; hence, experience with their treatment is limited. Whenever severe hypotension or complete AV block occurs following oral administration of verapamil, the appropriate emergency measures should be applied immediately; e.g., intravenously administered norepinephrine bitartrate, atropine sulfate, isoproterenol hydrochloride (all in the usual doses), or calcium gluconate (10% solution). In patients with hypertrophic cardiomyopathy (IHSS), alpha-adrenergic agents (phenylephrine hydrochl sulfate, isoproterenol hydrochloride (all in the usual doses), or calcium gluconate (10% solution). In patients with hypertrophic cardiomyopathy (IHSS), alpha-adrenergic agents (phenylephrine hydrochloride, metaraminol bitartrate, or methoxamine hydrochloride) should be used to maintain blood pressure, and isoproterenol and norepinephrine should be avoided. If further support is necessary, dopamine hydrochloride or dobutamine hydrochloride may be administered. Actual treatment and dosage should depend on the severity of the clinical situation and the judgment and experience of the treating physician. To report SUSPECTED ADVERSE REACTIONS, contact Actavis at 1-800-272-5525 or FDA at 1-800-FDA-1088 or www . fd a.gov/medwatch. Uses For the temporary relief of minor aches and pains of the muscle joints associated with • strains • sprains • bruises • arthritis Purposes Topical Analgesic Topical Analgesic Warnings For external use only. Do not apply to wounds or to damaged or irritated skin. When using this product • you may experience a burning sensation which is normal and related to the way the product works. With regular use, this sensation generally diminishes. • avoid contact with eyes. Do not get it on mucous membranes, into eyes, or on contact lenses. If this occurs, rinse the affected area thoroughly with water. • do not apply immediately before or after activities such as bathing, swimming, sun bathing, or strenuous exercise • do not apply heat to the treated areas immediately before or after use • do not tightly wrap or bandage the treated area • avoid inhaling airborne material from dried residue. This can result in coughing, sneezing, tearing, throat or respiratory irritation. Stop use and ask a doctor • conditions worsens, or if symptoms persist for more than 7 days or clear up and occur again within a few days • blisters occurs • difficulty breathing or swallowing occurs • severe burning pers ctor • conditions worsens, or if symptoms persist for more than 7 days or clear up and occur again within a few days • blisters occurs • difficulty breathing or swallowing occurs • severe burning persists Directions • for persons under 18 years of age, ask a doctor before using • apply a thin film of cream to the affected area and gently rub in until fully absorbed • for optimum relief, apply 3 to 4 times daily • best results typically occur after 2 to 4 weeks of continuous use • unless treating hands, wash hands thoroughly with soap and water immediately after use • see package insert for more information Keep Out of Reach of Children Keep Out of Reach of Children If swallowed, get medical help or contact a Poison Control Do not begin use of any hydrocortisone product unless you've asked a doctor. Do not use in the genital area if you have a vaginal discharge. Consult a doctor. Do not use more than directed unless told to do so by a doctor. Purpose Anti-itch Insect bite relief spray Warnings For external use only. Uses Temporarily relieves itching associated with minor skin irritations, inflammation and rashes due to: eczema, psoriasis, insect bites, detergents, jewelry, cosmetics, soaps, seborrheic dermatitis and more. Directions Apply to affected area not more than 3 to 4 times daily. Children under 2 years, do not use; ask a doctor. Stop use and ask a doctor if condition worsens or if symptoms persist for more than 7 days symptoms last more than 7 days or clear up and occur again within a few days Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center right away. INDICATIONS AND USAGE Hydrocortisone Tablets, USP are indicated in the following conditions: 1. Endocrine Disorders Primary or secondary adrenocortical insufficiency (hydrocortisone or cortisone is the first choice; synthetic analogs may be used in conjunction with mineralocorticoids where applicable; in infancy mineralocorticoid supplementation is of particular importance) Congenital adrenal hyperplasia Nonsuppurative thyroiditis Hypercalcemia associated with cancer 2. Rheumatic Disorders As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in: Psoriatic arthritis Rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy) Ankylosing spondylitis Acute and subacute bursitis Acute nonspecific tenosynovitis Acute gouty arthritis Post-traumatic osteoarthritis Synovitis or osteoarthritis Epicondylitis 3. Collagen Diseases During an exacerbation or as maintenance therapy in selected cases of: Systemic lupus erythematosus Acute rheumatic carditis Systemic dermatomyositis (polymyositis) 4. Dermatologic Diseases Pemphigus Bullous dermatitis herpetiformis Severe erythema mu selected cases of: Systemic lupus erythematosus Acute rheumatic carditis Systemic dermatomyositis (polymyositis) 4. Dermatologic Diseases Pemphigus Bullous dermatitis herpetiformis Severe erythema multiforme (Stevens-Johnson syndrome) Exfoliative dermatitis Mycosis fungoides Severe psoriasis Severe seborrheic dermatitis 5. Allergic States Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment: Seasonal or perennial allergic rhinitis Bronchial asthma Contact dermatitis Atopic dermatitis Serum sickness Drug hypersensitivity reactions 6. Ophthalmic Diseases Severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa, such as: Allergic conjunctivitis Keratitis Allergic corneal marginal ulcers Herpes zoster ophthalmicus Iritis and iridocyclitis Chorioretinitis Anterior segment inflammation Diffuse posterior uveitis and choroiditis Optic neuritis Sympathetic ophthalmia 7. Respiratory Disease Symptomatic sarcoidosis Loeffler’s syndrome not manageable by other means Berylliosis Fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculosis chemotherapy A tic sarcoidosis Loeffler’s syndrome not manageable by other means Berylliosis Fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculosis chemotherapy Aspiration pneumonitis 8. Hematologic Disorder Idiopathic thrombocytopenic purpura in adults Secondary thrombocytopenia in adults Acquired (autoimmune) hemolytic anemia Erythroblastopenia (RBC anemia) Congenital (erythroid) hypoplastic anemia 9. Neoplastic Diseases For palliative management of: Leukemias and lymphomas in adults Acute leukemia of childhood 10. Edematous States To induce a diuresis or remission of proteinuria in the nephrotic syndrome, without uremia, of the idiopathic type or that due to lupus erythematosus. 11. Gastrointestinal Diseases To tide the patient over a critical period of the disease in: Ulcerative colitis Regional enteritis 12. Miscellaneous Tuberculous meningitis with subarachnoid block or impending block when used concurrently with appropriate antituberculous chemotherapy Trichinosis with neurologic or myocardial involvement WARNINGS In patients on corticosteroid therapy subjected to unusual stress, increased dosage of rapidly acting corticosteroids before,