SILICEA y be slower than with the 0.5% or 0.75% solutions. 0.5%— provides motor blockade for caudal, epidural, or nerve block, but muscle relaxation may be inadequate for operations in which complete muscle relaxation is essential. 0.75%—produces complete motor block. Most useful for epidural block in abdominal operations requiring complete muscle relaxation, and for retrobulbar anesthesia. Not for obstetrical anesthesia. The duration of anesthesia with MARCAINE is such that for most indications, a single dose is sufficient. Maximum dosage limit must be individualized in each case after evaluating the size and physical status of the patient, as well as the usual rate of systemic absorption from a particular injection site. Most experience to date is with single doses of MARCAINE up to 225 mg with epinephrine 1:200,000 and 175 mg without epinephrine; more or less drug may be used depending on individualization of each case. These doses may be repeated up to once every three hours. In clinical studies to date, total daily doses have been up to 400 mg. Until further experience is gained, this dose should not be exceeded in 24 hours. The duration of anesthetic effect may be prolonged by the ad tudies to date, total daily doses have been up to 400 mg. Until further experience is gained, this dose should not be exceeded in 24 hours. The duration of anesthetic effect may be prolonged by the addition of epinephrine. The dosages in Table 1 have generally proved satisfactory and are recommended as a guide for use in the average adult. These dosages should be reduced for elderly or debilitated patients. Until further experience is gained, MARCAINE is not recommended for pediatric patients younger than 12 years. MARCAINE is contraindicated for obstetrical paracervical blocks, and is not recommended for intravenous regional anesthesia (Bier Block). Use in Epidural Anesthesia: During epidural administration of MARCAINE, 0.5% and 0.75% solutions should be administered in incremental doses of 3 mL to 5 mL with sufficient time between doses to detect toxic manifestations of unintentional intravascular or intrathecal injection. In obstetrics, only the 0.5% and 0.25% concentrations should be used; incremental doses of 3 mL to 5 mL of the 0.5% solution not exceeding 50 mg to 100 mg at any dosing interval are recommended. Repeat doses should be preceded by a test dose containing epinephr be used; incremental doses of 3 mL to 5 mL of the 0.5% solution not exceeding 50 mg to 100 mg at any dosing interval are recommended. Repeat doses should be preceded by a test dose containing epinephrine if not contraindicated. Use only the single-dose ampuls and single-dose vials for caudal or epidural anesthesia; the multiple-dose vials contain a preservative and therefore should not be used for these procedures. Test Dose for Caudal and Lumbar Epidural Blocks: The Test Dose of MARCAINE (0.5% bupivacaine with 1:200,000 epinephrine in a 3 mL ampul) is recommended for use as a test dose when clinical conditions permit prior to caudal and lumbar epidural blocks. This may serve as a warning of unintended intravascular or subarachnoid injection (See PRECAUTIONS ). The pulse rate and other signs should be monitored carefully immediately following each test dose administration to detect possible intravascular injection, and adequate time for onset of spinal block should be allotted to detect possible intrathecal injection. An intravascular or subarachnoid injection is still possible even if results of the test dose are negative. The test dose itself may produce a systemic toxic reaction t possible intrathecal injection. An intravascular or subarachnoid injection is still possible even if results of the test dose are negative. The test dose itself may produce a systemic toxic reaction, high spinal or cardiovascular effects from the epinephrine (See WARNINGS and OVERDOSAGE ). Use in Dentistry: The 0.5% concentration with epinephrine is recommended for infiltration and block injection in the maxillary and mandibular area when a longer duration of local anesthetic action is desired, such as for oral surgical procedures generally associated with significant postoperative pain. The average dose of 1.8 mL (9 mg) per injection site will usually suffice; an occasional second dose of 1.8 mL (9 mg) may be used if necessary to produce adequate anesthesia after making allowance for 2 to 10 minutes onset time (See CLINICAL PHARMACOLOGY ). The lowest effective dose should be employed and time should be allowed between injections; it is recommended that the total dose for all injection sites, spread out over a single dental sitting, should not ordinarily exceed 90 mg for a healthy adult patient (ten 1.8 mL injections of 0.5% MARCAINE with epinephrine). Injections should be made s on sites, spread out over a single dental sitting, should not ordinarily exceed 90 mg for a healthy adult patient (ten 1.8 mL injections of 0.5% MARCAINE with epinephrine). Injections should be made slowly and with frequent aspirations. Until further experience is gained, MARCAINE in dentistry is not recommended for pediatric patients younger than 12 years. Unused portions of solution not containing preservatives, i.e., those supplied in single-dose ampuls and single-dose vials, should be discarded following initial use. This product should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Solutions which are discolored or which contain particulate matter should not be administered. Table 1. Recommended Concentrations and Doses of MARCAINE 1 With continuous (intermittent) techniques, repeat doses increase the degree of motor block. The first repeat dose of 0.5% may produce complete motor block. Intercostal nerve block with 0.25% may also produce complete motor block for intra-abdominal surgery. 2 For single-dose use, not for intermittent epidural technique. Not for obstetrical anesthesia. 3 See PRECAUTIONS ve block with 0.25% may also produce complete motor block for intra-abdominal surgery. 2 For single-dose use, not for intermittent epidural technique. Not for obstetrical anesthesia. 3 See PRECAUTIONS . 4 Solutions with or without epinephrine. Type of Block Conc. Each Dose Motor Block 1 (mL) (mg) Local infiltration 0.25% 4 up to max. up to max. — Epidural 0.75% 2,4 10-20 75-150 complete 0.5% 4 10-20 50-100 moderate to complete 0.25% 4 10-20 25-50 partial to moderate Caudal 0.5% 4 15-30 75-150 moderate to complete 0.25% 4 15-30 37.5-75 moderate Peripheral nerves 0.5% 4 5 to max. 25 to max. moderate to complete 0.25% 4 5 to max. 12.5 to max. moderate to complete Retrobulbar 3 0.75% 4 2-4 15-30 complete Sympathetic 0.25% 20-50 50-125 — Dental 3 0.5% w/epi 1.8-3.6 per site 9-18 per site — Epidural 3 Test Dose 0.5% w/epi 2-3 10-15 (10-15 micrograms epinephrine) — Directions Open packet Remove pad Apply topically as needed to cleanse intended area. Discard after single use. 1.7 ADVERSE REACTIONS Adverse experiences following the administration of lidocaine are similar in nature to those observed with other amide local anesthetic agents. These adverse experiences are, in general, dose-rel IONS Adverse experiences following the administration of lidocaine are similar in nature to those observed with other amide local anesthetic agents. These adverse experiences are, in general, dose-related and may result from high plasma levels caused by excessive dosage, rapid absorption or inadvertent intravascular injection, or may result from a hypersensitivity, idiosyncrasy or diminished tolerance on the part of the patient. Serious adverse experiences are generally systemic in nature. The following types are those most commonly reported: Central nervous system: CNS manifestations are excitatory and/or depressant and may be characterized by light-headedness, nervousness, apprehension, euphoria, confusion, dizziness, drowsiness, tinnitus, blurred or double vision, vomiting, sensations of heat, cold or numbness, twitching, tremors, convulsions, unconsciousness, respiratory depression and arrest. The excitatory manifestations may be very brief or may not occur at all, in which case the first manifestation of toxicity may be drowsiness merging into unconsciousness and respiratory arrest. Drowsiness following the administration of lidocaine is usually an early sign of a high blood l e first manifestation of toxicity may be drowsiness merging into unconsciousness and respiratory arrest. Drowsiness following the administration of lidocaine is usually an early sign of a high blood level of the drug and may occur as a consequence of rapid absorption. Cardiovascular system: Cardiovascular manifestations are usually depressant and are characterized by bradycardia, hypotension, and cardiovascular collapse, which may lead to cardiac arrest. Allergic: Allergic reactions are characterized by cutaneous lesions, urticaria, edema or anaphylactoid reactions. Allergic reactions as a result of sensitivity to lidocaine are extremely rare and, if they occur, should be managed by conventional means. The detection of sensitivity by skin testing is of doubtful value. Neurologic: The incidences of adverse reactions associated with the use of local anesthetics may be related to the total dose of local anesthetic administered and are also dependent upon the particular drug used, the route of administration and the physical status of the patient. ADVERSE REACTIONS Reactions to MARCAINE are characteristic of those associated with other amide-type local anesthetics. A major cause of adv e of administration and the physical status of the patient. ADVERSE REACTIONS Reactions to MARCAINE are characteristic of those associated with other amide-type local anesthetics. A major cause of adverse reactions to this group of drugs is excessive plasma levels, which may be due to overdosage, unintentional intravascular injection, or slow metabolic degradation. The most commonly encountered acute adverse experiences which demand immediate counter-measures are related to the central nervous system and the cardiovascular system. These adverse experiences are generally dose related and due to high plasma levels which may result from overdosage, rapid absorption from the injection site, diminished tolerance, or from unintentional intravascular injection of the local anesthetic solution. In addition to systemic dose-related toxicity, unintentional subarachnoid injection of drug during the intended performance of caudal or lumbar epidural block or nerve blocks near the vertebral column (especially in the head and neck region) may result in underventilation or apnea ("Total or High Spinal"). Also, hypotension due to loss of sympathetic tone and respiratory paralysis or underventilatio especially in the head and neck region) may result in underventilation or apnea ("Total or High Spinal"). Also, hypotension due to loss of sympathetic tone and respiratory paralysis or underventilation due to cephalad extension of the motor level of anesthesia may occur. This may lead to secondary cardiac arrest if untreated. Patients over 65 years, particularly those with hypertension, may be at increased risk for experiencing the hypotensive effects of MARCAINE. Factors influencing plasma protein binding, such as acidosis, systemic diseases which alter protein production, or competition of other drugs for protein binding sites, may diminish individual tolerance. Central Nervous System Reactions: These are characterized by excitation and/or depression. Restlessness, anxiety, dizziness, tinnitus, blurred vision, or tremors may occur, possibly proceeding to convulsions. However, excitement may be transient or absent, with depression being the first manifestation of an adverse reaction. This may quickly be followed by drowsiness merging into unconsciousness and respiratory arrest. Other central nervous system effects may be nausea, vomiting, chills, and constriction of the pupils. Th This may quickly be followed by drowsiness merging into unconsciousness and respiratory arrest. Other central nervous system effects may be nausea, vomiting, chills, and constriction of the pupils. The incidence of convulsions associated with the use of local anesthetics varies with the procedure used and the total dose administered. In a survey of studies of epidural anesthesia, overt toxicity progressing to convulsions occurred in approximately 0.1% of local anesthetic administrations. Cardiovascular System Reactions: High doses or unintentional intravascular injection may lead to high plasma levels and related depression of the myocardium, decreased cardiac output, heartblock, hypotension, bradycardia, ventricular arrhythmias, including ventricular tachycardia and ventricular fibrillation, and cardiac arrest (See WARNINGS , PRECAUTIONS , and OVERDOSAGE ). Allergic: Allergic-type reactions are rare and may occur as a result of sensitivity to the local anesthetic or to other formulation ingredients, such as the antimicrobial preservative methylparaben contained in multiple-dose vials or sulfites in epinephrine-containing solutions. These reactions are characterized by signs such a on ingredients, such as the antimicrobial preservative methylparaben contained in multiple-dose vials or sulfites in epinephrine-containing solutions. These reactions are characterized by signs such as urticaria, pruritus, erythema, angioneurotic edema (including laryngeal edema), tachycardia, sneezing, nausea, vomiting, dizziness, syncope, excessive sweating, elevated temperature, and possibly, anaphylactoid-like symptomatology (including severe hypotension). Cross sensitivity among members of the amide-type local anesthetic group has been reported. The usefulness of screening for sensitivity has not been definitely established. Neurologic: The incidences of adverse neurologic reactions associated with the use of local anesthetics may be related to the total dose of local anesthetic administered and are also dependent upon the particular drug used, the route of administration, and the physical status of the patient. Many of these effects may be related to local anesthetic techniques, with or without a contribution from the drug. In the practice of caudal or lumbar epidural block, occasional unintentional penetration of the subarachnoid space by the catheter or needle may occur. Su with or without a contribution from the drug. In the practice of caudal or lumbar epidural block, occasional unintentional penetration of the subarachnoid space by the catheter or needle may occur. Subsequent adverse effects may depend partially on the amount of drug administered intrathecally and the physiological and physical effects of a dural puncture. A high spinal is characterized by paralysis of the legs, loss of consciousness, respiratory paralysis, and bradycardia. Neurologic effects following epidural or caudal anesthesia may include spinal block of varying magnitude (including high or total spinal block); hypotension secondary to spinal block; urinary retention; fecal and urinary incontinence; loss of perineal sensation and sexual function; persistent anesthesia, paresthesia, weakness, paralysis of the lower extremities and loss of sphincter control all of which may have slow, incomplete, or no recovery; headache; backache; septic meningitis; meningismus; slowing of labor; increased incidence of forceps delivery; and cranial nerve palsies due to traction on nerves from loss of cerebrospinal fluid. Neurologic effects following other procedures or routes of administration ncreased incidence of forceps delivery; and cranial nerve palsies due to traction on nerves from loss of cerebrospinal fluid. Neurologic effects following other procedures or routes of administration may include persistent anesthesia, paresthesia, weakness, paralysis, all of which may have slow, incomplete, or no recovery. • Keep out from reach of children . If swallowed, get medical help or contact a Poison Control Center right away. Uses helps prevent sunburn if used as directed with other sun protection measures (see Directions), decreases the risk of skin cancer and early skin aging caused by the sun Active Ingredient Purpose Zinc Oxide 15%............Sunscreen For external use only Do not use on damaged or broken skin When using this product keep out of eyes. Rinse with water to remove Stop use and ask doctor if rash occurs Directions Shake well before use Apply liberally 15 minutes before sun exposure Reapply at least every 2 hours Use a water-resistant sunscreen if swimming or sweating. Sun Protection Measures Spending time in the sun increases your risk of skin cancer and early skin aging. To decrease this risk, regularly use a sunscreen with a Broad Spectrum SPF value of 15 or higher and other sun protection measures including: Limit time in the sun, especially from 10 a.m. - 2 p.m. Wear long-sleeved shirts, pants, hats, and sunglasses. Children under 6 months of age: Ask a doctor. Keep out or reach of children. If swallowed, get medical help or contact a Poison Control Center right away. INDICATIONS AND USAGE INDICATIONS AND USAGE: Take an adequate amount to spread on face and massage with lifting bound vibrator for 2-3 minutes. When used with 3D lifting bound vibrator, it vibrates 9,000 times per minute which helps relieving and relaxing facial muscles. PURPOSE PURPOSE: Skin Protectant WARNINGS Warnings: 1. In case of having following symptoms after using this, you're advised to stop using it immediately. If you keep using it, the symptoms will get worse and need to consult a dermatologist. 1) In case of having problems such as red rash, swollenness, itching, stimulation during usage. 2) In case of having the same symptoms above on the part you put this product on by direct sunlight. 2. You are banned to use it on the part where you have a scar, eczema, or dermatitis. 3. In case of getting it into your eyes, you have to wash it immediately. DOSAGE AND ADMINISTRATION DOSAGE AND ADMINISTRATION: Take an adequate amount of this product. KEEP OUT OF REACH OF CHILDREN Keep out of reach of children: Keep out of reach of babies and children Uses Helps treat and prevent diaper rash Protects chafed skin due to diaper rash Helps seal out wetness Purpose Skin Protectant Warnings For external use only When using this product: keep out of eyes. Rinse with water to remove Stop use and ask a doctor if: condition worsens. If 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 Directions Apply an even layer for everyday protection and when a rash is present Stop use and ask a doctor if: condition worsens. If 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 Use For hand sanitizing to decrease bacteria on the skin Recommended for repeated use Purpose Antimicrobial Warnings For external use only. When using this product avoid contact with eyes. In case of eye contact, flush eyes with water. Stop use and a ask doctor if irritation or redness develops, or if condition persists for more than 72 hours. Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center right away. Directions Pump a small amount of liquid into palm of hand. Rub thoroughly over all surfaces of both hands. Rub hands together briskly until dry. Stop use and a ask doctor if irritation or redness develops, or if condition persists for more than 72 hours. Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center right away. Uses temporarily relieves these symptoms due to hay fever or other upper respiratory allergies: • runny nose • itchy, watery eyes • sneezing • itching of the nose or throat Purpose Antihistamine Warnings Do not use if you have ever had an allergic reaction to this product or any of its ingredients Ask a doctor before use if you have liver or kidney disease. Your doctor should determine if you need a different dose. When using this product do not take more than directed. Taking more than directed may cause drowsiness. Stop use and ask a doctor if an allergic reaction to this product occurs. Seek medical help right away. 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 adults and children 6 years and over 1 tablet daily; not more than 1 tablet in 24 hours children under 6 years of age ask a doctor consumers with liver or kidney disease ask a doctor Ask a doctor before use if you have liver or kidney disease. Your doctor should determine if you need a different dose. Stop use and ask a doctor if an allergic reaction to this y disease ask a doctor Ask a doctor before use if you have liver or kidney disease. Your doctor should determine if you need a different dose. Stop use and ask a doctor if an allergic reaction to this product occurs. Seek medical help right away. 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 cures most athlete's foot (tinea pedis), ringworm (tinea corporis) and jock itch (tinea cruris) can prevent recurrence of most athlete's foot relieves symptoms of athlete's foot, including itching, burning, cracking and chafing associated with jock itch Purpose Antifungal Warnings For external use only. Flammable: Do not use while smoking or near heat or flame. Do not puncture or incinerate. Contents under pressure. Do not store at temperature above 120ºF. Intentional misuse by deliberately concentrating and inhaling contents cans be harmful or fatal. ​When using this product do not get into eyes or mouth use only as directed ​Stop use and ask a doctor if irritation occurs no improvement within 4 weeks for athlete's foot, ringworm and 2 weeks for jock itch ​Do not use on children under 2 years of age unless directed by a doctor. Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center right away. Directions wash affected area and dry thoroughly shake can well and spray a thin layer over affected area twice daily (morning and night) or as directed by a doctor supervise children in the use of this product for athlete's foot: pay special at hly shake can well and spray a thin layer over affected area twice daily (morning and night) or as directed by a doctor supervise children in the use of this product for athlete's foot: pay special attention to spaces between the toes; wear well-fitting, ventilated shoes and change shoes and socks at least once daily use daily for 4 weeks for athletes foot, ringworm and for jock itch use daily for 2 weeks if conditions persist, consult a doctor to prevent athlete's foot, apply daily once or twice daily (morning and/or night) this product is not effective on the scalps or nails in case of clogging, clear nozzle under running water ​Stop use and ask a doctor if irritation occurs no improvement within 4 weeks for athlete's foot, ringworm and 2 weeks for jock itch Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center right away. Use controls symptoms of diarrhea, including Travelers' Diarrhea. Purpose Anti-diarrheal Warnings Allergy alert: Do not use if you have ever had a rash or other allergic reaction to loperamide HCl. Heart alert: Taking more than directed can cause serious heart problems or death. Do not use if you have bloody or black stool in children under 12 years of age Ask a doctor before use if you have fever mucus in the stool a history of liver disease Ask a doctor or pharmacist before use if you are taking antibiotics. When using this product tiredness, drowsiness, or dizziness may occur. Be careful when driving or operating machinery. Stop use and ask a doctor if symptoms get worse diarrhea lasts for more than 2 days you get abdominal swelling or bulging. These may 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. Directions drink plenty of clear fluids to help prevent dehydration caused by diarrhea not for use in children under 12 years of age adults and children 12 years of age and over: 2 softgels after the first loose st nk plenty of clear fluids to help prevent dehydration caused by diarrhea not for use in children under 12 years of age adults and children 12 years of age and over: 2 softgels after the first loose stool; 1 softgel after each subsequent loose stool; but no more than 4 softgels in 24 hours Ask a doctor before use if you have fever mucus in the stool a history of liver disease Stop use and ask a doctor if symptoms get worse diarrhea lasts for more than 2 days you get abdominal swelling or bulging. These may 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. apply proper amount to the skin and make the foam and rub, wash out skin conditioning ・Stop using the product when you have skin problems or the product disagrees with your skin ・Stop using the product immediately and consult a dermatologist if you have redness, swelling, itching or irritation on the skin while or after using the product. ・If the product gets into the eyes, don't rub but rinse with water. ・Don't place the product in any place where it will be subjected to extremely high or low temperatures or direct sunlight. for external use only keep out of reach of the children 1 INDICATIONS AND USAGE Valproic Acid Capsules, USP are an anti-epileptic drug indicated for: Monotherapy and adjunctive therapy of complex partial seizures; sole and adjunctive therapy of simple and complex absence seizures; adjunctive therapy in patients with multiple seizure types that include absence seizures ( 1 ) 1.1 Epilepsy Valproic Acid Capsules, USP are indicated as monotherapy and adjunctive therapy in the treatment of patients with complex partial seizures that occur either in isolation or in association with other types of seizures. Valproic Acid Capsules, USP are indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and adjunctively in patients with multiple seizure types which include absence seizures. Simple absence is defined as very brief clouding of the sensorium or loss of consciousness accompanied by certain generalized epileptic discharges without other detectable clinical signs. Complex absence is the term used when other signs are also present. See Warnings and Precaution (5.1) for statement regarding fatal hepatic dysfunction. 1.2 Important Limitations Because of the risk to the fetus of decreased IQ, neur when other signs are also present. See Warnings and Precaution (5.1) for statement regarding fatal hepatic dysfunction. 1.2 Important Limitations Because of the risk to the fetus of decreased IQ, neural tube defects, and other major congenital malformations, which may occur very early in pregnancy, valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition [see Warnings and Precautions (5.2 , 5.3 , 5.4) , Use in Specific Populations (8.1) , and Patient Counseling Information (17.3) ]. 2 DOSAGE AND ADMINISTRATION Valproic acid capsules are intended for oral administration. ( 2.1 ) Simple and Complex Absence Seizures: Start at 10 to 15 mg/kg/day, increasing at 1 week intervals by 5 to 10 mg/kg/week until seizure control or limiting side effects ( 2.1 ) Safety of doses above 60 mg/kg/day is not established ( 2.1 , 2.2 ) 2.1 Epilepsy Valproic acid capsules are intended for oral administration. Valproic acid capsules should be swallowed whole without chewing to avoid local irritation of the mouth and throat. Patients should be informed to take valproic acid capsules every day as prescribed. If a dose cid capsules should be swallowed whole without chewing to avoid local irritation of the mouth and throat. Patients should be informed to take valproic acid capsules every day as prescribed. If a dose is missed it should be taken as soon as possible, unless it is almost time for the next dose. If a dose is skipped, the patient should not double the next dose. Valproic acid capsules are indicated as monotherapy and adjunctive therapy in complex partial seizures in adults and pediatric patients down to the age of 10 years, and in simple and complex absence seizures. As the valproic acid capsules dosage is titrated upward, concentrations of clonazepam, diazepam, ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may be affected [see Drug Interactions (7.2) ] . Complex Partial Seizures For adults and children 10 years of age or older. Monotherapy (Initial Therapy) Valproic acid capsules have not been systematically studied as initial therapy. Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses uld initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of improved seizure control with higher doses should be weighed against the possibility of a greater incidence of adverse reactions. Conversion to Monotherapy Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50-100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction may be started at initiation of valproic acid capsules therapy, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the concomitant AED can be highly variable, and patients should be monitored closely during this period for increased seizure frequency. Adjunctive Therapy Valproic acid capsules may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured ptimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total daily dose exceeds 250 mg, it should be given in divided doses. In a study of adjunctive therapy for complex partial seizures in which patients were receiving either carbamazepine or phenytoin in addition to divalproex sodium tablets, no adjustment of carbamazepine or phenytoin dosage was needed [see Clinical Studies (14) ] . However, since valproate may interact with these or other concurrently administered AEDs as well as other drugs, periodic plasma concentration determinations of concomitant AEDs are recommended during the early course of therapy [see Drug Interactions (7) ] . Simple and Complex Absence Seizures The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10 mg/kg/day until seizures are controlled or side effects preclude further . Simple and Complex Absence Seizures The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10 mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given in divided doses. A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect. However, therapeutic valproate serum concentration for most patients with absence seizures is considered to range from 50 to 100 mcg/mL. Some patients may be controlled with lower or higher serum concentrations [see Clinical Pharmacology (12.3) ]. As the valproic acid capsules dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin may be affected [see Drug Interactions (7.2) ] . Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. The following Table is a guide for the initial daily dose of valproic acid capsules (15 mg/kg/day): Table ong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. The following Table is a guide for the initial daily dose of valproic acid capsules (15 mg/kg/day): Table 1. Initial Daily Dose Weight Total Daily Dose (mg) Number of Capsules (Kg) (Lb) Dose 1 Dose 2 Dose 3 10 - 24.9 22 - 54.9 250 0 0 1 25 - 39.9 55 - 87.9 500 1 0 1 40 - 59.9 88 - 131.9 750 1 1 1 60 - 74.9 132 - 164.9 1,000 1 1 2 75 - 89.9 165 - 197.9 1,250 2 1 2 2.2 General Dosing Advice Dosing in Elderly Patients Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the elderly, the starting dose should be reduced in these patients. Dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of both tolerability and clinical response [see Warnings and Precautions (5.15) , Use in Specific Populations (8.5) and Clinical Pharmaco The ultimate therapeutic dose should be achieved on the basis of both tolerability and clinical response [see Warnings and Precautions (5.15) , Use in Specific Populations (8.5) and Clinical Pharmacology (12.3) ] . Dose-Related Adverse Reactions The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-related. The probability of thrombocytopenia appears to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see Warnings and Precautions (5.9) ] . The benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse reactions. G.I. Irritation Patients who experience G.I. irritation may benefit from administration of the drug with food or by slowly building up the dose from an initial low level. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Hepatic failure (5.1) Birth defects (5.2) Decreased IQ following in utero exposure (5.3) Pancreatitis (5.5) Thrombocytopenia (5.9) Hyperammonemic encephalopathy (5.10 , 5.11) Multi-organ hypersensitivity reac failure (5.1) Birth defects (5.2) Decreased IQ following in utero exposure (5.3) Pancreatitis (5.5) Thrombocytopenia (5.9) Hyperammonemic encephalopathy (5.10 , 5.11) Multi-organ hypersensitivity reactions (5.13) Somnolence in the elderly (5.15) 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. Most common adverse reactions (reported >5%) are abdominal pain, alopecia, amblyopia/blurred vision, amnesia, anorexia, asthenia, ataxia, bronchitis, constipation, depression, diarrhea, diplopia, dizziness, dyspepsia, dyspnea, ecchymosis, emotional lability, fever, flu syndrome, headache, increased appetite, infection, insomnia, nausea, nervousness, nystagmus, peripheral edema, pharyngitis, rhinitis, somnolence, thinking abnormal, thrombocytopenia, tinnitus, tremor, vomiting, weight gain, weight loss. ( 6.1 ) The safety and tolerability of valproate in pediatric patients were shown to be comparable to those in adults ( 8.4 ). To report SUSPECTED ADVERSE REACTIONS, contact Upsher gain, weight loss. ( 6.1 ) The safety and tolerability of valproate in pediatric patients were shown to be comparable to those in adults ( 8.4 ). To report SUSPECTED ADVERSE REACTIONS, contact Upsher-Smith Laboratories, Inc. at 1-855-899-9180 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Epilepsy The data described in the following section were obtained using divalproex sodium tablets. Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures, divalproex sodium tablets were generally well tolerated with most adverse reactions rated as mild to moderate in severity. Intolerance was the primary reason for discontinuation in the divalproex sodium tablets-treated patients (6%), compared to 1% of placebo-treated patients. Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of divalproex sodium-treated patients and for which the incidence was greater than in the placebo group, in a placebo-controlled trial of adjunctive therapy for the treatment of complex partial seizures. Since patients were also treated with other antiepilepsy drugs, it is not possible, in most cases, to determine whether the following adverse ive therapy for the treatment of complex partial seizures. Since patients were also treated with other antiepilepsy drugs, it is not possible, in most cases, to determine whether the following adverse reactions can be ascribed to divalproex sodium tablets alone, or the combination of divalproex sodium tablets and other antiepilepsy drugs. Table 3. Adverse Reactions Reported by ≥ 5% of Patients Treated with Divalproex Sodium Tablets During Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures Body System/Reaction Divalproex Sodium Tablets (%) (n = 77) Placebo (%) (n = 70) Body as a Whole Headache 31 21 Asthenia 27 7 Fever 6 4 Gastrointestinal System Nausea 48 14 Vomiting 27 7 Abdominal Pain 23 6 Diarrhea 13 6 Anorexia 12 0 Dyspepsia 8 4 Constipation 5 1 Nervous System Somnolence 27 11 Tremor 25 6 Dizziness 25 13 Diplopia 16 9 Amblyopia/Blurred Vision 12 9 Ataxia 8 1 Nystagmus 8 1 Emotional Lability 6 4 Thinking Abnormal 6 0 Amnesia 5 1 Respiratory System Flu Syndrome 12 9 Infection 12 6 Bronchitis 5 1 Rhinitis 5 4 Other Alopecia 6 1 Weight Loss 6 0 Table 4 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in the high dose divalp me 12 9 Infection 12 6 Bronchitis 5 1 Rhinitis 5 4 Other Alopecia 6 1 Weight Loss 6 0 Table 4 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in the high dose divalproex sodium group, and for which the incidence was greater than in the low dose group, in a controlled trial of divalproex sodium tablets monotherapy treatment of complex partial seizures. Since patients were being titrated off another antiepilepsy drug during the first portion of the trial, it is not possible, in many cases, to determine whether the following adverse reactions can be ascribed to divalproex sodium tablets alone, or the combination of divalproex sodium tablets and other antiepilepsy drugs. Table 4. Adverse Reactions Reported by ≥ 5% of Patients in the High Dose Group in the Controlled Trial of Divalproex Sodium Tablets Monotherapy for Complex Partial Seizures Headache was the only adverse reaction that occurred in ≥ 5% of patients in the high dose group and at an equal or greater incidence in the low dose group. Body System/Reaction High Dose (%) (n = 131) Low Dose (%) (n = 134) Body as a Whole Asthenia 21 10 Digestive System Nausea 34 26 Diarrhea 23 19 Vomiting 23 15 A reater incidence in the low dose group. Body System/Reaction High Dose (%) (n = 131) Low Dose (%) (n = 134) Body as a Whole Asthenia 21 10 Digestive System Nausea 34 26 Diarrhea 23 19 Vomiting 23 15 Abdominal Pain 12 9 Anorexia 11 4 Dyspepsia 11 10 Hemic/Lymphatic System Thrombocytopenia 24 1 Ecchymosis 5 4 Metabolic/Nutritional Weight Gain 9 4 Peripheral Edema 8 3 Nervous System Tremor 57 19 Somnolence 30 18 Dizziness 18 13 Insomnia 15 9 Nervousness 11 7 Amnesia 7 4 Nystagmus 7 1 Depression 5 4 Respiratory System Infection 20 13 Pharyngitis 8 2 Dyspnea 5 1 Skin and Appendages Alopecia 24 13 Special Senses Amblyopia/Blurred Vision 8 4 Tinnitus 7 1 The following additional adverse reactions were reported by greater than 1% but less than 5% of the 358 patients treated with divalproex sodium tablets in the controlled trials of complex partial seizures: Body as a Whole : Back pain, chest pain, malaise. Cardiovascular System : Tachycardia, hypertension, palpitation. Digestive System : Increased appetite, flatulence, hematemesis, eructation, pancreatitis, periodontal abscess. Hemic and Lymphatic System : Petechia. Metabolic and Nutritional Disorders : SGOT increased, SGPT increased. Musc ased appetite, flatulence, hematemesis, eructation, pancreatitis, periodontal abscess. Hemic and Lymphatic System : Petechia. Metabolic and Nutritional Disorders : SGOT increased, SGPT increased. Musculoskeletal System : Myalgia, twitching, arthralgia, leg cramps, myasthenia. Nervous System : Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination, abnormal dreams, personality disorder. Respiratory System : Sinusitis, cough increased, pneumonia, epistaxis. Skin and Appendages : Rash, pruritus, dry skin. Special Senses : Taste perversion, abnormal vision, deafness, otitis media. Urogenital System : Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea, urinary frequency. 6.2 Mania Although valproic acid capsules have not been evaluated for safety and efficacy in the treatment of manic episodes associated with bipolar disorder, the following adverse reactions not listed above were reported by 1% or more of patients from two placebo-controlled clinical trials of divalproex sodium tablets. Body as a Whole : Chills, neck pain, neck rigidity. Cardiovascular System : Hypotension, postural hypotension, vasodilation. Digestive System : Fecal incontinence, gastroenteri alproex sodium tablets. Body as a Whole : Chills, neck pain, neck rigidity. Cardiovascular System : Hypotension, postural hypotension, vasodilation. Digestive System : Fecal incontinence, gastroenteritis, glossitis. Musculoskeletal System : Arthrosis. Nervous System : Agitation, catatonic reaction, hypokinesia, reflexes increased, tardive dyskinesia, vertigo. Skin and Appendages : Furunculosis, maculopapular rash, seborrhea. Special Senses : Conjunctivitis, dry eyes, eye pain. Urogenital System : Dysuria. 6.3 Migraine Although valproic acid capsules have not been evaluated for safety and efficacy in the treatment of prophylaxis of migraine headaches, the following adverse reactions not listed above were reported by 1% or more of patients from two placebo-controlled clinical trials of divalproex sodium tablets. Body as a Whole : Face edema. Digestive System : Dry mouth, stomatitis. Urogenital System : Cystitis, metrorrhagia, and vaginal hemorrhage. 6.4 Other Patient Populations Adverse reactions that have been reported with all dosage forms of valproate from epilepsy trials, spontaneous reports, and other sources are listed below by body system. Gastrointestinal : The most commonly reactions that have been reported with all dosage forms of valproate from epilepsy trials, spontaneous reports, and other sources are listed below by body system. Gastrointestinal : The most commonly reported side effects at the initiation of therapy are nausea, vomiting, and indigestion. These effects are usually transient and rarely require discontinuation of therapy. Diarrhea, abdominal cramps, and constipation have been reported. Both anorexia with some weight loss and increased appetite with weight gain have also been reported. The administration of delayed-release divalproex sodium may result in reduction of gastrointestinal side effects in some patients. CNS Effects : Sedative effects have occurred in patients receiving valproate alone but occur most often in patients receiving combination therapy. Sedation usually abates upon reduction of other antiepileptic medication. Tremor (may be dose-related), hallucinations, ataxia, headache, nystagmus, diplopia, asterixis, "spots before eyes", dysarthria, dizziness, confusion, hypesthesia, vertigo, incoordination, and Parkinsonism have been reported with the use of valproate. Rare cases of coma have occurred in patients receiving va eyes", dysarthria, dizziness, confusion, hypesthesia, vertigo, incoordination, and Parkinsonism have been reported with the use of valproate. Rare cases of coma have occurred in patients receiving valproate alone or in conjunction with phenobarbital. In rare instances encephalopathy with or without fever has developed shortly after the introduction of valproate monotherapy without evidence of hepatic dysfunction or inappropriately high plasma valproate levels. Although recovery has been described following drug withdrawal, there have been fatalities in patients with hyperammonemic encephalopathy, particularly in patients with underlying urea cycle disorders [see Warnings and Precautions (5.6) ] . There have been postmarketing reports of reversible and irreversible cerebral and cerebellar atrophy temporally associated with the use of valproate products. In some cases the patients recovered with permanent sequelae [see Warnings and Precautions (5.7) ] . Cerebral atrophy has been reported in children exposed to valproate in utero [see Use in Specific Populations (8.1) ] . Dermatologic : Transient hair loss, skin rash, photosensitivity, generalized pruritus, erythema multiforme, and S d in children exposed to valproate in utero [see Use in Specific Populations (8.1) ] . Dermatologic : Transient hair loss, skin rash, photosensitivity, generalized pruritus, erythema multiforme, and Stevens-Johnson syndrome. Rare cases of toxic epidermal necrolysis have been reported including a fatal case in a 6 month old infant taking valproate and several other concomitant medications. An additional case of toxic epidermal necrosis resulting in death was reported in a 35 year old patient with AIDS taking several concomitant medications and with a history of multiple cutaneous drug reactions. Serious skin reactions have been reported with concomitant administration of lamotrigine and valproate [see Drug Interactions (7) ] . Psychiatric : Emotional upset, depression, psychosis, aggression, hyperactivity, hostility, and behavioral deterioration. Musculoskeletal : Weakness. Hematologic : Thrombocytopenia and inhibition of the secondary phase of platelet aggregation may be reflected in altered bleeding time, petechiae, bruising, hematoma formation, epistaxis, and frank hemorrhage [see Warnings and Precautions (5.9) and Drug Interactions (7) ] . Relative lymphocytosis, macrocytosis, h ltered bleeding time, petechiae, bruising, hematoma formation, epistaxis, and frank hemorrhage [see Warnings and Precautions (5.9) and Drug Interactions (7) ] . Relative lymphocytosis, macrocytosis, hypofibrinogenemia, leucopenia, eosinophilia, anemia including macrocytic with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic anemia, agranulocytosis, and acute intermittent porphyria. Hepatic : Minor elevations of transaminases (e.g., SGOT and SGPT) and LDH are frequent and appear to be dose-related. Occasionally, laboratory test results include increases in serum bilirubin and abnormal changes in other liver function tests. These results may reflect potentially serious hepatotoxicity [see Warnings and Precautions (5.1) ] . Endocrine : Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, and parotid gland swelling. Abnormal thyroid function tests [see Warnings and Precautions (5.17) ] . There have been rare spontaneous reports of polycystic ovary disease. A cause and effect relationship has not been established. Pancreatic : Acute pancreatitis, including fatalities [see Warnings and Precautions (5.5) ] . Metabolic : Hyperammonemia [se ic ovary disease. A cause and effect relationship has not been established. Pancreatic : Acute pancreatitis, including fatalities [see Warnings and Precautions (5.5) ] . Metabolic : Hyperammonemia [see Warnings and Precautions (5.10) ] , hyponatremia, and inappropriate ADH secretion. There have been rare reports of Fanconi's syndrome occurring chiefly in children. Decreased carnitine concentrations have been reported although the clinical relevance is undetermined. Hyperglycinemia has occurred and was associated with a fatal outcome in a patient with preexistent nonketotic hyperglycinemia. Genitourinary : Enuresis and urinary tract infection. Special Senses : Hearing loss, either reversible or irreversible, has been reported; however, a cause and effect relationship has not been established. Ear pain has also been reported. Other : Allergic reaction, anaphylaxis, edema of the extremities, lupus erythematosus, bone pain, cough increased, pneumonia, otitis media, bradycardia, cutaneous vasculitis, fever, and hypothermia . There have been reports of developmental delay, autism and/or autism spectrum disorder in the offspring of women exposed to valproate during pregnancy. Use relieves redness of the eye due to minor eye irritations Purpose Redness reliever Warnings For external use only Ask a doctor before use if you have narrow angle glaucoma When using this product pupils may become enlarged temporarily to avoid contamination, do not touch tip of container to any surface. Replace cap after using. if solution changes color or becomes cloudy, do not use overuse may produce increased redness of the eye remove contact lenses before using Stop use and ask a doctor if you experience eye pain changes in vision continued redness or irritation of the eye, or if the condition worsens or persists for more than 72 hours If pregnant or breast-feeding, ask a health professional before use. Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center (1-800-222-1222) right away. Directions instill 1 to 2 drops in the affected eye(s) up to 4 times daily Ask a doctor before use if you have narrow angle glaucoma Stop use and ask a doctor if you experience eye pain changes in vision continued redness or irritation of the eye, or if the condition worsens or persists for more than 72 hours Keep out of reach of children. If swallowed ctor if you experience eye pain changes in vision continued redness or irritation of the eye, or if the condition worsens or persists for more than 72 hours Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center (1-800-222-1222) right away. Uses For the temporary relief of minor aches and pains of muscles and joints associated with simple backache arthritis strains bruises sprains Purpose Camphor 3.1%.................Topical Analgesic Menthol 5.3%..................Topical Analgesic Warnings For external use only Do not use on wounds or damaged skin When using this product avoid contact with the eyes do not bandage tightly Stop use and ask doctor if symptoms persist for more than 7 days or clear up and occur again within a few days condition worsens irritation occurs If pregnant or breastfeeding , ask a health professional before use. Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center right away. Directions Adults and children 2 years of age and older: Apply to affected area not more than 3 to 4 times daily. Children under 2 years of age: do not use, consult a doctor. Stop use and ask doctor if symptoms persist for more than 7 days or clear up and occur again within a few days condition worsens irritation occurs Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center right away. Uses For the temporary relief of minor aches and pains of muscles and joints associated with simple backache arthritis strains bruises sprains Purpose Camphor 3.1%.................Topical Analgesic Menthol 5.3%..................Topical Analgesic Warnings For external use only Do not use on wounds or damaged skin When using this product avoid contact with the eyes do not bandage tightly Stop use and ask doctor if symptoms persist for more than 7 days or clear up and occur again within a few days condition worsens irritation occurs If pregnant or breastfeeding, ask a health professional before use. Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center right away. Directions Adults and children 2 years of age and older : Apply to affected area not more than 3 to 4 times daily. Children under 2 years of age: do not use, consult a doctor. Stop use and ask doctor if symptoms persist for more than 7 days or clear up and occur again within a few days condition worsens irritation occurs Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center right away. 1 INDICATIONS AND USAGE Olanzapine is an atypical antipsychotic indicated: As oral formulation for the: Treatment of schizophrenia. ( 1.1 ) Adults: Efficacy was established in three clinical trials in patients with schizophrenia: two 6-week trials and one maintenance trial. ( 14.1 ) Adolescents (ages 13-17): Efficacy was established in one 6-week trial in patients with schizophrenia ( 14.1 ). The increased potential (in adolescents compared with adults) for weight gain and dyslipidemia may lead clinicians to consider prescribing other drugs first in adolescents. ( 1.1 ) Acute treatment of manic or mixed episodes associated with bipolar I disorder and maintenance treatment of bipolar I disorder. ( 1.2 ) Adults: Efficacy was established in three clinical trials in patients with manic or mixed episodes of bipolar I disorder: two 3- to 4-week trials and one maintenance trial. ( 14.2 ) Adolescents (ages 13-17): Efficacy was established in one 3-week trial in patients with manic or mixed episodes associated with bipolar I disorder ( 14.2 ). The increased potential (in adolescents compared with adults) for weight gain and dyslipidemia may lead clinicians to consider prescribing other drug sodes associated with bipolar I disorder ( 14.2 ). The increased potential (in adolescents compared with adults) for weight gain and dyslipidemia may lead clinicians to consider prescribing other drugs first in adolescents. ( 1.2 ) Medication therapy for pediatric patients with schizophrenia or bipolar I disorder should be undertaken only after a thorough diagnostic evaluation and with careful consideration of the potential risks. ( 1.3 ) Adjunct to valproate or lithium in the treatment of manic or mixed episodes associated with bipolar I disorder. ( 1.2 ) Efficacy was established in two 6-week clinical trials in adults ( 14.2 ). Maintenance efficacy has not been systematically evaluated. As Olanzapine and Fluoxetine in Combination for the: Treatment of depressive episodes associated with bipolar I disorder. ( 1.5 ) Efficacy was established with Symbyax (olanzapine and fluoxetine in combination); refer to the product label for Symbyax. Treatment of treatment resistant depression. ( 1.6 ) Efficacy was established with Symbyax (olanzapine and fluoxetine in combination) in adults; refer to the product label for Symbyax. 1.1 Schizophrenia Oral olanzapine is indicated for the treatment ) Efficacy was established with Symbyax (olanzapine and fluoxetine in combination) in adults; refer to the product label for Symbyax. 1.1 Schizophrenia Oral olanzapine is indicated for the treatment of schizophrenia. Efficacy was established in three clinical trials in adult patients with schizophrenia: two 6-week trials and one maintenance trial. In adolescent patients with schizophrenia (ages 13-17), efficacy was established in one 6-week trial [see Clinical Studies ( 14.1 )] . When deciding among the alternative treatments available for adolescents, clinicians should consider the increased potential (in adolescents as compared with adults) for weight gain and dyslipidemia. Clinicians should consider the potential long-term risks when prescribing to adolescents, and in many cases this may lead them to consider prescribing other drugs first in adolescents [see Warnings and Precautions ( 5.5 ] . 1.2 Bipolar I Disorder (Manic or Mixed Episodes) Monotherapy — Oral olanzapine is indicated for the acute treatment of manic or mixed episodes associated with bipolar I disorder and maintenance treatment of bipolar I disorder. Efficacy was established in three clinical trials in adult pati d for the acute treatment of manic or mixed episodes associated with bipolar I disorder and maintenance treatment of bipolar I disorder. Efficacy was established in three clinical trials in adult patients with manic or mixed episodes of bipolar I disorder: two 3- to 4-week trials and one monotherapy maintenance trial. In adolescent patients with manic or mixed episodes associated with bipolar I disorder (ages 13-17), efficacy was established in one 3-week trial [see Clinical Studies ( 14.2 )] . When deciding among the alternative treatments available for adolescents, clinicians should consider the increased potential (in adolescents as compared with adults) for weight gain and dyslipidemia. Clinicians should consider the potential long-term risks when prescribing to adolescents, and in many cases this may lead them to consider prescribing other drugs first in adolescents [see Warnings and Precautions ( 5.5 ] . Adjunctive Therapy to Lithium or Valproate — Oral olanzapine is indicated for the treatment of manic or mixed episodes associated with bipolar I disorder as an adjunct to lithium or valproate. Efficacy was established in two 6-week clinical trials in adults. The effectiveness r the treatment of manic or mixed episodes associated with bipolar I disorder as an adjunct to lithium or valproate. Efficacy was established in two 6-week clinical trials in adults. The effectiveness of adjunctive therapy for longer-term use has not been systematically evaluated in controlled trials [see Clinical Studies ( 14.2 )] . 1.3 Special Considerations in Treating Pediatric Schizophrenia and Bipolar I Disorder Pediatric schizophrenia and bipolar I disorder are serious mental disorders; however, diagnosis can be challenging. For pediatric schizophrenia, symptom profiles can be variable, and for bipolar I disorder, pediatric patients may have variable patterns of periodicity of manic or mixed symptoms. It is recommended that medication therapy for pediatric schizophrenia and bipolar I disorder be initiated only after a thorough diagnostic evaluation has been performed and careful consideration given to the risks associated with medication treatment. Medication treatment for both pediatric schizophrenia and bipolar I disorder should be part of a total treatment program that often includes psychological, educational and social interventions. 1.5 Olanzapine and Fluoxetine in Com pediatric schizophrenia and bipolar I disorder should be part of a total treatment program that often includes psychological, educational and social interventions. 1.5 Olanzapine and Fluoxetine in Combination: Depressive Episodes Associated with Bipolar I Disorder Oral olanzapine and fluoxetine in combination is indicated for the treatment of depressive episodes associated with bipolar I disorder, based on clinical studies. When using olanzapine and fluoxetine in combination, refer to the Clinical Studies section of the package insert for Symbyax. Olanzapine monotherapy is not indicated for the treatment of depressive episodes associated with bipolar I disorder. 1.6 Olanzapine and Fluoxetine in Combination: Treatment Resistant Depression Oral olanzapine and fluoxetine in combination is indicated for the treatment of treatment resistant depression (major depressive disorder in patients who do not respond to 2 separate trials of different antidepressants of adequate dose and duration in the current episode), based on clinical studies in adult patients. When using olanzapine and fluoxetine in combination, refer to the Clinical Studies section of the package insert for Symbyax. Olanzap the current episode), based on clinical studies in adult patients. When using olanzapine and fluoxetine in combination, refer to the Clinical Studies section of the package insert for Symbyax. Olanzapine monotherapy is not indicated for the treatment of treatment resistant depression. 2 DOSAGE AND ADMINISTRATION Schizophrenia in adults ( 2.1 ) Oral: Start at 5 mg to 10 mg once daily; Target: 10 mg/day within several days Schizophrenia in adolescents ( 2.1 ) Oral: Start at 2.5 mg to 5 mg once daily; Target: 10 mg/day Bipolar I Disorder (manic or mixed episodes) in adults ( 2.2 ) Oral: Start at 10 mg or 15 mg once daily Bipolar I Disorder (manic or mixed episodes) in adolescents ( 2.2 ) Oral: Start at 2.5 mg to 5 mg once daily; Target: 10 mg/day Bipolar I Disorder (manic or mixed episodes) with lithium or valproate in adults ( 2.2 ) Oral: Start at 10 mg once daily Depressive Episodes associated with Bipolar I Disorder in adults ( 2.5 ) Oral in combination with fluoxetine: Start at 5 mg of oral olanzapine and 20 mg of fluoxetine once daily Depressive Episodes associated with Bipolar I Disorder in children and adolescents ( 2.5 ) Oral in combination with fluoxetine: Start at 2.5 mg of f oral olanzapine and 20 mg of fluoxetine once daily Depressive Episodes associated with Bipolar I Disorder in children and adolescents ( 2.5 ) Oral in combination with fluoxetine: Start at 2.5 mg of oral olanzapine and 20 mg of fluoxetine once daily Treatment Resistant Depression in adults ( 2.6 ) Oral in combination with fluoxetine: Start at 5 mg of oral olanzapine and 20 mg of fluoxetine once daily Lower starting dose recommended in debilitated or pharmacodynamically sensitive patients or patients with predisposition to hypotensive reactions, or with potential for slowed metabolism. ( 2.1 ) Olanzapine may be given without regard to meals. ( 2.1 ) Olanzapine and Fluoxetine in Combination: Dosage adjustments, if indicated, should be made with the individual components according to efficacy and tolerability. ( 2.5 , 2.6 ) Olanzapine monotherapy is not indicated for the treatment of depressive episodes associated with bipolar I disorder or treatment resistant depression. ( 2.5 , 2.6 ) Safety of co-administration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in adults. ( 2.5 , 2.6 ) Safety of co-administration of doses above 12 mg olanzapine with 50 mg afety of co-administration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in adults. ( 2.5 , 2.6 ) Safety of co-administration of doses above 12 mg olanzapine with 50 mg fluoxetine has not been evaluated in children and adolescents ages 10 to 17. ( 2.5 ) 2.1 Schizophrenia Adults Dose Selection — Oral olanzapine should be administered on a once-a-day schedule without regard to meals, generally beginning with 5 mg to 10 mg initially, with a target dose of 10 mg/day within several days. Further dosage adjustments, if indicated, should generally occur at intervals of not less than 1 week, since steady state for olanzapine would not be achieved for approximately 1 week in the typical patient. When dosage adjustments are necessary, dose increments/decrements of 5 mg QD are recommended. Efficacy in schizophrenia was demonstrated in a dose range of 10 mg/day to 15 mg/day in clinical trials. However, doses above 10 mg/day were not demonstrated to be more efficacious than the 10 mg/day dose. An increase to a dose greater than the target dose of 10 mg/day (i.e., to a dose of 15 mg/day or greater) is recommended only after clinical assessment. Olanzapine is not in s than the 10 mg/day dose. An increase to a dose greater than the target dose of 10 mg/day (i.e., to a dose of 15 mg/day or greater) is recommended only after clinical assessment. Olanzapine is not indicated for use in doses above 20 mg/day. Dosing in Special Populations — The recommended starting dose is 5 mg in patients who are debilitated, who have a predisposition to hypotensive reactions, who otherwise exhibit a combination of factors that may result in slower metabolism of olanzapine (e.g., nonsmoking female patients ≥65 years of age), or who may be more pharmacodynamically sensitive to olanzapine [see Warnings and Precautions ( 5.14 ), Drug Interactions ( 7 ), and Clinical Pharmacology ( 12.3 )] . When indicated, dose escalation should be performed with caution in these patients. Maintenance Treatment — The effectiveness of oral olanzapine, 10 mg/day to 20 mg/day, in maintaining treatment response in schizophrenic patients who had been stable on olanzapine for approximately 8 weeks and were then followed for relapse has been demonstrated in a placebo-controlled trial [see Clinical Studies ( 14.1 )] . The healthcare provider who elects to use olanzapine for extended periods s eks and were then followed for relapse has been demonstrated in a placebo-controlled trial [see Clinical Studies ( 14.1 )] . The healthcare provider who elects to use olanzapine for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient. Adolescents Dose Selection — Oral olanzapine should be administered on a once-a-day schedule without regard to meals with a recommended starting dose of 2.5 mg or 5 mg, with a target dose of 10 mg/day. Efficacy in adolescents with schizophrenia was demonstrated based on a flexible dose range of 2.5 mg/day to 20 mg/day in clinical trials, with a mean modal dose of 12.5 mg/day (mean dose of 11.1 mg/day). When dosage adjustments are necessary, dose increments/decrements of 2.5 mg or 5 mg are recommended. The safety and effectiveness of doses above 20 mg/day have not been evaluated in clinical trials [see Clinical Studies ( 14.1 )] . Maintenance Treatment — The efficacy of olanzapine for the maintenance treatment of schizophrenia in the adolescent population has not been systematically evaluated; however, maintenance efficacy can be extrapolated from adult data along with comparisons of olanzapin nce treatment of schizophrenia in the adolescent population has not been systematically evaluated; however, maintenance efficacy can be extrapolated from adult data along with comparisons of olanzapine pharmacokinetic parameters in adult and adolescent patients. Thus, it is generally recommended that responding patients be continued beyond the acute response, but at the lowest dose needed to maintain remission. Patients should be periodically reassessed to determine the need for maintenance treatment. 2.2 Bipolar I Disorder (Manic or Mixed Episodes) Adults Dose Selection for Monotherapy — Oral olanzapine should be administered on a once-a-day schedule without regard to meals, generally beginning with 10 mg or 15 mg. Dosage adjustments, if indicated, should generally occur at intervals of not less than 24 hours, reflecting the procedures in the placebo-controlled trials. When dosage adjustments are necessary, dose increments/decrements of 5 mg QD are recommended. Short-term (3-4 weeks) antimanic efficacy was demonstrated in a dose range of 5 mg to 20 mg/day in clinical trials. The safety of doses above 20 mg/day has not been evaluated in clinical trials [see Clinical Studies ( 14.2 antimanic efficacy was demonstrated in a dose range of 5 mg to 20 mg/day in clinical trials. The safety of doses above 20 mg/day has not been evaluated in clinical trials [see Clinical Studies ( 14.2 )] . Maintenance Monotherapy — The benefit of maintaining bipolar I patients on monotherapy with oral olanzapine at a dose of 5 mg/day to 20 mg/day, after achieving a responder status for an average duration of 2 weeks, was demonstrated in a controlled trial [see Clinical Studies ( 14.2 )] . The healthcare provider who elects to use olanzapine for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient. Dose Selection for Adjunctive Treatment — When administered as adjunctive treatment to lithium or valproate, oral olanzapine dosing should generally begin with 10 mg once-a-day without regard to meals. Antimanic efficacy was demonstrated in a dose range of 5 mg to 20 mg/day in clinical trials [see Clinical Studies ( 14.2 )] . The safety of doses above 20 mg/day has not been evaluated in clinical trials. Adolescents Dose Selection — Oral olanzapine should be administered on a once-a-day schedule without regard to meals with a recomm y of doses above 20 mg/day has not been evaluated in clinical trials. Adolescents Dose Selection — Oral olanzapine should be administered on a once-a-day schedule without regard to meals with a recommended starting dose of 2.5 mg or 5 mg, with a target dose of 10 mg/day. Efficacy in adolescents with bipolar I disorder (manic or mixed episodes) was demonstrated based on a flexible dose range of 2.5 mg/day to 20 mg/day in clinical trials, with a mean modal dose of 10.7 mg/day (mean dose of 8.9 mg/day). When dosage adjustments are necessary, dose increments/decrements of 2.5 mg or 5 mg are recommended. The safety and effectiveness of doses above 20 mg/day have not been evaluated in clinical trials [see Clinical Studies ( 14.2 )] . Maintenance Treatment — The efficacy of olanzapine for the maintenance treatment of bipolar I disorder in the adolescent population has not been evaluated; however, maintenance efficacy can be extrapolated from adult data along with comparisons of olanzapine pharmacokinetic parameters in adult and adolescent patients. Thus, it is generally recommended that responding patients be continued beyond the acute response, but at the lowest dose needed to maintain r rmacokinetic parameters in adult and adolescent patients. Thus, it is generally recommended that responding patients be continued beyond the acute response, but at the lowest dose needed to maintain remission. Patients should be periodically reassessed to determine the need for maintenance treatment. 2.3 Administration of Olanzapine Orally Disintegrating Tablets Peel back foil on blister. Do not push tablet through foil. Immediately upon opening the blister or the bottle, using dry hands, remove tablet and place entire olanzapine orally disintegrating tablet in the mouth. Tablet disintegration occurs rapidly in saliva so it can be easily swallowed with or without liquid. 2.5 Olanzapine and Fluoxetine in Combination: Depressive Episodes Associated with Bipolar I Disorder When using olanzapine and fluoxetine in combination, also refer to the Clinical Studies section of the package insert for Symbyax. Adults Oral olanzapine should be administered in combination with fluoxetine once daily in the evening, without regard to meals, generally beginning with 5 mg of oral olanzapine and 20 mg of fluoxetine. Dosage adjustments, if indicated, can be made according to efficacy and tolerability in the evening, without regard to meals, generally beginning with 5 mg of oral olanzapine and 20 mg of fluoxetine. Dosage adjustments, if indicated, can be made according to efficacy and tolerability within dose ranges of oral olanzapine 5 mg to 12.5 mg and fluoxetine 20 mg to 50 mg. Antidepressant efficacy was demonstrated with olanzapine and fluoxetine in combination in adult patients with a dose range of olanzapine 6 mg to 12 mg and fluoxetine 25 mg to 50 mg. Safety of co-administration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in clinical studies. Children and Adolescents (10-17 years of age) Oral olanzapine should be administered in combination with fluoxetine once daily in the evening, without regard to meals, generally beginning with 2.5 mg of oral olanzapine and 20 mg of fluoxetine. Dosage adjustments, if indicated, can be made according to efficacy and tolerability. Safety of co-administration of doses above 12 mg olanzapine with 50 mg fluoxetine has not been evaluated in pediatric clinical studies. Safety and efficacy of olanzapine and fluoxetine in combination was determined in clinical trials supporting approval of Symbyax (fixed dose tine has not been evaluated in pediatric clinical studies. Safety and efficacy of olanzapine and fluoxetine in combination was determined in clinical trials supporting approval of Symbyax (fixed dose combination of olanzapine and fluoxetine). Symbyax is dosed between 3 mg/25 mg (olanzapine/fluoxetine) per day and 12 mg/50 mg (olanzapine/fluoxetine) per day. The following table demonstrates the appropriate individual component doses of olanzapine and fluoxetine versus Symbyax. Dosage adjustments, if indicated, should be made with the individual components according to efficacy and tolerability. Table 1: Approximate Dose Correspondence Between Symbyax a and the Combination of Olanzapine and Fluoxetine a Symbyax (olanzapine/fluoxetine HCl) is a fixed-dose combination of olanzapine and fluoxetine. For Use in Combination Symbyax Olanzapine Fluoxetine (mg/day) (mg/day) (mg/day) 3 mg olanzapine/25 mg fluoxetine 2.5 20 6 mg olanzapine/25 mg fluoxetine 5 20 12 mg olanzapine/25 mg fluoxetine 10+2.5 20 6 mg olanzapine/50 mg fluoxetine 5 40+10 12 mg olanzapine/50 mg fluoxetine 10+2.5 40+10 While there is no body of evidence to answer the question of how long a patient treated with olanzapine a 2.5 20 6 mg olanzapine/50 mg fluoxetine 5 40+10 12 mg olanzapine/50 mg fluoxetine 10+2.5 40+10 While there is no body of evidence to answer the question of how long a patient treated with olanzapine and fluoxetine in combination should remain on it, it is generally accepted that bipolar I disorder, including the depressive episodes associated with bipolar I disorder, is a chronic illness requiring chronic treatment. The healthcare provider should periodically reexamine the need for continued pharmacotherapy. Olanzapine monotherapy is not indicated for the treatment of depressive episodes associated with bipolar I disorder. 2.6 Olanzapine and Fluoxetine in Combination: Treatment Resistant Depression When using olanzapine and fluoxetine in combination, also refer to the Clinical Studies section of the package insert for Symbyax. Oral olanzapine should be administered in combination with fluoxetine once daily in the evening, without regard to meals, generally beginning with 5 mg of oral olanzapine and 20 mg of fluoxetine. Dosage adjustments, if indicated, can be made according to efficacy and tolerability within dose ranges of oral olanzapine 5 mg to 20 mg and fluoxetine 20 mg to 50 m lanzapine and 20 mg of fluoxetine. Dosage adjustments, if indicated, can be made according to efficacy and tolerability within dose ranges of oral olanzapine 5 mg to 20 mg and fluoxetine 20 mg to 50 mg. Antidepressant efficacy was demonstrated with olanzapine and fluoxetine in combination in adult patients with a dose range of olanzapine 6 mg to 18 mg and fluoxetine 25 mg to 50 mg. Safety and efficacy of olanzapine in combination with fluoxetine was determined in clinical trials supporting approval of Symbyax (fixed dose combination of olanzapine and fluoxetine). Symbyax is dosed between 3 mg/25 mg (olanzapine/fluoxetine) per day and 12 mg/50 mg (olanzapine/fluoxetine) per day. Table 1 above demonstrates the appropriate individual component doses of olanzapine and fluoxetine versus Symbyax. Dosage adjustments, if indicated, should be made with the individual components according to efficacy and tolerability. While there is no body of evidence to answer the question of how long a patient treated with olanzapine and fluoxetine in combination should remain on it, it is generally accepted that treatment resistant depression (major depressive disorder in adult patients who do not respon t treated with olanzapine and fluoxetine in combination should remain on it, it is generally accepted that treatment resistant depression (major depressive disorder in adult patients who do not respond to 2 separate trials of different antidepressants of adequate dose and duration in the current episode) is a chronic illness requiring chronic treatment. The healthcare provider should periodically reexamine the need for continued pharmacotherapy. Safety of co-administration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in clinical studies. Olanzapine monotherapy is not indicated for treatment of treatment resistant depression (major depressive disorder in patients who do not respond to 2 antidepressants of adequate dose and duration in the current episode). 2.7 Olanzapine and Fluoxetine in Combination: Dosing in Special Populations The starting dose of oral olanzapine 2.5 mg to 5 mg with fluoxetine 20 mg should be used for patients with a predisposition to hypotensive reactions, patients with hepatic impairment, or patients who exhibit a combination of factors that may slow the metabolism of olanzapine or fluoxetine in combination (female gender, geria hypotensive reactions, patients with hepatic impairment, or patients who exhibit a combination of factors that may slow the metabolism of olanzapine or fluoxetine in combination (female gender, geriatric age, nonsmoking status), or those patients who may be pharmacodynamically sensitive to olanzapine. Dosing modification may be necessary in patients who exhibit a combination of factors that may slow metabolism. When indicated, dose escalation should be performed with caution in these patients. Olanzapine and fluoxetine in combination have not been systematically studied in patients over 65 years of age or in patients under 10 years of age [see Warnings and Precautions ( 5.14 ), Drug Interactions ( 7 ), and Clinical Pharmacology ( 12.3 )] . 6 ADVERSE REACTIONS When using olanzapine and fluoxetine in combination, also refer to the Adverse Reactions section of the package insert for Symbyax. Most common adverse reactions (≥5% and at least twice that for placebo) associated with: Oral Olanzapine Monotherapy: Schizophrenia (Adults) – postural hypotension, constipation, weight gain, dizziness, personality disorder, akathisia ( 6.1 ) Schizophrenia (Adolescents) – sedation, weight increas nzapine Monotherapy: Schizophrenia (Adults) – postural hypotension, constipation, weight gain, dizziness, personality disorder, akathisia ( 6.1 ) Schizophrenia (Adolescents) – sedation, weight increased, headache, increased appetite, dizziness, abdominal pain, pain in extremity, fatigue, dry mouth ( 6.1 ) Manic or Mixed Episodes, Bipolar I Disorder (Adults) – asthenia, dry mouth, constipation, increased appetite, somnolence, dizziness, tremor ( 6.1 ) Manic or Mixed Episodes, Bipolar I Disorder (Adolescents) – sedation, weight increased, increased appetite, headache, fatigue, dizziness, dry mouth, abdominal pain, pain in extremity ( 6.1 ) Combination of Olanzapine and Lithium or Valproate: Manic or Mixed Episodes, Bipolar I Disorder (Adults) – dry mouth, weight gain, increased appetite, dizziness, back pain, constipation, speech disorder, increased salivation, amnesia, paresthesia ( 6.1 ) Olanzapine and Fluoxetine in Combination: Also refer to the Adverse Reactions section of the package insert for Symbyax. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Lannett Company, Inc. at 1-844-834-0530 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Becau e insert for Symbyax. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Lannett Company, Inc. at 1-844-834-0530 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 or predict the rates observed in practice. Clinical Trials in Adults The information below for olanzapine is derived from a clinical trial database for olanzapine consisting of 10,504 adult patients with approximately 4765 patient-years of exposure to olanzapine plus 722 patients with exposure to intramuscular olanzapine for injection. This database includes: (1) 2500 patients who participated in multiple-dose oral olanzapine premarketing trials in schizophrenia and Alzheimer's disease representing approximately 1122 patient-years of exposure as of February 14, 1995; (2) 182 patients who participated in oral olanzapine premarketing bipolar I disorder (manic or mixed episodes) trials representing approximately 66 patient-years of exposure; (3) 191 patients who par (2) 182 patients who participated in oral olanzapine premarketing bipolar I disorder (manic or mixed episodes) trials representing approximately 66 patient-years of exposure; (3) 191 patients who participated in an oral olanzapine trial of patients having various psychiatric symptoms in association with Alzheimer's disease representing approximately 29 patient-years of exposure; (4)5788 additional patients from 88 oral olanzapine clinical trials as of December 31, 2001; (5) 1843 additional patients from 41 olanzapine clinical trials as of October 31, 2011; and (6) 722 patients who participated in intramuscular olanzapine for injection premarketing trials in agitated patients with schizophrenia, bipolar I disorder (manic or mixed episodes), or dementia. Also included below is information from the premarketing 6-week clinical study database for olanzapine in combination with lithium or valproate, consisting of 224 patients who participated in bipolar I disorder (manic or mixed episodes) trials with approximately 22 patient-years of exposure. The conditions and duration of treatment with olanzapine varied greatly and included (in overlapping categories) open-label and double-blind ph trials with approximately 22 patient-years of exposure. The conditions and duration of treatment with olanzapine varied greatly and included (in overlapping categories) open-label and double-blind phases of studies, inpatients and outpatients, fixed-dose and dose-titration studies, and short-term or longer-term exposure. Adverse reactions were assessed by collecting adverse reactions, results of physical examinations, vital signs, weights, laboratory analytes, ECGs, chest x-rays, and results of ophthalmologic examinations. Certain portions of the discussion below relating to objective or numeric safety parameters, namely, dose-dependent adverse reactions, vital sign changes, weight gain, laboratory changes, and ECG changes are derived from studies in patients with schizophrenia and have not been duplicated for bipolar I disorder (manic or mixed episodes) or agitation. However, this information is also generally applicable to bipolar I disorder (manic or mixed episodes) and agitation. Adverse reactions during exposure were obtained by spontaneous report and recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a mean Adverse reactions during exposure were obtained by spontaneous report and recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse reactions without first grouping similar types of reactions into a smaller number of standardized reaction categories. In the tables and tabulations that follow, MedDRA and COSTART Dictionary terminology has been used to classify reported adverse reactions. 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. The reported reactions do not include those reaction terms that were so general as to be uninformative. Reactions listed elsewhere in labeling may not be repeated below. It is important to emphasize that, although the reactions occurred during treatment with olanzapine, they were not necessarily caused by it. The entire label should be read to gain a e repeated below. It is important to emphasize that, although the reactions occurred during treatment with olanzapine, they were not necessarily caused by it. The entire label should be read to gain a complete understanding of the safety profile of olanzapine. The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing healthcare provider with some basis for estimating the relative contribution of drug and nondrug factors to the adverse reactions incidence in the population studied. Incidence of Adverse Reactions in Short-Term, Placebo-Controlled and Combination Trials The following findings are based on premarketing trials of oral olanzapine for schizophrenia, bipolar I disorder (manic or mixed episodes), a subsequent trial of patients having variou bination Trials The following findings are based on premarketing trials of oral olanzapine for schizophrenia, bipolar I disorder (manic or mixed episodes), a subsequent trial of patients having various psychiatric symptoms in association with Alzheimer's disease, and premarketing combination trials. Adverse Reactions Associated with Discontinuation of Treatment in Short-Term, Placebo-Controlled Trials Schizophrenia — Overall, there was no difference in the incidence of discontinuation due to adverse reactions (5% for oral olanzapine vs 6% for placebo). However, discontinuations due to increases in ALT were considered to be drug related (2% for oral olanzapine vs 0% for placebo). Bipolar I Disorder (Manic or Mixed Episodes) Monotherapy — Overall, there was no difference in the incidence of discontinuation due to adverse reactions (2% for oral olanzapine vs 2% for placebo). Adverse Reactions Associated with Discontinuation of Treatment in Short-Term Combination Trials Bipolar I Disorder (Manic or Mixed Episodes), Olanzapine as Adjunct to Lithium or Valproate — In a study of patients who were already tolerating either lithium or valproate as monotherapy, discontinuation rates due to a (Manic or Mixed Episodes), Olanzapine as Adjunct to Lithium or Valproate — In a study of patients who were already tolerating either lithium or valproate as monotherapy, discontinuation rates due to adverse reactions were 11% for the combination of oral olanzapine with lithium or valproate compared to 2% for patients who remained on lithium or valproate monotherapy. Discontinuations with the combination of oral olanzapine and lithium or valproate that occurred in more than 1 patient were: somnolence (3%), weight gain (1%), and peripheral edema (1%). Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials The most commonly observed adverse reactions associated with the use of oral olanzapine (incidence of 5% or greater) and not observed at an equivalent incidence among placebo-treated patients (olanzapine incidence at least twice that for placebo) were: Table 9: Common Treatment-Emergent Adverse Reactions Associated with the Use of Oral Olanzapine in 6-Week Trials — SCHIZOPHRENIA a Personality disorder is the COSTART term for designating nonaggressive objectionable behavior. Adverse Reaction Percentage of Patients Reporting Event Olanzapine (N=248) Placebo (N=11 SCHIZOPHRENIA a Personality disorder is the COSTART term for designating nonaggressive objectionable behavior. Adverse Reaction Percentage of Patients Reporting Event Olanzapine (N=248) Placebo (N=118) Postural hypotension 5 2 Constipation 9 3 Weight gain 6 1 Dizziness 11 4 Personality disorder a 8 4 Akathisia 5 1 Table 10: Common Treatment-Emergent Adverse Reactions Associated with the Use of Oral Olanzapine in 3-Week and 4-Week Trials — Bipolar I Disorder (Manic or Mixed Episodes) Adverse Reaction Percentage of Patients Reporting Event Olanzapine (N=125) Placebo (N=129) Asthenia 15 6 Dry mouth 22 7 Constipation 11 5 Dyspepsia 11 5 Increased appetite 6 3 Somnolence 35 13 Dizziness 18 6 Tremor 6 3 Adverse Reactions Occurring at an Incidence of 2% or More among Oral Olanzapine-Treated Patients in Short-Term, Placebo-Controlled Trials Table 11 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred in 2% or more of patients treated with oral olanzapine (doses ≥2.5 mg/day) and with incidence greater than placebo who participated in the acute phase of placebo-controlled trials. Table 11: Treatment-Emergent Adverse Reactions: Inci with oral olanzapine (doses ≥2.5 mg/day) and with incidence greater than placebo who participated in the acute phase of placebo-controlled trials. Table 11: Treatment-Emergent Adverse Reactions: Incidence in Short-Term, Placebo-Controlled Clinical Trials with Oral Olanzapine Body System/Adverse Reaction Percentage of Patients Reporting Event Olanzapine (N=532) Placebo (N=294) Body as a Whole Accidental injury 12 8 Asthenia 10 9 Fever 6 2 Back pain 5 2 Chest pain 3 1 Cardiovascular System Postural hypotension 3 1 Tachycardia 3 1 Hypertension 2 1 Digestive System Dry mouth 9 5 Constipation 9 4 Dyspepsia 7 5 Vomiting 4 3 Increased appetite 3 2 Hemic and Lymphatic System Ecchymosis 5 3 Metabolic and Nutritional Disorders Weight gain 5 3 Peripheral edema 3 1 Musculoskeletal System Extremity pain (other than joint) 5 3 Joint pain 5 3 Nervous System Somnolence 29 13 Insomnia 12 11 Dizziness 11 4 Abnormal gait 6 1 Tremor 4 3 Akathisia 3 2 Hypertonia 3 2 Articulation impairment 2 1 Respiratory System Rhinitis 7 6 Cough increased 6 3 Pharyngitis 4 3 Special Senses Amblyopia 3 2 Urogenital System Urinary incontinence 2 1 Urinary tract infection 2 1 Dose Dependency of Adverse Reactions A dose System Rhinitis 7 6 Cough increased 6 3 Pharyngitis 4 3 Special Senses Amblyopia 3 2 Urogenital System Urinary incontinence 2 1 Urinary tract infection 2 1 Dose Dependency of Adverse Reactions A dose group difference has been observed for fatigue, dizziness, weight gain and prolactin elevation. In a single 8-week randomized, double-blind, fixed-dose study comparing 10 mg/day (N=199), 20 mg/day (N=200) and 40 mg/day (N=200) of oral olanzapine in adult patients with schizophrenia or schizoaffective disorder, incidence of fatigue (10 mg/day: 1.5%; 20 mg/day: 2.1%; 40 mg/day: 6.6%) was observed with significant differences between 10 mg/day vs 40 mg/day and 20 mg/day vs 40 mg/day. The incidence of dizziness (10 mg/day: 2.6%; 20 mg/day: 1.6%; 40 mg/day: 6.6%) was observed with significant differences between 20 mg vs 40 mg. Dose group differences were also noted for weight gain and prolactin elevation [see Warnings and Precautions ( 5.5 , 5.15 )] . The following table addresses dose relatedness for other adverse reactions using data from a schizophrenia trial involving fixed dosage ranges of oral olanzapine. It enumerates the percentage of patients with treatment-emergent adverse react dness for other adverse reactions using data from a schizophrenia trial involving fixed dosage ranges of oral olanzapine. It enumerates the percentage of patients with treatment-emergent adverse reactions for the 3 fixed-dose range groups and placebo. The data were analyzed using the Cochran-Armitage test, excluding the placebo group, and the table includes only those adverse reactions for which there was a trend. Table 12: Percentage of Patients from a Schizophrenia Trial with Treatment-Emergent Adverse Reactions for the 3 Dose Range Groups and Placebo Percentage of Patients Reporting Event Olanzapine Olanzapine Olanzapine Placebo 5 mg/day ± 2.5 mg/day 10 mg/day ± 2.5 mg/day 15 mg/day ± 2.5 mg/day Adverse Reaction (N=68) (N=65) (N=64) (N=69) Asthenia 15 8 9 20 Dry mouth 4 3 5 13 Nausea 9 0 2 9 Somnolence 16 20 30 39 Tremor 3 0 5 7 Commonly Observed Adverse Reactions in Short-Term Trials of Oral Olanzapine as Adjunct to Lithium or Valproate In the bipolar I disorder (manic or mixed episodes) adjunct placebo-controlled trials, the most commonly observed adverse reactions associated with the combination of olanzapine and lithium or valproate (incidence of ≥5% and at least twice place sodes) adjunct placebo-controlled trials, the most commonly observed adverse reactions associated with the combination of olanzapine and lithium or valproate (incidence of ≥5% and at least twice placebo) were: Table 13: Common Treatment-Emergent Adverse Reactions Associated with the Use of Oral Olanzapine in 6-Week Adjunct to Lithium or Valproate Trials — Bipolar I Disorder (Manic or Mixed Episodes) Adverse Reaction Percentage of Patients Reporting Event Olanzapine with lithium or valproate (N=229) Placebo with lithium or valproate (N=115) Dry mouth 32 9 Weight gain 26 7 Increased appetite 24 8 Dizziness 14 7 Back pain 8 4 Constipation 8 4 Speech disorder 7 1 Increased salivation 6 2 Amnesia 5 2 Paresthesia 5 2 Adverse Reactions Occurring at an Incidence of 2% or More among Oral Olanzapine-Treated Patients in Short-Term Trials of Olanzapine as Adjunct to Lithium or Valproate Table 14 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred in 2% or more of patients treated with the combination of olanzapine (doses ≥5 mg/day) and lithium or valproate and with incidence greater than lithium or valproate alone who participated in occurred in 2% or more of patients treated with the combination of olanzapine (doses ≥5 mg/day) and lithium or valproate and with incidence greater than lithium or valproate alone who participated in the acute phase of placebo-controlled combination trials. Table 14: Treatment-Emergent Adverse Reactions: Incidence in Short-Term, Placebo-Controlled Clinical Trials of Oral Olanzapine as Adjunct to Lithium or Valproate a Denominator used was for females only (olanzapine, N=128; placebo, N=51). Body System/Adverse Reaction Percentage of Patients Reporting Event Olanzapine with lithium or valproate (N=229) Placebo with lithium or valproate (N=115) Body as a Whole Asthenia 18 13 Back pain 8 4 Accidental injury 4 2 Chest pain 3 2 Cardiovascular System Hypertension 2 1 Digestive System Dry mouth 32 9 Increased appetite 24 8 Thirst 10 6 Constipation 8 4 Increased salivation 6 2 Metabolic and Nutritional Disorders Weight gain 26 7 Peripheral edema 6 4 Edema 2 1 Nervous System Somnolence 52 27 Tremor 23 13 Depression 18 17 Dizziness 14 7 Speech disorder 7 1 Amnesia 5 2 Paresthesia 5 2 Apathy 4 3 Confusion 4 1 Euphoria 3 2 Incoordination 2 0 Respiratory System Pharyngitis 4 1 Dyspnea 3 1 Skin emor 23 13 Depression 18 17 Dizziness 14 7 Speech disorder 7 1 Amnesia 5 2 Paresthesia 5 2 Apathy 4 3 Confusion 4 1 Euphoria 3 2 Incoordination 2 0 Respiratory System Pharyngitis 4 1 Dyspnea 3 1 Skin and Appendages Sweating 3 1 Acne 2 0 Dry skin 2 0 Special Senses Amblyopia 9 5 Abnormal vision 2 0 Urogenital System Dysmenorrhea a 2 0 Vaginitis a 2 0 For specific information about the adverse reactions observed with lithium or valproate, refer to the Adverse Reactions section of the package inserts for these other products. Extrapyramidal Symptoms The following table enumerates the percentage of patients with treatment-emergent extrapyramidal symptoms as assessed by categorical analyses of formal rating scales during acute therapy in a controlled clinical trial comparing oral olanzapine at 3 fixed doses with placebo in the treatment of schizophrenia in a 6-week trial. Table 16: Treatment-Emergent Extrapyramidal Symptoms Assessed by Rating Scales Incidence in a Fixed Dosage Range, Placebo-Controlled Clinical Trial of Oral Olanzapine in Schizophrenia — Acute Phase a Percentage of patients with a Simpson-Angus Scale total score >3. b Percentage of patients with a Barnes Akathisia Scale o-Controlled Clinical Trial of Oral Olanzapine in Schizophrenia — Acute Phase a Percentage of patients with a Simpson-Angus Scale total score >3. b Percentage of patients with a Barnes Akathisia Scale global score ≥2. Percentage of Patients Reporting Event Placebo Olanzapine 5 mg/day ± 2.5 mg/day Olanzapine 10 mg/day ± 2.5 mg/day Olanzapine 15 mg/day ± 2.5 mg/day Parkinsonism a 15 14 12 14 Akathisia b 23 16 19 27 The following table enumerates the percentage of patients with treatment-emergent extrapyramidal symptoms as assessed by spontaneously reported adverse reactions during acute therapy in the same controlled clinical trial comparing olanzapine at 3 fixed doses with placebo in the treatment of schizophrenia in a 6-week trial. Table 17: Treatment-Emergent Extrapyramidal Symptoms Assessed by Adverse Reactions Incidence in a Fixed Dosage Range, Placebo-Controlled Clinical Trial of Oral Olanzapine in Schizophrenia — Acute Phase a Patients with the following COSTART terms were counted in this category: dystonia, generalized spasm, neck rigidity, oculogyric crisis, opisthotonos, torticollis. b Patients with the following COSTART terms were counted in this category: akinesia, cogwhe in this category: dystonia, generalized spasm, neck rigidity, oculogyric crisis, opisthotonos, torticollis. b Patients with the following COSTART terms were counted in this category: akinesia, cogwheel rigidity, extrapyramidal syndrome, hypertonia, hypokinesia, masked facies, tremor. c Patients with the following COSTART terms were counted in this category: akathisia, hyperkinesia. d Patients with the following COSTART terms were counted in this category: buccoglossal syndrome, choreoathetosis, dyskinesia, tardive dyskinesia. e Patients with the following COSTART terms were counted in this category: movement disorder, myoclonus, twitching. Percentage of Patients Reporting Event Placebo (N=68) Olanzapine 5 mg/day ± 2.5 mg/day (N=65) Olanzapine 10 mg/day ± 2.5 mg/day (N=64) Olanzapine 15 mg/day ± 2.5 mg/day (N=69) Dystonic events a 1 3 2 3 Parkinsonism events b 10 8 14 20 Akathisia events c 1 5 11 10 Dyskinetic events d 4 0 2 1 Residual events e 1 2 5 1 Any extrapyramidal event 16 15 25 32 The following table enumerates the percentage of adolescent patients with treatment-emergent extrapyramidal symptoms as assessed by spontaneously reported adverse reactions during acute therapy (d 32 The following table enumerates the percentage of adolescent patients with treatment-emergent extrapyramidal symptoms as assessed by spontaneously reported adverse reactions during acute therapy (dose range: 2.5 mg/day to 20 mg/day). Table 18: Treatment-Emergent Extrapyramidal Symptoms Assessed by Adverse Reactions Incidence in Placebo-Controlled Clinical Trials of Oral Olanzapine in Schizophrenia and Bipolar I Disorder — Adolescents a Categories are based on Standard MedDRA Queries (SMQ) for extrapyramidal symptoms as defined in MedDRA version 12.0. Percentage of Patients Reporting Event Placebo Olanzapine Categories a (N=89) (N=179) Dystonic events 0 1 Parkinsonism events 2 1 Akathisia events 4 6 Dyskinetic events 0 1 Nonspecific events 0 4 Any extrapyramidal event 6 10 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, the frequency eck 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, the frequency and severity are greater with high potency and at higher doses of first generation antipsychotic drugs. In general, an elevated risk of acute dystonia may be observed in males and younger age groups receiving antipsychotics; however, events of dystonia have been reported infrequently (<1%) with olanzapine use. Other Adverse Reactions Other Adverse Reactions Observed During the Clinical Trial Evaluation of Oral Olanzapine Following is a list of treatment-emergent adverse reactions reported by patients treated with oral olanzapine (at multiple doses ≥1 mg/day) in clinical trials. This listing is not intended to include reactions (1) already listed in previous tables or elsewhere in labeling, (2) for which a drug cause was remote, (3) which were so general as to be uninformative, (4) which were not considered to have significant clinical implications, or (5) which occurred at a rate equal to or less than placebo. Reactions are classified by body system using the following definitions: fre re not considered to have significant clinical implications, or (5) which occurred at a rate equal to or less than placebo. Reactions are classified by body system using the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients. Body as a Whole — Infrequent: chills, face edema, photosensitivity reaction, suicide attempt 1 ; Rare: chills and fever, hangover effect, sudden death 1 . Cardiovascular System — Infrequent: cerebrovascular accident, vasodilatation. Digestive System — Infrequent: abdominal distension, nausea and vomiting, tongue edema; Rare: ileus, intestinal obstruction, liver fatty deposit. Hemic and Lymphatic System — Infrequent: thrombocytopenia. Metabolic and Nutritional Disorders — Frequent: alkaline phosphatase increased; Infrequent: bilirubinemia, hypoproteinemia. Musculoskeletal System — Rare: osteoporosis. Nervous System — Infrequent: ataxia, dysarthria, libido decreased, stupor; Rare: coma. Respiratory System — Infrequent: epistaxis; Rare: lung edema. Skin and Appendages — Infreq — Rare: osteoporosis. Nervous System — Infrequent: ataxia, dysarthria, libido decreased, stupor; Rare: coma. Respiratory System — Infrequent: epistaxis; Rare: lung edema. Skin and Appendages — Infrequent: alopecia. Special Senses — Infrequent: abnormality of accommodation, dry eyes; Rare: mydriasis. Urogenital System — Infrequent: amenorrhea 2 , breast pain, decreased menstruation, impotence 2 , increased menstruation 2 , menorrhagia 2 , metrorrhagia 2 , polyuria 2 , urinary frequency, urinary retention, urinary urgency, urination impaired. 1 These terms represent serious adverse events but do not meet the definition for adverse drug reactions. They are included here because of their seriousness. 2 Adjusted for gender. INDICATIONS: FeRivaFA ™ is a multivitamin/multimineral dietary supplement indicated for use in improving the nutritional status of patients with iron deficiency. DOSAGE AND ADMINISTRATION: One capsule daily with or without food or as prescribed by your healthcare provider. ADVERSE REACTIONS: Allergic sensitization has been reported following both oral and parenteral administration of folic acid. INDICATIONS AND USAGE To reduce the development of drug-resistant bacteria and maintain the effectiveness of sulfamethoxazole and trimethoprim tablets and other antibacterial drugs, sulfamethoxazole and trimethoprim 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 empiric selection of therapy. Urinary Tract Infections: For the treatment of urinary tract infections due to susceptible strains of the following organisms: Escherichia coli, Klebsiella species, Enterobacter species, Morganella morganii, Proteus mirabilis and Proteus vulgaris . It is recommended that initial episodes of uncomplicated urinary tract infections be treated with a single effective antibacterial agent rather than the combination. Acute Otitis Media: For the treatment of acute otitis media in pediatric patients due to susceptible strains of Streptococcus pneumoniae or Haemophilus influenzae when in the j r than the combination. Acute Otitis Media: For the treatment of acute otitis media in pediatric patients due to susceptible strains of Streptococcus pneumoniae or Haemophilus influenzae when in the judgment of the physician sulfamethoxazole and trimethoprim offers some advantage over the use of other antimicrobial agents. To date, there are limited data on the safety of repeated use of sulfamethoxazole and trimethoprim in pediatric patients under two years of age. Sulfamethoxazole and trimethoprim is not indicated for prophylactic or prolonged administration in otitis media at any age. Acute Exacerbations of Chronic Bronchitis in Adults: For the treatment of acute exacerbations of chronic bronchitis due to susceptible strains of Streptococcus pneumoniae or Haemophilus influenzae when a physician deems that sulfamethoxazole and trimethoprim could offer some advantage over the use of a single antimicrobial agent. Shigellosis: For the treatment of enteritis caused by susceptible strains of Shigella flexneri and Shigella sonnei when antibacterial therapy is indicated. Pneumocystis jiroveci Pneumonia: For the treatment of documented Pneumocystis jiroveci pneumonia and for prophylaxis a of Shigella flexneri and Shigella sonnei when antibacterial therapy is indicated. Pneumocystis jiroveci Pneumonia: For the treatment of documented Pneumocystis jiroveci pneumonia and for prophylaxis against P. jiroveci pneumonia in individuals who are immunosuppressed and considered to be at an increased risk of developing P. jiroveci pneumonia. Traveler's Diarrhea in Adults: For the treatment of traveler's diarrhea due to susceptible strains of enterotoxigenic E. coli. WARNINGS Embryofetal Toxicity Some epidemiologic studies suggest that exposure to sulfamethoxazole/trimethoprim during pregnancy may be associated with an increased risk of congenital malformations, particularly neural tube defects, cardiovascular malformations, urinary tract defects, oral clefts, and club foot. If sulfamethoxazole/trimethoprim is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be advised of the potential hazards to the fetus. Hypersensitivity and Other Fatal Reactions Fatalities associated with the administration of sulfonamides, although rare, have occurred due to severe reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, er Fatal Reactions Fatalities associated with the administration of sulfonamides, although rare, have occurred due to severe reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia and other blood dyscrasias. Sulfonamides, including sulfonamide-containing products such as sulfamethoxazole/trimethoprim, should be discontinued at the first appearance of skin rash or any sign of adverse reaction. In rare instances, a skin rash may be followed by a more severe reaction, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, hepatic necrosis, and serious blood disorders (see PRECAUTIONS ). Clinical signs, such as rash, sore throat, fever, arthralgia, pallor, purpura or jaundice may be early indications of serious reactions. Cough, shortness of breath, and pulmonary infiltrates are hypersensitivity reactions of the respiratory tract that have been reported in association with sulfonamide treatment. Thrombocytopenia Sulfamethoxazole/trimethoprim-induced thrombocytopenia may be an immune-mediated disorder. Severe cases of thrombocytopenia that are fatal or life threatening have been reported. Thrombocyto cytopenia Sulfamethoxazole/trimethoprim-induced thrombocytopenia may be an immune-mediated disorder. Severe cases of thrombocytopenia that are fatal or life threatening have been reported. Thrombocytopenia usually resolves within a week upon discontinuation of sulfamethoxazole/trimethoprim. Streptococcal Infections and Rheumatic Fever The sulfonamides should not be used for treatment of group A β-hemolytic streptococcal infections. In an established infection, they will not eradicate the streptococcus and, therefore, will not prevent sequelae such as rheumatic fever. Clostridium difficile associated diarrhea Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including sulfamethoxazole and trimethoprim, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile . C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require cole te to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile , and surgical evaluation should be instituted as clinically indicated. Adjunctive treatment with Leucovorin for Pneumocystis jiroveci pneumonia Treatment failure and excess mortality were observed when trimethoprim-sulfamethoxazole was used concomitantly with leucovorin for the treatment of HIV positive patients with Pneumocystis jiroveci pneumonia in a randomized placebo controlled trial. 6 Co-administration of trimethoprim-sulfamethoxazole and leucovorin during treatment of Pneumocystis jiroveci pneumonia should be avoided s jiroveci pneumonia in a randomized placebo controlled trial. 6 Co-administration of trimethoprim-sulfamethoxazole and leucovorin during treatment of Pneumocystis jiroveci pneumonia should be avoided. DOSAGE AND ADMINISTRATION Sulfamethoxazole and trimethoprim is contraindicated in pediatric patients less than 2 months of age. Urinary Tract Infections and Shigellosis in Adults and Pediatric Patients, and Acute Otitis Media in Children: Adults: The usual adult dosage in the treatment of urinary tract infections is 1 sulfamethoxazole and trimethoprim DS (double strength) tablet or 2 sulfamethoxazole and trimethoprim tablets every 12 hours for 10 to 14 days. An identical daily dosage is used for 5 days in the treatment of shigellosis. Children: The recommended dose for children with urinary tract infections or acute otitis media is 40 mg/kg sulfamethoxazole and 8 mg/kg trimethoprim per 24 hours, given in two divided doses every 12 hours for 10 days. An identical daily dosage is used for 5 days in the treatment of shigellosis. The following table is a guideline for the attainment of this dosage: Children 2 months of age or older: Weight Dose–every 12 hours lb kg Tablets 22 10 – 44 20 5 days in the treatment of shigellosis. The following table is a guideline for the attainment of this dosage: Children 2 months of age or older: Weight Dose–every 12 hours lb kg Tablets 22 10 – 44 20 1 66 30 1½ 88 40 2 or 1 DS tablet For Patients with Impaired Renal Function: When renal function is impaired, a reduced dosage should be employed using the following table: Creatinine Clearance (mL/min) Recommended Dosage Regimen Above 30 Usual standard regimen 15–30 ½ the usual regimen Below 15 Use not recommended Acute Exacerbations of Chronic Bronchitis in Adults: The usual adult dosage in the treatment of acute exacerbations of chronic bronchitis is 1 sulfamethoxazole and trimethoprim DS (double strength) tablet or 2 sulfamethoxazole and trimethoprim tablets every 12 hours for 14 days. Pneumocystis Jiroveci Pneumonia: Treatment: Adults and Children: The recommended dosage for treatment of patients with documented Pneumocystis jiroveci pneumonia is 75 to 100 mg/kg sulfamethoxazole and 15 to 20 mg/kg trimethoprim per 24 hours given in equally divided doses every 6 hours for 14 to 21 days. 11 The following table is a guideline for the upper limit of this dosage: Weight Dose–every 6 ho 5 to 20 mg/kg trimethoprim per 24 hours given in equally divided doses every 6 hours for 14 to 21 days. 11 The following table is a guideline for the upper limit of this dosage: Weight Dose–every 6 hours lb kg Tablets 18 8 – 35 16 1 53 24 1½ 70 32 2 or 1 DS tablet 88 40 2½ 106 48 3 or 1½ DS tablets 141 64 4 or 2 DS tablets 176 80 5 or 2½ DS tablets For the lower limit dose (75 mg/kg sulfamethoxazole and 15 mg/kg trimethoprim per 24 hours) administer 75% of the dose in the above table. Prophylaxis: Adults: The recommended dosage for prophylaxis in adults is 1 sulfamethoxazole and trimethoprim DS (double strength) tablet daily. 12 Children: For children, the recommended dose is 750 mg/m 2 /day sulfamethoxazole with 150 mg/m 2 /day trimethoprim given orally in equally divided doses twice a day, on 3 consecutive days per week. The total daily dose should not exceed 1600 mg sulfamethoxazole and 320 mg trimethoprim. 13 The following table is a guideline for the attainment of this dosage in children: Body Surface Area Dose–every 12 hours (m 2 ) Tablets 0.26 – 0.53 ½ 1.06 1 Traveler's Diarrhea in Adults: For the treatment of traveler's diarrhea, the usual adult dosage is 1 sulfamethoxazole hildren: Body Surface Area Dose–every 12 hours (m 2 ) Tablets 0.26 – 0.53 ½ 1.06 1 Traveler's Diarrhea in Adults: For the treatment of traveler's diarrhea, the usual adult dosage is 1 sulfamethoxazole and trimethoprim DS (double strength) tablet or 2 sulfamethoxazole and trimethoprim tablets every 12 hours for 5 days. ADVERSE REACTIONS The most common adverse effects are gastrointestinal disturbances (nausea, vomiting, anorexia) and allergic skin reactions (such as rash and urticaria). FATALITIES ASSOCIATED WITH THE ADMINISTRATION OF SULFONAMIDES, ALTHOUGH RARE, HAVE OCCURRED DUE TO SEVERE REACTIONS, INCLUDING STEVENS-JOHNSON SYNDROME, TOXIC EPIDERMAL NECROLYSIS, FULMINANT HEPATIC NECROSIS, AGRANULOCYTOSIS, APLASTIC ANEMIA AND OTHER BLOOD DYSCRASIAS (SEE WARNINGS SECTION). Hematologic: Agranulocytosis, aplastic anemia, thrombocytopenia, leukopenia, neutropenia, hemolytic anemia, megaloblastic anemia, hypoprothrombinemia, methemoglobinemia, eosinophilia. Allergic Reactions: Stevens-Johnson syndrome, toxic epidermal necrolysis, anaphylaxis, allergic myocarditis, erythema multiforme, exfoliative dermatitis, angioedema, drug fever, chills, Henoch-Schoenlein purpura, serum sickness-like son syndrome, toxic epidermal necrolysis, anaphylaxis, allergic myocarditis, erythema multiforme, exfoliative dermatitis, angioedema, drug fever, chills, Henoch-Schoenlein purpura, serum sickness-like syndrome, generalized allergic reactions, generalized skin eruptions, photosensitivity, conjunctival and scleral injection, pruritus, urticaria and rash. In addition, periarteritis nodosa and systemic lupus erythematosus have been reported. Gastrointestinal: Hepatitis (including cholestatic jaundice and hepatic necrosis), elevation of serum transaminase and bilirubin, pseudomembranous enterocolitis, pancreatitis, stomatitis, glossitis, nausea, emesis, abdominal pain, diarrhea, anorexia. Genitourinary: Renal failure, interstitial nephritis, BUN and serum creatinine elevation, toxic nephrosis with oliguria and anuria, crystalluria and nephrotoxicity in association with cyclosporine. Metabolic and Nutritional: Hyperkalemia, hyponatremia (see PRECAUTIONS: Electrolyte Abnormalities ). Neurologic: Aseptic meningitis, convulsions, peripheral neuritis, ataxia, vertigo, tinnitus, headache. Psychiatric: Hallucinations, depression, apathy, nervousness. Endocrine: The sulfonamides bear certain ch ic: Aseptic meningitis, convulsions, peripheral neuritis, ataxia, vertigo, tinnitus, headache. Psychiatric: Hallucinations, depression, apathy, nervousness. Endocrine: The sulfonamides bear certain chemical similarities to some goitrogens, diuretics (acetazolamide and the thiazides) and oral hypoglycemic agents. Cross-sensitivity may exist with these agents. Diuresis and hypoglycemia have occurred rarely in patients receiving sulfonamides. Musculoskeletal: Arthralgia and myalgia. Isolated cases of rhabdomyolysis have been reported with sulfamethoxazole and trimethoprim, mainly in AIDS patients. Respiratory: Cough, shortness of breath and pulmonary infiltrates (see WARNINGS ). Miscellaneous: Weakness, fatigue, insomnia. Postmarketing Experience The following adverse reactions have been identified during post-approval use of trimethoprim-sulfamethoxazole. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Thrombotic thrombocytopenia purpura Idiopathic thrombocytopenic purpura QT prolongation resulting in ventricular tachycardia and torsade d requency or establish a causal relationship to drug exposure: Thrombotic thrombocytopenia purpura Idiopathic thrombocytopenic purpura QT prolongation resulting in ventricular tachycardia and torsade de pointes INDICATIONS AND USAGE: For mydriasis and cycloplegia for diagnostic procedures. WARNINGS: For topical use only — not for injection. This preparation may cause CNS disturbances which may be dangerous in pediatric patients. The possibility of psychotic reactions and behavioral disturbances due to hypersensitivity to anticholinergic drugs should be considered. Mydriatics may produce a transient elevation of intraocular pressure. Remove contact lenses before using. DOSAGE AND ADMINISTRATION: For refraction, instill one or two drops of 1% solution in the eye(s), repeated in five minutes. If patient is not seen within 20 to 30 minutes, an additional drop may be instilled to prolong mydriatic effect. Individuals with heavily pigmented irides may require higher strength or more doses. Mydriasis will reverse spontaneously with time, typically in 4 to 8 hours. However, in some cases, complete recovery may take up to 24 hours. ADVERSE REACTIONS: Ocular: Transient stinging, blurred vision, photophobia and superficial punctate keratitis have been reported with the use of tropicamide. Increased intraocular pressure has been reported following the use of mydriatics. Non-Ocular: Dryness of the mou obia and superficial punctate keratitis have been reported with the use of tropicamide. Increased intraocular pressure has been reported following the use of mydriatics. Non-Ocular: Dryness of the mouth, tachycardia, headache, allergic reactions, nausea, vomiting, pallor, central nervous system disturbances and muscle rigidity have been reported with the use of tropicamide. Psychotic reactions, behavioral disturbances, and vasomotor or cardiorespiratory collapse in children have been reported with the use of anticholinergic drugs. INDICATIONS AND USAGE Sedative Anticonvulsant - For the treatment of generalized and partial seizures. WARNINGS Habit Forming. Phenobarbital may be habit forming. Tolerance and psychological and physical dependence may occur with continued use (see DRUG ABUSE AND DEPENDENCE and Pharmacokinetics under CLINICAL PHARMACOLOGY). Patients who have psychologic dependence on barbiturates may increase the dosage or decrease the dosage interval without consulting a physician and may subsequently develop a physical dependence on barbiturates. In order to minimize the possibility of overdosage or the development of dependence, the prescribing and dispensing of sedative-hypnotic barbiturates should be limited to the amount required for the interval until the next appointment. Abrupt cessation after prolonged use in a person who is dependent on the drug may result in withdrawal symptoms, including delirium, convulsions, and possibly death. Barbiturates should be withdrawn gradually from any patient known to be taking excessive doses over long periods of time (see DRUG ABUSE AND DEPENDENCE ). Acute or Chronic Pain. Caution should be exercised when barbiturates are administered to patients with ac known to be taking excessive doses over long periods of time (see DRUG ABUSE AND DEPENDENCE ). Acute or Chronic Pain. Caution should be exercised when barbiturates are administered to patients with acute or chronic pain, because paradoxical excitement could be induced or important symptoms could be masked. However, the use of barbiturates as sedatives in the postoperative surgical period and as adjuncts to cancer chemotherapy is well established. Usage in Pregnancy. Barbiturates can cause fetal damage when administered to a pregnant woman. Retrospective, case-controlled studies have suggested a connection between the maternal consumption of barbiturates and a higher than expected incidence of fetal abnormalities. Barbiturates readily cross the placental barrier and are distributed throughout fetal tissues; the highest concentrations are found in the placenta, fetal liver, and brain. Fetal blood levels approach maternal blood levels following parenteral administration. Withdrawal symptoms occur in infants born to women who receive barbiturates throughout the last trimester of pregnancy (see DRUG ABUSE AND DEPENDENCE ). If phenobarbital is used during pregnancy or if the patient beco ms occur in infants born to women who receive barbiturates throughout the last trimester of pregnancy (see DRUG ABUSE AND DEPENDENCE ). If phenobarbital is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Usage in Pediatric Patients. Phenobarbital has been reported to be associated with cognitive deficits in children taking it for complicated febrile seizures. Synergistic Effects. The concomitant use of alcohol or other CNS depressants may produce additive CNS depressant effects. DOSAGE AND ADMINISTRATION The dose of phenobarbital must be individualized with full knowledge of its particular characteristics. Factors of consideration are the patient's age, weight, and condition. Sedation For sedation, the drug may be administered in single dose of 30 to 120 mg repeated at intervals: frequency will be determined by the patient's response. It is generally considered that no more than 400 mg of phenobarbital should be administered during a 24-hour period. Adults Daytime Sedation: 30 to 120 mg daily in 2 to 3 divided doses. Oral Hypnotic: 100 to 200 mg. Anticonvulsant Use Clinical laborat of phenobarbital should be administered during a 24-hour period. Adults Daytime Sedation: 30 to 120 mg daily in 2 to 3 divided doses. Oral Hypnotic: 100 to 200 mg. Anticonvulsant Use Clinical laboratory reference values should be used to determine the therapeutic anticonvulsant level of phenobarbital in the serum. To achieve the blood levels considered therapeutic in pediatric patients, higher per-kilogram dosages are generally necessary for phenobarbital and most other anticonvulsants. In children and infants, phenobarbital at a loading dose of 15 to 20 mg/kg produces blood levels of about 20 mcg/mL shortly after administration. Phenobarbital has been used in the treatment and prophylaxis of febrile seizures. However, it has not been established that prevention of febrile seizures influences the subsequent development of epilepsy. Adults: 60 to 200 mg/day. Pediatric Patients: 3 to 6 mg/kg/day. Special Patient Population Dosage should be reduced in the elderly or debilitated because these patients may be more sensitive to barbiturates. Dosage should be reduced for patients with impaired renal function or hepatic disease. ADVERSE REACTIONS The following adverse reactions have been hese patients may be more sensitive to barbiturates. Dosage should be reduced for patients with impaired renal function or hepatic disease. ADVERSE REACTIONS The following adverse reactions have been reported: CNS Depression – Residual sedation or "hangover", drowsiness, lethargy, and vertigo. Emotional disturbances and phobias may be accentuated. In some persons, barbiturates such as phenobarbital repeatedly produce excitement rather than depression, and the patient may appear to be inebriated. Irritability and hyperactivity can occur in children. Like other nonanalgesic hypnotic drugs, barbiturates such as phenobarbital, when given in the presence of pain, may cause restlessness, excitement, and even delirium. Rarely, the use of barbiturates results in localized or diffuse myalgic, neuralgic, or arthritic pain, especially in psychoneurotic patients with insomnia. The pain may appear in paroxysms, is most intense in the early morning hours, and is most frequently located in the region of the neck, shoulder girdle, and upper limbs. Symptoms may last for days after the drug is discontinued. Respiratory/Circulatory – Respiratory depression, apnea, circulatory collapse. Allergic – Acq of the neck, shoulder girdle, and upper limbs. Symptoms may last for days after the drug is discontinued. Respiratory/Circulatory – Respiratory depression, apnea, circulatory collapse. Allergic – Acquired hypersensitivity to barbiturates consists chiefly in allergic reactions that occur especially in persons who tend to have asthma, urticaria, angioedema, and similar conditions. Hypersensitivity reactions in this category include localized swelling, particularly of the eyelids, cheeks, or lips, and erythematous dermatitis. Rarely, exfoliative dermatitis (e.g., Stevens-Johnson syndrome and toxic epidermal necrolysis) may be caused by phenobarbital and can prove fatal. The skin eruption may be associated with fever, delirium, and marked degenerative changes in the liver and other parenchymatous organs. In a few cases, megaloblastic anemia has been associated with the chronic use of phenobarbital. Other – Nausea and vomiting; headache, osteomalacia. The following adverse reactions and their incidence were compiled from surveillance of thousands of hospitalized patients who received barbiturates. Because such patients may be less aware of the milder adverse effects of barbiturates, th eir incidence were compiled from surveillance of thousands of hospitalized patients who received barbiturates. Because such patients may be less aware of the milder adverse effects of barbiturates, the incidence of these reactions may be somewhat higher in fully ambulatory patients. More than 1 in 100 Patients The most common adverse reaction, estimated to occur at a rate of 1 to 3 patients per 100, is: Nervous System: Somnolence Less than 1 in 100 Patients Adverse reactions estimated to occur at a rate of less than 1 in 100 patients are listed below, grouped by organ system and by decreasing order of occurrence: Nervous System: Agitation, confusion, hyperkinesia, ataxia, CNS depression, nightmares, nervousness, psychiatric disturbance, hallucinations, insomnia, anxiety, dizziness, abnormality in thinking Respiratory System: Hypoventilation, apnea Cardiovascular System: Bradycardia, hypotension, syncope Digestive System: Nausea, vomiting, constipation Other Reported Reactions: Headache, injection site reactions, hypersensitivity reactions (angioedema, skin rashes, exfoliative dermatitis), fever, liver damage, megaloblastic anemia following chronic phenobarbital use. 1 INDICATIONS AND USAGE BKEMV is a complement inhibitor indicated for: The treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis. ( 1.1 ) The treatment of patients with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy. ( 1.2 ) Limitation of Use BKEMV is not indicated for the treatment of patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS). The treatment of generalized myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AchR) antibody positive. ( 1.3 ) 1.1 Paroxysmal Nocturnal Hemoglobinuria (PNH) BKEMV is indicated for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis. 1.2 Atypical Hemolytic Uremic Syndrome (aHUS) BKEMV is indicated for the treatment of patients with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy. Limitation of Use BKEMV is not indicated for the treatment of patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS). 1.3 Generalized Myasthenia Gravis (gMG) BKEMV is indicated for treatment of generalized myasthenia for the treatment of patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS). 1.3 Generalized Myasthenia Gravis (gMG) BKEMV is indicated for treatment of generalized myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AchR) antibody positive. 2 DOSAGE AND ADMINISTRATION For intravenous infusion only PNH Dosage Regimen: ( 2.2 ) aHUS Dosage Regimen: ( 2.3 ) gMG Dosage Regimen: ( 2.4 ) 2.1 Recommended Vaccination and Prophylaxis for Meningococcal Infection Vaccinate patients against meningococcal infection (serogroups A, C, W, Y and B) according to current ACIP recommendations at least 2 weeks prior to initiation of BKEMV [ see Warnings and Precautions (5.1) ]. If urgent BKEMV therapy is indicated in a patient who is not up to date with meningococcal vaccines according to ACIP recommendations, provide the patient with antibacterial drug prophylaxis and administer these vaccines as soon as possible. Healthcare providers who prescribe BKEMV must enroll in the BKEMV REMS [see Warnings and Precautions (5.2) ]. 2.2 Recommended Dosage Regimen – PNH For patients 18 years of age and older, BKEMV therapy consists of: 600 mg weekly for the firs must enroll in the BKEMV REMS [see Warnings and Precautions (5.2) ]. 2.2 Recommended Dosage Regimen – PNH For patients 18 years of age and older, BKEMV therapy consists of: 600 mg weekly for the first 4 weeks, followed by 900 mg for the fifth dose 1 week later, then 900 mg every 2 weeks thereafter. Administer BKEMV at the recommended dosage regimen time points, or within two days of these time points [see Warnings and Precautions (5.4) ]. 2.3 Recommended Dosage Regimen – aHUS For patients 18 years of age and older, BKEMV therapy consists of: 900 mg weekly for the first 4 weeks, followed by 1,200 mg for the fifth dose 1 week later, then 1,200 mg every 2 weeks thereafter. For patients less than 18 years of age, administer BKEMV based upon body weight, according to the following schedule (Table 1): Table 1: Dosing Recommendations in aHUS Patients Less Than 18 Years of Age Patient Body Weight Induction Maintenance 40 kg and over 900 mg weekly × 4 doses 1,200 mg at week 5; then 1,200 mg every 2 weeks 30 kg to less than 40 kg 600 mg weekly × 2 doses 900 mg at week 3; then 900 mg every 2 weeks 20 kg to less than 30 kg 600 mg weekly × 2 doses 600 mg at week 3; then 600 mg every 2 weeks 10 ery 2 weeks 30 kg to less than 40 kg 600 mg weekly × 2 doses 900 mg at week 3; then 900 mg every 2 weeks 20 kg to less than 30 kg 600 mg weekly × 2 doses 600 mg at week 3; then 600 mg every 2 weeks 10 kg to less than 20 kg 600 mg weekly × 1 dose 300 mg at week 2; then 300 mg every 2 weeks 5 kg to less than 10 kg 300 mg weekly × 1 dose 300 mg at week 2; then 300 mg every 3 weeks Administer BKEMV at the recommended dosage regimen time points, or within two days of these time points. 2.4 Recommended Dosage Regimen – gMG For adult patients with generalized myasthenia gravis, BKEMV therapy consists of: 900 mg weekly for the first 4 weeks, followed by 1,200 mg for the fifth dose 1 week later, then 1,200 mg every 2 weeks thereafter. Administer BKEMV at the recommended dosage regimen time points, or within two days of these time points. 2.5 Dose Adjustment in Case of Plasmapheresis, Plasma Exchange, or Fresh Frozen Plasma Infusion For adult and pediatric patients with aHUS, and adult patients with gMG, supplemental dosing of BKEMV is required in the setting of concomitant plasmapheresis or plasma exchange, or fresh frozen plasma infusion (PE/PI) (Table 2). Table 2: Supplemental Dose of BKE with gMG, supplemental dosing of BKEMV is required in the setting of concomitant plasmapheresis or plasma exchange, or fresh frozen plasma infusion (PE/PI) (Table 2). Table 2: Supplemental Dose of BKEMV after PE/PI Type of Plasma Intervention Most Recent BKEMV Dose Supplemental BKEMV Dose with Each Plasma Intervention Timing of Supplemental BKEMV Dose Plasmapheresis or plasma exchange 300 mg 300 mg per each plasmapheresis or plasma exchange session Within 60 minutes after each plasmapheresis or plasma exchange 600 mg or greater 600 mg per each plasmapheresis or plasma exchange session Fresh frozen plasma infusion 300 mg or greater 300 mg per infusion of fresh frozen plasma 60 minutes prior to each infusion of fresh frozen plasma 2.6 Preparation Dilute BKEMV to a final admixture concentration of 5 mg/mL using the following steps: Withdraw the required amount of BKEMV from the vial into a sterile syringe. Transfer the recommended dose to an infusion bag. Dilute BKEMV to a final concentration of 5 mg/mL by adding the appropriate amount (equal volume of diluent to drug volume) of 0.9% Sodium Chloride Injection, USP; 0.45% Sodium Chloride Injection, USP; 5% Dextrose in Water Injection, tion of 5 mg/mL by adding the appropriate amount (equal volume of diluent to drug volume) of 0.9% Sodium Chloride Injection, USP; 0.45% Sodium Chloride Injection, USP; 5% Dextrose in Water Injection, USP; or Ringer's Injection, USP to the infusion bag. The final admixed BKEMV 5 mg/mL infusion volume is 60 mL for 300 mg doses, 120 mL for 600 mg doses, 180 mL for 900 mg doses or 240 mL for 1,200 mg doses (Table 3). Table 3: Preparation and Reconstitution of BKEMV BKEMV Dose Diluent Volume Final Volume 300 mg 30 mL 60 mL 600 mg 60 mL 120 mL 900 mg 90 mL 180 mL 1,200 mg 120 mL 240 mL Gently invert the infusion bag containing the diluted BKEMV solution to ensure thorough mixing of the product and diluent. Discard any unused portion left in a vial, as the product contains no preservatives. Prior to administration, the admixture should be allowed to adjust to room temperature [18°C to 25°C (64°F to 77°F)]. The admixture must not be heated in a microwave or with any heat source other than ambient air temperature. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. 2.7 Administration ent air temperature. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. 2.7 Administration Only administer as an intravenous infusion. Do not administer as an intravenous push or bolus injection. Administer the BKEMV admixture by intravenous infusion over 35 minutes in adults and 1 to 4 hours in pediatric patients via gravity feed, a syringe-type pump, or an infusion pump. Admixed solutions of BKEMV are stable for 64 hours at 2°C to 8°C (36°F to 46°F) or 24 hours at room temperature. If an adverse reaction occurs during the administration of BKEMV, the infusion may be slowed or stopped at the discretion of the physician. If the infusion is slowed, the total infusion time should not exceed two hours in adults. Monitor the patient for at least one hour following completion of the infusion for signs or symptoms of an infusion-related reaction. 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: Serious Meningococcal Infections [ see Warnings and Precautions (5.1) ] Other Infections [ see Warnings and Pre ous adverse reactions are discussed in greater detail in other sections of the labeling: Serious Meningococcal Infections [ see Warnings and Precautions (5.1) ] Other Infections [ see Warnings and Precautions (5.3) ] Monitoring Disease Manifestations after BKEMV Discontinuation [ see Warnings and Precautions (5.4) ] Thrombosis Prevention and Management [ see Warnings and Precautions (5.5) ] Infusion-Related Reactions [ see Warnings and Precautions (5.6) ] The most frequently reported adverse reactions in the PNH randomized trial (≥10% overall and greater than placebo) are: headache, nasopharyngitis, back pain, and nausea. ( 6.1 ) The most frequently reported adverse reactions in aHUS single arm prospective trials (≥20%) are: headache, diarrhea, hypertension, upper respiratory infection, abdominal pain, vomiting, nasopharyngitis, anemia, cough, peripheral edema, nausea, urinary tract infections, pyrexia. ( 6.1 ) The most frequently reported adverse reaction in the gMG placebo-controlled clinical trial (≥10%) is musculoskeletal pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Amgen Medical Information at 1-800-77-AMGEN (1-800-772-6436) or FDA at 1-800-FDA-1088 or www.fda. clinical trial (≥10%) is musculoskeletal pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Amgen Medical Information at 1-800-77-AMGEN (1-800-772-6436) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Meningococcal infections are the most important adverse reactions experienced by patients receiving eculizumab. In PNH clinical studies, two patients experienced meningococcal sepsis. Both patients had previously received a meningococcal vaccine. In clinical studies among patients without PNH, meningococcal meningitis occurred in one unvaccinated patient. Meningococcal sepsis occurred in one previously vaccinated patient enrolled in the retrospective aHUS study during the post-study follow-up period [ see Warnings and Precautions (5.1) ]. PNH The data described below reflect exposure to eculizumab in 196 adult patients with PNH, age 18-85, of whom 55% were female. All had signs or s low-up period [ see Warnings and Precautions (5.1) ]. PNH The data described below reflect exposure to eculizumab in 196 adult patients with PNH, age 18-85, of whom 55% were female. All had signs or symptoms of intravascular hemolysis. Eculizumab was studied in a placebo-controlled clinical study (PNH Study 1, in which 43 patients received eculizumab and 44, placebo); a single arm clinical study (PNH Study 2); and a long term extension study (E05-001). One hundred and eighty two patients were exposed for greater than one year. All patients received the recommended eculizumab dose regimen. Table 4 summarizes the adverse reactions that occurred at a numerically higher rate in the eculizumab group than the placebo group and at a rate of 5% or more among patients treated with eculizumab. Table 4: Adverse Reactions Reported in 5% or More of Eculizumab Treated Patients with PNH and Greater than Placebo in the Controlled Clinical Study Reaction eculizumab (N = 43) N (%) Placebo (N = 44) N (%) Headache 19 (44) 12 (27) Nasopharyngitis 10 (23) 8 (18) Back pain 8 (19) 4 (9) Nausea 7 (16) 5 (11) Fatigue 5 (12) 1 (2) Cough 5 (12) 4 (9) Herpes simplex infections 3 (7) 0 Sinusitis 3 (7) 0 Respira Headache 19 (44) 12 (27) Nasopharyngitis 10 (23) 8 (18) Back pain 8 (19) 4 (9) Nausea 7 (16) 5 (11) Fatigue 5 (12) 1 (2) Cough 5 (12) 4 (9) Herpes simplex infections 3 (7) 0 Sinusitis 3 (7) 0 Respiratory tract infection 3 (7) 1 (2) Constipation 3 (7) 2 (5) Myalgia 3 (7) 1 (2) Pain in extremity 3 (7) 1 (2) Influenza-like illness 2 (5) 1 (2) In the placebo-controlled clinical study, serious adverse reactions occurred among 4 (9%) patients receiving eculizumab and 9 (21%) patients receiving placebo. The serious reactions included infections and progression of PNH. No deaths occurred in the study and no patients receiving eculizumab experienced a thrombotic event; one thrombotic event occurred in a patient receiving placebo. Among 193 patients with PNH treated with eculizumab in the single arm, clinical study or the follow-up study, the adverse reactions were similar to those reported in the placebo-controlled clinical study. Serious adverse reactions occurred among 16% of the patients in these studies. The most common serious adverse reactions were: viral infection (2%), headache (2%), anemia (2%), and pyrexia (2%). aHUS The safety of eculizumab therapy in patients with aHUS was eval these studies. The most common serious adverse reactions were: viral infection (2%), headache (2%), anemia (2%), and pyrexia (2%). aHUS The safety of eculizumab therapy in patients with aHUS was evaluated in four prospective, single-arm studies, three in adult and adolescent patients (Studies C08-002A/B, C08-003A/B, and C10-004), one in pediatric and adolescent patients (Study C10-003), and one retrospective study (Study C09-001r). The data described below were derived from 78 adult and adolescent patients with aHUS in Studies C08-002A/B, C08-003A/B and C10-004. All patients received the recommended dosage of eculizumab. Median exposure was 67 weeks (range: 2-145 weeks). Table 5 summarizes all adverse events reported in at least 10% of patients in Studies C08-002A/B, C08-003A/B and C10-004 combined. Table 5: Per Patient Incidence of Adverse Events in 10% or More Adult and Adolescent Patients Enrolled in Studies C08-002A/B, C08-003A/B and C10-004 Separately and in Total Number (%) of Patients C08-002A/B (N=17) C08-003A/B (N=20) C10-004 (N=41) Total (N=78) Vascular Disorders Hypertension includes the preferred terms hypertension, accelerated hypertension, and malignant hypertension. atients C08-002A/B (N=17) C08-003A/B (N=20) C10-004 (N=41) Total (N=78) Vascular Disorders Hypertension includes the preferred terms hypertension, accelerated hypertension, and malignant hypertension. 10 (59) 9 (45) 7 (17) 26 (33) Hypotension 2 (12) 4 (20) 7 (17) 13 (17) Infections and Infestations Bronchitis 3 (18) 2 (10) 4 (10) 9 (12) Nasopharyngitis 3 (18) 11 (55) 7 (17) 21 (27) Gastroenteritis 3 (18) 4 (20) 2 (5) 9 (12) Upper respiratory tract infection 5 (29) 8 (40) 2 (5) 15 (19) Urinary tract infection 6 (35) 3 (15) 8 (20) 17 (22) Gastrointestinal Disorders Diarrhea 8 (47) 8 (40) 12 (32) 29 (37) Vomiting 8 (47) 9 (45) 6 (15) 23 (30) Nausea 5 (29) 8 (40) 5 (12) 18 (23) Abdominal pain 3 (18) 6 (30) 6 (15) 15 (19) Nervous System Disorders Headache 7 (41) 10 (50) 15 (37) 32 (41) Blood and Lymphatic System Disorders Anemia 6 (35) 7 (35) 7 (17) 20 (26) Leukopenia 4 (24) 3 (15) 5 (12) 12 (15) Psychiatric Disorders Insomnia 4 (24) 2 (10) 5 (12) 11 (14) Renal and Urinary Disorders Renal Impairment 5 (29) 3 (15) 6 (15) 14 (18) Proteinuria 2 (12) 1 (5) 5 (12) 8 (10) Respiratory, Thoracic and Mediastinal Disorders Cough 4 (24) 6 (30) 8 (20) 18 (23) General Disorders and Administration Si mpairment 5 (29) 3 (15) 6 (15) 14 (18) Proteinuria 2 (12) 1 (5) 5 (12) 8 (10) Respiratory, Thoracic and Mediastinal Disorders Cough 4 (24) 6 (30) 8 (20) 18 (23) General Disorders and Administration Site Conditions Fatigue 3 (18) 4 (20) 3 (7) 10 (13) Peripheral edema 5 (29) 4 (20) 9 (22) 18 (23) Pyrexia 4 (24) 5 (25) 7 (17) 16 (21) Asthenia 3 (18) 4 (20) 6 (15) 13 (17) Eye Disorder 5 (29) 2 (10) 8 (20) 15 (19) Metabolism and Nutrition Disorders Hypokalemia 3 (18) 2 (10) 4 (10) 9 (12) Neoplasms benign, malignant, and unspecified (including cysts and polyps) 1 (6) 6 (30) 1 (20) 8 (10) Skin and Subcutaneous Tissue Disorders Rash 2 (12) 3 (15) 6 (15) 11 (14) Pruritus 1 (6) 3 (15) 4 (10) 8 (10) Musculoskeletal and Connective Tissue Disorders Arthralgia 1 (6) 2 (10) 7 (17) 10 (13) Back pain 3 (18) 3 (15) 2 (5) 8 (10) In Studies C08-002A/B, C08-003A/B and C10-004 combined, 60% (47/78) of patients experienced a serious adverse event (SAE). The most commonly reported SAEs were infections (24%), hypertension (5%), chronic renal failure (5%), and renal impairment (5%). Five patients discontinued eculizumab due to adverse events; three due to worsening renal function, one due to new diagnosis o hypertension (5%), chronic renal failure (5%), and renal impairment (5%). Five patients discontinued eculizumab due to adverse events; three due to worsening renal function, one due to new diagnosis of Systemic Lupus Erythematosus, and one due to meningococcal meningitis. Study C10-003 included 22 pediatric and adolescent patients, of which 18 patients were less than 12 years of age. All patients received the recommended dosage of eculizumab. Median exposure was 44 weeks (range: 1 dose-87 weeks). Table 6 summarizes all adverse events reported in at least 10% of patients enrolled in Study C10-003. Table 6: Per Patient Incidence of Adverse Reactions in 10% or More Patients Enrolled in Study C10-003 1 month to <12 yrs (N=18) Total (N=22) Eye Disorders 3 (17) 3 (14) Gastrointestinal Disorders Abdominal pain 6 (33) 7 (32) Diarrhea 5 (28) 7 (32) Vomiting 4 (22) 6 (27) Dyspepsia 0 3 (14) General Disorders and Administration Site Conditions Pyrexia 9 (50) 11 (50) Infections and Infestations Upper respiratory tract infection 5 (28) 7 (32) Nasopharyngitis 3 (17) 6 (27) Rhinitis 4 (22) 4 (18) Urinary Tract infection 3 (17) 4 (18) Catheter site infection 3 (17) 3 (14) Musculoskeletal and Conne per respiratory tract infection 5 (28) 7 (32) Nasopharyngitis 3 (17) 6 (27) Rhinitis 4 (22) 4 (18) Urinary Tract infection 3 (17) 4 (18) Catheter site infection 3 (17) 3 (14) Musculoskeletal and Connective Tissue Disorders Muscle spasms 2 (11) 3 (14) Nervous System Disorders Headache 3 (17) 4 (18) Renal and Urinary Disorders 3 (17) 4 (18) Respiratory, Thoracic and Mediastinal Disorders Cough 7 (39) 8 (36) Oropharyngeal pain 1 (6) 3 (14) Skin and Subcutaneous Tissue Disorders Rash 4 (22) 4 (18) Vascular Disorders Hypertension 4 (22) 4 (18) In Study C10-003, 59% (13/22) of patients experienced a serious adverse event (SAE). The most commonly reported SAEs were hypertension (9%), viral gastroenteritis (9%), pyrexia (9%), and upper respiratory infection (9%). One patient discontinued eculizumab due to an adverse event (severe agitation). Analysis of retrospectively collected adverse event data from pediatric and adult patients enrolled in Study C09-001r (N=30) revealed a safety profile that was similar to that which was observed in the two prospective studies. Study C09-001r included 19 pediatric patients less than 18 years of age. Overall, the safety of eculizumab in pediatric patient t was similar to that which was observed in the two prospective studies. Study C09-001r included 19 pediatric patients less than 18 years of age. Overall, the safety of eculizumab in pediatric patients with aHUS enrolled in Study C09-001r appeared similar to that observed in adult patients. The most common (≥15%) adverse events occurring in pediatric patients are presented in Table 7. Table 7: Adverse Reactions Occurring in at Least 15% of Patients Less than 18 Years of Age Enrolled in Study C09-001r Number (%) of Patients <2 yrs (N=5) 2 to <12 yrs (N=10) 12 to <18 yrs (N=4) Total (N=19) General Disorders and Administration Site Conditions Pyrexia 4 (80) 4 (40) 1 (25) 9 (47) Gastrointestinal Disorders Diarrhea 1 (20) 4 (40) 1 (25) 6 (32) Vomiting 2 (40) 1 (10) 1 (25) 4 (21) Infections and Infestations Upper respiratory tract infection includes the preferred terms upper respiratory tract infection and nasopharyngitis. 2 (40) 3 (30) 1 (25) 6 (32) Respiratory, Thoracic and Mediastinal Disorders Cough 3 (60) 2 (20) 0 (0) 5 (26) Nasal congestion 2 (40) 2 (20) 0 (0) 4 (21) Cardiac Disorders Tachycardia 2 (40) 2 (20) 0 (0) 4 (21) Generalized Myasthenia Gravis (gMG) In a 26-week placebo-co orders Cough 3 (60) 2 (20) 0 (0) 5 (26) Nasal congestion 2 (40) 2 (20) 0 (0) 4 (21) Cardiac Disorders Tachycardia 2 (40) 2 (20) 0 (0) 4 (21) Generalized Myasthenia Gravis (gMG) In a 26-week placebo-controlled trial evaluating the effect of eculizumab for the treatment of gMG (gMG Study 1), 62 patients received eculizumab at the recommended dosage regimen and 63 patients received placebo [see Clinical Studies (14.3) ] . Patients were 19 to 79 years of age, and 66% were female. Table 8 displays the most common adverse reactions from gMG Study 1 that occurred in ≥ 5% of eculizumab-treated patients and at a greater frequency than on placebo. Table 8: Adverse Reactions Reported in 5% or More of Eculizumab-Treated Patients in gMG Study 1 and at a Greater Frequency than in Placebo-Treated Patients eculizumab (N=62) N(%) Placebo (N=63) N(%) Gastrointestinal Disorders Abdominal pain 5 (8) 3 (5) General Disorders and Administration Site Conditions Peripheral edema 5 (8) 3 (5) Pyrexia 4 (7) 2 (3) Infections and Infestations Herpes simplex virus infections 5 (8) 1 (2) Injury, Poisoning, and Procedural Complications Contusion 5 (8) 2 (3) Musculoskeletal and Connective Tissue Disorders Musculosk Infections and Infestations Herpes simplex virus infections 5 (8) 1 (2) Injury, Poisoning, and Procedural Complications Contusion 5 (8) 2 (3) Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain 9 (15) 5 (8) The most common adverse reactions (≥ 10%) that occurred in eculizumab-treated patients in the long-term extension to gMG Study 1, Study ECU-MG-302, and that are not included in Table 8 were headache (26%), nasopharyngitis (24%), diarrhea (15%), arthralgia (12%), upper respiratory tract infection (11%), and nausea (10%). 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of eculizumab products. 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 eculizumab products exposure. Adverse Reactions from Postmarketing Spontaneous Reports Fatal or serious infections: Neisseria gonorrhoeae, Neisseria meningitidis, Neisseria sicca/subflava, Neisseria spp unspecified. Cases of cholestatic or mixed pattern liver injury with increased serum liver enzymes and bilirubin levels have been re ae, Neisseria meningitidis, Neisseria sicca/subflava, Neisseria spp unspecified. Cases of cholestatic or mixed pattern liver injury with increased serum liver enzymes and bilirubin levels have been reported in adult and pediatric patients with aHUS who were treated with eculizumab. These events occurred within 3 to 27 days after starting treatment. The median time to resolution (or return to baseline) was approximately 3 weeks. How to use; At the last stage of basic care, apply an appropriate amount to the face, neck, arms, and legs that are easily exposed to UV rays. skin protect Precautions when using 1. When using cosmetics or after use, if there are any abnormal symptoms or side effects such as red spots, swelling, or itching in the area of use due to direct sunlight, consult with a specialist. 2. Refrain from using on areas with scars, etc. 3. Precautions for storage and handling A) Keep out of reach of children B) Store away from direct sunlight. topical use only KEEP OUT OF REACH OF THE CHILDREN INDICATIONS & USAGE Metronidazole vaginal gel USP, 0.75% is indicated in the treatment of bacterial vaginosis (formerly referred to as Haemophilus vaginitis, Gardnerella vaginitis, nonspecific vaginitis, Corynebacterium vaginitis, or anaerobic vaginosis). NOTE: For purposes of this indication, a clinical diagnosis of bacterial vaginosis is usually defined by the presence of a homogeneous vaginal discharge that (a) has a pH of greater than 4.5, (b) emits a “fishy” amine odor when mixed with a 10% KOH solution, and (c) contains clue cells on microscopic examination. Gram’s stain results consistent with a diagnosis of bacterial vaginosis include (a) markedly reduced or absent Lactobacillus morphology, (b) predominance of Gardnerella morphotype, and (c) absent or few white blood cells. Other pathogens commonly associated with vulvovaginitis, e.g., Trichomonas vaginalis , Chlamydia trachomatis , N . gonorrhoeae , Candida albicans , and Herpes simplex virus should be ruled out. WARNINGS Convulsive Seizures and Peripheral Neuropathy: Convulsive seizures and peripheral neuropathy, the latter characterized mainly by numbness or paresthesia of an extremity, have been reported in patients tre ulsive Seizures and Peripheral Neuropathy: Convulsive seizures and peripheral neuropathy, the latter characterized mainly by numbness or paresthesia of an extremity, have been reported in patients treated with oral or intravenous metronidazole. The appearance of abnormal neurologic signs demands the prompt discontinuation of metronidazole vaginal gel therapy. Metronidazole vaginal gel should be administered with caution to patients with central nervous system diseases. Psychotic Reactions: Psychotic reactions have been reported in alcoholic patients who were using oral metronidazole and disulfiram concurrently. Metronidazole vaginal gel should not be administered to patients who have taken disulfiram within the last two weeks. DOSAGE & ADMINISTRATION The recommended dose is one applicator full of metronidazole vaginal gel USP, 0.75% (approximately 5 grams containing approximately 37.5 mg of metronidazole) intravaginally once or twice a day for 5 days. For once a day dosing, metronidazole vaginal gel USP, 0.75% should be administered at bedtime. ADVERSE REACTIONS Clinical Trials There were no deaths or serious adverse events related to drug therapy in clinical trials involving 800 n le vaginal gel USP, 0.75% should be administered at bedtime. ADVERSE REACTIONS Clinical Trials There were no deaths or serious adverse events related to drug therapy in clinical trials involving 800 non-pregnant women who received metronidazole vaginal gel USP, 0.75%. In a randomized, single-blind clinical trial of 505 non-pregnant women who received metronidazole vaginal gel USP, 0.75% once or twice a day, 2 patients (one from each regimen) discontinued therapy early due to drug-related adverse events. One patient discontinued drug because of moderate abdominal cramping and loose stools, while the other patient discontinued drug because of mild vaginal burning. These symptoms resolved after discontinuation of drug. Medical events judged to be related, probably related, or possibly related to administration of metronidazole vaginal gel USP, 0.75% once or twice a day were reported for 195/505 (39%) patients. The incidence of individual adverse reactions were not significantly different between the two regimens. Unless percentages are otherwise stipulated, the incidence of individual adverse reactions listed below was less than 1%: Reproductive: Vaginal discharge (12%), Symptomatic C between the two regimens. Unless percentages are otherwise stipulated, the incidence of individual adverse reactions listed below was less than 1%: Reproductive: Vaginal discharge (12%), Symptomatic Candida cervicitis/vaginitis (10%), Vulva/vaginal irritative symptoms (9%), Pelvic discomfort (3%). Gastrointestinal: Gastrointestinal discomfort (7%), Nausea and/or vomiting (4%), Unusual taste (2%), Diarrhea/loose stools (1%), Decreased appetite (1%), Abdominal bloating/gas; thirsty, dry mouth. Neurologic: Headache (5%), Dizziness (2%), Depression. Dermatologic: Generalized itching or rash. Other: Unspecified cramping (1%), Fatigue, Darkened urine. In previous clinical trials submitted for approved labeling of metronidazole vaginal gel USP, 0.75% the following was also reported: Laboratory: Increased/decreased white blood cell counts (1.7%). Other Metronidazole Formulations: Other effects that have been reported in association with the use of topical (dermal) formulations of metronidazole include skin irritation, transient skin erythema, and mild skin dryness and burning. None of these adverse events exceeded an incidence of 2% of patients. Metronidazole vaginal gel USP, 0.75% affords include skin irritation, transient skin erythema, and mild skin dryness and burning. None of these adverse events exceeded an incidence of 2% of patients. Metronidazole vaginal gel USP, 0.75% affords minimal peak serum levels and systemic exposure (AUC) of metronidazole compared to 500 mg oral metronidazole dosing. Although these lower levels of exposure are less likely to produce the common reactions seen with oral metronidazole, the possibility of these and other reactions cannot be excluded presently. The following adverse reactions and altered laboratory tests have been reported with the oral or parenteral use of metronidazole: Cardiovascular: Flattening of the T-wave may be seen in electrocardiographic tracings. Central Nervous System: (See WARNINGS .) Headache, dizziness, syncope, ataxia, confusion, convulsive seizures, peripheral neuropathy, vertigo, incoordination, irritability, depression, weakness, insomnia. Gastrointestinal: Abdominal discomfort, nausea, vomiting, diarrhea, an unpleasant metallic taste, anorexia, epigastric distress, abdominal cramping, constipation, “furry” tongue, glossitis, stomatitis, pancreatitis, and modification of taste of alcoholic beverages. G an unpleasant metallic taste, anorexia, epigastric distress, abdominal cramping, constipation, “furry” tongue, glossitis, stomatitis, pancreatitis, and modification of taste of alcoholic beverages. Genitourinary: Overgrowth of Candida in the vagina, dyspareunia, decreased libido, proctitis. Hematopoietic: Reversible neutropenia, reversible thrombocytopenia. Hypersensitivity Reactions: Urticaria; erythematous rash; flushing; nasal congestion; dryness of the mouth, vagina, or vulva; fever; pruritus; fleeting joint pains. Renal: Dysuria, cystitis, polyuria, incontinence, a sense of pelvic pressure, darkened urine. 1 INDICATIONS AND USAGE ORFADIN ® is indicated for the treatment of adult and pediatric patients with hereditary tyrosinemia type 1 (HT-1) in combination with dietary restriction of tyrosine and phenylalanine. ORFADIN is a hydroxy-phenylpyruvate dioxygenase inhibitor indicated for the treatment of adult and pediatric patients with hereditary tyrosinemia type 1 (HT-1) in combination with dietary restriction of tyrosine and phenylalanine. ( 1 ) 2 DOSAGE AND ADMINISTRATION Recommended Dosage ( 2.1 ) : The recommended starting dosage is 0.5 mg/kg orally twice daily. In patients 5 years of age and older who have undetectable serum and urine succinylacetone concentrations after a minimum of 4 weeks on a stable dosage of nitisinone, the total daily dose may be given once daily. Titrate the dosage based on biochemical and/or clinical response, as described in the full prescribing information. The maximum total daily dosage is 2 mg/kg orally. Preparation and Administration Instructions ( 2.2 ) : For instructions on preparing, measuring and administering the oral suspension, see the full prescribing information. Maintain dietary restriction of tyrosine and phenylalanine Take ORFADIN capsules : For instructions on preparing, measuring and administering the oral suspension, see the full prescribing information. Maintain dietary restriction of tyrosine and phenylalanine Take ORFADIN capsules at least one hour before, or two hours after a meal For patients who have difficulties swallowing capsules and who are intolerant to the oral suspension, the capsules may be opened and the contents suspended in a small amount of water, formula or apple sauce immediately before use. Take ORFADIN oral suspension without regard to meals. 2.1 Dosage Starting Dosage The recommended starting dosage of ORFADIN is 0.5 mg/kg administered orally twice daily. Maintenance Regimen In patients 5 years of age and older who have undetectable serum and urine succinylacetone concentrations after a minimum of 4 weeks on a stable dosage of nitisinone, the total daily dose of ORFADIN may be given once daily (e.g., 1 to 2 mg/kg once daily) [see Clinical Pharmacology ( 12.2 )] . Dosage Titration Titrate the dosage in each individual patient based on biochemical and/or clinical response. Monitor plasma and/or urine succinylacetone concentrations, liver function parameters and alpha-fetoprotein levels. If suc age in each individual patient based on biochemical and/or clinical response. Monitor plasma and/or urine succinylacetone concentrations, liver function parameters and alpha-fetoprotein levels. If succinylacetone is still detectable in blood or urine 4 weeks after the start of nitisinone treatment, increase the nitisinone dosage to 0.75 mg/kg twice daily. A maximum total daily dosage of 2 mg/kg may be needed based on the evaluation of all biochemical parameters. If the biochemical response is satisfactory (undetectable blood and/or urine succinylacetone), the dosage should be adjusted only according to body weight gain and not according to plasma tyrosine levels. During initiation of therapy, when switching from twice daily to once daily dosing, or if there is a deterioration in the patient's condition, it may be necessary to follow all available biochemical parameters more closely (i.e. plasma and/or urine succinylacetone, urine 5-aminolevulinate (ALA) and erythrocyte porphobilinogen (PBG)-synthase activity). Maintain plasma tyrosine levels below 500 micromol/L by dietary restriction of tyrosine and phenylalanine intake [see Warnings and Precautions ( 5.1 )] . In patients who deve (PBG)-synthase activity). Maintain plasma tyrosine levels below 500 micromol/L by dietary restriction of tyrosine and phenylalanine intake [see Warnings and Precautions ( 5.1 )] . In patients who develop plasma tyrosine levels above 500 micromol/L, assess dietary tyrosine and phenylalanine intake. Do not adjust the ORFADIN dosage in order to lower the plasma tyrosine concentration. 2.2 Preparation and Administration Instructions Preparation of the Oral Suspension The oral suspension will be dispensed with an oral syringe of appropriate size and a bottle adaptor provided by a pharmacist or other healthcare provider. Preparing a Bottle Without the Adapter Already Inserted: Store the bottle in the refrigerator prior to first use. Remove the bottle from the refrigerator. Calculate 60 days from when the bottle is removed from the refrigerator. Write this date as the “Discard after” date on the bottle label. Allow the bottle to warm to room temperature (30 to 60 minutes). Shake the bottle vigorously for at least 20 seconds until the solid cake at the bottom of the bottle is completely dispersed. Check that there are no particles left at the bottom of the bottle. Foam will form in the bot gorously for at least 20 seconds until the solid cake at the bottom of the bottle is completely dispersed. Check that there are no particles left at the bottom of the bottle. Foam will form in the bottle. Insert the bottle adapter. Preparing a Bottle With the Adapter Inserted: Shake the bottle vigorously for at least 5 seconds. Check that there are no particles left at the bottom of the bottle. Foam will form in the bottle. Measuring and Administering the Dose Once the bottle is prepared with the adapter: Use the oral syringe to measure the dose. Keep the bottle upright and insert the oral syringe into the adapter. Carefully turn the bottle upside down with the oral syringe in place. Wait for the foam to rise to the top of the bottle. Pull back on the syringe plunger to withdraw the dose. Leave the syringe in the adapter and turn the bottle upright. Remove the syringe from the adapter by gently twisting it out of the bottle. Dispense the dose into the patient's mouth. Do not remove the bottle adapter. Store the bottle at room temperature (not above 25°C). Administration of ORFADIN Capsules and Oral Suspension Maintain dietary restriction of tyrosine and phenylalanine when taking OR bottle adapter. Store the bottle at room temperature (not above 25°C). Administration of ORFADIN Capsules and Oral Suspension Maintain dietary restriction of tyrosine and phenylalanine when taking ORFADIN. Capsules: Take at least one hour before, or two hours after a meal [see Clinical Pharmacology ( 12.3 )] . For patients who have difficulty swallowing the capsules and who are intolerant to the oral suspension [see Warnings and Precautions ( 5.3 )] , the capsules may be opened and the contents suspended in a small amount of water, formula or apple sauce immediately before use. Oral suspension: Take without regard to meals [see Clinical Pharmacology ( 12.3 )] . 6 ADVERSE REACTIONS Most common adverse reactions (>1%) are elevated tyrosine levels, thrombocytopenia, leukopenia, conjunctivitis, corneal opacity, keratitis, photophobia, eye pain, blepharitis, cataracts, granulocytopenia, epistaxis, pruritus, exfoliative dermatitis, dry skin, maculopapular rash and alopecia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Swedish Orphan Biovitrum at 1-866-773-5274 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted t SUSPECTED ADVERSE REACTIONS, contact Swedish Orphan Biovitrum at 1-866-773-5274 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. ORFADIN was studied in one open-label, uncontrolled study of 207 patients with HT-1, ages 0 to 22 years at enrollment (median age 9 months), who were diagnosed with HT-1 by the presence of succinylacetone in the urine or plasma. The starting dose of ORFADIN was 0.3 to 0.5 mg/kg twice daily, and the dose was increased in some patients to 1 mg/kg twice daily based on weight, biochemical, and enzyme markers. The recommended starting dosage of ORFADIN is 0.5 mg/kg twice daily [see Dosage and Administration ( 2.1 )] . Median duration of treatment was 22 months (range 0.1 to 80 months). The most serious adverse reactions reported during ORFADIN treatment were thrombocytopenia, leukopenia, porphyria, and ocular/visual complaints associated with elevated tyrosin ange 0.1 to 80 months). The most serious adverse reactions reported during ORFADIN treatment were thrombocytopenia, leukopenia, porphyria, and ocular/visual complaints associated with elevated tyrosine levels [see Warnings and Precautions ( 5.1 , 5.2 )] . Fourteen patients experienced ocular/visual events. The duration of the symptoms varied from 5 days to 2 years. Six patients had thrombocytopenia, three of which had platelet counts 30,000/microL or lower. In 4 patients with thrombocytopenia, platelet counts gradually returned to normal (duration up to 47 days) without change in ORFADIN dose. No patients developed infections or bleeding as a result of the episodes of leukopenia and thrombocytopenia. Patients with HT- 1 are at increased risk of developing porphyric crises, hepatic neoplasms, and liver failure requiring liver transplantation. These complications of HT-1 were observed in patients treated with nitisinone for a median of 22 months during the clinical trial (liver transplantation 13%, liver failure 7%, malignant hepatic neoplasms 5%, benign hepatic neoplasms 3%, porphyria 1%). The most common adverse reactions reported in the clinical trial are summarized in Table 1 . T tation 13%, liver failure 7%, malignant hepatic neoplasms 5%, benign hepatic neoplasms 3%, porphyria 1%). The most common adverse reactions reported in the clinical trial are summarized in Table 1 . TABLE 1 *reported in at least 1% of patients Most Common Adverse Reactions in Patients with HT-1 Treated with Nitisinone* Elevated tyrosine levels Leukopenia Thrombocytopenia Conjunctivitis Corneal opacity Keratitis Photophobia Eye pain Blepharitis Cataracts Granulocytopenia Epistaxis Pruritus Exfoliative dermatitis Dry skin Maculopapular rash Alopecia >10% 3% 3% 2% 2% 2% 2% 1% 1% 1% 1% 1% 1% 1% 1% 1% 1% Adverse reactions reported in less than 1% of the patients, included death, seizure, brain tumor, encephalopathy, hyperkinesia, cyanosis, abdominal pain, diarrhea, enanthema, gastrointestinal hemorrhage, melena, elevated hepatic enzymes, liver enlargement, hypoglycemia, septicemia, and bronchitis. Uses for the relief of nervousness and tension often associated with stress/anxiety. Active ingredients Purpose Allium sativum USDA Certified Organic 89C Remedy for Nervousness/Restlessness Avena sativa 30X For Nervous Exhaustion Angelica 89C For Difficulty Concentrating, Unable to Focus Coffea cruda 30C To Calm the System, Nervousness Ocimum 89C For Anxiety Passiflora 30C Quieting Effect on the Nervous System Scutellaria lateriflora 12C Restlessness, Nervousness Verbena 6C Eases Nervous System, Helps Mood Swings Piper methysticum 30C For Impaired Thinking, Sluggish Emotion Warnings For oral (sublingual) use. Ask a doctor before use in children under 6 years of age. Stop use and ask doctor if symptoms persist for more than 3 days or worsen. If pregnant or breast-feeding ask a doctor before use. Keep out of reach of children. Directions Use as needed. For best results, use at the first sign of symptoms. Shake well before use. For stress/anxiety: Take 5-10 drops under the tongue. Repeat 3-4 times per day when experiencing symptoms. Ask a doctor before use in children under 6 years of age. Stop use and ask doctor if symptoms persist for more than 3 days or worsen. Keep out of reach of 3-4 times per day when experiencing symptoms. Ask a doctor before use in children under 6 years of age. Stop use and ask doctor if symptoms persist for more than 3 days or worsen. Keep out of reach of children. Indications Indications: To be used for acute self-limiting conditions according to standard homeopathic indications Purpose Purpose: RUNNY NOSE Warning If pregnant or nursing, consult a practitioner before using. Directions Take at onset of symptoms. Repeat every 2 hours or as needed until relieved. If condition persists or worsens discontinue use and consult a practitioner. Adults: dissolve 5-10 pellets in 1 oz. of filtered water or take dry by mouth. Children and infants: 1-5 pellets. Keep Out of Reach of Children Keep these and all medications out of the reach of children. Uses helps prevent sunburn if used as directed with other sun protection measures (see Directions ), decreases the risk of skin cancer and early skin aging caused by the sun Active ingredients Purpose Titanium Dioxide (4.9%) Sunscreen Zinc Oxide (21.6%) Sunscreen Warnings For external use only Do not use ​• on damaged or broken skin When using this product keep out of eyes. Rinse with water to remove. Stop use and ask a doctor if • rash occurs. Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center right away Directions Shake bottle well before use. • For Sunscreen Use: • apply generously 15 minutes before sun exposure • reapply: • after 80 minutes of swimming or sweating • immediately after towel drying • at least every 2 hours • Sun Protection Measures. Spending time in the sun increases your risk of skin cancer and early skin aging. To decrease this risk, regularly use a sunscreen with a Broad Spectrum SPF value of 15 or higher and other sun protection measures including: • limit time in the sun, especially from 10 a.m. – 2 p.m. • wear long-sleeved shirts, pants, hats, and sunglasses • children under 6 months of age: Ask a doctor Stop us protection measures including: • limit time in the sun, especially from 10 a.m. – 2 p.m. • wear long-sleeved shirts, pants, hats, and sunglasses • children under 6 months of age: Ask a doctor Stop use and ask a doctor if • rash occurs. Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center right away Uses ■ Apply on hand to decrease bacteria on the skin that may cause disease ■ recommended for repeated use. Purpose Antiseptic Warnings For external use only: hands. Flammable, keep away from fire or flame. When using this product ■ keep out of eye, In case of contact with eyes, flush thoroughly with water ■ avoid contact with broken skin ■ do not inhale or ingest. Stop use and ask a doctor if ■ irritation and redness develop ■ condition persists for more than 72 hours. Keep out of reach of children. ■ if swallowed, get medical help or contact a Poison Control Center right away. Directions ■ Use enough amount of gel into palm and thoroughly spread on both hands. rub into skin and allow to dry. ■ for children under 6, must use under adult supervision. ■ not recommended for infants use. Keep out of reach of children. ■ if swallowed, get medical help or contact a Poison Control Center right away. INDICATIONS AND USAGE Supplementation of the diet with vitamins A, C and D. Tri-Vite Drops with Fluoride 0.25 mg also provides fluoride for caries prophylaxis. The American Academy of Pediatrics recommends that children up to age 16, in areas where drinking water contains less than optimal levels of fluoride, receive daily fluoride supplementation. The American Academy of Pediatrics recommend that infants and young children 6 months to 3 years of age, in areas where the drinking water contains less than 0.3 ppm of fluoride, and children 3-6 years of age, in areas where the drinking water contains 0.3 through 0.6 ppm of fluoride, receive 0.25 mg of supplemental fluoride daily which is provided in a dose of 1 mL of Tri-Vite Drops with Fluoride 0.25 mg (See Dosage and Administration ). Tri-Vite Drops with Fluoride 0.25 mg supply significant amounts of vitamins A, C and D to supplement the diet, and to help assure that nutritional deficiencies of these vitamins will not develop. Thus, in a single easy-to-use preparation, children obtain essential vitamins and fluoride. WARNINGS As in the case of all medications, keep out of reach of children. DOSAGE AND ADMINISTRATION 1.0 mL daily or a single easy-to-use preparation, children obtain essential vitamins and fluoride. WARNINGS As in the case of all medications, keep out of reach of children. DOSAGE AND ADMINISTRATION 1.0 mL daily or as directed by physician. May be dropped directly into the mouth with dropper; or mixed with cereal, fruit juice or other food. Tri-Vite Drops with Fluoride 0.25 mg is available in 50 mL bottles with accompanying calibrated dropper. ADVERSE REACTIONS Allergic rash and other idiosyncrasies have been rarely reported. INDICATIONS AND USAGE Levothyroxine sodium is used for the following indications: Hypothyroidism - As replacement or supplemental therapy in congenital or acquired hypothyroidism of any etiology, except transient hypothyroidism during the recovery phase of subacute thyroiditis. Specific indications include: primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) hypothyroidism and subclinical hypothyroidism. Primary hypothyroidism may result from functional deficiency, primary atrophy, partial or total congenital absence of the thyroid gland, or from the effects of surgery, radiation, or drugs, with or without the presence of goiter. Pituitary TSH Suppression - In the treatment or prevention of various types of euthyroid goiters (see WARNINGS and PRECAUTIONS ), including thyroid nodules (see WARNINGS and PRECAUTIONS ), subacute or chronic Iymphocytic thyroiditis (Hashimoto's thyroiditis), multinodular goiter (see WARNINGS and PRECAUTIONS ), and, as an adjunct to surgery and radioiodine therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer. WARNINGS WARNING: Thyroid hormones, including Levothyroxine Sodium Tablets, USP, either alone or and radioiodine therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer. WARNINGS WARNING: Thyroid hormones, including Levothyroxine Sodium Tablets, USP, either alone or with other therapeutic agents, should not be used for the treatment of obesity for weight loss. In euthyroid patients, doses within the range of daily hormonal requirements are ineffective for weight reduction. Larger doses may produce serious or even life threatening manifestations of toxicity, particularly when given in association with sympathomimetic amines such as those used for their anorectic effects. Levothyroxine sodium should not be used in the treatment of male or female infertility unless this condition is associated with hypothyroidism. In patients with nontoxic diffuse goiter or nodular thyroid disease, particularly the elderly or those with underlying cardiovascular disease, levothyroxine sodium therapy is contraindicated if the serum TSH level is already suppressed due to the risk of precipitating overt thyrotoxicosis (see CONTRAINDICATIONS ). If the serum TSH level is not suppressed, Levothyroxine Sodium Tablets, USP should be used with caution in conjunction with car the risk of precipitating overt thyrotoxicosis (see CONTRAINDICATIONS ). If the serum TSH level is not suppressed, Levothyroxine Sodium Tablets, USP should be used with caution in conjunction with careful monitoring of thyroid function for evidence of hyperthyroidism and clinical monitoring for potential associated adverse cardiovascular signs and symptoms of hyperthyroidism. DOSAGE AND ADMINISTRATION General Principles: The goal of replacement therapy is to achieve and maintain a clinical and biochemical euthyroid state. The goal of suppressive therapy is to inhibit growth and/or function of abnormal thyroid tissue. The dose of Levothyroxine Sodium Tablets, USP that is adequate to achieve these goals depends on a variety of factors including the patient's age, body weight, cardiovascular status, concomitant medical conditions, including pregnancy, concomitant medications, and the specific nature of the condition being treated (see WARNINGS and PRECAUTIONS ). Hence, the following recommendations serve only as dosing guidelines. Dosing must be individualized and adjustments made based on periodic assessment of the patient's clinical response and laboratory parameters (see PRECAUTION mendations serve only as dosing guidelines. Dosing must be individualized and adjustments made based on periodic assessment of the patient's clinical response and laboratory parameters (see PRECAUTIONS, Laboratory Tests ). Levothyroxine Sodium Tablets, USP should be taken in the morning on an empty stomach, at least one-half hour to one hour before any food is eaten. Levothyroxine Sodium Tablets, USP should be taken at least 4 hours apart from drugs that are known to interfere with its absorption (see PRECAUTIONS, Drug Interactions ). Due to the long half-life of levothyroxine, the peak therapeutic effect at a given dose of levothyroxine sodium may not be attained for 4-6 weeks. Caution should be exercised when administering Levothyroxine Sodium Tablets, USP to patients with underlying cardiovascular disease, to the elderly, and to those with concomitant adrenal insufficiency (see PRECAUTIONS ). Specific Patient Populations: Hypothyroidism in Adults and in Children in Whom Growth and Puberty are Complete (see WARNINGS and PRECAUTIONS, Laboratory Tests ). Therapy may begin at full replacement doses in otherwise healthy individuals less than 50 years old and in those older than 50 ye uberty are Complete (see WARNINGS and PRECAUTIONS, Laboratory Tests ). Therapy may begin at full replacement doses in otherwise healthy individuals less than 50 years old and in those older than 50 years who have been recently treated for hyperthyroidism or who have been hypothyroid for only a short time (such as a few months). The average full replacement dose of levothyroxine sodium is approximately 1.7 mcg/kg/day (e.g., 100-125 mcg/day for a 70 kg adult). Older patients may require less than 1 mcg/kg/day. Levothyroxine sodium doses greater than 200 mcg/day are seldom required. An inadequate response to daily doses ≥ 300 mcg/day is rare and may indicate poor compliance, malabsorption, and/or drug interactions. For most patients older than 50 years or for patients under 50 years of age with underlying cardiac disease, an initial starting dose of 25-50 mcg/day of levothyroxine sodium is recommended, with gradual increments in dose at 6-8 week intervals, as needed. The recommended starting dose of levothyroxine sodium in elderly patients with cardiac disease is 12.5-25 mcg/day , with gradual dose increments at 4-6 week intervals. The levothyroxine sodium dose is generally adjusted i ing dose of levothyroxine sodium in elderly patients with cardiac disease is 12.5-25 mcg/day , with gradual dose increments at 4-6 week intervals. The levothyroxine sodium dose is generally adjusted in 12.5-25 mcg increments until the patient with primary hypothyroidism is clinically euthyroid and the serum TSH has normalized. In patients with severe hypothyroidism, the recommended initial levothyroxine sodium dose is 12.5-25 mcg/day with increases of 25 mcg/day every 2-4 weeks, accompanied by clinical and laboratory assessment, until the TSH level is normalized. In patients with secondary (pituitary) or tertiary (hypothalamic) hypothyroidism, the levothyroxine sodium dose should be titrated until the patient is clinically euthyroid and the serum free-T 4 level is restored to the upper half of the normal range. Pediatric Dosage - Congenital or Acquired Hypothyroidism (see PRECAUTIONS, Laboratory Tests ) General Principles In general, levothyroxine therapy should be instituted at full replacement doses as soon as possible. Delays in diagnosis and institution of therapy may have deleterious effects on the child's intellectual and physical growth and development. Undertreatment and ov eplacement doses as soon as possible. Delays in diagnosis and institution of therapy may have deleterious effects on the child's intellectual and physical growth and development. Undertreatment and overtreatment should be avoided (see PRECAUTIONS, Pediatric Use ). Levothyroxine Sodium Tablets, USP may be administered to infants and children who cannot swallow intact tablets by crushing the tablet and suspending the freshly crushed tablet in a small amount (5-10 mL or 1-2 teaspoons) of water. This suspension can be administered by spoon or dropper. DO NOT STORE THE SUSPENSION. Foods that decrease absorption of levothyroxine, such as soybean infant formula, should not be used for administering levothyroxine sodium tablets. (see PRECAUTIONS, Drug-Food Interactions ). Newborns The recommended starting dose of levothyroxine sodium in newborn infants is 10-15 mcg/kg/day . A lower starting dose (e.g., 25 mcg/day) should be considered in infants at risk for cardiac failure, and the dose should be increased in 4-6 weeks as needed based on clinical and laboratory response to treatment. In infants with very low (< 5 mcg/dL) or undetectable serum T 4 concentrations, the recommended initial sta be increased in 4-6 weeks as needed based on clinical and laboratory response to treatment. In infants with very low (< 5 mcg/dL) or undetectable serum T 4 concentrations, the recommended initial starting dose is 50 mcg/day of levothyroxine sodium. Infants and Children Levothyroxine therapy is usually initiated at full replacement doses, with the recommended dose per body weight decreasing with age (see TABLE 3 ). However, in children with chronic or severe hypothyroidism, an initial dose of 25 mcg/day of levothyroxine sodium is recommended with increments of 25 mcg every 2-4 weeks until the desired effect is achieved. Hyperactivity in an older child can be minimized if the starting dose is one-fourth of the recommended full replacement dose, and the dose is then increased on a weekly basis by an amount equal to one-fourth the full-recommended replacement dose until the full recommended replacement dose is reached. Table 3: Levothyroxine Sodium Dosing Guidelines for Pediatric Hypothyroidism AGE Daily Dose Per Kg Body Weight a 0-3 months 10-15 mcg/kg/day 3-6 months 8-10 mcg/kg/day 6-12 months 6-8 mcg/kg/day 1-5 years 5-6 mcg/kg/day 6-12 years 4-5 mcg/kg/day >12 years but growth and oidism AGE Daily Dose Per Kg Body Weight a 0-3 months 10-15 mcg/kg/day 3-6 months 8-10 mcg/kg/day 6-12 months 6-8 mcg/kg/day 1-5 years 5-6 mcg/kg/day 6-12 years 4-5 mcg/kg/day >12 years but growth and puberty incomplete 2-3 mcg/kg/day Growth and puberty complete 1.7 mcg/kg/day a. The dose should be adjusted based on clinical response and laboratory parameters (see PRECAUTlONS, Laboratory Tests and Pediatric Use ). Pregnancy- Pregnancy may increase levothyroxine requirements (see PREGNANCY ). Subclinical Hypothyroidism- If this condition is treated, a lower levothyroxine sodium dose (e.g., 1 mcg/kg/day ) than that used for full replacement may be adequate to normalize the serum TSH level. Patients who are not treated should be monitored yearly for changes in clinical status and thyroid laboratory parameters. TSH Suppression in Well-differentiated Thyroid Cancer and Thyroid Nodules- The target level for TSH suppression in these conditions has not been established with controlled studies. In addition, the efficacy of TSH suppression for benign nodular disease is controversial. Therefore, the dose of Levothyroxine Sodium Tablets, USP used for TSH suppression should be individualized ba In addition, the efficacy of TSH suppression for benign nodular disease is controversial. Therefore, the dose of Levothyroxine Sodium Tablets, USP used for TSH suppression should be individualized based on the specific disease and the patient being treated. In the treatment of well differentiated (papillary and follicular) thyroid cancer, levothyroxine is used as an adjunct to surgery and radioiodine therapy. Generally, TSH is suppressed to <0.1 mU/L, and this usually requires a levothyroxine sodium dose of greater than 2 mcg/kg/day . However, in patients with high-risk tumors, the target level for TSH suppression may be <0.01 mU/L. In the treatment of benign nodules and nontoxic multinodular goiter, TSH is generally suppressed to a higher target (e.g., 0.1-0.5 mU/L for nodules and 0.5-1.0 mU/L for multinodular goiter) than that used for the treatment of thyroid cancer. Levothyroxine sodium is contraindicated if the serum TSH is already suppressed due to the risk of precipitating overt thyrotoxicosis (see CONTRAINDICATIONS , WARNINGS and PRECAUTIONS ). Myxedema Coma - Myxedema coma is a life-threatening emergency characterized by poor circulation and hypometabolism, and may result t thyrotoxicosis (see CONTRAINDICATIONS , WARNINGS and PRECAUTIONS ). Myxedema Coma - Myxedema coma is a life-threatening emergency characterized by poor circulation and hypometabolism, and may result in unpredictable absorption of levothyroxine sodium from the gastrointestinal tract. Therefore, oral thyroid hormone drug products are not recommended to treat this condition. Thyroid hormone products formulated for intravenous administration should be administered. ADVERSE REACTIONS Adverse reactions associated with levothyroxine therapy are primarily those of hyperthyroidism due to therapeutic overdosage (see PRECAUTIONS and OVERDOSAGE ). They include the following: General: fatigue, increased appetite, weight loss, heat intolerance, fever, excessive sweating; Central nervous system: headache, hyperactivity, nervousness, anxiety, irritability, emotional lability, insomnia; Musculoskeletal: tremors, muscle weakness; Cardiovascular: palpitations, tachycardia, arrhythmias, increased pulse and blood pressure, heart failure, angina, myocardial infarction, cardiac arrest; Respiratory: dyspnea; Gastrointestinal: diarrhea, vomiting, abdominal cramps and elevation in liver function tests; De and blood pressure, heart failure, angina, myocardial infarction, cardiac arrest; Respiratory: dyspnea; Gastrointestinal: diarrhea, vomiting, abdominal cramps and elevation in liver function tests; Dermatologic: hair loss; flushing; Endocrine: decreased bone mineral density; Reproductive: menstrual irregularities, impaired fertility. Pseudotumor cerebri and slipped capital femoral epiphysis have been reported in children receiving levothyroxine therapy. Overtreatment may result in craniosynostosis in infants and premature closure of the epiphyses in children with resultant compromised height. Seizures have been reported rarely with the institution of levothyroxine therapy. Inadequate levothyroxine dosage will produce or fail to ameliorate the signs and symptoms of hypothyroidism. Hypersensitivity reactions to inactive ingredients have occurred in patients treated with thyroid hormone products. These include urticaria, pruritus, skin rash, flushing, angioedema, various Gl symptoms (abdominal pain, nausea, vomiting and diarrhea), fever, arthralgia, serum sickness and wheezing. Hypersensitivity to levothyroxine itself is not known to occur. INDICATIONS AND USAGE Hypertension Atenolol tablets are indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure lowers 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 atenolol tablets. 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 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 conc s, 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 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 antihypertensiv 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. Atenolol tablets may be administered with other antihypertensive agents. Angina Pectoris Due to Coronary Atherosclerosis Atenolol tablets are indicated for the long-term management of patients with angina pectoris. Acute Myocardial Infarction Atenolol tablets are indicated in the management of hemodynamically stable patients with definite or suspected acute myocardial infarction to reduce cardiovascular mortality. Treatment can be initiated as soon as the patient's clinical condition allows. (See DOSAGE AND ADMINISTRATION , CONTRAINDICATIONS , and WARNINGS .) In general, there is no basis for treating patients like those who were excluded from the ISIS-1 trial (blood pressure less than 100 mm Hg systolic, heart rate ON , CONTRAINDICATIONS , and WARNINGS .) In general, there is no basis for treating patients like those who were excluded from the ISIS-1 trial (blood pressure less than 100 mm Hg systolic, heart rate less than 50 bpm) or have other reasons to avoid beta blockade. As noted above, some subgroups (e.g., elderly patients with systolic blood pressure below 120 mm Hg) seemed less likely to benefit. WARNINGS Cardiac Failure Sympathetic stimulation is necessary in supporting circulatory function in congestive heart failure, and beta blockade carries the potential hazard of further depressing myocardial contractility and precipitating more severe failure. In patients with acute myocardial infarction, cardiac failure which is not promptly and effectively controlled by 80 mg of intravenous furosemide or equivalent therapy is a contraindication to beta-blocker treatment. In Patients Without a History of Cardiac Failure Continued depression of the myocardium with beta-blocking agents over a period of time can, in some cases, lead to cardiac failure. At the first sign or symptom of impending cardiac failure, patients should be treated appropriately according to currently recommended guidelines, of time can, in some cases, lead to cardiac failure. At the first sign or symptom of impending cardiac failure, patients should be treated appropriately according to currently recommended guidelines, and the response observed closely. If cardiac failure continues despite adequate treatment, atenolol should be withdrawn. (See DOSAGE AND ADMINISTRATION .) Cessation of Therapy With Atenolol Patients with coronary artery disease, who are being treated with atenolol, should be advised against abrupt discontinuation of therapy. Severe exacerbation of angina and the occurrence of myocardial infarction and ventricular arrhythmias have been reported in angina patients following the abrupt discontinuation of therapy with beta blockers. The last two complications may occur with or without preceding exacerbation of the angina pectoris. As with other beta blockers, when discontinuation of atenolol is planned, the patients should be carefully observed and advised to limit physical activity to a minimum. If the angina worsens or acute coronary insufficiency develops, it is recommended that atenolol be promptly reinstituted, at least temporarily. Because coronary artery disease is common and may imum. If the angina worsens or acute coronary insufficiency develops, it is recommended that atenolol be promptly reinstituted, at least temporarily. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue atenolol therapy abruptly even in patients treated only for hypertension. (See DOSAGE AND ADMINISTRATION .) Concomitant Use of Calcium Channel Blockers Bradycardia and heart block can occur and the left ventricular end diastolic pressure can rise when beta blockers are administered with verapamil or diltiazem. Patients with preexisting conduction abnormalities or left ventricular dysfunction are particularly susceptible (see PRECAUTIONS ). Bronchospastic Diseases PATIENTS WITH BRONCHOSPASTIC DISEASE SHOULD, IN GENERAL, NOT RECEIVE BETA BLOCKERS. Because of its relative beta 1 selectivity, however, atenolol may be used with caution in patients with bronchospastic disease who do not respond to, or cannot tolerate, other antihypertensive treatment. Since beta 1 selectivity is not absolute, the lowest possible dose of atenolol should be used with therapy initiated at 50 mg and a beta 2 -stimulating agent (bronchodilator) should be made reatment. Since beta 1 selectivity is not absolute, the lowest possible dose of atenolol should be used with therapy initiated at 50 mg and a beta 2 -stimulating agent (bronchodilator) should be made available. If dosage must be increased, dividing the dose should be considered in order to achieve lower peak blood levels. Major Surgery Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery, however the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures. Diabetes and Hypoglycemia Atenolol should be used with caution in diabetic patients if a beta-blocking agent is required. Beta blockers may mask tachycardia occurring with hypoglycemia, but other manifestations such as dizziness and sweating may not be significantly affected. At recommended doses atenolol does not potentiate insulin-induced hypoglycemia and, unlike nonselective beta blockers, does not delay recovery of blood glucose to normal levels. Thyrotoxicosis Beta-adrenergic blockade may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism. Abrupt withdrawal of beta blockade migh