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ACEBUTOLOL Dosage Forms Excipient information presented when Warnings/Precautions Limit acetaminophen dose from available (limited, particularly for generics); consult specific product labeling. Capsule, oral, as hydrochloride: 200 mg, 400 mg Sectral®: 200 mg, 400 mg all sources (prescription and OTC) to <4 g/day. May cause severe hepatotoxicity on acute overdose; in addition, chronic daily dosing in adults has resulted in liver damage in some patients; hepatotoxicity is usually associated with excessive acetaminophen intake (>4 g/day). Use with caution in patients with alcoholic liver disease; consuming ≥3 alcoholic drinks/day may increase the risk of liver damage. Use caution in patients with hepatic impairment or active liver disease. Use of intravenous formulation is contraindicated in patients with severe hepatic impairment or severe active liver disease. Use caution in patients with known G6PD deficiency; rare reports of hemolysis have occurred. Use caution in patients with chronic malnutrition and hypovolemia (intravenous formulation). Use caution in patients with severe renal impairment; consider dosing adjustments. Hypersensitivity and anaphylactic reactions have been reported; discontinue immediately if symptoms of allergic or hypersensitivity reactions occur. ^ Acebutolol Hydrochloride see Acebutolol on page 27 ^ Aceon® see Perindopril Erbumine on page 1457 ^ Acephen™ [OTC] see Acetaminophen on page 28 ^ Acerola [OTC] see Ascorbic Acid on page 158 ^ Acetadote® see Acetylcysteine on page 35 ^ Aceta-Gesic® see Acetaminophen and Diphenhydr- amine on page 32 Acetaminophen (a seet a MIN oh fen) Brand Names: U.S. Acephen™ [OTC]; APAP 500 [OTC]; Aspirin Free Anacin® Extra Strength [OTC]; Cetafen® Extra [OTC]; Cetafen® [OTC]; Excedrin® Tension Headache [OTC]; Feverall® [OTC]; Infantaire [OTC]; Little Fevers™ [OTC]; Mapap® Arthritis Pain [OTC]; Mapap® Children's [OTC]; Mapap® Extra Strength [OTC]; Mapap® Infant's [OTC]; Mapap® Junior Rapid Tabs [OTC]; Mapap® [OTC]; Non-Aspirin Pain Reliever [OTC]; Nortemp Children's [OTC]; Ofirmev™; Pain & Fever Children's [OTC]; Pain Eze [OTC]; Q-Pap Children's [OTC]; Q-Pap Extra Strength [OTC]; Q-Pap Infant's [OTC]; Q-Pap [OTC]; RapiMed® Children's [OTC]; RapiMed® Junior [OTC]; Silapap Children's [OTC]; Silapap Infant's [OTC]; Triaminic™ Children's Fever Reducer Pain Reliever [OTC]; Tylenol® 8 Hour [OTC]; Tylenol® Arthritis Pain Extended Relief [OTC]; Tylenol® Children's Meltaways [OTC]; Tylenol® Children's [OTC]; Tylenol® Extra Strength [OTC]; Tylenol® Infant's Concentrated [OTC] [DSC]; Tylenol® Jr. Meltaways [OTC]; Tylenol® [OTC]; Valorin Extra [OTC]; Valorin [OTC] Brand Names: Canada Abenol®; Apo-Acetaminophen®; Atasol®; Novo-Gesic; Pediatrix; Tempra®; Tylenol® Index Terms APAP (abbreviation is not recommended); NAcetyl-P-Aminophenol; Paracetamol Pharmacologic Category Analgesic, Miscellaneous Use Treatment of mild-to-moderate pain and fever (analgesic/antipyretic) I.V.: Additional indication: Management of moderate-tosevere pain when combined with opioid analgesia Pregnancy Risk Factor C (intravenous) Pregnancy Considerations Animal reproduction studies have not been conducted with intravenous acetaminophen, therefore, acetaminophen I.V. is classified as pregnancy category C. Acetaminophen crosses the placenta and can be detected in cord blood, newborn serum, and urine immediately after delivery. An increased risk of teratogenic effects has not been observed following maternal use of acetaminophen during pregnancy. Prenatal constriction of the ductus arteriosus has been noted in case reports following maternal use during the third trimester. The use of acetaminophen in normal doses during pregnancy is not associated with an increased risk of miscarriage or still birth; however, an increase in fetal death or spontaneous abortion may be seen following maternal overdose if treatment is delayed. Frequent maternal use of acetaminophen during pregnancy may be associated with wheezing and asthma in early childhood. The absorption may be delayed and the bioavailability of acetaminophen may be decreased in some women during pregnancy due to delayed gastric emptying. Lactation Enters breast milk/use caution (AAP rates "compatible"; AAP 2001 update pending) Contraindications Hypersensitivity to acetaminophen or any component of the formulation; severe hepatic impairment or severe active liver disease (Ofirmev™) OTC labeling: When used for self-medication, patients should be instructed to contact healthcare provider if used for fever lasting >3 days or for pain lasting >10 days in adults or >5 days in children. OTC labeling limits the maximum daily dose to ≤3250 mg (dosage form specific). Adverse Reactions Oral, Rectal: Frequency not defined: Dermatologic: Rash Endocrine & metabolic: May increase chloride, uric acid, glucose; may decrease sodium, bicarbonate, calcium Hematologic: Anemia, blood dyscrasias (neutropenia, pancytopenia, leukopenia) Hepatic: Bilirubin increased, alkaline phosphatase increased Renal: Ammonia increased, nephrotoxicity with chronic overdose, analgesic nephropathy Miscellaneous: Hypersensitivity reactions (rare) I.V.: >10%: Gastrointestinal: Nausea (adults 34%; children ≥5%), vomiting (adults 15%; children ≥5%) 1% to 10%: Cardiovascular: Edema (peripheral), hypervolemia, hypo/ hypertension, tachycardia Central nervous system: Headache (adults 10%; children ≥1%), insomnia (adults 7%; children ≥1%), agitation (children ≥5%), anxiety, fatigue Dermatologic: Pruritus (children ≥5%), rash Endocrine & metabolic: Hypoalbuminemia, hypokalemia, hypomagnesemia, hypophosphatemia Gastrointestinal: Constipation (children ≥5%), abdominal pain, diarrhea Hematologic: Anemia Hepatic: Transaminases increased Local: Infusion site pain Neuromuscular & skeletal: Muscle spasms, pain in extremity, trismus Ocular: Periorbital edema Renal: Oliguria (children ≥1%) Respiratory: Atelectasis (children ≥5%), breath sounds abnormal, dyspnea, hypoxia, pleural effusion, pulmonary edema, stridor, wheezing All formulations: <1% (Limited to important or life-threatening): Anaphylaxis (rare), hypersensitivity reactions Drug Interactions Metabolism/Transport Effects Substrate of CYP1A2 (minor), CYP2A6 (minor), CYP2C9 (minor), CYP2D6 (minor), CYP2E1 (minor), CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP3A4 (weak) Avoid Concomitant Use Avoid concomitant use of Acetaminophen with any of the following: Pimozide 28 ACETAMINOPHEN Adults: ~2 hours (range: 2-3 hours); may be slightly prolonged in severe renal insufficiency (Clcr<30 mL/ minute): 2-5.3 hours Time to peak, serum: Oral: Immediate release: 10-60 minutes (may be delayed in acute overdoses); I.V.: 15 minutes Excretion: Urine (<5% unchanged; 60% to 80% as glucuronide metabolites; 20% to 30% as sulphate metabolites; ~8% cysteine and mercapturic acid metabolites) Dosage Note: No dose adjustment required if converting between different acetaminophen formulations. Limit acetaminophen dose from all sources (prescription and OTC) to <4 g daily. Increased Effect/Toxicity Acetaminophen may increase the levels/effects of: ARIPiprazole; Busulfan; Dasatinib; Imatinib; Lomitapide; Pimozide; Prilocaine; SORAfenib; Vitamin K Antagonists The levels/effects of Acetaminophen may be increased by: Dasatinib; Imatinib; Isoniazid; Metyrapone; Probenecid; SORAfenib Decreased Effect The levels/effects of Acetaminophen may be decreased by: Anticonvulsants (Hydantoin); Barbiturates; CarBAMazepine; Cholestyramine Resin; Peginterferon Alfa-2b Ethanol/Nutrition/Herb Interactions Ethanol: Excessive intake of ethanol may increase the risk of acetaminophen-induced hepatotoxicity. Avoid ethanol or limit to <3 drinks/day. Food: Rate of absorption may be decreased when given with food. Herb/Nutraceutical: St John's wort may decrease acetaminophen levels. Oral: Note: OTC dosing recommendations may vary by product and/or manufacturer. Infants and Children <12 years: 10-15 mg/kg/dose every 4-6 hours as needed; do not exceed 5 doses (2.6 g) in 24 hours; alternatively, the following age-based doses may be used; see table. Children ≥12 years, Adolescents, and Adults: Regular release: 325-650 mg every 4-6 hours or 1000 mg 3-4 times daily (maximum: 4 g daily) Extended release: 1300 mg every 8 hours (maximum: 3.9 g daily) Stability Injection: Store intact vials at room temperature of 20°C to 25°C (68°F to 77°F); do not refrigerate or freeze. Injectable solution may be administered directly from the vial without further dilution. Use within 6 hours of opening vial or transferring to another container. Discard any unused portion; single use vials only. Doses <1000 mg (<50 kg): Withdraw appropriate dose from vial and place into and transfer to a separate sterile container (eg, glass bottle, plastic I.V. container, syringe) for administration. Small volume pediatric doses (up to 60 mL) may be placed in a syringe and infused over 15 minutes via syringe pump. Doses of 1000 mg (≥50 kg): Insert vented I.V. set through vial stopper. Oral formulations: Store at controlled room temperature. Suppositories: Store at <27°C (80°F); do not freeze. Mechanism of Action Although not fully elucidated, believed to inhibit the synthesis of prostaglandins in the central nervous system and work peripherally to block pain impulse generation; produces antipyresis from inhibition of hypothalamic heat-regulating center Acetaminophen Pediatric Dosing (Oral)1 Dosage (mg) Weight (kg) Weight (lbs) Age 2.7-5.3 6-11 0-3 mo 40 5.4-8.1 12-17 4-11 mo 80 8.2-10.8 18-23 1-2 y 120 10.9-16.3 24-35 2-3 y 160 16.4-21.7 36-47 4-5 y 240 21.8-27.2 48-59 6-8 y 320 27.3-32.6 60-71 9-10 y 400 32.7-43.2 72-95 11 y 480 1 Manufacturer's recommendations; use of weight to select dose is preferred; if weight is not available, then use age. Manufacturer’s recommendations are based on weight in pounds (OTC labeling); weight in kg listed here is derived from pounds and rounded; kg weight listed also is adjusted to allow for continuous weight ranges in kg. OTC labeling instructs consumer to consult with physician for dosing instructions in children under 2 years of age. Pharmacodynamics/Kinetics Onset of action: Oral: <1 hour I.V.: Analgesia: 5-10 minutes; Antipyretic: Within 30 minutes Peak effect: I.V.: Analgesic: 1 hour Duration: I.V., Oral: Analgesia: 4-6 hours I.V.: Antipyretic: ≥6 hours Absorption: Primarily absorbed in small intestine (rate of absorption dependent upon gastric emptying); minimal absorption from stomach; varies by dosage form Distribution: ~1 L/kg at therapeutic doses Protein binding: 10% to 25% at therapeutic concentrations; 8% to 43% at toxic concentrations Metabolism: At normal therapeutic dosages, primarily hepatic metabolism to sulfate and glucuronide conjugates, while a small amount is metabolized by CYP2E1 to a highly reactive intermediate, N-acetyl-p-benzoquinone imine (NAPQI), which is conjugated rapidly with glutathione and inactivated to nontoxic cysteine and mercapturic acid conjugates. At toxic doses (as little as 4 g daily) glutathione conjugation becomes insufficient to meet the metabolic demand causing an increase in NAPQI concentrations, which may cause hepatic cell necrosis. Oral administration is subject to first pass metabolism. Half-life elimination: Prolonged following toxic doses Neonates: 7 hours (range: 4-10 hours) Infants: ~4 hours (range: 1-7 hours) Children: 3 hours (range: 2-5 hours) Adolescents: ~3 hours (range: 2-4 hours) Rectal: Infants and Children <12 years: 10-20 mg/kg/dose every 4-6 hours as needed; do not exceed 5 doses (2.6 g) in 24 hours. Note: Although the perioperative use of highdose rectal acetaminophen (eg, 25-45 mg/kg/dose) has been investigated in several studies, its routine use remains controversial; optimal doses and dosing frequency to ensure efficacy and safety have not yet been established (Buck, 2001). Children ≥12 years, Adolescents, and Adults: 325-650 mg every 4-6 hours or 1000 mg 3-4 times daily (maximum: 4 g daily) I.V.: Children 2-12 years: 15 mg/kg every 6 hours or 12.5 mg/kg every 4 hours; maximum single dose: 15 mg/kg/dose; maximum daily dose: 75 mg/kg/day (≤3.75 g daily) Adolescents and Adults: <50 kg: 15 mg/kg every 6 hours or 12.5 mg/kg every 4 hours; maximum single dose: 750 mg/dose; maximum daily dose: 75 mg/kg/day (≤3.75 g daily) ≥50 kg: 650 mg every 4 hours or 1000 mg every 6 hours; maximum single dose: 1000 mg/dose; maximum daily dose: 4 g daily 29