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Product Name
:
PARACETAMOL ELSaad
Chemical Name
:
Paracetamol
Therapeutic Category
:
Analgesic & Anesthetic
Pharmacologic Category
:
Analgesic, Miscellaneous
Pharmaceutical Form
:
Vial
Composition
:
Paracetamol 10mg/1ml
Monitoring Parameters
Dosing
 
Dosing: Adult
Note: No dose adjustment required if converting between different acetaminophen formulations.
Pain or fever:
I.V.:
<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/day)
≥50 kg: 650 mg every 4 hours or 1000 mg every 6 hours; maximum single dose: 1000 mg/dose; maximum daily dose: 4 g/day

Dosing: Pediatric

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/day)
Adolescents >12 years: Refer to adult dosing.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

I.V.: Clcr ≤30 mL/minute: Use with caution; consider decreasing daily dose and extending dosing interval.

Dosing: Hepatic Impairment

Use with caution. Limited, low-dose therapy is usually well tolerated in hepatic disease/cirrhosis. However, cases of hepatotoxicity at daily acetaminophen dosages <4 g/day have been reported. Avoid chronic use in hepatic impairment.
Use
 
Treatment of mild-to-moderate pain and fever (analgesic/antipyretic)
I.V.: Additional indication: Management of moderate-to-severe pain when combined with opioid analgesia
Adverse Reactions
 
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
Contraindications
 
Hypersensitivity to acetaminophen or any component of the formulation; severe hepatic impairment or severe active liver disease
Warnings / Precautions Drug
 
Concerns related to adverse effects:
• Hepatotoxicity: May cause severe hepatotoxicity on acute overdose; in addition, chronic daily dosing in adults has resulted in liver damage in some patients. Use with caution in patients with chronic malnutrition.
• Hypersensitivity/anaphylactic reactions: Hypersensitivity and anaphylactic reactions have been reported; discontinue immediately if symptoms of allergic or hypersensitivity reactions occur.
Disease-related concerns:
• Ethanol use: Use with caution in patients with alcoholic liver disease; consuming ≥3 alcoholic drinks/day may increase the risk of liver damage.
• G6PD deficiency: Use with caution in patients with known G6PD deficiency; rare reports of hemolysis have occurred.
• Hepatic impairment: Use with caution in patients with hepatic impairment or active liver disease; use of the intravenous formulation is contraindicated in patients with severe hepatic impairment or severe active liver disease.
• Hypovolemia: Use the intravenous formulation with caution in patients with severe hypovolemia (eg, due to dehydration or blood loss).
• Renal impairment: Use with caution in patients with severe renal impairment; consider dosing adjustments.
Other warnings/precautions:
• Dosage limit: Limit dose to <4 g/day.
• Self-medication (OTC use): 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.
Metabolism/Transport Effects
Substrate (minor) of CYP1A2, 2A6, 2C9, 2D6, 2E1, 3A4; Inhibits CYP3A4 (weak)
Interactions
 
Anticonvulsants (Hydantoin): May increase the metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen; and 2) increase the risk of liver damage. Risk C: Monitor therapy
Barbiturates: May increase the metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen; and 2) increase the risk of liver damage. Risk C: Monitor therapy
CarBAMazepine: May increase the metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen; and 2) increase the risk of liver damage. Risk C: Monitor therapy
Cholestyramine Resin: May decrease the absorption of Acetaminophen. Effect is minimal if cholestyramine is administered 1 hour after acetaminophen. Risk D: Consider therapy modification
Conivaptan: May increase the serum concentration of CYP3A4 Substrates (Low risk). Risk C: Monitor therapy
Cyproterone: May decrease the serum concentration of CYP1A2 Substrates. Risk C: Monitor therapy
Cyproterone: May decrease the serum concentration of CYP2E1 Substrates. Risk C: Monitor therapy
Dasatinib: Acetaminophen may enhance the hepatotoxic effect of Dasatinib. Dasatinib may increase the serum concentration of Acetaminophen. Risk D: Consider therapy modification
Imatinib: Acetaminophen may enhance the hepatotoxic effect of Imatinib. Imatinib may increase the serum concentration of Acetaminophen. Risk D: Consider therapy modification
Isoniazid: May enhance the adverse/toxic effect of Acetaminophen. Risk C: Monitor therapy
Metyrapone: May increase the serum concentration of Acetaminophen. More importantly, by inhibiting the conjugative metabolism of acetaminophen, metyrapone may shift the metabolism towards the oxidative route that produces a hepatotoxic metabolite. Risk C: Monitor therapy
Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy
Probenecid: May increase the serum concentration of Acetaminophen. Probenecid may also limit the formation of at least one major non-toxic metabolite, possibly increasing the potential for formation of the toxic NAPQI metabolite. Risk D: Consider therapy modification
SORAfenib: Acetaminophen may enhance the hepatotoxic effect of SORAfenib. SORAfenib may increase the serum concentration of Acetaminophen. Risk D: Consider therapy modification
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Vitamin K Antagonists (eg, warfarin): Acetaminophen may enhance the anticoagulant effect of Vitamin K Antagonists. Most likely with daily acetaminophen doses >1.3 g for >1 week. Risk C: Monitor therapy
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.
Pregnancy
 
C (intravenous)
Pregnancy Implications
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)
Breast-Feeding Considerations
Low concentrations of acetaminophen are excreted into breast milk and can be detected in the urine of nursing infants. Adverse reactions have generally not been observed; however, a rash caused by acetaminophen exposure was reported in one breast-feeding infant.
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
Pharmacodynamics / Kinetics
 
Onset of action:
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)
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)
 
   
 
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