information [33:<12 years of age is not recommended. 117 118 Possible increased severity of CNS effects in children compared with adults. a (See Nervous System Effects under Cautions.) Avoid use of caffeine and sodium benzoate injection in neonates; sodium benzoate may produce kernicterus. a Use caffeine citrate with caution in premature neonates with impaired renal or hepatic function, cardiovascular disease, or seizure disorders (see Cardiac Effects and also Nervous System Effects, under Cautions; also see Special Populations under Dosage and Administration). 115 Consider possible need for monitoring serum caffeine concentrations (see General under Dosage and Administration). 115 Monitor blood glucose concentrations periodically; hypoglycemia and hyperglycemia reported in neonates. 115 Long-term follow-up studies have not shown caffeine administration in premature neonates to adversely affect neurologic development or growth. 115 Hepatic Impairment Pharmacokinetics of caffeine citrate not evaluated in premature neonates with hepatic impairment; use with caution. 115 (See Hepatic Impairment under Dosage and Administration.) Renal Impairment Pharmacokinetics of caffeine citrate not evaluated in premature neonates with renal impairment; use with caution. 115 (See Renal Impairment under Dosage and Administration.) Common Adverse Effects CNS stimulation (e.g., insomnia, restlessness, nervousness, mild delirium), GI irritation (e.g., nausea, vomiting, gastric irritation). a In neonates with apnea of prematurity: Rash, feeding intolerance, sepsis, necrotizing enterocolitis. 115 Interactions for Caffeine; Caffeine and Sodium Benzoate Injection; Caffeine Citrate Appears to be metabolized principally by CYP1A2. 115 Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes Pharmacokinetic interactions likely with drugs metabolized by CYP1A2 or with CYP1A2 inducers or inhibitors. 115 Specific Drugs and Laboratory Tests Drug or Test Interaction Comments Anticonvulsants (phenobarbital, phenytoin) Possible increased elimination of caffeine and decreased serum caffeine concentrations 115 Possible increased metabolism of phenobarbital 120 Increased caffeine dosage may be required 115 β-Adrenergic agonists May increase cardiac inotropic effects 120 a Cimetidine Possible decreased elimination of caffeine and increased serum caffeine concentrations 115 Reduced caffeine dosage may be required 115 Disulfiram Potential inhibition of caffeine metabolism and substantially decreased clearance of caffeine; 103 possible exaggerated or prolonged caffeine effects 103 104 Clinical importance unknown 103 104 Ketoconazole Possible decreased elimination of caffeine and increased serum caffeine concentrations 115 a Reduced caffeine dosage may be required 115 a Ketoprofen Possible decreased urine volume 115 Clinical importance unknown 115 Tests for serum urate False-positive elevations of serum urate as measured by the Bittner method 120 a Tests for urinary 5-hydroxyindoleacetic acid (5-HIAA) Slight increase in urine 5-HIAA concentrations 120 a Tests for urinary catecholamines and vanillylmandelic acid (VMA) Slight increase in urine concentrations of VMA and catecholamines; possible false-positive results on tests for pheochromocytoma and neuroblastoma 120 a Avoid caffeine intake during test 120 Theophylline Interconversion between caffeine and theophylline reported in premature neonates 115 Concurrent use not recommended in premature neonates 115 Monitor serum caffeine concentrations prior to initiating caffeine therapy in neonates previously treated with theophylline 115 Caffeine; Caffeine and Sodium Benzoate Injection; Caffeine Citrate Pharmacokinetics Absorption Caffeine and caffeine citrate are well absorbed following oral administration. a Absorption following oral administration may be more rapid than that following IM injection of caffeine and sodium benzoate. a Absolute bioavailability of orally administered caffeine in preterm neonates not fully determined. 115 Onset Following oral administration of 100 mg of caffeine (as coffee), peak plasma concentrations reached after 50 75 minutes. a Following oral administration of 10 mg/kg of caffeine to preterm neonates, mean time to peak plasma concentration was 0.5 2 hours. 115 Food Feeding formula does not affect time to peak plasma concentration in infants. 115 Plasma Concentrations Serum caffeine concentrations >50 mcg/mL associated with serious toxicity. 115 Distribution Extent Rapidly distributed into body tissues; readily crosses the blood-brain barrier. 115 120 Concentrations in the CSF of preterm neonates approximates plasma concentration. 115 Readily crosses the placenta and is distributed into milk. 115 a Mean volume of distribution in infants is slightly larger than that in adults (0.6 L/kg). 115 Plasma Protein Binding Approximately 17 36% in adults; data not available for neonates or infants. 115 120 Elimination Metabolism Metabolized in the liver, principally via CYP1A2, to 1-methyluric acid, 1-methylxanthine, and 7-methylxanthine. 115 120 May induce own metabolism; clinical importance of autoinduction is unknown. 120 a Neonates: Limited hepatic metabolism due to immature hepatic enzyme systems. 115 Interconversion between caffeine and theophylline reported. 115 (See Specific Drugs and Laboratory Tests under Interactions.) Metabolism of caffeine by 9 months of age approximates that seen in adults. 115 Elimination Route Adults: Excreted principally in urine as metabolites (> <1% recovered in urine as unchanged drug). 120 a Neonates: Excreted principally in urine as unchanged drug (approximately 86%). 115 Mean fraction excreted unchanged in urine in infants is inversely related to gestational/postconceptional age; 115 by 9 months of age, fraction excreted as unchanged drug approximates that seen in adults. 115 Half-life Adults: 3 5 hours. 120 a Neonates: Approximately 3 4 days. 115 Elimination slower in young infants than in adults because of immature hepatic and/or renal function. 115 Mean half-life in infants is inversely related to gestational/postconceptional age; 115 by 9 months of age, half-life approximates that seen in adults. 115 Special Populations Pharmacokinetics in neonates with renal or hepatic insufficiency not evaluated. 115 Stability Storage Oral Tablets Room temperature. 117 118 Solution 15 30°C. 115 Caregivers should store vials of the oral solution in the child-resistant container provided by the manufacturer. 115 Parenteral Caffeine Citrate Injection 15 30°C. 115 Caffeine and Sodium Benzoate Injection 15 30°C. 120 Compatibility For information on systemic interactions resulting from concomitant use, see Interactions. Parenteral Solution Compatibility (for Caffeine Citrate) Compatible Amino acids 8.5% Dextrose 5 or 50% in water Fat emulsion 20%, IV Drug Compatibility (for Caffeine Citrate) Admixture Compatibility Compatible Calcium gluconate Dopamine HCl Fentanyl citrate Heparin sodium Actions Competitively inhibits phosphodiesterase, the enzyme that degrades cyclic 3 ,5 -adenosine monophosphate (AMP), increasing levels of intracellular cyclic AMP. 120 a Stimulates all levels of the CNS. 120 a Stimulates the cerebral cortex and produces a more rapid and clearer thought flow, wakefulness or arousal in fatigued patients; also improves psychomotor coordination. a Stimulates medullary vagal, vasomotor, and respiratory centers in slightly larger doses, promoting bradycardia, vasoconstriction, and increased respiratory rate. 120 a Produces a positive inotropic effect on the myocardium and a positive chronotropic effect at the SA node, causing transient increases in heart rate, force of contraction, cardiac output, and heart work. 115 120 a Constricts cerebral vasculature; also directly dilates peripheral blood vessels, decreasing peripheral vascular resistance. 120 a Overall effect on heart rate and BP depends on whether CNS or peripheral effects predominate. 120 a Stimulates voluntary skeletal muscle, increasing the force of contraction and decreasing muscular fatigue. 120 a Stimulates gastric acid secretion from parietal cells. 120 a Increases renal blood flow and GFR; decreases proximal tubular reabsorption of sodium and water, resulting in mild diuresis. 120 a Advice to Patients Risk of adverse CNS and cardiac effects if excessive doses are taken. 115 Risk of necrotizing enterocolitis in premature infants; importance of informing clinician if signs of GI intolerance (e.g., abdominal distention, vomiting, bloody stools) or lethargy develops. 115 a Importance of informing clinician if premature infant continues to experience apneic events despite caffeine therapy; do not increase dosage without advice of clinician. 115 a Importance of adhering to directions for use of caffeine citrate oral solution, including directions for storage, measurement and withdrawal of the prescribed dose, and administration. 115 Provide copy of manufacturer s patient information. 115 Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., cardiovascular disease). 115 Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed. a Importance of informing patients of other important precautionary information. (See Cautions.) Preparations Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details. Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations. * available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name Caffeine Routes Dosage Forms Strengths Brand Names Manufacturer Oral Tablets 100 mg* 200 mg* Tablets, film-coated 200 mg* No Doz Maximum Strength Caplets (with povidone and propylene glycol) Novartis Vivarin GlaxoSmithKline Also commercially available in combination with analgesics, antacids, antihistamines, antipyretics, antitussives, belladonna alkaloids, diuretics, ergotamine tartrate, expectorants, nasal decongestants, skeletal muscle relaxants, sympathomimetics, and vitamins. * available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name Caffeine and Sodium Benzoate Routes Dosage Forms Strengths Brand Names Manufacturer Parenteral Injection 250 mg/mL (equivalent to caffeine anhydrous 125 mg/mL and sodium benzoate 125 mg/mL)* Caffeine and Sodium Benzoate Injection American Regent, Bedford Caffeine Citrate Routes Dosage Forms Strengths Brand Names Manufacturer Oral Solution 20 mg/mL (equivalent to 10 mg/mL caffeine anhydrous) Cafcit MeadJohnson Caffeine Citrate Oral Solution Paddock, PharmaForce Parenteral Injection 20 mg/mL (equivalent to 10 mg/mL caffeine anhydrous) Cafcit MeadJohnson Caffeine Citrate Injection American Regent, Paddock, PharmaForce Bulk Powder AHFS DI Essentials. Copyright 2017, Selected Revisions November 20, 2012. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814. † Use is not currently included in the labeling approved by the US Food and Drug Administration. References 100. Council on Scientific Affairs. Caffeine labeling. JAMA . 1984; 252:803-6. [PubMed 6748182] 101. Robertson D, Wade D, Workman R et al. Tolerance to the humoral and hemodynamic effects of caffeine in man. J Clin Invest . 1981; 67:1111-7. [PubMed 7009653] 102. Robertson D, Hollister AS, Kincaid D et al. Caffeine and hypertension. Am J Med . 1984; 77:54-60. [PubMed 6377891] 103. Beach CA, Mays DC, Guiler RC et al. Inhibition of elimination of caffeine by disulfiram in normal subjects and recovering alcoholics. Clin Pharmacol Ther . 1986; 39:265-70. [PubMed 3948467] 104. Mangini RJ, ed. Drug interaction facts. St. Louis: JB Lippincott Co; 1986(Jul):123a. 105. Aranda JV, Cook CE, Gorman W. Pharmacokinetic profile of caffeine in the premature newborn infant with apnea. J Pediatr . 1979; 94:663-8. [PubMed 430317] 106. Murat I, Moriette G, Blin MC et al. The efficacy of caffeine in the treatment of recurrent idiopathic apnea in premature infants. J Pediatr . 1981; 99:984-9. [PubMed 7310594] 107. Brouard C, Moriette G, Murat I et al. Comparative efficacy of theophylline and caffeine in the treatment of idiopathic apnea in premature infants. Am J Dis Child . 1985; 139:698-700. [PubMed 4014092] 108. Le Guennec JC, Billon B, Paré C. Maturational changes of caffeine concentrations and disposition in infancy during maintenance therapy for apnea of prematurity: influence of gestational age, hepatic disease, and breast-feeding. Pediatrics . 1985; 76:834-40. [PubMed 4058995] 109. Anwar M, Modestin H, Mojica N et al. Effect of caffeine on pneumogram and apnoea of infancy. Arch Dis Child . 1986; 61:891-5. [PubMed 3767418] 110. Spitzer AR, Fox WW. Infant apnea. Pediatr Clin North Am . 1986; 33:561-81. [PubMed 3714338] 111. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414), to June 28, 1996. Rockville, MD; 1996 Jul. 112. Cerulli J, Lomaestro BM, Malone M. Update on the pharmacotherapy of obesity. Ann Pharmacother . 1998; 32:88-102. [PubMed 9475827] 113. Astrup A, Toubro S, Christensen NJ et al. Pharmacology of thermogenic drugs. Am J Clin Nutr . 1992; 55:246-8S. 114. Food and Drug Administration. Dietary supplements containing ephedrine alkaloids. Proposed rule. [21 FR Part 111] Fed Regist . 1997; 62:30678-724. 115. Mead Johnson and Co. Cafcit (caffeine citrate) injection and oral solution prescribing information. Evansville, IN: 2003 May. 116. Matchar DB, Young WB, Rosenberg JH et al. Evidence-based guidelines for migraine headache in the primary care setting: pharmacological management of acute attacks. St. Paul, MN; 2001. From the American Academy of Neurology web site. 117. GlaxoSmithKline Consumer Healthcare. Vivarin (caffeine) tablets patient information. Pittsburgh, PA; 2003. From website. Accessed 2007 May 17. 118. Novartis Consumer Health, Inc. Maximum Strength NoDoz (caffeine) tablets patient information. Parsippany, NJ; 2007. 119. Caffeine. In: Briggs GG, Freeman RK, Yaffe SJ, eds. Drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk. 7th ed. Philadelphia: Lippincott, Williams & Wilkins; 2005:201-7. 120. American Regent Laboratories, Inc. Caffeine and sodium benzoate injection prescribing information. Shirley, NY: 1998 Nov. 121. Watson Laboratories, Inc. Butalbital, acetaminophen, caffeine, and codeine phosphate capsules prescribing information. Corona, CA; 2007 Jan. a. AHFS drug information 2007. McEvoy GK, ed. Caffeine. Bethesda, MD: American Society of Health-System Pharmacists; 2007:2478-2481. b. Forest Pharmaceuticals, Inc. Esgic-Plus (butalbital, acetaminophen, and caffeine) capsules prescribing information. St. Louis, MO; 2002 Aug. c. Mikart, Inc. Butalbital, acetaminophen, and caffeine tablets prescribing information. Atlanta, GA; 2002 Aug. d. Novartis Consumer Health, Inc. Excedrin Tension Headache (acetaminophen and caffeine) tablets patient information. Parsippany, NJ; 2007. e. Mikart, Inc. Ergotamine tartrate and caffeine tablets prescribing information. Atlanta, GA; 2005 Feb. f. Actavis Elizabeth LLC. Butalbital, aspirin, and caffeine tablets prescribing information. Elizabeth, NJ; 2006 Jan. g. Novartis Consumer Health, Inc. Excedrin Migraine (acetaminophen, aspirin, and caffeine) tablets patient information. Parsippany, NJ; 2007. h. GlaxoSmithKline. Original Formula BC (aspirin, caffeine, and salicylamide) powder patient information. Pittsburgh, PA; 2007. i. Mikart, Inc. Butalbital, acetaminophen, and caffeine tablets prescribing information. Atlanta, GA; 2002 Aug. j. Watson Laboratories, Inc. Butalbital, aspirin, and caffeine capsules prescribing information. Corona, CA; 2006 Mar. k. Watson Laboratories, Inc. Butalbital, aspirin, caffeine, and codeine phosphate capsules prescribing information. Corona, CA; 2007 Jan. l. Novartis Consumer Health, Inc. Extra Strength Excedrin (acetaminophen, aspirin, and caffeine) tablets patient information. Parsippany, NJ; 2007. m. Novartis Pharmaceuticals Corporation. Cafergot (ergotamine tartrate and caffeine) suppositories prescribing information. East Hanover, NJ. Undated. Available from website. Accessed 2007 Dec 5. n. AHFS drug information 2007. McEvoy GK, ed. Ergotamine tartrate. Bethesda, MD: American Society of Health-System Pharmacists; 2007:1359-61. o. Insight Pharmaceuticals. Anacin Max Strength (aspirin and caffeine) tablets patient information. Langhorne, PA. Undated. Available from website. Accessed 2007 Dec 12. p. Mikart, Inc. Butalbital, acetaminophen, and caffeine capsules prescribing information. Atlanta, GA; 2003 Feb. Next Interactions Print this page Add to My Med List More about caffeine/sodium benzoate Side Effects During Pregnancy Drug Interactions Support Group Pricing & Coupons 0 Reviews Add your own review/rating Drug class: CNS stimulants Consumer resources Caffeine and sodium benzoate Injection (Advanced Reading) Related treatment guides Respiratory Failure> ]} FEATURED: CAR-T Cell Therapy Overview Mechanism of Action KTE-C19 Studies KTE-C19 Cancer Targets Adverse Events Manufacturing Drug Status Rx Availability Prescription only C Pregnancy Category Risk cannot be ruled out N/A CSA Schedule Not a controlled drug WADA Class Anti-Doping Classification Manufacturer American Regent, Inc. Drug Class CNS stimulants Related Drugs Respiratory Failure nitric oxide , INOmax , caffeine / sodium benzoate , More... Caffeine / sodium benzoate Rating No Reviews - Be the first! No Reviews - Be the first! Not Rated - Be the first!} } a petroleum
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