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Caffeine

Pronunciation

Pronunciation

(KAF een)

Index Terms

  • Caffeine and Sodium Benzoate
  • Caffeine Citrate
  • Caffeine Sodium Benzoate
  • Sodium Benzoate and Caffeine

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Injection, solution, as citrate [preservative free]:

Cafcit: 60 mg/3 mL (3 mL) [equivalent to 10 mg/mL caffeine base]

Generic: 60 mg/3 mL (3 mL) [equivalent to 10 mg/mL caffeine base]

Injection, solution [with sodium benzoate]:

Generic: Caffeine 125 mg/mL and sodium benzoate 125 mg/mL (2 mL)

Solution, oral, as citrate [preservative free]:

Cafcit: 60 mg/3 mL (3 mL) [equivalent to 10 mg/mL caffeine base] [DSC]

Generic: 60 mg/3 mL (3 mL) [equivalent to 10 mg/mL caffeine base]

Tablet, oral:

Keep Alert: 200 mg

NoDoz Maximum Strength: 200 mg

Stay Awake: 200 mg

Stay Awake Maximum Strength: 200 mg

Vivarin: 200 mg

Generic: 200 mg

Brand Names: U.S.

  • Cafcit
  • Keep Alert [OTC]
  • No Doz Maximum Strength [OTC]
  • Stay Awake Maximum Strength [OTC]
  • Stay Awake [OTC]
  • Vivarin [OTC]

Pharmacologic Category

  • Central Nervous System Stimulant
  • Phosphodiesterase Enzyme Inhibitor, Nonselective

Pharmacology

Increases levels of 3'5' cyclic AMP by inhibiting phosphodiesterase; CNS stimulant which increases medullary respiratory center sensitivity to carbon dioxide, stimulates central inspiratory drive, and improves skeletal muscle contraction (diaphragmatic contractility); prevention of apnea may occur by competitive inhibition of adenosine

Distribution

Vd: Neonates: 0.8 to 0.9 L/kg; Children >9 months to Adults: 0.6 L/kg

Metabolism

Hepatic, via demethylation by CYP1A2. Note: In neonates, interconversion between caffeine and theophylline has been reported (caffeine levels are ~25% of measured theophylline after theophylline administration and ~3% to 8% of caffeine would be expected to be converted to theophylline)

Excretion

Neonates ≤1 month: 86% excreted unchanged in urine

Infants >1 month and Adults: In urine, as metabolites

Clearance:

Neonates: 8.9 mL/hour/kg (range: 2.5 to 17)

Adults: 94 mL/hour/kg

Time to Peak

Serum: Oral: Within 30 minutes to 2 hours

Half-Life Elimination

Neonates: 72 to 96 hours (range: 40 to 230 hours)

Children >9 months and Adults: 5 hours

Protein Binding

17% (children) to 36% (adults)

Special Populations Note

Pregnancy, smoking, and cirrhosis: Half-life is increased.

Use: Labeled Indications

Caffeine citrate: Treatment of idiopathic apnea of prematurity

Caffeine and sodium benzoate: See Off-Label uses.

Caffeine [OTC labeling]: Restore mental alertness or wakefulness when experiencing fatigue

Off Label Uses

Augmentation of seizure induction during electroconvulsive therapy (caffeine and sodium benzoate)

Data from a randomized, double blind study as well as a few unblinded studies support the use of caffeine/sodium benzoate in the treatment of augmentation of seizure induction during electroconvulsive therapy (ECT) [Coffey 1987], [Hinkle 1987], [McCall 1993], [Shapira 1987]. Additional trials may be necessary to further define the role of caffeine/sodium benzoate in this setting.

Postdural puncture headache (caffeine and sodium benzoate)

Data from a randomized, double blind, placebo-controlled study (Note: Second phase of study was unblinded and open-label) supports the use of IV caffeine/sodium benzoate in the treatment of postdural puncture headache [Sechzer 1978]. One protocol for the treatment of this condition has been described [Jarvis 1986]. Data from a double-blind, placebo-controlled trial in post-partum patients with postdural puncture headache supports the use of oral caffeine base for the treatment of this condition [Camann 1990]. Additional trials may be necessary to further define the role of caffeine/sodium benzoate in this condition.

Additional Off-Label Uses

CNS stimulant

Contraindications

Hypersensitivity to caffeine or any component of the formulation; sodium benzoate is not for use in neonates

Dosing: Adult

Note: Caffeine citrate should not be interchanged with the caffeine sodium benzoate formulation. Dosing presented as the combination of caffeine and sodium benzoate unless otherwise noted (caffeine base amount is 50% of the caffeine and sodium benzoate combination).

Augmentation of seizure induction during electroconvulsive therapy (ECT) (off-label use): IV: Initial: 500 to 1,000 mg caffeine and sodium benzoate (equivalent to 250 to 500 mg caffeine base); if necessary during subsequent ECT sessions, may titrate dose up or down in increments of 250 to 500 mg caffeine and sodium benzoate (equivalent to 125 to 250 mg caffeine base); a maximum dose of 2,000 mg caffeine and sodium benzoate (equivalent to 1,000 mg caffeine base) during an ECT session has been reported (Coffey 1987; Hinkle 1987; McCall 1993; Shapira 1987).

Postdural puncture headache (off-label use):

IV: 500 mg caffeine and sodium benzoate (equivalent to 250 mg caffeine base) in 1,000 mL NS infused over 1 hour, followed by 1,000 mL NS infused over 2 hours; after 4 hours, a second course of caffeine can be given for unrelieved headache pain (Choi 1996; Jarvis 1986; Yucel 1999).

Oral: 300 mg (caffeine base) as a single dose (Camann 1990)

Stimulant: OTC labeling: Oral: 100 to 200 mg (caffeine base) every 3 to 4 hours as needed

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Caffeine citrate should not be interchanged with the caffeine sodium benzoate formulation.

Apnea of prematurity: Neonates: Caffeine citrate: Oral, IV: Note: Dose expressed as caffeine citrate; caffeine base amount is 50% of caffeine citrate.

Loading dose: Minimum dose: 20 mg/kg as caffeine citrate; loading doses as high as 80 mg/kg of caffeine citrate have been reported (Steer, 2004); some centers repeat a load of 20 mg/kg as caffeine citrate to a maximum cumulative dose load of 80 mg/kg as caffeine citrate in refractory patients (Schmidt, 2006; Schmidt, 2007; Steer, 2004).

Maintenance dose: 5 to 10 mg/kg/day as caffeine citrate once daily starting 24 hours after the loading dose; some centers increase maintenance dose in 5 mg/kg/day increments of caffeine citrate to a maximum of 20 mg/kg/day in refractory patients based on clinical response ± serum caffeine concentrations (Schmidt, 2006; Schmidt, 2007; Steer, 2004).

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer's labeling. Use with caution.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer's labeling. Use with caution.

Reconstitution

Parenteral:

Caffeine citrate: May administer without dilution or diluted with D5W to 10 mg caffeine citrate/mL.

Caffeine and sodium benzoate: For postdural puncture headaches (off-label use), dilute in 1,000 mL NS (Jarvis 1986; Yucel 1999).

Extemporaneously Prepared

A 10 mg/mL oral solution of caffeine (as citrate) may be prepared from 10 g citrated caffeine powder combined with 10 g citric acid USP and dissolved in 1000 mL distilled water. Label “shake well”. Stable for 3 months at room temperature (Nahata, 2014).

A 20 mg/mL oral solution of caffeine (as citrate) may be made from 10 g citrated caffeine powder and dissolved in 250 mL sterile water for irrigation. Stir solution until completely clear, then add a 2:1 mixture of simple syrup and cherry syrup in sufficient quantity to make 500 mL. Label “shake well” and “refrigerate”. Stable for 90 days (Eisenberg, 1984).

Eisenberg MG and Kang N, "Stability of Citrated Caffeine Solutions for Injectable and Enteral Use," Am J Hosp Pharm, 1984, 41(11):2405-6.6507449Nahata MC and Pai VB, Pediatric Drug Formulations, 6th ed, Cincinnati, OH: Harvey Whitney Books Co, 2014.

Administration

Oral: May be administered without regard to feedings or meals. May administer injectable formulation (caffeine citrate) orally.

Parenteral:

Caffeine citrate: Infuse loading dose over at least 30 minutes; maintenance dose may be infused over at least 10 minutes. May administer without dilution.

Caffeine and sodium benzoate: For direct IV injection, administer slowly.

Postdural puncture headaches (off-label use): Infuse diluted solution over 1 hour. Follow with 1,000 mL NS infused over 2 hours (Choi 1996; Jarvis 1986; Yucel 1999).

Compatibility

See Trissel’s IV Compatibility Database

Storage

Store at 20°C to 25°C (68°F to 77°F).

Caffeine citrate: Injection and oral solution contain no preservatives; injection is chemically stable for at least 24 hours at room temperature when diluted to 10 mg/mL (as caffeine citrate) with D5W, D50W, Intralipid® 20%, and Aminosyn® 8.5%; also compatible with dopamine (600 mcg/mL), calcium gluconate 10%, heparin (1 unit/mL), and fentanyl (10 mcg/mL) at room temperature for 24 hours.

Drug Interactions

Abiraterone Acetate: May increase the serum concentration of CYP1A2 Substrates. Monitor therapy

Acebrophylline: May enhance the stimulatory effect of CNS Stimulants. Avoid combination

Adenosine: Caffeine and Caffeine Containing Products may diminish the therapeutic effect of Adenosine. Management: Monitor for decreased effect of adenosine if patient is receiving caffeine. Discontinue caffeine in advance of scheduled diagnostic use of adenosine whenever possible. Consider therapy modification

AtoMOXetine: May enhance the hypertensive effect of Sympathomimetics. AtoMOXetine may enhance the tachycardic effect of Sympathomimetics. Monitor therapy

Cannabinoid-Containing Products: May enhance the tachycardic effect of Sympathomimetics. Exceptions: Cannabidiol. Monitor therapy

Ciprofloxacin (Systemic): May increase the serum concentration of Caffeine. Monitor therapy

CloZAPine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of CloZAPine. Monitor therapy

Cocaine: May enhance the hypertensive effect of Sympathomimetics. Management: Consider alternatives to use of this combination when possible. Monitor closely for substantially increased blood pressure or heart rate and for any evidence of myocardial ischemia with concurrent use. Consider therapy modification

CYP1A2 Inhibitors (Moderate): May decrease the metabolism of CYP1A2 Substrates. Monitor therapy

CYP1A2 Inhibitors (Strong): May decrease the metabolism of CYP1A2 Substrates. Consider therapy modification

Deferasirox: May increase the serum concentration of CYP1A2 Substrates. Monitor therapy

Doxofylline: Caffeine and Caffeine Containing Products may enhance the adverse/toxic effect of Doxofylline. Avoid combination

Formoterol: Caffeine and Caffeine Containing Products may enhance the adverse/toxic effect of Formoterol. Caffeine and Caffeine Containing Products may enhance the hypokalemic effect of Formoterol. Monitor therapy

Indacaterol: Caffeine and Caffeine Containing Products may enhance the adverse/toxic effect of Indacaterol. Caffeine and Caffeine Containing Products may enhance the hypokalemic effect of Indacaterol. Monitor therapy

Iobenguane I 123: Sympathomimetics may diminish the therapeutic effect of Iobenguane I 123. Avoid combination

Iohexol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iohexol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iohexol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic anticonvulsants. Consider therapy modification

Iomeprol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iomeprol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iomeprol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic anticonvulsants. Consider therapy modification

Iopamidol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iopamidol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iopamidol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic anticonvulsants. Consider therapy modification

Linezolid: May enhance the hypertensive effect of Sympathomimetics. Management: Reduce initial doses of sympathomimetic agents, and closely monitor for enhanced pressor response, in patients receiving linezolid. Specific dose adjustment recommendations are not presently available. Consider therapy modification

Lithium: Caffeine and Caffeine Containing Products may decrease the serum concentration of Lithium. Monitor therapy

Norfloxacin: May increase the serum concentration of Caffeine and Caffeine Containing Products. Monitor therapy

Obeticholic Acid: May increase the serum concentration of CYP1A2 Substrates. Monitor therapy

Olodaterol: Caffeine and Caffeine Containing Products may enhance the adverse/toxic effect of Olodaterol. Caffeine and Caffeine Containing Products may enhance the hypokalemic effect of Olodaterol. Monitor therapy

Peginterferon Alfa-2b: May increase the serum concentration of CYP1A2 Substrates. Monitor therapy

Regadenoson: Caffeine and Caffeine Containing Products may diminish the vasodilatory effect of Regadenoson. Management: Avoiding using caffeine or other methylxanthine containing products (e.g., theophylline) for at least 12 hours prior to the administration of regadenoson. Consider therapy modification

Stiripentol: May increase the serum concentration of Caffeine and Caffeine Containing Products. Avoid combination

Sympathomimetics: May enhance the adverse/toxic effect of other Sympathomimetics. Monitor therapy

Tedizolid: May enhance the hypertensive effect of Sympathomimetics. Tedizolid may enhance the tachycardic effect of Sympathomimetics. Monitor therapy

Teriflunomide: May decrease the serum concentration of Caffeine and Caffeine Containing Products. Monitor therapy

TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use cannot be avoided, initiate tizanidine at an adult dose of 2 mg and increase in 2-4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Consider therapy modification

Vemurafenib: May increase the serum concentration of CYP1A2 Substrates. Management: Consider alternatives to such combinations whenever possible, particularly if the CYP1A2 substrate has a relatively narrow therapeutic index. Consider therapy modification

Adverse Reactions

Frequency not specified; primarily serum-concentration related.

Cardiovascular: Angina pectoris, chest pain, flushing, palpitations, sinus tachycardia, supraventricular tachycardia, vasodilatation, ventricular arrhythmia

Central nervous system: Agitation, delirium, dizziness, hallucination, headache, insomnia, irritability, psychosis, restlessness

Dermatologic: Urticaria

Gastrointestinal: Esophageal motility disorder (sphincter tone decreased), gastritis

Genitourinary: Diuresis

Neuromuscular & skeletal: Fasciculations

Ophthalmic: Increased intraocular pressure (>180 mg caffeine), miosis

Warnings/Precautions

Disease-related concerns:

• Anxiety: Avoid use in patients with anxiety, agitation, or tremor.

• Cardiovascular disease: Use with caution in patients with cardiovascular disease; avoid use in patients with symptomatic cardiac arrhythmias.

• Gastrointestinal disease: Use with caution in patients with a history of peptic ulcer and/or gastroesophageal reflux.

• Hepatic impairment: Use with caution in patients with hepatic impairment.

• Renal impairment: Use with caution in patients with renal impairment.

• Seizure disorder: Use with caution in patients with a history of seizure disorder; may lower seizure threshold leading to new onset or breakthrough seizure activity.

Special populations:

• Neonates: Caffeine citrate should be closely monitored for the development of necrotizing enterocolitis in the neonate; caffeine serum levels should be closely monitored to optimize therapy and prevent serious toxicity. Avoid use of products containing sodium benzoate in neonates; has been associated with a potentially fatal toxicity ("gasping syndrome") in neonates, including metabolic acidosis, respiratory distress, gasping respirations, seizures, intracranial hemorrhage, hypotension, and cardiovascular collapse. In vitro and animal studies have shown that benzoate also displaces bilirubin from protein-binding sites.

Dosage form specific issues:

• OTC products: OTC products contain 200 mg of caffeine per tablet approximately the amount of caffeine similar to one cup of coffee; limit the use of other caffeine-containing beverages or foods.

• Product interchangeability: Caffeine citrate should not be interchanged with caffeine and sodium benzoate.

Other warnings and precautions:

• Transcutaneous electrical nerve stimulation: Analgesia from transcutaneous electrical nerve stimulation may be lessened with concomitant caffeine use (Marchand 1995).

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. Caffeine crosses the placenta; serum concentrations in the fetus are similar to those in the mother (Grosso 2005). Based on current studies, usual dietary exposure to caffeine is unlikely to cause congenital malformations (Brent 2011). However, available data shows conflicting results related to maternal caffeine use and the risk of other adverse events, such as spontaneous abortion or growth retardation (Brent 2011; Jahanfar 2013). The half-life of caffeine is prolonged during the second and third trimesters of pregnancy and maternal and fetal exposure is also influenced by maternal smoking or drinking (Brent 2011; Koren 2000). Current guidelines recommend limiting caffeine intake from all sources to ≤200 mg/day (ACOG 2010).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience irritability or insomnia. Have patient report immediately to prescriber tachycardia or severe anxiety (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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