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): Oral: 300 mg (caffeine base) as a single dose (Camann 1990).
Reversal of dipyridamole- or regadenoson-induced adverse reactions (eg, angina, hypotension) during nuclear cardiac stress testing (alternative agent) (off-label use): Caffeine citrate: IV: 60 mg (diluted in 25 mL of D5W) over 3 to 5 minutes (Doran 2017; Singleton 2018).
Stimulant: OTC labeling: Oral: 200 mg (caffeine base) every 3 to 4 hours as needed.
There are no dosage adjustments provided in the manufacturer's labeling. Use with caution.
There are no dosage adjustments provided in the manufacturer's labeling. Use with caution.
(For additional information see "Caffeine: Pediatric drug information")
Note: Caffeine citrate should not be interchanged with the caffeine sodium benzoate formulation. Caffeine and sodium benzoate dosing presented as the combination (caffeine base amount is 50% of the caffeine and sodium benzoate combination).
Stimulant: OTC labeling: Caffeine (base): Children ≥12 years and Adolescents: Oral: 100 to 200 mg every 3 to 4 hours as needed
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); use with caution.
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); use with caution.
Refer to adult dosing.
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 [DSC]
Stay Awake: 200 mg
Stay Awake Maximum Strength: 200 mg
Vivarin: 200 mg
Generic: 200 mg
Yes: Tablet, caffeine and sodium benzoate injection, injection, oral solution
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Infusion, solution, as citrate [preservative free]:
Peyona: 20 mg/mL (1 mL)
Solution, oral, as citrate [preservative free]:
Peyona: 20 mg/mL (1 mL)
Oral: May be administered without regard to feedings or meals. May administer injectable formulation (caffeine citrate) orally.
Parenteral:
Caffeine citrate: Reversal of dipyridamole- or regadenoson-induced adverse reactions during cardiac stress testing: Infuse dose (diluted in 25 mL D5W) over 3 to 5 minutes (Doran 2017).
Caffeine and sodium benzoate: Note: Use a 0.22 micron in-line filter when administering (American Regent 2019).
Direct IV injection: Administer slowly.
Oral: May be administered without regard to feedings or meals.
Parenteral: Caffeine citrate: IV: May administer undiluted or further diluted with D5W. Infuse loading dose over at least 30 minutes; maintenance dose may be infused over at least 10 minutes.
Caffeine citrate: Treatment of apnea of prematurity.
Caffeine and sodium benzoate: See Off-Label uses.
Caffeine [OTC labeling]: Helps restore mental alertness or wakefulness when experiencing drowsiness or fatigue.
Augmentation of seizure induction during electroconvulsive therapy (caffeine and sodium benzoate); Postdural puncture headache (caffeine and sodium benzoate); Reversal of dipyridamole- or regadenoson-induced adverse reactions (eg, angina, hypotension) during nuclear cardiac stress testing (alternative agent)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
1% to 10%:
Dermatologic: Skin rash (9%), epidermal thinning (2%), xeroderma (2%)
Endocrine & metabolic: Acidosis (2%)
Gastrointestinal: Gastritis (2%), gastrointestinal hemorrhage (2%)
Hematologic & oncologic: Disseminated intravascular coagulation (2%), hemorrhage (2%)
Infection: Sepsis (4%)
Nervous system: Cerebral hemorrhage (2%)
Ophthalmic: Retinopathy of prematurity (2%)
Renal: Renal failure syndrome (2%)
Respiratory: Dyspnea (2%), pulmonary edema (2%)
Miscellaneous: Reduced intake of food/liquids (9%, feeding intolerance), abnormal healing (2%), accidental injury (2%)
Frequency not defined: Gastrointestinal: Necrotizing enterocolitis
Postmarketing: Cardiac disorder (including increased left ventricular output, increased stroke volume), central nervous system stimulation, gastrointestinal disease (including gastric aspirate), hyperglycemia, hypoglycemia, increased creatinine clearance, increased heart rate, increased urinary sodium, increased urine calcium excretion, increased urine output, irritability, jitteriness, restlessness, tachycardia
Hypersensitivity to caffeine or any component of the formulation; sodium benzoate is not for use in neonates.
OTC labeling: When used for self-medication, do not use in children <12 years of age or as a substitute for sleep.
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:
• Product interchangeability: Caffeine citrate should not be interchanged with caffeine and sodium benzoate.
Other warnings and precautions:
• Self-medication (OTC use): OTC products contain 200 mg of caffeine per tablet, approximately the amount of caffeine similar to 1 cup of coffee. When used for self-medication (OTC), limit the use of caffeine containing medications, foods, or beverages; too much caffeine may cause irritability, nervousness, sleeplessness, and tachycardia. Discontinue use and contact health care provider if drowsiness or fatigue are persistent or recur.
• Transcutaneous electrical nerve stimulation: Analgesia from transcutaneous electrical nerve stimulation may be lessened with concomitant caffeine use (Marchand 1995).
During a caffeine citrate double-blind, placebo-controlled study, 6 of 85 patients developed necrotizing enterocolitis (NEC) with 3 cases resulting in death; 5 of these 6 patients had received caffeine citrate. In a large randomized, placebo-controlled trial which compared caffeine citrate to placebo in ~2,000 patients with apnea of prematurity, the incidence of NEC was similar between the caffeine group and placebo group (6.3% vs 6.7%) (Schmidt 2006). Although no causal relationship has been established, neonates who receive caffeine citrate should be closely monitored for the development of NEC. Caffeine serum levels should be closely monitored to optimize therapy and prevent serious toxicity.
The incidence of cerebellar hemorrhage was shown to be increased in patients receiving high-dose caffeine citrate (80 mg/kg total load over 36 hours) compared to those receiving standard doses (36% vs 10%) in a randomized, controlled trial in preterm neonates (n=74; GA ≤30 weeks; PNA ≤24 hours); in addition, this group also had subtle neurobehavioral differences including increased tone and abnormal movements at term equivalent age (McPherson 2015). In a post hoc analysis of this same group of neonates the high-dose group also trended towards a higher incidence of seizures (40% vs 58%; p = 0.1) and an increase in seizure duration (48.9 vs 170.9 seconds; p = 0.1) as indicated by continuous limited channel aEEG monitoring over the first 72 hours of life, although this was not statistically significant. No difference in the number of clinical seizures requiring treatment or status epilepticus were noted between the groups; also no difference in the rates of IVH, hypoglycemia or perinatal hypoxic ischemia were noted (Vesoulis 2016). Authors noted that these adverse effects discouraged the potential for a larger trial; if use deemed necessary, close monitoring is recommended (McPherson 2015; Vesoulis 2016). In a large randomized, placebo-controlled trial which compared caffeine citrate (load: 20 mg/kg; maintenance: 5 to 10 mg/kg/dose) to placebo in ~2,000 patients (birthweight: 500 to 1,250 g; GA: mean: 27 weeks) with apnea of prematurity, the incidence of brain injury as evidenced by ultrasound and death were similar between the caffeine citrate and placebo groups. Long-term follow up at both 18 months and 5 years corrected age again showed no difference in death or adverse neurodevelopmental outcomes between the 2 groups (Schmidt 2006; Schmidt 2007; Schmidt 2012).
Substrate of CYP1A2 (major), CYP2C9 (minor), CYP2D6 (minor), CYP2E1 (minor), CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP1A2 (weak)
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Acebrophylline: May enhance the stimulatory effect of CNS Stimulants. Risk X: 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; significantly higher adenosine doses or alternative agents may be required. Discontinue caffeine 24 hours in advance of scheduled diagnostic use of adenosine if possible. Risk D: Consider therapy modification
Amifampridine: Agents With Seizure Threshold Lowering Potential may enhance the neuroexcitatory and/or seizure-potentiating effect of Amifampridine. Risk C: Monitor therapy
Antipsychotic Agents: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Atomoxetine: May enhance the hypertensive effect of Sympathomimetics. Atomoxetine may enhance the tachycardic effect of Sympathomimetics. Risk C: Monitor therapy
Broccoli: May decrease the serum concentration of CYP1A2 Substrates (High risk with Inducers). Risk C: Monitor therapy
Bromperidol: Caffeine and Caffeine Containing Products may decrease the absorption of Bromperidol. Risk C: Monitor therapy
BuPROPion: May enhance the neuroexcitatory and/or seizure-potentiating effect of Agents With Seizure Threshold Lowering Potential. Risk C: Monitor therapy
Cannabinoid-Containing Products: May enhance the tachycardic effect of Sympathomimetics. Risk C: Monitor therapy
Cannabis: May decrease the serum concentration of CYP1A2 Substrates (High risk with Inducers). Risk C: Monitor therapy
CloZAPine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of CloZAPine. Risk C: Monitor therapy
Cocaine (Topical): 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. Risk D: Consider therapy modification
CYP1A2 Inducers (Moderate): May decrease the serum concentration of Caffeine and Caffeine Containing Products. Risk C: Monitor therapy
CYP1A2 Inhibitors (Moderate): May increase the serum concentration of Caffeine and Caffeine Containing Products. Risk C: Monitor therapy
CYP1A2 Inhibitors (Strong): May increase the serum concentration of Caffeine and Caffeine Containing Products. Risk C: Monitor therapy
Doxofylline: Caffeine and Caffeine Containing Products may enhance the adverse/toxic effect of Doxofylline. Risk X: Avoid combination
Esketamine: May enhance the hypertensive effect of CNS Stimulants. Risk C: Monitor therapy
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. Risk C: Monitor therapy
Guanethidine: May enhance the arrhythmogenic effect of Sympathomimetics. Guanethidine may enhance the hypertensive effect of Sympathomimetics. Risk C: 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. Risk C: Monitor therapy
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 antiseizure drugs. Risk D: 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 antiseizure drugs. Risk D: 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 antiseizure drugs. Risk D: Consider therapy modification
Kratom: May enhance the adverse/toxic effect of Sympathomimetics. Risk X: Avoid combination
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. Risk D: Consider therapy modification
Lithium: Caffeine and Caffeine Containing Products may decrease the serum concentration of Lithium. Risk C: Monitor therapy
Norfloxacin: May increase the serum concentration of Caffeine and Caffeine Containing Products. Risk C: 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. Risk C: Monitor therapy
Ozanimod: May enhance the hypertensive effect of Sympathomimetics. Risk C: Monitor therapy
Pipemidic Acid: May increase the serum concentration of Caffeine and Caffeine Containing Products. Risk C: 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. Risk D: Consider therapy modification
Sodium Phosphates: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Sodium Phosphates. Specifically, the risk of seizure or loss of consciousness may be increased in patients with significant sodium phosphate-induced fluid or electrolyte abnormalities. Risk C: Monitor therapy
Solriamfetol: Sympathomimetics may enhance the hypertensive effect of Solriamfetol. Sympathomimetics may enhance the tachycardic effect of Solriamfetol. Risk C: Monitor therapy
Solriamfetol: CNS Stimulants may enhance the hypertensive effect of Solriamfetol. CNS Stimulants may enhance the tachycardic effect of Solriamfetol. Risk C: Monitor therapy
Sympathomimetics: May enhance the adverse/toxic effect of other Sympathomimetics. Risk C: Monitor therapy
Tedizolid: May enhance the hypertensive effect of Sympathomimetics. Tedizolid may enhance the tachycardic effect of Sympathomimetics. Risk C: Monitor therapy
Theophylline Derivatives: CYP1A2 Inhibitors (Weak) may increase the serum concentration of Theophylline Derivatives. Risk C: Monitor therapy
TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use is necessary, initiate tizanidine at an adult dose of 2 mg and increase in 2 to 4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Risk D: Consider therapy modification
Tobacco (Smoked): May decrease the serum concentration of Caffeine and Caffeine Containing Products. Risk C: Monitor therapy
Warfarin: Caffeine and Caffeine Containing Products may diminish the anticoagulant effect of Warfarin. Risk C: Monitor therapy
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 show 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; Nehlig 1994). Chronic maternal consumption of high amounts of caffeine during pregnancy may lead to neonatal withdrawal at delivery (eg, apnea, irritability, jitteriness, vomiting) (Martin 2007).
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 tobacco or alcohol consumption (Brent 2011; Koren 2000). Current guidelines recommend limiting caffeine intake from all sources to ≤200 mg/day during pregnancy (ACOG 2010).
Caffeine and its metabolites are present in breast milk (Berlin 1981; Hildebrandt 1983; Martin 2007; Oo 1995; Ryu 1985a).
Actual breast milk concentrations vary widely. The source of caffeine, how caffeinated beverages are brewed, the amount ingested, and the postpartum age of the mother affect concentrations in breast milk (Berlin 1984; Davanzo 2014; Ryu 1985b; Staychansky 1998; Tyrala 1979)
Breast milk concentrations are dependent upon maternal intake from all sources and ability to metabolize caffeine (eg, smoker versus nonsmoker) (Brent 2011). Peak breast milk concentrations generally occur within 1 to 2 hours (Berlin 1984; Calvaresi 2016; Nehlig 1994; Stavchansky 1988). In one study, caffeine was not detected in the breast milk of women ingesting <100 mg (Berlin 1984). Caffeine can be detected in the saliva and serum of some breastfed infants (Hildebrandt 1983; Ryu 1985a). The ability of the breastfeeding child to metabolize caffeine is age-dependent and higher serum concentrations are found in preterm infants (Atkinson 1988; Hildebrant 1983).
Maternal caffeine ingestion may decrease iron concentrations of breast milk (Nehlig 1994). Irritability and jitteriness have been reported in the breastfeeding infant following larger than acceptable amounts of maternal caffeine ingestion (Clement 1989; Rustin 1989). Infant heart rates and sleep patterns were not found to be affected in normal, full-term infants exposed to lesser amounts of caffeine (Ryu 1985b) or older infants (Santos 2012). Long-term effects on infant exposure have not been evaluated (O'Connor 2016).
Moderate amounts of caffeine are considered acceptable with breastfeeding (Ito 2000). Ingestion of <300 mg/day is recommended (O'Connor 2016). Caution is recommended if breastfeeding premature infants, infants small for gestational age, or if exposure to unusually high amounts of caffeine occurs (Atkinson 1988; Nehlig 1994). When maternal caffeine is from dietary sources (eg, coffee), maternal ingestion right after breastfeeding may minimize infant exposure (Calvaresi 2016).
Apnea of prematurity: Heart rate, number and severity of apnea spells, serum caffeine concentration (as appropriate).
Stimulant: Insomnia, tachycardia.
Therapeutic: Apnea of prematurity: 8 to 20 mcg/mL
Potentially toxic: >20 mcg/mL
Toxic: >50 mcg/mL
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.
Adults: 0.6 L/kg.
Protein binding: 36%.
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).
Half-life elimination:
Neonates: 72 to 96 hours.
Infants ≥9 months, Children, Adolescents, and Adults: 5 hours.
Time to peak, serum: Preterm neonates: Oral: 30 minutes to 2 hours.
Excretion:
Neonates: Urine (86% unchanged).
Infants ≥9 months, Children, Adolescents, and Adults: Urine (1% unchanged).
Pregnancy and cirrhosis: Half-life is increased.
Solution (Cafcit Intravenous)
60 mg/3 mL (per mL): $4.00
Solution (Caffeine Citrate Intravenous)
60 mg/3 mL (per mL): $3.26 - $14.00
Solution (Caffeine Citrate Oral)
60 mg/3 mL (per mL): $7.96 - $9.60
Solution (Caffeine-Sodium Benzoate Injection)
125-125 mg/mL (per mL): $15.45
Tablets (Caffeine Oral)
200 mg (per each): $0.11
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