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Caffeine: Pediatric drug information

Caffeine: Pediatric drug information
(For additional information see "Caffeine: Drug information" and see "Caffeine: Patient drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
Brand Names: US
  • Cafcit;
  • FT Stay Awake [OTC];
  • Keep Alert [OTC];
  • Stay Awake Maximum Strength [OTC];
  • Stay Awake [OTC];
  • Vivarin [OTC]
Brand Names: Canada
  • Peyona
Therapeutic Category
  • Central Nervous System Stimulant;
  • Diuretic;
  • Respiratory Stimulant
Dosing: Neonatal

Apnea of prematurity: Caffeine citrate: Note: Dose expressed as caffeine citrate; caffeine base is 1/2 the dose of the caffeine citrate:

Manufacturer's labeling: Preterm neonates:

Loading dose: IV: 20 mg/kg caffeine citrate as a one-time dose.

Maintenance dose: Oral, IV: 5 mg/kg/dose caffeine citrate once daily, beginning 24 hours after loading dose.

Alternate dosing: GA <32 weeks:

Loading dose: IV: 20 to 40 mg/kg caffeine citrate (Mohammed 2015; Schmidt 2006); loading doses as high as 80 mg/kg of caffeine citrate have been reported (Gray 2011; Steer 2004), but should be utilized with caution (See Note).

Maintenance dose: Oral, IV: 5 to 20 mg/kg/dose caffeine citrate once daily starting 24 hours after the loading dose (Gray 2011; Mohammed 2015; Schmidt 2006).

Note: Higher doses (Load: 40 mg/kg and 80 mg/kg; maintenance dose: 20 mg/kg/dose) were shown to significantly decrease the incidence of apnea, need for oxygen therapy, and extubation failures; incidence of tachycardia was conflicting with one study showing an increased incidence with higher doses compared to low dose (23% vs 8%) while the other showed no significant difference between low and high dose (Mohammed 2015; Steer 2004). Loading doses of 80 mg/kg must be used with caution; one study evaluating the prophylactic use of high-dose caffeine (total dose of 80 mg/kg over 36 hours) compared to standard dose showed patients in the high-dose group had a higher incidence of cerebellar hemorrhage (36% vs 10%) along with increased tone and abnormal movements (McPherson 2015); although not statistically significant, these patients also trended towards a higher incidence of seizures and increased EEG measured seizure duration over the first 72 hours; however, there was no difference in the number of clinical seizures requiring treatment, status epilepticus, IVH, hypoglycemia, or perinatal hypoxic ischemia between the 2 groups (Vesoulis 2016).

Dosing adjustment in renal impairment: Preterm Neonates: Use with caution with impaired renal function; monitor serum concentrations and adjust dose to avoid toxicity; has not been studied.

Dosing adjustment in hepatic impairment: Preterm Neonates: Use with caution with impaired hepatic function; monitor serum concentrations and adjust dose to avoid toxicity; has not been studied.

Dosing: Pediatric

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

Stimulant: OTC labeling: Caffeine (base): Children ≥12 years and Adolescents: Oral: 100 to 200 mg every 3 to 4 hours as needed

Dosing: Kidney Impairment: Pediatric

There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); use with caution.

Dosing: Hepatic Impairment: Pediatric

There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); use with caution.

Dosing: Adult

(For additional information see "Caffeine: Drug information")

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

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

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 during nuclear cardiac stress testing

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

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

Dosing: Kidney Impairment: Adult

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

Dosing: Hepatic Impairment: Adult

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

Adverse Reactions

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

Contraindications

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.

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:

• 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).

Warnings: Additional Pediatric Considerations

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).

Dosage Forms: US

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

FT Stay Awake: 200 mg

Stay Awake: 200 mg

Stay Awake Maximum Strength: 200 mg

Vivarin: 200 mg

Generic: 200 mg

Generic Equivalent Available: US

Yes: Tablet, caffeine and sodium benzoate injection, injection, oral solution

Pricing: US

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): $17.77

Tablets (Caffeine Oral)

200 mg (per each): $0.11

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Dosage Forms: Canada

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)

Extemporaneous Preparations

Note: A caffeine citrate oral solution (20 mg/mL) is commercially available.

10 mg/mL Oral Solution

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).

Nahata MC and Pai VB, Pediatric Drug Formulations, 6th ed, Cincinnati, OH: Harvey Whitney Books Co, 2014.

20 mg/mL Oral Solution

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):2405-6.6507449
Administration: Pediatric

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.

Administration: Adult

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.

Storage/Stability

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.

Use

Caffeine citrate: Treatment of apnea of prematurity (FDA approved in preterm neonates).

Caffeine (base): Restore mental alertness or wakefulness when experiencing fatigue (OTC Product: FDA approved in ages ≥12 years and adults).

Caffeine and sodium benzoate: Treatment (in conjunction with supportive measures) of acute respiratory depression associated with overdose of CNS depressant drugs (not a preferred agent) (FDA approved in adults); has also been used for treatment of postdural puncture headaches.

Metabolism/Transport Effects

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)

Drug Interactions

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

Amisulpride (Oral): Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Amisulpride (Oral). Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

ARIPiprazole: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of ARIPiprazole. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

ARIPiprazole Lauroxil: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of ARIPiprazole Lauroxil. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

Asenapine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Asenapine. 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

Benperidol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Benperidol. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

Blonanserin: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Blonanserin. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

Brexpiprazole: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Brexpiprazole. Specifically, the risk of seizures may be increased. 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

Bromperidol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Bromperidol. Specifically, the risk of seizures may be increased. 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

Cariprazine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Cariprazine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

ChlorproMAZINE: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of ChlorproMAZINE. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

Clothiapine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Clothiapine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

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

CloZAPine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk of seizures may be increased. 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

DroPERidol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of DroPERidol. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

Esketamine: May enhance the hypertensive effect of CNS Stimulants. Risk C: Monitor therapy

Fezolinetant: CYP1A2 Inhibitors (Weak) may increase the serum concentration of Fezolinetant. Risk X: Avoid combination

Flupentixol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Flupentixol. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

FluPHENAZine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of FluPHENAZine. Specifically, the risk of seizures may be increased. 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

Haloperidol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Haloperidol. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

Iloperidone: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iloperidone. Specifically, the risk of seizures may be increased. 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

Levothyroxine: May enhance the adverse/toxic effect of Sympathomimetics. Specifically, the risk of coronary insufficiency may be increased in patients with coronary artery disease. Levothyroxine may enhance the therapeutic effect of Sympathomimetics. Sympathomimetics may enhance the therapeutic effect of Levothyroxine. Risk C: Monitor therapy

Linezolid: May enhance the hypertensive effect of Sympathomimetics. Management: Consider initial dose reductions of sympathomimetic agents, and closely monitor for enhanced blood pressure elevations, in patients receiving linezolid. Risk D: Consider therapy modification

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

Loxapine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Loxapine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

Lumateperone: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Lumateperone. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

Lurasidone: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Lurasidone. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

Methotrimeprazine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Methotrimeprazine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

MigALAstat: Caffeine and Caffeine Containing Products may decrease the serum concentration of MigALAstat. Risk X: Avoid combination

Molindone: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Molindone. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

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

OLANZapine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of OLANZapine. Specifically, the risk of seizures may be increased. 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

Paliperidone: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Paliperidone. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

Periciazine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Periciazine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

Perphenazine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Perphenazine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

Pimozide: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Pimozide. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

Pipamperone [INT]: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Pipamperone [INT]. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

Pipemidic Acid: May increase the serum concentration of Caffeine and Caffeine Containing Products. Risk C: Monitor therapy

Polyethylene Glycol-Electrolyte Solution: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Polyethylene Glycol-Electrolyte Solution. Specifically, the risk of seizure may be increased. Risk C: Monitor therapy

Prochlorperazine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Prochlorperazine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

Promazine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Promazine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

QUEtiapine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of QUEtiapine. Specifically, the risk of seizures may be increased. 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

RisperiDONE: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of RisperiDONE. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

Sertindole: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Sertindole. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

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

Sulpiride: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Sulpiride. Specifically, the risk of seizures may be increased. 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

Thioridazine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Thioridazine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

Thiothixene: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Thiothixene. Specifically, the risk of seizures may be increased. 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

Trifluoperazine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Trifluoperazine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

Warfarin: Caffeine and Caffeine Containing Products may diminish the anticoagulant effect of Warfarin. Risk C: Monitor therapy

Ziprasidone: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Ziprasidone. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

Zuclopenthixol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Zuclopenthixol. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

Pregnancy Considerations

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).

Monitoring Parameters

Apnea of prematurity: Heart rate, number and severity of apnea spells, serum caffeine concentration (as appropriate)

Stimulant: Insomnia, tachycardia

Reference Range

Therapeutic: Apnea of prematurity: 8 to 20 mcg/mL (SI: 41.2 to 103 micromole/L)

Potentially toxic: >20 mcg/mL (SI: >103 micromole/L)

Toxic: >50 mcg/mL (SI: >257.5 micromole/L)

Mechanism of Action

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

Pharmacokinetics (Adult Data Unless Noted)

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).

Pharmacokinetics: Additional Considerations (Adult Data Unless Noted)

Pregnancy and cirrhosis: Half-life is increased.

Brand Names: International
International Brand Names by Country
For country code abbreviations (show table)

  • (AE) United Arab Emirates: Peyona;
  • (AR) Argentina: Cafeina citrato richet | Enerjet;
  • (AT) Austria: Coffekapton | Gencebok | Lecikur | Peyona;
  • (AU) Australia: Amcal alert caffeine | Cafnea | Pharmacy choice stay alert;
  • (BE) Belgium: Gencebok | Peyona;
  • (BG) Bulgaria: Nymusa | Peyona;
  • (BR) Brazil: Fatigan Plus | Peyona;
  • (CH) Switzerland: Peyona;
  • (CL) Chile: Ativase;
  • (CO) Colombia: Caf clin | Cafeinnova | Citrato de cafeina | Peyona | Ticaff;
  • (CZ) Czech Republic: Nymusa | Peyona;
  • (DE) Germany: Coffein | Nymusa | Peyona;
  • (DK) Denmark: Nymusa;
  • (DO) Dominican Republic: Acrocaf;
  • (EC) Ecuador: Ticaff;
  • (EE) Estonia: Cofi-tabs | Gencebok | Kofeiini | Lecikur | Nymusa | Peyona;
  • (EG) Egypt: Caffeinospire;
  • (ES) Spain: Nymusa | Peyona;
  • (FI) Finland: Coffein pharmia | Cofi-tabs | Gencebok | Nymusa | Peyona;
  • (FR) France: Gencebok | Nymusa;
  • (GB) United Kingdom: Nymusa | Peyona | Pro plus;
  • (GR) Greece: Nymusa | Peyona;
  • (HR) Croatia: Peyona;
  • (HU) Hungary: Coffeini | Nymusa | Peyona;
  • (IE) Ireland: Peyona | Pro plus;
  • (IN) India: Apnicaf | Cafirate | Cafneon | Capnea | Noapnea;
  • (IT) Italy: Caffeina citrato monico | Nymusa | Peyona;
  • (JP) Japan: Kafe Soft | Respia;
  • (KW) Kuwait: Peyona;
  • (LT) Lithuania: Nymusa | Peyona;
  • (LV) Latvia: Nymusa | Peyona;
  • (MT) Malta: Nymusa;
  • (MX) Mexico: Peyona | Ticaff | Zaat;
  • (MY) Malaysia: Cafnea;
  • (NL) Netherlands: Gencebok | Nymusa | Peyona;
  • (NO) Norway: Koffein | Peyona;
  • (NZ) New Zealand: Caffeine | No doz | No doz plus;
  • (PE) Peru: Citrato de cafeina | Taxigen;
  • (PK) Pakistan: Peyona;
  • (PL) Poland: Cafcit | Nymusa | Peyona;
  • (PR) Puerto Rico: Cafcit | Lucidex | No doz;
  • (PT) Portugal: Nymusa | Peyona;
  • (RO) Romania: Nymusa;
  • (RU) Russian Federation: Coffeine sodium benzoate | Sodium caffeine benzoate;
  • (SA) Saudi Arabia: Peyona;
  • (SE) Sweden: Gencebok | Koffein recip | Nymusa | Peyona;
  • (SI) Slovenia: Nymusa | Peyona;
  • (SK) Slovakia: Nymusa | Peyona;
  • (TN) Tunisia: Cafeine;
  • (TR) Turkey: Kafesit | Kafsiton | Peyona;
  • (TW) Taiwan: Cafnea | Peyona;
  • (UA) Ukraine: Peyona;
  • (ZW) Zimbabwe: Peppalets
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