Caffeine; Caffeine and Sodium Benzoate Injection; Caffeine Citrate

Class: Anorexigenic Agents and Respiratory and Cerebral Stimulants, Miscellaneous
VA Class: CN809
CAS Number: 58-08-2
Brands: Cafcit, No Doz , Vivarin

Introduction

CNS stimulant; a xanthine derivative.^{115 120 a}

Uses for Caffeine; Caffeine and Sodium Benzoate Injection; Caffeine Citrate

CNS Stimulation

Used orally as an aid in staying awake and to restore mental alertness in fatigued patients.^{117 118 a}

Used in combination with antihistamines to overcome the sedative properties of antihistamines; however, efficacy and dosage required not adequately established.^a

Caffeine and sodium benzoate injection has been used in conjunction with supportive measures to treat respiratory depression associated with overdosage of CNS depressant drugs (e.g., opiate analgesics, alcohol) and with electric shock.^{120 a} However, most authorities believe caffeine and other analeptics should not be used in these conditions and recommend other supportive therapy because of caffeine’s questionable benefit and transient action.^{120 a}

Apnea of Prematurity

Short-term (10–12 days) treatment (as oral or IV caffeine citrate) of apnea of prematurity in neonates who are 28 to <33 weeks of gestational age (designated an orphan drug by FDA for this use).¹¹⁵

Use only after other causes of apnea (e.g., CNS disorders, primary lung disease, anemia, sepsis, metabolic disturbances, cardiovascular abnormalities, obstructive apnea) have been ruled out or treated appropriately.¹¹⁵

Headache

Used in combination with ergotamine to prevent or abort vascular headaches (e.g., migraine and cluster headaches).^{116 a e} However, there is conflicting evidence regarding efficacy of this combination in the treatment of acute migraine attacks.¹¹⁶

Used orally alone and in combination with analgesics (e.g., acetaminophen, aspirin) for treatment of headache,^{121 a d h l o} including migraine attacks.^{116 g}

Some evidence that analgesic-caffeine combinations may produce slightly more analgesia than analgesic agents alone and may have beneficial effect on mood; however, these results have not always been reproducible in well-controlled studies.^a Additional studies needed to determine the role, if any, of caffeine as an analgesic adjuvant.^a

Some experts state that the combination of acetaminophen, aspirin, and caffeine is a reasonable first-line therapy for mild to moderate migraine attacks or for severe migraine attacks that previously have responded to NSAIAs or nonopiate analgesics.¹¹⁶

Caffeine and sodium benzoate injection has been used for the symptomatic relief of headache following spinal puncture†.^a

Other Uses

Safety and efficacy of caffeine citrate in the prevention of sudden infant death syndrome† (SIDS) or prior to extubation in mechanically ventilated infants† not established.¹¹⁵

Has been used orally alone and in combination with other drugs (e.g., analgesics, diuretics) to relieve tension, fatigue, and fluid retention associated with menstruation.^a Usefulness is questionable because caffeine’s diuretic activity in patients with fluid retention is minimal.^a

Caffeine; Caffeine and Sodium Benzoate Injection; Caffeine Citrate Dosage and Administration

General

Apnea of Prematurity

• 
  

  Prior to initiating caffeine citrate therapy, determine baseline serum caffeine concentrations in neonates previously treated with theophylline (see Specific Drugs and Laboratory Tests under Interactions) and in infants born to mothers who consumed caffeine prior to delivery.¹¹⁵

  
  


• 
  

  May need to monitor serum caffeine concentrations periodically during therapy to avoid toxicity.¹¹⁵

  
  

Administration

Administer orally (caffeine tablets, caffeine citrate oral solution), by slow IV infusion (caffeine citrate), or by slow IV injection or IM or sub-Q† injection (caffeine and sodium benzoate).^{115 117 118 120 a} Administer rectally in combination with ergotamine tartrate.^m

Consult manufacturer’s product labeling for complete directions for appropriate administration of preparations containing caffeine in combination with analgesics, antacids, antihistamines, antipyretics, antitussives, belladonna alkaloids, diuretics, ergotamine tartrate, expectorants, nasal decongestants, skeletal muscle relaxants, sympathomimetics, and vitamins.

Oral Administration

Caffeine Citrate Oral Solution

Available as preservative-free oral solution in single-use vials; discard any unused portion.¹¹⁵

To administer a dose, remove the rubber stopper from the vial and then withdraw and administer the appropriate dose using a 1-mL or other appropriate syringe to ensure accurate measurement.¹¹⁵

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Caffeine citrate is available as a preservative-free injection in single-use vials; discard any unused portion.¹¹⁵ Use a syringe infusion pump to administer caffeine citrate injection to neonates.¹¹⁵

Rate of Administration

Caffeine citrate: For treatment of apnea of prematurity, administer loading dose by slow IV infusion over 30 minutes; infuse maintenance doses by slow IV infusion over 10 minutes.^{115 a}

Caffeine and sodium benzoate: Administer by slow IV injection.^{120 a}

Dosage

Available as caffeine, caffeine citrate, and caffeine and sodium benzoate; dosage of caffeine (alone or in fixed combination with sodium benzoate) expressed in terms of anhydrous caffeine; dosage of caffeine citrate expressed in terms of the salt.^{115 117 118 120 a}

Caffeine also is commercially available in combination with analgesics, antacids, antihistamines, antipyretics, antitussives, belladonna alkaloids, diuretics, ergotamine tartrate, expectorants, nasal decongestants, skeletal muscle relaxants, sympathomimetics, and vitamins; consult manufacturer’s product labeling for appropriate dosage of the specific preparation.

Pediatric Patients

CNS Stimulation

Oral

Caffeine: 100–200 mg administered no more frequently than every 3–4 hours in children ≥12 years of age.^{117 118 a}

IV†, IM†, or Sub-Q†

Caffeine and sodium benzoate injection: 8 mg/kg (maximum 500 mg) (4 mg/kg when expressed in terms of anhydrous caffeine) or 250 mg/m² (125 mg/m² when expressed in terms of anhydrous caffeine) administered up to every 4 hours if necessary has been recommended;^a however, most clinicians strongly discourage analeptic use of caffeine.^{120 a}

Apnea of Prematurity

Loading Dose of Caffeine Citrate

Oral†

Loading dose of 10–20 mg/kg† (5–10 mg/kg when expressed in terms of anhydrous caffeine) as a single dose has been used.^{106 107 108 109 110}

IV

Loading dose of 20 mg/kg (10 mg/kg when expressed in terms of anhydrous caffeine) as a single dose.¹¹⁵

Alternatively, loading dose of 10–20 mg/kg† (5–10 mg/kg when expressed in terms of anhydrous caffeine) as a single dose has been used.^{105 106 107 108 109 110}

IM†

Loading dose of 10–20 mg/kg† (5–10 mg/kg when expressed in terms of anhydrous caffeine) as a single dose has been used.^{105 106 107 108 109 110}

Maintenance Therapy with Caffeine Citrate

Oral

5 mg/kg (2.5 mg/kg when expressed in terms of anhydrous caffeine) every 24 hours for no longer than 10–12 days, beginning 24 hours after loading dose.¹¹⁵ (See Prescribing Limits under Dosage and Administration.)

Alternatively, 5–10 mg/kg† (2.5–5 mg/kg when expressed in terms of anhydrous caffeine) once daily, beginning 24 hours after loading dose, has been used.^{105 106 107 108 109 110} Adjust maintenance dosage according to the patient’s response and tolerance and plasma caffeine concentrations.^{105 106 107 108 109 110}

IV

5 mg/kg (2.5 mg/kg when expressed in terms of anhydrous caffeine) every 24 hours for no longer than 10–12 days, beginning 24 hours after loading dose.¹¹⁵ (See Prescribing Limits under Dosage and Administration.)

Alternatively, 5–10 mg/kg† (2.5–5 mg/kg when expressed in terms of anhydrous caffeine) once daily, beginning 24 hours after loading dose, has been used.^{105 106 107 108 109 110} Adjust maintenance dosage according to the patient’s response and tolerance and plasma caffeine concentrations.^{105 106 107 108 109 110}

IM†

5–10 mg/kg† (2.5–5 mg/kg when expressed in terms of anhydrous caffeine) once daily, beginning 24 hours after loading dose, has been used.^{105 106 107 108 109 110} Adjust maintenance dosage according to the patient’s response and tolerance and plasma caffeine concentrations.^{105 106 107 108 109 110}

Headache

Oral

Caffeine in fixed combination with analgesics (e.g., acetaminophen, aspirin, salicylamide) for self-medication: Combinations and dosage strengths vary; consult manufacturer's product labeling for appropriate dosage of the specific preparation.^{d h l o}

Tension Headache

Oral

Butalbital, acetaminophen, and caffeine in children ≥12 years of age: 1 or 2 capsules or tablets (each containing butalbital 50 mg, acetaminophen 325 mg, and caffeine 40 mg) every 4 hours (up to 6 capsules or tablets daily).^{c p} Alternatively, 1 capsule or tablet (containing butalbital 50 mg, acetaminophen 500 mg, and caffeine 40 mg) every 4 hours in children ≥12 years of age.^{b i} Avoid extended and repeated use.^{b c i p}

Butalbital, aspirin, and caffeine in children ≥12 years of age: 1 or 2 tablets (each containing butalbital 50 mg, aspirin 325 mg, and caffeine 40 mg) every 4 hours (up to 6 tablets daily).^f Avoid extended and repeated use.^f

Adults

CNS Stimulation

Mild CNS Stimulation

Oral

Caffeine: 100–200 mg administered no more frequently than every 3–4 hours.^{117 118 120 a}

Emergency Respiratory Failure

IV

Caffeine and sodium benzoate: 500 mg–1 g (250–500 mg when expressed in terms of anhydrous caffeine); however, most clinicians strongly discourage analeptic use of caffeine.^{120 a}

Respiratory Depression Associated with Overdosage of CNS Depressants and with Electric Shock

IM

Caffeine and sodium benzoate: 500 mg–1 g (250–500 mg when expressed in terms of anhydrous caffeine); however, most clinicians strongly discourage analeptic use of caffeine.^{120 a}

Headache

Oral

Caffeine in fixed combination with analgesics (e.g., acetaminophen, aspirin, salicylamide) for self-medication: Combinations and dosage strengths vary; consult manufacturer's product labeling for appropriate dosage of the specific preparation.^{d h l o}

Tension Headache

Oral

Butalbital, acetaminophen, and caffeine: 1 or 2 capsules or tablets (each containing butalbital 50 mg, acetaminophen 325 mg, and caffeine 40 mg) every 4 hours (up to 6 capsules or tablets daily).^{c p} Alternatively, 1 capsule or tablet (containing butalbital 50 mg, acetaminophen 500 mg, and caffeine 40 mg) every 4 hours.^{b i} Avoid extended and repeated use.^{b c i p}

Butalbital, aspirin, and caffeine: 1 or 2 capsules or tablets (each containing butalbital 50 mg, aspirin 325 mg, and caffeine 40 mg) every 4 hours (up to 6 capsules or tablets daily).^{f j} Avoid extended and repeated use.^f

Butalbital, acetaminophen, caffeine, and codeine phosphate: 1 or 2 capsules (each containing butalbital 50 mg, acetaminophen 325 mg, caffeine 40 mg, and codeine phosphate 30 mg) every 4 hours (up to 6 capsules daily).¹²¹ Avoid extended and repeated use.¹²¹

Butalbital, aspirin, caffeine, and codeine phosphate: 1 or 2 capsules (each containing butalbital 50 mg, aspirin 325 mg, caffeine 40 mg, and codeine phosphate 30 mg) every 4 hours (up to 6 capsules daily).^k Avoid extended and repeated use.^k

Vascular Headache

Oral

Acetaminophen, aspirin, and caffeine: 2 tablets (each containing acetaminophen 250 mg, aspirin 250 mg, and caffeine 65 mg) for treatment of migraine.^g

Ergotamine and caffeine: 2 tablets (each containing ergotamine tartrate 1 mg and caffeine 100 mg) initially, followed by 1 tablet at 30-minute intervals until attack has abated (maximum 6 tablets per attack).^e

Rectal

Ergotamine and caffeine: 1 suppository (containing ergotamine tartrate 2 mg and caffeine 100 mg) initially;^m if necessary, may give a second dose (1 suppository) in 1 hour.^m

In some patients with cluster headaches in the morning, 1–2 suppositories may be given at bedtime on a short-term basis.^{m n}

Prescribing Limits

Pediatric Patients

CNS Stimulation

Oral

Caffeine in children ≥12 years of age: Maximum 200 mg every 3–4 hours.^{117 118 a}

IV†, IM†, or Sub-Q†

Caffeine and sodium benzoate injection: Maximum 500 mg (250 mg when expressed as anhydrous caffeine) per dose.^a

Apnea of Prematurity

Maintenance Therapy with Caffeine Citrate

Oral, IV, or IM†

Safety and efficacy of dosing periods exceeding 10–12 days not established.¹¹⁵

Headache

Tension Headache

Oral

Butalbital, acetaminophen, and caffeine in children ≥12 years of age: Maximum 6 capsules or tablets (each containing butalbital 50 mg, acetaminophen 325 or 500 mg, and caffeine 40 mg) daily.^{b c i p}

Butalbital, aspirin, and caffeine in children ≥12 years of age: Maximum 6 tablets (each containing butalbital 50 mg, aspirin 325 mg, and caffeine 40 mg) daily.^f

Adults

CNS Stimulation

Mild CNS Stimulation

Oral

Caffeine: Maximum 200 mg every 3–4 hours.^{117 118 a}

Emergency Respiratory Failure

IV

Caffeine and sodium benzoate: Maximum 1 g (500 mg when expressed in terms of anhydrous caffeine) as a single dose.^{120 a} Maximum 2.5 g (1.25 g when expressed in terms of anhydrous caffeine) daily.¹²⁰

Respiratory Depression Associated with Overdosage of CNS Depressants and with Electric Shock

IM

Caffeine and sodium benzoate: Maximum 1 g (500 mg when expressed in terms of anhydrous caffeine) as a single dose.^{120 a} Maximum 2.5 g (1.25 g when expressed in terms of anhydrous caffeine) daily.¹²⁰

Headache

Tension Headache

Oral

Butalbital, acetaminophen, and caffeine: Maximum 6 capsules or tablets (each containing butalbital 50 mg, acetaminophen 325 or 500 mg, and caffeine 40 mg) daily.^{b c i p}

Butalbital, aspirin, and caffeine: Maximum 6 capsules or tablets (each containing butalbital 50 mg, aspirin 325 mg, and caffeine 40 mg) daily.^{f j}

Butalbital, acetaminophen, caffeine, and codeine phosphate: Maximum 6 capsules (each containing butalbital 50 mg, acetaminophen 325 mg, caffeine 40 mg, and codeine phosphate 30 mg) daily.¹²¹

Butalbital, aspirin, caffeine, and codeine phosphate: Maximum 6 capsules (each containing butalbital 50 mg, aspirin 325 mg, caffeine 40 mg, and codeine phosphate 30 mg) daily.^k

Vascular Headache

Oral

Acetaminophen, aspirin, and caffeine: Maximum 2 tablets (each containing acetaminophen 250 mg, aspirin 250 mg, and caffeine 65 mg) within any 24-hour period unless otherwise directed by a clinician.^g

Ergotamine and caffeine: Maximum 6 tablets (each containing ergotamine tartrate 1 mg and caffeine 100 mg) per attack or 10 tablets per week.^e

Rectal

Ergotamine and caffeine: Maximum 2 suppositories (each containing ergotamine tartrate 2 mg and caffeine 100 mg) per attack and 5 suppositories per week.^m

Special Populations

Hepatic Impairment

Apnea of Prematurity

Oral or IV

Adjust caffeine citrate dosage to avoid toxicity; use with caution and monitor serum caffeine concentrations.¹¹⁵

Renal Impairment

Apnea of Prematurity

Oral or IV

Adjust caffeine citrate dosage to avoid toxicity; use with caution and monitor serum caffeine concentrations.¹¹⁵

Cautions for Caffeine; Caffeine and Sodium Benzoate Injection; Caffeine Citrate

Contraindications

• 
  

  Known hypersensitivity to caffeine or any ingredient in the formulation.^{115 a e}

  
  

Warnings/Precautions

Warnings

Necrotizing Enterocolitis

Potentially fatal necrotizing enterocolitis reported in neonates receiving caffeine citrate.¹¹⁵ Careful monitoring for the development of necrotizing enterocolitis (as is recommended for all preterm infants) is recommended for those receiving caffeine citrate.¹¹⁵

General Precautions

Cardiac Effects

Tachycardia, extrasystoles, and possibly other cardiac arrhythmias may be associated with large doses;^{115 117 120} generally recommended that caffeine be avoided in patients with symptomatic cardiac arrhythmias and/or palpitations and during the first several days to weeks after an AMI.¹⁰⁰

Use with caution in infants with cardiovascular disease.¹¹⁵

Nervous System Effects

Large doses may result in insomnia, restlessness, nervousness, mild delirium, headache, excitement, agitation, a condition resembling anxiety neurosis, scintillating scotoma, hyperesthesia, tinnitus, and muscle tremors or twitches. ^{115 120}

Seizures reported with caffeine overdosage; use with caution in infants with seizure disorders.¹¹⁵

Overly vigorous treatment with caffeine and sodium benzoate may increase CNS depression in already depressed patients.^a

GI Effects

Chronic administration in animals associated with gastric ulceration; causal relationship in humans not adequately established.^a Use with caution in patients with history of peptic ulcer.^a

Blood Glucose Abnormalities

Hypoglycemia and hyperglycemia reported in patients receiving caffeine; periodic monitoring of blood glucose concentrations may be necessary in neonates receiving caffeine citrate.^{115 a}

Self-medication

Intended for occasional use only; should not be used as a substitute for sleep.^{117 118}

Use of Fixed Combinations

When used in fixed combination with other drugs (see Preparations), consider the cautions, precautions, and contraindications associated with the concomitant agent(s).^{121 e g}

Specific Populations

Pregnancy

Category C.^{115 120}

Lactation

Distributed into milk;^{119 a} milk-to-plasma ratios of 0.5–0.76 reported.¹¹⁹ Amount of caffeine ingested from usual quantities of caffeinated beverages is considered compatible with breast-feeding; caffeine may accumulate in nursing infants following moderate to heavy maternal consumption.¹¹⁹

Pediatric Use

Use of caffeine tablets for self-medication in children <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 concentrations115 Possible increased metabolism of phenobarbital120	Increased caffeine dosage may be required115
β-Adrenergic agonists	May increase cardiac inotropic effects120 a
Cimetidine	Possible decreased elimination of caffeine and increased serum caffeine concentrations115	Reduced caffeine dosage may be required115
Disulfiram	Potential inhibition of caffeine metabolism and substantially decreased clearance of caffeine;103 possible exaggerated or prolonged caffeine effects103 104	Clinical importance unknown103 104
Ketoconazole	Possible decreased elimination of caffeine and increased serum caffeine concentrations115 a	Reduced caffeine dosage may be required115 a
Ketoprofen	Possible decreased urine volume115	Clinical importance unknown115
Tests for serum urate	False-positive elevations of serum urate as measured by the Bittner method120 a
Tests for urinary 5-hydroxyindoleacetic acid (5-HIAA)	Slight increase in urine 5-HIAA concentrations120 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 neuroblastoma120 a	Avoid caffeine intake during test120
Theophylline	Interconversion between caffeine and theophylline reported in premature neonates115	Concurrent use not recommended in premature neonates115 Monitor serum caffeine concentrations prior to initiating caffeine therapy in neonates previously treated with theophylline115

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

ActionsActions

• 
  

  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.

* 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

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Butalbital-APAP-Caffeine 50-325-40MG Capsules (QUALITEST): 100/$39.99 or 300/$109.97

Butalbital-APAP-Caffeine 50-325-40MG Tablets (WEST-WARD): 30/$14.26 or 90/$38.96

Butalbital-APAP-Caffeine 50-500-40MG Tablets (WEST-WARD): 30/$18.99 or 90/$46.99

Butalbital-ASA-Caffeine 50-325-40MG Capsules (LANNETT): 30/$25.99 or 90/$72.97

Butalbital-Aspirin-Caffeine 50-325-40MG Tablets (WEST-WARD): 30/$19.99 or 90/$29.97

Cafergot 1-100MG Tablets (SANDOZ): 30/$49.99 or 90/$139.97

Dolgic Plus 50-750-40MG Tablets (VICTORY PHARMA): 100/$351.97 or 300/$989.99

Esgic 50-325-40MG Tablets (FOREST): 30/$69.99 or 90/$205.97

Esgic-Plus 50-500-40MG Tablets (FOREST): 30/$61.72 or 90/$175.24

Fioricet 50-325-40MG Tablets (WATSON LABS): 30/$63.09 or 90/$164.28

Fioricet/Codeine 50-325-40-30MG Capsules (WATSON LABS): 30/$115.99 or 90/$345.97

Fiorinal 50-325-40MG Capsules (WATSON LABS): 100/$178.6 or 200/$357.2

Migergot 2-100MG Suppositories (G &amp; W LABS): 12/$95.99 or 36/$259.98

Zebutal 50-500-40MG Capsules (VICTORY PHARMA): 30/$51.99 or 90/$135.97

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions February 2008. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, 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. [IDIS 188218] [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. [IDIS 142876] [PubMed 7009653]

102. Robertson D, Hollister AS, Kincaid D et al. Caffeine and hypertension. Am J Med. 1984; 77:54-60. [IDIS 187520] [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. [IDIS 213983] [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. [IDIS 103742] [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. [IDIS 143136] [PubMed 7310594]

107. Brouard C, Moriette G, Murat I et al. Comparative efficacy of theophylline and caffeine in the treatment of idiopathic apnea in pre