Caffeine/Caffeine and Sodium Benzoate

Drug class: Antineoplastic Agents

Usage of Caffeine/Caffeine and Sodium Benzoate

CNS Stimulation

Used orally as an aid in staying awake and to restore mental alertness in fatigued patients.

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

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. 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.

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).

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.

Headache

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

Used orally alone and in combination with analgesics (e.g., acetaminophen, aspirin) for treatment of headache, including migraine attacks.

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. Additional studies needed to determine the role, if any, of caffeine as an analgesic adjuvant.

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.

Caffeine and sodium benzoate injection has been used for the symptomatic relief of headache following spinal puncture† [off-label].

Other Uses

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

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. Usefulness is questionable because caffeine’s diuretic activity in patients with fluid retention is minimal.

Relate drugs

How to use Caffeine/Caffeine and Sodium Benzoate

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

    • 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† [off-label] injection (caffeine and sodium benzoate). Administer rectally in combination with ergotamine tartrate.

    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.

    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.

    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. Use a syringe infusion pump to administer caffeine citrate injection to neonates.

    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.

    Caffeine and sodium benzoate: Administer by slow IV injection.

    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.

    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.

    IV† [off-label], 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; however, most clinicians strongly discourage analeptic use of caffeine.

    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.

    IV

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

    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.

    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.

    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. (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. Adjust maintenance dosage according to the patient’s response and tolerance and plasma caffeine concentrations.

    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. (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. Adjust maintenance dosage according to the patient’s response and tolerance and plasma caffeine concentrations.

    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. Adjust maintenance dosage according to the patient’s response and tolerance and plasma caffeine concentrations.

    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.

    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). 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. Avoid extended and repeated use.

    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). Avoid extended and repeated use.

    Adults

    CNS Stimulation Mild CNS Stimulation Oral

    Caffeine: 100–200 mg administered no more frequently than every 3–4 hours.

    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.

    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.

    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.

    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). Alternatively, 1 capsule or tablet (containing butalbital 50 mg, acetaminophen 500 mg, and caffeine 40 mg) every 4 hours. Avoid extended and repeated use.

    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). Avoid extended and repeated use.

    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). Avoid extended and repeated use.

    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). Avoid extended and repeated use.

    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.

    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).

    Rectal

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

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

    Prescribing Limits

    Pediatric Patients

    CNS Stimulation Oral

    Caffeine in children ≥12 years of age: Maximum 200 mg every 3–4 hours.

    IV†, IM†, or Sub-Q†

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

    Apnea of Prematurity Maintenance Therapy with Caffeine Citrate Oral, IV, or IM†

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

    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.

    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.

    Adults

    CNS Stimulation Mild CNS Stimulation Oral

    Caffeine: Maximum 200 mg every 3–4 hours.

    Emergency Respiratory Failure IV

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

    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. Maximum 2.5 g (1.25 g when expressed in terms of anhydrous caffeine) daily.

    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.

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

    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.

    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.

    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.

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

    Rectal

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

    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.

    Renal Impairment

    Apnea of Prematurity Oral or IV

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

    Warnings

    Contraindications

  • Known hypersensitivity to caffeine or any ingredient in the formulation.

    • Warnings/Precautions

    Warnings

    Necrotizing Enterocolitis

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

    General Precautions

    Cardiac Effects

    Tachycardia, extrasystoles, and possibly other cardiac arrhythmias may be associated with large doses; 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.

    Use with caution in infants with cardiovascular disease.

    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.

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

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

    GI Effects

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

    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.

    Self-medication

    Intended for occasional use only; should not be used as a substitute for sleep.

    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).

    Specific Populations

    Pregnancy

    Category C.

    Lactation

    Distributed into milk; milk-to-plasma ratios of 0.5–0.76 reported. 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.

    Pediatric Use

    Use of caffeine tablets for self-medication in children <12 years of age is not recommended. Possible increased severity of CNS effects in children compared with adults. (See Nervous System Effects under Cautions.)

    Avoid use of caffeine and sodium benzoate injection in neonates; sodium benzoate may produce kernicterus.

    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). Consider possible need for monitoring serum caffeine concentrations (see General under Dosage and Administration). Monitor blood glucose concentrations periodically; hypoglycemia and hyperglycemia reported in neonates.

    Long-term follow-up studies have not shown caffeine administration in premature neonates to adversely affect neurologic development or growth.

    Hepatic Impairment

    Pharmacokinetics of caffeine citrate not evaluated in premature neonates with hepatic impairment; use with caution. (See Hepatic Impairment under Dosage and Administration.)

    Renal Impairment

    Pharmacokinetics of caffeine citrate not evaluated in premature neonates with renal impairment; use with caution. (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).

    In neonates with apnea of prematurity: Rash, feeding intolerance, sepsis, necrotizing enterocolitis.

    What other drugs will affect Caffeine/Caffeine and Sodium Benzoate

    Appears to be metabolized principally by CYP1A2.

    Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

    Pharmacokinetic interactions likely with drugs metabolized by CYP1A2 or with CYP1A2 inducers or inhibitors.

    Specific Drugs and Laboratory Tests

    Drug or Test

    Interaction

    Comments

    Anticonvulsants (phenobarbital, phenytoin)

    Possible increased elimination of caffeine and decreased serum caffeine concentrations

    Possible increased metabolism of phenobarbital

    Increased caffeine dosage may be required

    β-Adrenergic agonists

    May increase cardiac inotropic effects

    Cimetidine

    Possible decreased elimination of caffeine and increased serum caffeine concentrations

    Reduced caffeine dosage may be required

    Disulfiram

    Potential inhibition of caffeine metabolism and substantially decreased clearance of caffeine; possible exaggerated or prolonged caffeine effects

    Clinical importance unknown

    Ketoconazole

    Possible decreased elimination of caffeine and increased serum caffeine concentrations

    Reduced caffeine dosage may be required

    Ketoprofen

    Possible decreased urine volume

    Clinical importance unknown

    Tests for serum urate

    False-positive elevations of serum urate as measured by the Bittner method

    Tests for urinary 5-hydroxyindoleacetic acid (5-HIAA)

    Slight increase in urine 5-HIAA concentrations

    Tests for urinary catecholamines and vanillylmandelic acid (VMA)

    Slight increase in urine concentrations of VMA and catecholamines; possible false-positive results on tests for pheochromocytoma and neuroblastoma

    Avoid caffeine intake during test

    Theophylline

    Interconversion between caffeine and theophylline reported in premature neonates

    Concurrent use not recommended in premature neonates

    Monitor serum caffeine concentrations prior to initiating caffeine therapy in neonates previously treated with theophylline

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