Caffeine (Systemic)

This monograph includes information on the following:

1) Caffeine
2) Citrated Caffeine
3) Caffeine and Sodium Benzoate 

VA CLASSIFICATION
Caffeine
Primary: CN809
Secondary: RE900

Caffeine, Citrated
Primary: CN809
Secondary: RE900

Caffeine and Sodium Benzoate
Primary: CN809


Commonly used brand name(s): Cafcit2; Caffedrine Caplets1; Dexitac Stay Alert Stimulant1; Enerjets1; Keep Alert1; Maximum Strength SnapBack Stimulant Powders1; NoDoz Maximum Strength Caplets1; Pep-Back1; Quick Pep1; Ultra Pep-Back1; Vivarin1; Wake-Up1.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Not commercially available in Canada.



Category:


Central nervous system stimulant—Caffeine; Citrated Caffeine; Caffeine and Sodium Benzoate;

Analgesia adjunct—Caffeine;

Respiratory stimulant adjunct—Caffeine; Citrated Caffeine;

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Fatigue or
Drowsiness (treatment)—Caffeine is used as a mild central nervous system stimulant to help restore mental alertness or wakefulness when fatigue or drowsiness is experienced.{22}{66}{67}{109}

Apnea, neonatal (treatment adjunct)—Caffeine or citrated caffeine (but not caffeine and sodium benzoate combination) is indicated in the short-term management of neonatal apnea, especially apnea of prematurity, which is characterized by periodic breathing and apneic episodes of more than 15 seconds accompanied by cyanosis and bradycardia, in infants between 28 and 33 weeks gestational age{124}. Other treatments include increased stimulation (cutaneous, vestibular, or proprioceptive), nasal continuous positive airway pressure (CPAP), increased environmental oxygen, and artificial ventilation. Determination of which therapy is to be undertaken is based upon the assessment of each individual patient"s clinical status and therapeutic requirement.{122} Caffeine may be considered a desirable alternative to theophylline when initiating therapy for premature neonatal apnea because some infants are unable to convert theophylline to caffeine, a major metabolite of theophylline in neonates. Caffeine also has a wider therapeutic index than theophylline. Caffeine therapy in the management of apnea is usually required for only a few weeks and rarely for more than a few months, since the apnea usually resolves by about 34 to 36 weeks" gestational age.{18}{31}

[Apnea, infant, postoperative (prophylaxis)]—Caffeine or citrated caffeine is indicated for the prevention of postoperative apnea in former preterm infants.{81}{82}

[Electroconvulsive therapy (ECT) (treatment adjunct) ]—Caffeine pretreatment is indicated to augment ECT by increasing seizure duration and reducing the need for increases in stimulus intensity.{83}{84}

—Caffeine is used in combination with ergotamine to treat vascular headaches such as migraine and cluster headaches (histaminic cephalalgia, migrainous neuralgia, Horton"s headache).{04}

—Caffeine is also used, and has been shown to be effective, as an analgesic adjunct in combination with aspirin or acetaminophen and aspirin{20}{113}{114} to enhance pain relief, although it has no analgesic activity of its own.{04}{05}{06} However, caffeine"s efficacy as an analgesic adjunct in combination with acetaminophen alone has been questioned.{20}{111}

Unaccepted
Caffeine and sodium benzoate combination has been used in conjunction with other supportive measures to treat respiratory depression associated with overdose with central nervous system (CNS) depressants such as narcotic analgesics or alcohol; however, because of the availability of specific antagonists, such as flumazenil and naloxone, and caffeine"s{112} questionable benefit and transient effect, most authorities believe caffeine should not be used for these conditions and, therefore, recommend other supportive therapy.{01}{02}{03}{04}

Caffeine is used in combination with other agents such as analgesics and diuretics to relieve tension and fluid retention associated with menstruation; however, its usefulness for this purpose is in doubt because of its minimal diuretic action.{02}{04}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Coffee, tea, some soft drinks, cocoa or chocolate, and kola nuts{119}. May also be synthesized from urea or dimethylurea.{04}

Chemical group—
    Methylated xanthine.{10}
Molecular weight—
    Caffeine (anhydrous): 194.19{07}
    Citrated caffeine: 386.31{124}
    Sodium benzoate: 144.11{07}


pH
    Citrated caffeine injection: 4.7.{124}
    Caffeine and sodium benzoate injection: Between 6.5 and 8.5. {09}

Mechanism of action/Effect:

Central nervous system stimulant—Caffeine stimulates all levels of the CNS, although its cortical effects are milder and of shorter duration than those of amphetamines. In larger doses, caffeine stimulates medullary, vagal, vasomotor, and respiratory centers, promoting bradycardia, vasoconstriction, and increased respiratory rate. This action was previously believed to be due primarily to increased intracellular cyclic 3´,5´-adenosine monophosphate (cyclic AMP) following inhibition of phosphodiesterase, the enzyme that degrades cyclic AMP. More recent studies indicate that caffeine exerts its physiological effects in large part through antagonism of central adenosine receptors.{01}{10}{11}{12}{22}{60}{115}{117}

Analgesia adjunct—Caffeine constricts cerebral vasculature with an accompanying decrease in cerebral blood flow{116}{117}{121} and in the oxygen tension of the brain.{10} It has been suggested that the addition of caffeine to aspirin or aspirin and acetaminophen combinations may help to relieve headache by providing a more rapid onset of action and/or enhanced pain relief with a lower dose of the analgesic.{06} In some patients, caffeine may reduce headache pain by reversing caffeine withdrawal symptoms.{92} Recent studies with ergotamine indicate that the enhancement of effect by the addition of caffeine may be due to improved gastrointestinal absorption of ergotamine when administered with caffeine.{10}

Respiratory stimulant adjunct—Although the exact mechanism of action has not been completely established, caffeine, as other methylxanthines, is believed to act primarily through stimulation of the medullary respiratory center. This action is seen in certain pathophysiological states, such as in Cheyne-Stokes respiration and in apnea of preterm infants, and when respiration is depressed by certain drugs, such as barbiturates and opioids. Methylxanthines appear to increase the sensitivity of the respiratory center to the stimulatory actions of carbon dioxide, increasing alveolar ventilation, thereby reducing the severity and frequency of apneic episodes.{10}{14}


Other actions/effects:

Cardiac—Caffeine produces a positive inotropic effect on the myocardium and a positive chronotropic effect on the sinoatrial node, causing transient increases in heart rate, force of contraction, and cardiac output.{01}{02}{41} Low concentrations of caffeine may produce small decreases in heart rate, possibly as a result of stimulation of the medullary vagal nuclei. At higher concentrations, caffeine produces definite tachycardia and sensitive persons may experience other arrhythmias, such as premature ventricular contractions.{10}

Vascular—Caffeine causes constriction of cerebral vasculature with an accompanying decrease in cerebral blood flow{10}{116}{117}{121} and in the oxygen tension in the brain.{10} Caffeine also causes an increase in systemic vascular resistance, resulting in an increase in blood pressure. {115}{116} These effects are believed to be mediated by blockade of adenosine-induced vasodilation {115}{116}{117} and activation of the sympathetic nervous system.{118}

Skeletal muscles—Caffeine stimulates voluntary skeletal muscle,{01}{121} possibly by inducing the release of acetylcholine, increasing the force of contraction and decreasing muscle fatigue.{02} {10} This stimulation of diaphragmatic muscles decreases the work of breathing.{15}

Gastrointestinal secretions—Caffeine causes secretion of both pepsin and gastric acid from parietal cells.{02}{10}

Renal—Caffeine increases renal blood flow and glomerular filtration rate and decreases proximal tubular reabsorption of sodium and water, resulting in a mild diuresis.{01}{02}{22}

Caffeine also inhibits uterine contractions,{04} increases plasma and urinary catecholamine concentrations,{04} and transiently increases plasma glucose by stimulating glycogenolysis and lipolysis.{01}{04}

In neonates, caffeine causes a 25% increase in oxygen consumption,{120} blood vessel dilatation, cerebral vessel vasoconstriction, and smooth muscle relaxation.{120}{121}

Absorption:

Readily absorbed after oral{10}{61}{77} or parenteral administration.{10} Absorption of methylxanthines relates more to lipophilicity than to water solubility.{16}

Distribution:

Rapidly distributed to all body compartments; readily crosses the placenta{01}{61}{77} and blood-brain barrier.{01}{117} Volume of distribution (Vol D) in adults ranges from 0.4 to 0.6 liter per kg of body weight (L/kg).{10}{73} Vol D in neonates averages between 0.78 and 0.92 L/kg.{14}{124}

Protein binding:

Low (25 to 36%).{10}{73}{86}

Biotransformation:

Hepatic. In adults, about 80% of a dose of caffeine is metabolized to paraxanthine (1,7-dimethylxanthine),{92}{93}{94} about 10% is metabolized to theobromine (3,7-dimethylxanthine), and about 4% is metabolized to theophylline (1,3-dimethylxanthine). These compounds are further demethylated to monomethylxanthines and then to methyl uric acids.{92}{93} In premature neonates, cytochrome P450 1A2 is involved in caffeine biotransformation; however, caffeine metabolism is limited due to hepatic enzyme immaturity. In the neonate, caffeine and theophylline are interconverted, with caffeine concentrations measuring approximately 25% of theophylline concentrations after theophylline administration and theophylline concentrations measuring approximately 3% to 8% of caffeine concentrations after caffeine administration.{10}{117}{124}

Half-life:

Adults—3 to 7 hours.{01}{10}{22}{117}

Neonates—65 to 130 hours.{17}{19}{22}{41}{117} Decreases to adult values by 4 to 9 months post-term{19} and is inversely proportional to gestational/postconceptual age{124}.

Note: Half-life is increased in pregnant women{10}{85}{117} and in patients with cirrhosis.{10}{117}


Time to peak plasma concentration

In adults—50 to 75 minutes following oral administration .{04} {10}

In preterm neonates—30 to 120 minutes following oral administration of 10 mg of caffeine base per kg of body weight.{124}

Peak plasma concentration

6 to 10 mg per L following oral administration of 10 mg of caffeine base per kg of body weight to preterm neonates.{124}

Therapeutic plasma concentration

5 to 25 mcg per mL (25.8 to 128.8 micromoles per L).{08}{60}{62}{73}{75}{76}

Elimination:
    Adults—Renal; primarily as metabolites; about 1 to 2% excreted unchanged.{17}{19}
    Neonates—Renal; about 85% excreted unchanged.{17}{19}


Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to other xanthines (aminophylline, dyphylline, oxtriphylline, theobromine, theophylline) may be sensitive to caffeine also.

Pregnancy/Reproduction

Pregnancy—
Caffeine crosses the placenta and achieves blood and tissue concentrations in the fetus that are similar to maternal concentrations. {25} {41} {51} {52} Studies in humans have shown that heavy caffeine consumption by pregnant women may increase the risk of spontaneous abortion {61} and intrauterine growth retardation. {77} {85} Also, excessive intake of caffeine by pregnant women has resulted in fetal arrhythmias. {22} {41} {51} {52} It is therefore recommended that pregnant women limit their intake of caffeine to less than 300 mg (3 cups of coffee) per day. {61} {77}

Studies in animals have shown that caffeine causes skeletal abnormalities in the digits and phalanges when given in doses equivalent to the caffeine content of 12 to 24 cups of coffee daily throughout pregnancy or when given in very large single doses (i.e., 50 to 100 mg per kg of body weight), and causes retarded skeletal development when given in lower doses. {22}

FDA Pregnancy Category C. {01}

Breast-feeding

Caffeine is distributed into breast milk in very small amounts. Although the concentration of caffeine in breast milk is 1% of the mother's plasma concentration, caffeine can accumulate in the infant. The infant may show signs of caffeine stimulation such as hyperactivity and wakefulness when a breast-feeding mother drinks as much as 6 to 8 cups of caffeine-containing beverages. It is recommended that nursing mothers limit their intake of caffeine-containing beverages to 1 to 2 cups per day and avoid taking over-the-counter caffeine capsules or tablets. {21} At recommended doses of caffeine-containing analgesic combinations, concentration in the infant is considered to be insignificant.

Pediatrics

With the exception of infants, appropriate studies on the relationship of age to the effects of caffeine have not been performed in children up to 12 years of age; however, no pediatrics-specific problems have been documented to date.

Caffeine and sodium benzoate injection is not recommended in neonatal apnea because the benzoate may interact competitively with bilirubin at the albumin binding site, which could cause or increase jaundice. In addition, elevated serum concentrations of benzyl alcohol and benzoate have been associated with neurological disturbances, hypotension, gasping respirations, and metabolic acidosis. {17} {18}


Geriatrics


No information is available on the relationship of age to the effects of caffeine in geriatric patients.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Adenosine{13}    (effects of adenosine are antagonized by caffeine; larger doses of adenosine may be required, or adenosine may be ineffective)


Barbiturates{01}{87}{89} or
Primidone{89}    (concurrent use of barbiturates or primidone [because of the phenobarbital metabolite] with caffeine may increase the metabolism of caffeine by induction of hepatic microsomal enzymes, resulting in increased clearance of caffeine; in addition, concurrent use may antagonize the hypnotic or anticonvulsant effects of the barbiturates)


Beta-adrenergic blocking agents, systemic{02}{89} or
Beta-adrenergic blocking agents, ophthalmic{90}    (concurrent use of beta-blocking agents, including ophthalmic agents [significant systemic absorption possible], with caffeine may result in mutual inhibition of therapeutic effects)


Bronchodilators, adrenergic{90}    (concurrent use with caffeine may result in additive CNS stimulation and other additive toxic effects)


» Caffeine-containing beverages (coffee, tea, or soft drinks){66}{67} or
» Caffeine-containing medications, other{66}{67} or
» CNS stimulation–producing medications, other (see Appendix II)    (excessive CNS stimulation causing nervousness, irritability, insomnia, or possibly convulsions or cardiac arrhythmias may occur; close observation is recommended{13})


Calcium supplements{05}{24}    (concurrent use with excessive amounts of caffeine may inhibit absorption of calcium)


Cimetidine{22}{38}{50}{60}{63}{69}    (decreased hepatic metabolism of caffeine results in delayed elimination and increased blood concentrations)


Ciprofloxacin{22}{42}{43}{44}{45} or
Enoxacin{114} or
Norfloxacin{22}{53}{54}    (hepatic metabolism and clearance of caffeine may be reduced, increasing the risk of caffeine-related CNS stimulation{42}{43}{44}{45}{53}{54})


Contraceptives, oral{22}{23}{38}{56}{60}{117}    (concurrent use may decrease caffeine metabolism)


Disulfiram{39}{50}    (concurrent use may reduce the elimination rate of caffeine by inhibiting its metabolism; recovering alcoholic patients on disulfiram therapy are best advised to avoid the use of caffeine to prevent the possibility of complicating alcohol withdrawal by caffeine-induced cardiovascular and cerebral excitation )


Erythromycin{89}{90} or
Troleandomycin{89}{90}    (concurrent use may reduce the hepatic clearance of caffeine)


Hydantoin anticonvulsants, especially phenytoin{71}{91}    (concurrent use of phenytoin may increase the clearance of caffeine)


Lithium{27}{68}    (concurrent use with caffeine increases urinary excretion of lithium, possibly reducing its therapeutic effect)


Mexiletine{22}{58}{64}{65}    (concurrent use with caffeine reduces the elimination of caffeine by up to 50% and may increase the potential for adverse effects)


» Monoamine oxidase (MAO) inhibitors, including furazolidone, procarbazine, and selegiline{28}{105}{106}{107}{108}    (large amounts of caffeine may produce dangerous cardiac arrhythmias or severe hypertension because of the sympathomimetic side effects of caffeine; concurrent use with small amounts of caffeine may produce tachycardia and a mild increase in blood pressure)


Smoking, tobacco{40}{50}{55}{58}{59}{60}{63}{117}    (concurrent use of tobacco increases the elimination rate of caffeine)


Xanthines, other, such as:
Aminophylline
Dyphylline
Oxtriphylline
Theobromine
Theophylline    (caffeine may decrease the clearance of theophylline and possibly other xanthines, increasing{70}{94} the potential for additive pharmacodynamic{71} and toxic effects{87})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Dipyridamole- or adenosine-assisted cardiac diagnostic studies     (caffeine antagonizes the effects of dipyridamole and adenosine on myocardial blood flow, thereby interfering with test results; patients should be instructed to avoid ingesting caffeine [from a dietary or medicinal source] for 8 to 12 hours prior to the test {26}{46}{47}{48}{49}{103})


Urate measurements, serum    (false-positive elevations when measured by the Bittner method{01}{02}{04})


Vanillylmandelic acid (VMA) and
Catecholamines, including norepinephrine and epinephrine and
5-hydroxyindoleacetic acid    (urine concentrations are slightly increased; high urinary concentrations of VMA or catecholamines may result in a false-positive diagnosis of pheochromocytoma or neuroblastoma; caffeine intake should be avoided during tests{01}{02}{04}{22})

With physiology/laboratory test values
Blood urea nitrogen    (may be elevated following overdose{124})


Glucose, blood    (concentrations may be increased; glucose tolerance may be impaired in neonates{124} and in patients with diabetes)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Anxiety disorders, including agoraphobia and panic attacks{29}{71}    (increased risk of anxiety, nervousness, fear, nausea, palpitations, rapid heartbeat, restlessness, and trembling{29})


» Cardiac disease, severe    (high doses not recommended because of increased risk of tachycardia or extrasystoles, which may lead to heart failure{57})


» Hepatic function impairment    (half-life of caffeine may be prolonged, leading to toxic accumulation{30})


» Hypertension or
» Insomnia    (may be potentiated)


Seizure disorders, in neonates    (caution is recommended because seizures have been reported following toxic doses{124})


Sensitivity to caffeine or other xanthines

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):


For neonatal apnea
Caffeine concentrations, plasma{32} or serum{88}    (determinations recommended prior to initiation of therapy in infants previously treated with theophylline and in infants born to mothers who consumed caffeine prior to delivery,{124} 24 hours after loading dose, then 1 to 2 times a week;{32} alternatively, some clinicians recommend checking caffeine concentrations every 2 weeks once the infant has been stabilized{96}{97}{98}{99}{100})


Glucose concentrations, serum{124}    (hyperglycemia and hypoglycemia have been reported in neonates receiving citrated caffeine)


Theophylline concentrations, serum{96}    (determinations may be indicated in the presence of adverse effects possibly caused by conversion of caffeine to theophylline in the neonate)




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
CNS stimulation, excessive (dizziness; fast heartbeat; irritability, nervousness, or severe jitters—in neonates {33} {41}; tremors {101}; trouble in sleeping)
    
gastrointestinal irritation (diarrhea; nausea; vomiting)
    
hyperglycemia {124}(blurred vision; drowsiness; dry mouth; flushed, dry skin; fruit-like breath odor; increased urination [frequency and volume]; ketones in urine; loss of appetite; stomachache, nausea, or vomiting; tiredness; troubled breathing [rapid and deep]; unconsciousness; unusual thirst)—in neonates
    
hypoglycemia {124}(anxiety; blurred vision; cold sweats ; confusion; cool, pale skin; drowsiness; excessive hunger; fast heartbeat ; nausea; nervousness; restless sleep; shakiness; unusual tiredness or weakness)—in neonates

Incidence rare
    
Necrotizing enterocolitis {124}(abdominal distention; dehydration; diarrhea, bloody ; irritability; unusual tiredness or weakness ; vomiting)— in neonates



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
CNS stimulation, mild (nervousness or jitters)
    
gastrointestinal irritation, mild (nausea)



Those indicating possible withdrawal if they occur after medication is abruptly discontinued after prolonged use
    
Anxiety
    
dizziness
    
headache
    
irritability
    
muscle tension
    
nausea
    
nervousness
    
stuffy nose
    
unusual tiredness
{71}{72}{117}



Overdose
For specific information on the agents used in the management of caffeine overdose, see:   • Antacids (Oral-Local) monograph;
   • Charcoal, Activated (Oral-Local) monograph;
   • Diazepam in Benzodiazepines (Systemic) monograph;
   • Ipecac (Oral-Local) monograph;
   • Magnesium sulfate in Laxatives (Local) monograph;
   • Phenobarbital in Barbiturates (Systemic) monograph; and/or
   • Phenytoin in Anticonvulsants, Hydantoin (Systemic) monograph.


For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:{01}{03}{04}{10}{22}{75}{117}

Abdominal or stomach pain

agitation, anxiety, excitement, or restlessness

confusion or delirium

dehydration

fast or irregular heartbeat

fever

frequent urination

headache

increased sensitivity to touch or pain

irritability

leukocytosis —in neonates

muscle trembling or twitching

nausea and vomiting, sometimes with blood

opisthotonos {124}(hyperextension of the body with head and heels bent backward and body bowed forward)—in neonates

painful, swollen abdomen or vomiting —in neonates{75}

ringing or other sounds in ears

seeing flashes of “zig-zag” lights

seizures, usually tonic-clonic seizures —in acute overdose

tachypnea

trouble in sleeping

whole body tremors —in neonates{75}

Treatment of acute overdose
Acute caffeine toxicity has been reported rarely. Treatment is primarily symptomatic and supportive.


To decrease absorption:
Induction of emesis with ipecac syrup and/or gastric lavage {02} {22} {34} {37} {95} {102} if caffeine has been ingested within 4 hours in amounts over 15 mg per kg of body weight (mg/kg) {95} and emesis has not been induced by caffeine. {104}

Administration of activated charcoal may be useful within the first 4 hours {95} if precautions are taken to minimize the risk of aspiration; {104} magnesium sulfate cathartic may also be useful. {95}



To enhance elimination:
Hemoperfusion {22} {74} {78} {79} {80} is usually more effective than dialysis. {102} Use of exchange transfusion in neonates, if necessary.



Specific treatment:
Control of CNS stimulation or seizures with intravenous diazepam, phenobarbital, or phenytoin. {02} {22} {34} {36} {92} {95} {104}

Administration of antacids and iced saline lavage for hemorrhagic gastritis. {95}



Supportive care:
Maintenance of fluid and electrolyte balance. {95} {102} Maintenance of ventilation and oxygenation. {102} Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Caffeine (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to caffeine or other xanthines (aminophylline, dyphylline, oxtriphylline, theobromine, theophylline)

Pregnancy—Crosses placenta; excessive use during pregnancy may result in spontaneous abortion, intrauterine growth retardation, or fetal arrhythmias; animal studies have shown skeletal abnormalities with large doses and retarded skeletal development with lower doses





Breast-feeding—Distributed into breast milk in small amounts but accumulates in infant and may cause hyperactivity and wakefulness; nursing mothers should limit intake of caffeine from all sources





Use in children—Caffeine and sodium benzoate injection is not recommended in neonates because of the benzoate content. However, caffeine citrate may be used safely

Other medications, especially caffeine-containing medications or beverages, other CNS stimulation–producing medications, or monoamine oxidase (MAO) inhibitors
Other medical problems, especially anxiety disorders including agoraphobia and panic attacks, severe cardiac disease, hepatic function impairment, hypertension, or insomnia

Proper use of this medication
» Importance of not taking more medication and not taking it more often than directed because of increased risk of side effects and habit-forming potential; should be used only occasionally

Proper administration of powder: Stirring contents of packet into water or other beverage or placing on tongue and following with water or other beverage

For the oral solution: Using each vial only for one dose; discarding unused portion of medication; following manufacturer's instructions

» Caution if tolerance develops; not increasing dose

» Proper dosing

» Proper storage

Precautions while using this medication
» Checking with physician if fatigue or drowsiness persists or recurs often

Possible interference with cardiac diagnostic studies

Caution in concurrently drinking large amounts of coffee, tea, or colas or using other medications containing caffeine since amount of caffeine in medication is about the same as in a cup of coffee

Importance of knowing amounts of caffeine in common foods and beverages

» Discontinuing caffeine-containing medications and foods if fast pulse, dizziness, or pounding heartbeat occurs

Not taking too close to bedtime


Side/adverse effects
Signs of potential side effects, especially excessive CNS stimulation, gastrointestinal irritation, hyperglycemia or hypoglycemia (in neonates), and necrotizing enterocolitis (in neonates)


General Dosing Information
With prolonged use, habituation or psychological dependence and tolerance to cardiovascular, diuretic, and stimulant effects may occur.{04}{22}{35}

A dose of caffeine powder should be stirred into water or other beverage or placed on the tongue and followed with water or other beverage.{109}

Citrated caffeine oral solution for use in neonatal apnea is not available commercially but must be prepared extemporaneously from citrated caffeine powder. Caffeine tablets may also be crushed and made into an oral suspension. Caffeine citrate powder may be combined with lactose to add to infant feedings.

Citrated caffeine injection should not be administered intramuscularly because of its acidic nature (pH 4.7). It may be administered intravenously.{17}{124}

Caffeine and sodium benzoate injection is not recommended in neonatal apnea because of the benzoate content.{14}{17}{18}

Diet/Nutrition
The amount of caffeine from dietary sources is as follows:{22}{35}{71}



• Coffee, brewed—40 to 180 mg per cup.


• Coffee, instant—30 to 120 mg per cup.


• Coffee, decaffeinated—3 to 5 mg per cup.


• Tea, brewed American—20 to 90 mg per cup.


• Tea, brewed imported—25 to 110 mg per cup.


• Tea, instant—28 mg per cup.


• Tea, canned iced—22 to 36 mg per 12 ounces.


• Cola and other soft drinks, caffeine-containing—36 to 90 mg per 12 ounces.


• Cola and other soft drinks, decaffeinated—0 mg per 12 ounces.


• Cocoa—4 mg per cup.


• Chocolate, milk—3 to 6 mg per ounce.


• Chocolate, bittersweet—25 mg per ounce.

CAFFEINE


Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

CAFFEINE POWDER

Usual adult and adolescent dose
Fatigue; drowsiness
Oral, 200 mg, the dosage to be repeated no sooner than every three or four hours, as needed.{109}


Usual adult prescribing limits
1.6 grams a day.{109}

Usual pediatric dose
Fatigue; drowsiness
Children up to 12 years of age: Use is not recommended.{109}


Strength(s) usually available
U.S.—


200 mg per packet (OTC) [Maximum Strength SnapBack Stimulant Powders]{109}{123}

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from moisture.{109}

Auxiliary labeling:
   • Do not take at bedtime.


CAFFEINE TABLETS

Usual adult and adolescent dose
Fatigue; drowsiness
Oral, 100 to 200 mg (anhydrous caffeine), the dosage to be repeated no sooner than every three or four hours, as needed.{66} {67}


Usual adult prescribing limits
1 gram a day.

Usual pediatric dose
Fatigue; drowsiness
Children up to 12 years of age: Use is not recommended.{66}{67}

[Neonatal apnea]
Initial: Oral, 10 mg (anhydrous caffeine) per kg of body weight.{10}{14}{19}{73}

Maintenance: Oral, 2.5 mg (anhydrous caffeine) per kg of body weight{14}{19}{73} a day, starting twenty-four hours after the initial dose,{10}{73}{75}{79} to maintain a serum concentration of 5 to 25 mcg per mL (25.8 to 128.8 micromoles per L).{73}{75}{76}

Note: Caffeine tablets may be crushed and made into an oral suspension for use in neonatal apnea.



Strength(s) usually available
U.S.—


75 mg (anhydrous caffeine) (OTC) [Enerjets]


100 mg (anhydrous caffeine) (OTC) [Pep-Back]


150 mg (anhydrous caffeine) (OTC) [Quick Pep]


200 mg (anhydrous caffeine) (OTC) [Caffedrine Caplets] [Dexitac Stay Alert Stimulant] [Keep Alert] [NoDoz Maximum Strength Caplets (scored){66}] [Ultra Pep-Back] [Vivarin{67}]

Canada—


100 mg (caffeine alkaloid) (OTC) [Wake-Up]{110}

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • Do not take at bedtime.


CAFFEINE, CITRATED


Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

CITRATED CAFFEINE ORAL SOLUTION

Usual pediatric dose
Neonatal apnea
Initial: Oral, 20 mg (10 mg of anhydrous caffeine and 10 mg of anhydrous citric acid) per kg of body weight.{14}{19}{73}

Maintenance: Oral, 5 mg (2.5 mg of anhydrous caffeine and 2.5 mg of anhydrous citric acid) per kg of body weight{14}{19}{73} a day, starting twenty-four hours after the initial dose,{10}{73}{75}{79}{124} to maintain a serum concentration of 5 to 25 mcg per mL (25.8 to 128.8 micromoles per L).{73}{75}{76}

Note: Premature neonates may require a smaller dose.{112}



Strength(s) usually available
U.S.—


20 mg caffeine citrate (10 mg caffeine base) per mL (Rx) [Cafcit ( citric acid monohydrate 5 mg) (sodium citrate dihydrate 8.3 mg) (Water for Injection){124}]

Canada—
Dosage form not commercially available. Compounding required.

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F){124}

Preparation of dosage form:
Compounded product—Ten grams of citrated caffeine powder should be dissolved in 250 mL of sterile water for irrigation and stirred until completely clear; then flavoring should be added (simple syrup and cherry syrup 2:1) to make 500 mL. The final concentration is 20 mg (10 mg of anhydrous caffeine and 10 mg of anhydrous citric acid) per mL.{37}

Stability:
Compounded product as described above is stable for 3 months at room temperature.{37}

Auxiliary labeling:
   • For single use only. Discard unused portion.

Note: Citrated caffeine powder may also be combined with lactose and added to infant feedings.


Additional information:
Dispense patient instructions portion of the package insert with the prescription



Parenteral Dosage Forms

CITRATED CAFFEINE INJECTION

Usual pediatric dose
Neonatal apnea
Initial: Intravenous, 20 mg (10 mg of caffeine base ) per kg of body weight.{14}{19}{73}{124}

Maintenance: Intravenous, 5 mg (2.5 mg of caffeine base ){14}{19}{73}{124} per kg of body weight every twenty-four hours,{73}{75}{79}{124} starting twenty-four hours after the initial dose, {73}{75}{124} to maintain a serum concentration of 5 to 25 mcg per mL (25.8 to 128.8 micromoles per L).{73}{75}{76}


Strength(s) usually available
U.S.—


20 mg caffeine citrate (10 mg caffeine base) per mL (Rx) [Cafcit ( citric acid 5 mg) (sodium citrate dihydrate 8.3 mg) (Water for Injection){124}]

Canada—
Dosage form not commercially available. Compounding required.

Packaging and storage:
Store between 15 – 30 °C (59 – 86 °F)

Preparation of dosage form:
Compounded product—Ten grams of citrated caffeine powder should be dissolved in 250 mL of sterile water for injection and transferred to a 500-mL empty evacuated container (EEC). The container should be filled with sterile water to the 500-mL mark and filtered through a 0.22-micron filter into another 500-mL EEC. Then the solution should be transferred to 10-mL vials and autoclaved at 121 °C (250 °F) for 15 minutes and allowed to cool. The resulting concentration is 20 mg (10 mg of anhydrous caffeine and 10 mg of anhydrous citric acid) per mL.{37}

Stability:
Compounded product as described above is stable for 3 months at room temperature.{37}

Commercially available product is chemically stable for 24 hours at room temperature when combined with the following:{124}   • Aminosyn crystalline amino acid solution 8.5%
   • calcium gluconate injection, USP 10% (0.465 mEq of Ca +2per mL
   • dextrose injection, USP 5%
   • dextrose injection, USP 50%
   • dopamine HCl injection, USP 40 mg per mL diluted to 0.6 mg per mL with dextrose injection, USP 5%
   • fentanyl citrate injection, USP 50 mcg per mL diluted to 10 mcg per mL with dextrose injection, USP 5%
   • heparin sodium injection, USP 1000 units per mL diluted to 1 unit per mL with dextrose injection, USP 5%
   • Intralipid IV fat emulsion 20%


Additional information:
Commercially available product is preservative free.


CAFFEINE AND SODIUM BENZOATE


Parenteral Dosage Forms

CAFFEINE AND SODIUM BENZOATE INJECTION USP

Usual adult and adolescent dose
CNS stimulant
Intramuscular or intravenous, up to a maximum of 500 mg (250 mg of anhydrous caffeine and 250 mg of sodium benzoate), as needed and tolerated.{02}{03}


Usual adult prescribing limits
2.5 grams (1.25 grams of anhydrous caffeine and 1.25 grams of sodium benzoate) a day.{02}{03}

Usual pediatric dose
Dosage has not been established.

Note: Use not recommended in neonatal apnea because of benzoate content.{14}{17}{18}


Strength(s) usually available
U.S.—


250 mg (125 mg of anhydrous caffeine and 125 mg of sodium benzoate) per mL (Rx)

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer.



Revised: 05/25/2000



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