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  • CLASSES

    Respiratory Stimulants
    Xanthine Psychoanaleptics
    Xanthines, Plain

    DEA CLASS

    Rx, OTC

    DESCRIPTION

    Natural xanthine derivative; often combined with analgesics for the treatment of headache; used as a CNS and respiratory stimulant or mild diuretic; for prescription use for apnea of prematurity in neonates where caffeine is preferred over theophylline due to caffeine's wide therapeutic window.

    COMMON BRAND NAMES

    Cafcit, NoDoz, Stay Awake, Vivarin

    HOW SUPPLIED

    Cafcit/Caffeine/Caffeine Citrate Intravenous Inj Sol: 1mL, 20mg
    Cafcit/Caffeine/Caffeine Citrate Oral Sol: 1mL, 20mg
    Caffeine/NoDoz/Stay Awake/Vivarin Oral Tab: 200mg

    DOSAGE & INDICATIONS

    For the treatment of neonatal apnea (i.e., apnea of prematurity).
    NOTE: Do not use Caffeine and sodium benzoate injection because the benzoate may displace bilirubin and induce kernicterus, and has been associated with 'gasping syndrome'. Make sure to use Cafcit, or an injection NOT containing sodium benzoate.
    NOTE: Monitor serum caffeine concentrations and organ function (see Therapeutic Drug Monitoring below).
    NOTE: The dose of anhydrous caffeine base is equal to half the dose expressed as caffeine citrate.
    NOTE: Due to the extended half-life, caffeine should be discontinued for at least 5—7 days prior to discharge unless neonate is discharged with apnea monitor.
    Intravenous dosage (Cafcit injection, generic equivalents, or extemporaneously compounded caffeine citrate injection†)
    Premature neonates aged 28 and < 33 weeks of gestation

    Initially, 20—25 mg/kg caffeine citrate (10—12.5 mg/kg anhydrous caffeine base) IV for 1 dose; then after 24 hours, begin maintenance dose of 5—10 mg/kg/day caffeine citrate (2.5—5 mg/kg IV anhydrous caffeine base); adjust based on caffeine levels and clinical response. Under most circumstances, use is for a limited duration of treatment, usually not to exceed 10—12 days.

    Oral dosage (Cafcit oral solution, generic equivalents, or extemporaneously compounded caffeine citrate oral solution†)
    Premature neonates aged 28 and < 33 weeks of gestation

    Initially, 20—25 mg/kg caffeine citrate (10—12.5 mg/kg anhydrous caffeine base) PO for 1 dose; then after 24 hours, begin maintenance dose of 5—10 mg/kg/day PO caffeine citrate (2.5—5 mg/kg anhydrous caffeine base); adjust based on caffeine levels and clinical response. Under most circumstances, use is for a limited duration of treatment, usually not to exceed 10—12 days.

    To restore mental alertness when fatigue† or drowsiness† are present.
    NOTE: Many non-prescription products are not reviewed and approved by the FDA. However, they may be marketed if they comply with current regulations and policies. The FDA has not evaluated whether these products comply.
    Oral dosage (caffeine tablets)
    Adults

    100—200 mg (anhydrous caffeine) PO (dose dependent on product label); may repeat doses every 3—4 hours as needed. Do not exceed labeled dosage.

    For the treatment of postdural lumbar puncture headache†.
    Oral dosage (anhydrous caffeine base)
    Adults

    300 mg of anhydrous caffeine PO as a single dose may be effective for the treatment of post-dural puncture headache (PDPH) in some patients, although the data are limited. In one small placebo-controlled trial, 40 postpartum patients with PDPH were randomized to receive a compounded PO capsule formulation containing 300 mg of anhydrous caffeine powder or placebo. Headache intensity, as measured by the visual analogue pain scale (VAS), was assessed prior to drug administration, and at 4 and 24 hours post-treatment. More patients in the caffeine group experienced improvement in VAS at 4 hours post-treatment compared to those in the placebo group (90% vs 60%). The magnitude of improvement in VAS was more than 300% greater in the caffeine group than the placebo group. VAS scores did not differ between the two groups at 24 hours. Among the patients whose PDPH was relieved at 4 hours, 30% had a recurrence of symptoms the following day. One patient from the caffeine group and one from the placebo group reported transient flushing and jitteriness; however, no significant adverse effects were associated with caffeine treatment. Larger, well-controlled trials in more generalized patient populations are needed to systematically evaluate and establish the effectiveness of orally administered caffeine in the treatment of PDPH.

    Intravenous dosage
    Adults†

    Based on available data for caffeine sodium benzoate, equipotent doses of other IV caffeine formulations may theoretically be beneficial; however, current published data are limited to the use of caffeine sodium benzoate; the use of caffeine citrate for example, has not been specifically studied. 500 mg IV of caffeine sodium benzoate (see separate monograph) may be effective for the treatment of post-dural puncture headache (PDPH) in some patients, although the data are limited. In one small placebo-controlled trial, a single 500 mg dose of caffeine sodium benzoate (250 mg of caffeine and 250 mg of sodium benzoate per 2 ml) resulted in a decrease in the proportion of patients with PDPH persistence and in the number of patients requiring supplementary interventions compared with placebo. One brief correspondence describes the use of 1 or 2 doses of caffeine sodium benzoate 500 mg each administered in 1 liter of IV fluid 4 hours apart, plus additional IV fluid hydration, which resulted in relief of PDP headache in about 14 of 18 patients (75%). Large, well-controlled trials are needed to systematically evaluate and establish the effectiveness of intravenously administered caffeine in the treatment of PDPH.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    1200 mg/day PO has been suggested.

    Geriatric

    1200 mg/day PO has been suggested.

    Adolescents

    1200 mg/day PO has been suggested.

    Children

    < 12 years: Maximum dosage information is not available.
    12 years: 1200 mg/day PO has been suggested.

    Infants

    Caffeine base 2.5—5 mg/kg/day PO or IV for maintenance dosage.

    Neonates

    Caffeine base 2.5—5 mg/kg/day PO or IV for maintenance dosage.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment in adults are not available. In premature infants and neonates, caffeine metabolism is limited due to immature hepatic enzyme systems; dosage adjustments may be needed in neonates with impaired hepatic function and should be guided by clinical response and serum caffeine levels.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available. Premature infants and neonates are more dependent on renal function for proper caffeine elimination; dosage adjustments may be needed in neonates with impaired renal function and should be guided by clinical response and serum caffeine levels.

    ADMINISTRATION

    Oral Administration

    Do not take at bedtime.

    Oral Solid Formulations

    Tablets: Caffeine tablets may be crushed.

    Oral Liquid Formulations

    Oral solution (Cafcit): In infants, the solution may be administered concomitantly with formula feedings. Use a calibrated oral syringe to measure dose. Alternatively, the available intravenous injection may be administered by the oral route (Cafcit).
    Storage of Cafcit oral solution: Once oral solution vial is opened, use immediately and discard the unused portion, it is preservative-free.

    Other Oral Formulations

    Powder: Stir into water or other liquid or place on the tongue and follow with liquid.

    Extemporaneous Compounding-Oral

    Extemporaneous compounding instructions for citrated caffeine oral solution (20 mg/mL caffeine citrate; 10 mg/mL anhydrous caffeine base):
    NOTE: The extemporaneous preparation of caffeine is not approved by the FDA.
    Dissolve 10 grams of citrated caffeine powder (purified) in 250 mL of Sterile Water for Irrigation, USP. Stir the mixture until completely clear. Add a flavoring agent (simple syrup and cherry syrup in a 2:1 ratio) to the solution to increase the volume to 500 mL. The resulting enteral solution contains the equivalent of 20 mg/mL of caffeine citrate (10 mg/mL of anhydrous caffeine base) and is stable for 3 months when protected from light and stored at room temperature or under refrigeration.

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Intravenous injection:
    Using a syringe infusion pump, administer caffeine citrate dose slowly over 10 minutes into a vein or into the tubing of a freely-flowing compatible IV solution. Compatible IV solutions for Cafcit include: Dextrose 5%, Dextrose 50%, Aminosyn 8.5% solution, and Intralipid 20% emulsion.
    Administer daily IV dose at the same time each day (every 24 hours).
    Storage of Cafcit injection: Once vial is opened, use immediately and discard the unused portion, it is preservative-free.

    Extemporaneous Compounding-Injectable

    Compounding Instructions for preservative-free citrated caffeine injection:
    NOTE: The extemporaneous preparation of caffeine is not approved by the FDA.
    Perform all intravenous compounding operations using aseptic techniques.
    Dissolve 10 grams of citrated caffeine powder (purified) in 250 mL of Sterile Water for Injection, USP. Transfer to a 500-mL sterile empty evacuated container (EEC) and fill to the 500-mL mark with Sterile Water for Injection, USP. Filter through a 0.22-micron filter into another 500-mL sterile EEC. Transfer injectable solution to 2-mL or 10-mL sterile glass vials and autoclave at 121 degrees C for 15 minutes and allow to cool. The resulting parenteral solution contains the equivalent of 20 mg/mL of caffeine citrate (10 mg/mL of anhydrous caffeine base) and is stable for 3 months at room temperature or under refrigeration. Each vial prepared is for single-use only. Once vial is opened, use immediately and discard the unused portion, it is preservative-free. Protect from light.
    Quality assurance testing for sterility and caffeine concentration is recommended when preparing compounded products for parenteral administration; each batch should be quarantined until testing is complete.

    STORAGE

    Cafcit:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Store at controlled room temperature (between 68 and 77 degrees F)
    NoDoz:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Stay Awake:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Vivarin:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Caffeine with sodium benzoate injection is not recommended for use in premature neonates because the benzoate may displace bilirubin and induce kernicterus. Elevated serum concentrations of benzoate, similar to benzyl alcohol, have also been associated with neurological disturbances, hypotension, gasping respiration, and metabolic acidosis (i.e., 'gasping syndrome') in neonates. Clinicians should use Cafcit, which does not contain sodium benzoate, or use an extemporaneously compounded caffeine citrate injection in newborns and premature neonates. The safety and efficacy of the prescription use of caffeine in neonates and infants for longer than 12 days, prophylaxis of sudden infant death syndrome (SIDS), or for use prior to extubation in mechanically ventilated infants has not been established.

    Children

    The OTC use of caffeine products is not recommended in children under the age of 12 years.

    Anxiety, insomnia, panic disorder, seizure disorder

    Caffeine is a central nervous system stimulant. Caffeine should be used cautiously in patients with anxiety disorders and/or panic disorder because it can aggravate these conditions. Patients suffering from insomnia should not consume caffeine, nor should caffeine be consumed prior to retiring because it can cause insomnia. In overdoses, caffeine has been associated with seizures and it should be prescribed cautiously to those patients with a seizure disorder.

    Cardiac arrhythmias, cardiac disease, hypertension, myocardial infarction

    Caffeine should be used cautiously in those patients, including neonates, with cardiac disease. Caffeine can stimulate the force of contraction and can increase heart rate. It may increase left ventricular output and stroke volume. Patients who have angina or a history of cardiac arrhythmias should not receive or should minimize their intake of caffeine. Caffeine should not be taken in the first few days—weeks after a myocardial infarction. Patients with hypertension should minimize their intake of caffeine.

    Hepatic disease, premature neonates, renal impairment

    Caffeine should be used cautiously in those with hepatic disease or hepatic impairment. Caffeine clearance may be delayed, leading to toxicity. Renal impairment or renal failure may also delay caffeine clearance. It should be noted that caffeine elimination is more dependent on renal clearance in premature neonates and term neonates than in older infants or adults, due to the underdeveloped hepatic metabolism and renal elimination of drugs in general. Thus monitoring of serum caffeine concentrations is recommended in neonates or premature neonates, especially those with renal or hepatic impairment.

    Diabetes mellitus, hypoglycemia

    Patients with diabetes mellitus should not receive or should minimize their intake of caffeine. Although the effects are mild, caffeine can either raise or decrease blood sugar. In neonates, both hypoglycemia and hyperglycemia have been observed.

    Thyroid disease

    Patients with thyroid disease, especially hyperthyroidism, should not receive or should minimize their intake of caffeine. The stimulatory effects of caffeine can be augmented in hyperthyroidism.

    Necrotizing enterocolitis, peptic ulcer disease

    Caffeine can stimulate gastric secretions. Patients with peptic ulcer disease should minimize their intake of caffeine because the condition can be aggravated. In neonates, there are reports in the literature suggesting a possible association between the use of methylxanthines like caffeine and the development of necrotizing enterocolitis. Six cases of this disease were reported during clinical trials of caffeine injection. All preterm neonates treated with caffeine should be monitored for the development of gastric side-effects (i.e., abdominal distension, vomiting, bloody stools, and lethargy).

    Infertility, pregnancy

    A pregnancy risk category has not been assigned to oral caffeine tablets because they are available over-the-counter. Cafcit (injectable and oral solution) prescription products are classified in FDA pregnancy risk category C but concern for teratogenicity of caffeine is not relevant when such products are administered for neonatal apnea. Caffeine easily crosses the placenta; fetal blood and tissue concentrations approximate maternal concentrations. There are no large, well-controlled studies of caffeine administration in pregnant women; it is generally recommended that the intake of caffeine-containing beverages, like coffee, teas, and sodas, be limited in pregnancy (usually no more than 1—2 caffeine-containing beverages/day) or avoided if possible. Caffeine-containing medications should likewise, be limited to use only when absolutely necessary. Low to moderate caffeine intake does not appear to increase the risk of congenital malformation, spontaneous abortion, pre-term birth or low birth weight. The association between high daily intake (> 500 mg/day) of caffeine and increased rates of low birth weight, spontaneous abortion, difficulty in getting pregnant or infertility is still controversial, as some studies have not controlled for concomitant cigarette smoking. There are no adequate and well-controlled studies of caffeine administration in pregnant women. Neonatal arrhythmias (e.g., tachycardia, premature atrial contractions) and tachypnea have been reported when caffeine was consumed during pregnancy in amounts > 500 mg/day; caffeine withdrawal after birth may account for these symptoms.

    Breast-feeding

    Cytochrome P450 metabolism of caffeine is inhibited in infants who are breast-fed; formula feeding does not appear to affect the pharmacokinetics of caffeine in infants. Peak caffeine milk levels usually occur within 1 hour after the maternal ingestion of a caffeinated beverage; with milk:plasma ratios of 0.5—0.7 reported. Although only small amounts are secreted in breast-milk, caffeine can accumulate in the neonate if maternal ingestion is moderate to high. Higher caffeine intake (> 500 mg/day) by a nursing mother may cause irritability or poor sleeping patterns in the infant who is breast-feeding. Although the American Academy of Pediatrics generally considers the usual use of caffeinated beverages to be compatible with lactation, nursing mothers should limit their intake of beverages containing caffeine if possible. Caffeine containing drug-products should be used cautiously during lactation due to their high caffeine contents. Mothers who are breast-feeding infants who are prescribed caffeine for apnea should avoid additional caffeine. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Tobacco smoking

    Tobacco smoking (cigarettes) has been shown to increase the clearance of caffeine. Passive smoke exposure may also cause an increase in caffeine clearance. This may help to explain why tobacco smokers often have concomitantly high caffeine intakes. Tobacco smoke contains hydrocarbons that induce hepatic CYP450 microsomal enzymes. Because the effect on hepatic microsomal enzymes is not related to the nicotine component of tobacco, sudden smoking cessation may result in a reduced clearance of caffeine, despite the initiation of nicotine replacement. Caffeine dosage may need to be reduced at the cessation of smoking.

    Geriatric

    Caffeine can usually be ingested in normal amounts found in food or beverages (e.g., coffee) in the elderly; however, geriatric patients should be aware of the effects of caffeine on sleep and other physiologic functions, such as urination. Excessive caffeine intake, such as intake of non-prescription caffeine dietary supplements/medicines, should generally be avoided, as excessive use can cause tremor, insomnia, palpitations, and gastrointestinal complaints. Because caffeine is an ingredient in some non-prescription products, patients should be advised to read labels carefully or check with their prescriber or pharmacist if they are unsure if the medication contains caffeine. According to the Beers Criteria, caffeine is considered potentially inappropriate for use in geriatric patients with insomnia and should be avoided due to the potential for drug-induced CNS stimulant effects.

    MAOI therapy

    Caffeine intake should be limited along with MAOI therapy.

    ADVERSE REACTIONS

    Severe

    enterocolitis / Delayed / Incidence not known
    GI bleeding / Delayed / Incidence not known
    intracranial bleeding / Delayed / Incidence not known
    seizures / Delayed / Incidence not known
    pulmonary edema / Early / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known

    Moderate

    gastritis / Delayed / 0-2.2
    hypercalciuria / Delayed / Incidence not known
    hypoglycemia / Early / Incidence not known
    hyperglycemia / Delayed / Incidence not known
    tachypnea / Early / Incidence not known
    dyspnea / Early / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    palpitations / Early / Incidence not known
    withdrawal / Early / Incidence not known

    Mild

    nausea / Early / 1.0-10.0
    dyspepsia / Early / 1.0-10.0
    insomnia / Early / 1.0-10.0
    headache / Early / 1.0-10.0
    irritability / Delayed / 1.0-10.0
    tremor / Early / 10.0
    increased urinary frequency / Early / 10.0
    diarrhea / Early / Incidence not known
    vomiting / Early / Incidence not known
    gastroesophageal reflux / Delayed / Incidence not known
    anxiety / Delayed / Incidence not known
    polyuria / Early / Incidence not known
    rash (unspecified) / Early / Incidence not known
    xerosis / Delayed / Incidence not known
    spermatogenesis inhibition / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Certain foods that contain high amounts of caffeine or theobromine should be limited during the therapeutic use of caffeine in order to limit additive methylxanthine effects. While taking Caffeine-containing medicines, limit the use of foods, beverages (examples: coffee, tea, colas), herbs (examples: guarana, green tea) and other products that contain additional caffeine, such as chocolate and some non-prescription medications or dietary supplements for headache, insomnia, or weight loss. Too much Caffeine can cause effects like nausea, nervousness, or sleeplessness. Some drug products for adults that contain caffeine have about as much caffeine as a cup of coffee.
    Acetaminophen; Butalbital: (Minor) The hypnotic effects of barbiturates can be reduced by caffeine administration.
    Acetaminophen; Butalbital; Caffeine: (Moderate) Certain foods that contain high amounts of caffeine or theobromine should be limited during the therapeutic use of caffeine in order to limit additive methylxanthine effects. While taking Caffeine-containing medicines, limit the use of foods, beverages (examples: coffee, tea, colas), herbs (examples: guarana, green tea) and other products that contain additional caffeine, such as chocolate and some non-prescription medications or dietary supplements for headache, insomnia, or weight loss. Too much Caffeine can cause effects like nausea, nervousness, or sleeplessness. Some drug products for adults that contain caffeine have about as much caffeine as a cup of coffee. (Minor) The hypnotic effects of barbiturates can be reduced by caffeine administration.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Moderate) Certain foods that contain high amounts of caffeine or theobromine should be limited during the therapeutic use of caffeine in order to limit additive methylxanthine effects. While taking Caffeine-containing medicines, limit the use of foods, beverages (examples: coffee, tea, colas), herbs (examples: guarana, green tea) and other products that contain additional caffeine, such as chocolate and some non-prescription medications or dietary supplements for headache, insomnia, or weight loss. Too much Caffeine can cause effects like nausea, nervousness, or sleeplessness. Some drug products for adults that contain caffeine have about as much caffeine as a cup of coffee. (Minor) The hypnotic effects of barbiturates can be reduced by caffeine administration.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Certain foods that contain high amounts of caffeine or theobromine should be limited during the therapeutic use of caffeine in order to limit additive methylxanthine effects. While taking Caffeine-containing medicines, limit the use of foods, beverages (examples: coffee, tea, colas), herbs (examples: guarana, green tea) and other products that contain additional caffeine, such as chocolate and some non-prescription medications or dietary supplements for headache, insomnia, or weight loss. Too much Caffeine can cause effects like nausea, nervousness, or sleeplessness. Some drug products for adults that contain caffeine have about as much caffeine as a cup of coffee.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) Certain foods that contain high amounts of caffeine or theobromine should be limited during the therapeutic use of caffeine in order to limit additive methylxanthine effects. While taking Caffeine-containing medicines, limit the use of foods, beverages (examples: coffee, tea, colas), herbs (examples: guarana, green tea) and other products that contain additional caffeine, such as chocolate and some non-prescription medications or dietary supplements for headache, insomnia, or weight loss. Too much Caffeine can cause effects like nausea, nervousness, or sleeplessness. Some drug products for adults that contain caffeine have about as much caffeine as a cup of coffee.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) Certain foods that contain high amounts of caffeine or theobromine should be limited during the therapeutic use of caffeine in order to limit additive methylxanthine effects. While taking Caffeine-containing medicines, limit the use of foods, beverages (examples: coffee, tea, colas), herbs (examples: guarana, green tea) and other products that contain additional caffeine, such as chocolate and some non-prescription medications or dietary supplements for headache, insomnia, or weight loss. Too much Caffeine can cause effects like nausea, nervousness, or sleeplessness. Some drug products for adults that contain caffeine have about as much caffeine as a cup of coffee.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Acetaminophen; Dichloralphenazone; Isometheptene: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Acetaminophen; Guaifenesin; Phenylephrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Acetaminophen; Pseudoephedrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Acrivastine; Pseudoephedrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Adenosine: (Major) Methylxanthines, such as caffeine, competitively block the effects of adenosine. Patients receiving adenosine should be monitored for decreased efficacy of adenosine.
    Albuterol: (Moderate) Sensitive patients may wish to limit or avoid excessive caffeine intake from foods, beverages, dietary supplements and medications during therapy with beta-agonists. Additive side effects may occur between caffeine and beta-agonists. Caffeine is a CNS-stimulant and beta-agonists are sympathomimetic agents. Sensitive patients might experience tremor, sleep difficulties, or mild increases in heart rate.
    Albuterol; Ipratropium: (Moderate) Sensitive patients may wish to limit or avoid excessive caffeine intake from foods, beverages, dietary supplements and medications during therapy with beta-agonists. Additive side effects may occur between caffeine and beta-agonists. Caffeine is a CNS-stimulant and beta-agonists are sympathomimetic agents. Sensitive patients might experience tremor, sleep difficulties, or mild increases in heart rate.
    Alprazolam: (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
    Amantadine: (Major) Amantadine used concomitantly with psychostimulants, such as caffeine, can result in increased stimulant effects, such as nervousness, irritability, or insomnia, and can lead to seizures or cardiac arrhythmias. Close monitoring of the patient is recommended.
    Amiodarone: (Minor) Amiodarone is an inhibitor of CYP1A2 isoenzymes, and could theoretically reduce CYP1A2-mediated caffeine metabolism. The clinical significance of this potential interaction is not known.
    Amitriptyline; Chlordiazepoxide: (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
    Amobarbital: (Minor) The hypnotic effects of barbiturates can be reduced by caffeine administration.
    Amphetamine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Avoid excessive caffeine intake during use of the amphetamine salts. Excessive caffeine ingestion (via medicines, foods like chocolate, dietary supplements, or beverages including coffee, green tea, other teas, colas) may contribute to side effects like nervousness, irritability, nausea, insomnia, or tremor.
    Amphetamine; Dextroamphetamine Salts: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Avoid excessive caffeine intake during use of the amphetamine salts. Excessive caffeine ingestion (via medicines, foods like chocolate, dietary supplements, or beverages including coffee, green tea, other teas, colas) may contribute to side effects like nervousness, irritability, nausea, insomnia, or tremor. Patients should avoid medications and dietary supplements which contain high amounts of caffeine.
    Amphetamine; Dextroamphetamine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Avoid excessive caffeine intake during use of the amphetamine salts. Excessive caffeine ingestion (via medicines, foods like chocolate, dietary supplements, or beverages including coffee, green tea, other teas, colas) may contribute to side effects like nervousness, irritability, nausea, insomnia, or tremor.
    Anagrelide: (Moderate) Anagrelide has been shown to inhibit CYP1A2. In theory, coadministration of anagrelide with substrates of CYP1A2, including caffeine, could lead to increases in the serum concentrations of caffeine and, thus, adverse effects.
    Arformoterol: (Moderate) Sensitive patients may wish to limit or avoid excessive caffeine intake from foods, beverages, dietary supplements and medications during therapy with beta-agonists. Additive side effects may occur between caffeine and beta-agonists. Caffeine is a CNS-stimulant and beta-agonists are sympathomimetic agents. Sensitive patients might experience tremor, sleep difficulties, or mild increases in heart rate.
    Armodafinil: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with psychostimulants such as armodafinil. Patients taking armodafinil may need to be cautioned to avoid excessive intake of caffeine.
    Articaine; Epinephrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Certain foods that contain high amounts of caffeine or theobromine should be limited during the therapeutic use of caffeine in order to limit additive methylxanthine effects. While taking Caffeine-containing medicines, limit the use of foods, beverages (examples: coffee, tea, colas), herbs (examples: guarana, green tea) and other products that contain additional caffeine, such as chocolate and some non-prescription medications or dietary supplements for headache, insomnia, or weight loss. Too much Caffeine can cause effects like nausea, nervousness, or sleeplessness. Some drug products for adults that contain caffeine have about as much caffeine as a cup of coffee. (Minor) The hypnotic effects of barbiturates can be reduced by caffeine administration.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Certain foods that contain high amounts of caffeine or theobromine should be limited during the therapeutic use of caffeine in order to limit additive methylxanthine effects. While taking Caffeine-containing medicines, limit the use of foods, beverages (examples: coffee, tea, colas), herbs (examples: guarana, green tea) and other products that contain additional caffeine, such as chocolate and some non-prescription medications or dietary supplements for headache, insomnia, or weight loss. Too much Caffeine can cause effects like nausea, nervousness, or sleeplessness. Some drug products for adults that contain caffeine have about as much caffeine as a cup of coffee. (Minor) The hypnotic effects of barbiturates can be reduced by caffeine administration.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Certain foods that contain high amounts of caffeine or theobromine should be limited during the therapeutic use of caffeine in order to limit additive methylxanthine effects. While taking Caffeine-containing medicines, limit the use of foods, beverages (examples: coffee, tea, colas), herbs (examples: guarana, green tea) and other products that contain additional caffeine, such as chocolate and some non-prescription medications or dietary supplements for headache, insomnia, or weight loss. Too much Caffeine can cause effects like nausea, nervousness, or sleeplessness. Some drug products for adults that contain caffeine have about as much caffeine as a cup of coffee.
    Aspirin, ASA; Dipyridamole: (Major) Methylxanthines, through antagonism of adenosine and thus pharmacologic-induced coronary vasodilation, have been associated with false-negative results during dipyridamole-thallium 201 stress testing. It is recommended that caffeine be discontinued for at least 24 hours prior to stress testing. An interaction is not expected when methylxanthines are used concomitantly with the chronic dipyridamole therapy.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Minor) The hypnotic effects of barbiturates can be reduced by caffeine administration.
    Barbiturates: (Minor) The metabolism of caffeine can be increased by concurrent use with barbiturates. The hypnotic effects of barbiturates can be reduced by caffeine administration.
    Barium Sulfate: (Major) Avoid caffeine containing products for at least 48 hours before myelography and for at least 24 hours postprocedure.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Minor) The hypnotic effects of barbiturates can be reduced by caffeine administration.
    Benzodiazepines: (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
    Benzphetamine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Beta-agonists: (Moderate) Sensitive patients may wish to limit or avoid excessive caffeine intake from foods, beverages, dietary supplements and medications during therapy with beta-agonists. Additive side effects may occur between caffeine and beta-agonists. Caffeine is a CNS-stimulant and beta-agonists are sympathomimetic agents. Sensitive patients might experience tremor, sleep difficulties, or mild increases in heart rate.
    Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Brompheniramine; Pseudoephedrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Budesonide; Formoterol: (Moderate) Sensitive patients may wish to limit or avoid excessive caffeine intake from foods, beverages, dietary supplements and medications during therapy with beta-agonists. Additive side effects may occur between caffeine and beta-agonists. Caffeine is a CNS-stimulant and beta-agonists are sympathomimetic agents. Sensitive patients might experience tremor, sleep difficulties, or mild increases in heart rate.
    Bupropion: (Moderate) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including caffeine, is associated with an increased seizure risk and may increase this risk during the concurrent use of bupropion. Carefully consider a patient's caffeine intake from all sources, including medicines. Monitor for irritability, tremor, increased blood pressure, insomnia and seizures. Many non-prescription medicines and weight loss aids may contain caffeine and patients should read labels carefully. Examples of foods and beverages containing caffeine include coffee, teas, colas, energy drinks, chocolate, and some herbal or dietary supplements. Patients should be advised to limit excessive caffeine intake during bupropion therapy.
    Bupropion; Naltrexone: (Moderate) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including caffeine, is associated with an increased seizure risk and may increase this risk during the concurrent use of bupropion. Carefully consider a patient's caffeine intake from all sources, including medicines. Monitor for irritability, tremor, increased blood pressure, insomnia and seizures. Many non-prescription medicines and weight loss aids may contain caffeine and patients should read labels carefully. Examples of foods and beverages containing caffeine include coffee, teas, colas, energy drinks, chocolate, and some herbal or dietary supplements. Patients should be advised to limit excessive caffeine intake during bupropion therapy.
    Butabarbital: (Minor) The hypnotic effects of barbiturates can be reduced by caffeine administration.
    Caffeine; Ergotamine: (Moderate) Certain foods that contain high amounts of caffeine or theobromine should be limited during the therapeutic use of caffeine in order to limit additive methylxanthine effects. While taking Caffeine-containing medicines, limit the use of foods, beverages (examples: coffee, tea, colas), herbs (examples: guarana, green tea) and other products that contain additional caffeine, such as chocolate and some non-prescription medications or dietary supplements for headache, insomnia, or weight loss. Too much Caffeine can cause effects like nausea, nervousness, or sleeplessness. Some drug products for adults that contain caffeine have about as much caffeine as a cup of coffee.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Carbetapentane; Guaifenesin; Phenylephrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Carbetapentane; Phenylephrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Carbetapentane; Phenylephrine; Pyrilamine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Carbetapentane; Pseudoephedrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Carbinoxamine; Phenylephrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Carbinoxamine; Pseudoephedrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Cetirizine; Pseudoephedrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Chlophedianol; Guaifenesin; Phenylephrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Chlordiazepoxide: (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
    Chlordiazepoxide; Clidinium: (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Chlorpheniramine; Phenylephrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Chlorpheniramine; Pseudoephedrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Cimetidine: (Minor) Inhibitors of CYP1A2, such as cimetidine, may inhibit the hepatic oxidative metabolism of caffeine. In patients who complain of caffeine-related side effects caffeine dosage or intake may need to be reduced.
    Ciprofloxacin: (Moderate) Reduction or limitation of the caffeine dosage in medications and limitation of caffeine in beverages and food may be necessary during concurrent ciprofloxacin therapy. Ciprofloxacin can decrease the clearance of caffeine. Caffeine toxicity may occur and can manifest as nausea, vomiting, anxiety, tachycardia, or seizures. Ciprofloxacin is a CYP1A2 inhibitor and caffeine is a CYP1A2 substrate.
    Clonazepam: (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
    Clorazepate: (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
    Clozapine: (Major) Caffeine may inhibit clozapine metabolism via CYP1A2. Clozapine clearance has been decreased by roughly 14 percent during coadministration of caffeine, and a documented increase in clozapine serum concentrations has occurred in selected patients. In addition, a single case report associates the appearance of psychiatric symptoms with caffeine ingestion in one patient taking clozapine. Until more data are available, caffeine consumption should be minimized during clozapine treatment.
    Codeine; Phenylephrine; Promethazine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Darifenacin: (Minor) Consuming > 400 mg/day caffeine has been associated with the development of urinary incontinence. Caffeine may aggravate bladder symptoms and counteract the effectiveness of darifenacin to some degree. Patients may wish to limit their intake of caffeinated drugs, dietary supplements (e.g., guarana), or beverages (e.g., green tea, other teas, coffee, colas).
    Desloratadine; Pseudoephedrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Dexmethylphenidate: (Moderate) Caffeine is a CNS stimulant and such actions are expected to be additive when coadministered with psychostimulants such as dexmethylphenidate. Avoid excessive caffeine intake during use of dexmethylphenidate. Excessive caffeine ingestion (via medicines, foods like chocolate, dietary supplements, or beverages including coffee, green tea, other teas, colas) may contribute to side effects like nervousness, irritability, nausea, insomnia, tachycardia, or tremor. Patients should avoid medications and dietary supplements which contain high amounts of caffeine.
    Dextroamphetamine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Avoid excessive caffeine intake during use of the amphetamine salts. Excessive caffeine ingestion (via medicines, foods like chocolate, dietary supplements, or beverages including coffee, green tea, other teas, colas) may contribute to side effects like nervousness, irritability, nausea, insomnia, or tremor.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Diazepam: (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
    Diethylpropion: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Diphenhydramine; Phenylephrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Dipyridamole: (Major) Methylxanthines, through antagonism of adenosine and thus pharmacologic-induced coronary vasodilation, have been associated with false-negative results during dipyridamole-thallium 201 stress testing. It is recommended that caffeine be discontinued for at least 24 hours prior to stress testing. An interaction is not expected when methylxanthines are used concomitantly with the chronic dipyridamole therapy.
    Disulfiram: (Moderate) Disulfiram has been shown to inhibit caffeine elimination. Caffeine elimination decreased by 30 percent in those patients that were not recovering alcoholics and by 24 percent in those patients that were recovering alcoholics. During disulfiram therapy, patients may need to limit their caffeine intake if nausea, nervousness, tremor, restlessness, palpitations, or insomnia complaints occur. Adverse events were not noted during this pharmacokinetic study; however, the decrease could be significant in some patients, including some patients with cardiovascular disease.
    Dobutamine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Dopamine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Drospirenone; Ethinyl Estradiol: (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine in an effort to minimize caffeine-related side effects such as nausea or tremors.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine in an effort to minimize caffeine-related side effects such as nausea or tremors.
    Dyphylline: (Major) The concurrent administration of caffeine to patients taking dyphylline may produce excessive caffeine-like side effects such as nausea, irritability, or nervousness. Adverse effects such as tremors, insomnia, seizures, or cardiac arrhythmias are also possible when excessive dosages of caffeine are taken concurrently with methylxanthine drugs. Patients taking dyphylline; guaifenesin should avoid medications containing caffeine when possible. Patients may also need to limit their intake of caffeine-containing beverages or foods (e.g., coffee, green tea, other teas, guarana, colas, or chocolate) to avoid caffeine-like side effects.
    Dyphylline; Guaifenesin: (Major) The concurrent administration of caffeine to patients taking dyphylline may produce excessive caffeine-like side effects such as nausea, irritability, or nervousness. Adverse effects such as tremors, insomnia, seizures, or cardiac arrhythmias are also possible when excessive dosages of caffeine are taken concurrently with methylxanthine drugs. Patients taking dyphylline; guaifenesin should avoid medications containing caffeine when possible. Patients may also need to limit their intake of caffeine-containing beverages or foods (e.g., coffee, green tea, other teas, guarana, colas, or chocolate) to avoid caffeine-like side effects.
    Echinacea: (Moderate) Echinacea may inhibit the metabolism of caffeine. Monitor patients for signs of increased caffeine serum concentrations if these drugs are coadministered until more data are available.
    Ephedrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Epinephrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Erythromycin: (Moderate) Inhibitors of the hepatic CYP4501A2, such as erythromycin, may inhibit the hepatic oxidative metabolism of caffeine. No specific management is recommended except in patients who complain of caffeine related side effects. In such patients, the dosage of caffeine containing medications or the ingestion of caffeine containing products may need to be reduced.
    Erythromycin; Sulfisoxazole: (Moderate) Inhibitors of the hepatic CYP4501A2, such as erythromycin, may inhibit the hepatic oxidative metabolism of caffeine. No specific management is recommended except in patients who complain of caffeine related side effects. In such patients, the dosage of caffeine containing medications or the ingestion of caffeine containing products may need to be reduced.
    Estazolam: (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
    Eszopiclone: (Moderate) In general, patients taking medications for insomnia should not use caffeine-containing products including medications, dietary supplements (e.g., guarana), and beverages (e.g., coffee, green tea, other teas, or colas) prior to going to bed as these products, theoretically, may pharmacodynamically antagonize the sedative effects of eszopiclone.
    Ethinyl Estradiol: (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine in an effort to minimize caffeine-related side effects such as nausea or tremors.
    Ethinyl Estradiol; Desogestrel: (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine in an effort to minimize caffeine-related side effects such as nausea or tremors.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine in an effort to minimize caffeine-related side effects such as nausea or tremors.
    Ethinyl Estradiol; Etonogestrel: (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine in an effort to minimize caffeine-related side effects such as nausea or tremors.
    Ethinyl Estradiol; Levonorgestrel: (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine in an effort to minimize caffeine-related side effects such as nausea or tremors.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine in an effort to minimize caffeine-related side effects such as nausea or tremors.
    Ethinyl Estradiol; Norelgestromin: (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine in an effort to minimize caffeine-related side effects such as nausea or tremors.
    Ethinyl Estradiol; Norethindrone Acetate: (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine in an effort to minimize caffeine-related side effects such as nausea or tremors.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine in an effort to minimize caffeine-related side effects such as nausea or tremors.
    Ethinyl Estradiol; Norethindrone: (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine in an effort to minimize caffeine-related side effects such as nausea or tremors.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine in an effort to minimize caffeine-related side effects such as nausea or tremors.
    Ethinyl Estradiol; Norgestimate: (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine in an effort to minimize caffeine-related side effects such as nausea or tremors.
    Ethinyl Estradiol; Norgestrel: (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine in an effort to minimize caffeine-related side effects such as nausea or tremors.
    Fexofenadine; Pseudoephedrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Fluconazole: (Moderate) Fluconazole has been shown to inhibit the clearance of caffeine by 25 percent. The clinical significance of these interactions has not been determined.
    Flurazepam: (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
    Fluticasone; Salmeterol: (Moderate) Sensitive patients may wish to limit or avoid excessive caffeine intake from foods, beverages, dietary supplements and medications during therapy with beta-agonists. Additive side effects may occur between caffeine and beta-agonists. Caffeine is a CNS-stimulant and beta-agonists are sympathomimetic agents. Sensitive patients might experience tremor, sleep difficulties, or mild increases in heart rate.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Sensitive patients may wish to limit or avoid excessive caffeine intake from foods, beverages, dietary supplements and medications during therapy with beta-agonists. Additive side effects may occur between caffeine and beta-agonists. Caffeine is a CNS-stimulant and beta-agonists are sympathomimetic agents. Sensitive patients might experience tremor, sleep difficulties, or mild increases in heart rate.
    Fluticasone; Vilanterol: (Moderate) Sensitive patients may wish to limit or avoid excessive caffeine intake from foods, beverages, dietary supplements and medications during therapy with beta-agonists. Additive side effects may occur between caffeine and beta-agonists. Caffeine is a CNS-stimulant and beta-agonists are sympathomimetic agents. Sensitive patients might experience tremor, sleep difficulties, or mild increases in heart rate.
    Fluvoxamine: (Moderate) Inhibitors of CYP1A2, such as fluvoxamine, may inhibit the hepatic oxidative metabolism of caffeine. No specific management is recommended except in patients who complain of caffeine-related side effects. In such patients, the dosage of caffeine-containing medications or the ingestion of caffeine-containing products may need to be reduced.
    Formoterol: (Moderate) Sensitive patients may wish to limit or avoid excessive caffeine intake from foods, beverages, dietary supplements and medications during therapy with beta-agonists. Additive side effects may occur between caffeine and beta-agonists. Caffeine is a CNS-stimulant and beta-agonists are sympathomimetic agents. Sensitive patients might experience tremor, sleep difficulties, or mild increases in heart rate.
    Formoterol; Mometasone: (Moderate) Sensitive patients may wish to limit or avoid excessive caffeine intake from foods, beverages, dietary supplements and medications during therapy with beta-agonists. Additive side effects may occur between caffeine and beta-agonists. Caffeine is a CNS-stimulant and beta-agonists are sympathomimetic agents. Sensitive patients might experience tremor, sleep difficulties, or mild increases in heart rate.
    Glycopyrrolate; Formoterol: (Moderate) Sensitive patients may wish to limit or avoid excessive caffeine intake from foods, beverages, dietary supplements and medications during therapy with beta-agonists. Additive side effects may occur between caffeine and beta-agonists. Caffeine is a CNS-stimulant and beta-agonists are sympathomimetic agents. Sensitive patients might experience tremor, sleep difficulties, or mild increases in heart rate.
    Grapefruit juice: (Minor) Data are limited and conflicting as to whether grapefruit juice significantly alters the serum concentrations and/or AUC of caffeine. Caffeine is primarily a CYP1A2 substrate, and grapefruit juice appears to have but a small effect on this enzyme in vivo. One report suggests that grapefruit juice decreases caffeine elimination by inhibition of flavin-containing monooxygenase, a P450 independent system. This interaction might increase caffeine levels and mildly potentiate the clinical effects and common side effects of caffeine. If side effects appear, patients may need to limit either caffeine or grapefruit juice intake.
    Green Tea: (Major) Some green tea products contain caffeine. Additive CNS stimulant effects are likely to occur when caffeine is coadministered with green tea. Avoid this combination.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Guaifenesin; Phenylephrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Guaifenesin; Pseudoephedrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Guarana: (Major) Caffeine and, to a small extent, theophylline are active constituents of guarana. The concurrent administration of guarana to patients taking methylxanthines may produce excessive caffeine-like side effects, such as nausea, irritability or nervousness. Adverse effects such as tremors, insomnia, seizures, or cardiac arrhythmias are also possible when excessive dosages of guarana are taken concurrently with caffeine, aminophylline or theophylline, or with dyphylline. Patients prescribed these methylxanthine-containing medications should avoid ingesting dietary supplements containing guarana. Patients may also need to limit their intake of guarana-containing beverages to avoid caffeine-like side effects.
    Hydantoins: (Minor) The metabolism of caffeine, can be increased by concurrent use with medications that cause induction of hepatic CYP450 enzymes like the hydantoin anticonvulsants.
    Hydrocodone; Phenylephrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Hydrocodone; Pseudoephedrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Major) Sodium phosphates should be used with caution in patients using concomitant medications that lower the seizure threshold like psychostimulants.
    Ibritumomab Tiuxetan: (Major) Sodium phosphates should be used with caution in patients using concomitant medications that lower the seizure threshold like psychostimulants.
    Ibuprofen; Pseudoephedrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Indacaterol: (Moderate) Sensitive patients may wish to limit or avoid excessive caffeine intake from foods, beverages, dietary supplements and medications during therapy with beta-agonists. Additive side effects may occur between caffeine and beta-agonists. Caffeine is a CNS-stimulant and beta-agonists are sympathomimetic agents. Sensitive patients might experience tremor, sleep difficulties, or mild increases in heart rate.
    Indacaterol; Glycopyrrolate: (Moderate) Sensitive patients may wish to limit or avoid excessive caffeine intake from foods, beverages, dietary supplements and medications during therapy with beta-agonists. Additive side effects may occur between caffeine and beta-agonists. Caffeine is a CNS-stimulant and beta-agonists are sympathomimetic agents. Sensitive patients might experience tremor, sleep difficulties, or mild increases in heart rate.
    Iohexol: (Major) Use of medications that lower the seizure threshold should be carefully evaluated when considering intrathecal radiopaque contrast agents. Caffeine and caffeine containing products should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
    Iopamidol: (Major) Use of medications that lower the seizure threshold should be carefully evaluated when considering intrathecal radiopaque contrast agents. Caffeine and caffeine containing products should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
    Iopromide: (Major) Use of medications that lower the seizure threshold should be carefully evaluated when considering intrathecal radiopaque contrast agents. Caffeine and caffeine containing products should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
    Ioversol: (Major) Use of medications that lower the seizure threshold should be carefully evaluated when considering intrathecal radiopaque contrast agents. Caffeine and caffeine containing products should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
    Isocarboxazid: (Major) Excessive use of caffeine in any form should be avoided in patients receiving monoamine oxidase inhibitors (MAOIs). Limit caffeine intake during MAOI use and for 1 to 2 weeks after discontinuation of any MAOI. the use of non-prescription medicines or dietary supplements containing caffeine should be avoided. Patients should try to avoid or limit the intake of all items containing caffeine such as tea, coffee, chocolate, and cola. Cardiac arrhythmias or severe hypertension may occur because of the potentiation of caffeine's sympathomimetic effects by MAOIs if caffeine intake is excessive.Selegiline can only be used safely without dietary restrictions at doses where it presumably selectively inhibits MAO-B (e.g., 10 mg/day). At doses of 20 mg/day, selegiline can interact with foods and beverages. The precise dose at which selegiline becomes a non-selective inhibitor of all MAO is unknown, but may be in the range of 30 to 40 mg per day. Attention to the dose dependent nature of selegiline's selectivity is critical if it is to be used without elaborate restrictions being placed on diet.
    Isoniazid, INH: (Moderate) Although isoniazid does not inhibit mitochondrial MAO, it does appear to inhibit plasma MAO. Dangerous cardiac arrhythmias or severe hypertension can occur because of the potentiation of caffeine's sympathomimetic effects by MAOIs. Caffeine use should be minimized or avoided during and for 1 to 2 weeks after discontinuation of any MAOI.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Although isoniazid does not inhibit mitochondrial MAO, it does appear to inhibit plasma MAO. Dangerous cardiac arrhythmias or severe hypertension can occur because of the potentiation of caffeine's sympathomimetic effects by MAOIs. Caffeine use should be minimized or avoided during and for 1 to 2 weeks after discontinuation of any MAOI.
    Isoniazid, INH; Rifampin: (Moderate) Although isoniazid does not inhibit mitochondrial MAO, it does appear to inhibit plasma MAO. Dangerous cardiac arrhythmias or severe hypertension can occur because of the potentiation of caffeine's sympathomimetic effects by MAOIs. Caffeine use should be minimized or avoided during and for 1 to 2 weeks after discontinuation of any MAOI.
    Isosulfan Blue: (Major) Use of medications that lower the seizure threshold should be carefully evaluated when considering intrathecal radiopaque contrast agents. Caffeine and caffeine containing products should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
    Ketoconazole: (Moderate) Ketoconazole has been shown to inhibit the clearance of caffeine by 11 percent. The clinical significance of these interactions has not been determined.
    Levalbuterol: (Moderate) Sensitive patients may wish to limit or avoid excessive caffeine intake from foods, beverages, dietary supplements and medications during therapy with beta-agonists. Additive side effects may occur between caffeine and beta-agonists. Caffeine is a CNS-stimulant and beta-agonists are sympathomimetic agents. Sensitive patients might experience tremor, sleep difficulties, or mild increases in heart rate.
    Linezolid: (Moderate) Linezolid is an antibiotic that is also a reversible, non-selective inhibitor of MAO. Dangerous cardiac arrhythmias or severe hypertension can occur because of the potentiation of caffeine's sympathomimetic effects by MAOIs. Caffeine use should be minimized or avoided during and for 1 to 2 weeks after discontinuation of any MAOI.
    Lisdexamfetamine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
    Lithium: (Major) Caffeine appears to reduce serum lithium concentrations. In 11 coffee-drinking patients stabilized on lithium, serum lithium concentrations increased during 2 weeks when coffee was withheld and fell when coffee was resumed. Lithium ADRs have also been noted to increase simultaneously with a reduction in caffeine intake. Patients taking lithium should be counseled regarding their intake of caffeine. Clinicians should note, however, that coffee, not pure caffeine, was the variable in this study. Other beverages that contain significant amounts of caffeine include green tea, other teas, and cola. Because guarana contains a substantial caffeine content, this herb should be avoided in patients taking lithium.
    Loratadine; Pseudoephedrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Lorazepam: (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
    Mephobarbital: (Minor) The hypnotic effects of barbiturates can be reduced by caffeine administration.
    Metaproterenol: (Moderate) Sensitive patients may wish to limit or avoid excessive caffeine intake from foods, beverages, dietary supplements and medications during therapy with beta-agonists. Additive side effects may occur between caffeine and beta-agonists. Caffeine is a CNS-stimulant and beta-agonists are sympathomimetic agents. Sensitive patients might experience tremor, sleep difficulties, or mild increases in heart rate.
    Methamphetamine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Methenamine; Sodium Acid Phosphate: (Major) Sodium phosphates should be used with caution in patients using concomitant medications that lower the seizure threshold like psychostimulants.
    Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Major) Sodium phosphates should be used with caution in patients using concomitant medications that lower the seizure threshold like psychostimulants.
    Methohexital: (Minor) The hypnotic effects of barbiturates can be reduced by caffeine administration.
    Methylphenidate: (Moderate) Caffeine is a CNS stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Avoid excessive caffeine intake during use of methylphenidate. Excessive caffeine ingestion (via medicines, foods like chocolate, dietary supplements, or beverages including coffee, green tea, other teas, colas) may contribute to side effects like nervousness, irritability, nausea, insomnia, or tremor. Patients should avoid medications and dietary supplements which contain high amounts of caffeine.
    Midazolam: (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
    Midodrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Modafinil: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Monoamine oxidase inhibitors: (Major) Excessive use of caffeine in any form should be avoided in patients receiving Monoamine oxidase inhibitors (MAOIs). Limit caffeine intake during MAOI use and for 1 to 2 weeks after discontinuation of any MAOI. the use of non-prescription medicines or dietary supplements containing caffeine should be avoided. Patients should try to avoid or limit the intake of all items containing caffeine such as tea, coffee, chocolate, and cola. Cardiac arrhythmias or severe hypertension may occur because of the potentiation of caffeine's sympathomimetic effects by MAOIs if caffeine intake is excessive. Ordinarily, selegiline may be an exception, it can only be used safely without dietary restrictions at doses where it presumably selectively inhibits MAO-B (e.g., 10 mg/day). At doses of 20 mg/day, selegiline can interact with foods and beverages. The precise dose at which selegiline becomes a non-selective inhibitor of all MAO is unknown, but may be in the range of 30 to 40 mg per day. Attention to the dose dependent nature of selegiline's selectivity is critical if it is to be used without elaborate restrictions being placed on diet.
    Naproxen; Pseudoephedrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Non-Ionic Contrast Media: (Major) Use of medications that lower the seizure threshold should be carefully evaluated when considering intrathecal radiopaque contrast agents. Caffeine and caffeine containing products should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours post-procedure.
    Norepinephrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Obeticholic Acid: (Moderate) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as caffeine. Concomitant administration of 200 mg caffeine as a single dose with obeticholic acid 10 mg once daily resulted in a 42% increase in caffeine AUC and a 6% increase in caffeine Cmax. Therapeutic monitoring is recommended with coadministration. No specific management is recommended except in patients who complain of caffeine-related side effects like nausea, tremor, or palpitations. In such patients, the dosage of caffeine-containing medications or the ingestion of caffeine-containing products may need to be reduced.
    Olodaterol: (Moderate) Sensitive patients may wish to limit or avoid excessive caffeine intake from foods, beverages, dietary supplements and medications during therapy with beta-agonists. Additive side effects may occur between caffeine and beta-agonists. Caffeine is a CNS-stimulant and beta-agonists are sympathomimetic agents. Sensitive patients might experience tremor, sleep difficulties, or mild increases in heart rate.
    Oxazepam: (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
    Oxybutynin: (Minor) Consuming greater than 400 mg/day caffeine has been associated with the development of urinary incontinence. Caffeine may aggravate bladder symptoms and counteract the effectiveness of drugs used to treat overactive bladder such as oxybutynin.
    Oxymetazoline: (Moderate) Caffeine is a CNS stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Caffeine should be avoided or used cautiously with oxymetazoline.
    Pentobarbital: (Minor) The hypnotic effects of barbiturates can be reduced by caffeine administration.
    Phendimetrazine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Phenelzine: (Major) Excessive use of caffeine in any form should be avoided in patients receiving monoamine oxidase inhibitors (MAOIs). Limit caffeine intake during MAOI use and for 1 to 2 weeks after discontinuation of any MAOI. the use of non-prescription medicines or dietary supplements containing caffeine should be avoided. Patients should try to avoid or limit the intake of all items containing caffeine such as tea, coffee, chocolate, and cola. Cardiac arrhythmias or severe hypertension may occur because of the potentiation of caffeine's sympathomimetic effects by MAOIs if caffeine intake is excessive.Selegiline can only be used safely without dietary restrictions at doses where it presumably selectively inhibits MAO-B (e.g., 10 mg/day). At doses of 20 mg/day, selegiline can interact with foods and beverages. The precise dose at which selegiline becomes a non-selective inhibitor of all MAO is unknown, but may be in the range of 30 to 40 mg per day. Attention to the dose dependent nature of selegiline's selectivity is critical if it is to be used without elaborate restrictions being placed on diet.
    Phenobarbital: (Minor) The hypnotic effects of barbiturates can be reduced by caffeine administration.
    Phentermine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Phentermine; Topiramate: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Phenylephrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Phenylephrine; Promethazine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Phosphorus Salts: (Major) Sodium phosphates should be used with caution in patients using concomitant medications that lower the seizure threshold like psychostimulants.
    Pirbuterol: (Moderate) Sensitive patients may wish to limit or avoid excessive caffeine intake from foods, beverages, dietary supplements and medications during therapy with beta-agonists. Additive side effects may occur between caffeine and beta-agonists. Caffeine is a CNS-stimulant and beta-agonists are sympathomimetic agents. Sensitive patients might experience tremor, sleep difficulties, or mild increases in heart rate.
    Potassium Phosphate; Sodium Phosphate: (Major) Sodium phosphates should be used with caution in patients using concomitant medications that lower the seizure threshold like psychostimulants.
    Prilocaine; Epinephrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Primidone: (Minor) The hypnotic effects of barbiturates can be reduced by caffeine administration.
    Procarbazine: (Major) Ingestion of certain products should be minimized while receiving procarbazine therapy, as the drug has some MAO inhibiting actions. Caffeine may produce hypertension or hypertensive crisis or induce cardiac arrhythmias if administered to patients taking drugs with strong MAOI properties. All preparations containing caffeine should be used sparingly such as teas, coffee, chocolate, cola, guarana, or 'stay awake' products. Some non-prescription medicines also contain caffeine and should not be taken without health care professional advice. Following discontinuation of procarbazine, dietary restrictions should continue for at least 2 weeks due to the slow recovery from the enzyme-inhibiting effects.
    Pseudoephedrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Quazepam: (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
    Racepinephrine: (Moderate) Patients who are using racepinephrine inhalation are advised to avoid foods and beverages that contain caffeine. They should also avoid dietary supplements containing ingredients, such as caffeine, that are reported or claimed to have a stimulant effect. If a patient is taking prescribed medications containing caffeine, then they should seek health care professional advice prior to the use of racepinephrine. Additive adverse effects on the cardiovascular and nervous system are possible, some which may be undesirable. Side effects such as nausea, tremor, nervousness, difficulty with sleep, and increased heart rate may be additive. Consider alternatives to racepinephrine for the treatment of asthma.
    Regadenoson: (Major) Regadenoson may cause an increased coronary blood flow without regard to prior caffeine ingestion. Patients should avoid consumption of any products containing caffeine (including caffeine from foods and beverages such as coffee, green tea, other teas, colas, and chocolate) for at least 12 hours before regadenoson administration.
    Riluzole: (Minor) Caffeine may increase plasma concentrations of riluzole via CYP1A2 inhibition. Also, because riluzole is a substrate for the CYP1A2 isoenzyme, it may in turn effect the clearance of caffeine.
    Salmeterol: (Moderate) Sensitive patients may wish to limit or avoid excessive caffeine intake from foods, beverages, dietary supplements and medications during therapy with beta-agonists. Additive side effects may occur between caffeine and beta-agonists. Caffeine is a CNS-stimulant and beta-agonists are sympathomimetic agents. Sensitive patients might experience tremor, sleep difficulties, or mild increases in heart rate.
    Secobarbital: (Minor) The hypnotic effects of barbiturates can be reduced by caffeine administration.
    Selegiline: (Major) Excessive use of caffeine in any form should be avoided in patients receiving monoamine oxidase inhibitors (MAOIs). Limit caffeine intake during MAOI use and for 1 to 2 weeks after discontinuation of any MAOI. the use of non-prescription medicines or dietary supplements containing caffeine should be avoided. Patients should try to avoid or limit the intake of all items containing caffeine such as tea, coffee, chocolate, and cola. Cardiac arrhythmias or severe hypertension may occur because of the potentiation of caffeine's sympathomimetic effects by MAOIs if caffeine intake is excessive.Selegiline can only be used safely without dietary restrictions at doses where it presumably selectively inhibits MAO-B (e.g., 10 mg/day). At doses of 20 mg/day, selegiline can interact with foods and beverages. The precise dose at which selegiline becomes a non-selective inhibitor of all MAO is unknown, but may be in the range of 30 to 40 mg per day. Attention to the dose dependent nature of selegiline's selectivity is critical if it is to be used without elaborate restrictions being placed on diet.
    Sodium Oxybate: (Major) Caffeine should be avoided or used cautiously with sodium oxybate. This combination may be associated with adverse effects such as nervousness, irritability, insomnia, and/or cardiac arrhythmias.
    Solifenacin: (Minor) Beverages containing caffeine may aggravate bladder symptoms and counteract the effectiveness of solifenacin to some degree. Patients may wish to limit their intake of caffeinated drugs, dietary supplements, or beverages.
    Tacrine: (Moderate) Inhibitors of CYP1A2, such as tacrine, may inhibit the hepatic oxidative metabolism of caffeine. No specific management is recommended except in patients who complain of caffeine-related side effects like nausea, tremor, or palpitations. In such patients, the dosage of caffeine-containing medications or the ingestion of caffeine-containing products may need to be reduced.
    Temazepam: (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
    Terbinafine: (Minor) Terbinafine has been shown to inhibit the clearance of caffeine. The clinical significance of this interaction has not been determined.
    Terbutaline: (Moderate) Sensitive patients may wish to limit or avoid excessive caffeine intake from foods, beverages, dietary supplements and medications during therapy with beta-agonists. Additive side effects may occur between caffeine and beta-agonists. Caffeine is a CNS-stimulant and beta-agonists are sympathomimetic agents. Sensitive patients might experience tremor, sleep difficulties, or mild increases in heart rate.
    Theophylline, Aminophylline: (Major) Caffeine is a CNS stimulant. The concurrent administration of caffeine to patients taking aminophyllinemay produce excessive caffeine-like side effects, such as nausea, irritability or nervousness. Adverse effects such as tremors, insomnia, seizures, or cardiac arrhythmias are also possible when excessive dosages of caffeine are taken concurrently. Patients should avoid medications containing caffeine when possible. Patients may also need to limit their intake of caffeine-containing beverages or foods (e.g., coffee, green tea, other teas, colas, or chocolate) to avoid caffeine-like side effects. (Moderate) Caffeine is a CNS stimulant. The concurrent administration of caffeine to patients taking theophylline may produce excessive caffeine-like side effects, such as nausea, irritability or nervousness. Adverse effects such as tremors, insomnia, seizures, or cardiac arrhythmias are also possible when excessive dosages of caffeine are taken concurrently with theophylline. Patients taking theophylline should avoid medications containing caffeine when possible. Patients may also need to limit their intake of caffeine-containing beverages or foods (e.g., coffee, green tea, other teas, colas, or chocolate) to avoid caffeine-like side effects.
    Thiabendazole: (Moderate) Thiabendazole is a potent inhibitor of CYP1A2 hepatic enzymes. Thiabendazole can interfere with the CYP1A2 metabolism of xanthine derivatives such as caffeine, reducing clearance by up to 50%. Excessive caffeine-related side effects, such as nausea, tremor, or nervousness, may result. Reduction or limitation of the caffeine dosage in medications and limitation of caffeine in beverages and food may be necessary during concomitant treatment.
    Thiopental: (Minor) The hypnotic effects of barbiturates can be reduced by caffeine administration.
    Tiotropium; Olodaterol: (Moderate) Sensitive patients may wish to limit or avoid excessive caffeine intake from foods, beverages, dietary supplements and medications during therapy with beta-agonists. Additive side effects may occur between caffeine and beta-agonists. Caffeine is a CNS-stimulant and beta-agonists are sympathomimetic agents. Sensitive patients might experience tremor, sleep difficulties, or mild increases in heart rate.
    Tobacco: (Moderate) Inducers of the hepatic CYP450 isoenzyme CYP1A2 may induce the hepatic oxidative metabolism of caffeine. Tobacco smoke contains hydrocarbons that induce hepatic CYP450 microsomal enzymes (e.g., CYP1A1, CYP1A2, CYP2E1). The increased clearance of caffeine by smokers may contribute to the higher consumption of caffeinated beverages reported to occur in this group. Because the effect on hepatic microsomal enzymes is not related to the nicotine component of tobacco, the sudden cessation of tobacco smoking may result in a reduced clearance of caffeine, despite the initiation of a nicotine replacement product. Following several days of abstinence from chronic tobacco smoking, caffeine clearance may decrease by roughly 40%, leading to the possible occurrence of caffeine-related side effects like nausea, nervousness, irritability, tremors, or insomnia, if caffeine use remains the same.
    Tolterodine: (Minor) Beverages containing caffeine may aggravate bladder symptoms and counteract the effectiveness of tolterodine to some degree. Patients may wish to limit their intake of caffeinated drugs, dietary supplements, or beverages.
    Trandolapril; Verapamil: (Minor) Verapamil reduces the clearance of caffeine and increases serum caffeine concentrations, presumably via inhibition of hepatic metabolism. During concomitant therapy with verapamil, it may be prudent to advise patients to limit or minimize the intake of caffeinated products to minimize caffeine-related side effects.
    Tranylcypromine: (Major) Excessive use of caffeine in any form should be avoided in patients receiving monoamine oxidase inhibitors (MAOIs). Limit caffeine intake during MAOI use and for 1 to 2 weeks after discontinuation of any MAOI. the use of non-prescription medicines or dietary supplements containing caffeine should be avoided. Patients should try to avoid or limit the intake of all items containing caffeine such as tea, coffee, chocolate, and cola. Cardiac arrhythmias or severe hypertension may occur because of the potentiation of caffeine's sympathomimetic effects by MAOIs if caffeine intake is excessive.Selegiline can only be used safely without dietary restrictions at doses where it presumably selectively inhibits MAO-B (e.g., 10 mg/day). At doses of 20 mg/day, selegiline can interact with foods and beverages. The precise dose at which selegiline becomes a non-selective inhibitor of all MAO is unknown, but may be in the range of 30 to 40 mg per day. Attention to the dose dependent nature of selegiline's selectivity is critical if it is to be used without elaborate restrictions being placed on diet.
    Triazolam: (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
    Trospium: (Minor) Consuming > 400 mg/day caffeine has been associated with the development of urinary incontinence. Caffeine may aggravate bladder symptoms and counteract the effectiveness of drugs used to treat overactive bladder, like trospium, to some degree. Patients with overactive bladder may wish to limit their intake of caffeine including caffeine from drugs, dietary supplements (i.e., guarana), beverages (i.e., teas, coffee, colas), or foods (i.e., chocolate).
    Umeclidinium; Vilanterol: (Moderate) Sensitive patients may wish to limit or avoid excessive caffeine intake from foods, beverages, dietary supplements and medications during therapy with beta-agonists. Additive side effects may occur between caffeine and beta-agonists. Caffeine is a CNS-stimulant and beta-agonists are sympathomimetic agents. Sensitive patients might experience tremor, sleep difficulties, or mild increases in heart rate.
    Vemurafenib: (Minor) Coadministration of vemurafenib and caffeine increased the caffeine AUC by 2.6-fold. Vemurafenib is a CYP1A2 inhibitor and caffeine is a CYP1A2 substrate. The manufacturer of vemurafenib suggests that concomitant use with agents with narrow therapeutic windows that are metabolized by CYP1A2 is not recommended. Theophylline (or aminophylline), another methylxanthine, is also primarily a CYP1A2 substrate with a narrow therapeutic index. If coadministration cannot be avoided, the manufacturer recommends considering a dose reduction of the concomitant drug; it may also be prudent to monitor for signs and symptoms of theophylline toxicity during coadministration. Some patients may need to reduce intake of caffeine from non-drug sources (e.g., beverages) during treatment to avoid caffeine-related side effects.
    Verapamil: (Minor) Verapamil reduces the clearance of caffeine and increases serum caffeine concentrations, presumably via inhibition of hepatic metabolism. During concomitant therapy with verapamil, it may be prudent to advise patients to limit or minimize the intake of caffeinated products to minimize caffeine-related side effects.
    Vincristine Liposomal: (Major) Sodium phosphates should be used with caution in patients using concomitant medications that lower the seizure threshold like psychostimulants.
    Yohimbine: (Moderate) Dangerous cardiac arrhythmias or severe hypertension can occur because of the potentiation of caffeine's sympathomimetic effects by drugs with MAOI activity such as high doses of yohimbine.
    Zileuton: (Moderate) Inhibitors of CYP1A2, such as zileuton, may inhibit the hepatic oxidative metabolism of caffeine. No specific management is recommended except in patients who complain of caffeine-related side effects like nausea, tremor, or palpitations. In such patients, the dosage of caffeine-containing medications or the ingestion of caffeine-containing products may need to be reduced.
    Zolpidem: (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking medications for sleep, such as zolpidem should avoid caffeine-containing medications, dietary supplements, foods, and beverages within the hours close to bedtime. Patients should be encouraged to avoid excessive total daily caffeine intake, as part of proper sleep hygiene, since caffeine intake can interfere with proper sleep. However, in healthy subjects (without insomnia) in a pharmacokinetic study, coadministration of caffeine at a dosage of 150 to 300 mg with zolpidem did not counteract the sedative effects of a single 10 mg dose of zolpidem..

    PREGNANCY AND LACTATION

    Pregnancy

    Cytochrome P450 metabolism of caffeine is inhibited in infants who are breast-fed; formula feeding does not appear to affect the pharmacokinetics of caffeine in infants. Peak caffeine milk levels usually occur within 1 hour after the maternal ingestion of a caffeinated beverage; with milk:plasma ratios of 0.5—0.7 reported. Although only small amounts are secreted in breast-milk, caffeine can accumulate in the neonate if maternal ingestion is moderate to high. Higher caffeine intake (> 500 mg/day) by a nursing mother may cause irritability or poor sleeping patterns in the infant who is breast-feeding. Although the American Academy of Pediatrics generally considers the usual use of caffeinated beverages to be compatible with lactation, nursing mothers should limit their intake of beverages containing caffeine if possible. Caffeine containing drug-products should be used cautiously during lactation due to their high caffeine contents. Mothers who are breast-feeding infants who are prescribed caffeine for apnea should avoid additional caffeine. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Caffeine is a mild, direct stimulant at all levels of the CNS and also stimulates the heart and cardiovascular system. The related xanthine, theophylline, shares these properties and is widely used in the treatment of pulmonary disease. Both caffeine and theophylline are CNS stimulants, with theophylline exerting more dramatic effects than caffeine at higher concentrations. Caffeine also stimulates the medullary respiratory center and relaxes bronchial smooth muscle. Caffeine stimulates voluntary muscle and gastric acid secretion, increases renal blood flow, and is a mild diuretic.
     
    While the clinical responses to caffeine are well known, the cellular mechanism of action is uncertain. Several theories have been proposed. At high concentrations, caffeine interferes with the uptake and storage of calcium by sarcoplasmic reticulum of striated muscle. While this action would explain the effects of caffeine on cardiac and skeletal muscle, it does not appear to occur at clinically achievable concentrations. Inhibition of phosphodiesterases (and subsequent accumulation of cyclic nucleotides) also does not appear to occur at clinically achievable concentrations.
     
    Currently, it is believed that xanthines act as adenosine-receptor antagonists. Adenosine acts as an autocoid, and virtually every cell contains adenosine receptors within the plasma membrane. Adenosine exerts complex actions. It inhibits the release of neurotransmitters from presynaptic sites but works in concert with norepinephrine or angiotensin to augment their actions. Antagonism of adenosine receptors by caffeine would appear to promote neurotransmitter release, thus explaining the stimulatory effects of caffeine.

    Recently, a distinct syndrome has been associated with caffeine withdrawal. It is possible that the manifestations of caffeine withdrawal may be secondary to catecholamine or neurotransmitter depletion.
     
    The following mechanisms of action are hypothesized for caffeine's action in apnea of prematurity: 1) stimulation of the respiratory center, 2) increased minute ventilation, 3) decreased threshold to hypercapnia, 4) increased response to hypercapnia, 5) increased skeletal muscle tone, 6) decreased diaphragmatic fatigue, 7) increased metabolic rate, and 8) increased oxygen consumption. All of these actions are thought to be related to adenosine receptor antagonism.

    PHARMACOKINETICS

    Caffeine is administered orally and intravenously. Therapeutic concentrations are reported to be 5—25 mg/L in adults. It is distributed rapidly to all body tissues and readily crosses the blood-brain and placental barriers. It is distributed into breast milk. Caffeine is roughly 36% bound to plasma proteins. In adults, it is partially metabolized in the liver via demethylation reactions dependent on the CYP-450 1A2 isoenzyme; major metabolites include paraxanthine (80%), theobromine (10%) and theophylline (4%). The plasma half-life is 3—7 hours in adults.
     
    Affected cytochrome P450 isoenzymes: CYP1A2

    Oral Route

    Caffeine and citrated caffeine are well absorbed from the GI tract. Following oral administration, peak plasma concentrations in adults are reached within 50—75 minutes. In neonates, the oral administration of caffeine results in peak concentrations in 0.5—2 hours; formula feedings do not affect the time to maximum concentrations after oral dosing.