Aminophylline

Pharmacologic Category

Phosphodiesterase Enzyme Inhibitor, Nonselective

Dosing: Adult

Note: All dosages expressed as aminophylline; use ideal body weight (theophylline distributes poorly into body fat) to calculate dose; individualize dose based on steady-state serum concentrations. Theophylline dose is ~79% of aminophylline dose. The treatment of asthma exacerbations with aminophylline is not supported or recommended by current clinical practice guidelines (GINA 2019; NAEPP 2007). The treatment of acute COPD exacerbations with aminophylline is not recommended by current clinical practice guidelines (Global Initiative for COPD Guidelines 2018).

Reversible airflow obstruction, acute symptoms:

Loading dose: IV:

Patients who have not received aminophylline or theophylline in the previous 24 hours: 5.7 mg/kg.

Patients who have received aminophylline or theophylline in the previous 24 hours: A loading dose should not be given before obtaining a serum theophylline concentration. The loading dose should be calculated as follows:

Loading dose = (desired serum theophylline concentration - measured serum theophylline concentration) (Vd)

Maintenance dose: IV: Note: Dosing presented is to achieve a target theophylline concentration of 10 mcg/mL. Lower initial doses may be required in patients with reduced theophylline clearance. Dosage should be adjusted according to serum level measurements.

Adults ≤60 years: 0.51 mg/kg/hour; maximum dose: 1,139 mg/day unless serum levels indicate need for larger dose.

Adults >60 years: 0.38 mg/kg/hour; maximum dose: 507 mg/day unless serum levels indicate need for larger dose.

Cardiac decompensation, cor pulmonale, sepsis with multiorgan failure, and shock: 0.25 mg/kg/hour; maximum dose: 507 mg/day unless serum levels indicate need for larger dose.

Dosage adjustment based on serum theophylline concentrations: Note: Recheck serum theophylline concentration 24 hours after dosage adjustment.

<9.9 mcg/mL: If dosage is tolerated, but symptoms are not controlled, increase infusion rate ~25%.

10 to 14.9 mcg/mL: Maintain infusion rate if dosage is tolerated and symptoms controlled. Recheck serum concentrations at 24-hour intervals. If symptoms are not controlled and dosage is tolerated, consider adding additional medications to treatment regimen.

15 to 19.9 mcg/mL: Consider 10% dose reduction in infusion rate to improve safety margin even if dose is tolerated.

20 to 24.9 mcg/mL: Decrease infusion rate by 25% even if no adverse effects present.

25 to 30 mcg/mL: Stop infusion for 24 hours and decrease subsequent infusion rate at least 25%. If symptomatic, stop infusion and consider whether overdose treatment is indicated.

>30 mcg/mL: Stop infusion and treat overdose; if resumed, decrease subsequent infusion rate at least 50%.

Reversal of dipyridamole- or regadenoson-induced adverse reactions (eg, angina, hypotension) during nuclear cardiac stress testing (off-label use): IV: 50 to 250 mg administered over 30 to 60 seconds, repeat as necessary. Note: Since adenosine-induced side effects are short lived after discontinuation of the infusion, aminophylline administration is only very rarely required (ASNC [Henzlova 2016]). In the setting of aminophylline shortage, IV theophylline or caffeine may be used as alternatives (Singleton 2018).

Dosing: Geriatric

Refer to adult dosing. Maximum dose: 507 mg/day unless serum levels indicate need for a larger dose.

Dosing: Renal Impairment: Adult

No dosage adjustment necessary.

Dosing: Hepatic Impairment: Adult

Initial: 0.25 mg/kg/hour; maximum dose: 507 mg/day unless serum concentrations indicate need for larger dose. Use with caution and monitor serum theophylline concentrations frequently.

Dosing: Pediatric

Note: All dosages expressed as aminophylline; use ideal body weight to calculate dose; adjust dose based on steady-state serum concentrations.

Reversible airflow obstruction, acute symptoms: Infants, Children, and Adolescents: Note: Not recommended for the treatment of asthma exacerbations (GINA 2018; NAEPP 2007).

Loading dose: IV:

Patients not currently receiving aminophylline or theophylline: 5.7 mg/kg/dose

Patients currently receiving aminophylline or theophylline: A loading dose is not recommended without first obtaining a serum theophylline concentration in patients who have received aminophylline or theophylline within the past 24 hours. The loading dose should be calculated as follows:

Dose = (C desired – C measured) (Vd)

C desired = desired serum theophylline concentration

C measured = measured serum theophylline concentration

Maintenance dose: Continuous IV infusion: Note: Dosing presented is to achieve a target concentration of 10 mcg/mL. Lower initial doses may be required in patients with reduced theophylline clearance. Dosage should be adjusted according to serum concentration measurements during the first 12- to 24-hour period.

Infants 4 to 6 weeks: 1.9 mg/kg/dose every 12 hours

Infants 6 to 52 weeks: Dose (mg/kg/hour) = [(0.008 X age in weeks) + 0.21] divided by 0.79

Children 1 to <9 years: 1.01 mg/kg/hour

Children 9 to <12 years: 0.89 mg/kg/hour

Adolescents 12 to <16 years (otherwise healthy, nonsmokers): 0.63 mg/kg/hour; maximum dose: 1,139 mg/day unless serum concentrations indicate need for larger dose

Adolescents 12 to <16 years (cigarette or marijuana smokers): 0.89 mg/kg/hour

Adolescents ≥16 years (otherwise healthy, nonsmokers): 0.51 mg/kg/hour; maximum dose: 1,139 mg/day unless serum concentrations indicate need for larger dose

Cardiac decompensation, cor pulmonale, hepatic dysfunction, sepsis with multiorgan failure, shock: Infants, Children, and Adolescents: Initial: 0.25 mg/kg/hour; maximum dose: 507 mg/day unless serum concentrations indicate need for larger dose.

Dosage adjustment based on serum theophylline concentrations: Infants, Children, and Adolescents: Note: Recheck serum theophylline concentrations in 12 hours (ages 1 month to <16 years) or 24 hours (ages ≥16 years) after IV dose; adjust dose based on the following serum concentration results:

<9.9 mcg/mL: If tolerated, but symptoms remain, increase dose by ~25%. Recheck serum theophylline concentrations.

10 to 14.9 mcg/mL: Maintain dosage if tolerated and symptoms controlled. Recheck serum concentrations at 24-hour intervals. If symptoms not controlled, consider additional medications for management.

15 to 19.9 mcg/mL: Consider 10% dose reduction to improve safety margin even if dose is tolerated.

20 to 24.9 mcg/mL: Decrease dose by ~25%. Recheck serum concentrations.

25 to 30 mcg/mL: Stop infusion for 12 hours (ages 1 month to <16 years) or 24 hours (ages ≥16 years) and decrease subsequent doses by at least 25%. Recheck serum concentrations.

>30 mcg/mL: Stop dosing and treat overdose; if resumed, decrease subsequent doses by at least 50%. Recheck serum concentrations.

Dosing: Renal Impairment: Pediatric

Infants 1 to 3 months: There are no specific dosage adjustments provided in the manufacturer's labeling; consider dose reduction and frequent monitoring of serum theophylline concentrations.

Infants >3 months, Children, and Adolescents: No adjustment necessary.

Dosing: Hepatic Impairment: Pediatric

Infants, Children, and Adolescents: Initial: 0.25 mg/kg/hour; maximum dose: 507 mg/day unless serum concentrations indicate need for larger dose. Use with caution and monitor serum theophylline concentrations frequently.

Use: Labeled Indications

Reversible airflow obstruction: Treatment of acute exacerbations of symptoms and reversible airflow obstruction due to asthma or other chronic lung diseases (eg, emphysema, chronic bronchitis) as an adjunct to inhaled beta-2 selective agonists and systemically administered corticosteroids.

Guideline recommendations:

Asthma: The 2007 National Heart, Lung, and Blood Institute Asthma Guidelines and the 2019 Global Initiative for Asthma Guidelines recommend against aminophylline for the treatment of asthma exacerbations because of poor efficacy and safety concerns (GINA 2019; NAEPP 2007).

Chronic obstructive pulmonary disease: The 2019 Global Initiative for Chronic Obstructive Lung Disease Guidelines recommends against aminophylline for the treatment of chronic obstructive pulmonary disease exacerbations because of significant adverse effects (GOLD 2019).

Use: Off-Label: Adult

Reversal of dipyridamole- or regadenoson-induced adverse reactions (eg, angina, hypotension) during nuclear cardiac stress testingLevel of Evidence [G]

Based on the American Society of Nuclear Cardiology (ASNC) Guidelines for Nuclear Cardiology Procedures, aminophylline given for the reversal of adenosine-, dipyridamole-, or regadenoson-induced adverse reactions (eg, angina, hypotension) during nuclear cardiac stress testing is effective and recommended in this setting. Use of aminophylline with adenosine-induced adverse reactions specifically is usually not warranted due to adenosine's short half-life (adverse reactions will usually stop within seconds of stopping adenosine). In the setting of aminophylline shortage, theophylline or caffeine may be used as alternatives to reverse regadenoson or dipyridamole. In addition, to reduce aminophylline use overall, adenosine or dobutamine can be used as alternative pharmacologic testing agents, if appropriate, since aminophylline reversal is not typically required Ref.

Level of Evidence Definitions

Level of Evidence Scale

Clinical Practice Guidelines

Asthma:

NHLBI and NAEPP The Expert Panel Report 3: “Guidelines for the Diagnosis and Management of Asthma,” Full Report 2007

Chronic Obstructive Pulmonary Disease:

ACCP/CTS, “Prevention of Acute Exacerbations of Chronic Obstructive Pulmonary Disease: American College of Chest Physicians and Canadian Thoracic Society Guideline,” 2014

"Canadian Thoracic Society Recommendations for Management of Chronic Obstructive Pulmonary Disease," 2007 Update

GOLD, “Global Strategy for Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease”, 2019

Usual Infusion Concentrations: Pediatric

IV infusion: 1 mg/mL

Usual Infusion Concentrations: Adult

IV infusion: 250 mg in 250 mL (concentration: 1 mg/mL) of D5W or NS

Administration: IV

For IV administration only. Loading doses should be administered IV over 30 minutes. In patients with cor pulmonale, cardiac decompensation, hepatic impairment, patients >60 years of age, or patients taking medications that reduce theophylline clearance, the initial maintenance infusion rate should not exceed 21 mg/hour.

Off-label use: For reversal of adenosine-, dipyridamole-, or regadenoson-induced adverse events during nuclear cardiac stress testing, administer IV undiluted over 30 to 60 seconds, repeat as necessary. Since adenosine-induced side effects are short lived after discontinuation of the infusion, aminophylline administration is only very rarely required (ASNC [Henzlova 2016]).

Vesicant; ensure proper needle or catheter placement prior to and during IV infusion. Avoid extravasation.

Extravasation management: If extravasation occurs, stop infusion immediately and disconnect (leave needle/cannula in place); gently aspirate extravasated solution (do NOT flush the line); initiate hyaluronidase antidote; remove needle/cannula; apply dry cold compresses (Hurst 2004; Reynolds 2014); elevate extremity.

Hyaluronidase: Intradermal or SubQ: Inject a total of 1 to 1.7 mL (15 units/mL) as five separate 0.2 to 0.3 mL injections (using a 25-gauge needle) into area of extravasation at the leading edge in a clockwise manner (MacCara 1983; Reynolds 2014; Zenk 1981).

Administration: Injectable Detail

pH: 8.6 to 9

Administration: Pediatric

IV: For IV administration only. Infusion time is based on indication:

Apnea of prematurity: Neonates: Infuse dose over 15 to 30 minutes (Bhatt-Mehta 1995)

Reversible airflow obstruction, acute symptoms: Infants, Children, and Adolescents: Infuse loading dose over 30 minutes

Vesicant; ensure proper needle or catheter placement prior to and during IV infusion. Avoid extravasation. If extravasation occurs, stop infusion immediately and disconnect (leave needle/cannula in place); gently aspirate extravasated solution (do NOT flush the line); initiate hyaluronidase antidote (See Management of Drug Extravasations for more details); remove needle/cannula; apply dry cold compresses (Hurst 2004; Reynolds 2014); elevate extremity.

Vesicant/Extravasation Risk

Vesicant

Storage/Stability

Store at 20°C to 25°C (68°F to 77°F) in original carton. Protect from light. Do not use if discolored or if crystals are present.

Preparation for Administration: Pediatric

IV: May administer undiluted at 25 mg/mL (Klaus 1989) or may further dilute to a concentration of ≥1 mg/mL.

Compatibility

See Trissel’s IV Compatibility Database

Open Trissel's IV Compatibility

Medication Patient Education with HCAHPS Considerations

What is this drug used for?

• It is used to treat breathing problems.

Frequently reported side effects of this drug

• Diarrhea

• Anxiety

• Headache

• Abdominal pain

• Agitation

• Trouble sleeping

• Passing a lot of urine

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Low potassium like muscle pain or weakness, muscle cramps, or an abnormal heartbeat.

• High blood sugar like confusion, fatigue, increased thirst, increased hunger, passing a lot of urine, flushing, fast breathing, or breath that smells like fruit.

• Muscle pain

• Muscle weakness

• Fast heartbeat

• Abnormal heartbeat

• Fast breathing

• Severe dizziness

• Passing out

• Nausea

• Vomiting

• Irritability

• Confusion

• Seizures

• Tremors

• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Medication Safety Issues

Sound-alike/look-alike issues:

Contraindications

Hypersensitivity to aminophylline, theophylline, ethylenediamine, or any component of the formulation.

Canadian labeling: Additional contraindications (not in US labeling): Coronary artery disease where cardiac stimulation might prove harmful; peptic ulcer disease.

Warnings/Precautions

Concerns related to adverse effects:

• Extravasation: Vesicant; ensure proper catheter or needle position prior to and during infusion. Avoid extravasation.

• Theophylline toxicity: Severe and potentially fatal theophylline toxicity may occur if reduced theophylline clearance occurs. Theophylline clearance may be decreased in patients with acute pulmonary edema, heart failure, cor pulmonale, fever (≥102°F for ≥24 hours or lesser temperature elevations for longer periods), hepatic disease, acute hepatitis, cirrhosis, hypothyroidism, sepsis with multiorgan failure, shock, neonates (term and premature), infants <3 months of age with decreased renal function, infants <1 year, elderly >60 years, and patients following cessation of smoking. Consider benefits versus risks and the need for more intensive monitoring in these patients; reduced infusion rate required. If a patient develops signs and symptoms of theophylline toxicity (eg, nausea or persistent, repetitive vomiting), a serum theophylline level should be measured immediately and subsequent doses withheld.

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with cardiac arrhythmias (excluding bradyarrhythmias); use may exacerbate arrhythmias.

• Cystic fibrosis: Use with caution in patients with cystic fibrosis; increased theophylline clearance may occur.

• Hepatic impairment: Use with caution in patients with hepatic impairment (eg, cirrhosis, acute hepatitis, cholestasis); risk of severe and potentially fatal theophylline toxicity is increased. Theophylline clearance is decreased ≥50% in these patients. Dose reduction and frequent monitoring of serum theophylline concentrations are required.

• Hyperthyroidism: Use with caution in patients with hyperthyroidism; increased theophylline clearance may occur.

• Peptic ulcer disease: Use with caution in patients with active peptic ulcer disease; use may exacerbate peptic ulcer.

• Seizure disorder: Use with caution in patients with seizure disorders; use may exacerbate seizure disorder.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Use extreme caution in the elderly; these patients are at greater risk of serious theophylline toxicity.

• Pediatric: Select dose with caution and with frequent monitoring of concentrations (especially <1 year); rate of clearance is highly variable in these patients.

Other warnings/precautions:

• Appropriate use: Do not increase dose in response to acute exacerbation of symptoms unless steady state serum theophylline concentration is <10 mcg/mL. As the rate of theophylline clearance may be dose-dependent, an increase in dose based upon a subtherapeutic serum concentration measurement should be limited to ~25% increase of the previous infusion rate or daily dose.

Geriatric Considerations

Although there is a great intersubject variability for half-lives of methylxanthines (2-10 hours), elderly, as a group, have slower hepatic clearance. Therefore, use lower initial doses and monitor closely for response and adverse reactions. Additionally, elderly patients are at greater risk for toxicity due to concomitant disease (eg, congestive heart failure, arrhythmias), and drug use (eg, cimetidine, ciprofloxacin, etc).

Pregnancy Considerations

Aminophylline is a complex of theophylline and ethylenediamine. Theophylline crosses the placenta. Refer to Theophylline monograph for additional information.

Breast-Feeding Considerations

Aminophylline is a complex of theophylline and ethylenediamine. Theophylline is present in breast milk.

Maternal use of aminophylline is considered compatible with breastfeeding (WHO 2002). Refer to Theophylline monograph for additional information.

Briggs' Drugs in Pregnancy & Lactation

• Aminophylline

Adverse Reactions

Frequency not defined. Adverse events observed at therapeutic serum levels:

Central nervous system: Headache, insomnia, irritability, restlessness, seizure

Dermatologic: Allergic skin reaction, exfoliative dermatitis

Gastrointestinal: Diarrhea, nausea, vomiting

Genitourinary: Diuresis (transient)

Neuromuscular & skeletal: Tremor

Toxicology

• Methylxanthine Derivatives

Metabolism/Transport Effects

Substrate of CYP1A2 (major), CYP2C9 (minor), CYP2D6 (minor), CYP2E1 (minor), CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions Open Interactions

Acebrophylline: May enhance the stimulatory effect of Theophylline Derivatives. Risk X: Avoid combination

Adalimumab: May decrease the serum concentration of Theophylline Derivatives. Risk C: Monitor therapy

Adenosine: Theophylline Derivatives may diminish the therapeutic effect of Adenosine. Management: Consider alternatives to this combination if possible. Theophylline may decrease adenosine efficacy and higher adenosine doses may be required. When using adenosine for diagnostic studies, discontinue theophylline derivatives 5 half-lives prior to test. Risk D: Consider therapy modification

Alcohol (Ethyl): May increase the serum concentration of Aminophylline. Risk C: Monitor therapy

Allopurinol: May increase the serum concentration of Theophylline Derivatives. Risk C: Monitor therapy

Amifampridine: Agents With Seizure Threshold Lowering Potential may enhance the neuroexcitatory and/or seizure-potentiating effect of Amifampridine. Risk C: Monitor therapy

Antithyroid Agents: May increase the serum concentration of Theophylline Derivatives. Risk C: Monitor therapy

AtoMOXetine: May enhance the hypertensive effect of Sympathomimetics. AtoMOXetine may enhance the tachycardic effect of Sympathomimetics. Risk C: Monitor therapy

Barbiturates: May decrease the serum concentration of Theophylline Derivatives. Risk C: Monitor therapy

Benzodiazepines: Theophylline Derivatives may diminish the therapeutic effect of Benzodiazepines. Risk C: Monitor therapy

Beta-Blockers (Beta1 Selective): May diminish the bronchodilatory effect of Theophylline Derivatives. Management: Monitor for reduced theophylline efficacy during concomitant use with any beta-blocker. Beta-1 selective agents are less likely to antagonize theophylline than nonselective agents, but selectivity may be lost at higher doses. Risk C: Monitor therapy

Beta-Blockers (Nonselective): May diminish the bronchodilatory effect of Theophylline Derivatives. Risk C: Monitor therapy

Broccoli: May decrease the serum concentration of CYP1A2 Substrates (High risk with Inducers). Risk C: Monitor therapy

BuPROPion: May enhance the neuroexcitatory and/or seizure-potentiating effect of Agents With Seizure Threshold Lowering Potential. Risk C: Monitor therapy

Cambendazole: May increase the serum concentration of Theophylline Derivatives. Risk C: Monitor therapy

Cannabinoid-Containing Products: May enhance the tachycardic effect of Sympathomimetics. Exceptions: Cannabidiol. Risk C: Monitor therapy

Cannabis: May decrease the serum concentration of CYP1A2 Substrates (High risk with Inducers). Risk C: Monitor therapy

CarBAMazepine: May decrease the serum concentration of Theophylline Derivatives. Theophylline Derivatives may decrease the serum concentration of CarBAMazepine. Management: Seek alternatives to this combination when possible. If these agents are used together, monitor closely for decreased serum concentrations/therapeutic effects of both medications. Risk D: Consider therapy modification

Cocaine (Topical): May enhance the hypertensive effect of Sympathomimetics. Management: Consider alternatives to use of this combination when possible. Monitor closely for substantially increased blood pressure or heart rate and for any evidence of myocardial ischemia with concurrent use. Risk D: Consider therapy modification

CYP1A2 Inducers (Moderate): May decrease the serum concentration of Theophylline Derivatives. Risk C: Monitor therapy

CYP1A2 Inhibitors (Moderate): May increase the serum concentration of Theophylline Derivatives. Management: Consider avoidance of this combination. If coadministration is necessary, monitor for increased theophylline serum concentrations and toxicities when combined. Theophylline dose reductions will likely be required. Risk D: Consider therapy modification

CYP1A2 Inhibitors (Strong): May increase the serum concentration of Theophylline Derivatives. Management: Consider avoidance of this combination. If coadministration is necessary, consider an empiric theophylline dose reduction to one-third of the original theophylline dose. Monitor for increased theophylline serum concentrations and toxicities when combined. Risk D: Consider therapy modification

CYP1A2 Inhibitors (Weak): May increase the serum concentration of Theophylline Derivatives. Risk C: Monitor therapy

Doxofylline: Theophylline Derivatives may enhance the adverse/toxic effect of Doxofylline. Risk X: Avoid combination

Febuxostat: May increase serum concentrations of the active metabolite(s) of Theophylline Derivatives. Specifically, concentrations of 1-methylxanthine, a metabolite of unknown clinical importance, may become elevated. Risk C: Monitor therapy

Fluconazole: May increase the serum concentration of Theophylline Derivatives. Risk C: Monitor therapy

Formoterol: Theophylline Derivatives may enhance the adverse/toxic effect of Formoterol. Theophylline Derivatives may enhance the hypokalemic effect of Formoterol. Risk C: Monitor therapy

Fosphenytoin: May decrease the serum concentration of Theophylline Derivatives. Theophylline Derivatives may decrease the serum concentration of Fosphenytoin. Management: Seek alternatives when possible. If used together, monitor for decreased concentrations/effects of phenytoin or theophylline if the other agent is initiated/dose increased, or increased concentrations/effects if the other is discontinued/dose decreased. Risk D: Consider therapy modification

Guanethidine: May enhance the arrhythmogenic effect of Sympathomimetics. Guanethidine may enhance the hypertensive effect of Sympathomimetics. Risk C: Monitor therapy

Indacaterol: Theophylline Derivatives may enhance the adverse/toxic effect of Indacaterol. Theophylline Derivatives may enhance the hypokalemic effect of Indacaterol. Risk C: Monitor therapy

Iohexol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iohexol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iohexol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic anticonvulsants. Risk D: Consider therapy modification

Iomeprol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iomeprol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iomeprol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic anticonvulsants. Risk D: Consider therapy modification

Iopamidol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iopamidol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iopamidol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic anticonvulsants. Risk D: Consider therapy modification

Isoniazid: May increase the serum concentration of Theophylline Derivatives. Risk C: Monitor therapy

Isoproterenol: May decrease the serum concentration of Theophylline Derivatives. Risk C: Monitor therapy

Linezolid: May enhance the hypertensive effect of Sympathomimetics. Management: Reduce initial doses of sympathomimetic agents, and closely monitor for enhanced pressor response, in patients receiving linezolid. Specific dose adjustment recommendations are not presently available. Risk D: Consider therapy modification

Lithium: Theophylline Derivatives may decrease the serum concentration of Lithium. Risk C: Monitor therapy

Macrolide Antibiotics: May decrease the metabolism of Theophylline Derivatives. Management: Consider avoiding erythromycin and troleandomycin in patients receiving theophylline derivatives. Monitor for toxic effects of theophylline derivatives if a macrolide is initiated/dose increased. Other macrolides appear to have little to no effect. Exceptions: Azithromycin (Systemic); Fidaxomicin; Roxithromycin; Spiramycin; Telithromycin. Risk D: Consider therapy modification

Methotrexate: May increase the serum concentration of Theophylline Derivatives. Risk C: Monitor therapy

Olodaterol: Theophylline Derivatives may enhance the adverse/toxic effect of Olodaterol. Theophylline Derivatives may enhance the hypokalemic effect of Olodaterol. Risk C: Monitor therapy

Ozanimod: May enhance the hypertensive effect of Sympathomimetics. Management: Concomitant use of ozanimod with sympathomimetic agents is not recommended. If combined, monitor patients closely for the development of hypertension, including hypertensive crises. Risk D: Consider therapy modification

Pancuronium: Theophylline Derivatives may enhance the adverse/toxic effect of Pancuronium. Theophylline Derivatives may diminish the neuromuscular-blocking effect of Pancuronium. Management: Pancuronium dosage adjustment may be necessary to induce paralysis in patients receiving concomitant theophylline derivatives. Monitor closely for adverse effects (e.g., cardiac effects) with concomitant use of these agents. Risk D: Consider therapy modification

Pentoxifylline: May increase the serum concentration of Theophylline Derivatives. Risk C: Monitor therapy

Phenytoin: May decrease the serum concentration of Theophylline Derivatives. Theophylline Derivatives may decrease the serum concentration of Phenytoin. Management: Seek alternatives when possible. If used together, monitor for decreased concentrations/effects of phenytoin or theophylline if the other agent is initiated/dose increased, or increased concentrations/effects if the other is discontinued/dose decreased. Risk D: Consider therapy modification

QuiNINE: May increase the serum concentration of Theophylline Derivatives. Risk C: Monitor therapy

Quinolones: May increase the serum concentration of Theophylline Derivatives. Exceptions: Ciprofloxacin (Systemic); Delafloxacin; Gemifloxacin; LevoFLOXacin (Oral Inhalation); LevoFLOXacin (Systemic); Lomefloxacin; Moxifloxacin (Systemic); Nalidixic Acid; Pefloxacin; Pipemidic Acid; Sparfloxacin; Zabofloxacin. Risk C: Monitor therapy

Regadenoson: Aminophylline may diminish the vasodilatory effect of Regadenoson. Management: Avoid using aminophylline or other methylxanthines (eg, caffeine) for at least 12 hours prior the the administration of regadenoson. Risk D: Consider therapy modification

Riociguat: Theophylline Derivatives may enhance the hypotensive effect of Riociguat. Risk X: Avoid combination

Ritonavir: May decrease the serum concentration of Theophylline Derivatives. Risk C: Monitor therapy

Solriamfetol: Sympathomimetics may enhance the hypertensive effect of Solriamfetol. Sympathomimetics may enhance the tachycardic effect of Solriamfetol. Risk C: Monitor therapy

Sulfinpyrazone: May decrease the serum concentration of Theophylline Derivatives. Risk C: Monitor therapy

Sympathomimetics: May enhance the adverse/toxic effect of other Sympathomimetics. Risk C: Monitor therapy

Tedizolid: May enhance the hypertensive effect of Sympathomimetics. Tedizolid may enhance the tachycardic effect of Sympathomimetics. Risk C: Monitor therapy

Thiopental: Aminophylline may diminish the therapeutic effect of Thiopental. Risk C: Monitor therapy

Thyroid Products: May increase the metabolism of Theophylline Derivatives. Risk C: Monitor therapy

Tobacco (Smoked): May decrease the serum concentration of Theophylline Derivatives. Risk C: Monitor therapy

Verapamil: May increase the serum concentration of Theophylline Derivatives. Risk C: Monitor therapy

Zafirlukast: Theophylline Derivatives may decrease the serum concentration of Zafirlukast. Zafirlukast may increase the serum concentration of Theophylline Derivatives. Risk C: Monitor therapy

Food Interactions

Ethanol: Ethanol may decrease theophylline clearance. Management: Monitor theophylline concentrations, particularly when alcohol consumption patterns change.

Food: Theophylline clearance is increased and half-life decreased by low carbohydrate/high protein diets, parenteral nutrition, and daily consumption of charcoal-broiled beef; a high carbohydrate/low protein diet can decrease the clearance and prolong the half-life of theophylline. Management: Avoid extremes of dietary protein and carbohydrate intake.

Test Interactions

Plasma glucose, uric acid, free fatty acids, total cholesterol, HDL, HDL/LDL ratio, and urinary free cortisol excretion may be increased by theophylline. Theophylline may decrease triiodothyronine.

Genes of Interest

• Cytochrome P450 1A2

Monitoring Parameters

Heart rate; CNS effects (insomnia, irritability); respiratory rate (COPD patients often have resting controlled respiratory rates in low 20s); arterial or capillary blood gases (if applicable)

Theophylline levels: Serum theophylline levels should be monitored after initiation of therapy and prior to making dose increases; in the presence of signs or symptoms of toxicity; or when a new illness, worsening of a present illness, or change in patient’s treatment regimen that may alter theophylline clearance (eg, fever >102°F or sustained for 24 hours or more, hepatitis, or drugs that are added or discontinued); changes in fluid balance; electrolyte concentrations, acid-base balance during prolonged therapy.

Loading dose: Measure serum concentrations 30 minutes after the end of an IV loading dose in patients who have not received theophylline in the previous 24 hours to determine the need for an additional loading (serum concentration <10 mcg/mL) or to delay starting the constant IV infusion (serum concentration >20 mcg/mL).

Infusion: Measure serum concentrations one half-life (eg, ~4 hours in children 1 to 9 years of age or 8 hours in nonsmoking, otherwise healthy adults) after starting a continuous infusion, then every 12 to 24 hours for duration of infusion; measure more frequently in acutely ill patients.

Monitor infusion site.

Reference Range

Therapeutic levels:

Children: 5 to 15 mcg/mL

Adults: 10 to 20 mcg/mL

Toxic concentration: >20 mcg/mL

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution, Intravenous, as dihydrate:

Generic: 25 mg/mL (10 mL, 20 mL [DSC])

Solution, Intravenous, as dihydrate [preservative free]:

Generic: 25 mg/mL (10 mL, 20 mL)

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution, Injection:

Generic: 50 mg/mL (10 mL)

Solution, Intravenous, as dihydrate:

Generic: 25 mg/mL (10 mL, 20 mL)

Tablet, Oral, as dihydrate:

Generic: 100 mg [DSC]

Anatomic Therapeutic Chemical (ATC) Classification

• R03DA05

Generic Available (US)

Yes

Pricing: US

Solution (Aminophylline Intravenous)

25 mg/mL (per mL): $1.49

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Mechanism of Action

Theophylline has two distinct actions; smooth muscle relaxation (ie, bronchodilation) and suppression of the response of the airways to stimuli (ie, non-bronchodilator prophylactic effects). Bronchodilation is mediated by inhibition of two isoenzymes, phosphodiesterase (PDE III and, to a lesser extent, PDE IV) while non-bronchodilation effects are mediated through other molecular mechanisms. Theophylline increases the force of contraction of diaphragmatic muscles through enhancement of calcium uptake through adenosine-mediated channels.

Pharmacodynamics/Kinetics

Theophylline:

Distribution: Theophylline: ~0.45 L/kg based on ideal body weight; distributes poorly into body fat; Vd may increase in premature neonates, hepatic cirrhosis, acidemia (uncorrected), elderly, and third trimester of pregnancy.

Protein binding: Theophylline: ~40%, primarily to albumin; decreased in neonates (due to a greater percentage of fetal albumin), hepatic cirrhosis, acidemia (uncorrected), elderly, third trimester of pregnancy.

Metabolism: Theophylline: Hepatic via demethylation (CYP 1A2) and hydroxylation (CYP 2E1 and 3A4); forms active metabolites (caffeine and 3-methylxanthine)

Half-life elimination: Theophylline: Highly variable and dependent upon age, hepatic function, cardiac function, lung disease, and smoking history

Premature infants, postnatal age 3 to 15 days: 30 hours (range: 17 to 43 hours)

Premature infants, postnatal age 25 to 57 days: 20 hours (range: 9.4 to 30.6 hours)

Term infants, postnatal age 1 to 2 days: 25.7 hours (range: 25 to 26.5 hours)

Term infants, postnatal age 3 to 30 weeks: 11 hours (range: 6 to 29 hours)

Children 1 to 4 years: 3.4 hours (range: 1.2 to 5.6 hours)

Children and Adolescents 6 to 17 years: 3.7 hours (range: 1.5 to 5.9 hours)

Adults ≥18 years to ≤60 years (asthma, nonsmoking, otherwise healthy): 8.7 hours (range: 6.1 to 12.8 hours)

Elderly >60 years (nonsmoking, healthy): 9.8 hours (range: 1.6 to 18 hours)

Clearance: Certain conditions may significantly alter theophylline clearance; severe and potentially fatal theophylline toxicity may occur if reduced theophylline clearance occurs.

Decreased theophylline clearance: Neonates and infants; elderly >60 years; acute pulmonary edema, cor pulmonale; fever (≥102°F for ≥24 hours or lesser temperature elevations for longer periods); heart failure; hepatic impairment (eg, cirrhosis, acute hepatitis, cholestasis); hypothyroidism; patients following cessation of smoking; sepsis with multiple organ failure; shock; third trimester of pregnancy.

Increased theophylline clearance: Hyperthyroidism; cystic fibrosis; smoking (ie, marijuana or tobacco).

Time to peak, serum: Within 30 minutes

Excretion: Theophylline: Urine (~50% as unchanged drug [Neonates]; ~10% as unchanged drug [Infants >3 months, Adolescents, and Adults])

Pharmacodynamics/Kinetics: Additional Considerations

Renal function impairment: Clearance is decreased in infants <3 months with decreased renal function.

Hepatic function impairment: Clearance is decreased by ≥50% in patients with hepatic impairment (eg, cirrhosis, acute hepatitis, cholestasis).

Pediatric: Clearance is very low in neonates and reaches max values by 1 year of age, remains relatively constant until about 9 years of age, and then slowly decreases by approximately 50% to adult values at about 16 years of age. Renal excretion of unchanged theophylline in neonates amounts to about 50% of the dose, compared to about 10% in children older than three months and in adults.

Geriatric: Clearance is decreased by an average of 30% in patients >60 years.

Gender: Significant reduction in theophylline clearance has been reported in women on the 20th day of the menstrual cycle and during the third trimester of pregnancy.

Smoking: Clearance is increased by smoking (ie, marijuana or tobacco) by ~50% in young adult and ~80% in elderly tobacco smokers. Cessation of smoking for 1 week causes a reduction in theophylline clearance by ~40%.

Local Anesthetic/Vasoconstrictor Precautions

No information available to require special precautions

Effects on Dental Treatment

Prescribe erythromycin products with caution to patients taking theophylline products. Erythromycin will delay the normal metabolic inactivation of theophyllines leading to increased blood levels; this has resulted in nausea, vomiting, and CNS restlessness.

Effects on Bleeding

No information available to require special precautions

Related Information

• Management of Drug Extravasations
• Narrow Therapeutic Index Drugs

Pharmacotherapy Pearls

Aminophylline is a 2:1 complex of theophylline and ethylenediamine.

Index Terms

Theophylline Ethylenediamine

FDA Approval Date

November 26, 1975

References

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Last Updated 4/21/20