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Theophylline

Pronunciation

Pronunciation

(thee OFF i lin)

Index Terms

  • Theo-Dur
  • Theobid Duracaps
  • TheoCap
  • Theophylline Anhydrous
  • Uniphyl

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule Extended Release 24 Hour, Oral:

Theo-24: 100 mg

Theo-24: 200 mg [contains fd&c yellow #10 (quinoline yellow)]

Theo-24: 300 mg [contains brilliant blue fcf (fd&c blue #1), fd&c red #40]

Theo-24: 400 mg [contains fd&c red #40]

Elixir, Oral:

Elixophyllin: 80 mg/15 mL (473 mL) [contains fd&c red #40, saccharin sodium; mixed fruit flavor]

Solution, Intravenous:

Generic: 400 mg (250 mL, 500 mL); 800 mg (500 mL)

Solution, Oral:

Generic: 80 mg/15 mL (473 mL)

Tablet Extended Release 12 Hour, Oral:

Theochron: 100 mg, 200 mg, 300 mg [scored]

Generic: 100 mg, 200 mg, 300 mg, 450 mg

Tablet Extended Release 24 Hour, Oral:

Generic: 400 mg, 600 mg

Brand Names: U.S.

  • Elixophyllin
  • Theo-24
  • Theochron

Pharmacologic Category

  • Phosphodiesterase Enzyme Inhibitor, Nonselective

Pharmacology

Causes bronchodilatation, diuresis, CNS and cardiac stimulation, and gastric acid secretion by blocking phosphodiesterase which increases tissue concentrations of cyclic adenine monophosphate (cAMP) which in turn promotes catecholamine stimulation of lipolysis, glycogenolysis, and gluconeogenesis and induces release of epinephrine from adrenal medulla cells

Absorption

Oral: Rapid and complete with up to 100% absorption depending upon the formulation used

Distribution

0.45 L/kg (range: 0.3 to 0.7 L/kg) based on ideal body weight; distributes poorly into body fat; Vd may increase in premature neonates, patients with hepatic cirrhosis, acidemia (uncorrected), the elderly

Metabolism

Hepatic via demethylation (CYP 1A2) and hydroxylation (CYP 2E1 and 3A4); theophylline is metabolized to active metabolites, caffeine and 3-methylxanthine; in neonates this theophylline-derived caffeine accumulates due to decreased hepatic metabolism and significant concentrations of caffeine may occur; a substantial decrease in serum caffeine concentrations occurs after 40 weeks postmenstrual age

Excretion

Urine:

Neonates: 50% as unchanged theophylline

Children >3 months and Adults: ~10% as unchanged theophylline

Clearance: Note: Maturation of clearance in premature infants and term infants is most closely related to postconceptional age (PCA); adult clearance values are reached at approximately 55 weeks PCA and higher pediatric values at approximately 60 weeks PCA (Kraus1993).

Premature infants, postnatal age 3 to 15 days: 0.29 mL/kg/minute

Premature infants, postnatal age 25 to 27 days: 0.64 mL/kg/minute

Children 1 to 4 years: 1.7 mL/kg/minute

Children 4 to 12 years: 1.6 mL/kg/minute

Children 13 to 15 years: 0.9 mL/kg/minute

Children 16 to 17 years: 1.4 mL/kg/minute

Adults ≥18 years to ≤ 60 years (nonsmoking, asthmatic): 0.65 mL/kg/minute

Adults >60 years (nonsmoking, healthy): 0.41mL/kg/minute

Acute pulmonary edema: 0.33 mL/kg/minute

Cystic fibrosis (14 to 28 years): 1.25 mL/kg/minute

Acute hepatitis: 0.35 mL/kg/minute

Cholestasis: 0.65 mL/kg/minute

Cirrhosis: 0.31 mL/kg/minute

Sepsis with multiorgan failure: 0.46 mL/kg/minute

Hypothyroid: 0.38 mL/kg/minute

Hyperthyroid: 0.8 mL/kg/minute

Onset of Action

IV: <30 minutes

Time to Peak

Serum: Oral: Liquid: 1 hour

Half-Life Elimination

Highly variable and age, liver and cardiac function, lung disease, and smoking history dependent (Hendeles 1995):

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 hours

Term infants, postnatal age 3 to 30 weeks: 11 hours

Children 1 to 4 years: 3.4 hours

Children 16 to 17 years: 3.7 hours (range: 1.5 to 5.9 hours)

Adults ≥18 years to ≤ 60 years (nonsmoking, asthmatic): 8.2 hours

Adults >60 years (nonsmoking, healthy): 9.8 hours

Acute pulmonary edema: 19 hours

Cystic fibrosis (14 to 28 years): 6 hours

Acute hepatitis: 19.2 hours

Cholestasis: 14.4 hours

Cirrhosis: 32 hours

Sepsis with multiorgan failure: 18.8 hours

Hypothyroid: 11.6 hours

Hyperthyroid: 4.5 hours

Protein Binding

40%, primarily to albumin; decreased protein binding in neonates (due to a greater percentage of fetal albumin), hepatic cirrhosis, uncorrected acidemia, third trimester of pregnancy, and geriatric patients

Special Populations: Renal Function Impairment

No dosage adjustment is required for adults or children older than 3 mo of age with renal function impairment. In neonates with reduced renal function, dose reduction and frequent monitoring of serum concentrations is required.

Special Populations: Hepatic Function Impairment

Cl is decreased at least 50% in patients with hepatic impairment.

Special Populations: Gender

Pharmacokinetic differences between men and women are small and not expected to be clinically important.

Special Populations Note

Smoking

Theophylline Cl is increased by smoking (ie, marijuana or tobacco)by approximately 50% in young adult smokers and 80% in elderly tobacco smokers. Cessation of smoking for 1 wk improves theophylline Cl by 40%.

Use: Labeled Indications

Treatment of symptoms and reversible airway obstruction due to chronic asthma, or other chronic lung diseases

Guideline recommendations:

Asthma: The 2015 Global Initiative for Asthma Guidelines (GINA) and the 2007 National Heart, Lung and Blood Institute Asthma Guidelines do not recommend oral theophylline as a long-term control medication for asthma in children ≤5 years of age. Additionally, GINA guidelines do not recommend oral theophylline for asthma in children 6 to 11 years of age. Oral theophylline is a potential alternative option (not preferred) in adolescents and adults as a long-term control medication in mild asthma or as an add-on long-term control medication in moderate to severe asthma; however, a stepwise approach using inhaled corticosteroids (+/- inhaled long-acting beta agonists depending on asthma severity) is preferred to theophylline due to efficacy concerns and potential for adverse events (GINA 2015). Both guidelines recommend against theophylline for the treatment of asthma exacerbations due to poor efficacy and safety concerns (GINA 2015; NAEPP 2007).

COPD: The Global Initiative for Chronic Obstructive Lung Disease Guidelines (2013) suggest that while higher doses of slow release formulations of theophylline have been proven to be effective for use in COPD, it is not a preferred agent due to its potential for toxicity.

Contraindications

Hypersensitivity to theophylline or any component of the formulation; premixed injection may contain corn-derived dextrose and its use is contraindicated in patients with allergy to corn-related products

Dosing: Adult

Doses should be individualized based on steady-state serum concentrations and ideal body weight.

Acute symptoms: Manufacturer's labeling:

Loading dose: Oral, IV:

Asthma exacerbations: The treatment of asthma exacerbations with theophylline is not supported or recommended by current clinical practice guidelines (GINA 2015; NAEPP 2007).

COPD treatment: Theophylline is currently considered second-line intravenous therapy in the emergency department or hospital setting when there is inadequate or insufficient response to short acting bronchodilators (Global Initiative for COPD Guidelines 2013).

If no theophylline received within the previous 24 hours: 4.6 mg/kg loading dose (~5.8 mg/kg hydrous aminophylline) IV or 5 mg/kg orally. Loading dose intended to achieve a serum level of approximately 10 mcg/mL; loading doses should be given intravenously (preferred) or with a rapidly absorbed oral product (not an extended-release product). Note: On the average, for every 1 mg/kg theophylline given, blood levels will rise 2 mcg/mL.

If theophylline has been administered in the previous 24 hours: A loading dose is not recommended without obtaining a serum theophylline concentration. The loading dose should be calculated as follows:

Dose = (desired serum theophylline concentration - measured serum theophylline concentration) (Vd)

Acute symptoms: Manufacturer's labeling:

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

Adults 16-60 years (otherwise healthy, nonsmokers): 0.4 mg/kg/hour; maximum: 900 mg/day unless serum levels indicate need for larger dose

Adults >60 years: 0.3 mg/kg/hour; maximum: 400 mg/day unless serum levels indicate need for larger dose

Treatment of chronic conditions: With newer guidelines suggesting lower therapeutic theophylline ranges, it is unlikely that doses larger than >10 mg/kg/day will be required in children ≥1 year of age.

Oral solution: Initial dose: 300 mg/day administered in divided doses every 6-8 hours; Maintenance: 400-600 mg/day (maximum: 600 mg/day)

Oral extended release formulations: Initial dose: 300-400 mg once daily; Maintenance: 400-600 mg once daily (maximum: 600 mg/day)

Dosage adjustment after serum theophylline measurement: Asthma: Within normal limits: Adults: 5-15 mcg/mL: Maintain dosage if tolerated. Recheck serum theophylline concentration at 24-hour intervals (for acute IV dosing) or at 6- to 12-month intervals (for oral dosing). Finer adjustments in dosage may be needed for some patients. If levels ≥15 mcg/mL, consider 10% dose reduction to improve safety margin.

Note: Recheck serum theophylline levels after 3 days when using oral dosing, or after 12 hours (children) or 24 hours (adults) when dosing intravenously. Patients maintained with oral therapy may be reassessed at 6- to 12-month intervals.

Dosing: Geriatric

Acute symptoms: Adults >60 years:

Loading dose: Oral, IV: Refer to adult dosing.

Maintenance dose: IV: 0.3 mg/kg/hour; maximum 400 mg/day unless serum levels indicate need for larger dose

Chronic conditions: Oral: Adults >60 years: Do not exceed a dose of 400 mg/day

Cardiac decompensation, cor pulmonale, hepatic dysfunction, sepsis with multiorgan failure, shock: Refer to adult dosing.

Dosing: Pediatric

Doses should be individualized based on steady-state serum concentrations and ideal body weight.

Acute symptoms: Manufacturer's labeling:

Loading dose: Oral, IV:

Asthma exacerbations: The treatment of asthma exacerbations with theophylline is not supported or recommended by current clinical practice guidelines (GINA 2015; NAEPP 2007).

If no theophylline received within the previous 24 hours: 4.6 mg/kg loading dose (~5.8 mg/kg hydrous aminophylline) IV or 5 mg/kg orally. Loading dose intended to achieve a serum level of approximately 10 mcg/mL; loading doses should be given intravenously (preferred) or with a rapidly absorbed oral product (not an extended-release product). Note: On the average, for every 1 mg/kg theophylline given, blood levels will rise 2 mcg/mL.

If theophylline has been administered in the previous 24 hours: A loading dose is not recommended without obtaining a serum theophylline concentration. The loading dose should be calculated as follows:

Dose = (desired serum theophylline concentration - measured serum theophylline concentration) (Vd)

Acute symptoms: Manufacturer's labeling:

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

Infants 6-52 weeks: mg/kg/hour = (0.008) (age in weeks) + 0.21

Children 1-9 years: 0.8 mg/kg/hour

Children 9-12 years: 0.7 mg/kg/hour

Adolescents 12-16 years (cigarette or marijuana smokers): 0.7 mg/kg/hour

Adolescents 12-16 years (nonsmokers): 0.5 mg/kg/hour; maximum: 900 mg/day unless serum levels indicate need for larger dose

Treatment of chronic conditions: With newer guidelines suggesting lower therapeutic theophylline ranges, it is unlikely that doses larger than >10 mg/kg/day will be required in children ≥1 year of age.

Oral solution:

Infants <1 year: Note: Doses should be adjusted to maintain the peak steady state serum concentrations. The time to reach steady state will vary based on age and the presence of risk factors which may affect theophylline clearance.

Full-term Infants and Infants <26 weeks: Total daily dose (mg)= [(0.2 x age in weeks) +5] x (weight in kg); divide dose into 3 equal amounts and administer at 8-hour intervals

Full-term Infants and Infants ≥26 weeks and <52 weeks: Total daily dose (mg) = [(0.2 x age in weeks) +5] x (weight in kg); divide dose into 4 equal amounts and administer at 6-hour intervals

Children ≥1 year and <45 kg: Initial dose: 10-14 mg/kg/day (maximum: 300 mg/day) administered in divided doses every 4-6 hours; Maintenance: Up to 20 mg/kg/day (maximum: 600 mg/day)

Children >45 kg: Refer to adult dosing.

Oral extended release formulations:

Children ≥1 year and <45 kg: Initial: 10-14 mg/kg once daily (maximum: 300 mg/day); Maintenance up to 20 mg/kg/day (maximum: 600 mg/day)

Children >45 kg: Refer to adult dosing.

Dosage adjustment after serum theophylline measurement: Asthma: Within normal limits: Children: 5-10 mcg/mL: Maintain dosage if tolerated. Recheck serum theophylline concentration at 24-hour intervals (for acute IV dosing) or at 6- to 12-month intervals (for oral dosing). Finer adjustments in dosage may be needed for some patients. If levels ≥15 mcg/mL, consider 10% dose reduction to improve safety margin.

Note: Recheck serum theophylline levels after 3 days when using oral dosing, or after 12 hours (children) or 24 hours (adults) when dosing intravenously. Patients maintained with oral therapy may be reassessed at 6- to 12-month intervals.

Dosing: Renal Impairment

Oral: IV:

Infants 1 to 3 months: Consider dose reduction and frequent monitoring of serum theophylline concentrations.

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

Dosing: Hepatic Impairment

Oral: Infants, Children, Adolescents, and Adults: No dosage adjustment provided in manufacturer’s labeling. However, dose reduction and frequent monitoring of serum theophylline concentration are required in patients with decreased hepatic function (eg, cirrhosis, acute hepatitis, cholestasis). Maximum dose: 400 mg daily

IV: Infants, Children, Adolescents, and Adults: Initial: 0.2 mg/kg/hour; maximum daily dose: 400 mg daily unless serum concentrations indicate need for larger dose. Use with caution and monitor serum theophylline concentrations frequently.

Dosing: Obesity

Use ideal body weight for obese patients.

Extemporaneously Prepared

Note: An alcohol-containing commercial oral solution is available (80 mg/15mL).

A 5 mg/mL oral suspension may be made with tablets. Crush one 300 mg extended release tablet in a mortar and reduce to a fine powder. Add small portions of a 1:1 mixture of Ora-Sweet® and Ora-Plus® and mix to a uniform paste; mix while adding the vehicle in equal proportions to almost 60 mL; transfer to a calibrated bottle, rinse mortar with vehicle, and add sufficient quantity of vehicle to make 60 mL. Label "shake well". Stable for 90 days at room temperature.

Johnson CE, VanDeKoppel S, and Myers E, "Stability of Anhydrous Theophylline in Extemporaneously Prepared Alcohol-Free Oral Suspensions," Am J Health-Syst Pharm, 2005, 62(23):2518-20.16303910

Administration

IV: Administer loading dose over 30 minutes; follow with a continuous infusion as appropriate

Oral: Long-acting preparations should be taken with a full glass of water, swallowed whole, or cut in half if scored. Do not crush. Extended release capsule forms may be opened and the contents sprinkled on soft foods; do not chew beads.

Dietary Considerations

Should be taken with water 1 hour before or 2 hours after meals. Premixed injection may contain corn-derived dextrose and its use is contraindicated in patients with allergy to corn-related products.

Compatibility

Stable in D5W.

Y-site administration: Incompatible with cefepime, hetastarch in NS, phenytoin.

Compatibility in syringe: Incompatible with ceftriaxone.

Storage

Tablet, premixed infusion, solution: Store at controlled room temperature of 25°C (77°F).

Drug Interactions

Abiraterone Acetate: May increase the serum concentration of CYP1A2 Substrates. Monitor therapy

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

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

Adenosine: Theophylline Derivatives may diminish the therapeutic effect of Adenosine. Consider therapy modification

Alcohol (Ethyl): May increase the serum concentration of Theophylline. Monitor therapy

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

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

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

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

Benzodiazepines: Theophylline Derivatives may diminish the therapeutic effect of Benzodiazepines. Consider therapy modification

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. Monitor therapy

Beta-Blockers (Nonselective): May diminish the bronchodilatory effect of Theophylline Derivatives. Consider therapy modification

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

Cannabis: May decrease the serum concentration of CYP1A2 Substrates. 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. Consider therapy modification

Cimetidine: May decrease the metabolism of Theophylline Derivatives. Consider therapy modification

CYP1A2 Inducers (Strong): May increase the metabolism of CYP1A2 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP1A2 Inhibitors (Moderate): May decrease the metabolism of CYP1A2 Substrates. Monitor therapy

CYP1A2 Inhibitors (Strong): May decrease the metabolism of CYP1A2 Substrates. Consider therapy modification

Cyproterone: May decrease the serum concentration of CYP1A2 Substrates. Monitor therapy

Deferasirox: May increase the serum concentration of Theophylline. Avoid combination

Disulfiram: May increase the serum concentration of Theophylline Derivatives. Monitor therapy

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

Estrogen Derivatives: May increase the serum concentration of Theophylline Derivatives. Monitor therapy

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. Monitor therapy

FluvoxaMINE: May decrease the metabolism of Theophylline Derivatives. Consider therapy modification

Formoterol: Theophylline Derivatives may enhance the adverse/toxic effect of Formoterol. Theophylline Derivatives may enhance the hypokalemic effect of Formoterol. 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. Consider therapy modification

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

Interferons: May decrease the metabolism of Theophylline Derivatives. Monitor therapy

Iobenguane I 123: Sympathomimetics may diminish the therapeutic effect of Iobenguane I 123. Avoid combination

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

Isoproterenol: May decrease the serum concentration of Theophylline Derivatives. 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. Consider therapy modification

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

Macrolide Antibiotics: May decrease the metabolism of Theophylline Derivatives. Exceptions: Azithromycin (Systemic); Fidaxomicin; Roxithromycin; Spiramycin; Telithromycin. Consider therapy modification

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

Metreleptin: May decrease the serum concentration of Theophylline. Metreleptin may increase the serum concentration of Theophylline. Monitor therapy

Mexiletine: May decrease the metabolism of Theophylline Derivatives. Consider therapy modification

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

Osimertinib: May decrease the serum concentration of CYP1A2 Substrates. Monitor therapy

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. Consider therapy modification

Peginterferon Alfa-2b: May increase the serum concentration of CYP1A2 Substrates. Monitor therapy

Pentoxifylline: May increase the serum concentration of Theophylline Derivatives. 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. Consider therapy modification

Propafenone: May increase the serum concentration of Theophylline Derivatives. Monitor therapy

Protease Inhibitors: May decrease the serum concentration of Theophylline Derivatives. Exceptions: Fosamprenavir. Monitor therapy

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

Quinolone Antibiotics: May decrease the metabolism of Theophylline Derivatives. Ciprofloxacin and enoxacin are of greatest concern. Theophylline/quinolone therapy might augment the seizure-producing potential of each of the individual agents. Exceptions: Gemifloxacin; Levofloxacin (Systemic); Lomefloxacin; Moxifloxacin (Systemic); Nalidixic Acid; Sparfloxacin. Consider therapy modification

Regadenoson: Theophylline may diminish the vasodilatory effect of Regadenoson. Consider therapy modification

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

Stiripentol: May increase the serum concentration of Theophylline. Avoid combination

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

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

Teriflunomide: May decrease the serum concentration of CYP1A2 Substrates. Monitor therapy

Thiabendazole: May decrease the metabolism of Theophylline Derivatives. Consider therapy modification

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

Ticlopidine: May decrease the metabolism of Theophylline Derivatives. Monitor therapy

TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use cannot be avoided, initiate tizanidine at an adult dose of 2 mg and increase in 2-4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Consider therapy modification

Vemurafenib: May increase the serum concentration of CYP1A2 Substrates. Management: Consider alternatives to such combinations whenever possible, particularly if the CYP1A2 substrate has a relatively narrow therapeutic index. Consider therapy modification

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

Zileuton: May increase the serum concentration of Theophylline. Management: Reduce theophylline dose by 50% upon initiation of zileuton therapy. If theophylline is added to existing zileuton therapy, use a lower starting dose. Monitor for increased serum concentrations and effects of theophylline. Consider therapy modification

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.

Adverse Reactions

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

Cardiovascular: Flutter, tachycardia

Central nervous system: Headache, hyperactivity (children), insomnia, restlessness, seizures, status epilepticus (nonconvulsive)

Endocrine & metabolic: Hypercalcemia (with concomitant hyperthyroid disease)

Gastrointestinal: Nausea, reflux or ulcer aggravation, vomiting

Genitourinary: Difficulty urinating (elderly males with prostatism)

Neuromuscular & skeletal: Tremor

Renal: Diuresis (transient)

Warnings/Precautions

Concerns related to adverse effects:

• Central nervous system: Theophylline-induced nonconvulsive status epilepticus has been reported (rarely) and should be considered in patients who develop CNS abnormalities.

• Theophylline toxicity: If a patient develops signs and symptoms of theophylline toxicity (eg, persistent, repetitive vomiting), a serum level should be measured and subsequent doses held. Theophylline clearance may be decreased in patients with acute pulmonary edema, congestive heart failure, cor pulmonale, fever, hepatic disease, acute hepatitis, cirrhosis, hypothyroidism, sepsis with multiorgan failure, and shock; clearance may also be decreased in neonates, infants <3 months of age with decreased renal function, infants <1 year of age, the elderly >60 years of age, and patients following cessation of smoking. Note: Elderly >75 years of age have a 16-fold greater risk of death from theophylline overdose than do 25-year-olds due to reduced clearance in the elderly patient.

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with tachyarrhythmias (eg, sinus tachycardia, atrial fibrillation) since use may exacerbate these arrhythmias.

• Hyperthyroidism: Use with caution in patients with hyperthyroidism; use may exacerbate this condition.

• Peptic ulcer disease: Use with caution in patient with peptic ulcer disease; use may exacerbate this condition.

• Seizure disorder: Use with caution in patients with a history of seizure disorder; use may exacerbate this condition.

Dosage form specific issues:

• Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP, 1997; Zar 2007).

Other warnings/precautions:

• Monitoring: Frequent continued monitoring of serum theophylline after therapeutic levels have been achieved may not be required as long as there is no apparent risk of decreased theophylline metabolism due to concurrent drug therapies or disease states. Monitoring serum theophylline concentrations at yearly intervals should be adequate in such cases.

Monitoring Parameters

Monitor 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 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 medication changes occur that may change theophylline clearance

IV loading dose: Measure serum concentrations 30 minutes after the end of an IV loading dose

IV infusion: Measure serum concentrations one half-life after starting a continuous infusion, then every 12-24 hours

Pregnancy Risk Factor

C

Pregnancy Considerations

Teratogenic effects were observed in animal reproduction studies. Theophylline crosses the placenta; adverse effects may be seen in the newborn. Use is generally safe when used at the recommended doses (serum concentrations 5-12 mcg/mL) however maternal adverse events may be increased and efficacy may be decreased in pregnant women. Theophylline metabolism may change during pregnancy; the half-life is similar to that observed in otherwise healthy, nonsmoking adults with asthma during the first and second trimesters (~8.7 hours), but may increase to 13 hours (range: 8-18 hours) during the third trimester. The volume of distribution is also increased during the third trimester. Monitor serum levels. The recommendations for the use of theophylline in pregnant women with asthma are similar to those used in nonpregnant adults (National Heart, Lung, and Blood Institute Guidelines 2004).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience akathisia or polyuria. Have patient report immediately to prescriber tachycardia, arrhythmia, severe dizziness, syncope, considerable anxiety, significant nausea, intolerable diarrhea, severe headache, illogical thinking, insomnia, tremors, or decreased peak/flow measurement (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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