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Medication Safety Issues
Sound-alike/look-alike issues:
Theolair™ may be confused with Thiola®, Thyrolar®
Pronunciation
(thee OFF i lin)
U.S. Brand Names
Index Terms
Generic Available
Yes: Extended release capsule and tablet, infusion
Canadian Brand Names
Pharmacologic Category
Use
Treatment of symptoms and reversible airway obstruction due to chronic asthma, chronic bronchitis, or COPD
Pregnancy Risk Factor
C
Pregnancy Implications
Theophylline crosses the placenta; adverse effects may be seen in the newborn. Theophylline metabolism may change during pregnancy; monitor serum levels.
Lactation
Enters breast milk/compatible (AAP rates “compatible”)
Breast-Feeding Considerations
Irritability may be observed in the nursing infant.
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
Warnings/Precautions
Concerns related to adverse effects:
• 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.
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.
• Peptic ulcer disease: Use with caution in patient with peptic ulcer disease.
• Seizure disorder: Use with caution in patients with a history of seizure disorder.
Other warnings/precautions:
• Dosage adjustments: Due to potential saturation of theophylline clearance at serum levels within (or in some patients less than) the therapeutic range, dosage adjustment should be made in small increments (maximum: 25% reduction).
• Monitoring: Due to wide interpatient variability, theophylline serum level measurements must be used to optimize therapy and prevent serious toxicity.
Adverse Reactions
Adverse reactions/theophylline serum level: (Adverse effects do not necessarily occur according to serum levels. Arrhythmia and seizure can occur without seeing the other adverse effects).
15-25 mcg/mL: GI upset, diarrhea, nausea/vomiting, abdominal pain, nervousness, headache, insomnia, agitation, dizziness, muscle cramp, tremor
25-35 mcg/mL: Tachycardia, occasional PVC
>35 mcg/mL: Ventricular tachycardia, frequent PVC, seizure
Uncommon at serum theophylline concentrations ?20 mcg/mL:
1% to 10%:
Cardiovascular: Tachycardia
Central nervous system: Nervousness, restlessness
Gastrointestinal: Nausea, vomiting
<1% (Limited to important or life-threatening): Insomnia, irritability, seizure, tremor
Drug Interactions
Substrate of CYP1A2 (major), 2C9 (minor), 2D6 (minor), 2E1 (major), 3A4 (major); Inhibits CYP1A2 (weak)
CYP1A2 inducers: May decrease the levels/effects of theophylline. Example inducers include aminoglutethimide, carbamazepine, phenobarbital, and rifampin.
CYP1A2 inhibitors: May increase the levels/effects of theophylline. Example inhibitors include ciprofloxacin, fluvoxamine, ketoconazole, norfloxacin, ofloxacin, and rofecoxib.
CYP2E1 inhibitors: May increase the levels/effects of theophylline. Example inhibitors include disulfiram, isoniazid, and miconazole.
CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of theophylline. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins.
CYP3A4 inhibitors: May increase the levels/effects of theophylline. Example inhibitors include azole antifungals, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, telithromycin, and verapamil.
Ethanol/Nutrition/Herb Interactions
Food: Food does not appreciably affect the absorption of liquid, fast-release products, and most sustained release products; however, food may induce a sudden release (dose-dumping) of once-daily sustained release products resulting in an increase in serum drug levels and potential toxicity. Avoid excessive amounts of caffeine. Avoid extremes of dietary protein and carbohydrate intake. Changes in diet may affect the elimination of theophylline; charbroiled foods may increase elimination, reducing half-life by 50%.
Compatibility
Stable in D5W.
Y-site administration: Compatible: Acyclovir, ampicillin, ampicillin/sulbactam, aztreonam, cefazolin, cefotetan, ceftazidime, ceftriaxone, cimetidine, cisatracurium, clindamycin, dexamethasone sodium phosphate, diltiazem, dobutamine, dopamine, doxycycline, erythromycin lactobionate, famotidine, fluconazole, gatifloxacin, gentamicin, haloperidol, heparin, hydrocortisone sodium succinate, lidocaine, linezolid, methyldopate, methylprednisolone sodium succinate, metronidazole, midazolam, milrinone, nafcillin, nitroglycerin, penicillin G potassium, piperacillin, potassium chloride, ranitidine, remifentanil, sodium nitroprusside, ticarcillin, ticarcillin/clavulanate potassium, tobramycin, vancomycin. Incompatible: Hetastarch, phenytoin.
Compatibility when admixed: Compatible: Cefepime, chlorpromazine, deslanoside, fluconazole, furosemide, hydrocortisone hemisuccinate, lidocaine, methylprednisolone sodium succinate, papaverine, verapamil. Incompatible: Ascorbic acid injection, ceftriaxone, cimetidine.
Mechanism of Action
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
Pharmacodynamics/Kinetics
Absorption: Oral: Dosage form dependent
Distribution: 0.45 L/kg based on ideal body weight
Metabolism: Children >1 year and Adults: Hepatic; involves CYP1A2, 2E1 and 3A4; forms active metabolites (caffeine and 3-methylxanthine)
Half-life elimination: Highly variable and dependent upon age, liver function, cardiac function, lung disease, and smoking history
Time to peak, serum:
Oral: Liquid: 1 hour; Tablet, enteric-coated: 5 hours; Tablet, uncoated: 2 hours
I.V.: Within 30 minutes
Excretion: Urine
Neonates: 50% unchanged
Children >3 months and Adults: 10% unchanged
Dosage
Use ideal body weight for obese patients
I.V.: Initial: Maintenance infusion rates:
Children:
6 weeks to 6 months: 0.5 mg/kg/hour
6 months to 1 year: 0.6-0.7 mg/kg/hour
Children >1 year and Adults:
Acute bronchospasm: See table.
Approximate I.V. Theophylline Dosage for Treatment of Acute Bronchospasm
Group
Dosage for Next 12 h1
Dosage After 12 h1
Infants 6 wk - 6 mo
0.5 mg/kg/h
Children 6 mo - 1 y
0.6-0.7 mg/kg/h
Children 1-9 y
0.95 mg/kg/h
(1.2 mg/kg/h)
0.79 mg/kg/h
(1 mg/kg/h)
Children 9-16 y and young adult smokers
0.79 mg/kg/h
(1 mg/kg/h)
0.63 mg/kg/h
(0.8 mg/kg/h)
Healthy, nonsmoking adults
0.55 mg/kg/h
(0.7 mg/kg/h)
0.39 mg/kg/h
(0.5 mg/kg/h)
Older patients and patients with cor pulmonale
0.47 mg/kg/h
(0.6 mg/kg/h)
0.24 mg/kg/h
(0.3 mg/kg/h)
Patients with congestive heart failure or liver failure
0.39 mg/kg/h
(0.5 mg/kg/h)
0.08-0.16 mg/kg/h
(0.1-0.2 mg/kg/h)
1Equivalent hydrous aminophylline dosage indicated in parentheses.
Table has been converted to the following text.
Approximate I.V. Theophylline Dosage for Treatment of Acute Bronchospasm
Note: Equivalent hydrous aminophylline dosage is indicated in parentheses.
Infants 6 weeks to 6 months:
• 0.5 mg/kg/hour for next 12 hours
Children 6 months to 1 year:
• 0.6-0.7 mg/kg/hour for next 12 hours
Children 1-9 years:
• 0.95 mg/kg/hour (1.2 mg/kg/hour) for next 12 hours; 0.79 mg/kg/hour (1 mg/kg/hour) after 12 hours
Children 9-16 years and young adult smokers:
• 0.79 mg/kg/hour (1 mg/kg/hour) for next 12 hours; 0.63 mg/kg/hour (0.8 mg/kg/hour) after 12 hours
Healthy, nonsmoking adults:
• 0.55 mg/kg/hour (0.7 mg/kg/hour) for next 12 hours; 0.39 mg/kg/hour (0.5 mg/kg/hour) after 12 hours
Older patients and patients with cor pulmonale:
• 0.47 mg/kg/hour (0.6 mg/kg/hour) for next 12 hours; 0.24 mg/kg/hour (0.3 mg/kg/hour) after 12 hours
Patients with congestive heart failure or liver failure:
• 0.39 mg/kg/hour (0.5 mg/kg/hour) for next 12 hours; 0.08-0.16 mg/kg/hour (0.1-0.2 mg/kg/hour) after 12 hours
Approximate I.V. maintenance dosages are based upon continuous infusions; bolus dosing (often used in children <6 months of age) may be determined by multiplying the hourly infusion rate by 24 hours and dividing by the desired number of doses/day. See the following:
Maintenance dose for acute symptoms: See table.
Maintenance Dose for Acute Symptoms
Population Group
Oral Theophylline
(mg/kg/day)
I.V. Aminophylline
Premature infant or newborn - 6 wk (for apnea/bradycardia)
4
5 mg/kg/day
6 wk - 6 mo
10
12 mg/kg/day or continuous I.V. infusion1
Infants 6 mo - 1 y
12-18
15 mg/kg/day or continuous I.V. infusion1
Children 1-9 y
20-24
1 mg/kg/h
Children 9-12 y, and adolescent daily smokers of cigarettes or marijuana, and otherwise healthy adult smokers <50 y
16
0.9 mg/kg/h
Adolescents 12-16 y (nonsmokers)
13
0.7 mg/kg/h
Otherwise healthy nonsmoking adults (including elderly patients)
10
(not to exceed 900 mg/day)
0.5 mg/kg/h
Cardiac decompensation, cor pulmonale, and/or liver dysfunction
5
(not to exceed 400 mg/day)
0.25 mg/kg/h
1For continuous I.V. infusion divide total daily dose by 24 = mg/kg/h.
Table has been converted to the following text.
Maintenance Dose for Acute Symptoms
Premature infant or newborn to 6 weeks (for apnea/bradycardia):
• Oral theophylline: 4 mg/kg/day
• I.V. aminophylline: 5 mg/kg/day
6 weeks to 6 months:
• Oral theophylline: 10 mg/kg/day
• I.V. aminophylline: 12 mg/kg/day or continuous I.V. infusion1
Infants 6 months to 1 year:
• Oral theophylline: 12-18 mg/kg/day
• I.V. aminophylline: 15 mg/kg/day or continuous I.V. infusion1
Children 1-9 years:
• Oral theophylline: 20-24 mg/kg/day
• I.V. aminophylline: 1 mg/kg/hour
Children 9-12 years, and adolescent daily smokers of cigarettes or marijuana, and otherwise healthy adult smokers <50 years:
• Oral theophylline: 16 mg/kg/day
• I.V. aminophylline: 0.9 mg/kg/hour
Adolescents 12-16 years (nonsmokers):
• Oral theophylline: 13 mg/kg/day
• I.V. aminophylline: 0.7 mg/kg/hour
Otherwise healthy nonsmoking adults (including elderly patients):
• Oral theophylline: 10 mg/kg/day (not to exceed 900 mg/day)
• I.V. aminophylline: 0.5 mg/kg/hour
Cardiac decompensation, cor pulmonale, and/or liver dysfunction:
• Oral theophylline: 5 mg/kg/day (not to exceed 400 mg/day)
• I.V. aminophylline: 0.25 mg/kg/hour
1For continuous I.V. infusion, divide total daily dose by 24 = mg/kg/hour.
Dosage should be adjusted according to serum level measurements during the first 12- to 24-hour period. See table
Dosage Adjustment After Serum Theophylline Measurement
Serum Theophylline
Guidelines
Within normal limits
10-20 mcg/mL
Maintain dosage if tolerated. Recheck serum theophylline concentration at 6- to 12-month intervals.1
Too high
20-25 mcg/mL
Decrease doses by about 10%. Recheck serum theophylline concentration after 3 days and then at 6- to 12-month intervals.1
25-30 mcg/mL
Skip next dose and decrease subsequent doses by about 25%. Recheck serum theophylline.
>30 mcg/mL
Skip next 2 doses and decrease subsequent doses by 50%. Recheck serum theophylline.
Too low
7.5-10 mcg/mL
Increase dose by about 25%.2 Recheck serum theophylline concentration after 3 days and then at 6- to 12-month intervals.1
5-7.5 mcg/mL
Increase dose by about 25% to the nearest dose increment2 and recheck serum theophylline for guidance in further dosage adjustment (another increase will probably be needed, but this provides a safety check).
1Finer adjustments in dosage may be needed for some patients.
2Dividing the daily dose into 3 doses administered at 8-hour intervals may be indicated if symptoms occur repeatedly at the end of a dosing interval.
From Weinberger M and Hendeles L, “Practical Guide to Using Theophylline,” J Resp Dis, 1981,2:12-27.
Table has been converted to the following text.
Dose Adjustment After Serum Theophylline Measurement
Theophylline level within normal limits:
• 10-20 mcg/mL: Maintain dosage if tolerated. Recheck serum theophylline concentration at 6- to 12-month intervals.1
Theophylline level too high:
• 20-25 mcg/mL: Decrease doses by about 10%. Recheck serum theophylline concentration after 3 days and then at 6- to 12-month intervals.1
• 25-30 mcg/mL: Skip next dose and decrease subsequent doses by about 25%. Recheck serum theophylline.
• >30 mcg/mL: Skip next two doses and decrease subsequent doses by 50%. Recheck serum theophylline.
Theophylline level too low:
• 7.5-10 mcg/mL: Increase dose by about 25%.2 Recheck serum theophylline concentration after 3 days and then at 6- to 12-month intervals.1
• 5-7.5 mcg/mL: Increase dose by about 25% to the nearest dose increment2 and recheck serum theophylline for guidance in further dosage adjustment (another increase will probably be needed, but this provides a safety check).
1Finer adjustments in dosage may be needed for some patients.
2Dividing the daily dose into 3 doses administered at 8-hour intervals may be indicated if symptoms occur repeatedly at the end of a dosing interval.
From Weinberger M. and Hendeles L., “Practical Guide to Using Theophylline,” J Resp Dis,1981, 2:12-27.)
Oral theophylline: Initial dosage recommendation: Loading dose (to achieve a serum level of about 10 mcg/mL; loading doses should be given using a rapidly absorbed oral product not a sustained release product):
If no theophylline has been administered in the previous 24 hours: 4-6 mg/kg theophylline
If theophylline has been administered in the previous 24 hours: administer 1/2 loading dose or 2-3 mg/kg theophylline can be given in emergencies when serum levels are not available
On the average, for every 1 mg/kg theophylline given, blood levels will rise 2 mcg/mL
Ideally, defer the loading dose if a serum theophylline concentration can be obtained rapidly. However, if this is not possible, exercise clinical judgment. If the patient is not experiencing theophylline toxicity, this is unlikely to result in dangerous adverse effects.
Oral theophylline dosage for bronchial asthma (by age): See table
Oral Theophylline Dosage for Bronchial Asthma1
Age
(y)
Initial 3 Days
Second 3 Days
Steady-State Maintenance
<1
0.2 x (age in weeks) + 5
0.3 x (age in weeks) + 8
1-9
16 up to a maximum of 400 mg/24 h
20
22
9-12
16 up to a maximum of 400 mg/24 h
16 up to a maximum of 600 mg/24 h
20 up to a maximum of 800 mg/24 h
12-16
16 up to a maximum of 400 mg/24 h
16 up to a maximum of 600 mg/24 h
18 up to a maximum of 900 mg/24 h
Adults
400 mg/24 h
600 mg/24 h
900 mg/24 h
1Dose in mg/kg/24 hours of theophylline.
Table has been converted to the following text.
Oral Theophylline Dosage for Bronchial Asthma
<1 year:
• Initial 3 days and second 3 days: 0.2 x (age in weeks) + 5 = mg/kg/24 hours of theophylline
• Steady-state maintenance: 0.3 x (age in weeks) + 8 = mg/kg/24 hours of theophylline
1-9 years:
• Initial 3 days: 16 mg/kg/24 hours of theophylline, up to a maximum of 400 mg/24 hours
• Second 3 days: 20 mg/kg/24 hours of theophylline
• Steady-state maintenance: 22 mg/kg/24 hours of theophylline
9-12 years:
• Initial 3 days: 16 mg/kg/24 hours of theophylline, up to a maximum of 400 mg/24 hours
• Second 3 days: 16 mg/kg/24 hours of theophylline, up to a maximum of 600 mg/24 hours
• Steady-state maintenance: 20 mg/kg/24 hours of theophylline, up to a maximum of 800 mg/24 hours
12-16 years:
• Initial 3 days: 16 mg/kg/24 hours of theophylline, up to a maximum of 400 mg/24 hours
• Second 3 days: 16 mg/kg/24 hours of theophylline, up to a maximum of 600 mg/24 hours
• Steady-state maintenance: 18 mg/kg/24 hours of theophylline, up to a maximum of 900 mg/24 hours
Adults:
• Initial 3 days: 400 mg/24 hours
• Second 3 days: 600 mg/24 hours
• Steady-state maintenance: 900 mg/24 hours
Increasing dose: The dosage may be increased in approximately 25% increments at 2- to 3-day intervals so long as the drug is tolerated or until the maximum dose is reached
Maintenance dose: In children and healthy adults, a slow-release product can be used; the total daily dose can be divided every 8-12 hours
Administration: 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.
Administration: I.V. Detail
pH: 4.3
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.
Patient Education
Take exactly as directed; do not exceed recommended dosage. Avoid smoking (smoking may interfere with drug absorption as well as exacerbate condition for which medication is prescribed). If you are smoking when dosage is prescribed; inform prescriber if you stop smoking (dosage may need to be adjusted to prevent toxicity). Preferable to take on empty stomach, 1 hour before or 2 hours after meals, with a full glass of water. Do not chew of crush sustained release forms; capsules may be opened and contents sprinkled on soft food (do not chew beads). Avoid dietary stimulants (eg, caffeine, tea, colas, or chocolate; may increase adverse side effects). Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. You may experience nausea, vomiting, or lose of appetite (small frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help). Report acute insomnia or restlessness, chest pain or rapid heartbeat, emotional lability or agitation, muscle tremors or cramping, acute headache, abdominal pain and cramping, blackened stool, or worsening of respiratory condition. Pregnancy precaution: Inform prescriber if you are or intend to become pregnant.
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 are at greater risk for toxicity due to concomitant disease (eg, CHF, arrhythmias), and drug use (eg, cimetidine, ciprofloxacin).
Additional Information
Theophylline salt / theophylline content (percent)
Theophylline anhydrous (eg, most oral solids): 100% theophylline
Theophylline monohydrate (eg, oral solutions): 91% theophylline
Aminophylline (theophylline) (eg, injection): 80% (79% to 86%) theophylline
Oxtriphylline (choline theophylline) (eg, Choledyl®): 64% theophylline
Cardiovascular Considerations
Theophylline results in significant tachycardia and, at higher doses, may impair ventricular rate control in patients with atrial fibrillation. This is particularly a concern since patients with underlying chronic obstructive lung disease often have coexisting atrial fibrillation. A theophylline derivative can be used to treat patients who have adverse hemodynamic responses to adenosine or dipyridamole during cardiovascular stress testing. Theophylline has been used for neurocardiogenic (vasovagal) syncope.
Dental Health: 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. Azithromycin does not cause these effects in combination with theophylline products.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May cause nervousness and restlessness; may rarely cause insomnia and irritability
Mental Health: Effects on Psychiatric Treatment
Barbiturates and carbamazepine may decrease serum levels while disulfiram, propranolol, and fluvoxamine may increase theophylline levels
Nursing: Physical Assessment/Monitoring
Assess effectiveness and interactions of other medications patient may be taking. Monitor effectiveness of therapy (respiratory rate, lung sounds, characteristics of cough and sputum) and adverse reactions at beginning of therapy and periodically with long-term use. For inpatient care, monitor vital signs and lung sounds prior to and periodically during therapy. Assess knowledge/teach patient appropriate use, interventions to reduce side effects, and adverse symptoms to report.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Capsule, extended release: 100 mg; 125 mg [DSC]; 200 mg; 300 mg
TheoCap™: 125 mg, 200 mg; 300 mg [DSC] [12 hour]
Theo-24®: 100 mg, 200 mg, 300 mg, 400 mg [24 hours]
Elixir:
Elixophyllin®: 80 mg/15 mL (480 mL) [contains alcohol 20%; fruit flavor] [DSC]
Infusion [premixed in D5W]: 200 mg (50 mL, 100 mL); 400 mg (100 mL [DSC]; 250 mL, 500 mL); 800 mg (250 mL, 500 mL, 1000 mL)
Tablet, controlled release:
Uniphyl®: 400 mg, 600 mg [24 hours; contains cetostearyl alcohol]
Tablet, extended release: 100 mg, 200 mg, 300 mg, 400 mg, 450 mg, 600 mg
Theochron®: 100 mg, 200 mg, 300 mg, 450 mg [12-24 hours]
Pricing: U.S. (www.drugstore.com)
Capsule, 12-hour (Theophylline CR)
125 mg (60): $43.57
200 mg (60): $29.99
300 mg (60): $49.99
Capsule, 24-hour (Theo-24)
100 mg (60): $34.97
200 mg (60): $55.99
300 mg (60): $69.95
400 mg (60): $89.99
Elixir (Elixophyllin)
80 mg/15 mL (480): $97.01
Tablet, 12-hour (Theophylline CR)
100 mg (60): $17.99
200 mg (60): $23.74
300 mg (60): $18.99
450 mg (60): $41.99
Tablet, 24-hour (Uniphyl)
400 mg (60): $80.99
600 mg (60): $114.80
References
“American Academy of Pediatrics Committee on Drugs. The Transfer of Drugs and Other Chemicals Into Human Milk,” Pediatrics, 2001, 108(3):776-89.
Mokhlesi B, Leikin JB, Murray P, et al, “Adult Toxicology in Critical Care: Part II: Specific Poisonings,” Chest, 2003, 123(3):897-922.
International Brand Names
Lexi-Comp.com
Last full review/revision May 2008
Content last modified May 2008
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