Theophylline

Pronunciation

(thee OFF i lin)


U.S. Brand Names

Elixophyllin®; Quibron®-T; Quibron®-T/SR; Theo-24®; Theochron®; Theolair™; Theolair-SR® [DSC]; T-Phyl®; Uniphyl®



Synonyms

Theophylline Anhydrous



Generic Available

Yes: Elixir, extended release tablet, infusion, oral solution



Canadian Brand Names

Apo-Theo LA®; Novo-Theophyl SR; PMS-Theophylline; Pulmophylline; Quibron®-T/SR; ratio-Theo-Bronc; Theochron® SR; Theo-Dur®; Theolair™; Uniphyl® SRT



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")



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

If a patient develops signs and symptoms of theophylline toxicity (eg, persistent, repetitive vomiting), a serum theophylline level should be measured and subsequent doses held. Due to potential saturation of theophylline clearance at serum levels in or (in some patients) less than the therapeutic range, dosage adjustment should be made in small increments (maximum: 25%). Due to wider interpatient variability, theophylline serum level measurements must be used to optimize therapy and prevent serious toxicity. Use with caution in patients with peptic ulcer, hyperthyroidism, seizure disorders, hypertension, and patients with cardiac arrhythmias (excluding bradyarrhythmias).



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

Overdosage/Toxicology

Symptoms of overdose include nausea, vomiting, insomnia, irritability, tachycardia, seizures, tonic-clonic seizures, insomnia, and circulatory failure. If seizures have not occurred, induce vomiting; ipecac syrup is preferred. Do not induce emesis in the presence of impaired consciousness. Repeated doses of charcoal have been shown to be effective in enhancing the total body clearance of theophylline. Do not repeat charcoal doses if an ileus is present. Charcoal hemoperfusion may be considered if serum theophylline levels exceed 40 mcg/mL, the patient is unable to tolerate repeat oral charcoal administrations, or if severe toxic symptoms are present. Clearance with hemoperfusion is better than clearance from hemodialysis. Administer a cathartic, especially if sustained release agents were used. Phenobarbital administered prophylactically may prevent seizures.



Drug Interactions

of CYP1A2 (major), 2C8/9 (minor), 2D6 (minor), 2E1 (major), 3A4 (major); CYP1A2 (weak)

SubstrateInhibits

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 amiodarone, 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, ciprofloxacin, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, 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. maintenance dosages are based upon continuous infusions

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 &nbsp;
Children 6 mo - 1 y 0.6-0.7 mg/kg/h &nbsp;
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.

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.

Oral theophylline:

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.

Dosage should be adjusted according to serum level measurements during the first 12- to 24-hour period. See table

Oral theophylline:

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.

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

Increasing dose:

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.

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 crush. Extended release capsule forms may be opened and the contents sprinkled on soft foods; do chew beads.

notnot

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. Inform prescriber if you are or intend to become pregnant.

Pregnancy precaution:

Nursing Implications

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



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. Aminophylline can be used to treat patients who have adverse hemodynamic responses to adenosine or dipyridamole, when used during cardiovascular stress testing.



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



Dosage Forms

[DSC] = Discontinued product

Capsule, extended release (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]

Infusion [premixed in D5W]: 0.8 mg/mL (500 mL, 1000 mL); 1.6 mg/mL (250 mL, 500 mL); 2 mg/mL (100 mL); 3.2 mg/mL (250 mL); 4 mg/mL (50 mL, 100 mL)

Solution, oral: 80 mg/15 mL (15 mL, 18.75 mL, 500 mL) [dye free, sugar free; contains alcohol 0.4% and benzoic acid; orange flavor]

Tablet, controlled release:

T-Phyl®: 200 mg [12 hours; contains cetostearyl alcohol]

Uniphyl®: 400 mg, 600 mg [24 hours; contains cetostearyl alcohol]

Tablet, extended release: 100 mg, 200 mg, 300 mg, 450 mg

Theochron®: 100 mg, 200 mg, 300 mg [12-24 hours]

Tablet, immediate release:

Quibron®-T: 300 mg

Theolair™: 125 mg, 250 mg

Tablet, sustained release (Quibron®-T/SR): 300 mg [8-12 hours]

Tablet, timed release (Theolair™-SR [DSC]): 300 mg, 500 mg

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

Aerobin® (DE); Aerobin® [inj.] (DE); Aerobin Mite® (TH); Aerodyne® (AT); Aerodyne retard® (AT); Afonilum® (CZ, DE, PL); Afonilum SR® (PL, RO); afpred forte-Theo® (DE); Almarion® (TH); Aminofilin® (AR); Aminofilin Forte® (AR); Aminomal Elisir® (IT); Apo-Theo LA® (CA, SG); Asmafilina® (EC); Asmanyl® (BD); Asmasolon® (TH); Asthma-T® (IL); Austyn® (AU); Bronchoparat® (DE); Bronchophylin® (ID); Bronchoretard® (DE); Bronkolin® (TR); Bronsolvan® (ID); Contiphyllin® (DE); Crisasma® (AR); Cronasma® (DE); Diffumal® (IT); Dilatrane® (FR); Ditenate® (DE); Drilyna® (AR); Drilyna forte® (AR); Duraphyllin® (DE); Durofilin® (RU, YU); Egifilin® (HU); Elixifilin® (ES); Elixine® (CL); Elixofilina® (DO); Eufilina® (PT); Euphyllina® (IT); Euphyllin® (BE, CH, CZ, PL); Euphylline L.A.® (FR); Euphyllin Quick® (RO); Euphyllin Retard® (AT, EG, FI, ID, JO, KW, LB, PL, ZA); Euphyllin retard N® (CH); Euphylong® (DE, EG, HU, JO, KW, LB, RU, SE, YU); Franol® (TH); Frivent® (IT); Glyphyllin® (IL); G-Theophylline® (BD); Histafilin® (ES); Jasonphylin® (BD); Kalbron® (ID); Lasma® (IE); Liopect® (AR); Med-Phylline® (TH); Nefoben® (AR); Novo-Theophyl SR (CA); Nuelin® (CR, DK, DO, FI, GB, GT, HK, HN, NO, NZ, PA, SG, SV, TH); Nuelin SA® (GB, IE); Paidomal® (IT); Pediaphyllin PL® (BE, LU); Pharphylline® (HK); Phylobid® (IN, ZA); Phyloday® (IN); Pirasmin® (TR); PMS-Theophylline (CA); Pneumogéine® (MC); Pro-Vent® (IE); Pulmeno® (ES); Pulmidur® (AT); PulmiDur® (DE); Pulmophylline (CA); Pulmo-Timelets® (DE, DK); Quibron® (ID); Quibron®-T/SR (CA); Ramaphyllin® (IL); ratio-Theo-Bronc (CA); Respicur® (AT, IT); Retafyllin® (FI, HU, SG, TH); Retafyl® (RU); Retaphy SRl® (ID); Sedacris® (AR); Sinasmal® (AR); Slo-Bid® (HK, MX); Slo-Phyllin® (GB, IE); Sodip-phylline Aquasol® (CH); Solosin® (DE); Solucao de Teofilina Bermácia® (BR); Spophyllin® [compr.] (CZ, RU, SK); Spophyllin® (CZ); Spophyllin® [liqu.oral] (CZ); Talotren® (TR); Tédralan® (MC); Tefamin Elisir® (IT); Temaco® (TH); Teobid® (CO, GT, PA, SV); Teoficol® (BE); Teofilina Bermacia® (BR); Teofilina Biocrom® (AR); Teofilina® (BR); Teofilina Ecar® (CO); Teofilina Fabra® (AR); Teofilina Genfar® (EC); Teofilina Lafedar® (AR); Teofilina Northia® (AR); Teofilina Northia® [compr.] (AR); Teofilina Ratiopharm® (ES); Teofilinar® (CO); Teofilina Retard® (RO); Teokap® (TR); Teolin® (HR, SI); Teolixir® (CO, ES); Teolong® (BR, CR, DO, GT, HN, MX, PA, SV); Teosona® (AR); Teotard® (CZ, HR, PL, RO, SI); Teovent® (PT); Terizol® (AR); Teromol® (ES); Thenglate® (BD); Theo-2® (BE, LU); Theo-24® (IT); Theobilong® (AT); Theobron® (ID); Theo-Caps® (PL); Theochron® SR (CA); Theo-Dur® (AR, AU, BE, CA, CZ, DK, ES, FI, GB, HK, IE, IT, LU, NO, NZ, PL, SE); Theofol® (FI); Theofylamin "Medic"® (DK); Theojap® (BD); Theolair® (BE); Theolair™ (CA); Theolair® (CH, DE, ES, IT, LU, NL); Theolin® (JO, NL, RO, SG); Theolong® (JP); Theo Max® (ES); Theomol® (DE); Theonate® (BD); Theo Pa® (IN); Theophtard® (HU); Theophyllin AL® (DE); Theophyllin AZU® (DE); Theophylline Bruneau® (LU); Theophylline® (IL); Theophyllin Heumann® (DE); Theophyllin Ratiopharm® (DE, LU); Theophyllin Sandoz® (DE); Theophyllin Stada® (DE); Theophyllinum® (PL); Theophyllinum prolongatum® (PL); Theoplus® (AT, CR, CZ, DO, ES, GT, HN, PA, PL, SV, ZA); Theospirex® (AT); Theospirex® [caps./compr.] (AT, HU); Theospirex retard® (PL); Theo-SR® (RO); Théostat® (FR); Theostat® (LU, RU); Theotard® (IL, RU); Theotrim® (IL, TH); Theovent® (HK, PL); theo von ct® [caps.] (DE); theo von ct® [inj.] (DE); Tromphyllin® (DE); Unicontin® (BD, IN); Uni-Dur® (HR); Unidur® (ID); Uni-Dur® Ltec (RO); Uni-Dur® (MX, PL, RO); Unifyl® (AT); Unifyl Continus® (CH); Unilair® (DE); Unilong® (ES); Uniphyl® (HK); Uniphyllin Continus® (GB, IE); Uniphyllin® (DE, IE); Uniphyl® SRT (CA); UniXan® (DK); Uno-Lin® (DK); Vent retard® (ES); Xanthium® (BE, FR, LU, SG, TH, TR); Zepholin® (IE)



Review Date: 1969-12-31 Reviewed By: Keywords: ,
Adam Data Copyright The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition. A licensed medical professional should be consulted for diagnosis and treatment of any and all medical conditions. Call 911 for all medical emergencies. Links to other sites are provided for information only--they do not constitute endorsements of those other sites. © 1997- 2010 A.D.A.M., Inc. Any duplication or distribution of the information contained herein is strictly prohibited.

For information 410.787.4000

© 2013 UM Baltimore Washington Medical Center.  All rights reserved.

301 Hospital Drive, Glen Burnie, MD 21061 | 410-787-4000 | TTY 410-787-4498