Aminophylline

Pronunciation

(am in OFF i lin)

Synonyms

Theophylline Ethylenediamine

Generic Available

Yes

Canadian Brand Names

Phyllocontin®; Phyllocontin®-350

Use

Bronchodilator in reversible airway obstruction due to asthma or COPD; increase diaphragmatic contractility

Pregnancy Risk Factor

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, ethylenediamine, or any component of the formulation

Warnings/Precautions

If a patient develops signs and symptoms of theophylline toxicity, a serum level should be measured and subsequent doses held. 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). Due to wide interpatient variability, theophylline serum level measurements must be used to optimize therapy and prevent serious toxicity. Use caution with peptic ulcer, hyperthyroidism, seizure disorder, hypertension, or tachyarrhythmias.

Adverse Reactions

Uncommon at serum theophylline concentrations 15 mcg/mL

1% to 10%:

Cardiovascular: Tachycardia

Central nervous system: Nervousness, restlessness

Gastrointestinal: Nausea, vomiting

<1%: Insomnia, irritability, seizure, skin rash, gastric irritation, tremor, allergic reactions

Drug Interactions

Substrate of CYP1A2 (major), 2E1 (minor), 3A4 (minor)

CYP1A2 inducers: May decrease the levels/effects of aminophylline. Example inducers include aminoglutethimide, carbamazepine, phenobarbital, and rifampin.

CYP1A2 inhibitors: May increase the levels/effects of aminophylline. Example inhibitors include amiodarone, ciprofloxacin, fluvoxamine, ketoconazole, norfloxacin, ofloxacin, and rofecoxib.

Ethanol/Nutrition/Herb Interactions

Food: Food does not appreciably affect absorption. Avoid extremes of dietary protein and carbohydrate intake. Changes in diet may affect the elimination of theophylline; charcoal-broiled foods may increase elimination, reducing half-life by 50%.

Stability

Do not use solutions if discolored or if crystals are present

Compatibility

Stable in dextran 6% in D5W, dextran 6% in NS, D5LR, D5NS, D5¹ /2NS, D5¹ /4NS, D5W, D10W, D20W, LR, ¹ /2NS, NS; variable stability (consult detailed reference) in fat emulsion 10%

Y-site administration: Compatible: Allopurinol, amifostine, amphotericin B cholesteryl sulfate complex, aztreonam, ceftazidime, cimetidine, cladribine, docetaxel, doxorubicin liposome, enalaprilat, esmolol, etoposide, famotidine, filgrastim, fluconazole, fludarabine, foscarnet, gatifloxacin, gemcitabine, granisetron, heparin with hydrocortisone sodium succinate, inamrinone, labetalol, levofloxacin, linezolid, melphalan, meropenem, morphine, paclitaxel, pancuronium, piperacillin/tazobactam, potassium chloride, propofol, ranitidine, remifentanil, sargramostim, tacrolimus, teniposide, thiotepa, tolazoline, vecuronium, vitamin B complex with C. Incompatible: Amiodarone, ciprofloxacin, clarithromycin, dobutamine, hydralazine, ondansetron, vinorelbine, warfarin. Variable (consult detailed reference): Cisatracurium, diltiazem

Compatibility in syringe: Compatible: Heparin, metoclopramide, pentobarbital, thiopental. Incompatible: Doxapram

Compatibility when admixed: Compatible: Amobarbital, bretylium, calcium gluconate, chloramphenicol, cimetidine, dexamethasone, diphenhydramine, dopamine, erythromycin lactobionate, esmolol, floxacillin, flumazenil, furosemide, heparin, hydrocortisone sodium succinate, lidocaine, mephentermine, meropenem, methyldopate, metronidazole with sodium bicarbonate, nitroglycerin, pentobarbital, phenobarbital, potassium chloride, ranitidine, sodium bicarbonate, terbutaline. Incompatible: Atracurium, bleomycin, cefepime, ceftazidime, ceftriaxone, chlorpromazine, ciprofloxacin, clindamycin, dobutamine, doxorubicin, epinephrine, hydralazine, hydrocortisone sodium succinate with cephalothin sodium, hydroxyzine, insulin (regular), isoproterenol, levorphanol, meperidine, morphine, norepinephrine, papaverine with trimecaine, penicillin G potassium, pentazocine, prochlorperazine edisylate, prochlorperazine mesylate, promazine, promethazine, vitamin B complex with C. Variable (consult detailed reference): Amikacin, ascorbic acid, corticotropin, dimenhydrinate, methylprednisolone sodium succinate, nafcillin, procaine, vancomycin, verapamil, zinc

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

Theophylline:

Absorption: Oral: Dosage form dependent

Distribution: 0.45 L/kg based on ideal body weight

Protein binding: 40%, primarily to albumin

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: Immediate release: 1-2 hours

I.V.: Within 30 minutes

Excretion: Urine Children >3 months and Adults: 10% unchanged

Dosage

Treatment of acute bronchospasm: I.V.:

Loading dose (in patients not currently receiving aminophylline or theophylline): 6 mg/kg (based on aminophylline) administered I.V. over 20-30 minutes; administration rate should not exceed 25 mg/minute (aminophylline)

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

6 weeks to 6 months: 0.5 mg/kg/hour

6 months to 1 year: 0.6-0.7 mg/kg/hour

1-9 years: 1 mg/kg/hour

9-16 years and smokers: 0.8 mg/kg/hour

Adults, nonsmoking: 0.5 mg/kg/hour

Older patients and patients with cor pulmonale: 0.3 mg/kg/hour

Patients with congestive heart failure: 0.1-0.2 mg/kg/hour

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

Bronchodilator: Oral: Children 45 kg and Adults: Initial: 380 mg/day (equivalent to theophylline 300 mg/day) in divided doses every 6-8 hours; may increase dose after 3 days; maximum dose: 928 mg/day (equivalent to theophylline 800 mg/day)

Administration

Dilute with I.V. fluid to a concentration of 1 mg/mL and infuse over 20-30 minutes; maximum concentration: 25 mg/mL; maximum rate of infusion: 0.36 mg/kg/minute, and no greater than 25 mg/minute. I.M. administration is not recommended. Oral and I.V. should be administered around-the-clock rather than 4 times/day, 3 times/day, etc (ie, 12-6-12-6, not 9-1-5-9) to promote less variation in peak and trough serum levels.

Patient Education

Do not drink or eat large quantities of caffeine-containing beverages or food (colas, coffee, chocolate).

Nursing Implications

Encourage patient to drink adequate fluids (2 L/day) to decrease mucous viscosity in airways; monitor vital signs, I & O, serum concentrations, and CNS effects (insomnia, irritability)

Additional Information

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

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.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

May cause nervousness or restlessness

Mental Health: Effects on Psychiatric Treatment

Carbamazepine and barbiturates may decrease aminophylline levels; disulfiram and propranolol may increase aminophylline levels

Dosage Forms

[DSC] = Discontinued product

Injection, solution: 25 mg/mL (10 mL, 20 mL)

Liquid, oral [DSC]: 105 mg/5 mL (500 mL) [apricot flavor]

Tablet: 100 mg, 200 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.

Cummins LH, et al, "Erythromycin's Effect on Theophylline Blood Levels. Correspondence," Pediatrics , 1977, 59:144-5.

Delaforge M and Sartori E, "In Vivo Effects of Erythromycin, Oleandomycin, and Erythralosamine Derivatives on Hepatic Cytochrome P450," Biochem Pharmacol , 1990, 40(2):223-8.

Ludden TM, "Pharmacokinetic Interactions of the Macrolide Antibiotics," Clin Pharmacokinet , 1985, 10(1):63-79.

International Brand Names

Afonilum® [inj.] (DE); Aminocardol® (TR); Aminocont® (FI); Aminofilina® (AR, BR, CL, PL); Aminofilina Ariston® (EC); Aminofilina Biocrom® (AR); Aminofilina Bioquim® (AR); Aminofilina Czopki pediatryczne® (PL); Aminofilina Fabra® (AR); Aminofilina Inyectable® (CL); Aminofilina L.CH.® (CL); Aminofilina Northia® (AR); Aminofilina Rigo® (AR); Aminofilina (RO); Aminofilin® (RO, YU); Aminofillina Fisiopharma® (IT); Aminofillina® (IT); Aminoima® (BR); Aminomal® (BD, IT, RO); Aminophyllin® (DE, HR, NO, ZA); Aminophylline Atlantic® (SG, TH); Aminophylline® (AU, BD, GB, IL, NZ, RO, RU); Aminophylline DBL® (SG); Aminophyllinum® (CZ, HU, PL, RO, SI, YU); Aminophyllinum Retard® (PL, RO); Aminoslow® (LU); Amnivent® (GB); Amofilin® (RO); Asmafilin® (TR); Cardiomin® (CL); Cardirenal® (AR); Cardophyllin® (BD); Caréna® (TR); Carine® (AU); Clonofillin SR® (HU); Diaphyllin® (HU, RO); Diaphyllin Venosum® (HU); Drafilyn® (MX); Elixophyllin® (IL); Eufilina® (ES, RO); Eufilin® (BR); Euphyllin® (CZ, EG, HK, JO, KW, LB, LU, NL, RU); Fadafilina® (AR); Larjanfilina® (AR); Min-I-Jet Aminophylline® (GB); Miofilin® (RO); Mundiphyllin® (AT); N-Aminofilina® (RO); Neophyllin® (JP); Norphyllin® (GB); Novphyllin® (BG); Peterphyllin Injection® (ZA); Pharophyllin® (CZ); Phyllocontin®-350 (CA); Phyllocontin® (CA, IE, ZA); Phyllocontin Continus® (GB, ID, IE); Phyllotemp® (CH, DE); Q-Med Theophyllin® (ZA); Retafilin® (HR); Syntophyllin® (CZ); Tefamin® (IT); Teofyllamin Ipex® (SE); Theofylline FNA® (NL); Theophyllamin Jenapharm® (DE); Theophyllin EDA-ratiopharm® (DE)

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