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Aminophylline

Pronunciation
( Theophylline Ethylenediamine )

Pronunciation: AM-i-NOF-i-lin
Class: Xanthine derivative

Trade Names

Aminophylline
- Injection 250 mg (equiv. to theophylline 197 mg) per 10 mL

Aminophylline
- Tablets 100 mg
- Tablets 200 mg

Phyllocontin (Canada)
Phyllocontin-350 (Canada)

Pharmacology

Relaxes bronchial smooth muscle and pulmonary blood vessels; stimulates central respiratory drive; increases diaphragmatic contractility.

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Pharmacokinetics

Absorption

(Note: Information for the pharmacokinetics/dynamics section was taken from theophylline because aminophylline is a mixture of theophylline and base.) Rapidly and completely absorbed in solution or immediate-release. C max is 10 mcg/mL (5 to 15 mcg/mL). T max is 1 to 2 h. Food and antacid does not cause any clinically important changes; therapeutic range is 10 to 20 mcg/mL.

Distribution

40% protein bound (primarily albumin). Unbound theophylline distributes throughout the body water, but distributes poorly into body fat. Vd is 0.45 L/kg (0.3 to 0.7 L/kg) based on ideal body weight. Freely passes across the placenta into breast milk and into CSF.

Metabolism

Does not undergo any measurable first-pass elimination. About 90% of dose is metabolized in the liver in adults and children older than 1 yr of age. Caffeine and 3-methylxanthine are the only theophylline metabolites with pharmacological activity.

Elimination

In neonates, about 50% of theophylline dose is excreted unchanged in the urine (ie, excretion is by the kidneys). 10% of theophylline dose is excreted unchanged in the urine in infants 0 to 3 mo of age.

Special Populations

Renal Function Impairment

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

Hepatic Function Impairment

Theophylline Cl is decreased 50% or more in patients with hepatic insufficiency. Dose reduction is required.

Elderly

Cl is decreased by an average of 30% in healthy patients older than 60 yr of age compared with younger adults.

Children

Cl is very low in neonates and reaches max values by 1 yr of age, remains relatively constant until about 9 yr of age, and then slowly decreases by approximately 50% to adult values at about 16 yr of age.

Gender

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

Race

Pharmacokinetics have not been studied.

Concurrent illness

Theophylline Cl is decreased in patients with acute pulmonary edema, CHF, cor pulmonale, fever, hypothyroidism, liver disease (eg, acute hepatitis, cirrhosis), reduced renal function in infants younger than 3 mo of age, sepsis with multiorgan failure, and shock.

Smoking

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

Special risk patients

Pharmacokinetics vary widely among similar patients and cannot be predicted by age, sex, body weight, or other demographic parameters. However, a prolonged half-life may occur in patients with CHF, liver dysfunction, alcoholism, and respiratory infection patients.

Indications and Usage

Oral

Treatment of the symptoms and reversible airflow obstruction associated with chronic asthma and other chronic lung diseases (eg, chronic bronchitis, emphysema).

Parenteral

Adjunct to inhaled beta-2 selective agonists and systemically administered corticosteroids for the treatment of acute exacerbations of the symptoms and reversible airflow obstruction associated with asthma and other chronic lung disease (eg, chronic bronchitis, emphysema).

Contraindications

Hypersensitivity to theophyllines or any component of the product, including ethylenediamine.

Dosage and Administration

Aminophylline is approximately 79% anhydrous theophylline by weight. The steady-state theophylline peak plasma concentration is a function of the dose, the dosing interval, and the rate of theophylline absorption and Cl in individual patients. The dose required to achieve a theophylline peak plasma concentration in the 10 to 20 mcg/mL range varies 4-fold among similar patients in the absence of factors known to alter theophylline Cl. For a given population, there is no single dose that will provide both safe and effective concentrations for all patients. The dose of theophylline must be individualized on the basis of plasma theophylline concentration measurement in order to achieve a dose that provides max potential benefit with minimal risk of adverse reactions. The dose should be calculated based on ideal body weight.

Parenteral Loading Dose
Adults and Children

IV Loading dose may be calculated as follows: Loading dose = the desired plasma theophylline concentration minus the measured theophylline concentration times the Vd. The Vd can be assumed to be 0.5 mL/kg and the desired plasma theophylline concentration should be conservative (eg, 10 mcg/mL). The loading dose should not be given before obtaining a plasma theophylline concentration if the patient has received theophylline in the previous 24 h.

Theophylline Infusion Rates Following Appropriate Loading Dose

IV Following an appropriate loading dose, initial theophylline infusion rates are:

Neonates Postnatal age up to 24 days

The theophylline administration rate is 1 mg/kg every 12 h to achieve a target concentration of 7.5 mcg/mL for neonatal apnea.

Postnatal age beyond 24 days

The theophylline administration rate is 1.5 mg/kg every 12 h to achieve a target concentration of 7.5 mcg/mL for neonatal apnea.

Infants 6 to 52 wk of age

The mg/kg/h theophylline administer rate is 0.008 times the age in wk plus 0.21.

Children 1 to 9 yr of age

The theophylline infusion rate is 0.8 mg/kg/h.

9 to 12 yr of age

The theophylline infusion rate is 0.7 mg/kg/h.

Adolescents Cigarette or marijuana smokers 12 to 16 yr of age

The theophylline infusion rate is 0.7 mg/kg/h.

Nonsmokers 12 to 16 yr of age

The theophylline infusion rate is 0.5 mg/kg/h, not to exceed 900 mg/day unless plasma levels indicate the need for a larger dose.

Adults Otherwise healthy nonsmokers 16 to 60 yr of age

The theophylline infusion rate is 0.4 mg/kg/h, not to exceed 900 mg/day unless plasma levels indicate the need for a larger dose.

Elderly Older than 60 yr of age

The theophylline infusion rate is 0.3 mg/kg/h, not to exceed 400 mg/day unless plasma levels indicate the need for a larger dose.

Cardiac decompensation, cor pulmonale, liver dysfunction, sepsis with multiorgan failure, or shock

The theophylline infusion rate is 0.2 mg/kg/h, not to exceed 400 mg/day unless plasma levels indicate the need for a larger dose.

IV Dosage Adjustments Guided by Theophylline Plasma Concentration

IV

If C max is less than 9.9 mcg/mL

If symptoms are not controlled and current dosage is tolerated, increase infusion rate by about 25%. Recheck plasma concentration after 12 h in children and 24 h in adults for further dosage adjustments.

If C max is 10 to 14.9 mcg/mL

If symptoms are controlled and current dosage is tolerated, maintain infusion rate and recheck plasma concentration at 24-h intervals. (Dose reduction and/or plasma theophylline concentration measurement is indicated whenever adverse reactions or physiologic abnormalities that can reduce theophylline Cl [eg, sustained fever] are present, or when a drug that interacts with theophylline is added or discontinued.) If symptoms are not controlled and current dosage is tolerated, consider adding additional medication(s) to the treatment regimen.

If C max is 15 to 19.9 mcg/mL

Consider a 10% decrease in infusion rate to provide a greater margin of safety even if current dosage is tolerated. (Dose reduction and/or plasma theophylline concentration measurement is indicated whenever adverse reactions or physiologic abnormalities that can reduce theophylline Cl [eg, sustained fever] are present, or when a drug that interacts with theophylline is added or discontinued.)

If C max is 20 to 24.9 mcg/mL

Decrease infusion rate by 25% even if no adverse reactions are present. Recheck plasma concentration after 12 h in children and 24 h in adults to guide further dosage adjustment.

If C max is 25 to 30 mcg/mL

Stop infusion for 12 h in children and 24 h in adults and decrease subsequent infusion rate at least 25% even if no adverse reactions are present. Recheck serum concentration after 12 h in children and 24 h in adults to guide further dosage adjustment. If symptomatic, stop infusion and consider whether overdose treatment is indicated.

If C max is more than 30 mcg/mL

Stop the infusion and treat overdose as indicated. If theophylline is resumed subsequently, decrease infusion rate by at least 50% and recheck plasma concentration after 12 h in children and 24 h in adults to guide further dosage adjustment.

Dosing Initiation and Titration
Adults 16 to 60 yr of age and Children weighing more than 45 kg

PO Start with theophylline 300 mg/day (aminophylline equivalent 380 mg/day) divided every 6 to 8 h. After 3 days, if tolerated, increase dosage to theophylline 400 mg/day (aminophylline equivalent 507 mg/day) divided every 6 to 8 h. After 3 more days, if tolerated, increase dosage to theophylline 600 mg/day (aminophylline equivalent 760 mg/day) divided every 6 to 8 h.

Children

PO

Children weighing more than 45 kg

Start with theophylline 300 mg/day (aminophylline equivalent 380 mg/day) divided every 6 to 8 h. After 3 days, if tolerated, increase dosage to theophylline 400 mg/day (aminophylline equivalent 507 mg/day) divided every 6 to 8 h. After 3 more days, if tolerated, increase dosage to theophylline 600 mg/day (aminophylline equivalent 760 mg/day) divided every 6 to 8 h.

Children weighing less than 45 kg

Start with theophylline 12 to 14 mg/kg/day (aminophylline equivalent 15.2 to 17.7 mg/kg/day) up to a max of 300 mg/day (aminophylline equivalent 380 mg/day) divided every 4 to 6 h. After 3 days, if tolerated, increase dosage to 16 mg/kg/day (aminophylline equivalent 20.3 mg/kg/day) up to a max of 400 mg/day (aminophylline equivalent 507 mg/day) divided every 4 to 6 h. After 3 more days, if tolerated, increase dosage to 20 mg/kg/day (aminophylline equivalent 25.3 mg/kg/day) up to a max of 600 mg/day (aminophylline equivalent 760 mg/day) divided every 4 to 6 h.

Patients With Risk Factors for Impaired Cl, Patients Older Than 60 Yr of Age, and Patients in Whom it is Not Feasible to Monitor Plasma Theophylline Levels
Adults, including Elderly patients, and Children 16 yr of age and older

PO Final theophylline dosage should not exceed 400 mg/day (aminophylline equivalent 507 mg/day) in the presence of risk factors to reduce theophylline Cl or if it is not feasible to monitor plasma theophylline concentrations.

Children 1 to 15 yr of age

PO Final theophylline dosage should not exceed 16 mg/kg/day (aminophylline equivalent 20.3 mg/kg/day), up to a max of 400 mg/day (aminophylline equivalent 507 mg/day), in the presence of risk factors for reduced theophylline Cl or if it is not feasible to monitor plasma theophylline concentrations.

Loading Dose for Acute Bronchitis

PO A single theophylline 5 mg/kg dose in patients who have not received any theophylline in the previous 24 h will produce an average theophylline C max of 10 mcg/mL (range, 5 to 15 mcg/mL). If dosing is to be continued beyond the loading dose, the following should be utilized and plasma theophylline levels monitored at 24-h intervals to adjust the final dosage: In adults and children weighing more than 45 kg, after 3 days, if tolerated, increase dosage to theophylline 600 mg/day (aminophylline equivalent 760 mg/day) divided every 6 to 8 h. In children weighing less than 45 kg, after 3 days, if tolerated, increase dosage to 20 mg/kg/day (aminophylline equivalent 25.3 mg/kg/day) up to a max of 600 mg/day (aminophylline equivalent 760 mg/day) divided every 4 to 6 h. Or, follow the guidelines previously described in Patients With Risk Factors for Impaired Cl, Patients Older Than 60 Yr of Age, and Patients in Whom it is Not Feasible to Monitor Plasma Theophylline Levels.

Oral Dosage Adjustment Guided by Plasma Theophylline Levels

PO

If C max is less than 9.9 mcg/mL

If symptoms are not controlled and current dosage is tolerated, increase dose about 25%. Recheck plasma concentration after 3 days for further dosage adjustments.

If C max is 10 to 14.9 mcg/mL

If symptoms are controlled and current dosage is tolerated, maintain dose and recheck plasma concentration at 6- to 12-month intervals. (Dose reduction and/or plasma theophylline concentration measurement is indicated whenever adverse reactions or physiologic abnormalities that can reduce theophylline Cl [eg, sustained fever] are present, or when a drug that interacts with theophylline is added or discontinued.) If symptoms are not controlled and current dosage is tolerated, consider adding additional medication(s) to the treatment regimen.

If C max is 15 to 19.9 mcg/mL

Consider a 10% decrease in dose to provide a greater margin of safety even if current dosage is tolerated. (Dose reduction and/or plasma theophylline concentration measurement is indicated whenever adverse reactions or physiologic abnormalities that can reduce theophylline Cl [eg, sustained fever] are present, or when a drug that interacts with theophylline is added or discontinued.)

If C max is 20 to 24.9 mcg/mL

Decrease dose by 25% even if no adverse reactions are present. Recheck plasma concentration after 3 days to guide further dosage adjustment.

If C max is 25 to 30 mcg/mL

Skip next dose and decrease subsequent doses at least 25% even if no adverse reactions are present. Recheck plasma concentration after 3 days to guide further dosage adjustment. If symptomatic, consider whether overdose treatment is indicated.

If C max is more than 30 mcg/mL

Treat overdose as indicated. If theophylline is resumed subsequently, decrease dose by at least 50% and recheck plasma concentration after 3 days to guide further dosage adjustment.

General Advice

  • IV infusion
  • Do not mix aminophylline injection in a syringe with other drugs. Add aminophylline separately to the IV solution.
  • When an IV solution containing aminophylline is given piggyback, the IV system already in place should be turned off while aminophylline is infused if there is a potential problem with admixture compatibility.
  • Because of the alkalinity of aminophylline-containing solutions, drugs that are alkali labile (eg, epinephrine, isoproterenol, norepinephrine, penicillin G potassium) should be avoided in admixture.

Storage/Stability

Store injection at 59° to 86°F. Protect from light. Store tablets at 68° to 77°F. Protect from light and moisture.

Drug Interactions

Acyclovir, alcohol, allopurinol, calcium channel blockers (ie, diltiazem, verapamil), cimetidine, corticosteroids (eg, hydrocortisone, prednisone), disulfiram, estrogen-containing hormonal contraceptives, fluvoxamine, influenza virus vaccine, interferon, macrolide antibiotics (azithromycin), methotrexate, mexiletine, nonselective beta-blockers (eg, propranolol), pentoxifylline, propafenone, quinolone antibiotics (ie, ciprofloxacin, norfloxacin), tacrine, thiabendazole, thyroid hormones (eg, levothyroxine), ticlopidine, zileuton

Theophylline levels may be increased.

Aminoglutethimide, barbiturates (eg, pentobarbital, phenobarbital, primidone, secobarbital), hydantoins (eg, phenytoin), isoproterenol IV, ketoconazole, moricizine, rifampin, smoking (ie, marijuana or tobacco), St. John's wort, sulfinpyrazone, sympathomimetics (eg, albuterol, isoproterenol, terbutaline)

Theophylline levels may be decreased.

Benzodiazepines, propofol

Aminophylline may antagonize sedative effects.

Beta-agonists

Effects of both drugs may be antagonized.

Carbamazepine, isoniazid, loop diuretics

May increase or decrease aminophylline levels.

Ephedrine, tetracycline

Increased risk of theophylline toxicity.

Erythromycin

Elevated theophylline levels, increasing the risk of toxicity, while erythromycin levels may be reduced.

Food

Low-protein, high-carbohydrate diet may increase aminophylline levels. Charcoal-broiled foods or high-protein, low-carbohydrate diet may decrease aminophylline levels.

Halothane

May cause catecholamine-induced arrhythmias.

Ketamine

May result in seizures.

Lithium

Aminophylline may reduce lithium levels.

Nondepolarizing muscle relaxants

May antagonize neuromuscular blockade.

Laboratory Test Interactions

None well documented.

Adverse Reactions

See also, signs and symptoms of overdosage.

Cardiovascular

Atrial flutter and tachycardia.

CNS

Headache; insomnia; irritability; restlessness; seizures.

Dermatologic

Contact dermatitis; exfoliative dermatitis.

GI

Diarrhea; nausea; vomiting.

Genitourinary

Transient diuresis.

Musculoskeletal

Fine skeletal muscle tremors.

Precautions

Monitor

Frequently monitor theophylline levels in elderly patients and smokers, as well as in patients with hepatic or renal impairment. Determine appropriate theophylline concentrations before making a dose increase as follows: determine whether the plasma level is subtherapeutic in a patient who continues to be symptomatic; whenever signs or symptoms of theophylline toxicity are present; and whenever there is a new illness, worsening of an existing concurrent illness, or a change in the treatment regimen.


Pregnancy

Category C .

Lactation

Excreted in breast milk.

Children

Safe and effective for the approved indications in children.

Elderly

Elderly patients are at increased risk of experiencing serious theophylline adverse reactions and toxicity compared with younger patients because of pharmacodynamic and pharmacokinetic changes associated with aging.

Special Risk Patients

Use with caution in patients with active peptic ulcer disease, cardiac arrhythmias, or seizure disorders.

Overdosage

Symptoms

General

Acute MI; death due to cardiorespiratory arrest and/or hypoxic encephalopathy; increased serum calcium, creatine kinase, myoglobin and leukocyte count; decreased serum phosphate and magnesium; urinary retention in men with obstructive uropathy. Many manifestations of acute and chronic overdosage are similar.

Acute overdosage

Abdominal pain, acid/base disturbance, atrial fibrillation or flutter, death, disorientation, hyperglycemia, hypokalemia, hypotension/shock, nervousness, rhabdomyolysis, seizures, sinus tachycardia, supraventricular tachycardia, tremors, ventricular arrhythmias, ventricular premature beats, vomiting.

Chronic overdosage

Abdominal pain, acid/base disturbance, atrial fibrillation or flutter, atrial tachycardia, death, diarrhea, disorientation, hematemesis, hyperglycemia, hypokalemia, hypotension/shock, nervousness, seizures, sinus tachycardia, supraventricular tachycardia, tremors, ventricular arrhythmias, ventricular premature beats, vomiting.

Patient Information

  • Advise patient not to smoke. If patient changes smoking habits or stops smoking, dosage adjustment may be necessary.
  • For patients taking theophylline, emphasize that serum theophylline levels should be tested every 6 to 12 mo.
  • Advise elderly patients to take safety precautions (eg, rise slowly, use handrails, request assistance in ambulation) if dizziness occurs.
  • Instruct patient to avoid foods or beverages containing caffeine and to limit intake of charcoal-broiled foods.
  • Instruct patients to contact health care provider if they experience insomnia, nausea, new illness accompanied by fever, persistent headache, rapid heart rate, or vomiting.
  • Instruct patients that if a dose is missed, the patient should take the next dose at the usual scheduled time and not to attempt to make up for the missed dose.
  • Instruct patients not to alter the dose, timing of the dose, or frequency of administration without contacting health care provider.

Copyright © 2009 Wolters Kluwer Health.

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