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Theophylline

Pronunciation

Pronunciation: thee-OF-i-lin
Class: Xanthine derivative

Trade Names

Elixophyllin
- Elixir, oral 80 mg per 15 mL (26.7 mg per 5 mL)

Theo-24
- Capsules, timed-release (24 h) 100 mg
- Capsules, timed-release (24 h) 200 mg
- Capsules, timed-release (24 h) 300 mg
- Capsules, timed-release (24 h) 400 mg

Theophylline
- Solution, oral 80 mg per 15 mL

Theophylline
- Tablets, ER 100 mg
- Tablets, ER 200 mg
- Tablets, ER 300 mg
- Tablets, ER 450 mg

Apo-Theo LA (Canada)

Pharmacology

Relaxes bronchial smooth muscle and stimulates central respiratory drive.

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Pharmacokinetics

Absorption

Theophylline is rapidly and completely absorbed after oral administration. Theophylline C max is 10 mcg/mL (range, 5 to 15 mcg/mL) and T max is 1 to 2 h. Food and antacids do no cause any clinically significant changes. The therapeutic range is 10 to 20 mcg/mL.

Distribution

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

Metabolism

Theophylline does not undergo any measurable first-pass elimination. In adults and children older than 1 y of age, about 90% of the dose is metabolized in the liver. Caffeine and 3-methylxanthine are the only theophylline metabolites with pharmacologic activity.

Elimination

Excretion is via the kidneys. In neonates, approximately 50% of a theophylline dose is excreted unchanged in the urine. Beyond 0 to 3 mo, 10% of a theophylline dose is excreted unchanged in the urine.

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.

Hepatic Function Impairment

Cl is decreased at least 50% in patients with hepatic impairment. Select dose with care and frequently monitor theophylline levels

Elderly

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

Children

Cl is very low in neonates and reaches max values by 1 y of age, remains relatively constant until about 9 y of age, and then slowly decreases by approximately 50% to adult values at about 16 y 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), sepsis with multiorgan failure, and shock, and in infants younger than 3 mo of age with reduced renal function.

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%.

Indications and Usage

Prevention or treatment of reversible bronchospasm associated with asthma or COPD.

Contraindications

Hypersensitivity to theophyllines or any component of the product.

Dosage and Administration

The steady-state theophylline C max 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 C max 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.

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

PO

Theophylline ER tablet

Start with theophylline 300 mg/day divided every 12 h. After 3 days, if tolerated, increase dosage to theophylline 400 mg/day divided every 12 h. After 3 more days, if tolerated, increase dosage to theophylline 600 mg/day divided every 12 h.

Theophylline oral solution

Start with theophylline 300 mg/day divided every 6 to 8 h. After 3 days, if tolerated, increase dosage to theophylline 400 mg/day divided every 6 to 8 h. After 3 more days, if tolerated, increase dosage to theophylline 600 mg/day divided every 6 to 8 h.

Theo-24 ER capsules

Start with theophylline 300 to 400 mg/day every 24 h. After 3 days, if tolerated, increase dosage to theophylline 400 to 600 mg/day every 24 h. After 3 more days, if tolerated, doses more than theophylline 600 mg should be titrated according to blood levels.

Children

PO

Children 1 to 15 y of age weighing less than 45 kg Theophylline oral solution

Start with theophylline 12 to 14 mg/kg/day up to a max of 300 mg/day divided every 4 to 6 h. After 3 days, if tolerated, increase dosage to 16 mg/kg/day up to a max of 400 mg/day divided every 4 to 6 h. After 3 more days, if tolerated, increase dosage to 20 mg/kg/day up to a max of 600 mg/day divided every 4 to 6 h.

Children 1 to 15 y of age weighing more than 45 kg Theophylline oral solution

Start with theophylline 300 mg/day divided every 6 to 8 h. After 3 days, if tolerated, increase dosage to theophylline 400 mg/day divided every 6 to 8 h. After 3 more days, if tolerated, increase dosage to theophylline 600 mg/day divided every 6 to 8 h.

Children 6 to 15 y of age weighing less than 45 kg Theophylline ER tablets

Start with theophylline 12 to 14 mg/kg/day up to a max of 300 mg/day divided every 12 h. After 3 days, if tolerated, increase dosage to 16 mg/kg/day up to a max of 400 mg/day divided every 12 h. After 3 more days, if tolerated, increase dosage to 20 mg/kg/day up to a max of 600 mg/day divided every 12 h.

Children 6 to 15 y of age weighing more than 45 kg Theophylline ER tablets

Start with theophylline 300 mg/day divided every 12 h. After 3 days, if tolerated, increase dosage to theophylline 400 mg/day divided every 12 h. After 3 more days, if tolerated, increase dosage to theophylline 600 mg/day divided every 12 h.

Children 12 to 15 y of age weighing less than 45 kg Theo-24 ER capsules

Start with theophylline 12 to 14 mg/kg/day up to a max of 300 mg/day dosed every 24 h. After 3 days, if tolerated, increase dosage to 16 mg/kg/day up to a max of 400 mg/day dosed every 24 h. After 3 more days, if tolerated, increase dosage to 20 mg/kg/day up to a max of 600 mg/day dosed every 24 h.

Children 12 to 15 y of age weighing more than 45 kg Theo-24 ER capsules

Start with theophylline 300 to 400 mg/day every 24 h. After 3 days, if tolerated, increase dosage to theophylline 400 to 600 mg/day every 24 h. After 3 more days, if tolerated, doses more than theophylline 600 mg should be titrated according to blood levels.

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

PO The final theophylline dose should not exceed 400 mg/day.

Children

PO

Theophylline ER tablets Children 6 to 15 y of age

The final theophylline dose should not exceed 16 mg/kg/day, up to a max of 400 mg/day.

Theophylline oral solution Children 1 to 15 y of age

The final theophylline dose should not exceed 16 mg/kg/day, up to a max of 400 mg/day.

Theo-24 ER capsules Children 12 to 15 y of age

The final theophylline dose should not exceed 16 mg/kg/day, up to a max of 400 mg/day. Note: Patients with more rapid metabolism, clinically identified by higher than average dose requirements, should receive a smaller dose more frequently to prevent breakthrough symptoms resulting from low trough levels before the next dose. A reliable absorbed slow-release formulation will decrease fluctuations and permit longer dosing intervals.

Infants younger than 1 y old

PO

Theophylline oral solution Premature neonates younger than 24 days postnatal age

1 mg/kg every 12 h.

Premature neonates older than 24 days postnatal age

1.5 mg/kg every 12 h.

Full-term infants and infants up to 52 wk of age

Total dose in mg is [(0.2 × age in wk) + 5] × weight in kg. In infants 26 wk of age and younger, divide the dose into 3 equal amounts administered at 8-h intervals. In infants older than 26 wk of age, divide the dose into 4 equal amounts administered at 6-h intervals.

Dosage Adjustments Guided by Plasma Theophylline Concentration

PO

If C max is less than 9.9 mcg/mL

If symptoms are not controlled and current dosage is tolerated, increase dose by 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-mo intervals. (Dose reduction and/or plasma theophylline concentration measurement is indicated whenever the following are present: physiologic abnormalities that can reduce theophylline Cl [eg, sustained fever], or 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 the following are present: physiologic abnormalities that can reduce theophylline Cl [eg, sustained fever], or 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

  • Medication should be taken at approximately the same time each day and should not exceed the prescribed dose.
  • Theophylline ER tablets may be given on a once-daily schedule to adult nonsmokers with appropriate total body Cl and to other patients with low dosage requirements. Once-daily administration should be considered only after gradual titration to therapeutic levels with 12-h dosing. Once-daily dosing should be based on twice the 12-h dose and should be initiated at the end of the last 12-h interval. It is essential that theophylline plasma levels be monitored before and after transfer to once-daily dosing.
  • Theo-24 ER capsules should be taken in the morning at approximately the same time.
  • Theo-24 should not be taken with food by patients requiring a relatively high dose of theophylline (ie, a dose equal to or more than 900 mg or 13 mg/kg, whichever is less).

Storage/Stability

Elixophyllin

Store at 59° to 86°F. Protect from light.

Theo-24 ER capsules

Store below 77°F.

Theophylline ER tablets and oral solution

Store at 68° to 77°F.

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 and tobacco), St. John's wort, sulfinpyrazone, sympathomimetics (eg, albuterol, isoproterenol, terbutaline)

Theophylline levels may be decreased.

Benzodiazepines, propofol

Theophylline may antagonize sedative effects.

Beta-agonists

CV adverse reactions may be additive. However, may be used together for additive beneficial effects.

Carbamazepine, isoniazid, loop diuretics

May increase or decrease theophylline levels.

Ephedrine, tetracycline

Increased risk of theophylline toxicity.

Erythromycin

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

Halothane

Coadministration has caused catecholamine-induced arrhythmias.

Ketamine

Coadministration may result in seizures.

Lithium

Theophylline may reduce lithium levels.

Nondepolarizing muscle relaxants

Theophylline may antagonize neuromuscular blockade.

Incompatibility

Do not mix following solutions with theophylline in IV fluids: ascorbic acid, chlorpromazine, corticotropin, dimenhydrinate, epinephrine hydrochloride, erythromycin gluceptate, hydralazine, hydroxyzine hydrochloride, insulin, levorphanol tartrate, meperidine, methadone, methicillin sodium, morphine sulfate, norepinephrine bitartrate, oxytetracycline, papaverine, penicillin G potassium, phenobarbital sodium, phenytoin sodium, procaine, prochlorperazine maleate, promazine, promethazine, tetracycline, vancomycin, vitamin B complex with C.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Atrial flutter and tachycardia, cardiac arrhythmias.

CNS

Headache, insomnia, irritability, restlessness, seizures.

GI

Diarrhea, nausea, vomiting.

Genitourinary

Transient diuresis.

Musculoskeletal

Fine skeletal muscle tremors.

Miscellaneous

Death.

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 concentration 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 caused by 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

  • Emphasize importance of follow-up with health care provider to monitor drug levels.
  • Explain to patient that the medication is used to prevent asthma attacks and to use it continuously.
  • Explain that some sustained-release forms should be taken on empty stomach, and not to crush or chew sustained-release forms.
  • Explain that low-protein, high-carbohydrate diets may increase theophylline levels, while high-protein, low-carbohydrate diets and charcoal-broiled foods may decrease theophylline levels.
  • Instruct patient to avoid food products containing caffeine.
  • Instruct patient not to take extra doses of theophylline for acute asthma attack.
  • 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, to take the next dose at the usually 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.
  • Advise patients not to start or stop smoking without contacting health care provider. If patients change their smoking habits or stop smoking, dosage adjustment may be necessary.

Copyright © 2009 Wolters Kluwer Health.

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