theophylline

Absorption: Well absorbed from PO dosage forms; absorption from extended-release dosage forms is slow but complete. IV administration results in complete bioavailability.

Distribution: Widely distributed; does not distribute into adipose tissue.

Metabolism/Excretion: 90% metabolized by the liver to several metabolites (including the active metabolites, caffeine, and 3-methylxanthine); metabolites are renally excreted; 10% excreted unchanged by the kidneys.

Half-Life: Premature infants: 20–30 hr; Term infants: 11–25 hr; Children 1–4 yr: 3.4 hr; Children 6–17 yr: 3.7 hr; Adults: 9–10 hr (↑ in patients >60 yr, patients with HF or liver disease; ↓ in cigarette smokers ).

Time/Action Profile ⬆ ⬇

(bronchodilation)

ROUTE	ONSET‡	PEAK	DURATION
PO	rapid	1–2 hr	6 hr
PO-ER	delayed	4–8 hr	8–24 hr
IV	rapid	end of infusion	6–8 hr

‡Provided that a loading dose has been given and steady-state blood levels exist.

Contraind./Precautions ⬆ ⬇

Contraindicated in:

Hypersensitivity to aminophylline or theophylline.

Use Cautiously in:

Cardiac arrhythmias;
HF, liver disease, or hypothyroidism (↓ dose);
Peptic ulcer disease;
Seizure disorders;
OB: Safety not established in pregnancy;
Lactation: Safety not established in breastfeeding;
Pedi: Dose required for children 1 yr;
Geri: Dose required for patients >60 yr.

Adv. Reactions/Side Effects ⬆ ⬇

CV: tachycardia, angina, ARRHYTHMIAS, palpitations

GI: nausea, vomiting, anorexia

Neuro: anxiety, headache, insomnia, irritability, SEIZURES, tremor

Interactions ⬆ ⬇

Drug-drug:

Additive CV and CNS side effects with adrenergics (sympathomimetic).
May ↓ the therapeutic effect of lithium and phenytoin.
Smoking, barbiturates, carbamazepine, phenytoin, nevirapine and rifampin may ↑ metabolism and may decrease effectiveness.
Erythromycin, beta blockers, clarithromycin, calcium channel blockers, cimetidine,hormonal contraceptives, disulfiram, doxycycline, estrogens, fluvoxamine, isoniazid, ketoconazole, mexiletine, nefazodone, protease inhibitors, quinidine, some fluoroquinolones, and large doses of allopurinol↓ metabolism and may lead to toxicity.

Drug-Natural Products:

Caffeine-containing herbs (cola nut, guarana, mate, tea, coffee) may ↑ levels and risk of CNS and CV side effects.
↓levels and effectiveness with St. John’s wort.

Excessive regular intake of charcoal-broiled foods may ↓ effectiveness.

Route/Dosage ⬆ ⬇

Dose should be determined by theophylline serum level monitoring. Loading dose should be ↓ or eliminated if theophylline preparation has been used in preceding 24 hr. Aminophylline is 80% theophylline (100 mg aminophylline = 80 mg theophylline). Extended-release (controlled-release, sustained-release) products may be given every 8–24 hr, depending upon the formulation.
PO (Adults Healthy, Nonsmoking): Loading dose: 5 mg/kg, followed by 10 mg/kg/day divided every 8–12 hr (not to exceed 900 mg/day).
PO (Adults with HF, Cor Pulmonale, or Liver Dysfunction): Loading dose: 5 mg/kg, followed by 5 mg/kg/day divided every 8–12 hr (not to exceed 400 mg/day).
PO (Children 12–16 yr, Nonsmoking): Loading dose: 5 mg/kg, followed by 13 mg/kg/day divided every 8–12 hr.
PO (Children 9–12 yr, adolescent and adult smokers <50 yr): Loading dose: 5 mg/kg, followed by 16 mg/kg/day divided every 8–12 hr.
PO (Children 1–9 yr): Loading dose: 5 mg/kg, followed by 20–24 mg/kg/day divided every 8–12 hr.
PO (Infants 6 mo–1 yr): Loading dose: 5 mg/kg, followed by 12–18 mg/kg/day divided every 6–8 hr.
PO (Infants 6 wk–6 mo): Loading dose: 5 mg/kg, followed by 10 mg/kg/day divided every 6–8 hr.
PO (Neonates up to 6 wk): Loading dose: 4 mg/kg, followed by 4 mg/kg/day divided every 12 hr.
IV (Adults and Children ): See aminophylline monograph for IV doses.

Availability ⬆ ⬇

(Generic available)

Extended-release tablets (12 hr): 300 mg; 450 mg
Extended-release tablets (24 hr): 400 mg; 600 mg
Extended-release capsules (24 hr): 100 mg; 200 mg; 300 mg; 400 mg
Elixirorange/raspberry, mixed fruit, and other flavors: 80 mg/15 mL
Premixed infusion: 400 mg/500 mL D5W

Assessment ⬆ ⬇

Assess BP, pulse, and respiratory status (rate, lung sounds, use of accessory muscles) before and throughout therapy. Ensure that oxygen therapy is correctly instituted during acute asthma attacks.
- Monitor intake and output ratios for an increase in diuresis or fluid overload.
- Patients with a history of cardiovascular problems should be monitored for chest pain and ECG changes (premature atrial complexes, supraventricular tachycardia, premature ventricular contractions, ventricular tachycardia). Resuscitative equipment should be readily available.
- Monitor pulmonary function tests before and periodically during therapy to determine therapeutic efficacy in patients with chronic bronchitis or emphysema.

Lab Test Considerations:

Monitor ABGs, acid-base, and fluid and electrolyte balance in patients receiving parenteral therapy or whenever required by patient’s condition.

Toxicity and Overdose:

Monitor drug levels routinely, especially in patients requiring high doses or during prolonged intensive therapy. Obtain serum sample at time of peak absorption. Evaluate peak levels 30 min after a 30 min IV loading dose, 12–24 hr after initiation of a continuous infusion and 1–2 hr after rapid-acting oral forms, and 4–12 hr after extended-release oral forms. Therapeutic plasma levels range from 10–15 mcg/mL for asthma and 6–14 mcg/mL for apnea of prematurity. Drug levels in excess of 20 mcg/mL are associated with toxicity. Caffeine ingestion may falsely elevate drug concentration levels.
- Observe patient for symptoms of drug toxicity (anorexia, nausea, vomiting, stomach cramps, diarrhea, confusion, headache, restlessness, flushing, increased urination, insomnia, tachycardia, arrhythmias, seizures). Notify health care professional immediately if these occur. Tachycardia, ventricular arrhythmias, or seizures may be the first sign of toxicity. Patients over 60 yr have ↑ risk of toxicity and sensitivity to toxic effects due to age-related pharmacodynamic and pharmacokinetic changes. Theophylline doses should not exceed 400 mg/day. .

Implementation ⬆ ⬇

Administer around the clock to maintain therapeutic plasma levels. Administer once-a-day doses in the morning.
- Do not refrigerate elixirs or solutions; crystals may form. Crystals should dissolve when liquid is warmed to room temperature.
- Wait at least 4–6 hr after stopping IV therapy to begin immediate-release oral dosage; for extended-release oral dosage form, give 1st oral dose at time of IV discontinuation.
PO: Administer oral preparations with food or a full glass of water to minimize GI irritation. Food slows but does not reduce the extent of absorption. May be administered 1 hr before or 2 hr after meals for more rapid absorption. Swallow tablets and capsules whole; do not crush, break, open, or chew controlled-release or extended-release tablets or capsules (extended-release tablets may be broken if scored). Pedi: Use calibrated measuring device to ensure accurate dose of liquid preparations.

IV Administration:

IV theophylline in 5% dextrose is packed in a moisture-barrier overwrap. Remove immediately before administration and squeeze bag to check for leaks. Discard if solution is not clear.
Loading Dose: Administer over 20–30 min. If patient has had another form of theophylline before loading dose, obtain serum theophylline level and reduce loading dose proportionately.
Rate: Rapid administration may cause chest pain, dizziness, hypotension, tachypnea, flushing, arrhythmias, or a reaction to the solution or administration technique (chills; fever; redness, pain, or swelling at injection site). Infusion rate may be ↑ after 12 hr. Administer via infusion pump to ensure accurate dose. Monitor ECG continuously; tachyarrhythmias may occur.

Patient/Family Teaching ⬆ ⬇

Emphasize the importance of taking only the prescribed dose at the prescribed time intervals. Take missed doses as soon as possible or omit if close to next dose.
Encourage the patient to drink adequate liquids (2000 mL/day minimum) to decrease the viscosity of the airway secretions.
Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications, especially OTC cough, cold, or breathing preparations ; may increase side effects and cause arrhythmias.
Encourage patients not to smoke. A change in smoking habits may necessitate a change in dose.
Advise patient to minimize intake of xanthine-containing foods or beverages (colas, coffee, chocolate) and not to eat charcoal-broiled foods daily.
Instruct patient not to change brands without consulting health care professional.
Advise patient to contact health care professional promptly if the usual dose of medication fails to produce the desired results, symptoms worsen after treatment, or toxic effects occur.
Rep: Advise females of reproductive potential to notify health care professional if pregnancy is planned or suspected or if breastfeeding.
Emphasize the importance of having serum levels routinely tested every 6–12 mo.

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Pronunciation ⬇

Classifications ⬆ ⬇

Indications ⬆ ⬇

Action ⬆ ⬇

Pharmacokinetics ⬆ ⬇