Adult: In patients who are not currently receiving theophylline preparations: Loading dose: As aminophylline: 250-500 mg or up to 5 mg/kg via slow inj or infusion over 20-30 minutes. As aminophylline hydrate: Loading dose: 6 mg/kg via slow inj or infusion. Max rate: 25 mg/minute. In patients who are already receiving theophylline: Loading dose must be deferred until serum theophylline levels are determined, or if necessary, dose must be selected based on potential benefits and risks. Maintenance: As aminophylline: 0.5 mg/kg/hour. As aminophylline hydrate: 0.7 mg/kg/hour, decreasing to 0.5 mg/kg/hour after 12 hours. Dose is individualised based on patient characteristics, clinical response, and serum theophylline levels. Use ideal (lean) body weight to calculate dose. Dosage recommendations may vary among countries or individual products (refer to detailed product guideline). Elderly: Maintenance: As aminophylline: 0.3 mg/kg/hour. As aminophylline hydrate: 0.6 mg/kg/hour, decreasing to 0.3 mg/kg/hour after 12 hours. Child: In patients who are not currently receiving theophylline preparations: Loading dose: Same as adult dose. Maintenance: 6 months to 9 years As aminophylline: 1 mg/kg/hour. As aminophylline hydrate: 1.2 mg/kg/hour, decreasing to 1 mg/kg/hour after 12 hours; 10-16 years As aminophylline: 0.8 mg/kg/hour. As aminophylline hydrate: 1 mg/kg/hour, decreasing to 0.8 mg/kg/hour after 12 hours. Dosage recommendations may vary among countries or individual products (refer to detailed product guideline).
Oral Chronic bronchospasm
Adult: For the prophylaxis and treatment of bronchospasm associated with asthma, COPD, and chronic bronchitis: As aminophylline hydrate modified-release tab: Usual dose: 225-450 mg bid; initiate with the lower dose then increase as necessary. Child: ≥6 years As aminophylline hydrate modified-release tab: Usual maintenance: 10 mg/kg bid. In some cases of chronic asthma: 11-18 mg/kg bid.
Special Patient Group
IV
Acute severe bronchospasm:
In patients with CHF: Maintenance: As aminophylline hydrate: 0.5 mg/kg/hour, decreasing to 0.1-0.2 mg/kg/hour after 12 hours.
In patients with cor pulmonale: Maintenance: As aminophylline: Reduced infusion rate may be required. As aminophylline hydrate: 0.6 mg/kg/hour, decreasing to 0.3 mg/kg/hour after 12 hours.
Young adult smokers: Maintenance: As aminophylline: 0.8 mg/kg/hour. As aminophylline hydrate: 1 mg/kg/hour, decreasing to 0.8 mg/kg/hour after 12 hours.
Hepatic Impairment
IV:
Dose reduction may be required. Maintenance: As aminophylline hydrate: 0.5 mg/kg/hour, decreasing to 0.1-0.2 mg/kg/hour after 12 hours.
Administration
Should be taken on an empty stomach.
Reconstitution
IV infusion: Infused with either 0.9% NaCl or 5% dextrose.
Incompatibility
Incompatible with chlorpromazine, corticotrophin, clindamycin, doxorubicin, dimenhydrinate, erythromycin gluceptate, hydralazine hydrochloride, hydroxyzine hydrochloride, oxytetracycline hydrochloride, opioid analgesics, procaine hydrochloride, phenytoin sodium, prochlorperazine salts, promazine hydrochloride, promethazine hydrochloride, vancomycin hydrochloride, and sulfafurazole diethanolamine. Avoid drugs known to be alkali labile (e.g. isoproterenol hydrochloride, epinephrine hydrochloride, norepinephrine bitartrate, penicillin G potassium) in admixtures with aminophylline.
Contraindications
Acute porphyria. IV: Concomitant use with other xanthine drugs. Oral: Concomitant use with ephedrine (in children <6 years or <22 kg).
Special Precautions
Patient with history of seizure, active influenza infection or undergoing influenza immunisation, acute febrile illness, cardiac arrhythmias or other CV disease, chronic alcoholism, active or history of peptic ulcer, thyroid disorder, glaucoma, diabetes mellitus, severe hypoxaemia, sepsis with multiorgan failure, shock, hypertension, cystic fibrosis, acute pulmonary oedema, cor pulmonale, compromised circulatory function. Simultaneous administration by >1 route/preparation. Not recommended for infants <6 months. Avoid extravasation (IV). Smokers. Renal and hepatic impairment. Children and elderly. Pregnancy and lactation.
Adverse Reactions
Significant: May exacerbate seizure, arrhythmias, and peptic ulcer; urinary retention (particularly in elderly males). Cardiac disorders: Palpitations, tachycardia. Ear and labyrinth disorders: Vertigo. Eye disorders: Visual disturbances. Gastrointestinal disorders: Nausea, vomiting, diarrhoea, abdominal pain, gastrointestinal haemorrhage, GERD; gastric irritation (oral). General disorders and administration site conditions: Hyperthermia and extreme thirst (at higher dose). Immune system disorders: Hypersensitivity. Metabolism and nutrition disorders: Hypokalaemia, hyponatraemia, hypophosphataemia. Nervous system disorders: Headache, confusional state, dizziness, tremor. Psychiatric disorders: Anxiety, insomnia, restlessness; delirium and maniacal behaviour (high dose). Respiratory, thoracic and mediastinal disorders: Hyperventilation. Skin and subcutaneous tissue disorders: Rash, pruritus, urticaria, exfoliative dermatitis, rash maculo-papular, erythema. Vascular disorders: Hypotension. Potentially Fatal: Severe theophylline toxicity.
Monitor serum theophylline levels following initiation of treatment and before increasing the dose, in the presence of signs or symptoms of toxicity, when new or worsening of illness occurs, during changes in treatment regimen; changes in fluid balance, electrolyte concentrations, or acid-balance (during prolonged use). For oral maintenance, measure theophylline serum concentrations 3 days after dosage adjustment. Observe the infusion site (IV). Monitor heart and respiratory rate, serum K levels; arterial or capillary blood gases (if applicable); CNS effects (e.g. insomnia, irritability).
Overdosage
Symptoms: Tachycardia, anorexia, diarrhoea, nausea, haematemesis, vomiting, agitation, irritability, insomnia, headache, restlessness, hallucinations, extreme thirst, dilated pupils, tinnitus, slight fever, seizures, hypertonia, exaggerated limb reflexes, palpitations, arrhythmias, hypotension, hypokalaemia, hypomagnesaemia, hypophosphataemia, hyperglycaemia, hyperthermia, albuminuria, hypercalcaemia, respiratory alkalosis, metabolic acidosis, rhabdomyolysis, and coma (in severe cases). Management: Symptomatic and supportive treatment. Maintain airway of the patient; provide oxygen for administration or mechanical ventilation as required. Monitor ECG, serum theophylline, serum electrolytes (e.g. K) and glucose levels. Administer repeated oral doses of activated charcoal to enhance elimination of theophylline. Aggressive antiemetic treatment may be necessary to allow administration and retention of activated charcoal. Consider performing gastric lavage within 1-2 hours of ingestion. Restore fluid and electrolyte balances. Correct hypokalaemia using IV infusion of K chloride. In case of seizures, may give 0.1-0.3 mg/kg up to 10 mg IV diazepam. In agitated patients, diazepam may also be used for sedation. May give IV propranolol to reverse extreme tachycardia, hyperglycaemia and hypokalaemia provided that patient is not asthmatic. Administer antiemetics (e.g. metoclopramide, ondansetron) in case of vomiting. Consider charcoal haemoperfusion if ileus or intestinal obstruction prevents the administration of activated charcoal, or if plasma theophylline levels is >80 mg/L (acute) or >60 mg/L (chronic), >40 mg/L (elderly).
Drug Interactions
May increase plasma theophylline concentration with fluvoxamine, cimetidine, fluconazole, macrolides (e.g. clarithromycin, erythromycin), quinolones (e.g. norfloxacin, ciprofloxacin), propranolol, isoniazid, allopurinol (at high doses e.g. 600 mg daily), estrogen-containing oral contraceptives, disulfiram, Ca channel blockers (e.g. verapamil), mexiletine, propafenone, interferon-alfa, influenza vaccine, tacrine, thiabendazole, methotrexate, thyroid hormones, or zafirlukast. May decrease plasma theophylline concentration with rifampicin, ritonavir, antiepileptic drugs (e.g. carbamazepine, phenytoin, phenobarbital, primidone), sulfinpyrazone, and aminoglutethimide. Increased risk of convulsions with ketamine. May diminish the effects of benzodiazepines and lithium. Increased risk of arrhythmias with halothane. May antagonise the neuromuscular blocking effects of pancuronium. Diminished bronchodilatory effects with β-blockers. May inhibit the effects of adenosine receptor agonists (e.g. adenosine, dipyridamole, regadenoson). May enhance the sensitivity and toxic potential of cardiac glycosides. Increased CNS stimulation with doxapram. Increased risk of hypokalaemia with β2-adrenergic agonists, corticosteroids, and diuretics. Potentially Fatal: Increased risk of toxicity with other xanthine derivatives (e.g. theophylline, pentoxifylline) and ephedrine.
Food Interaction
Increased clearance with St. John’s wort, low carbohydrate/high protein diet, and daily consumption of charcoal-broiled beef. Alcohol may decrease the clearance of theophylline.
Lab Interference
May decrease triiodothyronine. May increase levels of plasma glucose, uric acid, urinary free cortisol excretion, free fatty acids, total cholesterol, HDL, and HDL/LDL ratio that may affect the respective tests.
Action
Description: Mechanism of Action: Aminophylline, a xanthine derivative, is a complex of theophylline and ethylenediamine that readily liberates theophylline in the body. Theophylline has 2 distinct actions; bronchodilation, which may be mediated by inhibition of phosphodiesterase (PDE) isoenzymes (PDE III, and to a lesser extent, PDE IV), and non-bronchodilation effects, which may be mediated through other molecular mechanisms. It increases the force of contraction of diaphragmatic muscles by increasing the Ca uptake through adenosine-mediated channels. Pharmacokinetics: Absorption: Theophylline: Time to peak plasma concentration: Within 30 minutes; approx 5 hours (modified-release). Distribution: Theophylline: Widely distributed throughout the body except in body fat. Crosses the placenta and enters breast milk. Volume of distribution: Approx 0.45 L/kg (range: 0.3-0.7 L/kg). Plasma protein binding: Approx 40%, mainly to albumin. Metabolism: Theophylline: Metabolised in the liver by CYP1A2 via demethylation and by CYP2E1 and CYP3A3/4 via hydroxylation to form caffeine and 3-methylxanthine (active metabolites). Excretion: Theophylline: Via urine (approx 10% as unchanged drug). Elimination half-life: 8.7 hours (range: 6.1-12.8 hours).
Chemical Structure
Aminophylline Source: National Center for Biotechnology Information. PubChem Database. Aminophylline, CID=9433, https://pubchem.ncbi.nlm.nih.gov/compound/Aminophylline (accessed on Jan. 20, 2020)
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