Theophylline


Concise Prescribing Info
Indications/Uses
Listed in Dosage.
Dosage/Direction for Use
Adult : PO Acute bronchospasm Individualise dosing based on serum theophylline levels; use ideal body weight to calculate dose. As theophylline (anhydrous) immediate-release solution: Patients who have not received theophylline or other xanthine agents in the previous 24 hours: Loading dose: 5 mg/kg to achieve an average of approx 10 mcg/mL peak serum levels. Chronic bronchospasm For the prophylaxis and treatment of bronchospasm and reversible bronchoconstriction associated with asthma, COPD, and chronic bronchitis: As theophylline (anhydrous) modified-release tab/cap: 250-500 mg bid. Alternatively, 400 or 600 mg once daily. As theophylline monohydrate modified-release tab: Usual maintenance dose: 200 mg 12 hourly, may be adjusted to 300 mg or 400 mg 12 hourly based on clinical response. Dosage requirement must be guided by the patient’s serum theophylline concentrations, safety, and tolerability (refer to detailed product guideline). IV Acute severe bronchospasm As adjunct to inhaled β2-agonists and systemic corticosteroids for the treatment of acute exacerbations of symptoms and reversible airflow obstruction associated with asthma and other chronic lung diseases: As theophylline (anhydrous) in dextrose 5%: Patients who have not received theophylline or other xanthine agents in the previous 24 hours: Loading dose: 4.6 mg/kg via infusion over 30 minutes. Maintenance dose: Initial: 0.4 mg/kg/hour. Dosing recommendations are designed to achieve approx 10 mcg/mL serum levels. Dosage requirement must be guided by the patient’s serum theophylline concentrations, clinical response, lifestyle, and co-morbidities (refer to detailed product guideline).
Dosage Details
Intravenous
Acute severe bronchospasm
Adult: Individualise dosing based on serum theophylline levels; use ideal body weight to calculate dose. As adjunct to inhaled β2-agonists and systemic corticosteroids for the treatment of acute exacerbations of symptoms and reversible airflow obstruction associated with asthma and other chronic lung diseases: As theophylline (anhydrous) in dextrose 5%: In patients who have not received theophylline or other xanthine agents in the previous 24 hours: Loading dose: 4.6 mg/kg via infusion over 30 minutes. Maintenance dose: Initially, 0.4 mg/kg/hour. Dosing recommendations are designed to achieve approx 10 mcg/mL serum levels. Dosage requirement must be guided by the patient’s serum theophylline concentrations, clinical response, lifestyle, and co-morbidities (refer to detailed product guideline).
Child: Individualise dosing based on serum theophylline levels; use ideal body weight to calculate dose. In patients who have not received theophylline or other xanthine agents in the previous 24 hours: Loading dose: 4.6 mg/kg via infusion over 30 minutes. Maintenance dose: 1-<9 years Initially, 0.8 mg/kg/hour; 9-<12 years Initially, 0.7 mg/kg/hour. Dosing recommendations are designed to achieve approx 10 mcg/mL serum levels. Dosage requirement must be guided by the patient’s serum theophylline concentrations, clinical response, lifestyle, and co-morbidities (refer to detailed product guideline).
Elderly: Dose reduction may be necessary.

Oral
Acute bronchospasm
Adult: Individualise dosing based on serum theophylline levels; use ideal body weight to calculate dose. As theophylline (anhydrous) immediate-release solution: In patients who have not received theophylline or other xanthine agents in the previous 24 hours: Loading dose: 5 mg/kg to achieve an average of approx 10 mcg/mL peak serum levels. Dosage requirement must be guided by the patient’s serum theophylline concentrations, safety, and tolerability (refer to detailed product guideline).
Elderly: Dose reduction may be necessary.

Oral
Chronic bronchospasm
Adult: Individualise dosing based on serum theophylline levels; use ideal body weight to calculate dose. For the prophylaxis and treatment of bronchospasm and reversible bronchoconstriction associated with asthma, COPD, and chronic bronchitis: As theophylline (anhydrous) modified-release tab/cap: 250-500 mg bid. Alternatively, 400 or 600 mg once daily. As theophylline monohydrate modified-release tab: Usual maintenance dose: 200 mg 12 hourly, may be adjusted to 300 mg or 400 mg 12 hourly based on clinical response. Dosage requirement must be guided by the patient’s serum theophylline concentrations, safety, and tolerability (refer to detailed product guideline).
Child: Individualise dosing based on serum theophylline levels; use ideal body weight to calculate dose. As theophylline monohydrate modified-release tab: ≥6 years Usual maintenance dose: 9 mg/kg bid. As theophylline (anhydrous) modified-release tab/cap: 6-12 years 20-35 kg: 125-250 mg bid; >12 years Same as adult dose. Dosage requirement must be guided by the patient’s serum theophylline concentrations, safety, and tolerability (refer to detailed product guideline).
Elderly: Dose reduction may be necessary.
Special Patient Group
Patients with CHF, fever, cardiac decompensation, cor pulmonale, sepsis with multi-organ failure, or shock: Dose reduction may be necessary.

Smokers: Dose adjustments may be necessary.
Hepatic Impairment
Dose reduction may be necessary.
Administration
May be taken with or without food. May be taken w/ meals to reduce GI discomfort. Some individual prep must be taken w/ meals or on an empty stomach. Refer to monographs for individual formulations.
Contraindications
Porphyria, recent MI, acute tachyarrhythmia. Concomitant use with ephedrine (in children <6 years or with bodyweight <22 kg).
Special Precautions
Patient with cardiac diseases (e.g. CHF, cardiac arrhythmias except bradyarrhythmias, hypertension); cor pulmonale, acute pulmonary oedema, hypo- or hyperthyroidism, acute febrile illness or sustained fever, cirrhosis, acute hepatitis, cholestasis, sepsis with multiorgan failure, shock, cystic fibrosis, seizure disorders, active peptic ulcer, chronic alcoholism, pre-existing partial urinary tract obstruction (e.g. prostatic enlargement particularly in elderly males), viral infections, severe asthma. Smokers (including cessation of smoking). Not indicated as 1st drug of choice in the treatment of asthma in children. Concomitant electroconvulsive therapy. Hepatic and renal impairment. Children and elderly. Pregnancy and lactation.
Adverse Reactions
Significant: Exacerbated cardiac arrhythmias, urinary retention (particularly in elderly males), exacerbated seizures, status epilepticus, exacerbated peptic ulcer.
Cardiac disorders: Atrial or sinus tachycardia, palpitations.
Gastrointestinal disorders: Abdominal pain, diarrhoea, gastric irritation, GERD, nausea, vomiting.
Immune system disorders: Hypersensitivity (e.g. anaphylactic reaction, urticaria, bronchospasm).
Investigations: Increased serum calcium, increased blood creatinine.
Metabolism and nutrition disorders: Hyperuricaemia, hypokalaemia, hyperglycaemia, electrolyte imbalance.
Nervous system disorders: Dizziness, headache, tremor.
Psychiatric disorders: Agitation, anxiety, insomnia, sleep disorder, restlessness.
Renal and urinary disorders: Diuresis.
Skin and subcutaneous tissue disorders: Rash, pruritus.
Vascular disorders: Hypotension.
Potentially Fatal: Theophylline toxicity (with reduced clearance).
IV/Parenteral/PO: C
Patient Counseling Information
This drug may impair your ability to react, if affected, do not drive or operate machinery. Do not switch between different brands or dosage forms unless instructed by your doctor.
MonitoringParameters
Monitor serum theophylline concentrations after treatment initiation and prior to dose increases (especially in patients with conditions that may alter theophylline clearance); heart rate, respiratory rate, arterial or capillary blood gases (as necessary), fluid balance, electrolyte concentrations, acid-base balance (during prolonged IV treatment); cardiac and CNS changes prior to and periodically during therapy. Assess treatment effectiveness; signs of worsening asthma symptoms, and CNS effects (e.g. irritability, insomnia).
Overdosage
Symptoms: Nausea, vomiting (often severe), epigastric pain, haematemesis, restlessness, hypertonia, headache, insomnia, exaggerated limb reflexes, convulsions, hypotension, sinus tachycardia, ectopic beats, supraventricular and ventricular tachycardia, hypokalaemia, hyperglycaemia, hypomagnesaemia, metabolic acidosis, rhabdomyolysis, and coma in severe cases. Management: Symptomatic and supportive treatment. Perform gastric lavage or administer activated charcoal (0.5 g/kg up to 20 g) within 1-2 hours of ingestion. Monitor serial plasma theophylline levels immediately and at regular intervals. If adequate response to treatment is not achieved, may consider haemoperfusion or haemodialysis. May administer antiemetics (e.g. metoclopramide, ondansetron) to treat vomiting; IV diazepam to control isolated convulsions. Monitor ECG; assess serum electrolytes and glucose as clinically indicated. In extreme cases of tachycardia, β-blockers may be given in non-asthmatic patient.
Drug Interactions
May increase the frequency of nausea, nervousness, and insomnia with ephedrine. Increased clearance with aminoglutethimide, carbamazepine, isoprenaline, phenytoin, rifampicin, ritonavir, sulfinpyrazone, and barbiturates (e.g. phenobarbital). Decreased clearance with aciclovir, allopurinol, carbimazole, cimetidine, clarithromycin, erythromycin, ciprofloxacin, enoxacin, disulfiram, fluconazole, fluvoxamine, interferon alfa, isoniazid, methotrexate, mexiletine, pentoxifylline, propafenone, propranolol, tiabendazole, verapamil, and oral contraceptives. May increase plasma levels with influenza vaccines. May inhibit the effects of adenosine receptor agonists (e.g. adenosine, regadenoson). May antagonise the sedative effect of benzodiazepines (e.g. diazepam, flurazepam). May increase the risk of arrhythmias with halothane. May reduce the convulsive threshold with ketamine. May increase renal clearance of lithium. May potentiate the hypokalaemic effect of β2-agonists, corticosteroids, and diuretics.
Food Interaction
Increased clearance with St. John’s wort. Clearance may either be increased or decreased by alcohol. May decrease the rate of absorption with food.
Lab Interference
May decrease triiodothyronine. May increase levels of plasma glucose, uric acid, free fatty acids, total cholesterol, HDL, HDL/LDL ratio, and urinary free cortisol excretion that may affect the respective tests.
Action
Description: Theophylline is a xanthine that stimulates respiration, relaxes bronchial smooth muscle (bronchodilation), and suppresses the response of airways to stimuli (non-bronchodilator prophylactic activity). Although its mechanism is not yet fully understood, it is expected to exert its effects through inhibition of phosphodiesterase and elevation of intracellular cyclic adenosine monophosphate (cAMP).
Pharmacokinetics:
Absorption: Rapidly and completely absorbed from the gastrointestinal tract (immediate-release). May decrease the rate of absorption with food. Time to peak plasma concentration: 1-2 hours (oral solution, immediate-release tab/cap); within 30 minutes (IV).
Distribution: Distributed throughout the body except in fatty tissues. Crosses the placenta and enters breast milk. Volume of distribution: Approx 0.45 (range: 0.3-0.7) L/kg. Plasma protein binding: Approx 40-60%, primarily to albumin.
Metabolism: Metabolised in the liver via demethylation by CYP1A2 into 3-methylxanthine (active) and 1 methylxanthine, and via hydroxylation by CYP2E1 and 3A3 into 1,3-dimethyluric acid. 1-methylxanthine undergoes further hydroxylation by xanthine oxidase into 1-methyluric acid. Approx 6% is metabolised via N-methylation into caffeine (active).
Excretion: Mainly via urine (approx 10% as unchanged drug). Elimination half-life: 8.7 (range: 6.1-12.8) hours (healthy adults).
Chemical Structure

Chemical Structure Image
Theophylline

Source: National Center for Biotechnology Information. PubChem Database. Theophylline, CID=2153, https://pubchem.ncbi.nlm.nih.gov/compound/Theophylline (accessed on Jan. 23, 2020)

Storage
Cap/tab: Store between 20-25°C. Oral solution/IV inj: Store at 25°C. Avoid excessive heat exposure.
ATC Classification
R03DA04 - theophylline ; Belongs to the class of xanthines. Used in the systemic treatment of obstructive airway diseases.
References
Anon. Theophylline. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 19/03/2020.

Buckingham R (ed). Theophylline. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 19/03/2020.

Joint Formulary Committee. Theophylline. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 14/05/2020.

Nuelin SA 250 mg Tablets (Mylan Products Ltd). MHRA. https://products.mhra.gov.uk/. Accessed 19/03/2020.

Pharmaniaga Theophylline Tablet (Pharmaniaga Manufacturing Berhad). National Pharmaceutical Regulatory Agency - Ministry of Health Malaysia. https://www.npra.gov.my/. Accessed 19/03/2020.

Slo-Phyllin 125 mg Capsules (Merck Serono Ltd). MHRA. https://products.mhra.gov.uk/. Accessed 19/03/2020.

Theophylline Anhydrous and Dextrose Injection, Solution (B. Braun Medical Inc). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 19/03/2020.

Theophylline Extended Release Tablet (Glenmark Pharmaceuticals Inc., USA). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 19/03/2020.

Theophylline Solution (American Health Packaging). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 19/03/2020.

Uniphyllin Continus 300 mg Prolonged Release Tablets (Napp Pharmaceuticals Ltd). MHRA. https://products.mhra.gov.uk/. Accessed 19/03/2020.

Disclaimer: This information is independently developed by MIMS based on Theophylline from various references and is provided for your reference only. Therapeutic uses, prescribing information and product availability may vary between countries. Please refer to MIMS Product Monographs for specific and locally approved prescribing information. Although great effort has been made to ensure content accuracy, MIMS shall not be held responsible or liable for any claims or damages arising from the use or misuse of the information contained herein, its contents or omissions, or otherwise. Copyright © 2020 MIMS. All rights reserved. Powered by MIMS.com
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