• Acute severe asthma
• Acute exacerbation of chronic pulmonary disease (COPD)

Contra-indications

• Consider allergy or hypersensitivity to aminophylline or theophylline, caffeine or theobromine
• Contraindicated in acute porphyria

Drug interactions

• Several medications may increase or decrease theophylline concentration
• Always check current BNF
• Aminophylline can increase digoxin level

Common drugs that increase plasma concentration of aminophylline

• Antibiotics e.g. clarithromycin, erythromycin, ciprofloxacin, azithromycin
• Antifungals e.g. fluconazole, ketoconazole
• Antivirals e.g. aciclvoir
• Calcium channel blockers
• Fluvoxamine
• Cimetidine
• Combined hormonal contraceptives

Common drugs that decrease plasma concentration of aminophylline

• Antiepileptic medication e.g. phenytoin and carbamazepine, phenobarbital
• Lithium
• Methotrexate 
• Ritonavir
• Rifampicin
• Primidone
• Smoking (present several weeks after cessation)
• Alcohol

• Check potassium normal 
• If patient on maintenance oral theophylline, perform baseline theophylline levels 
• Only if patient has NOT received maintenance oral theophylline or aminophylline within last 24 hr, give loading dose

Find preparations

• Aminophylline injection = 25 mg/mL, 10 mL ampoules

Diluents

• Sodium chloride 0.9%, glucose 5%

Weight

• In obese and overweight patients (BMI ≥ 25), use ideal body weight (IBW) to calculate maintenance and loading dose(s)
• In patients who are not overweight (BMI < 25), use actual body weight (ABW) to calculate maintenance and loading dose(s)

How to calculate body mass index (BMI)

• BMI = weight in kg / (height in m)² - BMI Calculator

How to calculate IBW

• See Ideal Body Weight guideline

• 5 mg/kg of selected ABW or IBW (up to a maximum of 500mg) IV by infusion over 20-30 min
  • diluted in 100ml bag of diluent (see Diluents)
• Monitor heart rate continuously during infusion

Checks during loading infusion

• Maximum infusion rate 25 mg/min
• Monitor heart rate continuously during infusion
• Label as 'loading dose' on infusion section of drug chart or electronic prescribing and medicines administration system (EPMA)
• If patient experiences acute adverse effects (see below) while loading dose is being infused, slow rate or stop infusion for 5-10 min

Adverse effects

• Hypotension
• Arrhythmias and convulsions (especially if given rapidly) 
• Hypersensitivity reactions: 
  
  • nausea
  • vomiting
  • dizziness
  • headache CNS stimulation
  • insomnia

• Plasma-theophylline concentration is increased in heart failure and hepatic impairment, and is decreased in smokers
• Administer maintenance dose immediately after loading dose

Preparation of maintenance dose

• Add 500 mg to 500 mL or 250 mg to 250 mL (= 1 mg/mL) of sodium chloride 0.9% or glucose 5% 
  
  • reconstituted aminophylline has a 24 hr expiry
• Infusion rates based on concentration of 1 mg/mL 
  
  • prescribe as mg/hr NOT mL/hr
• Administer using a rate-controlled infusion pump
• Maximum rate of administration = 25 mg/min

Maintenance dose in elderly/frail/cor-pulmonale/hepatic or cardiac failure

• Infusion rate is 0.3 mg/kg/hr of selected ABW or IBW
• Infusion rates based on concentration of 1 mg/mL

Table 1: Infusion rate (mL/hr=mg/hr) for a range of body weights (dosage 0.3 mg/kg/hr)

Maintenance dose in non-smoking adult

• Infusion rate is 0.5 mg/kg/hr of selected ABW or IBW

Table 2: Infusion rate (mL/hr) for a range of body weights (dosage 0.5 mg/kg/hr)

Maintenance dose in smoking adult

• Infusion rate is 0.7 mg/kg/hr of selected ABW or IBW

Table 3: Infusion rate (mL/hr) for a range of body weights (dosage 0.7 mg/kg/hr)

Potassium

• If low potassium, replace - potential to cause hypokalaemia and arrhythmia
• If loading dose given, monitor heart rate continuously throughout infusion and check serum potassium 1-2 hr after dose
• Monitor serum potassium daily while infusion continues

Heart rate and blood pressure

• Monitor every hour for first 4 hr, then every 2 hr if stable

Symptoms and signs of toxicity

• Vomiting which may be severe and intractable
• Agitation, restlessness
• Dilated pupils
• Sinus tachycardia
• Hyperglycaemia
• Refer to Toxbase - https://www.toxbase.org/

Initial monitoring to exclude toxicity

• After starting maintenance infusion, monitor serum theophylline 4-6 hr later
  
  • do NOT use this level to determine if aminophylline is in therapeutic range (see steady state monitoring below)

Theophylline level <10 mg/L

• Do not increase rate of infusion

Theophylline level >20 mg/L and patient has symptoms or signs of toxicity

• Stop infusion and repeat level every 6 hr 
• When level <20 mg/L and patient does not have symptoms or signs of toxicity, restart infusion at previous rate reduced by ≥25% 
  
  • repeat level at 4-6 hr after restarting infusion

Theophylline level >20 mg/L and patient does not have symptoms or signs of toxicity

• Restart infusion at previous rate reduced by ≥25% 
  
  • repeat level at 4-6 hr after restarting infusion

Steady state monitoring

• After any dose adjustment, re-check plasma theophylline level within 4-6 hr later
• Even if level is stable, monitor theophylline levels every 24 hr
• Titrate dose accordingly - target range 10-20 mg/L
• Adjust maintenance dose according to plasma theophylline concentration

Dose adjustment based on serum theophylline

Table 4: IV dosage adjustment based on serum theophylline concentration - target range 10-20 mg/L

How long to continue infusion

• Continue infusions for ≥24 hr with review by medical staff at agreed intervals
• Only if instructed by respiratory consultant/specialist trainee, continue longer than a further 24-48 hr 
• Respiratory consultant/specialist decides if patient is stabilised enough to step down treatment 

How to wean off infusion

• Start weaning aminophylline in the morning 
• Halve infusion rate every 2 hr
• Aim to reduce and stop infusion over a 10-12 hr period

Oral theophylline

• If patient previously on theophylline, commence usual dose by giving first dose in the evening
• If patient was not on theophylline before admission, but baseline control was not adequate, refer to respiratory medicine to consider oral theophylline

How to calculate oral theophylline dose

• Calculate total dose of aminophylline given in 24 hr of steady state infusion = hourly dose x 24 x 0.8 (for salt correction) mg
• Dose of theophylline to give every 12 hr = total dose of aminophylline in 24 hr ÷ 2 
• Adjust doses to those of brand of slow-release theophylline to be prescribed
• Give first dose of slow-release theophylline on evening of day weaned off aminophylline infusion
• See Example below

• If IV aminophylline dose is 35 mg/hr, then total daily dose is 840 mg

  1. Oral theophylline dose: 840 mg x 0.8 = 672 mg daily

  2. If dosing interval for oral administration is every 12 hr i.e. twice daily, divide 672 mg by 2. This gives oral dose of 336 mg twice daily

  3. Suitable theophylline dosing regimen e.g. Uniphyllin Continus^®, 300 mg in the morning and 400 mg in the evening

Check plasma theophylline levels

• If converted from aminophylline IV to slow-release theophylline oral, check within 3 days: 4-6 hr after morning dose
• If patient has not been on theophylline/aminophylline before starting twice daily dosing, check after 5 days of twice daily dosing; 4-6 hr after morning dose