Theophylline is a non-selective phosphodiesterase inhibitor that has bronchodilating properties and acts to increase diaphragmatic contractility. It relaxes smooth muscles and has diuretic effects as well.

Theophylline Uses:

• Reversible airflow obstruction:

  • For the treatment of chronic asthma symptoms and reversible airflow blockage, as well as other chronic lung conditions like emphysema and chronic bronchitis, it is taken orally.
  • It is used as an adjunct to inhaled beta-2 selective agonists and systemically administered corticosteroids in the intravenous formulation to treat acute exacerbations of symptoms and reversible airflow obstruction associated with asthma and other chronic lung diseases (such as chronic bronchitis and emphysema).

  • Guideline recommendations:

    • Asthma:
      • The use of oral theophylline as a long-term asthma control medication in children under the age of five is discouraged by both the 2018 Global Initiative for Asthma Guidelines (GINA) and the 2007 National Heart, Lung, and Blood Institute Asthma Guidelines.
      • Additionally, oral theophylline is not recommended by GINA guidelines for asthma in children 6 to 11 years of age.
      • When used as an additional long-term control medication for moderate to severe asthma or as a long-term control medication for mild asthma in adults and adolescents, oral theophylline is a potential alternative but not the recommended therapy.
      • However, due to effectiveness issues and the risk for side events, a progressive approach utilising inhaled corticosteroids with or without inhaled long-acting beta-agonists depending on the severity of asthma is preferred to theophylline.
      • Due to ineffectiveness and safety concerns, both recommendations advise against using theophylline to treat asthma exacerbations.
    • COPD:
      • Theophylline has been shown to be effective in COPD at higher doses when taken in slow-release formulations, according to the Global Initiative for Chronic Obstructive Lung Disease Guidelines (2018), but it is not a preferred treatment for COPD exacerbations because of the possibility of systemic toxicity. In patients with chronic stable COPD, it provides a mild bronchodilator effect.

  • Off Label Use of Theophylline in Adults:

    • Bradycardia
    • Patients who underwent heart transplants.
    • Reversal of unfavourable effects caused by regadenoson or dipyridamole, such as angina and hypotension during nuclear cardiac stress testing. They are not, however, the front-line agent.

Theophylline Dose in Adults

It is significant to highlight that dos should be tailored based on serum concentrations at steady state. Use should be made of ideal body weight. Poor distribution of theophylline occurs in body fat.

Theophylline Dose for Bradycardia during heart transplantation (off-label):

• Oral: Initial dosage is 150 mg twice daily. based on the heart rate response and tolerability, then titrate up as necessary.
  Up to 900 mg of the drug per day have been recorded and utilised in clinical settings.

Theophylline Dose in the treatment of Reversible airflow obstruction for acute symptoms:

• Loading dose: IV, Oral (immediate release solution):

  • Asthma exacerbations:

    • Theophylline medication for acute asthma attacks is neither suggested nor advised by the most recent clinical practise recommendations.:
      • Due to a substantial side effect profile, theophylline IV therapy for acute COPD is neither supported nor advised by current clinical practise standards.
    • Patients who haven't taken theophylline in the last day:
      • It is administered as 4.6 mg/kg/dose intravenously, which is the preferred method, or as a 5 mg/kg oral solution for immediate release alone.
      • It is important to note that the loading dose is intended to produce a serum level that is between 5 and 16 mcg/mL, with an average of 10 mcg/mL.
      • On average, blood levels will increase by 2 mcg/mL for every 1 mg/kg of theophylline administered.
        30 minutes for intravenous formulations and 24 hours for oral formulations after the loading dosage, measure theophylline blood levels.
      • When the distribution is finished, this is done. In order to determine the necessity, appropriateness, and dosage of further loading doses as well as to direct maintenance therapy.
    • Those who had taken theophylline within the previous day:
      • Before measuring theophylline levels in the serum, a loading dose shouldn't be given.
      • You should compute the loading dose as follows:
      • Measured serum theophylline concentration minus intended serum theophylline concentration equals the dose (Vd)

Maintenance: Continuous IV infusion:

Unless otherwise stated, the dose is administered to reach a target concentration of 10 mcg/mL. In patients with reduced theophylline clearance, lower starting doses could be advised. During the initial 12- to 24-hour period, serum level assessments should be used to adjust the dosage.

• Adults ≤60 years:

  • 0.4 mg/kg/hour is administered, with a daily dose cap of 900 mg, unless serum levels call for a higher dose.

• Adults >60 years:

  • It is administered at a rate of 0.3 mg/kg/hour, with a daily dose cap of 400 mg, unless serum levels call for a higher rate.

• Dose for treating Cardiac decompensation, cor pulmonale, sepsis with multiorgan failure, or shock:

  • 0.2 mg/kg/hour is the recommended dosage, with a daily maximum of 400 mg, unless serum levels call for a higher dose.

Theophylline Dose in the treatment of Reversible airflow obstruction, chronic conditions: Oral:

It should be emphasised that an additional dose should only be given if necessary and tolerated. If side effects similar to those from coffee appear, think about reducing the dose or employing a gentler titration. In order to prevent breakthrough symptoms in individuals who require greater than usual doses, one can administer smaller doses more frequently. 

• Immediate release:

  • At first, 300 mg/day are administered in divided doses every 6 to 8 hours.
  • Increase the dose to 400 mg/day divided every 6 to 8 hours after three days if tolerated. And if tolerated even better, raise to 600 mg/day distributed every 6 to 8 hours after another 3 days.

• Extended-release:

  • 12-hour formulation (tablets):
    • The dosage is first 300 mg/day in divided doses administered every 12 hours, increasing to 400 mg/day in divided doses administered every 12 hours after 3 days if tolerated.
    • After three days, raise the dosage to 600 mg/day in divided doses every 12 hours if it is still well tolerated.
  • 24-hour formulation (capsules and tablets):
    • It is initially administered as 300–400 mg once daily. Increase to 400 to 600 mg once daily if tolerated after three days.
    • If a dose of more than 600 mg is recommended, increase the dose based on the serum level.

Theophylline Dose for treating Reversal of dipyridamole- or regadenoson-induced adverse reactions during nuclear cardiac stress testing (alternative agent) (off-label):

• IV: 50 mg are administered over one minute. If necessary, take the dose again.

• Dosage adjustment based on serum theophylline concentrations:

• IV, Oral:

  • <9.9 mcg/mL:
    • If the current dose is tolerated and symptoms are not well managed, up the dose or infusion rate by about 25%.
    • For further dosage adjustment, recheck serum levels after 24 hours for IV formulations and 3 days for oral formulations.
  • 10 to 14.9 mcg/mL:
    • Maintain the dose and reassess serum concentrations at 24-hour intervals for IV formulations or 6- to 12-month intervals for oral formulations if symptoms are effectively managed and the current dose is tolerated.
      If symptoms are not under control and the dosage is well tolerated, think about adding other drugs.
  • 15 to 19.9 mcg/mL:
    • Even if the present dosage is well tolerated, think about decreasing the dose or infusion rate by 10%.
  • 20 to 24.9 mcg/mL:
    • Even in the absence of any negative effects, lower the dose or infusion rate by 25%.
    • For guidance on additional dose adjustments, recheck blood concentrations after 24 hours for intravenous formulations and 3 days for oral formulations.
  • 25 to 30 mcg/mL:
    • Skip the following oral dose if the infusion is stopped for 24 hours. Even if there are no side effects, reduce subsequent doses or infusion rates by at least 25%.
    • For guidance on additional dosage modifications, recheck serum concentrations after 24 hours for the IV formulation or 3 days for the oral formulation.
    • Withhold the infusion if the patient is still exhibiting symptoms and think about whether an overdose therapy is necessary.
  • >30 mcg/mL:
    • As needed, stop the infusion and treat the overdose. If theophylline is resumed, reduce the dose or infusion rate by at least 50% and monitor blood concentrations again after 24 hours or 3 days for oral formulations and IV formulations, respectively, to inform further dose changes.

Theophylline Dose in Childrens

Based on the serum concentrations in steady state, the dose should be tailored. Age-dependent variations in theophylline pharmacokinetics may change the recommended doses, especially in paediatric patients. For patients who are obese, the dose should be calculated using their optimal body weight.

Theophylline Dose in the treatment of Acute symptoms of asthma or other chronic lung conditions:

It is not advised for the treatment of severe asthmatic flare-ups.

• Loading dose:

It should be mentioned that the doses given are meant to produce a blood level of roughly 10 mcg/mL. The recommended method for administering the loading dosage is intravenously, while a fast absorbed oral medication may also be used (not an extended-release product). Blood concentrations will typically increase by 2 mcg/mL for every 1 mg/kg of theophylline administered.

• Patients not currently receiving methylxanthines:

  • IV: 4.6 mg/kg/dose
  • Oral: Immediate release product: 5 mg/kg

• Patients currently receiving methylxanthines:

  • Patients who have recently taken theophylline or aminophylline do not require a loading dosage without first measuring their serum theophylline concentration. Following should be used to calculate the loading dose:
    • Dose = (C desired – C measured) x (Vd)
    • C desired = desired serum theophylline concentration
    • C measured = measured serum theophylline concentration
  • Maintenance dose: Continuous IV infusion:

In order to get the desired concentration of 10 mcg/mL, the dose is administered. In patients with decreased theophylline clearance, lower starting doses could be advised. During the initial 12- to 24-hour period, serum concentration measurements should be used to adjust the dosage.

• Infants 4 to 6 weeks:

  • 1.5 mg/kg/dose every 12 hours

• Infants 6 to 52 weeks:

  • Dose (mg/kg/hour) = (0.008 X age in weeks) + 0.21

• Children 1 to <9 years:

  • 0.8 mg/kg/hour

• Children 9 to <12 years:

  • 0.7 mg/kg/hour

• Adolescents 12 to <16 years (otherwise healthy, nonsmokers):

  • Unless serum concentrations indicate a need for a higher dose, it is administered at a rate of 0.5 mg/kg/hour with a daily dose cap of 900 mg.

• Adolescents 12 to <16 years (cigarette or marijuana smokers):

  • 0.7 mg/kg/hour

• Adolescents 16 to 18 years (otherwise healthy, nonsmokers):

  • 0.4 mg/kg/hour is administered, with a daily dose cap of 900 mg, unless serum concentrations call for higher doses.

• Theophylline Dose in the treatment of Cardiac decompensation, cor pulmonale, hepatic dysfunction, sepsis with multiorgan failure, shock:

  • A maximum dose of 400 mg per day is initially administered, unless serum concentrations point to the necessity for higher doses.

Theophylline Dose in the treatment of Chronic conditions of asthma or other chronic lung conditions:

If the dose is tolerated, only increase it. If side effects similar to those from caffeine appear, think about reducing the dose or employing a slower up-titration. Patients who have a faster metabolism can benefit from smaller dosages administered more frequently to avoid breakthrough symptoms that could arise from low trough concentrations prior to the next dose.

• Immediate-release formulation: Oral:

Do not exceed 16 mg/kg/day if the patient is at risk for poor clearance or if it is not practical to monitor serum theophylline concentrations. The daily dosage cap is 400 mg.

• Manufacturer's labeling: Frequency-based upon age.

  • Infants:
    • Total daily dose (mg/day) = [(0.2 x age in weeks) + 5] x (weight in kg); frequency is based on age
  • Dosing interval:
  • ≤26 weeks:
    • Divide into 3 equal doses and administer every 8 hours
  • >26 weeks:
    • Divide into 4 equal doses and administer every 6 hours
  • Children and Adolescents 1 to 15 years and ≤45 kg: Initial:
  • Days 1 to 3:
    • it is given as 12 to 14 mg/kg/day in divided doses every 4 to 6 hours. The maximum daily dose is 300 mg/day
  • Days 4 to 6:
    • it is given as 16 mg/kg/day in divided doses every 4 to 6 hours. The maximum daily dose is 400 mg/day
  • Maintenance:
    •  it is given as 20 mg/kg/day in divided doses every 4 to 6 hours. The maximum daily dose is 600 mg/day
  • Children and Adolescents >45 kg or Adolescents ≥16 years: Initial:
  • Days 1 to 3:
    • it is given as 300 mg/day in divided doses every 6 to 8 hours.
  • Days 4 to 6:
    • then it is given as 400 mg/day in divided doses every 6 to 8 hours.
  • Maintenance:
    • and then 600 mg/day in divided doses every 6 to 8 hours.

• Alternate dosing; age-directed:

  • Children 1 to <9 years:
    • it is given as 20 to 24 mg/kg/day. The maximum daily dose is 600 mg/day.
  • Children 9 to 12 years:
    • it is given as 16 mg/kg/day. The maximum daily dose is 600 mg/day.
  • Children and Adolescents >12 to 16 years (nonsmokers):
    • it is given as 13 mg/kg/day. The maximum daily dose is 600 mg/day.
  • Children >12 years and Adolescents (smokers):
    • it is given as 16 mg/kg/day. The maximum daily dose is 600 mg/day.
  • Adolescents >16 years (nonsmokers):
    • it is given as10 mg/kg/day. The maximum daily dose is 600 mg/day.

• Extended-release formulations: Oral:

It is crucial to remember not to exceed 16 mg/kg/day if there is a chance of poor clearance or if it is not practical to monitor serum theophylline concentrations. The highest daily dose advised is 400 mg.

• Manufacturer's labeling:

  • Children ≥6 years and Adolescents <16 years, weighing ≤45 kg: Initial:
    • Days 1 to 3:
      • it is given as 12 to 14 mg/kg/day. The maximum daily dose is 300 mg/day.
    • Days 4 to 6:
      • it is given as 16 mg/kg/day. The maximum daily dose is 400 mg/day.
    • Maintenance:
      • it is given as 20 mg/kg/day. The maximum daily dose is 600 mg/day.

  • Dosing interval (product specific):

    • 12-hour extended-release tablets:
      • Children ≥6 years and Adolescents:
        • Divide into 2 equal doses and administer every 12 hours
    • 24-hour extended-release tablets:
      • Children ≥12 years and Adolescents:
        • Administer every 24 hours
      • Children ≥6 years and Adolescents, weighing >45 kg or Adolescents ≥16 years:
    • 12-hour extended-release tablets:
      • Children ≥6 years and Adolescents, weighing >45 kg or Adolescents ≥16 years: Initial:
      • Days 1 to 3:
        • it is given as 300 mg/day in divided doses every 12 hours
      • Days 4 to 6:
        • it is given as 400 mg/day in divided doses every 12 hours
      • Maintenance:
        • it is given as 600 mg/day in divided doses every 12 hours
      • 24-hour extended-release tablets:
      • Children ≥12 years and Adolescents, weighing >45 kg or Adolescents ≥16 years: Initial:
      • Days 1 to 3:
        • it is given as300 to 400 mg once a day.
      • Days 4 to 6:
        • it is given as400 to 600 mg once a day.
      • Maintenance:
        • Titration should be done according to serum concentrations.

  • Alternate dosing; age-directed:

    • Children 6 to <9 years:
      • it is given as 20 to 24 mg/kg/day.
      • The maximum daily dose is 600 mg/day
    • Children 9 to 12 years:
      • it is given as 16 mg/kg/day.
      • The maximum daily dose is 600 mg/day
    • Children and Adolescents >12 to 16 years (nonsmokers):
      • it is given as 13 mg/kg/day.
      • The maximum daily dose is 600 mg/day
    • Children >12 years and Adolescents (smokers):
      • it is given as 16 mg/kg/day.
      • the maximum daily dose is 600 mg/day
    • Adolescents >16 years (nonsmokers):
      • it is given as 10 mg/kg/day.
      • The maximum daily dose is 600 mg/day

Chronic conditions: Oral:

The dose is only raised if tolerated, it should be mentioned. If side effects similar to those from coffee appear, think about reducing the dose or employing a gentler titration. Patients who have a faster metabolism may benefit from smaller dosages administered more frequently to avoid breakthrough symptoms that could arise from low trough concentrations prior to the next dose.

• Immediate-release oral solution:

  • The starting dose is 300 mg/day divided into 6–8 hourly doses, while the maintenance dose is 400–600 mg/day.
  • The daily dosage cap is 600 mg.

• Extended-release formulations:

  • A maintenance dose of 400 to 600 mg is given once daily after the initial dose of 300 to 400 mg.
  • The highest daily dose advised is 600 mg.

• Dosage adjustment based on serum theophylline concentrations:

  • Infants, Children, and Adolescents:

Serum theophylline concentrations need to be evaluated again after 3 days when using the oral formulation, or after 12 hours for kids and 24 hours for adults when using the intravenous route. When clinically necessary or if a concurrent drug is administered that could impact theophylline serum levels, patients who are being maintained with oral treatment should have reevaluations every 6 to 12 months.

• <9.9 mcg/mL:
  • If tolerated, but symptoms remain, increase the dose by approximately 25%. Recheck serum theophylline concentrations.
• 10 to 14.9 mcg/mL:
  • Maintain the current dose if tolerated. Recheck serum concentrations at 24-hour intervals for acute IV dosing, or at 6- to 12-month intervals for oral dosing.
• 15 to 19.9 mcg/mL:
  • Consider 10% dose reduction to improve safety margin even if the dose is tolerated.
• 20 to 24.9 mcg/mL:
  • Reduce the dose by approximately 25%. Recheck serum concentrations.
• 25 to 30 mcg/mL:
  • Skip next oral dose or stop infusion for 12 hours in children or for 24 hours in adults and decrease subsequent doses by at least 25%. Recheck serum concentrations.
• >30 mcg/mL:
  • Stop dosing and treat overdosage. If it is resumed, decrease subsequent doses by at least half. Recheck serum concentrations.

Theophylline Pregnancy Risk Factor C

• Animal reproduction studies have shown adverse effects.
• It can cause adverse effects in newborns because it crosses the placenta.
• The use of it at the recommended doses, keeping serum concentrations between 5 and 12 mcg/mL is safe.
• Pregnant women, however, may experience increased maternal negative effects and lower efficacy.
• During pregnancy, theophylline metabolism may alter.
• Half-life is approximately the same as that in healthy, nonsmoking adults who have asthma.
• It can increase to 13 hours during the first and second trimesters.
• The third trimester may see an 8 to 18 hour range.
• The third trimester also sees an increase in distribution volume.
• Monitor serum levels.
• Theophylline should be used in pregnant women with severe asthma just like in adults.

Use of theophylline during breastfeeding

• Breast milk contains theophylline.
• Breast milk contains the same amount of theophylline as maternal serum.
• Nursing infants may experience irritability. If toxic serum levels are not present in the mother, then serious adverse effects are unlikely for the infant.

Theophylline Dose in Kidney Disease:

No specific dose adjustments are required for both oral or intravenous formulation in kidney disease.

Theophylline Dose in Liver disease:

Oral:

• There are no specific dosage adjustments provided in the literature.
• Dose reduction and frequent monitoring of serum theophylline concentration are required, however.
• The risk of severe and potentially fatal toxicity can occur. The maximum recommended dose is 400 mg/day.

IV:

• Initially, it is given as 0.2 mg/kg/hour.
• The maximum dose is 400 mg daily unless serum concentrations indicate the need for a larger dose.
• Use with caution and monitor serum theophylline concentrations frequently. The risk of severe and potentially fatal toxicity may occur.

Side effects of Theophylline:

Adverse events were observed at therapeutic serum levels.

• Cardiovascular:

  • Cardiac Flutter
  • Tachycardia

• Central Nervous System:

  • Headache
  • Hyperactivity (Children)
  • Insomnia
  • Restlessness
  • Seizure
  • Status Epilepticus (Nonconvulsive)

• Endocrine & Metabolic:

  • Hypercalcemia (With Concomitant Hyperthyroid Disease)

• Gastrointestinal:

  • Gastroesophageal Reflux (Aggravation)
  • Gastrointestinal Ulcer (Aggravation)
  • Nausea
  • Vomiting

• Genitourinary:

  • Difficulty In Micturition (Elderly Males With Prostatism)
  • Diuresis (Transient)

• Neuromuscular & Skeletal:

  • Tremor

Contraindications to Theophylline:

Hypersensitivity to theophylline is a serious contraindication.

Canadian labeling: Additional contraindications, not in US labeling

• Hypersensitivity to xanthine derivatives
• Cardiac stimulation can be harmful in cases of coronary artery disease and heart failure.
• Peptic ulcers.
• Children can be co-administered with ephedrine.

Warnings and precautions

• Toxicology of theophylline:

  • Reduced clearance of theophylline can lead to severe and possibly fatal theophylline poisoning.
  • Theophylline clearance may be lowered in patients with severe pulmonary edoema, cardiac illness, cor pulmonale, and fever.
  • These patients will need to be monitored more closely and benefits should be considered. You can reduce the infusion rate.
  • Patients should immediately be tested for theophylline poisoning if they experience nausea, persistent vomiting, or nausea. Do not take any further doses.

• Cardiovascular disease

  • Patients with cardiac arrhythmias, excluding bradyarrhythmias, should exercise caution. It can worsen arrhythmias.

• Cystic Fibrosis:

  • Cystic fibrosis patients should exercise caution. Patients with cystic fibrosis may have a higher clearance of theophylline.

• Hepatic impairment

  • Patients with hepatic impairment (eg cirrhosis or acute hepatitis) should be cautious. There is a greater risk of serious and possibly fatal theophylline poisoning. Theophylline clearance in these patients is reduced by more than half.
  • It is important to reduce doses and monitor the serum theophylline levels frequently.

• Hyperthyroidism:

  • Hyperthyroidism patients should be cautious as it can increase renal clearance.

• Peptic ulcer disease:

  • It can also cause an exacerbation or worsening of pre-existing conditions such as peptic ulcer disease.

• Seizure disorder:

  • If already present, it can also worsen seizure disorders.

Theophylline: Drug Interaction

Risk Factor C (Monitor therapy)
Abiraterone Acetate	May elevate CYP1A2 substrates' serum concentration (High risk with Inhibitors).
Adalimumab	Theophylline derivatives' serum levels could drop.
Alcohol (Ethyl)	Theophylline serum concentration can rise.
Allopurinol	Theophylline derivatives' serum levels might rise.
Amifampridine	Amifampridine may have a stronger neuroexcitatory and/or seizure-potentiating impact when combined with substances with seizure threshold lowering potential.
Antithyroid Agents	Theophylline derivatives' serum levels might rise.
AtoMOXetine	Could make sympathomimetics' hypertensive effects stronger. The tachycardic impact of sympathomimetics may be increased by atoMOXetine.
Barbiturates	Theophylline derivatives' serum levels could drop.
Beta-Blockers (Beta1 Selective)	May lessen theophylline derivatives' bronchodilator effects. Management: Keep an eye out for decreased theophylline effectiveness when using any beta-blocker at the same time. Compared to nonselective medicines, beta-1 selective drugs are less likely to antagonise theophylline, but selectivity may be lost at larger dosages.
Broccoli	May lower the serum level of CYP1A2 substrates (High risk with Inducers).
BuPROPion	Agents With Seizure Threshold Lowering Potential may have an enhanced neuroexcitatory and/or seizure-potentiating impact.
Cannabinoid-Containing Products	Makes sympathomimetics' tachycardic effect stronger. Exceptions: Cannabidiol.
Cannabis	May lower the serum level of CYP1A2 substrates (High risk with Inducers).
CYP1A2 Inducers (Moderate)	May lower the serum level of CYP1A2 substrates (High risk with Inducers).
CYP1A2 Inhibitors (Moderate)	May lower the serum level of CYP1A2 substrates (High risk with Inducers).
Cyproterone	May lower the serum level of CYP1A2 substrates (High risk with Inducers).
Disulfiram	Theophylline derivatives' serum levels might rise.
Estrogen Derivatives	Theophylline derivatives' serum levels might rise.
Febuxostat	May raise the active metabolite(s) of theophylline derivatives' serum level. In particular, levels of 1-methylxanthine, a metabolite of uncertain therapeutic significance, may rise.
Fluconazole	Theophylline derivatives' serum levels might rise.
Formoterol	Theophylline derivatives might make formoterol's harmful or hazardous effects worse. Formoterol's effect on hypokalemia may be strengthened by derivatives of theophylline.
Guanethidine	Could make sympathomimetics more arrhythmogenic. Guanethidine might make sympathomimetic drugs more hypertensive.
Indacaterol	The harmful or toxic effects of indacaterol may be increased by theophylline derivatives. The hypokalemic action of indacaterol may be strengthened by theophylline derivatives.
Interferons	Theophylline derivatives' serum levels could drop.
Isoniazid	Theophylline derivatives' serum levels might rise.
Isoproterenol	Theophylline derivatives' serum levels could drop.
Lithium	Theophylline derivatives may lower the level of lithium in the blood.
Methotrexate	Theophylline derivatives' serum levels might rise.
Metreleptin	Theophylline serum concentration can drop. Theophylline's serum levels may rise in response to metreleptin.
Obeticholic Acid	May elevate CYP1A2 substrates' serum concentration (High risk with Inhibitors).
Olodaterol	Theophylline derivatives may intensify Olodaterol's harmful or hazardous effects. Olodaterol's effect on hypokalemia may be strengthened by derivatives of theophylline.
Pefloxacin	Theophylline derivatives' serum levels might rise.
Peginterferon Alfa-2b	May elevate CYP1A2 substrates' serum concentration (High risk with Inhibitors).
Pentoxifylline	Theophylline derivatives' serum levels might rise.
Propafenone	Theophylline derivatives' serum levels might rise.
QuiNINE	Theophylline derivatives' serum levels might rise.
Ritonavir	Theophylline derivatives' serum levels could drop.
Solriamfetol	Sympathomimetics may intensify Solriamfetol's hypertensive effects.
Sulfinpyrazone	Theophylline derivatives' serum levels could drop.
Sympathomimetics	Could intensify the hazardous or harmful effects of other sympathomimetics.
Tedizolid	Could make sympathomimetics' hypertensive effects stronger. The tachycardic impact of sympathomimetics may be increased by tedizolid.
Teriflunomide	May lower the serum level of CYP1A2 substrates (High risk with Inducers).
Thyroid Products	Theophylline derivatives' metabolism might be increased.
Ticlopidine	Theophylline derivatives' serum levels might rise.
Tobacco (Smoked)	Theophylline derivatives' serum levels could drop.
Zafirlukast	The serum concentration of zafirlukast may drop if theophylline derivatives are present. Theophylline derivatives' serum levels may rise when zafirlukast is used.
Risk Factor D (Consider therapy modification)
Adenosine	Theophylline Derivatives may diminish the therapeutic effect of Adenosine.
Benzodiazepines	Theophylline Derivatives may diminish the therapeutic effect of Benzodiazepines.
Beta-Blockers (Nonselective)	May lessen theophylline derivatives' bronchodilator effects.
CarBAMazepine	Theophylline derivatives' serum levels could drop. CarBAMazepine serum concentrations may be reduced by derivatives of theophylline. Management: When possible, look for substitutions for this combination. If you combine these medications, keep a watchful eye out for any changes in serum levels or therapeutic effects.
Cimetidine	Theophylline derivatives' metabolism might be slowed down.
Cocaine (Topical)	Could make sympathomimetics' hypertensive effects stronger. Management: Whenever possible, look at alternatives to using this combo. When used concurrently, keep a close eye out for noticeably elevated blood pressure or heart rate as well as any signs of myocardial ischemia.
FluvoxaMINE	Theophylline derivatives' metabolism might be slowed down.
Fosphenytoin	Theophylline derivatives' serum levels could drop. Theophylline derivatives may lower the level of fosphenytoin in the blood. Management: When possible, look for alternatives. If both medications are being used, keep an eye out for higher concentrations or effects of theophylline or phenytoin if the other is started or the dose is increased, or decreased concentrations or effects if the other is stopped or the dose is decreased.
Iohexol	The negative/toxic effects of iohexol may be amplified by substances with the potential to lower seizure thresholds. More specifically, there may be a higher chance of seizures. Treatment: Stop using medications 48 hours before using intrathecal iohexol that could lower the seizure threshold. To restart using such agents, give the treatment at least 24 hours. Prophylactic anticonvulsants may be used in nonelective surgeries.
Iomeprol	The negative/toxic effect of Iomeprol may be increased by substances with the potential to lower seizure thresholds. More specifically, there may be a higher chance of seizures. Treatment: Stop using medications 48 hours before using intrathecal iomeprol if they could lower the seizure threshold. To restart using such agents, give the treatment at least 24 hours. Prophylactic anticonvulsants may be used in nonelective surgeries.
Iopamidol	The negative/toxic effects of iopamidol may be increased by substances with the potential to lower seizure thresholds. More specifically, there may be a higher chance of seizures. Treatment: 48 hours before using intrathecal iopamidol, stop using any medications that could lower the seizure threshold. To restart using such agents, give the treatment at least 24 hours. Prophylactic anticonvulsants may be used in nonelective surgeries.
Linezolid	Could make sympathomimetics' hypertensive effects stronger. Reduce the first doses of sympathomimetic drugs and closely monitor individuals on linezolid for an augmented pressor response. There are currently no suggestions for specific dose adjustments.
Macrolide Antibiotics	Theophylline derivatives' metabolism might be slowed down. Azithromycin (Systemic), Fidaxomicin, Roxithromycin, Spiramycin, and Telithromycin are exceptions.
Mexiletine	Theophylline derivatives' metabolism might be slowed down.
Pancuronium	The harmful or poisonous effects of pancuronium may be increased by derivatives of theophylline. Pancuronium's ability to suppress neuromuscular activity may be lessened by theophylline derivatives. Management: Patients receiving concurrent theophylline derivatives may require a dose adjustment of pancuronium to cause paralysis. When using these drugs concurrently, keep a cautious eye out for any negative consequences (such cardiac problems, for example).
Phenytoin	Theophylline derivatives' serum levels could drop. Phenytoin serum levels may be decreased by theophylline derivatives. Management: When possible, look for alternatives. If both medications are being used, keep an eye out for higher concentrations or effects of theophylline or phenytoin if the other is started or the dose is increased, or decreased concentrations or effects if the other is stopped or the dose is decreased.
Quinolones	Theophylline derivatives' metabolism might be slowed down. The most dangerous antibiotics include ciprofloxacin and enoxacin. The potential for each medicine to cause seizures may be increased by theophylline/quinolone therapy. Delafloxacin, Gemifloxacin, LevoFLOXacin (Systemic), Lomefloxacin, Moxifloxacin, Nalidixic Acid, Pefloxacin, and Sparfloxacin are the exceptions.
Regadenoson	Regadenoson's vasodilatory action may be lessened by theophylline.
Thiabendazole	Theophylline derivatives' metabolism might be slowed down.
Vemurafenib	May elevate CYP1A2 substrates' serum concentration (High risk with Inhibitors). Management: Whenever possible, look into alternatives to such combinations, especially if the CYP1A2 substrate has a relatively limited therapeutic index. Drugs marked as exclusions from this document are covered in separate monographs on drug interactions.
Zileuton	May increase the serum concentration of Theophylline. Management: Reduce theophylline dose by 50% upon initiation of zileuton therapy. If theophylline is added to existing zileuton therapy, use a lower starting dose. Monitor for increased serum concentrations and effects of theophylline.
Risk Factor X (Avoid combination)
Acebrophylline	Theophylline derivatives' stimulant effects should be improved.
Deferasirox	Theophylline serum concentration can rise.
Doxofylline	Doxofylline's harmful or poisonous effects may be increased by derivatives of theophylline.
Riociguat	The hypotensive action of rociguat may be strengthened by theophylline derivatives.
Stiripentol	Theophylline serum concentration can rise.

Monitoring parameters

• Heart rate.
• CNS 
• Respiratory rate 
• Arterial or capillary blood gases
• Fluid balance
• Electrolyte concentrations

Theophylline levels:

• Following the start of therapy, prior to dose increases, in the presence of toxic signs and symptoms, or whenever a new illness, worsening of an existing illness, or change in the patient's treatment regimen occur that may affect theophylline clearance (e.g., fever >102°F or sustained for 24 hours or more, hepatitis, or drugs that are added or discontinued), serum theophylline levels should be monitored.
• For oral formulations, if symptoms are adequately controlled, check blood concentrations every year for everyone else and every six months for children who are rapidly growing.
• Patients who have not received theophylline in the previous 24 hours should have their serum concentrations measured 30 minutes after an IV loading dose to determine whether they require an additional loading dose if their serum concentration is below 10 mcg/mL or whether they should delay starting their constant IV infusion if their serum concentration is above 20 mcg/mL.
• Measure blood concentrations after initiating a continuous infusion for infusion administration one estimated half-life (e.g., 4 hours in children 1 to 9 years of age or 8 hours in non-smoking, otherwise healthy people), then every 12 to 24 hours to see if further changes are necessary.

How to administer Theophylline?

IV:

• Give a loading dosage during a 30-minute period.
• As necessary, proceed with a continuous infusion.
• The maximum infusion rate should not exceed 17 mg/hour for patients with cor pulmonale, cardiac decompensation, hepatic impairment, the elderly, or patients taking medications that decrease theophylline clearance unless the patient is still symptomatic, steady-state serum concentrations are 10 mcg/mL, and serum concentrations can be monitored at 24-hour intervals.
• Avoid giving dextrose-containing solutions at the same time as blood through the same administration set since doing so could cause hemolysis or pseudo-agglutination.

Oral: Extended-release:

• Continuously administer with or without food (to maintain a consistent drug level).
• Avoid chewing or crushing pills. If scored, the tablet may be divided. A complete matrix tablet could pass through the bowels.

12-hour formulation:

• Patients with low dosage needs and non-smokers (with the proper total body clearance) can receive it as a once-daily dose.
• It ought to be taken into account only after being titrated to therapeutic levels.
• Start once daily dosing at the end of the previous 12-hour dosing interval, basing it on twice daily dose. Once-daily dosage shouldn't be given in the evening following dinner.

24-hour formulation:

• Every morning, administer at roughly the same time.
• Avoid giving medication at night after dinner.
• Patients who need a high dose, greater than 900 mg or 13 mg/kg, whichever is less, should take their medication no more than one hour before a high-fat meal since it can significantly enhance peak blood levels and absorption.
• Theophylline should always be taken by patients with food or while fasting.
• Patients who quickly metabolise theophylline (such as younger patients, smokers, and certain non-smoking adults) and who have symptoms at the conclusion of a dose interval may want to consider taking their medication twice daily.
• Give the first dose in the morning and the second dose between 10 and 12 hours later, but before dinner. Avoid administering medication at night.

Mechanism of action of Theophylline:

• Smooth muscle relaxation (bronchodilation) and suppression of the airway response to non-bronchodilator prophylactic stimuli are two separate uses for theophylline.
• Inhibition of two phosphodiesterase (PDE III, and to a lesser extent, PDE IV) enzymes causes bronchodilation, but other molecular processes can provide non-bronchodilation effects.
• Theophylline improves calcium uptake through adenosine-mediated mechanisms, which increases diaphragmatic muscular contraction.

Absorption:

• Oral (solution, immediate release): Rapid, complete

Distribution

• It is poorly distributed into body fat. Preterm neonates, elderly women, pregnant women in the third trimester, and those with hepatic dysfunction may experience an increase in distribution.

Metabolism:

• Hepatic via demethylation and hydroxylation (CYP 1A2 and 3A4); forms active metabolites such as caffeine and 3-methylxanthine

Protein binding

• It binds to approximately 40% of albumin, but its binding is reduced in neonates (due a higher percentage of fetalalbumin), hepatic dysfunction, acidemia (uncorrected), the third trimester, and the elderly).

Half-life elimination: Variable and highly dependent on age, hepatic function and cardiac function.

Premature infants, postnatal age 3 to 15 days:

• • 30 hours (range: 17 to 43 hours).
• Premature infants, postnatal age 25 to 57 days:
  • 20 hours (range: 9.4 to 30.6 hours).
• Term infants, postnatal age 1 to 2 days:
  • 25.7 hours (range: 25 to 26.5 hours).
• Term infants, postnatal age 3 to 30 weeks:
  • 11 hours (range: 6 to 29 hours).
• Children 1 to 4 years: 3.4 hours (range:
  • 1.2 to 5.6 hours).
• Children and Adolescents 6 to 17 years:
  • 3.7 hours (range: 1.5 to 5.9 hours).
• Adults ≥18 years to ≤60 years (nonsmoking, asthmatic, otherwise healthy):
  • 8.7 hours (range: 6.1 to 12.8 hours).
• Elderly >60 years (nonsmoking, healthy):
  • 9.8 hours (range: 1.6 to 18 hours)

Time to peak, serum:

• Oral (solution and immediate release): 1 to 2 hours;
• IV: Within 30 minutes

Excretion:

• Urine (~50% as an unchanged drug [Neonates]; ~10% as unchanged drug [Infants >3 months, Adolescents, and Adults])

Clearance: Certain conditions may significantly alter theophylline clearance. Severe and fatal theophylline toxicity can occur if reduced theophylline clearance occurs.

Decreased theophylline clearance:

• Neonates.
• infants <3 months with decreased renal function.
• infants <1 year.
• elderly >60 years.
• acute pulmonary edema and cor pulmonale.
• fever (≥ 102°F for ≥24 hours or lesser temperature elevations for longer periods)
• heart failure.
• hepatic impairment (eg, cirrhosis, acute hepatitis, and cholestasis).
• hypothyroidism.
• Patients following cessation of smoking.
• sepsis with multiple organ failure and shock.
• third trimester of pregnancy.

Increased theophylline clearance:

• Hyperthyroidism;
• cystic fibrosis;
• smoking (ie, marijuana or tobacco).

International Brand Names of Theophylline:

• Elixophyllin
• Theo-24
• Theochron
• Aerobin
• Amriphylline
• Austyn
• Bronchoretard
• Bronsolvan
• Bufabron
• Contine
• Diaphyllin
• Ditenaten
• Duralyn-CR
• Egifilin
• Elixifilin
• Elixine
• Eteophyl
• Etipramid
• Euphyllin
• Euphyllin Retard
• Euphyllin Retard Mite
• Euphylline
• Euphylong
• Euphylong Retardkaps
• Franol
• Frezma
• Lasma
• Meridian AP
• Minophylline
• Nefoben
• Neoffilin
• Neulin SA
• Neulin-SR
• Nosma
• Nuelin
• Nuelin SA
• Nuelin SR
• Pediaphyllin
• Pediaphyllin PL
• Pellapenta
• Pharmafil
• Phylobid
• Quibron T SR
• Quibron TSR
• Respicur retard
• Retafyllin
• Slo-Phyllin
• Slo-Theo
• Solosin
• Somofillina
• Teoclear
• Teoclear LA
• Teofilina Retard
• Teolex
• Teolex CR
• Teolex SR
• Teolin
• Teolong
• Teosona
• Teotard
• Teromol Retard
• Theo PA
• Theo-2
• Theo-24
• Theo-Bros
• Theo-Dur
• Theobron
• Theoclear
• Theodex
• Theolair
• Theolair LA
• Theolair S
• Theolan
• Theolin
• Theolin SR
• Theolong
• Theonate
• Theophar
• Theophtard
• Theophyllin-ratiopharm
• Theophylline Bruneau
• Theoplus Retard
• Theosol Elixir
• Theospirex
• Theospirex Retard
• Theostat
• Theostat LP
• Theotard
• Theotrim
• Uni-Dur
• Unicontin
• Unicontin-400 Continus
• Unidur
• Unifyl Retard
• Uniphyllin
• Uniphyllin Continus
• Uniphylline
• Ventophyl
• Xanthium
• Zepholin
• AA-Theo LA
• PMS-Theophylline
• Pulmophylline
• TEVA-Theophylline SR
• Theo ER
• Theolair
• Uniphyl

Theophylline Brand Names in Pakistan:

Theophylline Syrup 30 Mg/5ml in Pakistan
Theophylline	Lisko Pakistan (Pvt) Ltd
Theophylline	Reckitt Benckiser Pakistan Ltd.
Theophylline	Mian Brothers Laboratories (Pvt) Ltd.
Theophylline	Hizat Pharmaceutical Industries (Pvt) Ltd.
Theophylline	Mian Brothers Laboratories (Pvt) Ltd.
Theophylline	Lisko Pakistan (Pvt) Ltd

 

Theophylline Tablets 100 Mg in Pakistan
Neophylline	Agp (Private) Ltd.

 

Theophylline Tablets 300 Mg in Pakistan
Broncheez Sr	Csh Pharmaceuticals-North (Pvt) Ltd
Fynkoline	Fynk Pharmaceuticals
Neophylline	Agp (Private) Ltd.
Nuelin-Sa	Searle Pakistan (Pvt.) Ltd.
Theo-Dur	Pacific Pharmaceuticals Ltd.

 

Theophylline Tablets 350 Mg in Pakistan
Asthalin Forte	Eros Pharmaceuticals
Biothyllin	Biogen Pharma

 

Theophylline Tablets SR 200 Mg in Pakistan
Respro	Searle Pakistan (Pvt.) Ltd.
Theo-Dur	Pacific Pharmaceuticals Ltd.

 

Theophylline Tablets SR 300 Mg in Pakistan
Quibron-T/Sr	Glaxosmithkline
Respro	Searle Pakistan (Pvt.) Ltd.

 

Theophylline Tablets SR 350 Mg in Pakistan
Theograd Gradumet	Abbott Laboratories (Pakistan) Limited.