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Theophylline

R03D - Other systemic drugs for obstructive airway diseases ATC R03DA04 Protein approved 1976 Oral Parenteral Narrow therapeutic index

JFDA label: Theolin S.R 200 Capsules

Mechanism of Action

Inhibitor of Phosphodiesterase 4 — Phosphodiesterase 4 inhibitor; Inhibitor of Phosphodiesterase 3 — Phosphodiesterase 3 inhibitor; Antagonist of Adenosine receptor — Adenosine receptor antagonist

TargetActionGene / class
Adenosine receptor efficacy ANTAGONIST
Phosphodiesterase 3 efficacy INHIBITOR
Phosphodiesterase 4 efficacy INHIBITOR

Indications

Approved

  • Asthma
  • COPD
  • Injection
  • Oral
  • Reversible airflow obstruction

Contraindications

Source: Lexicomp

  • Additional contraindications (not in US labeling): Hypersensitivity to xanthine derivatives Absolute
  • Hypersensitivity to theophylline or any component of the formulation Absolute
  • allergy to corn-related products (injection only) Absolute
  • coadministration with ephedrine in children Absolute
  • coronary artery disease (where cardiac stimulation might prove harmful) Absolute
  • peptic ulcers Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (2)

Not Known Cardiac flutter · tachycardia

Nervous system disorders (6)

Not Known Headache · hyperactivity (children) · insomnia · restlessness · seizure · status epilepticus (nonconvulsive)

Renal and urinary disorders (2)

Not Known Difficulty in micturition (elderly males with prostatism) · diuresis (transient)

Metabolism and nutrition disorders (1)

Not Known Hypercalcemia (with concomitant hyperthyroid disease)

Gastrointestinal disorders (4)

Not Known Gastroesophageal reflux (aggravation) · gastrointestinal ulcer (aggravation) · nausea · vomiting

Musculoskeletal and connective tissue disorders (1)

Not Known Tremor

Dosing

Source: Lexicomp

Note: Individualize dose based on steady-state serum concentrations; use ideal body weight (theophylline distributes poorly into body fat) to calculate dose. Reversible airflow obstruction, acute symptoms: Loading dose: IV, Oral (immediate release solution): Asthma exacerbations: The treatment of asthma exacerbations with theophylline is not supported or recommended by current clinical practice guidelines (GINA 2017; NAEPP 2007). COPD treatment: The treatment of acute COPD with theophylline IV is not supported or recommended by current clinical practice guidelines due to significant side effects (Global Initiative for COPD Guidelines 2017). Patients who have not received theophylline in the previous 24 hours: 4.6 mg/kg/dose IV (preferred route) or 5 mg/kg orally (immediate release only [oral solution]). Note: Loading dose intended to achieve a serum level of ~10 mcg/mL (range: 5 to 16 mcg/mL). On the average, for every 1 mg/kg theophylline given, blood levels will rise 2 mcg/mL. Obtain theophylline serum concentration 30 minutes (IV) or 24 hours (oral) after loading dose (when distribution is complete) to assess the need for and size of subsequent loading doses (and for guidance of continuing therapy). Patients who have received theophylline in the previous 24 hours: A loading dose should not be given before obtaining a serum theophylline concentration. The loading dose should be calculated as follows: Dose = (desired serum theophylline concentration - measured serum theophylline concentration) (Vd) Maintenance: Continuous IV infusion: Note: Dosing presented is to achieve a target concentration of 10 mcg/mL unless otherwise noted. Lower initial doses may be required in patients with reduced theophylline clearance. Dosage should be adjusted according to serum level measurements during the first 12- to 24-hour period. Adults ≤60 years: 0.4 mg/kg/hour; maximum: 900 mg/day unless serum levels indicate need for larger dose. Adults >60 years: 0.3 mg/kg/hour; maximum: 400 mg/day unless serum levels indicate need for larger dose. Cardiac decompensation, cor pulmonale, sepsis with multiorgan failure, or shock: 0.2 mg/kg/hour; maximum: 400 mg/day, unless serum levels indicate need for larger dose. Reversible airflow obstruction, chronic conditions: Oral: Note: Increase dose only if tolerated and if needed. Consider lowering dose or using a slower titration if caffeine-like adverse events occur. May use smaller doses more frequently in patients requiring higher than average doses prevent breakthrough symptoms. If at risk for impaired theophylline clearance or not feasible to monitor serum theophylline concentrations, do not exceed maximum dose of 400 mg/day. Immediate release (oral solution) (without risk factors for impaired clearance): Initial: 300 mg/day in divided doses every 6 to 8 hours; if tolerated, after 3 days increase to 400 mg/day divided every 6 to 8 hours; if tolerated, after 3 more days increase to 600 mg/day divided every 6 to 8 hours. Exten
(For additional information see "Theophylline: Pediatric drug information") Note: Individualize dose based on steady-state serum concentrations; use ideal body weight (theophylline distributes poorly into body fat) to calculate dose. Reversible airflow obstruction, acute symptoms: Manufacturer's labeling: Loading dose: Oral (immediate release solution), IV: Refer to adult dosing. Maintenance dose: IV: Note: Dosing presented is to achieve a target concentration of 10 mcg/mL unless otherwise noted. Lower initial doses may be required in patients with reduced theophylline clearance. Dosage should be adjusted according to serum level measurements during the first 12- to 24-hour period. Infants 4 to Infants 6 to 52 weeks: mg/kg/hour = (0.008) (age in weeks) + 0.21 Children 1 to Children 9 to Adolescents 12 to Adolescents 16 to 18 years: Refer to adult dosing. Patients with cardiac decompensation, cor pulmonale, sepsis with multiorgan failure, or shock: Refer to adult dosing. Reversible airflow obstruction, chronic conditions: Oral: Note: Increase dose only if tolerated and if needed. Consider lowering dose or using a slower titration if caffeine-like adverse events occur. May use smaller doses more frequently in patients requiring higher than average doses to prevent breakthrough symptoms. If at risk for impaired theophylline clearance or not feasible to monitor serum theophylline concentrations, do not exceed 16 mg/kg/day (400 mg/day). Immediate release (oral solution) (without risk factors for impaired clearance): Manufacturer’s labeling: Infants: Total daily dose (mg/day) = [(0.2 x age in weeks) + 5] x (weight in kg); frequency is based on age Dosing interval (frequency based on age): ≤26 weeks: Divide in 3 equal doses and administer every 8 hours >26 weeks: Divide in 4 equal doses and administer every 6 hours Children 1 year to Adolescents 15 years and weight ≤45 kg: Initial: 12 to 14 mg/kg/day in divided doses every 4 to 6 hours (maximum: 300 mg/day); if tolerated, after 3 days increase to 16 mg/kg/day in divided doses every 4 to 6 hours (maximum 400 mg/day); if tolerated, after 3 days, increase to 20 mg/kg/day in divided doses every 4 to 6 hours (maximum: 600 mg/day). Children 1 year to Adolescents 15 years and weight >45 kg or Adolescents ≥16 years: Refer to adult dosing. Alternate dosing (Kliegman 2007): Children 1 to Children 9 to 12 years: 16 mg/kg/day; maximum: 600 mg/day Children >12 years to Adolescents 16 years: 13 mg/kg/day (16 mg/kg/day in smokers); maximum: 600 mg/day Adolescents >16 years: 10 mg/kg/day; maximum: 600 mg/day Extended release (without risk factors for impaired clearance): Manufacturer’s labeling: 12-hour formulation (tablets): Children 6 years to Adolescents 15 years and weight ≤45 kg: Initial: 12 to 14 mg/kg/day divided every 12 hours (maximum: 300 mg/day); if tolerated, after 3 days increase to 16 mg/kg/day divided every 12 hours (maximum: 400 mg/day); if tolerated, after 3 days increase to 20 mg/kg/day divided every
Reversible airflow obstruction, acute symptoms: Loading dose: Oral (immediate release oral solution), IV: Refer to adult dosing. Maintenance dose: IV: 0.3 mg/kg/hour; maximum: 400 mg/day unless serum levels indicate need for larger dose. Reversible airflow obstruction, chronic conditions: Oral: Refer to adult dosing. Maximum dose: 400 mg/day (unless symptomatic and the peak steady-state serum theophylline concentration is Cardiac decompensation, cor pulmonale, sepsis with multiorgan failure, shock: Refer to adult dosing.
Oral: IV: Infants 1 to 3 months: There are no specific dosage adjustments provided in the manufacturer's labeling; however dose reduction and frequent monitoring of serum theophylline concentrations required. Infants >3 months, Children, Adolescents, and Adults: No dosage adjustment necessary.
Oral: Infants, Children, Adolescents, and Adults: There are no specific dosage adjustments provided in manufacturer's labeling. Dose reduction and frequent monitoring of serum theophylline concentration are required; risk of severe and potentially fatal toxicity may occur. Maximum dose: 400 mg/day IV: Infants, Children, Adolescents, and Adults: Initial: 0.2 mg/kg/hour; maximum dose: 400 mg daily unless serum concentrations indicate need for larger dose. Use with caution and monitor serum theophylline concentrations frequently; risk of severe and potentially fatal toxicity may occur.

Warnings & Precautions

Source: Lexicomp

Theophylline toxicity

Severe and potentially fatal theophylline toxicity may occur if reduced theophylline clearance occurs. Theophylline clearance may be decreased in patients with acute pulmonary edema, heart failure, cor pulmonale, fever (≥102°F for ≥24 hours or lesser temperature elevations for longer periods), hepatic disease, acute hepatitis, cirrhosis, hypothyroidism, sepsis with multiorgan failure, shock, neonates (term and premature), infants 60 years of age, and patients following cessation of smoking. Consider benefits versus risks and the need for more intensive monitoring in these patients; reduced infusion rate required. If a patient develops signs and symptoms of theophylline toxicity (eg, nausea or persistent, repetitive vomiting), a serum theophylline level should be measured immediately and subsequent doses withheld. Disease-related concerns:

Cardiovascular disease

Use with caution in patients with cardiac arrhythmias (excluding bradyarrhythmias); use may exacerbate arrhythmias.

Cystic fibrosis

Use with caution in patients with cystic fibrosis; increased theophylline clearance may occur.

Hepatic impairment

Use with caution in patients with hepatic impairment (eg, cirrhosis, acute hepatitis, cholestasis); risk of severe and potentially fatal theophylline toxicity is increased; theophylline clearance is decreased ≥50% in these patients. Dose reduction and frequent monitoring of serum theophylline concentration are required.

Hyperthyroidism

Use with caution in patients with hyperthyroidism; increased theophylline clearance may occur.

Peptic ulcer disease

Use with caution in patients with active peptic ulcer disease; use may exacerbate peptic ulcer.

Seizure disorder

Use with caution in patients with seizure disorders; use may exacerbate seizure disorder. Concurrent drug therapy issues:

Drug-drug interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Special populations:

Elderly

Use extreme caution in the elderly; these patients are at greater risk of serious theophylline toxicity.

Pediatric

Select dose with caution and with frequent monitoring of concentrations (especially Dosage form specific issues:

Propylene glycol

Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Zar 2007). Other warnings/precautions:

Appropriate use

Do not increase dose in response to acute exacerbation of symptoms unless steady state serum theophylline concentration is

Pregnancy & Lactation

Pregnancy

FDA category C

Adverse effects have been observed in animal reproduction studies. Theophylline crosses the placenta; adverse effects may be seen in the newborn. Use is generally safe when used at the recommended doses (serum concentrations 5 to 12 mcg/mL) however maternal adverse events may be increased and efficacy may be decreased in pregnant women. Theophylline metabolism may change during pregnancy; the half-life is similar to that observed in otherwise healthy, nonsmoking adults with asthma during the first and second trimesters (~8.7 hours), but may increase to 13 hours (range: 8 to 18 hours) during the third trimester. The volume of distribution is also increased during the third trimester. Monitor serum levels. The recommendations for the use of theophylline in pregnant women with asthma are similar to those used in nonpregnant adults (National Heart, Lung, and Blood Institute Guidelines 2004).

Lactation

Theophylline is present in breast milk. The concentration of theophylline in breast milk is similar to the maternal serum concentration. Irritability may be observed in the nursing infant. Serious adverse events in the infant are unlikely unless toxic serum levels are present in the mother.

LactMed: monitor the infant.

Monitoring

EfficacySerum theophylline 10–20 mg/L (non-smokers); 10–15 mg/L (elderly); lung function (FEV₁/PEFR)
ToxicityNausea, palpitations, tremor at 20–30 mg/L; seizures and arrhythmias at > 40 mg/L; ECG for cardiac monitoring
Clinical pearlClearance is dramatically affected by smoking (induces CYP1A2), CYP1A2/3A4 inhibitors (erythromycin, ciprofloxacin, cimetidine), and heart failure or cirrhosis. Level can rise dangerously if smoking is stopped abruptly.
CounselingTake at the same time each day with or without food. Do not abruptly change smoking habits without medical review. Report palpitations, persistent vomiting, or agitation.

Chemistry & Properties

2D structure
FormulaC7H10N4O3
Molecular weight198.18 g/mol
IUPAC name1,3-dimethyl-7H-purine-2,6-dione
CAS58-55-9
PubChem CID2153
InChIKeyINQSMEFCAIHTJG-UHFFFAOYSA-N
logP-1.04 (XLogP 0.0)
Polar surface area72.68 Ų
H-bond acceptors / donors5 / 1
Drug-likeness (QED)0.56
Lipinski violations0
SMILESCn1c(=O)c2nc[nH]c2n(C)c1=O.O

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrantYes (logBB -0.3)

Enzyme interactions

EnzymeRoleDetail
CYP1A2Substrate
CYP2B6Substrate
CYP2C19Substrate
CYP2C9Substrate
CYP2D6Substrate
CYP3A4Substrate

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MCT1 (Inhibitor)MRP1 (Inhibitor)MRP3 (Inhibitor)MRP4 (Inhibitor)OAT1 (Inhibitor)OAT2 (Inhibitor)OATP1B1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OATP1B3 (Inhibitor)OATP2B1 (Inhibitor)OCT1 (Inhibitor)OCT3 (Inhibitor)P-gp (Inhibitor)MDR1 (Substrate)OAT2 (Substrate)P-gp (Substrate)Transporter(unspecified) (Substrate)

Drug–drug interactions (100+, DDInter)

Interacting drugSeverityManagement
Acebutolol major
Atenolol major
Betaxolol major
Betaxolol (ophthalmic) major
Bisoprolol major
Bupropion major
Carteolol major
Carteolol (ophthalmic) major
Carvedilol major
Ciprofloxacin major
Deferasirox major
Enoxacin major
Esmolol major
Fluvoxamine major
Halothane major
Iohexol major
Iopamidol major
Labetalol major
Levobetaxolol (ophthalmic) major
Levobunolol (ophthalmic) major
Metipranolol (ophthalmic) major
Metoprolol major
Mexiletine major
Nadolol major
Nebivolol major
Penbutolol major
Pindolol major
Propranolol major
Riociguat major
Sotalol major
Timolol major
Timolol (ophthalmic) major
Tramadol major
Abametapir (topical) moderate
Activated charcoal moderate
Adalimumab moderate
Adenosine moderate
Alefacept moderate
Aminoglutethimide moderate
Amiodarone moderate

Showing 40 of 100+.

Registered Products (4)

BrandForm / strengthPackAgentCitizen (JOD)
Theolin S.R 200 Capsules Capsule 200 mg 20 cap pack varies UNITED PHARM.MFG.CO.LTD(UPM)/JORDAN 1.250
Theolin S.R 300 Capsules Capsule 300 mg 20 cap pack varies UNITED PHARM.MFG.CO.LTD(UPM)/JORDAN 1.900
Theolin S.R 200 Capsules Capsule 200 mg 500 cap pack varies UNITED PHARM.MFG.CO.LTD(UPM)/JORDAN 25.630
Theolin S.R 300 Capsules Capsule 300 mg 500 cap pack varies UNITED PHARM.MFG.CO.LTD(UPM)/JORDAN 38.950