Clinical medicine profile
Theophylline
Methylxanthine [EPC]
- Route
- See product SmPC
- Schedule
- POM
- ATC
- Not assigned
- PPB status
- registered
Safety essentials
The information most likely to change a prescribing or dispensing decision.
Contraindications
- CONTRAINDICATIONS Theophylline (Anhydrous) Extended-Release Tablets are contraindicated in patients with a history of hypersensitivity to theophylline or other components in the product.
Precautions
- WARNINGS Concurrent Illness Theophylline should be used with extreme caution in patients with the following clinical conditions due to the increased risk of exacerbation of the concurrent condition: Active peptic ulcer disease Seizure disorders Cardiac arrhythmias (not including bradyarrhythmias) Conditions That Reduce Theophylline Clearance There are several readily identifiable causes of reduced theophylline clearance.
- If the total daily dose is not appropriately reduced in the presence of these risk factors, severe and potentially fatal theophylline toxicity can occur .
- Careful consideration must be given to the benefits and risks of theophylline use and the need for more intensive monitoring of serum theophylline concentrations in patients with the following risk factors: Age Neonates (term and premature) Children <1 year Elderly (>60 years) Concurrent Diseases Acute pulmonary edema Congestive heart failure Cor-pulmonale Fever
- ��102° for 24 hours or more
- or lesser temperature elevations for longer periods Hypothyroidism Liver disease
- cirrhosis, acute hepatitis Reduced renal function in infants <3 months of age Sepsis with multi-organ failure Shock Cessation of Smoking Drug Interactions Adding a drug that inhibits theophylline metabolism (e.g., cimetidine, erythromycin, tacrine) or stopping a concurrently administered drug that enhances theophylline metabolism (e.g., carbamazepine, rifampin).
- (see PRECAUTIONS, Drug Interactions, Table II ).
- When Signs or Symptoms of Theophylline Toxicity Are Present Whenever a patient receiving theophylline develops nausea or vomiting, particularly repetitive vomiting, or other signs or symptoms consistent with theophylline toxicity (even if another cause may be suspected), additional doses of theophylline should be withheld and a serum theophylline concentration measured immediately .
- Patients should be instructed not to continue any dosage that causes adverse effects and to withhold subsequent doses until the symptoms have resolved, at which time the healthcare professional may instruct the patient to resume the drug at a lower dosage (see DOSAGE AND ADMINISTRATION, Dosing Guidelines, Table VI ).
- Dosage Increases Increases in the dose of theophylline should not be made in response to an acute exacerbation of symptoms of chronic lung disease since theophylline provides little added benefit to inhaled beta2-selective agonists and systemically administered corticosteroids in this circumstance and increases the risk of adverse effects.
- A peak steady‑state serum theophylline concentration should be measured before increasing the dose in response to persistent chronic symptoms to ascertain whether an increase in dose is safe.
- Before increasing the theophylline dose on the basis of a low serum concentration, the healthcare professional should consider whether the blood sample was obtained at an appropriate time in relationship to the dose and whether the patient has adhered to the prescribed regimen (see PRECAUTIONS, Laboratory Tests ).
Dosing matrix
Population and organ-function guidance, shown together for faster comparison.
DOSAGE AND ADMINISTRATION Theophylline (Anhydrous) Extended-Release Tablets 400 or 600 mg can be taken once a day in the morning or evening. It is recommended that Theophylline (Anhydrous) Extended-Release Tablets be taken with meals. Patients should be advised that if they choose to take Theophylline (Anhydrous) Extended-Release Tablets with food it should be taken consistently with food and if they take it in a fasted condition it should routinely be taken fasted. It is important that the product whenever dosed be dosed consistently with or without food. Theophylline (Anhydrous) Extended-Release Tablets are not to be chewed or crushed because it may lead to a rapid release of theophylline with the potential for toxicity. The scored tablet may be split. Infrequently, patients receiving Theophylline (Anhydrous) Extended-Release Tablets 400 or 600 mg may pass an intact matrix tablet in the stool or via colostomy. These matrix tablets usually contain little or no residual theophylline. Stabilized patients, 12 years of age or older, who are taking an immediate-release or controlled-release theophylline product may be transferred to once-daily administration of 400 or 600 mg Theophylline (Anhydrous) Extended-Release Tablets on a mg-for-mg basis. It must be recognized that the peak and trough serum theophylline levels produced by the once-daily dosing may vary from those produced by the previous product and/or regimen. General Considerations The steady-state peak serum theophylline concentration is a function of the dose, the dosing interval, and the rate of theophylline absorption and clearance in the individual patient. Because of marked individual differences in the rate of theophylline clearance, the dose required to achieve a peak serum theophylline concentration in the 10-20 mcg/mL range varies fourfold among otherwise similar patients in the absence of factors known to alter theophylline clearance (e.g., 400‑1600 mg/day in adults <60 years old and 10-36 mg/kg/day in children 1-9 years old). For a given population there is no single theophylline dose that will provide both safe and effective serum concentrations for all patients. Administration of the median theophylline dose required to achieve a therapeutic serum theophylline concentration in a given population may result in either sub-therapeutic or potentially toxic serum theophylline concentrations in individual patients. For example, at a dose of 900 mg/d in adults <60 years or 22 mg/kg/d in children 1-9 years, the steady-state peak serum theophylline concentration will be <10 mcg/mL in about 30% of patients, 10-20 mcg/mL in about 50% and 20-30 mcg/mL in about 20% of patients. The dose of theophylline must be individualized on the basis of peak serum theophylline concentration measurements in order to achieve a dose that will provide maximum potential benefit with minimal risk of adverse effects . Transient caffeine-like adverse effects and excessive serum concentrations in slow metabolizers can be avoided in most patients by starting with a sufficiently low dose and slowly increasing the dose, if judged to be clinically indicated , in small increments (See Table V ). Dose increases should only be made if the previous dosage is well tolerated and at intervals of no less than 3 days to allow serum theophylline concentrations to reach the new steady-state. Dosage adjustment should be guided by serum theophylline concentration measurement (see PRECAUTIONS, Laboratory Tests and DOSAGE AND ADMINISTRATION, Table VI ). Healthcare providers should instruct patients and caregivers to discontinue any dosage that causes adverse effects, to withhold the medication until these symptoms are gone and to then resume therapy at a lower, previously tolerated dosage (see WARNINGS ). If the patient's symptoms are well controlled, there are no apparent adverse effects, and no intervening factors that might alter dosage requirements (see WARNINGS and PRECAUTIONS ), serum theophylline concentrations should be monitored at 6 month intervals for rapidly growing children and at yearly intervals for all others. In acutely ill patients, serum theophylline concentrations should be monitored at frequent intervals, e.g., every 24 hours. Theophylline distributes poorly into body fat, therefore, mg/kg dose should be calculated on the basis of ideal body weight. Table V contains theophylline dosing titration schema recommended for patients in various age groups and clinical circumstances. Table VI contains recommendations for theophylline dosage adjustment based upon serum theophylline concentrations. Application of these general dosing recommendations to individual patients must take into account the unique clinical characteristics of each patient. In general, these recommendations should serve as the upper limit for dosage adjustments in order to decrease the risk of potentially serious adverse events associated with unexpected large increases in serum theophylline concentration . Table V. Dosing initiation and titration (as anhydrous theophylline). Patients with more rapid metabolism clinically identified by higher than average dose requirements, should receive a smaller dose more frequently (every 12 hours) to prevent breakthrough symptoms resulting from low trough concentrations before the next dose. A. Children (12-15 years) and adults (16-60 years) without risk factors for impaired clearance . Titration Step Children <45 kg Children >45 kg and adults 1. Starting Dosage 12-14 mg/kg/day up to a maximum of 300 mg/day admin. QD 300 mg/day If caffeine-like adverse effects occur, then consideration should be given to a lower dose and titrating the dose more slowly (see ADVERSE REACTIONS ). admin. QD 2. After 3 days, if tolerated , increase dose to: 16 mg/kg/day up to a maximum of 400 mg/day admin. QD 400-600 mg/day admin. QD 3. After 3 more days, if tolerated , and if needed increase dose to: 20 mg/kg/day up to a maximum of 600 mg/day admin. QD As with all theophylline products, doses greater than 600 mg should be titrated according to blood level (See Table VI ). B. Patients With Risk Factors For Impaired Clearance, The Elderly (>60 Years), And Those In Whom It Is Not Feasible To Monitor Serum Theophylline Concentrations : In children 12-15 years of age, the theophylline dose should not exceed 16 mg/kg/day up to a maximum of 400 mg/day in the presence of risk factors for reduced theophylline clearance (see WARNINGS ) or if it is not feasible to monitor serum theophylline concentrations. In adolescents ≥16 years and adults, including the elderly, the theophylline dose should not exceed 400 mg/day in the presence of risk factors for reduced theophylline clearance (see WARNINGS ) or if it is not feasible to monitor serum theophylline concentrations. Table VI. Dosage adjustment guided by serum theophylline concentration. Peak Serum Concentration Dosage Adjustment <9.9 mcg/mL If symptoms are not controlled and current dosage is tolerated, increase dose about 25%. Recheck serum concentration after three days for further dosage adjustment. 10-14.9 mcg/mL If symptoms are controlled and current dosage is tolerated, maintain dose and recheck serum concentration at 6-12 month intervals. Dose reduction and/or serum theophylline concentration measurement is indicated whenever adverse effects are present physiologic abnormalities that can reduce theophylline clearance occur (e.g., sustained fever), or a drug that interacts with theophylline is added or discontinued (see WARNINGS ). If symptoms are not controlled and current dosage is tolerated consider adding additional medication(s) to treatment regimen. 15-19.9 mcg/mL Consider 10% decrease in dose to provide greater margin of safety even if current dosage is tolerated. 20-24.9 mcg/mL Decrease dose by 25% even if no adverse effects are present. Recheck serum concentration after 3 days to guide further dosage adjustment. 25-30 mcg/mL Skip next dose and decrease subsequent doses at least 25% even if no adverse effects are present. Recheck serum concentration after 3 days to guide further dosage adjustment. If symptomatic, consider whether overdose treatment is indicated (see recommendations for chronic overdosage ). >30 mcg/mL Treat overdose as indicated (see recommendations for chronic overdosage ). If theophylline is subsequently resumed, decrease dose by at least 50% and recheck serum concentration after 3 days to guide further dosage adjustment.
Pediatric Use Theophylline is safe and effective for the approved indications in pediatric patients. The maintenance dose of theophylline must be selected with caution in pediatric patients since the rate of theophylline clearance is highly variable across the pediatric age range (see CLINICAL PHARMACOLOGY, Table I , WARNINGS , and DOSAGE AND ADMINISTRATION, Table V ).
Review renal impairment dosing; many agents need CrCl/eGFR adjustment.
- CrCl 0–120: Confirm renal dosing in product SmPC / primary label.
Review hepatic impairment dosing; monitor LFTs if agent is hepatically cleared or hepatotoxic.
Use, effects & interactions
Indications
INDICATIONS AND USAGE Theophylline is indicated for the treatment of the symptoms and reversible airflow obstruction associated with chronic asthma and other chronic lung diseases, e.g., emphysema and chronic bronchitis.
Adverse effects
- ADVERSE REACTIONS Adverse reactions associated with theophylline are generally mild when peak serum theophylline concentrations are <20 mcg/mL and mainly consist of transient caffeine-like adverse effects such as nausea, vomiting, headache and insomnia.
- When peak serum theophylline concentrations exceed 20 mcg/mL, however, theophylline produces a wide range of adverse reactions including persistent vomiting, cardiac arrhythmias, and intractable seizures which can be lethal (see OVERDOSAGE ).
- The transient caffeine-like adverse reactions occur in about 50% of patients when theophylline therapy is initiated at doses higher than recommended initial doses (e.g., >300 mg/day in adults and >12 mg/kg/day in children beyond >1 year of age).
- During the initiation of theophylline therapy, caffeine-like adverse effects may transiently alter patient behavior, especially in school age children, but this response rarely persists.
- Initiation of theophylline therapy at a low dose with subsequent slow titration to a predetermined age-related maximum dose will significantly reduce the frequency of these transient adverse effects (see DOSAGE AND ADMINISTRATION, Table V ).
- In a small percentage of patients (<3% of children and <10% of adults) the caffeine-like adverse effects persist during maintenance therapy, even at peak serum theophylline concentrations within the therapeutic range (i.e., 10-20 mcg/mL).
- Dosage reduction may alleviate the caffeine-like adverse effects in these patients, however, persistent adverse effects should result in a reevaluation of the need for continued theophylline therapy and the potential therapeutic benefit of alternative treatment.
- Other adverse reactions that have been reported at serum theophylline concentrations <20 mcg/mL include abdominal pain, agitation, anaphylactic reaction, anaphylactiod reaction, anxiety, cardiac arrhythmias, diarrhea, dizziness, fine skeletal muscle tremors, gastric irritation, gastroesophageal reflux, hyperuricemia, irritability, palpitations, pruritus, rash, sinus tachycardia, restlessness, transient diuresis, urinary retention and urticaria.
- In patients with hypoxia secondary to COPD, multifocal atrial tachycardia and flutter have been reported at serum theophylline concentrations ≥15 mcg/mL.
- There have been a few isolated reports of seizures at serum theophylline concentrations <20 mcg/mL in patients with an underlying neurological disease or in elderly patients.
- The occurrence of seizures in elderly patients with serum theophylline concentrations <20 mcg/mL may be secondary to decreased protein binding resulting in a larger proportion of the total serum theophylline concentration in the pharmacologically active unbound form.
- The clinical characteristics of the seizures reported in patients with serum theophylline concentrations <20 mcg/mL have generally been milder than seizures associated with excessive serum theophylline concentrations resulting from an overdose (i.e., they have generally been transient, often stopped without anticonvulsant therapy, and did not result in neurological residua).
- To report SUSPECTED ADVERSE REACTIONS, contact Westminster Pharmaceuticals, LLC at 1-844-221-7294 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch Table IV.
- Manifestations of theophylline toxicity.
Drug interactions
Open multi-drug checker ↗- Drug interactions:Drugs that increases its plasma levels:- thiabendazole, norfloxacin, ciprofloxacin, erythromycin. isoniazid, fluconazole, verapamil, diltiazem, cimetidine, oral contraceptives, disulfirum.
- Drugs that reduce its plasma level: carbamazepine, phenobarbitone, primidone, phenytoin, rifampicin
Mechanism & disposition
Mechanism of Action Theophylline has two distinct actions in the airways of patients with reversible obstruction; smooth muscle relaxation (i.
Read complete mechanism
Mechanism of Action Theophylline has two distinct actions in the airways of patients with reversible obstruction; smooth muscle relaxation (i.e., bronchodilation) and suppression of the response of the airways to stimuli (i.e., non-bronchodilator prophylactic effects). While the mechanisms of action of theophylline are not known with certainty, studies in animals suggest that bronchodilation is mediated by the inhibition of two isozymes of phosphodiesterase (PDE III and, to a lesser extent, PDE IV) while non-bronchodilator prophylactic actions are probably mediated through one or more different molecular mechanisms, that do not involve inhibition of PDE III or antagonism of adenosine receptors. Some of the adverse effects associated with theophylline appear to be mediated by inhibition of PDE III (e.g., hypotension, tachycardia, headache, and emesis) and adenosine receptor antagonism (e.g., alterations in cerebral blood flow). Theophylline increases the force of contraction of diaphragmatic muscles. This action appears to be due to enhancement of calcium uptake through an adenosine-mediated channel.
Product-specific
Product-specific
See product SmPC
Theophylline (Anhydrous) Extended-Release Tablets administered in the fed state is completely absorbed after oral administration. In a single-dose crossover study, two 400 mg Theophylline (Anhydrous) Extended-Release Tablets were administered to 19 normal volunteers in the mornin...
has also been reported in some studies, especially in acutely ill patients. It is, therefore, recommended that serum theophylline concentrations be measured frequently in acutely ill patients (e.g., at 24-hr intervals) and periodically in patients receiving long-term therapy, e.g...
and consequent dosage requirements have been observed among other peoples. Population Characteristics Total body clearance Clearance represents the volume of blood completely cleared of theophylline by the liver in one minute. Values listed were generally determined at serum theo...
of theophylline related to age and altered physiological states. For various North American patient populations from literature reports. Different rates of
Pregnancy, lactation & diet
Use only if potential benefit justifies potential risk; prefer agents with better reproductive data when alternatives exist.
Nursing Mothers Theophylline is excreted into breast milk and may cause irritability or other signs of mild toxicity in nursing human infants. The concentration of theophylline in breast milk is about equivalent to the maternal serum concentration. An infant ingesting a liter of breast milk containing 10-20 mcg/mL of theophylline per day is likely to receive 10-20 mg of theophylline per day. Serious adverse effects in the infant are unlikely unless the mother has toxic serum theophylline concentrations.
Brands & loaded prices
| Brand | Manufacturer | Pack | Observed price |
|---|---|---|---|
| UNICONTIN 400 *100`S | Not recorded | — | KES 3,688.59Daima Chemist price-list reference ↗ Source date not recorded · verify current price |
Sources & review state
Decision support only. Confirm patient-specific decisions against the current product SmPC, Kenya STG/EML, and professional judgement.