Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 08 February 2017

Indication(s)

INDICATIONS & USAGE Theophylline extended-release tablets are 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.

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Advisory information

contraindications
CONTRAINDICATIONS Theophylline extended-release tablets are contraindicated in patients with a history of hypersensitivity to theophylline or other components in the product.
Special warnings and precautions

PRECAUTIONS General Careful consideration of the various interacting drugs and physiologic conditions that can alter theophylline clearance and require dosage adjustment should occur prior to initiation of theophylline therapy, prior to increases in theophylline dose, and during follow up (seeWARNINGS).

The dose of theophylline selected for initiation of therapy should be low and, if tolerated, increased slowly over a period of a week or longer with the final dose guided by monitoring serum theophylline concentrations and the patient 's clinical response (seeDOSAGE AND ADMINISTRATION, Table V).

Monitoring Serum Theophylline Concentrations Serum theophylline concentration measurements are readily available and should be used to determine whether the dosage is appropriate.

Specifically, the serum theophylline concentration should be measured as follows:

When initiating therapy to guide final dosage adjustment after titration.

Before making a dose increase to determine whether the serum concentration is subtherapeutic in a patient who continues to be symptomatic.

Whenever signs or symptoms of theophylline toxicity are present.

Whenever there is a new illness, worsening of a chronic illness or a change in the patient 's treatment regimen that may alter theophylline clearance (e.g., fever >102 sustained forhours, hepatitis, or drugs listed in Table II are added or discontinued).

To guide a dose increase, the blood sample should be obtained at the time of the expected peak serum theophylline concentration: 6 to 7 hours after a dose at steady-state.

For most patients, steady-state will be reached after 3 days of dosing when no doses have been missed, no extra doses have been added, and none of the doses have been taken at unequal intervals.

A trough concentration (i.e., at the end of the dosing interval) provides no additional useful information and may lead to an inappropriate dose increase since the peak serum theophylline concentration can be two or more times greater than the trough concentration with an immediate-release formulation.

If the serum sample is drawn more than seven hours after the dose, the results must be interpreted with caution since the concentration may not be reflective of the peak concentration.

In contrast, when signs or symptoms of theophylline toxicity are present, the serum sample should be obtained as soon as possible, analyzed immediately, and the result reported to the clinician without delay.

In patients in whom decreased serum protein binding is suspected (e.g., cirrhosis, women during the third trimester of pregnancy), the concentration of unbound theophylline should be measured and the dosage adjusted to achieve an unbound concentration of 6 to 12 mcg/mL. Saliva concentrations of theophylline can not be used reliably to adjust dosage without special techniques.

Effects on Laboratory Tests As a result of its pharmacological effects, theophylline at serum concentrations within the 10 to 20 mcg/mL range modestly increases plasma glucose (from a mean of 88 mg % to 98 mg %), uric acid (from a mean of 4 mg/dL to 6 mg/dL), free fatty acids (from a mean of 451 to 800 total cholesterol (from a mean of 140 vs 160 mg/dL), HDL (from a mean of 36 to 50 mg/dL), HDL/LDL ratio (from a mean of 0.5 to 0.7), and urinary free cortisol excretion (from a mean of 44 to 63 mcg/24 hr).

Theophylline at serum concentrations within the 10 to 20 mcg/mL range may also transiently decrease serum concentrations of triiodothyronine (144 before, 131 after one week and 142 ng/dl after 4 weeks of theophylline).

The clinical importance of these changes should be weighed against the potential therapeutic benefit of theophylline in individual patients.

Adverse reactions

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 (seeOVERDOSAGE).

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 (seeDOSAGE 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 to 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 diarrhea, irritability, restlessness, fine skeletal muscle tremors, and transient diuresis.

In patients with hypoxia secondary to COPD, multifocal atrial tachycardia and flutter have been reported at serum theophylline concentrationsmcg/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).

Table IV.

Manifestations of theophylline toxicity.

* Percentage of patients reported with sign or symptom * NR = Not reported in a comparable manner.

Acute

Overdose (Large Single Ingestion)Chronic Overdosage (Multiple Excessive Doses)Sign/Symptom Asymotomatic GastointestinalStudy 1 Study 2 (n = 157) (n = 14) NR0Study 1 Study 2 (n = 92) (n = 102) NR6Vomiting Abdominal Pain Diarrhea Hematemesis73 93 NR21 NR0 NR030 61 NR12 NR14 NR2Metabolic/Other Hypokalemia Hyperglycemia Acid/base disturbance Rhabdomyolysis85 79 98 NR34 21 NR744 43 18 NR9 5 NR0Cardiovascular Sinus tachycardia Other supraventricular tachycardias Ventricular premature beats Atrial fibrillation or flutter Multifocal atrial tachycardia Ventricular arrhythmias hemodynamic instability Hypotension/shock100 86 2 21 3 21 1 NR0 NR7 14 NR21100 62 12 14 10 19 12 NR2 NR40 0 NR8Neurologic Nervousness Tremors Disorientation Seizures DeathNR64 38 29 NR7 5 14 3 21NR21 16 14 NR11 14 5 10 4

Usage information

Pregnancy and lactation

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 to 20 mcg/mL of theophylline a day is likely to receive 10 to 20 mg of theophylline per day.

Serious adverse effects in the infant are unlikely unless the mother has toxic serum theophylline concentrations.

Interactions

DRUG INTERACTIONS Drug-Drug Interactions Theophylline interacts with a wide variety of drugs.

The interaction may be pharmacodynamic, i.e., alterations in the therapeutic response to theophylline or another drug or occurrence of adverse effects without a change in serum theophylline concentration.

More frequently, however, the interaction is pharmacokinetic, i.e., the rate of theophylline clearance is altered by another drug resulting in increased or decreased serum theophylline concentrations.

Theophylline only rarely alters the pharmacokinetics of other drugs.

The drugs listed in Table II have the potential to produce clinically significant pharmacodynamic or pharmacokinetic interactions with theophylline.

The information in theEffectcolumn of Table II assumes that the interacting drug is being added to a steady-state theophylline regimen.

If theophylline is being initiated in a patient who is already taking a drug that inhibits theophylline clearance (e.g., cimetidine, erythromycin), the dose of theophylline required to achieve a therapeutic serum theophylline concentration will be smaller.

Conversely, if theophylline is being initiated in a patient who is already taking a drug that enhances theophylline clearance (e.g., rifampin), the dose of theophylline required to achieve a therapeutic serum theophylline concentration will be larger.

Discontinuation of a concomitant drug that increases theophylline clearance will result in accumulation of theophylline to potentially toxic levels, unless the theophylline dose is appropriately reduced.

Discontinuation of a concomitant drug that inhibits theophylline clearance will result in decreased serum theophylline concentrations, unless the theophylline dose is appropriately increased.

The drugs listed in Table III have either been documented not to interact with theophylline or do not produce a clinically significant interaction (i.e., <15 % change in theophylline clearance).

The listing of drugs in Tables II and III are current as of February 9, 1995.

New interactions are continuously being reported for theophylline, especially with new chemical entities.

The clinician should not assume that a drug does not interact with theophylline if it is not listed in Table II.

Before addition of a newly available drug in a patient receiving theophylline, the package insert of the new drug and/or the medical literature should be consulted to determine if an interaction between the new drug and theophylline has been reported.

Table II.

Clinically significant drug interactions with theophylline.

* * Refer to PRECAUTIONS, Drug Interactions for further information regarding table.

Average effect on steady-state theophylline concentration or other clinical effect for pharmacologic interactions.

Individual patients may experience larger changes in serum theophylline concentration than the value listed.

DrugType of InteractionEffectAdenosineTheophylline blocks adenosine receptors.

Higher doses of adenosine may be required to achieve desired effect.

AlcoholA single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours.30 % increaseAllopurinolDecreases theophylline clearance at allopurinol dosesmg/day.25 % increaseAminoglutethimideIncreases theophylline clearance by induction of microsomal enzyme activity.25 % decreaseCarbamazepineSimilar to aminoglutethimide.30 % decreaseCimetidineDecreases theophylline clearance by inhibiting cytochrome P450 1A2.70 % increaseCiprofloxacinSimilar to cimetidine.40 % increaseClarithromycinSimilar to erythromycin.25 % increaseDiazepamBenzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors.

Larger diazepam doses may be required to produce desired level of sedation.

Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.

DisulfiramDecreases theophylline clearance by inhibiting hydroxylation and demethylation.50 % increaseEnoxacinSimilar to cimetidine.300 % increaseEphedrineSynergistic CNS effectsIncreased frequency of nausea, nervousness, and insomnia.

ErythromycinErythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.35 % increase.

Erythromycin steady-state serum concentrations decrease by a similar amount.

EstrogenEstrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion.

The effect of progesterone on theophylline clearance is unknown.30 % increaseFlurazepamSimilar to diazepam.

Similar to diazepam.

FluvoxamineSimilar to cimetidine.

Similar to cimetidine.

HalothaneHalothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.

Increased risk of ventricular arrhythmias.

Interferon, human recombinant alpha-ADecreases theophylline clearance.100 % increaseIsoproterenol (IV)Increase theophylline clearance.20 % increaseKetaminePharmacologicMay lower theophylline seizure threshold.

LithiumTheophylline increases renal lithium clearance.

Lithium dose required to achieve a therapeutic serum concentration increased an average of 60 %.LorazepamSimilar to diazepam.

Similar to diazepam.

Methotrexate (MTX)Decreases theophylline clearance.20 % increase after low dose MTX, higher dose MTX may have a greater effect.

MexiletineSimilar to disulfiram.80 % increaseMidazolamSimilar to diazepam.

Similar to diazepam.

MoricizineIncreases theophylline clearance.25 % decreasePancuroniumLarger dose of pancuronium may be required to achieve neuromuscular blockade.

PentoxifyllineDecreases theophylline clearance.30 % increasePhenobarbital (PB)Similar to aminoglutethimide.25 % decrease after two weeks of concurrent PB.PhenytoinPhenytoin increases theophylline clearance by increasing microsomal enzyme activity.

Theophylline decreases phenytoin absorption.

Serum theophylline and phenytoin concentrations decrease about 40 %.

PropafenoneDecreases theophylline clearance and pharmacologic interaction.40 % increase.

Beta-2 blocking effect may decrease efficacy of theophylline.

PropranololSimilar to cimetidine and pharmacologic interaction.100 % increase.

Beta-2 blocking effect may decrease efficacy of theophylline.

RifampinIncreases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.20 to 40 % decreaseSulfinpyrazoneIncrease theophylline clearance by increasing demethylation and hydroxylation.

Decreases renal clearance of theophylline.20 % increaseTacrineSimilar to cimetidine, also increases renal clearance of theophylline.90 % increaseThiabendazoleDecreases theophylline clearance.190 % increaseTiclopidineDecreases theophylline clearance.60 % increaseTroleandomycinSimilar to erythromycin.33 to 100 % increase depending on troleandomycin dose.

VerapamilSimilar to disulfiram.20 % increase Table III.

Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.

*

* Refer to PRECAUTIONS, Drug Interactions for information regarding table.albuterol, famotidinenizatidinesystemic and inhaledfelodipinenorfloxacinamoxicillinfinasterideofloxacinampicillin, hydrocortisoneomeprazolewith or withoutisofluraneprednisone, prednisolonesulbactamisoniazidranitidineatenololisradipinerifabutinazithromycininfluenza vaccineroxithromycincaffeine, ketoconazolesorbitoldietary ingestionlomefloxacin (purgative doses do notcefaclormebendazoleinhibit theophyllineco-trimoxazolemedroxyprogesteroneabsorption) (trimethoprim andmethylprednisolonesucralfatesulfamethoxazole)metronidazoleterbutaline

systemicdiltiazemmetoprololterfenadinedirithromycinnadololtetracyclineenfluranenifedipinetocainide Drug-Food Interactions Taking theophylline extended-release tablets immediately after ingesting a high fat content meal (45 g fat, 55 g carbohydrates, 28 g protein, 789 calories) may result in a somewhat higher Cmax and delayed Tmax, and a somewhat greater extent of absorption when compared to taking it in the fasting state.

The influence of the type and amount of other foods, as well as the time interval between drug and food, has not been studied.

The Effect of Other Drugs on Theophylline Serum Concentration Measurements Most serum theophylline assays in clinical use are immunoassays which are specific for theophylline.

Other xanthines such as caffeine, dyphylline, and pentoxifylline are not detected by these assays.

Some drugs (e.g., cefazolin, cephalothin), however, may interfere with certain HPLC techniques.

Caffeine and xanthine metabolites in neonates or patients with renal dysfunction may cause the reading from some dry reagent office methods to be higher than the actual serum theophylline concentration.

More information

Category Value
Authorisation number ANDA089763
Orphan designation No
Product NDC 49349-010
Date Last Revised 07-07-2011
Type HUMAN PRESCRIPTION DRUG
RXCUI 317769
Marketing authorisation holder REMEDYREPACK INC.