Aminophylline (aminophylline)

Dosage of theophylline in children younger than 1 year of age, particularly in premature and term neonates, must be carefully individualized. Elimination of the drug in children younger than 1 year of age, especially in neonates, generally appears to be reduced. Because of potential toxicity, use of the drug in children younger than 1 year of age should be carefully considered and, if used, the initial and maintenance dosages (particularly the latter) should be conservative. Maintenance dosage should not be exceeded and therapy with the drug should not be continued unless the drug is well tolerated and clinically beneficial. Recommended initial maintenance dosages for neonates and infants for the treatment of bronchospasm are shown in the following table:

Table 8. Recommended Dosage Titration for Children <1 Year of Age using Immediate-Release Preparations

Age Dosage Titration Premature neonates <24 days Initially, 1 mg/kg every 12 hours. postnatal age Adjust dosage to maintain a peak steady-state serum concentration of 5-10 mcg/mL Premature neonates >=24 days Initially, 1.5 mg/kg every 12 hours. postnatal age Adjust dosage to maintain a peak steady-state serum concentration of 5-10 mcg/mL Full-term infants <26 weeks of age ((0.2 x age in weeks) + 5) x body weight (kg) = total daily dosage (mg); administer in 3 equally divided doses every 8 hours. Adjust dose to maintain a peak steady-state serum concentration of 5-10 mcg/mL in neonates or 10-15 mcg/mL in older infants Infants 26-52 weeks of age ((0.2 x age in weeks) + 5) x body weight (kg) = total daily dosage (mg); administer in 4 equally divided doses every 6 hours. Adjust dosage to maintain a peak steady-state serum concentration of 10-15 mcg/mL

No dosing information is available for this tab.

Theophylline increases excretion of lithium and may decrease its therapeutic effectiveness. Higher doses of lithium may be required during concurrent administration of theophylline. The direct stimulatory effect of theophylline on the myocardium may enhance the sensitivity and toxic potential of the cardiac glycosides. Theophylline may exhibit synergistic toxicity with ephedrine and other sympathomimetics and, when administered concomitantly, these agents may further predispose the patient to the development of cardiac arrhythmias.

Theophylline may enhance the effects of the oral anticoagulants by increasing plasma prothrombin and factor V, but therapeutic theophylline dosages will probably have little or no effect on anticoagulant response.

Cimetidine, high-dose allopurinol (e.g., 600 mg daily), oral contraceptives, propranolol, ciprofloxacin, erythromycin, and troleandomycin may increase serum theophylline concentrations by decreasing theophylline's hepatic clearance. Rifampin may decrease serum theophylline concentrations by increasing theophylline's hepatic clearance. Concomitant theophylline and phenytoin administration can result in decreased serum concentrations of either or both agents by increasing hepatic metabolism.

Methotrexate may decrease clearance of theophylline; plasma theophylline concentrations should be monitored in patients receiving theophylline concomitantly with methotrexate.

There is some evidence from animal studies that concomitant administration of a beta-adrenergic agonist (e.g., isoproterenol) and a theophylline derivative (e.g., aminophylline) may produce increased cardiotoxic effects. Although such an interaction has not been established in humans, a few reports have suggested that such a combination may have the potential for producing cardiac arrhythmias. Further accumulation of clinical data is needed to determine whether this potential interaction exists in humans.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Pde Inhibitors/Riociguat

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Riociguat stimulates the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate (cGMP) pathway and also increases cGMP.(1) Aminophylline, avanafil, dipyridamole, sildenafil, tadalafil, theophylline, and vardenafil inhibit phosphodiesterase (PDE), which is responsible for the breakdown of cGMP.(1)

CLINICAL EFFECTS: The concurrent use of PDE inhibitors and riociguat potentiates the hypotensive effects of both agents, which may result in dizziness, syncope, heart attack, or stroke.(1)

PREDISPOSING FACTORS: Plasma levels of the PDE type-5 inhibitors may be higher in the following patients: those older than 65, with hepatic impairment, with severe renal impairment, or using concomitant CYP3A4 inhibitors. This may increase the severity of the interaction.

PATIENT MANAGEMENT: The administration of riociguat to patients receiving PDE inhibitors, including specific PDE-5 inhibitors (avanafil (5), sildenafil (2), tadalafil (3,6), or vardenafil (4)) and nonspecific PDE inhibitors (aminophylline, dipyridamole, theophylline) is contraindicated.(1) If transitioning from sildenafil to riociguat, discontinue sildenafil at least 24 hours prior to administering riociguat.(1) If transitioning from tadalafil to riociguat, discontinue tadalafil at least 48 hours prior to administering riociguat. Consider starting riociguat at 0.5 mg in patients at risk for hypotension.(1) If transitioning from riociguat to a PDE inhibitor, discontinue riociguat at least 24 hours prior to administering a PDE inhibitor.(1)

DISCUSSION: In a study of 7 PAH patients maintained on sildenafil (20 mg TID), single doses of riociguat (0.5 mg and 1 mg, sequentially) showed additive hemodynamic effects.(1) In clinical trials, there was a high rate of discontinuation for hypotension among patients receiving sildenafil (20 mg TID) and riociguat (1 mg to 2.5 mg TID) and one death.(1)

Selected Cyp1a2 Substrates/Viloxazine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Viloxazine is a strong inhibitor of CYP1A2 and may increase the total exposure of sensitive CYP1A2 substrates.(1) The FDA defines strong inhibition as an increase in drug area-under-curve (AUC) greater than 5-fold.(2)

CLINICAL EFFECTS: Concurrent use of viloxazine with drugs primarily metabolized by CYP1A2 may lead to elevated drug levels and increase the risk of adverse reactions associated with the CYP1A2 substrate.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Drugs linked to this monograph have a narrow therapeutic window or are sensitive to CYP1A2 inhibition. Coadministration of viloxazine with sensitive CYP1A2 substrates or CYP1A2 substrates with a narrow therapeutic window is contraindicated.(1)

DISCUSSION: Concomitant use of viloxazine significantly increases the total exposure, but not peak exposure, of sensitive CYP1A2 substrates, which may increase the risk of adverse reactions associated with these CYP1A2 substrates. In a study, viloxazine increased the AUC of caffeine by almost 6-fold.(1) CYP1A2 substrates linked to this monograph include: agomelatine, alosetron, aminophylline, duloxetine, ramelteon, tasimelteon, and theophylline.(2,3)

Xanthine Derivatives/Adenosine; Hexobendine; Regadenoson

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Xanthine derivatives may antagonize the effects of endogenous(1) and exogenous adenosine,(2,3) regadenoson,(4) and hexobendine.(5)

CLINICAL EFFECTS: Concurrent use of a xanthine derivative use may result in decreased effectiveness of adenosine, hexobendine and regadenoson. Aminophylline may increase the risk of adenosine-induced seizures.(3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent therapy with adenosine and a xanthine derivative should be monitored for decreased effectiveness of adenosine. The dosage of adenosine may need to be increased. Whenever possible, withhold xanthine derivatives for 5 half-lives prior to using adenosine in cardiac stress tests.(6) Methylxanthines should not be used to reverse the effects of adenosine in patients who experience adenosine-induced seizures.(3) Concurrent therapy with hexobendine and a xanthine oxidase derivative should also be monitored for decreased effectiveness of hexobendine.(5) The US manufacturer of regadenoson recommends that patients avoid methylxanthines (e.g. caffeine, pentoxifylline, and theophylline) for 12 hours prior to regadenoson administration. Aminophylline may be used to attenuate severe and/or persistent adverse reactions to regadenoson.(4)

DISCUSSION: In a study in six healthy subjects, theophylline significantly reduced the heart-rate response to adenosine. In addition, theophylline reduced the amount of abdominal and chest discomfort reported by subjects, allowing significantly higher infusion rates of adenosine.(7) Theophylline has also been reported to antagonize the vasorelaxant action of adenosine in human forearm arterioles.(8) In a study in five subjects, theophylline decreased the amounts of adenosine-induced side effects, including chest pain. There was no change in blood pressure or respiratory rate during concurrent adenosine and theophylline.(9) In a study in ten dog and twelve human subjects, the administration of adenosine after hexobendine increased coronary sinus blood flow. Aminophylline administration significantly decreased the coronary vasodilation response to adenosine and hexobendine.(5) In a study in ten healthy subjects, caffeine reduced the mean adenosine-induced increases in systolic blood pressure by 7.2 mmHg and heart rate by 8.4 beats/min when compared to placebo.(2) In another study in ten healthy subjects, caffeine was shown to lower the adenosine-induced response of blood pressure and heart rate.(3) Caffeine has also been reported to reduced adenosine-induced changes in minute ventilation and tidal volume.(3) Aminophylline has been shown to shorten the duration of coronary blood flow response to regadenoson.(3) Coronary flow reserve was 8% lower in patients who received caffeine (200 mg single dose) 2 hours prior to regadenoson administration when compared to subjects who received placebo instead of caffeine.(4)

Xanthine Derivatives/Dipyridamole Injectable

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The xanthine derivatives are adenosine receptor antagonists. Concurrent administration may inhibit dipyridamole-induced increases in endogenous plasma adenosine levels, thus decreasing dipyridamole's vasodilator effects.(1)

CLINICAL EFFECTS: Concurrent administration may result in a decrease in dipyridamole's vasodilator effects. This may produce false-negative results during dipyridamole-thallium imaging tests.(1-3)

PREDISPOSING FACTORS: In patients with congestive heart failure and decreased hepatic function, the metabolism of xanthine derivatives may be decreased. These patients may need a longer xanthine-free period prior to dipyridamole-thallium imaging tests.(2)

PATIENT MANAGEMENT: Patients scheduled for dipyridamole-thallium imaging tests should have a xanthine-free period (including caffeine-containing products) for at least 24 hours prior to their exam.(3)

DISCUSSION: In a study in eight male subjects with documented coronary artery disease, intravenous dipyridamole administered during a dipyridamole-thallium 201 SPECT image test produced a significant increase in heart rate, a decrease in blood pressure, and angina in seven patients and ST segment depression in four patients. SPECT imaging showed reversible perfusion defects in myocardial segments supplied by stenotic coronary arteries. When the exam was repeated when the subjects were receiving therapeutic dosages of theophylline, there was no appearance of angina, ST depression, or hemodynamic changes and SPECT imaging shown total absence of reversible perfusion defects.(1) A study in eight patients with coronary artery disease evaluated the effects of caffeine on dipyridamole-201Tl myocardial imaging. The administration of dipyridamole alone resulted in chest pain and ST-segment depression in four patients. Concurrent caffeine infusion decreased the dipyridamole-induced decrease in blood pressure and heart rate. No patients experience chest pain or ST-segment depression. Six patients had false negative test results.(2) Another study found that the attenuation of the hemodynamic response to dipyridamole by caffeine was dose-dependent.(3)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Pde Inhibitors/Vericiguat

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Vericiguat stimulates the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate (cGMP) pathway and also increases cGMP.(1) Aminophylline, avanafil, dipyridamole, sildenafil, tadalafil, theophylline, and vardenafil inhibit phosphodiesterase (PDE), which is responsible for the breakdown of cGMP.(1-6)

CLINICAL EFFECTS: The concurrent use of PDE inhibitors and vericiguat potentiates the hypotensive effects of both agents, which may result in dizziness, syncope, heart attack, or stroke.(1)

PREDISPOSING FACTORS: Plasma levels of the PDE type-5 inhibitors may be higher in the following patients: those older than 65, with hepatic impairment, or with severe renal impairment. This may increase the severity of the interaction.

PATIENT MANAGEMENT: The manufacturer of vericiguat states that administration of vericiguat to patients receiving PDE inhibitors, including specific PDE-5 inhibitors (avanafil,(2) sildenafil,(3) tadalafil,(4,5) or vardenafil(6)) and nonspecific PDE inhibitors (aminophylline, dipyridamole, theophylline) is not recommended.(1) The manufacturers of the PDE-5 inhibitors state that concurrent use of guanylate cyclase stimulators is contraindicated.(2-6)

DISCUSSION: Concomitant use of vericiguat 10 mg with single doses of sildenafil (25, 50, or 100 mg) was associated with additional seated BP reduction of up to 5.4 mm Hg (systolic/diastolic BP, MAP), compared to administration of vericiguat alone.(1)

Selected Cyp1a2 Or Cyp2d6 Substrates/Givosiran

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Givosiran interferes with the first and rate-limiting step in hepatic heme biosynthesis, which may lower hepatic heme levels and decrease production and/or activity of cytochrome P450 enzymes.(1,2)

CLINICAL EFFECTS: Concurrent use of givosiran may result in elevated levels of and toxicity from agents metabolized by CYP1A2 or CYP2D6.(1)

PREDISPOSING FACTORS: With tricyclic antidepressants, the risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids). With anticholinergic agents, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(3)

PATIENT MANAGEMENT: Avoid the concurrent use of givosiran with agents that are sensitive substrates of CYP1A2 or CYP2D6, or CYP1A2 or CYP2D6 substrates with a narrow therapeutic index. If concurrent use is unavoidable, decrease the dose of the CYP1A2 or CYP2D6 substrate and monitor patients for toxicity.

DISCUSSION: A study of 9 patients with acute intermittent porphyria found that givosiran decreased the maximum concentration (Cmax) and area-under-curve (AUC) of caffeine (a CYP1A2 substrate) by 1.3- and 3.1-fold, respectively, compared to caffeine alone. Givosiran also decreased the Cmax and AUC of dextromethorphan (a CYP2D6 substrate) by 2- and 2.4-fold, respectively, compared to dextromethorphan alone.(1,2) Selected CYP2D6 substrates linked to this monograph include: atomoxetine, desipramine, deutetrabenazine, dextromethorphan, doxepin, encainide, methoxyphenamine, metoprolol, nebivolol, nefazodone, paroxetine, perphenazine, risperidone, tetrabenazine, trimipramine, and venlafaxine. Selected CYP1A2 substrates linked to this monograph include: agomelatine, aminophylline, rasagiline, tacrine, theophylline, tizanidine, and yohimbine.

Selected Cyp1a2 Substrates/Capmatinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Capmatinib is a moderate inhibitor of CYP1A2.(1) The FDA defines moderate inhibition as an increase in drug area-under-curve (AUC) greater than two fold, but less than 5 fold.(2)

CLINICAL EFFECTS: Concurrent use of capmatinib with drugs primarily metabolized by CYP1A2 may lead to elevated drug levels and increased side effects.(1)

PREDISPOSING FACTORS: Greater risk for adverse events would be expected for drugs with a narrow therapeutic window, or for drugs especially sensitive to CYP1A2 inhibition.

PATIENT MANAGEMENT: Drugs linked to this monograph have a narrow therapeutic window or are sensitive to CYP1A2 inhibition. If coadministration is unavoidable, decrease the CYP1A2 substrate dosage in accordance with the approved prescribing information.(1)

DISCUSSION: Coadministration with caffeine (a CYP1A2 substrate) increased area-under-curve (AUC) by 134% with no change in its maximum concentration (Cmax).(1) CYP1A2 substrates linked to this monograph include: agomelatine, aminophylline, and theophylline.(2)

Selected Cyp1a2 Substrates/Deferasirox

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Deferasirox is a weak inhibitor of CYP1A2. The FDA defines weak inhibition as an increase in drug area-under-curve (AUC) greater than 1.25 fold, but less than 2 fold.(1-3)

CLINICAL EFFECTS: Concurrent use of deferasirox may lead to increased levels and effects of drugs primarily metabolized by CYP1A2.(1)

PREDISPOSING FACTORS: Greater risk for adverse events would be expected for drugs with a narrow therapeutic window, or for drugs especially sensitive to CYP1A2 inhibition. With tizanidine, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(4)

PATIENT MANAGEMENT: The US manufacturer of deferasirox recommends avoiding concomitant therapy with theophylline or CYP1A2 narrow therapeutic range substrates such as tizanidine.(1) The Australian and UK manufacturers of deferasirox state that concomitant use with theophylline or other substances predominantly metabolized by CYP1A2 and with a narrow therapeutic index (e.g., clozapine, tizanidine) is not recommended.(5,6) If concomitant use is necessary in patients already receiving CYP1A2 substrates such as clozapine, theophylline, or tizanidine, the dose of the CYP1A2 substrate may need to be reduced when deferasirox is started. Theophylline AUC and elimination half-life may double. Monitor theophylline concentrations and adjust dose accordingly.(1) Patients already receiving deferasirox when a CYP1A2 substrate is started may be more susceptible to adverse effects. A lower than usual dose of the CYP1A2 substrate may be needed. The US manufacturer of tizanidine recommends avoiding concomitant therapy with CYP1A2 inhibitors. If concurrent therapy is necessary, tizanidine should be initiated at 2 mg dose and increased in 2-4 mg steps daily based on patient response to therapy. If adverse reactions such as hypotension, bradycardia, or excessive drowsiness occur, reduce or discontinue tizanidine therapy.(7) The US manufacturer of clozapine recommends monitoring patients closely when clozapine is coadministered with moderate or weak CYP1A2 inhibitors. Consider reducing the clozapine dosage if necessary.(8)

DISCUSSION: In a study with healthy volunteers, deferasirox dosage of 30mg/kg/day (duration not stated) and a single dose of theophylline 120 mg led to an approximate doubling of the theophylline area-under-curve (AUC) and elimination half-life.(1) Although interactions between deferasirox and clozapine or tizanidine have not been specifically studied, clozapine and tizanidine are considered CYP1A2 narrow therapeutic range substrates.

Selected Cyp1a2 Substrates/Vemurafenib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Vemurafenib is a moderate inhibitor of CYP1A2. The FDA defines moderate inhibition as an increase in drug area-under-curve (AUC) greater than two fold, but less than 5 fold.

CLINICAL EFFECTS: Concurrent use of vemurafenib with drugs primarily metabolized by CYP1A2 may lead to elevated drug levels and increased side effects.

PREDISPOSING FACTORS: Greater risk for adverse events would be expected for drugs with a narrow therapeutic window, or for drugs especially sensitive to CYP1A2 inhibition. With tizanidine, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(5)

PATIENT MANAGEMENT: Drugs linked to this monograph have a narrow therapeutic window or are sensitive to CYP1A2 inhibition. If coadministration cannot be avoided, the manufacturer of vemurafenib recommends close monitoring and possible dose reduction of the affected drug. Steady-state levels of vemurafenib are not attained for approximately 15 days and so extended monitoring for interaction onset and severity may be required. The US manufacturer of tizanidine states that if concurrent therapy is necessary, tizanidine should be initiated at 2 mg dose and increased in 2-4 mg steps daily based on patient response to therapy. If adverse reactions such as hypotension, bradycardia, or excessive drowsiness occur, reduce of discontinue tizanidine therapy.(4)

DISCUSSION: An interaction study was performed in cancer patients treated with vemurafenib 960 mg twice daily for 15 days. The AUC of caffeine, a sensitive substrate for CYP1A2, was increased 2.6-fold. Coadministration with tizanidine (2mg, a sensitive CYP1A2 substrate) on day 21 with vemurafenib (960 mg twice daily for 21 days) increased tizanidine AUC and Cmax by 4.7-fold and 2.2-fold in 16 cancer patients. (1)

Theophylline Derivatives/Cimetidine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Cimetidine inhibits the metabolism of theophylline by CYP1A2.(1-10) The duration of cimetidine's inhibitory action is uncertain. Short-term cimetidine therapy appears to reverse rapidly(2) but may persist in prolonged therapy. Increased pentoxifylline serum levels may be the result of an increase in the oral bioavailability of pentoxifylline.(11)

CLINICAL EFFECTS: Concurrent cimetidine and theophylline derivative therapy may result in elevated theophylline derivative concentration levels, prolonged elimination half-life, and decreased clearance.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Theophylline derivative blood levels should be very closely monitored if cimetidine therapy is to be initiated, changed, or discontinued. Theophylline has a narrow therapeutic range; therefore, dosage reductions up to 30-50%(4) should be considered to prevent intoxication when cimetidine therapy is started. Antacids, famotidine, or possibly ranitidine might be more judicious choices than cimetidine in patients receiving theophylline derivatives.

DISCUSSION: It is well documented that cimetidine impairs the elimination of theophylline when the two agents are co-administered to patients.(1-10, 12-22) This interaction has been noted by a variety of routes including continuous intravenous infusion.(22) Reports indicate that with concurrent cimetidine, theophylline plasma concentrations increase, theophylline half-life is prolonged from 29% to 73%(1-3;9,12-14) and theophylline clearance is decreased by 18.5% to 46%.(1-3,9,13,23) Age and smoking do not appear to affect the magnitude of the interaction.(17,18,20) Significant changes can be seen within 24 hours(3,5) and may progress as co-therapy continues.(3) A study involving ten healthy patients demonstrated that concomitant administration of cimetidine significantly decreased the plasma clearance of oxtriphylline.(24) Aminophylline is involved in a similar interaction as theophylline as seen in one case report.(25) In one report cimetidine also decreased the clearance and prolonged the half-life of caffeine.(26,27) A study demonstrated that cimetidine caused a significant increase in plasma levels of pentoxifylline.(11) Information on ranitidine is conflicting. Several studies have shown that ranitidine does not influence theophylline.(9,15,16,19,28,29) One case report noted toxic theophylline levels after ranitidine;(30) however, this case report has been challenged.(31) In another case report, theophylline levels rose from 16.6 mcg/ml to 39.7 mcg/ml(32) when the patient was given ranitidine. Other reports have also noted a reduction in theophylline elimination by ranitidine.(33,34) Famotidine has shown to have no effect on theophylline metabolism in a clinical trial;(35) however, there is one case report of decreased theophylline clearance during famotidine therapy.(36) Dyphylline, a theophylline derivative that is not converted to theophylline in vivo, is not to be expected to interact with cimetidine. A study showed that cimetidine increased the average steady state plasma concentration of pentoxifylline and its metabolite by 25% and 30%, respectively.(37)

Theophylline/Rifampin

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The hepatic metabolism of theophyllines is increased by rifampin.

CLINICAL EFFECTS: Serum theophylline concentrations are reduced, possibly resulting in a decrease in therapeutic effects.

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Monitor the patients for a change in therapeutic response to theophylline if rifampin therapy is started or stopped. Adjust the dose of theophylline accordingly.

DISCUSSION: Concurrent administration of theophylline and rifampin can produce a clinically significant increase in theophylline clearance. This interaction has been documented in adult and pediatric patients.

Theophyllines/Allopurinol

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Allopurinol may inhibit the metabolism of theophylline.

CLINICAL EFFECTS: Increased levels of theophylline may result in theophylline toxicity.

PREDISPOSING FACTORS: Larger doses of allopurinol given for greater than two weeks.

PATIENT MANAGEMENT: Monitor theophylline levels in patients receiving concurrent therapy with theophylline and allopurinol. The dosage of theophylline may need to be decreased during concurrent therapy.

DISCUSSION: Decreased metabolism of theophylline has been reported during concurrent administration with large doses of allopurinol (600 mg daily) given over two weeks. There is one case report of a 38% increase in theophylline levels following the addition of allopurinol (100 mg daily) to therapy. Other authors have reported no effect on theophylline clearance by allopurinol when allopurinol was administered in smaller doses for shorter courses of therapy.

Theophyllines/Carbamazepine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Theophylline may induce the metabolism of carbamazepine. Carbamazepine may induce the metabolism of theophylline.

CLINICAL EFFECTS: Decreased levels of carbamazepine and theophylline may result in decreased clinical effectiveness of these agents.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: During concurrent therapy, theophylline and carbamazepine serum concentrations should be monitored. The dosage of one or both agents may need to be adjusted.

DISCUSSION: In one case report, concurrent administration of carbamazepine and theophylline resulted in sub-therapeutic levels of theophylline, a decrease in theophylline half-life, and a worsening of the patient's clinical condition. In another report, a patient maintained on carbamazepine for eight months experienced a convulsion eight days after beginning theophylline therapy. The patient had previously received theophylline three times without adverse effect. In a follow-up study in this patient, concurrent administration of theophylline and carbamazepine resulted in decreases in carbamazepine levels by 29.6-36.7%, a decrease in carbamazepine half-life by 11.8%, and another grand mal seizure. Theophylline levels in this patient were high; however, not enough information is given in the report to determine if carbamazepine inhibited the metabolism of theophylline.

Theophyllines/Halothane

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Halothane is known to sensitize the heart to the effects of adrenergic agonists.(1) It is probable that halothane similarly sensitizes the heart to theophylline's arrhythmogenic effect, but the exact mechanism is uncertain.

CLINICAL EFFECTS: In several patients receiving chronic aminophylline therapy, onset of serious arrhythmias within a few minutes after initiation of halothane anesthesia has been reported.(2-4)

PREDISPOSING FACTORS: Animal studies indicate an increased likelihood of arrhythmias when aminophylline administration precedes halothane anesthesia.(5,6)

PATIENT MANAGEMENT: Avoid coadministration of these drugs; enflurane and isoflurane appear less likely to interact with theophylline than halothane.

DISCUSSION: Ventricular arrhythmias have been reported in patients during concomitant administration of theophylline and halothane. Based upon the limited documentation available in humans, this interaction appears to be pharmacodynamic.

Theophyllines/Selected Quinolones

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Quinolones may inhibit the hepatic microsomal enzymes responsible for the metabolism of theophyllines.

CLINICAL EFFECTS: May see an increase in the pharmacologic and toxic effects of theophylline due to elevated serum levels. Fatalities have been reported.

PREDISPOSING FACTORS: Older age.

PATIENT MANAGEMENT: Monitor theophylline serum levels and observe the patient for symptoms of theophylline toxicity (e.g, nausea, seizure). Adjust the dose of theophylline as needed.

DISCUSSION: Several studies have demonstrated that quinolones (e.g., ciprofloxacin, enoxacin, norfloxacin) may increase serum theophylline levels and decrease theophylline clearance. In addition, ciprofloxacin has been reported to increase the half-life and volume of distribution of theophylline. Theophylline toxicity has been associated with concurrent administration of quinolone antibiotics. Some studies indicate that norfloxacin does not interact with theophyllines.

Theophyllines/Tacrine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Unknown. However, tacrine alters the elimination of theophylline.

CLINICAL EFFECTS: Serum theophylline concentrations may be elevated, increasing the pharmacological and toxic effects of theophylline.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: In patients receiving theophylline, monitor serum theophylline concentrations and observe the patient for a change in therapeutic response if tacrine therapy is initiated or discontinued. If both drugs are being started at the same time, or if the patient is receiving tacrine when theophylline is being started, reduce the dose of theophylline by 25% to 50% and monitor serum theophylline concentrations. In all instances, adjust the dose of theophylline accordingly.

DISCUSSION: Documentation for this interaction consists of data on file with the manufacturer of tacrine. Concurrent administration of tacrine and theophylline produced a twofold increase in theophylline elimination half-life and average plasma theophylline concentrations. In order to minimize the occurrence of the theophylline toxicity when starting tacrine in a patient who is receiving theophylline, monitor serum theophylline concentrations and observe the patient for signs and symptoms of theophylline toxicity which may include tachycardia, anorexia, diarrhea, insomnia, restlessness and headache. Other symptoms of toxicity are extreme thirst, agitation, frequent vomiting, arrhythmias, delirium, hyperthermia and diaphoresis. Seizures may occur and may result in death.

Moderate Interaction: Assess the risk to the patient and take action as needed.

Beta-Agonists; Anticholinergics; Theophylline/Methacholine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Beta-agonists, anticholinergics, and theophylline may inhibit the action of methacholine on the airway.(1)

CLINICAL EFFECTS: The result of the methacholine challenge test may not be accurate.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The following drugs should be held before a methacholine challenge for the the duration indicated:(1) - short-acting beta-agonists: 6 hours - long-acting beta-agonists: 36 hours - short-acting anti-cholinergics: 12 hours - long-acting anti-cholinergics: at least 168 hours (7 days) - oral theophylline: 12-48 hours

DISCUSSION: Beta-agonists, anticholinergics, and theophylline may inhibit the action of methacholine on the airway and cause inaccurate test results.

Selected Cyp1a2 Substrates/Osilodrostat

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Osilodrostat is a moderate inhibitor of CYP1A2.(1) The FDA defines moderate inhibition as an increase in drug area-under-curve (AUC) greater than two fold, but less than 5 fold.(2)

CLINICAL EFFECTS: Concurrent use of osilodrostat with drugs primarily metabolized by CYP1A2 may lead to elevated drug levels and increased side effects.(1)

PREDISPOSING FACTORS: Greater risk for adverse events would be expected for drugs with a narrow therapeutic window, or for drugs especially sensitive to CYP1A2 inhibition.

PATIENT MANAGEMENT: Drugs linked to this monograph have a narrow therapeutic window or are sensitive to CYP1A2 inhibition. Use caution when osilodrostat is coadministered with CYP1A2 substrates with narrow therapeutic index.(1)

DISCUSSION: In a study of 20 healthy volunteers, a single dose of osilodrostat 50 mg increased the AUC of caffeine, a CYP1A2 substrate, by 2.5-fold.(1)

Selected Theophylline Derivatives/Moricizine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Moricizine may induce the metabolism of hepatically metabolized theophylline derivatives.(1)

CLINICAL EFFECTS: Concurrent use of moricizine may result in reduced theophylline levels and clinical effectiveness.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Theophylline levels should be carefully monitored if moricizine is added to or withdrawn from concurrent therapy. The dose of theophylline may need to be adjusted.

DISCUSSION: In a study in 12 healthy subjects, the effects of moricizine (250 mg every 8 hours) on single doses of immediate-release aminophylline and controlled-release theophylline was examined. Theophylline clearance increased for both the aminophylline and the controlled-release theophylline preparation (43% and 66%, respectively). Theophylline half-life decreased, although the magnitude of decrease was less with the controlled-release formulation than with the aminophylline formulation (20% and 33%, respectively). The theophylline area-under-curve (AUC) was decreased for both the aminophylline and theophylline (32% and 36%, respectively). Moricizine also decreased the maximum concentration (Cmax) of theophylline with the controlled-release theophylline, but not with aminophylline.(1)

Selected Xanthine Derivatives/Fluvoxamine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Fluvoxamine may inhibit the metabolism of the xanthine derivatives by CYP1A2.(1,2)

CLINICAL EFFECTS: Concurrent use of fluvoxamine and xanthine derivatives may result in elevated levels of the xanthine derivative and toxicity.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of fluvoxamine recommends that the dose of theophylline be decreased to one-third of the usual daily dose in patients receiving concurrent therapy. Theophylline levels should be closely monitored and patients should be observed for signs of theophylline toxicity.(3) The dosage of theophylline may need to be adjusted if fluvoxamine is discontinued. Patients receiving fluvoxamine should be instructed to consume caffeine containing beverages and/or medications with caution.

DISCUSSION: In a study in 12 healthy subjects, the administration of a single dose of theophylline ethylenediamine (300 mg) on Day 4 of fluvoxamine (50 mg Day 1, 100 mg daily Days 2-6) decreased theophylline total clearance by 70%. The half-life of theophylline increased 2.3-fold (from 6.6 hours to 22 hours).(1) In a study in 12 healthy males, the administration of a single dose of theophylline (375 mg given as 442 mg aminophylline) with fluvoxamine (50 mg twice daily at steady state) decreased theophylline clearance by 3-fold.(3) Fluvoxamine has been shown to inhibit the metabolism of theophylline in vitro.(2) There are four case reports of theophylline toxicity during concurrent fluvoxamine therapy.(4-7) In a study in eight healthy subjects, the administration of a single dose of caffeine (200 mg) on Day 8 of fluvoxamine (50 mg daily Days 1-4, 100 mg daily Days 5-12) decreased caffeine clearance by 80%. The half-life of caffeine increased 5.2-fold (from 5 hours to 31 hours).(8) In a study, seven reports of impaired caffeine clearance were reported in patients whom received single 250mg doses of caffeine together with fluvoxamine (four doses of 100mg over two days). Fluvoxamine reduced the apparent oral clearance of caffeine by 91.3%, and prolonged its elimination half-life by 11.4-fold (from 4.9 hours to 56 hours). There were no changes in the pharmacodynamic effects of caffeine.(9)

Selected Xanthine Derivatives/Selected Macrolide Antibiotics

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The macrolides may inhibit the metabolism of the xanthine derivatives at CYP3A4. Theophylline decreases the bioavailability and increases the renal clearance of erythromycin by unknown mechanisms.

CLINICAL EFFECTS: The concurrent administration of xanthine derivatives and some macrolides may result in elevated levels and increased clinical and adverse effects of the xanthine derivatives. The serum levels of erythromycin may be decreased.

PREDISPOSING FACTORS: This interaction may be more severe in patients who have decreased xanthine clearance rates secondary to CHF, viral URI's, hepatic impairment, acute pulmonary edema, or cor pulmonale. Large xanthine doses may also pre-dispose patients to the clinical effects of the interaction.

PATIENT MANAGEMENT: Patients receiving concurrent therapy with these agents should be monitored for signs of xanthine toxicity (e.g. nausea, seizures, nervousness, etc.). Theophylline levels should be monitored during and following concurrent macrolide therapy. The dosage of the xanthine derivative may need to be adjusted.

DISCUSSION: Several controlled studies have demonstrated that concurrent administration of erythromycin and aminophylline,(1-5) oxtriphylline,(6) and theophylline(7-17) may reduce theophylline clearance and increase theophylline serum levels and half-life. Theophylline toxicity has been reported with concomitant administration of these drugs, usually after concurrent therapy exceeds five days. In contrast to these reports, other studies found that concurrent erythromycin and aminophylline(18-20) or theophylline(21-24) had no effects on theophylline levels. Studies have shown that aminophylline(3) and theophylline(7-8,25) can increase the clearance of erythromycin, resulting in lower erythromycin levels. Elevated theophylline levels have also been reported during concurrent administration of theophylline with clarithromycin.(26) Elevated theophylline levels have also been reported during concurrent administration of theophylline with troleandomycin.(27-28) Azithromycin,(29) dirithromycin,(30-32) miocamycin,(33-34) ponsinomycin, (35) roxithromycin,(36-38) and spiramycin(39) have been shown to not have clinically significant effects on theophylline levels.

Theophylline Derivatives/Favipiravir

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The mechanism of this interaction is not fully understood but may involve competitive inhibition of xanthine oxidase by theophylline derivatives. Favipiravir is primarily metabolized by aldehyde oxidase and partly metabolized by xanthine oxidase.(1)

CLINICAL EFFECTS: The plasma concentrations of favipiravir may increase and result in a greater risk of toxicity from favipiravir, including hyperuricemia, diarrhea, and hepatotoxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent therapy with favipiravir and theophylline derivatives should be undertaken with caution. Monitor patients for signs and symptoms of adverse effects of favipiravir.(1)

DISCUSSION: In a study, theophylline (200 mg twice daily on Days 1 to 9 then 200 mg daily on Day 10) increased the maximum concentration (Cmax) and area-under-curve (AUC) of favipiravir (600 mg twice daily on Day 6 then 600 mg daily on Days 7 to 10) by 33% and 27%, respectively.(1)

Theophylline Derivatives/Lithium

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Theophylline derivatives increase the renal excretion of lithium.

CLINICAL EFFECTS: Decreased levels of lithium which may result in decreased clinical effectiveness.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Lithium levels and response should be monitored in patients in whom theophylline therapy is initiated or withdrawn. Patients receiving concurrent therapy should be monitored for increased adverse effects.

DISCUSSION: In a study involving ten volunteers, the concurrent administration of lithium and theophylline resulted in a significant decrease in lithium serum levels. Upon discontinuation of theophylline, lithium levels and half-life increased, and the clearance of lithium decreased. Individual variability in these parameters was significant. The overall incidence of adverse effects was significantly greater with concurrent therapy including restlessness, tremor, and anorexia. In another study in ten normal subjects, lithium (1200 mg/day for seven days) was administered and it was reported that theophylline infusion (dosed to achieve a plasma level of 14 mcg/ml) increased lithium clearances by 51%. In a case report, reduced lithium levels as well as worsening of manic symptoms occurred after increasing doses of theophylline were administered. It has been shown that aminophylline increases the lithium/creatinine clearance ratio, which may result in decreased serum lithium below the therapeutic level. Caffeine withdrawal has been reported to increase lithium levels in several case reports. This interaction is most important to consider in patients who have been previously sensitive to relapse with decreased lithium levels and in whom levels are maintained at the therapeutic/prophylactic borderline.

Theophylline Derivatives/Selected Cyp1a2 Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: CYP1A2 inhibitors may reduce the elimination rate of theophylline derivatives.

CLINICAL EFFECTS: The concurrent administration of selected CYP1A2 inhibitors and theophylline or their derivatives may result in increased levels and toxicity of theophylline.(1-19)

PREDISPOSING FACTORS: Concomitant therapy with inhibitors of CYP3A4 (e.g. clarithromycin, itraconazole, ritonavir) which block a secondary metabolic pathway for theophylline, may increase the magnitude of this interaction.

PATIENT MANAGEMENT: Theophylline levels should be closely monitored in patients receiving concurrent therapy. The dosage of theophylline may need to be decreased after a CYP1A2 inhibitor is initiated. If the CYP1A2 inhibitor is discontinued in a patient stabilized on the combination, the theophylline level may fall. Monitor theophylline levels and adjust dose accordingly.

DISCUSSION: A study in 5 patients with active hepatitis B and 4 healthy subjects examined the effects of a single dose of interferon alpha (9 million units in 8 subjects, 18 million units in 1 subject). There was no effect on theophylline in 1 subject. In the other 8 subjects, interferon increased theophylline half-life by 70% and decreased theophylline clearance by 49% (range 33% to 81%).(1) A study in 11 healthy subjects examined the effects of interferon alpha (3 million International Units daily for 3 days) on a single aminophylline (4 mg/kg) infusion. Interferon increased the half-life, area-under-curve (AUC), and mean residence time by 13.7%, 17.9%, and 16.3%, respectively. Theophylline clearance decreased by 9.1%.(2) In a study in healthy males, peginterferon alfa-2a (180 mcg once weekly for 4 weeks) increased theophylline AUC by 25%.(3,4) Concurrent interferon alfa has been shown to increase theophylline levels by 100%.(5) A study in 7 patients with chronic hepatitis C examined the effects of interferon beta (3 million to 9 million International Units daily for 8 weeks) on theophylline ethylenediamine (single 250 mg infusion). Interferon decreased theophylline clearance by 26.3% and increased theophylline half-life by 39.3%. There was no correlation between interferon dose and effect. The greatest effect was seen in a patient who received 3 million International Units daily, while no effect was seen in a patient who received 9 million International Units daily.(6) Increased serum theophylline levels with signs and symptoms of theophylline toxicity have been reported in patients following the addition of mexiletine to their treatment.(7-15) In a study evaluated the combination of disulfiram and theophylline in 20 recovering alcoholics. Patients received a single IV dose of theophylline while being given either 250 mg or 500 mg of disulfiram daily. Both dosages of disulfiram decreased the clearance of theophylline. However, the effect was greatest in patients receiving disulfiram 500 mg daily.(16) Increases in serum theophylline concentration and half-life have been reported during concurrent administration of theophylline and ticlopidine.(17) In healthy subjects, rofecoxib (12.5 mg/day, 25 mg/day, or 50 mg/day for seven days) increased the area-under-curve (AUC) of a single dose of theophylline (300 mg) by 38% to 60%. Therefore, the manufacturer of rofecoxib recommends that theophylline levels be monitored if rofecoxib is initiated or changed in patients receiving theophylline.(18) Selected CYP1A2 inhibitors linked to this monograph include: acyclovir, Angelica dahurica, artemisinin, belumosudil, centanafadine, cannabidiol, curcumin, danshen, dipyrone, disulfiram, echinacea, enasidenib, fexinidazole, genistein, ginseng, interferons, methoxsalen, mexiletine, parsley, phenylpropanolamine, pipemidic acid, piperine, propafenone, ribociclib, rofecoxib, rucaparib, simeprevir, ticlopidine, triclabendazole, valacyclovir, and verapamil.(19)

Theophylline/Barbiturates; Hydantoins

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Theophylline is primarily metabolized by CYP1A2 with CYP3A4 playing a lesser role in theophylline clearance.(1) Hydantoins (e.g. phenytoin) and barbiturates are inducers of both metabolic pathways. Primidone is metabolized to phenobarbital.

CLINICAL EFFECTS: Concomitant treatment with barbiturates or hydantoins may lower serum theophylline concentrations resulting in reduced pharmacologic effects.

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Monitor serum theophylline concentrations and observe the patient for a change in the therapeutic effects of theophylline when barbiturate or phenytoin therapy is initiated. The onset of induction is gradual but may begin within one week. The time to maximal induction may be 2 or more weeks depending upon the half-life and dose of the inducer. Adjust the dose of theophylline accordingly. If concomitant therapy with a barbiturate or hydantoin is discontinued, theophylline levels will increase over a number of weeks depending upon the elimination half-life of the barbiturate or hydantoin. Substantial lowering of the theophylline dose may be required to prevent toxicity. Check serum theophylline levels and monitor for signs and symptoms of theophylline toxicity.

DISCUSSION: Data reported from infants, children and adults demonstrate that therapeutic doses of barbiturates and hydantoins increase the clearance of theophylline. There appears to be considerable interindividual differences. In some patients the decrease in plasma theophylline concentration may interfere with clinical management. Discontinuation of chronic barbiturate or hydantoin therapy in patients stabilized on this combination will lead to increased theophylline levels as induction wanes. Monitor closely as theophylline doses may need to be lowered to prevent toxicity.

Theophylline/Bupropion

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Both bupropion and theophylline are known to lower the seizure threshold.(1,2)

CLINICAL EFFECTS: Concurrent use of bupropion and theophylline may result in additive effects on the seizure threshold, increasing the risk of seizures.(1,2)

PREDISPOSING FACTORS: The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants an anorectics; a total daily dose of bupropion greater than 450 mg or single doses greater than 150 mg; rapid escalation of bupropion dosage; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antidepressants, antipsychotics, systemic steroids).(1,2)

PATIENT MANAGEMENT: The concurrent use of bupropion and theophylline should be undertaken only with extreme caution and with low initial dosing of bupropion and small gradual dosage increases.(1,2) Single doses should not exceed 150 mg.(1,2) The maximum daily dose of bupropion should not exceed 300 mg for smoking cessation(2) or 450 mg for depression.(1)

DISCUSSION: Because of the risk of seizure from concurrent bupropion and other agents that lower seizure threshold, the manufacturer of bupropion states that the concurrent use of bupropion and theophylline should be undertaken only with extreme caution and with low initial bupropion dosing and small, gradual dosage increases.(1,2)

Theophylline/Febuxostat

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Febuxostat may inhibit the metabolism of theophylline by xanthine oxidase.(1)

CLINICAL EFFECTS: Concurrent use of febuxostat may result in elevated levels of and toxicity from theophylline.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of febuxostat states that the concurrent use of theophylline should be approached with caution.(1)

DISCUSSION: Concurrent febuxostat (80 mg daily) increased the maximum concentration (Cmax) and area-under-curve (AUC) of theophylline by 6% and 6.5%, respectively. The amount of 1-methylxanthine, a major theophylline metabolite, excreted in the urine increased 400-fold. The safety of long-term exposure to 1-methylxanthine has not been determined.(1)

Theophylline/Marijuana Smoke

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Theophylline is primarily metabolized by CYP1A2 with CYP3A4 playing a lesser role in theophylline clearance.(1) Marijuana, when consumed by smoking, has been shown to induce CYP1A2.(2)

CLINICAL EFFECTS: Smoking marijuana may lower serum theophylline concentrations resulting in reduced pharmacologic effects.

PREDISPOSING FACTORS: Patients who smoke both marijuana and tobacco may have larger increases in theophylline clearance.(3)

PATIENT MANAGEMENT: Monitor serum theophylline concentrations and observe the patient for a change in the therapeutic effects of theophylline if the patient starts, alters, or discontinues marijuana use.

DISCUSSION: In a study in chronic marijuana users, users of both marijuana and tobacco, and control subjects, theophylline clearance was 42% higher in marijuana users. Theophylline clearance was increased 79% in subjects who smoked both marijuana and tobacco.(3)

Theophylline/Zileuton

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Zileuton may inhibit the metabolism of theophylline(1).

CLINICAL EFFECTS: Concurrent administration may result in increased levels of theophylline (up to two-fold) with possible theophylline toxicity.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of zileuton recommends that patients receiving concurrent therapy have their theophylline dosages reduced by one-half and that these patients be monitored for theophylline toxicity.(2)

DISCUSSION: In a study in 16 subjects, the concurrent administration of theophylline and zileuton resulted in increased levels of theophylline and adverse effects. During concurrent administration, theophylline area-under-curve (AUC), maximum concentration (Cmax), and minimum concentration (Cmin) increased 92%, 73%, and 125%, respectively. During administration of theophylline with placebo, eight of 16 subjects reported a single adverse effect, while 14 subjects reported a total of 44 adverse effects during administration of theophylline with zileuton.(1)

Theophyllines/Selected Beta-Blockers

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Certain beta-blockers may inhibit theophylline metabolism. In addition, beta-blockers, especially non-selective agents, can antagonize the pharmacologic effects of theophylline.

CLINICAL EFFECTS: Even though theophylline concentrations may increase leading to increased possibility of theophylline toxicity, beta-blockers decrease theophylline's therapeutic effects.

PREDISPOSING FACTORS: Cigarette smoking may exacerbate this interaction.

PATIENT MANAGEMENT: Avoid the use of non-selective beta-blockers with theophylline. If a beta-blocker must be used, a cardioselective agent that does not decrease the clearance of theophylline (e.g., atenolol) should be considered. However, since cardioselectivity is not absolute and is less selective at higher doses, cardioselective beta-blockers should be used with caution in patients with bronchospastic disease.

DISCUSSION: Inhibition of theophylline metabolism is greatest with lipophilic beta-blockers undergoing hepatic metabolism (e.g., propranolol). Additionally, the decrease in theophylline clearance appears to be dose dependent as the higher the beta-blocker dose, the greater the decrease in theophylline clearance. If the patient is on both drugs and the beta-blocker is discontinued, serum theophylline concentrations may decrease. In these cases, monitor for a decrease in theophylline therapeutic effect and adjust the dose as needed.

Theophyllines/Thiabendazole

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Unknown. Possibly inhibition of theophylline metabolism by thiabendazole.

CLINICAL EFFECTS: Possible theophylline toxicity.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor serum theophylline concentrations and observe the patient for signs of theophylline toxicity when thiabendazole is started. Adjust the dose of theophylline as needed.

DISCUSSION: Three case reports and the results of a randomized crossover study in 6 healthy volunteers have found theophylline concentrations to be increased by the administration of thiabendazole. The crossover study also demonstrated that thiabendazole increased theophylline half-life and decreased the clearance and elimination rate constant of theophylline. Symptoms of theophylline toxicity were observed in some cases.

Xanthine Derivatives/Estrogens

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Estrogens may inhibit the hepatic microsomal enzymes responsible for the metabolism of the theophyllines.

CLINICAL EFFECTS: Concurrent use of estrogens may result in an increase in the pharmacologic effects of xanthine derivatives as a result of elevated serum levels. Signs and symptoms of theophylline toxicity including anorexia, nausea, vomiting, nervousness, agitation, headache, tachycardia, arrhythmias, and convulsions.

PREDISPOSING FACTORS: Smoking.

PATIENT MANAGEMENT: Patients receiving concurrent estrogens should be monitored for elevated xanthine levels and signs of toxicity. Adjust dosages accordingly.

DISCUSSION: Although there are no reports of toxicity due to concurrent administration of oral contraceptives and theophylline, use of this combination has been associated with a decrease in the plasma clearance and an increase in the elimination half-life of theophylline. One study involving a small number of patients found that low dose oral contraceptive administration (i.e., 35 mcg) for up to 9 months, did not alter the pharmacokinetics of theophylline. Other studies demonstrate the effect of caffeine, a xanthine alkaloid chemically similar to theophylline, when administered to patients taking oral contraceptives or hormone replacement. Concomitant administration resulted in decreased caffeine metabolism by ethinyl estradiol's metabolic inhibition. A study of 20 healthy women evaluated the effect of caffeine elimination prior to and during one cycle of oral contraception. Compared to pretreatment values, it was determined that clearance of caffeine was reduced by approximately 55%. Another study evaluated the pharmacokinetics of caffeine in seven women receiving an oral depot contraceptive containing ethinyl estradiol. After six months, the oral contraceptive was found to significantly decrease the elimination half-life of caffeine: half-life prior to therapy was 4.9h, and after oral contraceptive therapy, the half-life of caffeine increased to 8.0h.

There is no enhanced messaging for this drug.

There are no contraindication contraindications for this drug.

• Acute myocardial infarction
• Angina
• Peptic ulcer
• Seizure disorder
• Tachyarrhythmia

• Acute hepatitis
• Alcohol use disorder
• Chronic heart failure
• Continuous fever
• Cor pulmonale
• Cystic fibrosis
• Diabetes mellitus
• Disease of liver
• Hypertension
• Hyperthyroidism
• Hypothyroidism
• Multiple organ failure
• Pregnancy- third trimester
• Pulmonary edema
• Sepsis
• Shock
• Smoking cessation

There is no enhanced messaging for this drug.

Less Frequent

• Tachycardia

Rare or Very Rare

• Atrial flutter
• Chest pain
• Headache disorder
• Hypotension
• Multifocal atrial tachycardia
• Palpitations
• Seizure disorder
• Sinus tachycardia
• Tachypnea

More Frequent

• Nausea
• Nervousness

Less Frequent

• Abdominal pain with cramps
• Anorexia
• Insomnia

Rare or Very Rare

• Diarrhea
• Irritability
• Tremor
• Vomiting

No enhanced messaging available.

No enhanced messaging available.

Animal reproduction studies have not been performed with theophyllines. It is not known whether theophyllines can cause fetal harm when administered to pregnant women. Although safe use of theophyllines during pregnancy has not been established relative to the potential risk to the fetus, the drugs have been used during pregnancy without teratogenicity or other adverse fetal effect; because of the risk of uncontrolled asthma, their safety during pregnancy when clearly needed is generally not seriously questioned.

Theophylline is distributed into milk and may occasionally induce irritability or other signs of toxicity in nursing infants. The risk to the breast-fed infant must be weighed against the benefit of nursing in lactating women who are receiving theophylline.

No enhanced messaging available.