Elixophylline (Theophylline) - Drug Interactions, Contraindications, Overdosage, etc

DRUG INTERACTIONS

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 the “Effect” column 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 Table 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*.

Drug	Type of Interaction	Effect**
* Refer to PRECAUTIONS, Drug Interactions for further information regarding table.
** Average effect on steady state theophylline concentration or other clinical effect forpharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
Adenosine	Theophylline blocks	Higher doses of adenosine
	adenosine receptors.	may be required to achieve
		desired effect.
Alcohol	A single large dose of alcohol	30% increase
	(3 ml/kg of whiskey) decreases
	theophylline clearance for up
	to 24 hours
Allopurinol	Decreases theophylline clearance	25% increase at allopurinol
	doses ≥600 mg/day.
Amino glutethimide	Increases theophylline clearance	25% decrease
	by induction of microsomal enzyme
	activity.
Carbamazepine	Similar to aminoglutethimide	30% decrease
Cimetidine	Decreases theophylline clearance	70% increase
	by inhibiting cytochrome P450 1A2.
Ciprofloxacin	Similar to cimetidine.	40% increase
Clarithromycin	Similar to erythromycin.	25% increase
Diazepam	Benzodiazepines increase CNS	Larger diazepam doses
	concentrations of adenosine, a potent	may be required to
	CNS depressant, while theophylline	produce desired level of
	blocks adenosine receptors.	sedation. Discontinuation
		of theophylline without
		reduction of diazepam
		dose may result in
		respiratory depression.
Disulfiram	Decreases theophylline clearance	50% increase
	by inhibiting hydroxylation and
	demethylation.
Enoxacin	Similar to cimetidine.	300% increase
Ephedrine	Synergistic CNS effects.	Increased frequency of
		nausea, nervousness,
		and insomnia.
Erythromycin	Erythromycin metabolite decreases	35% increase.
	theophylline clearance by inhibiting	Erythromycin steady-state
	cytochrome P450 3A3	serum concentrations
		decrease by a similar amount.
Estrogen	Estrogen containing oral contraceptives decrease theophylline	30% increase
	clearance in a dose-dependent fashion.
	The effect of progesterone on theophylline
	clearance is unknown.
Flurazepam	Similar to diazepam.	Similar to diazepam.
Fluvoxamine	Similar to cimetidine.	Similar to cimetidine.
Halothane	Halothane sensitizes the	Increased risk of ventricular
	myocardium to catecholamines,	arrhythmias
	theophylline increases release of
	endogenous catecholamines.
Interferon, human	Decreases theophylline clearance.	100% increase
recombinant alpha-A
Isoproterenol (IV)	Increases theophylline clearance.	20% decrease
Ketamine	Pharmacologic	May lower theophylline
		seizure threshold.
Lithium	Theophylline increases renal	Lithium dose required to
	lithium clearance.	achieve a therapeutic
		serum concentration
		increased an average of
		60%.
Lorazepam	Similar to diazepam.	Similar to diazepam.
Methotrexate (MTX)	Decreases theophylline clearance.	20% increase after low dose
		MTX, higher dose MTX may
		have a greater effect.
Mexiletine	Similar to disulfiram.	80% increase
Midazolam	Similar to diazepam.	Similar to diazepam.
Moricizine	Increases theophylline clearance.	25% decrease
Pancuronium	Theophylline may antagonize	Larger dose of pancuronium may be required to
	non-depolarizing neuromuscular
	blocking effects; possibly due to	achieve neuromuscular
	phosphodiesterase inhibition.	blockade.
Pentoxifylline	Decreases theophylline clearance.	30% increase
Phenobarbital (PB)	Similar to aminoglutethimide.	25% decrease after two
		weeks of concurrent PB.
Phenytoin	Phenytoin increases theophylline	Serum theophylline and
	clearance by increasing microsomal	phenytoin concentrations
	enzyme activity. Theophylline decreases phenytoin absorption.	decrease about 40%.
Propafenone	Decreases theophylline clearance	40% increase. Beta-2
	and pharmacologic interaction.	blocking effect may
		decrease efficacy of theophylline.
Propranolol	Similar to cimetidine and	100% increase. Beta-2
	pharmacologic interaction.	blocking effect may
		decrease efficacy
		of theophylline.
Rifampin	Increases theophylline clearance	20-40% decrease
	by increasing cytochrome P450 1A2
	and 3A3 activity.
Sulfinpyrazone	Increases theophylline clearance by	20% decrease
	increasing demethylation and hydroxyllation.
	Decreases renal clearance of
	theophylline.
Tacrine	Similar to cimetidine, also increases	90% increase
	renal clearance of theophylline.
Thiabendazole	Decreases theophylline clearance.	190% increase
Ticlopidine	Decreases theophylline clearance.	60% increase
Troleandomycin	Similar to erythromycin.	33-100% increase depending
		on troleandomycin dose.
Verapamil	Similar 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,	lomefloxacin
systemic and inhaled	mebendazole
amoxicillin	medroxyprogesterone
ampicillin,	methylprednisolone
with or without sulbactam	metronidazole
atenolol	metoprolol
azithromycin	nadolol
Caffeine,	nifedipine
dietary ingestion	nizatidine
cefactor	norfloxacin
co-trimoxazole	ofloxacin
(trimethoprim and	omeprazole
sulfamethoxazole)	prednisone, prednisolone
diltiazem	ranitidine
dirithromycin	rifabutin
enflurane	roxithromycin
famotidine	sorbitol
felodipine	(purgative doses do not
finasteride	inhibit theophylline
hydrocortisone	absorption)
isoflurane	sucralfate
isoniazid terbutaline,	systemic
isradipine	terfenadine
influenza vaccine	tetracycline
ketoconazole	tocainide

OVERDOSAGE

General:

The chronicity and pattern of theophylline overdosage significantly influences clinical manifestations of toxicity, management and outcome. There are two common presentations: (1) acute overdose, i.e., ingestion of a single large excessive dose (>10 mg/kg) as occurs in the context of an attempted suicide or isolated medication error, and (2) chronic overdosage, i.e., ingestion of repeated doses that are excessive for the patient's rate of theophylline clearance. The most common causes of chronic theophylline overdosage include patient or care giver error in dosing, clinician prescribing of an excessive dose or a normal dose in the presence of factors known to decrease the rate of theophylline clearance, and increasing the dose in response to an exacerbation of symptoms without first measuring the serum theophylline concentration to determine whether a dose increase is safe.

Severe toxicity from theophylline overdose is a relatively rare event. In one health maintenance organization, the frequency of hospital admissions for chronic overdosage of theophylline was about 1 per 1000 person-years exposure. In another study, among 6000 blood samples obtained for measurement of serum theophylline concentration, for any reason, from patients treated in an emergency department, 7% were in the 20-30 mcg/mL range and 3% were >30 mcg/mL. Approximately two-thirds of the patients with serum theophylline concentrations in the 20-30 mcg/mL range had one or more manifestations of toxicity while >90% of patients with serum theophylline concentrations >30mcg/mL were clinically intoxicated. Similarly, in other reports, serious toxicity from theophylline is seen principally at serum concentrations >30 mcg/mL.

Several studies have described the clinical manifestations of theophylline overdose and attempted to determine the factors that predict life-threatening toxicity. In general, patients who experience an acute overdose are less likely to experience seizures than patients who have experienced a chronic overdosage, unless the peak serum theophylline concentration is >100 mcg/mL. After a chronic overdosage, generalized seizures, life-threatening cardiac arrhythmias, and death may occur at serum theophylline concentrations >30 mcg/mL. The severity of toxicity after chronic overdosage is more strongly correlated with the patient's age than the peak serum theophylline concentration; patients >60 years are at the greatest risk for severe toxicity and mortality after a chronic overdosage. Pre-existing or concurrent disease may also significantly increase the susceptibility of a patient to a particular toxic manifestation, e.g., patients with neurologic disorders have an increased risk of seizures and patients with cardiac disease have an increased risk of cardiac arrhythmias for a given serum theophylline concentration compared to patients without the underlying disease.

The frequency of various reported manifestations of theophylline overdose according to the mode of overdose are listed in Table IV.

Other manifestations of theophylline toxicity include increases in serum calcium, creatine kinase, myoglobin and leukocyte count, decreases in serum phosphate and magnesium, acute myocardial infarction, and urinary retention in men with obstructive uropathy.

Seizures associated with serum theophylline concentrations >30 mcg/mL are often resistant to anticonvulsant therapy and may result in irreversible brain injury if not rapidly controlled. Death from theophylline toxicity is most often secondary to cardiorespiratory arrest and/or hypoxic encephalopathy following prolonged generalized seizures or intractable cardiac arrhythmias causing hemodynamic compromise.

Overdose Management:

General Recommendations for Patients with Symptoms of Theophylline Overdose or Serum Theophylline Concentrations >30 mcg/mL (Note: Serum theophylline concentrations may continue to increase after presentation of the patient for medical care.)

1. While simultaneously instituting treatment, contact a regional poison center to obtain updated information and advice on individualizing the recommendations that follow.
2. Institute supportive care, including establishment of intravenous access, maintenance of the airway, and electrocardiographic monitoring.
3. Treatment of seizures Because of the high morbidity and mortality associated with theophylline-induced seizures, treatment should be rapid and aggressive. Anticonvulsant therapy should be initiated with an intravenous benzodiazepine, e.g., diazepam, in increments of 0.1-0.2 mg/kg every 1-3 minutes until seizures are terminated. Repetitive seizures should be treated with a loading dose of phenobarbital (20 mg/kg infused over 30-60 minutes). Case reports of theophylline overdose in humans and animal studies suggest that phenytoin is ineffective in terminating theophylline-induced seizures. The doses of benzodiazepines and phenobarbital required to terminate theophylline-induced seizures are close to the doses that may cause severe respiratory depression or respiratory arrest; the clinician should therefore be prepared to provide assisted ventilation. Elderly patients and patients with COPD may be more susceptible to the respiratory depressant effects of anticonvulsants. Barbiturate-induced coma or administration of general anesthesia may be required to terminate repetitive seizures or status epilepticus. General anesthesia should be used with caution in patients with theophylline overdose because fluorinated volatile anesthetics may sensitize the myocardium to endogenous catecholamines released by theophylline. Enflurane appears to less likely to be associated with this effect than halothane and may, therefore, be safer. Neuromuscular blocking agents alone should not be used to terminate seizures since they abolish the musculoskeletal manifestations without terminating seizure activity in the brain.
4. Anticipate Need for Anticonvulsants In patients with theophylline overdose who are at high risk for theophyllineinduced seizures, e.g., patients with acute overdoses and serum theophylline concentrations >100 mcg/mL chronic overdosage in patients >60 years of age with serum theophylline concentrations >30 mcg/mL, the need for anticonvulsant therapy should be anticipated. A benzodiazepine such as diazepam should be drawn into a syringe and kept at the patient's bedside and medical personnel qualified to treat seizures should be immediately available. In selected patients at high risk for theophylline-induced seizures, consideration should be given to the administration of prophylactic anticonvulsant therapy. Situations where prophylactic anticonvulsant therapy should be considered in high risk patients include anticipated delays in instituting methods for extracorporeal removal of theophylline (e.g., transfer of a high risk patient from one health care facility to another for extracorporeal removal) and clinical circumstances that significantly interfere with efforts to enhance theophylline clearance (e.g., a neonate where dialysis may not be technically feasible or a patient with vomiting unresponsive to antiemetics who is unable to tolerate multiple-dose oral activated charcoal). In animal studies, prophylactic administration of phenobarbital, but not phenytoin, has been shown to delay the onset of theophylline induced generalized seizures and to increase the dose of theophylline required to induce seizures (i.e., markedly increases the LD50). Although there are no controlled studies in humans, a loading dose of intravenous Phenobarbital (20 mg/kg infused over 60 minutes) may delay or prevent life-threatening seizures in high risk patients while efforts to enhance theophylline clearance are continued. Phenobarbital may cause respiratory depression, particularly in elderly patients and patients with COPD.
5. Treatment of cardiac arrhythmias Sinus tachycardia and simple ventricular premature beats are not harbingers of life-threatening arrhythmias, they do not require treatment in the absence of hemodynamic compromise, and they resolve with declining serum theophylline concentrations. Other arrhythmias, especially those associated with hemodynamic compromise, should be treated with antiarrhythmic therapy appropriate for the type of arrhythmia.
6. Gastrointestinal decontamination Oral activated charcoal (0.5 g/kg up to 20 g and repeat at least once 1-2 hours after the first dose) is extremely effective in blocking the absorption of theophylline throughout the gastrointestinal tract, even when administered several hours after ingestion. If the patient is vomiting, the charcoal should be administered through a nasogastric tube or after administration of an antiemetic. Phenothiazine antiemetics such as prochlorperazine or perphenazine should be avoided since they can lower the seizure threshold and frequently cause dystonic reactions. A single dose of sorbitol may be used to promote stooling to facilitate removal of theophylline bound to charcoal from the gastrointestinal tract. Sorbitol, however, should be dosed with caution since it is a potent purgative which can cause profound fluid and electrolyte abnormalities, particularly after multiple doses. Commercially available fixed combinations of liquid charcoal and sorbitol should be avoided in young children and after the first dose in adolescents and adults since they do not allow for individualization of charcoal and sorbitol dosing. Ipecac syrup should be avoided in theophylline overdoses. Although ipecac induces emesis, it does not reduce the absorption of theophylline unless administered within 5 minutes of ingestion and even then is less effective than oral activated charcoal. Moreover, ipecac induced emesis may persist for several hours after a single dose and significantly decrease the retention and the effectiveness of oral activated charcoal.
7. Serum Theophylline Concentration Monitoring The serum theophylline concentration should be measured immediately upon presentation, 2-4 hours later, and then at sufficient intervals, e.g., every 4 hours, to guide treatment decisions and to assess the effectiveness of therapy. Serum theophylline concentrations may continue to increase after presentation of the patient for medical care as a result of continued absorption of theophylline from the gastrointestinal tract. Serial monitoring of serum theophylline serum concentrations should be continued until it is clear that the concentration is no longer rising and has returned to non-toxic levels.
8. General Monitoring Procedures Electrocardiographic monitoring should be initiated on presentation and continued until the serum theophylline level has returned to a non-toxic level. Serum electrolytes and glucose should be measured on presentation and at appropriate intervals indicated by clinical circumstances. Fluid and electrolyte abnormalities should be promptly corrected. Monitoring and treatment should be continued until the serum concentration decreases below 20 mcg/mL.
9. Enhance clearance of theophylline Multiple-dose oral activated charcoal (e.g., 0.5 mg/kg up to 20 g, every two hours) increases the clearance of theophylline at least twofold by adsorption of theophylline secreted into gastrointestinal fluids. Charcoal must be retained in, and pass through, the gastrointestinal tract to be effective; emesis should therefore be controlled by administration of appropriate antiemetics. Alternatively, the charcoal can be administered continuously through a nasogastric tube in conjunction with appropriate antiemetics. A single dose of sorbitol may be administered with the activated charcoal to promote stooling to facilitate clearance of the adsorbed theophylline from the gastrointestinal tract. Sorbitol alone does not enhance clearance of theophylline and should be dosed with caution to prevent excessive stooling which can result in severe fluid and electrolyte imbalances. Commercially available fixed combinations of liquid charcoal and sorbitol should be avoided in young children and after the first dose in adolescents and adults since they do not allow for individualization of charcoal and sorbitol dosing. In patients with intractable vomiting, extracorporeal methods of theophylline removal should be instituted (see OVERDOSAGE, Extracorporeal Removal).

CONTRAINDICATIONS

ELIXOPHYLLIN Elixir is contraindicated in patients with a history of hypersensitivity to theophylline or other components in the product.