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Theophylline Injection (Theophylline Injection) - 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., less than 15% change in theophylline clearance).

The listing of drugs in Tables II and III are current as of September 1, 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. 1
Drug Type of Interaction Effect 2
Adenosine Theophylline blocks adenosine receptors. Higher doses of adenosine may be required to achieve desired effect.
Alcohol A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours. 30% increase
Allopurinol Decreases theophylline clearance at allopurinol doses greater than or equal to 600 mg/day. 25% increase
Aminoglutethimide Increases theophylline clearance by induction of microsomal enzyme activity. 25% decrease
Carbamazepine Similar to aminoglutethimide. 30% decrease
Cimetidine Decreases theophylline clearance by inhibiting cytochrome P450 1A2. 70% increase
Ciprofloxacin Similar to cimetidine. 40% increase
Clarithromycin Similar to erythromycin. 25% increase
Diazepam Benzodiazepines 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.
Disulfiram Decreases theophylline clearance by inhibiting hydroxylation and demethylation. 50% increase
Enoxacin Similar to cimetidine. 300% increase
Ephedrine Synergistic CNS effects. Increased frequency of nausea, nervousness, and insomnia.
Erythromycin Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown. 30% increase
Flurazepam Similar to diazepam. Similar to diazepam.
Fluvoxamine Similar to cimetidine. Similar to cimetidine.
Halothane Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A Decreases theophylline clearance. 100% increase
Isoproterenol (IV) Increases theophylline clearance. 20% decrease
Ketamine Pharmacologic May lower theophylline seizure threshold.
Lithium Theophylline increases renal lithium clearance. Lithium dose required to 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 non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline Decreases theophylline clearance. 30% increase
Phenobarbital (PB) Similar to aminoglutethimide. 25% decrease after two weeks of concurrent PB.
Phenytoin Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone Decreases theophylline clearance and pharmacologic interaction. 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol Similar to cimetidine and pharmacologic interaction. 100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. 20–40% decrease
Sulfinpyrazone Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. 20% decrease
Tacrine Similar to cimetidine, also increases renal clearance theophylline. 90% increase
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

1 Refer to PRECAUTIONS, Drug Interactions for further information regarding table.
2 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.

Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline. 1
 albuterol, systemic and inhaled  medroxyprogesterone
 amoxicillin  methylprednisolone
 ampicillin, with or without sulbactam  metronidazole
 atenolol  metoprolol
 azithromycin  nadolol
 caffeine, dietary ingestion  nifedipine
 cefaclor  nizatidine
 co-trimoxazole  norfloxacin
   (trimethoprim and sulfamethoxazole)  ofloxacin
 diltiazem  omeprazole
 dirithromycin  prednisone, prednisolone
 enflurane  ranitidine
 famotidine  rifabutin
 felodipine  roxithromycin
 finasteride  sorbitol
 hydrocortisone    (purgative doses do not inhibit
 isoflurane      theophylline absorption)
 isoniazid  sucralfate
 isradipine  terbutaline, systemic
 influenza vaccine  terfenadine
 ketoconazole  tetracycline
 lomefloxacin  tocainide
 mebendazole  
1 Refer to PRECAUTIONS, Drug Interactions for information regarding table.

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., infusion of an excessive loading dose or excessive maintenance infusion rate for less than 24 hours, and (2) chronic overdosage, i.e., excessive maintenance infusion rate for greater than 24 hours. The most common causes of chronic theophylline overdosage include 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.

Several studies have described the clinical manifestations of theophylline overdose following oral administration 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 greater than 100 mcg/mL. After a chronic overdosage, generalized seizures, life-threatening cardiac arrhythmias, and death may occur at serum theophylline concentrations greater than 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 greater than 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 oral 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. Hypercalcemia has been reported in a patient with hyperthyroid disease at therapeutic theophylline concentrations.

Seizures associated with serum theophylline concentrations greater than 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 greater than 30 mcg/mL while receiving intravenous theophylline

  1. Stop the theophylline infusion.
  2. While simultaneously instituting treatment, contact a regional poison center to obtain updated information and advice on individualizing the recommendations that follow.
  3. Institute supportive care, including establishment of intravenous access, maintenance of the airway, and electrocardiographic monitoring.
  4. 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 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.
  5. Anticipate Need for Anticonvulsants In patients with theophylline overdose who are at high risk for theophylline-induced seizures, e.g., patients with acute overdoses and serum theophylline concentrations greater than 100 mcg/mL or chronic overdosage in patients greater than 60 years of age with serum theophylline concentrations greater than 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.
  6. 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.
  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 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 ).

Specific Recommendations

Acute Overdose (e.g, excessive loading dose or excessive infusion rate for less than 24 hours)

  1. Serum Concentration greater than 20 less than 30 mcg/mL
      Stop the theophylline infusion.
    1. Monitor the patient and obtain a serum theophylline concentration in 2–4 hours to insure that the concentration is decreasing.
  2. Serum Concentration greater than 30 less than 100 mcg/mL
      Stop the theophylline infusion.
    1. Administer multiple dose oral activated charcoal and measures to control emesis.
    2. Monitor the patient and obtain serial theophylline concentrations every 2–4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.
    3. Institute extracorporeal removal if emesis, seizures, or cardiac arrhythmias cannot be adequately controlled (see OVERDOSAGE, Extracorporeal Removal ).
  3. Serum Concentration greater than 100 mcg/mL
      Stop the theophylline infusion.
    1. Consider prophylactic anticonvulsant therapy.
    2. Administer multiple-dose oral activated charcoal and measures to control emesis.
    3. Consider extracorporeal removal, even if the patient has not experienced a seizure (see OVERDOSAGE, Extracorporeal Removal ).
    4. Monitor the patient and obtain serial theophylline concentrations every 2–4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.

Chronic Overdosage (e.g, excessive infusion rate for greater than 24 hours)

  1. Serum Concentration greater than 20 less than 30 mcg/mL (with manifestations of theophylline toxicity)
      Stop the theophylline infusion.
    1. Monitor the patient and obtain a serum theophylline concentration in 2–4 hours to insure that the concentration is decreasing.
  2. Serum Concentration greater than 30 mcg/mL in patients less than 60 years of age
      Stop the theophylline infusion.
    1. Administer multiple-dose oral activated charcoal and measures to control emesis.
    2. Monitor the patient and obtain serial theophylline concentrations every 2–4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.
    3. Institute extracorporeal removal if emesis, seizures, or cardiac arrhythmias cannot be adequately controlled (see OVERDOSAGE, Extracorporeal Removal ).
  3. Serum Concentration greater than 30 mcg/mL in patients greater than or equal to 60 years of age
      Stop the theophylline infusion.
    1. Consider prophylactic anticonvulsant therapy.
    2. Administer multiple-dose oral activated charcoal and measures to control emesis.
    3. Consider extracorporeal removal even if the patient has not experienced a seizure (see OVERDOSAGE, Extracorporeal Removal ).
    4. Monitor the patient and obtain serial theophylline concentrations every 2–4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.

Extracorporeal Removal

Increasing the rate of theophylline clearance by extracorporeal methods may rapidly decrease serum concentrations, but the risks of the procedure must be weighed against the potential benefit. Charcoal hemoperfusion is the most effective method of extracorporeal removal, increasing theophylline clearance up to six fold, but serious complications, including hypotension, hypocalcemia, platelet consumption and bleeding diatheses may occur. Hemodialysis is about as efficient as multiple-dose oral activated charcoal and has a lower risk of serious complications than charcoal hemoperfusion. Hemodialysis should be considered as an alternative when charcoal hemoperfusion is not feasible and multiple-dose oral charcoal is ineffective because of intractable emesis. Serum theophylline concentrations may rebound 5–10 mcg/mL after discontinuation of charcoal hemoperfusion or hemodialysis due to redistribution of theophylline from the tissue compartment. Peritoneal dialysis is ineffective for theophylline removal; exchange transfusions in neonates have been minimally effective.

CONTRAINDICATIONS

Theophylline in 5% Dextrose Injections USP are contraindicated in patients with a history of hypersensitivity to theophylline or other components in the product.

Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products.

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