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Aminophylline (Aminophylline Dihydrate) - Warnings and Precautions

 
 



WARNINGS

Concurrent Illness:

Theophylline should be used with extreme caution in patients with the following clinical conditions due to the increased risk of exacerbation of the concurrent condition:

Active peptic ulcer disease

Seizure disorders

Cardiac arrhythmias (not including bradyarrhythmias)

Conditions That Reduce Theophylline Clearance:

There are several readily identifiable causes of reduced theophylline clearance. If the infusion rate is not appropriately reduced in the presence of these risk factors, severe and potentially fatal theophylline toxicity can occur. Careful consideration must be given to the benefits and risks of theophylline use and the need for more intensive monitoring of serum theophylline concentrations in patients with the following risk factors:

            Age

                Neonates (term and premature)

                Children <1 year

                Elderly (>60 years)

            Concurrent Diseases

                Acute pulmonary edema

                Congestive heart failure

                Cor pulmonale

                Fever; ≥102° for 24 hours or more; or lesser temperature

                    elevations for longer periods

                Hypothyroidism

                Liver disease; cirrhosis, acute hepatitis

                Reduced renal function in infants <3 months of age

                Sepsis with multi-organ failure

                Shock

            Cessation of Smoking

            Drug Interactions

                Adding a drug that inhibits theophylline metabolism (e.g., cimetidine, erythromycin, tacrine) or stopping a concurrently administered drug that enhances theophylline metabolism (e.g., carbamazepine, rifampin). (See PRECAUTIONS ,  Drug Interactions , Table II .)

When Signs or Symptoms of Theophylline Toxicity Are Present:

Whenever a patient receiving theophylline develops nausea or vomiting, particularly repetitive vomiting, or other signs or symptoms consistent with theophylline toxicity (even if another cause may be suspected), the intravenous infusion should be stopped and a serum theophylline concentration measured immediately.

Dosage Increases

Increases in the dose of intravenous theophylline should not be made in response to an acute exacerbation of symptoms unless the steady-state serum theophylline concentration is <10 mcg/mL.

As the rate of theophylline clearance may be dose-dependent (i.e., steady-state serum concentrations may increase disproportionately to the increase in dose), an increase in dose based upon a sub-therapeutic serum concentration measurement should be conservative. In general, limiting infusion rate increases to about 25% of the previous infusion rate will reduce the risk of unintended excessive increases in serum theophylline concentration (see DOSAGE AND ADMINISTRATION , TABLE VI ).

PRECAUTIONS

General

Careful consideration of the various interacting drugs and physiologic conditions that can alter theophylline clearance and require dosage adjustment should occur prior to initiation of theophylline therapy and prior to increases in theophylline dose (see WARNINGS ).

Monitoring Serum Theophylline Concentrations:

Serum theophylline concentration measurements are readily available and should be used to determine whether the dosage is appropriate. Specifically, the serum theophylline concentration should be measured as follows:

  1. Before making a dose increase to determine whether the serum concentration is sub-therapeutic in a patient who continues to be symptomatic.
  2. Whenever signs or symptoms of theophylline toxicity are present.
  3. Whenever there is a new illness, worsening of an existing concurrent illness or a change in the patient’s treatment regimen that may alter theophylline clearance (e.g., fever >102°F sustained for ≥24 hours, hepatitis, or drugs listed in Table   II are added or discontinued).

In patients who have received no theophylline in the previous 24 hours, a serum concentration should be measured 30 minutes after completion of the intravenous loading dose to determine whether the serum concentration is <10 mcg/mL indicating the need for an additional loading dose or >20 mcg/mL indicating the need to delay starting the constant I.V. infusion. Once the infusion is begun, a second measurement should be obtained after one expected half-life (e.g., approximately 4 hours in children 1 to 9 years and 8 hours in non-smoking adults; See Table I for the expected half-life in additional patient populations). The second measurement should be compared to the first to determine the direction in which the serum concentration has changed. The infusion rate can then be adjusted before steady state is reached in an attempt to prevent an excessive or sub-therapeutic theophylline concentration from being achieved.

If a patient has received theophylline in the previous 24 hours, the serum concentration should be measured before administering an intravenous loading dose to make sure that it is safe to do so. If a loading dose is not indicated (i.e., the serum theophylline concentration is ≥10 mcg/mL), a second measurement should be obtained as above at the appropriate time after starting the intravenous infusion. If, on the other hand, a loading dose is indicated (See DOSAGE AND ADMINISTRATION for guidance on selection of the appropriate loading dose), a second blood sample should be obtained after the loading dose and a third sample should be obtained one expected half-life after starting the constant infusion to determine the direction in which the serum concentration has changed.

Once the above procedures related to initiation of intravenous theophylline infusion have been completed, subsequent serum samples for determination of theophylline concentration should be obtained at 24-hour intervals for the duration of the infusion. The theophylline infusion rate should be increased or decreased as appropriate based on the serum theophylline levels.

When signs or symptoms of theophylline toxicity are present, the intravenous infusion should be stopped and a serum sample for theophylline concentration should be obtained as soon as possible, analyzed immediately, and the result reported to the clinician without delay. In patients in whom decreased serum protein binding is suspected (e.g., cirrhosis, women during the third trimester of pregnancy), the concentration of unbound theophylline should be measured and the dosage adjusted to achieve an unbound concentration of 6-12 mcg/mL.

Saliva concentrations of theophylline cannot be used reliably to adjust dosage without special techniques.

Effects on Laboratory Tests:

As a result of its pharmacological effects, theophylline at serum concentrations within the 10 ‑ 20 mcg/mL range modestly increases plasma glucose (from a mean of 88 mg% to 98 mg%), uric acid (from a mean of 4 mg/dl to 6 mg/dl), free fatty acids (from a mean of 451 µEq/L to 800 µEq/L), total cholesterol (from a mean of 140 vs 160 mg/dl), HDL (from a mean of 36 to 50 mg/dl), HDL/LDL ratio (from a mean of 0.5 to 0.7), and urinary free cortisol excretion (from a mean of 44 to 63 mcg/24 hr). Theophylline at serum concentrations within the 10 - 20 mcg/mL range may also transiently decrease serum concentrations of triiodothyronine (144 before, 131 after one week and 142 ng/dl after 4 weeks of theophylline). The clinical importance of these changes should be weighed against the potential therapeutic benefit of theophylline in individual patients.

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 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*
Drug
Type Of Interaction
Effect**

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 ≥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 (I.V.)

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 nondepolarizing 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 Phenobarbital.

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 of 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

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

** Average effect on steady-state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.

Table III. Drugs That Have Been Documented Not to Interact With Theophylline or Drugs That Produce No Clinically Significant Interaction With Theophylline*

albuterol,

   systemic and inhaled

amoxicillin

ampicillin,

   with or without sulbactam

atenolol

azithromycin

caffeine,

   dietary ingestion

cefaclor

co-trimoxazole

   (trimethoprim and sulfamethoxazole)

diltiazem

dirithromycin

enflurane

famotidine

felodipine

finasteride

hydrocortisone

isoflurane

isoniazid

isradipine

influenza vaccine

ketoconazole

 

lomefloxacin

mebendazole

medroxyprogesterone

methylprednisolone

metronidazole

metoprolol

nadolol

nifedipine

nizatidine

norfloxacin

ofloxacin

omeprazole

prednisone, prednisolone

ranitidine

rifabutin

roxithromycin

sorbitol

  (purgative doses do not inhibit

  theophylline absorption)

sucralfate

terbutaline, systemic

terfenadine

tetracycline

tocainide

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

The Effect of Other Drugs on Theophylline Serum Concentration Measurements:

Most serum theophylline assays in clinical use are immunoassays which are specific for theophylline. Other xanthines such as caffeine, dyphylline, and pentoxifylline are not detected by these assays. Some drugs (e.g., cefazolin, cephalothin), however, may interfere with certain HPLC techniques. Caffeine and xanthine metabolites in neonates or patients with renal dysfunction may cause the reading from some dry reagent office methods to be higher than the actual serum theophylline concentration.

Carcinogenesis, Mutagenesis, and Impairment of Fertility:

Long term carcinogenicity studies have been carried out in mice (oral doses 30 - 150 mg/kg) and rats (oral doses 5 - 75 mg/kg). Results are pending.

Theophylline has been studied in Ames salmonella, in vivo and in vitro cytogenetics, micronucleus and Chinese hamster ovary test systems and has not been shown to be genotoxic.

In a 14 week continuous breeding study, theophylline, administered to mating pairs of B6C3F1 mice at oral doses of 120, 270 and 500 mg/kg (approximately 1.0 - 3.0 times the human dose on a mg/m2 basis) impaired fertility, as evidenced by decreases in the number of live pups per litter, decreases in the mean number of litters per fertile pair, and increases in the gestation period at the high dose as well as decreases in the proportion of pups born alive at the mid and high dose. In 13 week toxicity studies, theophylline was administered to F344 rats and B6C3F1 mice at oral doses of 40 - 300 mg/kg (approximately 2 times the human dose on a mg/m2 basis). At the high dose, systemic toxicity was observed in both species including decreases in testicular weight.

Pregnancy:

Category C: There are no adequate and well controlled studies in pregnant women. Additionally, there are no teratogenicity studies in nonrodents (e.g., rabbits). Theophylline was not shown to be teratogenic in CD-1 mice at oral doses up to 400 mg/kg, approximately 2.0 times the human dose on a mg/m2 basis or in CD-1 rats at oral doses up to 260 mg/kg, approximately 3.0 times the recommended human dose on a mg/m2 basis.  At a dose of 220 mg/kg, embryotoxicity was observed in rats in the absence of maternal toxicity.

Nursing Mothers:

Theophylline is excreted into breast milk and may cause irritability or other signs of mild toxicity in nursing human infants. The concentration of theophylline in breast milk is about equivalent to the maternal serum concentration. An infant ingesting a liter of breast milk containing 10 ‑ 20 mcg/mL of theophylline per day is likely to receive 10 - 20 mg of theophylline per day. Serious adverse effects in the infant are unlikely unless the mother has toxic serum theophylline concentrations.

Pediatric Use:

Theophylline is safe and effective for the approved indications in pediatric patients (see INDICATIONS AND USAGE ). The constant infusion rate of intravenous theophylline must be selected with caution in pediatric patients since the rate of theophylline clearance is highly variable across the age range of neonates to adolescents (see CLINICAL   PHARMACOLOGY , Table I , WARNINGS , and DOSAGE AND ADMINISTRATION , Table V ). Due to the immaturity of theophylline metabolic pathways in pediatric patients under the age of one year, particular attention to dosage selection and frequent monitoring of serum theophylline concentrations are required when theophylline is prescribed to pediatric patients in this age group.

Geriatric Use:

Elderly patients are at significantly greater risk of experiencing serious toxicity from theophylline than younger patients due to pharmacokinetic and pharmacodynamic changes associated with aging. Theophylline clearance is reduced in patients greater than 60 years of age, resulting in increased serum theophylline concentrations in response to a given theophylline infusion rate. Protein binding may be decreased in the elderly resulting in a larger proportion of the total serum theophylline concentration in the pharmacologically active unbound form. Elderly patients also appear to be more sensitive to the toxic effects of theophylline after chronic overdosage than younger patients. For these reasons, the maximum infusion rate of theophylline in patients greater than 60 years of age ordinarily should not exceed
17 mg/hr (21 mg/hr as aminophylline) unless the patient continues to be symptomatic and the peak steady state serum theophylline concentration is <10 mcg/mL (see DOSAGE AND ADMINISTRATION ). Theophylline infusion rates greater than 17 mg/hr (21 mg/hr as aminophylline) should be prescribed with caution in elderly patients.

Page last updated: 2014-03-03

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