AMINOPHYLLINE 3. 3.

2009, RH
" " ." : 2009 .
This leaflet format has been determined by the Ministry of Health and the content thereof has been
checked and approved. Date of approval: February 2009.

AMINOPHYLLINE

INJECTION

Composition

Each ampoule of 10 ml contains:

Active Ingredient
Aminophylline dihydrate 250 mg

Other Ingredient
Water for injection.

Mechanism of Action
Aminophylline is a soluble compound of theophylline with ethylenediamine.
The main action of theophylline is a direct relaxation of the smooth muscles of the
bronchial airways and pulmonary blood vessels, thus acting as a bronchodilator.
It has also been demonstrated that aminophylline has a potent effect on
diaphragmatic contractility in normal persons and may then be capable of reducing
fatigability and therapy improve contractility in patients with chronic obstructive airway
disease. The exact mode of action remains unsettled. Although theophylline does
cause inhibition of phosphodiesterase with a resultant increase in intracellular cyclic
AMP, other agents similarly inhibit the enzyme producing a rise of cyclic AMP but are
unassociated with any demonstrable bronchodilation. Other mechanisms proposed
include an effect on translocation of intracellular calcium, prostaglandin antagonism,
stimulation of catecholamines endogenously, inhibition of cyclic guanosine
monophosphate metabolism and adenosine receptor antagonisms. None of these
mechanisms has been proved.
In vitro, theophylline has been shown to act synergistically with beta agonists and
there is now available data which demonstrates an additive effect in vivo with
combined use.
Theophylline also manifests other actions typical of the xanthine derivatives such as
coronary vasodilation and diuresis.

Indications
For symptomatic relief or prevention of bronchial asthma and for treatment of
reversible bronchospasm associated with chronic bronchitis and emphysema.

Contraindications
Known hypersensitivity to theophylline or to other xanthine derivatives.
It is also contraindicated in patients with active peptic ulcer disease, and in
individuals with underlying seizure disorders (unless receiving appropriate
anticonvulsant medication.
Aminophylline should not be administered concomitantly with other xanthine drugs.
When therapeutic doses of aminophylline and/or theophylline are administered
simultaneously by more than one route or in more than one preparation, the hazard of
serious toxicity is increased.
Aminophylline Injection is contraindicated in patients with coronary artery disease
where myocardial stimulation might prove harmful.
Aminophylline Injection is contraindicated in patients with bronchiolitis
(bronchopneumonia).
The use of aminophylline is contraindicated in patients with acute porphyria.
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AMINOPHYLLINE 3. 3 2009, RH

Warnings
Excessive theophylline doses may be associated with toxicity. The determination of
serum theophylline levels is mandatory to assure maximal benefit without excessive
risk. The margin between therapeutic and toxic plasma levels is narrow so adverse
events may easily occur; plasma levels should be monitored. Incidence of toxicity
increases at serum theophylline levels greater than 20 micrograms/ml. Patients
on oral theophylline preparations must have their plasma level measured prior to
administration of I.V.. aminophylline.

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 (and hence toxicity may be more
likely):
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: premature or neonatal infants, children < 1 year, elderly (> 60 years)
-Concurrent Diseases: acute pulmonary edema or pneumonia, patients with
congestive heart failure, cor pulmonale, acute febrile illness, chronic alcoholism,
chronic obstructive pulmonary disease, influenza or those undergoing influenza
immunization, 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 also
Precautions, and Drug Interactions, Table I.)

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.
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AMINOPHYLLINE 3. 3 2009, RH

High blood levels of theophylline resulting from conventional doses are correlated
with clinical manifestations of toxicity in patients with lowered body plasma clearance,
patients with liver dysfunction or chronic obstructive lung disease, patients who are
older than 55 years of age, particularly males, those with cardiac failure from any
cause, patients with sustained high fever, neonates and infants under 1 year of age,
and those patients taking certain drugs (see Drug Interactions). Frequently, such
patients have markedly prolonged theophylline serum levels following discontinuation
of the drug. Reduction of dosage and laboratory monitoring is especially appropriate
in the above individuals.
Patients manifesting a decrease in total body theophylline clearance rate, include
those patients with generalized debility, and acute hypoxias.
Many patients who have high theophylline serum levels exhibit tachycardia.
Theophylline products may worsen preexisting arrhythmias.

Use in Pregnancy
Safe use in pregnancy has not been established. Since xanthines may cross the
placental barrier possibly resulting in potentially dangerous serum xanthine levels in
the neonate, risk-benefit must be considered when this drug is used in pregnancy.
The pharmacokinetics of aminophylline may be altered during pregnancy, and
therefore serum theophylline concentrations may need to be measured more
frequently in patients undergoing aminophylline therapy during pregnancy.

Use During Lactation
Since theophylline is excreted in breast milk (in concentrations about equivalent to
the maternal serum concentrations: 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.), and breastfed infants may exhibit irritability and other side effects, use of
theophylline is not recommended in nursing mothers.

Use in Pediatrics
Infants
Due to marked variation in theophylline metabolism in infants less than six months
of age, use is not recommended in this age group. Drug elimination may be prolonged
in premature infants and neonates.

Children
Children have a marked sensitivity to the CNS stimulant action of theophylline. This
should be taken into consideration for proper dosage adjustment and monitoring.
Rapid intravenous injection is not recommended in children.

Use in the Elderly
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.
Caution should be exercised when aminophylline is administered to patients older
than 60 years of age. Theophylline clearance in healthy adults older than 60 years of
age is 30% lower than healthy younger adults. These patients may require adjustment
in dosage or dosing interval

Adverse Reactions
Adverse reactions are uncommon at serum theophylline levels below
20 micrograms/ml, although they may occasionally occur at a lower level.
At a serum level between 20-25 micrograms/ml, the adverse reactions usually
experienced are nausea, vomiting, diarrhea, headache and insomnia.
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AMINOPHYLLINE 3. 3 2009, RH

At a level above 30 micrograms/ml, the adverse reactions that appear represent the
symptoms of overdosage. These are, in addition to the above, hematemesis, reflex
hyperexcitability, muscle twitching, clonic and tonic generalized convulsions,
tachycardia, circulatory failure, life-threatening ventricular arrhythmia, tachypnea and
albuminuria.

Immune system:
Hypersensitivity reactions (see also Skin and Appendages).

Cardiovascular System:
Tachycardia, palpitations, extrasystoles, increased pulse rate, flushing, hypotension,
circulatory failure, atrial and ventricular arrhythmia, peripheral vasocontriction.

Central Nervous System:
Headache, nervousness, insomnia, confusion, hyperventilation, irritability,
restlessness, vertigo/dizziness, reflex hyperexcitability, seizures, anxiety, tremor,
lightheadedness, excitement. Higher doses may lead to maniacal behavior, delirium
and convulsions

Eye Disorders:
Visual disturbances.

Gastrointestinal System:
Nausea, vomiting, heartburn, epigastric pain, abdominal cramps, anorexia, diarrhea,
gastroesophageal reflux, gastrointestinal bleeding, haematemesis.

Genitourinary:
Increased urination, albuminuria.

Respiratory System:
Tachypnea.

Skin and Appendages:
Ethylenediamine hypersensitivity induced dermatitis (hives, maculo-papular skin
rash, erythema, pruritus, urticaria, exfoliative dermatitis, sloughing of skin).

Other:
Fever.

Adverse reactions that may occur after too rapid intravenous administration:
Chest pain, decrease in blood pressure, dizziness, fast breathing, flushing,
headache, pounding heartbeat, reaction to solution or administration technique (chills,
fever, pain, redness or swelling at site of injection).

Adverse reactions whose incidence is rare:
Allergic reaction to ethylenediamine in aminophylline (skin rash or hives) {see also
above}.
Note: These may not occur for 12 to 24 hours after initial administration.

Precautions
(see Warnings)
Theophylline should not be administered concurrently with other xanthine
medications (see Contraindications).
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AMINOPHYLLINE 3. 3 2009, RH


This drug should be used with caution in patients with severe cardiac disease,
compromised cardiac or circulatory functions, angina pectoris, acute myocardial injury
(since myocardial stimulation would be harmful), severe hypoxemia, hypertension,
hyperthyroidism, hypothyroidism, sepsis, seizure disorder, acute myocardial injury,
cor pulmonale, congestive heart failure, liver disease, glaucoma, diabetes mellitus,
tachyarrhythmias, in the elderly (particularly males) and in neonates. In particular,
great caution should be used in giving theophylline to patients with congestive heart
failure. Frequently, such patients have markedly prolonged theophylline serum levels.
Theophylline should be used cautiously in patients with gastritis or with a history of
peptic ulcer.
Mean half-life in smokers is shorter than in nonsmokers, therefore smokers may
require larger doses of theophylline.
Therapeutic doses of xanthines have been shown to induce gastroesophageal reflux
when the patient is asleep or recumbent, thereby increasing the potential for
aspiration which can aggravate bronchospasm; infants less than 2 years of age and
elderly, debilitated, and stuporous patients with feeble gag and cough reflexes are
especially susceptible to this effect.
Aminophylline Injection may lower the seizure threshold and should be administered
with caution in patients with seizure disorder unless the patient is receiving
appropriate anticonvulsant therapy. Dose adjustment of any anticonvulsant
medication may be required.
Intravenous aminophylline must be administered slowly and cautiously to prevent
dangerous CNS or cardiovascular toxicity. Too rapid intravenous administration may
result in the following symptoms: anxiety, headache, nausea and vomiting, severe
hypotension, dizziness, faintness, lightheadedness, palpitations, syncope, precordial
pain, flushing, profound bradycardia, premature ventricular contractions, cardiac
arrest.
Intramuscular administration is not recommended as it causes intense local
pain (lasting for several hours) and sloughing of tissue.
The coagulation time of the blood is shortened with aminophylline therapy.
During regular therapy serum potassium levels must be monitored. This is essential
during combination therapy with beta2-agonists, corticosteroids or diuretics (which
possess hypokalemic effect), or in the presence of hypoxia.

Monitoring Serum Theophylline Concentrations:
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

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 patients treatment regimen that may alter theophylline
clearance (e.g., fever, hepatitis, or drugs listed in Table I are added or
discontinued).

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AMINOPHYLLINE 3. 3 2009, RH

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. 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 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.

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 I have the potential to produce clinically significant
pharmacodynamic or pharmacokinetic interactions with theophylline. The information
in the Effect column of Table I 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.
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AMINOPHYLLINE 3. 3 2009, RH

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 II 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 I and II are not conclusive. 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 I. 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 I. 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

Aminoglutethimid
e
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.

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AMINOPHYLLINE 3. 3 2009, RH

Table I. Clinically Significant Drug Interactions With Theophylline*-continued

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

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AMINOPHYLLINE 3. 3 2009, RH
Table I. Clinically Significant Drug Interactions With Theophylline*-continued


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 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 II. Drugs That Have Been Documented Not To Interact With Theophylline Or Drugs
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AMINOPHYLLINE 3. 3 2009, RH
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 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.

Other Drug Interactions
Theophylline/Cigarette and Marijuana Smoking: Cigarette and marijuana smoking
induce hepatic metabolism of theophylline. Smokers may therefore require a 50%-
100% increase in dosage.
Theophylline/St. Johns Wort (Hypericum perforatum): Plasma concentration of
theophylline can be reduced by concomitant use of the herbal remedy St John's wort
(Hypericum perforatum).
Theophylline/Nicotine Chewing Gum/Other Smoking Deterrents/Cessation of Tobacco
Smoking: Smoking cessation may increase the therapeutic effects of the xanthines
(except dyphylline) by decreasing metabolism, thereby increasing their serum
concentrations; however, after cessation of smoking, normalization of theophylline's
pharmacokinetics may not occur for 3 months to 2 years, dosage adjustments may be
necessary.
Theophylline/ Digitalis: Theophylline may enhance the sensitivity to and toxicity of
digitalis.
Theophylline/ Oral Anticoagulants: Higher than usual doses may increase the effect of
oral anticoagulants.
Theophylline/ Reserpine: Administration of theophylline with reserpine can cause
tachycardia.
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AMINOPHYLLINE 3. 3 2009, RH

Theophylline/Fluconazole/Zafirlukast: These drugs may increase plasma theophylline
concentrations.
Theophylline/Ritonavir: Plasma theophylline concentrations may be decreased.

Drug/Food Interactions
Theophylline elimination is increased by a low carbohydrate, high protein diet and
charcoal boiled foods. Conversely, the elimination is decreased by a high
carbohydrate low protein diet.

Diagnostic Interference
When spectrophotometric methods are used, plasma theophylline concentrations
may be falsely increased by coffee, tea, cola beverages, chocolate and paracetamol.
When high pressure liquid chromatography (HPLC) method is used, plasma
theophylline concentrations may be falsely increased by caffeine, some
cephalosporins and sulfa medications.
Theophylline/Dipyridamole-Assisted Myocardial Perfusion Studies: The theophylline
bronchodilators, reverse the effects of dipyridamole on myocardial blood flow, thereby
interfering with the test results. Therefore dipyridamole-assisted myocardial perfusion
studies should not be performed if therapy with aminophylline, oxtriphylline, or
theophylline cannot be withheld for 36 hours prior to the test.

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 Eq/L to 800 Eq/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.

Serum levels should be monitored periodically to determine the theophylline level
associated with observed clinical response and as the method of predicting toxicity.

For such measurements, the serum sample should be obtained at the time of peak
concentration, 1 or 2 hours after administration for immediate release products. It is
important that the patient will not have missed or taken additional doses during the
previous 48 hours and that dosing intervals will have been reasonably equally spaced.
Dosage adjustment based on serum theophylline measurements when these
instructions have not been followed may result in recommendations that present risk
of toxicity to the patient.

Uric acid serum determinations:
Aminophylline produces false-positive elevations of serum uric acid as measured by
the Bittner or colorimetric methods, but not by the uricase method.

Dosage and Administration
Parenteral drug products should be inspected visually for particulate matter and
discoloration, prior to administration, whenever solution and container permit.
Aminophylline Injection should be administered by the intravenous route.
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AMINOPHYLLINE 3. 3 2009, RH


Aminophylline Injection should always be well diluted and warmed to room
temperature.

Acute Symptoms of Bronchospasm Requiring Rapid Attainment of Theophylline
Serum Levels for Bronchodilation.
Status asthmaticus should be considered a medical emergency and defined as that
degree of bronchospasm which is not rapidly responsive to usual doses of
conventional bronchodilators. Optimal therapy for such patients frequently requires
both additional medication, parenterally administered, and close monitoring,
preferably in an intensive care setting.

Loading Dose
Adults: In patients not currently receiving theophylline products, a loading dose of 6
mg aminophylline/kg body weight should be infused at a rate not exceeding 25
mg/minute. The loading dose should be reduced in patients receiving any
theophylline-containing product. Each 0.6 mg aminophylline/kg body weight will result
in approximately 1 microgram/ml increase in serum theophylline concentration.

Children: Doses are proportionally smaller and should be determined according to the
child's weight.

Maintenance Infusions
The maintenance infusion rates recommended for continuous intravenous infusion
of aminophylline are set out in the table below.
Monitoring of serum theophylline concentrations is recommended to accurately
maintain therapeutic concentrations and as a guide to dosage adjustments.


Aminophylline Maintenance Infusion Rates (mg/kg body weight/hr)

Patient Group First 12 hours Beyond 12 hours
Children 6 months- 9 years

Children 9-16 years and young adult
smokers

Otherwise-healthy
nonsmoking adults

Older patients and
patients with cor pulmonale

Patients with congestive
heart failure or liver disease
1.2


1.0


0.7


0.6


0.5
1.0


0.8


0.5


0.3


0.1-0.2


Overdosage
Manifestations
Less severe toxicities do not always precede major toxicities. Chronic overdose may
produce toxicity at serum levels lower than those in acute overdose. Potentially life
threatening toxicities may occur at serum concentration greater than 40
microgram/mL (220 micromole/L) in chronic overdose. In acute overdose serum
concentrations greater than 90 microgram/mL (495 micromole/L) are generally
associated with severe toxicity.
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AMINOPHYLLINE 3. 3 2009, RH

The following signs and symptoms may be present in aminophylline overdose:
cardiovascular: tachycardia, arrythmias, palpitations, hypotension.
central nervous system: agitation, confusion or altered behaviour including
toxic psychosis, seizures.
gastrointestinal: nausea, vomiting, diarrhoea and/or hematemesis, continuing
or severe abdominal pain, acute pancreatitis.
genitourinary: renal failure.
metabolic: hyperglycaemia, hypokalaemia, metabolic acidosis,
hypophosphataemia, hypercalcaemia.
respiratory: tachypnea, respiratory arrest, respiratory alkalosis.
other: extreme thirst, slight fever, tinnitus.

Treatment
There is no specific antidote for aminophylline overdose. Treatment of overdose is
symptomatic and supportive. Administration of sympathomimetic drugs should be
avoided. Treatment may involve the following measures:
administration of oral activated charcoal, regardless of the route of exposure to
aminophylline (this assists in decreasing the serum concentration of
theophylline by interrupting the enterohepatic circulation). Oral activated
charcoal should be repeated until the serum theophylline concentration is
below 20 microgram/mL.
charcoal hemoperfusion to increase the elimination of aminophylline.
Hemodialysis is less effective in eliminating aminophylline, but may be
warranted in some patients.
administration of intravenous diazepam to control seizures. Where diazepam
is ineffective, phenytoin, phenobarbitone, or thiopentone may be considered.
correction of fluid and electrolyte balance.
support of respiratory functions by airway management, oxygen administration
or mechanical ventilation as required.
support of cardiac functions. Propranolol may be warranted in the presence of
extreme tachycardia, and antiarrythmic therapy may be required.
administration of phenothiazines in the presence of life threatening
hypothermia.
monitoring of serum theophylline concentrations and ECG.

Pharmaceutical Precautions
Do not use Aminophylline Injection if the crystals are present. Although there have
been reports of aminophylline precipitating in acidic media, these reports do not apply
to the dilute solutions found in IV infusions. Aminophylline Injection should not be
mixed in a syringe with other drugs but should be added separately to the IV solution.

When an IV solution containing aminophylline is given "piggyback", the IV system
already in place should be turned off while the aminophylline is infused if there is a
potential problem with admixture incompatibility.

Aminophylline is reported to be incompatible with the following drugs:
Strong acid solutions, ascorbic acid, corticotrophin, adrenaline, amiodarone,
ascorbic acid, benzylpenicillin, chlorpromazine hydrochloride, ciprofloxacin,
clindamycin, codeine phosphate, diltiazem, dimenhydrinate, dobutamine, doxapram,
erythromycin gluceptate, hydralazine, hydroxyzine HCl, insulin, methadone HCl,
methicillin sodium, morphine sulfate, noradrenaline acid tartrate, oxytetracycline
hydrochloride, penicillin G potassium, pentazocine lactate, pethidine HCl,
(meperidine) phenobarbitone sodium, phenytoin sodium, potassium,
prochlorperazine edisylate, promazine hydrochloride, promethazine hydrochloride,
ondansetron, tetracycline hydrochloride, vancomycin hydrochloride, vitamin B
complex with C.
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AMINOPHYLLINE 3. 3 2009, RH





Aminophylline containing solutions are alkaline, and hence drugs known to be alkali
labile should not be added to aminophylline containing solutions.


Storage
Store below 25C.

Drug Registration No.: 063 85 22594 21

Manufacturer
Teva Pharmaceutical Works Private Limited Company,
Hungary

License Holder
Teva Pharmaceutical Industries Ltd.,
[Link] 3190, Petach-Tikva.