Special Warning : אזהרת שימוש

Warnings
To reduce the undesirable stimulating effects of aminophylline on the central nervous and cardiovascular systems, intravenous administration of the drug should be slow and should not exceed a rate of 25 mg/min.

Aminophylline has a narrow therapeutic index and serum levels should be monitored regularly, particularly during initiation of therapy.

Aminophylline injection should be administered cautiously to patients over 55 years of age.

Elderly patients or those with cardiac or hepatic disease should be monitored carefully for signs of theophylline toxicity.

Care should be taken in patients undergoing influenza immunisation or who have active influenza infection or acute febrile illness.

Aminophylline should be given with caution to patients with cardiac failure, chronic obstructive pulmonary disease, renal or hepatic dysfunction and in chronic alcoholism since clearance of aminophylline is decreased.

During regular therapy serum potassium levels must be monitored. This is essential during combination therapy with β-2 agonists, corticosteroids or diuretics, or in the presence of hypoxia.

Aminophylline should be used with caution in patients with peptic ulcer, hyperthyroidism, glaucoma, diabetes mellitus, severe hypoxaemia, hypertension and compromised cardiac or circulatory function, as these conditions may be exacerbated.

Methylxanthines may increase gastric acidity and care should be taken when they are used in patients with a history of peptic ulceration.

Aminophylline should not be administered concurrently with other xanthine medications.


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)

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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.

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.


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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.
Animal reproduction studies have not been performed with theophyllines. It is not known whether theophyllines can cause fetal harm when administered to pregnant women. Although the safe use of theophylline during pregnancy has not been established relative to potential risk to the foetus, theophyllines have been used during pregnancy without teratogenicity or other adverse fetal effect 
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.
There have been reports of seizures in children with theophylline plasma levels within the accepted therapeutic range.
Alternative treatment should be considered in patients with a history of seizure activity and, if Aminophylline Injection is used in such patients, they should be carefully observed for possible signs of central stimulation.
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 55 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.
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.
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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

Metabolism and nutrition disorders:
Metabolic disturbances such as            hypokalaemia,    hypophosphataemia,     and hyponatraemia may occur.

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).

General disorders and administration site conditions :
Intramuscular injections are painful, the pain lasting several hours.
Higher doses may result in hyperthermia and extreme thirst.

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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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 patient’s 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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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.

Effects on Driving