AMINOPHYLLINE 250 MG10 ML

Israel - English - Ministry of Health

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Active ingredient:
AMINOPHYLLINE
Available from:
TEVA PHARMACEUTICAL INDUSTRIES LTD, ISRAEL
ATC code:
R03DA05
Pharmaceutical form:
SOLUTION FOR INJECTION
Composition:
AMINOPHYLLINE 250 MG / 10 ML
Administration route:
I.V
Prescription type:
Required
Manufactured by:
TEVA PHARMACEUTICAL WORKS PRIVATE LIMITED COMPANY, HUNGARY
Therapeutic group:
AMINOPHYLLINE
Therapeutic area:
AMINOPHYLLINE
Therapeutic indications:
For symptomatic relief or prevention of bronchial asthma and for treatment of reversible bronchospasm associated with chronic bronchitis and emphysema.
Authorization number:
063 85 22594 21
Authorization date:
2014-05-31

העדוה העדוה

לע לע

הרמחה הרמחה

(

(

עדימ עדימ

ןולעב )תוחיטב ןולעב )תוחיטב

ל

ל

אפור אפור

ןכדועמ( ןכדועמ(

05.2013

05.2013

ךיראת

___________

March 27, 2014

______

םש

רישכת

תילגנאב

רפסמו

םושירה

____________

Aminophylline

Injection: 063 85 22594 21

_

םש

לעב

םושירה

_

עבט

תוישעת

תויטבצמרפ

.ד.ת ,מ"עב

3190

ת"פ ,

_

_

ספוט

הז

דעוימ

טורפל

תורמחהה

דבלב

תורמחהה

תושקובמה קרפ

ןולעב טסקט

יחכונ טסקט

שדח

Indication

contraindications

Posology, dosage &

administration

Special Warnings and

Special Precautions for

Use

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

recommended in children.

Use in the Elderly

Elderly patients are at significantly greater risk

experiencing

serious

toxicity

from

theophylline than

younger

patients due

pharmacokinetic and pharmacodynamic changes

associated with aging.

Caution

should

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

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

aminophylline

decreased.

During regular therapy serum potassium levels must be

monitored. This is essential during combination therapy

with

-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

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

administered

concurrently with other xanthine medications.

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

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

possible

signs

central

stimulation.

Use in the Elderly

Elderly patients are at significantly greater risk of

experiencing serious toxicity from theophylline than

younger

patients

pharmacokinetic

pharmacodynamic changes associated with aging.

Caution should be exercised when aminophylline is

administered to patients older than 55 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

Interaction with Other

Medicaments and Other

Forms of Interaction

Table

I.

Clinically

Significant

Drug

Interactions With Theophylline

Fluvoxamine

Similar

cimetidine.

Similar to

cimetidine.

Table I. Clinically Significant Drug Interactions

With Theophylline

Fluvoxamine

Similar

cimetidine.

The concomitant

theophylline and

fluvoxamine

should usually be

avoided.

Where

this

possible, patients

should have their

theophylline dose

halved

plasma

theophylline

should

monitored

closely

Similar to

cimetidine.

Other Drug Interactions

Drugs that may decrease aminophylline clearance

resulting

increased

plasma

theophylline

concentrations and the potential for increased toxicity.

Quinolone antibiotics

Fluconazole

Isonaizid

Oral contraceptives

Zafirlukast

Thyroid hormones

Drugs

that

may

decrease

plasma

theophylline

concentrations

Ritonavir

Other Interactions

Xanthines: Concurrent use of other xanthine derivatives,

including

theophylline

pentoxifylline

contraindicated due to the risk of toxicity.

Benzodiazepines: Theophylline may reduce the effects

of benzodiazepines.

Quinolones: Increased risk of convulsions.

General anaesthetics: Increased risk of convulsions with

ketamine; increased risk of arrhythmias with halothane.

Pancuronium: Resistance to neuromuscular block with

pancuronium has been reported in patients receiving

aminophylline.

Sympathomimetics:

Aminophylline

exhibit

synergistic

toxicity

with

ephedrine

other

sympathomimetics and concurrent use may dispose the

patient to cardiac arrhythmias.

2-adrenergic

agonists

Increased

risk

cardiac

arrhythmias

-blockers

: Antagonism of bronchodilator effects.

Cardiac glycosides: The direct stimulatory effect of

aminophylline on the myocardium may enhance the

sensitivity and toxic potential of the cardiac glycosides.

Adenosine: The anti-arrhythmic effect of adenosine is

antagonised by theophylline.

Leukotriene

antagonists:

clinical

trials

administration with theophylline resulted in decreased

plasma levels of zafirlukast, by approximately 30%, but

with no effect on plasma theophylline levels. However,

during post-marketing surveillance, there have been rare

cases of patients experiencing increased theophylline

levels when co-administered zafirlukast.

Doxapram: Increased CNS stimulation.

Hypokalaemia:

The hypokalaemic effects of

2-adrenergic agonists may

potentiated

concomitant

treatment

with

aminophylline.

There is an increased risk of hypokalaemia when

theophylline derivatives are given with corticosteroids or

diuretics

Fertility, pregnancy and

Lactation

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 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

need

measured

more

frequently in patients undergoing aminophylline therapy

during pregnancy.

Animal reproduction studies have not been performed

with

theophyllines.

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

Adverse events

Metabolism and nutrition disorders:

Metabolic disturbances such as hypokalaemia,

hypophosphataemia, and hyponatraemia may occur.

General disorders and administration site conditions :

Intramuscular injections are painful, the pain lasting

several hours.

Higher doses may result in hyperthermia and extreme

thirst.

Pharmaceutical Precautions

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

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.

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,

doxorubicin,

erythromycin gluceptate, hydralazine, hydroxyzine HCl,

insulin, methadone HCl, methicillin sodium, morphine

sulfate, noradrenaline acid tartrate, opioid analgesics,

oxytetracycline hydrochloride, penicillin G potassium,

pentazocine

lactate,

pethidine

HCl,

(meperidine)

phenobarbitone sodium, phenytoin sodium, potassium,

prochlorperazine

edisylate,

procaine

hydrochloride,

promazine hydrochloride, promethazine hydrochloride,

ondansetron, sulphafurazole diethanolamine, tetracycline

hydrochloride, vancomycin hydrochloride, vitamin B

complex with C.

AMINOPHYLLINE 4. 5. 2014, RH

"

ע עבקנ הז ןולע טמרופ

"

רשואו קדבנ ונכותו תואירבה דרשמ י

."

רשואמ ןולע

יאמ

2014

“This leaflet form

at has been determined by the Ministry of Health and the content thereof has

been checked and approved.” Date of approval: May 2014.

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.

also

been

demonstrated

that

aminophylline

potent

effect

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

catecholamines

endogenously,

inhibition

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

aminophylline

and/or

theophylline

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

contraindicated

patients

with

bronchiolitis

(bronchopneumonia).

The use of aminophylline is contraindicated in patients with acute porphyria.

AMINOPHYLLINE 4. 5. 2014, RH Page 2 of 16

Warnings

reduce

undesirable

stimulating

effects

aminophylline

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

-2 agonists, corticosteroids or diuretics, or in the

presence of hypoxia.

Aminophylline

should

used

with

caution

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

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

increased

risk

exacerbation

concurrent

condition:

- Active peptic ulcer disease

- Seizure disorders

- Cardiac arrhythmias (not including bradyarrhythmias)

AMINOPHYLLINE 4. 5. 2014, RH Page 3 of 16

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

pneumonia,

patients

with

congestive heart failure, cor pulmonale, acute febrile illness, chronic alcoholism,

chronic

obstructive

pulmonary

disease,

influenza

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

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

have

high

theophylline

serum

levels

exhibit

tachycardia.

Theophylline products may worsen preexisting arrhythmias.

AMINOPHYLLINE 4. 5. 2014, RH Page 4 of 16

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

need

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

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

uncommon

serum

theophylline

levels

below

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

tonic

generalized

convulsions,

tachycardia, circulatory failure, life-threatening ventricular arrhythmia, tachypnea and

albuminuria.

AMINOPHYLLINE 4. 5. 2014, RH Page 5 of 16

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

hypokalaemia,

hypophosphataemia,

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

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

administered

concurrently

with

other

xanthine

medications (see Contraindications).

AMINOPHYLLINE 4. 5. 2014, RH Page 6 of 16

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

patient

asleep

recumbent,

thereby

increasing

potential

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

patients

with

seizure

disorder

unless

patient

receiving

appropriate

anticonvulsant

therapy.

Dose

adjustment

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

determine

whether

dosage

appropriate.

Specifically,

serum

theophylline concentration should be measured as follows:

Before making a dose increase to determine whether the serum concentration

is sub-therapeutic in a patient who continues to be symptomatic.

Whenever signs or symptoms of theophylline toxicity are present.

Whenever there is a new illness, worsening of an existing concurrent illness or

change

patient’s

treatment

regimen

that

alter theophylline

clearance (e.g., fever, hepatitis, or drugs listed in Table I are added or

discontinued).

AMINOPHYLLINE 4. 5. 2014, RH Page 7 of 16

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.

patient

received

theophylline

previous

hours,

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

≥10

mcg/mL),

second

measurement

should

obtained as above at the appropriate time after starting the intravenous infusion. If, on

other

hand,

loading

dose

indicated

guidance

selection

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

constant

infusion

determine

direction

which

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

third

trimester

pregnancy),

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

wide

variety

drugs.

interaction

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

drug

that

inhibits

theophylline

clearance

(e.g.,

cimetidine,

erythromycin), the dose of theophylline required to achieve a therapeutic serum

theophylline concentration will be smaller.

AMINOPHYLLINE 4. 5. 2014, RH Page 8 of 16

Conversely, if theophylline is being initiated in a patient who is already taking a drug

that

enhances

theophylline

clearance

(e.g.,

rifampin),

dose

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

appropriately

reduced.

Discontinuation

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

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.

AMINOPHYLLINE 4. 5. 2014, RH Page 9 of 16

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.

concomitant

theophylline

fluvoxamine should usually be avoided. Where

this is not possible, patients

should have their

theophylline

dose

halved

plasma

theophylline should be monitored closely

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.

AMINOPHYLLINE 4. 5. 2014, RH Page 10 of 16

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

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-

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.

AMINOPHYLLINE 4. 5. 2014, RH Page 11 of 16

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

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

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.

John’s

Wort

(Hypericum

perforatum):

Plasma

concentration

theophylline can be reduced by concomitant use of the herbal remedy St John's Wort

(Hypericum perforatum).

AMINOPHYLLINE 4. 5. 2014, RH Page 12 of 16

Theophylline/Nicotine Chewing Gum/Other Smoking Deterrents/Cessation of Tobacco

Smoking:

Smoking cessation may increase the therapeutic effects of the xanthines

(except

dyphylline)

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.

Theophylline/Fluconazole/Zafirlukast:

These drugs may increase plasma theophylline

concentrations.

Theophylline/Ritonavir:

Plasma theophylline concentrations may be decreased.

Other Drug Interactions

Drugs that may decrease aminophylline clearance resulting in increased plasma

theophylline concentrations and the potential for increased toxicity.

Quinolone antibiotics

Fluconazole

Isonaizid

Oral contraceptives

Zafirlukast

Thyroid hormones

Drugs that may decrease plasma theophylline concentrations

Ritonavir

Other Interactions

Xanthines: Concurrent use of other xanthine derivatives, including theophylline and

pentoxifylline are contraindicated due to the risk of toxicity.

Benzodiazepines

: Theophylline may reduce the effects of benzodiazepines.

Quinolones: Increased risk of convulsions.

General anaesthetics

: Increased risk of convulsions with ketamine; increased risk of

arrhythmias with halothane.

Pancuronium

Resistance

neuromuscular

block

with

pancuronium

been

reported in patients receiving aminophylline.

Sympathomimetics: Aminophylline may exhibit synergistic toxicity with ephedrine and

other sympathomimetics and concurrent use may dispose the patient to cardiac

arrhythmias.

2-adrenergic agonists: Increased risk of cardiac arrhythmias

-blockers: Antagonism of bronchodilator effects.

Cardiac glycosides: The direct stimulatory effect of aminophylline on the myocardium

may enhance the sensitivity and toxic potential of the cardiac glycosides.

AMINOPHYLLINE 4. 5. 2014, RH Page 13 of 16

Adenosine

: The anti-arrhythmic effect of adenosine is antagonised by theophylline.

Leukotriene antagonists: In clinical trials co-administration with theophylline resulted

in decreased plasma levels of zafirlukast, by approximately 30%, but with no effect on

plasma theophylline levels. However, during post-marketing surveillance, there have

been rare cases of patients experiencing increased theophylline levels when co-

administered zafirlukast.

Doxapram:

Increased CNS stimulation.

Hypokalaemia:

hypokalaemic

effects

2-adrenergic

agonists

potentiated

concomitant treatment with aminophylline.

There is an increased risk of hypokalaemia when theophylline derivatives are given

with corticosteroids or diuretics

Drug/Food Interactions

Theophylline elimination is increased by a low carbohydrate, high protein diet and

charcoal

boiled

foods.

Conversely,

elimination

decreased

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

used,

plasma

theophylline

concentrations

falsely

increased

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

performed

therapy

with

aminophylline,

oxtriphylline,

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 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

weighed

against

potential

therapeutic

benefit

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.

AMINOPHYLLINE 4. 5. 2014, RH Page 14 of 16

Dosage

adjustment

based

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.

Aminophylline

Injection

should

always

well

diluted

warmed

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

bronchospasm

which

rapidly

responsive

usual

doses

conventional bronchodilators. Optimal therapy for such patients frequently requires

both

additional

medication,

parenterally

administered,

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.

loading

dose

should

reduced

patients

receiving

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

0.1-0.2

AMINOPHYLLINE 4. 5. 2014, RH Page 15 of 16

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

occur

serum

concentration

greater

than

microgram/mL (220 micromole/L) in chronic overdose. In acute overdose serum

concentrations

greater

than

microgram/mL

(495

micromole/L)

generally

associated with severe toxicity.

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

decreasing

serum

concentration

theophylline

interrupting

enterohepatic

circulation).

Oral

activated

charcoal should be repeated until the serum theophylline concentration is

below 20 microgram/mL.

charcoal

hemoperfusion

increase

elimination

aminophylline.

Hemodialysis

less

effective

eliminating

aminophylline,

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

phenothiazines

presence

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 4. 5. 2014, RH Page 16 of 16

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,

doxorubicin,

erythromycin

gluceptate,

hydralazine,

hydroxyzine

HCl,

insulin,

methadone HCl, methicillin sodium, morphine sulfate, noradrenaline acid tartrate,

opioid analgesics, oxytetracycline hydrochloride, penicillin G potassium, pentazocine

lactate, pethidine HCl, (meperidine) phenobarbitone sodium, phenytoin sodium,

potassium,

prochlorperazine

edisylate,

procaine

hydrochloride,

promazine

hydrochloride,

promethazine

hydrochloride,

ondansetron,

sulphafurazole

diethanolamine,

tetracycline

hydrochloride,

vancomycin

hydrochloride,

vitamin

complex with C.

Aminophylline containing solutions are alkaline, and hence drugs known to be alkali

labile should not be added to aminophylline containing solutions.

Storage

Store below 25

Drug Registration No

.: 063 85 22594 21

Manufacturer

Teva Pharmaceutical Works Private Limited Company,

Hungary

License Holder

Teva Pharmaceutical Industries Ltd.,

P.O.Box 3190, Petach-Tikva.

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