Consumer medicine information

DBL Aminophylline Injection

Aminophylline

BRAND INFORMATION

Brand name

DBL Aminophylline Injection

Active ingredient

Aminophylline

Schedule

SUMMARY CMI

DBL™ Aminophylline Injection

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I being treated with DBL Aminophylline Injection?

DBL Aminophylline Injection contains the active ingredient aminophylline (theophylline and ethylenediamine). DBL Aminophylline Injection is used to relieve breathing problems which may occur with asthma, emphysema, bronchitis, chronic obstructive pulmonary disease (COPD), or left-sided heart failure.

For more information, see Section 1. Why am I being treated with DBL Aminophylline Injection? in the full CMI.

2. What should I know before treatment with DBL Aminophylline Injection?

Do not start treatment if you have ever had an allergic reaction to aminophylline, theophylline, ethylenediamine or any medicines or substances.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before treatment with DBL Aminophylline Injection? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with DBL Aminophylline Injection and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How is DBL Aminophylline Injection given?

Your doctor will decide what dose you will receive. This depends on your condition and other factors, such as your weight. This medicine is given as a slow injection or a slow infusion (eg. a ‘drip’) into a vein. It must only be given by a doctor or a nurse.

More instructions can be found in Section 4. How is DBL Aminophylline Injection given? in the full CMI.

5. What should I know during treatment with DBL Aminophylline Injection?

Things you should do	Tell your doctor or nurse straight away if you notice any of the following: anxiety, headache, feeling sick or need to vomit, feeling dizzy, faint or light-headed, your heart beating very slowly or stabbing pains in your chest with heavy, rapid, irregular heartbeat, or fever/hot flushes. Remind any doctor, nurse, pharmacist or dentist you visit that you are using this medicine, especially if you are planning to have surgery that needs a general anaesthetic.
Things you should not do	Do not stop taking this medicine or change the dosage without consulting with your doctor. Do not use this medicine to treat any other complaints unless your doctor or pharmacist tells you so.
Driving or using machines	Avoid driving or using any machines or tools until you know how this medicine affects you, as it may cause dizziness, light-headedness or fits/convulsions.
Drinking alcohol	Drinking alcohol while using DBL Aminophylline Injection can affect the way it works or make any side effects (such as dizziness or light-headedness) worse.

For more information, see Section 5. What should I know during treatment with DBL Aminophylline Injection? in the full CMI.

6. Are there any side effects?

Side effects include: nausea (feeling sick), vomiting/diarrhoea, unable to sleep, headache/fever, irritability/restlessness, nervousness/anxiety or excitement, tremor (shaking/trembling), muscle jerking, changes in the amount of urine produced, hot flushes, skin rashes/redness, swelling/itching or peeling, feeling weak/tired, dizzy/faint and thirsty with muscle cramps, heartburn, abdominal pain/cramps, anorexia. Serious side effects include: persistent vomiting, diarrhoea and/or vomiting blood, continuing/severe stomach pain, especially if it spreads to your back/chest, fast/fluttery or irregular heartbeat, or extremely slow heartbeat with rapid/shallow breathing, agitation, confusion or altered behaviour, extreme thirst, unable to urinate, especially in males, buzzing/whistling/ringing in your ears (tinnitus), convulsions (fits).

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

FULL CMI

DBL™ Aminophylline Injection

Active ingredient(s): aminophylline (theophylline and ethylenediamine)

Consumer Medicine Information (CMI)

This leaflet provides important information about using DBL Aminophylline Injection.

You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using DBL Aminophylline Injection.

Where to find information in this leaflet:

1. Why am I being treated with DBL Aminophylline Injection?
2. What should I know before treatment with DBL Aminophylline Injection?
3. What if I am taking other medicines?
4. How is DBL Aminophylline Injection given?
5. What should I know during treatment with DBL Aminophylline Injection?
6. Are there any side effects?
7. Product details

1. Why am I being treated with DBL Aminophylline Injection?

DBL Aminophylline Injection belongs to a group of medicines known as "xanthines" and contains the active ingredient aminophylline (theophylline and ethylenediamine).

DBL Aminophylline Injection is used to relieve breathing problems which may occur with asthma, emphysema, bronchitis, COPD or left-sided heart failure.

Aminophylline works by helping to open up your airways, allowing more air into your lungs.

Your doctor may have prescribed it for another reason.

Ask your doctor if you have any questions about why it has been prescribed for you.

2. What should I know before treatment with DBL Aminophylline Injection?

Warnings

You must not be given DBL Aminophylline Injection if:

you are allergic to aminophylline, theophylline (or other "xanthines" such as caffeine, linagliptin, pentoxifylline or theobromine), or to ethylenediamine or any of the ingredients listed at the end of this leaflet.

Symptoms of an allergic reaction may include:

shortness of breath, wheezing or difficulty breathing
swelling of the face, lips, tongue or other parts of the body
rash, itching or hives on the skin.

Always check the ingredients to make sure you can use this medicine.

You have heart disease caused by poor blood flow in the blood vessels of the heart (coronary artery disease)
You have bronchiolitis (bronchopneumonia, a serious lung infection with fever, chills and coughing).
You are already taking similar medicines, such as aminophylline or theophylline tablets, capsules or syrups.

DBL Aminophylline Injection should be given with caution to newborns or babies (< 1 year old) and the elderly (> 60 years old). If given, your doctor or pharmacist should monitor more closely.

If you are not sure whether you should be given DBL Aminophylline Injection, talk to your doctor or pharmacist.Check with your doctor if you:

have allergies to:
- any other medicines
- any other substances, such as foods, preservatives or dyes.
have or have had any other medical conditions, especially the following:
- liver disease, including hepatitis or cirrhosis
- kidney disease eg. you are receiving dialysis
- over- or under-active thyroid gland (hyperthyroidism or hypothyroidism)
- heart disease or chest pain (angina)
- irregular or fast heartbeat (tachyarrhythmia)
- seizures, fits or convulsions (epilepsy)
- lung problems, including pneumonia or serious lung infection
- stomach ulcer (burning or gnawing stomach pain or indigestion)
- diabetes mellitus (sugar in your blood)
- gastric reflux (pain while swallowing, heartburn, hoarseness, nausea, chest pain, loss of appetite).
- alcohol abuse problems
- high blood pressure (hypertension)
- glaucoma (high pressure in your eyes)
- poor circulation
- low blood oxygen
take any medicines for any other condition.

Tell your doctor if have or have recently had:

the flu or flu vaccine
a fever

Tell your doctor if you smoke, are currently trying to give up or have recently given up:

cigarettes or e-cigarettes
marijuana
or are regularly exposed to tobacco smoke

Tell your doctor if you are due to have blood tests or heart scans, as this medicine may interfere with the results of several tests, including blood sugars and cholesterol or other fats.

If you have not told your doctor about any of the above, tell them before you are given this medicine.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Your doctor will discuss the risks and benefits of being given aminophylline during pregnancy.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

Your doctor will discuss the risks and benefits of being given aminophylline when breast-feeding.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with DBL Aminophylline Injection and affect how it works. These include:

other "xanthines" ie. caffeine, theophylline, linagliptin, pentoxifylline or theobromine
alcohol and disulfiram (a medicine for alcohol problems)
tobacco or marijuana smoking
allopurinol or sulfinpyrazone (medicines to prevent gout)
cimetidine (used for gastric reflux ie. heartburn or indigestion)
"beta-agonists" (medicines used for asthma or other breathing issues) such as salbutamol, albuterol, levalbuterol, formoterol, salmeterol or indacaterol
oral contraceptives ("The Pill")
certain antibiotics (eg. erythromycin, clarithromycin, azithromycin, fidaxomicin, ciprofloxacin, moxifloxacin, enoxacin, ofloxacin, lomefloxacin and rifampicin)
alpha-interferon (used to treat some viral infections)
some medicines used to treat depression and/or OCD, including lithium and fluvoxamine
St John's Wort (hypericum perforatum)
some medicines used to treat epilepsy, including phenytoin, phenobarbital (phenobarbitone), primidone and carbamazepine
some medicines used to treat heart disease eg. digoxin, diltiazem, dobutamine, dopamine or verapamil
"beta-blockers" (medicines used to treat heart disease or glaucoma) such as propranolol, bisoprolol, carvedilol, nebivolol, metoprolol), timolol, betaxolol or nebivolol
sedatives known as "benzodiazepines" (eg. alprazolam, chlordiazepoxide, clobazam, clonazepam, clorazepate, diazepam, lorazepam, midazolam, oxazepam, temazepam and triazolam)
halothane or ketamine (general anaesthetics)
pancuronium, atracurium, rocuronium or vecuronium (muscle relaxants used during surgery)
certain stimulant medicines such as adrenaline, noradrenaline, phenylephrine, isoprenaline, ephedrine and amphetamine
aminoglutethimide (used to treat certain hormone conditions, such as Cushing's syndrome)
propylthiouracil (PTU), carbimazole, levothyroxine or other thyroid hormones (used to control thyroid diseases)
other medicines such as methotrexate, mexiletine, tacrine, adenosine, thiabendazole or ticlopidine.

These medicines may be affected by DBL Aminophylline Injection or may affect how well it works. You may need different amounts of your medicine, or you may need to take/use different medicines. Your doctor or pharmacist will advise you.

Your doctor and pharmacist may have more information on medicines to be careful with or avoid while you are being given this medicine.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect DBL Aminophylline Injection.

4. How is DBL Aminophylline Injection given?

How much is given

Your doctor will decide what dose you will receive. This depends on your condition and other factors, such as your weight.

How it is given

DBL Aminophylline Injection may be given as a slow injection or a slow infusion (eg. a ‘drip’) into a vein.

It must only be given by a doctor or nurse.

How many injections will you need

Your doctor will decide how long you should continue to be given DBL Aminophylline Injection. After you are given the initial dose, you may need further doses.

Your doctor may want to take blood samples to make sure that you have the correct blood levels of this medicine.

If you are given too much DBL Aminophylline Injection

As DBL Aminophylline Injection is given to you under the supervision of your doctor, it is very unlikely that you will receive too much.

However, if you feel anxious, develop a headache, feel sick or need to vomit, feel dizzy, faint or light-headed, notice your heart beating very slowly, or get stabbing pains in your chest with your heart beating heavily, rapidly or missing beats, get feverish or have hot flushes when you are being given DBL Aminophylline Injection, tell the person who is giving you the injection straight away.

These may be signs that the injection is being given too quickly or may need to be stopped.

If you think that you have been given too much DBL Aminophylline Injection and/or if you experience severe side effects, you should immediately:

contact your doctor, or
phone the Poisons Information Centre
(by calling 13 11 26), or
go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

Symptoms of an overdose include the side effects listed below in Section 6. Are there any side effects? but are usually of a more severe nature.

Ask your doctor or pharmacist if you have any concerns.

5. What should I know during treatment with DBL Aminophylline Injection?

Things you should do

Remind any doctor, nurse, pharmacist or dentist you visit that you are using DBL Aminophylline Injection.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are being given this medicine.

If you plan to have surgery that needs a general anaesthetic, tell your doctor or dentist that you are being given this medicine.

If you become pregnant while being given DBL Aminophylline Injection, tell your doctor or pharmacist.

Things you should not do

Do not stop taking this medicine or change the dosage without consulting with your doctor.

Do not give your medicine to anyone else, even if they have the same condition as you.

DBL Aminophylline Injection should not be used to treat any other complaints unless your doctor or pharmacist tells you so.

Driving or using machines

Avoid driving or using any machines or tools until you know how DBL Aminophylline Injection affects you.

Aminophylline may cause dizziness, light-headedness or fits (convulsions) in some people.

Make sure you know how you react to this medicine before you drive a car, operate machinery, or do anything else that could be dangerous if you are dizzy or light-headed. If this occurs, do not drive.

Drinking alcohol

Tell your doctor if you drink alcohol.

Drinking alcohol while using this medicine may interfere with the way aminophylline works or make dizziness, lightheadedness or other side effects worse.

Looking after your medicine

DBL Aminophylline Injection will be stored in the pharmacy or on the ward.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

If you are over 60 years of age you may have an increased chance of getting side effects.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Side effects

Side effect	What to do
feeling anxious feeling sick or need to vomit headache dizziness, faintness or light-headedness slow, irregular heartbeat, heavy or rapid heartbeat stabbing pain in your chest fever or hot flushes	Tell your doctor or nurse immediately if you notice any of the following while you are being given the injection. These may be signs that the injection is being given too quickly or may need to be stopped.
Side effect	What to do
nausea (feeling sick), vomiting or diarrhoea unable to sleep headache or fever irritability, restlessness, nervousness, anxiety or excitement tremor (unintentional shaking or trembling) or muscle jerking changes in the amount of urine produced by your body feeling hot or having flushes skin rashes, redness,swelling or itching or peeling of skin feeling weak/tired, dizziness, severe headache, muscle cramps, turning pale, vision disturbances dizziness or faintness, especially when standing up heartburn or other abdominal pain or cramps loss of appetite	Tell your doctor or nurse if you notice any of the following during treatment with aminophylline These side effects are usually mild.
Side effect	What to do
persistent vomiting, diarrhoea and/or vomiting blood continuing or severe stomach pain, especially if it spreads to your back or chest fast, fluttery or irregular heartbeat or extremely slow heartbeat rapid, shallow breathing agitation, confusion or altered behaviour extreme thirst unable to urinate, especially in males buzzing, whistling or ringing in your ears (tinnitus) convulsions (fits)	Tell your doctor or nurse immediately if you notice any of the following These may be more serious side effects. You may need urgent medical attention. Serious side effects are rare.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop treatment with any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What DBL Aminophylline Injection contains

Active ingredient (main ingredient)	Aminophylline (theophylline and ethylenediamine)
Other ingredients (inactive ingredients)	Water for Injections

DBL Aminophylline Injection does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Do not use this medicine if you are allergic to any of these ingredients.

What DBL Aminophylline Injection looks like

DBL Aminophylline Injection is a clear, colourless solution.

It is available as follows:

250 mg/10 mL ampoules (AUST R 16355)

How is DBL Aminophylline Injection stored

DBL Aminophylline Injection will usually be stored in the pharmacy or on the ward. The injection should be kept in a cool dry place, protected from light, where the temperature stays below 25°C.

Who distributes DBL Aminophylline Injection

Pfizer Australia Pty Ltd
Sydney NSW
Toll Free Number: 1800 675 229
www.pfizermedinfo.com.au

This leaflet was prepared in August 2023.

™ Trademark

Published by MIMS September 2023

BRAND INFORMATION

Brand name

DBL Aminophylline Injection

Active ingredient

Aminophylline

Schedule

1 Name of Medicine

Aminophylline.

2 Qualitative and Quantitative Composition

Each mL contains 25 mg of aminophylline (equivalent to 20.63 mg of theophylline) in water for injections. The pH of the solution is between 8.8 and 10.0.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

DBL Aminophylline Injection 250 mg in 10 mL is a clear, colourless, sterile solution for injection, containing aminophylline (theophylline and ethylenediamine) in water for injections.

4 Clinical Particulars

4.1 Therapeutic Indications

DBL Aminophylline Injection is indicated for the treatment of reversible bronchospasm associated with chronic bronchitis, emphysema, bronchial asthma and chronic obstructive pulmonary disease. It may also be used for paroxysmal dyspnoea associated with left heart failure.

4.2 Dose and Method of Administration

Dosage.

Recommended doses are given as a guide only. Dosage must be individualised based on patient characteristics, clinical response, and steady-state theophylline concentration. Doses should be calculated on lean (ideal) body weight. Oral theophylline therapy should be substituted for intravenous therapy as soon as adequate improvement has been made.
A loading dose is generally administered over 20 to 30 minutes, followed by a maintenance dose.

Adults and children 6 months and over.

For patients not currently undergoing aminophylline or theophylline therapy, a dose of 6 mg aminophylline/kg lean bodyweight should be infused over 20 to 30 minutes, to provide a peak serum theophylline concentration of approximately 10 microgram/mL (55 micromol/L).
For patients currently undergoing aminophylline or theophylline therapy, a serum theophylline concentration should be obtained (see Section 4.4 Special Warnings and Precautions for Use). The dose of aminophylline may be administered on the principle that 0.6 mg aminophylline/kg lean bodyweight will increase the serum theophylline concentration by 1 microgram/mL. If it is not possible to obtain serum theophylline concentration, a dose of 3 mg aminophylline/kg lean bodyweight may be administered. See Table 1.

Use in elderly.

DBL Aminophylline Injection should be administered with caution in elderly patients (see Section 4.4 Special Warnings and Precautions for Use).

Method of administration.

DBL Aminophylline Injection may be administered by intravenous infusion, or by slow intravenous injection at a rate not exceeding 20 to 25 mg/min.

4.3 Contraindications

DBL Aminophylline Injection is contraindicated in patients hypersensitive to xanthines or to ethylenediamine.
DBL Aminophylline Injection is also contraindicated in patients with coronary artery disease where myocardial stimulation might prove harmful.
DBL Aminophylline Injection is also contraindicated in patients with bronchiolitis (bronchopneumonia).

4.4 Special Warnings and Precautions for Use

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.

General.

Prior to initiation of theophylline therapy or an increase in theophylline dose, careful consideration should be given to the various interacting drugs and physiologic conditions that can alter theophylline clearance and may require dosage adjustment.

Monitoring serum theophylline concentrations.

Serum theophylline concentration measurements should be used to determine whether the dosage is appropriate and should be measured as follows:
1. Before making a dose increase to determine whether the serum concentration is subtherapeutic 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. > 39°C sustained for ≥ 24 hours, hepatitis, or drugs listed in Section 4.5 are added or discontinued).
In patients who have received no theophylline in the previous 24 hours, a serum concentration should be measured 30 minutes after completion of the intravenous loading dose to determine whether the serum concentration is < 10 microgram/mL indicating the need for an additional loading dose or > 20 microgram/mL indicating the need to delay starting the constant intravenous infusion. Once the infusion is begun, a second measurement should be obtained after one expected half life (e.g. approximately 4 hours in children aged 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 microgram/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, 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, analysed 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 microgram/mL.
Saliva concentrations of theophylline cannot be used reliably to adjust dosage without special techniques.

Conditions that reduce theophylline clearance.

DBL Aminophylline Injection should be used with extreme caution in patients currently undergoing therapy with other xanthines, such as theophylline, as the hazard of serious toxicity is increased.
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 more intensive monitoring of serum theophylline concentrations should always be obtained in these patients prior to any aminophylline administration since clearance may be decreased and hence toxicity may be more likely in these patients. DBL Aminophylline Injection should be used with caution in patients with the following risk factors:

Smoking cessation.

Age.

Neonates (term and premature).
Children < 1 year.
Elderly (> 60 years).

Concurrent diseases.

Congestive heart failure;
chronic alcoholism;
acute febrile illness (> 39°C for 24 hours or more) or lesser temperature elevations for longer periods;
chronic obstructive pulmonary disease;
cor pulmonale;
influenza or those undergoing influenza immunisation;
renal dysfunction including reduced renal function in infants < 3 months of age;
hepatic dysfunction, including hepatic cirrhosis, acute hepatitis;
hypothyroidism;
acute pulmonary oedema or pneumonia;
sepsis with multi-organ failure;
shock.
DBL 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.
DBL Aminophylline Injection should be administered with caution in patients with the following clinical conditions due to the increased risk of exacerbation of the concurrent condition: active peptic ulcer; seizure disorders; hyperthyroidism; hypertension; glaucoma; diabetes mellitus; cardiac arrhythmias (excluding bradyarrhythmias); gastroesophageal reflux.
Where myocardial stimulation would be harmful, DBL Aminophylline Injection should be administered with caution in patients with: compromised cardiac or circulatory function, angina pectoris or acute myocardial injury.
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, light-headedness, palpitations, syncope, precordial pain, flushing, profound bradycardia, premature ventricular contractions, cardiac arrest.
Intramuscular administration is not recommended as it causes intense local pain and sloughing of tissue.
The coagulation time of the blood is shortened with aminophylline therapy.

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 microgram/mL (also see Section 4.2 Dose and Method of Administration).
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.

Use in hepatic impairment.

Theophylline clearance is decreased with hepatic (e.g. cirrhosis, acute hepatitis, cholestasis). Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in patients with reduced hepatic function.

Use in renal impairment.

About 10% of the administered theophylline dose is excreted unchanged in the urine of adults. In contrast, approximately 50% of the administered theophylline dose is excreted unchanged in the urine of neonates. Therefore, careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in neonates with decreased renal function.

Use in the elderly.

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

Paediatric use.

DBL Aminophylline Injection should be administered with caution in premature or neonatal infants and children < 1 year.
The constant infusion rate of intravenous theophylline must be selected with caution in paediatric patients since the rate of theophylline clearance is highly variable across the age range of neonates to adolescents.
Due to the immaturity of theophylline metabolic pathways in paediatric patients under the age of one year, particular attention to dosage selection and frequent monitoring of serum theophylline concentrations are required when theophylline is prescribed to paediatric patients in this age group.
Children are particularly sensitive to xanthines, especially the CNS stimulant effects. The margin of safety above therapeutic doses is small. Rapid intravenous injection is not recommended in children.

Effects on laboratory tests.

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.

Dipyridamole assisted myocardial perfusion studies.

Aminophylline reverses the effects of dipyridamole on myocardial blood flow, thereby interfering with the test results. Dipyridamole assisted myocardial perfusion studies should not be performed if therapy with aminophylline cannot be withheld for 36 hours prior to the test.

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.

General.

As a result of its pharmacological effects, theophylline at serum concentrations within the 10-20 microgram/mL range modestly increases plasma glucose (from a mean of 88 mg/dL to 98 mg/dL [4.9 mmol/L to 5.4 mmol/L]), uric acid (from a mean of 4 mg/dL to 6 mg/dL [0.24 mmol/L to 0.36 mmol/L]), free fatty acids (from a mean of 451 microEq/L to 800 microEq/L), total cholesterol (from a mean of 140 vs 160 mg/dL [3.6 vs 4.1 mmol/L]), HDL (from a mean of 36 to 50 mg/dL [0.9 to 1.3 mmol/L]), HDL/LDL ratio (from a mean of 0.5 to 0.7), and urinary free cortisol excretion (from a mean of 44 to 63 microgram/24 hr [121.4 to 173.9 nanomol/24 hr]). Theophylline at serum concentrations within the 10-20 microgram/mL range may also transiently decrease serum concentrations of triiodothyronine (144 nanogram/dL [2.22 nanomol/L] before, 131 nanogram/dL [2.02 nanomol/L] after one week and 142 nanogram/dL [2.19 nanomol/L] after 4 weeks of theophylline). The clinical importance of these changes should be weighed against the potential therapeutic benefit of theophylline in individual patients.

4.5 Interactions with Other Medicines and Other Forms of 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.
The interactions listed in this section are not intended to be inclusive or comprehensive, Individual prescribing information from relevant drugs should be consulted.
The following drugs may inhibit theophylline metabolism and decrease aminophylline clearance resulting in increased serum levels and the potential for increased toxicity: alcohol, high dose allopurinol (> 600 mg/day), beta-blockers including propranolol, cimetidine, fluvoxamine, estrogen containing oral contraceptives, diltiazem, disulfiram, recombinant alpha-interferon, methotrexate, mexiletine, tacrine, thiabendazole, thyroid hormones, ticlopidine, verapamil, pentoxifylline, and macrolide and quinolone antibiotics (including erythromycin, clarithromycin, ciprofloxacin, and enoxacin).
The following drugs may enhance theophylline metabolism and increase the clearance of aminophylline, and thereby decrease serum concentrations, possibly resulting in subtherapeutic dosing: aminoglutethimide, barbiturates including phenobarbital (phenobarbitone) and primidone, carbamazepine, isoprenaline, phenytoin, rifampicin, St John's wort (Hypericum perforatum), sulfinpyrazone, thioamines and tobacco and marijuana smoking.
If theophylline is being initiated in a patient who is already taking a drug that inhibits theophylline clearance (e.g. cimetidine, erythromycin), the dose of theophylline required to achieve a therapeutic serum theophylline concentration will be smaller. Conversely, if theophylline is being initiated in a patient who is already taking a drug that enhances theophylline clearance (e.g. rifampicin), 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.
In addition, the following drugs may interact with aminophylline.

Adenosine.

Aminophylline may antagonise the cardiovascular effects of adenosine.

Beta-agonists.

Concurrent use of aminophylline and beta-agonists may produce increased cardiotoxic effects. Also, aminophylline may potentiate the hypoglycaemia which may be associated with administration of beta-agonists.

Beta-blocking agents (including ophthalmic agents).

Concurrent use of aminophylline and beta-blockers may result in an inhibition of the bronchodilatory effects of aminophylline.

Benzodiazepines.

Concurrent use of aminophylline and benzodiazepines may result in a reduction or reversal of the sedative effects of benzodiazepines.

Cardiac glycosides.

Aminophylline may enhance the sensitivity of the myocardium to, and the toxic potential of cardiac glycosides.

Ephedrine and other sympathomimetic amines.

Concurrent use of aminophylline and sympathomimetic amines may result in increased nausea, nervousness or insomnia.

Halothane.

Concurrent use of aminophylline and halothane may result in ventricular arrythmias.

Ketamine.

Concurrent use of aminophylline and ketamine may result in a lowered seizure threshold.

Lithium.

Concurrent use of aminophylline and lithium may result in increased excretion of lithium, and hence a reduction in the therapeutic effect of lithium. Adjustment of the lithium dosage may be required.

Neuromuscular blocking agents, nondepolarising.

Aminophylline may antagonise the neuromuscular blocking effects of these agents.

Xanthines.

Concurrent use of aminophylline and other xanthine containing medications may result in additive toxicity and should be avoided (see Section 4.3 Contraindications).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(Category A)
Category A: Drugs which have been taken by a large number of pregnant women and women of childbearing age without any proven increase in the frequency of malformations or other direct or indirect harmful effects on the fetus having been observed.
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.
Aminophylline, as theophylline, is distributed into breast milk, and may occasionally induce irritability or other signs of toxicity in the breastfed infants of mothers undergoing aminophylline therapy.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

Adverse reactions associated with theophylline are generally mild when peak serum theophylline concentrations are < 20 microgram/mL and mainly consist of transient caffeine-like adverse effects such as nausea, vomiting, headache, and insomnia. When peak serum theophylline concentrations exceed 20 microgram/mL, however, theophylline produces a wide range of adverse reactions including persistent vomiting, cardiac arrhythmias, and intractable seizures which can be lethal (see Section 4.9 Overdose).
Other adverse reactions that have been reported at serum theophylline concentrations < 20 microgram/mL include diarrhoea, irritability, restlessness, fine skeletal muscle tremors, and transient diuresis. In patients with hypoxia secondary to COPD, multifocal atrial tachycardia and flutter have been reported at serum theophylline concentrations ≥ 15 microgram/mL. There have been a few isolated reports of seizures at serum theophylline concentrations < 20 microgram/mL in patients with an underlying neurological disease or in elderly patients. The occurrence of seizures in elderly patients with serum theophylline concentrations < 20 microgram/mL may be secondary to decreased protein binding resulting in a larger proportion of the total serum theophylline concentration in the pharmacologically active unbound form. The clinical characteristics of the seizures reported in patients with serum theophylline concentrations < 20 microgram/mL have generally been milder than seizures associated with excessive serum theophylline concentrations resulting from an overdose (i.e. they have generally been transient, often stopped without anticonvulsant therapy, and did not result in neurological residua).
Products containing aminophylline may rarely produce severe allergic reactions of the skin, including exfoliative dermatitis, after systemic administration in a patient who has been previously sensitised by topical application of a substance containing ethylenediamine. In such patients skin patch tests are positive for ethylenediamine, a component of aminophylline, and negative for theophylline. Pharmacists and other individuals who experience repeated skin exposure while physically handling aminophylline may develop a contact dermatitis due to the ethylenediamine component.

Adverse reactions related to aminophylline administration.

Cardiovascular system.

Tachycardia, palpitations, extrasystoles, increased pulse rate, flushing, hypotension, circulatory failure, atrial and ventricular arrhythmia, peripheral vasoconstriction.

Central nervous system.

Headache, nervousness, insomnia, irritability, restlessness, dizziness, reflex hyperexcitability, seizures, anxiety, tremor, lightheadedness, excitement.

Gastrointestinal system.

Nausea, vomiting, heartburn, epigastric pain, abdominal cramps, anorexia, diarrhoea, haematemesis.

Genitourinary.

Increased urination, albuminuria.

Other.

Fever.

Respiratory system.

Tachypnoea.

Skin and appendages.

Ethylenediamine hypersensitivity induced dermatitis (hives, skin rash, sloughing of skin).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

The chronicity and pattern of theophylline overdosage significantly influences clinical manifestations of toxicity, management and outcome. There are two common presentations:
1) acute overdose, i.e. infusion of an excessive loading dose or excessive maintenance infusion rate for less than 24 hours, and
2) chronic overdosage, i.e. excessive maintenance infusion rate for greater than 24 hours.

Clinical features.

Less severe toxicities do not always precede major toxicities. Chronic overdose may produce toxicity at serum levels lower than those in acute overdose. In general, patients who experience an acute overdose are less likely to experience severe toxicity than patients who have experienced a chronic overdosage, unless the peak serum theophylline concentration is > 90-100 microgram/mL. After a chronic overdosage, generalised seizures, life-threatening cardiac arrhythmias, and death may occur at serum theophylline concentrations > 30 microgram/mL. The following signs and symptoms may be present in aminophylline overdose:

Cardiovascular.

Tachycardia, arrhythmias, 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.

Tachypnoea, respiratory arrest, respiratory alkalosis.

Other.

Extreme thirst, slight fever, tinnitus.
The severity of toxicity after chronic overdosage is more strongly correlated with the patient's age than the peak serum theophylline concentration; patients > 60 years are at the greatest risk for severe toxicity and mortality after a chronic overdosage. Pre-existing or concurrent disease may also significantly increase the susceptibility of a patient to a particular toxic manifestation, e.g. patients with neurologic disorders have an increased risk of seizures and patients with cardiac disease have an increased risk of cardiac arrhythmias for a given serum theophylline concentration compared to patients without the underlying disease.
Other manifestations of theophylline toxicity include increases in serum calcium, creatine kinase, myoglobin and leukocyte count, decreases in serum phosphate and magnesium, acute myocardial infarction, and urinary retention in men with obstructive uropathy.
Seizures associated with serum theophylline concentrations > 30 microgram/mL are often resistant to anticonvulsant therapy and may result in irreversible brain injury if not rapidly controlled. Death from theophylline toxicity is most often secondary to cardio-respiratory arrest and/or hypoxic encephalopathy following prolonged generalised seizures or intractable cardiac arrhythmias causing haemodynamic compromise.

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, phenobarbital (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 antiarrhythmic therapy may be required.
Administration of phenothiazines in the presence of life threatening hypothermia.
Monitoring of serum theophylline concentrations and ECG.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Aminophylline is a 2:1 complex of theophylline and ethylenediamine. Aminophylline has greater water solubility than theophylline. In biological fluids aminophylline dissociates to theophylline, hence the pharmacological effects of aminophylline are those of theophylline. Theophylline is a xanthine derivative with the main pharmacological action of direct relaxation of bronchial smooth muscle, relieving bronchospasm. The bronchodilatory effect of theophylline is minimal if bronchospasm is not the cause. The bronchodilatory effect may be via inhibition of selected phosphodiesterases, which produces an increase in intracellular cyclic AMP. Theophylline also directly stimulates the medullary respiratory centre. Other pharmacological effects of theophylline include stimulation of cardiac muscle (increasing both heart rate and myocardial contractility at higher doses), stimulation of the central nervous system, transient diuresis, increased gastric secretion, decreased peripheral resistance and cerebral vasoconstriction.

Clinical trials.

No data available.

Serum concentration-effect relationship.

Theophylline, (and hence aminophylline), has a low therapeutic index. Serum theophylline concentrations of around 5 to 20 microgram/mL (27.5 to 110 micromol/L) are generally considered therapeutic. Serum theophylline concentrations greater than 20 microgram/mL (110 micromol/L) are often associated with adverse reactions.

5.2 Pharmacokinetic Properties

The pharmacokinetics of theophylline vary widely among individuals due to differences in age, body weight, diet, smoking habits, certain concurrent illnesses and co-administration of other drugs that can significantly alter the pharmacokinetics of theophylline. Within-subject variability in metabolism has also been reported in some studies, especially in acutely ill patients. Thus, monitoring of serum theophylline concentrations is recommended (see Section 4.4 Special Warnings and Precautions for Use, Monitoring serum theophylline concentrations).

Absorption.

Aminophylline dissociates rapidly to theophylline in biological fluids.

Distribution.

Theophylline is rapidly distributed throughout nonadipose tissues and extracellular fluids. Theophylline crosses the placenta, and is distributed into breast milk. The concentration of theophylline in breast milk is approximately 70% that found in the serum. The apparent volume of distribution of theophylline is 0.3 to 0.7 L/kg (average 0.45 L/kg). Approximately 60% of theophylline in adults and 35% in premature infants and neonates is bound to plasma proteins.

Metabolism.

Theophylline undergoes hepatic metabolism via the cytochrome P450 system. In adults the main metabolites are 1,3-dimethyl uric acid, 1-methyl uric acid, and 3-methylxanthine. The metabolism of theophylline has been reported to be capacity limited in some individuals, resulting in non-linear pharmacokinetics.

Excretion.

Theophylline and its metabolites undergo renal excretion.
There is significant interpatient variability in the pharmacokinetics of theophylline, and hence aminophylline. The serum half-life of theophylline in otherwise healthy, nonsmoking, asthmatic adults averages 7 to 9 hours, and theophylline clearance in this group is reported to be approximately 0.65 mL/kg/hr. Serum half-life is increased and clearance decreased in the elderly and in patients with congestive heart failure, chronic obstructive pulmonary disease, cor pulmonale or liver disease. Serum half life is decreased and clearance increased in cigarette or marijuana smokers. Clearance in premature infants and neonates is reduced. Theophylline clearance increases during the first year of life and remains relatively constant during the first 9 years, then gradually declines to adult values by 16 years of age.

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

No data available.

6 Pharmaceutical Particulars

6.1 List of Excipients

Water for injections.

6.2 Incompatibilities

Aminophylline precipitates in acidic media, but this does not apply to the dilute solutions in intravenous infusion fluids.
Aminophylline containing solutions are alkaline, and hence drugs known to be alkali labile should not be added to aminophylline containing solutions.
Aminophylline injection should not be mixed in a syringe with other drugs but should be added separately to the intravenous solution. When an intravenous solution containing aminophylline is given "piggyback", the intravenous 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: adrenaline (epinephrine) HCl, amiodarone, ascorbic acid, benzylpenicillin, chlorpromazine hydrochloride, ciprofloxacin, clindamycin, codeine phosphate, diltiazem, dimenhydrinate, dobutamine, doxapram, erythromycin gluceptate, hydralazine, hydroxyzine HCl, insulin, isoprenaline HCl, methadone HCl, methicillin sodium, morphine sulfate, noradrenaline (norepinephrine) acid tartrate monohydrate, oxytetracycline hydrochloride, pentazocine lactate, pethidine HCl, phenobarbital (phenobarbitone) sodium, phenytoin sodium, potassium, prochlorperazine edisylate, promazine hydrochloride, promethazine hydrochloride, ondansetron, tetracycline hydrochloride, vancomycin hydrochloride, vitamin B complex with C.
It is suggested that specialised literature be consulted before preparing admixtures with aminophylline and other drugs.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer unless solution is clear and container is undamaged. Discard unused portion. Do not use if crystals have separated from solution.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C. Protect from light.

6.5 Nature and Contents of Container

See Table 2.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.

The molecular formula of aminophylline is (C₇H₈N₄O₂)₂.C₂H₄(NH₂)₂. Its molecular weight is 420.4.

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