Aminophylline

(British Approved Name, rINN)

What Is Aminophylline?

Aminophylline is a medication that belongs to a class of drugs known as methylxanthines. It is used primarily to treat respiratory conditions, particularly those associated with bronchospasm and reversible airway obstruction, such as asthma and chronic obstructive pulmonary disease (COPD).
Aminophylline works by relaxing the muscles in the airways, which helps to open up the air passages in the lungs. This relaxation effect is due to its action as a bronchodilator. Additionally, aminophylline can stimulate the respiratory drive and increase the contractility of the diaphragm.
While aminophylline can be effective in managing certain respiratory conditions, it’s essential to use it under the supervision of a healthcare professional, as it has a narrow therapeutic window, and the dosage needs to be carefully monitored to avoid side effects and toxicity.
Common side effects of aminophylline may include nausea, vomiting, headache, and increased heart rate. In cases of overdose, it can lead to more severe symptoms, including seizures and life-threatening arrhythmias.
Aminophylline may interact with other medications, and its levels in the blood can be affected by factors such as age, liver function, and smoking habits. It’s crucial to inform your healthcare provider about all your medications and any medical conditions you may have.
As with any prescription medication, it’s essential to use aminophylline according to your healthcare provider’s instructions and attend regular check-ups to monitor its effectiveness and address any concerns.

Pharmacokinetics

Aminophylline, a complex of theophylline with ethylenediamine, readily liberates theophylline in the body. The pharmacokinetics of theophylline are discussed.

Studies in healthy subjects suggested that ethylenediamine does not affect the pharmacokinetics of theophylline after oral or intravenous dosage.

Uses and Administration

Aminophylline has the actions and uses of theophylline and is used similarly as a bronchodilator in managing asthma and chronic obstructive pulmonary disease. Aminophylline is also used to relieve neonatal apnoea. It was formerly used as an adjunct in the treatment of heart failure. It may occasionally be used in patients suffering from obstructive airways disease. Aminophylline is usually preferred to theophylline when greater solubility in water is required, particularly in intravenous formulations.

Aminophylline may be given in the anhydrous form or as the hydrate, and doses may be expressed as either aminophylline hydrate 1.09 mg is equivalent to about 1 mg of aminophylline. The United States Pharmacopeia 31, 2008 specifies that aminophylline preparations should be labeled according to their anhydrous theophylline content. As the pharmacokinetics of theophylline are affected by several factors, including age, smoking, disease, diet, and drug interactions, the dose of aminophylline must be carefully individualized and serum-theophylline concentrations monitored.

In managing acute severe bronchospasm, aminophylline may be given intravenously by slow injection or infusion. To reduce adverse effects, intravenous aminophylline should not be given at a rate greater than 25 mg/minute. In adults who have not been taking aminophylline, theophylline, or other xanthine-containing medication, a loading dose of 5 mg/kg ideal (lean) body weight or 250 to 500 mg of aminophylline may be given intravenously over 20 to 30 minutes by slow injection or infusion, followed by a maintenance infusion dose of 500 micrograms/kg per hour.

Older patients and those with cor pulmonale, heart failure, or liver disease may require lower maintenance doses, and smokers often need higher maintenance doses. A loading dose may not be considered necessary unless the patient’s condition is deteriorating. Intravenous aminophylline is best avoided in patients already taking theophylline, aminophylline, or other xanthine-containing medication. Still, if considered necessary, the serum-theophylline concentration should first be assessed. The initial loading dose should be calculated on the basis that every 600 micrograms/kg of aminophylline (equivalent to 500 micrograms/kg theophylline) will increase serum-theophylline concentration by 1 microgram/mL.

In managing chronic bronchospasm, aminophylline may be given orally as modified-release preparations. A usual dose is aminophylline hydrate 225 to 450 mg twice daily. Therapy should start with the lower dose and be increased as appropriate. Registration of the dosage is required if the patient is changed from one modified-release preparation to another, as the bioavailability of modified-release aminophylline preparations may vary.

For doses of aminophylline used in children, see Administration in Children. Intramuscular injection of aminophylline causes intense local pain and is not recommended. Aminophylline has also been used as a hydrochloride.

Rectal Administration

Absorption from aminophylline suppositories is erratic, and this dose form has been associated with toxicity, hence the warnings that suppositories should not be used, especially in children. In the UK, suppositories are no longer readily available, and one hospital wishing to use the rectal route for apnoea in premature infants (see Neonatal Apnoea) achieved therapeutic plasma-theophylline concentrations with a specially formulated rectal gel.

Administration in Children

Aminophylline may be given intravenously, by slow injection or infusion, to manage acute severe bronchospasm in children. Doses should be calculated using ideal or lean body weight. In children who have not been taking aminophylline, theophylline, or other xanthine-containing medicine, UK-licensed product information recommends a loading dose of 5 mg/kg given by slow injection or infusion over 20 to 30 minutes. Initial maintenance dose ranges are:

• 6 months up to 10 years of age: 1 mg/kg per hour;
• 10 to 16 years of age: 800 micrograms/kg per hour.

Although unlicensed in the UK for use in children under 6 months, the BNFC allows a dose of 1 mg/kg per hour from 1 month of age. Children aged 16 years and above may be given adult doses. Serum-theophylline concentrations should be used to guide further dose adjustments.

Children receiving theophylline, aminophylline, or other xanthine-containing medicines should not usually receive intravenous aminophylline unless serum-theophylline concentration is available to guide dosage. Loading doses are based on the expectation that each 500 micrograms/kg lean body weight of theophylline will result in a 1-microgram/mL increase in serum-theophylline concentration.

Oral modified-release preparations are given to children with weight over 40 kg in the long-term management of chronic bronchospasm. An initial dose of 225 mg twice daily may be given if the child has not previously received xanthine preparations, increased after one week to 450 mg twice daily according to serum-theophylline concentrations. Different modified-release preparations are not considered interchangeable. Aminophylline may also be used in the management of neonatal apnoea.

Although the injection is unlicensed in the UK in children under 6 months of age, the BNFC recommends an initial dose of 6 mg/kg by intravenous injection over 20 minutes. This is followed by 2.5 mg/kg every 12 hours, increased if necessary to 3.5 mg/kg every 12 hours. The plasma theophylline concentration for optimum response in neonatal apnoea is 8 to 12 mg/liter. 

Methotrexate Neurotoxicity

For reference to the use of aminophylline or theophylline to relieve the acute neurotoxicity of methotrexate, see Adverse Effects.

Motor Neurone Disease

A study in 25 patients with amyotrophic lateral sclerosis found that aminophylline improved the endurance of respiratory muscles and increased the handgrip strength of skeletal muscles. It may have some potential therapeutic benefits in such patients.

Reduction of Body Fat

Cosmetic aminophylline cream has been promoted for its supposed ability to remove fat (‘cellulite’) from the thighs. Concern has been raised about the potential for topical sensitization.

Interactions

As for Theophylline.

Aminophylline solutions should not be allowed to come into contact with metals.

Solutions of aminophylline are alkaline, and if the pH falls below 8, crystals of theophylline will deposit. Drugs known to be unstable in alkaline solutions or that would lower the pH below the critical value should not be mixed with aminophylline.

Adverse Effects, Treatment, and Precautions

As for Theophylline. Hypersensitivity has been associated with the ethylenediamine content.

Porphyria

Aminophylline is considered to be unsafe in patients with porphyria because it is porphyrinogenic in animals or in-vitro systems.

Drug Nomenclature

International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):

Synonyms: Aminofilina; Aminofylin; Aminofylliini; Aminofyllin; Aminophyllinum; Euphyllinum; Metaphyllin; Teofilinas-etilendiaminas; Teofillinetiléndiamin; Teofylliinietyleenidiamiini; Teofyllinetylendiamin; Theophyllaminum; Theophylline Ethylenediamine Compound; Theophylline and Ethylenediamine; Theophyllinum Et Ethylenediaminum; Theophyllinum et Ethylenediaminum

BAN: Aminophylline

INN: Aminophylline [pINN (en)]

INN: Aminofilina [pINN (es)]

INN: Aminophylline [pINN (fr)]

INN: Aminophyllinum [pINN (la)]

INN: Аминофиллин [pINN (ru)]

Chemical name: A mixture of theophylline and ethylenediamine (2:1), its composition approximately corresponding to the formula below

Molecular formula: (C7H8N4O2)2,C2H4(NH2)2 =420.4

CAS: 317-34-0 (anhydrous aminophylline)

ATC code: R03DA05

Read code: y01qq

Pharmacopoeias. In Europe, Int, US. Some pharmacopeias include anhydrous and hydrated aminophylline in one monograph. Some pharmacopeias do not specify the hydration state.

European Pharmacopoeia, 6th ed. (Theophylline-ethylenediamine; Aminophylline British Pharmacopoeia 2008). It contains 84.0 to 87.4% of anhydrous theophylline and 13.5 to 15.0% of anhydrous ethylenediamine. A white or slightly yellowish powder, sometimes granular. Freely soluble in water (the solution becomes cloudy through absorption of carbon dioxide), it is practically insoluble in dehydrated alcohol. Store in airtight containers. Protect from light.

The United States Pharmacopeia 31, 2008 (Aminophylline). It is anhydrous or contains not more than two water molecules of hydration. It contains not less than 84.0 and not more than 87.4% of anhydrous theophylline. It consists of white or slightly yellowish granules or powder, having a slight ammoniacal odor. Upon exposure to air, it gradually loses ethylenediamine and absorbs carbon dioxide with the liberation of theophylline. 1 g dissolves in 25 mL of water to give a clear solution. 1 g dissolved in 5 mL of water crystallizes upon standing but redissolves when a small amount of ethylenediamine is added, insoluble in alcohol and in ether. Its solutions are alkaline to litmus. Store in airtight containers.

Aminophylline Hydrate

(British Approved Name Modified, rINNM)

Drug Nomenclature

Synonyms: Aminofilina hidratada; Aminofylin hydratovaný; Aminophyllinum Hydricum; Teofylliinietyleenidiamiinihydraatti; Teofyllinetylendiaminhydrat; Theophyllinum Et Ethylenediaminum Hydricum

BAN: Aminophylline Hydrate [BANM]

INN: Aminophylline Hydrate [pINNM (en)]

INN: Aminofilina hidratada [pINNM (es)]

INN: Aminophylline, Hydrate d’ [pINNM (fr)]

INN: Aminophylline Hydratum [pINNM (la)]

INN: Аминофиллина Гидрат [pINNM (ru)]

Molecular formula: (C7H8N4O2)2,C2H4(NH2)2,2H2O =456.5

CAS: 49746-06-7 (aminophylline dihydrate)

ATC code: R03DA05

Pharmacopoeias. In China, Europe, Japan, US. Some pharmacopeias include anhydrous and hydrated aminophylline in one monograph. Some pharmacopeias do not specify the hydration state.

European Pharmacopoeia, 6th ed. (Theophylline-ethylenediamine Hydrate; Aminophylline Hydrate British Pharmacopoeia 2008). It contains 84.0 to 87.4% of anhydrous theophylline and 13.5 to 15.0% of anhydrous ethylenediamine. A white or slightly yellowish powder, sometimes granular. Freely soluble in water (the solution becomes cloudy through absorption of carbon dioxide), it is practically insoluble in dehydrated alcohol. Store in well-filled, airtight containers. Protect from light.

The United States Pharmacopeia 31, 2008 (Aminophylline). It is anhydrous or contains not more than two water molecules of hydration. It contains not less than 84.0 and not more than 87.4% of anhydrous theophylline. It consists of white or slightly yellowish granules or powder, having a slight ammoniacal odor. Upon exposure to air, it gradually loses ethylenediamine and absorbs carbon dioxide with the liberation of theophylline. One g dissolves in 25 mL of water to give a clear solution. 1 g dissolved in 5 mL of water crystallizes upon standing but redissolves when a small amount of ethylenediamine is added, insoluble in alcohol and in ether. Its solutions are alkaline to litmus. Store in airtight containers.

Preparations

British Pharmacopoeia 2008: Aminophylline Injection; Aminophylline Tablets

The United States Pharmacopeia 31, 2008: Aminophylline Delayed-release Tablets; Aminophylline Injection; Aminophylline Oral Solution; Aminophylline Rectal Solution; Aminophylline Suppositories; Aminophylline Tablets.

Proprietary Preparations

Argentina: Cardirenalf Fadafilina Larjanfilina

Austria: Euphyllin Mundiphyllin

Brazil: Aminoima Aminoliv Asmafin Asmapen Asmodrin Asmoquinol Minoton Unifilin

Canada: Phyllocontin

Chile: Cardiominf

Czech Republic: Pharophyllin Syntophyllin

Denmark: Teofylamin

Finland: Aminocont

Germany: Phyllotemp

Hungary: Diaphyllin

Indonesia: Phyllocontin

Ireland: Phyllocontin

Italy: Aminomal Tefamin

Japan: Neophyllin

Mexico: Amofilin Drafilyn-Z

The Netherlands: Euphyllin

Portugal: Filotempo

South Africa: Peterphyllin Phyllocontin

Sweden: Teofyllamin

Switzerland: Escophylline-H Phyllotemp

Thailand: Asmalia Fileen-P Turfc Aminocardol Asmafilin Carena

UK: Amnivent Phyllocontin

USA: Truphylline

Venezuela: Broncophilina

Multi-ingredient

Austria: Asthma-Hilfe Limptar Myocardon

Brazil: Alergo Filinal Alergotox Expectorante Alergotox Dispneitrat

Germany: Limptar

Hong Kong: Asmeton

Mexico: Isobutil Paliatil

Portugal: Anti-Asmatico

Thailand: Asmeton

USA: Emergent-Ez

Venezuela: Fedratal