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Terbutaline Sulfate

(British Approved Name, US Adopted Name, rINN)

Drug Nomenclature

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

Synonyms: KWD-2019; Terbutaliinisulfaatti; Terbutalin-sulfát; Terbutalin-szulfát; Terbutalina, sulfato de; Terbutaline Sulphate; Terbutalini Sulfas; Terbutalino sulfatas; Terbutalinsulfat
BAN: Terbutaline Sulphate [BANM]
USAN: Terbutaline Sulfate
INN: Terbutaline Sulfate [rINNM (en)]
INN: Sulfato de terbutalina [rINNM (es)]
INN: Terbutaline, Sulfate de [rINNM (fr)]
INN: Terbutalini Sulfas [rINNM (la)]
INN: Тербуталина Сульфат [rINNM (ru)]
Chemical name: 2-tert-Butylamino-1-(3,5-dihydroxyphenyl)ethanol sulphate
Molecular formula: (C12H19NO3)2,H2SO4 =548.6
CAS: 23031-25-6 (terbutaline); 23031-32-5 (terbutaline sulfate)
ATC code: R03AC03; R03CC03
Read code: y00UB [Myometrial Relaxant]; y01pE [Respiratoty Use]

Pharmacopoeias. In China, Europe, Japan, and US.

European Pharmacopoeia, 6th ed. (Terbutaline Sulphate). A white or almost white crystalline powder. It exhibits polymorphism. Freely soluble in water slightly soluble in alcohol.

The United States Pharmacopeia 31, 2008 (Terbutaline Sulfate). A white to grey-white crystalline powder odourless or has a faint odour of acetic acid. Soluble in water and in 0.1N hydrochloric acid insoluble in chloroform slightly soluble in methyl alcohol. Store at 15° to 30°. Protect from light.

Adverse Effects and Precautions

As for Salbutamol.

Overdosage. An overdose of terbutaline due to transcutaneous absorption has been reported after inappropriate topical application to skin infected with tinea. Transcutaneous absorption should be considered especially when children with facial eczema or dermatitis are given terbutaline via a nebuliser and mask. For general effects of beta2 agonists after overdose, see Salbutamol.

Pulmonary oedema. Pulmonary oedema has occurred in women given beta2 agonists, including terbutaline, for premature labour. The risk factors, the most important of which is fluid overload, are discussed under Precautions for Salbutamol.

Tolerance. As with other beta2 agonists there is some evidence that tolerance may develop to terbutaline when it is used regularly.

Tooth erosion. The pH of some inhaled powder formulations of terbutaline, as well as of some corticosteroids, was found to be below 5.5, and it was suggested that this might contribute to the dissolution of enamel surfaces of teeth. A later cohort study found no association between asthma and tooth erosion however only about 10% of the medication prescribed for asthma in the cohort had a pH lower than 5.5.

Terbutaline_Sulfate

Interactions

As for Salbutamol.

Xanthines. The metabolic and cardiovascular responses to terbutaline infusion were significantly enhanced by theophylline in a study in 7 healthy subjects in particular the fall in serum potassium was greater when both drugs were given. Careful monitoring of serum potassium is recommended in severe asthma where theophylline and beta2-agonists may be given together. Terbutaline conversely has an effect on theophylline. Terbutaline can reduce serum-theophylline concentrations by increasing its systemic clearance. This may, or may not, have clinical implications, as improved clinical scores have still occurred with combined therapy despite the theophylline concentration being lower than when used alone if respiratory symptoms persist, an increase in dosage may be contemplated while monitoring theophylline adverse effects and concentration.

Pharmacokinetics

On inhalation of terbutaline, less than 10% of the drug is absorbed from the airways. The remainder is swallowed where it is variably absorbed from the gastrointestinal tract. Fasting bioavailability after oral doses is reported to be about 14 to 15% and is reduced by food. Terbutaline undergoes extensive first-pass metabolism by sulfate (and some glucuronide) conjugation in the liver and the gut wall. It is excreted in the urine and faeces partly as the inactive sulfate conjugate and partly as unchanged terbutaline, the ratio depending upon the route by which it is given. The terminal half-life after single and multiple dosing is reported to be between 16 and 20 hours. There is some placental transfer. Trace amounts are distributed into breast milk.

Stereoselectivity. Terbutaline, like many other sympathomimetics, exists in two stereoisometric forms but only the (-)-enantiomer of terbutaline is pharmacologically active. Pharmacokinetic studies have been conducted on the two enantiomers and on the racemate.

The oral bioavailability of (-)-terbutaline was 14.8%, which was similar to that of the racemate the bioavailability of (+)-terbutaline was much lower at 7.5%. The difference in bioavailability between the two enantiomers was mainly due to a difference in absorption (about 75% and 50% respectively) although a small difference in subsequent first-pass metabolism also occurred, with the (+)-isomer undergoing slightly more metabolism. It appeared that the (+)-isomer governed the elimination behaviour, both first-pass metabolism and renal clearance, of the racemate whereas the (-)-isomer determined the absorption. Other studies have also shown stereoselective sulfate conjugation of terbutaline with sulfation of the (+)-enantiomer being double that of the (-)-enantiomer. The primary site of terbutaline sulfation for both enantiomers appears to be in the gut and is significantly correlated with the activity of catechol sulfotransferase.

Uses and Administration

Terbutaline sulfate is a directacting sympathomimetic with mainly beta-adrenergic activity and a selective action on beta2 receptors (a beta2 agonist). It has actions and uses similar to those of salbutamol. Terbutaline is given as the sulfate for its bronchodilating properties in reversible airways obstruction, as occurs in asthma and in some patients with chronic obstructive pulmonary disease. It also decreases uterine contractility and may be used to arrest premature labour. On inhalation, the bronchodilating effect of terbutaline usually begins within 5 minutes and lasts for up to 6 hours. The onset of action after oral doses is 30 to 45 minutes and its duration is up to 8 hours the maximum effect occurs 1 to 4 hours after the dose. Current asthma guidelines recommend that inhaled short-acting beta2 agonists such as terbutaline be used on an ‘as-required’, not regular, basis. In those patients requiring more than occasional use of terbutaline, anti-inflammatory therapy is also needed. An increased requirement for, or decreased duration of effect of, terbutaline indicates deterioration of asthma control and the need for increased anti-inflammatory therapy.

• To relieve acute bronchospasm the usual dose is 1 or 2 inhalations of terbutaline sulfate 250 micrograms as required from a metered-dose aerosol every 4 to 6 hours, to a maximum of 8 inhalations in 24 hours.

• A breath-actuated metered-dose powder inhaler containing terbutaline sulfate is also available one inhalation of 500 micrograms is taken when required up to a maximum of 6 inhalations in 24 hours.

• When inhalation is ineffective, terbutaline sulfate may be given orally the usual initial dose is 2.5 or 3 mg three times daily increased up to 5 mg three times daily as necessary. Modified-release tablets are also available the usual adult dose is 7.5 mg twice daily.

• Severe or unresponsive bronchospasm may require the use of terbutaline sulfate intermittently via a neb-uliser. A usual dose is 5 to 10 mg inhaled 2 to 4 times daily. Single-dose units or a suitable dilution of a concentrated solution containing terbutaline sulfate 1% are used for this purpose.

Guidelines also allow for beta2 agonists to be given more frequently or by continuous dosage at a higher rate in acute severe asthma (see under Asthma).

• In the treatment of severe forms of bronchospasm, terbutaline sulfate may be given by subcutaneous, intramuscular, or slow intravenous injection a dose of 250 to 500 micrograms may be given up to 4 times daily. Terbutaline sulfate may also be given by intravenous infusion, as a solution containing 3 to 5 micrograms/mL at a rate of 0.5 to 1 mL/minute.

Terbutaline sulfate is also used to arrest uncomplicated premature labour between 24 and 33 weeks of gestation. It is given by intravenous infusion in glucose 5%, preferably by syringe pump when the concentration is 100 micrograms/mL. If no syringe pump is available then the concentration of the infusion should be 10 micrograms/mL. The recommended initial rate of infusion is 5 micrograms/minute increased by 2.5 micrograms/minute at intervals of 20 minutes until contractions stop. Usually, a rate of up to 10 micrograms/minute is sufficient rates in excess of 20 micrograms/minute should not be used and if that maximum rate does not delay labour then the infusion should be stopped. The maternal pulse should be monitored throughout the infusion which should be adjusted to avoid a maternal heart rate of more than 135 beats/minute. A close watch should also be kept on the patient’s state of hydration since fluid overload is considered to be a key risk factor for pulmonary oedema. Once contractions have ceased, the infusion should be given for 1 hour, then the dose may be decreased by 2.5 micrograms/minute at 20-minute intervals to the lowest maintenance dose that produces continued suppression of contractions. After a further 12 hours, oral maintenance therapy with 5 mg three times daily may be started. However, such usage is not recommended by the BNF as the risks to the mother (see Precautions under Salbutamol) increase after 48 hours, and furthermore there is a lack of evidence of benefit from further treatment. Subcutaneous doses of 250 micrograms four times daily have been given for a few days before oral treatment was commenced. For terbutaline sulfate doses used for bronchospasm in children, see Administration in Children, below. Terbutaline in a bioadhesive vaginal gel is under investigation for the treatment of infertility linked to endometriosis.

Administration in children. To relieve acute bronchospasm

in children, the BNFC recommends a dose of 500 micrograms of terbutaline sulfate, inhaled via a metered-dose powder inhaler, up to four times daily in children aged 5 years and over. Oral doses, although not recommended and unlicensed in the UK for children under 7 years of age, may be given in doses ranging from:

• 1 month to 7 years of age, 75 micrograms/kg (maximum dose 2.5 mg) three times daily

• 7 to 15 years of age, 2.5 mg two or three times daily

• over 15 years of age, as for adults (see Uses and Administration, above)

Severe or unresponsive bronchospasm may require the use of terbutaline sulfate inhaled via a nebuliser. UK licensed product information gives doses based on weight and age:

• under 3 years of age, average body-weight 10 kg, 2 mg given 2 to 4 times daily

• 3 to 5 years of age, average body-weight 15 kg, 3 mg given 2 to 4 times daily

• 6 to 7 years of age, average body-weight 20 kg, 4 mg given 2 to 4 times daily

• 8 years of age and over, body-weight greater than 25 kg, 5 mg given 2 to 4 times daily

In the treatment of severe forms of bronchospasm, terbutaline sulfate may be given by subcutaneous or slow intravenous injection in children 2 years of age and over, the BNFC recommends a dose of 10 micrograms/kg given every 6 hours as required. A maximum single dose of 300 micrograms is recommended in children from 2 to 15 years of age, and in children over 15 years a maximum single dose of 500 micrograms is recommended. Terbutaline sulfate may also be given by intravenous infusion the BNFC recommends an initial dose of 2 to 4 micrograms/kg, then 1 to 10 micrograms/kg per hour according to response and heart rate. Although the injection is unlicensed in the UK for children under 2 years of age, the BNFC allows this dose for children from 1 month of age.

Cardiac disorders. A case report on the use of oral terbutaline for chronotropic support, in the setting of acute rejection after heart transplantation, found it to be effective and without any significant adverse effects.

Hypoglycaemia. Giving terbutaline 5 mg orally at night reduced the risk of nocturnal hypoglycaemia in a study in patients with type 1 diabetes. A later study reproduced these results in 21 patients with type 1 diabetes however, hyperglycaemia was seen the next morning.

Systemic capillary leak syndrome. Systemic capillary leak syndrome is a rare disorder marked by shifts of plasma from the intravascular to the extracellular space, and is often fatal. Acute attacks are treated with intravenous fluid resuscitation, but there is some anecdotal evidence that treatment with terbutaline combined with aminophylline or theophylline, both orally, may be useful in preventing further attacks. Infusion of epoprostenol has also been used in acute management.

Urticaria. Patients with various types of urticaria unresponsive to conventional therapy with antihistamines have obtained benefit from treatment with a combination of terbutaline and ketotifen the urticarias have included chronic idiopathic urticaria, dermographism, and cold urticaria. Terbutaline on its own was relatively ineffective and the mechanism of the combination was believed to be due to a stabilising effect on mast cells.

Treatment of cold urticaria with a combination of terbutaline and aminophylline has also been studied. The effectiveness of this combined therapy was reported to vary considerably between patients, but complete remission of the urticarial response was eventually seen in 37 of the 42 patients. Treatment was stopped in 3 patients in the first week due to cardiac adverse effects.

Preparations

British Pharmacopoeia 2008: Terbutaline Tablets

The United States Pharmacopeia 31, 2008: Terbutaline Sulfate Inhalation Aerosol Terbutaline Sulfate Injection Terbutaline Sulfate Tablets.

Proprietary Preparations

 

Argentina: Bricanyl

Australia: Bricanyl

Austria: Bricanyl

Belgium: Bricanyl

Brazil: Bricanyl Terbutil

Canada: Bricanyl

Chile: Bricanylf

Czech Republic: Bricanyl

Denmark: Bricanyl

Finland: Bricanyl

France: Bricanyl

Germany: Aerodur Arubendol Asthmoprotect Bricanyl Butaliret Butalitab Contimit Terbul Terbuturmant

Greece: Bricanyl Dracanyl

Hong Kong: Ataline Bricanyl Butylinf Dhatalin Lanterbine Terbron Terbuta Vida-Butaline

Hungary: Bricanyl

India: Bricanyl

Indonesia: Astherin Brasmatic Bricasma Forasma Lasmalin Nairet Pulmobron Relivan Sedakter Tabas Terasma Tismalin Yarisma

Ireland: Bricanyl

Israel: Bricalin Terbulin

Italy: Bricanyl

Malaysia: Bricanyl Bucanil Butaline Butanil Terbron Terbulin-H Tolbin

Mexico: Bricanyl Taziken Terbuken

Norway: Bricanyl

New Zealand: Bricanyl

Portugal: Bricanyl

South Africa: Bricanyl

Singapore: Ataline Bricanyl Bucanill Tolbin

Spain: Tedipulmo Terbasmin

Sweden: Bricanyl

Switzerland: Bricanyl

Thailand: Asmaline Asthmasian Bricanyl Broncholine Bronchonyl Bronco Asmo Bucaril Cencanyl Med-Broncodil Proasma-T Sulterline Terbron Terbulin Terbuno Tolbin Vacanyl

Turkey: Bricanyl

UK: Bricanyl Monoventl

USA: Brethine Bricanyl

Venezuela: Bricanil Nortol

Multi-ingredient

Austria: Bricanyl comp

Brazil: Bricanyl Composto

Germany: Bricanyl comp

Hong Kong: Bricanyl Expectorant

India: Ascoril + Asmotone Plus Bricarex Bro-Zedex Bronchosolvin CofQX Grilinctus-BM Mucaryl-AX Mucosol Okaril Plus Tergil Tergil-T Terpect Terphylate Terphylin Theobric Tuspel Plus

Indonesia: Bricasma Expectorant Terasma Expectorant

Ireland: Bricanyl Expectorant

Mexico: Bricanyl EX

Philippines: Bricanyl Expectorant

South Africa: Benylin Bronchospect Bronchoped Bronchospect

Spain: Terbasmin Expectorante

Thailand: Bricanyl Expectorant Cofbron Med-Broncodil Expectorant Terbosil Terbron Expectorant Tolbin.

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