1552 Cough Suppressants Expectorants Mucolytics and Nasal Decongestants Giving ammonium chloride produces a transient diuresis and There may be drowsiness. Benzonatate has local anaesthetic Adverse Effects acidosis. It may be used in the treatment of severe metabolic alka- properties and can produce numbness of the mouth, tongue, and Gastrointestinal adverse effects may occur occasionally with losis (p.1667). Each g of ammonium chloride represents pharynx. CNS stimulation and convulsions, followed by CNS bromhexine and a transient rise in serum aminotransferase val- 18.69 mmol of chloride. It is usually given as a 1 to 2% solution depression, may occur in overdosage. ues has been reported. Other reported adverse effects include by slow intravenous infusion, in a dosage depending on the se- headache, dizziness, sweating, and skin rashes. Inhalation of brom- verity of the alkalosis. A concentrated solution of ammonium Uses and Administration hexine has occasionally produced cough or bronchospasm in Benzonatate is a cough suppressant used in non-productive chloride may be diluted by sodium chloride injection. susceptible subjects. cough (p.1547); it is stated to act peripherally. It is related to tet- Ammonium chloride may also be used to maintain the urine at racaine (p.1871) and has a local anaesthetic action on mucosa. It Precautions an acid pH in the treatment of some urinary-tract disorders. It is is given to adults and children over the age of 10 years in an oral usually given orally, often as enteric-coated tablets, in a dose of Since mucolytics may disrupt the gastric mucosal barrier brom- dose of 100 mg three times daily; up to 600 mg daily in divided hexine should be used with care in patients with a history of pep- 1 to 2 g every four to six hours. Higher doses were sometimes doses may be given if necessary. Benzonatate is reported to act used in forced acid diuresis procedures to aid the excretion of tic ulcer disease. Care is also advisable in asthmatic patients. within about 20 minutes and its effects are reported to last for 3 Clearance of bromhexine or its metabolites may be reduced in basic drugs, such as amfetamines, in severe cases of overdosage to 8 hours. (but see p.2153). patients with severe hepatic or renal impairment. Ammonium chloride has been promoted for self administration Preparations Pharmacokinetics as a diuretic, for example in premenstrual water retention; an oral USP 31: Benzonatate Capsules. Bromhexine hydrochloride is rapidly absorbed from the gas- dose of 650 mg three times daily for up to 6 days has been sug- Proprietary Preparations (details are given in Part 3) trointestinal tract; peak plasma concentrations occur after about gested, but such use is generally considered inappropriate. Mex.: Alzomed-F†; Beknol; Benzonal; Bronpax; Capsicof; D-Tato; Lem- 1 hour. Bromhexine undergoes extensive first-pass metabolism tosid; Nactol†; Novapsyl; Parven†; Pebegal; Pharben; Supracof; Tesalon; Preparations in the liver: its oral bioavailability is stated to be only about 20%. Tesopen; Texoven; Tusical; Tusitato; Tuzzil; Velpro; USA: Tessalon. It is widely distributed to body tissues. About 85 to 90% of a dose BP 2008: Ammonium Chloride Mixture; Aromatic Ammonia Solution; Ar- omatic Ammonia Spirit; Strong Ammonium Acetate Solution; White Lini- is excreted in the urine mainly as metabolites. Ambroxol ment; (p.1550) is a metabolite of bromhexine. Bromhexine is highly USP 31: Ammonium Chloride Delayed-release Tablets; Ammonium Chlo- Bibenzonium Bromide (BAN, rINN) bound to plasma proteins. It has a terminal elimination half-life ride Injection; Aromatic Ammonia Spirit; Potassium Gluconate, Potassium of 13 to 40 hours. Bromhexine crosses the blood-brain barrier Bibenzonii Bromidum; Bibenzonium, Bromure de; Bromuro de Citrate, and Ammonium Chloride Oral Solution. and small amounts cross the placenta. Proprietary Preparations (details are given in Part 3) bibenzonio; Diphenetholine Bromide; ES-132. [2-(1,2-Diphe- Austral.: Nyal Bronchitis; Fr.: Chlorammonic†; Ger.: Extin N; Switz.: nylethoxy)ethyl]trimethylammonium bromide. Uses and Administration Chloramon. Бибензония Бромид Bromhexine is a mucolytic used in the treatment of respiratory Multi-ingredient: numerous preparations are listed in Part 3. disorders associated with productive cough (p.1547). Bromhex- C19H26BrNO = 364.3. CAS — 59866-76-1 (bibenzonium); 15585-70-3 (biben- ine is usually given orally in a dose of 8 to 16 mg of the hydro- zonium bromide). chloride three times daily. It has also been given by deep intra- ATC — R05DB12. muscular or slow intravenous injection or inhaled as an aerosol Benproperine (rINN) solution. ASA-158/5 (benproperine phosphate); Benproperiini; Ben- ATC Vet — QR05DB12. Bromhexine has also been used orally and topically in the treat- properin; Benproperina; Benpropérine; Benproperinum. 1-[2-(2- ment of dry eye syndromes associated with abnormal mucus pro- Benzylphenoxy)-1-methylethyl]piperidine. duction (see below). Бенпроперин O N(CH3)3 Dry eye. Bromhexine has been used orally in the treatment of C21H27NO = 309.4. CAS — 2156-27-6. dry eye (p.2140) in Sjögren’s syndrome but results have been Br conflicting; it appears to have no effect on tear secretion in ATC — R05DB02. 1 ATC Vet — QR05DB02. healthy subjects. It has also been tried topically. 1. Avisar R, et al. Oral bromhexine has no effect on tear secretion in healthy subjects. Ann Pharmacother 1996; 30: 1498.

Profile Respiratory-tract infection. USE WITH AN ANTIBACTERIAL. Bibenzonium bromide is a cough suppressant used in non-pro- Bromhexine has been shown to enhance the penetration of ductive cough (p.1547) which is stated to have a central action. erythromycin into bronchial secretions.1 Although bromhex- It has been given in a usual oral dose of 30 to 60 mg two or three ine is used as an adjuvant in the treatment of respiratory infec- O times daily. tions, few controlled studies appear to have been conducted to N determine if any additional benefit is obtained. However, Preparations some studies have found improved responses with cefalexin2 H3C Proprietary Preparations (details are given in Part 3) and amoxicillin.3 Austria: Lysbex. 1. Bergogne-Berezin E, et al. Etude de l’influence d’un agent mu- Pharmacopoeias. Chin. includes the phosphate. colytique (bromhexine) sur le passage de l’érythromycine dans Profile les sécrétions bronchiques. Therapie 1979; 34: 705–11. Benproperine is used as a cough suppressant in non-productive Bromhexine (BAN, rINN) 2. Boraldi F, Palmieri B. Antibiotic and mucolytic therapy in elder- ly patients with different cases of bronchopulmonary diseases. cough (p.1547). It is reported to have a peripheral and central Bromexina; Bromhexin; Bromhexina; Bromhexinum; Bromihek- Curr Ther Res 1983; 33: 686–91. action and has been given in usual oral doses of 25 to 50 mg two siini; Butamirat. 2-Amino-3,5-dibromobenzyl(cyclohexyl)methyl- 3. Roa CC, Dantes RB. Clinical effectiveness of a combination of to four times daily as the phosphate. Benproperine embonate has amine. bromhexine and amoxicillin in lower respiratory tract infection: been used similarly. Бромгексин a randomized controlled trial. Arzneimittelforschung 1995; 45: Preparations 267–72. C14H20Br2N2 = 376.1. Proprietary Preparations (details are given in Part 3) CAS — 3572-43-8. Preparations Ger.: Tussafug; Hong Kong: Cofrel; Jpn: Flaveric. ATC — R05CB02. Proprietary Preparations (details are given in Part 3) ATC Vet — QR05CB02. Arg.: Amiorel; Aseptobron Expectorante; Balsasulf; Bisolvon; Brometos; Bromexidryl; Broncocalmine; Brondilax; Bronquisedan Elixir; Bronquisedan Benzonatate (BAN, rINN) Paediatrico; Catarrosine; Expectosan Extra Forte; Funciobron B; Jarabe Me- dex; Lisi-Tos; Lorbi; Lorbi-Bis; Namir; Nastizol Expectorante; No-Tos Muco- Bensonatat; Bentsonataatti; Benzonatato; Benzonatatum; Ben- litico; Pectoral Pagliano†; Pulmonix; Pulmosan; Qura Plus; Sandival; To- zononatine; KM-65. 3,6,9,12,15,18,21,24,27-Nonaoxaoctacosyl scalmin; Tostop; Austral.: Bisolvon Chesty; Duro-Tuss Mucolytic Cough Br Liquid; Austria: Bisolvon; Belg.: Bisolvon; Bromex; Bronchi-Mereprine; 4-butylaminobenzoate. N Braz.: Bisolvon; Clarus†; Chile: Bisolvon; Flumed; Cz.: Bisolvon†; Flegami- Бензонатат na†; Mucohex; Paxirasol; Denm.: Bisolvon; Viscolyt†; Fin.: Bisolvon; CH3 Medipekt; Mucovin; Fr.: Bisolvon; Ger.: Aparsonin N†; Bisolvon; Hustent- C13H18NO2(OCH2CH2)nOCH3, where n has an average NH2 abs†; Omniapharm†; Gr.: Bisolvon; Bolisegna†; Bromiramin†; Bronchotuss- value of 8. ine; Hong Kong: Asthmaxine; Bisolvon; Bromoson; Bromxine; Duro-Tuss CAS — 104-31-4 (where n = 8). Br Mucolytic; Exolit; Vasican; Hung.: Paxirasol; India: Bromex; Indon.: Bi- ATC — R05DB01. solvon; Bromika; Dexolut; Ethisolvan; Exovon; Farmavon; Hexon; Lexavon; Mucobron; Mucohexin; Mucosolvan; Poncosolvon; Solvinex; Thephidron; ATC Vet — QR05DB01. Yavon; Irl.: Bisolvon; Israel: Movex; Solvex; Ital.: Bisolvon; Broncokin†; Bromhexine Hydrochloride (BANM, USAN, rINNM) Jpn: Bisolvon; Malaysia: Beacolytic; Bislan; Bisolvon†; Bromxine; Disol; Ekxine†; Hexolvon†; Vasican; Mex.: Bisolvon; Bromicof; Dibroxin†; Di- O Bromheksino hidrochloridas; Bromhexine, chlorhydrate de; zolvin†; Meroxan; Nastizol Ex; Normoflex; Tesacof; Toridran-N; Neth.: Bi- Brómhexin-hidroklorid; Bromhexin-hydrochlorid; Bromhexinhy- solvon; Darolan Slijmoplossende; Famel Broomhexine†; Kruidvat Hoestel- (CH2CH2O)9CH3 ixer; Kruidvat Hoesttabletten; Streptuss vastzittende hoest†; Trekpleister O droklorid; Bromhexini hydrochloridum; Bromiheksiinihydroklori- Hoesttabletten†; Norw.: Bisolvon; NZ: Bisolvon; Duro-Tuss Mucolytic†; di; Bromoheksyny chlorowodorek; Cloridrato de Bromexina; Philipp.: Bisolvon; Dur-Elix; Easepex; Fleminate; Mucolyptus; Xinebrom; Hidrocloruro de bromhexina; NA-274. Pol.: Flegamina; Port.: Bisolvon; Bromocal; Lisomucin; Tosseque; Rus.: Fle- H3C N gamin (Флегамин); S.Afr.: Bisolvon; Bronkese; Singapore: Bislan; Bisolvon; H Бромгексина Гидрохлорид Bromxine; Broxine†; Duro-Tuss Mucolytic; Mucosol†; Vasican; Spain: Bi- solvon; Swed.: Bisolvon; Switz.: Bisolvon; Hustosol†; Solvolin; Thai.: As- C14H20Br2N2,HCl = 412.6. Pharmacopoeias. In US. ovon; Axistal; Behexine†; Bisoltab; Bisolvon; Bomexin; Bromex†; Bromoson; CAS — 611-75-6. Bromso; Bromxin†; Bromxine; Bronclear; Disol; Dutross†; Exolit†; Ida; USP 31 (Benzonatate). A clear, pale yellow, viscous liquid hav- ATC — R05CB02. Manovon; Mihexine; Mucine†; Mucola†; Mucoxin; Ohexine; Romulin; Tro- ing a faint characteristic odour. Soluble 1 in less than 1 of water, ATC Vet — QR05CB02. madil; Turk.: Bromek; Bromeksin; Viscol; UAE: Mucolyte; Venez.: Bedena; Bexilon; Bisectron; Bisolvon; Bromedrina; Brometix†; Bromexol; Bromox; of alcohol, of chloroform, and of ether; freely soluble in benzene. Pharmacopoeias. In Chin., Eur. (see p.vii), and Jpn. Store in airtight containers. Protect from light. Bronacim†; Drometox†; Inquixol; Kecnitril; Lisomucin; Mucobrol; Reosil; Ph. Eur. 6.2 (Bromhexine Hydrochloride). A white or almost Teraflem; Tolmix†. Adverse Effects white crystalline powder. It exhibits polymorphism. Very slightly Multi-ingredient: numerous preparations are listed in Part 3. Headache, dizziness, gastrointestinal disturbances, nasal conges- soluble in water; slightly soluble in alcohol and in dichlorometh- tion, hypersensitivity, pruritus, and skin rash have been reported. ane. Protect from light. Benproperine/Carbocisteine 1553

Brovanexine Hydrochloride (rINNM) Brovanexine, Chlorhydrate de; Brovanexini Hydrochloridum; CH O Hidrocloruro de brovanexina. 4-(Acetyloxy)-N-[2,4-dibromo-6- 3 HNH2 [(cyclohexylmethylamino)methyl]phenyl]-3-methoxybenzamide SOH monohydrochloride. O HO N CH3 Брованексина Гидрохлорид O C24H29Br2ClN2O4 = 604.8. O CH CAS — 54340-61-3 (brovanexine); 54340-60-2 (brovan- 3 Pharmacopoeias. In Chin., Eur. (see p.vii), and Jpn. exine hydrochloride). (butetamate) Ph. Eur. 6.2 (Carbocisteine). A white or almost white, crystal- line powder. Practically insoluble in water and in alcohol; dis- solves in dilute mineral acids and in dilute solutions of alkali hy- CH3 Profile Butetamate citrate is reported to be an antispasmodic and bron- droxides. A 1% suspension in water has a pH of 2.8 to 3.0. N chodilator and has been used alone or in combination prepara- Protect from light. tions for the symptomatic treatment of coughs and other associ- Incompatibility. UK licensed product information states that ated respiratory-tract disorders. mixing carbocisteine with pholcodine linctus causes precipita- H3C Preparations tion of carbocisteine from solution but no information is given on Br NH O whether this incompatibility is with the pholcodine or some com- Proprietary Preparations (details are given in Part 3) ponent of the formulation used. O Arg.: Heliphenicol. Br O Multi-ingredient: Arg.: Febrigrip; Fugafebril; Kiper; Mejoral Grip; Muco Cortos†; Mucoprednibron; Piritos; Pulmocler; Refenax Jarabe; Tavinex An- Carbocisteine Lysine (BANM, rINNM) O CH3 tigripal; Austria: Coldadolin; Influbene; Switz.: Bronchotussine. Carbocisteína lisina; Carbocistéine Lysine; Carbocisteinum Lysi- num; Carbocysteine Lysine. (brovanexine) Карбоцистеина Лизин Calcium Iodide CAS — 49673-81-6. Profile Calcii Iodidum; Calciumjodid; Ioduro de calcio; Kalcio jodidas; Kal- ATC — R05CB03. Brovanexine is a derivative of bromhexine (above) and is given siumjodidi. ATC Vet — QR05CB03. orally as the hydrochloride, usually as an adjunct to antibacterials in preparations for the treatment of respiratory-tract infections. Йодид Кальция Carbocisteine Sodium (BANM, rINNM) Preparations CaI2 = 293.9. CAS — 10102-68-8. Carbocisteína sódica; Carbocistéine Sodique; Carbocysteine So- Proprietary Preparations (details are given in Part 3) Braz.: Bronquimucil; Port.: Bronquimucil†; Pulmo-San†; Spain: Broncimu- Pharmacopoeias. Eur. (see p.vii) includes the tetrahydrate for dium; Natrii Carbocisteinum. cil. homoeopathic preparations. Натрий Карбоцистеин Ph. Eur. 6.2 (Calcium Iodide Tetrahydrate for Homoeopathic Multi-ingredient: Arg.: Trifamox Bronquial; Spain: Bronquimucil†; Eu- CAS — 49673-84-9 (carbocisteine sodium, L-form). pen Bronquial. Preparations; Calcii Iodidum Tetrahydricum ad Praeparationes ATC — R05CB03. . A white or almost white, very hygroscopic, Homoeopathicas) ATC Vet — QR05CB03. powder. Very soluble to freely soluble in water and in alcohol. Store in airtight containers. Butamirate Citrate (BANM, USAN, rINNM) Adverse Effects and Precautions Abbott-36581; Butamirát-citrát; Butamirate, Citrate de; Butami- Profile Nausea and gastric discomfort, and gastrointestinal Calcium iodide has been used orally in expectorant mixtures. rati Citras; Butamyrate Citrate; Citrato de butamirato; HH-197. The limitations of iodides as expectorants are discussed under bleeding have occasionally occurred with carbo- 2-(2-Diethylaminoethoxy)ethyl 2-phenylbutyrate dihydrogen cit- Cough, p.1547. The actions of the iodides are discussed under cisteine. Skin rashes have also been reported. rate. Iodine (p.2169). Carbocisteine should be used with caution in patients Бутамирата Цитрат Homoeopathy. Calcium iodide has been used in homoeopath- with a history of peptic ulcer disease because of the risk C18H29NO3,C6H8O7 = 499.6. ic medicines under the following names: Calcium iodatum; Cal- CAS — 18109-80-3 (butamirate); 18109-81-4 (butami- cium jodatum; Calcarea iodata; Cal. iod. that mucolytics may disrupt the gastric mucosal barri- rate citrate). er. ATC — R05DB13. Preparations ATC Vet — QR05DB13. Proprietary Preparations (details are given in Part 3) Effects on endocrine function. Transient hypothyroidism as- sociated with the use of carbocisteine developed in a patient with Multi-ingredient: Arg.: Zantril†; Gr.: Vitreolent; USA: Calcidrine; Nori- 1 sodrine with Calcium Iodide. compromised thyroid function. 1. Wiersinga WM. Antithyroid action of carbocisteine. BMJ 1986; CH3 293: 106. H3C N Caramiphen Edisilate (BANM, rINNM) O CH Pharmacokinetics 3 Caramiphen Edisylate; Caramiphène, Edisilate de; Caramipheni Carbocisteine is rapidly and well absorbed from the Edisilas; Edisilato de caramifeno. 2-Diethylaminoethyl 1-phenylcy- gastrointestinal tract with peak plasma concentrations O clopentane-1-carboxylate ethane-1,2-disulphonate. occurring about 2 hours after an oral dose. It appears to Карамифена Эдизилат O penetrate into lung tissue and respiratory mucus. Car- C38H60N2O10S2 = 769.0. bocisteine is excreted in the urine as unchanged drug (butamirate) CAS — 77-22-5 (caramiphen); 125-86-0 (caramiphen ed- isilate); 125-85-9 (caramiphen hydrochloride). and metabolites. Acetylation, decarboxylation, and Profile sulfoxidation have been identified as the major meta- Butamirate citrate is a cough suppressant used in non-productive bolic pathways. Sulfoxidation may be governed by CH3 cough (p.1547) and stated to have a central action. The usual oral O genetic polymorphism. dose is up to 30 mg daily in 3 or 4 divided doses; some countries ◊ References. permit up to 90 mg daily in divided doses. Modified-release tab- N CH3 lets containing 50 mg have been given 2 or 3 times daily. O 1. Karim EFIA, et al. An investigation of the metabolism of S-car- boxymethyl-L-cysteine in man using a novel HPLC-ECD meth- Preparations od. Eur J Drug Metab Pharmacokinet 1988; 13: 253–6. (details are given in Part 3) 2. Brockmoller J, et al. Evaluation of proposed sulphoxidation Proprietary Preparations pathways of carbocysteine in man by HPLC quantification. Eur Arg.: Dosodos; Talasa NF; Tossec; Belg.: Quintex†; Sinecod; Braz.: Bese- (caramiphen) J Clin Pharmacol 1991; 40: 387–92. dan†; Cz.: Sinecod; Tussin; Gr.: Antis; Antitoss; Betavix; Boutavixal; Bron- chofyl; Butacodin; Butagan; Butamir; Butrin; Buvastin; Chemisolv; Chributan; 3. Steventon GB. Diurnal variation in the metabolism of S-car- Codexine-R; Codimin; Cyne†; Devix; Doctamine; Drosten; Ellisek-S; Ger- Profile boxymethyl-L-cysteine in humans. Drug Metab Dispos 1999; totus; Leogumil; Mebronol; Minatuss; Nontoss; Novamir; Oaxen; Pandigal; Caramiphen is a centrally acting cough suppressant that has been 27: 1092–7. Pintal; Roctylan; Rondover; Safarol; Sinecod; Siroflex; Stilex; Velkacet; Veroc- 4. Jovanovic D, et al. A comparative bioavailability study of a ge- od; Vilvom; Zeleven; Zestapron†; Zetapron; Hung.: NeoCitran Antitussive; used as the edisilate in combination preparations for coughs neric capsule formulation containing carbocysteine. Pharmazie Sinecod; Ital.: Butiran; Lenistar; Lexosedin; Sinecod Tosse Sedativo; Neth.: (p.1547). Caramiphen hydrochloride was originally used simi- 2006; 61: 446–9. Sinecod; Philipp.: Sinecod; Pol.: Sinecod; Supremin; Port.: Sinecod; Rus.: larly to trihexyphenidyl (p.820) for its antimuscarinic actions. Sinecod (Синекод); Switz.: DemoTussol; NeoCitran Antitussif; Sinecod; Thai.: Sinecod; Turk.: Kreval; Sinecod. Uses and Administration Multi-ingredient: Arg.: Muco Dosodos; Braz.: Novotussan†; Cz.: Stop- Carbocisteine is used for its mucolytic activity in respi- tussin; Rus.: Stoptussin (Стоптуссин); Switz.: Hicoseen. ratory disorders associated with productive cough Carbocisteine (BAN, rINN) (p.1547). It is given orally in a dose of 750 mg three AHR-3053; Carbocisteína; Carbocistéine; Carbocisteinum; Car- times daily, reduced by one-third when a response is Butetamate Citrate (BANM, rINNM) bocysteine (USAN); Karbocistein; Karbocisteinas; Karbocisztein; obtained. Carbocisteine is also given orally as the sodi- Karbocystein; Karbocysteina; Karbosisteiini; Karbosistein; LJ-206. Butétamate, Citrate de; Butetamati Citras; Butethamate Citrate; um or lysine salts. Butethamate Dihydrogen Citrate; Citrato de butetamato. 2-Di- S-Carboxymethyl-L-cysteine. ethylaminoethyl 2-phenylbutyrate citrate. Карбоцистеин For children’s doses, see Administration in Children, below. Бутетамата Цитрат C5H9NO4S = 179.2. CAS — 2387-59-9; 638-23-3 (carbocisteine, L-form). C16H25NO2,C6H8O7 = 455.5. Administration in children. Children from 2 to 5 years may CAS — 14007-64-8 (butetamate); 13900-12-4 (buteta- ATC — R05CB03. be given oral carbocisteine 62.5 to 125 mg four times daily and mate citrate). ATC Vet — QR05CB03. those aged 5 to 12 years 250 mg three times daily. The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)