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AMBROXOL

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Ambroxol is a metabolite of bromhexine, and primarily used as a mucolytic.

Specific Substances

    1) NA-872
    2) trans-4-(2-amino-3,5-dibromobenzylamino)
    3) cyclohexanol hydrochloride
    4) Molecular formula: C13-H18-Br2-N2-O, HCl
    5) CAS 18683-91-5 (ambroxol)
    6) CAS 15942-05-9 (ambroxol hydrochloride)

Available Forms Sources

    A) FORMS
    1) An oral form of ambroxol is under investigation by Boehinger Ingelheim Pharmaceuticals.
    a) BOEHRINGER INGELHEIM LTD: Medical Services Dept, PO Box 368, 90 East Ridge, Ridgefield, CT 06877. Telephone: (203) 798-9988
    2) TRADE NAMES IN OTHER COUNTRIES
    a) Trade names for ambroxol in other countries include Abramen(R), Ambril(R), AmbroHexal(R), Ambrolitic(R), Ambroten(R), Ambroxocompren(R), Amobronc(R), Anabron(R), Bronchopront(R), Broncoxan(R), Broxol(R), Dignobroxol(R), Duramucal(R), Expit(R), Fluibron(R), Fluixol(R), Frenopect(R), Ilvico(R)-Hustenloser, Lasolvan(R), Lindoxyl(R), Lisopulm(R), Litusix(R), Motosol(R), Mucibron(R), Muciclar(R), Muco-Aspecton(R), Mucobron(R), Mucoclear(R), Mucolin(R), Mucophlogat(R), Mucosan(R), Mucusolvon(R), Mucotablin(R), Muco-Tablinen(R), Mucovent(R), Naxpa(R), Pect Hustenloser(R), Pulmonal(R), Pulmybrom(R), Ringelheimer(R) Pulmonal S, Secretil(R), Stas(R), Stas(R)-Hustenloser, Surbronc(R), Surfactal(R), Surfactil(R), Tauxolo(R), Tusso-Basan(R), Tussol(R), Vaksan(R), and Viscomucil(R).
    B) USES
    1) The primary role of ambroxol in pulmonary medicine is to act as an expectorant/mucolytic. Its main use is in the treatment of bronchitis and pulmonary infections to facilitate the removal of secretions from the respiratory tract.
    2) The mucolytic and pulmonary surfactant stimulating properties of ambroxol have generated interest in its use in the prevention and treatment of neonatal respiratory distress syndrome, also known as hyaline membrane disease, and in the prophylaxis of antineoplastic-induced pulmonary injury.

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) WITH THERAPEUTIC USE
    1) Symptoms seen as adverse effects include gastrointestinal upset, diarrhea, vomiting, skin rashes, and fatigue.
    B) WITH POISONING/EXPOSURE
    1) Serious symptoms due to overdose have not been reported.
    0.2.7) NEUROLOGIC
    A) WITH THERAPEUTIC USE
    1) Fatigue was infrequently reported in patients receiving ambroxol for bronchitis.
    0.2.8) GASTROINTESTINAL
    A) WITH THERAPEUTIC USE
    1) Dry mouth, diarrhea, constipation, nausea and vomiting, and sialorrhea have all been reported with therapeutic use.
    0.2.10) GENITOURINARY
    A) WITH THERAPEUTIC USE
    1) Dysuria occurred infrequently with ambroxol therapy.
    0.2.14) DERMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Contact dermatitis, urticaria, exanthema, itching, pruritic erythema and vesicular eruptions about the nose, upper lips, and cheeks, and pharyngeal soreness and spasm have been reported with therapeutic use.
    0.2.20) REPRODUCTIVE
    A) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.
    B) At the time of this review, no data were available to assess the teratogenic potential of this agent.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, no data were available to assess the carcinogenic potential of this agent.

Laboratory Monitoring

    A) No specific laboratory measures are required, overdose experience is very limited.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    0.4.3) INHALATION EXPOSURE
    A) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.
    0.4.4) EYE EXPOSURE
    A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Range Of Toxicity

    A) Minimum lethal human exposure is unknown.

Clinical Effects

Summary Of Exposure

    A) WITH THERAPEUTIC USE
    1) Symptoms seen as adverse effects include gastrointestinal upset, diarrhea, vomiting, skin rashes, and fatigue.
    B) WITH POISONING/EXPOSURE
    1) Serious symptoms due to overdose have not been reported.

Heent

    3.4.5) NOSE
    A) WITH THERAPEUTIC USE
    1) RHINORRHEA was observed in 3 of 63 patients receiving ambroxol 60 to 120 mg/day for bronchitis (Ericsson et al, 1986).

Neurologic

    3.7.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Fatigue was infrequently reported in patients receiving ambroxol for bronchitis.
    3.7.2) CLINICAL EFFECTS
    A) FATIGUE
    1) WITH THERAPEUTIC USE
    a) Fatigue was reported in 1 of 63 patients receiving ambroxol 60 mg/day for bronchitis (Ericsson et al, 1986).

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Dry mouth, diarrhea, constipation, nausea and vomiting, and sialorrhea have all been reported with therapeutic use.
    3.8.2) CLINICAL EFFECTS
    A) APTYALISM
    1) WITH THERAPEUTIC USE
    a) Xerostomia and dryness of the airways were reported in 5 of 63 patients receiving ambroxol, 60 to 120 mg/day, for bronchitis (Ericsson et al, 1986).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Approximately 3% of patients receiving ambroxol therapy, 75 mg per day, subsequently developed diarrhea (Anon, 1989).
    C) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) Constipation occurred in 1 of 63 patients receiving ambroxol 120 mg/day for bronchitis (Ericsson et al, 1986).
    D) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Approximately 13% of patients taking ambroxol 75 mg per day subsequently developed nausea, and 2.6% experienced vomiting (Anon, 1989).
    E) EXCESSIVE SALIVATION
    1) WITH THERAPEUTIC USE
    a) Sialorrhea was observed in 3 of 63 patients receiving ambroxol 60 to 120 mg/day for bronchitis (Ericsson et al, 1986).

Genitourinary

    3.10.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Dysuria occurred infrequently with ambroxol therapy.
    3.10.2) CLINICAL EFFECTS
    A) DYSURIA
    1) WITH THERAPEUTIC USE
    a) Dysuria occurred in 1 of 63 patients receiving ambroxol 120 mg/day for bronchitis (Ericsson et al, 1986).

Dermatologic

    3.14.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Contact dermatitis, urticaria, exanthema, itching, pruritic erythema and vesicular eruptions about the nose, upper lips, and cheeks, and pharyngeal soreness and spasm have been reported with therapeutic use.
    3.14.2) CLINICAL EFFECTS
    A) CONTACT DERMATITIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - A case of contact allergy was reported in a 60-year-old woman who used a 0.75% ambroxol solution via oral nebulization. Approximately 10 days after starting therapy, the patient developed pruritic erythema and vesicular eruptions about the nose, upper lips, and cheeks, and pharyngeal soreness and spasm.
    1) Symptoms resolved promptly upon discontinuation of the ambroxol solution and treatment with systemic and topical steroids. Subsequent patch testing was positive to ambroxol, but not to the paraben preservatives used in the product (Mancuso & Berdondini, 1989).
    B) URTICARIA
    1) WITH THERAPEUTIC USE
    a) Urticaria has been reported with therapeutic use (Mancuso & Berdondini, 1989).
    C) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Exanthema has been reported with therapeutic use (Mancuso & Berdondini, 1989).
    D) ITCHING OF SKIN
    1) WITH THERAPEUTIC USE
    a) Approximately 4 percent of patients ingesting ambroxol, 75 mg per day, developed itching (Anon, 1989).

Reproductive

    3.20.1) SUMMARY
    A) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.
    B) At the time of this review, no data were available to assess the teratogenic potential of this agent.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the teratogenic potential of this agent.
    3.20.3) EFFECTS IN PREGNANCY
    A) ANIMAL STUDIES
    1) In animal experiments, the administration of ambroxol to the mother leads to increased accumulation of phospholipid complexes in fetal granular pneumocytes, alveolar spaces, and tracheal fluid (Lachmann et al, 1981).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, no data were available to assess the carcinogenic potential of this agent.
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the carcinogenic potential of this agent.

Genotoxicity

    A) At the time of this review, no data were available to assess the mutagenic or genotoxic potential of this agent.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) No specific laboratory measures are required, overdose experience is very limited.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) No specific laboratory measures are required, overdose experience is very limited.
    2) A number of chemicals produce abnormalities of the hematopoietic system, liver, and kidneys. Monitoring complete blood count, urinalysis, and liver and kidney function tests is suggested for patients with significant exposure.
    4.1.3) URINE
    A) URINALYSIS
    1) A number of chemicals produce abnormalities of the hematopoietic system, liver, and kidneys. Monitoring urinalysis is suggested for patients with significant exposure.

Methods

    A) CHROMATOGRAPHY
    1) A high-performance liquid chromatographic (HPLC) method with ultraviolet detection was used to determine the presence of ambroxol in human plasma, following oral administration of 90 milligrams. The detection limit, using this method, was 4 ng/mL (Nobilis et al, 1992).
    2) A capillary gas-liquid chromatographic method, with electron-capture detection, was described by Schmid (1987) for rapid determination of ambroxol in human plasma and urine. The limit of quantification in plasma was 3 ng/mL.
    B) OTHER
    1) Perez-Ruiz et al (1997) reported the use of capillary zone electrophoresis (CZE) in determining the presence of ambroxol and its parent compound, bromhexine, in human urine and blood serum. Advantages of this method over high-performance liquid chromatography include a shorter overall running time and lower solvent and sample consumption. Also, in comparison with gas chromatography, the thermal degradation of analytes is much less with CZE.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) No specific laboratory measures are required, overdose experience is very limited.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) After decontamination, treatment is symptomatic and supportive. More overdose data are required to indicate any specific treatments.

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
    B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DERMAL DECONTAMINATION
    1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
    6.9.2) TREATMENT
    A) DERMATITIS
    1) Symptoms resolved promptly upon discontinuation of the ambroxol solution and treatment with systemic and topical steroids (Mancuso & Berdondini, 1989).
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Enhanced Elimination

    A) SUMMARY
    1) No studies have addressed the utilization of extracorporeal elimination techniques in poisoning with this agent.

Range Of Toxicity

Summary

    A) Minimum lethal human exposure is unknown.

Therapeutic Dose

    7.2.1) ADULT
    A) ROUTE OF ADMINISTRATION
    1) INTRAVENOUS -
    a) The optimal dose of ambroxol has not been defined. For surgical prophylaxis, intravenous ambroxol in doses of 1 gram daily for 6 days has been used (Romanini et al, 1986).
    b) In the prophylaxis of hyaline membrane disease, antenatal maternal ambroxol has been given in doses of 1 gram via intravenous infusion daily for 5 doses (Wauer et al, 1982).
    2) ORAL -
    a) The optimal dose of ambroxol has not been defined. In alveolar proteinosis, chemotherapy induced pulmonary injury, bronchitis, otitis media, and Sjogren's syndrome, most studies have used oral adult doses of 75 to 180 milligrams/day in 2 or 3 divided doses (Diaz et al, 1984; Gaetani et al, 1987; Germouty & Jirou-Najou, 1987; Ericsson et al, 1986; Olivieri et al, 1987; Anon, 1989; Spatola et al, 1987; Passali & Zavattini, 1987; Manthorpe et al, 1984).
    7.2.2) PEDIATRIC
    A) ROUTE OF ADMINISTRATION
    1) INTRAVENOUS -
    a) In the treatment of hyaline membrane disease, ambroxol has been used in doses of 10 milligrams/kilogram twice a day for 7 days via intravenous infusion (Marini et al, 1987).
    2) ORAL -
    a) As a mucolytic, oral ambroxol has been given to children in doses of 1.5 to 2 milligrams/kilogram/day in 2 divided doses (Principi et al, 1986).

Minimum Lethal Exposure

    A) GENERAL/SUMMARY
    1) The minimum lethal human dose to this agent has not been delineated.

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) The maximum tolerated human exposure to this agent has not been delineated.

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) GENERAL
    a) THERAPEUTIC DRUG CONCENTRATION - After a single 30-milligram oral dose of ambroxol, the mean peak plasma concentration was 88.8 nanograms/milliliter (Couet et al, 1989).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (INTRAPERITONEAL)MOUSE:
    1) 268 mg/kg (Budavari, 1996)
    B) LD50- (ORAL)MOUSE:
    1) 2720 mg/kg (Budavari, 1996)
    C) LD50- (INTRAPERITONEAL)RAT:
    1) 380 mg/kg (Budavari, 1996)
    D) LD50- (ORAL)RAT:
    1) 13,400 mg/kg (Budavari, 1996)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Ambroxol is an active N-desmethyl metabolite of the mucolytic bromhexine (Mancuso & Berdondini, 1989).
    B) Although its mechanism of action has not been fully defined, it may increase the quantity and decrease the viscosity of tracheobronchial secretions (Mistretta et al, 1989). It may also act as an expectorant, increasing mucociliary transport via stimulation of ciliary motility (Disse, 1987; Curti & Genghini, 1989).
    C) Ambroxol may stimulate the synthesis and secretion of pulmonary surfactant (Disse, 1987) Ericsson et al, 1987); the drug has been referred to as a "surfactant activator" (Diaz et al, 1984).

Physicochemical

Physical Characteristics

    A) Ambroxol hydrochloride is a crystal when isolated from ethanol (Budavari, 1996).

Molecular Weight

    A) 378.11

References

General Bibliography

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    2) Anon: Prevention of chronic bronchitis exacerbations with ambroxol (mucosolvan retard): an open, long-term, multicenter study in 5,635 patients. Respiration 1989; 55(Suppl 1):84-96.
    3) Budavari S: The Merck Index, 12th ed, Merck & Company, Inc, Rahway, NJ, 1996.
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    8) Dagnone D, Matsui D, & Rieder MJ: Assessment of the palatability of vehicles for activated charcoal in pediatric volunteers. Pediatr Emerg Care 2002; 18:19-21.
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    10) Disse BG: The pharmacology of ambroxol-review and new results. Eur J Respir Dis 1987; 71(Suppl 153):255-262.
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    12) Ericsson EC, Juhasz J, & Jonsson E: Ambroxol therapy in simple chronic bronchitis: effects on subjective symptoms and ventilatory function. Eur J Respir Dis 1986; 69:248-255.
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