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AMBROXOL
DRUGDEX® Evaluations
OVERVIEW
1) Contraindications
a) Absolute contraindications and precautions to this agent have not been determined;
no information found at the time of this review
DOSING INFORMATION
Drug Properties
A) Information on specific products and dosage forms can be obtained by
referring to the Tradename List (Product Index)
B) Synonyms
Ambroxol
Adult Dosage
Normal Dosage
Intravenous route
1) For ATELECTACTIC PROPHYLAXIS a dose of 1 gram daily 3
days before and 2 days after the operation is recommended
[19]
; 1 gram daily for 6 days has also been used in surgical prophylaxis
[18]
.
2) 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
[13]
.
Oral route
1) 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 60 to 180 milligrams/day in 2 or 3 divided doses
[1]
[3]
[4]
[9]
[8]
[5]
[20]
; (Passali et al, 1987)
[16]
.
Pediatric Dosage
Normal Dosage
Intravenous route
1) The recommended daily mucolytic dose for children is 1.2 to 1.6
milligrams/kilogram
[19]
.
2) 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
[15]
.
Oral route
1) Recommended oral doses are as follows: children up to 2 years 15 milligrams (mg) daily; children ages 2 to 5 years - 15 to 30 mg
daily; children 5 to 12 years - 30 to 45 mg daily and children 12
years and older - 60 to 90 mg daily
[21]
.
2) As a mucolytic, oral ambroxol has been given to children in doses
of 1.5 to 2 milligrams/kilogram/day in 2 divided doses
[22]
.
PHARMACOKINETICS
Drug Concentration Levels
A) Time to Peak Concentration
1) Oral: approximately 2 hours
[26]
.
a) After a single 30-mg oral dose of AMBROXOL, the mean peak plasma
concentration was 88.8 ng/mL
[26]
.
ADME
Absorption
A) Bioavailability
1) ORAL: approximately 70% to 80%
[26]
.
a) AMBROXOL is rapidly absorbed after oral administration
[26]
.
Distribution
A) Distribution Kinetics
1) Distribution Half-Life
a) 1.3 hours
[26]
.
1) Elimination of AMBROXOL is biphasic, with an alpha half-life of 1.3
hours and a beta half-life of 8.8 hours
[26]
.
Metabolism
A) Metabolites
1) Dibromoanthranilic acid (activity unspecified)
[27]
.
Excretion
A) Kidney
1) Renal Clearance (rate)
a) approximately 53 mL/minute
[26]
.
1) Approximately 5% to 6% of a dose is excreted unchanged in the urine
[26]
.
Elimination Half-life
A) Parent Compound
1) ELIMINATION HALF-LIFE
a) 8.8 hours
[26]
.
1) Elimination of AMBROXOL is biphasic, with an alpha half-life of 1.3
hours and a beta half-life of 8.8 hours
[26]
.
CAUTIONS
Contraindications
A) Absolute contraindications and precautions to this agent have not been
determined; no information found at the time of this review
Precautions
A) Absolute contraindications and precautions to this agent have not been
determined; no information found at the time of this review
Adverse Reactions
Dermatologic Effects
Contact dermatitis
1) Summary
a) 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. Symptoms resolved promptly upon discontinuation of the
ambroxol solution. Subsequent patch testing was positive to
ambroxol, but not to the paraben preservatives used in the product
[25]
.
Dermatological finding
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.
Pruritus
1) Summary
a) Approximately 4% of patients taking ambroxol, 75 milligram per
day, developed itching
[24]
.
Rash
1) Summary
a) EXANTHEMA has been reported with therapeutic use
[25]
.
Urticaria
1) Summary
a) Urticaria has been reported with therapeutic use
[25]
.
2) EXANTHEMA has been reported with therapeutic use
[25]
.
Gastrointestinal Effects
Constipation
1) Summary
a) Constipation occurred in 2 of 63 patients receiving ambroxol 60 to
120 milligrams/day for bronchitis
[23]
.
Diarrhea
1) Summary
a) Approximately 3% of patients taking ambroxol, 75 milligrams per
day, subsequently developed diarrhea
[24]
.
Excessive salivation
1) Summary
a) Sialorrhea was observed in 3 of 63 patients receiving ambroxol
60 to 120 milligrams/day for bronchitis
[23]
.
Gastrointestinal tract finding
1) Dry mouth, diarrhea, constipation, nausea and vomiting, and
sialorrhea have all been reported with therapeutic use.
Nausea and vomiting
1) Summary
a) Approximately 13% of patients taking ambroxol 75 milligrams per
day subsequently developed nausea, and 2.6% experienced
vomiting
[24]
.
Xerostomia
1) Summary
a) DRY MOUTH and dryness of the airways were reported in 5 of 63
patients receiving ambroxol 60 to 120 milligrams/day for bronchitis
[23]
.
Neurologic Effects
Central nervous system finding
1) Fatigue was infrequently reported in patients receiving ambroxol
therapy.
Renal Effects
Dysuria
1) Summary
a) Dysuria occurred in 1 of 63 patients receiving ambroxol 120
milligram/day for bronchitis
[23]
.
Urogenital finding
1) Dysuria occurred infrequently with ambroxol therapy.
Respiratory Effects
Nasal discharge
1) Summary
a) Rhinorrhea was observed in 3 of 63 patients receiving ambroxol
60 to 120 mg/day for bronchitis
[23]
.
Respiratory finding
1) Rhinorrhea reported in patients with ambroxol therapy.
Other
Fatigue
1) Summary
a) Fatigue was reported in 1 of 63 patients receiving ambroxol 60 to
120 milligrams/day for bronchitis
[23]
.
CLINICAL APPLICATIONS
Monitoring Parameters
A) Therapeutic
1) Physical Findings
a) Patients should be monitored for symptomatic improvement.
Place In Therapy
A) The primary role of ambroxol in contemporary therapeutics is likely to be in
pulmonary medicine as an expectorant/mucolytic. Its main use will probably be in
the treatment of bronchitis and pulmonary infections to facilitate the removal of
secretions from the respiratory tract.
B) 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. Although initial
research has been encouraging, further study is needed to determine the role of
ambroxol in these disorders.
Mechanism of Action / Pharmacology
A) MECHANISM OF ACTION
1) Ambroxol is an active N-desmethyl metabolite of the mucolytic bromhexine.
Although its mechanism of action has not been fully defined, it may increase the
quantity and decrease the viscosity of tracheobronchial secretions. It may also act
as an expectorant, increasing mucociliary transport via stimulation of ciliary
motility
[28]
.
2) Ambroxol may stimulate the synthesis and secretion of pulmonary surfactant
[28]
[29]
; the drug has been referred to as a "surfactant activator"
[30]
.
3) The effects of ambroxol in preventing bronchial hyper-reactivity were
investigated
[31]
. Methacholine provocation doses were significantly higher (p less than 0.01) after
ambroxol treatment versus placebo. It was postulated that ambroxol decreased
airway hyper-reactivity by either increasing lysophosphatidyl-choline turnover
and/or modifying epithelial secretions.
4) Recent research attributes antioxidative characteristics to ambroxol. Ambroxol
has been demonstrated to be a direct scavenger of reactive oxygen metabolites.
In an in-vitro study using specimens from 46 healthy human volunteers, ambroxol
significantly reduced reactive oxygen species (ROS) produced by activated
human polymorphonuclear cells (PMN) after 1 hour (p less than 0.001); after 2
hours, the level was comparable to that of nonactivated PMN (p less than 0.001);
the reduction of mononuclear cells mimicked that of PMNs; reduction in the
prooxidative metabolism of inflammatory cells is another postulated mechanism of
action
[32]
.
B) REVIEW ARTICLES
1) A review of the animal pharmacology of ambroxol has been provided
[28]
.
2) One article reviewed the risks and benefits of antenatal prevention of hyaline
membrane disease for both the mother and infant, including ambroxol therapy
[33]
.
3) One author reviewed the alternatives to antenatal glucocorticoid administration
for the prophylaxis of hyaline membrane disease, including the use of ambroxol
[34]
.
Therapeutic Uses
Antineoplastic adverse reaction - Pulmonary toxicity
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence is inconclusive
Recommendation: Adult, Class III
Strength of Evidence: Adult, Category B
See Drug Consult reference:
RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
AMBROXOL has reduced pulmonary toxicity caused by some
antineoplastic agents
3) Adult:
a) AMBROXOL showed efficacy against lung injury induced by
NITROSOUREA and BLEOMYCIN in 24 patients undergoing
chemotherapy
[2]
. Patients received either AMBROXOL 30 milligrams or placebo every 8
hours from day 9 to day 45 of the intervals between courses of
chemotherapy. There were statistically significant decreases in pulmonary
function test parameters in patients receiving placebo; such deterioration
was not seen in patients receiving AMBROXOL. Although these results
were encouraging, more study was suggested to define the role of
AMBROXOL in chemotherapy-induced lung injury.
b) Another study demonstrated beneficial effects of AMBROXOL in the
prevention of pulmonary toxicity in patients receiving nitrosourea
antineoplastic drugs
[3]
. In this double-blind, placebo-controlled study, 40 patients with malignant
glioma were randomized to receive AMBROXOL 40 milligrams or placebo
orally 3 times a day for 40 days starting 10 days after therapeutic courses
of CARMUSTINE (BCNU). No cases of pulmonary fibrosis were seen in
either the group treated with AMBROXOL or the control group. However,
pulmonary function test parameters were significantly impaired in the
control group compared to the group treated with AMBROXOL.
Bronchiolar disease, Stasis
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence is inconclusive
Recommendation: Adult, Class III
Strength of Evidence: Adult, Category B
See Drug Consult reference:
RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
AMBROXOL may be helpful in patients with bronchial stasis
Doses of 120 milligrams/day were effective, but 30-milligram/day doses
were not
3) Adult:
a) A placebo-controlled trial found AMBROXOL to be efficacious in the
treatment of patients admitted to the hospital for bronchial stasis due to
acute or OBSTRUCTIVE AIRWAY DISEASE
[4]
. A total of 120 patients were evaluated; 30 patients received AMBROXOL
120 milligrams/day and 30 patients received placebo orally for 10 days.
AMBROXOL was shown to increase sputum volume, decrease sputum
viscosity, and reduce the severity of cough in all patients, while placebo
had no effect. The difference between groups was statistically significant (p
less than 0.05). In a subsequent trial, 30 milligrams/day AMBROXOL was
ineffective.
Bronchitis
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence is inconclusive
Recommendation: Adult, Class III
Strength of Evidence: Adult, Category B
See Drug Consult reference:
RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
AMBROXOL has been shown to be effective in ameliorating symptoms of
bronchitis in controlled studies
Doses of 75 to 120 illigrams/day were efficacious, but 60 milligrams/day
had little effect
Two small studies did not confirm statistically significant beneficial effects,
but the small size of these studies may have limited their ability to detect
differences
3) Adult:
a) AMBROXOL was effective and well-tolerated for the prophylaxis of
exacerbations of chronic bronchitis in an open, long-term multicenter study
[5]
. Prophylactic effects of AMBROXOL were assessed in 5635 patients with
chronic bronchitis. Patients received 75 milligrams oral AMBROXOL daily
for 6 months. After the first, third, and sixth months, the percentage of
patients who did not experience exacerbations of symptoms was 81.6%,
58%, and 44.9%, respectively. The number of patients without difficulty in
expectorating increased by 51.6% over basal values at 6 months.
Pathological auscultatory signs were judged as intense by 19.8 and 0.9%
of patients at the beginning and end of the study, respectively.
b) Other studies have failed to confirm the positive effects of AMBROXOL
on tracheobronchial clearance
[6]
or the ability to clear secretions in chronic bronchitics
[7]
. Both trials were limited in the ability to detect significant differences due to
small sample sizes.
c) AMBROXOL was effective for prophylaxis of acute exacerbations of
chronic bronchitis in 110 patients enrolled in a placebo-controlled, doubleblind study
[8]
. One hundred ten patients received AMBROXOL 75 milligrams/day in a
sustained-release dosage form and 104 received placebo for 6 months.
Initially, there were no differences between treatment groups. By the end of
the 2nd month of treatment, 67.2% of patients receiving AMBROXOL had
no exacerbations, compared to 50.3% in the placebo group. At the end of
the 6-month period, 45.5% of patients who received AMBROXOL had not
experienced exacerbations while only 14.4% of controls had not had
exacerbations. These differences were statistically significant (p less than
0.01). In addition, AMBROXOL produced statistically significant
symptomatic improvement compared to controls; symptoms measured
included severity of coughing, presence of dyspnea, difficulty of
expectoration, and auscultatory signs.
d) Positive effects were associated with use of AMBROXOL in patients
with early hypersecretory chronic bronchitis
[9]
. In a double-blind, randomized, placebo-controlled trial, 92 patients
received AMBROXOL 60 or 120 milligrams/day or placebo orally for 2
weeks. At the end of the treatment period, significantly more patients
treated with AMBROXOL 120 milligrams/day showed improvement in
symptoms, including cough, dyspnea, color and consistency of sputum,
and ease of expectoration, when compared to placebo (p less than 0.05).
AMBROXOL in doses of 60 milligrams/day had little effect. In addition,
pulmonary function tests showed no difference between any of the groups.
However, little or no airway obstruction was present, so no influence on
spirometry values was expected.
1) COMBINATION THERAPY
a) AMBROXOL combined with AMOXICILLIN was superior to
AMOXICILLIN alone in the treatment of acute exacerbations of chronic
bronchitis
[10]
. Twenty-three patients with clinical signs of bronchitis with concurrent
infection were randomized to receive either AMOXICILLIN 500 milligrams
(mg) 3 times a day (n=13) or AMOXICILLIN 500 mg 3 times a day plus
AMBROXOL 30 milligrams 3 times a day orally for 10 days (n=10).
Patients were evaluated according to severity of symptoms, ie, dyspnea,
difficulty in expectoration, and cough. Cough and ease of expectoration
improved in both groups, but improvement was greater and occurred
earlier in the group receiving AMOXICILLIN plus AMBROXOL (p less than
0.001). The daily sputum volume was increased in the group receiving both
drugs, but decreased in those receiving AMOXICILLIN alone. Before
treatment, all patients had purulent sputum (more than 50
neutrophils/microscopic field). On the third day of treatment, 7 patients in
the group receiving both drugs had non-purulent sputum (neutrophil counts
under 10/microscopic field); only 3 of those receiving AMOXICILLIN alone
had non-purulent sputum.
Chronic obstructive pulmonary disease
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Ineffective
Recommendation: Adult, Class III
Strength of Evidence: Adult, Category B
See Drug Consult reference:
RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
Long-term ambroxol therapy was not effective in the prevention of acute
exacerbations in patients with chronic obstructive pulmonary disease
(COPD)
Some benefit was seen in a subset of COPD patients with more severe
respiratory symptoms
3) Adult:
a) Overall, long-term ambroxol therapy was not effective in the prevention
of acute exacerbations in patients with chronic obstructive pulmonary
disease (COPD), however, some benefit was seen in a subset of COPD
patients with more severe respiratory symptoms. In a randomized, doubleblind, placebo-controlled, multicenter study, patients with COPD with a
clinical history of chronic bronchitis and with a forced expiratory volume in
one second (FEV-1) between 60% and 80% of predicted value received
oral ambroxol (retard formulation) 75 milligrams twice daily (n=115) or
placebo (n=119) for 12 months. A higher percentage of patients treated
with ambroxol as compared with placebo were exacerbation-free at 6
months (63% vs 59%, respectively) and at 12 months (56% vs 53%,
respectively), however the difference was not statistically significant (p=ns,
both values). In a subgroup analysis of patients with more severe
symptoms at baseline (overall symptom score of at least 5 of a possible
12), a significantly greater number of ambroxol-treated patients were
exacerbation-free at 12 months as compared with placebo (63%(15/24) vs
38%(8/21), respectively; p=0.038). Ambroxol treatment was well tolerated
throughout the study and was not associated with a greater risk of adverse
events than placebo
[11]
.
Otitis media
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence is inconclusive; Pediatric, Evidence is
inconclusive
Recommendation: Adult, Class III; Pediatric, Class III
Strength of Evidence: Adult, Category B; Pediatric, Category B
See Drug Consult reference:
RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
AMBROXOL may be beneficial in the treatment of otitis media based on
limited data
3) Adult:
a) AMBROXOL produced improvement of symptoms in 413 adult and
pediatric patients with SECRETORY OTITIS MEDIA in a multicenter,
placebo-controlled, double-blind trial (Passali et al, 1987). Patients were
randomized to receive oral AMBROXOL (30 milligrams 3 times a day in
adults; 9 milligrams 4 times a day in children) or placebo for 15 days.
Concurrent antibiotic therapy was allowed. At the end of the 15-day study
period, the group treated with AMBROXOL showed definite improvement.
In the ambroxol-treated group, patients reporting serious occlusion of the
ear dropped from 22.1% to 3.2% and those reporting a "fair" degree of
occlusion fell from 51.7% to 14.3%. With placebo, serious occlusion fell
from 13.8% to 5%, and fair occlusion fell from 59.2% to 24.3%. The
difference was statistically significant. Other parameters measured showed
no significant difference between groups except audiometry and overall
improvement, which were significantly improved over placebo at the end of
the study. AMBROXOL was of benefit in the treatment of secretory otitis
media.
4) Pediatric:
a) AMBROXOL produced improvement of symptoms in 413 adult and
pediatric patients with SECRETORY OTITIS MEDIA in a multicenter,
placebo-controlled, double-blind trial (Passali et al, 1987). Patients were
randomized to receive oral AMBROXOL (30 milligrams 3 times a day in
adults; 9 milligrams 4 times a day in children) or placebo for 15 days.
Concurrent antibiotic therapy was allowed. At the end of the 15-day study
period, the group treated with AMBROXOL showed definite improvement.
In the ambroxol-treated group, patients reporting serious occlusion of the
ear dropped from 22.1% to 3.2% and those reporting a "fair" degree of
occlusion fell from 51.7% to 14.3%. With placebo, serious occlusion fell
from 13.8% to 5%, and fair occlusion fell from 59.2% to 24.3%. The
difference was statistically significant. Other parameters measured showed
no significant difference between groups except audiometry and overall
improvement, which were significantly improved over placebo at the end of
the study. AMBROXOL was of benefit in the treatment of secretory otitis
media.
Pain in throat
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence favors efficacy
Recommendation: Adult, Class III
Strength of Evidence: Adult, Category B
See Drug Consult reference:
RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
In lozenges, relieved sore throat to greater degree than a mint lozenge
3) Adult:
a) Ambroxol hydrochloride-containing lozenges were more effective for
relieving the pain of sore throat than were similar lozenges that contained
no active drug. In a randomized, double-blind study, 215 subjects with
acute, uncomplicated sore throat of recent onset suspected of being of
viral cause were given mint-flavored lozenges containing either ambroxol
hydrochloride 20 milligrams or no active ingredient. Subjects were
instructed to suck up to 6 lozenges per day for 2 days. Pain scores were
recorded before the first lozenge and at 30 minutes, 60 minutes, 2 hours,
and 3 hours after the first lozenge. Both treatments led to a reduction in
pain intensity; the reduction was significantly more in the ambroxol
hydrochloride group (p=0.0058). By the end of 2 days, significantly more
subjects in the ambroxol group than in the placebo group scored the
treatment as good or very good (p=0.0035). Nine occurrences of adverse
events, including application site reactions, paraesthesias, dysphagia, dry
mouth, nausea, and coughing, were considered to be related to treatment
with ambroxol
[17]
.
Pulmonary alveolar proteinosis
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence is inconclusive
Recommendation: Adult, Class III
Strength of Evidence: Adult, Category C
See Drug Consult reference:
RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
AMBROXOL may be efficacious in the treatment of proteinosis, based on
limited data.
3) Adult:
a) AMBROXOL was used successfully in a 39-year-old patient with
alveolar proteinosis
[1]
. The patient had a 3-month history of dyspnea, fever, chest pain, cough,
and clubbing of the fingers. Serial alveolar lavage, the treatment of choice
for this condition, was refused. The patient was subsequently started on
AMBROXOL nebulizations and 30 milligrams orally every 6 hours.
Dyspnea decreased rapidly and clubbing of the fingers subsided promptly.
Six months later, chest x-ray, symptoms, and pulmonary function tests
showed dramatic resolution of the proteinosis. AMBROXOL appeared
effective in the treatment of this condition.
Respiratory distress syndrome in the newborn
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Pediatric, Evidence is inconclusive
Recommendation: Pediatric, Class III
Strength of Evidence: Pediatric, Category B
See Drug Consult reference:
RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
Limited data suggest that AMBROXOL may be beneficial for HYALINE
MEMBRANE DISEASE TREATMENT in premature neonates
3) Pediatric:
a) In preterm neonates with respiratory distress syndrome, early
AMBROXOL produced modest improvements in lung mechanics compared
with placebo-treated neonates, while no differences occurred in ventilatory
parameters, including tidal volume, respiratory frequency, and minute
ventilation. The duration of artificial ventilation was a median of 178 hours
in the ambroxol group compared with 246 hours in the placebo group (p
less than 0.05). After extubation, the ratio of tidal volume to maximal
esophageal pressure changes reached the tenth percentile on day 10 in
the ambroxol group compared with day 23 in the control group (p less than
0.05). During the first 5 days of life, each neonate randomly received saline
(n=50) or ambroxol 30 milligrams/kilogram/day (n=52) in this double-blind,
multi-center trial; ambroxol (concentration 15 milligrams (mg) in 2 mL
saline) was given in 4 divided doses of 7.5 mg/kg infused over 5 minutes
every 6 hours
[14]
.
b) AMBROXOL appeared to confer an advantage to neonates (birth weight
2000 g or less) with severe RESPIRATORY FAILURE due to IDIOPATHIC
RESPIRATORY DISTRESS SYNDROME (IRDS)
[15]
. In a double-blind, placebo-controlled, multicenter study, patients requiring
mechanical ventilation within the first 12 hours of life were randomized to
receive either AMBROXOL 10 milligrams/kilogram twice a day for 7 days
via intravenous infusion (n=13) or placebo (n=15). The mortality rate in the
group receiving AMBROXOL was 39%, compared with 53% in the
placebo-treated group. IRDS was the cause of death in 1 of 5 patients
(20%) receiving AMBROXOL, and in 6 of 8 (75%) receiving placebo. The
mean duration of mechanical ventilation was 270 hours in the treated
group versus 396 hours in the placebo-treated group. AMBROXOL used
as a "rescue" drug was of value in improving survival in premature infants
with severe respiratory distress syndrome. Although these initial results are
encouraging, more research is needed.
Respiratory distress syndrome in the newborn; Prophylaxis
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Pediatric, Evidence is inconclusive
Recommendation: Pediatric, Class III
Strength of Evidence: Pediatric, Category B
See Drug Consult reference:
RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
Mixed and inconsistent results have occurred with use of AMBROXOL for
HYALINE MEMBRANE DISEASE PROPHYLAXIS
One study reported lack of efficacy in the prevention of hyaline membrane
disease in neonates born between 24 and 34 weeks gestation
An earlier study indicated AMBROXOL was beneficial in deterring hyaline
membrane disease in premature infants of 33 to 36 weeks gestation, but
NOT in infants of less than 33 weeks gestation
3) Pediatric:
a) Antenatal AMBROXOL treatment was not effective in preventing
neonatal respiratory distress syndrome (RDS) or in reducing its severity as
measured by frequency of RDS, intermittent mandatory ventilation (IMV),
and oxygen therapy at 12 hours of age in a randomized, placebo-controlled
trial of 88 infants born between 24 to 34 weeks gestation. RDS was
observed in 55% of ambroxol-treated patients versus 65% of the placebo
group (p less than 0.318); mechanical ventilation for more than 12 hours
was necessary in 71% of the treated versus 72% of the placebo group (p
equals 0.974). Also, 74% of the treated and 75% of the placebo group
were oxygen dependent for more than 12 hours (p equals 0.992), and 31%
of the treated and 25% of the placebo group received natural surfactant (p
equals 0.75). No statistical difference could be demonstrated between the
two groups in overall RDS severity markers, such as initial and highest
mean airway pressure (MAP) and oxygen index, IMV, and oxygen therapy
duration
[12]
.
b) A double-blind, placebo-controlled trial found AMBROXOL to be
efficacious in some of 246 infants born to 224 mothers in premature labor
(28 to 36 weeks gestation)
[13]
. Each woman received 1000 milligrams AMBROXOL via intravenous
infusion daily for 5 days; this regimen was repeated in mothers who
ceased and subsequently reentered premature labor. Of the 246 births,
116 received AMBROXOL and 130 received placebo. A total of 116 infants
were born at 36 weeks gestation or less; 56 of these received
AMBROXOL, and 60 received placebo. Of the infants in the AMBROXOL
group, 23.2% developed hyaline membrane disease compared to 41.7% in
the placebo group. The difference was statistically significant (p less than
0.05). However, there was no difference between groups among those
born at 32 weeks or less. There was no difference in neonatal mortality
between groups. Nausea was reported in 5 mothers receiving AMBROXOL
and in 3 receiving placebo; all 8 had also received beta-adrenergic
tocolytics. Although AMBROXOL was of benefit in promoting lung
maturation and reducing the incidence of hyaline membrane disease, the
apparent lack of benefit in premature infants of less than 33 weeks
duration was not explainable. More research was recommended to assess
the role of AMBROXOL in the prevention of hyaline membrane disease.
Sjögren's syndrome
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Ineffective
Recommendation: Adult, Class III
Strength of Evidence: Adult, Category B
See Drug Consult reference:
RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
Although AMBROXOL produced no measurable effect on exocrine gland
function, some patients with Sjogren's syndrome reported symptom
improvement after use of this agent
More research is needed
3) Adult:
a) Researchers studied the effects of AMBROXOL in the treatment of the
exocrine gland insufficiency of Sjogren's syndrome
[16]
. In a double-blind, placebo-controlled, randomized cross-over trial, 36
patients with keratoconjunctivitis sicca and xerostomia received either
AMBROXOL 60 milligrams or placebo orally twice a day for 3 weeks and
were crossed over after a 1 week washout period. No demonstrable effect
on salivary or tear secretion was observed. However, several patients
reported subjective improvement with AMBROXOL, especially with
symptoms of xerostomia. AMBROXOL may be of benefit in primary
Sjogren's syndrome, despite the lack of objective evidence of efficacy.
Surgical procedure on thorax; Prophylaxis
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence is inconclusive
Recommendation: Adult, Class III
Strength of Evidence: Adult, Category B
See Drug Consult reference:
RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
AMBROXOL used prior to, during, and after thoracic surgery may result in
favorable post-operative effects
3) Adult:
a) One study suggested that perioperative AMBROXOL had positive
effects related to postoperative morbidity in patients hospitalized for chest
surgery
[18]
. In a double-blind, placebo-controlled trial, 40 patients received either
AMBROXOL 1 gram or placebo via intravenous infusion 3 days prior to
surgery, on the day of surgery, and for 5 days postoperatively. They found
that postoperative recovery of normal pulmonary surfactant levels was
faster in patients who received AMBROXOL as measured by surface
tension of bronchoalveolar lavage fluid. Better oxygenation, as measured
via arterial blood gases, and re-expansion of residual lung tissue
demonstrated by chest x-ray were also observed in the group treated with
AMBROXOL. Patients receiving AMBROXOL also had a better sputum
quality with easier expectoration and reduced intensity of cough.
AMBROXOL stimulated surfactant production and appeared to improve the
overall clinical picture of patients in this setting.
Comparative Efficacy / Evaluation With Other Therapies
Acetylcysteine
Cystic fibrosis
a) A clinical trial compared the efficacy of oral ambroxol and Nacetylcysteine as a mucolytic in 36 pediatric patients with cystic
fibrosis
[38]
. Patients were randomized to receive either ambroxol 30 milligrams
(mg), N-acetylcysteine 200 mg, or placebo 3 times a day for 12
weeks. Thirty-two patients completed the study. All changes in
pulmonary function test parameters were below the statistical
detection limit (p greater than 0.05); no significant clinical
differences were found between the 3 groups. Significant
impairment was noted in the placebo group, but was felt to be
coincidental. None of the patients' parents reported improvement
and 66% of the total felt that their child had received placebo. A
therapeutic effect with either drug was not demonstrated, thus more
study is needed.
Betamethasone
Respiratory distress syndrome in the newborn
a) Betamethasone and ambroxol were compared for the prevention
of respiratory distress syndrome (RDS; hyaline membrane disease)
of prematurity
[37]
. In a randomized multicenter trial, women at 27 to 34 weeks
gestation with threatened or planned premature labor received
either betamethasone phosphate 6 mg with betamethasone acetate
intramuscularly, repeated 24 hours later, or ambroxol either 1
gram/day intravenously for 5 days or 1 gram every 12 hours for a
total of 4 doses. Of 169 evaluable neonates born before the 37th
week of gestation, 86 received betamethasone and 83 received
ambroxol. All patients in the betamethasone group received a full
course of treatment, but 14 patients in the ambroxol group received
an incomplete course due to the onset of labor. The overall
incidence of RDS was 31% in the betamethasone group and 13% in
the ambroxol group. The difference was statistically significant.
Nausea and headache were noted in approximately 10% of the
mothers who received ambroxol. Ambroxol was well tolerated and
was at least as effective as steroids for the in utero prevention of
hyaline membrane disease.
Carbocysteine
Chronic obstructive pulmonary disease, Reversible
a) Ambroxol and cineol were clinically equivalent and significant
when compared to placebo in improving lung function in a crossover, randomized, double-blind 4-day trial with 23 evaluable patients
with chronic obstructive pulmonary disease; a statistically significant
increase of ciliary frequency of 8.2% (p less than 0.001) and
decrease in saccharine-time by 241 seconds (p value no
available)was only seen with Cineol. Forced vital capacity (FVC)
rose by 5.5% following ambroxol and 5.3% after cineol treatment (p
less than 0.01 compared to initial measurements) and forced
expiratory volume in 1 second (FEV1) increased by 4.8% and 4.2%
following ambroxol and cineol treatments, respectively (p less than
0.05 compared to initial values); peak-flow values rose by 7.2% and
9.1%, respectively but were only clinically significant for cineol (p
less than 0.05); cough scores did not improve significantly with any
treatment. Adverse reactions were rare with a gastrointestinal
complaint reported in all three treatment groups (ambroxol, cineol,
placebo)
[36]
.
Cystic fibrosis
a) Carbocysteine showed similar improvement in symptoms,
respiratory functions and expectorate properties (viscosity and
elasticity) as compared with ambroxol in patients with cystic fibrosis.
In a randomized, single-blind trial twenty-six patients, 8 to 40-yearsold, were treated for 80 consecutive days with a S-carboxymethyl-Lcysteine (SCMC-Lys) or an ambroxol syrup. In the SCMC-Lys
group, children under 14 years received 270 milligrams (mg) three
times a day, whereas adults received 900 mg three times a day; in
the ambroxol group, dosages were 10 mg four times a day and 33
mg three times a day, respectively. With SCMC-Lys improvement in
cough and chest sounds scores was better than with ambroxol,
whereas dyspnea and tachypnea did not improve with respect to
baseline. Respiratory function test showed similar results in both
groups. Viscosity and elasticity of the expectorate decreased and
amount increased during both treatments, without any significant
difference between the groups. Carbocysteine lysine salt (SCMCLys) showed the same effect as ambroxol in the respiratory
impairment associated with cystic fibrosis
[35]
.
Erdosteine
Bronchitis, chronic
a) In a double-blind trial of 29 patients with exacerbated chronic
bronchitis receiving treatment for 7 days, erdosteine 300 milligrams
(mg) twice daily reduced sputum adhesiveness from baseline by
89%, versus 60% reduction with ambroxol 30 mg twice daily. Both
regimens produced significant, comparable reductions in severity of
cough and sputum purulence, compared to baseline
[39]
.
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Last Modified: November 21, 2008
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