Increased fluids to ease expectoration are usually recommended for first line treatment in the mother. If use of guaifenesin is necessary, it is best to avoid the use of guaifenesin products with a high alcohol content; check product ingredients. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition.
If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA. There are no particular precautions for the use of guaifenesin in the ambulatory, non-debilitated geriatric patient compared to use in younger adults.
According to the OBRA guidelines, cough, cold, and allergy medications should be used only for a limited duration less than 14 days unless there is documented evidence of enduring symptoms that cannot otherwise be alleviated and for which a cause cannot be identified and corrected.
Guaifenesin loosens and thins phlegm and bronchial secretions to ease expectoration. By reducing the viscosity and adhesiveness of secretions, guaifenesin increases the efficacy of the mucociliary mechanism in removing accumulated secretions from the upper and lower airway. The increased flow of less viscous secretions promotes ciliary action and changes a dry, unproductive cough to one that is more productive and less frequent. Despite its long history of use since the 's, the efficacy of guaifenesin has only recently been substantiated.
The results of a few studies have favored active treatment with guaifenesin over placebo in treating productive cough due to upper respiratory illness URI. Guaifenesin is administered orally. The plasma half-life is approximately 1 hour. No unchanged drug was detected in the urine following administration. Renal stones that developed during drug therapy have been documented to contain beta- 2-methoxyphenoxy -lactic acid and other guaifenesin metabolites.
Other pharmacokinetic parameters of guaifenesin are not known. Guaifenesin is rapidly and well absorbed from the gastrointestinal tract. Extended release products e. Guaifenesin has a plasma half-life of approximately 1 hour. PDR Search. Required field. Your Name Your name is required. Recipient's Email Separate multiple email address with a comma Please enter valid email address Recipient's email is required. Thank you. Your email has been sent.
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Animal studies showed that guaifenesin is generally well absorbed and has an established pharmacokinetic profile. The time to reach C max T max in rats was faster when given as an oral bolus 27 min than with gastric, jejunal or cecal infusions min [ 18 ].
Guaifenesin is well absorbed from the human GI tract. Following a single oral dose of guaifenesin in pediatric subjects, C max was reached in approximately 0. In adult subjects, C max was achieved in 1. Once absorbed, guaifenesin is efficiently metabolized and subsequently excreted in the urine. Guaifenesin is not known to interfere with the cytochrome P CYP system, nor is it an inhibitor or inducer of this system. Guaifenesin appears to undergo both oxidation and demethylation.
O-demethylase seems to be the main enzyme for the metabolism of GGE [ 22 , 23 ]. The major metabolites of guaifenesin both inactive are betamethoxyphenoxy-lactic acid [ 21 , 25 ] and hydroxy-guaifenesin [ 22 ]. To date, several mechanisms of action have been described for guaifenesin.
It has been postulated that guaifenesin exerts its expectorant activity via a neurogenic mechanism: a stimulation of vagal afferent nerves in the gastric mucosa activates the gastro-pulmonary reflex, and increases the hydration of airway mucus [ 26 , 27 ].
In support of this hypothesis, a study in rats demonstrated that oral but not intravenous guaifenesin administration increased respiratory secretions [ 18 ]. The viscoelastic behavior of bronchial mucus has important consequences for mucociliary clearance. This mucus is an adhesive, viscoelastic gel, the biophysical properties of which are largely determined by entanglements of long polymeric gel-forming mucins: MUC5AC expressed in goblet cells and MUC5B originating from submucosal glands [ 11 ].
Inflammatory airway diseases and infections cause mucus including mucin glycoproteins overproduction and hypersecretion from metaplastic and hyperplastic goblet cells which contributes to mucus obstruction of airways [ 6 ]. Medications that decrease viscoelasticity, such as certain mucolytics, may benefit ciliary clearance. Recent in vitro studies using differentiated human airway epithelial cells, grown at an air-liquid interface to mimic physiological conditions in the respiratory tract, revealed direct effects of guaifenesin on the airway epithelium [ 13 , 28 ].
At clinically relevant doses, guaifenesin was found to significantly decrease mucin MUC5AC production, mucus viscosity and elasticity, and to enhance MCC [ 13 ]. These results were replicated in another study on airway epithelial cells pre-treated with an inflammatory mediator, IL, to increase secretions prior to treatment with guaifenesin, N-acetylcysteine, or ambroxol [ 28 ].
Guaifenesin was more effective than N-acetylcysteine or ambroxol at increasing MCC rates, inhibiting mucin secretion, and improving mucus rheology. Figure 1 shows some of these putative mechanisms of action Fig. Additional in vivo pharmacology and clinical studies will be needed to further elucidate these findings and determine how these mechanisms can be most effectively recruited to produce clinically relevant effects in the target populations. Putative effects of guaifenesin on mucus in chronic or acute hypersecretory respiratory conditions.
The mucociliary complex can be subdivided into two layers — an upper mucus gel layer containing MUC5AC and MUC5B mucins, and a lower layer of periciliary fluid containing cell surface-tethered mucins. Mucociliary clearance MCC is effected by the rhythmic sweeping motion of cilia. Prolonged exposure to irritants such as cigarette smoke or allergens can lead to overproduction and hypersecretion of mucus. Guaifenesin has been postulated to promote mucociliary clearance via a number of mechanisms.
Guaifenesin also affects secretion from goblet and Clara cells red stars , resulting in 2 decreased mucin production and secretion green circles, goblet cells; blue squares, Clara cells , and 3 reduced viscoelasticity of mucus, which increases the ability of ciliary movement to remove mucus.
Together these changes serve to enhance MCC and mucus clearance. Panels b-d adapted from Seagrave et al. Studies in patients with chronic bronchitis demonstrated that guaifenesin increases MCC [ 29 ] and reduces sputum viscosity [ 30 ]. Bennett and coworkers compared the effects of guaifenesin and placebo on in vivo MCC by measuring the rate of removal of inhaled radioactive tracer particles from the lungs of healthy, non-smoking adults.
A study in healthy volunteers with a history of sinus disease did not detect significant differences between guaifenesin and placebo treatment in terms of their effects on in vivo nasal MCC [ 33 ]. Guaifenesin has been shown to make coughs more productive [ 34 ], and additionally has been found to inhibit cough reflex sensitivity in subjects with acute URTIs [ 15 , 16 ]. Guaifenesin significantly reduced cough reflex sensitivity in patients with viral URTIs [ 15 , 16 ], but not in healthy volunteers.
The authors suggested that this effect was limited to patients with URTIs due to their transiently increased cough receptor sensitivity. Details of clinical studies mentioned in this section are in Table 3. Despite the large number of clinical studies on different clinical aspects of guaifenesin therapy, its expectorant indication is currently the only one that the FDA considers to be supported by sufficient medical evidence.
The Monograph indication for guaifenesin is limited to symptomatic treatment of acute URTIs and stable chronic bronchitis [ 3 ]. The FDA approved labels for guaifenesin include an OTC label for its use in the treatment of chest congestion associated with an URTI but also a professional label for chest congestion associated with stable chronic bronchitis for its detailing to healthcare professionals.
This professional label indication mirrors the outcome of clinical studies conducted on chronic bronchitis patients.
The exact wording of the indications is listed below:. A review of the literature supporting the clinical utility of guaifenesin shows effects across three categories of respiratory conditions: chronic bronchitis and chronic respiratory conditions Table 4 , URTIs Table 5 , and rhinosinusitis Table 6.
Almost all studies discussed here were conducted in adults, with the exception of one published study in children on the use of guaifenesin for relieving cough symptoms [ 35 ]. It should be noted that stable chronic respiratory conditions, such as chronic bronchitis, have proved more reliable as clinical models for studying the effects of expectorants and other mucoactive drugs.
Mucus production and associated cough symptoms tend to be more stable in chronic respiratory conditions, allowing the effects of guaifenesin to be observed more consistently. The inclusion of guaifenesin in the Final OTC Monograph was essentially supported by four clinical studies in patients with chronic bronchitis [ 36 — 39 ].
All of these definitive studies demonstrated statistically superior efficacy of guaifenesin versus controls in improving ease of expectoration, decrease in sputum surface tension and viscosity, or reduction in the frequency and severity of cough Table 4. Although results for cough assessments in patients with chronic bronchopulmonary disease were mixed, guaifenesin-treated patients reported increased sputum volume compared with placebo, as well as greater ease of expectoration [ 41 ].
These findings are consistent with an earlier study on objective sputum changes in patients with chronic bronchitis; guaifenesin was found to significantly decrease sputum adhesiveness and quantity dry weight , and was also reported to improve expectoration [ 30 ].
The efficacy of guaifenesin as an expectorant has also been examined in the context of acute URTIs Table 5. In adults with acute URTIs, guaifenesin significantly reduced sputum thickness and quantity compared to placebo [ 41 ]. A large placebo-controlled pilot study explored a range of objective and subjective outcome measures in patients with acute URTIs.
The most promising measures included a daily diary for patient-reported outcome PRO parameters. These described symptoms such as severity of chest congestion, mucus thickness and cough. Some of these 11 exploratory parameters showed strong trends or statistically significant differences between guaifenesin and placebo. A PRO validation process served to qualify more focused subsets of 4 and 8 questions. To explore effects on sputum as objective endpoints, laboratory analyses were performed on patient mucus samples from the pilot study.
The laboratory analyses could not demonstrate differences in mucus properties with guaifenesin compared to placebo; however, it should be noted that methodological issues with mucus sample collection and shipping were present, raising some questions about the interpretation of the laboratory results [ 44 ].
Guaifenesin was reported to be effective for improving symptomatic rhinitis and sinusitis by decreasing nasal congestion and postnasal discharge in immunocompromised HIV positive patients [ 45 , 46 ]. Despite some conflicting data available, some patients with rhinitis benefit from using guaifenesin [ 12 ]. As a single agent, guaifenesin has a well-established and favorable safety and tolerability profile.
Its safety record is supported by data from published clinical studies and a history of post-marketing surveillance safety reports covering more than 50 years in the US and around the world. Common side effects reported for the drug include dizziness, headache, and gastrointestinal disturbances at high doses [ 17 ].
Guaifenesin had the lowest frequency of mentions for non-fatal AEs by system organ class SOC at estimated supra-therapeutic and even at estimated unknown dosing; and the second lowest frequency of mentions for non-fatal AEs by SOC at estimated therapeutic dosing.
The few published reports of serious adverse events related to the use of guaifenesin have mostly been in the context of overdose and use as part of multiple-drug combinations for various cough and cold indications. Published reports include renal stone formation with chronic guaifenesin overdose [ 49 ], and acute fatal intoxication by a combination of guaifenesin, diphenhydramine, and chlorpheniramine, although the relative contribution of guaifenesin to the fatality could not be determined [ 50 ].
Pregnancy category C status for GGE was determined by the FDA based on the absence of definitive studies assessing potential risks to the fetus [ 3 , 51 ]. Results of a recently published study in female, pregnant rats, after testing very high doses of guaifenesin, suggest that the risk of fetal abnormalities cannot be ruled out [ 52 ]. The medical literature and safety databases do not show meaningful signals suggesting a significant risk of fetal development issues after pregnant women used guaifenesin.
Thus, caution regarding the use of GGE in pregnant women is warranted [ 51 ]. Immediate-release IR and extended-release ER guaifenesin are available in single-agent formulations Table 7. There are also many popular guaifenesin-containing combination OTC and prescription products available on the market, but these are outside the scope of this article. The dual dosing range of guaifenesin in the US allows patients the flexibility to titrate doses to achieve optimal efficacy.
In the US, adults and children above 12 years old may take guaifenesin in oral doses of to mg every 4 h, up to a maximum of mg over 24 h [ 17 ]. Pediatric doses cater to children aged 2—12 years, and differ according to age groups, i. In Canada, guaifenesin is not recommended for children aged 12 years and below.
Dosing regimens and daily maximum doses for adults and children above 12 years old in Canada daily dose of mg maximum also differ from those in the US [ 53 ]. Examples of currently available over-the-counter guaifenesin formulations and recommended doses in the US and Canada. Because of guaifenesin short half-life, frequent dosing with IR guaifenesin is required to maintain therapeutic levels of the drug in the body Fig.
Subsequently h extended release form of guaifenesin were designed to provide bioequivalent pharmacokinetic characteristics to generic IR guaifenesin products [ 20 ] and are currently approved as h tablet ER guaifenesin formulation in the US market. An example of such ER products is a bi-layer tablet formulation containing mg of guaifenesin and comprising an IR layer that allows rapid release of guaifenesin to achieve an early C max , and an ER layer that allows sustained release of guaifenesin to produce a steady plasma concentration over a h period Fig.
Following approval of this extended release form of guaifenesin NDA in , the FDA required the removal of all marketed, but unapproved, timed-release guaifenesin products from the market by Schematic pharmacokinetic profile of extended-release ER vs immediate-release IR guaifenesin formulations.
Extended-release ER guaifenesin blue line attained bioequivalent plasma concentrations to those obtained with 3 immediate-release IR guaifenesin doses orange line. The unique bi-layer tablet formulation comprises an IR layer that permits immediate release of guaifenesin to rapidly attain maximum plasma concentrations C max , and an ER layer that permits sustained release of guaifenesin to maintain prolonged blood plasma levels of guaifenesin over 12 h.
Figure adapted from Vilson and Owen, [ 20 ]. This review provides an updated and comprehensive perspective on the use of guaifenesin in treating respiratory disorders in which excessive mucus is an important clinical feature.
Excessive mucus secretion and local accumulation in the airway occurs in both acute URTIs and chronic respiratory disorders with an underlying inflammatory etiology such as chronic bronchitis and COPD.
The expectorant properties of guaifenesin, which help to thin bronchial secretions and promote mucus clearance, were demonstrated in studies involving patients with chronic bronchitis or other chronic respiratory conditions. Studies in symptomatic chest congestion and acute cough, as well as in acute rhino-sinusitis indications, have yielded mixed results.
This may be understandable, given the context of rapidly changing symptoms in acute URTIs, which are challenging to study under standard clinical trial conditions. Some studies showed evidence of efficacy based on improvements in subjective measures as patients assessed their cough, mucus clearance, or chest congestion symptoms.
However, in many cases the methods were not validated or results were not confirmed by subsequent studies. For this reason, the effects of guaifenesin have been more consistently demonstrated in stable chronic respiratory disease models. Further research is needed to clarify the antitussive effectiveness of guaifenesin and its ability to relieve chest congestion in acute URTIs in children and adults, and the utility of the drug in improving symptoms of rhino-sinusitis.
To date, the approved indications for guaifenesin have not changed from those included in the Final Monograph. Interestingly, the secondary indication for stable chronic bronchitis remains largely underutilized or unrecognized even among US medical professionals. A large body of AE reporting data supports the safety of guaifenesin for adult and pediatric use.
Well-established as a safe expectorant drug, guaifenesin has achieved common usage for the relief of mucus-related symptoms of acute URTIs and for patients with mucus-related symptoms in the context of stable chronic bronchitis.
Additional, up-to-date, and high-quality data are needed to explore the full potential of this compound in established uses, and in new respiratory indications associated with mucus hypersecretion.
The authors would like to thank the subjects, clinicians, and scientists who participated in the design, conduct, and analysis of the studies described in this review paper.
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