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CLINICAL REVIEW

CLINICAL REVIEW

According to documentation provided by Bionorica, the manufacturer, from inception of Sinupret to January 2002, the efficacy of Sinupret has been evaluated in 5 placebo-controlled studies, 7 comparative trials, and 1 post-marketing surveillance study. Since then, 2 systematic reviews of clinical trials, numerous abstracts, and several other studies have been published. Most of the scientific literature is published in German. This monograph reviews all of the studies that have been published in English or translated into English from inception to October 2008.

The studies reviewed here include a total of 4 clinical trials on the efficacy of Sinupret preparations for treating acute sinusitis. One study was in children and only 2 of the 4 studies have been published in their entirety in English (the other two were abstracts from conference proceedings). The studies reviewed here also include 2 clinical trials evaluating the efficacy of Sinupret for treating chronic sinusitis. Only one of these trials has been published in a peer-reviewed journal, the other is an abstract from a conference proceeding. One meta-analysis evaluating Sinupret for the treatment of sinusitis has also been included in the clinical review. The meta-analysis is interesting from the perspective that it includes 4 clinical trials, three of which are unpublished reports that have not been translated into English and as a consequence have not been reviewed in this monograph. The efficacy of Sinupret for treating bronchitis is reviewed in 2 clinical trials; unfortunately, these reviews are based solely on data presented at conference proceedings; peer-reviewed publications were not available in English. A post-marketing surveillance study of patients with bronchitis is also reviewed.

A systematic review of various botanical products used for acute or chronic sinusitis identified 4 randomized controlled trials on Sinupret.44 The authors conclude, “There is some evidence that Sinupret and bromelain [an enzyme from pineapple (Ananas comosus, Anonaceae)] may be effective adjunctive treatments in acute rhinosinusitis.”

Acute Sinusitis

Neubauer & Marz, 1994.45 A randomized, placebo-controlled, double-blind trial was conducted in men (mean age: 24.5 years) with acute bacterial sinusitis who were receiving antimicrobial (Vibramycin, Pfizer, United States) and decongestant (Otriven, Novartis, Germany) therapy. The purpose was to determine whether the response rates could be improved by adding Sinupret to the therapeutic regimen. Patients were treated 3 times per day with 2 Sinupret Sugar Coated tablets (n = 81) or placebo (n = 79) for 2 weeks in addition to the standard pharmaceutical therapy. Patients were randomized to treatment groups via a computer generated sequence. The primary outcome measure was sinus radiographic findings (rated as completely opaque, shadowed, or nothing abnormal). Entry criteria ensured that all patients had opaque sinus radiograms at baseline. Compared with placebo-treated patients, significantly more patients in the Sinupret group had improvements from baseline on their radiograms (p = 0.008). Changes in clinical signs showed good correlation with the radiographic findings, with significantly more Sinupret-treated patients having improvement in mucosal swelling, nasal obstruction, and headache (p-value not provided). According to the patient assessment, significantly more Sinupret-treated patients found treatment favorable than placebo-treatment (p < 0.001). Tolerability (i.e., safety profile) was good. There were no drug-herb interactions. The authors conclude that Sinupret can enhance basic (i.e., conventional drug) therapy.45

The authors’ conclusions, however, appear to be too broad. Rather than concluding that Sinupret can enhance basic therapy, the evidence from this trial suggests that the authors should have concluded that Sinupret can enhance the specific therapy evaluated in the study. That is, a more accurate conclusion would be that Sinupret enhances Vibramycin and Otriven treatment of acute sinusitis, or that Sinupret appears to act as an adjunct with Vibramycin and Otriven.

Biebach & Kramer, 2004.46 The efficacy and safety of Sinupret was evaluated in children (n = 3109) with acute sinusitis. Girls and boys (n = 1638 girls; n = 1471 boys; mean age 6.9 years) with typical symptoms of sinusitis participated in this open-label, multicenter study conducted at 967 medical practices in Germany. The dosage of Sinupret drops varied with the patients’ age. Two-thirds (64%) of the children received an average of 20 Sinupret drops 3 times per day. The number of drops was slightly reduced over the course of the study; specific details were not reported. In lieu of the drops, 10% of the children aged 2-6 years received 1 Sinupret Sugar Coated tablet 3 times per day and 26% children aged 7-12 years received 1 Sinupret Sugar Coated tablet 3 times per day. The authors did not report the duration of treatment. At baseline the most frequently documented symptoms were “much” and “viscous” nasopharyngeal discharge, impaired nasal breathing, and “moderately severe” cough. At the final check-up (average of 12 days after entering the study), 93% of the patients reported “little” nasal discharge or no discharge and 90% of the cases reported the discharge as “thin” and “clear.” At study end only 0.3% of the children reported severe impairment of nasal breathing and 75% had no cough. The effects of the 2 dosage forms were similar in children 7-12 years old. However, in the children 2-6 years old the Sugar Coated tablets were slightly superior to the drops in treating stuffy nose and cough, while the drops were more effective at improving facial pain and headache. Most of the physicians (88%) judged Sinupret to be “very good” or “good.” Approximately 74% of the patients were treated with concomitant medications, including rhinological agents and/or antibiotics. There were 25 AEs (0.8%), all classified as not severe and self-limiting. Most of the AEs were gastrointestinal complaints and skin reactions. The investigators attributed 50% of the AEs to the concomitant medications. The authors concluded that the study documents the efficacy and tolerability of Sinupret in children.46

A limitation of this study was that there was no placebo group or no untreated control group. Acute rhinitis is often a self-limiting disease,46 so a control group is necessary to prove efficacy. Without a control group there is no way to know definitively if Sinupret was producing an effect. Another limitation of the study was the flexible dosing and no report of the treatment duration, and a large percentage of the patients were taking concomitant cold/flu medication. Nevertheless, one conclusion from this trial is the high degree of safety of Sinupret, particularly since half of the AEs were observed in patients taking concomitant pharmaceutical preparations.

Kraus & Schwender, 1992.47 A randomized, open-label, comparative study was conducted in patients at the Germany Army Hospital (Bundeswehrkrankenhaus) in Amberg, Germany. The patients (n = 134), who had radiologically certified acute sinusitis, were treated for 3 weeks with Sinupret Sugar Coated tablets (dose not reported) or GeloMyrtol® Forte (Gelomytrol, Germany); a mucolytic agent containing volatile oils of myrtle (Myrica gale, Myricaceae), lime (Citrus spp., Rutaceae; species unreported), pine (Pinus spp., Pinaceae, species unreported), and eucalyptus (Eucalyptus spp., Myrtaceae; species unreported). After 3 weeks of treatment the percent of improvement was equivalent between the treatments, with 49% of patients in both groups classified as having “nothing abnormal detected” or “improved.” Note that this review lacks some details because it is from an abstract presented at an international conference.47 A peer-reviewed manuscript was not available.

A limitation of the study was that there was no untreated or placebo control group. It is unclear whether the 49% of patients who improved at 3 weeks responded to therapy or if the sinusitis resolved spontaneously.

Braum & Marz, 1990.48 A randomized, open-label, comparative study was conducted in patients at the Germany Army Hospital (Bundeswehrkrankenhaus) in Amberg, Germany. The patients (n = 114), who had x-ray proven acute sinusitis, were treated for 21 days with Sinupret Sugar Coated tablets (2 tablets, 3 times per day) or N-acetylcysteine (manufacturer identity not reported; 200 mg, 3 times per day). Concomitant medication was permitted. After 21 days of treatment, as determined by x-ray, 12.3% (7/57) of Sinupret-treated patients improved and 56.1% (32/57) were without pathologic findings, which was similar to 13.7% (7/51) of N-acetylcysteine–treated patients who improved and 43.1% (22/51) who were without pathologic findings. Approximately 85% of the Sinupret-treated patients and 86.8% of N-acetylcysteine–treated patients reported that they were “improved” or “cured.” The authors concluded that Sinupret was at least as effective as N-acetylcysteine. Note that this review lacks some details because it is from an internal report abstract.48 A peer-reviewed manuscript was not available.

This study is limited by the need for an untreated or placebo control group. Also, the researchers permitted the use of concomitant medications, which could affect the outcome. The abstract did not detail the use of concomitant medications.

Melzer J et al, 2006.49 A systematic review identified 2 placebo-controlled trials with almost identical design that could be examined by meta-analysis.45,50 These trials were considered to be “key” trials. In both of these studies Sinupret was used as an adjunct to standard care of acute and chronic sinusitis. Nearly all of the participants (98-99%) were treated with antibiotics and decongestants. The studies included a predominantly male population of young adults (mean ≤ 29 years old). Patients received placebo (n = 160) or Sinupret (n = 159, 2 Sugar Coated tablets 3 times per day45 or 50 drops 3 times per day50) for 14 days. The pooled analysis showed that the patients’ global assessment was that Sinupret was significantly better than placebo (p < 0.001). Compared with placebo, Sinupret had significantly better rates of absence of any symptom (p < 0.05, 39% vs 51%, respectively) or objective sign (p < 0.05, 24% vs. 36%, respectively).49 Sinupret was significantly better in reducing drain obstruction (p < 0.01) and headache (p < 0.05) compared with placebo. When the analysis was restricted to patients with acute sinusitis the results were similar to the total study population, with Sinupret producing a significantly better “cure” and “improvement” rate then placebo (p < 0.001). A multiple stepwise regression analysis confirmed that there was a highly significant difference between treatments (p-value not reported).49 Sinupret was well tolerated and had an incidence of AEs that was comparable to placebo.

In the same systematic review, Melzer J et al49 also identified 2 comparative trials with almost identical design that could be examined by meta-analysis.51,52 These trials were likewise considered to be “key” trials. The studies included only men, with a mean age of 23 years in one study52 and 40 years in the other study.51 Patients with sinusitis received ambroxol (n = 150, 100 drops 3 times per day) or Sinupret (n = 151, 50 drops 3 times per day) for 14 days. Antibiotics were co-prescribed in 12% of the Sinupret-treated patients and 15% of the ambroxol-treated patients, and 75% of both groups were treated with decongestants. The primary efficacy variable was the patients’ global assessment. There was no significant difference in the percent of Sinupret- or ambroxol-treated patients who were rated as “cured” or “improved.” Likewise, when only the patients with acute sinusitis were analyzed, there was no significant difference in the global assessment. When looking at the secondary variables (symptoms), pyorrhea (pus discharge) and headache were more frequently improved with Sinupret (p < 0.05).49 A multiple stepwise regression analysis confirmed that there was no significant difference between treatments.49

Three of the studies compared by Melzer J et al (described above) are not individually reviewed in this monograph because they are unpublished reports that have not been translated into English. One is a double-blind, placebo-controlled trial on patients with acute sinusitis by Berghorn et al (1990)50 and two are double-blind clinical trials published in 1990 by Simm & Pape51 and in 1992 by Wahls52 that compared Sinupret against a nasal drop in cases of acute sinusitis.

Acute Sinusitis Summary

Aside from the one pediatric study, it is unusual that all of the studies included mostly men. There are no known gender differences in the incidence, clinical presentation, or clinical course of sinusitis.49 Nonetheless, it might be preferable if the studies evaluated the general population and not just men. Based on the results of 1 placebo-controlled study and the meta-analysis of 2 placebo-controlled trials it appears that Sinupret is effective at augmenting the effects of standard pharmaceutical therapy. A small meta-analysis revealed that Sinupret is as effective as ambroxol. Additional studies are needed to confirm the findings, and placebo or untreated control studies are needed to determine the efficacy of Sinupret as a monotherapy for the treatment of acute sinusitis. More methodologically rigorous studies in children are also needed.

Chronic Sinusitis

Richstein & Mann, 1999.53 A randomized, double-blind, placebo-controlled trial was conducted in patients (n = 31) with chronic sinusitis. The patients (age range: 6-73 years) were treated for 7 days with either placebo, 2 Sinupret Sugar Coated tablets 3 times per day, or 50 Sinupret drops 3 times per day. At baseline both the Sinupret-treated patients (n = 16) and placebo-treated patients (n = 15) had similar symptoms (headache, fever, nasal discharge). Radiologic and ultrasonographic findings of the paranasal sinuses revealed that 12 of 16 Sinupret-treated patients had considerable improvement or complete recovery compared with 6 of 15 placebo-treated patients (p-value not reported). Significantly more patients treated with Sinupret were headache-free after treatment compared with patients treated with placebo (p = 0.025). X-ray findings of the paranasal sinuses showed significantly greater improvement with Sinupret treatment than with placebo treatment (p = 0.001). There was no difference between the groups on posterior nasal secretion. The tablets and liquid formulations performed similarly. There were no adverse effects. The authors concluded that Sinupret had a positive effect on subjective and objective findings in patients with chronic sinusitis.53

As with acute sinusitis, chronic sinusitis can also spontaneously recover. Nonetheless, this study showed that there was a benefit beyond that of placebo treatment. Although this study is limited by its small size, the objective measures provide credibility to support the conclusion that Sinupret is efficacious in treating chronic sinusitis.

Braum & Marz, 1990.48 A randomized, open-label, comparative study was conducted in patients at the Germany Army Hospital (Bundeswehrkrankenhaus) in Amberg, Germany. The patients (n = 46), who had x-ray proven exacerbation of chronic sinusitis, were treated for 21 days with Sinupret Sugar Coated tablets (2 tablets, 3 times per day) or N-acetylcysteine (manufacturer identity not reported; 200 mg, 3 times per day). Concomitant medication was permitted. As determined by x-ray, 23.5% (4/17) of Sinupret-treated patients improved and 41.7% (10/24) were without pathologic findings compared with 41.7% (10/24) of N-acetylcysteine–treated patients who improved and 20.8% (5/24) who were without pathologic findings after treatment (it is not clear if the assessment was made after 7 days or 21 days). Approximately 65% of the Sinupret-treated patients and 61.9% of N-acetylcysteine–treated patients reported that they were “improved” or “cured.” The authors concluded that Sinupret was equivalent to N-acetylcysteine therapy. Note that this review lacks some details because it is from an internal report abstract.48 A peer-reviewed manuscript was not available.

This study is limited by the size and the lack of an untreated or placebo control group. Also, the researchers permitted the use of concomitant medications, which could affect the clinical outcome. The abstract did not detail the use of concomitant medications.

Melzer J et al, 2006.49 A systematic review identified 2 placebo-controlled trials and conducted a meta-analysis on the data.45,50 In both of these studies Sinupret was used as an adjunct to standard care of chronic sinusitis. Nearly all of the participants (98-99%) were treated with antibiotics and decongestants. The studies included a predominantly male population of young adults (mean ≤ 29 years old). Patients with chronic sinusitis received placebo (n = 30) or Sinupret (n = 24, 2 Sugar Coated tablets 3 times per day45 or 50 drops 3 times per day50) for 14 days. In patients with chronic sinusitis there was no statistical difference between Sinupret treatment and placebo in the rate of “cure” or “improvement.”49 Sinupret was well tolerated and had an incidence of AEs that was comparable to placebo.

In the same systematic review, Melzer J et al49 also examined by meta-analysis 2 comparative trials with almost identical design.51,52 The studies included only men, and the mean age was 23 years in one study52 and 40 years in the other study.51 Patients with chronic sinusitis received ambroxol (n = 26, 100 drops 3 times per day) or Sinupret (n = 36, 50 drops 3 times per day) for 14 days. Some patients were co-prescribed antibiotics and/or decongestants to be taken with ambroxol or Sinupret (percent of patients not reported). However, the only baseline differences between the groups were duration of chronic sinusitis and body weight. The primary efficacy variable was the patient’s global assessment. Significantly more Sinupret-treated patients than ambroxol-treated patients were rated as “cured” or “improved” (p = 0.036). However, when looking at the secondary variables (symptoms) there were no significant differences between treatment groups.49 The authors acknowledge that the findings require confirmation by larger studies.

Three of the studies compared by Melzer J et al (described above) are not individually reviewed in this monograph because they are unpublished reports that have not been translated into English. One study is a double-blind, placebo-controlled trial on 21 patients with chronic sinusitis (Berghorn et al 1990)50 and the other 2 are comparative trials (Simm & Pape51 and Wahls52).

Chronic Sinusitis Summary

A placebo-controlled study demonstrated that Sinupret may benefit patients with chronic sinusitis and a meta-analysis concluded that Sinupret is equal or better than ambroxol. However, a meta-analysis of 2 placebo-controlled studies concluded that Sinupret as adjunct therapy for chronic sinusitis is not significantly better than placebo. All of these studies were small and should be viewed as preliminary findings. A larger prospective trial is needed to confirm Sinupret’s efficacy in patients with chronic sinusitis.

Acute Bronchitis

Pinnow & Egentenmaier, 1992.54 A blinded, active-controlled study evaluated the efficacy of Sinupret compared with a mucolytic agent in patients with uncomplicated acute bronchitis. Patients (n = 158) were treated with either Sinupret Sugar Coated tablets (dose not reported) or N-acetylcysteine (Mucret®, Astra Zeneca, sustained release tablets—dose not reported) for an unreported duration. The age and gender of the patients were not reported. The efficacy of Sinupret was statistically equivalent to the pharmaceutical treatment. Sinupret had good or better effects on frequency of cough, sensation of pain, expectoration, and auscultation (breathing sounds) (p-value not reported). Note that this review lacks specific details because it is from an abstract presented at an international conference.54 A peer-reviewed manuscript was not available.

Egentenmaier & Marz, 1991.55 A double-blinded, active-controlled study evaluated the efficacy of Sinupret compared with a mucolytic agent in patients with uncomplicated acute bronchitis. Patients (n = 80) were treated with either Sinupret drops (dose not reported) or ambroxol hydrochloride drops (Mucosolvan®, Boehringer Ingelheim GmbH—dose not reported) for 14 days. The age and gender of the patients was not reported. After 14 days of treatment the efficacy of Sinupret was significantly better than the efficacy of ambroxol in well-matched patients (p < 0.05). Sinupret was superior to ambroxol in daytime coughing frequency and sputum/amount (p-values not reported). Note that this summary lacks specific details because it is from an abstract presented at an international conference and an internal report abstract.54,55 A peer-reviewed manuscript was not available.

Ernst et al, 1997.42,56 The efficacy and safety of Sinupret for treating acute bronchitis or exacerbated chronic bronchitis was evaluated in a post-marketing surveillance study. General and internal medicine test centers in Germany (n = 330) recruited 3187 patients who were 1–94 years old. The physicians were instructed to treat 5 patients with Sinupret (2 sugar coated tablets 3 times per day or 50 drops 3 times per day for adults) and 5 patients with an expectorant of their choice (dose recommended by manufacturer). Using a specially prepared form, physicians assessed clinical symptoms at baseline and at the end of the 10-day treatment period. A total of 72 different expectorants were used, classified into 7 categories: Sinupret (56.6%, 1805/3178), ambroxol (18.1%, 576/3178), N-acetylcysteine (17.1%, 544/3178), myrtol (3.5%, 111/3178), bromhexine (2.4%, 76/3178), carbocysteine (0.7%, 22/3178), and others (1.6%, 51/3178). The authors concluded that Sinupret was at least as effective as the other expectorants, if not superior.42 The adverse event rate was 0.8% (8/1013) for Sinupret, compared with the AE rate of 1.0% (3/313) for ambroxol, 4.3% (12/277) for N-acetylcysteine, and 5.8% (4/69) for myrtol.42,42,43 The rate of AEs was 3.4% (27/792) when Sinupret was taken with concomitant medication (medications not specified).43

A limitation of this study was that there were no statistics reported. The authors state that the differences between treatments were small for body temperature, diurnal coughing, coughing pain, and cough quality but “marked for the remaining criteria” (nocturnal coughing, sputum quality, sputum viscosity, sputum type, patient criteria, and auscultation). However, there was no statistical analysis reported so it is unknown whether the differences were statistically or clinically relevant. Further, Sinupret appears to be superior to the other treatments when the data from all of the other expectorants are compiled. This compilation is not the preferred method because the 72 different expectorants can have vastly different effects. There is very little difference between treatments when the most popular treatment (ambroxol) is compared with Sinupret. Hence, the study might not actually prove superiority over other expectorants, but rather equivalency. It would appear that Sinupret is as effective as the other expectorants; however, concomitant medications were permitted. The authors report only that concomitant medications were used but do not elaborate. The impact of concomitant medications on study outcome is not known.

Bronchitis Summary

The acute bronchitis studies available for review were all comparator studies; none were placebo controlled. Thus, efficacy cannot be concluded based solely on a claim of equivalence to other treatments. Placebo-controlled or untreated control studies are needed to confirm the efficacy of Sinupret for treating bronchitis.