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| ORIGINAL ARTICLE |
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| Year : 2017 | Volume
: 3
| Issue : 3 | Page : 152-158 |
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An Assessment of Availability, Cost and Rationality of Serratiopeptidase Preparations in India
Vandana Tayal, Vandana Roy
Department of Pharmacology, Maulana Azad Medical College and Associated Hospitals, University of Delhi, New Delhi, India
| Date of Web Publication | 24-Oct-2017 |
Correspondence Address:
Vandana Roy
Department of Pharmacology, Maulana Azad Medical College, New Delhi 110002, Delhi
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/mamcjms.mamcjms_41_17
Background and Objectives: Serratiopeptidase is available as an oral preparation. The effectiveness of this enzymatic preparation is questionable. Despite this fact, serratiopeptidase is prescribed for a variety of inflammatory conditions. The study was conducted to determine the availability, cost and rationality of serratiopeptidase preparations available in Indian market. Materials and Methods: Serratiopeptidase preparations were assessed for total number, composition, strength and cost. Data were collected from ‘The Drug Today’ of the years 2009 (October–December) and 2015 (April–June). The rationality of preparations was assessed on validated 6-point scoring criteria. An extensive literature search was made using evidence-based print and electronic databases for the studies on efficacy and safety of serratiopeptidase. Results: A total of 642 serratiopeptidase preparations were available in the year 2009, which increased to 647 in 2015. Eighty percent preparations were fixed-dose combinations (FDCs) with either non-steroidal anti-inflammatory drugs (NSAIDs), antibiotics, muscle relaxants or miscellaneous drugs. Of all FDCs, 96% preparations were combinations with one or more NSAIDs. Single drug preparations showed a decline from 19.9 to 12.3%. Serratiopeptidase was available in strengths from 2.5 to 50 mg. The cost of 10 mg dose of serratiopeptidase preparations ranged between Rs. 1.35 and Rs. 8.16. The cost of FDCs was more than that of single non-serratiopeptidase agent. FDCs scored poorly on rationality assessment scale in both years, and an increase in irrational preparations was observed. Conclusion: Too many serratiopeptidase preparations are available. Evidence on their efficacy and safety is lacking. The rationality of available FDCs of serratiopeptidase is poor. The availability of expensive FDCs of unknown efficacy and safety is an important contributory factor for the irrational use of drugs. Keywords: Anti-inflammatory, fixed-dose combinations, serrapeptase, serratiopeptidase
How to cite this article:
Tayal V, Roy V. An Assessment of Availability, Cost and Rationality of Serratiopeptidase Preparations in India. MAMC J Med Sci 2017;3:152-8 |
How to cite this URL:
Tayal V, Roy V. An Assessment of Availability, Cost and Rationality of Serratiopeptidase Preparations in India. MAMC J Med Sci [serial online] 2017 [cited 2023 Jun 5];3:152-8. Available from: https://www.mamcjms.in/text.asp?2017/3/3/152/217125 |
| Introduction | |  |
Serratiopeptidase is a proteolytic enzyme isolated from the cultures of non-pathogenic enterobacteria, Serratia marcescens E15.[1] It is marketed as an oral preparation mostly in fixed-dose combinations (FDCs) and is claimed to be effective for a variety of inflammatory conditions.[2],[3],[4],[5] Serratiopeptidase is in clinical use for almost six decades now with most use reported from Japan and Europe and is also prescribed by Indian practitioners.[2],[6],[7],[8],[9] However, the efficacy of this oral enzyme preparation is questionable.[10] Despite this, the number of preparations of serratiopeptidase are available. To the best of our knowledge, there are no published data on the magnitude of the availability and cost of serratiopeptidase preparations alone and in FDCs. Keeping this in view, the present study was undertaken to determine the availability, cost and rationality of serratiopeptidase preparations in the Indian market.
| Materials and Methods | | |
The study was conducted at the Department of Pharmacology, Maulana Azad Medical College. It was an observational, cross-sectional study conducted at two different time points. The data for the study were collected from a Drug Compendium entitled ‘The Drug Today’ of the year 2009 (October–December) and 2015 (April–June).[11],[12],[13],[14],[15],[16] This publication gives a list of most of the medicines commercially available in the Indian market in a very systematic manner. Serratiopeptidase preparations were enlisted under the chapter of ‘Musculoskeletal disorders’ (subchapter entitled ‘Non opioid analgesics’), ‘Surgical and vaccines’ (subchapter entitled ‘Mucolytics, proteolytics and other enzymes’) and ‘Antibiotics’.[11],[12],[13],[14],[15],[16]
Serratiopeptidase preparations were assessed for the total number, their composition, strength and cost. The data for the same were collected during the years 2009 and 2015. It was compared to determine the change, if any, in the number, nature and cost of FDCs of serratiopeptidase available in India over a period of 6 years. In addition, the cost of non-steroidal anti-inflammatory drugs (NSAIDs) such as diclofenac, aceclofenac and nimesulide alone and in combination with paracetamol was also determined for comparison with the respective cost of their FDCs with serratiopeptidase.
The rationality of available preparations was based on validated 6-point criteria [Table 1]. It was validated by face and content validation. Similar criteria were also used in our earlier study for assessing rationality of FDCs for cough and cold in India.[17] The criteria used in the earlier study differ slightly, because there are differences in the nature of FDCs of cough and cold and serratiopeptidase preparations available in the market. Each criterion was given a score. The total score ranged from 0 to 16. A higher total score indicated better rationality. Drugs banned by Drug Controller General of India (DCGI), if available, were considered irrational. Some of the other criteria included availability of published data in animals, availability of clinical trial data of FDCs of serratiopeptidase on efficacy and safety. The studies with good design (randomized controlled trials or meta-analysis) were given higher weightage in the scoring system. An extensive literature search was made for determining the availability of any reported or published data on efficacy and safety of serratiopeptidase using evidence-based print and electronic database. Internet search on Pubmed, Google, the Cochrane library and MEDLINE was made using various keywords such as serratiopeptidase, serrapeptidase, serrapeptase, serralysin and oral enzyme preparations. The search on efficacy and safety studies was conducted from 15 January 2010 till 15 October 2011 and from 15 July 2015 till 1 May 2016. | Table 1: Criteria for rationality assessment of serratiopeptidase preparations (the numbers in brackets indicate the points for each parameter)
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| Results | | |
Number and strength of serratiopeptidase preparations
A total of 642 preparations of serratiopeptidase were available in the year 2009 which showed a marginal increase to 647 preparations in the year 2015 [Table 2]. Over 80% preparations were FDCs. Single drug preparations showed a decrease from 19.9% in the year 2009 to 12.3% in the year 2015 [Table 2]. Serratiopeptidase was available in strengths ranging from 2.5 to 50 mg in the year 2009 and from 2.5 to 20 mg in the year 2015. Majority of these were available in a strength of 10 mg [Table 2]. A decline of 37 and 10%, respectively, was observed in the number of serratiopeptidase 10 mg alone preparations and FDCs containing 10 mg over a period of 6 years [Table 2]. | Table 2: Serratiopeptidase preparations available in the years 2009 and 2015
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Number of fixed-dose combinations and constituents
An increase in the number of FDCs from 80% (514 out of 642) in the year 2009 to 87% (567 out of 647) in the year 2015 was noted. Out of the total number of FDCs, 11.4% increase in FDCs containing 15 mg serratiopeptidase was observed in the year 2015 compared to the year 2009 [Table 2].
Of all FDCs, 96% preparations were combinations with one or more NSAIDs whereas remaining included combinations with antibiotics, probiotics, muscle relaxants and miscellaneous drugs [Table 3]. Maximum number of preparations included FDC of diclofenac 50 mg with serratiopeptidase 10 mg [Table 3]. In the year 2009, maximum number of preparations had diclofenac as one of the constituents, whereas in the year 2015, paracetamol was present in addition in maximum number of FDCs. Further, there was a 95% increase in the number of FDCs containing aceclofenac (98 preparations in the year 2009 versus 191 preparations in the year 2015) [Table 3].
Cost
Variations in the cost of serratiopeptidase preparations were observed. The cost of 10 mg dose of serratiopeptidase preparations ranged between Rs. 1.35 (minimum cost) and Rs. 8.16 (maximum cost) [Table 4]. The minimum cost of FDCs of serratiopeptidase with NSAIDs ranged from Rs. 1.04 to Rs. 5.4 in the year 2009 and Rs. 1.3 to Rs. 6.5 in the year 2015 whereas the minimum cost of NSAIDs alone ranged from Rs. 0.199 to Rs. 1.49 in the year 2009 [Table 4]. The cost of FDC was more than that of the single non-serratiopeptidase agent [Figure 1] (note: 1 Rupee = 0.015 US Dollar). | Table 4: Cost variation in preparations of serratiopeptidase alone and in fixed-dose combination in the years 2009 and 2015
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 | Figure 1: Comparison of minimum cost of non-steroidal anti-inflammatory drugs alone and in combination with serratiopeptidase
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Rationality scores
The FDCs scored poorly on the rationality assessment scale both in the years 2009 and 2015. In the year 2009, the rationality score of the preparations ranged from 0 to 12 with majority achieving a score of 4, whereas in the year 2015, the score range was 0–7 and majority achieved a score of 6 [Figure 2]. | Figure 2: Rationality scores of fixed-dose combinations of serratiopeptidase available in the years 2009 and 2015
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Our assessment revealed that 76% (390 out of 514) and 85% (481 out of 567) of the FDCs of serratiopeptidase preparations which were available in the Indian market during the years 2009 and 2015, respectively, were not approved by DCGI. The list of such FDCs is given below:[18]- Serratiopeptidase with aceclofenac and paracetamol.
- Serrapeptase with amoxycillin, cloxacillin and lactic acid bacillus.
- Serratiopeptidase with diclofenac potassium.
- Serratiopeptidase with diclofenac and paracetamol.
- Serratiopeptidase with nimesulide and paracetamol.
- Serratiopeptidase with doxycycline.
The number of these preparations available in the Indian market as per Drug Today is mentioned in [Table 3].
Our literature search revealed the following findings on efficacy and safety studies. Mostly placebo-controlled studies were available with serratiopeptidase with very few randomized controlled trials. There was a lack of data on the efficacy studies of various FDCs of serratiopeptidase. Studies evaluating the pharmacokinetic parameters of serratiopeptidase in humans were lacking. Further, there were no meta-analysis and postmarketing surveillance studies with serratiopeptidase. We found only few case reports on the adverse effects of serratiopeptidase. These included bullous pemphigoid,[19] pneumonitis,[20] acute eosinophilic pneumonia[21] and diclofenac-serratiopeptidase combination-induced Stevens–Johnson syndrome, a severe cutaneous adverse reaction.[22]
| Discussion | | |
The results of this study show that there are numerous serratiopeptidase preparations (alone and in FDCs) available in the Indian market and the number of FDCs has increased over a period of 6 years. These preparations are marketed in India for their anti-inflammatory action and are used in controlling edema, pain and inflammation associated with surgical, obstetrical, dental procedures, accidental trauma, infections or allergic manifestations.[2],[3],[4]
We used a drug compendium, which is a commercial publication and is commonly used by prescribers as a source of information on drug formulations available in India.
Some striking observations were made during our literature research on serratiopeptidase preparations. First, published trials evaluating the efficacy of serratiopeptidase were few and generally of poor methodological quality with mostly placebo-controlled trials.[23],[27],[28],[29],[30] Similar findings have been reported in an earlier review which reported that in several studies, there was no mention of the dose and duration of treatment, and in few even the outcome of the study was not clearly defined.[6],[28],[31],[32] Second, the availability of serratiopeptidase preparations in the strengths of 2.5 and 50 mg is not understandable when the recommended daily dose is 30 mg. Further, the studies evaluating pharmacokinetic parameters of serratiopeptidase in humans are lacking. Only one study states that the orally administered serratiopeptidase gets absorbed from the intestinal tract of rats and transferred into the circulation in an enzymically active form.[33] The fact that serratiopeptidase is a peptide and would be digested in the stomach makes it difficult to envisage how it can reach its site of action.
Majority of the serratiopeptidase preparations were available as FDCs. There has been a 7% increase in the availability of FDCs over a period of 6 years. The reason for this is the federal nature of the Drug Regulatory System in India, in which some aspects are under the Central Government and some under the State Government.
A report of Indian Parliamentary Committee (59th) highlighted that manufacturing licenses of many FDCs were issued directly by State Authorities without approval from Central Drugs Standard Control Organization.[34] As a result of this violation of rule, Indian market abounds with FDCs which have unproven efficacy and safety. In 2007, the DCGI made an attempt to uproot the irrational combinations of drugs marketed in India and directed state drug controllers to withdraw 294 FDCs (which also included FDCs of serratiopeptidase) from the market.[18],[35] However, the drug companies opposed the order and challenged it in Madras High Court. The case has not been settled till date[35] It is interesting to note that just after the completion of our study, the Ministry of Health and Family Welfare issued a ban on 344 FDCs of drugs vide gazette notifications dated 10.03.2016.[36] The list of banned drugs also included some FDCs of serratiopeptidase such as serratiopeptidase with nimesulide, serratiopeptidase with doxycycline and serratiopeptidase with roxithromycin. However, these account for only 11% of the total number (62 out of 567) of FDCs of serratiopeptidase available in the year 2015 [Table 3]. So, the remaining 89% of FDCs still prevail in the market.
Our study revealed that majority of FDCs of serratiopeptidase were with diclofenac, diclofenac with paracetamol and aceclofenac with paracetamol. The reason for preferring these NSAIDs is not very clear.
The analysis of efficacy studies revealed that the superiority of serratiopeptidase alone or of FDCs of serratiopeptidase over existing NSAIDs or other single preparations is questionable.[24],[37],[38],[39] An earlier study reported that the efficacy of serratiopeptidase alone was not significantly more than that of placebo, ibuprofen or betamethasone in postoperative sequel following removal of impacted 3rd molar.[37] Similarly, another study revealed that the combination of serratiopeptidase and diclofenac sodium does not cause more reduction in oedema as compared with diclofenac sodium alone in rats.[38] Recent findings of a study evaluating the prescribing trends of proteolytic enzymes including serratiopeptidase in orthopaedic setting revealed that these drugs were never prescribed alone but in combination with one of the NSAIDs.[9] This may account for the decline in the availability of single preparations in market and rise in FDCs as observed in our study. Authors found that 98% of the prescribing doctors believed that proteolytic enzyme preparations were effective orally. It is surprising and worth noting that majority of the doctors during the survey said that their information on the effectiveness was not based on any clinical trial report but was gained from their seniors and medical representatives.[9]
Additionally, there are safety concerns regarding the use of serratiopeptidase preparations, because there are only few isolated case reports on adverse effects of serratiopeptidase with no postmarketing surveillance studies.
The cost analysis in our study revealed that the cost of FDCs of NSAIDs with serratiopeptidase is more than five times the cost of NSAIDs alone [Figure 1]. Similar findings have been reported in an earlier study.[9] It needs to be considered whether increasing the cost of therapy for the patient by using the drugs of uncertain efficacy is justified.
Assessment of the rationality score showed that the FDCs of serratiopeptidase were irrational. Majority of the FDCs had a poor score. Fall in the rationality score over the period of 6 years can be attributed primarily due to a decline in the number of single preparations (from 19.9% in the year 2009 to 12.3% in the year 2015) and an increase in the number of FDCs (from 80% in year 2009 to 87% in year 2015). In addition, there was an increase in the availability of preparations not approved by DCGI, that is, from 76% in the year 2009 to 85% in the year 2015. Availability of such banned FDCs of serratiopeptidase in the market is a clear evidence of irrationality.Health Sciences Authority initiated phasing out of serratiopeptidase preparations in Singapore and Philippines based on their report which concluded that there is no substantive scientific evidence to support a favourable risk-benefit profile for the use of serratiopeptidase as a medicinal product.[40] In 2011, Danzen (serratiopeptidase) tablets in Japan was voluntarily recalled by its proprietor as the drug failed to show superior efficacy to placebo as an expectorant and anti-inflammatory agent.[40]
Although the Ministry of Health and Family Welfare, Government of India has also taken a step forward to ban few FDCs of serratiopeptidase, numerous preparations still prevail in the market. The availability of such FDCs with no therapeutic rationale or substantial documentation of efficacy and questionable safety is a cause for concern. To curtail the use of such irrational preparations, the healthcare providers including doctors, nurses and pharmacists need to be made aware about the lack of scientific evidence as regards the efficacy and safety of serratiopeptidase preparations.
| Conclusion | | |
Many serratiopeptidase preparations lacking scientific evidence for efficacy and safety are available in the Indian market mostly as FDCs. Availability of such preparations unnecessarily adds to the economic burden. Further, sensitizing doctors about the same is equally imperative to reduce the problem arising out of availability of irrational FDCs.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]
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