PERK

 

For the use of a Registered Medical Practitioner or a Hospital or a Laboratory only

TERRAZEN - NT

(Nimesulide, Serratiopeptidase and Tizanidine Tablets)

 Description

Pain is the universal problem which is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. Pain does not lead to mortality but it definately causes morbidity.The most common causes of pain are soft tissue injuries ( sprains, strains), arthritis and post operative pain. The important aspect in overcoming pain is early and rapid relief from pain and return of mobility. Analgesics such as non steroidal anti inflammatory agents are today the drugs of choice for the management of pain and inflammation. The inherent limitations of the newer agents such as nimesulide, rofecoxib, celecoxib is the delayed onset of action leading to slow relief from pain and inflammation.    TERRAZEN-NT tablets is a formulation which contains a rapid acting nimesulide since it is complexed with beta cyclodextrin. It provides pain relief in as rapid as 15 minutes.7,8

TERRAZEN-NT is a fixed dose combination (FDC) of Nimesulide, Serratiopeptidase and Tizanidine Hcl. Nimesulide is chemically 4-Nitro-2-phenoxymethane sulphonanilide, Serratiopeptidase is proteolytic enzyme and Tizanidine Hcl Tizanidine is chemically 5-chloro-N-(4, 5-dihydro-IH-imidazol-2-yl) -2, 1, 3-benzothiadiazol-4-amine and is an strong muscle relaxant with anti-spasm action. TERRAZEN-NT is pinkish-white round tablet.

Composition

Each Uncoated Tablet contains:
Nimesulide BP............100mg  (in Beta-Cyclo Dextrin Complex Uncoated)
Serratiopeptidase........10mg (equivalent to enzyme activity 20,000 units, as enteric coated granules)

Tizanidine hydrochloride Equivalent to Tizanidine.....................2 mg

 

Pharmacology

The anti-inflammatory, analgesic and antipyretic activities of Nimesulide, a nonsteroidal anti-inflammatory drug (NSAID) of the sulfonanilide class, have been demonstrated in a number of experimental models and in numerous clinical trials1.

Nimesulide appears to exert its therapeutic effects through a variety of mechanisms viz :2

·         Selective cyclooxygenase 2 inhibitor

·         Inhibition of generation of superoxide anions from stimulated polymorphonuclear leucocytes.

·         Inhibition of platelet activating factor synthesis

·         Prevention of Bradykinin/Cytokine induced hyperalgesia of nerves (Inhibiting release of TNF-a )

·         Scavenging of hypochlorous acid

·         Blocking of histamine release

·         Prevention of cartilage damage by inhibition of metalloprotease synthesis

·         Phosphodiesterase type IV inhibition.

Serratiopeptidase: Serratiopeptidase is a proteolytic enzyme available for clinical use more than a decade. It binds to alpha-2-macroglobulin in the blood in the ratio of 1:1 which helps to mask its antigenicity but retains its enzymatic activity and is slowly, transferred to site of inflammation. Serratiopeptidase hydrolyses bradykinin, histamine and serotonin responsible for oedematic status5. It reduces swelling improves microcirculation & expectoration of sputum etc. Thus it can be concluded that serratiopeptidase has anti-inflammatory, anti-oedemic and fibrinolytic activity and acts rapidly on localized inflammation6.

Tizanidine: Tizanidine is a myotonolytic agent used in the treatment of spasticity. The effects of tizanidine are linked mainly with its (-2 adrenergic agonist properties, although its effects on the imidazoline receptor may also play a role2.

Rationality
Various painful inflammatory conditions including those associated with osteoarthritis, post operative trauma, sports injuries, bronchitis, sinusitis etc are improved with Nimesulide. Nimesulide is a potent and time tested NSAID and its spectrum of activity is improved by Serratiopeptidase, as Serratiopeptidase exhibits following activities:

1.       Antiinflammatory and antiswelling:

a.       Inhibition of vascular permeability due to scald or injury

b.       Inhibition of inflammatory edema due to carrageenin, serotonin, bradykinin

c.       Excellent decomposability of bradykinin

d.       Strong decomposability of fibrin

e.       No effects of alpha-, beta-globulin and albumin

2.       Action to promote the lysis and discharge of sputum and pus:

a.       Decreased pus and viscosity in patients with chronic sinusitis.

b.       Decreased sputum and viscosity in patients with subacute bronchitis.

3.       Action to promote transfer of antibiotics to the focal site:

It can promote the transfer of ampicillin and sulbenicillin to the palate of patients with chronic sinusitis.

The pharmacokinetic behaviour of the three drugs should be similar to support the use of the three agents in fixed-dose-combination.

Both the drugs in Co-trimoxazole, which is an established combination of sulphamethoxazole and trimethoprim, have their pharmacokinetic parameters like t 1/2 (about 10 hrs for both the drugs) matching with that of each other.

Similarly, the half-lives of nimesulide (1.56 to 4.95 hr) 1 and tizanidine (2.12 to 4.2 hr) 2 fall in the same range and hence, the time course of action of the two drugs might be similar which is an important criterion for the possibility of a rational fixed-dose-combination.

Hence, it can be said that Nimesulide, Serratiopeptidase and Tizanidine show synergistic potential which is one of the most important factor in deciding the feasibility of a FDC.

Pharmacokinetics

Nimesulide
After oral administration of Nimesulide 50 to 200 mg to healthy adult volunteers, peak serum concentrations of 1.98 to 9.85 mg/L are achieved within 1.22 to 3.17 hours. Oral drug absorption is nearly complete and concomitant administration of food may decrease the rate, but not the extent, of absorption of Nimesulide. The drug is extensively bound (99%) to plasma proteins and has an estimated apparent volume of distribution of 0.19 to 0.35 L/kg following oral administration. Nimesulide is extensively metabolised (1 to 3% of a dose is excreted unchanged in the urine) to several metabolites which are excreted mainly in the urine (
» 70%) or the faeces (» 20%). The drug is almost completely biotransformed into 4-Hydroxy-Nimesulide in both free and conjugated forms and this metabolite appears to contribute to the anti-inflammatory activity of the compound. Peak concentrations of 4-Hydroxy-Nimesulide ranged from 0.84 to 3.03 mg/L and were attained within 2.61 to 5.33 hours after oral administration of Nimesulide 50 to 200 mg to healthy adult volunteers. The elimination half-life of 4-Hydroxy-Nimesulide ranges from 2.89 to 4.78 hours and is generally similar to or slightly higher than that of the parent compound (1.56 to 4.95 h).

The pharmacokinetic profile of Nimesulide is not significantly altered in children, elderly volunteers and patients with moderately impaired renal function [creatinine clearance 1.8 to 4.8 L/h (30 to 80 ml/min)]. Slight accumulation of 4-Hydroxy-Nimesulide was noted in patients with moderate renal impairment; however, the clinical significance of this finding is unknown.

Serratiopeptidase
Serratiopeptidase when consumed in unprotected form is destroyed by acid in the stomach. However, enteric coated granules, enable the enzyme to pass through the stomach unchanged, and be absorbed in the intestine. It is found negligibly in urine suggesting that it is transported directly from the intestine into the blood stream.

Tizanidine

The dosage, plasma concentration and antispastic activity of tizanidine are related in individual patients but not between patients. Moderate interpatient variation has been demonstrated in the pharmacokinetics of tizanidine, but maximum plasma concentrations appear to be reached 0.75 to 2 hours after administration. Between 53 and 66% of the dose is absorbed and food has no effect on the pharmacokinetics of this drug.

The bioavailability of tizanidine is estimated to be 21% and there is a low propensity for plasma protein binding (about 30%). Extensive first-pass metabolism  of tizanidine occurs, with less than 3% of unchanged drug excreted. The metabolites have no pharmacological activity. Total recovery analysis indicated that 19 to 23% of the administered dose is excreted in the faeces, and 53 to 66% in the urine. The elimination half-life ranges from 2.1 to 4.2 hours in patients with normal renal function compared with a mean value of 13.6 hours in those with renal impairment (creatinine clearance < 1.5l/h)

 

Indications

Terrazen-NT is indicated in conditions like:                                                                                              

Trauma Surgery: In sports injuries, sprains, laceration, fractures, dislocation and osteoarthritis etc. It reduces inflammation and pain thus helps faster healing and repair.

Surgery: Reduces Post Operative Edema at injection sites. Reduces internal tissue edema and inflammation caused at post-operative handling. Reduction in edema reduces chances of rupture at tissue site as well as risk of graft rejection along with reduction in pain .

Plastic Surgery: Reduces Post Operative Edema and restores micro-circulation at the site of graft rejection.

Respiratory Medicine: Breaks down complex sputum molecules in smaller peptides with lower viscosity, helping in expectorating them more easily. Reduced viscosity of secretion helps in better antibiotic penetration to enable control over stubborn infections like bronchitis, lung abscess and bronchectasis. Nimesulide helps in controlling pain and inflammation.

Infections: Mucolytic activity in sinuses, ear cavities and anti-inflammatory activity in upper respiratory tract organs help in faster resolution, better antibiotic bioavailability and faster cure rates.

Dermatology: Used in acute painful inflamed dermatoses.

Dentistry: Helps better control over dental infections and inflammation.

Obstetrics & Gyneacology: The anti-inflammatory activity helps in resolution of post-partum haematomas, breast engorgements and pregnancy-related thrombophlebitis.

Contraindications

Hypersensitivity to any of the ingredients of the preparation. TERRAZEN-NT is contraindicated in patients of active peptic ulcer disease, moderate to severe hepatic impairment, severe renal failure and with blood coagulation disorders. Because of significant effect on impairment of performance, patients should be cautioned about engaging in activities requiring alertness. Terrazen-NT should be used with great caution in patients with compromised renal function, cirrhosis of liver, congestive heart failure, renovascular disease or those who are volume or salt depleted. It is important to monitor hepatic injury parameters when using Terrazen-NT. Therefore; it is recommended that the serum levels of liver function tests be assayed periodically. Discontinue the drug immediately in cases with worsening liver tests.

Warning

Usage in pregnancy and nursing mothers : No well controlled studies are available regarding the use of nimesulide , Serratiopeptidase or Tizanidine in pregnancy and lactation. Avoid the use of Terrazen-NT in such cases.

Usage in children : Safety and efficacy of Nimesulide in children is well established. Experience with Serratiopeptidase in children is not available.

Adverse Reactions

Nimesulide - The most common adverse reactions are gastrointestinal disturbances (epigastralgia, heart burns, nausea, diarrhoea and vomiting). Dermatological reactions include rash and pruritus; central nervous system associated side effects are dizziness, somnolence and headache. Occasionally, excessive perspiration, flushing, hyperexcitability and sleep disorders have been reported. Rarely, a rise in liver enzyme levels have also been reported.

Serratiopeptidase - Hypersensitivity reactions, such as rash or redness, may infrequently occur. If such reactions occur, TERRAZEN-NT should be discontinued.

Tizanidine- Side effects with the doses prescribed for muscle weakness, are usually mild.  The most common adverse effects associated with Tizanidine are dry mouth, somnolence, drowsiness, hallucinations, muscle weakness and dizziness. Clinically significant increase in liver enzymes might occur. Intravenous and oral administration of Tizanidine in animal models resulted in an initial transient hypertensive response accompanied by tachycardia in some studies followed by gradual hypotensive effect and bradycardia in most of the investigations.

Gastrointestinal: Anorexia, gastric discomfort, nausea or vomiting may infrequently occur. These can be minimised if the tablets are taken after meals.

Drug Interactions

Nimesulide: Due to the extensive plasma protein binding Nimesulide may be displaced from the binding site by concurrent administration of Fenofibrate, Salicylic acid, Valproic acid and Tolbutamide. Moreover, Nimesulide may displace Salicylic acid, Methotrexate and Furosemide from binding sites. Nimesulide reduced the diuretic effect for concomitantly administered Furosemide. Although Nimesulide does not appear to interact with Warfarin, in clinical practice, interaction with oral anticoagulants or other highly protein bound drugs cannot be ruled out. Nimesulide may cause enzymatic induction of Theophylline when administered concomitantly with it. Nimesulide had no significant effect on fasting blood and glucose tolerance in patients treated with anitdiabetic agents.

Serratiopeptidase: With anticoagulative agents, it may increase anticoagulative effect and therefore TERRAZEN-NT must not be used in such patients.

Overdosage and Treatment

No data is available on overdosage toxicity. In the event of an overdosage the stomach may be emptied and symptomatic treatment should be given.

 

Dosage and Administration

1 Tablet, 2 - 3 times daily after meals. Dose to be adjusted according to age or symptoms or as directed by the physician.

 

Storage instructions

Store at a temperature below 25°C, protect from light and moisture.

 

Presentation

Available in blister strips of 10 x 10's tablets'.

 

References

1.       Davis R and Brogden RN. Nimesulide: An update of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy. Drugs 1994; 48(3) : 431-454.

2.       Tognella S. Nimesulide : New clinical opportunities. Drugs 1993; 46 (Suppl 1) : 275 - 276.

3.       Ward A and Brogden RN. Nimesulide : A preliminary Review of its pharmacological properties and Therapeutic efficacy in inflammation and pain states. Drugs 1988;36 : 732 - 753.

4.       Insel PA. Analgesic - Antipyretic and Antiinflammatory agents and drugs employed in the treatment of gout, cited in, Goodman & Gillman's .The pharmacological basis of therapeutics 1996; 9th ed.: 617-657.

5.       Sharma AK. Correspondence, A Preliminary trial of Serratiopeptidase in patients with Carpal Tunnel Syndrome. JAPI 2000; 48 (11): 1130.

6.       Mazzone A, Catalani M, Costanzo M et al. Evaluation of serratia peptidase in acute or chronic inflammation of ortorhinolaryngology pathology: a multicentric, double- blind, randomised trial versus placebo. J Int Med Res 1990; 18(5): 379 - 88.

7.      Scolari, G., et al., A comparison of nimesulide beta cyclodextrin and nimesulide in postoperative dental pain. Int J Clin Pract, 1999. 53(5): p. 345-8.

      The aim of this study was to assess the efficacy and tolerability of single doses of nimesulide beta cyclodextrin compared with nimesulide in patients with dental pain following surgical procedures. This was a randomised, double-blind, between-patient, multicentre study involving 148 outpatients suffering from moderate to severe pain, who received single doses of either 400 mg nimesulide beta cyclodextrin or 100 mg nimesulide. The principal criterion for efficacy was pain intensity assessed on a visual analogue scale (VAS) 15 minutes after drug intake. Pain intensity was further evaluated 30, 45, 90, 120, 180, 240 and 360 minutes after dosing. Pain relief was evaluated at the same time points by means of a categorical scale. The time point of first pain relief, the use of rescue medication and the global evaluation of efficacy were also recorded. The reduction in pain intensity was significantly more pronounced in the nimesulide beta cyclodextrin group at 15, 30, 45 and 60 minutes (p 0.01). Pain relief was significantly greater (p 0.05) and more rapid with nimesulide beta cyclodextrin. In the patient overall assessment of efficacy, nimesulide beta cyclodextrin and nimesulide were rated excellent or good by 95% and 92% respectively; only one patient in the nimesulide beta cyclodextrin group needed rescue medication. Both study drugs were effective and well tolerated in the treatment of acute dental pain, with nimesulide beta cyclodextrin showing a faster onset of analgesic action.

8.       Research Analysis Report Evaluation of Efficacy of Nimesulide in Beta Cyclodextrin versus Conventional Nimesulide Tablets in Gynaecological Postoperative Pain

by TAPAN KR LAHIRI, Department of Gynaecology and Obstetrics, Institute of Postgraduate Medical Education and Research & SSKM Hospital, Kolkata 700020,

ISHITA MISHRA Department of Gynaecology and Obstetrics, Institute of Postgraduate Medical Education and Research & SSKM Hospital, Kolkata 700020 &

JAYITA CHAKRABARTY Department of Gynaecology and Obstetrics, Institute of Postgraduate Medical Education and Research & SSKM Hospital, Kolkata 700020

This randomised comparative trial was conducted among 47 patients, aged 18-70 years admitted for major gynaecological surgeries. The group A consisted of 24 patients (received conventional nimesulide for postoperative pain relief) and the group B consisted of 23 patients (received nimesulide complexed with beta cyclodextrin for postoperative pain relief). The group B patients (stated as N-BCD ie, Nimesulide with Beta cyclodextrin as in Terrazen-NT of Perk’s brand of nimesulide combination) showed superior pharmacokinetic properties translated into superior clinical efficacy as compared to conventional nimesulide.                           

Nimesulide is a non-steroidal anti-inflammatory drug (NSAID) chemically 4-nitro-2-phenoxymethane-sulfonilide that has shown efficacy and favourable tolerability in the treatmjent of patients with postoperative pain. One of the major drawbacks of nimesulide is its poor solubility which leads to a slower onset of action and poor bio-availability. In order to improve its solubility, rate of absorption and bio-availability, nimesulide is complexed with beta cyclodextrin (henceforth referred as N-BCD). In-vitro dissolution studies have shown rapid and complete dissolution of N-BCD as compared to plain nimesulide across the pH range (1.2 to 7.5). In-vivo plasma level versus time curve have also shown rapid and better absorption of N-BCD versus plain nimesulide. The present study was conducted with the aim to evaluate the rapid onset of effect of N-BCD as compared to plain nimesulide tablets in gynaecological postoperative pain.                                    

 Observations and Discussions
Forty-seven patients were recruited for gynaecological operation with the mean age of 44 years (age range 18-70 years). Group A ie, conventional nimesulide group consisted of 24 patients and group B ie, Terrazen-NT (N-BCD) group consisted of 23 patients. Mean ages of group A and group B patients were 43 (18-70) years and 45.1 (18-65) years respectively. The onset of action of Terrazen-NT (N-BCD) starts as early as in 15 minutes, whereas the similar effect is produced by conven-tional nimesulide in 30 minutes (Table 2). The reduction in pain intensity from baseline is 91.92% at 4 hours while it is only 79% with conventional nimesulide. This difference is statistically significant. The reduction in pain intensity is significantly more with Terrazen-NT at all the time points studied as compared with conventional nimesulide (Table 3). The need for rescue analgesics was found to be more with conventional nimesulide (n=4;17%) than with Terrazen-NT (n=0;0%).

 

Table2- Pain Intensity as Measured by VAS

 

Duration of time

Conventional nimesulide

Terrazen-NT (TNT)

 

Baseline

95.80

93.24

15 minutes

82.32

74.72*

30 minutes

70.73

58.42*

45 minutes

61.24

48.92*

60 minutes

53.64

39.93*

90 minutes

45.73

29.23*

120 minutes

35.12

18.82*

240 minutes

20.03

7.53*

 

*p<0.05

 

Table3- Reduction in Visual Analogue Score(%) from Baseline

 

Duration of time

Conventional nimesulide

TERRAZEN-NT (TNT)

 

15 minutes

13.48(14.07)

18.52(19.86)*

30 minutes

25.07(26.17)

34.82(37.34)*

45 minutes

34.56(36.08)

44.32(47.53)*

60 minutes

42.16(44.01)

53.31(57.18)*

90 minutes

50.07(52.26)

64.01(68.65)*

120 minutes

60.68(63.34)

74.42(79.82)*

240 minutes

75.77(79.09)

85.71(91.92)*

 

*p<0.05

 

Material and Method

A total of 47 patients aged 18-70 years were enrolled for this randomised, comparative trial. Patients underwent various major gynaecological surgeries. Patients were divided into two groups A and B. Immediately after surgery, all patients were initiated on parenteral analgesics (Table 1), the choice of which was left to the discretion of the operating gynaecologist. Forty-eight hours after operation, patients were given either conventional nimesulide (group A) or TNT (group B) for a period of 5 days. Before beginning the oral analgesic, pain was recorded by a visual analogue scale (VAS). Patients with a score in VAS of less than 50 were excluded from the study. Patients with a history of allergy to nimesulide, active peptic ulcer disease, pregnant and lactating mothers were also excluded. Concomitant administration of other NSAIDs or corticosteroids were forbidden. Rescue analgesics were permitted if requested for relief from severe pain. The clinical assessment was estimated by assessing spontaneous pain on a visual analogue score ranging from 0 (no pain) to 100 (unberable pain) on the day of initiating oral analgesics. The need for rescue analgesics was recorded to evaluate efficacy.

 

Table 1- Distribution of Cases according to Use of Parenteral Analgesics Immediately after operation

 

Analgesics(Parenteral)

Group

 

 

A(conventional nimesulide)

B(TNT)

 

Pentazocine+diazepam

4

1

Pentazocine+diazepam+tramadol

4

-

Diazepam+tramadol

-

1

Pentazocine+diazepam+tramadol

12

13

Diazepam+tramadol

2

2

Pethidine+phenergan

1

4

Pethidine+phenergan+tramadol

1

2

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