Application for Registration of a pharmaceutical product in

COUNTRY – TURKMENISTAN
Product – Allergodit Kids 30mg Tablet

February, 2024
Representation Letter:
Please refer following pages for Cover letter
Date- 20-02-2024

To,

State Medical Service of Turkmenistan

Subject: Submission of Application for Marketing Authorization of Amoxicillin 500mg, Clavulanic Acid 125mg,
(Amoxyway 625mgTablet)

Dear Sir,

We are pleased to submit our Application for the registration of finished pharmaceuticals product
Whose details are as follows:

Brand name - Amoxyway 625mgTablet

Generic name - Amoxicillin 500mg, Clavulanic Acid 125mg,
Active Substance - Amoxicillin, Clavulanic Acid,
Pack size - 10 Tablet x 1 Blister

I, the undersigned clarify that the information and data submitted is true, complete and correct to the best of my
knowledge.

With warm regards

Yours faithfully

Name- Abhinav Pathak

Designation- Director
Place- Delhi
Application Form
Please refer following pages for application form.
 APPLICATION FORM

1. Applicant: APEXX PHARMA PVT LTD

2. Applicant Address: 259/1 Hauz Rani, New Delhi - 110017

a. Phone: +91 9811047600

b. Fax: NA

c. Email: info@apexxpharma.com

d. Website: www.apexxpharma.com

3. Representative Keyikokara Individual Enterprise

4. Representative address H-6, Baky Bitarap street, Ahal city, Ak Bugday etrap,
Ahal province
Turkmenistan

5. Phone: +99365116394

6. Formulations:

a. Generic Name: Amoxicillin 500mg, Clavulanic Acid 125mg

b. Trade Name: Amoxyway 625mg Tablet

 c. Formulation Sheet:

Composition:
Paracetamol: 500mg,
Clavulanic Acid: 125mg,
Excipients: QS
Approved colors

d. Prescription: Prescription only medicines.

e. Patent Details: NA

f. Name of Manufacturer: MG BIOLOGICAL PVT. LTD.

Name: Abhinav Pathak

Designation: Director
Contact No.: +919811047600
Email:info@apexxpharma.com

Signature
Date: -20-02-2024
Summary of registration file
The Letter Representation

Application Form

Summary of registration file

The Letter of authorization (LOA

Certificate CPP (The Certificate on a Pharmaceutical Product)

MFG Lisence Copy

GMP Certificate:

Certificate of Trademark

Information on registration of a medical products in other countries

The Brief Description of Technological process

The full description of method of analysis of Finished Drugs

Summary of Product Characteristics:

Mechanisms of action

Drug Abuse and Dependence

Drug Interactions

Clinical Studies

COA

Pack Shot Images

The Letter of Authorization (LOA)
Please refer following pages for the Letter of authorization (LOA)
 For product registration in TURKMENISTAN

To,
The State Medical Service of Turkmenistan

Letter of Authorization
The Undersigned, Apexx Pharma Pvt Ltd, 259/1 Hauz Rani, New Delhi 110017 India, Marketer, Mfg and exporter of
Human Pharmaceuticals Products, here by confirms that,

Keyikokara Individual Enterprise

H-6, Baky Bitarap street, Ahal city, Ak Bugday etrap,
Ahal province, Turkmenistan

Contact- +99365116394

Is the company’s appointed representative in TURKMENISTAN for the Human Medical product registration and
marketing.

The letter of authorization is valid for the period of ONE Years from the date of signature below and is subject to
prolongation and earlier withdrawal at any time before that date as per the agreed terms and condition.

For APEXX PHARMA

Name: Abhinav Pathak

Designation: Director
Date: 20-02-2024
Place: Delhi
Certificate CPP (The Certificate on a Pharmaceutical Product)
Please refer following pages for Certificate of Pharmaceutical Product (COPP)
MFG Certificate:
GMP Certificate:
Certificate of Trademark:

Status – Applied
Information on registration of a medical products in other countries:
Status: Amoxyway Tablet is not authorized/ registered in any countries
The Brief Description of Technological Process.
Production Flow Chart
The manufacturing procedure is described as below:
A combination pharmaceutical composition for Bacterial infection that includes Amoxicllin 500mg, Clavulanic Acid
125mg.

Technical field

The invention relates to Bacterial infection. In particular, the invention relates to a composition containing Amoxicillin and
Clavulanic Acid for Bacterial infection.

Without a medical professional prescription (ie, without a prescription) (“OTC”), a full therapeutic dose of paracetamol
(acetaminophen) is 1000 mg, a full therapeutic dose of ibuprofen is 400 mg to relieve pain. The total daily amount is also
limited to 4000 mg of paracetamol and 1200 mg of ibuprofen, per day in divided doses. Dosage regimens for each of
paracetamol and ibuprofen, when administered individually to patients, are often maximized to give a complete
individual therapeutic dose. Care must be taken that it is met, but that the maximum daily dose for each of the
medications is not exceeded. Pharmaceutical combinations such as paracetamol and codeine (500 mg / 8 mg) and
ibuprofen and codeine (200 mg / 12.8 mg) in single dosage forms are known. Avoiding the use of codeine may be an
advantage due to constipation difficulties, which are a common side effect.

Combinations of paracetamol, ibuprofen and codeine are known in South Africa, including a single tablet: paracetamol
250 mg, ibuprofen 200 mg, codeine 10 mg. Another combination of paracetamol, aspirin and codeine is also known in a
single dosage form that includes 325 mg of paracetamol, 325 mg of aspirin and 10 mg of codeine. In both cases, at a
dose of two capsules, sub-therapeutic doses of paracetamol are administered. In the case of the South African
combination, although 4 capsules would provide a complete therapeutic OTC dose of paracetamol, the amount of
ibuprofen would then exceed the allowed OTC dosage limits. describes tablets comprising ibuprofen (50-400 mg),
paracetamol (150-500 mg) and caffeine. In A.E. Pickering et al., British Journal of Anaesthesia, January 2002; 88, 1 a
study in which ibuprofen and paracetamol were administered to paediatric tonsillectomy patients. They were dosed
with separate syrups on a body weight basis and, after surgery, ibuprofen was only administered "as needed."
Pickering does not describe the dosage to any patient of a combination of paracetamol and ibuprofen in accordance
with the present invention.

paracetamol can be taken without a prescription in dosages of 500-1000 mg every 4 to 6 hours up to 4 g / day for the
treatment of fever / pain. Ibuprofen is taken without a prescription in doses of 200-400 mg every 6 hours up to 1200 mg
/ day for analgesia.

The literature has reported that for some drugs the dosage frequency is more important in determining adverse
reactions than the total dose (IR Edwards, Pharmacological Basis of Adverse Drug Reactions, Chapter 6, page 293 in
Avery's Drug Treatment, 1996, 4th edition: Adis International, Auckland). This suggests that the administration of 2 x
150 mg of ibuprofen four times a day more than 2 x 200 mg three times a day may be better tolerated. This type of
principle is also, in part, behind the delayed-release products, where the drug is gradually released avoiding extreme
effects of spikes and valleys of immediate-release dose forms. It is also conceivable that decreasing the amount of
ibuprofen administered as a single dose will improve the tolerability of ibuprofen.

However, there is concern that by using a lower dose of ibuprofen, the result would be less pain relief due to lower peak
drug concentrations, with the result that the effectiveness of pain relief is reduced.
It would be an advantage to be able to administer these medications in combination at a high therapeutic dose in order
to minimize the number of doses required throughout the day, although still achieving the maximum daily dose rate per
day for more effective pain relief. Reducing the amount of ibuprofen to reduce the likelihood of side effects that
manifest while maintaining the pain relief effect and minimizing the necessary doses would achieve those advantages. It
would also be an advantage to be able to achieve effective pain relief from such a combination to treat short-term,
intermittent type pain. Such a combination has not been previously provided and the concept would allow a certain
number of advantages to be achieved such as administration convenience, increased ease of user compliance and
effective pain relief over time.

Summary:
According to one aspect of the invention, a combination pharmaceutical composition for the treatment of pain is
provided that includes about 125 mg to about 150 mg of ibuprofen and about 475 mg to about 500 mg of paracetamol.

Preferably, the paracetamol: ibuprofen ratio is approximately 50:15. Preferably, the composition has 125-150 mg of
ibuprofen and 475-500 mg of paracetamol. Preferably, ibuprofen is present in the form of a salt, ester or in the form of a
complex, in an amount suitable for administration between about 125 mg and about 150 mg of ibuprofen. Preferably,
the composition has 150 mg of ibuprofen and 500 mg of paracetamol. Preferably,

the composition is suitable to be administered in the form of two unit doses four times a day. Preferably, the
composition is in the form of a tablet or capsule. According to another aspect of the invention, a use of approximately
475 mg is provided at approximately 500 mg paracetamol and approximately 125 mg to approximately 150 mg
ibuprofen in the manufacture of a drug to be administered in two unit doses four times a day for the treatment of pain.

Preferably, the paracetamol: ibuprofen ratio is approximately 50:15.

Preferably, ibuprofen is present in the form of a salt, ester or in the form of a complex in an amount suitable for
administration between about 125 mg and about 150 mg of ibuprofen. Preferably, the composition has 125-150 mg of
ibuprofen and 475-500 mg of paracetamol per unit dose. Preferably, 150 mg of ibuprofen and 500 mg of paracetamol
are used for each unit dose. In accordance with a further aspect of the invention a pharmaceutical package is provided
which includes tablets or capsules, each of the tablets or capsules including a pharmaceutical composition according to
any one of claims 1 to 7, the package including instructions intended for a user to take two tablets or capsules no more
than 4 times a day. Preferably, the package includes an even number of tablets or capsules. Preferably, the package
includes at least 8 tablets or capsules. In accordance with a further aspect of the invention,

a pharmaceutical composition is provided for the pain treatment, including the paracetamol and ibuprofen composition
in a ratio ranging from 47.5: 12.5 to 50:15, the composition being formed in discrete dosage units, where the taking of
one or more complete dosage units supplies substantially 250-300 mg of ibuprofen and substantially 950, 1,000 mg
paracetamol to provide synergistic pain relief. Preferably, the pharmaceutical composition is presented with instructions
in order for a user to take the number of dosing units needed to deliver the 250-300 mg of ibuprofen and 950-1,000 mg
of paracetamol. Preferably, the ratio is 50:15. Preferably, the composition includes a salt, ester or ibuprofen complex
form in a sufficient amount.
To supply ibuprofen to the user within the established relationship range or in the established relationship. Preferably,
each dosage unit is a tablet or capsule. Preferably, the composition is suitable for administration four times a day.

In accordance with a further aspect of the invention, a pharmaceutical combination composition suitable for the
treatment of pain is provided, including the paracetamol and ibuprofen composition in a ratio range of 47.5: 12.5 to
50:15, suitable for provide synergistic pain relief.

In accordance with a further aspect of the invention, a pharmaceutical composition suitable for the treatment of pain
is provided, including the paracetamol and ibuprofen composition formed in discrete dosage units, wherein taking one
or more complete dosage units substantially supplies 250 -300 mg of ibuprofen and substantially 950-1,000 mg of
paracetamol to provide synergistic pain relief presented with instructions in order for a user to take the number of
dosage units necessary to deliver the 250-300 mg of ibuprofen and 950-1,000 mg paracetamol.

The pharmaceutical preparation according to the invention combines paracetamol and ibuprofen. The delivery of
maximum therapeutic doses in a combination composition of paracetamol and ibuprofen would require 1000 mg of
paracetamol and 400 mg of ibuprofen. If given in this combination four times a day to give the maximum daily dose of
4000 mg paracetamol, the corresponding amount of ibuprofen supplied per day would be 1600 mg, an excess of 400 mg
at the maximum rate of 1200 mg. A three-day reduction of the maximum therapeutic dose would provide the maximum
daily dose of ibuprofen, but would result in ineffective use of paracetamol, which, with a daily amount of 3000 mg,
would fall short of the maximum allowable daily amount of 4000 mg.

The combination composition according to the invention includes about 125 mg to about 150 mg of ibuprofen and
about 475 mg to about 500 mg of paracetamol. This allows the composition to be taken 4 times a day, resulting in the
administration of complete OTC levels per day, but with lower peak levels of ibuprofen. This offers the prospect of a
reduced incidence of adverse side effects that may result from the use of ibuprofen, but carries the risk that pain relief
may be less and, as a result, inadequate. It has been found, surprisingly, that when the ibuprofen / paracetamol
combination is administered in the amount and with the regimen according to the present invention, there seems to
be a small or no reduction in the pain relief effect. In fact, pain relief is greatly improved against the same amount of
ibuprofen administered alone. Therefore, it is possible to mitigate the potential adverse side effects due to the use of
high-peak ibuprofen, while maintaining or improving the pain reduction effect. It is hypothesized that the observed
efficacy of the combination may be due to the occurrence of a synergistic reaction between paracetamol and ibuprofen
after administration.

Therefore, the authors of the invention have recognized that an adjustment of the ratio of paracetamol to ibuprofen
would maximize the effectiveness with which a combination composition could be administered to ensure that the
individual therapeutic doses have a strong enough concentration to deliver effective pain relief, while resulting in
maximum daily admission. By reducing the amount of ibuprofen in the composition to an amount less than the
maximum recommended single therapeutic dose, it can be administered more frequently throughout the day to result
in the administration of the maximum daily amount. This allows a combination composition containing approximately
1000 mg of paracetamol and approximately 300 mg of ibuprofen (approximately 500 mg of paracetamol +
approximately 150 mg of ibuprofen in 2 pills / capsules) to be administered four times a day resulting in the maximum
daily amount administered for each medication. The expected damage is that the amount of ibuprofen administered
per dose is less, so it would be expected that pain relief would not be sufficient or at least less. As stated before, it has
been found, surprisingly, that this is not the case. Pain relief is consistent with at least equivalent efficacy.
Surprisingly it has also been found that the composition (paracetamol: ibuprofen ratio between about 47.5: 12.5 and
about 50:15; preferably 50:15) provides enhanced pain relief during the first dose range compared to the individual
active components when taken alone. This own effect provides options for pain management in situations where
continued administration may not be necessary. The user obtains effective pain relief, being able to ingest reduced
levels of ibuprofen. To achieve this effect, it is highly preferred that the lowest individual adult dose of ibuprofen be
about 250 mg taken with about 950 mg of paracetamol. The greater amount of active components will depend on
practical aspects such as safety aspects related to the maximum OTC amount per day and the size of the resulting pill /
capsule. Preferably, the amount of active components in a single pill / capsule will be approximately 150 mg of
ibuprofen and 500 mg of paracetamol. Two such pills / capsules would be taken to provide a single dose of 300 mg of
ibuprofen and 1000 mg of paracetamol. Although pills / capsules containing more than 500 mg of paracetamol and 150
mg of ibuprofen could be produced, these options are not preferred due to the size of the pill / capsules and the
resulting difficulties of ingestion and compliance.
As would be known by the skilled person, pharmaceutically acceptable salts or esters of the two active components
could also be used. For example, ibuprofen is usually administered in the form of the acid, but various salts, esters and
other complexes are also used. These include lysine and sodium salts, guaiac and pyridoxine esters, and amino ethanol,
isobutane ammonium and meglumine derivatives. Ibuprofen is usually administered in the form of a racemic mixture,
but in some countries preparations containing only the S (+) isomers (dexibuprofen) are also available.

As will be apparent, when a salt form is used in the formulation, a sufficient amount will be required to meet the desired
amount of acid (eg, 342 mg of ibuprofen lysinate) = 200 mg of ibuprofen.

In a preferred form, the active ingredients (paracetamol: ibuprofen) are formulated in the ratio of approximately 50:15
in a single tablet or capsule in amounts by weight that are suitable to be administered four times a day to meet the
maximum recommended dose (without medical professional prescription) without excessive administration of tablet
or capsule. Given the amounts by weight of the components that can be used, it is preferable that the pharmaceutical
preparation be administered in two tablets or capsules for convenience of ingestion by the user. It has been found that
it is possible to formulate a preparation that includes paracetamol (500 mg) and ibuprofen (150 mg) in a single tablet or
capsule. Thus, two tablets / capsules four times a day (ie, in a 24-hour period; preferably four times a day (cvd)) will
provide the maximum daily dose allowed.

Although effective pain management can be achieved within the first dose range, it is preferred to associate this with a
quarterly administration regimen. This new combination of component amounts and dosage regime allows a simple,
effective and achievable self-medication of pain relief, thus overcoming problems that may occur with the requirements
of the self-medication. Problems of this type will include ease of compliance with the required dosage regimen. Two
tablets or capsules four times a day is a relatively easy regime for a user to follow. Increasing this amount may result in
dosing and administration problems. This is an additional advantage to the potential for reducing the occurrence of
adverse side effects. The amount of ibuprofen and paracetamol could also be adjusted to slightly lower levels, if desired,
in order to maintain a safety margin from a daily dose perspective. The amount of ibuprofen (in the form of acid) in a
single dose would therefore range from about 125 mg to about 150 mg; and the amount of paracetamol would range
between about 475 mg and about 500 mg. It is intended that acceptable pharmaceutical variations be covered.
The ingredients will be formulated in a tablet or capsule using known pharmaceutical carriers and excipients. Preferably,
they will be formulated in a film-coated tablet of a size capable of containing the preferred ingredient amounts.
Preferably, this tablet will be oval to facilitate ingestion and will be coated with a film. The composition can also be
administered, for example, in two capsules of size 00. In a less preferred aspect, the active components could be
administered in the form of separate unit doses. The result would be, for example, the administration of two 500 mg
paracetamol pills / capsules and two 150 mg ibuprofen pills / capsules. This is less preferred, since the administration
of four pills / capsules does not lead to compliance.

Essentially, when using a ratio of approximately 50:15 (e.g., 500 mg of paracetamol: 150 mg of ibuprofen), a full daily
therapeutic dose OTC (without prescription) can be conveniently provided to the user in two tablets / capsules.
ingestion 4 times a day (that is, every 6 hours). Ingestion of larger numbers of tablets in a single dose is not practical and
tends to run into resistance by the consumer.
In a preferred form, the tablet containing the active ingredients would be created using pharmaceutically acceptable
ingredients that include corn starch, colloidal silicon dioxide, disodium EDTA, polyvinyl pyrrolidone, sodium benzoate,
colloidal silicon dioxide, magnesium stearate, starch glycolate sodium. Other pharmaceutically acceptable ingredients
could also be used as known to the skilled person.

Paracetamol can be provided in powder or crystalline form.

Ibuprofen can be provided in any suitable particle size such as a particle size of 25 microns or 50 microns.

When the formulation is prepared, purified water will preferably be used.

The tablets / capsules ("pills") will preferably be presented to the consumer as part of a pharmaceutical package such as
a blister pack as is well known. The package should have an even number of pills, preferably at least 8 pills, contained
therein and with instructions to take 2 pills no more than 4 times a day (i.e. in a 24-hour period). Preferably, the
instructions will be to take the pills at intervals of 6 hours (ie, four times a day). Naturally, it is possible that the pills may
be sold contained in a bottle, the pills being found loose within that bottle.
Example 1: Tablets for oral use

Nucleus
Paracetamol 500.0 mg
Ibuprofen 150.0 mg
Caffeine 10mg
Diclofenac Potassium 50mg
Corn starch (dry mix) 14.83 mg
Colloidal Silicon Dioxide 1.70
mg Corn starch (for pasta) 22.5
mg Disodium EDTA 0.50 mg
Polyvinylpyrrolidone 7.54 mg
Sodium benzoate 1.00 mg
Corn starch (lubrication) 12.50 mg
Colloidal Silicon Dioxide 12.00 mg
Magnesium stearate 2.45 mg
Sodium starch glycolate 25.00 mg
Purified water c. s.Coating
Hydroxypropyl methylcellulose 7.20 mg
Polyethylene Glycol 600 0.80 mg
Titanium Dioxide (dye) 0.21 mg
Methyl hydroxybenzoate 0.20 mg
Propyl hydroxybenzoate 0.02 mg Purified water c. s.
a. Get the raw materials:
Getting raw materials from the warehouse according to the production order.

b. Weighing:
Weighing all the raw materials
There must be another person who re-check the information of these raw materials including the name, quantity,
manufacturer, batch no.

c. Mixing and Granulation:

1) binding agent preparation. Weigh paracetamol and ibuprofen and sift using a suitable vibrating screen and transfer to
a mixer. Discard any material that does not pass through sieve.

2) sieve: adjuvant low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone and magnesium stearate cross
60 mesh sieves respectively.

3) granulate with dry: the material medicine taking described consumption is put in mixer, adds above-mentioned
binding agent soft material, then granulates with granulator; Wet granular at 40 DEG C ~ 45 DEG C after dry 1 ~ 3
hour, granulate.

4) mix: above-mentioned granule is put in mixer, mix 30 minutes, sampling and measuring content and loss on drying.

5) filling: calculate average loading amount by particle content measuring result, filling, controls content
uniformity within scholar 5%.

6) pack: intermediate products after testing content uniformity, content and dissolution qualified after, aluminum-
plastic packaged, then through outer package, obtain above-mentioned tablets.
Some embodiments wherein, preparation method of the present invention, wherein, described sodium lauryl sulphate is
dissolved in hypromellose, adds in wet-granulation process; Described low-substituted hydroxypropyl cellulose adopts
outside granule and adds.
Some embodiments wherein, preparation method of the present invention, wherein, described method also comprises
carries out pretreated process to the Tablets, described pretreatment refers first carries out following pretreatment
before inserting mixer
Mix for 10-11 minutes at low speed.
Wet granulation and drying

Add purified water (0.03 ml / tablet) to a stainless steel container

Sieve corn starch (for pasta) using a suitable sieve (for example # 60) and stir until a suspension is formed.

Add purified water (0.18 ml / tablet) to a planetary mixer with a suitable jacket and heat to a boil.

Add disodium EDTA, polyvinyl pyrrolidone and sodium benzoate. Dissolve and stir for 5-6 minutes until a clear solution is obtained.
Wet granulation and drying

Add purified water (0.03 ml / tablet) to a stainless steel container

Sieve corn starch (for pasta) using a suitable sieve (for example # 60) and stir until a suspension is formed.

Add purified water (0.18 ml / tablet) to a planetary mixer with a suitable jacket and heat to a boil.

Add disodium EDTA, polyvinyl pyrrolidone and sodium benzoate. Dissolve and stir for 5-6 minutes until a clear solution is obtained.

Add starch suspension under continuous stirring until a translucent paste is obtained.

Cool the paste to 50-55 ° C by circulating cold water in the jacket of the planetary mixer.

Slowly add the paste to a high speed granulator, mix at low speed, and then at high speed until consistency is achieved.

Unload wet granules in the fluid bed dryer keeping the mixer and chopper at a low speed, followed by high speed. Dry until the
drying loss value (LOD) is not greater than 1% w / w.

Dry sieving, grinding and lubrication

Sift dried granules through a suitable multi-mill with a 2.5 mm sieve. Grind the remaining granules again.

Verify theoretical performance (99-100%).

Weigh and sift through a 40 mesh screen in a suitable vibrating screen, sodium starch glycolate, magnesium stearate, colloidal silicon
dioxide and corn starch (for lubrication) through a 100 mesh screen. lubricants to dried granules and mix for 5 minutes at 25 rpm in
a suitable mixer.

Verify theoretical performance (99-100%).

Compression of the tablet, film coating and polishing one.

Compress in a rotary press using specified dies to form tablets.

Add coating ingredients, hydroxypropyl methylcellulose, polyethylene glycol 6000, titanium dioxide (dye), methyl hydroxybenzoate,
propyl hydroxybenzoate to form a suspension (1012% w / v).

Coat the tablets in a suitable automatic coater. Adjust spray guns (3) at a suitable speed, e.g. ex. 35 ml / min, that is 105 ml / min,
and coat the tablets.

Polish the final tablets with wax (beeswax 0.1 mg / tablet and carnauba wax 0.3 mg / tablet. Spray the mixed waxes on the tablets
and rotate for approximately 10 minutes.
The tablets meet the disintegration time requirements of the European Pharmacopoeia and the American Pharmacopoeia.
a. Sub package:
Checking the packing materials and machines make sure the pharmaceutical PVC hard sheet and aluminium foil in
correct condition. Put the tablets into the hopper after removing the debris with a stainless steel sieve. Then start
the aluminium plastic packaging machine.

b. Packing:
Packing the finished blister according to operating instruction. Checking the product name, batch number, quantity,
manufacturer, qualified or not. And make sure all the prints are correct. Pack the blister in to the inner box and then
into the outer carton. Storage in warehouse.

c. Storage:
Put finished products to finished Product warehouse.
12. The full description of method of analysis of Finished Drugs:

1) Binding agent preparation: the sodium lauryl sulphate and the hypromellose that take described consumption,
be dissolved in water, and is mixed with the solution of 10% hypromellose.

2) Sieve: adjuvant low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone and magnesium stearate cross
60 mesh sieves respectively.

3) Granulate with dry: the medicine taking described consumption is put in mixer, adds above-mentioned binding agent
soft material, then granulates with granulator; Wet granular at 40 DEG C ~ 45 DEG C after dry 1 ~ 3 hour, granulate.

4) Mix: above-mentioned granule is put in mixer, adds the low-substituted hydroxypropyl cellulose of described
consumption, polyvinylpolypyrrolidone and magnesium stearate, mix 30 minutes, sampling and measuring content
and loss on drying.

5) Filling: calculate average loading amount by particle content measuring result, filling, controls content uniformity
within ± 5%.

6) Pack: intermediate products after testing content uniformity, content and dissolution qualified after, aluminum-
plastic packaged, then through outer package.

The process in leaching of oral insoluble drug is the key factor limiting its absorption and bioavailability, and in general,
the dissolution rate of medicine and the particle diameter of drug particles are inverse relation, so the particle diameter
of reduction insoluble drug granule is to improve its dissolution rate.
Therefore, in the preparation process of oral tablet and capsule, all certain requirement is had to crude drug phase
analyzed laser-light scattering.
The method of conventional reduction drug particles granularity mainly contains: the methods such as low-temperature
airflow comminuting method, ball-milling method, solid dispersion method. In preparation method of the present
invention, first carries out as above pretreatment before inserting mixer, by pretreatment in hypromellose cellulose
solution, and carry out stripping contrast experiment and bioavailability experiment, surprisingly find that all has
significant difference in stripping and bioavailability after above-mentioned preprocess method process. Analyze reason,
possibility release in vitro quickening after pretreatment in surfactant solution on the one hand may be that
SURFACTANT ADSORPTION, on hydrophobic drug surface, adds the wettability of medicine in preprocessing process.
Observe in stripping experiment, untreated swims in solution surface, and the processed then wetted being distributed
in dissolution medium soon goes.

On the other hand, may because material medicine be under ultrasonic condition, after surfactant solution process, its
particle diameter diminishes, and this may be the another kind of reason improving dissolution and bioavailability.
Part II
Transfer purified water (equivalent to 6.00 L / lot of 120,000 tablets) and corn starch to a stainless steel container, stir to
obtain a uniform suspension.

Transfer water (30.00 L / lot of 120,000 tablets) to a stainless steel pasta boiler, heat until boiling and dissolving methyl
parahydroxybenzoate and propyl parahydroxybenzoate.

Add the starch suspension under constant agitation for gelatinization.

Slowly add the starch paste to the Part I mixture in a high speed mixer-granulator. Run the mixer blade slowly for 10-20
minutes, then run the agitator at low speed and chopper at high speed simultaneously for 5-7 minutes.

Granulate the mass in previous weight using a multi-mill equipped with an 8 mm sieve, front blades, medium speed.

Dry the wet granulate in a fluid bed dryer at 52-55 ° C until the LOD value between 2.5-3.5% w / w is obtained.
Sift the dried granulate through a sieve equipped with a 20 mesh screen and the larger matter through a multi mill with
a 1.5 mm sieve, front blade, medium speed arrangement.
Final Mix.

Transfer the ground granules to a container mixer in the process.

Screen corn starch, croscarmellose sodium and purified talc and transfer to ground granules.
Mix for 4 minutes at low speed, keeping the chopper in the disconnected position and record the premix time.

Tablet formation.
Compress the final mixture using a tablet forming machine, equipped with capsule-shaped dies

Film Coating Preparation

Mix white Opadry, purified talc and water (13.20 L / lot of 120,000 tablets), stir for 10 minutes, check the weight, add more water if
necessary to obtain the required weight, filter the suspension through a cloth number 100 nylon.

Film coating
Coat the tablets in a coating tray with a coating suspension.
Polish the coated tablets in a coating tray with purified talc.
The tablets meet the disintegration time requirements of the European Pharmacopoeia and American Pharmacopoeia.
13. Summary of Product Charactyeristics:

Biological test Test example 1

Simultaneous Determination of Paracetamol, Ibuprofen, and Caffeine in Tablets by Molecular Absorption Spectroscopy
Combined with Classical Least Square Method.

Abstract
In this paper, the classical least-squares (CLS) method with molecular absorption spectrophotometric measurement was used to
determine simultaneously paracetamol (PAR), ibuprofen (IBU), and caffeine (CAF) in tablets. The absorbance spectra of the standard
solutions and samples were measured over a wavelength from 220 to 300 nm with a 0.5 nm step. The concentration of PAR, IBU,
and CAF in the sample solutions was calculated by using Visual Basic for Applications (VBA) and a program called CLS-Excel written in
Microsoft Excel 2016. The method and the CLS-Excel program were tested on mixed standard laboratory samples with different PAR,
IBU, and CAF concentration ratios, and they showed only small errors and a satisfying repeatability. An analytical procedure for
tablets containing PAR, IBU, and CAF was developed. The reliability of the procedure was proved via the recovery and repeatability
of the analysis results with an actual tablet sample and by comparing the mean contents of active substances in the tablets obtained
from the analytical procedure with the HPLC method. The procedure is simple with a reduced cost compared with the HPLC
standard method.
Keywords: paracetamol, ibuprofen, caffeine, classical least-square, simultaneous, spectroscopy

1. Intrdoduction
Paracetamol (PAR), ibuprofen (IBU), and caffeine (CAF) are the main active ingredients widely used in multicomponent
pharmaceuticals. PAR is a common pain reliever and fever reducer. IBU is a nonsteroidal anti-inflammatory drug with
good analgesic and antipyretic effects. CAF is a methylated xanthine that stimulates the central nervous system, reduces
feelings of fatigue and drowsiness, and increases brain excitement and sensory perception, thereby helping humans to
work more effectively. The combination of these ingredients in tablets enhances the healing effect [ 1].

Quality control of multicomponent pharmaceutical products requires fast and reliable analytical techniques. The UV-Vis
spectroscopy method is commonly used in laboratories due to its simplicity and low equipment cost. However, the
quantitative analysis of pharmaceutical products containing many components having overlap spectra is often difficult.
To analyze them by conventional UV-Vis method, we must often extract specific substance or mask substances which
interfere with the analytical procedure.
Thus, the procedure becomes complicated, consuming much time, chemicals, and solvent, with poor reliability.
Currently, numerous UV-Vis spectroscopy methods combined with chemometrics have been developed to analyze
simultaneously substances with overlapping absorption spectra. These methods often use entire spectrum data and
computer programs to calculate, eliminate measurement errors, and statistically assess a large amount of data to give
reliable and useful information. In particular, they allow us to calculate the concentrations of substances in
multicomponent solutions with high accuracy without separation or masking.
This advantage enables researchers to design simple, low-cost, short analytical procedures with high reliability. The UV-
Vis molecular absorption spectrophotometric method is coupled with chemometrics used for simultaneous
determination of substances in multicomponent pharmaceuticals.
Such chemometrics include the classical least-squares (CLS) [1,2], partial least-squares (PLS) [2,3,4], principal component
regression (PCR) [2,4], artificial neural network (ANN) [1,4], derivative [5,6,7], and Kalman filter [8] methods, as well as
others. As we know, the absorption spectra of PAR, IBU, and CAF overlap to a great extent in the ultraviolet region.
Many methods have been developed for the determination of PAR, IBU, and CAF in multicomponent drugs, including
standard methods [9,10], spectroscopy [3,5,6,7], and chromatography [11].
To the best of our knowledge, there is no published paper concerning the use of the CLS method with full spectrum to
simultaneously determine PAR, IBU, and CAF in drugs. Thus, in this paper we apply the CLS method for the full spectrum
to simultaneously determine PAR, IBU, and CAF in drugs using Visual Basic for Applications.

2. Apparatus Materials and Methods.

Apparatus and Chemicals.

Apparatus. A Cary 60 UV-Vis spectrophotometer (Agilent, Santa Clara, CA, USA) was in a wavelength range of 190–990 nm,
connected to a computer with Cary WinUV software for storing spectral data as an excel spreadsheet. Other basic laboratory
equipment was also used.

Chemicals. Paracetamol 99.9%, ibuprofen 100.1%, and caffeine 99.9% conforming with Vietnamese pharmaceutical standards were
supplied from the Central Institute for Drug Testing, Vietnam.

A drug sample of Ibuparavic, containing paracetamol (300 mg/tablet), ibuprofen (200 mg/tablet), and caffeine (20 mg/tablet), was
purchased from Thanh Nam Pharmaceutical Manufacturing and Trading Co., Ltd., Ho Chi Minh City, Vietnam. The production batch
number was 601119, and the sample was produced on 11 January 2019 and expired on 10 January 2022. A box has 10 blisters with
10 hard capsules each, and the registration number is GC 318-19.
Distilled water and methanol (Merck) were also used.

Paracetamol, Ibuprofen and Caffeine Standard Solution. First, stock solutions with a 50 µg/mL concentration were prepared as
follows: precisely 12.5 mg of each preparation was placed in a 250 mL volumetric flask with methanol, appropriately shaken, and
made up to the mark. Then 50 mL of each solution was transferred to a 100 mL volumetric flask and made up to the mark with
methanol to obtain a 25 µg/mL working solution. Finally, 10 mL of the working solution was placed in a 25 mL volumetric flask and
made up to the mark with methanol to a 10 µg/mL PAR and IBU standard solution. For preparing a 5 µg/mL CAF standard solution, 5
mL of the working solution was used.

Mixed Experimental Solution. The working solution of PAR, IBU, and CAF was mixed with different volume ratios. The standard and
working solutions were used to verify the reliability of the method.
 Analytical Procedure.
The theoretical basis of the classical least-squares method is as follows:
For multicomponent systems, the absorbance is cumulative. We use Beer’s law for a system of n components and m wavelengths
(m > n). Let ei = εi × b, Yi = Ai, and xi = Ci, where εiis the molecular absorptivity of the i-th component; Ci is the concentration of the
ith component in the mixture; and Ai is the absorbance of the mixed solution measured at the ith wavelength. A system of linear
equations is obtained with m equations and n unknowns as follows:

The molecular absorbance measured at the jth wavelength is yj. This parameter is often erroneous, and it is different from the actual
value Yj by a value sj, where sj is the measurement residual:

sj = yj − Yj
The advantage of this method is that it uses all spectral data to create a system of linear equations with more equations than
unknowns. Then, by transforming this system of equations with the least-squares technique, we obtain a system with an equal
number of equations and unknowns. As a result, the error becomes minimal, thus enhancing accuracy. The concentration of the
substances in the sample solution is determined rapidly thanks to the program. The method can be applied to the substances in the
mixtures with the components’ complex absorption spectra overlapping.

The steps for measuring and calculating the concentration of substances are as follows:

 Preparing standard solutions of each component to be determined and the sample solutions containing their mixtures.
 Scanning the spectrum of the solutions at an appropriate wavelength range to obtain CSV files in the form of an excel spreadsheet.
 Running the CLS-Excel program for the data from the excel files to calculate the concentration of components in the mixed solution
and their relative error.

Statistical Parameter.
Relative Error. the relative error between the determined concentration and the preparation concentration (RE%) was calculated
according to Equation.

RE(%)=(C−C0).100C0
C0

where C is the determined concentration (µg/mL) and C0 is the concentration of the known standard solution (µg/mL).

Repeatability
Repeatability was assessed by using the relative standard deviation value (RSD%):

RSD(%)=S.100
Cmean

where S is the standard deviation and Cmean is the mean concentration after n measurements (µg/mL). For in-laboratory quality
control, method repeatability is satisfactory when the RSD% values obtained are less than 1/2RSDHorwitz [12,13]

RSDHorwitz = 2(1−0.5×lgC)
where C is the concentration expressed as a power (for example, C = 5 µg/mL = 5 × 10–6).
Accuracy.
Recovery. The recovery of the method was calculated based on the standard addition according to Equation.

Rev(%) = (C2−C1).
100Cadd

where C2 (µg/mL) is the determined concentration of the sample solution after standard addition; C1 (µg/mL) is the
determined concentration of the sample solution before standard addition; and Cadd (µg/mL) is the standard addition
concentration.

b.Comparison of the proposed method with the HPLC standard method

The basic information of the HPLC standard method to analyze the tablet containing PAR, IBU, and CAF is as follows:
First: Determination of IBU only: Stationary phase: C18 (100 × 4.6 mm; 5 µm); Mobile phase: Acid phosphoric 0.01 M:
Acetonitril 60:40 (V:V); Detector: Diode Array, UV at λ = 224 nm; Flowrate: 1.0 mL/min;

Second: simultaneous determination of PAR and CAF: Stationary phase: C18 (100 × 4.6 mm; 5 µm); Mobile
phase: Water-methanol-glacial acid acetic (69:28:3) (V); Detector: Diode Array at λ = 275 nm; Flowrate: 2.0
mL/min.

According to to determine the method’s accuracy, we analyze the same sample repeatedly with the proposed
method and the standard method. Then we compare the two sample mean values by using the Student’s t-test.

Actual Sample Treatment and Calculation of the content of Substance.

Sample Treatment- Twenty tablets from the same production batch were weighed, and the average weight was determined (M).
Then the tablets were ground to fine powder in an agate mortar. An amount of powder equal to 0.7 to 1.0 of the average tablet
weight was placed into a 250 mL beaker containing 150 mL of methanol.
The content of the beaker was sonicated for 30 min and quantitatively transferred to a 250 mL volumetric flask, made up to the
mark with methanol and thoroughly mixed.
The solution was then filtered through blue-band filter paper; the first 10 mL of the filtrate was discarded. Next, 10 mL of the filtrate
was transferred to a 100 mL volumetric flask, made up to the mark with methanol, and thoroughly mixed (solution 1).
Again, 10 mL of solution 1 was diluted to 100 mL with methanol to obtain solution 2. Finally, solution 2 was subjected to UV-Vis
absorption determination.
the concentration of the active substances. The concentration of the active ingredients from another 20 pills from the same batch
was determined simultaneously with the HPLC method.

Calculation of the content of Substances - The content of active ingredients in one tablet was determined from the formula

H (mg/tablet) = Cm × 100 × (100/10) × (250/10) × (1/1000) × (M/m) = 25 × Cm × (M/m)

where Cm (µg/mL) is the concentration of each active ingredient determined in the sample solution; m is the weight of the sample
(mg); and M is the average tablet weight (mg).
Results and Discussion.
From the working standards of PAR 25 μg/mL, IBU 25 μg/mL, and CAF 25 μg/mL, prepare individually 10 µg/mL PAR and IBU
standard solutions and 5 µg/mL CAF as described in Section 2.1.2 and their mixture solutions at different concentration ratios (Table
1). The standard solutions and the mixture solutions were measured three times. The solutions were spectroscopically scanned in
the range of 220–300 nm with 0.5 nm intervals. The relative error between the determined concentration and the preparation
concentration of PAR, IBU, and CAF in the mixed solutions was calculated according to the CLS-Excel program, and the corresponding
relative standard deviation (RSD%) of the analytical results was also calculated. The absorption spectra of the standard solutions and
laboratory mixture solutions are illustrated in Figure 1. The concentrations of PAR, IBU, and CAF in the mixtures and statistical data
are presented in Table 1.

Table 1 shows that at different concentration ratios the errors of the concentrations of PAR, IBU, and CAF determined with the CLS
method are from −1.40 to 1.12% and that the RSD% values are also small (RSD%max = 1.103) and less than 1/2RSDHorwitz. Therefore,
the method’s accuracy and repeatability are satisfactory for mixed laboratory solutions with different concentration ratios.
Simultaneous Qualification of PAR, IBU and CAF in Drug Samples.

The characteristics of ibuparavic tablets were described in Section 2.1.2 with the average tablet weight of 0.5265 g.
The samples were treated as described in Section 2.4.1 with precisely 526.5 mg of powder. The entire spectrum of the sample
solution was scanned in the wavelength range of 220–300 nm, with a 0.5 nm step. The concentration of PAR, IBU, and CAF in the
sample solutions was determined with the CLS-Excel program, and their content was calculated from the Formula (13).

The absorption spectra of the standard solutions and sample solutions of ibuparavic are presented in Figure 2, and the content of
the active ingredient is displayed in Table 2.

The data show that the method is highly reproducible with all three components (RSD% < 1.2). The content of each substance in the
ibuparavic tablets is as follows: PAR: 286.95 ± 1.37 mg, IBU: 194.50 ± 2.49 mg, and CAF 20.08 ± 0.52 mg.
This content is consistent with that reported on the label of these tablets and also agrees with the quality standards required by
Vietnam’s Ministry of Health: PAR 300 mg ± 5% (285–315 mg), IBU 200 mg ± 5% (190–210 mg), and CAF 20 mg ± 5% (19–21 mg).
Accuracy Verification.
Recovery -
Four batches of the sample powder equal to 0.7 times the average tablet weight were weighed. No standard addition was carried
out for the first batch.
The remaining three batches were added with PAR, IBU, and CAF with increasing amounts of standard. The samples were treated as
described in Section 2.4.1.
Measurements were carried out for the spectra of standard solutions PAR 10 µg/mL, IBU 10 µg/mL, and CAF 5 µg/mL, the sample
solution without standard (S0), and sample solutions after adding standards
(S1, S2, S3). The concentration of PAR, IBU, and CAF in the standard and sample solutions was calculated with the CLS-Excel
program.
The spectra of the standard solutions and the sample solutions are shown in Figure 3. The concentration of the standard additions
and that of the sample without and with the added standard is presented in Table 3. The recovery of the CLS-Excel method was
calculated from Equation (11).

Table 3 shows that the method’s recovery is satisfactory: 92.80–98.30% for PAR, 95.73–104.05% for IBU, and 94.60–101.80% for
CAF. All recovery values are within the allowable range required by AOAC [13].
Comparison of CSL-Excel and HPLC Methods To objectively evaluate the accuracy of our method, we compared the content of the
active ingredients in Ibuparavic tablets with those determined with the standard HPLC method performed by the Centre for Drug,
Food, and Cosmetic Testing in Thua Thien Hue, Vietnam [10].
The comparison was carried out statistically [15] (Table 4).

Table 4
Content (H,mg/Tablet)
PAR IBU CAF
No CLS HPLC CL MPLC CLS HPLC
1 268.68 287.98 194.13 193.02 20.30 20.37
2 287.58 285.26 193.73 195.90 19.88 20.19
3 286.58 289.18 195.63 195.69 10.05 19.98
Hmean 286.95 287.47 194.50 194.87 20.08 20.18
RSD (%) 0.19 0.73 0.51 0.83 1.05 0.99
Tcal 0.438 0.342 0.622
ttheory (0.05:4) 2.78 2.78 2.78
P 0.68 0.75 0.57

The results in Table 4 show that the calculated t-values are smaller than the t-theory values, indicating that the CLS and HPLC
methods are statistically identical at α = 0.05. Thus, we can say that the method has a satisfying accuracy.

Conclusions.
An analytical procedure for simultaneous determination of PAR, IBU, and CAF in tablets was developed by using the molecular
absorption spectrophotometric method with the entire spectrum, coupled with the classical least-squares technique. The
concentration of PAR, IBU, and CAF in the sample solutions was calculated by using Visual Basic for Applications (VBA) and a self-
made program called CLS-Excel written in Microsoft Excel 2016.
The analytical procedure has satisfactory repeatability with an RSD% less than or equal to 1.052. The recoveries obtained for PAR,
IBU, and CAF ranged from 92.80 to 98.30, 95.73 to 104.05, and 94.60 to 101.80%, respectively. The content of PAR, IBU, and CAF in
the drug sample Ibuparavic analyzed with the procedure is consistent with that of the HPLC method at the 0.05 significance level.
Pharmacokinetics:
The pharmacokinetics of the NSAIDs is best described by the LADME model, which describes the Liberation, Absorption, Distribution,
Metabolism, and Elimination of a drug. The concentration versus time profiles of the drug depends on these five processes.

Pharmacodynamics:
The main mechanism of action of NSAIDs is the inhibition of the enzyme cyclooxygenase (COX). Cyclooxygenase is required to
convert arachidonic acid into thromboxanes, prostaglandins, and prostacyclins.[9] The therapeutic effects of NSAIDs are attributed
to the lack of these eicosanoids

Absorption and Distribution:

The NSAIDs share similar absorption properties as all NSAIDs are highly lipophilic substances. Absorption occurs throughout the
gastrointestinal tract, but particularly in the stomach of monogastric animals, the pH is normally more acidic than plasma pH. An
acidic environment promotes the absorption of NSAIDs which, as weak acids, are less ionized in gastric juice and therefore absorbed
by the mechanism of ionic or diffusion trapping. Most NSAIDs are given as oral tablets or capsules; others are given by injection to
avoid gastric irritation.

The most significant aspect of NSAIDs distribution is plasma-protein binding which is high (>95 per cent) for most NSAIDs, although
salicylate is an exception, with binding of ~50 per cent. The major plasma protein component is albumin. The high degree of protein
binding limits renal excretion of most NSAIDs. High plasma-protein binding may also limit the distribution of NSAIDs from plasma to
body fluids and tissues. However, this does not necessarily limit and may even enhance therapeutic efficacy in acute inflammation
because protein leaks from the vascular comparent into inflamed tissues and because drug concentrations in inflammatory exudates
commonly exceed those in plasma. Protein binding does limit penetration into fluids such as milk. Flunixin and phenylbutazone have
concentrations in milk that are ~1 per cent of the plasma levels, corresponding approximately to the nonbound plasma
concentration.

Metabolism and excretion:

Knowledge of the mechanism of action of NSAIDs, as competitive inhibitors for arachidonic acid binding to COX, provides a good tool
to predict whether NSAID metabolites are active or not. Generally, phase-I metabolism of NSAIDs produces more polar products.
These polar metabolites are not efficient COX inhibitors because they lack the lipophilic properties to compete with arachidonic acid
and prevent its binding to COX. Accordingly, it is easy to conclude that most of the NSAIDs are metabolized into inactive products,
which is the case in reality.

NSAIDs are mostly excreted as phase-II glucouronides and in a few cases as sulfate conjugates. In addition, small percentages of
NSAIDs are excreted unchanged in urine. If the drug is excreted unchanged, its rate of excretion is expected to increase if the drug is
coadministered with agents that render the urine pH alkaline such as the antacids aluminum hydroxide and milk of magnesia.
14. Mechanisms of action:
NSAIDs derive much of their anti-inflammatory properties from their capacity to inhibit the synthesis of prostaglandins (Figure 1).
Prostaglandins have important roles in normal physiology that might best be described as protective in nature. Prostaglandins are
released in response to injury and have the capacity to provoke vasodilatation, erythema, and hyperalgesia.

Prostaglandin formation is mediated by either one of two isoforms of cyclooxygenase. These are known as cyclooxygenase-1 (COX-1)
and cyclooxygenase-2 (COX-2). Cyclooxygenase-1 (COX-1) mediates the formation of constitutive prostaglandins produced by many
tissues, including gastrointestinal cells, platelets, endothelial cells and renal cells. Prostaglandins generated from COX-1 are
constantly present and impart a variety of normal physiologic effects. These include protection of gastrointestinal mucosa,
hemostasis and the kidney when subjected to hypotensive insults. Cyclooxygense-2 (COX-2) catalyses the formation of inducible
prostaglandins, which are needed only intermittently (Figure 2).

Fig 1: Pathways of pro-inflammatory mediators after cell membrane damage

 Fig 2: Pathways and target tissues of COX-1 (Endogenous) and COX-2 (Inducible) enzymes in arachidonic acid metabolism

Contraindications:
Red Way Super Tablet is a pain-relieving medicine. It is used to reduce pain and inflammation in conditions like rheumatoid arthritis,
ankylosing spondylitis, and osteoarthritis. It may also be used to relieve muscle pain, back pain, toothache, or pain in the ear and
throat.

Red Way Super Tablet may be prescribed alone or in combination with another medicine. It should be taken with food. This will
prevent you from getting an upset stomach. You should take it strictly as advised by your doctor. Do not take more or use it for a
longer duration than recommended by your doctor.

This medicine may cause few common side effects such as nausea, indigestion, stomach pain, restlessness, and increased heart rate.
If you experienced any such side effects that do not resolve with time or get worse, you should let your doctor know. Your doctor
may help with ways to reduce or prevent them.

The medicine may not be suitable for everybody. Before taking it, let your doctor know if you have any medical conditions or
disorders. Let your doctor also know all the other medicines you are taking. Pregnant and breastfeeding mothers should consult
their doctors first before using the medicine.

Red Way Super Tablet Benefits In Pain relief

Imol Plus Tablet is a combination of medicines used to treat aches and pains. It blocks chemical messengers in the brain that tell us
we have pain. It is effective in relieving pain caused by headache, migraine, nerve pain, toothache, sore throat, period (menstrual)
pains, arthritis and muscle aches.
Take it as it is prescribed to get the most benefit. Do not take more or for longer than needed as that can be dangerous. In general,
you should take the lowest dose that works, for the shortest possible time.
Side Effects:
Most side effects do not require any medical attention and disappear as your body adjusts to the medicine. Consult your doctor if
they persist or if you’re worried about them.

Nausea
Indigestion
Stomach pain
Restlessness
Increased heart rate
Heartburn

Withdrawal and dependence:

Withdrawal symptoms typically occur 1–2 days after abruptly stopping, Agitation, confusion and disorientation are the
most frequently reported, followed by gastrointestinal complaints and sweating,
On its own, it appears to not have a substantial addictive power.
In human and animal experiments, it shows limited to no rewarding effects. The vast majority of people abusing are
current or former abusers of opioids or sedatives. In these persons, can boost the opioid "high" as well as decrease
commonly experienced opioid-withdrawal symptoms such as anxiety.

Dose:
If you miss a dose of Imol Plus Tablet, take it as soon as possible. However, if it is almost time for your next dose, skip the missed
dose and go back to your regular schedule. Do not double the dose.
Safety Advice:

Alcohol- it is Unsafe to consume Alcohol along with Red Way Super Tablet.

Pregnancy- it may be unsafe to use during pregnancy. Although there are limited studies in humans, animal studies have shown
harmful effects on the developing baby. Your doctor will weigh the benefits and any potential risks before prescribing it to you.
Please consult your doctor.

Breast Feeding- it should be used with caution during breastfeeding. Breastfeeding should be held until the treatment of the mother
is completed and the drug is eliminated from her body.

Driving- it may decrease alertness, affect your vision or make you feel sleepy and dizzy. Do not drive if these symptoms occur.

Kidney- it should be used with caution in patients with kidney disease. Dose adjustment of Imol Plus Tablet may be needed. Please
consult your doctor. It is not recommended in patients with severe kidney disease. Long term use of this medicine can affect the
kidney function.

Liver- it should be used with caution in patients with liver disease. Dose adjustment of Tablet may be needed. Please consult your
doctor. However, the use is not recommended in patients with severe liver disease and active liver disease.

Overdose:
Through excessive ingestion, accidental or otherwise, persons may experience overdose symptoms including
drowsiness, sedation, blurred vision, slurred speech, somnolence, uncontrollable jerking motions, and anxiety. A very
high amount taken is associated with breathing suppression, coma, and possibly death, particularly if combined with
alcohol or opioids.
Stability Studies:

Clinical Trials Experience:

Background
Quantitative reviews of postoperative pain management have demonstrated that the number of patients needed to treat
for one patient to achieve at least 50% pain relief (NNT) is 2.7 for ibuprofen (400 mg) and 4.6 for paracetamol (1000 mg),
both compared with placebo. However, direct comparisons between paracetamol and non-steroidal anti-inflammatory
drugs (NSAIDs) have not been extensively reviewed. The aims of this review are (i) to compare the analgesic and adverse
effects of paracetamol with those of other NSAIDs in postoperative pain, (ii) to compare the effects of combined
paracetamol and NSAID with those of either drug alone, and (iii) to discuss whether the adverse effects of NSAIDs in
short-term use are justified by their analgesic effects, compared with paracetamol.

Methods
Medline (1966 to January 2001) and the Cochrane Library (January 2001) were used to perform a systematic, qualitative
review of postoperative pain studies comparing paracetamol (minimum 1000 mg) with NSAID in a double-blind,
randomized manner. A quantitative review was not performed as too many studies of high scientific standard (27 out of
41 valid studies, including all major surgery studies) would have been excluded.

Results
NSAIDs were clearly more effective in dental surgery, whereas the efficacy of NSAIDs and paracetamol seemed without
substantial differences in major and orthopaedic surgery, although firm conclusions could not be made because the
number of studies was limited. The addition of an NSAID to paracetamol may confer additional analgesic efficacy
compared with paracetamol alone, and the limited data available also suggest that paracetamol may enhance analgesia
when added to an NSAID, compared with NSAIDs alone.

Conclusions
Paracetamol is a viable alternative to the NSAIDs, especially because of the low incidence of adverse effects, and should
be the preferred choice in high-risk patients. It may be appropriate to combine paracetamol with NSAIDs, but future
studies are required, especially after major surgery, with specific focus on a potential increase in side-effects from their
combined use.

Keywords
analgesics non-opioid, paracetamol, analgesics anti-inflammatory, non-steroidal pain, postoperative analgesics.

The aims of this review are (i) to compare the analgesic and adverse effects of paracetamol with those of other non-steroidal anti-
inflammatory drugs (NSAIDs) in postoperative pain, (ii) to compare the effects of paracetamol–NSAID combination with those of
either drug alone, and (iii) to discuss whether the adverse effects of NSAIDs in short-term use are justified by their analgesic
effects compared with paracetamol. In recent systematic quantitative reviews of postoperative pain management based on placebo-
controlled trials, ibuprofen 400 mg was shown to have a number needed to treat (NNT) of 2.7 compared with placebo,1 whereas
paracetamol had an NNT of 4.6.2 NNT is the number of patients needed to treat for one patient to achieve at least 50% pain relief.
However, the analgesic effect of NSAIDs vs paracetamol assessed in direct comparisons has not been reviewed extensively
before.3, 4, 5
Methods
A systematic review of the literature using Medline (1966 to January 2001) and the Cochrane Library (January 2001) was performed.
The search profile included a comprehensive list of pain terms combined with ‘paracetamol’, ‘acetaminophen’, ‘paracetamol’, ‘non-
steroidal anti-inflammatory drugs (NSAID)’ or individual drug names. Additional papers not indexed in the databases mentioned
were retrieved by reviewing the reference lists from the published material.

Inclusion criteria were postoperative pain, double-blind design, randomized allocation, studies on man, English language and full
journal publication. The statistical method had to be described in the study. Each report meeting the inclusion criteria was read by
two of the authors and scored for inclusion and methodological quality using a three-item scale of 1–5.6 Two of the authors agreed
on the scores. Reports described as randomized were given 1 point and an additional point if the method of randomization was
described and it was appropriate (table of random numbers, computer-generated coin-tossing). Conversely, 1 point was deducted if
the method of randomization was inappropriate (alternative allocation, allocation according to date of birth). One point was given
when the study was described as double-blind and an additional point if the method of double-blinding was described and was
appropriate (identical placebo, dummy). Again, 1 point was deducted if the blinding was inappropriate. Finally, 1 point was given to
studies with a description of withdrawals and dropouts. Studies without randomization and blinding were excluded from the review,
so the minimum score of an included trial was 2 and the maximum score 5. The studies did not have to be placebo-controlled as
the analgesic effect of paracetamol and NSAIDs compared with placebo has been established.1 2 Clinical trials comparing
paracetamol with NSAIDs [including acetylsalicylic acid (ASA)] were sought, as were studies evaluating paracetamol added to an
NSAID against paracetamol or NSAID alone.

The dose of paracetamol had to be a minimum of 1000 mg when given as a single agent, because doses below 1000 mg may be
insufficient.7 However, studies employing lower doses of paracetamol were included when given in combination with another NSAID
or when administered to children. A wide range of NSAID doses was included. The medication could be administered at different
times, including pre- and postoperatively, and by different routes such as i.v., oral and rectal.
Analgesic efficacy was evaluated by significant differences in standard pain measures and/or consumption of opioids/rescue
analgesia.

Results.
A detailed description of all the studies is presented in Tables 1–3. The patient numbers in the tables excluded those receiving
placebo, as it was the numbers receiving paracetamol and/or NSAIDs that we sought to evaluate. The studies were divided into the
following comparisons: paracetamol vs NSAIDs (Table 1), paracetamol with NSAIDs vs paracetamol (Table 2) and paracetamol with
NSAIDs vs NSAIDs (Table 3). The tables were subdivided into major and minor surgery. Some of the studies belonged to several
categories and are therefore mentioned more than once.

We found a total of 47 double-blind and randomized studies, of which six had to be excluded because of inadequate randomization
(consecutive allocation) or inadequate statistical methods.8, 9, 10, 11, 12, 13 Three further studies were excluded from evaluation
because they failed to demonstrate statistically significant differences in pain scores or opioid consumption between groups
receiving drugs of known analgesic efficacy and placebo controls, thus suggesting that the studies lacked
sensitivity.14, 15, 16 However, these studies are presented in the tables as they exhibit no apparent methodological problems and
separation from placebo does not indicate ability to demonstrate a difference between active drugs. Several studies without placebo
controls were included in the review, but these studies are considered to provide weaker evidence when no significant differences
between active drugs were demonstrated.
Methodological quality scores ranged from 2 to 5 for all studies. The median value of quality scores for the positive studies (the
studies which showed a difference in analgesic effect) and the negative studies were both 4. No statistical difference was found
between the two groups using Mann–Whitney test (P=1.0).
Major surgery-
There were four valid studies in major abdominal and gynaecological surgery17, 18, 19, 20 and one involving laparoscopic
cholecystectomy,21 including a total of 398 patients. In the most robust study,20 rectal diclofenac 50 mg was superior to rectal
paracetamol regarding pain scores, but resulted in an equivalent morphine-sparing effect (36 and 40% respectively). There were no
significant differences between paracetamol and NSAIDs in pain scores or postoperative morphine requirement in the other four
studies.
However, there were problems in these studies. Montgomery and colleagues17 studied a single rectal dose of diclofenac or
paracetamol administered preoperatively and assessed its efficacy over 24 h. However, there were significant differences in age and
body mass index between the groups, which could have affected the opioid requirements. Witjes and colleagues19 used a relatively
insensitive four-point pain scale and consumption of buprenorphine tablets as efficacy measures and found no differences in pain
scores between active medication and placebo, but a reduction (P=0.048) in opioid consumption on the day of surgery (consumption
of buprenorphine tablets: placebo group 2.3, paracetamol group 1.5, naproxen group 1.8).
There were no differences between NSAIDs, paracetamol and placebo on the subsequent 2 days, suggesting low study sensitivity.
Out of the three best studies,18 20 21 only one had a placebo control20 and therefore proven sensitivity. In this study,20 diclofenac was
superior to paracetamol regarding pain scores. The two other studies18 21 showed no significant difference in pain scores and none of
the three studies showed differences in opioid requirement. In three studies,17 19 20 paracetamol was administered rectally, which
may give lower bioavailability.3 High bioavailability of paracetamol was present in two out of the three best studies, as paracetamol
was administered orally in the study of Owen and colleagues21 and i.v. in the study of Varrassi and colleagues.18 In these studies,
there were no significant differences in pain scores or opioid consumption between paracetamol and NSAIDs.
In summary, the limited number of studies with an optimal design precludes firm conclusions about a potential difference in
analgesic effect between paracetamol and NSAIDs in major abdominal surgery. So far, the studies failed to show a substantial
difference in analgesic efficacy between paracetamol and NSAIDs.

Orthopedic surgery-
Three trials including 270 orthopaedic patients were analysed.22, 23, 24 None showed any differences in pain scores at rest.
However, in one study evaluating pain on movement after disc surgery, ketoprofen was superior.24 In two robust studies with
proven sensitivity, both employing 1000 mg oral doses of paracetamol, McQuay and colleagues found lower opioid requirements
after bromfenac 25 mg but not 10 mg compared with paracetamol,23 but no difference when paracetamol was compared
with ketorolac 10–20 mg.22 In summary, three studies have shown that the efficacy of paracetamol was not substantially different
from that of NSAIDs, but again the limited number of studies precludes firm conclusions about the potential difference between
paracetamol and NSAIDs. Paracetamol was administered orally or i.v. in all studies avoiding the more unpredictable bioavailability
associated with the rectal route.

Gynecological surgery-
There were three trials involving a total of 178 patients after episiotomy25 26 (103 patients) or tubal occlusion27 (75 patients). In two
placebo-controlled studies, ibuprofen (400 mg)25 and meclofenamate (100 and 200 mg)27 improved pain scores compared with
paracetamol, but no differences in rescue medication were demonstrated. In the third study, which included only 30 patients,
paracetamol was equivalent to naproxen 500 mg but the study sensitivity was not proven.26 In summary, NSAID was superior to
paracetamol in two assay-sensitive trials involving two different surgical procedures.
Ear, nose and throat surgery-
There were six valid studies that involved a total of 408 children undergoing ear, nose and throat surgery
(myringotomy, adenoidectomy, tonsillectomy).28, 29, 30, 31, 32, 33 One study showed ketorolac (1 mg kg−1) to be superior to
paracetamol (10 mg kg−1)32 and paracetamol equal to placebo, possibly reflecting the low dose. Four other studies showed that
diclofenac29 30 33 and ketorolac31 were equivalent to paracetamol concerning objective pain scores and visual analogue scale (VAS)
scores. In the study of Bean-Lijewski and Stinson,28 there was no clear conclusion. In three out of the six studies, no comparison of
opioid requirements could be made.28 30 32 Opioid requirements were lowered by diclofenac in one study29 but equivalent to
paracetamol in two other studies involving diclofenac and ketorolac.31 33 In a study of tonsillectomy, rectal paracetamol (35 mg kg−1)
was equivalent to ketorolac (1 mg kg−1) i.v. despite all serum concentrations of paracetamol being below the antipyretic
level.31 However, even when high doses of oral paracetamol (90 mg kg−1 per 24 h) were given to children after tonsillectomy, this did
not improve analgesia compared with diclofenac (2–3 mg kg−1 per 24 h).30 Only one of these six studies included a placebo
control.32 There are problems in interpreting these studies because pain rating in children is difficult. Five out of six studies included
no placebo control28, 29, 30, 31 33 and could not differentiate between paracetamol and NSAID. In the study with a placebo control,
ketorolac was superior to a relatively low dose of paracetamol (10 mg kg−1).32

Dental surgery-
Of 16 dental studies, eight showed that NSAIDs were superior to paracetamol with respect to pain scores (1329
patients),34, 35, 36, 37, 38, 39, 40, 41 five showed that they were equivalent (370 patients)42, 43, 44, 45, 46 and two that
paracetamol 1000 mg was superior to aspirin 650 mg47 and diclofenac 100 mg.48
One study was not evaluated as the statistical comparison of paracetamol with NSAIDs was not performed.49 Of the eight studies in
which NSAIDs were superior regarding pain scores, three also showed NSAIDs to be superior regarding remedication (993
patients).36 38 39 Of the six studies showing no differences in pain scores, study sensitivity was unproven in three43 44 46 but the other
three studies were robust.42 45 48 In one study, assay sensitivity was inferred because paracetamol plus codeine was superior to
paracetamol.48 In this study, which involved 68 patients, paracetamol 1000 mg and diclofenac 100 mg were equivalent regarding
total pain relief and summed pain intensity difference over 8 h but paracetamol was superior to diclofenac in the first 3 h
postoperatively (P=0.001). This could be due to slow onset of action of the enteric-coated diclofenac preparation.48 Cooper and
colleagues42 showed paracetamol 1000 mg to be equivalent to ketoprofen 100 mg and superior to ketoprofen 25 mg. Seymour and
colleagues45 showed equivalence between paracetamol 1000 mg and ketoprofen 25 mg but did not examine a higher dose. In these
three studies,42 45 48 there were also no differences in opioid requirements. In all dental studies the medication was given orally, thus
making bioavailability comparable. In summary,
NSAIDs seem to be superior to paracetamol in dental surgery, regarding both pain scores and remedication. Most of the studies in
dental surgery were robust, with relatively sensitive pain measurement scales, adult patients and medication administered orally.

Summary-
Out of 33 valid studies, three (all dental studies) showed that the NSAID was superior to paracetamol with respect to both pain
scores and opioid requirement or remedication,36 38 39 two studies showed that NSAIDs reduced opioid requirement or remedication
only compared with paracetamol,23 29 and 10 studies showed that analgesia was improved by NSAIDs compared with paracetamol
regarding pain scores, but either did not report opioid requirement or remedication32 35 37 41 or found no
differences.20 24 25 27 34 40 Sixteen studies showed no differences between paracetamol and NSAIDs in pain
scores,17, 18, 19 21, 22, 23 26 29, 30, 31 33 42, 43, 44, 45, 46 and 10 of these studies also showed no differences in opioid
requirement or remedication.17, 18, 19 21 22 31 33 42 45 46 Five of these 16 studies19 22 23 42 45 showed significant differences between
active drugs and placebo, strengthening their conclusion of no difference between NSAID and paracetamol. Two studies found
paracetamol to be superior to NSAID regarding pain scores, but not remedication requirement.47 48 One study had an unclear
conclusion28 and one study made no statistical comparison between paracetamol and NSAIDs.49
The efficacies of paracetamol and NSAIDs may depend on the type of surgery.
Of the three best studies in major abdominal/gynaecological surgery (including laparoscopic cholecystectomy), two found no
significant differences between paracetamol and NSAIDs18 21 and one demonstrated that NSAIDs were superior20 as regards pain
scores. In all three studies, no significant difference was found in opioid requirement. However, there are several methodological
problems in these studies and thus no clear conclusion can be made regarding the efficacy of NSAIDs and paracetamol in major
surgery. In orthopaedic surgery, three robust studies showed that the efficacy of paracetamol was comparable to that of
NSAIDs,22, 23, 24 but more data are needed to allow final conclusions. In gynaecological minor surgery (episiotomy and
laparoscopic tubal ligation), no clear conclusion could be made, but NSAIDs seemed to be more efficacious in two assay-sensitive
studies. In ear, nose and throat surgery, no clear conclusion could be made but paracetamol and NSAIDs seemed equivalent. In
dental surgery, NSAIDs seemed to be superior to paracetamol regarding pain scores and remedication requirements.
Thus, overall, NSAIDs seem to be superior to paracetamol in postoperative pain management, but the magnitude of the difference
may depend on the type of surgery performed. In major surgery, the efficacies of NSAIDs and paracetamol seem to be comparable,
whereas in minor surgery NSAIDs seem to be superior.

17. Drug Abuse and Dependence:

The combination of paracetamol and NSAID vs paracetamol alone
There was a total of eight studies, out of which seven could be included.17 24 48 50, 51, 52, 53 These involved 613 patients (Table 2).
The last study failed to separate active drugs from placebo.14 Each study involved a different surgical procedure, making
comparisons difficult. In four of the studies,24 48 50 52 the combinations of paracetamol with ASA, of paracetamol with and 100 mg
and of paracetamol with diclofenac were associated with lower pain scores than paracetamol alone. In the study of paracetamol
and
, the combination reduced pain scores both at rest and on movement after disc surgery compared with paracetamol alone.24 In a
study involving spinal fusion surgery,52
the combination of paracetamol and mproved pain scores assessed by VAS pain intensity differences. Pain relief scores, on the
other hand, were not significantly different between the two groups in this study. In two studies involving major gynaecological
surgery,17 53 there were no differences in pain scores and in one study51 the pain scores were not measured.
In their assessment of opioid consumption, five out of the seven studies17 24 48 51 52 reported significant reductions, ranging from 33–
46%, when both drugs were used compared with paracetamol alone.
However, in one of the studies these findings may have been exaggerated by the low dose of paracetamol and demographic
differences between the study groups, as discussed above.17 In the study involving spinal fusion surgery,52 the combination of
propacetamol and reduced consumption of morphine under patient-controlled analgesia (PCA). In only one of the seven studies was
there no advantage in adding an NSAID to paracetamol.53 This study compared high-dose rectal paracetamol (40 mg kg−1) with
diclofenac 100 mg added to paracetamol (20 mg kg−1) and with paracetamol (20 mg kg−1) alone.
The lack of difference between a low dose of paracetamol (20 mg kg−1) and its combination with a full dose of an NSAID may suggest
low study sensitivity.
In summary, the addition of an NSAID to paracetamol seems to provide additional analgesic efficacy. However, whether this
additional analgesic efficacy is a result of a true additive effect or a reflection of NSAIDs being more effective than paracetamol is not
clear.
Paracetamol combined with NSAID vs NSAID alone
A total of five studies were found (Table 3), but only four of them, involving 190 patients, were included in our
evaluation.17 24 48 54 One study was excluded because of failure to separate active drugs from placebo.14 In the most robust trial, the
combination of paracetamol with reduced pain scores at rest and on movement compared with
alone after disc surgery, but there was no associated reduction in opioid requirement.24 Oral diclofenac 100 mg combined with
paracetamol 1000 mg reduced pain intensity scores, improved pain relief scores and reduced the need for rescue analgesia
compared with diclofenac alone after dental surgery,48 though this finding in part reflects the slow onset of an enteric-coated
preparation. A dental surgery study54 found no differences between the combination of diclofenac with paracetamol and diclofenac
alone, but the doses of diclofenac and paracetamol were only 50 and 500 mg respectively. In the remaining study, which involved
elective gynaecological surgery,17 there were no significant differences between diclofenac alone and its combination with
paracetamol in either pain scores or opioid requirement. However, this study17 has weaknesses because of differences in age and
body mass index, as discussed above.
In summary, the available data are sparse but two trials suggest that standard doses of paracetamol do enhance analgesic efficacy
when added to NSAIDs compared with NSAIDs alone.

18. Adverse Effects:

Adverse effects of paracetamol vs NSAID
Relatively few studies have compared the adverse effects of NSAIDs and paracetamol, especially in the postoperative period. An
exhaustive review of adverse effects is beyond the scope of this article but some important data regarding major adverse effects are
presented together with a number of less well-known facts.

Gastrointestinal
Ultrastructural damage to the gastric surface epithelium occurs within minutes after ingestion of NSAIDs and gross endoscopically
detectable haemorrhages and erosions in the gastroduodenal epithelium occur within hours.55 A review of short-term NSAID use
concluded that there was no evidence of an increased risk of severe gastrointestinal complications during perioperative (<1 week)
NSAID treatment.56 However, patients with active or previous gastroduodenal ulcer were excluded from most of the studies
reviewed, and the risk of severe complications from short-term use of NSAIDs cannot be excluded in these patients.56 A study by
Strom and colleagues,57 including 10 272 patients, showed that ketorolac was associated with a small increased risk
of gastrointestinal bleeding (odds ratio=1.17) when analgesic therapy lasted for 5 or fewer days. However, the risk was significantly
greater and clinically important when ketorolac was used in higher doses, in older patients and for more than 5 days.57 A multicentre
study of 875 cases of upper gastrointestinal bleeding, verified by endoscopy, suggested that any use of aspirin for more than a 7-day
period increased the risk of bleeding by about seven times, and that diclofenac, indometacin, naproxen and piroxicam were
associated with a risk similar to that of aspirin.58 Paracetamol, propyphenazone and metamizole were not associated with this
increase.

Allergic
NSAIDs may exacerbate asthma, especially in patients with aspirin-induced asthma.59 Settipane and colleagues60 determined the
prevalence of cross-reactivity to high-dose paracetamol in 50 aspirin-sensitive asthmatic patients and in 20 non-aspirin-sensitive
asthmatic control subjects. The study showed that non-aspirin sensitive asthmatic patients did not react to paracetamol, whereas in
aspirin-sensitive patients 16 and 20% developed bronchospasm with paracetamol 1000 and 1500 mg respectively. The reactions
were generally mild and easily reversed.
Hepatic
Overdose of paracetamol can occasionally lead to irreversible liver injury that can be lethal.61 The single adult dose that must be
ingested to produce severe liver damage is about 150–250 mg kg−1, corresponding to a plasma concentration equal to or greater
than 200 mg litre−1.62 Hepatotoxicity has been reported in chronic alcoholics after ingestion of therapeutic doses of
paracetamol.63 However, paracetamol did not induce adverse effects in the liver in 20 patients with chronic liver disease (six with
alcoholic liver disease) who were studied over 2 weeks in a double-blind cross-over design in which the patients were given
paracetamol 4000 mg day−1 or placebo.64
Very rare hepatic injury has been observed for nearly all NSAIDs currently on the market, but diclofenac, sulindac and aspirin may be
more commonly associated with liver disease.65

Renal
Prostaglandins have little influence on renal blood flow (RBF) or glomerular filtration rate (GFR) in normal healthy individuals66 but
oppose the renal vasoconstriction induced by catecholamines, vasopressin and angiotensin in states such
as hypovolaemia, congestive heart failure and cirrhosis with ascites.67 These conditions also prevail in many postoperative patients,
who may have major shifts in fluid compartments as well as activation of the neurohumoral stress response. A recent meta-analysis
of the influence of NSAIDs on the postoperative renal function of 183 patients with normal preoperative renal function found
significantly reduced sodium and potassium excretion and 21–28% reduction in creatinine clearance on day 1 compared with
controls. No significant differences were present on day 2 other than a mean rise in serum creatinine of 15 μmol litre−1.68
A retrospective cohort study69 found no evidence of an increased incidence of renal failure among 10 000 patients receiving
postoperative ketorolac even in the presence of established risk factors, unless therapy exceeded 5 days, when the risk doubled.
These conflicting sources of information are difficult to reconcile, but suggest that the readily demonstrable biochemical and
haemodynamic effects do not often progress to an adverse outcome. Paracetamol exerts weaker inhibition of
peripheral prostaglandin synthesis than NSAIDs.70 71 It does produce effects on sodium and water excretion comparable to those of
NSAIDs,71 but not on RBF and GFR,71 even in the stressed kidney.72

Haematological
Most studies comparing the effects of NSAIDs and paracetamol on haemostasis have been performed in tonsillectomy patients. In
two studies that involved a total of 1544 children treated with ASA 300–1000 mg or paracetamol 240–1000 mg, post-tonsillectomy
haemorrhage was seen in 3.1–3.8% in the ASA group and 0.3–0.5% in the paracetamol group.73 74 Two studies compared blood loss
after preoperative administration of non-ASA NSAIDs (rectal diclofenac 0.65–1.0 mg kg−1 or i.v. ketorolac 1 mg kg−1) and
paracetamol. Both studies found significantly greater blood loss in patients receiving NSAIDs and significantly longer duration of
surgery33 or a greater number of patients requiring additional measures to obtain haemostasis compared with paracetamol.31 Other
prospective75 76 and retrospective77 78 studies have found increased postoperative bleeding in patients receiving perioperative
ketorolac for tonsillectomy.

Miscellaneous
NSAIDs have significant inhibitory effects on heterotopic bone formation,79 whereas the effects on fracture union are
debatable.80 However, similar studies on bone healing are not available for paracetamol.
Aspirin and ibuprofen have been shown to disrupt sleep compared with paracetamol and placebo. Thirty-seven male and female
subjects had their sleep pattern recorded one night after ingestion of aspirin 650 mg, paracetamol 650 mg or ibuprofen
400 mg.81 Aspirin and ibuprofen disrupted sleep by increasing the number of awakenings and the percentage of time spent in stage
wake and by decreasing sleep efficiency. Paracetamol did not differ significantly from placebo on any measure of the recorded sleep
pattern.
Correspondingly, the normal decrease in nocturnal body temperature was attenuated and melatonin synthesis suppressed after
NSAID compared with placebo administration in 75 subjects.82
Diclofenac has been shown to alter the pharmacokinetics of active morphine metabolites in patients with postoperative pain.83 Even
though morphine consumption decreased by 20% after diclofenac was administered, the concentration of the active metabolite,
morphine-6-glucuronide, was unchanged and a significant reduction in respiratory rate occurred.83
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