Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Pamaryl 1 mg Tablets
Pamaryl 2 mg Tablets
Pamaryl 3 mg Tablets
Pamaryl 4 mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Pamaryl 1 mg Tablets contains 1 mg of glimepiride.

Pamaryl 2 mg Tablets contains 2 mg of glimepiride.
Pamaryl 3 mg Tablets contains 3 mg of glimepiride.
Pamaryl 4 mg Tablets contains 4 mg of glimepiride.

For full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Tablet.
Pamaryl 1 mg is a Light Blue coloured octagonal, uncoated tablets with imposing of Himont logo.
Pamaryl 2 mg is a Pink coloured octagonal, uncoated tablets with imposing of Himont logo.
Pamaryl 3 mg is a Yellow coloured octagonal, uncoated tablets with imposing of Himont logo.
Pamaryl 4 mg is a Green coloured octagonal, uncoated tablets with imposing of Himont logo.

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

Glimepiride is indicated for the treatment of type 2 diabetes mellitus, when diet, physical excercise and weight
reducation alone are not adequate.

4.2 Posology and method of administration

For oral administration.

The basis for successful treatment of diabetes is a good diet, regular physical activity, as well as routine checks of
blood and urine. Tablets or insulin cannot compensate if the patient does not keep to the recommended diet.

Posology

The dosage is determined by the results of blood and urinary glucose determinations.

The starting dose is 1 mg glimepiride per day. If good control is achieved, this dosage should be used for
maintenance therapy.

For the different dosage regimens appropriate strengths are available.

If control is unsatisfactory, the dosage should be increased, based on the glycaemic control, in a stepwise manner
with an interval of about 1 to 2 weeks between each step, to 2, 3, or 4 mg glimepiride per day.

A dosage of more than 4 mg glimepiride per day gives better results only in exceptional cases.

The maximum recommended dose is 6 mg glimepiride per day.

In patients not adequately controlled with the maximum daily dose of metformin, concomitant glimepiride therapy
can be initiated. While maintaining the metformin dose, the glimepiride therapy is started with a low dose, and is
then titrated up depending on the desired level of metabolic control up to the maximum daily dose. The
combination therapy should be initiated under close medical supervision.

In patients not adequately controlled with the maximum daily dose of glimepiride, concomitant insulin therapy can
be initiated if necessary. While maintaining the glimepiride dose, insulin treatment is started at a low dose and
titrated up depending on the desired level of metabolic control. The combination therapy should be initiated under
close medical supervision.

Normally a single daily dose of glimepiride is sufficient. It is recommended that this dose be taken shortly before
or during a substantial breakfast or - if none is taken - shortly before or during the first main meal. If a dose is
forgotten, this should not be corrected by increasing the next dose.

If a patient has a hypoglycaemic reaction on 1 mg glimepiride daily, this indicates that they can be controlled by
diet alone.

In the course of treatment, as an improvement in control of diabetes is associated with higher insulin sensitivity,
glimepiride requirements may fall. To avoid hypoglycaemia timely dose reduction or cessation of therapy must
therefore be considered.
Change in dosage may also be necessary if there are changes in weight or life style of the patient, or other factors
that increase the risk of hypo- or hyperglycaemia.

Switch over from other oral hypoglycaemic agents to glimepiride

A switch over from other oral hypoglycaemic agents to glimepiride can generally be done. For the switch over to
glimepiride the strength and the half-life of the previous medicinal product has to be taken into account. In some
cases, especially in antidiabetics with a long half-life (e.g. chlorpropamide), a wash out period of a few days is
advisable in order to minimise the risk of hypoglycaemic reactions due to the additive effect.

The recommended starting dose is 1 mg glimepiride per day. Based on the response the glimepiride dosage may be
increased stepwise, as indicated earlier.

Switch over from insulin to glimepiride

In exceptional cases, where type 2 diabetic patients are regulated on insulin, a changeover to glimepiride may be
indicated.
The changeover should be undertaken under close medical supervision.
 Special Populations

Patients with renal or hepatic impairment

See section 4.3.

Paediatric population
There are no data available on the use of glimepiride in patients under 8 years of age. For children aged 8 to 17
years, there are limited data on glimepiride as monotherapy (see sections 5.1 and 5.2).
The available data on safety and efficacy are insufficient in the paediatric population and therefore such use is not
recommended.

Method of administration
Tablets should be swallowed without chewing with some liquid.

4.3 Contraindications

Glimepiride is contraindicated in patients with the following conditions:

- hypersensitivity to glimepiride, other sulfonylureas or sulfonamides or to any of the excipients listed in section 6.1.
- insulin dependent diabetes
- diabetic coma
- ketoacidosis
- severe renal or hepatic function disorders.

In case of severe renal or hepatic function disorders, a change over to insulin is required.

4.4 Special warnings and precautions for use

Glimepiride must be taken shortly before or during a meal.

When meals are taken at irregular hours or skipped altogether, treatment with ”Glimepiride Tablets” may lead to
hypoglycaemia. Possible symptoms of hypoglycaemia include: headache, ravenous hunger, nausea, vomiting,
lassitude,
sleepiness, disordered sleep, restlessness, aggressiveness, impaired concentration, alertness and reaction time,
depression, confusion, speech and visual disorders, aphasia, tremor, paresis, sensory disturbances, dizziness,
helplessness, loss of self-control, delirium, cerebral convulsions, somnolence and loss of consciousness up to and
including coma, shallow respiration and bradycardia. In addition, signs of adrenergic counter-regulation may be
present such as sweating, clammy skin, anxiety, tachycardia, hypertension, palpitations, angina pectoris and cardiac
arrhythmias.

The clinical picture of a severe hypoglycaemic attack may resemble that of a stroke.

Symptoms can almost always be promptly controlled by immediate intake carbohydrates (sugar). Artificial
sweeteners have no effect.

It is known from other sulfonylureas that, despite initially successful countermeasures, hypoglycaemia may recur.

Severe hypoglycaemia or prolonged hypoglycaemia, only temporarily controlled by the usual amounts of sugar,
require
immediate medical treatment and occasionally hospitalisation.

Factors favouring hypoglycaemia include:

- unwillingness or (more commonly in older patients) incapacity of the patient to cooperate
- undernutrition, irregular mealtimes or missed meals or periods of fasting
- alterations in diet
-imbalance between physical exertion and carbohydrate intake
-consumption of alcohol; especially in combination with skipped meals
-impaired renal function
-serious liver dysfunction
-overdosage with Glimepiride Tablets
-certain uncompensated disorders of the endocrine system affecting carbohydrate metabolism or
counterregulation of hypoglycaemia (as for example in certain disorders of thyroid function and in anterior
pituitary or adrenocortical insufficiency)
-concurrent administration of certain other medicinal products (see section 4.5)

Treatment with glimepiride tablets requires regular monitoring of glucose levels in blood and urine. In addition
determination of the proportion of glycosylated haemoglobin is recommended.

Regular hepatic and heamatological monitoring (especially leucocytes and thrombocytes) are required during
treatment with glimepiride tablets

In stress-situations (e.g. accidents, acute operations, infections with fever etc) a temporary switch to insulin may be
indicated.

No experience has been gained concerning the use of glimepiride tablets in patients with severe impairment of liver
function or dialysis patients. In patients with severe impairment of renal or liver function change over to insulin is
indicated.

Treatment of patients with G6PD-deficiency with sulfonylurea agents can lead to hemolytic anaemia. Since
glimepiride belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD-deficiency
and a non-sulfonylurea alternative should be considered.

4.5 Interaction with other medicinal products and other forms of interactions

If glimepiride is taken simultaneously with certain other medicinal products, both undesired increases and
decreases in the hypoglycaemic action of glimepiride can occur. For this reason, other medicinal products should
only be taken with the knowledge (or at the prescription) of the doctor.

Glimepiride is metabolized by cytochrome P450 2C9 (CYP2C9). Its metabolism is known to be influenced by
concomitant administration of CYP2C9 inducers (e.g. rifampicin) or inhibitors (e.g. fluconazole).
Results from an in-vivo interaction study reported in literature show that glimepiride AUC is increased
approximately 2-fold by fluconazole, one of the most potent CYP2C9 inhibitors.

Based on the experience with glimepiride and with other sulfonylureas, the following interactions have to be
mentioned.

Potentiation of the blood-glucose-lowering effect and, thus in some instances hypoglycaemia may occur when one
of the following medicinal products is taken, for example:

- phenylbutazone, azapropazone and oxyfenbutazone,

- insulin and oral antidiabetic products, such as metformin,
- salicylates and p-amino-salicylic acid,
- anabolic steroids and male sex hormones,
- chloramphenicol, certain long acting sulfonamides, tetracyclines, quinolone antibiotics and clarithromycin,
- coumarin anticoagulants,
- fenfluramine,
- disopyramide,
- fibrates,
- ACE inhibitors,
- fluoxetine, MAO-inhibitors,
- allopurinol, probenecid sulfinpyrazone,
- sympatholytics,
- cyclophosphamide, trophosphamide and iphosphamides,
- miconazol, fluconazole,
- pentoxifylline (high dose parenteral),
- tritoqualine

Weakening of the blood-glucose-lowering effect and, thus raised blood glucose levels may occur when one of the
following medicinal products is taken for example:

- oestrogens and progestogens

- saluretics, thiazide diuretics
- thyroid stimulating agents, glucocorticoids
- phenothiazine derivatives, chlorpromazine
- adrenaline and sympathicomimetics
- nicotinic acid (high dosages) and nicotinic acid derivatives
- laxatives (long term use)
- phenytoin, diazoxide
- glucagon, barbiturates and rifampicin
- acetazolamide

H2 antagonists, beta-blockers, clonidine and reserpine may lead to either potentiation or weakening of the
blood-glucose-lowering effect.

Under the influence of sympatholytic medicinal products such as beta-blockers, clonidine, guanethidine and
reserpine, the signs of adrenergic counter-regulation to hypoglycaemia may be reduced or absent.

Alcohol intake may potentiate or weaken the hypoglycaemic action of glimepiride in an unpredictable fashion.

Glimepiride may either potentiate or weaken the effects of coumarin derivatives.

Colesevelam binds to glimepiride and reduces glimepiride absorption from the gastro-intestinal tract. No
interaction was
observed when glimepiride was taken at least 4 hours before colesevelam. Therefore, glimepiride should be
administered at
least 4 hours prior to colesevelam.

4.6 Fertility, pregnancy and lactation

Pregnancy
Risk related to the diabetes
Abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital
abnormalities and
perinatal mortality. So the blood glucose level must be closely monitored during pregnancy in order to avoid the
teratogenic risk. The use of insulin is required under such circumstances. Patients who consider pregnancy should
inform their physician.

Risk related to glimepiride

There are no adequate data from the use of glimepiride in pregnant women. Animal studies have shown
reproductive toxicity which likely was related to the pharmacologic action (hypoglycaemia) of glimepiride (see
section 5.3).
Consequently, glimepiride should not be used during the whole pregnancy. In case of treatment by glimepiride, if
the patient plans to become pregnant or if a pregnancy is discovered, the treatment should be switched as soon as
possible to insulin therapy.

Lactation
The excretion in human milk is unknown. Glimepiride is excreted in rat milk. As other sulfonylureas are excreted
in human milk
and because there is a risk of hypoglycaemia in nursing infants, breast-feeding is advised against during treatment
with
glimepiride.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

The patient’s ability to concentrate and react may be impaired as a result of hypoglycaemia or hyperglycaemia or,
for example, as a result of visual impairment. This may constitute a risk in situations where these abilities are of
special importance (e.g. driving a car or operating machinery).

Patients should be advised to take precautions to avoid hypoglycaemia whilst driving. This is particularly important
in those who have reduced or absent awareness of the warning symptoms of hypoglycaemia or have frequent
episodes of
hypoglycaemia. It should be considered whether it is advisable to drive or operate machinery in these
circumstances.

4.8 Undesirable effects

The following adverse reactions from clinical investigations werebased on experience with glimepiride and other
sulfonylureas, were listed below by system organ class and in order of decreasing incidence (very common: ≥1/10;
common: ≥1/100 to <1/10; uncommon: ≥1/1,000 to < 1/100; rare: ≥1/10,000 to <1/1,000; very rare: < 1/10,000),
not known (cannot be estimated from the available data).

Blood and lymphatic system disorders

Rare: thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, erythropenia, haemolytic anaemia and
pancytopenia, which are in general reversible upon discontinuation of medication.
Not known: severe thrombocytopenia with platelet count less than 10,000/µl and thrombocytopenic purpura.

Immune system disorders

Very rare: leukocytoclastic vasculitis, mild hypersensitivity reactions that may develop into serious reactions with
dyspnoea, fall in blood pressure and sometimes shock.
Not known:cross-allergenicity with sulfonylureas, sulfonamides or related substances is possible.
Metabolism and nutrition disorders
Rare: hypoglycaemia.
These hypoglycaemic reactions mostly occur immediately, may be severe and are not always easy to correct. The
occurrence of such reactions depends, as with other hypoglycaemic therapies, on individual factors such as dietary
habits and dosage (see further under section 4.4).

Eye disorders
Not known:visual disturbances, transient, may occur especially on initiation of treatment, due to changes in blood
glucose levels.

Gastrointestinal disorders
Very rare: nausea, vomiting, diarrhoea, abdominal distension, abdominal discomfort and abdominal pain, which
seldom lead to discontinuation of therapy.

Hepato-biliary disorders
Very rare: hepatic function abnormal (e.g. with cholestasis and jaundice), hepatitis and hepatic failure.
Not known:hepatic enzymes increased.

Skin and subcutaneous tissue disorders

Not known:hypersensitivity reactions of the skin may occur as pruritus, rash, urticaria and photosensitivity.

Investigations
Very rare: blood sodium decrease.

4.9 Overdose

Symptoms
After ingestion of an overdosage hypoglycaemia may occur, lasting from 12 to 72 hours, and may recur after
an initial
recovery. Symptoms may not be present for up to 24 hours after ingestion. In general observation in hospital is
recommended. Nausea, vomiting and epigastric pain may occur. The hypoglycaemia may in general be
accompanied by
neurological symptoms like restlessness, tremor, visual disturbances, co-ordination problems, sleepiness, coma and
convulsions.

Management
Treatment primarily consists of preventing absorption by inducing vomiting and then drinking water or lemonade
with
activated charcoal (adsorbent) and sodium-sulphate (laxative). If large quantities have been ingested gastric lavage
is
indicated, followed by activated charcoal and sodium-sulphate. In case of (severe) overdosage hospitalisation in an
intensive
care department is indicated. Start the
intravenous
injection of 50 ml of a 50% solution, followed by an infusion of a 10% solution with strict monitoring of blood
glucose. Further treatment should be symptomatic.
In particular when treating hypoglycaemia due to accidental intake of glimepiride in infants and young children,
the dose of glucose given must be carefully controlled to avoid the possibility of producing dangerous
hyperglycaemia. Blood glucose should be closely monitored.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group : Blood

ATC Code : A10B

Glimepiride is an orally active hypoglycaemic substance belonging to the sulphonylurea group. It may be used in
non-insulin dependent diabetes mellitus.

Glimepiride acts mainly by stimulating insulin release from pancreatic beta cells. As with other sulfonylureas this
effect is based on an increase of responsiveness of the pancreatic beta cells to the physiological glucose stimulus.
In addition, glimepiride seems to have pronounced extrapancreatic effects also postulated for other sulfonylureas.

Insulin release:
Sulfonylureas regulate insulin secretion by closing the ATP-sensitive potassium channel in the beta cell membrane.
Closing the potassium channel induces depolarisation of the beta cell and results -by opening of calcium channels -
in an increased influx of calcium into the cell. This leads to insulin release through exocytosis.
Glimepiride binds with a high exchange rate to a beta cell membrane protein which is associated with the ATP-
sensitive
potassium channel but which is different from the usual sulfonylureas binding site.

Extrapancreatic activity
The extrapancreatic effects are for example an improvement of the sensitivity of the peripheral tissue for insulin
and a decrease of the insulin uptake by the liver.
The uptake of glucose from blood into peripheral muscle and fat tissues occurs via special transport proteins,
located in the cells membrane. The transport of glucose in these tissues is therate limiting step in the use of glucose.
Glimepiride increases very rapidly the number of active glucose transport molecules in the plasma membranes of
muscle and fat cells, resulting in stimulated glucose uptake.
Glimepiride increases the activity of the glycosyl-phosphatidylinositol-specific phospholipase C, which may be
correlated with the drug-induced lipogenesis and glycogenesis in isolated fat and muscle cells.
Glimepiride inhibits the glucose production in the liver by increasing the intracellular concentration of
fructose-2,6-bisphosphate, which in its turn inhibits the gluconeogenesis.

General
In healthy persons, the minimum effective oral dose is approximately 0.6 mg. The effect of glimepiride is dose-
dependent and reproducible. The physiological response to acute physical exercise, reduction of insulin secretion,
is still present under glimepiride.
There was no significant difference in effect regardless of whether the medicinal product was given 30 minutes or
immediately before a meal. In diabetic patients, good metabolic control over 24 hours can be achieved with a single
daily dose.
Although the hydroxy metabolite of glimepiride caused a small but significant decrease in serum glucose in healthy
persons, it accounts for only a minor part of the total drug effect.

Combination therapy with metformin

Improved metabolic control for concomitant glimepiride therapy compared to metforminalone in patients not
adequately
controlled with the maximum dosage of metformin has been shown in one study.

Combination therapy with insulin

Data for combination therapy with insulin are limited. In patients not adequately controlled with the maximum
dosage of glimepiride, concomitant insulin therapy can be initiated. In two studies, thecombination achieved the
same improvement in
metabolic control as insulin alone; however, a lower average dose of insulin was required in combination therapy.

Special populations
Children and adolescents
An active controlled clinical trial (glimepiride up to 8 mg daily or metformin up to 2,000 mg daily) of 24 weeks
duration was performed in 285 children (8-17 years of age) with type 2 diabetes.
Both glimepiride and metformin exhibited a significant decrease from baseline in HbA 1c(glimepiride -0.95 (se
0.41); metformin -1.39 (se 0.40)). However, glimepiride did not achieve the criteria of non-inferiority to metformin
in mean change from baseline of HbA1c. The difference between treatments was 0.44% in favour of metformin.
The upper limit (1.05) of the 95% confidence interval for the difference was not below the 0.3% non-inferiority
margin.
Following glimepiride treatment, there were no new safety concerns noted in children compared to adult patients
with type 2 diabetes mellitus. No long-term efficacy and safety data are available in paediatric patients.

5.2 Pharmacokinetic properties

Absorption
The bioavailability of glimepiride after oral administration is complete. Food intake has no relevant influence on
absorption, only the absorption rate is slightly diminished. Maximum serum concentrations (Cmax) are reached
approx 2.5 hours after oral intake (mean 0.3 μg/ml during multiple dosing of 4 mg/daily) and there is a linear
relationship between dose and both Cmax and AUC (area under the time concentration curve).

Distribution
Glimepiride has a very low distribution volume (approx. 8.8 litres), which is roughly equal to the albumin
distribution space, high protein binding (>99%) and a low clearance (approx. 48 ml/min).

In animals, glimepiride is excreted in milk. Glimepiride is transferred to the placenta. Passage of the blood-brain
barrier is low.

Biotransformation and elimination

Mean dominant serum half-life, which is of relevance for the serum concentrations under multiple-dose conditions,
is about 5 to 8 hours. After high doses, slightly longer half-lives were noted.

After a single dose of radiolabelled glimepiride, 58% of the radioactivity was recovered in the urine, and 35% in
the faeces. No unchanged substance was detected in the urine. Two metabolites most probably resulting from
hepatic metabolism (major enzyme is CYP2C9) were identified both in urine and faeces: the hydroxy derivative
and the carboxy derivative. After oral administration of glimepiride, the terminal half-lives of these metabolites
were 3 to 6 and 5 to 6 hours respectively.

Comparison of single and multiple once-daily dosing revealed no significant differences in pharmacokinetics, and
the intra individual variability was very low. There was no relevant accumulation.

Special populations
Pharmacokinetics were similar in males and females, as well as in young and elderly (above 65 years) patients. In
patients with low creatinine clearance, there was a tendency for glimepiride clearance to increase and for average
serum concentrations to decrease, most probably resulting from a more rapid elimination because of lower protein
binding.
Renal elimination of the two metabolites was impaired. Overall no additional risk of accumulation is to be assumed
in such patients.
Pharmacokinetics in five non-diabetic patients after bile duct surgery were similar to those in healthy persons.
 Paediatric population

A fed study investigating the pharmacokinetics, safety, and tolerability of a 1 mg single dose of glimepiride in 30
paediatric patients (4 children aged 10-12 years and 26 children aged 12-17 years) with type 2 diabetes showed
mean AUC(0-last) , Cmax and t1/2 similar to that previously observed in adults.

5.3 Preclinical safety data

Preclinical effects observed occurred at exposures sufficiently in excess of the maximum human exposure as to
indicate little relevance to clinical use, or were due to the pharmacodynamic action (hypoglycaemia) of the
compound. This finding is based on conventional safety pharmacology, repeated dose toxicity, genotoxicity,
carcinogenicity, and reproduction toxicity studies.
In the latter (covering embryotoxicity, teratogenicity and developmental toxicity), adverse effects observed were
considered to be secondary to the hypoglycaemic effects induced by the compound in dams and in offspring.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Pamaryl 1mg Tablet:

Avicel ph 102,lactose,
magnesium
stearate, primojel , Kollidon k-
30,
Brilliant blue colo
Avicel ph 102,lactose,
magnesium
stearate, primojel , Kollidon k-
30,
Brilliant blue colo
Avicel ph 102,lactose
Magnesium stearate
Primojel
Kollidon k-30
Brilliant blue colour

Pamaryl 2mg Tablet:

Avicel ph 102,lactose,
magnesium
stearate, primojel , Kollidon k-
30,
Brilliant blue colo
Avicel ph 102,lactose,
magnesium
stearate, primojel , Kollidon k-
30,
Brilliant blue colo
Avicel ph 102,lactose
Magnesium stearate
Primojel
Kollidon k-30
Erythrosine Red Colour

Pamaryl 3mg Tablet:

Avicel ph 102,lactose,
magnesium
stearate, primojel , Kollidon k-
30,
Brilliant blue colo
Avicel ph 102,lactose,
magnesium
stearate, primojel , Kollidon k-
30,
Brilliant blue colo
Avicel ph 102,lactose
Magnesium stearate
Primojel
Kollidon k-30
Tartar zine Yellow Colour

Pamaryl 4mg Tablet:

Avicel ph 102,lactose,
magnesium
stearate, primojel , Kollidon k-
30,
Brilliant blue colo
Avicel ph 102,lactose,
magnesium
stearate, primojel , Kollidon k-
30,
Brilliant blue colo
Avicel ph 102,lactose
Magnesium stearate
Primojel
Kollidon k-30
Apple Green Colour

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years.

6.4 Special precautions for storage

This medicinal product does not require any special temperature storage conditions. Store in the original package in
order to protect from moisture. Keep th

6.5 Nature and contents of container

The blisters, of PVC/PVdC, are heat sealed with hard tempered aluminium foil and packaged in a carton with a
pack insert. PVC/PVdC/Aluminum blisters are clear/transparent.
Pack sizes: 2 X 10’s in blister strips.

Not all pack size may be marketed.

6.6 Special precautions for disposal

No special requirements for disposal.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Himont Pharmaceuticals (Pvt.) Ltd.

Address:
17-Km, Ferozpur, Road, Lahore, Pakistan

Telephone WWW

+92 (042) 35814393 https://www.himont.com

8 MARKETING AUTHORISATION NUMBER

030499, 030500, 030501, 030502

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

19 May 2003

10 DATE OF REVISION OF THE TEXT

May 2023