METFORMIN

Main information

  • Trade name:
  • METFORMIN XR 1000 APOTEX metformin hydrochloride 1000 mg modified release tablet bottle
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • METFORMIN XR 1000 APOTEX metformin hydrochloride 1000 mg modified release tablet bottle
    Australia
  • Language:
  • English

Other information

Status

  • Source:
  • Dept. of Health,Therapeutic Goods Administration - Australia
  • Authorization number:
  • 218272
  • Last update:
  • 08-10-2017

Public Assessment Report

Public Summary

Summary for ARTG Entry:

218272

METFORMIN XR 1000 APOTEX metformin hydrochloride 1000 mg modified release tablet bottle

ARTG entry for

Medicine Registered

Sponsor

Apotex Pty Ltd

Postal Address

PO Box 280,NORTH RYDE BC, NSW, 1670

Australia

ARTG Start Date

9/09/2014

Product category

Medicine

Status

Active

Approval area

Drug Safety Evaluation Branch

Conditions

Conditions applicable to all therapeutic goods as specified in the document "Standard Conditions Applying to Registered or Listed Therapeutic Goods

Under Section 28 of the Therapeutic Goods Act 1989" effective 1 July 1995.

Conditions applicable to the relevant category and class of therapeutic goods as specified in the document "Standard Conditions Applying to Registered

or Listed Therapeutic Goods Under Section 28 of the Therapeutic Goods Act 1989" effective 1 July 1995.

Products

1. METFORMIN XR 1000 APOTEX metformin hydrochloride 1000 mg modified release tablet bottle

Product Type

Single Medicine Product

Effective date

9/12/2016

Warnings

See Product Information and Consumer Medicine Information for this product

Standard Indications

Specific Indications

Treatment of type 2 diabetes mellitus in adults, particularly in overweight patients, when dietary management and exercise alone does not result in

adequate glycaemic control. Metformin may be used as monotherapy or in combination with other oral hypoglycaemic agents, or with insulin.

Additional Product information

Container information

Type

Material

Life Time

Temperature

Closure

Conditions

Bottle

HDPE

36 Months

Store below 25

degrees Celsius

Child resistant closure

Not recorded

Pack Size/Poison information

Pack Size

Poison Schedule

500 Tablets (Bulk pack for Dose Administration Aid Packers)

(S4) Prescription Only Medicine

60 Tablets

(S4) Prescription Only Medicine

Components

1. METFORMIN XR 1000 APOTEX metformin hydrochloride 1000 mg modified release tablet bottle

Dosage Form

Tablet, modified release

Route of Administration

Oral

Visual Identification

White to off-white capsule-shaped biconvex tablet engraved MXR 1000 on

one side and plain on the other side.

Active Ingredients

Metformin hydrochloride

1000 mg

© Commonwealth of Australia.This work is copyright.You are not permitted to re-transmit, distribute or commercialise the material without obtaining prior

written approval from the Commonwealth.Further details can be found at http://www.tga.gov.au/about/website-copyright.htm.

Public Summary

Page 1 of

Produced at 26.11.2017 at 05:13:17 AEDT

This is not an ARTG Certificate document.

The onus is on the reader to verify the current accuracy of the information on the document subsequent to the date shown.

Visit www.tga.gov.au for contact information

Summary of Product characteristics

Product Information – Australia

Metformin XR APOTEX tablets

Page 1

METFORMIN XR (500 & 1000) APOTEX TABLETS

Life-threatening lactic acidosis can occur due to accumulation of metformin. The main risk

factor is renal impairment; other risk factors include old age associated with reduced renal

function and high doses of metformin hydrochloride (≥ 2 g per day).

NAME OF THE MEDICINE

Metformin hydrochloride.

Chemical Name:

1,1-dimethylbiguanide hydrochloride

Structural Formula:

. HCl

Molecular Formula:

Molecular Weight:

165.62

CAS Registry Number:

1115-70-4

DESCRIPTION

White crystals easily soluble in water, sparingly soluble in alcohol and practically insoluble in acetone

and methylene chloride.

Metformin is a strong base with a pKa greater than 12. At pH < 12, which is always the case in the

body, metformin is very hydrophilic: the octanol/water partition coefficient is 0.05. The melting point of

metformin hydrochloride is 224°C. Metformin hydrochloride is a very stable molecule.

Each modified release tablet contains either 500 mg or 1000 mg metformin hydrochloride (HCl). The

tablets also contain the following excipients: hypromellose, methylcellulose, colloidal anhydrous silica

and magnesium stearate.

Tablet shells may be present in the faeces (see PRECAUTIONS, Other Precautions).

PHARMACOLOGY

Pharmacodynamics

Metformin is an oral hypoglycaemic agent; it is a biguanide with antihyperglycaemic effects, lowering

both basal and postprandial plasma glucose. It does not stimulate insulin secretion and therefore

does not produce hypoglycaemia.

Metformin may act via three mechanisms:

Reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis.

In muscle, by increasing insulin sensitivity, improving peripheral glucose uptake and utilization.

Delay of intestinal glucose absorption.

Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase.

Metformin increases the transport capacity of all types of membrane glucose transporters.

Product Information – Australia

Metformin XR APOTEX tablets

Page 2

In humans, independently of its action on glycaemia, metformin has favourable effects on lipid

metabolism. This has been shown at therapeutic doses in controlled, medium-term and long-term

clinical studies: metformin reduces total cholesterol, LDL cholesterol and triglyceride levels.

Pharmacokinetics

Absorption

At steady state, similar to the immediate release formulation, C

and AUC do not increase in

proportion with the administered dose. The administration of two, three, or four tablets 500 mg

modified release tablets results in a 1.8-, 2.4- and 3.0-fold increase for C

and a 2.0-, 2.7- and 3.2-

fold increase in AUC.

Intrasubject variability of C

and AUC of metformin modified release tablets is comparable to that

observed with metformin immediate release tablets.

No accumulation is observed after repeated administration of up to 2000 mg metformin hydrochloride

as modified release tablets (administered as four 500 mg modified release tablets).

Metformin absorption from the modified release formulation is not altered by meal composition.

Pharmacokinetic parameters, from healthy volunteers, for this medicine, are presented below.

After an oral dose of the 500 mg modified release tablet, under fasted conditions, metformin

absorption is slightly delayed compared to an immediate release tablet; delay is approximately an hour

for the modified release tablet is 3½ hours and t

for the immediate release tablet is 2½ hours).

AUC is decreased by ~35% when the modified release tablet is administered under fasted conditions

compared to fed, C

is unaffected and the t

is reduced by 1–2 hours.

Cross-study comparison of Metformin XR 500 and Metformin XR 1000

Dose (± food)

Median t

max

(range)

[h]

Mean C

max

[ng/mL]

Mean AUC

0-∞

[ng*h/mL]

500 mg steady state (fasted)

3.5 (2.0 – 5.0)

686.8

5,007.6*

500 mg single dose (fasted)

4.0 (2.0 – 6.0)

635.3

5,013.5

500 mg single dose (fed)

6.0 (4.5 – 9.0)

618.8

7,968.1

1000 mg single dose (fasted)

3.5 (1.5 – 4.5)

1,051.7

8,242.5

1000 mg single dose (fed)

4.5 (4.0 – 10.0)

1,072.6

12,539.7

1000 mg steady state (fed)

5.0 (4.5 – 10.3)

1,243.7

14,679.7*

* = AUC

Distribution

Plasma protein binding is negligible. Metformin partitions into erythrocytes. The blood peak is lower

than the plasma peak and appears at approximately the same time. The red blood cells most likely

represent a secondary compartment of distribution. The mean volume of distribution V

ranged 63–

276 L.

Metabolism

Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.

Excretion

Renal clearance of metformin is > 400 mL/min, indicating that metformin is eliminated by glomerular

filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is

approximately 6½ hours. When renal function is impaired, renal clearance is decreased in proportion

to that of creatinine and thus the elimination half-life is prolonged, leading to increased levels of

metformin in plasma.

Product Information – Australia

Metformin XR APOTEX tablets

Page 3

CLINICAL TRIALS

Metformin

modified

release

tablet

been

evaluated

three

double-blind,

randomized,

multicentre, parallel-group clinical trials, two of which employed a placebo control. These studies were

each followed by a 52-week open-label extension study involving subjects who completed double-blind

treatment and/or were withdrawn for inadequate glycaemic control. The primary endpoint was the

mean change in HbA

from baseline in each case.

Both placebo-controlled studies were in diet-failed patients previously not exposed to metformin. One

study evaluated once-daily metformin HCl modified release tablet at daily doses of 500 mg, 2 × 500

mg, 3 × 500 mg and 4 × 500 mg, and also twice-daily 2 × 500 mg, for 16 weeks. Treatment with once-

daily metformin HCl modified release tablet resulted in dose-related reductions in indices of glycaemic

control (HbA

, fasting plasma glucose and the proportions of patients achieving HbA

< 7.0% at

study end or last prior measurement) that were significant at all doses relative to placebo (Table 1).

The results of a 52-week open-label extension to this study (Table 1)

showed that the

anti-

hyperglycaemic effects of metformin HCl modified release tablet were maintained over time. There

was no weight gain in any treatment group.

Table 1. Placebo-controlled dose-ranging evaluation of metformin HCl modified release tablet

in diet-failed patients (double-blind 16 weeks; open-label 52 weeks)

Double-blind:

Placebo

Double-blind:

Metformin HCl modified release tablet

Open-label:

Metformin HCl

modified

release tablet

1000 mg once

daily

500 mg

once

daily

1000 mg

once

daily

1500 mg

once

daily

2000 mg

once

daily

1000 mg

twice

daily

Haemoglobin A1c

n = 111

n = 115

n = 115

n = 111

n = 125

n = 112

n = 404

Baseline Mean (%)

Final Mean (%)

Difference from

placebo/baseline

-0.6*

-0.7*

-1.0*

-1.0*

-1.2*

-1.0

Fasting Plasma

Glucose

n = 113

n = 126

n = 118

n = 120

n = 132

n = 122

n = 387

Baseline Mean

(mmol/L)

10.0

10.1

10.2

10.0

10.1

Final Mean (mmol/L)

10.4

Difference from

placebo/baseline

-1.3*

-1.5*

-2.0*

-2.1*

-2.3*

-1.5

Body Weight Mean

Change from

baseline (kg)

-0.8

-0.6

-0.6

-0.3

-0.7

-1.0

-1.2

Final HBA

Distribution

n = 111

n = 115

n = 115

n = 111

n = 126

n = 112

n = 404

< 7% (%)

≥ 7% (%)

p<0.05; * p< 0.001 vs. placebo (statistical evaluation for double-blind study only).

difference from placebo for double-blind studies and difference from baseline for the open-label study.

The second placebo-controlled study evaluated metformin HCl modified release tablet at a target dose

of 2 × 500 mg once-daily for a period of 12 weeks. Indices of glycaemic control (as above) improved

significantly compared with placebo (Table 2). The magnitudes of improvements were comparable to

those observed in the dose-ranging study (Table 1). The accompanying 52-week open-label study

again showed that improvements in glycaemia were durable over time. No weight gain was

associated with metformin HCl modified release tablet treatment.

Product Information – Australia

Metformin XR APOTEX tablets

Page 4

Table 2. Placebo-controlled evaluation of metformin HCl modified release tablet

in diet-failed patients (double-blind 12 weeks; open-label 52 weeks)

Double-blind:

Open-label:

Metformin HCl modified

release tablet

Placebo

Metformin HCl

modified release

tablet

1000 mg once daily

Haemoglobin A1c

n = 79

n = 155

n = 59

Baseline Mean (%)

Final Mean (%)

Difference from

placebo/baseline

-0.6*

-0.6

Fasting Plasma Glucose

n = 79

n = 159

n = 57

Baseline Mean (mmol/L)

Final Mean (mmol/L)

Difference from

placebo/baseline

-1.2*

-0.5

Body Weight Mean Change

from Baseline (kg)

-0.8

-0.3

-0.4

Final HBA1c Distribution

n = 79

n = 155

n = 59

< 7% (%)

≥ 7% (%)

p<0.05; * p< 0.001 vs. placebo (statistical evaluation for double-blind study only).

difference from placebo for double-blind studies and difference from baseline for the open-label study.

The third randomized, double-blind study evaluated the effects of switching from the immediate-

release formulation of metformin HCl to metformin HCl modified release tablet. Patients sub-optimally

controlled with metformin received immediate-release metformin HCl 500 mg twice daily, were

randomized to continue on immediate-release metformin HCl or to receive once-daily metformin HCl

modified release tablet at a dose of 2 × 500 mg or 3 × 500 mg, for a period of 12 weeks. Indices of

glycaemia were not markedly altered after switching between the formulations, either in the double-

blind study or an associated 52-week open-label study (Table 3).

Table 3. Double-blind, randomized study evaluating the effects of a switch from

immediate-release metformin HCl to metformin HCl modified release tablet

Double-blind:

Open-label:

Metformin HCl

modified release

tablet

Metformin HCl

immediate-release

tablet 500 mg

twice daily

Metformin HCl

modified release

tablet 1000 mg

once daily

Metformin HCl

modified release

tablet 1500 mg

once daily

Haemoglobin A

n = 66

n = 70

n = 65

n = 112

Baseline Mean (%)

Final Mean

Mean change

0.04

Fasting Plasma Glucose

n = 69

n = 72

n = 70

n = 109

Baseline Mean (mmol/L)

Final Mean (mmol/L)

Mean change

Final HBA

Distribution

n = 66

n = 70

n = 65

n = 112

< 7% (%)

≥ 7% (%)

Product Information – Australia

Metformin XR APOTEX tablets

Page 5

The prospective randomized study (UKPDS) has established the long-term benefit of intensive blood

glucose control in overweight type 2 diabetes. The immediate release tablet form of metformin was

used in the UKPDS.

Analysis of the results for overweight patients treated with metformin after failure of diet alone showed:

A significant reduction of the absolute risk of any diabetes-related complication in the metformin

group (29.8 events/1000 patient-years) versus diet alone (43.3 events/1000 patient-years), p =

0.0023,

versus

combined

sulfonylurea

insulin

monotherapy

groups

(40.1

events/1000 patient-years), p = 0.0034.

significant

reduction

absolute

risk

diabetes-related

mortality:

metformin

events/1000 patient-years, diet alone 12.7 events/1000 patient-years, p = 0.017;

A significant reduction of the absolute risk of overall mortality: metformin 13.5 events/1000

patient-years versus diet alone 20.6 events/1000 patient-years (p = 0.011), and versus the

combined sulfonylurea and insulin monotherapy groups 18.9 events/1000 patient-years (p =

0.021);

A significant reduction in the absolute risk of myocardial infarction: metformin 11 events/1000

patient-years, diet alone 18 events/1000 patient-years (p = 0.01).

For metformin used as second-line therapy, in combination with a sulfonylurea, benefit regarding

clinical outcome has not been shown.

In type 1 diabetes, the combination of metformin and insulin has been used in selected patients, but

the clinical benefit of this combination has not been formally established.

INDICATIONS

Treatment of type 2 diabetes mellitus in adults, particularly in overweight patients, when dietary

management and exercise alone does not result in adequate glycaemic control. Metformin may be

used as monotherapy or in combination with other oral hypoglycaemic agents, or with insulin.

CONTRAINDICATIONS

Hypersensitivity to metformin or to any of the excipients

Diabetic ketoacidosis, diabetic pre-coma

Renal failure or renal dysfunction (creatinine clearance < 60 mL/min)

Acute conditions with the potential to alter renal function such as:

Dehydration

Severe infection

Shock

Intravascular

administration

iodinated

contrast

agents

(see

PRECAUTIONS,

Administration of Iodinated Contrast Materials)

Acute or chronic disease which may cause tissue hypoxia such as:

Cardiac failure

Recent myocardial infarction

Respiratory failure

Pulmonary embolism

Shock

Acute significant blood loss

Sepsis

Gangrene

Pancreatitis

Major surgery (see PRECAUTIONS, Surgery)

Severe hepatic insufficiency, acute alcohol intoxication, alcoholism

Lactation (see PRECAUTIONS, Use in Lactation).

Product Information – Australia

Metformin XR APOTEX tablets

Page 6

PRECAUTIONS

Lactic Acidosis

Lactic acidosis is a rare, but serious (high mortality in the absence of prompt treatment), metabolic

complication that can occur due to metformin accumulation. Reported cases of lactic acidosis in

patients on metformin have occurred primarily in diabetic patients with significant renal failure. The

incidence of lactic acidosis can and should be reduced by assessing other associated risk factors such

poorly

controlled

diabetes,

ketosis,

prolonged

fasting,

excessive

alcohol

intake,

hepatic

insufficiency and any condition associated with hypoxia.

Diagnosis

The risk of lactic acidosis must be considered in the event of non-specific signs such as muscle

cramps with digestive disorders such as abdominal pain and severe asthenia.

Lactic acidosis is characterised by acidotic dyspnea, abdominal pain and hypothermia followed by

coma. Diagnostic laboratory findings are decreased blood pH, plasma lactate levels above 5 mmol/L

and an increased anion gap and lactate/pyruvate ratio. If metabolic acidosis is suspected, metformin

should be discontinued and the patient should be hospitalised immediately (see OVERDOSAGE,

Treatment).

Renal Function

As metformin is excreted by the kidney, it is recommended that creatinine clearance and/or serum

creatinine levels be determined before initiating treatment and regularly thereafter:

At least annually in patients with normal renal function;

At least 2–4 times a year in patients with serum creatinine levels at the upper limit of normal and

in elderly subjects.

Decreased renal function in elderly subjects is frequent and asymptomatic. Special caution should be

exercised in situations where renal function may become impaired, for example when initiating

antihypertensive therapy or diuretic therapy and when starting therapy with a non-steroidal anti-

inflammatory drug (NSAID).

Administration of Iodinated Contrast Materials

The intravascular administration of iodinated contrast materials in radiologic studies can lead to renal

failure. This may induce metformin accumulation and may expose the patient to lactic acidosis.

Therefore, metformin must be discontinued either 48 hours before the test when renal function is

known to be impaired, or from the time of the test when renal function is known to be normal. It should

not be reinstituted until 48 hours after the test and only after renal function has been re-evaluated and

found to be normal (see CONTRAINDICATIONS and INTERACTIONS WITH OTHER MEDICINES).

Surgery

Metformin must be discontinued 48 hours before elective surgery. Therapy may be restarted no

earlier than 48 hours following surgery and only after renal function has been re-evaluated and found

to be normal.

Other Precautions

All patients should continue their diet with a regular distribution of carbohydrate intake during

the day. Overweight patients should continue their energy-restricted diet.

The usual laboratory tests for diabetes monitoring should be performed regularly.

Metformin alone does not cause hypoglycaemia; however, caution is advised when it is used in

combination with other hypoglycaemic agents (sulfonylureas, glitinides, insulin).

The tablet shells may be present in the faeces. Patients should be advised that this is normal.

Use in Pregnancy (Category C)

Category C - Drugs which, owing to their pharmacological effects, have caused or may be suspected

of causing, harmful effects on the human foetus or neonate without causing malformations. These

effects may be reversible. Accompanying texts should be consulted for further details.

To date, no relevant epidemiological data are available. Animal studies do not indicate harmful effects

with respect to pregnancy, embryonal or foetal development, parturition or postnatal development.

Product Information – Australia

Metformin XR APOTEX tablets

Page 7

When the patient plans to become pregnant and during pregnancy, diabetes should not be treated

with metformin but insulin should be used to maintain blood glucose levels as close to normal as

possible in order to lower the risk of foetal malformations associated with abnormal blood glucose

levels.

Use in Lactation

Metformin is excreted into milk in lactating rats. Similar data are not available in humans and a

decision should be made whether to discontinue breast feeding or to discontinue metformin, taking

into account the importance of the medicinal product to the mother.

Paediatric Use

In absence of available data, metformin HCl modified release tablets should not be used in children.

Genotoxicity

Preclinical data reveal no specific hazard for humans based on conventional studies on genotoxicity.

Carcinogenicity

Preclinical data reveal no specific hazard for humans based on conventional studies on safety

pharmacology, repeated dose toxicity, carcinogenic potential or reproductive toxicity.

Effect on Ability to Drive and Use Machinery

Metformin monotherapy does not cause hypoglycaemia and therefore has no effect on the ability to

drive or to use machinery.

However, patients should be alerted to the risk of hypoglycaemia when metformin is used in

combination with other hypoglycaemic agents (sulfonylureas, glitinides, insulin).

INTERACTIONS WITH OTHER MEDICINES

Contraindicated Combination

Iodinated Contrast Materials

Metformin must be discontinued either 48 hours before the test when renal function is known to be

impaired, or from the time of the test when renal function is known to be normal. It should not be

reinstituted until 48 hours after the test and only after renal function has been re-evaluated and found

normal

(see

CONTRAINDICATIONS

PRECAUTIONS,

Administration

of

Iodinated

Contrast Materials).

Inadvisable Combination

Alcohol

Increased risk of lactic acidosis in acute alcohol intoxication, particularly in case of:

Fasting or malnutrition;

Hepatic insufficiency.

Avoid consumption of alcohol and alcohol-containing medications.

Combinations Requiring Precautions for Use

Medicines with Intrinsic Hyperglycaemic Activity

[e.g. glucocorticoids, thyroid products and tetracosactides (systemic and local routes),

2

-agonists,

danazol, chlorpromazine at high dosages of 100 mg per day and diuretics]

More frequent blood glucose monitoring may be required, especially at the beginning of treatment. If

necessary, adjust the metformin dosage during therapy with the respective medicinal product and

upon discontinuation.

ACE-Inhibitors

ACE-inhibitors may decrease the blood glucose levels. Therefore, dose adjustment of metformin

hydrochloride may be necessary when such medicinal products are added or discontinued.

Product Information – Australia

Metformin XR APOTEX tablets

Page 8

Anticoagulants

Metformin increases the elimination rate of vitamin K antagonists. Consequently, the prothrombin time

should be closely monitored in patients in whom metformin and vitamin K antagonists are being co-

administered. Cessation of metformin in patients receiving vitamin K antagonists can cause marked

increases in the prothrombin time.

Beta-blockers

Co-administration

metformin

beta-blockers

result

potentiation

anti-

hyperglycaemic action. In addition, some of the premonitory signs of hypoglycaemia, in particular

tachycardia, may be masked. Monitoring of blood glucose should be undertaken during dosage

adjustment of either agent.

Calcium Channel Blockers

Calcium channel blockers may affect glucose control in diabetic patients; regular monitoring of

glycaemic control is recommended.

Cimetidine

Reduced clearance of metformin has been reported during cimetidine therapy, so a dose reduction

should be considered.

Diuretics, especially Loop Diuretics

May increase the risk of lactic acidosis due to their potential to decrease renal function.

Hypoglycaemic Agents

Metformin alone does not cause hypoglycaemia; however, caution is advised when it is used in

combination with other hypoglycaemic agents (sulfonylureas, glitinides, insulin).

Nifedipine

A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated

that co-administration of metformin and nifedipine increased plasma metformin C

and AUC by 20%

and 9%, respectively, and increased the amount of metformin excreted in the urine. T

and half-life

of metformin were unaffected. Nifedipine appears to enhance the absorption of metformin. Metformin

had minimal effects on the pharmacokinetics of nifedipine.

Thyrotropin

Reduction

thyrotropin

(TSH)

serum

levels

been

reported

diabetic

patients

with

hypothyroidism when metformin therapy is initiated.

ADVERSE EFFECTS

In post-marketing data and in controlled clinical studies, adverse event reporting in patients treated

with metformin HCl modified release tablets (containing metformin 500 mg, 750 mg or 1000 mg) was

similar in nature and severity to that reported in patients treated with metformin immediate release

tablets.

The following undesirable effects may occur under treatment with metformin. Frequencies are defined

as follows:

very common - > 1/10

common -

≥ 1/100, <1/10

uncommon -

≥ 1/1,000, <1/100

rare -

≥ 1/10,000, <1/1,000

very rare -

< 1/10,000

not known -

(cannot be estimated from the available data).

Within each frequency grouping, adverse effects are presented in order of decreasing seriousness.

Product Information – Australia

Metformin XR APOTEX tablets

Page 9

Gastrointestinal Disorders

Very common:

Gastrointestinal disorders such as nausea, vomiting, diarrhoea, abdominal pain

and loss of appetite. These undesirable effects occur most frequently during

initiation of therapy and resolve spontaneously in most cases. A slow increase of

the dose may improve gastrointestinal tolerability.

Hepatobiliary Disorders

Not Known:

Isolated reports of liver function test abnormalities or hepatitis resolving upon

metformin discontinuation.

Metabolism and Nutrition Disorders

Uncommon:

Decrease of vitamin B

absorption with a decrease of serum levels during long-

term use of metformin has been observed in patients treated long-term with

metformin. Consideration of such aetiology is recommended if a patient presents

with megaloblastic anaemia. Therefore, serum B

levels should be appropriately

monitored or periodic parenteral B

supplementation considered.

Very rare:

Lactic acidosis (see PRECAUTIONS).

Not known:

Reduction of thyrotropin (TSH) serum levels has been reported in diabetic patients

with hypothyroidism when metformin therapy is initiated.

Nervous System Disorders

Common:

Taste disturbance.

Skin and Subcutaneous Tissue Disorders

Very rare:

Skin reactions such as erythema, pruritus, urticaria.

DOSAGE AND ADMINISTRATION

Life-threatening lactic acidosis can occur due to accumulation of metformin. The main risk

factor is renal impairment; other risk factors include old age associated with reduced renal

function and high doses of metformin HCl (≥ 2 g per day).

Monotherapy and Combination with other Oral Hypoglycaemic Agents

Initiating Therapy with Metformin XR

For patients new to metformin, the usual starting dose is one Metformin XR 500 tablet, once daily, with

the evening meal. If the starting dose requires 750 mg modified release metformin HCl, then

alternative brands will be required, as Metformin XR 500 cannot be divided.

After 10 to 15 days the dose should be adjusted on the basis of blood glucose measurements. A slow

increase of dose may improve gastro-intestinal tolerability.

Dosage increases should be made in increments of 500 mg every 10

15 days, up to a maximum of

2000 mg once daily with the evening meal. If the dosage increases require 750 mg modified release

metformin HCl, then alternative brands will be required, as Metformin XR 500 cannot be divided.

Combining Different Metformin XR Dosage Strengths

The combined use of different strengths of Metformin XR 500 and Metformin XR 1000 is not

recommended – only one strength should be used at a time in order to avoid accidentally exceeding

the recommended upper daily dose limit of 2000 mg.

Maintenance Therapy with Metformin XR

Metformin XR 1000 is intended as a maintenance therapy for patients currently treated with either

1000 mg or 2000 mg metformin HCl. In patients already treated with metformin HCl immediate

release tablets, the starting dose of metformin HCl modified release tablets should be equivalent to the

daily dose of metformin HCl immediate release tablets.

Product Information – Australia

Metformin XR APOTEX tablets

Page 10

The maximum recommended dose is four tablets of Metformin XR 500 or two tablets of 750mg

modified release metformin HCl (alternative brands) or two tablets of Metformin XR 1000, once daily,

with the evening meal.

Switching from Metformin XR to immediate release metformin

If glycaemic control is not achieved with the maximum recommended dose of four Metformin XR 500

tablets or two tablets of 750mg modified release metformin HCl (alternative brands) or two Metformin

XR 1000 tablets, patients may be switched to metformin HCl immediate release tablets to a maximum

dose of 3000 mg daily.

Switching from immediate release metformin to Metformin XR

In patients already treated with metformin HCl immediate release tablets, the starting dose of

Metformin XR 500 or Metformin XR 1000 should be equivalent to the daily dose of metformin HCl

immediate release tablets. In patients treated with immediate release metformin HCl at a dose above

2000 mg daily, switching to Metformin XR 500 or MetforminXR 1000 is not recommended.

Transferring from other oral hypoglycaemic agents

If transfer from another oral hypoglycaemic agent is intended, discontinue the other agent. Initiate with

one Metformin XR 500 tablet, once daily, with the evening meal and titrate as described under

“Initiating therapy with Metformin XR”.

Combination with Insulin

Metformin and insulin may be used in combination therapy to achieve better blood glucose control.

The usual starting dose is one Metformin XR 500 tablet, once daily, with the evening meal, while

insulin dosage is adjusted on the basis of blood glucose measurements. If the starting dose requires

750 mg modified release metformin HCl, then alternative brands will be required, as Metformin XR 500

cannot be divided. After titration, switching to Metformin XR 1000 should be considered.

Elderly

Due to the potential for decreased renal function in elderly subjects, the metformin dosage should be

adjusted based on renal function. Regular assessment of renal function is necessary.

Children

In absence of available data, Metformin XR 500 or Metformin XR 1000 should not be used in children.

OVERDOSAGE

Symptoms

Although hypoglycaemia has not been seen with ingestion of up to 85 g of metformin alone, lactic

acidosis has occurred in such circumstances. This disorder is a medical emergency and must be

treated in hospital. The onset of lactic acidosis is often subtle and accompanied only by non-specific

symptoms such as malaise, myalgia, respiratory distress, increasing somnolence and non-specific

abdominal

distress.

There

also

associated

hypothermia,

hypotension

resistant

bradyarrhythmias with more marked acidosis. Lactic acidosis should be suspected in any diabetic

patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonaemia).

Treatment

Lactic acidosis may develop in diabetic metformin-treated patients with overdose. Lactic acidosis is

diagnosed and monitored by measurement of serum electrolytes, arterial pH and pCO

and arterial

lactate plasma levels.

The aim of treatment is to manage any underlying disorder, and, in some cases this will be sufficient to

enable the body's homeostatic mechanism to correct the acid-base imbalance. The advantages of

more active treatment of the acidosis must be balanced against the risks, including over-alkalinization

with sodium bicarbonate. As metformin is dialysable (with a clearance of up to 170 mL/min under

good haemodynamic conditions), prompt haemodialysis is recommended to correct the acidosis and

remove the accumulated metformin.

Contact the Poisons Information Centre on 13 11 26 (Australia) for advice on the management

of overdosage.

Product Information – Australia

Metformin XR APOTEX tablets

Page 11

PRESENTATION AND STORAGE CONDITIONS

Metformin XR 500 APOTEX

Each modified release tablet contains 500 mg metformin hydrochloride and is intended for oral

administration.

White to off-white capsule-shaped, unscored tablet; engraved “APO” on one side and “XR500” on the

other side.

Bottles (HDPE) of 120 and 500 tablets: AUST R 197407

Metformin

XR

1000

APOTEX

Each

modified

release

tablet

contains

1000

metformin

hydrochloride and is intended for oral administration.

White to off-white capsule-shaped biconvex tablet; engraved “MXR 1000” on one side and plain on the

other side.

Bottle (HDPE) of 60 and 500 tablets: AUST R 218272

Not all pack types or sizes may be marketed.

Storage

Store below 25°C.

POISON SCHEDULE OF THE MEDICINE

Prescription Only Medicine.

NAME AND ADDRESS OF THE SPONSOR

Apotex Pty Ltd

16 Giffnock Avenue

Macquarie Park NSW 2113

APO and APOTEX are registered trade marks of Apotex Inc.

DATE OF FIRST INCLUSION IN THE ARTG

25 January 2013 (XR 500); 9 September 2014 (XR 1000)

DATE OF MOST RECENT AMENDMENT:

23 February 2016

4-6-2018

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4-6-2018

Naloxone Hydrochloride Injection, USP, 0.4 mg/mL, 1 mL in 2.5 mL in the Carpuject™ Single-use Cartridge Syringe System   by Hospira: Recall - Due to the Potential Presence of Particulate Matter

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14-11-2018

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Europe -DG Health and Food Safety

13-11-2018

EU/3/17/1836 (Zogenix GmbH)

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EU/3/17/1836 (Active substance: Fenfluramine hydrochloride) - Transfer of orphan designation - Commission Decision (2018)7576 of Tue, 13 Nov 2018 European Medicines Agency (EMA) procedure number: EMA/OD/233/16/T/01

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13-11-2018

EU/3/13/1219 (Zogenix GmbH)

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EU/3/13/1219 (Active substance: Fenfluramine hydrochloride) - Transfer of orphan designation - Commission Decision (2018)7575 of Tue, 13 Nov 2018 European Medicines Agency (EMA) procedure number: EMA/OD/140/13/T/01

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1-11-2018

Dexdomitor (Orion Corporation)

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Dexdomitor (Active substance: dexmedetomidine hydrochloride) - Centralised - Yearly update - Commission Decision (2018)7380 of Thu, 01 Nov 2018

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31-10-2018

Evista (Daiichi Sankyo Europe GmbH)

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Evista (Active substance: Raloxifene hydrochloride) - Centralised - Yearly update - Commission Decision (2018)7342 of Wed, 31 Oct 2018

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2-10-2018

Xigduo (AstraZeneca AB)

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26-9-2018

Sileo (Orion Corporation)

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Sileo (Active substance: Dexmedetomidine hydrochloride) - Centralised - Yearly update - Commission Decision (2018)6325 of Wed, 26 Sep 2018

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15-8-2018

Komboglyze (AstraZeneca AB)

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10-8-2018

Brinavess (Correvio)

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30-7-2018

Segluromet (Merck Sharp and Dohme B.V.)

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30-7-2018

Ceplene (Noventia Pharma Srl)

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23-7-2018

Optruma (Eli Lilly Nederland B.V.)

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Optruma (Active substance: Raloxifene hydrochloride) - Centralised - Yearly update - Commission Decision (2018)4893 of Mon, 23 Jul 2018

Europe -DG Health and Food Safety

12-7-2018

Econor (Elanco Europe Ltd)

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Econor (Active substance: Valnemulin hydrochloride) - Centralised - Yearly update - Commission Decision (2018)4580 of Thu, 12 Jul 2018

Europe -DG Health and Food Safety

11-7-2018

Ariclaim (Eli Lilly Nederland B.V.)

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Ariclaim (Active substance: duloxetine hydrochloride) - Centralised - Withdrawal - Commission Decision (2018)4515 of Wed, 11 Jul 2018

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5-7-2018

Scientific guideline:  Draft pegylated liposomal doxorubicin hydrochloride concentrate for solution 2 mg/ml product-specific bioequivalence guidance, draft: consultation open

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3-7-2018

Efficib (Merck Sharp and Dohme B.V.)

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Efficib (Active substance: sitagliptin / metformin hydrochloride) - Centralised - Transfer Marketing Authorisation Holder - Commission Decision (2018) 4254 of Tue, 03 Jul 2018 European Medicines Agency (EMA) procedure number: EMEA/H/C/896/T/90

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3-7-2018

Ristfor (Merck Sharp and Dohme B.V.)

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Ristfor (Active substance: sitagliptin / metformin hydrochloride) - Centralised - Transfer Marketing Authorisation Holder - Commission Decision (2018) 4249 of Tue, 03 Jul 2018 European Medicines Agency (EMA) procedure number: EMEA/H/C/1235/T/77

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3-7-2018

Velmetia (Merck Sharp and Dohme B.V.)

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Velmetia (Active substance: sitagliptin / metformin hydrochloride) - Centralised - Transfer Marketing Authorisation Holder - Commission Decision (2018) 4252 of Tue, 03 Jul 2018 European Medicines Agency (EMA) procedure number: EMEA/H/C/862/T/93

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3-7-2018

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29-6-2018

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14-6-2018

Kuvan (BioMarin International Limited)

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12-6-2018

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12-6-2018

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12-6-2018

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12-6-2018

EU/3/11/886 (Gilead Sciences Ireland UC)

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EU/3/11/886 (Active substance: N-(cyanomethyl)-4-(2-{[4-(morpholin-4-yl)phenyl]amino}pyrimidin-4-yl)benzamide, dihydrochloride salt) - Transfer of orphan designation - Commission Decision (2018)3799 of Tue, 12 Jun 2018 European Medicines Agency (EMA) procedure number: EMA/OD/019/11/T/03

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30-5-2018

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30-5-2018

Vokanamet (Janssen-Cilag International NV)

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29-5-2018

EU/3/18/2017 (Spedding Research Solutions SAS)

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