For adult patients with type 2 diabetes mellitus:
Sitavic is indicated as an adjunct to diet and exercise to improve glycaemic control in patients
inadequately controlled on their maximal tolerated dose of metformin alone or those already being
treated with the combination of sitagliptin and metformin.
Sitavic is indicated in combination with a sulphonylurea (i.e., triple combination therapy) as an adjunct
to diet and exercise in patients inadequately controlled on their maximal tolerated dose of metformin and
a sulphonylurea.
Sitavic is indicated as triple combination therapy with a peroxisome proliferator-activated receptor
gamma (PPARγ) agonist (i.e., a thiazolidinedione) as an adjunct to diet and exercise in patients
inadequately controlled on their maximal tolerated dose of metformin and a PPARγ agonist.
Sitavic is also indicated as add-on to insulin (i.e., triple combination therapy) as an adjunct to diet and
exercise to improve glycaemic control in patients when stable dose of insulin and metformin alone do
not provide adequate glycaemic control.

The dose of antihyperglycaemic therapy with Sitavic should be individualized on the basis of the
patient's current regimen, effectiveness, and tolerability while not exceeding the maximum
recommended daily dose of 100 mg sitagliptin.
Adults with normal renal function (GFR ≥ 90 mL/min)
For patients inadequately controlled on maximal tolerated dose of metformin monotherapy
For patients not adequately controlled on metformin alone, the usual starting dose should provide
sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) plus the dose of metformin already
being taken.

For patients switching from co-administration of sitagliptin and metformin
For patients switching from co-administration of sitagliptin and metformin, Sitavic should be initiated
at the dose of sitagliptin and metformin already being taken.
For patients inadequately controlled on dual combination therapy with the maximal tolerated dose of
metformin and a sulphonylurea
The dose should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) and a dose of
metformin similar to the dose already being taken. When Sitavic is used in combination with a
sulphonylurea, a lower dose of the sulphonylurea may be required to reduce the risk of hypoglycaemia
(see section 4.4).
For patients inadequately controlled on dual combination therapy with the maximal tolerated dose of
metformin and a PPARγ agonist
The dose should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) and a dose of
metformin similar to the dose already being taken.
For patients inadequately controlled on dual combination therapy with insulin and the maximal tolerated
dose of metformin
The dose should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) and a dose of
metformin similar to the dose already being taken. When Sitavic is used in combination with insulin, a
lower dose of insulin may be required to reduce the risk of hypoglycaemia (see section 4.4).
For the different doses on metformin, Sitavic is available in strengths of 50 mg sitagliptin and 850 mg
metformin hydrochloride or 1,000 mg metformin hydrochloride.
All patients should continue their recommended diet with an adequate distribution of carbohydrate
intake during the day.
Special populations
Renal impairment
No dose adjustment is needed for patients with mild renal impairment (glomerular filtration rate [GFR]
≥ 60 mL/min). A GFR should be assessed before initiation of treatment with metformin-containing
products and at least annually thereafter. In patients at increased risk of further progression of renal
impairment and in the elderly, renal function should be assessed more frequently, e.g. every 3-6 months.
The maximum daily dose of metformin should preferably be divided into 2-3 daily doses. Factors that
may increase the risk of lactic acidosis (see section 4.4) should be reviewed before considering initiation
of metformin in patients with GFR < 60 mL/min.
If no adequate strength of Sitavic is available, individual monocomponents should be used instead of
the fixed-dose combination
GFR mL/min Metformin Sitagliptin
60-89 Maximum daily dose is 3000 mg.
Dose reduction may be considered in
relation to declining renal function.
Maximum daily dose is 100 mg.
45-59 Maximum daily dose is 2000 mg.
The starting dose is at most half of the
maximum dose.
Maximum daily dose is 100 mg.
30-44 Maximum daily dose is 1000 mg. Maximum daily dose is 50 mg.

Hepatic impairment
Sitavic must not be used in patients with hepatic impairment (see section 5.2).
Elderly
As metformin and sitagliptin are excreted by the kidney, Sitavic should be used with caution as age
increases. Monitoring of renal function is necessary to aid in prevention of metformin-associated lactic
acidosis, particularly in the elderly (see sections 4.3 and 4.4).
Paediatric population
The safety and efficacy of Sitavic in children and adolescents from birth to < 18 years of age have not
been established. No data are available.
Method of administration
Sitavic should be given twice daily with meals to reduce the gastrointestinal adverse reactions
associated with metformin.

Sitavic is contraindicated in patients with: - hypersensitivity to the active substances or to any of the excipients listed in section 6.1 (see sections 4.4 and 4.8); - any type of acute metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis); - diabetic pre-coma; - severe renal failure (GFR< 30 mL/min) (see section 4.4); - acute conditions with the potential to alter renal function such as: - dehydration, - severe infection, - shock, - intravascular administration of iodinated contrast agents (see section 4.4); - acute or chronic disease which may cause tissue hypoxia such as: - cardiac or respiratory failure, - recent myocardial infarction, - shock; - hepatic impairment; - acute alcohol intoxication, alcoholism; - breast-feeding.

General
Sitavic should not be used in patients with type 1 diabetes and must not be used for the treatment of
diabetic ketoacidosis.
Acute pancreatitis
Use of DPP-4 inhibitors has been associated with a risk of developing acute pancreatitis. Patients should
be informed of the characteristic symptom of acute pancreatitis: persistent, severe abdominal pain.
Resolution of pancreatitis has been observed after discontinuation of sitagliptin (with or without
supportive treatment), but very rare cases of necrotising or haemorrhagic pancreatitis and/or death have
been reported. If pancreatitis is suspected, Sitavic and other potentially suspect medicinal products
should be discontinued; if acute pancreatitis is confirmed, Sitavic should not be restarted. Caution
should be exercised in patients with a history of pancreatitis.
Lactic acidosis
Lactic acidosis, a rare but serious metabolic complication, most often occurs at acute worsening of renal
function or cardiorespiratory illness or sepsis. Metformin accumulation occurs at acute worsening of
renal function and increases the risk of lactic acidosis.
In case of dehydration (severe vomiting, diarrhoea, fever or reduced fluid intake), metformin should be
temporarily discontinued and contact with a health care professional is recommended.
Medicinal products that can acutely impair renal function (such as antihypertensives, diuretics and
NSAIDs) should be initiated with caution in metformin-treated patients. Other risk factors for lactic
acidosis are excessive alcohol intake, hepatic insufficiency, inadequately controlled diabetes, ketosis,
prolonged fasting and any conditions associated with hypoxia, as well as concomitant use of medicinal
products that may cause lactic acidosis (see sections 4.3 and 4.5).
Patients and/or care-givers should be informed of the risk of lactic acidosis. Lactic acidosis is
characterised by acidotic dyspnoea, abdominal pain, muscle cramps, asthenia and hypothermia followed
by coma. In case of suspected symptoms, the patient should stop taking metformin and seek immediate
medical attention. Diagnostic laboratory findings are decreased blood pH (< 7.35), increased plasma
lactate levels (> 5 mmol/L) and an increased anion gap and lactate/pyruvate ratio.
Renal function
GFR should be assessed before treatment initiation and regularly thereafter (see section 4.2). Sitavic is
contraindicated in patients with GFR < 30 mL/min and should be temporarily discontinued during
conditions with the potential to alter renal function (see section 4.3).
Hypoglycaemia
Patients receiving Sitavic in combination with a sulphonylurea or with insulin may be at risk for
hypoglycaemia. Therefore, a reduction in the dose of the sulphonylurea or insulin may be necessary.
Hypersensitivity reactions
Post-marketing reports of serious hypersensitivity reactions in patients treated with sitagliptin have been
reported. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions including
Stevens-Johnson syndrome. Onset of these reactions occurred within the first 3 months after initiation of
treatment with sitagliptin, with some reports occurring after the first dose. If a hypersensitivity reaction is suspected, Sitavic should be discontinued, other potential causes of the event should be assessed, and
alternative treatment for diabetes should be instituted (see section 4.8).
Bullous pemphigoid
There have been post-marketing reports of bullous pemphigoid in patients taking DPP-4 inhibitors
including sitagliptin. If bullous pemphigoid is suspected, Sitavic should be discontinued.
Surgery
Sitavic must be discontinued at the time of surgery under general, spinal or epidural anaesthesia.
Therapy may be restarted no earlier than 48 hours following surgery or resumption of oral nutrition and
provided that renal function has been re-evaluated and found to be stable.
Administration of iodinated contrast agent
Intravascular administration of iodinated contrast agents may lead to contrast-induced nephropathy,
resulting in metformin accumulation and an increased risk of lactic acidosis. Sitavic should be
discontinued prior to or at the time of the imaging procedure and not restarted until at least 48 hours
after, provided that renal function has been re-evaluated and found to be stable (see sections 4.3 and
4.5).
Change in clinical status of patients with previously controlled type 2 diabetes
A patient with type 2 diabetes previously well controlled on Sitavic who develops laboratory
abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated
promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes
and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If
acidosis of either form occurs, treatment must be stopped immediately and other appropriate corrective
measures initiated.
Sodium
This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially
'sodium-free'.

 

Co-administration of multiple doses of sitagliptin (50 mg twice daily) and metformin (1,000 mg twice
daily) did not meaningfully alter the pharmacokinetics of either sitagliptin or metformin in patients with
type 2 diabetes.
Pharmacokinetic drug interaction studies with Sitavic have not been performed; however, such studies
have been conducted with the individual active substances, sitagliptin and metformin.
Concomitant use not recommended
Alcohol
Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in cases of
fasting, malnutrition or hepatic impairment.
Iodinated contrast agents
Sitavic must be discontinued prior to or at the time of the imaging procedure and not restarted until at
least 48 hours after, provided that renal function has been re-evaluated and found to be stable (see
sections 4.3 and 4.4).

Combinations requiring precautions for use
Some medicinal products can adversely affect renal function, which may increase the risk of lactic
acidosis, e.g. NSAIDs, including selective cyclo-oxygenase (COX) II inhibitors, ACE inhibitors,
angiotensin II receptor antagonists and diuretics, especially loop diuretics. When starting or using such
products in combination with metformin, close monitoring of renal function is necessary.
Concomitant use of drugs that interfere with common renal tubular transport systems involved in the
renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2] / multidrug and toxin
extrusion [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) could
increase systemic exposure to metformin and may increase the risk for lactic acidosis. Consider the
benefits and risks of concomitant use. Close monitoring of glycaemic control, dose adjustment within
the recommended posology and changes in diabetic treatment should be considered when such products
are co administered.
Glucocorticoids (given by systemic and local routes) beta-2-agonists, and diuretics have intrinsic
hyperglycaemic activity. The patient should be informed and more frequent blood glucose monitoring
performed, especially at the beginning of treatment with such medicinal products. If necessary, the dose
of the anti-hyperglycaemic medicinal product should be adjusted during therapy with the other
medicinal product and on its discontinuation.
ACE-inhibitors may decrease the blood glucose levels. If necessary, the dose of the anti-hyperglycaemic
medicinal product should be adjusted during therapy with the other medicinal product and on its
discontinuation.
Effects of other medicinal products on sitagliptin
In vitro and clinical data described below suggest that the risk for clinically meaningful interactions
following co-administration of other medicinal products is low.
In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin is
CYP3A4, with contribution from CYP2C8. In patients with normal renal function, metabolism,
including via CYP3A4, plays only a small role in the clearance of sitagliptin. Metabolism may play a
more significant role in the elimination of sitagliptin in the setting of severe renal impairment or endstage
renal disease (ESRD). For this reason, it is possible that potent CYP3A4 inhibitors (i.e.,
ketoconazole, itraconazole, ritonavir, clarithromycin) could alter the pharmacokinetics of sitagliptin in
patients with severe renal impairment or ESRD. The effects of potent CYP3A4 inhibitors in the setting
of renal impairment have not been assessed in a clinical study.
In vitro transport studies showed that sitagliptin is a substrate for p-glycoprotein and organic anion
transporter-3 (OAT3). OAT3 mediated transport of sitagliptin was inhibited in vitro by probenecid,
although the risk of clinically meaningful interactions is considered to be low. Concomitant
administration of OAT3 inhibitors has not been evaluated in vivo.
Ciclosporin: A study was conducted to assess the effect of ciclosporin, a potent inhibitor of pglycoprotein,
on the pharmacokinetics of sitagliptin. Co-administration of a single 100 mg oral dose of
sitagliptin and a single 600 mg oral dose of ciclosporin increased the AUC and Cmax of sitagliptin by
approximately 29 % and 68 %, respectively. These changes in sitagliptin pharmacokinetics were not
considered to be clinically meaningful. The renal clearance of sitagliptin was not meaningfully altered.
Therefore, meaningful interactions would not be expected with other p-glycoprotein inhibitors.
Effects of sitagliptin on other medicinal products
Digoxin: Sitagliptin had a small effect on plasma digoxin concentrations. Following administration of
0.25 mg digoxin concomitantly with 100 mg of sitagliptin daily for 10 days, the plasma AUC of digoxin was increased on average by 11 %, and the plasma Cmax on average by 18 %. No dose adjustment of
digoxin is recommended. However, patients at risk of digoxin toxicity should be monitored for this
when sitagliptin and digoxin are administered concomitantly.
In vitro data suggest that sitagliptin does not inhibit nor induce CYP450 isoenzymes. In clinical studies,
sitagliptin did not meaningfully alter the pharmacokinetics of metformin, glyburide, simvastatin,
rosiglitazone, warfarin, or oral contraceptives, providing in vivo evidence of a low propensity for
causing interactions with substrates of CYP3A4, CYP2C8, CYP2C9, and organic cationic transporter
(OCT). Sitagliptin may be a mild inhibitor of p-glycoprotein in vivo.

 

Pregnancy
There are no adequate data from the use of sitagliptin in pregnant women. Studies in animals have
shown reproductive toxicity at high doses of sitagliptin (see section 5.3).
A limited amount of data suggests the use of metformin in pregnant women is not associated with an
increased risk of congenital malformations. Animal studies with metformin do not indicate harmful
effects with respect to pregnancy, embryonic or foetal development, parturition or postnatal
development (see also section 5.3).
Sitavic should not be used during pregnancy. If a patient wishes to become pregnant or if a pregnancy
occurs, treatment should be discontinued and the patient switched to insulin treatment as soon as
possible.
Breast-feeding
No studies in lactating animals have been conducted with the combined active substances of this
medicinal product. In studies performed with the individual active substances, both sitagliptin and
metformin are excreted in the milk of lactating rats. Metformin is excreted in human milk in small
amounts. It is not known whether sitagliptin is excreted in human milk. Sitavic must therefore not be
used in women who are breast-feeding (see section 4.3).
Fertility
Animal data do not suggest an effect of treatment with sitagliptin on male and female fertility. Human
data are lacking.

Sitavic has no or negligible influence on the ability to drive and use machines. However, when driving
or using machines, it should be taken into account that dizziness and somnolence have been reported
with sitagliptin.
In addition, patients should be alerted to the risk of hypoglycaemia when Sitavic is used in combination
with a sulphonylurea or with insulin.

Summary of the safety profile
There have been no therapeutic clinical trials conducted with Sitavic tablets however bioequivalence of
Sitavic with co-administered sitagliptin and metformin has been demonstrated (see section 5.2). Serious adverse reactions including pancreatitis and hypersensitivity reactions have been reported.
Hypoglycaemia has been reported in combination with sulphonylurea (13.8%) and insulin (10.9%).
Sitagliptin and metformin
Tabulated list of adverse reactions
Adverse reactions are listed below as MedDRA preferred term by system organ class and absolute
frequency (Table 1). Frequencies are defined as: 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) and not known
(cannot be estimated from the available data).
Table 1: The frequency of adverse reactions identified from placebo-controlled clinical studies of
sitagliptin and metformin alone, and post-marketing experience
Adverse reaction Frequency of adverse reaction
Blood and lymphatic system disorders
thrombocytopenia Rare
Immune system disorders
hypersensitivity reactions including anaphylactic
responses*,†
Frequency not known
Metabolism and nutrition disorders
hypoglycaemia† Common
Nervous system disorders
somnolence Uncommon
Respiratory, thoracic and mediastinal disorders
interstitial lung disease* Frequency not known
Gastrointestinal disorders
diarrhoea Uncommon
nausea Common
flatulence Common
constipation Uncommon
upper abdominal pain Uncommon
vomiting Common
acute pancreatitis*,†,‡ Frequency not known
fatal and non-fatal haemorrhagic and necrotizing
pancreatitis*,†
Frequency not known
Skin and subcutaneous tissue disorders
pruritus* Uncommon
angioedema*,† Frequency not known
rash*,† Frequency not known
urticaria*,† Frequency not known
cutaneous vasculitis*,† Frequency not known
exfoliative skin conditions including Stevens-Johnson
syndrome*,† Frequency not known

bullous pemphigoid* Frequency not known
Musculoskeletal and connective tissue disorders
arthralgia* Frequency not known
myalgia* Frequency not known
pain in extremity* Frequency not known
back pain* Frequency not known
arthropathy* Frequency not known
Renal and urinary disorders
impaired renal function* Frequency not known
acute renal failure* Frequency not known
*Adverse reactions were identified through post-marketing surveillance.
† See section 4.4.
‡ See TECOS Cardiovascular Safety Study below.
Description of selected adverse reactions
Some adverse reactions were observed more frequently in studies of combination use of sitagliptin and
metformin with other anti-diabetic medicinal products than in studies of sitagliptin and metformin alone.
These included hypoglycaemia (frequency very common with sulphonylurea or insulin), constipation
(common with sulphonylurea), peripheral oedema (common with pioglitazone), and headache and dry
mouth (uncommon with insulin).
Sitagliptin
In monotherapy studies of sitagliptin 100 mg once daily alone compared to placebo, adverse reactions
reported were headache, hypoglycaemia, constipation, and dizziness.
Among these patients, adverse events reported regardless of causal relationship to medicinal product
occurring in at least 5 % included upper respiratory tract infection and nasopharyngitis. In addition,
osteoarthritis and pain in extremity were reported with frequency uncommon (> 0.5 % higher among
sitagliptin users than that in the control group).
Metformin
Gastrointestinal symptoms were reported very commonly in clinical studies and post-marketing use of
metformin. Gastrointestinal symptoms such as nausea, vomiting, diarrhoea, abdominal pain and loss of
appetite occur most frequently during initiation of therapy and resolve spontaneously in most cases.
Additional adverse reactions associated with metformin include metallic taste (common); lactic acidosis,
liver function disorders, hepatitis, urticaria, erythema, and pruritus (very rare). Long-term treatment with
metformin has been associated with a decrease in vitamin B12 absorption which may very rarely result
in clinically significant vitamin B12 deficiency (e.g., megaloblastic anaemia). Frequency categories are
based on information available from metformin Summary of Product Characteristics available in the EU.
TECOS Cardiovascular Safety Study
The Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) included 7,332 patients treated
with sitagliptin, 100 mg daily (or 50 mg daily if the baseline eGFR was ≥ 30 and < 50 mL/min/1.73 m2),
and 7,339 patients treated with placebo in the intention-to-treat population. Both treatments were added
to usual care targeting regional standards for HbA1c and CV risk factors. The overall incidence of
serious adverse events in patients receiving sitagliptin was similar to that in patients receiving placebo.

In the intention-to-treat population, among patients who were using insulin and/or a sulfonylurea at
baseline, the incidence of severe hypoglycaemia was 2.7 % in sitagliptin-treated patients and 2.5 % in
placebo-treated patients; among patients who were not using insulin and/or a sulfonylurea at baseline,
the incidence of severe hypoglycaemia was 1.0 % in sitagliptin-treated patients and 0.7 % in placebotreated
patients. The incidence of adjudication-confirmed pancreatitis events was 0.3 % in sitagliptintreated
patients and 0.2 % in placebo-treated patients.
Reporting of suspected adverse reactions
• Saudi Arabia:
The National Pharmacovigilance and Drug Safety Centre (NPC)
Fax: +966-11-205-7662
Call NPC at +966-11-2038222,
Ext: 2317-2356-2340.
Reporting hotline: 19999
E-mail: npc.drug@sfda.gov.sa
Website: www.sfda.gov.sa/npc
• Other GCC States:
− Please contact the relevant competent authority.

During controlled clinical trials in healthy subjects, single doses of up to 800 mg sitagliptin were
administered. Minimal increases in QTc, not considered to be clinically relevant, were observed in one
study at a dose of 800 mg sitagliptin. There is no experience with doses above 800 mg in clinical
studies. In Phase I multiple-dose studies, there were no dose-related clinical adverse reactions observed
with sitagliptin with doses of up to 600 mg per day for periods of up to 10 days and 400 mg per day for
periods of up to 28 days.
A large overdose of metformin (or co-existing risks of lactic acidosis) may lead to lactic acidosis which
is a medical emergency and must be treated in hospital. The most effective method to remove lactate and
metformin is haemodialysis.
In clinical studies, approximately 13.5 % of the dose was removed over a 3- to 4-hour haemodialysis
session. Prolonged haemodialysis may be considered if clinically appropriate. It is not known if
sitagliptin is dialysable by peritoneal dialysis.
In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove
unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an
electrocardiogram), and institute supportive therapy if required.

Pharmacotherapeutic group: Drugs used in diabetes, Combinations of oral blood glucose lowering drugs,
ATC code: A10BD07
Sitavic combines two antihyperglycaemic medicinal products with complementary mechanisms of
action to improve glycaemic control in patients with type 2 diabetes: sitagliptin phosphate, a dipeptidyl
peptidase 4 (DPP-4) inhibitor, and metformin hydrochloride, a member of the biguanide class.
Sitagliptin Mechanism of action
Sitagliptin phosphate is an orally-active, potent, and highly selective inhibitor of the dipeptidyl peptidase
4 (DPP-4) enzyme for the treatment of type 2 diabetes. The DPP-4 inhibitors are a class of agents that
act as incretin enhancers. By inhibiting the DPP-4 enzyme, sitagliptin increases the levels of two known
active incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic
polypeptide (GIP). The incretins are part of an endogenous system involved in the physiologic
regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1
and GIP increase insulin synthesis and release from pancreatic beta cells. GLP-1 also lowers glucagon
secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. When blood
glucose levels are low, insulin release is not enhanced and glucagon secretion is not suppressed.
Sitagliptin is a potent and highly selective inhibitor of the enzyme DPP-4 and does not inhibit the
closely-related enzymes DPP-8 or DPP-9 at therapeutic concentrations. Sitagliptin differs in chemical
structure and pharmacological action from GLP-1 analogues, insulin, sulphonylureas or meglitinides,
biguanides, peroxisome proliferator-activated receptor gamma (PPARγ) agonists, alpha-glucosidase
inhibitors, and amylin analogues.
In a two-day study in healthy subjects, sitagliptin alone increased active GLP-1 concentrations, whereas
metformin alone increased active and total GLP-1 concentrations to similar extents. Co-administration
of sitagliptin and metformin had an additive effect on active GLP-1 concentrations. Sitagliptin, but not
metformin, increased active GIP concentrations.
Clinical efficacy and safety
Overall, sitagliptin improved glycaemic control when used as monotherapy or in combination treatment.
In clinical trials, sitagliptin as monotherapy improved glycaemic control with significant reductions in
haemoglobin A1c (HbA1c) and fasting and postprandial glucose. Reduction in fasting plasma glucose
(FPG) was observed at 3 weeks, the first time point at which FPG was measured. The observed
incidence of hypoglycaemia in patients treated with sitagliptin was similar to placebo. Body weight did
not increase from baseline with sitagliptin therapy. Improvements in surrogate markers of beta cell
function, including HOMA-β (Homeostasis Model Assessment-β), proinsulin to insulin ratio, and
measures of beta cell responsiveness from the frequently-sampled meal tolerance test were observed.
Studies of sitagliptin in combination with metformin
In a 24-week, placebo-controlled clinical study to evaluate the efficacy and safety of the addition of
sitagliptin 100 mg once daily to ongoing metformin, sitagliptin provided significant improvements in
glycaemic parameters compared with placebo. Change from baseline in body weight was similar for
patients treated with sitagliptin relative to placebo. In this study there was a similar incidence of
hypoglycaemia reported for patients treated with sitagliptin or placebo.
In a 24-week placebo-controlled factorial study of initial therapy, sitagliptin 50 mg twice daily in
combination with metformin (500 mg or 1,000 mg twice daily) provided significant improvements in
glycaemic parameters compared with either monotherapy. The decrease in body weight with the
combination of sitagliptin and metformin was similar to that observed with metformin alone or placebo;
there was no change from baseline for patients on sitagliptin alone. The incidence of hypoglycaemia was
similar across treatment groups.
Study of sitagliptin in combination with metformin and a sulphonylurea
A 24-week placebo-controlled study was designed to evaluate the efficacy and safety of sitagliptin (100
mg once daily) added to glimepiride (alone or in combination with metformin). The addition of
sitagliptin to glimepiride and metformin provided significant improvements in glycaemic parameters.

Patients treated with sitagliptin had a modest increase in body weight (+1.1 kg) compared to those given
placebo.
Study of sitagliptin in combination with metformin and a PPARγ agonist
A 26-week placebo-controlled study was designed to evaluate the efficacy and safety of sitagliptin (100
mg once daily) added to the combination of pioglitazone and metformin. The addition of sitagliptin to
pioglitazone and metformin provided significant improvements in glycaemic parameters. Change from
baseline in body weight was similar for patients treated with sitagliptin relative to placebo. The
incidence of hypoglycaemia was also similar in patients treated with sitagliptin or placebo.
Study of sitagliptin in combination with metformin and insulin
A 24-week placebo-controlled study was designed to evaluate the efficacy and safety of sitagliptin (100
mg once daily) added to insulin (at a stable dose for at least 10 weeks) with or without metformin (at
least 1,500 mg). In patients taking pre-mixed insulin, the mean daily dose was 70.9 U/day. In patients
taking non-pre-mixed (intermediate/long-acting) insulin, the mean daily dose was 44.3 U/day. Data from
the 73 % of patients who were taking metformin are presented in Table 2. The addition of sitagliptin to
insulin provided significant improvements in glycaemic parameters. There was no meaningful change
from baseline in body weight in either group.
Table 2: HbA1c results in placebo-controlled combination therapy studies of sitagliptin and
metformin*
Study
Mean baseline
HbA1c (%)
Mean change from
baseline HbA1c (%)
Placebo-corrected mean change
in HbA1c (%)
(95 % CI)
Sitagliptin 100 mg once daily
added to ongoing metformin
therapy%
(N=453)
8.0 -0.7† -0.7†,‡
(-0.8, -0.5)
Sitagliptin 100 mg once daily
added to ongoing glimepiride
+ metformin therapy%
(N=115)
8.3 -0.6† -0.9†,‡
(-1.1, -0.7)
Sitagliptin 100 mg once daily
added to ongoing
pioglitazone + metformin
therapy¶
(N=152)
8.8 -1.2† -0.7†,‡
(-1.0, -0.5)
Sitagliptin 100 mg once daily
added to ongoing insulin +
metformin therapy %
(N=223)
8.7 -0.7§ -0.5§,‡
(-0.7, -0.4)
Initial Therapy (twice
daily)%:
Sitagliptin 50 mg +
metformin 500 mg
(N=183)
8.8 -1.4† -1.6†,‡
(-1.8, -1.3)
Initial Therapy (twice
daily)%:
8.8 -1.9† -2.1†,‡
(-2.3, -1.8)

Sitagliptin 50 mg +
metformin 1,000 mg
(N=178)
* All Patients Treated Population (an intention-to-treat analysis).
† Least squares means adjusted for prior antihyperglycaemic therapy status and baseline value.
‡ p< 0.001 compared to placebo or placebo + combination treatment.
% HbA1c (%) at week 24.
¶ HbA1c (%) at week 26.
§ Least squares mean adjusted for insulin use at Visit 1 (pre-mixed vs. non-pre-mixed [intermediate- or
long-acting]), and baseline value.
In a 52-week study, comparing the efficacy and safety of the addition of sitagliptin 100 mg once daily or
glipizide (a sulphonylurea ) in patients with inadequate glycaemic control on metformin monotherapy,
sitagliptin was similar to glipizide in reducing HbA1c (-0.7 % mean change from baselines at week 52,
with baseline HbA1c of approximately 7.5 % in both groups). The mean glipizide dose used in the
comparator group was 10 mg per day with approximately 40 % of patients requiring a glipizide dose of
≤ 5 mg/day throughout the study. However, more patients in the sitagliptin group discontinued due to
lack of efficacy than in the glipizide group. Patients treated with sitagliptin exhibited a significant mean
decrease from baseline in body weight (-1.5 kg) compared to a significant weight gain in patients
administered glipizide (+1.1 kg). In this study, the proinsulin to insulin ratio, a marker of efficiency of
insulin synthesis and release, improved with sitagliptin and deteriorated with glipizide treatment. The
incidence of hypoglycaemia in the sitagliptin group (4.9 %) was significantly lower than that in the
glipizide group (32.0 %).
A 24-week placebo-controlled study involving 660 patients was designed to evaluate the insulin-sparing
efficacy and safety of sitagliptin (100 mg once daily) added to insulin glargine with or without
metformin (at least 1,500 mg) during intensification of insulin therapy. Among patients taking
metformin, baseline HbA1c was 8.70 % and baseline insulin dose was 37 IU/day. Patients were
instructed to titrate their insulin glargine dose based on fingerstick fasting glucose values. Among
patients taking metformin, at Week 24, the increase in daily insulin dose was 19 IU/day in patients
treated with sitagliptin and 24 IU/day in patients treated with placebo. The reduction in HbA1c for
patients treated with sitagliptin, metformin, and insulin was -1.35 % compared to -0.90 % for patients
treated with placebo, metformin, and insulin, a difference of -0.45 % [95 % CI: -0.62, -0.29]. The
incidence of hypoglycaemia was 24.9 % for patients treated with sitagliptin, metformin, and insulin and
37.8 % for patients treated with placebo, metformin, and insulin. The difference was mainly due to a
higher percentage of patients in the placebo group experiencing 3 or more episodes of hypoglycaemia
(9.1 vs. 19.8 %). There was no difference in the incidence of severe hypoglycaemia.
Metformin
Mechanism of action
Metformin 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:
- by reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis - in muscle, by modestly increasing insulin sensitivity, improving peripheral glucose uptake and
utilisation
- by delaying intestinal glucose absorption
Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase. Metformin
increases the transport capacity of specific types of membrane glucose transporters (GLUT-1 and
GLUT-4).
Clinical efficacy and safety
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 or long-term clinical
studies: metformin reduces total cholesterol, LDLc and triglyceride levels.
The prospective randomised (UKPDS) study has established the long-term benefit of intensive blood
glucose control in type 2 diabetes. 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/1,000 patient-years) versus diet alone (43.3 events/1,000 patient-years), p=0.0023, and
versus the combined sulphonylurea and insulin monotherapy groups (40.1 events/1,000 patient-years),
p=0.0034
- a significant reduction of the absolute risk of any diabetes-related mortality: metformin 7.5
events/1,000 patient-years, diet alone 12.7 events/1,000 patient-years, p=0.017
- a significant reduction of the absolute risk of overall mortality: metformin 13.5 events/1,000 patientyears
versus diet alone 20.6 events/1,000 patient-years, (p=0.011), and versus the combined
sulphonylurea and insulin monotherapy groups 18.9 events/1,000 patient-years (p=0.021)
- a significant reduction in the absolute risk of myocardial infarction: metformin 11 events/1,000 patientyears,
diet alone 18 events/1,000 patient-years, (p=0.01).
The TECOS was a randomised study in 14,671 patients in the intention-to-treat population with an
HbA1c of ≥ 6.5 to 8.0 % with established CV disease who received sitagliptin (7,332) 100 mg daily (or
50 mg daily if the baseline eGFR was ≥ 30 and < 50 mL/min/1.73 m2) or placebo (7,339) added to usual
care targeting regional standards for HbA1c and CV risk factors. Patients with an eGFR < 30
mL/min/1.73 m2 were not to be enrolled in the study. The study population included 2,004 patients ≥ 75
years of age and 3,324 patients with renal impairment (eGFR < 60 mL/min/1.73 m2).
Over the course of the study, the overall estimated mean (SD) difference in HbA1c between the
sitagliptin and placebo groups was 0.29 % (0.01), 95 % CI (-0.32, -0.27); p < 0.001.
The primary cardiovascular endpoint was a composite of the first occurrence of cardiovascular death,
nonfatal myocardial infarction, nonfatal stroke, or hospitalisation for unstable angina. Secondary
cardiovascular endpoints included the first occurrence of cardiovascular death, nonfatal myocardial
infarction, or nonfatal stroke; first occurrence of the individual components of the primary composite;
all-cause mortality; and hospital admissions for congestive heart failure.
After a median follow up of 3 years, sitagliptin, when added to usual care, did not increase the risk of
major adverse cardiovascular events or the risk of hospitalisation for heart failure compared to usual
care without sitagliptin in patients with type 2 diabetes (Table 3).
Table 3: Rates of Composite Cardiovascular Outcomes and Key Secondary Outcomes
Sitagliptin 100 mg Placebo Hazard Ratio p-value

Analysis in the Intention-to-Treat Population
Number of patients 7,332 7,339 0.98 (0.89–
1.08)
<0.001
Primary Composite Endpoint
(Cardiovascular death, nonfatal
myocardial infarction, nonfatal
stroke, or hospitalisation for
unstable angina) 839 (11.4) 4.1 851 (11.6) 4.2
Secondary Composite Endpoint
(Cardiovascular death, nonfatal
myocardial infarction, or nonfatal
stroke) 745 (10.2) 3.6 746 (10.2) 3.6
0.99 (0.89–
1.10) <0.001
Secondary Outcome
Cardiovascular death 380 (5.2) 1.7 366 (5.0) 1.7 1.03 (0.89-1.19) 0.711
All myocardial infarction (fatal
and non-fatal) 300 (4.1) 1.4 316 (4.3) 1.5
0.95 (0.81–
1.11) 0.487
All stroke (fatal and non-fatal)
178 (2.4) 0.8 183 (2.5) 0.9
0.97 (0.79–
1.19) 0.760
Hospitalisation for unstable
angina 116 (1.6) 0.5 129 (1.8) 0.6
0.90 (0.70–
1.16) 0.419
Death from any cause
547 (7.5) 2.5 537 (7.3) 2.5
1.01 (0.90–
1.14) 0.875
Hospitalisation for heart failure‡
228 (3.1) 1.1 229 (3.1) 1.1
1.00 (0.83–
1.20) 0.983
* Incidence rate per 100 patient-years is calculated as 100 × (total number of patients with ≥ 1 event
during eligible exposure period per total patient-years of follow-up).
† Based on a Cox model stratified by region. For composite endpoints, the p-values correspond to a test
of non-inferiority seeking to show that the hazard ratio is less than 1.3. For all other endpoints, the pvalues
correspond to a test of differences in hazard rates.
‡ The analysis of hospitalisation for heart failure was adjusted for a history of heart failure at baseline.
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with Sitavic
in all subsets of the paediatric population in type 2 diabetes mellitus (see section 4.2 for information on
paediatric use).

Sitavic
A bioequivalence study in healthy subjects demonstrated that the Sitavic (sitagliptin/metformin
hydrochloride) combination tablets are bioequivalent to co-administration of sitagliptin phosphate and
metformin hydrochloride as individual tablets.

The following statements reflect the pharmacokinetic properties of the individual active substances of
Sitavic
Sitagliptin
Absorption
Following oral administration of a 100-mg dose to healthy subjects, sitagliptin was rapidly absorbed,
with peak plasma concentrations (median Tmax) occurring 1 to 4 hours post-dose, mean plasma AUC of
sitagliptin was 8.52 μM•hr, Cmax was 950 nM. The absolute bioavailability of sitagliptin is
approximately 87 %. Since co-administration of a high-fat meal with sitagliptin had no effect on the
pharmacokinetics, sitagliptin may be administered with or without food.
Plasma AUC of sitagliptin increased in a dose-proportional manner. Dose-proportionality was not
established for Cmax and C24hr (Cmax increased in a greater than dose-proportional manner and
C24hr increased in a less than dose-proportional manner).
Distribution
The mean volume of distribution at steady state following a single 100-mg intravenous dose of
sitagliptin to healthy subjects is approximately 198 litres. The fraction of sitagliptin reversibly bound to
plasma proteins is low (38 %).
Biotransformation
Sitagliptin is primarily eliminated unchanged in urine, and metabolism is a minor pathway.
Approximately 79 % of sitagliptin is excreted unchanged in the urine.
Following a [14C]sitagliptin oral dose, approximately 16 % of the radioactivity was excreted as
metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute
to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme
responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.
In vitro data showed that sitagliptin is not an inhibitor of CYP isoenzymes CYP3A4, 2C8, 2C9, 2D6,
1A2, 2C19 or 2B6, and is not an inducer of CYP3A4 and CYP1A2.
Elimination
Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100 % of the
administered radioactivity was eliminated in faeces (13 %) or urine (87 %) within one week of dosing.
The apparent terminal t½ following a 100-mg oral dose of sitagliptin was approximately 12.4 hours.
Sitagliptin accumulates only minimally with multiple doses. The renal clearance was approximately 350
mL/min.
Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion.
Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the
renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been
established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating
the renal elimination of sitagliptin. However, ciclosporin, a p-glycoprotein inhibitor, did not reduce the
renal clearance of sitagliptin. Sitagliptin is not a substrate for OCT2 or OAT1 or PEPT1/2
transporters. In vitro, sitagliptin did not inhibit OAT3 (IC50=160 μM) or p-glycoprotein (up to 250 μM)
mediated transport at therapeutically relevant plasma concentrations. In a clinical study sitagliptin had a
small effect on plasma digoxin concentrations indicating that sitagliptin may be a mild inhibitor of pglycoprotein.

Characteristics in patients
The pharmacokinetics of sitagliptin were generally similar in healthy subjects and in patients with type 2
diabetes.
Renal impairment
A single-dose, open-label study was conducted to evaluate the pharmacokinetics of a reduced dose of
sitagliptin (50 mg) in patients with varying degrees of chronic renal impairment compared to normal
healthy control subjects. The study included patients with mild, moderate, and severe renal impairment,
as well as patients with ESRD on haemodialysis. In addition, the effects of renal impairment on
sitagliptin pharmacokinetics in patients with type 2 diabetes and mild, moderate, or severe renal
impairment (including ESRD) were assessed using population pharmacokinetic analyses.
Compared to normal healthy control subjects, plasma AUC of sitagliptin was increased by
approximately 1.2-fold and 1.6-fold in patients with mild renal impairment (GFR ≥ 60 to < 90 mL/min)
and patients with moderate renal impairment (GFR ≥ 45 to < 60 mL/min), respectively. Because
increases of this magnitude are not clinically relevant, dosage adjustment in these patients is not
necessary.
Plasma AUC of sitagliptin was increased approximately 2-fold in patients with moderate renal
impairment (GFR ≥ 30 to < 45 mL/min), and approximately 4-fold in patients with severe renal
impairment (GFR < 30 mL/min), including patients with ESRD on haemodialysis. Sitagliptin was
modestly removed by haemodialysis (13.5 % over a 3- to 4-hour haemodialysis session starting 4 hours
post-dose).
Hepatic impairment
No dose adjustment for sitagliptin is necessary for patients with mild or moderate hepatic impairment
(Child-Pugh score ≤ 9). There is no clinical experience in patients with severe hepatic impairment
(Child-Pugh score > 9). However, because sitagliptin is primarily renally eliminated, severe hepatic
impairment is not expected to affect the pharmacokinetics of sitagliptin.
Elderly
No dose adjustment is required based on age. Age did not have a clinically meaningful impact on the
pharmacokinetics of sitagliptin based on a population pharmacokinetic analysis of Phase I and Phase II
data. Elderly subjects (65 to 80 years) had approximately 19 % higher plasma concentrations of
sitagliptin compared to younger subjects.
Paediatric
No studies with sitagliptin have been performed in paediatric patients.
Other patient characteristics
No dose adjustment is necessary based on gender, race, or body mass index (BMI). These characteristics
had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a composite analysis
of Phase I pharmacokinetic data and on a population pharmacokinetic analysis of Phase I and Phase II
data.
Metformin
Absorption

After an oral dose of metformin, Tmax is reached in 2.5 h. Absolute bioavailability of a 500 mg
metformin tablet is approximately 50-60 % in healthy subjects. After an oral dose, the non-absorbed
fraction recovered in faeces was 20-30 %.
After oral administration, metformin absorption is saturable and incomplete. It is assumed that the
pharmacokinetics of metformin absorption is non-linear. At the usual metformin doses and dosing
schedules, steady state plasma concentrations are reached within 24-48 h and are generally less than 1
μg/mL. In controlled clinical trials, maximum metformin plasma levels (Cmax) did not exceed 5 μg/mL,
even at maximum doses.
Food decreases the extent and slightly delays the absorption of metformin. Following administration of a
dose of 850 mg, a 40 % lower plasma peak concentration, a 25 % decrease in AUC and a 35 min
prolongation of time to peak plasma concentration was observed. The clinical relevance of this decrease
is unknown.
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 Vd ranged between 63 – 276 L.
Biotransformation
Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.
Elimination
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 6.5 h. 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.

No animal studies have been conducted with Sitavic
In 16-week studies in which dogs were treated with either metformin alone or a combination of
metformin and sitagliptin, no additional toxicity was observed from the combination. The NOEL in
these studies was observed at exposures to sitagliptin of approximately 6 times the human exposure and
to metformin of approximately 2.5 times the human exposure.
The following data are findings in studies performed with sitagliptin or metformin individually.
Sitagliptin
Renal and liver toxicity were observed in rodents at systemic exposure values 58 times the human
exposure level, while the no-effect level was found at 19 times the human exposure level. Incisor teeth
abnormalities were observed in rats at exposure levels 67 times the clinical exposure level; the no-effect
level for this finding was 58-fold based on the 14-week rat study. The relevance of these findings for
humans is unknown. Transient treatment-related physical signs, some of which suggest neural toxicity,
such as open-mouth breathing, salivation, white foamy emesis, ataxia, trembling, decreased activity,
and/or hunched posture were observed in dogs at exposure levels approximately 23 times the clinical
exposure level. In addition, very slight to slight skeletal muscle degeneration was also observed
histologically at doses resulting in systemic exposure levels of approximately 23 times the human exposure level. A no-effect level for these findings was found at an exposure 6-fold the clinical exposure
level.
Sitagliptin has not been demonstrated to be genotoxic in preclinical studies. Sitagliptin was not
carcinogenic in mice. In rats, there was an increased incidence of hepatic adenomas and carcinomas at
systemic exposure levels 58 times the human exposure level. Since hepatotoxicity has been shown to
correlate with induction of hepatic neoplasia in rats, this increased incidence of hepatic tumours in rats
was likely secondary to chronic hepatic toxicity at this high dose. Because of the high safety margin (19-
fold at this no-effect level), these neoplastic changes are not considered relevant for the situation in
humans.
No treatment related effects on fertility were observed in male and female rats given sitagliptin prior to
and throughout mating.
In a pre-/post-natal development study performed in rats sitagliptin showed no adverse effects.
Reproductive toxicity studies showed a slight treatment-related increased incidence of foetal rib
malformations (absent, hypoplastic and wavy ribs) in the offspring of rats at systemic exposure levels
more than 29 times the human exposure levels. Maternal toxicity was seen in rabbits at more than 29
times the human exposure levels. Because of the high safety margins, these findings do not suggest a
relevant risk for human reproduction. Sitagliptin is secreted in considerable amounts into the milk of
lactating rats (milk/plasma ratio: 4:1).
Metformin
Preclinical data for metformin reveal no special hazard for humans based on conventional studies of
safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to
reproduction.

 

Polyvinylpyrrolidone
Sodium Lauryl sulphate
Microcrystalline cellulose
Sodium Stearyl Fumarate
Iron Oxide Red
Opadry Pink II 85F240109
Purified Water

Not applicable

24 Months

Do not store above 30° C.

Sitavic 50mg/ 850mg film coated tablets re available in a box of 8 blisters, 7 tablets per each blister

No special requirements for disposal.