Consumer medicine information

Sitagliptin Sun

Sitagliptin

BRAND INFORMATION

Brand name

Sitagliptin Sun

Active ingredient

Sitagliptin

Schedule

SUMMARY CMI

SITAGLIPTIN SUN

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using Sitagliptin SUN?

Sitagliptin SUN contains the active ingredient sitagliptin fumarate. Sitagliptin SUN is used to lower blood sugar levels in patients with type 2 diabetes mellitus alone or in combination with certain other medicines, when diet plus exercise or the other medicine(s) do not provide adequate blood sugar level control.

For more information, see Section 1. Why am I using Sitagliptin SUN? in the full CMI.

2. What should I know before I use Sitagliptin SUN?

Do not use if you have ever had an allergic reaction to Sitagliptin SUN or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use Sitagliptin SUN? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Sitagliptin SUN and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Sitagliptin SUN?

Take Sitagliptin SUN only when prescribed by your doctor.
The recommended dose is to take one 100 mg tablet once a day, by mouth, with or without food.

More instructions can be found in Section 4. How do I use Sitagliptin SUN? in the full CMI.

5. What should I know while using Sitagliptin SUN?

Things you should do	If you become pregnant while taking Sitagliptin SUN, tell your doctor immediately. If you are about to be started on any new medicine, tell your doctor and pharmacist that you are taking Sitagliptin SUN.
Things you should not do	Do not stop using this medicine suddenly. Do not give Sitagliptin SUN to anyone else, even if they have the same condition as you.
Driving or using machines	Sitagliptin SUN is not expected to affect the ability to drive and use machines.
Looking after your medicine	Keep Sitagliptin SUN in a cool dry place where the temperature stays below 25°C. Do not store it or any other medicine in the bathroom or near a sink.

For more information, see Section 5. What should I know while using Sitagliptin SUN? in the full CMI.

6. Are there any side effects?

Side effects include runny nose, sore throat, cough, soreness in the back of the nose and throat and discomfort when swallowing, headache, flu‐like symptoms.

Tell your doctor immediately if you notice low blood sugar when this medicine is used in combination with a sulfonylurea medicine or with insulin and if you develop blisters or the breakdown of your skin (erosion).

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

FULL CMI

SITAGLIPTIN SUN

Active ingredient(s): sitagliptin fumarate

Consumer Medicine Information (CMI)

This leaflet provides important information about using Sitagliptin SUN. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Sitagliptin SUN.

Where to find information in this leaflet:

1. Why am I using Sitagliptin SUN?
2. What should I know before I use Sitagliptin SUN?
3. What if I am taking other medicines?
4. How do I use Sitagliptin SUN?
5. What should I know while using Sitagliptin SUN?
6. Are there any side effects?
7. Product details

1. Why am I using Sitagliptin SUN?

Sitagliptin SUN contains the active ingredient sitagliptin fumarate. Sitagliptin SUN is a member of a class of oral anti‐hyperglycaemic agents which improve glycaemic control in patients with type 2 diabetes by enhancing the levels of active incretin hormones.

Sitagliptin SUN is a member of a class of medicines you take by mouth called DPP‐4 inhibitors (dipeptidyl peptidase‐4 inhibitors) that lowers blood sugar levels in patients with type 2 diabetes mellitus. Type 2 diabetes mellitus is also called non‐insulin‐dependent diabetes mellitus, or NIDDM.

Sitagliptin SUN helps to improve the levels of insulin after a meal.
Sitagliptin SUN decreases the amount of sugar made by the body.
Sitagliptin SUN works when blood sugar is high, especially after a meal. This is when the body needs the greatest amount of help in lowering blood sugar. Sitagliptin SUN also lowers blood sugar between meals.
Sitagliptin SUN by itself is unlikely to cause low blood sugar (hypoglycaemia) because it does not work when your blood sugar is low.

2. What should I know before I use Sitagliptin SUN?

Warnings

Do not use Sitagliptin SUN if:

you are allergic to sitagliptin fumarate, or any of the ingredients listed at the end of this leaflet.
Always check the ingredients to make sure you can use this medicine.
the packaging is torn or shows signs of tampering.
the expiry date on the pack has passed.
If you take this medicine after the expiry date has passed, it may not work.

Check with your doctor if you:

have any other medical conditions:
- have or have had type 1 diabetes mellitus or a condition called diabetic ketoacidosis (increased ketones in the blood or urine)
Sitagliptin SUN should not be used for the treatment of these conditions.
- any kidney problems or any past or present medical problems
If you have kidney problems, your doctor may prescribe lower doses.
- an allergic reaction to Sitagliptin SUN or you have any allergies to any other medicines or other substances such as foods, preservatives or dyes
take any medicines for any other condition

If you have not told your doctor about any of the above, tell him/ her before you take any Sitagliptin SUN.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Sitagliptin SUN is not recommended for use during pregnancy.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

Sitagliptin SUN should not be used while breastfeeding or if planning to breastfeed.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Sitagliptin SUN can be taken with most other medicines.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Sitagliptin SUN.

4. How do I use Sitagliptin SUN?

How much to take / use

Take Sitagliptin SUN only when prescribed by your doctor.
The recommended dose is to take is one 100 mg tablet, once a day, by mouth, with or without food.
If you have kidney problems, your doctor may prescribe lower doses, and monitor your kidney function.
Your doctor may prescribe Sitagliptin SUN on its own, or with certain other medicines that lower blood sugar.
Follow the instructions provided and use Sitagliptin SUN until your doctor tells you to stop.

When to take / use Sitagliptin SUN

Sitagliptin SUN should be taken once a day, by mouth, with or without food.
Continue to take Sitagliptin SUN as long as your doctor prescribes it so you can continue to help control your blood sugar.
Diet and exercise can help your body use its blood sugar better. It is important to stay on your doctor's recommended diet, exercise and weight loss program while taking Sitagliptin SUN.

If you forget to use Sitagliptin SUN

Sitagliptin SUN should be used regularly at the same time each day. If you miss a dose, take it as soon as you remember. If you do not remember until it is time for your next dose, skip the missed dose and go back to your regular schedule.

If you are not sure whether to skip the dose, talk to your doctor or pharmacist.

Do not take a double dose to make up for the dose you missed.

If you have trouble remembering to take your tablet, ask your pharmacist for some hints.

If you use too much Sitagliptin SUN

If you think that you have used too much Sitagliptin SUN, you may need urgent medical attention.

You should immediately:

phone the Poisons Information Centre
(by calling 13 11 26), or
contact your doctor, or
go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using Sitagliptin SUN?

Things you should do

If you become pregnant while taking Sitagliptin SUN, tell your doctor immediately.

If you are about to be started on any new medicine, tell your doctor and pharmacist that you are taking Sitagliptin SUN.

Things you should not do

Do not stop using this medicine suddenly.
Do not give Sitagliptin SUN to anyone else, even if they have the same condition as you.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Sitagliptin SUN affects you.

Sitagliptin SUN is not expected to affect the ability to drive and use machines.

Looking after your medicine

Keep your tablets in the blister pack until it is time to take them.

If you take the tablets out of the blister pack they may not keep well.

Keep Sitagliptin SUN in a cool dry place where the temperature stays below 25°C. Do not store it or any other medicine in the bathroom or near a sink.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

in the bathroom or near a sink, or
in the car or on window sills.

Keep it where young children cannot reach it.

A locked cupboard at least one‐and‐a‐half metres above the ground is a good place to store medicines.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effects

What to do

Infection related:

signs of an infection of the breathing passages, including runny nose, sore throat, cough
soreness in the back of the nose and throat and discomfort when swallowing
flu‐like symptoms

Nervous system related:

headache

Gastrointestinal system related:

Sitagliptin may occasionally cause stomach discomfort and diarrhoea.

Speak to your doctor if you have any of these less serious side effects and they worry you.

Metabolism related:

Low blood sugar (hypoglycaemia) when Sitagliptin is used in combination with a sulfonylurea medicine or with insulin. Due to the sulfonylurea or insulin, causing hypoglycaemia, the dose of your sulfonylurea medicine or insulin may need to be reduced while you use Sitagliptin.

Skin related:

Cases of a skin reaction called bullous pemphigoid that can require treatment in a hospital have been reported in patients receiving Sitagliptin. Tell your doctor if you develop blisters or the breakdown of your skin (erosion). Your doctor may tell you to stop taking Sitagliptin.

Tell your doctor immediately if you notice any of the following.

Serious side effects

Serious side effects

What to do

Allergic reactions

Allergic reactions which may be serious including rash, hives, and swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing. If you have an allergic reaction, stop taking Sitagliptin and call your doctor right away. Your doctor may prescribe a medication to treat your allergic reaction and a different medication for your diabetes.

Gastrointestinal system related:

Severe and persistent stomach pain, often with nausea and vomiting. These may be symptoms of pancreatitis. Pancreatitis can be a serious, potentially life‐threatening medical condition. Stop taking Sitagliptin and call your doctor right away if you experience these symptoms.

Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Additional side effects have been reported in general use with Sitagliptin SUN, by itself and/or with other diabetes medicines:

Kidney problems (sometimes requiring dialysis)
Constipation
Diarrhoea
Vomiting
Joint pain
Muscle aches
Arm or leg pain
Back pain
Itching
Blisters

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Do not be alarmed by this list of possible side effects.

You may not experience any of them.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What Sitagliptin Sun contains

Active ingredient (main ingredient)

Sitagliptin fumarate

Other ingredients (inactive ingredients)

The tablet contains the following inactive ingredients:

calcium hydrogen phosphate
crospovidone
hydrogenated castor oil
glycerol dibehenate
magnesium stearate
Opadry Pink 02F540038 (139708)
Opadry Beige 02F570009 (139707)
Opadry Beige 02F570006 (139717)

Potential allergens

none

Do not take this medicine if you are allergic to any of these ingredients.

What Sitagliptin SUN looks like

Sitagliptin SUN Tablet 25 mg ‐ Light pink colour, round film coated tablets debossed with F1 on one side and plain on the other side (Aust R 352533).

Sitagliptin SUN Tablet 50 mg ‐ Light beige colour, round film coated tablets debossed with F2 on one side and plain on the other side (Aust R 352532).

Sitagliptin SUN Tablet 100 mg ‐ Beige colour, round film coated tablets debossed with F3 on one side and plain on the other side (Aust R 352534).

Sitagliptin SUN tablets come in a blister strip. Each box contains 28 tablets.

Who distributes Sitagliptin SUN

Sun Pharma ANZ Pty Ltd
12 Waterloo Road
Macquarie Park NSW 2113
Australia
Tel No. 1800 726 229
Email: [email protected]

This leaflet was prepared in 07 Sept 2022.

Published by MIMS October 2022

BRAND INFORMATION

Brand name

Sitagliptin Sun

Active ingredient

Sitagliptin

Schedule

1 Name of Medicine

Sitagliptin fumarate.

2 Qualitative and Quantitative Composition

Sitagliptin Sun is available for oral use as film coated tablets containing sitagliptin fumarate equivalent to 25, 50 or 100 mg of free base.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Sitagliptin Sun tablet 25 mg.

Light pink colour, round film coated tablets debossed with F1 on one side and plain on the other side.

Sitagliptin Sun tablet 50 mg.

Light beige colour, round film coated tablets debossed with F2 on one side and plain on the other side.

Sitagliptin Sun tablet 100 mg.

Beige colour, round film coated tablets debossed with F3 on one side and plain on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Sitagliptin Sun (sitagliptin fumarate) is indicated as an adjunct to diet and exercise to improve glycaemic control in adults with type 2 diabetes mellitus as:
monotherapy when metformin is considered inappropriate due to intolerance; or
in combination with other anti-hyperglycaemic agents, including insulin [see Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions for available data on different add-on combination therapies].

4.2 Dose and Method of Administration

Each Sitagliptin Sun tablet contains sitagliptin fumarate. The innovator product contains sitagliptin phosphate monohydrate. All clinical data in this product information (including pharmacokinetic, pharmacodynamic and clinical trial data) are based on sitagliptin phosphate monohydrate. Bioequivalence with respect to sitagliptin has been established between the two salt forms.
The recommended dose of Sitagliptin Sun is 100 mg once daily as monotherapy, or as combination therapy with metformin, or a sulfonylurea (clinical experience is with glimepiride as dual therapy), insulin (with or without metformin), a thiazolidinedione (clinical experience is with pioglitazone as dual therapy), or combination therapy with metformin and a sulfonylurea (clinical experience is with addition of sitagliptin to glimepiride or gliclazide and metformin as triple therapy). Sitagliptin Sun can be taken with or without food.
When Sitagliptin Sun is used in combination with a sulfonylurea or with insulin, reduction in the dose of sulfonylurea or insulin may be considered to reduce the risk of sulfonylurea- or insulin-induced hypoglycaemia (see Section 4.4 Special Warnings and Precautions for Use, Hypoglycaemia in combination with a sulfonylurea or with insulin).

Patients with renal impairment.

Because there is a dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of Sitagliptin Sun and periodically thereafter.
For patients with eGFR ≥ 45 mL/min/1.73 m² to < 90 mL/min/1.73 m², no dosage adjustment for Sitagliptin Sun is required.
For patients with eGFR ≥ 30 mL/min/1.73 m² to < 45 mL/min/1.73 m², the dose of Sitagliptin Sun is 50 mg once daily.
For patients with eGFR ≥ 15 mL/min/1.73 m² to < 30 mL/min/1.73 m² or with ESRD (eGFR < 15 mL/min/1.73 m²), including those requiring haemodialysis or peritoneal dialysis, the dose of Sitagliptin Sun is 25 mg once daily. Sitagliptin Sun may be administered without regard to the timing of dialysis.
The use of Sitagliptin Sun in combination with insulin has not been studied in patients with moderate or severe renal impairment.

4.3 Contraindications

Sitagliptin is contraindicated in patients who are hypersensitive to any components of this product (see Section 4.4 Special Warnings and Precautions for Use, Hypersensitivity reactions; Section 4.8 Adverse Effects (Undesirable Effects), Postmarketing experience).

4.4 Special Warnings and Precautions for Use

General.

Sitagliptin should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

Pancreatitis.

There have been reports of acute pancreatitis, including fatal and non-fatal haemorrhagic or necrotising pancreatitis (see Section 4.8 Adverse Effects (Undesirable Effects)), in patients taking sitagliptin. 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. If pancreatitis is suspected, sitagliptin and other potentially suspect medicinal products should be discontinued.

Use in renal impairment.

Because sitagliptin is renally excreted, to achieve plasma concentrations of sitagliptin similar to those in patients with normal renal function, lower dosages are recommended in patients with eGFR < 45 mL/min/1.73 m², as well as in ESRD patients requiring haemodialysis or peritoneal dialysis (see Section 4.2 Dose and Method of Administration, Patients with renal impairment). Because there is a dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of sitagliptin and periodically thereafter. The use of sitagliptin in combination with other antihyperglycaemic agents (i.e. metformin, sulfonylureas, thiazolidinediones or insulin) has not been studied in patients with moderate or severe renal impairment.

Hypoglycaemia in combination with a sulfonylurea or with insulin.

In clinical trials of sitagliptin as monotherapy and sitagliptin as part of combination therapy with metformin or pioglitazone, rates of hypoglycaemia reported with sitagliptin were similar to rates in patients taking placebo.
As typical with other antihyperglycaemic agents used in combination with sulfonylurea or with insulin, hypoglycaemia has been observed when sitagliptin was used in combination with insulin or a sulfonylurea (see Section 4.8 Adverse Effects (Undesirable Effects)). Therefore, to reduce the risk of sulfonylurea- or insulin-induced hypoglycaemia, reduction in the dose of sulfonylurea or insulin may be considered (see Section 4.2 Dose and Method of Administration).

Hypersensitivity reactions.

There have been postmarketing reports of serious hypersensitivity reactions in patients treated with sitagliptin. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. 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, discontinue sitagliptin, assess for other potential causes for the event, and institute alternative treatment for diabetes (see Section 4.3 Contraindications; Section 4.8 Adverse Effects (Undesirable Effects), Postmarketing experience).

Arthralgia.

There have been post-marketing reports of joint pain, which may be severe, in patients taking DPP-4 inhibitors. Onset of symptoms following initiation of treatment may be rapid or may occur after longer periods. Discontinuation of therapy should be considered in patients who present with or experience an exacerbation of joint symptoms during treatment with DPP-4 inhibitors.

Bullous pemphigoid.

Postmarketing cases of bullous pemphigoid requiring hospitalisation have been reported with DPP-4 inhibitor use. In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP-4 inhibitor. Tell patients to report development of blisters or erosions while receiving sitagliptin. If bullous pemphigoid is suspected, sitagliptin should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.

Use in the elderly.

In clinical studies, the safety and effectiveness of sitagliptin in the elderly (≥ 65 years) were comparable to those seen in younger patients (< 65 years). No dosage adjustment is required based on age. Elderly patients are more likely to have renal impairment; as with other patients, dosage adjustment may be required in the presence of significant renal impairment (see Section 4.2 Dose and Method of Administration, Patients with renal impairment).

Paediatric use.

Safety and effectiveness of sitagliptin in paediatric patients under 18 years have not been established.

Effects on laboratory tests.

The incidence of laboratory adverse experiences was similar in patients treated with sitagliptin 100 mg compared to patients treated with placebo. Across clinical studies, a small increase in white blood cell count (approximately 200 cells/microL difference in WBC vs placebo; mean baseline WBC approximately 6600 cells/microL) was observed due to an increase in neutrophils. This observation was seen in most but not all studies. This change in laboratory parameters is not considered to be clinically relevant.

4.5 Interactions with Other Medicines and Other Forms of Interactions

In vitro assessment of drug interactions.

Sitagliptin is not an inhibitor of CYP isozymes CYP3A4, 2C8, 2C9, 2D6, 1A2, 2C19 or 2B6 and is not an inducer of CYP3A4. Sitagliptin is a p-glycoprotein substrate, but does not inhibit p-glycoprotein mediated transport of digoxin. Based on these results, sitagliptin is considered unlikely to cause interactions with other drugs that utilise these pathways.
Sitagliptin is not extensively bound to plasma proteins. Therefore, the propensity of sitagliptin to be involved in clinically meaningful drug-drug interactions mediated by plasma protein binding displacement is very low.

In vivo assessment of drug interactions.

Effects of sitagliptin on other drugs. In clinical studies, as described below, sitagliptin did not meaningfully alter the pharmacokinetics of metformin, glibenclamide, ertugliflozin, simvastatin, rosiglitazone, warfarin, or oral contraceptives, providing in vivo evidence of a low propensity for causing drug interactions with substrates of CYP3A4, CYP2C8, CYP2C9, and organic cationic transporter (OCT). Multiple doses of sitagliptin slightly increased digoxin concentrations; however, these increases are not considered likely to be clinically meaningful and are not attributed to a specific mechanism.

Metformin.

Coadministration of multiple twice-daily doses of sitagliptin with metformin, an OCT substrate, did not meaningfully alter the pharmacokinetics of metformin in patients with type 2 diabetes. Therefore, sitagliptin is not an inhibitor of OCT-mediated transport.

Sulfonylureas.

Single-dose pharmacokinetics of glibenclamide, a CYP2C9 substrate, were not meaningfully altered in subjects receiving multiple doses of sitagliptin. Clinically meaningful interactions would not be expected with other sulfonylureas (e.g. glipizide, tolbutamide, and glimepiride) which, like glibenclamide, are primarily eliminated by CYP2C9.

Ertugliflozin.

Single-dose administration of sitagliptin 100 mg had no clinically meaningful effect on the exposure of ertugliflozin 15 mg. The geometric mean ratios (GMR) and 90% CI (expressed as percentages) for ertugliflozin AUC_inf and C_max for coadministration with sitagliptin vs. ertugliflozin alone were 102.27% (99.72%, 104.89%) and 98.18% (91.20%, 105.70%), respectively.

Simvastatin.

Single-dose pharmacokinetics of simvastatin, a CYP3A4 substrate, were not meaningfully altered in subjects receiving multiple daily doses of sitagliptin. Therefore, sitagliptin is not an inhibitor of CYP3A4-mediated metabolism.

Thiazolidinediones.

Single-dose pharmacokinetics of rosiglitazone were not meaningfully altered in subjects receiving multiple daily doses of sitagliptin. Therefore, sitagliptin is not an inhibitor of CYP2C8-mediated metabolism. Clinically meaningful interactions with pioglitazone are not expected because pioglitazone predominantly undergoes CYP2C8- or CYP3A4-mediated metabolism.

Warfarin.

Multiple daily doses of sitagliptin did not meaningfully alter the pharmacokinetics, as assessed by measurement of S(-) or R(+) warfarin enantiomers, or pharmacodynamics (as assessed by measurement of prothrombin INR) of a single dose of warfarin. Since S(-) warfarin is primarily metabolised by CYP2C9, these data also support the conclusion that sitagliptin is not a CYP2C9 inhibitor.

Oral contraceptives.

Coadministration with sitagliptin did not meaningfully alter the steady-state pharmacokinetics of norethindrone or ethinyl estradiol.

Digoxin.

Sitagliptin had a minimal effect on the pharmacokinetics of digoxin. Following administration of 0.25 mg digoxin concomitantly with 100 mg of sitagliptin daily for 10 days, the plasma AUC of digoxin was increased by 11%, and the plasma C_max by 18%. These increases are not considered to be clinically meaningful.
Effects of other drugs on sitagliptin. Clinical data described below suggest that sitagliptin is not susceptible to clinically meaningful interactions by coadministered medications.

Ertugliflozin.

No clinically meaningful change in sitagliptin exposure was observed following concomitant administration of a single 100 mg sitagliptin dose with 15 mg ertugliflozin compared to sitagliptin alone. The GMR and 90% CI (expressed as percentages) for sitagliptin AUC_inf and C_max for coadministration with ertugliflozin vs. sitagliptin alone were 101.67% (98.40%, 105.04%) and 101.68% (91.65%, 112.80%), respectively.

Metformin.

Coadministration of multiple twice-daily doses of metformin with sitagliptin did not meaningfully alter the pharmacokinetics of sitagliptin in patients with type 2 diabetes.

Ciclosporin.

A study was conducted to assess the effect of ciclosporin, a potent inhibitor of p-glycoprotein, on the pharmacokinetics of sitagliptin. Coadministration of a single 100 mg oral dose of sitagliptin and a single 600 mg oral dose of ciclosporin increased the AUC and C_max of sitagliptin by approximately 29% and 68%, respectively. These modest changes in sitagliptin pharmacokinetics were not considered to be clinically meaningful. The renal clearance of sitagliptin was also not meaningfully altered. Therefore, meaningful interactions would not be expected with other p-glycoprotein inhibitors.

Population pharmacokinetics.

Population pharmacokinetic analyses have been conducted in patients with type 2 diabetes. Concomitant medications did not have a clinically meaningful effect on sitagliptin pharmacokinetics. Medications assessed were those that are commonly administered to patients with type 2 diabetes including, but not restricted to, cholesterol lowering agents (including statins, fibrates, ezetimibe), anti-platelet agents (including clopidogrel), antihypertensives (including ACE inhibitors, angiotensin receptor blockers, beta-blockers, calcium channel blockers, hydrochlorothiazide), analgesics and non-steroidal anti-inflammatory agents (including naproxen, diclofenac, celecoxib), anti-depressants (including bupropion, fluoxetine, sertraline), antihistamines (including cetirizine), proton-pump inhibitors (including omeprazole, lansoprazole), and medications for erectile dysfunction (including sildenafil).
Use with other antidiabetic agents. The safety and efficacy of sitagliptin in combination with GLP-1 mimetics, or alpha-glucosidase inhibitors has not been established.
Other drugs. Sitagliptin has not been studied in combination with orlistat.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No adverse effects on fertility were observed in male and female rats given sitagliptin orally at doses up to 1000 mg/kg/day (approximately 100 times the AUC in humans at the clinical dose of 100 mg/day) prior to and throughout mating.
(Category B3)
Sitagliptin was not teratogenic in rats at oral doses up to 250 mg/kg/day or in rabbits given up to 125 mg/kg/day during organogenesis (up to 32 and 22 times, respectively, the AUC in humans at the clinical dose of 100 mg/day). A slight increase in the incidence of foetal rib abnormalities (absent, hypoplastic and wavy ribs) was observed among foetuses of rats given sitagliptin at 1000 mg/kg/day (approximately 100 times the AUC in humans at 100 mg/day). Pups of rats administered sitagliptin at 1000 mg/kg/day from gestation day 6 to lactation day 20 showed reduced birth weight and postnatal body weight gain (observed prior to and after weaning). No functional or behavioural toxicity was observed in the offspring of treated rats.
Sitagliptin crosses the placenta in rats and rabbits.
There are no adequate and well-controlled studies with sitagliptin in pregnant women. Sitagliptin, like other oral antihyperglycaemic agents, is not recommended for use in pregnancy.
Treatment of rats with sitagliptin during pregnancy and lactation caused decreased pup body weight gain (see Use in pregnancy). Sitagliptin is excreted in the milk of lactating rats at a milk to plasma ratio of 4:1. It is not known whether sitagliptin is excreted in human milk. Therefore, sitagliptin should not be used by a woman who is nursing.

4.7 Effects on Ability to Drive and Use Machines

No studies of the effects of sitagliptin on the ability to drive and use machines have been performed. However, sitagliptin is not expected to affect the ability to drive and use machines.

4.8 Adverse Effects (Undesirable Effects)

Clinical trials.

In controlled clinical studies as both monotherapy and combination therapy with metformin or pioglitazone, the overall incidence of adverse reactions, hypoglycaemia, and discontinuation of therapy due to clinical adverse reactions with sitagliptin were similar to placebo (discontinuation rates: sitagliptin monotherapy, 24-week study, 2.1% vs placebo 1.6%, 18-week study 2% vs placebo 2.7%; sitagliptin add-on to metformin 2.4% vs placebo and metformin 3%; sitagliptin add-on to pioglitazone 5.7% vs placebo and pioglitazone 1.1%).
In combination with glimepiride, with or without metformin, the overall incidence of clinical adverse reactions with sitagliptin was higher than with placebo, in part related to a higher incidence of hypoglycaemia (see Table 1); the incidence of discontinuation due to clinical adverse reactions was similar to placebo (discontinuation rates: sitagliptin add-on to glimepiride, with or without metformin, 2.3% vs placebo and glimepiride, with or without metformin, 1.4%; sitagliptin add-on to metformin and a sulfonylurea, at 54 weeks, 1.4% vs placebo/pioglitazone, metformin and a sulfonylurea 3.8%). In combination with stable-dose insulin, with or without metformin, the overall incidence of clinical adverse reactions with sitagliptin was higher than placebo, in part related to a higher incidence of hypoglycaemia (see Table 1); the incidence of discontinuation due to clinical adverse reactions was slightly higher than placebo (discontinuation rates: sitagliptin add-on to insulin, with or without metformin, 3.4% vs placebo and insulin, with or without metformin, 1.3%).

Monotherapy and add-on combination therapy.

Two placebo-controlled monotherapy studies, one of 18- and one of 24-week duration, included patients treated with sitagliptin 100 mg daily, sitagliptin 200 mg daily, and placebo. Five 24-week, placebo-controlled add-on combination therapy studies, one with metformin, one with pioglitazone, one with glimepiride with or without metformin, one with metformin and a sulfonylurea (glimepiride or gliclazide) and one with stable-dose insulin with or without metformin were also conducted. In addition to a stable dose of metformin, pioglitazone, glimepiride, glimepiride and metformin, gliclazide and metformin, insulin, or insulin and metformin, patients whose diabetes was not adequately controlled were given either sitagliptin 100 mg daily or placebo. The adverse reactions, reported regardless of investigator assessment of causality in ≥ 5% of patients treated with sitagliptin 100 mg daily as monotherapy, sitagliptin in combination with pioglitazone, sitagliptin in combination with glimepiride, with or without metformin, or sitagliptin in combination with metformin and a sulfonylurea, or sitagliptin in combination with insulin, with or without metformin, and more commonly than in patients treated with placebo, are shown in Table 1.

In the study of patients receiving sitagliptin as monotherapy compared to metformin, there were no adverse reactions reported regardless of investigator assessment of causality in ≥ 5% of patients and more commonly than in patients given placebo. In another 24-week study of patients receiving sitagliptin as add-on therapy while undergoing insulin intensification (with or without metformin), there were no drug-related adverse reactions reported that occurred with an incidence of ≥ 1% in patients treated with sitagliptin 100 mg and more commonly than in patients treated with placebo.
The adverse reactions, reported regardless of investigator assessment of causality in ≥ 5% of patients treated with sitagliptin 100 mg daily or patients treated with metformin as monotherapy are shown in Table 2.

A total of 1262 patients with type 2 diabetes participated in two double-blind, placebo-controlled studies, one of 18-week and another of 24-week duration, to evaluate the efficacy and safety of sitagliptin monotherapy. Patients with inadequate glycaemic control (HbA_1c 7% to 10%) were randomized to receive a 100 mg (443 patients) or 200 mg dose (456 patients) of sitagliptin or placebo (363 patients) once daily. Sitagliptin as monotherapy is indicated for use when metformin cannot be used (see Section 4.1 Therapeutic Indications).
Treatment with sitagliptin at 100 mg daily provided significant improvements in HbA_1c, FPG, and 2-hour PPG compared to placebo (see Table 4 and Table 5). These studies included patients with a wide range of baseline HbA_1c. The improvement in HbA_1c compared to placebo was not affected by gender, age, race, prior antihyperglycaemic therapy, baseline BMI, presence of metabolic syndrome, or a standard index of insulin resistance (HOMA-IR). Patients with a shorter length of time since diagnosis of diabetes (< 3 years) or with higher baseline HbA_1c had greater reductions in HbA_1c. In the 18- and 24-week studies, among patients who were not on an antihyperglycaemic agent at study entry, the reduction from baseline in HbA1c was -0.67% (95% CI -0.87, -0.48) and -0.85% (95% CI -1.02, -0.68), respectively, for those given sitagliptin and -0.10% (95% CI -0.39, 0.19) and -0.18% (95% CI -0.35, -0.02), respectively, for those given placebo. In both studies, sitagliptin provided a significant reduction compared with placebo in FPG (-1.07 mmol/L in the 18-week study and -0.88 mmol/L in the 24-week study) at 3 weeks, the first time point at which FPG was measured. Overall, the 200 mg daily dose did not provide greater glycaemic efficacy than the 100 mg daily dose. The effect of sitagliptin on lipid endpoints was similar to placebo. Body weight did not increase from baseline with sitagliptin therapy in either study, compared to a small reduction in patients given placebo. The observed incidence of hypoglycaemia in patients treated with sitagliptin was similar to placebo.

These two studies were extended to examine the efficacy and safety of sitagliptin monotherapy long-term. In the 24 week study, patients receiving placebo were redistributed (1:1) between the 2 sitagliptin doses (100 mg q.d. or 200 mg q.d.) for an 80-week single-blind (blind to dose) treatment period. Patients in the sitagliptin treatment groups in Phase A continued on the same dose of sitagliptin during the single-blind treatment period (Phase B).
In the 18 week study, patients receiving placebo were started on therapy with pioglitazone at a dose of 30 mg q.d. for a 36-week active-controlled double-blind treatment period. Patients in a sitagliptin treatment group continued on the same dose of sitagliptin during the active-controlled, double-blind treatment period. Patients in the placebo/pioglitazone arm showed a -0.87% reduction in HbA_1c at Week 54, compared to -0.28% and -0.19% for the sitagliptin 100 mg and 200 mg groups, respectively.
Treatment with sitagliptin 100 mg q.d. and 200 mg q.d. provided similar reductions in glycaemic parameters over the duration of each study.

Active-controlled study with metformin.

The efficacy of sitagliptin compared to that of metformin was evaluated in a 24-week, double-blind, metformin-controlled trial in patients with type 2 diabetes and inadequate glycaemic control on diet and exercise and who were not on antihyperglycaemic therapy (patients who were treated with oral antihyperglycaemic therapy at enrolment discontinued all antihyperglycaemic therapy for at least 4 months before beginning study therapy). In this study, patients were randomized to receive either sitagliptin 100 mg daily (N=528) or metformin (N=522) for 24 weeks. Patients receiving metformin were given an initial dosage of 500 mg/day and then titrated by the investigator to a dose of 1500 to 2000 mg/day over a period of up to 5 weeks based on tolerability.
The mean dose of metformin after the titration period was approximately 1900 mg/day. Glycaemic endpoints measured included HbA_1c and fasting glucose.
Both treatments resulted in a statistically significant improvement in glycaemic control from baseline. The mean baseline HbA_1c was 7.2% in the per protocol population. At 24 weeks, the least squares means adjusted reduction from baseline in HbA_1c were -0.43% (95% CI -0.48, -0.38) for sitagliptin 100 mg daily and -0.57% (95% CI -0.62, -0.51) for metformin group, with a difference of 0.14% (95% CI 0.06, 0.21). The difference met the pre-specified criterion for confirming comparable efficacy of the two agents. In a pre-defined subgroup analysis, patients with baseline HbA_1c ≥ 8% also had similar reductions in both groups (sitagliptin, -1.13%; metformin, -1.24%).
The reduction in FPG was -0.64 mmol/L for sitagliptin and -1.08 mmol/L for metformin. Standard indices of insulin resistance (HOMA-IR) and insulin secretion (HOMA-β) showed similar improvements in both groups. Slightly smaller proportions of patients in the sitagliptin group relative to the metformin group had an HbA_1c value < 6.5% (33.6% vs. 39.2%) and < 7.0% (68.8% vs. 75.9%) at Week 24. Slight increases were also observed in the sitagliptin group relative to the metformin group for LDL-C, non-HDL-C and total-C. Both the sitagliptin and metformin treatment groups exhibited a decrease in fasting insulin, fasting proinsulin and the proinsulin to insulin ratio, with a greater reduction observed for the metformin group in fasting proinsulin, which resulted in a larger reduction in the proinsulin to insulin ratio. A smaller increase in 1,5-anhydroglucitol at Week 24 was observed in the sitagliptin group compared to the metformin group.
The overall incidence of gastrointestinal adverse reactions in patients treated with sitagliptin was 11.6% compared with 20.7% in patients treated with metformin. The incidence of selected gastrointestinal adverse experiences was: diarrhoea (sitagliptin, 3.6%; metformin, 10.9%), nausea (1.1%, 3.1%), abdominal pain (2.1%, 3.8%), and vomiting (0.4%, 1.3%). The incidence of hypoglycaemia was not significantly different between the treatment groups (sitagliptin, 1.7%; metformin, 3.4%). Body weight decreased from baseline in both treatment groups (sitagliptin, -0.6 kg; metformin -1.9 kg).

Sitagliptin and metformin as initial therapy in patients with type 2 diabetes.

This study consisted of a 24-week, placebo-controlled Phase A, a 30-week, active-controlled Phase B, and a 50-week active-controlled Extension Phase, where 1091 patients with type 2 diabetes and inadequate glycaemic control on diet and exercise were enrolled in a, randomized, double-blind, parallel-group factorial study designed to assess the safety and efficacy of initial therapy with the combination of sitagliptin and metformin. Patients on an antihyperglycaemic agent (N=541) underwent a diet, exercise, and drug washout period of up to 12 weeks duration. After the washout period, patients with inadequate glycaemic control (A_1c 7.5% to 11%) were randomized after completing a 2-week single-blind placebo run-in period. Patients not on antihyperglycaemic agents at study entry (N=550) with inadequate glycaemic control (A_1c 7.5% to 11%) immediately entered the 2-week single-blind placebo run-in period and then were randomized. A total of 685 patients entered the 50-week extension study, and among these patients, 517 (74.5%) completed the study. Approximately equal numbers of patients were randomized to receive initial therapy with placebo; 100 mg of sitagliptin once daily; 500 mg or 1000 mg of metformin twice daily; or 50 mg of sitagliptin twice daily in combination with 500 mg or 1000 mg of metformin twice daily. Patients receiving active therapy continued with their assigned treatment regimen until the end of the study, unless rescue (glibenclamide) was required. Patients receiving placebo were switched to 1000 mg of metformin twice daily at the beginning of Phase B.
Initial combination therapy with sitagliptin 100 mg and metformin 1000 mg or 2000 mg daily provides sustained improvements in HbA_1c and FPG and 2-hour PPG compared with either corresponding monotherapy dose over 104 weeks; (see Table 6 and Figure 1). An improvement in FPG, with near maximal FPG reduction, was achieved by the 3-week time point (the first time point assessed after initiation of therapy) and sustained over time. A slight upward trend in the reduction in HbA_1c was observed during the extension phase in each treatment group. Measures of beta cell function, HOMA-β and the proinsulin to insulin ratio generally showed greater improvement with the coadministration of sitagliptin and metformin compared with either monotherapy alone. Lipid effects were generally neutral. The decrease in body weight in the groups given sitagliptin in combination with metformin was similar to that in the groups given metformin alone or placebo. Mean reductions from baseline in HbA_1c compared with placebo were generally greater for patients with higher baseline HbA_1c values. The improvement in HbA_1c was generally consistent across subgroups defined by gender, age, race, or baseline BMI. Mean reductions from baseline in HbA_1c for patients not on an antihyperglycaemic agent at study entry were: sitagliptin 100 mg once daily, -1.14%; metformin 500 mg bid, -1.20%; metformin 1000 mg bid, -1.22%; sitagliptin 50 mg bid with metformin 500 mg bid, -1.65%; and sitagliptin 50 mg bid with metformin 1000 mg bid, -1.74%; and for patients receiving placebo, -1.11%.

In addition, this study included patients (N=117) with more severe hyperglycaemia (HbA_1c > 11% or blood glucose > 15.54 mmol/L) who were treated with open-label sitagliptin at 50 mg and metformin at 1000 mg twice daily for 24 weeks, but were not eligible to enter Phase B of the study. In this group of patients, the baseline HbA_1c value was 11. 15%, FPG was 17.45 mmol/L, and 2-hour PPG was 24.48 mmol/L. After 24 weeks, decreases from baseline of -2.94% for HbA_1c, -7.03 mmol/L for FPG, and -11.54 mmol/L for 2-hour PPG were observed. In this open-label cohort, a modest increase in body weight of 1.3 kg was observed at 24 weeks.

Add-on therapy to metformin.

A total of 701 patients with type 2 diabetes with inadequate glycaemic control on metformin alone participated in a 24-week, randomised, double-blind, placebo-controlled study designed to assess the efficacy of sitagliptin in combination with metformin (HbA_1c 7% to 10%). All patients were started on metformin monotherapy and the dose increased to at least 1500 mg per day. Patients were randomised to the addition of either 100 mg of sitagliptin or placebo, administered once daily.
In combination with metformin, sitagliptin provided significant improvements in HbA_1c (the primary endpoint), FPG, and 2-hour PPG compared to placebo with metformin (see Table 7). A pre-specified secondary endpoint was the number of patients in each group who required therapeutic "rescue" with pioglitazone. Twenty-one of 464 patients (5%) randomised to sitagliptin and 32 of 237 patients (14%) randomised to placebo required pioglitazone "rescue".
The improvement in HbA_1c compared to placebo was not affected by baseline HbA_1c, prior anti-hyperglycaemic therapy, gender, age, baseline BMI, length of time since diagnosis of diabetes, presence of metabolic syndrome, or standard indices of insulin resistance (HOMA-IR) or insulin secretion (HOMA-β). Compared to patients taking placebo, patients taking sitagliptin demonstrated slight decreases in total cholesterol, non-HDL cholesterol and triglycerides. A similar decrease in body weight was observed in both treatment groups.

Active-controlled study against glipizide as add-on therapy to metformin.

Long-term maintenance of effect was evaluated in a 52-week, double-blind, glipizide-controlled trial in patients with type 2 diabetes. Patients with inadequate glycaemic control on metformin at ≥ 1500 mg/day were randomized to treatment with sitagliptin 100 mg daily (N=588) or glipizide (N=584) for 52 weeks. Patients receiving glipizide were given an initial dosage of 5 mg/day and then electively titrated over the next 18 weeks, to a maximum dosage of 20 mg/day as needed to optimise glycaemic control. Thereafter, the glipizide dose was to have been kept constant. The mean dose of glipizide after the titration period was 10.3 mg. The objective of the study was to test whether sitagliptin was not inferior to glipizide, at a non-inferiority margin of 0.3%. After 52 weeks, both treatments resulted in a statistically significant improvement in glycaemic control from baseline. The reduction from baseline in HbA_1c (primary endpoint) was 0.67% for sitagliptin 100 mg daily and 0.67% for glipizide, confirming the noninferiority of sitagliptin compared to glipizide.
With respect to other analyses, the reduction in FPG was 0.56 mmol/L for sitagliptin and 0.42 mmol/L for glipizide. In a post-hoc analysis, patients with higher baseline HbA_1c (≥ 9%) in both groups had greater reductions from baseline in HbA_1c (sitagliptin, -1.68%; glipizide, -1.76%). The incidence of hypoglycaemia in the sitagliptin group (4.9%) was significantly lower than that in the glipizide group (32.0%). Patients treated with sitagliptin exhibited a significant mean decrease from baseline in body weight compared to a significant weight gain in patients administered glipizide (-1.5 kg vs. +1.1 kg).

Add-on therapy to pioglitazone.

A total of 353 patients with type 2 diabetes inadequately controlled on pioglitazone alone participated in a 24-week, randomised, double-blind, placebo-controlled study designed to assess the efficacy of sitagliptin in combination with pioglitazone. All patients were started on pioglitazone monotherapy at a dose of 30-45 mg per day. Patients were randomised to the addition of either 100 mg of sitagliptin or placebo, administered once daily. Glycaemic endpoints measured included HbA_1c and fasting glucose. Another pre-specified secondary endpoint was the number of patients in each group who required therapeutic "rescue" with metformin.
In combination with pioglitazone, sitagliptin provided significant improvements in HbA_1c and FPG compared to placebo with pioglitazone (see Table 8). The improvement in HbA_1c compared to placebo was not affected by baseline HbA_1c, prior anti-hyperglycaemic therapy, gender, age, race, baseline BMI, length of time since diagnosis of diabetes, presence of metabolic syndrome, or standard indices of insulin resistance (HOMA-IR) or insulin secretion (HOMA-β). Compared to patients taking placebo, patients taking sitagliptin demonstrated a slight decrease in triglycerides. There was no significant difference between sitagliptin and placebo in body weight change. Twelve of 175 patients (7%) randomised to sitagliptin and 25 of 178 patients (14%) randomised to placebo required metformin "rescue".

Add-on therapy to metformin and a sulfonylurea.

A total of 422 patients with type 2 diabetes inadequately controlled on combination therapy with metformin and a sulfonylurea participated in a randomised, double-blind, study designed to assess the efficacy of sitagliptin in combination with metformin and a sulfonylurea. The study consisted of a 24-week placebo-controlled phase followed by a 30-week active-controlled phase. All patients were on a stable dose of metformin (≥ 1500 mg/day) and either glimepiride (≥ 2 mg once daily) or gliclazide (≥ 60 mg [modified-release formulation] or ≥ 160 mg [non-modified-release formulation] once daily) prior to enrolment. Patients were randomised to the addition of either 100 mg of sitagliptin or placebo, administered once daily. Glycaemic endpoints measured included HbA_1c, 2-hour PPG and fasting glucose. Another pre-specified secondary endpoint was the number of patients in each group who required therapeutic "rescue" with pioglitazone.
In combination with metformin and a sulfonylurea, sitagliptin provided significant improvements in HbA_1c compared to placebo with metformin and a sulfonylurea (see Table 9) after 24 weeks of treatment. The improvement in HbA_1c compared to placebo was not affected by baseline HbA_1c, type of sulfonylurea, gender, age, race, baseline BMI, or length of time since diagnosis of diabetes. There was no significant difference between sitagliptin and placebo in body weight change. Three of 210 patients (1%) randomised to sitagliptin and 15 of 212 patients (7%) randomised to placebo required pioglitazone "rescue". After 54 weeks, treatment with sitagliptin, metformin and a sulfonylurea continued to provide clinically meaningful improvement in HbA_1c relative to baseline.

Add-on combination therapy with insulin (with or without metformin).

A total of 641 patients with type 2 diabetes participated in a 24-week, randomised, double-blind, placebo-controlled study designed to assess the efficacy of sitagliptin as add-on combination therapy with stable dose of insulin (with or without metformin). Patients on pre-mixed, long-acting, or intermediate-acting insulin with or without metformin (≥ 1500 mg per day) were randomized to the addition of either 100 mg of sitagliptin or placebo, administered once daily. Patients with moderate or severe renal impairment and patients with NYHA Class II, III or IV congestive heart failure were not eligible for inclusion in the study. Glycaemic endpoints measured included HbA_1c, fasting glucose, and 2-hour post-prandial glucose.
In combination with insulin (with or without metformin), sitagliptin provided significant improvements in HbA_1c, FPG, and 2 hour PPG compared to placebo (see Table 10). The improvement in HbA_1c compared to placebo was generally consistent across subgroups defined by gender, age, race, baseline BMI, length of time since diagnosis of diabetes, presence of metabolic syndrome, and standard indices of insulin resistance (HOMA-IR) and insulin secretion (HOMA-β). There was no significant difference between sitagliptin and placebo in body weight change.

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. Baseline HbA_1c was 8.74% and baseline insulin dose was 37 IU/day. Patients were instructed to titrate their insulin glargine dose based on fingerstick fasting glucose values.
At Week 24, the mean increase in daily insulin dose was 19 IU/day in patients treated with sitagliptin, and 24 IU/day in patients treated with placebo. The mean reduction in HbA_1c in patients treated with sitagliptin and insulin (with or without metformin) was -1.31% compared to -0.87% in patients treated with placebo and insulin (with or without metformin), a difference of -0.45% [95% CI: -0.60, -0.29]. The mean reduction in FPG in patients treated with sitagliptin and insulin (with or without metformin) was -3.1 mmol/L compared to -2.5 mmol/L in patients treated with placebo and insulin (with or without metformin), a difference of -0.6 mmol/L [95% CI: -1.0, -0.2]. The incidence of symptomatic hypoglycaemia was 25.2% in patients treated with sitagliptin and insulin (with or without metformin) and 36.8% in patients treated with placebo and insulin (with or without metformin). The difference was mainly due to a higher percentage of patients in the placebo group experiencing 3 or more episodes of hypoglycaemia (9.4 vs. 19.2%). There was no difference in the incidence of severe hypoglycaemia.

Factorial study with ertugliflozin (Steglatro) and sitagliptin as add-on combination therapy with metformin.

A total of 1,233 patients with type 2 diabetes participated in a randomised, double-blind, multi-centre, 26-week, active-controlled study to evaluate the efficacy and safety of Steglatro 5 mg or 15 mg in combination with sitagliptin 100 mg compared to the individual components. Patients with type 2 diabetes inadequately controlled on metformin monotherapy (≥ 1,500 mg/day) were randomised to one of five active-treatment arms: Steglatro 5 mg or 15 mg, sitagliptin 100 mg, or sitagliptin 100 mg in combination with 5 mg or 15 mg Steglatro administered once daily in addition to continuation of background metformin therapy.
At Week 26, Steglatro 5 mg or 15 mg used in combination with sitagliptin 100 mg provided statistically significant improvement in HbA_1c and FPG compared to the individual components (see Table 11). More patients receiving Steglatro 5 mg or 15 mg in combination with sitagliptin 100 mg achieved an HbA_1c < 7% compared to the individual components. Treatment with Steglatro 5 mg or 15 mg in combination with sitagliptin 100 mg also resulted in a statistically significant reduction in body weight and systolic blood pressure compared to sitagliptin 100 mg.

Ertugliflozin (Steglatro) as add-on combination therapy with metformin and sitagliptin.

A total of 463 patients with type 2 diabetes inadequately controlled on metformin (≥ 1,500 mg/day) and sitagliptin 100 mg once daily participated in a randomised, double-blind, multi-centre, 26-week, placebo-controlled study to evaluate the efficacy and safety of Steglatro. Patients were randomised to Steglatro 5 mg, Steglatro 15 mg, or placebo administered once daily in addition to continuation of background metformin and sitagliptin therapy.
At Week 26, treatment with Steglatro at 5 mg or 15 mg daily provided statistically significant improvements in HbA_1c, FPG, body weight, and systolic blood pressure compared to placebo. Steglatro also resulted in a greater proportion of patients achieving an HbA_1c < 7% compared to placebo (see Table 12).

Initial combination therapy of ertugliflozin (Steglatro) and sitagliptin.

A total of 291 patients with type 2 diabetes inadequately controlled on diet and exercise participated in a randomised, double-blind, multi-centre, placebo-controlled 26-week study to evaluate the efficacy and safety of Steglatro in combination with sitagliptin. These patients, who were not receiving any background antihyperglycaemic treatment, were randomised to Steglatro 5 mg or Steglatro 15 mg in combination with sitagliptin (100 mg) or to placebo once daily.
At Week 26, treatment with Steglatro 5 mg and 15 mg in combination with sitagliptin at 100 mg daily provided significant improvements in HbA_1c, FPG, body weight, 2-hour PPG, and systolic blood pressure compared to placebo. Steglatro 5 mg and 15 mg in combination with sitagliptin at 100 mg daily also resulted in a significantly higher proportion of patients achieving an HbA_1c < 7% compared with placebo (see Table 13).

TECOS cardiovascular safety study.

The Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) was a randomized study in 14,671 patients in the intention-to-treat population with an HbA_1c 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 estimated glomerular filtration rate (eGFR) was ≥ 30 and < 50 mL/min/1.73 m²) or placebo (7,339) added to usual care targeting regional standards for HbA_1c 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 HbA_1c 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, non-fatal myocardial infarction, non-fatal stroke, or hospitalisation for unstable angina. Secondary cardiovascular endpoints included the first occurrence of cardiovascular death, non-fatal myocardial infarction, or non-fatal 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 (see Table 14).

Clinical studies in patients with renal insufficiency.

A study comparing sitagliptin at 25 or 50 mg once daily to glipizide at 2.5 to 20 mg/day was conducted in patients with moderate to severe renal impairment. In this study, 277 patients with chronic renal impairment were included in the Per-protocol population (135 patients on sitagliptin: moderate [n=98], severe [n=37]; and 142 patients on glipizide: moderate [n=106], severe [n=36]). After 54 weeks, the mean reduction from baseline in HbA_1c was -0.76% with sitagliptin and -0.64% with glipizide (Per-Protocol Analysis). In this study, the efficacy and safety profile of sitagliptin at 25 or 50 mg once daily was generally similar to that observed in other monotherapy studies in patients with normal renal function. The incidence of hypoglycaemia in the sitagliptin group (6.2%) was significantly lower than that in the glipizide group (17.0%), while the incidence of severe hypoglycaemia was not significantly different between the two treatment groups (sitagliptin, 1.4%; glipizide, 2.8%).
Another study comparing sitagliptin at 25 mg once daily to glipizide at 2.5 to 20 mg/day was conducted in 129 patients with ESRD who were on dialysis (64 patients on sitagliptin; and 65 patients on glipizide). After 54 weeks, the mean reduction from baseline in HbA_1c was -0.72% with sitagliptin and -0.87% with glipizide. In this study, the efficacy and safety profile of sitagliptin at 25 mg once daily was generally similar to that observed in other monotherapy studies in patients with normal renal function. The incidence of hypoglycaemia was not significantly different between the treatment groups (sitagliptin, 6.3%; glipizide, 10.8%), whereas the incidence of severe hypoglycaemia was significantly lower in the sitagliptin group (0.0%) compared to the glipizide group (7.7%).
A multinational, randomised, double-blind, placebo-controlled study was also conducted to assess the safety and tolerability of sitagliptin in 91 patients with type 2 diabetes and chronic renal insufficiency (creatinine clearance < 50 mL/min). Patients with moderate renal insufficiency received 50 mg daily of sitagliptin and those with severe renal insufficiency or with ESRD on haemodialysis or peritoneal dialysis received 25 mg daily. In this study, the safety and tolerability of sitagliptin were generally similar to placebo. (See Section 5.2 Pharmacokinetic Properties, Characteristics in patients, Renal impairment.)

Long term efficacy of sitagliptin.

Improvements in glycaemic control with sitagliptin have been demonstrated over periods of up to 2 years in both the Phase II studies and Phase III studies. Importantly, the effect size and the durability of these improvements over 104-106 weeks were similar to those observed in the active-comparator groups. The observed reduction in glycaemic efficacy after initial improvement is believed to be a consequence of the natural history of the disease with continued loss of β-cell function, and/or an additional increase in insulin resistance, and/or diminishing compliance with diet and exercise, and is similar to that observed with other classes of antihyperglycaemic therapies.

General.

In patients with type 2 diabetes, administration of single oral doses of sitagliptin leads to inhibition of DPP-4 enzyme activity for a 24-hour period, resulting in a 2- to 3-fold increase in circulating levels of active GLP-1 and GIP, increased plasma levels of insulin and C-peptide, decreased glucagon concentrations, reduced fasting glucose, and reduced glucose excursion following an oral glucose load or a meal.
In a study of patients with type 2 diabetes inadequately controlled on metformin monotherapy, glucose levels monitored throughout the day were significantly lower in patients who received sitagliptin 100 mg per day (50 mg twice daily) in combination with metformin compared with patients who received placebo with metformin (see Figure 2).

In Phase III clinical studies of 18- and 24-week duration, treatment with sitagliptin 100 mg daily in patients with type 2 diabetes significantly improved beta cell function, as assessed by several markers, including HOMA-β (Homeostasis Model Assessment-β), proinsulin to insulin ratio, and measures of beta cell responsiveness from the frequently-sampled meal tolerance test. There are no clinical studies that demonstrate that sitagliptin alters the natural history of impaired glucose tolerance or type 2 diabetes mellitus. The durability of efficacy requires further study.
In Phase II studies, sitagliptin 50 mg twice daily provides no additional glycaemic efficacy compared to 100 mg once daily.
In studies with healthy subjects, sitagliptin did not lower blood glucose or cause hypoglycaemia, suggesting that the insulinotropic and glucagon suppressive actions of the drug are glucose dependent (see Section 4.4 Special Warnings and Precautions for Use, Hypoglycaemia in combination with a sulfonylurea or with insulin; Section 4.8 Adverse Effects (Undesirable Effects) in respect of use with sulfonylureas or insulin).

Effects on blood pressure.

In a randomised, placebo-controlled crossover study in hypertensive patients on one or more anti-hypertensive drugs (including angiotensin-converting enzyme inhibitors, angiotensin-II antagonists, calcium-channel blockers, beta-blockers and diuretics), coadministration with sitagliptin was generally well tolerated. In these patients, sitagliptin had a modest blood pressure lowering effect; 100 mg per day of sitagliptin reduced 24-hour mean ambulatory systolic blood pressure by approximately 2 mmHg, as compared to placebo. Reductions have not been observed in subjects with normal blood pressure. As per good medical practice, hypertensive patients who receive sitagliptin should continue to have their blood pressure monitored.

Cardiac electrophysiology.

In a randomised, placebo-controlled crossover study, 79 healthy subjects were administered a single oral dose of sitagliptin 100 mg, sitagliptin 800 mg (8 times the recommended dose), and placebo. At the recommended dose of 100 mg, there was no effect on the QTc interval obtained at the peak plasma concentration, or at any other time during the study. Following the 800 mg dose, the maximum increase in the placebo-corrected mean change in QTc from baseline at 3 hours post dose was 8.0 msec. This small increase was not considered to be clinically significant. At the 800 mg dose, peak sitagliptin plasma concentrations were approximately 11-fold higher than the peak concentrations following a 100 mg dose.
In patients with type 2 diabetes administered sitagliptin 100 mg (N=81) or sitagliptin 200 mg (N=63) daily, there were no meaningful changes in QTc interval based on ECG data obtained at the time of expected peak plasma concentration.

5.2 Pharmacokinetic Properties

The pharmacokinetics of sitagliptin have been extensively characterised in healthy subjects and patients with type 2 diabetes. After oral administration of a 100 mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median T_max) occurring 1 to 4 hours post-dose. Plasma AUC of sitagliptin increased in a dose-proportional manner. Following a single oral 100 mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 microM.hr, C_max was 950 nanoM, and apparent terminal half-life (t_1/2) was 12.4 hours. Plasma AUC of sitagliptin increased approximately 14% following 100 mg doses at steady-state compared to the first dose. The intra-subject and inter-subject coefficients of variation for sitagliptin AUC were small (5.8% and 15.1%). The pharmacokinetics of sitagliptin were generally similar in healthy subjects and in patients with type 2 diabetes.

Absorption.

The absolute bioavailability of sitagliptin is approximately 87%. Since coadministration of a high-fat meal with sitagliptin had no effect on the pharmacokinetics, sitagliptin may be administered with or without food.

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%).

Metabolism.

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.

Excretion.

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 t_1/2 following a 100 mg oral dose of sitagliptin was approximately 12.4 hours and 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.

Characteristics in patients.

Renal impairment.

A single-dose, open-label study was conducted to evaluate the pharmacokinetics of sitagliptin (50 mg dose) 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 end stage renal disease (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 (eGFR ≥ 60 mL/min/1.73 m² to < 90 mL/min/1.73 m²) and patients with moderate renal impairment (eGFR ≥ 45 mL/min/1.73 m² to < 60 mL/min/1.73 m²), 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 (eGFR ≥ 30 mL/min/1.73 m² to < 45 mL/min/1.73 m²), and approximately 4-fold in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m²), 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 postdose). To achieve plasma concentrations of sitagliptin similar to those in patients with normal renal function, lower dosages are recommended in patients with eGFR < 45 mL/min/1.73 m² (see Section 4.2 Dose and Method of Administration, Patients with renal impairment).

Hepatic impairment.

In patients with moderate hepatic impairment (Child-Pugh score 7 to 9), mean AUC and C_max of sitagliptin increased approximately 21% and 13%, respectively, compared to healthy matched controls following administration of a single 100 mg dose of sitagliptin. These differences are not considered to be clinically meaningful. No dosage adjustment for sitagliptin is necessary for patients with mild or moderate hepatic impairment.
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 patients.

No dosage 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 patients.

No studies with sitagliptin have been performed in paediatric patients.

Sex.

No dosage adjustment is necessary based on sex of the patient. The sex of the subject 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.

Race.

No dosage adjustment is necessary based on race. Race 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, including subjects of white, Hispanic, black, Asian, and other racial groups.

Body mass index.

No dosage adjustment is necessary based on BMI. Body mass index 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.

Type 2 diabetes.

The pharmacokinetics of sitagliptin in patients with type 2 diabetes are generally similar to those in healthy subjects.

5.3 Preclinical Safety Data

Genotoxicity.

Sitagliptin was not mutagenic or clastogenic in a battery of genetic toxicology studies, including the Ames bacterial mutagenicity assay, a chromosome aberration assay in Chinese hamster ovary cells, an in vitro rat hepatocyte DNA alkaline elution assay (an assay which measures the compound's ability to induce single strand breaks in DNA), and an in vivo mouse micronucleus assay.

Carcinogenicity.

A two-year carcinogenicity study was conducted in rats given oral doses of sitagliptin of 50, 150, and 500 mg/kg/day. There was an increased incidence of focal eosinophilic cellular alterations in the liver in both sexes at 150 mg/kg/day and at 500 mg/kg/day. There was an increased incidence of basophilic cellular alterations in females at 500 mg/kg/day. Eosinophilic and basophilic cellular alterations are regarded as preneoplastic lesions. There was an increase in hepatic adenomas and carcinomas in males, and hepatic carcinomas in females at 500 mg/kg/day. Systemic exposure in rats at 150 and 500 mg/kg/day are 19 and 58 times, respectively, that of humans at 100 mg/day. The no-observed effect level for induction of hepatic neoplasia in rats was 150 mg/kg/day, producing exposure approximately 19-fold higher than the human exposure at the 100 mg/day clinical dose. The increased incidence of hepatic tumours was likely secondary to chronic hepatic toxicity at this high dose. The clinical significance of these findings for humans is unknown.
In a two-year carcinogenicity study conducted in mice, sitagliptin did not increase tumour incidence at oral doses up to 500 mg/kg/day (approximately 68 times human exposure at the clinical dose of 100 mg/day).

6 Pharmaceutical Particulars

6.1 List of Excipients

Tablet core.

The tablet contains the following inactive ingredients: calcium hydrogen phosphate, crospovidone, hydrogenated castor oil, glycerol dibehenate, magnesium stearate, Opadry Pink 02F540038 (139708), Opadry Beige 02F570009 (139707), Opadry Beige 02F570006 (139717).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

The expiry date can be found on the packaging. In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG).

6.4 Special Precautions for Storage

Store below 25°C. Store in original packaging.

6.5 Nature and Contents of Container

Sitagliptin Sun is available in the following presentations:
Sitagliptin Sun tablet 25 mg, 50 mg and 100 mg - available in oriented polyamide/ aluminium foil/ PE with desiccant/ aluminium foil blister of 28 tablets.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Sitagliptin (sitagliptin fumarate) is an orally-active inhibitor of the dipeptidyl peptidase 4 (DPP-4) enzyme for the treatment of type 2 diabetes. Sitagliptin differs in chemical structure and pharmacological action from GLP-1 analogues, insulin, sulfonylureas or meglitinides, biguanides, peroxisome proliferators-activated receptor gamma (PPARγ) agonists, alpha-glucosidase inhibitors, and amylin analogues.

Chemical structure.

The chemical name of sitagliptin fumarate is 7-[(3R)-3-Amino-1-oxo-4-(2,4,5-trifluorophenyl) butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine fumarate.
The empirical formula is C₂₀H₁₉F₆N₅O₅ and the molecular weight is 523.38. The structural formula is:

Sitagliptin fumarate is a white to off-white powder. It is soluble in water and DMF, practically insoluble in isopropanol and isopropyl acetate. The partition coefficient is 2.06 ± 0.67 (calculated) and the pKa is 7.20 ± 0.10. Sitagliptin fumarate is found to be non-hygroscopic in nature, the melting point is about 178.06°C, has one chiral center and has a consistent polymorphic form.

CAS number.

The CAS Registry Number is 837430-24-7.

7 Medicine Schedule (Poisons Standard)

Prescription Only Medicine (Schedule 4).

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