Active ingredients: Sitagliptin, Metformin (Metformin hydrochloride)
Janumet 50 mg / 850 mg film-coated tablets
Janumet package inserts are available for pack sizes:- Janumet 50 mg / 850 mg film-coated tablets
- Janumet 50 mg / 1,000 mg film-coated tablets
Why is Janumet used? What is it for?
Janumet contains two different medicines called sitagliptin and metformin.
- sitagliptin belongs to a class of drugs called DPP-4 inhibitors (dipeptyl peptidase 4 inhibitors)
- metformin belongs to a class of drugs called biguanides.
They work together to control the blood sugar levels of adult patients with a form of diabetes called "type 2 diabetes mellitus".This medicine helps to increase the levels of insulin produced after meals and decreases the amount of sugar produced by the body.
Along with diet and exercise, this medicine helps lower blood sugar levels. This medicine can be used alone or with some other diabetes medicines (insulin, sulphonylureas or glitazones).
What is type 2 diabetes?
Type 2 diabetes is a disease in which the body does not make enough insulin and the insulin produced by the body does not work as well as it should. Your body can also make too much sugar. When this happens, the sugar (glucose) builds up in the blood.This can lead to serious medical problems such as heart disease, kidney disease, blindness and amputation.
Contraindications When Janumet should not be used
Do not take Janumet:
- if you are allergic to sitagliptin, metformin or any of the other ingredients of this medicine (listed in section 6)
- if you have diabetic ketoacidosis (a complication of diabetes with rapid weight loss, nausea or vomiting) or have had a diabetic coma
- if you have kidney problems
- if you have a severe infection or are dehydrated
- if you are about to have an x-ray that involves the use of a contrast agent. You will need to stop taking Janumet at the time of the x-ray and for 2 or more days thereafter as directed by your doctor, depending on how your kidneys are working
- if you have recently had a heart attack or have severe circulation problems, such as 'shock' or difficulty in breathing
- if you have liver problems
- if you drink alcohol to excess (both every day and only occasionally)
- if you are breast-feeding
Do not take Janumet if you have any of the above problems and talk to your doctor about other methods of managing your diabetes.
If you are not sure, talk to your doctor, pharmacist or nurse before taking Janumet.
Precautions for use What you need to know before taking Janumet
Cases of inflammation of the pancreas (pancreatitis) have been reported in patients treated with Janumet (see section 4).
Talk to your doctor or pharmacist before taking Janumet:
- if you have or have ever had a disease of the pancreas (such as pancreatitis)
- if you have or have had gallstones, alcohol dependence or very high levels of triglycerides (a type of fat) in your blood. These medical conditions may increase your risk of developing pancreatitis (see section 4)
- if you have type 1 diabetes. This is sometimes called insulin dependent diabetes
- if you have ketoacidosis diabetes (a complication of diabetes with high blood sugar, rapid weight loss, nausea or vomiting)
- if you have any of the following symptoms: feeling cold or uncomfortable, having severe nausea or vomiting, stomach pain, unnecessary weight loss, muscle cramps, breathing too frequently. Metfomine hydrochloride, one of the active substances in Janumet, can cause a rare but serious side effect called lactic acidosis (an increase in lactic acid in the blood) which can cause death. Lactic acidosis is a medical emergency and must be treated in a hospital. If you have any of the symptoms of lactic acidosis stop taking Janumet and consult a doctor immediately (see section 4).
- if you have ever had an allergic reaction to sitagliptin, metformin or Janumet (see section 4)
- if you are taking a sulphonylurea or insulin, diabetes medicine, together with Janumet, as too much lowering of blood sugar (hypoglycaemia) may occur. Your doctor may reduce the dose of the sulphonylurea or insulin
- if you have to undergo an operation under general, spinal or epidural anesthesia. You may need to stop taking Janumet for a couple of days before and after your surgery.
If you are not sure if any of the above apply to you, consult your doctor or pharmacist before taking Janumet. During treatment with Janumet, your doctor will check your kidney function at least once a year and more frequently if you are elderly or if your kidney function is at the limit of normal or if you are at risk of getting worse.
Children and adolescents
Children and adolescents under the age of 18 should not use this medicine. It is not known whether the use of this medicine is safe and effective in children and adolescents under the age of 18 years.
Interactions Which drugs or foods can change the effect of Janumet
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
The following medicines are particularly important:
- medicines (taken by mouth, by inhalation or by injection) used to treat inflammatory diseases, such as asthma and arthritis (corticosteroids)
- specific medicines for the treatment of high blood pressure (ACE inhibitors)
- medicines that increase urine production (diuretics)
- specific medicines for the treatment of bronchial asthma (beta-sympathomimetics)
- iodinated contrast agents or medicines containing alcohol
- some medicines used to treat stomach problems such as cimetidine
- digoxin (to treat irregular heartbeat and other heart problems). The level of digoxin in your blood may need to be checked if taken with Janumet.
Janumet with alcohol
Avoid alcohol while taking Janumet as alcohol may increase the risk of lactic acidosis (see section 4).
Warnings It is important to know that:
Pregnancy and breastfeeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.
You should not take this medicine during pregnancy or if you are breastfeeding.
See section 2, Do not take Janumet.
Driving and using machines
This medicine has no or negligible influence on the ability to drive and use machines. However, dizziness and somnolence have been reported with sitagliptin, which may affect your ability to drive or use machines.
Taking this medicine with other medicines called sulphonylureas or with insulin may cause hypoglycaemia, which may affect your ability to drive, use machines or work without protective barriers.
Dose, Method and Time of Administration How to use Janumet: Posology
Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.
- Take a tablet:
- twice a day by mouth,
- with meals to decrease the chances of stomach upset.
- Your doctor may need to increase your dose to control the sugar in your blood.
You must continue the diet recommended by your doctor during treatment with this medicine and ensure that your carbohydrate intake is evenly distributed throughout the day.
This medicine alone is unlikely to cause abnormal lowering of blood sugar levels (hypoglycaemia). When this medicine is used with a sulphonylurea medicine or with insulin, low blood sugar can occur and your doctor may reduce the dose of the sulphonylurea or insulin.
Occasionally you may need to stop taking the medicine for a short time. Talk to your doctor for instructions if you:
- have a condition that may be associated with dehydration (large loss of body fluids) such as severe vomiting, diarrhea or fever, or if you drink far less fluids than normal
- is planning to undergo surgery
- you must inject a contrast agent to take an x-ray
If you forget to take Janumet
If you miss a dose, take it as soon as you remember. If you don't remember until your next dose is due, skip the missed dose and continue with your normal dose.
Do not take a double dose of this medicine.
If you stop taking Janumet
Keep taking this medicine for as long as your doctor prescribes it so that you can continue to monitor your blood sugar level. You should not stop taking this medicine without first talking to your doctor. If you stop taking Janumet your blood sugar may rise again.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Overdose What to do if you have taken too much Janumet
If you take more than the prescribed dosage of this medicine, contact your doctor immediately. Go to the hospital if you have symptoms of lactic acidosis such as feeling cold or sick, severe nausea or vomiting, stomach pain, unexplained weight loss, muscle cramps or breathing too frequently.
Side Effects What are the side effects of Janumet
Like all medicines, this medicine can cause side effects, although not everybody gets them.
STOP taking Janumet and contact a doctor immediately if you notice any of the following serious side effects:
- Severe and persistent pain in the abdomen (stomach area) which may extend to the back with or without nausea and vomiting, as these could be signs of inflammation of the pancreas (pancreatitis).
Very rarely (may affect up to 1 in 10,000 people) patients taking metformin (one of the active substances in Janumet) have had a serious condition called lactic acidosis (an excess of lactic acid in the blood). This event is more common in people whose kidneys are not functioning properly.
Stop taking this medicine and contact a doctor immediately if you notice any of the following symptoms:
- nausea or retching, stomach pain (abdominal pain), muscle cramps, unexplained weight loss, rapid breathing and feeling cold or uncomfortable.
If you have a severe allergic reaction (frequency not known), including rash, hives, blistering of the skin / peeling of the skin and swelling of the face, lips, tongue and throat which may cause difficulty in breathing or swallowing, stop the treatment. with this medicine and contact your doctor immediately. Your doctor may prescribe a medicine to treat your allergic reaction and a different medicine for your diabetes.
Some patients have experienced the following side effects after starting sitagliptin while taking metformin:
Common (may affect up to 1 in 10 people): low blood sugar, nausea, flatulence, vomiting
Uncommon (may affect up to 1 in 100 people): stomach pain, diarrhea, constipation, sleepiness.
Some patients have experienced diarrhea, nausea, flatulence, constipation, stomach pain or vomiting when they started the combination of sitagliptin and metformin together (frequency is common).
Some patients have experienced the following side effects while taking this medicine with a sulphonylurea such as glimepiride:
Very common (may affect more than 1 in 10 people): low blood sugar
Common: constipation
Some patients have experienced the following side effects when taking this medicine in combination with pioglitazone:
Common: swelling of the hands or legs
Some patients have experienced the following side effects when taking this medicine in combination with insulin:
Very common: low blood sugar
Uncommon: dry mouth, headache
Some patients have experienced the following side effects during clinical trials when taking sitagliptin alone (one of the medicines contained in Janumet) or during post-approval use of Janumet or sitagliptin alone or with other diabetes medicines:
Common: low blood sugar, headache, upper respiratory tract infection, runny or stuffy nose and sore throat, osteoarthritis, pain in the arms or legs
Uncommon: dizziness, constipation, itching
Frequency not known: kidney problems (sometimes requiring dialysis), vomiting, joint pain, muscle pain, back pain, interstitial lung disease
Some patients have experienced the following side effects while taking metformin alone:
Very common: nausea, vomiting, diarrhea, stomach pain and loss of appetite.
These symptoms can occur when you start taking metformin and usually go away:
Common: metallic taste
Very rare: decreased levels of vitamin B12, hepatitis (a liver problem), hives, redness of the skin (rash) or itching.
Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the blister and carton after "EXP". The expiry date refers to the last day of that month.
Do not store above 30 ° C.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Deadline "> Other information
What Janumet contains
- The active substances are sitagliptin and metformin. Each film-coated tablet (tablet) contains sitagliptin phosphate monohydrate equivalent to 50 mg of sitagliptin and 850 mg of metformin hydrochloride.
- The other ingredients are: in the tablet core: microcrystalline cellulose (E460), povidone K 29/32 (E1201), sodium lauryl sulfate and sodium stearyl fumarate. Additionally, the tablet coating contains: polyvinyl alcohol, macrogol 3350, talc (E553b), titanium dioxide (E171), red iron oxide (E172), and black iron oxide (E172).
What Janumet looks like and contents of the pack
Capsule-shaped, pink film-coated tablets debossed with "515" on one side.
Opaque blister (PVC / PE / PVDC and aluminum).
Packs of 14, 28, 56, 60, 112, 168, 180, 196 film-coated tablets, multipacks containing 196 (2 packs of 98) and 168 (2 packs of 84) film-coated tablets.
Packs of 50 x 1 film-coated tablets in perforated single-dose blisters.
Not all pack sizes may be marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT -
JANUMET 50 MG / 850 MG TABLETS COATED WITH FILM
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -
Each tablet contains sitagliptin phosphate monohydrate equivalent to 50 mg of sitagliptin and 850 mg of metformin hydrochloride.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM -
Film-coated tablet (tablet).
Capsule-shaped, pink film-coated tablet debossed with "515" on one side.
04.0 CLINICAL INFORMATION -
04.1 Therapeutic indications -
For adult patients with type 2 diabetes mellitus:
Janumet is indicated as an adjunct to diet and exercise to improve glycemic control in patients who do not have adequate glycemic control on their maximum tolerated dose of metformin alone or in those patients already on the combination of sitagliptin. and metformin.
Janumet is indicated in combination with a sulphonylurea (eg, triple combination therapy) as an adjunct to diet and exercise in patients who do not have adequate glycemic control on their maximal tolerated dose of metformin and a sulphonylurea.
Janumet is indicated in triple combination therapy with a peroxisome proliferator-activated receptor agonist (PPARγ) (eg, a thiazolidinedione) as an adjunct to diet and exercise in patients who do not have adequate glycemic control with their maximum tolerated dose of metformin and a PPARγ agonist.
Janumet is also indicated as add-on insulin therapy (eg, triple combination therapy) in addition to diet and exercise to improve glycemic control in patients when a stable dose of insulin and metformin alone does not provide adequate glycemic control.
04.2 Posology and method of administration -
Dosage
The dose of antihyperglycaemic therapy with Janumet should be individualized based on the patient's current treatment regimen, efficacy, and tolerability by not exceeding the maximum recommended daily dose of 100 mg sitagliptin.
Adults with normal renal function (GFR ≥ 90 mL / min)
Patients who do not have adequate glycemic control on the maximum tolerated dose of metformin monotherapy
For patients who do not have adequate glycemic control with metformin alone, the usual starting dose should be sitagliptin 50 mg twice daily (100 mg total daily dose) plus unchanged metformin.
Patients switching from a co-administered regimen of sitagliptin and metformin
For patients switching from a co-administered regimen of sitagliptin and metformin, Janumet therapy should be initiated with the dose of sitagliptin and metformin unchanged.
Patients who do not have adequate glycemic control on dual combination therapy with the maximum tolerated dose of metformin and a sulphonylurea
The dose should be sitagliptin 50 mg twice daily (100 mg total daily dose) and a dose of metformin similar to that already taken. When Janumet 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).
Patients who do not have adequate glycemic control with dual combination therapy with the maximum tolerated dose of metformin and a PPARγ agonist
The dose should be sitagliptin 50 mg twice daily (100 mg total daily dose) and a dose of metformin similar to that already taken.
Patients who do not have adequate glycemic control on dual combination therapy with insulin and the maximum tolerated dose of metformin
The dose should be sitagliptin 50 mg twice daily (100 mg total daily dose) and a dose of metformin similar to that already taken. When Janumet is used in combination with insulin, a lower dose of the insulin may be required to reduce the risk of hypoglycaemia (see section 4.4).
For different doses of metformin, Janumet 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 adequate distribution of carbohydrate intake throughout the day.
Special populations
Renal impairment
No dose adjustment is required for patients with mild renal impairment (glomerular filtration rate [GFR] ≥ 60 mL / min). GFR should be assessed prior to initiating treatment with metformin-containing medicinal 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 evaluated more frequently. eg 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 treatment in patients with GFR
If an adequate dosage of Janumet is not available, the individual monocomponents should be used instead of the fixed dose combination.
Hepatic impairment
Janumet must not be used in patients with hepatic impairment (see section 5.2).
Senior citizens
Since metformin and sitagliptin are excreted by the kidney, Janumet should be used with caution with increasing age. Monitoring of renal function is necessary to prevent lactic acidosis associated with the use of metformin, particularly in the elderly (see sections 4.3 and 4.4).
Pediatric population
The safety and efficacy of Janumet in children and adolescents from birth a
Method of administration
Janumet should be taken twice daily with meals to reduce gastrointestinal adverse reactions associated with the use of metformin.
04.3 Contraindications -
Janumet 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 precoma;
- severe renal insufficiency (GFR
- acute states that can potentially alter renal function such as:
- dehydration,
- severe infection,
- shock,
- intravascular administration of iodinated contrast agents (see section 4.4);
- acute or chronic disease which can cause tissue hypoxia such as:
- heart or respiratory failure,
- recent myocardial infarction,
- shock;
- hepatic impairment;
- acute alcohol intoxication, alcoholism;
- feeding time.
04.4 Special warnings and appropriate precautions for use -
Generality
Janumet should not be used in patients with type 1 diabetes and should not be used for the treatment of diabetic ketoacidosis.
Acute pancreatitis
The use of DPP-4 inhibitors has been associated with the 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 therapy. with sitagliptin (with or without supportive treatment), but very rare cases of necrotizing or haemorrhagic pancreatitis and / or death have been reported. If pancreatitis is suspected, therapy with Janumet and other potentially suspect medicinal products should be discontinued; if the diagnosis of acute pancreatitis is confirmed, Janumet therapy should not be restarted. Caution should be exercised in patients with a history of pancreatitis.
Lactic acidosis
Lactic acidosis, a very rare but serious metabolic complication, occurs more frequently due to acute worsening of kidney function or cardiorespiratory disease or sepsis. Accumulation of metformin occurs with acute worsening of kidney function and increases the risk of lactic acidosis.
In case of dehydration (severe vomiting, diarrhea, fever or reduced fluid intake), administration of metformin should be temporarily interrupted and the patient should be advised to consult a healthcare professional.
Caution should be exercised in initiating treatment with medicinal products that may acutely impair renal function (such as antihypertensives, diuretics and NSAIDs) in patients treated with metformin. Other risk factors for lactic acidosis are excessive alcohol consumption, hepatic impairment, poorly controlled diabetes, ketosis, prolonged fasting and any other conditions associated with hypoxia, as well as concomitant use of medicinal products that can cause lactic acidosis (see sections 4.3 and 4.5).
Patients and / or caregivers should be informed of the risk of lactic acidosis. Lactic acidosis is characterized by acidotic dyspnoea, abdominal pain, muscle cramps, asthenia and hypothermia followed by coma. If symptoms are suspected, the patient should stop taking metformin and seek immediate medical attention. Diagnostic laboratory findings are decreased blood pH (plasma lactate (> 5 mmol / L) and increased anion gap and lactate / pyruvate ratio.
Kidney function
GFR should be assessed prior to initiation of treatment and at regular intervals thereafter (see section 4.2). Janumet is contraindicated in patients with GFR
Hypoglycemia
Patients being treated with Janumet in combination with a sulphonylurea or insulin may be at risk for hypoglycaemia. Therefore, a reduction in the dose of the sulphonylurea or insulin may be necessary.
Hypersensitivity reactions
Serious hypersensitivity reactions have been reported in patients treated with sitagliptin in post-marketing experience. These reactions include anaphylaxis, angioedema, exfoliative skin disorders including Stevens-Johnson syndrome. The onset of these reactions occurs within the next 3 months. at initiation of sitagliptin therapy, in some cases it occurred after the first administration. If a hypersensitivity reaction is suspected, Janumet therapy should be discontinued, other potential causes of this event should be considered, and alternative treatment for diabetes instituted (see section 4.8).
Surgical interventions
Janumet should be discontinued at the time of surgery under general, spinal or epidural anesthesia. Therapy can be resumed no earlier than 48 hours following surgery or restarting oral nutrition, provided that renal function has been re-evaluated and found to be stable.
Administration of iodinated contrast agents
Intravascular administration of iodinated contrast agents can lead to contrast-induced nephropathy. This causes accumulation of metformin and increases the risk of lactic acidosis. Administration of Janumet should be discontinued before or at the time of the imaging investigation and should not be restarted until at least 48 hours have elapsed since the examination. , provided that renal function has been re-evaluated and found to be stable (see sections 4.2 and 4.5).
Change in the clinical status of patients with previously controlled type 2 diabetes
A patient with type 2 diabetes previously controlled with Janumet who develops laboratory abnormalities or clinical disease (especially vague and poorly defined disease) should be promptly evaluated for ketoacidosis or lactic acidosis. Serum electrolytes and ketones, blood glucose and, if indicated, blood pH, blood levels of lactate, pyruvate, and metformin should be evaluated. If any form of acidosis occurs, therapy should be discontinued immediately and other appropriate corrective measures implemented.
04.5 Interactions with other medicinal products and other forms of interaction -
In patients with type 2 diabetes, concomitant administration of multiple doses of sitagliptin (50 mg twice daily) and metformin (1,000 mg twice daily) did not significantly alter the pharmacokinetics of sitagliptin or metformin.
No pharmacokinetic interaction studies have been performed with Janumet; however, these studies were conducted with the individual active substances, sitagliptin and metformin.
Concomitant use not recommended
Alcohol
Acute alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in cases of fasting, malnutrition or hepatic impairment.
Iodized contrast agents
Administration of Janumet should be discontinued before or at the time of imaging and should not be resumed until at least 48 hours have elapsed since the examination, provided that renal function has been re-evaluated and found to be stable (see sections 4.2 and 4.4).
Associations requiring precautions for use
Some medicines can adversely affect kidney function, thereby increasing the risk of lactic acidosis, eg. NSAIDs, including selective cyclooxygenase (COX) II inhibitors, ACE inhibitors, angiotensin II receptor antagonists and diuretics, particularly loop diuretics. When these medicinal products are used in combination with metformin, close monitoring of renal function is required.
Cationic medicinal products eliminated by renal tubular secretion (e.g., cimetidine), may interact with metformin via a competitive mechanism with common renal tubular transport systems. A study performed in seven healthy volunteers showed that cimetidine, given at a dose of 400 mg twice daily, increased systemic metformin exposure (AUC) by 50% and plasma Cmax by 81%. Therefore, when cationic medicinal products eliminated by renal tubular secretion are co-administered, close monitoring of glycemic control, dose adjustment within the recommended posology and some changes in diabetes therapy should be considered.
Glucocorticoids (administered systemically or locally), beta-2 agonists, and diuretics have intrinsic hyperglycemic activity. The patient should be informed and more frequent blood glucose monitoring should be performed, especially at the start of treatment with such medicinal products. If necessary, the dose of antihyperglycemic medicinal products should be adjusted during therapy with the other drug and upon its discontinuation. .
ACE inhibitors can reduce blood glucose levels. If necessary, the dose of antihyperglycemic drugs should be adjusted during therapy with the other drug and upon its discontinuation.
Effects of other medicinal products on sitagliptin
The data in vitro and clinicians described below suggest that the risk of clinically relevant interactions with other concomitant medicinal products is low.
Education in vitro indicated that the primary enzyme responsible for the limited metabolism of sitagliptin is CYP3A4 with a contribution from CYP2C8. In patients with normal renal function, metabolism, including that by CYP3A4, has a limited role in the clearance of sitagliptin. a more significant role in the elimination of sitagliptin in the context of severe renal impairment or end stage renal disease (ESRD). For this reason it is possible that potent CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, ritonavir, clarithromycin) may alter the pharmacokinetics of sitagliptin in patients with severe renal impairment or ESRD. The effects of potent CYP3A4 inhibitors in renal impairment have not been established in any clinical study.
Transport studies in vitro showed that sitagliptin is a substrate for p-glycoprotein and organic anion transporter 3 (OAT3). OAT3-mediated transport of sitagliptin was inhibited in vitro probenecid, although the risk of clinically relevant interactions is considered limited. Concomitant administration of OAT3 inhibitors has not been evaluated in vivo.
Ciclosporin: A study was performed to evaluate the effect of ciclosporin, a potent inhibitor of p-glycoprotein, on the pharmacokinetics of sitagliptin. Concomitant administration of a single oral dose of 100 mg sitagliptin and a single oral dose of 600 mg cyclosporine increased sitagliptin AUC and Cmax of approximately 29% and 68%, respectively. These changes in sitagliptin pharmacokinetics were not considered clinically relevant. The renal clearance of sitagliptin was not significantly altered. Therefore, no relevant interactions are expected. with other p-glycoprotein inhibitors.
Effects of sitagliptin on other medicinal products
Digoxin: Sitagliptin had a limited effect on plasma digoxin concentrations. Following administration of 0.25 mg digoxin concomitantly with 100 mg sitagliptin daily for 10 days, the plasma AUC of digoxin increased by an average of 11%, and the plasma Cmax increased by an average of 18%. No dose adjustments of digoxin are recommended. However, digoxin toxicity should be monitored in patients at risk of digoxin toxicity when sitagliptin and digoxin are co-administered.
Data in vitro suggest that sitagliptin does not inhibit or induce CYP450 isoenzymes. In clinical trials sitagliptin did not significantly alter the pharmacokinetics of metformin, glyburide, simvastatin, rosiglitazone, warfarin, or oral contraceptives, providing evidence in vivo a low propensity to cause interactions with substrates of CYP3A4, CYP2C8, CYP2C9, and with the organic cation transporter (OCT). Sitagliptin may be a weak inhibitor of p-glycoprotein in vivo.
04.6 Pregnancy and breastfeeding -
Pregnancy
There are no adequate data on the use of sitagliptin in pregnant women. Animal studies have shown reproductive toxicity at high doses of sitagliptin (see section 5.3).
The limited data available suggest that 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 on pregnancy, embryonic or fetal development, natal or postnatal development (see also section 5.3).
Janumet should not be used during pregnancy. If a patient wishes to become pregnant or if pregnancy occurs, therapy should be discontinued and the patient should be switched to insulin treatment as soon as possible.
Feeding time
Studies in lactating animals have not been performed with the associated active substances of this medicinal product. Studies performed with the individual active substances have shown the excretion of sitagliptin and metformin in the milk of lactating rats. Metformin is excreted in human milk in small quantities. It is not known whether sitagliptin is excreted in human milk. Janumet should therefore not be excreted in human milk. used during lactation (see section 4.3).
Fertility
Animal data do not suggest an effect of sitagliptin treatment on male or female fertility. There is a lack of human data.
04.7 Effects on ability to drive and use machines -
Janumet has no or negligible influence on the ability to drive or use machines. However, when driving or operating machinery it should be taken into account that dizziness and somnolence have been reported with sitagliptin.
In addition, when Janumet is used in combination with a sulphonylurea or insulin, patients should be made aware of the risk of hypoglycaemia.
04.8 Undesirable effects -
Summary of the safety profile
No therapeutic clinical studies have been performed with Janumet tablets although bioequivalence of Janumet with co-administered sitagliptin and metformin has been demonstrated (see section 5.2). Serious adverse reactions including pancreatitis and hypersensitivity reactions have been reported. & EGRAVE; Hypoglycaemia has been reported in association with sulphonylurea (13.8%) and insulin (10.9%).
Sitagliptin and metformin
Table of adverse reactions
Adverse reactions are listed below using the MeDRA system organ class and absolute frequency (Table 1). Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100,
Table 1: Frequency of adverse reactions identified in placebo-controlled clinical trials of sitagliptin and metformin alone and in post-marketing experience
* Adverse reactions that have been identified in post-marketing surveillance.
† See section 4.4.
‡ See below TECOS Cardiovascular Safety Study.
Description of selected adverse reactions
Some adverse reactions were observed with a higher frequency in studies of the combination use of sitagliptin and metformin with other anti-diabetic medicinal products than in studies of sitagliptin and metformin alone. These include hypoglycaemia (frequency very common with sulphonylurea or insulin), constipation (common with sulphonylurea), peripheral edema (common with pioglitazone) and headache and dry mouth (uncommon with insulin).
Sitagliptin
In monotherapy studies with sitagliptin 100 mg alone once daily compared with placebo, adverse reactions reported were headache, hypoglycaemia, constipation, and dizziness.
Among these patients, adverse events reported regardless of causal relationship to the medicinal product that occurred in at least 5% of cases included upper respiratory tract infection and nasopharyngitis. In addition, osteoarthritis and pain in extremity were reported uncommonly (> 0.5% higher among those using sitagliptin than in the control group).
Metformin
Gastrointestinal symptoms have been reported very commonly in clinical trials and post-marketing use of metformin. Gastrointestinal symptoms such as nausea, vomiting, diarrhea, abdominal pain and loss of appetite occur more frequently at initiation of therapy and in most of cases resolve spontaneously. 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 reduction in vitamin B12 absorption which very rarely can lead to clinically significant vitamin B12 deficiency (eg, megaloblastic anemia). The frequency categories are based on information in the Summary of Product Characteristics for metformin available in the European Union.
TECOS Cardiovascular Safety Study
The Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) study included 7,332 patients treated with sitagliptin, 100 mg per day (or 50 mg per day if baseline eGFR was ≥ 30 and HbA1c and for CV risk factors. L " Overall incidence of serious adverse events in sitagliptin-treated patients was similar to that in placebo-treated patients.
In the intention-to-treat population, among patients who were using insulin and / or a sulphonylurea at baseline, the incidence of severe hypoglycaemia was 2.7% in patients treated with sitagliptin and 2.5% in patients treated with placebo; among patients who were not using insulin and / or a sulphonylurea at baseline, the incidence of severe hypoglycaemia was 1.0% in patients treated with sitagliptin and 0.7% in patients treated with placebo. The incidence of confirmed diagnoses of pancreatitis events was 0.3% in patients treated with sitagliptin and 0.2% in patients treated with placebo.
Reporting of suspected adverse reactions
The reporting of suspected adverse reactions that occur after the authorization of the medicinal product is important, as it allows continuous monitoring of the benefit / risk ratio of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Italian Medicines Agency. , website: www.agenziafarmaco.gov.it/it/responsabili.
04.9 Overdose -
During controlled clinical trials in healthy subjects, single doses of sitagliptin up to 800 mg were administered. Minimal increases in QTc, not considered clinically relevant, were observed with a sitagliptin dose of 800 mg in one study. There is no experience with doses above 800 mg in clinical studies. In Phase I multiple-dose studies, there were no adverse clinical reactions considered to be related with sitagliptin doses up to 600 mg per day for periods up to 10 days and 400 mg per day for periods up to 28 days.
A large overdose of metformin (or co-existing risk factors for lactic acidosis) can lead to lactic acidosis which is a medical emergency and must be treated in the hospital. Hemodialysis is the most effective method of removing lactate and metformin.
In clinical studies, approximately 13.5% of the dose was removed over a 3-4 hour hemodialysis session. Prolonged hemodialysis may be considered if deemed clinically appropriate. The dialyzability of sitagliptin with peritoneal dialysis is unknown.
In the event of an overdose, it is reasonable to use common supportive measures, for example, removing unabsorbed material from the gastrointestinal tract, using clinical monitoring (including electrocardiography), and instituting supportive care if required.
05.0 PHARMACOLOGICAL PROPERTIES -
05.1 "Pharmacodynamic properties -
Pharmacotherapeutic group: drugs used in diabetes, combinations of oral hypoglycemic drugs.
ATC code: A10BD07.
Janumet is a "combination of two antihyperglycemic drugs with complementary mechanism of action" to improve glycemic control in patients with type 2 diabetes: sitagliptin phosphate, a dipeptidyl peptidase 4 (DPP-4) inhibitor, and metformin hydrochloride, belonging to to the biguanide class.
Sitagliptin
Mechanism of action
Sitagliptin phosphate is an orally active, potent, and highly selective inhibitor of the enzyme dipeptidyl peptidase 4 (DPP-4) for the treatment of type 2 diabetes. DPP-4 inhibitors are a class of drugs that work by increasing the Incretin Levels: By inhibiting the enzyme DPP-4, sitagliptin increases the levels of the two known active hormones of the incretin group, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Incretins are part of an endogenous system involved in the physiological regulation of glucose homeostasis. When blood glucose is normal or elevated, GLP-1 and GIP increase the synthesis and release of insulin by pancreatic beta cells. GLP-1 decreases. in addition, glucagon secretion by alpha pancreatic cells, with reduced hepatic glucose production. When blood glucose is low, insulin release is not increased and glucagon secretion is not suppressed. Sitagliptin is a potent and highly selective inhibitor of the enzyme DPP-4 and does not inhibit the activity of closely related enzymes DPP-8 or DPP-9 at therapeutic concentrations. Sitagliptin differs in chemical structure and pharmacological action from analogues of GLP-1, insulin, sulfonylureas or meglitinides, biguanides, peroxisome proliferator-activated gamma receptor agonists (PPARγ), alpha-glucosidase inhibitors, and amylin analogs.
In a 2-day study in healthy subjects, sitagliptin alone increased active GLP-1 concentrations, while metformin alone increased active and total GLP-1 concentrations similarly. 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 glycemic control when used alone or in combination therapy.
In clinical studies, sitagliptin alone improved glycemic control with significant reductions in hemoglobin A1c (HbA1c) and fasting and postprandial plasma glucose.
The reduction in fasting plasma glucose (FPG) was observed at 3 weeks when the first FPG measurement was taken. The incidence of hypoglycaemia observed in patients treated with sitagliptin was similar to that of placebo. Body weight did not increase from baseline with sitagliptin therapy.
Improvements were observed in surrogate markers of beta cell function, including HOMA-β (Homeostasis Model Assessment-β), proinsulin / insulin ratio, and measures of beta cell response to meal tolerance testing with frequent sampling.
Studies with sitagliptin in combination with metformin
In a 24-week, placebo-controlled study evaluating the efficacy and safety of adding sitagliptin 100 mg once daily to ongoing metformin treatment, sitagliptin produced significant improvements in glycemic parameters compared to placebo. The change in body weight from baseline in sitagliptin-treated patients was similar to that in placebo-treated patients. In this study, there was a similar incidence of hypoglycaemia in patients treated with sitagliptin or placebo.
In a 24-week placebo-controlled initial therapy factorial study, sitagliptin 50 mg twice daily in combination with metformin (500 mg or 1,000 mg twice daily) provided significant improvements in glycemic parameters compared to both monotherapies. Body weight reduction with concomitant sitagliptin and metformin therapy was similar to that seen with metformin alone or with placebo; There was no change from baseline in patients taking sitagliptin alone. The incidence of hypoglycaemia was similar between treatment groups.
Study with 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 glycemic parameters. Patients treated with sitagliptin had a modest increase in body weight (+1.1 kg) compared to patients treated with placebo.
Study with 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 resulted in significant improvements in glycemic parameters. The change in body weight from baseline was similar in patients treated with sitagliptin and in those treated with placebo. The incidence of hypoglycemia was also similar in the patients treated with placebo. patients treated with sitagliptin or placebo.
Study with 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 premixed insulin, the average daily dose was 70.9 U / day. In patients taking non-premixed (intermediate-acting / long-acting) insulin, the average daily dose was 44.3 U / day. Table 2 shows data for 73% of patients who were taking metformin. The addition of sitagliptin to insulin induced significant improvements in glycemic parameters. There was no significant change in body weight from baseline in either group.
Table 2: Results for HbA1c in combination therapy studies of sitagliptin e
placebo-controlled metformin *
* All patients treated (intention-to-treat analysis).
† Least squares means adjusted for previous antihyperglycemic therapy status and baseline value.
‡ p
|| HbA1c (%) at 24 weeks.
¶ HbA1c (%) at 26 weeks.
§ Least squares means adjusted for insulin use at Visit 1 [premixed versus non-premixed (intermediate-acting or long-acting)], and baseline.
In a 52-week study comparing the efficacy and safety of adding sitagliptin 100 mg once daily or glipizide (a sulphonylurea) in patients with inadequate glycemic control on metformin monotherapy, sitagliptin was similar to glipizide in reducing HbA1c. (-0.7% mean change from baseline to week 52, with baseline HbA1c approximately 7.5% in both groups.) The mean dose of glipizide used in the comparison group was 10 mg / day with approximately 40% of patients requiring a glipizide dose of ≤ 5 mg / day throughout the study. Patients in the sitagliptin group however experienced more discontinuations due to lack of efficacy than in the glipizide group. with sitagliptin showed a significant mean decrease in body weight from baseline (-1.5 kg) compared to a significant weight gain seen in patients receiving glipizide (+1.1 kg). study, the proinsulin / insulin ratio, a marker of insulin synthesis and release efficiency, improved with sitagliptin and worsened with treatment with glipizide. The incidence of hypoglycemia 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 the insulin glargine dose based on fasting glucose values measured by fingerstick. Among patients taking metformin, at week 24, the increase in daily insulin dose was 19 IU / day in sitagliptin-treated patients and 24 IU / day in placebo-treated patients. The reduction in HbA1c in patients treated with sitagliptin, metformin and insulin was -1.35% versus -0.90% in 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% in patients treated with sitagliptin, metformin and insulin and 37.8% in patients treated with placebo, metformin and insulin. The difference was mainly due to a higher percentage of patients in the placebo group who experienced 3 or more episodes of hypoglycemia (9.1 vs. 19.8%). There was no difference in the incidence of severe hypoglycemia.
Metformin
Mechanism of action
Metformin is a biguanide with antihyperglycemic effects, which lowers both basal and postprandial plasma glucose levels. It does not stimulate insulin secretion and therefore does not produce hypoglycemia.
Metformin can act by three mechanisms:
- reducing hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis
- in muscle, by slightly increasing insulin sensitivity, improving peripheral glucose uptake and its utilization
- slowing the intestinal absorption of glucose.
Metformin stimulates the intracellular synthesis of glycogen 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, regardless of its action on blood glucose, metformin has a favorable effect on lipid metabolism. This effect has been demonstrated at therapeutic doses in medium and long-term controlled clinical trials: metformin reduces the levels of total cholesterol, LDL cholesterol and triglycerides.
The prospective randomized UKPDS trial demonstrated the long-term benefit of intensive glycemic control in type 2 diabetes. Analysis of results in overweight patients treated with metformin after diet failure alone showed:
- a significant reduction in the absolute risk of any diabetes-related complications in the metformin treatment group (29.8 events / 1,000 patient-years) versus diet alone (43.3 events / 1,000 patient-years), p = 0.0023, e versus the combined sulphonylurea and insulin monotherapy treatment groups (40.1 events / 1,000 patient-years), p = 0.0034 - a significant reduction in the absolute risk of any type of diabetes-related death: metformin 7.5 events / 1,000 patient-years, diet alone 12.7 events / 1,000 patient-years, p = 0.017
- a significant reduction in the absolute risk of total mortality: metformin 13.5 events / 1,000 patient-years versus diet alone 20.6 events / 1,000 patient-years, (p = 0.011), and versus combined sulphonylurea and insulin monotherapy treatment 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 patient-years, diet alone 18 events / 1,000 patient-years, (p = 0.01).
TECOS was a randomized study in 14,671 patients in the intention-to-treat population with HbA1c values ranging from ≥ 6.5 to 8.0% and with established CV disease treated with sitagliptin (7,332) 100 mg daily (or 50 mg per day if baseline eGFR was ≥ 30 e
Over the course of the study, the overall estimated mean (SD) difference in HbA1c between the sitagliptin and placebo groups was 0.29%, 95% CI (-0.32, -0.27); p
The primary cardiovascular endpoint was a composite of early-onset cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for unstable angina. Secondary cardiovascular endpoints included early onset of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke; onset of the individual components of the composite primary endpoint; death from any cause; and hospital admissions for congestive heart failure.
After a median follow-up of three years, sitagliptin, when added to usually used therapy, did not increase the risk of major adverse cardiovascular events or the risk of hospitalization for heart failure compared to therapy usually used without sitagliptin in patients with type diabetes. 2 (Table 3).
Table 3: Rates of composite cardiovascular outcomes and main secondary outcomes
* The incidence rate per 100 patient-years is calculated as 100 × (total number of patients with ≥1 event during the eligible exposure period for the total patient-years of follow-up).
† Based on a regionally stratified Cox model. For composite endpoints, the p-value corresponds to a non-inferiority test to demonstrate that the hazard ratio is less than 1.3. For all other endpoints, the p-value corresponds to a test for differences in risk ratios.
‡ Analysis of hospitalization for heart failure was adjusted for anamnestic history of heart failure at baseline.
Pediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with Janumet in all subsets of the pediatric population in type 2 diabetes mellitus (see section 4.2 for information on pediatric use).
05.2 "Pharmacokinetic properties -
Janumet
A bioequivalence study performed in healthy people demonstrated that Janumet (sitagliptin / metformin hydrochloride) combination tablets are bioequivalent to the concomitant administration of single sitagliptin phosphate and metformin hydrochloride tablets.
The pharmacokinetic properties of the individual active substances of Janumet are presented below.
Sitagliptin
Absorption
After oral administration of a 100 mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) 1 to 4 hours post-dose, the mean plasma AUC of sitagliptin was 8. 52 mcM • now, 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 pharmacokinetics, sitagliptin can be taken with or without meals.
The plasma AUC of sitagliptin increased in a dose-proportional manner. Dose-proportionality was not established for Cmax and C24h (Cmax increased more than dose-proportionality and C24h increased to a lesser extent. with respect to dose-proportionality).
Distribution
The mean steady-state volume of distribution following a single 100 mg intravenous dose of sitagliptin to healthy subjects is approximately 198 liters. The fraction of sitagliptin bound to plasma proteins in a reversible manner is low (38%).
Biotransformation
Sitagliptin is eliminated unchanged primarily via the urine, and metabolism is a minor metabolic pathway. Approximately 79% of sitagliptin is excreted unchanged in the urine.
Following an oral [14C] sitagliptin dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Traces of 6 metabolites of sitagliptin have been found and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. in vitro indicated that the enzyme primarily responsible for the limited metabolism of sitagliptin is CYP3A4, with a contribution from CYP2C8.
Data in vitro 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
After the administration of one dose of [14C] sitagliptin per osin healthy subjects, approximately 100% of the administered radioactivity was eliminated in faeces (13%) or urine (87%) within one week of administration. The apparent terminal t1 / 2 after a 100 mg dose of sitagliptin per os it was about 12.4 hours. Sitagliptin accumulates only minimally with multiple doses. Renal clearance was approximately 350 mL / min.
The elimination of sitagliptin takes place primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for the human organic anion transporter 3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in the transport of sitagliptin has not been established. Sitagliptin is also a substrate for p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporin, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin. Sitagliptin is not a substrate for sitagliptin. OCT2 or OAT1 or PEPT1 / 2 transporters. In vitro, sitagliptin did not inhibit OAT3 (IC50 = 160 mcM) or p-glycoprotein (up to 250 mcM) mediated transport at therapeutically relevant plasma concentrations. In a clinical study sitagliptin had a limited effect on plasma digoxin concentrations indicating that sitagliptin may be a weak inhibitor of p-glycoprotein.
Characteristics of patients
The pharmacokinetics of sitagliptin were generally similar in healthy subjects and in patients with type 2 diabetes.
Renal impairment
An open-label single-dose 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 healthy control subjects. The study included patients with renal impairment classified by creatinine clearance as mild (50 to
Patients with mild renal impairment had no clinically significant increases in sitagliptin plasma concentrations compared with healthy controls. An approximately 2-fold increase in plasma AUC of sitagliptin was observed in patients with moderate renal impairment, and an approximately 4-fold increase in plasma AUC was observed in patients with severe renal impairment and ESRD on hemodialysis. healthy control subjects. Sitagliptin was removed to a limited extent by hemodialysis (13.5% over a 3 to 4 hour hemodialysis session starting 4 hours post-dose).
Hepatic impairment
No dose adjustment of sitagliptin is required in 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, since sitagliptin is primarily renally eliminated, severe hepatic impairment is not expected to affect sitagliptin pharmacokinetics.
Senior citizens
No dose adjustment is required based on age. Age had no clinically significant impact on the pharmacokinetics of sitagliptin based on data from a Phase I and Phase II population pharmacokinetic analysis. In the elderly ( 65 to 80 years), approximately 19% higher plasma concentrations of sitagliptin were observed than in young people.
Pediatric population
No studies have been conducted with sitagliptin in pediatric patients.
Other characteristics of patients
No dose adjustment is necessary based on gender, ethnicity, or body mass index (BMI). These characteristics did not have a clinically significant effect on sitagliptin pharmacokinetics based on data from a Phase I composite pharmacokinetic analysis and data from a Phase I and Phase II population pharmacokinetic analysis.
Metformin
Absorption
After an oral dose of metformin, T is reached in 2.5 hours. In healthy subjects, the absolute bioavailability of metformin 500 mg tablets is approximately 50-60%. After an oral dose, the unabsorbed fraction recovered in faeces was 20-30%.
After oral administration, the absorption of metformin is saturable and incomplete. The pharmacokinetics of the absorption of metformin are assumed to be non-linear. At the usual doses and dosing schedules of metformin, steady-state plasma concentrations are achieved within 24-48 hours and are generally less than 1 mcg / mL. In controlled clinical trials, maximum metformin plasma levels (Cmax) did not exceed 5 mcg / mL, even at maximum doses.
Food reduces the extent of metformin absorption and slows it down slightly. Following administration of an 850 mg dose there was a 40% decrease in peak plasma concentrations, a 25% decrease in AUC and a 35 minute prolongation of the time to peak plasma concentration. The clinical relevance of this reduction is unknown.
Distribution
The protein binding is negligible. Metformin breaks down in red blood cells. The blood peak is lower than the plasma peak and is reached at approximately the same time. Red blood cells most likely represent a secondary compartment of distribution. The mean volume of distribution ranged from 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 hours. When there is renal impairment, renal clearance is reduced in proportion to that of creatinine and hence there is a prolongation of "half-life, resulting in increased plasma levels of metformin.
05.3 Preclinical safety data -
No animal studies have been performed with Janumet.
In 16-week studies in which dogs were treated with metformin alone or with a combination of metformin and sitagliptin, no additional toxicity was observed with the combination therapy. The no observed effect level (NOEL) in these studies was observed at sitagliptin exposures approximately 6 times the human exposure and metformin exposures approximately 2.5 times the human exposure.
The following data are derived from studies performed with sitagliptin or metformin separately.
Sitagliptin
Renal and hepatic toxicity were observed in rodents at systemic exposure values equal to 58 times the human exposure, while the no effect level was found to be 19 times the human exposure. In rats, incisor abnormalities were observed at exposure levels equal to 67 times the human clinical exposure; the no-effect level for this event was 58-fold based on a 14-week rat study. The relevance of these data to humans is unknown. Transient, treatment-related physical signs have been observed in dogs at exposure levels approximately 23 times the clinical exposure level, some of which suggest neural toxicity, such as open mouth breathing. , salivation, white foamy emesis, ataxia, tremor, decreased activity and / or bent posture. At doses equivalent to approximately 23 times the systemic exposure level in humans, very mild to mild skeletal muscle degeneration was also observed histologically. A no effect level for these events was found at exposure equal to 6 times the clinical exposure level.
Sitagliptin did not demonstrate genotoxicity in preclinical studies. Sitagliptin was not carcinogenic in mice. In rats there was an increase in the incidence of liver adenomas and carcinomas at systemic exposure levels equal to 58 times the human exposure. Since hepatotoxicity was shown to be correlated with the induction of liver cancer in the rat , this increase in liver tumors in the rat is likely secondary to the chronic liver toxicity occurring at these high doses.
Due to the large margin of safety (19 times at this level with no effect), these neoplastic lesions are not considered relevant to the exposure circumstances in humans.
No treatment-related adverse effects on fertility were observed in male and female rats treated with sitagliptin before and during mating.
In pre- / postnatal development studies conducted in rats sitagliptin showed no adverse effects.
Reproductive toxicity studies showed a small treatment-related increase in the incidence of fetal rib malformations (absent, hypoplastic and wavy ribs) in the offspring of rats at systemic exposure levels 29 times higher than human exposure levels. Maternal toxicity was observed in rabbits at exposure levels greater than 29 times the human exposure levels. Due to the wide safety margins, these findings do not suggest the presence of relevant reproductive risks in humans. Sitagliptin is secreted in appreciable quantities in the milk of lactating rats (milk / plasma ratio: 4: 1).
Metformin
Non-clinical data relating to metformin show no special risk for humans based on conventional safety pharmacological studies, repeated dose toxicity, genotoxicity, carcinogenic potential, reproductive toxicity.
06.0 PHARMACEUTICAL INFORMATION -
06.1 Excipients -
Core of the tablet
microcrystalline cellulose (E460),
povidone K29 / 32 (E1201),
sodium lauryl sulfate,
sodium stearyl fumarate.
Tablet coating
polyvinyl alcohol,
macrogol 3350,
talc (E553b),
titanium dioxide (E171),
red iron oxide (E172),
black iron oxide (E172).
06.2 Incompatibility "-
Not relevant.
06.3 Period of validity "-
2 years.
06.4 Special precautions for storage -
Do not store above 30 ° C.
06.5 Nature of the immediate packaging and contents of the package -
Opaque blisters (PVC / PE / PVDC and aluminum).
Packs of 14, 28, 56, 60, 112, 168, 180, 196 film-coated tablets, multipacks containing 196 (2 packs of 98) and 168 (2 packs of 84) film-coated tablets. Pack size of 50 x 1 film-coated tablets in perforated single-dose blisters.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling -
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
07.0 HOLDER OF THE "MARKETING AUTHORIZATION" -
Merck Sharp & Dohme Ltd.
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
UK
08.0 MARKETING AUTHORIZATION NUMBER -
EU / 1/08/455/001
038672010
EU / 1/08/455/002
038672022
EU / 1/08/455/003
038672034
EU / 1/08/455/004
038672046
EU / 1/08/455/005
038672059
EU / 1/08/455/006
038672061
EU / 1/08/455/007
038672073
EU / 1/08/455/015
EU / 1/08/455/017
038672174
EU / 1/08/455/019
038672198
EU / 1/08/455/020
038672200
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION -
Date of first authorization: 16 July 2008
Date of most recent renewal: 13 March 2013
10.0 DATE OF REVISION OF THE TEXT -
12 December 2016
