Active ingredients: Pioglitazone, Metformin (Metformin hydrochloride)
Competact 15 mg / 850 mg film-coated tablets
Indications Why is Competact used? What is it for?
Competact contains pioglitazone and metformin. It is an anti-diabetic medicine used in adults to treat type 2 (non-insulin dependent) diabetes mellitus when treatment with metformin is not sufficient. This type of diabetes usually occurs in adults, particularly as a result of being overweight and where the body is unable to produce enough insulin (a hormone that controls blood sugar levels), or is unable to effectively use the insulin it produces. Your doctor will check if Competact works 3-6 months after starting treatment.
Competact helps to control the level of sugar in your blood when you have type 2 diabetes by allowing your body to make better use of the insulin it produces.
Contraindications When Competact should not be used
Do not take Competact
- if you are allergic to pioglitazone, metformin or any of the other ingredients of this medicine (listed in section 6).
- if you have heart failure or have suffered from heart failure in the past.
- if you have recently had a heart attack or have severe circulatory problems including shock, or difficulty in breathing.
- if you suffer from liver problems.
- if you drink too much alcohol (whether you do so on a daily basis or only occasionally).
- if you have diabetic ketoacidosis (a complication of diabetes with rapid weight loss, nausea or vomiting).
- if you have or have ever had bladder cancer (bladder cancer).
- if you have blood in your urine that your doctor has not yet checked
- If you have kidney problems.
- if you have a severe infection or are dehydrated.
- if you are to undergo a radiological examination with an injectable contrast agent. You will need to stop taking Competact at the time of taking the test and for a few days after taking it.
- if you are breast-feeding.
Precautions for use What you need to know before taking Competact
Talk to your doctor or pharmacist before taking Competact (see also section 4)
- if you have problems with your heart. Some patients with long-standing type 2 diabetes mellitus and heart disease or previous stroke who were treated with pioglitazone and insulin together have experienced heart failure. Tell your doctor as soon as possible if you experience signs of heart failure such as unusual shortness of breath or rapid weight gain or localized swelling (edema).
- if you hold back water (fluid retention) or have problems with heart failure, especially if you are over 75 years old. You should also tell your doctor if you are taking anti-inflammatory medicines, which can also cause fluid retention and swelling,
- if you have a particular type of diabetic eye disease. called macular edema (swelling of the back of the eye).
- if you are about to have an operation under general anesthesia, as you may need to stop taking Competact for a couple of days before and after your surgery.
- if you have ovarian cysts (polycystic ovary syndrome). The chance of becoming pregnant may increase as ovulation may resume when you take Competact. If this is the case, use adequate contraception to avoid the risk of an unscheduled pregnancy.
- if you have liver problems. Before you start taking Competact, you will be given a blood test to check how well your liver is working. This examination should be repeated periodically. Tell your doctor right away if you experience any symptoms that suggest a problem with your liver (such as unexplained feeling of nausea, vomiting, abdominal pain, fatigue, loss of appetite and / or dark urine) as this should be checked for function. hepatic.
There may also be a decrease in the blood cell count (anemia).
Hypoglycemia
If you take Competact with other diabetes medicines, your blood sugar is more likely to drop below normal (hypoglycaemia).
Bone fractures
A higher number of bone fractures have been found in patients, particularly in women taking pioglitazone. Your doctor will take this into account when treating your diabetes.
Children and adolescents
Use in children and adolescents under the age of 18 is not recommended.
Interactions Which drugs or foods can modify the effect of Competact
Other medicines and Competact Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription.
The following medicines in particular are likely to affect the amount of sugar in the blood: - gemfibrozil (used to lower cholesterol levels) - rifampicin (used to treat tuberculosis and other infections) - cimetidine (used to reduce stomach acid) ) - glucocorticoids (used to treat inflammation) - beta-2-agonists (used to treat asthma) - diuretics (used to eliminate excess fluids) - ACE inhibitors (used to treat high blood pressure)
Tell your doctor or pharmacist if you are taking any of these medicines. Your blood sugar level will be checked and your dose of Competact may need to be changed.
Competact with food, drink and alcohol
You can take the tablets with or without food to reduce the possibility of stomach upset. You should avoid the consumption of alcohol or medicinal products containing alcohol while taking Competact because alcohol may increase the risk of lactic acidosis (see section "Possible side effects").
Warnings It is important to know that:
Pregnancy and breastfeeding
- If you are pregnant, think you may be pregnant or are planning to become pregnant, please tell your doctor. Competact is not recommended during pregnancy. If you wish to become pregnant, your doctor will advise you to stop taking this medicine.
- Do not use Competact if you are breastfeeding or planning to breastfeed your baby.
Driving and using machines
This medicine does not affect your ability to drive or use machines, but be careful if you have visual disturbances.
Dose, Method and Time of Administration How to use Competact: Posology
Always take this medicine exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist. The recommended dose is one tablet to be taken twice a day. If necessary, your doctor may tell you to take a different dose. You must take the tablets with a glass of water. You can take the tablets with or shortly after a meal to reduce the possibility of stomach upset.
If you are on a special diabetes diet, you must continue this while you are taking Competact.
Your weight must be checked at regular intervals; if your weight increases, please tell your doctor.
Your doctor will ask you to have blood tests periodically during treatment with Competact. This is to check the normal functioning of your liver. At least once a year (more often if you are elderly or have kidney problems) your doctor will check that your kidneys are functioning normally.
Overdose What to do if you have taken an overdose of Competact
If you take more Competact than you should
If you accidentally take too many tablets, or if someone or a child takes your tablets, talk to your doctor or pharmacist immediately. Your blood sugar level may drop below normal levels and can be raised by " sugar intake. It is advisable to carry sugar cubes, candies, cookies or sugary fruit juices with you.
If you forget to take Competact
Take Competact every day as prescribed. However, if you forget to take a dose, just carry on with the next dose as normal. Do not take a double dose to make up for a forgotten tablet.
If you stop taking Competact
Competact must be used every day to function properly. If you stop using Competact, your blood sugar may go up. Talk to your doctor before stopping treatment.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Side Effects What are the side effects of Competact
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Very rarely, patients taking metformin (one of the active substances in Competact) have experienced a condition called lactic acidosis (excess lactic acid in the blood), particularly those with poor kidney function. Symptoms include: feeling cold and sick, intense nausea or vomiting, abdominal pain, unexplained weight loss, shortness of breath. If you experience any of these symptoms stop taking Competact and tell your doctor immediately.
Uncommon cases of bladder cancer (bladder cancer) (may affect up to 1 in 100 people) have occurred in patients taking Competact. Signs and symptoms include blood in the urine, pain when urinating or the sudden need to urinate. If you get any of these symptoms, talk to your doctor as soon as possible.
Blurred vision due to swelling (or fluid) of the back of the eye has been reported (frequency cannot be estimated from the available data). Tell your doctor as soon as possible if you notice these symptoms first. Also tell your doctor as soon as possible if you already have blurred vision and these symptoms get worse.
Allergic reactions have been reported (frequency cannot be estimated from the available data) in patients taking Competact. If you have a severe allergic reaction, which includes hives and swelling of the face, lips, tongue or throat which may cause difficulty in breathing or swallowing, stop taking this medicine and talk to your doctor as soon as possible. possible.
The following side effects have occurred in some patients taking Competact
Very common (may affect more than 1 in 10 people)
- abdominal pain
- feeling sick (nausea)
- He retched
- diarrhea
- loss of appetite
Common (may affect up to 1 in 10 people)
- localized swelling (edema)
- weight gain
- headache
- respiratory infection
- abnormal vision
- joint pain
- impotence
- blood in the urine
- decreased blood cell count (anemia)
- numbness
- change in taste
- bone fractures
Uncommon (may affect up to 1 in 100 people)
- inflammation of the sinuses (sinusitis)
- intestinal gas
- difficulty sleeping (insomnia)
Very rare (may affect up to 1 in 10,000 people)
- decrease in the amount of vitamin B12 in the blood
- lactic acidosis (excess lactic acid in the blood)
- redness of the skin
- itchy skin
- raised, itchy rash (hives)
Not known (frequency cannot be estimated from the available data)
- blurred vision due to swelling (or fluid) in the back of the eye
- inflammation of the liver (hepatitis)
- the liver does not work as it should (change in liver enzymes)
- allergic reactions
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. 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. By reporting 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 carton and blister after "EXP / EXP". The expiry date refers to the last day of that month.
This medicine does not require any special storage conditions.
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.
Composition and pharmaceutical form
What Competact contains
- The active substances are pioglitazone (as hydrochloride) 15 mg and metformin hydrochloride 850 mg.
- The other ingredients are: microcrystalline cellulose, povidone (K30), croscarmellose sodium, magnesium stearate, hypromellose, macrogol 8000, talc and titanium dioxide.
Description of what Competact looks like and contents of the pack
Competact tablets are white to off-white, oblong, film-coated tablets (tablets), debossed '15 / 850 "on one side and" 4833M "on the other. The tablets are supplied in aluminum / aluminum blisters of 14, 28, 30, 50, 56, 60, 90, 98, 112, 180, 196 (2 x 98) tablets or 60 x 1 tablets in aluminum / aluminum perforated dose blisters. unitary.
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
COMPETACT 15 MG / 850 MG TABLETS COATED WITH FILM
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 15 mg of pioglitazone (as hydrochloride) and 850 mg of metformin hydrochloride.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Film-coated tablet (tablet).
The tablets are white to off-white, oblong, film-coated tablets, debossed "15/850" on one side and "4833M" on the other.
After initiation of pioglitazone therapy, patients should be re-evaluated after 3-6 months to verify the adequacy of response to treatment (eg, reduction in HbA1c). In patients who do not respond adequately, pioglitazone treatment should be discontinued. In light of the potential risks of prolonged therapy, prescribers should confirm at subsequent visits that the benefits of pioglitazone treatment are maintained (see section 4.4).
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Competact is indicated for the second-line treatment of adult patients with type 2 diabetes mellitus, particularly in overweight patients who are unable to achieve sufficient glycemic control with maximum tolerated doses of oral metformin alone.
04.2 Posology and method of administration
Dosage
The usual dose of Competact is 30 mg / day of pioglitazone plus 1,700 mg / day of metformin hydrochloride (this dose is achieved by taking one Competact 15 mg / 850 mg tablet twice a day).
Dose titration of pioglitazone (added to the optimal metformin dose) should be considered before the patient switches to Competact treatment.
If clinically appropriate, direct transfer from metformin monotherapy to Competact treatment may be considered.
Special populations
Senior citizens
Renal function of elderly patients taking Competact should be monitored regularly as metformin is excreted by the kidney, and elderly patients have a tendency to have reduced renal function (see sections 4.3 and 4.4).
Physicians should start treatment with the lowest available dose and gradually increase it, particularly when pioglitazone is used in combination with insulin (see section 4.4 Fluid retention and heart failure).
Kidney failure
Competact must not be used in patients with renal insufficiency or renal dysfunction (creatinine clearance
Hepatic insufficiency
Competact must not be used in patients with hepatic insufficiency (see sections 4.3 and 4.4).
Pediatric population
The safety and efficacy of Competact in children and adolescents aged below 18 years have not yet been established. There are no data available.
Method of administration
The tablets should be swallowed with a glass of water. Taking Competact with food, or immediately after a meal, may reduce the gastrointestinal symptoms associated with metformin.
04.3 Contraindications
Competact is contraindicated in patients with:
Hypersensitivity to the active substances or to any of the excipients
Heart failure or history of heart failure (NYHA classes I to IV)
Active bladder cancer or history of bladder cancer
Macroscopic hematuria of an undetermined nature
Acute or chronic conditions that can cause tissue hypoxia, such as heart or respiratory failure, recent myocardial infarction, shock
Hepatic insufficiency
Acute alcohol intoxication, alcoholism
Diabetic ketoacidosis or diabetic pre-coma
Renal failure or renal dysfunction (creatinine clearance
Acute conditions potentially capable of altering renal function such as:
Dehydration
Severe infection
Shock
Intravascular administration of iodinated contrast media (see section 4.4)
Breastfeeding
04.4 Special warnings and appropriate precautions for use
There is no clinical experience with pioglitazone in triple combination with other oral anti-diabetic medicinal products.
Lactic acidosis
Lactic acidosis is a very rare but serious metabolic complication which can occur due to the accumulation of metformin. The reported cases of lactic acidosis in patients receiving metformin have mainly occurred in diabetic patients with significant renal insufficiency.
The incidence of lactic acidosis can and should also be reduced by testing for other associated risk factors such as insufficient control of diabetes, ketosis, prolonged fasting, excessive alcohol intake, liver failure and any conditions associated with hypoxia.
Lactic acidosis is characterized by acidotic dyspnoea, abdominal pain and hypothermia followed by coma. Diagnostic laboratory findings are decreased blood pH, plasma lactate levels above 5 mmol / l, and an increase in the anion gap and lactate ratio. If metabolic acidosis is suspected, treatment with the medicinal product should be discontinued and the patient hospitalized immediately (see section 4.9).
Kidney function
Since metformin is excreted by the kidney, serum creatinine concentrations should be checked regularly:
at least annually in patients with normal renal function
at least two to four times a year in patients with serum creatinine levels at the upper limit of normal and in elderly patients
Decreased renal function in elderly patients is common and asymptomatic. Particular caution should be exercised in situations where renal function may become insufficient, for example when initiating antihypertensive or diuretic therapy and when initiating treatment with an NSAID.
Water retention and heart failure
Pioglitazone can cause fluid retention which can exacerbate or precipitate heart failure. When treating patients who have at least one risk factor for developing congestive heart failure (e.g. previous myocardial infarction, symptomatic coronary artery disease, or the elderly), physicians should start treatment with the lowest available dose and gradually increase the dose. . Patients should be observed for signs and symptoms of heart failure, weight gain or edema; particularly those with reduced cardiac reserve.
There have been post-marketing reports of heart failure when pioglitazone was used in combination with insulin or in patients with a history of heart failure. Since both insulin and pioglitazone are associated with water retention, concomitant administration of insulin and Competact may increase the risk of edema. Competact should be discontinued if any deterioration in cardiac status occurs.
A cardiovascular outcome study of pioglitazone was performed in patients less than 75 years of age with type 2 diabetes mellitus and pre-existing major macrovascular disease. Pioglitazone or placebo were added to ongoing antidiabetic and cardiovascular therapy for up to 3.5 years. This study showed an increase in heart failure reports, however this did not lead to an increase in mortality in this study.
Senior citizens
The combined use of pioglitazone and insulin should be considered with caution in the elderly due to the increased risk of severe heart failure.
In light of age-related risks (particularly bladder cancer, fractures and heart failure), the balance of benefits and risks in the elderly should be carefully considered both before and during treatment with pioglitazone.
Bladder cancer
In a meta-analysis of controlled clinical trials cases of bladder cancer were reported more frequently with pioglitazone (19 cases out of 12,506 patients, 0.15%) than in control groups (7 cases out of 10,212 patients, 0.07%) HR = 2.64 (95% CI; 1.11-6.31; P = 0.029). After excluding patients in whom study drug exposure was less than one year at the time of bladder cancer diagnosis, pioglitazone cases were 7 (0.06%) while those in the control groups were 2 (0.02%). Available epidemiological data also suggest a slightly increased risk of bladder cancer in diabetic patients treated with pioglitazone, particularly in patients treated for longer periods and with the higher cumulative doses. a possible risk after short-term treatments is excluded.
Risk factors for bladder cancer should be evaluated before starting treatment with pioglitazone (risks include age, smoking, exposure to certain substances used in the workplace or chemotherapy such as cyclophosphamide or previous radiotherapy with exposure to the pelvic area. ). Any gross hematuria should be investigated before initiating therapy with pioglitazone.
Patients should consult their physician immediately if symptoms such as gross haematuria, dysuria, or urgency of urination occur during treatment.
Monitoring of liver function
During post-marketing experience, elevated liver enzymes and hepatocellular dysfunction have rarely been reported with pioglitazone (see section 4.8). Although fatal events have been reported in very rare cases, the causal relationship has not been established.
It is therefore recommended that patients treated with Competact undergo periodic monitoring of liver enzymes. Liver enzymes should be checked before starting Competact therapy in all patients. Competact therapy should not be initiated in patients with elevated baseline liver enzyme levels (ALT> 2.5 times the upper limit of normal) or with any evidence of liver disease.
Following initiation of Competact therapy, it is recommended that liver enzymes be monitored periodically as needed clinically. If ALT levels are increased 3 times the ULN during Competact therapy, liver enzyme levels should be re-evaluated. As soon as possible. If ALT levels remain> 3 times the upper limit of normal, therapy should be discontinued. If any patient experiences symptoms suggestive of hepatic dysfunction, which may include unexplained nausea, vomiting, abdominal pain, fatigue, anorexia and / or dark urine, liver enzymes should be checked.Decision whether to continue to treat the patient with Competact should be guided by clinical judgment pending laboratory evaluations.If jaundice occurs, the medicinal product should be discontinued.
Weight gain
In clinical studies with pioglitazone there has been evidence of dose related weight gain, which may be due to fat accumulation and in some cases associated with fluid retention. In some cases weight gain can be a symptom of heart failure, so weight needs to be closely monitored.
Hematology
A slight reduction in mean hemoglobin (relative reduction of 4%) and hematocrit (relative reduction of 4.1%) was observed during therapy with pioglitazone, consisting of haemodilution. Similar changes were observed in patients treated with metformin (relative reduction in hemoglobin 3 - 4% and hematocrit 3.6 - 4.1%) in comparative controlled studies with pioglitazone.
Hypoglycemia
Patients receiving pioglitazone in dual oral therapy with a sulphonylurea may be at risk for dose-related hypoglycaemia, and a reduction in the dose of the sulphonylurea may be required.
Visual disturbances
Post-marketing cases of new onset or worsening of diabetic macular edema with decreased visual acuity have been reported with thiazolidinediones, including pioglitazone. Many of these patients experienced concomitant peripheral edema. It is unclear whether or not there is a direct association between pioglitazone and macular edema but physicians should be alert to the possibility of macular edema if patients report visual acuity disturbances; appropriate ophthalmological examination should be considered.
Surgery
Since Competact contains metformin hydrochloride, treatment should be stopped 48 hours before elective surgery under general anesthesia and should not normally be restarted until 48 hours after surgery.
Administration of iodinated contrast media
Intravascular administration of iodinated contrast media in radiological examinations can lead to renal failure. Therefore, due to the presence of the active ingredient metformin, Competact should be discontinued before, or at the time of the radiological examination and should not be resumed before the next 48 hours, and only after renal function has been re-evaluated and detected. normal (see section 4.5).
Polycystic ovary syndrome
As a consequence of the increased action of insulin, treatment with pioglitazone in patients with polycystic ovary syndrome may cause ovulation to resume. These patients may be at risk for pregnancy. Patients should be aware of the risk of pregnancy and if a patient wishes to become pregnant or if pregnancy occurs, treatment should be stopped (see section 4.6).
Other
In a cumulative analysis of adverse reactions of bone fractures reported from randomized, controlled, double-blind clinical trials in over 8,100 patients treated with pioglitazone and 7,400 treated with comparator over 3.5 years, a "increased incidence of bone fractures in women.
Fractures were observed in 2.6% of women treated with pioglitazone compared with 1.7% of women treated with comparator. No increase in the incidence of fractures was observed in men treated with pioglitazone (1.3% ) compared to the comparison group (1.5%).
The calculated incidence of fractures was 1.9 fractures per 100 patient-years in women treated with pioglitazone and 1.1 fractures per 100 patient-years in women treated with a comparator. Hence the increased risk fractures for women in this dataset for pioglitazone were 0.8 fractures per 100 patient-years.
In the 3.5-year cardiovascular risk study PROactive, 44/870 (5.1%; 1.0 fractures per 100 patient-years) of female patients treated with pioglitazone experienced fractures compared to 23 / 905 (2.5%; 0.5 fractures per 100 patient-years) female patients treated with comparator. There was no increase in the incidence of fractures in men treated with pioglitazone (1.7%) compared with those treated with comparator (2.1%). The observed excess risk of fractures in women treated with pioglitazone in this study it is therefore 0.5 fractures per 100 patient-years.
The risk of fractures should be considered in long-term therapy in women treated with pioglitazone.
Pioglitazone should be used with caution during concomitant administration of inhibitors (e.g. gemfibrozil) or inducers (e.g. rifampicin) of cytochrome P450 2C8. Glycemic control must be monitored closely. Pioglitazone dose adjustment within the recommended posology or changes in diabetes treatment should be considered (see section 4.5).
04.5 Interactions with other medicinal products and other forms of interaction
No formal interaction studies have been conducted with Competact. The following data reflect the information available on the individual active substances (pioglitazone and metformin).
Intravascular administration of iodinated contrast media in radiological examinations can lead to renal failure, with consequent accumulation of metformin and risk of lactic acidosis. Metformin treatment should be discontinued before or at the time of radiological examination and should not be resumed until the next 48 hours, and only after renal function has been re-evaluated and found to be normal.
The presence of the active substance metformin in Competact causes an increased risk of lactic acidosis in acute alcohol intoxication (particularly in cases of fasting, malnutrition or hepatic insufficiency) (see section 4.4). Alcohol and drug consumption should be avoided. medicines containing alcohol.
Cationic medicinal products that are eliminated via renal tubular secretion (e.g. cimetidine) may interact with metformin through competition on shared renal tubular transport systems. A study in seven healthy volunteers showed that cimetidine, given at a dose of 400 mg twice daily, increased the systemic exposure to metformin (AUC) by 50% and Cmax by 81%. Therefore, careful monitoring of glycemic control, dose adjustment within the recommended posology and modification of diabetic treatment should be considered when cationic medicinal products that are eliminated via renal tubular secretion are co-administered.
Co-administration of pioglitazone with gemfibrozil (a cytochrome P450 2C8 inhibitor) resulted in a 3-fold increase in the AUC of pioglitazone. As an increase in dose-related adverse events is possible, it may be necessary to decrease the dose of pioglitazone when gemfibrozil is administered concomitantly. Close monitoring of glycemic control should be considered (see section 4.4). Co-administration of pioglitazone with rifampicin (a cytochrome P450 2C8 inducer) resulted in a 54% decrease in pioglitazone AUC. The dose of pioglitazone may need to be increased when rifampicin is administered concomitantly.Close monitoring of glycemic control should be considered (see section 4.4).
Glucocorticoids (administered both systemically and locally), beta-2 agonists, and diuretics possess intrinsic hyperglycemic activity. The patient should be informed and blood glucose monitoring should be performed more frequently, especially at the start of treatment. If necessary, the dosage of the hypoglycaemic medicinal product should be adjusted during therapy with the other medicinal product taken concomitantly and at the same time. time of its interruption.
ACE inhibitors can decrease blood glucose levels. If necessary, the dosage of the glucose-lowering medicinal product should be adjusted during therapy with the other medicinal product taken concomitantly and at the time of its discontinuation.
Interaction studies have shown that pioglitazone has no relevant effect on either the pharmacokinetics or the pharmacodynamics of digoxin, warfarin, phenprocoumon and metformin. Studies in humans suggest that there is no induction of the major inducible cytochrome P450, 1A, 2C8 / 9 and 3A4. in vitro showed no inhibition of any cytochrome P450 subtype. No interactions with drugs metabolised by these enzymes are expected, eg. oral contraceptives, cyclosporine, calcium antagonists and HMGCoA reductase inhibitors.
04.6 Pregnancy and lactation
For Competact, no preclinical or clinical data on exposure to the drug during pregnancy or lactation are available.
Women of childbearing potential / Contraception in men and women
Competact is not recommended in women of childbearing potential who are not using contraception. If a patient wishes to become pregnant, treatment with Competact should be discontinued.
Pregnancy
Risk related to pioglitazone
There are no adequate human data from the use of pioglitazone in pregnant women. Studies in animals have not shown teratogenic effects, but have shown fetotoxicity related to pharmacological action (see section 5.3).
Risk related to metformin
Animal studies did not reveal any teratogenic effects. Small clinical studies have not revealed that metformin can cause malformations.
Competact should not be used during pregnancy. If pregnancy occurs, Competact treatment should be discontinued.
Feeding time
Both pioglitazone and metformin were found in the milk of lactating rats. It is not known whether breastfeeding will expose the infant to the medicinal product. Therefore, Competact should not be administered to breastfeeding women (see section 4.3).
Fertility
In animal fertility studies with pioglitazone no effect on copulation, fertilization or fertility index was observed.
Fertility in male or female rats was not affected by metformin given at doses of 600 mg / kg / day, which corresponds to approximately three times the maximum recommended human daily dose in proportion to body surface area.
04.7 Effects on ability to drive and use machines
Competact has no or negligible effect on the ability to drive or use machines. However, patients with visual disturbances should be cautious when driving or operating machinery.
04.8 Undesirable effects
Summary of the safety profile
Clinical studies with Competact tablets have been performed with the co-administration of pioglitazone and metformin (see section 5.1). The bioequivalence of Competact with concomitant administration of pioglitazone and metformin has also been demonstrated (see section 5.2). Abdominal pain, diarrhea, loss of appetite, nausea and vomiting may occur at the start of treatment. These are very common reactions but usually resolve spontaneously in most cases. Lactic acidosis is a serious reaction that can occur. in less than 1 case in 10,000 patients (see section 4.4) while other reactions such as bone fractures, weight gain and edema may occur in less than 1 case in 10 patients (see section 4.4).
Table of adverse reactions
Adverse reactions reported in double-blind studies and post-marketing experience are listed below according to MedDRA terminology by system organ class and absolute frequency. Frequencies are defined as: very common (≥ 1/10); common ( ≥ 1/100,
Description of selected adverse reactions
1 Long-term use of metformin has been associated with decreased absorption of vitamin B12 with decreased serum levels. It is recommended that this etiology be considered if a patient presents with megaloplastic anemia.
2 Visual disturbances have been reported mainly at the start of treatment and are related to changes in blood glucose due to a "temporary alteration in turgidity and" refractive index of the lens.
3 Gastrointestinal disorders occur more frequently at the start of therapy and resolve spontaneously in most cases.
4 Isolated cases: liver function test abnormalities or hepatitis which resolve upon discontinuation of metformin treatment.
5 A "cumulative analysis of adverse reactions of bone fractures reported from randomized, comparator-controlled, double-blind clinical trials was conducted in over 8,100 patients treated with pioglitazone and 7,400 treated with comparator over a period of more than 3.5 A higher incidence of fractures was observed in women treated with pioglitazone (2.6%) than in those treated with comparator (1.7%). There was no increase in the incidence of fractures in men treated with pioglitazone (1.3%) compared with those treated with comparator drugs (1.5%).
In the PROactive 3.5-year study, 44/870 (5.1%) female patients treated with pioglitazone experienced fractures compared with 23/905 (2.5%) female patients treated with comparative medicines. There was no increase in the incidence of fractures in men treated with pioglitazone (1.7%) compared with those treated with the comparator (2.1%).
6 Edema was reported in 6.3% of patients treated with metformin and pioglitazone in active controlled clinical trials, with the addition of sulphonylurea to metformin treatment resulting in edema in 2.2% of patients. edema was generally mild to moderate and usually did not require discontinuation of treatment.
7 In active-controlled studies, mean weight gain with pioglitazone given as monotherapy for one year was 2 - 3 kg. In combination studies, treatment with pioglitazone added to metformin for one year resulted in a mean increase in weight of 1.5 kg.
8 In clinical trials with pioglitazone, the incidence of ALT elevations of 3 times the upper limit of normal was equal to placebo but lower than that observed in the metformin or sulphonylurea comparator groups. Mean liver enzyme levels decreased with pioglitazone treatment.
In controlled clinical trials the incidence of heart failure reports reported with pioglitazone treatment was the same as observed in the placebo, metformin and sulphonylurea groups, but was increased when pioglitazone was used in combination therapy with insulin. In one Outcome study in patients with pre-existing major macrovascular disease, the incidence of severe heart failure was 1.6% higher with pioglitazone than with placebo when added to therapy that included insulin. However, this did not result in a Increased mortality in this study Heart failure has been reported rarely with the marketing of pioglitazone, but more frequently when pioglitazone was used in combination with insulin or in patients with a history of heart failure.
04.9 Overdose
There are no data on overdose with Competact.
In clinical studies, some patients took pioglitazone at a dose higher than the maximum recommended dose of 45 mg per day. The maximum reported dose of 120 mg / day for four days and subsequently 180 mg / day for seven days was not associated with any symptoms.
A large overdose of metformin (or coexisting risks of lactic acidosis) can lead to lactic acidosis which is an emergency medical condition and must be treated in hospital.
The most effective method of removing lactate and metformin is hemodialysis.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: drugs used in diabetes, combinations of oral hypoglycemic drugs; ATC code: A10BD05
Competact is a combination of two hypoglycemic active ingredients with complementary mechanism of action aimed at improving glycemic control in patients with type 2 diabetes: pioglitazone, a component of the thiazolidinediones class and metformin hydrochloride, a component of the biguanide class.
The thiazolidinediones act mainly by reducing insulin resistance and the biguanides act mainly by reducing the endogenous production of glucose by the liver.
Combination of pioglitazone and metformin
In a randomized, double-blind, parallel-group study, the fixed-dose combination of pioglitazone 15 mg / metformin 850 mg BID (N = 201), pioglitazone 15 mg BID (N = 189), and metformin 850 mg BID were evaluated. (N = 210), in patients with type 2 diabetes mellitus, with mean baseline HbA1c values of 9.5%. All previous diabetes treatments were discontinued 12 weeks prior to baseline assessments. After 24 weeks of treatment, the mean change from baseline in HbA1c, the primary endpoint, was - 1.83% in the combination group versus - 0.96% in the pioglitazone group (p
The safety profile observed in the study reflected the known adverse reactions already observed with the individual medicines and did not reveal any new safety concerns.
Pioglitazone
The effects of pioglitazone may be mediated by a reduction in insulin resistance. Pioglitazone appears to act by activating specific receptors in the nucleus (activated gamma receptor for peroxisome proliferation) which leads to an increase in insulin sensitivity of the liver, fat and skeletal muscle cells in animals. Pioglitazone treatment has been shown to reduce hepatic glucose production and increase peripheral glucose availability in case of insulin resistance.
Fasting and postprandial glycemic control is improved in patients with type 2 diabetes mellitus. This improved glycemic control is associated with a reduction in both fasting and postprandial plasma insulin concentrations. A clinical study conducted with pioglitazone vs gliclazide alone was extended to two years to assess the time to treatment failure (defined as HbA1c ≥ 8.0% after the first six months of therapy). Kaplan-Meier analysis showed a shorter time to treatment failure in patients treated with gliclazide than in those treated with pioglitazone. At two years, glycemic control (defined as HbA1c
In a placebo-controlled study, patients with inadequate glycemic control despite a 3-month period of optimized insulin therapy were randomized to pioglitazone or placebo for 12 months. Patients treated with pioglitazone had a mean reduction in HbA1c of 0.45% compared to those who continued insulin alone, and a reduction in insulin dose in the pioglitazone group.
The HOMA analysis shows that pioglitazone improves beta cell function as well as increases sensitivity to insulin. Clinical studies lasting two years have shown the maintenance of this effect.
In one-year clinical trials, pioglitazone consistently caused a statistically significant reduction in the albumin / creatinine ratio from baseline.
The effect of pioglitazone (monotherapy 45 mg vs placebo) was evaluated in a small 18-week study in patients with type 2 diabetes. Pioglitazone was associated with significant weight gain. Visceral fat was significantly decreased, while there was an increase in extra-abdominal fat mass. These changes in body fat distribution with pioglitazone were accompanied by an increase in insulin sensitivity. In most clinical trials, decreases in total plasma triglyceride and free fatty acid levels and increases in HDL cholesterol levels were observed compared to placebo, with small but not clinically significant increases in LDL cholesterol levels. In two-year clinical trials, pioglitazone reduced total plasma triglycerides and free fatty acids, and increased HDL cholesterol levels compared to placebo, metformin and gliclazide. Pioglitazone did not cause statistically significant increases in LDL cholesterol levels compared to placebo, while reductions were observed with metformin and gliclazide. In a 20-week study, in addition to reducing fasting triglycerides, pioglitazone reduced postprandial hypertriglyceridaemia with an effect on both absorbed and hepatically synthesized triglycerides. These effects were independent of the effects of pioglitazone on blood glucose and are statistically significantly different states than glibenclamide.
In PROactive, a cardiovascular outcome study, 5238 patients with type 2 diabetes mellitus and pre-existing major macrovascular disease were randomized to pioglitazone or placebo in addition to ongoing antidiabetic and cardiovascular therapy for up to 3.5 years. The study population had a mean age of 62 years; the mean duration of diabetes was 9.5 years. Approximately one third of patients were taking insulin in combination with metformin and / or a sulphonylurea. To be eligible, patients had to have had one or more of the following conditions: myocardial infarction, stroke, percutaneous heart surgery or coronary artery bypass graft, acute coronary syndrome, coronary artery disease, or peripheral obstructive arterial disease. Almost half of the patients had a previous myocardial infarction and approximately 20% had had a stroke. About half of the study population had at least two of the inclusion criteria on cardiovascular history. Almost all subjects (95%) were taking cardiovascular medicinal products (beta blockers, ACE inhibitors, angiotensin II antagonists, calcium channel blockers, nitrates, diuretics, aspirin, statins, fibrates).
Although the study did not meet the primary endpoint, which was a composite endpoint of all cause mortality, nonfatal myocardial infarction, stroke, acute coronary syndrome, major leg amputation, coronary and leg revascularization, the results suggest that there are no long-term cardiovascular problems with the use of pioglitazone. However, the incidences of edema, weight gain and heart failure were increased. No increase in mortality due to heart failure was observed.
Metformin
Metformin is a biguanide with hypoglycemic effects, which reduces both fasting and postprandial blood glucose. It does not stimulate insulin secretion so it does not induce hypoglycemia.
Metformin can act by three mechanisms:
reducing hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis
in muscle, moderately increasing insulin sensitivity, improving peripheral glucose uptake and utilization
delaying intestinal absorption of glucose.
Metformin stimulates the intracellular synthesis of glycogen by acting on the glycogen synthetase. Metformin increases the transposing capacity of specific types of membrane glucose transporters (GLUT-1 and GLUT-4).
In humans, regardless of its action on blood glucose, metformin has favorable effects on lipid metabolism. This has been shown at therapeutic doses in medium or long-term controlled clinical trials: metformin reduces the levels of total cholesterol, LDL cholesterol and triglycerides. .
The prospective randomized study (UKPDS) established the long-term benefit of intensive glycemic control in type 2 diabetes. Analysis of the outcomes of overweight patients treated with metformin after diet-only failure demonstrated:
a significant reduction in the absolute risk of any diabetes-related complications in the metformin group (29.8 events / 1,000 patient-years) compared to the diet-only group (43.3 events / 1,000 patient-years) p = 0.0023, and compared to the combination of the sulfonylurea and insulin monotherapy groups (40.1 events / 1,000 patient-years) p = 0.0034
a significant reduction in the absolute risk of diabetes-related mortality: metformin 7.5 events / 1,000 patient-years, diet alone 12.7 events / 1,000 patient-years p = 0.017
a significant reduction in the absolute risk for 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 the combination of the sulfonylurea and insulin monotherapy groups 18.9 events / 1,000 patient-years (p = 0.021)
a significant reduction in the absolute risk of myocardial infarction: metformin 11 events / 1,000 patient-years, diet alone 18 events / 1,000 patient-years (p = 0.01).
Pediatric population
The European Medicines Agency has released the MAH from the obligation to submit the results of studies with Competact in all subsets of the pediatric population with Type 2 Diabetes Mellitus. See section 4.2 for information on pediatric use.
05.2 "Pharmacokinetic properties
Competact
Bioequivalence studies in healthy volunteers have shown that Competact is bioequivalent to the impromptu administration of pioglitazone and metformin.
Food had no effect on the AUC and Cmax of pioglitazone when Competact was administered to healthy volunteers. However, in the case of metformin, under fed conditions, the mean AUC and Cmax were lower (13% and 28% respectively) T was delayed from food by approximately 1.9 hours for pioglitazone and 0.8 hours for metformin.
The following data reflect the pharmacokinetic properties of the individual active substances of Competact.
Pioglitazone
Absorption
Following oral administration, pioglitazone is rapidly absorbed and peak plasma concentrations of unchanged pioglitazone are generally achieved 2 hours post dose. Proportional increases in plasma concentration were observed for doses ranging from 2 to 60 mg. Steady state is achieved after 4 to 7 days of dosing. Repeated dosing does not result in accumulation of the drug or metabolites. Absorption is not affected by food intake. The absolute bioavailability is greater than 80%.
Distribution
The estimated volume of distribution in humans is 0.25 l / kg.
Pioglitazone and all active metabolites are extensively bound to plasma proteins (> 99%).
Biotransformation
Pioglitazone is extensively metabolised by the liver by hydroxylation of aliphatic methylene groups. This occurs mainly via cytochrome P450 2C8 although other isoforms may be involved to a lesser degree. Three of the six identified metabolites are active (M-II, M-III and M-IV). When activity, concentrations and protein binding are taken into account, pioglitazone and the metabolite M-III contribute equally to efficacy. On this basis, the contribution of M-IV to efficacy is approximately three times that of pioglitazone, while the relative efficacy of M-II is minimal.
Education in vitro have not shown that pioglitazone inhibits any subtype of cytochrome P450. There is no induction of the main inducible isoenzymes of P450 in humans, 1A, 2C8 / 9 and 3A4.
Interaction studies have shown that pioglitazone has no relevant effect on either the pharmacokinetics or the pharmacodynamics of digoxin, warfarin, phenprocoumon and metformin. Concomitant administration of pioglitazone with gemfibrozil (a cytochrome P450 2C8 inhibitor) or rifampicin (a cytochrome P450 2C8 inducer) caused an increase or decrease in the plasma concentrations of pioglitazone, respectively (see section 4.5).
Elimination
After oral administration of radiolabelled pioglitazone in humans, the major portion of the labeled substance was recovered in the faeces (55%) and a minor amount in the urine (45%). In animals, only a small amount of unchanged pioglitazone can be detected. in urine or faeces. The mean plasma elimination half-life in humans is 5-6 hours for unchanged pioglitazone, and 16-23 hours for its total active metabolites.
Senior citizens
Steady-state pharmacokinetics are similar in patients 65 years of age and older and in young subjects.
Patients with renal insufficiency
In patients with renal insufficiency, the plasma concentrations of pioglitazone and its metabolites are lower than those observed in subjects with normal renal function, but with similar oral clearance for the parent medicinal product. Thus the concentration of free (unbound) pioglitazone is unchanged.
Patients with hepatic insufficiency
The total plasma concentration of pioglitazone is unchanged but with an increased volume of distribution. Consequently intrinsic clearance is reduced, associated with a higher fraction of unbound pioglitazone.
Metformin
Absorption
After taking an oral dose of metformin, T is reached in 2.5 hours. The absolute bioavailability of a 500 mg tablet is approximately 50 - 60% in healthy subjects. After taking an oral dose, the unabsorbed fraction found in the faeces is 20-30%.
After oral administration, the absorption of metformin is saturable and incomplete. The absorption kinetics of metformin are assumed to be non-linear. At normal doses and posology of metformin, steady state plasma concentrations are achieved within 24 to 48 hours. and are generally less than 1 μg / mL In controlled clinical trials, maximum plasma metformin levels (Cmax) did not exceed 4 μg / mL, even at maximum doses.
Food decreases the degree of absorption of metformin and delays it slightly. Following administration of the 850 mg dose, a 40% decrease in peak plasma concentration, a 25% decrease in AUC and a 35 min increase in time to peak plasma concentration were observed. this decrease is unknown.
Distribution
Plasma protein binding is negligible. Metformin distributes into erythrocytes. The blood peak is lower than the plasma peak and occurs at approximately the same time.
Red blood cells most likely represent a secondary distribution compartment. The mean Vd varied between 63-276 liters.
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. After administration of an oral dose, the apparent terminal elimination half-life is approximately 6.5 hours. When renal function is impaired, renal clearance is decreased in proportion to that of creatinine and thus the elimination half-life is prolonged with resulting in increased plasma metformin levels.
05.3 Preclinical safety data
Animal studies have not been performed with the combined active substances present in Competact.
The data below are the results of studies performed with pioglitazone or metformin separately.
Pioglitazone
In toxicological studies, plasma volume expansion with hemodilution, anemia and reversible eccentric cardiac hypertrophy occurred consistently after repeated administration in mice, rats, dogs and monkeys. In addition, increased fat deposition and infiltration was observed. These results were observed across species at plasma concentrations ≤ 4 times the clinical exposure. Reduced fetal growth occurred in studies with pioglitazone in animals. This is attributable to the action of pioglitazone in decreasing maternal hyperinsulinemia and to the increased insulin resistance that occurs during pregnancy thus reducing the availability of metabolic substrates for fetal growth.
Pioglitazone was found to be devoid of genotoxic potential in a comprehensive series of genotoxicity tests performed in vivo and in vitro. An increased incidence of hyperplasia (males and females) and tumors (males) of the urinary bladder epithelium was observed in rats treated with pioglitazone for up to 2 years.
It has been hypothesized that the formation and presence of urinary stones with subsequent irritation and hyperplasia is the mechanistic basis of the tumorigenic response observed in the male rat.
A 24-month mechanistic study in male rats showed that administration of pioglitazone resulted in an increased incidence of hyperplastic changes in the bladder. Dietary acidification significantly reduced, but did not abolish, the incidence of tumors. presence of microcrystals exacerbated the hyperplastic response but was not considered the main cause of hyperplastic changes. The relevance for humans of the tumorigenic effects observed in the male rat cannot be excluded.
There was no tumorigenic response in either sex of mice. Bladder hyperplasia was not observed in dogs or monkeys treated with pioglitazone for up to 12 months.
In an animal model of familial adenomatous polyposis (FAP), treatment with two other thiazolidinediones increased the multiplicity of colon cancer. The relevance of this finding is unknown.
Metformin
Non-clinical data on metformin reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, reproductive toxicity.
Environmental Risk Assessment: Clinical use of pioglitazone is not expected to have an impact on the environment.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Core of the tablet
Microcrystalline cellulose
Povidone (K 30)
Croscarmellose sodium
Magnesium stearate
Coating film
Hypromellose
Macrogol 8000
Talc
Titanium dioxide
06.2 Incompatibility
Not relevant.
06.3 Period of validity
3 years.
06.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
06.5 Nature of the immediate packaging and contents of the package
Aluminum / aluminum blisters in packs of 14, 28, 30, 50, 56, 60, 90, 98, 112, 180, 196 (2 x 98) tablets or 60 x 1 tablets in aluminum / aluminum perforated unit dose blisters.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
Takeda Global Research and Development Center (Europe) Ltd.
61 Aldwych
London WC2B 4AE
UK
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/06/354/001
037225051
EU / 1/06/354/002
037225063
EU / 1/06/354/003
037225075
EU / 1/06/354/004
037225087
EU / 1/06/354/005
037225099
EU / 1/06/354/006
037225101
EU / 1/06/354/007
037225113
EU / 1/06/354/008
037225125
EU / 1/06/354/009
037225137
EU / 1/06/354/010
EU / 1/06/354/011
EU / 1/06/354/012
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 28/07/2006
Date of the last renewal: 27/05/2011
