Active ingredients: Pioglitazone
Actos 15 mg tablets
Actos package inserts are available for pack sizes:- Actos 15 mg tablets
- Actos 30 mg tablets
- Actos 45 mg tablets
Why is Actos used? What is it for?
Actos contains pioglitazone. It is an anti-diabetic medicine used to treat type 2 (non-insulin dependent) diabetes mellitus, when metformin is not suitable or has not worked properly. This type of diabetes usually occurs in adults.
Actos helps control the blood sugar level when you have type 2 diabetes by helping your body make better use of the insulin it produces. Your doctor will check if Actos works 3-6 months after starting treatment.
Actos can be used on its own in patients who are unable to take metformin, and where diet and exercise therapy has not led to blood glucose control, or it can be added to other therapies (such as metformin, a sulphonylurea ol "insulin), which did not provide sufficient blood glucose control.
Contraindications When Actos should not be used
Do not take Actos
- if you are hypersensitive (allergic) to pioglitazone or any of the other ingredients of Actos.
- if you have heart failure or have suffered from heart failure in the past.
- if you suffer from liver problems.
- if you have suffered from diabetic ketoacidosis (a complication of diabetes causing 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.
Precautions for use What you need to know before taking Actos
Take special care with Actos
Tell your doctor before you start taking this medicine
- 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 special type of diabetic eye disease called macular edema (swelling of the back of the eye).
- if you have ovarian cysts (polycystic ovary syndrome). The likelihood of becoming pregnant may increase, as ovulation may resume when you take Actos. If this is the case, use adequate contraception to avoid the risk of an unscheduled pregnancy.
- if you have liver or heart problems. Before you start taking Actos, you will have a blood test to check your liver function. This test may be repeated periodically. Some patients with long-standing type 2 diabetes mellitus and heart disease or previous stroke who were treated with Actos and insulin 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 take Actos with other diabetes medicines, your blood sugar is more likely to drop below normal (hypoglycaemia). It may also have a decrease in the blood cell count (anemia).
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
Use in children under the age of 18 is not recommended.
Interactions Which drugs or foods can modify the effect of Actos
Taking Actos with other medicines
Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.
You can usually continue to take other medicines while you are being treated with Actos.
However, some 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)
Tell your doctor or pharmacist if you are taking any of these medicines. Your blood sugar level will be checked and the dose of Actos may need to be changed.
Taking Actos with food and drink
You can take the tablets with or without food. You must take the tablets with a glass of water.
Warnings It is important to know that:
Pregnancy and breastfeeding
Tell your doctor if
- are pregnant, if you think you may be or are planning to become pregnant.
- you are breast-feeding or planning to breast-feed your baby.
Your doctor will advise you to stop taking this medicine.
Driving and using machines
Pioglitazone has no effect on the ability to drive or use machines, but be careful if you have visual disturbances.
Important information about some of the ingredients of Actos
This medicinal product contains lactose monohydrate. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking Actos.
Dose, Method and Time of Administration How to use Actos: Posology
One pioglitazone 15 mg tablet should be taken once a day. If necessary, your doctor may tell you to take a different dose. If you have the impression that the effect of Actos is too weak, talk to your doctor.
When Actos tablets are taken in combination with other medicines used to treat diabetes (such as insulin, chlorpropamide, glibenclamide, gliclazide, tolbutamide) your doctor will tell you if you need to take a lower dose of the other medicines.
Your doctor will ask you to have blood tests periodically during treatment with Actos. This is to check the normal functioning of the liver.
If you are following a diabetic diet, you must continue it while you are taking Actos.
The weight must be checked at regular intervals; if your weight increases, tell your doctor.
Overdose What to do if you have taken too much Actos
If you take more Actos tablets 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 Actos tablets
Try to take Actos 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 Actos
Actos must be used every day to work properly. If you stop using Actos, 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 Actos
Like all medicines, Actos can cause side effects, although not everybody gets them.
In particular, the following serious side effects have occurred in some patients:
Heart failure has occurred commonly (1 to 10 users in 100) in patients taking Actos in combination with insulin. Symptoms are unusual shortness of breath or rapid weight gain or localized swelling (edema). If you experience any of these symptoms, especially if you are over 65, seek immediate medical attention.
Uncommon cases of bladder cancer (bladder cancer) have occurred (1 to 10 out of 1000 patients) in patients taking Actos. 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.
There have been very common cases of localized swelling (edema) in patients taking Actos in combination with insulin. If you get this side effect, tell your doctor as soon as possible.
There have been common reports (1 to 10 users in 100) of bone fractures in women taking Actos. If you experience this side effect, tell your doctor as soon as possible.
Blurred vision due to swelling (or fluid) of the back of the eye (frequency not known) has also been reported in patients taking Actos. Tell your doctor as soon as possible if you notice these symptoms for the first time. Tell your doctor as soon as possible even if you already have blurred vision and the symptom gets worse.
Allergic reactions have been reported (frequency not known) in patients taking Actos. 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 other side effects that have occurred in some patients taking Actos are:
common (affects 1 to 10 out of 100 patients)
- respiratory infections
- abnormal vision
- weight gain
- numbness
uncommon (affects 1 to 10 users in 1,000)
- inflammation of the sinuses (sinusitis)
- difficulty sleeping (insomnia)
not known (frequency cannot be estimated from the available data)
- increased liver enzymes.
- allergic reactions
The other side effects that have occurred in some patients when taking Actos together with other antidiabetic medicines are:
very common (affects more than one patient in 10)
- decreased blood sugar (hypoglycaemia)
common (affects 1 to 10 out of 100 patients)
- headache
- dizziness
- joint pain
- impotence
- backache
- shortness of breath
- a small reduction in the number of red blood cells in the blood
- flatulence
uncommon (affects 1 to 10 users in 1,000)
- sugar in the urine, protein in the urine
- increased enzymes
- spinning sensation (vertigo)
- sweating
- tiredness
- increased appetite
If any of the side effects gets serious or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.
Expiry and Retention
Keep out of the reach and sight of children.
Do not use Actos after the expiry date which is stated on the carton and on the blister after the word "EXP". The expiry date refers to the last day of the month.
This medicinal product does not require any special storage conditions.
Medicines should not be disposed of 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 Actos contains
- The active ingredient in Actos is pioglitazone. Each tablet contains 15 mg of pioglitazone (as hydrochloride).
- The other ingredients are lactose monohydrate, hyprolose, carmellose calcium and magnesium stearate.
What Actos looks like and contents of the pack
Actos tablets are white to off-white, round, convex, debossed "15" on one side and "ACTOS" on the other. The tablets are supplied in blisters, in packs of 14, 28, 30, 50, 56, 84, 90, 98, 112 or 196 tablets 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
ACTOS 15 MG TABLETS
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 15 mg of pioglitazone (as hydrochloride).
Excipients:
Each tablet contains 92.87 mg of lactose monohydrate (see section 4.4).
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Tablet.
The tablets are white to off-white, round, convex and marked "15" on one side and "ACTOS" on the other.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Pioglitazone is indicated as a second or third line treatment for type 2 diabetes mellitus, as detailed below:
in monotherapy
• in adult patients (particularly overweight patients) inadequately controlled by diet and exercise for whom metformin treatment is inappropriate due to contraindications or intolerance.
In dual oral therapy in combination with
• metformin, in adult patients (particularly overweight patients) with insufficient glycemic control despite the maximum tolerated dose of metformin monotherapy
• a sulphonylurea, only in adult patients who show intolerance to metformin or for whom metformin is contraindicated, with insufficient glycemic control despite the maximum tolerated dose of monotherapy with a sulphonylurea
In triple oral therapy in combination with
• metformin and a sulphonylurea, in adult patients (particularly overweight patients) with insufficient glycemic control despite dual oral therapy
• Pioglitazone is also indicated in combination with insulin in adult patients with type 2 diabetes mellitus who do not achieve sufficient glycemic control with insulin, for whom the use of metformin is inappropriate due to contraindications or intolerance (see section 4.4).
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).
04.2 Posology and method of administration
Dosage
Pioglitazone treatment can be initiated with a starting dose of 15 mg or 30 mg once daily. The dose can be gradually increased to 45 mg once a day.
In combination with insulin, the current insulin dose can be maintained at the start of treatment with pioglitazone. If patients report hypoglycaemia, the insulin dose should be reduced.
Special populations
Senior citizens
No dose adjustment is necessary in elderly patients (see section 5.2). 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
No dose adjustment is required in patients with impaired renal function (creatinine clearance> 4 ml / min) (see section 5.2). No information is available in dialysis patients, therefore pioglitazone should not be used in such patients.
Hepatic insufficiency
Pioglitazone must not be used in patients with hepatic insufficiency (see sections 4.3 and 4.4).
Pediatric population
The safety and efficacy of Actos in children and adolescents aged less than 18 years have not yet been established.
No data are available.
Method of administration
Pioglitazone tablets are taken orally once daily with or without food. The tablets should be swallowed with a glass of water.
04.3 Contraindications
Pioglitazone is contraindicated in patients with:
• hypersensitivity to the active substance or to any of the excipients.
• heart failure or history of heart failure (NYHA stages I to IV)
• liver failure
• diabetic ketoacidosis
• active bladder cancer or history of bladder cancer
• gross haematuria of an undetermined nature
04.4 Special warnings and appropriate precautions for use
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. Patients should be observed for signs and symptoms of heart failure, weight gain and edema when pioglitazone is used in combination with insulin. Since both insulin and pioglitazone are associated with fluid retention, concomitant administration may increase the risk of edema. There have also been post-marketing reports of peripheral edema and heart failure in patients with concomitant use of pioglitazone and non-steroidal anti-inflammatory drugs, including selective COX-2 inhibitors. Pioglitazone 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
Hepatocellular dysfunction has rarely been reported during post-marketing experience (see section 4.8). It is therefore recommended that patients treated with pioglitazone undergo periodic monitoring of liver enzymes. Liver enzymes should be checked prior to initiation of therapy. with pioglitazone in all patients Pioglitazone therapy should not be initiated in patients with elevated baseline liver enzyme levels (ALT> 2.5 times ULN) or with any evidence of liver disease.
Following initiation of pioglitazone therapy, it is recommended that liver enzymes be monitored periodically as needed clinically. If ALT levels are increased 3 times the upper limit of normal during pioglitazone 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 pioglitazone 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 should be closely monitored. Diet control is part of diabetes treatment. Patients should be advised that they must strictly follow a calorie controlled diet.
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 in hematocrit 3.6-4.1%) and to a lesser extent in those treated with sulphonylurea and insulin (relative reduction in hemoglobin 1-2% and hematocrit 1-3.2%) in comparative controlled studies with pioglitazone.
Hypoglycemia
As a consequence of increased insulin sensitivity, patients receiving pioglitazone in dual or triple oral therapy with a sulphonylurea or dual insulin therapy may be at risk for dose-related hypoglycaemia, and a reduction in the dose of the sulphonylurea may be required. or insulin.
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.
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 for more than 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%).
Some epidemiological studies have suggested a similar increased risk of fractures in both men and women.
The risk of fractures should be considered in long-term therapy in patients treated with pioglitazone.
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 the patient wishes to become pregnant or if a pregnancy occurs, the treatment should be stopped (see section 4.6).
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).
Actos tablets contain lactose monohydrate and therefore should not be administered to patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
04.5 Interactions with other medicinal products and other forms of interaction
Interaction studies have shown that pioglitazone has no relevant effect on either the pharmacokinetics or the pharmacodynamics of digoxin, warfarin, phenprocoumon and metformin. Co-administration of pioglitazone with sulphonylureas does not appear to affect the pharmacokinetics of the sulphonylurea. 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 are expected with medicinal products metabolised by these enzymes, eg. oral contraceptives, cyclosporine, calcium antagonists and HMGCoA reductase inhibitors.
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. Pioglitazone dose may need to be increased when rifampicin is coadministered. Close monitoring of glycemic control should be considered (see section 4.4).
04.6 Pregnancy and lactation
Pregnancy
There are no adequate human data to determine the safety of pioglitazone during pregnancy. Animal studies with pioglitazone have shown a slowed development of the fetus. This observation has been attributed to the action of pioglitazone in decreasing maternal hyperinsulinemia and to the increased insulin resistance that occurs during pregnancy thereby reducing the availability of metabolic substrates for fetal growth. man is unclear and pioglitazone should not be used in pregnancy.
Feeding time
Pioglitazone was found in the milk of lactating rats. It is not known whether pioglitazone passes into breast milk. Therefore, pioglitazone should not be given to breastfeeding women.
Fertility
No effects on copulation, fertilization or fertility index were observed in animal fertility studies.
04.7 Effects on ability to drive and use machines
Actos 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
Adverse reactions reported to a greater extent (> 0.5%) than placebo and in more than one isolated case in patients receiving pioglitazone in double-blind studies are listed below in MedDRA terminology by system organ class and absolute frequency. Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100,
1 Hypersensitivity reactions have been reported in patients treated with pioglitazone after marketing. These reactions include anaphylaxis, angioedema and urticaria.
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 of the turgidity and refractive index of the lens as observed with other hypoglycemic agents
3 Edema was reported in 6-9% of patients treated with pioglitazone for one year in controlled clinical trials. The rates of edema in the comparison groups (sulphonylurea, metformin) were 2-5%. Cases of edema were generally mild to moderate and usually did not require discontinuation of treatment.
4 In controlled clinical trials the incidence of heart failure reports reported with pioglitazone treatment was the same as 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 lead to a increase in mortality in this study. In this study, in patients who received pioglitazone and insulin, a higher percentage of patients with heart failure was observed in those aged ≥ 65 years, compared to patients less than 65 years (9 (7% versus 4.0%). In patients on insulin therapy without pioglitazone, the incidence of heart failure was 8 , 2% in patients ≥ 65 years of age, compared with 4.0% in patients less than 65 years of age. Heart failure has been reported during the marketing of pioglitazone, and more frequently when pioglitazone was used in combination with insulin or in patients with a history of heart failure.
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 (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 comparator medicine. There was no increase in the incidence of fractures in men treated with pioglitazone (1.7%) compared with those treated with comparator (2.1%).
6 In active-controlled studies, mean weight gain with pioglitazone given as monotherapy was 2 to 3 kg over one year. This result was similar to that seen in the sulphonylurea comparator group. Mean weight gain was was 1.5 kg in studies where pioglitazone was combined with metformin and 2.8 kg in studies where pioglitazone was combined with sulphonylurea for more than one year. In the comparison groups, the addition of sulphonylurea to metformin resulted in an average weight increase of 1.3 kg and the addition of metformin to the sulphonylurea resulted in an average weight loss of 1.0 kg.
7 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 are decreased with pioglitazone treatment. Rare cases of hepatic enzyme elevations and hepatocellular dysfunction have occurred in post-marketing experience. Although fatal events have been reported in very rare cases, the causal relationship has not been established.
04.9 Overdose
In clinical trials, 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.
Hypoglycaemia may occur in combination with sulphonylureas or insulin. In the event of an overdose, symptomatic and general supportive measures should be taken.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: drugs used in diabetes, drugs that lower blood glucose, excluding insulins; ATC code: A10BG03.
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 clinical trials of up to two years duration, 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 end point, which was a composite end point of all-cause mortality, non-fatal 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.
Pediatric population
The European Medicines Agency has released the MAH from the obligation to submit the results of studies with Actos 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
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 4-7 days of administration. 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.
05.3 Preclinical safety data
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.
Environmental Risk Assessment: Clinical use of pioglitazone is not expected to have an impact on the environment.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Calcium Carmellose
Hyprolose
Lactose monohydrate
Magnesium stearate.
06.2 Incompatibility
Not applicable.
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, 84, 90, 98, 112 and 196 tablets.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
Takeda Pharma A / S
Langebjerg 1
DK-4000 Roskilde
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/00/150/001
034946018
EU / 1/00/150/002
034946020
EU / 1/00/150/003
034946032
EU / 1/00/150/007
034946071
EU / 1/00/150/009
034946095
EU / 1/00/150/016
034946160
EU / 1/00/150/017
034946172
EU / 1/00/150/018
034946184
EU / 1/00/150/025
EU / 1/00/150/026
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 13/10/2000
Date of last renewal: 31/08/2010
10.0 DATE OF REVISION OF THE TEXT
D.CCE November 2013
