Trelagliptin Tablets 25 mg / 50 mg / 100 mg

Trelaglip 25

Each film coated tablet contains :

Trelagliptin Succinate

equivalent to Trelagliptin 25 mg

Excipients q.s.

Colours : Ferric Oxide USP NF (Yellow)and Titanium Dioxide IP

Trelaglip 50

Each film coated tablet contains :

Trelagliptin Succinate equivalent to Trelagliptin 50 mg

Excipients q.s.

Colours : Ferric Oxide USP NF (Yellow) and Titanium Dioxide IP

Trelaglip 100

Each film coated tablet contains :

Trelagliptin Succinate

equivalent to Trelagliptin 100 mg

Excipients q.s.

Colours : Ferric Oxide USP NF (Yellow) and Titanium Dioxide IP

Tablet, 25 mg / 50 mg / 100 mg

4.1 Therapeutic indications

For the treatment of type 2 diabetes mellitus.

4.2 Posology and method of administration

The usual adult dosage is 100 mg of Trelaglip administered orally once a week.

Patients with moderate or severe renal dysfunction

The blood concentration of this drug increases due to delayed excretion; therefore, the dose should be reduced according to the degree of renal function, referring to the table below.

Dosage for patients with moderate or severe renal impairment

¹ Conversion value equivalent to CCR (age 60 years, weight 65 kg).

² For patients with end-stage renal disease, the time relationship between administration of this drug and haemodialysis does not matter.

Elderly

Carefully administer the drug while paying attention to the occurrence of side effects and carefully observing the course. In general, renal function is often impaired.

Method of administration

• Trelaglip is to be taken once a week and should be taken on the same day of the week.
• If you forget to take this drug, take only the prescribed dose at the time you notice it and then take it on a predetermined day of the week.

4.3 Contraindications

• Patients with severe ketosis, diabetic coma or precoma, Type 1 diabetes.
• Patients with severe infections, those undergoing surgery or those with severe trauma.
• Patients with a history of hypersensitivity to the ingredients of this drug.

4.4 Special warnings and precautions for use

• This drug may cause hypoglycemia. When using this drug, patients should be fully informed of the symptoms of hypoglycemia and how to deal with them and caution should be exercised.
• Acute pancreatitis may occur, so instruct patients to consult a doctor immediately if they experience initial symptoms such as persistent severe abdominal pain or vomiting.
• This drug is orally administered once a week and its action continues even after discontinuation of administration. Therefore, pay close attention to the blood glucose level and the occurrence of side effects. In addition, when using other diabetic drugs after discontinuation of this drug, the start time and dose of the drug should be examined based on the blood glucose control status.
• During administration of this drug, blood glucose levels should be checked regularly and the patient's condition should be closely monitored. If the patient shows no satisfactory response after 2 to 3 months of administration of this drug, consideration should be given to changing to a more appropriate treatment.
• Trelaglip and GLP-1 receptor agonists have a blood glucose lowering effect via the GLP-1 receptor. There are no clinical trial results when the two drugs are used together and their efficacy and safety have not been confirmed.

4.5 Drug Interactions

• When Trelagliptin was used in combination with Glimepiride or Metformin, no clear effect was observed on the pharmacokinetics of Trelagliptin and these concomitant drugs.
• When Trelagliptin was used in combination with Caffeine, Tolbutamide, Dextromethorphan or Midazolam, no clear effect was observed on the pharmacokinetics of these concomitant drugs.

4.6 Use in special populations (such as pregnant women, lactating women, paediatric patients, geriatric patients etc.)

Patients with complications / medical history

Patients or conditions at risk of hypoglycemia :

• Pituitary or adrenal insufficiency.
• Malnutrition, starvation, irregular food intake, insufficient food intake or debilitation.
• Intense muscle exercise.
• People who consume excessive amounts of alcohol. Patients with a history of abdominal surgery or intestinal obstruction may cause intestinal obstruction.

Patients with moderate or severe renal dysfunction

Reduce the dose and carefully observe the patient's condition. The blood concentration of this drug increases due to delayed excretion depending on the degree of renal function.

Pregnant women

Pregnant women or women who may be pregnant should only be administered if the therapeutic benefits are judged to outweigh the risks. Placental crossing of drug has been reported in animal studies (rats).

Lactating women

Consider whether to continue or discontinue breast-feeding, taking into account the therapeutic benefits and the benefits of breast-feeding. Animal studies (rats) have shown that the drug is excreted in breast milk.

Pediatric population

No clinical trials have been conducted in children.

Elderly

Pay attention to the occurrence of side effects and administer with caution while closely monitoring the progress. Renal function is generally reduced in many cases.

4.7 Effects on ability to drive and use machines

Hypoglycemic symptoms may occur, so caution should be exercised when administering to patients engaged in activities such as working at heights or driving a car.

4.8 Undesirable effects

Serious side effects

Since the following side effects may appear, observe them thoroughly and if any abnormalities are found, take appropriate measures such as discontinuing administration.

Hypoglycemia (Less than 0.1 - 5%)

Hypoglycemia may occur. When used concomitantly with sulfonylurea agents or insulin preparations, severe hypoglycemic symptoms, including loss of consciousness, have been reported. If hypoglycemic symptoms are observed, appropriate measures should be taken, such as having the patient ingest foods containing carbohydrates. However, glucose should be administered when used concomitantly with an α-glucosidase inhibitor.

Pemphigoid (incidence unknown)

If blisters or erosions appear, consult with a dermatologist and take appropriate measures, such as discontinuing administration. Acute pancreatitis (incidence unknown) If any abnormalities such as persistent severe abdominal pain or vomiting are observed, discontinue administration and take appropriate measures.

Bowel obstruction (incidence unknown)

If any abnormalities such as severe constipation, abdominal distention, persistent abdominal pain, or vomiting are observed, discontinue administration and take appropriate measures.

Other side effects

The following adverse reactions may occur, so observe closely and if any abnormalities found, discontinue administration or take appropriate measures.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to : medico@zuventus.com Website : https://www.zuventus.com/drug-safety-reporting By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

In clinical studies, QT prolongation has been reported when a single dose of 800 mg of Trelagliptin was administered.

Removal of this drug by hemodialysis is not considered useful.

5.1 Mechanism of action

Trelagliptin inhibits the activity of Dipeptidyl Peptidase-4 (DPP-4), which inactivates glucagon-like peptide-1 (GLP-1), which is secreted into the bloodstream from the intestinal tract in response to oral ingestion of a meal, thereby increasing the blood concentration of GLP-1 and promoting insulin secretion from the pancreas in a glucose concentration-dependent manner.

5.2 Pharmacodynamic properties

Inhibitory effects on DPP-4 Trelagliptin selectively inhibited DPP-4 activity in human plasma (IC50 value : 4.2 nmol/L) (in vitro). In order to compare the DPP-4 inhibitory activity of Trelagliptin and Alogliptin, the IC50 were compared under the same conditions (in vitro) and were found to be 1.3 and 5.3 nmol/L respectively. In a placebo-controlled, double-blind, parallel-group comparative study in which 100 mg of Trelagliptin was orally administered once weekly (before breakfast) for 12 weeks to type 2 diabetes patients with insufficient blood sugar control despite dietary and exercise therapy, the mean DPP-4 activity inhibition rate 7 days after the final administration was 77.4% in the 100 mg Trelagliptin. The plasma Trelagliptin concentration estimated to yield 50% inhibition of plasma DPP-4 activity (IC50) was 1.43 ng/mL (4.02 nmol/L).

Increased concentration of active GLP-1

In a placebo-controlled, double-blind, parallel-group comparative study in which 100 mg of Trelagliptin was orally administered (once a week before breakfast) for 12 weeks to type 2 diabetes patients with insufficient blood sugar control despite diet and exercise therapy, active GLP-1 concentrations in a meal loading test 12 weeks after administration were significantly increased compared to the placebo group.

Improvement of glucose tolerance

Trelagliptin was orally administered once to an overnight fasted obese type 2 diabetes model (Wistar fatty rats) and a non-obese type 2 diabetes model (N-STZ-1.5 rats) and a glucose tolerance test in which glucose was orally administered one hour after administration showed that Trelagliptin improved glucose tolerance.

Phase III clinical trial in India

A trial was conducted on Trelaglip to compare the efficacy and safety of once-weekly Trelaglip (Trelagliptin 100 mg) with twice-daily Vildagliptin 50 mg in patients with type 2 diabetes. Non-inferiority was assessed based on the difference in mean change from baseline in HbA1c at the end of the treatment period. The mean change in HbA1c (± SD) was 0.89 (± 1.46) % in the Trelagliptin group and 0.97 (± 1.42) % in the Vildagliptin group. The incidence of adverse effects was lower in the Trelagliptin group (6.67%) compared to the Vildagliptin group (9.17%), with no cases of hypoglycemia reported in either group. Trelaglip was found to be having better safety and similar efficacy to that of Vildagliptin. 

5.3 Pharmacokinetic properties

Single dose study

The pharmacokinetic parameters of Trelagliptin in plasma after a single dose of Trelaglip 100 were as follows. The average plasma concentration after 72 hours of administration was 17.233 ng/mL.

In an internationally conducted study, a single oral dose of 100 mg of Trelagliptin was administered orally 30 minutes before the start of breakfast in healthy adults, the changes in plasma concentrations and pharmacokinetic parameters were as follows and the average plasma concentration after 168 hours of administration was 2.1 ng/mL.

Mean value (standard deviation)

Repeated administration

In healthy adults (9 cases), a single oral dose of 100 mg of Trelagliptin was administered once daily 30 minutes before breakfast and three days later, it was administered once daily for 11 days 30 minutes before breakfast. The average values (standard deviation) of Cmax and AUC0-inf on the first day of administration were 544.3 (122.0) ng/mL and 5572.3 (793.2) ng·h/mL, respectively, while the average th values (standard deviation) of Cmax and AUC0-tau on the 14 day of administration were 602.6 (149.5) ng/mL and 5292.9 (613.8) ng·h/mL respectively.

The steady state was achieved after 12-week treatment with once-weekly Trelagliptin. The plasma concentration of unchanged Trelagliptin was 6.062 ng/mL at 7 days after the last dose. No drug accumulation was observed with repeated dosing of Trelagliptin.

Absorption

When 100 mg of Trelagliptin was orally administered to healthy adults (12 subjects) 30 minutes after the start of breakfast, the Cmax and AUC(0-inf) increased by 16.8% and decreased by 2.5% respectively, compared to when it was administered without breakfast.

Distribution

14 [ C] When Trelagliptin was added to human plasma at a concentration of 0.1 to 10 μg/mL, the protein binding rate was 22.1 to 27.6% (in vitro).

Metabolism

Trelagliptin is metabolized to the active metabolite MI, mainly via N -demethylation by CYP2D6. The amount of the active metabolite MI in human plasma was less than 1% of the amount of unchanged Trelagliptin. Trelagliptin exhibited weak inhibitory effects on CYP3A4/5 (direct inhibitory effect IC50 value : 100 μmol/L or more, metabolic inhibitory effect IC50 values : 12 μmol/L (midazolam 1'-hydroxylation activity) and 28 μmol/L (testosterone 6β-hydroxylation activity)), but did not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 and did not induce CYP1A2, CYP2B6 or CYP3A4 (in vitro).

Excretion

When a single oral dose of 100 mg of Trelagliptin was administered to 12 healthy adults during breakfast fasting or 30 minutes after the start of breakfast, the cumulative urinary excretion rates of Trelagliptin up to 168 hours were 76.6% and 76.1% respectively. Trelagliptin is a substrate of P-glycoprotein and slightly inhibited the transport of Digoxin through P-glycoprotein (IC50 value : ≥ 500 μmol/L). In addition, Trelagliptin showed an inhibitory effect on the uptake of Metformin, which is a substrate of the organic cation transporter OCT2 (IC50 value : 55.9 μmol/L) (in vitro).

Patients with impaired renal function

When a single dose of 50 mg of Trelagliptin was orally administered to patients with renal impairment and healthy adults, the AUC(0-tlqc) and Cmax were increased by 55.7% and 36.3% in patients with mild renal impairment (Ccr = 50 - 80 mL/min, 6 cases), 105.7% and 12.9% in patients with moderate renal impairment (Ccr = 30 - 50 mL/min, 6 cases), 201.4% and 9.1% in patients with severe renal impairment (Ccr < 30 mL/min, 6 cases), and 268.1% and 13.8% in patients with end-stage renal failure (6 cases) respectively, compared with healthy adults matched for age, sex, race and weight.

In addition, 9.2% of the administered dose of Trelagliptin was removed by 4 hours of hemodialysis.

Patients with impaired hepatic function

When a single dose of 50 mg of Trelagliptin was orally administered to patients with moderate hepatic impairment (Child-Pugh score 7-9, 8 cases) and healthy adults (8 cases), the AUC(0-inf) and Cmax were increased by 5.1% and decreased by 4.3% respectively, compared to healthy adults matched for age, sex, race, smoking history and weight.

6.1 Animal toxicology or pharmacology

Toxicity studies of Trelagliptin included single-dose toxicity, repeated-dose toxicity, genotoxicity, carcinogenicity, reproductive and developmental toxicity and other toxicity studies (phototoxicity study, skin toxicity studies).

Single dose toxicity

A single-dose toxicity study of Trelaglip was conducted in male and female Mus musculus mice and Wistar rats, with oral doses of 0 (vehicle), 10, 25, 50, 100 or 200 mg/kg body weight. No mortality, biochemical or hematological changes or signs of acute systemic toxicity were observed at the highest dose of 200 mg/kg. An international single-dose toxicity study was performed in male and female Sprague-Dawley (SD) rats with oral doses of 0 (vehicle), 600 or 2000 mg/kg body weight. Salivation was observed immediately after administration and no deaths occurred. The approximate lethal dose of Trelagliptin was determined to be > 2000 mg/kg. In a dose escalation study, escalating single oral doses of Trelagliptin 0 (control), 30, 300 and 2000 mg/kg were administered to male and female beagle dogs. Vomiting, erythema and swelling of the auricle and face, salivation and increases in aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase and alkaline phosphatase (ALP) were observed in animals receiving ≥ 300 mg/kg and a decrease in locomotor activity, lateral position and decreased body temperature were observed in animals receiving 2000 mg/kg but no deaths were observed. Thus, the approximate lethal dose was determined to be > 2000 mg/kg.

Repeated dose toxicity

Four-week repeated oral dose toxicity study in mice and rabbits

A four-week repeated-dose toxicity study of Trelaglip was conducted in male and female Swiss albinomice (0, 20.41, 102.9, 204.1 mg/kg) and New Zealand rabbits (0, 5.2, 25.7, 51.46 mg/kg), followed by a recovery phase in the vehicle and high-dose groups to evaluate toxicity reversibility after a two-week recovery period. No adverse effects were observed on growth, body weight or feed consumption in the test animals. While slight elevations in neutrophil and monocyte levels were observed, these remained within the normal laboratory range. Hematological and biochemical parameters showed no signifcant deviations from controls. Any external or internal pathological ndings were not observed after necropsy and gross examination.

Four-week repeated oral dose toxicity study in rats

Male and female SD rats orally received daily Trelagliptin at 0 (vehicle-0.5% Methylcellulose solution), 50, 250 or 1000 mg/kg/day for 4 weeks. In addition, a recovery study was conducted in the 0 and 1000 mg/kg/day groups to assess the reversibility of toxicity after a 2-week recovery period. Stained perianogenital fur; increase in neutrophil, lymphocyte and white blood cell counts; increase in inorganic phosphorus, total cholesterol and ALP; decrease in sodium, chloride, albumin and total protein : a trend towards increased urine protein; an increase in liver weight; a decrease in thymus weight; centrilobular hepatocellular hypertrophy and a decrease in lymphocytes in the thymic cortex were observed in the 1000 mg/kg/day group.

All findings were reversible after the 2-week recovery period.

As described above, stained fur associated with worsening of clinical signs and increased white blood cell count suggestive of inflammation were observed in the 1000 mg/kg/day group and therefore the no observed adverse effect level (NOAEL) was determined to be 250 mg/kg/day.

Genotoxicity Bacterial reverse mutation assay, gene mutation assay with mouse lymphoma (L5178Y/TK+/-) and mouse bone marrow micronucleus assay were conducted in a study. The result showed Trelagliptin to have no genotoxicity. Carcinogenecity Carcinogenicity dose-range finding study Male and female ICR mice orally received daily Trelagliptin at 0 (vehicle-0.5% Methylcellulose solution), 100, 300, 1000 or 2000 mg/kg/day for 1 week. Death occurred in 1 of 10 females in the 100 mg/kg/day group, 1 of 10 females in the 300 mg/kg/day group, 2 of 10 males and 1 of 10 females in the 1000 mg/kg/day group and 1 of 10 males and 1 of 10 females in the 2000 mg/kg/day group. In addition, among animals evaluated for toxicokinetics, 1 of 21 females died in the 1000 mg/kg/day group and 1 of 21 males and 7 of 21 females died in the 2000 mg/kg/day group. The deaths observed in the 2000 mg/kg/day group were considered attributable to Trelagliptin because of the high incidence of death. Findings in the 2000 mg/kg/day group were a decrease in locomotor activity, convulsion, abdominal distension, unkept fur, ataxia, decreased food consumption, decrease in lymphocyte and white blood cell counts and increase in ALP, ALT, AST and urea nitrogen.

Separately, an additional group of male and female ICR mice orally received daily 1000 mg/kg/day of Trelagliptin for 1 week.

A decrease in locomotor activity, prone position, bradypnea and hypothermia were observed after the first dose, but not after the second or subsequent doses. In addition, deaths or effects on body weight associated with Trelagliptin were not noted.

Furthermore, male and female ICR mice orally received daily Trelagliptin at 0 (vehicle-0.5% Methylcellulose solution), 150, 300, 600 or 1200 mg/kg/day for 13 weeks. No deaths associated with Trelagliptin occurred, nor were any toxicological findings observed in clinical signs, body weight, food consumption, ophthalmology, haematology, clinical chemistry, organ weights, necropsy or histopathology.

Trelaglip (Trelagliptin Succinate) is a pharmaceutical drug used for the treatment of type 2 diabetes (diabetes mellitus).

Chemical name : R 22-({6-[(3 )-3-Aminopiperidin-1-yl] H -3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2 ) -yl} methyl) -4-fluorobenzonitrile monosuccinate

Molecular formula : C₁₈H₂₀FN₅O₂.C₄H₆O₄

Molecular weight : 475.47 g/mol

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

Refer on the pack.

8.3 Packaging information

A wallet pack of 4 tablets.

8.4 Storage and handling instructions

Store below 30°C. Protect from moisture.

Keep out of reach of children

Instruct patients on the following points when administering the drug.

• This drug should be taken once a week and should be taken on the same day of the week.
• If you forget to take this drug, take only the prescribed dose when you notice it and then take it on the predetermined day of the week.
• Since there is a risk of hypoglycemia, patients should be fully informed of the symptoms of hypoglycemia and how to deal with them and caution should be called to them before using this drug.
• Patients should be instructed to seek immediate medical attention if they experience initial symptoms such as persistent severe abdominal pain or vomiting, as acute pancreatitis may occur.
• Since this drug is to be administered orally once a week and the effect continues even after discontinuation, pay close attention to blood glucose levels and the occurrence of side effects. In addition, when using other diabetes drugs after discontinuing administration of this drug, consider the timing and dose of administration based on the status of blood glucose management.
• During the course of administration of the drug, blood glucose should be tested regularly, the progress should be monitored thoroughly and if the effect of the drug is insufficient after 2 to 3 months, a change to a more appropriate treatment should be considered.
• Caution should be exercised when administering to patients who are engaged in high-altitude work, driving a car etc., as it may cause hypoglycemic symptoms.

06 January 2025

Trelagliptin Tablets 25 mg / 50 mg / 100 mg

Trelaglip 25

Each film coated tablet contains :

Trelagliptin Succinate

equivalent to Trelagliptin 25 mg

Excipients q.s.

Colours : Ferric Oxide USP NF (Yellow)and Titanium Dioxide IP

Trelaglip 50

Each film coated tablet contains :

Trelagliptin Succinate equivalent to Trelagliptin 50 mg

Excipients q.s.

Colours : Ferric Oxide USP NF (Yellow) and Titanium Dioxide IP

Trelaglip 100

Each film coated tablet contains :

Trelagliptin Succinate

equivalent to Trelagliptin 100 mg

Excipients q.s.

Colours : Ferric Oxide USP NF (Yellow) and Titanium Dioxide IP

Tablet, 25 mg / 50 mg / 100 mg

4.1 Therapeutic indications

For the treatment of type 2 diabetes mellitus.

4.2 Posology and method of administration

The usual adult dosage is 100 mg of Trelaglip administered orally once a week.

Patients with moderate or severe renal dysfunction

The blood concentration of this drug increases due to delayed excretion; therefore, the dose should be reduced according to the degree of renal function, referring to the table below.

Dosage for patients with moderate or severe renal impairment

¹ Conversion value equivalent to CCR (age 60 years, weight 65 kg).

² For patients with end-stage renal disease, the time relationship between administration of this drug and haemodialysis does not matter.

Elderly

Carefully administer the drug while paying attention to the occurrence of side effects and carefully observing the course. In general, renal function is often impaired.

Method of administration

• Trelaglip is to be taken once a week and should be taken on the same day of the week.
• If you forget to take this drug, take only the prescribed dose at the time you notice it and then take it on a predetermined day of the week.

4.3 Contraindications

• Patients with severe ketosis, diabetic coma or precoma, Type 1 diabetes.
• Patients with severe infections, those undergoing surgery or those with severe trauma.
• Patients with a history of hypersensitivity to the ingredients of this drug.

4.4 Special warnings and precautions for use

• This drug may cause hypoglycemia. When using this drug, patients should be fully informed of the symptoms of hypoglycemia and how to deal with them and caution should be exercised.
• Acute pancreatitis may occur, so instruct patients to consult a doctor immediately if they experience initial symptoms such as persistent severe abdominal pain or vomiting.
• This drug is orally administered once a week and its action continues even after discontinuation of administration. Therefore, pay close attention to the blood glucose level and the occurrence of side effects. In addition, when using other diabetic drugs after discontinuation of this drug, the start time and dose of the drug should be examined based on the blood glucose control status.
• During administration of this drug, blood glucose levels should be checked regularly and the patient's condition should be closely monitored. If the patient shows no satisfactory response after 2 to 3 months of administration of this drug, consideration should be given to changing to a more appropriate treatment.
• Trelaglip and GLP-1 receptor agonists have a blood glucose lowering effect via the GLP-1 receptor. There are no clinical trial results when the two drugs are used together and their efficacy and safety have not been confirmed.

4.5 Drug Interactions

• When Trelagliptin was used in combination with Glimepiride or Metformin, no clear effect was observed on the pharmacokinetics of Trelagliptin and these concomitant drugs.
• When Trelagliptin was used in combination with Caffeine, Tolbutamide, Dextromethorphan or Midazolam, no clear effect was observed on the pharmacokinetics of these concomitant drugs.

4.6 Use in special populations (such as pregnant women, lactating women, paediatric patients, geriatric patients etc.)

Patients with complications / medical history

Patients or conditions at risk of hypoglycemia :

• Pituitary or adrenal insufficiency.
• Malnutrition, starvation, irregular food intake, insufficient food intake or debilitation.
• Intense muscle exercise.
• People who consume excessive amounts of alcohol. Patients with a history of abdominal surgery or intestinal obstruction may cause intestinal obstruction.

Patients with moderate or severe renal dysfunction

Reduce the dose and carefully observe the patient's condition. The blood concentration of this drug increases due to delayed excretion depending on the degree of renal function.

Pregnant women

Pregnant women or women who may be pregnant should only be administered if the therapeutic benefits are judged to outweigh the risks. Placental crossing of drug has been reported in animal studies (rats).

Lactating women

Consider whether to continue or discontinue breast-feeding, taking into account the therapeutic benefits and the benefits of breast-feeding. Animal studies (rats) have shown that the drug is excreted in breast milk.

Pediatric population

No clinical trials have been conducted in children.

Elderly

Pay attention to the occurrence of side effects and administer with caution while closely monitoring the progress. Renal function is generally reduced in many cases.

4.7 Effects on ability to drive and use machines

Hypoglycemic symptoms may occur, so caution should be exercised when administering to patients engaged in activities such as working at heights or driving a car.

4.8 Undesirable effects

Serious side effects

Since the following side effects may appear, observe them thoroughly and if any abnormalities are found, take appropriate measures such as discontinuing administration.

Hypoglycemia (Less than 0.1 - 5%)

Hypoglycemia may occur. When used concomitantly with sulfonylurea agents or insulin preparations, severe hypoglycemic symptoms, including loss of consciousness, have been reported. If hypoglycemic symptoms are observed, appropriate measures should be taken, such as having the patient ingest foods containing carbohydrates. However, glucose should be administered when used concomitantly with an α-glucosidase inhibitor.

Pemphigoid (incidence unknown)

If blisters or erosions appear, consult with a dermatologist and take appropriate measures, such as discontinuing administration. Acute pancreatitis (incidence unknown) If any abnormalities such as persistent severe abdominal pain or vomiting are observed, discontinue administration and take appropriate measures.

Bowel obstruction (incidence unknown)

If any abnormalities such as severe constipation, abdominal distention, persistent abdominal pain, or vomiting are observed, discontinue administration and take appropriate measures.

Other side effects

The following adverse reactions may occur, so observe closely and if any abnormalities found, discontinue administration or take appropriate measures.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to : medico@zuventus.com Website : https://www.zuventus.com/drug-safety-reporting By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

In clinical studies, QT prolongation has been reported when a single dose of 800 mg of Trelagliptin was administered.

Removal of this drug by hemodialysis is not considered useful.

5.1 Mechanism of action

Trelagliptin inhibits the activity of Dipeptidyl Peptidase-4 (DPP-4), which inactivates glucagon-like peptide-1 (GLP-1), which is secreted into the bloodstream from the intestinal tract in response to oral ingestion of a meal, thereby increasing the blood concentration of GLP-1 and promoting insulin secretion from the pancreas in a glucose concentration-dependent manner.

5.2 Pharmacodynamic properties

Inhibitory effects on DPP-4 Trelagliptin selectively inhibited DPP-4 activity in human plasma (IC50 value : 4.2 nmol/L) (in vitro). In order to compare the DPP-4 inhibitory activity of Trelagliptin and Alogliptin, the IC50 were compared under the same conditions (in vitro) and were found to be 1.3 and 5.3 nmol/L respectively. In a placebo-controlled, double-blind, parallel-group comparative study in which 100 mg of Trelagliptin was orally administered once weekly (before breakfast) for 12 weeks to type 2 diabetes patients with insufficient blood sugar control despite dietary and exercise therapy, the mean DPP-4 activity inhibition rate 7 days after the final administration was 77.4% in the 100 mg Trelagliptin. The plasma Trelagliptin concentration estimated to yield 50% inhibition of plasma DPP-4 activity (IC50) was 1.43 ng/mL (4.02 nmol/L).

Increased concentration of active GLP-1

In a placebo-controlled, double-blind, parallel-group comparative study in which 100 mg of Trelagliptin was orally administered (once a week before breakfast) for 12 weeks to type 2 diabetes patients with insufficient blood sugar control despite diet and exercise therapy, active GLP-1 concentrations in a meal loading test 12 weeks after administration were significantly increased compared to the placebo group.

Improvement of glucose tolerance

Trelagliptin was orally administered once to an overnight fasted obese type 2 diabetes model (Wistar fatty rats) and a non-obese type 2 diabetes model (N-STZ-1.5 rats) and a glucose tolerance test in which glucose was orally administered one hour after administration showed that Trelagliptin improved glucose tolerance.

Phase III clinical trial in India

A trial was conducted on Trelaglip to compare the efficacy and safety of once-weekly Trelaglip (Trelagliptin 100 mg) with twice-daily Vildagliptin 50 mg in patients with type 2 diabetes. Non-inferiority was assessed based on the difference in mean change from baseline in HbA1c at the end of the treatment period. The mean change in HbA1c (± SD) was 0.89 (± 1.46) % in the Trelagliptin group and 0.97 (± 1.42) % in the Vildagliptin group. The incidence of adverse effects was lower in the Trelagliptin group (6.67%) compared to the Vildagliptin group (9.17%), with no cases of hypoglycemia reported in either group. Trelaglip was found to be having better safety and similar efficacy to that of Vildagliptin. 

5.3 Pharmacokinetic properties

Single dose study

The pharmacokinetic parameters of Trelagliptin in plasma after a single dose of Trelaglip 100 were as follows. The average plasma concentration after 72 hours of administration was 17.233 ng/mL.

In an internationally conducted study, a single oral dose of 100 mg of Trelagliptin was administered orally 30 minutes before the start of breakfast in healthy adults, the changes in plasma concentrations and pharmacokinetic parameters were as follows and the average plasma concentration after 168 hours of administration was 2.1 ng/mL.

Mean value (standard deviation)

Repeated administration

In healthy adults (9 cases), a single oral dose of 100 mg of Trelagliptin was administered once daily 30 minutes before breakfast and three days later, it was administered once daily for 11 days 30 minutes before breakfast. The average values (standard deviation) of Cmax and AUC0-inf on the first day of administration were 544.3 (122.0) ng/mL and 5572.3 (793.2) ng·h/mL, respectively, while the average th values (standard deviation) of Cmax and AUC0-tau on the 14 day of administration were 602.6 (149.5) ng/mL and 5292.9 (613.8) ng·h/mL respectively.

The steady state was achieved after 12-week treatment with once-weekly Trelagliptin. The plasma concentration of unchanged Trelagliptin was 6.062 ng/mL at 7 days after the last dose. No drug accumulation was observed with repeated dosing of Trelagliptin.

Absorption

When 100 mg of Trelagliptin was orally administered to healthy adults (12 subjects) 30 minutes after the start of breakfast, the Cmax and AUC(0-inf) increased by 16.8% and decreased by 2.5% respectively, compared to when it was administered without breakfast.

Distribution

14 [ C] When Trelagliptin was added to human plasma at a concentration of 0.1 to 10 μg/mL, the protein binding rate was 22.1 to 27.6% (in vitro).

Metabolism

Trelagliptin is metabolized to the active metabolite MI, mainly via N -demethylation by CYP2D6. The amount of the active metabolite MI in human plasma was less than 1% of the amount of unchanged Trelagliptin. Trelagliptin exhibited weak inhibitory effects on CYP3A4/5 (direct inhibitory effect IC50 value : 100 μmol/L or more, metabolic inhibitory effect IC50 values : 12 μmol/L (midazolam 1'-hydroxylation activity) and 28 μmol/L (testosterone 6β-hydroxylation activity)), but did not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 and did not induce CYP1A2, CYP2B6 or CYP3A4 (in vitro).

Excretion

When a single oral dose of 100 mg of Trelagliptin was administered to 12 healthy adults during breakfast fasting or 30 minutes after the start of breakfast, the cumulative urinary excretion rates of Trelagliptin up to 168 hours were 76.6% and 76.1% respectively. Trelagliptin is a substrate of P-glycoprotein and slightly inhibited the transport of Digoxin through P-glycoprotein (IC50 value : ≥ 500 μmol/L). In addition, Trelagliptin showed an inhibitory effect on the uptake of Metformin, which is a substrate of the organic cation transporter OCT2 (IC50 value : 55.9 μmol/L) (in vitro).

Patients with impaired renal function

When a single dose of 50 mg of Trelagliptin was orally administered to patients with renal impairment and healthy adults, the AUC(0-tlqc) and Cmax were increased by 55.7% and 36.3% in patients with mild renal impairment (Ccr = 50 - 80 mL/min, 6 cases), 105.7% and 12.9% in patients with moderate renal impairment (Ccr = 30 - 50 mL/min, 6 cases), 201.4% and 9.1% in patients with severe renal impairment (Ccr < 30 mL/min, 6 cases), and 268.1% and 13.8% in patients with end-stage renal failure (6 cases) respectively, compared with healthy adults matched for age, sex, race and weight.

In addition, 9.2% of the administered dose of Trelagliptin was removed by 4 hours of hemodialysis.

Patients with impaired hepatic function

When a single dose of 50 mg of Trelagliptin was orally administered to patients with moderate hepatic impairment (Child-Pugh score 7-9, 8 cases) and healthy adults (8 cases), the AUC(0-inf) and Cmax were increased by 5.1% and decreased by 4.3% respectively, compared to healthy adults matched for age, sex, race, smoking history and weight.

6.1 Animal toxicology or pharmacology

Toxicity studies of Trelagliptin included single-dose toxicity, repeated-dose toxicity, genotoxicity, carcinogenicity, reproductive and developmental toxicity and other toxicity studies (phototoxicity study, skin toxicity studies).

Single dose toxicity

A single-dose toxicity study of Trelaglip was conducted in male and female Mus musculus mice and Wistar rats, with oral doses of 0 (vehicle), 10, 25, 50, 100 or 200 mg/kg body weight. No mortality, biochemical or hematological changes or signs of acute systemic toxicity were observed at the highest dose of 200 mg/kg. An international single-dose toxicity study was performed in male and female Sprague-Dawley (SD) rats with oral doses of 0 (vehicle), 600 or 2000 mg/kg body weight. Salivation was observed immediately after administration and no deaths occurred. The approximate lethal dose of Trelagliptin was determined to be > 2000 mg/kg. In a dose escalation study, escalating single oral doses of Trelagliptin 0 (control), 30, 300 and 2000 mg/kg were administered to male and female beagle dogs. Vomiting, erythema and swelling of the auricle and face, salivation and increases in aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase and alkaline phosphatase (ALP) were observed in animals receiving ≥ 300 mg/kg and a decrease in locomotor activity, lateral position and decreased body temperature were observed in animals receiving 2000 mg/kg but no deaths were observed. Thus, the approximate lethal dose was determined to be > 2000 mg/kg.

Repeated dose toxicity

Four-week repeated oral dose toxicity study in mice and rabbits

A four-week repeated-dose toxicity study of Trelaglip was conducted in male and female Swiss albinomice (0, 20.41, 102.9, 204.1 mg/kg) and New Zealand rabbits (0, 5.2, 25.7, 51.46 mg/kg), followed by a recovery phase in the vehicle and high-dose groups to evaluate toxicity reversibility after a two-week recovery period. No adverse effects were observed on growth, body weight or feed consumption in the test animals. While slight elevations in neutrophil and monocyte levels were observed, these remained within the normal laboratory range. Hematological and biochemical parameters showed no signifcant deviations from controls. Any external or internal pathological ndings were not observed after necropsy and gross examination.

Four-week repeated oral dose toxicity study in rats

Male and female SD rats orally received daily Trelagliptin at 0 (vehicle-0.5% Methylcellulose solution), 50, 250 or 1000 mg/kg/day for 4 weeks. In addition, a recovery study was conducted in the 0 and 1000 mg/kg/day groups to assess the reversibility of toxicity after a 2-week recovery period. Stained perianogenital fur; increase in neutrophil, lymphocyte and white blood cell counts; increase in inorganic phosphorus, total cholesterol and ALP; decrease in sodium, chloride, albumin and total protein : a trend towards increased urine protein; an increase in liver weight; a decrease in thymus weight; centrilobular hepatocellular hypertrophy and a decrease in lymphocytes in the thymic cortex were observed in the 1000 mg/kg/day group.

All findings were reversible after the 2-week recovery period.

As described above, stained fur associated with worsening of clinical signs and increased white blood cell count suggestive of inflammation were observed in the 1000 mg/kg/day group and therefore the no observed adverse effect level (NOAEL) was determined to be 250 mg/kg/day.

Genotoxicity Bacterial reverse mutation assay, gene mutation assay with mouse lymphoma (L5178Y/TK+/-) and mouse bone marrow micronucleus assay were conducted in a study. The result showed Trelagliptin to have no genotoxicity. Carcinogenecity Carcinogenicity dose-range finding study Male and female ICR mice orally received daily Trelagliptin at 0 (vehicle-0.5% Methylcellulose solution), 100, 300, 1000 or 2000 mg/kg/day for 1 week. Death occurred in 1 of 10 females in the 100 mg/kg/day group, 1 of 10 females in the 300 mg/kg/day group, 2 of 10 males and 1 of 10 females in the 1000 mg/kg/day group and 1 of 10 males and 1 of 10 females in the 2000 mg/kg/day group. In addition, among animals evaluated for toxicokinetics, 1 of 21 females died in the 1000 mg/kg/day group and 1 of 21 males and 7 of 21 females died in the 2000 mg/kg/day group. The deaths observed in the 2000 mg/kg/day group were considered attributable to Trelagliptin because of the high incidence of death. Findings in the 2000 mg/kg/day group were a decrease in locomotor activity, convulsion, abdominal distension, unkept fur, ataxia, decreased food consumption, decrease in lymphocyte and white blood cell counts and increase in ALP, ALT, AST and urea nitrogen.

Separately, an additional group of male and female ICR mice orally received daily 1000 mg/kg/day of Trelagliptin for 1 week.

A decrease in locomotor activity, prone position, bradypnea and hypothermia were observed after the first dose, but not after the second or subsequent doses. In addition, deaths or effects on body weight associated with Trelagliptin were not noted.

Furthermore, male and female ICR mice orally received daily Trelagliptin at 0 (vehicle-0.5% Methylcellulose solution), 150, 300, 600 or 1200 mg/kg/day for 13 weeks. No deaths associated with Trelagliptin occurred, nor were any toxicological findings observed in clinical signs, body weight, food consumption, ophthalmology, haematology, clinical chemistry, organ weights, necropsy or histopathology.

Trelaglip (Trelagliptin Succinate) is a pharmaceutical drug used for the treatment of type 2 diabetes (diabetes mellitus).

Chemical name : R 22-({6-[(3 )-3-Aminopiperidin-1-yl] H -3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2 ) -yl} methyl) -4-fluorobenzonitrile monosuccinate

Molecular formula : C₁₈H₂₀FN₅O₂.C₄H₆O₄

Molecular weight : 475.47 g/mol

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

Refer on the pack.

8.3 Packaging information

A wallet pack of 4 tablets.

8.4 Storage and handling instructions

Store below 30°C. Protect from moisture.

Keep out of reach of children

Instruct patients on the following points when administering the drug.

• This drug should be taken once a week and should be taken on the same day of the week.
• If you forget to take this drug, take only the prescribed dose when you notice it and then take it on the predetermined day of the week.
• Since there is a risk of hypoglycemia, patients should be fully informed of the symptoms of hypoglycemia and how to deal with them and caution should be called to them before using this drug.
• Patients should be instructed to seek immediate medical attention if they experience initial symptoms such as persistent severe abdominal pain or vomiting, as acute pancreatitis may occur.
• Since this drug is to be administered orally once a week and the effect continues even after discontinuation, pay close attention to blood glucose levels and the occurrence of side effects. In addition, when using other diabetes drugs after discontinuing administration of this drug, consider the timing and dose of administration based on the status of blood glucose management.
• During the course of administration of the drug, blood glucose should be tested regularly, the progress should be monitored thoroughly and if the effect of the drug is insufficient after 2 to 3 months, a change to a more appropriate treatment should be considered.
• Caution should be exercised when administering to patients who are engaged in high-altitude work, driving a car etc., as it may cause hypoglycemic symptoms.

06 January 2025

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
• If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.

What is in this leaflet

1. What Trelaglip Tablet is and what it is used for
2. What you need to know before you take Trelaglip Tablet
3. How to take Trelaglip Tablet
4. Possible side effects
5. How to store Trelaglip Tablet
6. Contents of the pack and other information

Trelagliptin Tablets 25 mg / 50 mg / 100 mg

Trelaglip 25

Each film coated tablet contains :

Trelagliptin Succinate

equivalent to Trelagliptin 25 mg

Excipients q.s.

Colours : Ferric Oxide USP NF (Yellow)and Titanium Dioxide IP

Trelaglip 50

Each film coated tablet contains :

Trelagliptin Succinate equivalent to Trelagliptin 50 mg

Excipients q.s.

Colours : Ferric Oxide USP NF (Yellow) and Titanium Dioxide IP

Trelaglip 100

Each film coated tablet contains :

Trelagliptin Succinate

equivalent to Trelagliptin 100 mg

Excipients q.s.

Colours : Ferric Oxide USP NF (Yellow) and Titanium Dioxide IP

Tablet, 25 mg / 50 mg / 100 mg

4.1 Therapeutic indications

For the treatment of type 2 diabetes mellitus.

4.2 Posology and method of administration

The usual adult dosage is 100 mg of Trelaglip administered orally once a week.

Patients with moderate or severe renal dysfunction

The blood concentration of this drug increases due to delayed excretion; therefore, the dose should be reduced according to the degree of renal function, referring to the table below.

Dosage for patients with moderate or severe renal impairment

¹ Conversion value equivalent to CCR (age 60 years, weight 65 kg).

² For patients with end-stage renal disease, the time relationship between administration of this drug and haemodialysis does not matter.

Elderly

Carefully administer the drug while paying attention to the occurrence of side effects and carefully observing the course. In general, renal function is often impaired.

Method of administration

• Trelaglip is to be taken once a week and should be taken on the same day of the week.
• If you forget to take this drug, take only the prescribed dose at the time you notice it and then take it on a predetermined day of the week.

4.3 Contraindications

• Patients with severe ketosis, diabetic coma or precoma, Type 1 diabetes.
• Patients with severe infections, those undergoing surgery or those with severe trauma.
• Patients with a history of hypersensitivity to the ingredients of this drug.

4.4 Special warnings and precautions for use

• This drug may cause hypoglycemia. When using this drug, patients should be fully informed of the symptoms of hypoglycemia and how to deal with them and caution should be exercised.
• Acute pancreatitis may occur, so instruct patients to consult a doctor immediately if they experience initial symptoms such as persistent severe abdominal pain or vomiting.
• This drug is orally administered once a week and its action continues even after discontinuation of administration. Therefore, pay close attention to the blood glucose level and the occurrence of side effects. In addition, when using other diabetic drugs after discontinuation of this drug, the start time and dose of the drug should be examined based on the blood glucose control status.
• During administration of this drug, blood glucose levels should be checked regularly and the patient's condition should be closely monitored. If the patient shows no satisfactory response after 2 to 3 months of administration of this drug, consideration should be given to changing to a more appropriate treatment.
• Trelaglip and GLP-1 receptor agonists have a blood glucose lowering effect via the GLP-1 receptor. There are no clinical trial results when the two drugs are used together and their efficacy and safety have not been confirmed.

4.5 Drug Interactions

• When Trelagliptin was used in combination with Glimepiride or Metformin, no clear effect was observed on the pharmacokinetics of Trelagliptin and these concomitant drugs.
• When Trelagliptin was used in combination with Caffeine, Tolbutamide, Dextromethorphan or Midazolam, no clear effect was observed on the pharmacokinetics of these concomitant drugs.

4.6 Use in special populations (such as pregnant women, lactating women, paediatric patients, geriatric patients etc.)

Patients with complications / medical history

Patients or conditions at risk of hypoglycemia :

• Pituitary or adrenal insufficiency.
• Malnutrition, starvation, irregular food intake, insufficient food intake or debilitation.
• Intense muscle exercise.
• People who consume excessive amounts of alcohol. Patients with a history of abdominal surgery or intestinal obstruction may cause intestinal obstruction.

Patients with moderate or severe renal dysfunction

Reduce the dose and carefully observe the patient's condition. The blood concentration of this drug increases due to delayed excretion depending on the degree of renal function.

Pregnant women

Pregnant women or women who may be pregnant should only be administered if the therapeutic benefits are judged to outweigh the risks. Placental crossing of drug has been reported in animal studies (rats).

Lactating women

Consider whether to continue or discontinue breast-feeding, taking into account the therapeutic benefits and the benefits of breast-feeding. Animal studies (rats) have shown that the drug is excreted in breast milk.

Pediatric population

No clinical trials have been conducted in children.

Elderly

Pay attention to the occurrence of side effects and administer with caution while closely monitoring the progress. Renal function is generally reduced in many cases.

4.7 Effects on ability to drive and use machines

Hypoglycemic symptoms may occur, so caution should be exercised when administering to patients engaged in activities such as working at heights or driving a car.

4.8 Undesirable effects

Serious side effects

Since the following side effects may appear, observe them thoroughly and if any abnormalities are found, take appropriate measures such as discontinuing administration.

Hypoglycemia (Less than 0.1 - 5%)

Hypoglycemia may occur. When used concomitantly with sulfonylurea agents or insulin preparations, severe hypoglycemic symptoms, including loss of consciousness, have been reported. If hypoglycemic symptoms are observed, appropriate measures should be taken, such as having the patient ingest foods containing carbohydrates. However, glucose should be administered when used concomitantly with an α-glucosidase inhibitor.

Pemphigoid (incidence unknown)

If blisters or erosions appear, consult with a dermatologist and take appropriate measures, such as discontinuing administration. Acute pancreatitis (incidence unknown) If any abnormalities such as persistent severe abdominal pain or vomiting are observed, discontinue administration and take appropriate measures.

Bowel obstruction (incidence unknown)

If any abnormalities such as severe constipation, abdominal distention, persistent abdominal pain, or vomiting are observed, discontinue administration and take appropriate measures.

Other side effects

The following adverse reactions may occur, so observe closely and if any abnormalities found, discontinue administration or take appropriate measures.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to : medico@zuventus.com Website : https://www.zuventus.com/drug-safety-reporting By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

In clinical studies, QT prolongation has been reported when a single dose of 800 mg of Trelagliptin was administered.

Removal of this drug by hemodialysis is not considered useful.

5.1 Mechanism of action

Trelagliptin inhibits the activity of Dipeptidyl Peptidase-4 (DPP-4), which inactivates glucagon-like peptide-1 (GLP-1), which is secreted into the bloodstream from the intestinal tract in response to oral ingestion of a meal, thereby increasing the blood concentration of GLP-1 and promoting insulin secretion from the pancreas in a glucose concentration-dependent manner.

5.2 Pharmacodynamic properties

Inhibitory effects on DPP-4 Trelagliptin selectively inhibited DPP-4 activity in human plasma (IC50 value : 4.2 nmol/L) (in vitro). In order to compare the DPP-4 inhibitory activity of Trelagliptin and Alogliptin, the IC50 were compared under the same conditions (in vitro) and were found to be 1.3 and 5.3 nmol/L respectively. In a placebo-controlled, double-blind, parallel-group comparative study in which 100 mg of Trelagliptin was orally administered once weekly (before breakfast) for 12 weeks to type 2 diabetes patients with insufficient blood sugar control despite dietary and exercise therapy, the mean DPP-4 activity inhibition rate 7 days after the final administration was 77.4% in the 100 mg Trelagliptin. The plasma Trelagliptin concentration estimated to yield 50% inhibition of plasma DPP-4 activity (IC50) was 1.43 ng/mL (4.02 nmol/L).

Increased concentration of active GLP-1

In a placebo-controlled, double-blind, parallel-group comparative study in which 100 mg of Trelagliptin was orally administered (once a week before breakfast) for 12 weeks to type 2 diabetes patients with insufficient blood sugar control despite diet and exercise therapy, active GLP-1 concentrations in a meal loading test 12 weeks after administration were significantly increased compared to the placebo group.

Improvement of glucose tolerance

Trelagliptin was orally administered once to an overnight fasted obese type 2 diabetes model (Wistar fatty rats) and a non-obese type 2 diabetes model (N-STZ-1.5 rats) and a glucose tolerance test in which glucose was orally administered one hour after administration showed that Trelagliptin improved glucose tolerance.

Phase III clinical trial in India

A trial was conducted on Trelaglip to compare the efficacy and safety of once-weekly Trelaglip (Trelagliptin 100 mg) with twice-daily Vildagliptin 50 mg in patients with type 2 diabetes. Non-inferiority was assessed based on the difference in mean change from baseline in HbA1c at the end of the treatment period. The mean change in HbA1c (± SD) was 0.89 (± 1.46) % in the Trelagliptin group and 0.97 (± 1.42) % in the Vildagliptin group. The incidence of adverse effects was lower in the Trelagliptin group (6.67%) compared to the Vildagliptin group (9.17%), with no cases of hypoglycemia reported in either group. Trelaglip was found to be having better safety and similar efficacy to that of Vildagliptin. 

5.3 Pharmacokinetic properties

Single dose study

The pharmacokinetic parameters of Trelagliptin in plasma after a single dose of Trelaglip 100 were as follows. The average plasma concentration after 72 hours of administration was 17.233 ng/mL.

In an internationally conducted study, a single oral dose of 100 mg of Trelagliptin was administered orally 30 minutes before the start of breakfast in healthy adults, the changes in plasma concentrations and pharmacokinetic parameters were as follows and the average plasma concentration after 168 hours of administration was 2.1 ng/mL.

Mean value (standard deviation)

Repeated administration

In healthy adults (9 cases), a single oral dose of 100 mg of Trelagliptin was administered once daily 30 minutes before breakfast and three days later, it was administered once daily for 11 days 30 minutes before breakfast. The average values (standard deviation) of Cmax and AUC0-inf on the first day of administration were 544.3 (122.0) ng/mL and 5572.3 (793.2) ng·h/mL, respectively, while the average th values (standard deviation) of Cmax and AUC0-tau on the 14 day of administration were 602.6 (149.5) ng/mL and 5292.9 (613.8) ng·h/mL respectively.

The steady state was achieved after 12-week treatment with once-weekly Trelagliptin. The plasma concentration of unchanged Trelagliptin was 6.062 ng/mL at 7 days after the last dose. No drug accumulation was observed with repeated dosing of Trelagliptin.

Absorption

When 100 mg of Trelagliptin was orally administered to healthy adults (12 subjects) 30 minutes after the start of breakfast, the Cmax and AUC(0-inf) increased by 16.8% and decreased by 2.5% respectively, compared to when it was administered without breakfast.

Distribution

14 [ C] When Trelagliptin was added to human plasma at a concentration of 0.1 to 10 μg/mL, the protein binding rate was 22.1 to 27.6% (in vitro).

Metabolism

Trelagliptin is metabolized to the active metabolite MI, mainly via N -demethylation by CYP2D6. The amount of the active metabolite MI in human plasma was less than 1% of the amount of unchanged Trelagliptin. Trelagliptin exhibited weak inhibitory effects on CYP3A4/5 (direct inhibitory effect IC50 value : 100 μmol/L or more, metabolic inhibitory effect IC50 values : 12 μmol/L (midazolam 1'-hydroxylation activity) and 28 μmol/L (testosterone 6β-hydroxylation activity)), but did not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 and did not induce CYP1A2, CYP2B6 or CYP3A4 (in vitro).

Excretion

When a single oral dose of 100 mg of Trelagliptin was administered to 12 healthy adults during breakfast fasting or 30 minutes after the start of breakfast, the cumulative urinary excretion rates of Trelagliptin up to 168 hours were 76.6% and 76.1% respectively. Trelagliptin is a substrate of P-glycoprotein and slightly inhibited the transport of Digoxin through P-glycoprotein (IC50 value : ≥ 500 μmol/L). In addition, Trelagliptin showed an inhibitory effect on the uptake of Metformin, which is a substrate of the organic cation transporter OCT2 (IC50 value : 55.9 μmol/L) (in vitro).

Patients with impaired renal function

When a single dose of 50 mg of Trelagliptin was orally administered to patients with renal impairment and healthy adults, the AUC(0-tlqc) and Cmax were increased by 55.7% and 36.3% in patients with mild renal impairment (Ccr = 50 - 80 mL/min, 6 cases), 105.7% and 12.9% in patients with moderate renal impairment (Ccr = 30 - 50 mL/min, 6 cases), 201.4% and 9.1% in patients with severe renal impairment (Ccr < 30 mL/min, 6 cases), and 268.1% and 13.8% in patients with end-stage renal failure (6 cases) respectively, compared with healthy adults matched for age, sex, race and weight.

In addition, 9.2% of the administered dose of Trelagliptin was removed by 4 hours of hemodialysis.

Patients with impaired hepatic function

When a single dose of 50 mg of Trelagliptin was orally administered to patients with moderate hepatic impairment (Child-Pugh score 7-9, 8 cases) and healthy adults (8 cases), the AUC(0-inf) and Cmax were increased by 5.1% and decreased by 4.3% respectively, compared to healthy adults matched for age, sex, race, smoking history and weight.

6.1 Animal toxicology or pharmacology

Toxicity studies of Trelagliptin included single-dose toxicity, repeated-dose toxicity, genotoxicity, carcinogenicity, reproductive and developmental toxicity and other toxicity studies (phototoxicity study, skin toxicity studies).

Single dose toxicity

A single-dose toxicity study of Trelaglip was conducted in male and female Mus musculus mice and Wistar rats, with oral doses of 0 (vehicle), 10, 25, 50, 100 or 200 mg/kg body weight. No mortality, biochemical or hematological changes or signs of acute systemic toxicity were observed at the highest dose of 200 mg/kg. An international single-dose toxicity study was performed in male and female Sprague-Dawley (SD) rats with oral doses of 0 (vehicle), 600 or 2000 mg/kg body weight. Salivation was observed immediately after administration and no deaths occurred. The approximate lethal dose of Trelagliptin was determined to be > 2000 mg/kg. In a dose escalation study, escalating single oral doses of Trelagliptin 0 (control), 30, 300 and 2000 mg/kg were administered to male and female beagle dogs. Vomiting, erythema and swelling of the auricle and face, salivation and increases in aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase and alkaline phosphatase (ALP) were observed in animals receiving ≥ 300 mg/kg and a decrease in locomotor activity, lateral position and decreased body temperature were observed in animals receiving 2000 mg/kg but no deaths were observed. Thus, the approximate lethal dose was determined to be > 2000 mg/kg.

Repeated dose toxicity

Four-week repeated oral dose toxicity study in mice and rabbits

A four-week repeated-dose toxicity study of Trelaglip was conducted in male and female Swiss albinomice (0, 20.41, 102.9, 204.1 mg/kg) and New Zealand rabbits (0, 5.2, 25.7, 51.46 mg/kg), followed by a recovery phase in the vehicle and high-dose groups to evaluate toxicity reversibility after a two-week recovery period. No adverse effects were observed on growth, body weight or feed consumption in the test animals. While slight elevations in neutrophil and monocyte levels were observed, these remained within the normal laboratory range. Hematological and biochemical parameters showed no signifcant deviations from controls. Any external or internal pathological ndings were not observed after necropsy and gross examination.

Four-week repeated oral dose toxicity study in rats

Male and female SD rats orally received daily Trelagliptin at 0 (vehicle-0.5% Methylcellulose solution), 50, 250 or 1000 mg/kg/day for 4 weeks. In addition, a recovery study was conducted in the 0 and 1000 mg/kg/day groups to assess the reversibility of toxicity after a 2-week recovery period. Stained perianogenital fur; increase in neutrophil, lymphocyte and white blood cell counts; increase in inorganic phosphorus, total cholesterol and ALP; decrease in sodium, chloride, albumin and total protein : a trend towards increased urine protein; an increase in liver weight; a decrease in thymus weight; centrilobular hepatocellular hypertrophy and a decrease in lymphocytes in the thymic cortex were observed in the 1000 mg/kg/day group.

All findings were reversible after the 2-week recovery period.

As described above, stained fur associated with worsening of clinical signs and increased white blood cell count suggestive of inflammation were observed in the 1000 mg/kg/day group and therefore the no observed adverse effect level (NOAEL) was determined to be 250 mg/kg/day.

Genotoxicity Bacterial reverse mutation assay, gene mutation assay with mouse lymphoma (L5178Y/TK+/-) and mouse bone marrow micronucleus assay were conducted in a study. The result showed Trelagliptin to have no genotoxicity. Carcinogenecity Carcinogenicity dose-range finding study Male and female ICR mice orally received daily Trelagliptin at 0 (vehicle-0.5% Methylcellulose solution), 100, 300, 1000 or 2000 mg/kg/day for 1 week. Death occurred in 1 of 10 females in the 100 mg/kg/day group, 1 of 10 females in the 300 mg/kg/day group, 2 of 10 males and 1 of 10 females in the 1000 mg/kg/day group and 1 of 10 males and 1 of 10 females in the 2000 mg/kg/day group. In addition, among animals evaluated for toxicokinetics, 1 of 21 females died in the 1000 mg/kg/day group and 1 of 21 males and 7 of 21 females died in the 2000 mg/kg/day group. The deaths observed in the 2000 mg/kg/day group were considered attributable to Trelagliptin because of the high incidence of death. Findings in the 2000 mg/kg/day group were a decrease in locomotor activity, convulsion, abdominal distension, unkept fur, ataxia, decreased food consumption, decrease in lymphocyte and white blood cell counts and increase in ALP, ALT, AST and urea nitrogen.

Separately, an additional group of male and female ICR mice orally received daily 1000 mg/kg/day of Trelagliptin for 1 week.

A decrease in locomotor activity, prone position, bradypnea and hypothermia were observed after the first dose, but not after the second or subsequent doses. In addition, deaths or effects on body weight associated with Trelagliptin were not noted.

Furthermore, male and female ICR mice orally received daily Trelagliptin at 0 (vehicle-0.5% Methylcellulose solution), 150, 300, 600 or 1200 mg/kg/day for 13 weeks. No deaths associated with Trelagliptin occurred, nor were any toxicological findings observed in clinical signs, body weight, food consumption, ophthalmology, haematology, clinical chemistry, organ weights, necropsy or histopathology.

Trelaglip (Trelagliptin Succinate) is a pharmaceutical drug used for the treatment of type 2 diabetes (diabetes mellitus).

Chemical name : R 22-({6-[(3 )-3-Aminopiperidin-1-yl] H -3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2 ) -yl} methyl) -4-fluorobenzonitrile monosuccinate

Molecular formula : C₁₈H₂₀FN₅O₂.C₄H₆O₄

Molecular weight : 475.47 g/mol

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

Refer on the pack.

8.3 Packaging information

A wallet pack of 4 tablets.

8.4 Storage and handling instructions

Store below 30°C. Protect from moisture.

Keep out of reach of children

Instruct patients on the following points when administering the drug.

• This drug should be taken once a week and should be taken on the same day of the week.
• If you forget to take this drug, take only the prescribed dose when you notice it and then take it on the predetermined day of the week.
• Since there is a risk of hypoglycemia, patients should be fully informed of the symptoms of hypoglycemia and how to deal with them and caution should be called to them before using this drug.
• Patients should be instructed to seek immediate medical attention if they experience initial symptoms such as persistent severe abdominal pain or vomiting, as acute pancreatitis may occur.
• Since this drug is to be administered orally once a week and the effect continues even after discontinuation, pay close attention to blood glucose levels and the occurrence of side effects. In addition, when using other diabetes drugs after discontinuing administration of this drug, consider the timing and dose of administration based on the status of blood glucose management.
• During the course of administration of the drug, blood glucose should be tested regularly, the progress should be monitored thoroughly and if the effect of the drug is insufficient after 2 to 3 months, a change to a more appropriate treatment should be considered.
• Caution should be exercised when administering to patients who are engaged in high-altitude work, driving a car etc., as it may cause hypoglycemic symptoms.

06 January 2025

Rosuvastatin / Aspirin / Clopidogrel Hard Gelatin Capsule (20 / 75 / 75 mg)

REVOSTAT GOLD® 20

Each hard gelatin capsule contains:

Rosuvastatin Calcium IP equivalent to

Rosuvastatin (As granules) - 20 mg

Aspirin IP - 75 mg

Colour: Titanium Dioxide IP

Clopidogrel Bisulphate IP equivalent to

Clopidogrel IP - 75 mg

Colour: Sunset yellow FCF

Excipients - q.s

Approved colours used in empty hard gelatin capsule shells.

Hard Gelatin Capsules.

20 / 75 / 75 mg.

4.1. Therapeutic indication

REVOSTAT GOLD® is indicated for the treatment of dyslipidaemia associated with atherosclerotic arterial disease with risk of myocardial infarction, stroke or peripheral vascular disease.

4.2. Posology and method of administration

Before treatment initiation the patient should be placed on a standard cholesterol-lowering diet that should continue during treatment. The dose should be individualised according to the goal of therapy and patient response, using current consensus guidelines.

REVOSTAT GOLD® may be given at any time of day, with or without food.

ROSUVASTATIN

Treatment of hypercholesterolaemia

The recommended start dose is 5 or 10 mg orally once daily in both statin-naive or patients switched from another HMG CoA reductase inhibitor. The choice of start dose should take into account the individual patient's cholesterol level and future cardiovascular risk as well as the potential risk for adverse reactions. A dose adjustment to the next dose level can be made after 4 weeks, if necessary. In light of the increased reporting rate of adverse reactions with the 40 mg dose compared to lower doses, a final titration to the maximum dose of 40 mg should only be considered in patients with severe hypercholesterolaemia at high cardiovascular risk (in particular those with familial hypercholesterolaemia), who do not achieve their treatment goal on 20 mg, and in whom routine follow-up will be performed. Specialist supervision is recommended when the 40 mg dose is initiated.

Use in the elderly

A start dose of 5 mg is recommended in patients >70 years. No other dose adjustment is necessary in relation to age.

Dosage in patients with renal insufficiency

No dose adjustment is necessary in patients with mild to moderate renal impairment. The recommended start dose is 5 mg in patients with moderate renal impairment (creatinine clearance <60 ml/min). The 40 mg dose is contraindicated in patients with moderate renal impairment. The use of rosuvastatin in patients with severe renal impairment is contraindicated for all doses.

Dosage in patients with hepatic impairment

There was no increase in systemic exposure to rosuvastatin in subjects with Child-Pugh scores of 7 or below. However, increased systemic exposure has been observed in subjects with Child-Pugh scores of 8 and 9. In these patients an assessment of renal function should be considered. There is no experience in subjects with Child-Pugh scores above 9. Rosuvastatin is contraindicated in patients with active liver disease.

Race

Increased systemic exposure has been seen in Asian subjects. The recommended start dose is 5 mg for patients of Asian ancestry. The 40 mg dose is contraindicated in these patients.

Genetic polymorphisms

Specific types of genetic polymorphisms are known that can lead to increased rosuvastatin exposure. For patients who are known to have such specific types of polymorphisms, a lower daily dose of rosuvastatin is recommended.

Dosage in patients with pre-disposing factors to myopathy

The recommended start dose is 5 mg in patients with predisposing factors to myopathy.

The 40 mg dose is contraindicated in some of these patients.

Concomitant therapy

Rosuvastatin is a substrate of various transporter proteins (e.g. OATP1B1 and BCRP). The risk of myopathy (including rhabdomyolysis) is increased when rosuvastatin is administered concomitantly with certain medicinal products that may increase the plasma concentration of rosuvastatin due to interactions with these transporter proteins (e.g. ciclosporin and certain protease inhibitors including combinations of ritonavir with atazanavir, lopinavir and/or tipranavir;). Whenever possible, alternative medications should be considered, and, if necessary, consider temporarily discontinuing rosuvastatin therapy. In situations where co-administration of these medicinal products with rosuvastatin is unavoidable, the benefit and the risk of concurrent treatment and rosuvastatin dosing adjustments should be carefully considered.

ASPIRIN

Elderly

In general, acetylsalicylic acids should be used with caution in elderly patients who are more prone to adverse events. The usual adult dose is recommended in the absence of severe renal or hepatic insufficiency. Treatment should be reviewed at regular intervals.

Paediatric population

Acetylsalicylic acid should not be administered to children and adolescents younger than 16 years, except on medical advice where the benefit outweighs the risk

CLOPIDOGREL

Adults and elderly

Clopidogrel should be given as a single daily dose of 75 mg.

In patients suffering from acute coronary syndrome:

• −Non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction): clopidogrel treatment should be initiated with a single 300-mg loading dose and then continued at 75 mg once a day (with acetylsalicylic acid (ASA) 75 mg-325 mg daily). Since higher doses of ASA were associated with higher bleeding risk it is recommended that the dose of ASA should not be higher than 100 mg. The optimal duration of treatment has not been formally established. Clinical trial data support use up to 12 months, and the maximum benefit was seen at 3 months.
• −ST segment elevation acute myocardial infarction: clopidogrel should be given as a single daily dose of 75 mg initiated with a 300-mg loading dose in combination with ASA and with or without thrombolytics. For patients over 75 years of age clopidogrel should be initiated without a loading dose. Combined therapy should be started as early as possible after symptoms start and continued for at least four weeks. The benefit of the combination of clopidogrel with ASA beyond four weeks has not been studied in this setting.

In patients with atrial fibrillation, clopidogrel should be given as a single daily dose of 75 mg. ASA (75-100 mg daily) should be initiated and continued in combination with clopidogrel.

If a dose is missed:

• −Within less than 12 hours after regular scheduled time: patients should take the dose immediately and then take the next dose at the regular scheduled time.
• −For more than 12 hours: patients should take the next dose at the regular scheduled time and should not double the dose.

• Paediatric population
  • Clopidogrel should not be used in children because of efficacy concerns.

• Renal impairment
  • Therapeutic experience is limited in patients with renal impairment.

• Hepatic impairment
  • Therapeutic experience is limited in patients with moderate hepatic disease who may have bleeding diatheses.

Method of administration
For oral use.

4.3. Contraindications

ROSUVASTATIN
REVOSTAT GOLD® must not be used in the following conditions:

• in patients with hypersensitivity to rosuvastatin or to any of the excipients.
• in patients with active liver disease including unexplained, persistent elevations of serum transaminases and any serum transaminase elevation exceeding 3 times the upper limit of normal (ULN).
• in patients with severe renal impairment (creatinine clearance <30 ml/min).
• in patients with myopathy.
• in patients receiving concomitant combination of sofosbuvir / velpatasvir / voxilaprevir 
• in patients receiving concomitant ciclosporin.
• during pregnancy and lactation and in women of childbearing potential not using appropriate contraceptive measures.
• The 40 mg dose is contraindicated in patients with pre-disposing factors for myopathy/rhabdomyolysis. Such factors include:
• moderate renal impairment (creatinine clearance < 60 ml/min)
• hypothyroidism
• personal or family history of hereditary muscular disorders
• previous history of muscular toxicity with another HMG-CoA reductase inhibitor or fibrate
• alcohol abuse
• situations where an increase in plasma levels may occur
• Asian patients
• concomitant use of fibrates.

ASPIRIN

• Hypersensitivity to salicylic acid compounds or prostaglandin synthetase inhibitors (e.g. certain asthma patients who may suffer an attack or faint) or to any of the excipients;
• Active, or history of recurrent peptic ulcer and/or gastric/intestinal haemorrhage, or other kinds of bleeding such as cerebrovascular haemorrhages;
• Haemorrhagic diathesis; coagulation disorders such as haemophilia and thrombocytopenia;
• Severe hepatic impairment;
• Severe renal impairment;
• Gout;
• Doses >100 mg/day during the third trimester of pregnancy;
• Methotrexate used at doses >15mg/week

CLOPIDOGREL

• Severe hepatic impairment.
• Active pathological bleeding such as peptic ulcer or intracranial haemorrhage.

4.4. Special warnings and precautions for use

ROSUVASTATIN
Renal Effects
Proteinuria, detected by dipstick testing and mostly tubular in origin, has been observed in patients treated with higher doses of rosuvastatin, in particular 40 mg, where it was transient or intermittent in most cases. Proteinuria has not been shown to be predictive of acute or progressive renal disease. The reporting rate for serious renal events in post-marketing use is higher at the 40 mg dose. An assessment of renal function should be considered during routine follow-up of patients treated with a dose of 40 mg.

Skeletal Muscle Effects
Effects on skeletal muscle e.g. myalgia, myopathy and, rarely, rhabdomyolysis have been reported in rosuvastatin-treated patients with all doses and in particular with doses > 20 mg. Very rare cases of rhabdomyolysis have been reported with the use of ezetimibe in combination with HMG-CoA reductase inhibitors. A pharmacodynamic interaction cannot be excluded and caution should be exercised with their combined use. As with other HMG-CoA reductase inhibitors, the reporting rate for rhabdomyolysis associated with rosuvastatin in post-marketing use is higher at the 40 mg dose.

Creatine Kinase Measurement
Creatine Kinase (CK) should not be measured following strenuous exercise or in the presence of a plausible alternative cause of CK increase which may confound interpretation of the result. If CK levels are significantly elevated at baseline (>5xULN) a confirmatory test should be carried out within 5 – 7 days. If the repeat test confirms a baseline CK >5xULN, treatment should not be started.

Before Treatment
Rosuvastatin, as with other HMG-CoA reductase inhibitors, should be prescribed with caution in patients with pre-disposing factors for myopathy/rhabdomyolysis. Such factors include:

• renal impairment
• hypothyroidism
• personal or family history of hereditary muscular disorders
• previous history of muscular toxicity with another HMG-CoA reductase inhibitor or fibrate
• alcohol abuse
• age >70 years
• situations where an increase in plasma levels may occur 
• concomitant use of fibrates.

In such patients the risk of treatment should be considered in relation to possible benefit and clinical monitoring is recommended. If CK levels are significantly elevated at baseline (>5xULN) treatment should not be started.

Whilst on Treatment
Patients should be asked to report inexplicable muscle pain, weakness or cramps immediately, particularly if associated with malaise or fever. CK levels should be measured in these patients. Therapy should be discontinued if CK levels are markedly elevated (>5xULN) or if muscular symptoms are severe and cause daily discomfort (even if CK levels are ≤5xULN). If symptoms resolve and CK levels return to normal, then consideration should be given to re-introducing rosuvastatin or an alternative HMG-CoA reductase inhibitor at the lowest dose with close monitoring. Routine monitoring of CK levels in asymptomatic patients is not warranted. There have been very rare reports of an immune-mediated necrotising myopathy (IMNM) during or after treatment with statins, including rosuvastatin. IMNM is clinically characterised by proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment.

In clinical trials, there was no evidence of increased skeletal muscle effects in the small number of patients dosed with rosuvastatin and concomitant therapy. However, an increase in the incidence of myositis and myopathy has been seen in patients receiving other HMG-CoA reductase inhibitors together with fibric acid derivatives including gemfibrozil, ciclosporin, nicotinic acid, azole antifungals, protease inhibitors and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when given concomitantly with some HMG-CoA reductase inhibitors. Therefore, the combination of rosuvastatin and gemfibrozil is not recommended. The benefit of further alterations in lipid levels by the combined use of rosuvastatin with fibrates or niacin should be carefully weighed against the potential risks of such combinations. The 40 mg dose is contraindicated with concomitant use of a fibrate.

Rosuvastatinn must not be co-administered with systemic formulations of fusidic acid or within 7 days of stopping fusidic acid treatment. In patients where the use of systemic fusidic acid is considered essential, statin treatment should be discontinued throughout the duration of fusidic acid treatment. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving fusidic acid and statins in combination. Patients should be advised to seek medical advice immediately if they experience any symptoms of muscle weakness, pain or tenderness. Statin therapy may be re-introduced seven days after the last dose of fusidic acid. In exceptional circumstances, where prolonged systemic fusidic acid is needed, e.g. for the treatment of severe infections, the need for co-administration of rosuvastatin and fusidic acid should only be considered on a case by case basis and under close medical supervision.

Rosuvastatin should not be used in any patient with an acute, serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g. sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders; or uncontrolled seizures).

Liver Effects

As with other HMG-CoA reductase inhibitors, rosuvastatin should be used with caution in patients who consume excessive quantities of alcohol and/or have a history of liver disease.

It is recommended that liver function tests be carried out prior to, and 3 months following, the initiation of treatment. Rosuvastatin should be discontinued or the dose reduced if the level of serum transaminases is greater than 3 times the upper limit of normal. The reporting rate for serious hepatic events (consisting mainly of increased hepatic transaminases) in post-marketing use is higher at the 40 mg dose. In patients with secondary hypercholesterolaemia caused by hypothyroidism or nephrotic syndrome, the underlying disease should be treated prior to initiating therapy with rosuvastatin.

Race
Pharmacokinetic studies show an increase in exposure in Asian subjects compared with Caucasians.

Protease Inhibitors
Increased systemic exposure to rosuvastatin has been observed in subjects receiving rosuvastatin concomitantly with various protease inhibitors in combination with ritonavir. Consideration should be given both to the benefit of lipid lowering by use of rosuvastatin in HIV patients receiving protease inhibitors and the potential for increased rosuvastatin plasma concentrations when initiating and up titrating rosuvastatin doses in patients treated with protease inhibitors. The concomitant use with certain protease inhibitors is not recommended unless the dose of rosuvastatin is adjusted. 

Lactose Intolerance
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Interstitial Lung Disease
Exceptional cases of interstitial lung disease have been reported with some statins, especially with long-term therapy. Presenting features can include dyspnoea, non-productive cough and deterioration in general health (fatigue, weight loss and fever). If it is suspected a patient has developed interstitial lung disease, statin therapy should be discontinued.

Diabetes Mellitus
Some evidence suggests that statins as a class raise blood glucose and in some patients, at high risk of future diabetes, may produce a level of hyperglycaemia where formal diabetes care is appropriate. This risk, however, is outweighed by the reduction in vascular risk with statins and therefore should not be a reason for stopping statin treatment. Patients at risk (fasting glucose 5.6 to 6.9 mmol/l, BMI >30 kg/m2, raised triglycerides, hypertension) should be monitored both clinically and biochemically according to national guidelines.

In the JUPITER study, the reported overall frequency of diabetes mellitus was 2.8% in rosuvastatin and 2.3% in placebo, mostly in patients with fasting glucose 5.6 to 6.9 mmol/l.

ASPIRIN
Aspirin Tablets is not suitable for use as an anti-inflammatory / analgesic / antipyretic.

Recommended for use in adults and adolescents from 16 years of age. This medicinal product is not recommended for use in adolescents/children under 16 years unless the expected benefits outweigh the risks. Acetylsalicylic acid may be a contributory factor in the causation of Reye's Syndrome in some children.
There is an increased risk of haemorrhage particularly during or after operative procedures (even in cases of minor procedures, e.g. tooth extraction). Use with caution before surgery, including tooth extraction. Temporary discontinuation of treatment may be necessary.

Aspirin Tablets is not recommended during menorrhagia where it may increase menstrual bleeding.
Aspirin Tablets is to be used with caution in cases of hypertension and when patients have a past history of gastric or duodenal ulcer or haemorrhagic episodes or are undergoing therapy with anticoagulants.
Patients should report any unusual bleeding symptoms to their physician. If gastrointestinal bleeding or ulceration occurs the treatment should be withdrawn.

Acetylsalicylic acid should be used with caution in patients with moderately impaired renal or hepatic function (contraindicated if severe), or in patients who are dehydrated since the use of NSAIDs may result in deterioration of renal function. Liver function tests should be performed regularly in patients presenting slight or moderate hepatic insufficiency.

Acetylsalicylic acid may promote bronchospasm and asthma attacks or other hypersensitivity reactions. Risk factors are existing asthma, hay fever, nasal polyps or chronic respiratory diseases. The same applies for patients who also show allergic reaction to other substances (e.g. with skin reactions, itching or urticaria).
Serious skin reactions, including Steven-Johnsons syndrome, have rarely been reported in association with the use of acetylsalicylic acid. Aspirin Tablets should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Elderly patients are particularly susceptible to the adverse effects of NSAIDs, including acetylsalicylic acid especially gastrointestinal bleeding and perforation which may be fatal. Where prolonged therapy is required, patients should be reviewed regularly.

Concomitant treatment with Aspirin Tablets and other drugs that alter haemostasis (i.e. anticoagulants such as warfarin, thrombolytic and antiplatelet agents, anti-inflammatory drugs and selective serotonin reuptake inhibitors) is not recommended, unless strictly indicated, because they may enhance the risk of haemorrhage. If the combination cannot be avoided, close observation for signs of bleeding is recommended.

Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration, such as oral corticosteroids, selective serotonin-reuptake inhibitors and deferasirox.

Acetylsalicylic acid should be avoided in late pregnancy and generally during breast feeding.

Acetylsalicylic acid in low doses reduces uric acid excretion. Due to this fact, patients who tend to have reduced uric acid excretion may experience gout attacks.

The risk of hypoglycaemic effect with sulfonylureas and insulins may be potentiated with Aspirin Tablets taken at over dosage.

CLOPIDOGREL
Bleeding and haematological disorders
Due to the risk of bleeding and haematological adverse reactions, blood cell count determination and/or other appropriate testing should be promptly considered whenever clinical symptoms suggestive of bleeding arise during the course of treatment. As with other antiplatelet agents, clopidogrel should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery or other pathological conditions and in patients receiving treatment with ASA, heparin, glycoprotein IIb/IIIa inhibitors or non-steroidal anti-inflammatory drugs (NSAIDs) including Cox-2 inhibitors, or selective serotonin reuptake inhibitors (SSRIs), or CYP2C19 strong inducers or other medicinal products with bleeding risk such as pentoxifyllin). Patients should be followed carefully for any signs of bleeding including occult bleeding, especially during the first weeks of treatment and/or after invasive cardiac procedures or surgery. The concomitant administration of clopidogrel with oral anticoagulants is not recommended since it may increase the intensity of bleedings.

If a patient is to undergo elective surgery and antiplatelet effect is temporarily not desirable, clopidogrel should be discontinued 7 days prior to surgery. Patients should inform physicians and dentists that they are taking clopidogrel before any surgery is scheduled and before any new medicinal product is taken. Clopidogrel prolongs bleeding time and should be used with caution in patients who have lesions with a propensity to bleed (particularly gastrointestinal and intraocular).

Patients should be told that it might take longer than usual to stop bleeding when they take clopidogrel (alone or in combination with ASA), and that they should report any unusual bleeding (site or duration) to their physician.

Thrombotic Thrombocytopenic Purpura (TTP)
Thrombotic Thrombocytopenic Purpura (TTP) has been reported very rarely following the use of clopidogrel, sometimes after a short exposure. It is characterised by thrombocytopenia and microangiopathic haemolytic anaemia associated with either neurological findings, renal dysfunction or fever. TTP is a potentially fatal condition requiring prompt treatment including plasmapheresis.

Acquired haemophilia
Acquired haemophilia has been reported following use of clopidogrel. In cases of confirmed isolated activated Partial Thromboplastin Time (aPTT) prolongation with or without bleeding, acquired haemophilia should be considered. Patients with a confirmed diagnosis of acquired haemophilia should be managed and treated by specialists, and clopidogrel should be discontinued.

Recent ischaemic stroke
In view of the lack of data, clopidogrel cannot be recommended during the first 7 days after acute ischaemic stroke.

Cytochrome P450 2C19 (CYP2C19)
Pharmacogenetics: In patients who are poor CYP2C19 metabolisers, clopidogrel at recommended doses forms less of the active metabolite of clopidogrel and has a smaller effect on platelet function. Tests are available to identify a patient's CYP2C19 genotype.

Since clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of medicinal products that inhibit the activity of this enzyme would be expected to result in reduced drug levels of the active metabolite of clopidogrel. The clinical relevance of this interaction is uncertain. As a precaution, concomitant use of strong or moderate CYP2C19 inhibitors should be discouraged.

Use of medicinal products that induce the activity of CYP2C19 would be expected to result in increased drug levels of the active metabolite of clopidogrel and might potentiate the bleeding risk. As a precaution concomitant use of strong CYP2C19 inducers should be discouraged.

CYP2C8 substrates
Caution is required in patients treated concomitantly with clopidogrel and CYP2C8 substrate medicinal products.

Cross-reactions among thienopyridines
Patients should be evaluated for history of hypersensitivity to thienopyridines (such as clopidogrel, ticlopidine, prasugrel), since cross-reactivity among thienopyridines has been reported. Thienopyridines may cause mild to severe allergic reactions such as rash, angioedema, or haematological cross-reactions such as thrombocytopaenia and neutropaenia. Patients who had developed a previous allergic reaction and/or haematological reaction to one thienopyridine may have an increased risk of developing the same or another reaction to another thienopyridine. Monitoring for signs of hypersensitivity in patients with a known allergy to thienopyridines is advised.

Renal impairment
Therapeutic experience with clopidogrel is limited in patients with renal impairment. Therefore, clopidogrel should be used with caution in these patients.

Hepatic impairment
Experience is limited in patients with moderate hepatic disease who may have bleeding diatheses. Clopidogrel should, therefore, be used with caution in this population.

4.5. Interaction with other medicinal products and other forms of interaction
ROSUVASTATIN
Effect of co-administered medicinal products on rosuvastatin

Transporter protein inhibitors: Rosuvastatin is a substrate for certain transporter proteins including the hepatic uptake transporter OATP1B1 and efflux transporter BCRP. Concomitant administration of rosuvastatin with medicinal products that are inhibitors of these transporter proteins may result in increased rosuvastatin plasma concentrations and an increased risk of myopathy.

Ciclosporin: During concomitant treatment with rosuvastatin and ciclosporin, rosuvastatin AUC values were on average 7 times higher than those observed in healthy volunteers (see Table 1). Rosuvastatin is contraindicated in patients receiving concomitant ciclosporin. Concomitant administration did not affect plasma concentrations of ciclosporin.

Protease inhibitors: Although the exact mechanism of interaction is unknown, concomitant protease inhibitor use may strongly increase rosuvastatin exposure (see Table 1). For instance, in a pharmacokinetic study, co-administration of 10 mg rosuvastatin and a combination product of two protease inhibitors (300 mg atazanavir/100 mg ritonavir) in healthy volunteers was associated with an approximately three-fold and seven-fold increase in rosuvastatin AUC and Cmax respectively. The concomitant use of rosuvastatin and some protease inhibitor combinations may be considered after careful consideration of rosuvastatin dose adjustments based on the expected increase in rosuvastatin exposure.

Gemfibrozil and other lipid-lowering products: Concomitant use of rosuvastatin and gemfibrozil resulted in a 2-fold increase in rosuvastatin Cmax and AUC. Based on data from specific interaction studies no pharmacokinetic relevant interaction with fenofibrate is expected, however a pharmacodynamic interaction may occur. Gemfibrozil, fenofibrate, other fibrates and lipid lowering doses (> or equal to 1 g/day) of niacin (nicotinic acid) increase the risk of myopathy when given concomitantly with HMG-CoA reductase inhibitors, probably because they can produce myopathy when given alone. The 40 mg dose is contraindicated with concomitant use of a fibrate. These patients should also start with the 5 mg dose.

Ezetimibe: Concomitant use of 10 mg rosuvastatin and 10 mg ezetimibe resulted in a 1.2-fold increase in AUC of rosuvastatin in hypercholesterolaemic subjects (Table 1). A pharmacodynamic interaction, in terms of adverse effects, between rosuvastatin and ezetimibe cannot be ruled out.

Antacid: The simultaneous dosing of rosuvastatin with an antacid suspension containing aluminium and magnesium hydroxide resulted in a decrease in rosuvastatin plasma concentration of approximately 50%. This effect was mitigated when the antacid was dosed 2 hours after rosuvastatin. The clinical relevance of this interaction has not been studied.

Erythromycin: Concomitant use of rosuvastatin and erythromycin resulted in a 20% decrease in AUC and a 30% decrease in Cmax of rosuvastatin. This interaction may be caused by the increase in gut motility caused by erythromycin.

Cytochrome P450 enzymes: Results from in vitro and in vivo studies show that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. In addition, rosuvastatin is a poor substrate for these isoenzymes. Therefore, drug interactions resulting from cytochrome P450-mediated metabolism are not expected. No clinically relevant interactions have been observed between rosuvastatin and either fluconazole (an inhibitor of CYP2C9 and CYP3A4) or ketoconazole (an inhibitor of CYP2A6 and CYP3A4).

Interactions requiring rosuvastatin dose adjustments (see also Table 1): When it is necessary to co-administer rosuvastatin with other medicinal products known to increase exposure to rosuvastatin, doses of rosuvastatin should be adjusted. Start with a 5 mg once daily dose of rosuvastatin if the expected increase in exposure (AUC) is approximately 2-fold or higher. The maximum daily dose of rosuvastatin should be adjusted so that the expected rosuvastatin exposure would not likely exceed that of a 40 mg daily dose of rosuvastatin taken without interacting medicinal products, for example a 20 mg dose of rosuvastatin with gemfibrozil (1.9-fold increase), and a 10 mg dose of rosuvastatin with combination ritonavir/atazanavir (3.1-fold increase).

If medicinal product is observed to increase rosuvastatin AUC less than 2-fold, the starting dose need not be decreased but caution should be taken if increasing the rosuvastatin dose above 20mg.

 

The following medical product/combinations did not have a clinically significant effect on the AUC ratio of rosuvastatin at coadministration:

Aleglitazar 0.3 mg 7 days dosing; Fenofibrate 67 mg 7 days TID dosing; Fluconazole 200mg 11 days OD dosing; Fosamprenavir 700 mg/ritonavir 100 mg 8 days BID dosing; Ketoconazole 200 mg 7 days BID dosing; Rifampin 450 mg 7 days OD dosing; Silymarin 140 mg 5 days TID dosing.

Effect of rosuvastatin on co-administered medicinal products
Vitamin K antagonists: As with other HMG-CoA reductase inhibitors, the initiation of treatment or dosage up-titration of rosuvastatin in patients treated concomitantly with vitamin K antagonists (e.g. warfarin or another coumarin anticoagulant) may result in an increase in International Normalised Ratio (INR). Discontinuation or down-titration of rosuvastatin may result in a decrease in INR. In such situations, appropriate monitoring of INR is desirable.

Oral contraceptive/hormone replacement therapy (HRT): Concomitant use of rosuvastatin and an oral contraceptive resulted in an increase in ethinyl estradiol and norgestrel AUC of 26% and 34%, respectively. These increased plasma levels should be considered when selecting oral contraceptive doses. There are no pharmacokinetic data available in subjects taking concomitant rosuvastatin and HRT, therefore, a similar effect cannot be excluded. However, the combination has been extensively used in women in clinical trials and was well tolerated.

Other medicinal products:
Digoxin: Based on data from specific interaction studies no clinically relevant interaction with digoxin is expected.

Fusidic Acid: Interaction studies with rosuvastatin and fusidic acid have not been conducted. The risk of myopathy, including rhabdomyolysis may be increased by the concomitant administration of systemic fusidic acid with statins. The mechanism of this interaction (whether it is pharmacodynamic or pharmacokinetic, or both) is yet unknown. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving this combination. If treatment with systemic fusidic acid is necessary, rosuvastatin treatment should be discontinued throughout the duration of the fusidic acid treatment. 

Paediatric population: Interaction studies have only been performed in adults. The extent of interactions in the paediatric population is not known.

ASPIRIN
Contraindicated combinations

Methotrexate (used at doses >15 mg/week):
The combined drugs, methotrexate and acetylsalicylic acid, enhance haematological toxicity of methotrexate due to the decreased renal clearance of methotrexate by acetylsalicylic acid. Therefore, the concomitant use of methotrexate (at doses >15 mg/week) with Aspirin Tablets is contraindicated. Not recommended combinations

Uricosuric agents, e.g. probenecid
Salicylates reverse the effect of probenecid. The combination should be avoided. Combinations requiring precautions for use or to be taken into account

Anticoagulants e.g. coumarin, heparin, warfarin
Increased risk of bleeding due to inhibited thrombocyte function, injury of the duodenal mucosa and displacement of oral anticoagulants from their plasma protein binding sites. The bleeding time should be monitored.
Anti-platelet agents (e.g clopidogrel and dipyridamole) and selective serotonin reuptake inhibitors (SSRIs; such as sertraline or paroxetine) Increased risk of gastrointestinal bleeding.

Antidiabetics, e.g. sulfonylureas
Salicylics may increase the hypoglycaemic effect of sulfonylureas.
Digoxin and lithium
Acetylsalicylic acid impairs the renal excretion of digoxin and lithium, resulting in increased plasma concentrations. Monitoring of plasma concentrations of digoxin and lithium is recommended when initiating and terminating treatment with acetylsalicylic acid. Dose adjustment may be necessary

Diuretics and antihypertensives
NSAIDs may decrease the antihypertensive effects of diuretics and other antihypertensive agents. As for other NSAIDs concomitant administration with ACE-inhibitors increases the risk of acute renal insufficiency.
Diuretics: Risk of acute renal failure due to the decreased glomerual filtration via decreased renal prostaglandin synthesis. Hydrating the patient and monitoring renal function at the start of the treatment is recommended.

Carbonic anhydrase inhibitors (acetazolamide)
May result in severe acidosis and increased central nervous system toxicity

Systemic corticosteroids
The risk of gastrointestinal ulceration and bleeding may be increased when acetylsalicylic acid and corticosteroids are co-administered.

Methotrexate (used at doses <15 mg/week):
The combined drugs, methotrexate and acetylsalicylic acid, may increase haematological toxicity of methotrexate due to decreased renal clearance of methotrexate by acetylsalicylic acid. Weekly blood count checks should be done during the first weeks of the combination. Enhanced monitoring should take place in the presence of even mildly impaired renal function, as well, as in elderly.

Other NSAIDs
Increased risk of ulcerations and gastrointestinal bleeding due to synergistic effects.

Ibuprofen
Experimental data suggest that ibuprofen may inhibit the effect of low dose acetylsalicylic acid on platelet aggregation when they are dosed concomitantly. However, the limitations of these data and the uncertainties regarding extrapolation of ex vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no clinically relevant effect is considered to be likely for occasional ibuprofen use.

Metamizole
Metamizole may reduce the effect of acetylsalicylic acid on platelet aggregation, when taken concomitantly. Therefore, this combination should be used with caution in patients taking low dose aspirin for cardioprotection.

Ciclosporin, tacrolimus
Concomitant use of NSAIDs and ciclospoin or tacrolimus may increase the nephrotoxic effect of ciclosporin and tacrolimus. The renal function should be monitored in case of concomitant use of these agents and acetylsalicylic acid.

Antacids
The excretion of acetylsalicylic acid is increased by alkaline urine, which can occur with some antacids.

Alcohol
Concomitant administration of alcohol and acetylsalicylic acid increases the risk of gastrointestinal bleeding.

CLOPIDOGREL

Medicinal products associated with bleeding risk: There is an increased risk of bleeding due to the potential additive effect. The concomitant administration of medicinal products associated with bleeding risk should be undertaken with caution.

Oral anticoagulants: the concomitant administration of clopidogrel with oral anticoagulants is not recommended since it may increase the intensity of bleedings. Although the administration of clopidogrel 75 mg/day did not modify the pharmacokinetics of S-warfarin or International Normalised Ratio (INR) in patients receiving long-term warfarin therapy, coadministration of clopidogrel with warfarin increases the risk of bleeding because of independent effects on hemostasis.

Glycoprotein IIb/IIIa inhibitors: clopidogrel should be used with caution in patients who receive concomitant glycoprotein IIb/IIIa inhibitors.

Acetylsalicylic acid (ASA): ASA did not modify the clopidogrel-mediated inhibition of ADP-induced platelet aggregation, but clopidogrel potentiated the effect of ASA on collagen-induced platelet aggregation. However, concomitant administration of 500 mg of ASA twice a day for one day did not significantly increase the prolongation of bleeding time induced by clopidogrel intake. A pharmacodynamic interaction between clopidogrel and acetylsalicylic acid is possible, leading to increased risk of bleeding. Therefore, concomitant use should be undertaken with caution. However, clopidogrel and ASA have been administered together for up to one year.
Heparin: in a clinical study conducted in healthy subjects, clopidogrel did not necessitate modification of the heparin dose or alter the effect of heparin on coagulation. Co-administration of heparin had no effect on the inhibition of platelet aggregation induced by clopidogrel. A pharmacodynamic interaction between clopidogrel and heparin is possible, leading to increased risk of bleeding. Therefore, concomitant use should be undertaken with caution.

Thrombolytics: the safety of the concomitant administration of clopidogrel, fibrin or non-fibrin specific thrombolytic agents and heparins was assessed in patients with acute myocardial infarction. The incidence of clinically significant bleeding was similar to that observed when thrombolytic agents and heparin are co-administered with ASA.

NSAIDs: in a clinical study conducted in healthy volunteers, the concomitant administration of clopidogrel and naproxen increased occult gastrointestinal blood loss. However, due to the lack of interaction studies with other NSAIDs it is presently unclear whether there is an increased risk of gastrointestinal bleeding with all NSAIDs. Consequently, NSAIDs including Cox-2 inhibitors and clopidogrel should be co-administered with caution.

SSRIs: since SSRIs affect platelet activation and increase the risk of bleeding, the concomitant administration of SSRIs with clopidogrel should be undertaken with caution.

Other concomitant therapy:
Inducers of CYP2C19
Since clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of medicinal products that induce the activity of this enzyme would be expected to result in increased drug levels of the active metabolite of clopidogrel.

Rifampicin strongly induces CYP2C19, resulting in both an increased level of clopidogrel active metabolite and platelet inhibition, which in particular might potentiate the risk of bleeding. As a precaution, concomitant use of strong CYP2C19 inducers should be discouraged.

Inhibitors of CYP2C19
Since clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of medicinal products that inhibit the activity of this enzyme would be expected to result in reduced drug levels of the active metabolite of clopidogrel. The clinical relevance of this interaction is uncertain. As a precaution, concomitant use of strong or moderate CYP2C19 inhibitors should be discouraged. Medicinal products that are strong or moderate CYP2C19 inhibitors include, for example, omeprazole and esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, carbamazepine, and efavirenz.

Proton Pump Inhibitors (PPI)
Omeprazole 80 mg once daily administered either at the same time as clopidogrel or with 12 hours between the administrations of the two drugs decreased the exposure of the active metabolite by 45% (loading dose) and 40% (maintenance dose). The decrease was associated with a 39% (loading dose) and 21% (maintenance dose) reduction of inhibition of platelet aggregation. Esomeprazole is expected to give a similar interaction with clopidogrel.

Inconsistent data on the clinical implications of this pharmacokinetic (PK)/pharmacodynamic (PD) interaction in terms of major cardiovascular events have been reported from both observational and clinical studies. As a precaution, concomitant use of omeprazole or esomeprazole should be discouraged. Less pronounced reductions of metabolite exposure has been observed with pantoprazole or lansoprazole. 

The plasma concentrations of the active metabolite was 20% reduced (loading dose) and 14% reduced (maintenance dose) during concomitant treatment with pantoprazole 80 mg once daily. This was associated with a reduction of the mean inhibition of platelet aggregation by 15% and 11%, respectively. These results indicate that clopidogrel can be administered with pantoprazole. There is no evidence that other medicinal products that reduce stomach acid such as H2 blockers or antacids interfere with antiplatelet activity of clopidogrel.
Other medicinal products: A number of other clinical studies have been conducted with clopidogrel and other concomitant medicinal products to investigate the potential for pharmacodynamic and pharmacokinetic interactions. No clinically significant pharmacodynamic interactions were observed when clopidogrel was co-administered with atenolol, nifedipine, or both atenolol and nifedipine. Furthermore, the pharmacodynamic activity of clopidogrel was not significantly influenced by the co- administration of phenobarbital or oestrogen.
The pharmacokinetics of digoxin or theophylline were not modified by the co-administration of clopidogrel. Antacids did not modify the extent of clopidogrel absorption.  Data from the CAPRIE study indicate that phenytoin and tolbutamide which are metabolised by CYP2C9 can be safely co-administered with clopidogrel.
CYP2C8 substrate medicinal products: Clopidogrel has been shown to increase repaglinide exposure in healthy volunteers. In vitro studies have shown the increase in repaglinide exposure is due to inhibition of CYP2C8 by the glucuronide metabolite of clopidogrel. Due to the risk of increased plasma concentrations, concomitant administration of clopidogrel and drugs primarily cleared by CYP2C8 metabolism (e.g., repaglinide, paclitaxel) should be undertaken with caution.

Apart from the specific medicinal product interaction information described above, interaction studies with clopidogrel and some medicinal products commonly administered in patients with atherothrombotic disease have not been performed. However, patients entered into clinical trials with clopidogrel received a variety of concomitant medicinal products including diuretics, beta blockers, ACEI, calcium antagonists, cholesterol lowering agents, coronary vasodilators, antidiabetic agents (including insulin), antiepileptic agents and GPIIb/IIIa antagonists without evidence of clinically significant adverse interactions.

A significantly lower exposure to clopidogrel active metabolite and reduced platelet inhibition have been demonstrated in HIV-infected patients treated with ritonavir- or cobicistat-boosted anti-retroviral therapies (ART). Although the clinical relevance of these findings is uncertain, there have been spontaneous reports of HIV-infected patients treated with boosted ART, who have experienced re-occlusive events after de-obstruction or have suffered thrombotic events under a clopidogrel loading treatment schedule. Exposure of clopidogrel and average platelet inhibition can be decreased with concomitant use of ritonavir. Therefore, concomitant use of clopidogrel with boosted ART should be discouraged.

As with other oral P2Y12 inhibitors, co-administration of opioid agonists has the potential to delay and reduce the absorption of clopidogrel presumably because of slowed gastric emptying. The clinical relevance is unknown. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring co-administration of morphine or other opioid agonists. 

4.6. Fertility, pregnancy and lactation

ROSUVASTATIN
Rosuvastatin is contraindicated in pregnancy and lactation. Women of child bearing potential should use appropriate contraceptive measures. Since cholesterol and other products of cholesterol biosynthesis are essential for the development of the foetus, the potential risk from inhibition of HMG-CoA reductase outweighs the advantage of treatment during pregnancy. Animal studies provide limited evidence of reproductive toxicity. If a patient becomes pregnant during use of this product, treatment should be discontinued immediately.
Rosuvastatin is excreted in the milk of rats. There are no data with respect to excretion in milk in humans.

ASPIRIN
Pregnancy
Low doses (up to 100 mg/day):
Clinical studies indicate that doses up to 100 mg/day for restricted obstetrical use, which require specialised monitoring, appear safe.

Doses of 100- 500 mg/day:
There is insufficient clinical experience regarding the use of doses above 100 mg/day up to 500 mg/day. Therefore, the recommendations below for doses of 500 mg/day and above apply also for this dose range.

Doses of 500 mg/day and above:
Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development. Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk for cardiovascular malformation was increased from less than 1%, up to approximately 1.5 %. The risk is believed to increase with dose and duration of therapy. In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and post-implantation loss and embryo-foetal lethality. In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period. During the first and second trimester of pregnancy, acetylsalicylic acid should not be given unless clearly necessary. If acetylsalicylic acid is used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept as low and duration of treatment as short as possible.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to:

• cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);
• renal dysfunction, which may progress to renal failure with oligo- hydroamniosis; 
• the mother and the neonate, at the end of pregnancy, to:
• possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses.
• inhibition of uterine contractions resulting in delayed or prolonged labour.

Consequently, acetylsalicylic acid at doses of 100 mg/day and higher is contraindicated during the third trimester of pregnancy.

Breastfeeding
Low quantities of salicylates and of their metabolites are excreted into the breast milk. Since adverse effects for the infant have not been reported up to now, short-term use of the recommended dose does not require suspending lactation. In cases of long-term use and/or administration of higher doses, breastfeeding should be discontinued.

CLOPIDOGREL
Pregnancy
As no clinical data on exposure to clopidogrel during pregnancy are available, it is preferable not to use clopidogrel during pregnancy as a precautionary measure. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development.

Breast-feeding
It is unknown whether clopidogrel is excreted in human breast milk. Animal studies have shown excretion of clopidogrel in breast milk. As a precautionary measure, breast-feeding should not be continued during treatment with Clopidogrel film-coated tablet.

Fertility
Clopidogrel was not shown to alter fertility in animal studies.

4.7. Effects on ability to drive and use machines

ROSUVASTATIN
Studies to determine the effect of rosuvastatin on the ability to drive and use machines have not been conducted. However, based on its pharmacodynamic properties, rosuvastatin is unlikely to affect this ability. When driving vehicles or operating machines, it should be taken into account that dizziness may occur during treatment. 

ASPIRIN
No studies on the effects on the ability to drive and use machines have been performed with Aspirin 75mg Tablets.

Based on the pharmacodynamic properties and the side effects of acetylsalicylic acid, no influence on the reactivity and the ability to drive or use machines is expected.

CLOPIDOGREL
Clopidogrel has no or negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

ROSUVASTATIN
The adverse reactions seen with rosuvastatin are generally mild and transient. In controlled clinical trials, less than 4% of rosuvastatin-treated patients were withdrawn due to adverse reactions.

Tabulated list of adverse reactions
Based on data from clinical studies and extensive post-marketing experience, the following table presents the adverse reaction profile for rosuvastatin. Adverse reactions listed below are classified according to frequency and system organ class (SOC).

The frequencies of adverse reactions are ranked according to the following convention: Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1000); Very rare (<1/10,000); Not known (cannot be estimated from the available data).

Table 2. Adverse reactions based on data from clinical studies and post-marketing experience
 

As with other HMG-CoA reductase inhibitors, the incidence of adverse drug reactions tends to be dose dependent.

Renal effects: Proteinuria, detected by dipstick testing and mostly tubular in origin, has been observed in patients treated with rosuvastatin. Shifts in urine protein from none or trace to ++ or more were seen in <1% of patients at some time during treatment with 10 and 20 mg, and in approximately 3% of patients treated with 40 mg. A minor increase in shift from none or trace to + was observed with the 20 mg dose. In most cases, proteinuria decreases or disappears spontaneously on continued therapy. Review of data from clinical trials and post-marketing experience to date has not identified a causal association between proteinuria and acute or progressive renal disease. Haematuria has been observed in patients treated with rosuvastatin and clinical trial data show that the occurrence is low.

Skeletal muscle effects: Effects on skeletal muscle e.g. myalgia, myopathy (including myositis) and, rarely, rhabdomyolysis with and without acute renal failure have been reported in rosuvastatin-treated patients with all doses and in particular with doses > 20 mg. A dose-related increase in CK levels has been observed in patients taking rosuvastatin; the majority of cases were mild, asymptomatic and transient. If CK levels are elevated (>5xULN), treatment should be discontinued. 

Liver effects: As with other HMG-CoA reductase inhibitors, a dose-related increase in transaminases has been observed in a small number of patients taking rosuvastatin; the majority of cases were mild, asymptomatic and transient.

The following adverse events have been reported with some statins:

• Sexual dysfunction.
• Exceptional cases of interstitial lung disease, especially with long term therapy.
• The reporting rates for rhabdomyolysis, serious renal events and serious hepatic events (consisting mainly of increased hepatic transaminases) is higher at the 40 mg dose.

ASPIRIN
Side effects are grouped on the basis of System Organ Class. Within each system organ class the frequencies are defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data)

 

CLOPIDOGREL

Summary of the safety profile
Clopidogrel has been evaluated for safety in more than 44,000 patients who have participated in clinical studies, including over 12,000 patients treated for 1 year or more. Overall, clopidogrel 75 mg/day was comparable to ASA 325 mg/day in CAPRIE regardless of age, gender and race. The clinically relevant adverse reactions observed in the CAPRIE, CURE, CLARITY, COMMIT and ACTIVE-A studies are discussed below. In addition to clinical studies experience, adverse reactions have been spontaneously reported.

Bleeding is the most common reaction reported both in clinical studies as well as in post-marketing experience where it was mostly reported during the first month of treatment.

In CAPRIE, in patients treated with either clopidogrel or ASA, the overall incidence of any bleeding was 9.3%. The incidence of severe cases was similar for clopidogrel and ASA.

In CURE, there was no excess in major bleeds with clopidogrel plus ASA within 7 days after coronary bypass graft surgery in patients who stopped therapy more than five days prior to surgery. In patients who remained on therapy within five days of bypass graft surgery, the event rate was 9.6% for clopidogrel plus ASA, and 6.3% for placebo plus ASA.

In CLARITY, there was an overall increase in bleeding in the clopidogrel plus ASA group vs. the placebo plus ASA group. The incidence of major bleeding was similar between groups. This was consistent across subgroups of patients defined by baseline characteristics, and type of fibrinolytic or heparin therapy. In COMMIT, the overall rate of noncerebral major bleeding or cerebral bleeding was low and similar in both groups.

In ACTIVE-A, the rate of major bleeding was greater in the clopidogrel + ASA group than in the placebo + ASA group (6.7% versus 4.3%). Major bleeding was mostly of extracranial origin in both groups (5.3% in the clopidogrel + ASA group; 3.5% in the placebo +ASA group), mainly from the gastrointestinal tract (3.5% vs. 1.8%). There was an excess of intracranial bleeding in the clopidogrel + ASA treatment group compared to the placebo + ASA group (1.4% versus 0.8%, respectively). There was no statistically significant difference in the rates of fatal bleeding (1.1% in the clopidogrel + ASA group and 0.7% in the placebo +ASA group) and haemorrhagic stroke (0.8% and 0.6%, respectively) between groups.

Tabulated list of adverse reactions
Adverse reactions that occurred either during clinical studies or that were spontaneously reported are presented in the table below. Their frequency is defined using the following conventions: common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data). Within each system organ class, adverse reactions are presented in order of decreasing seriousness.

*Information related to clopidogrel with frequency “not known”.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zuventus.com

Website: Website: https://www.zuventus.co.in/drug-safety-reporting

By reporting side effects, you can help provide more information on the safety of this medicine.

4.9. Overdose

ROSUVASTATIN
There is no specific treatment in the event of overdose. In the event of overdose, the patient should be treated symptomatically and supportive measures instituted as required. Liver function and CK levels should be monitored. Haemodialysis is unlikely to be of benefit.

ASPIRIN
Although considerable inter-individual variations are involved, it can be considered that the toxic dose is about 200 mg/kg in adults and 100 mg/kg in children. The lethal dose of acetylsalicylic acid is 25-30 grams. Plasma salicylate concentrations above 300 mg/l indicate intoxication. Plasma concentrations above 500 mg/l in adults and 300 mg/l in children generally cause severe toxicity. Overdose may be harmful for elderly patients and particularly for small children (therapeutic overdose or frequent accidental intoxications may be fatal).

Symptoms of moderate intoxications
Tinnitus, hearing disorders, headache, vertigo, confusion and gastrointestinal symptoms (nausea, vomiting and abdominal pain).

Symptoms of severe intoxications
Symptoms are related to severe disruption of the acid-base balance. In the first instance hyperventilation occurs, which results in respiratory alkalosis. Respiratory acidosis ensues due to suppression of the respiratory centre. In addition, metabolic acidosis occurs as a result of the presence of salicylate.
Since younger children are often not seen until they have reached a late stage of intoxication, they are usually in the stage of acidosis. Furthermore, the following symptoms may occur: hyperthermia and perspiration, resulting in dehydration: feelings of restlessness, convulsions, hallucinations and hypoglycaemia. Depression of the nervous system may lead to coma, cardiovascular collapse or respiratory arrest.

Treatment of overdose
If a toxic dose has been ingested, hospital admission is required. In the event of moderate intoxication, inducing the patient to vomit should be attempted. If this fails, gastric lavage may be attempted during the first hour after ingestion of a substantial amount of the medicine. Afterwards, administer activated carbon (adsorbent) and sodium sulfate (laxative).

Activated charcoal may be given as a single dose (50 g for an adult, 1 g/kg body weight for a child up to 12 years).

Alkalisation of the urine (250 mmol NaHCO3, for three hours) whilst checking urine pH levels. In the event of severe intoxication, haemodialysis is to be preferred. Other symptoms to be treated symptomatically.

CLOPIDOGREL
Overdose following clopidogrel administration may lead to prolonged bleeding time and subsequent bleeding complications. Appropriate therapy should be considered, if bleedings are observed. No antidote to the pharmacological activity of clopidogrel has been found. If prompt correction of prolonged bleeding time is required, platelet transfusion may reverse the effects of clopidogrel.

1. Pharmacodynamic properties

ROSUVASTATIN

Mechanism of action
Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor for cholesterol. The primary site of action of rosuvastatin is the liver, the target organ for cholesterol lowering.

Rosuvastatin increases the number of hepatic LDL receptors on the cell-surface, enhancing uptake and catabolism of LDL and it inhibits the hepatic synthesis of VLDL, thereby reducing the total number of VLDL and LDL particles.

Pharmacodynamic effects
Rosuvastatin reduces elevated LDL-cholesterol, total cholesterol and triglycerides and increases HDL-cholesterol. It also lowers ApoB, non-HDL-C, VLDL-C, VLDL-TG and increases ApoA-I (see Table 3). Crestor also lowers the LDL-C/HDL-C, total C/HDL-C and non-HDL-C/HDL-C and the ApoB/ApoA-I ratios.

Table 3 Dose response in patients with primary hypercholesterolaemia (type IIa and IIb) (adjusted mean percent change from baseline)
 

A therapeutic effect is obtained within 1 week following treatment initiation and 90% of maximum response is achieved in 2 weeks. The maximum response is usually achieved by 4 weeks and is maintained after that.

Clinical efficacy and safety
Rosuvastatin is effective in adults with hypercholesterolaemia, with and without hypertriglyceridaemia, regardless of race, sex or age and in special populations such as diabetics or patients with familial hypercholesterolaemia.

From pooled phase III data, Rosuvastatin has been shown to be effective at treating the majority of patients with type IIa and IIb hypercholesterolaemia (mean baseline LDL-C about 4.8 mmol/L) to recognised European Atherosclerosis Society (EAS; 1998) guideline targets; about 80% of patients treated with 10 mg reached the EAS targets for LDL-C levels (<3 mmol/L).

In a large study, 435 patients with heterozygous familial hypercholesterolaemia were given rosuvastatin from 20 mg to 80 mg in a force-titration design. All doses showed a beneficial effect on lipid parameters and treatment to target goals. Following titration to a daily dose of 40 mg (12 weeks of treatment), LDL-C was reduced by 53%. Thirty-three percent (33%) of patients reached EAS guidelines for LDL-C levels (<3 mmol/L).

In a force-titration, open label trial, 42 patients (including 8 paediatric patients) with homozygous familial hypercholesterolaemia were evaluated for their response to rosuvastatin 20 – 40 mg. In the overall population, the mean LDL-C reduction was 22%.

In clinical studies with a limited number of patients, rosuvastatin has been shown to have additive efficacy in lowering triglycerides when used in combination with fenofibrate and in increasing HDL-C levels when used in combination with niacin.

In a multi-centre, double-blind, placebo-controlled clinical study (METEOR), 984 patients between 45 and 70 years of age and at low risk for coronary heart disease (defined as Framingham risk <10% over 10 years), with a mean LDL-C of 4.0 mmol/L (154.5 mg/dL), but with subclinical atherosclerosis (detected by Carotid Intima Media Thickness) were randomised to 40 mg rosuvastatin once daily or placebo for 2 years. Rosuvastatin significantly slowed the rate of progression of the maximum CIMT for the 12 carotid artery sites compared to placebo by -0.0145 mm/year [95% confidence interval -0.0196, -0.0093; p<0.0001]. The change from baseline was -0.0014 mm/year (-0.12%/year (non-significant)) for rosuvastatin compared to a progression of +0.0131 mm/year (1.12%/year (p<0.0001)) for placebo. No direct correlation between CIMT decrease and reduction of the risk of cardiovascular events has yet been demonstrated. The population studied in METEOR is low risk for coronary heart disease and does not represent the target population of rosuvastatin 40 mg. The 40 mg dose should only be prescribed in patients with severe hypercholesterolaemia at high cardiovascular risk.

In the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) study, the effect of rosuvastatin on the occurrence of major atherosclerotic cardiovascular disease events was assessed in 17,802 men (≥50 years) and women (≥60 years).

Study participants were randomly assigned to placebo (n=8901) or rosuvastatin 20 mg once daily (n=8901) and were followed for a mean duration of 2 years.

LDL-cholesterol concentration was reduced by 45% (p<0.001) in the rosuvastatin group compared to the placebo group.

In a post-hoc analysis of a high-risk subgroup of subjects with a baseline Framingham risk score >20% (1558 subjects) there was a significant reduction in the combined end-point of cardiovascular death, stroke and myocardial infarction (p=0.028) on rosuvastatin treatment versus placebo. The absolute risk reduction in the event rate per 1000 patient-years was 8.8. Total mortality was unchanged in this high-risk group (p=0.193). In a post-hoc analysis of a high-risk subgroup of subjects (9302 subjects total) with a baseline SCORE risk ≥5% (extrapolated to include subjects above 65 yrs) there was a significant reduction in the combined end-point of cardiovascular death, stroke and myocardial infarction (p=0.0003) on rosuvastatin treatment versus placebo. The absolute risk reduction in the event rate was 5.1 per 1000 patient-years. Total mortality was unchanged in this high-risk group (p=0.076).

In the JUPITER trial, there were 6.6% of rosuvastatin and 6.2% of placebo subjects who discontinued use of study medication due to an adverse event. The most common adverse events that led to treatment discontinuation were: myalgia (0.3% rosuvastatin, 0.2% placebo), abdominal pain (0.03% rosuvastatin, 0.02% placebo) and rash (0.02% rosuvastatin, 0.03% placebo). The most common adverse events at a rate greater than or equal to placebo were urinary tract infection (8.7% rosuvastatin, 8.6% placebo), nasopharyngitis (7.6% rosuvastatin, 7.2% placebo), back pain (7.6% rosuvastatin, 6.9% placebo) and myalgia (7.6% rosuvastatin, 6.6% placebo).

ASPIRIN
Acetylsalicylic acid inhibits the platelet activation: blocking the platelet cyclooxygenase by acetylation, it inhibits thromboxane A2 synthesis, a physiological activating substance released by the platelets and which would play a role in the complications of the atheromatosic lesions.

Inhibition of TXA2-synthesis is irreversible, because thrombocytes, which have no nucleus, are not capable (due to lack of protein synthesis capability) to synthesise new cyclooxygenase, which had been acetylated by acetylsalicylic acid.

The repeated doses from 20 to 325 mg involve an inhibition of the enzymatic activity from 30 to 95%.
Due to the irreversible nature of the binding, the effect persists for the lifespan of a thrombocyte (7-10 days). The inhibiting effect does not exhaust during prolonged treatments and the enzymatic activity gradually begins again upon renewal of the platelets 24 to 48 hours after treatment interruption.

Acetylsalicylic acid extends bleeding time on average by approximately 50 to 100%, but individual variations can be observed.

Experimental data suggest that ibuprofen may inhibit the effect of low dose acetylsalicylic acid on platelet aggregation when they are dosed concomitantly.

In one study, when a single dose of ibuprofen 400 mg was taken within 8 h before or within 30 min after immediate release acetylsalicylic acid dosing (81 mg), a decreased effect of acetylsalicylic acid on the formation of thromboxane or platelet aggregation occurred. However, the limitations of these data and the uncertainties regarding extrapolation of ex vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no clinically relevant effect is considered to be likely for occasional ibuprofen use.

CLOPIDOGREL

Mechanism of action
Clopidogrel is a prodrug, one of whose metabolites is an inhibitor of platelet aggregation. Clopidogrel must be metabolised by CYP450 enzymes to produce the active metabolite that inhibits platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet P2Y12 receptor and the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. Due to the irreversible binding, platelets exposed are affected for the remainder of their lifespan (approximately 7-10 days) and recovery of normal platelet function occurs at a rate consistent with platelet turnover. Platelet aggregation induced by agonists other than ADP is also inhibited by blocking the amplification of platelet activation by released ADP.

Because the active metabolite is formed by CYP450 enzymes, some of which are polymorphic or subject to inhibition by other medicinal products, not all patients will have adequate platelet inhibition.

Pharmacodynamic effects
Repeated doses of 75 mg per day produced substantial inhibition of ADP-induced platelet aggregation from the first day; this increased progressively and reached steady state between Day 3 and Day 7. At steady state, the average inhibition level observed with a dose of 75 mg per day was between 40% and 60%. Platelet aggregation and bleeding time gradually returned to baseline values, generally within 5 days after treatment was discontinued.

Clinical efficacy and safety
The safety and efficacy of clopidogrel have been evaluated in 5 double-blind studies involving over 88,000 patients: the CAPRIE study, a comparison of clopidogrel to ASA, and the CURE, CLARITY, COMMIT and ACTIVE-A studies comparing clopidogrel to placebo, both medicinal products given in combination with ASA and other standard therapy.

Recent myocardial infarction (MI), recent stroke or established peripheral arterial disease
The CAPRIE study included 19,185 patients with atherothrombosis as manifested by recent myocardial infarction (<35 days), recent ischaemic stroke (between 7 days and 6 months) or established peripheral arterial disease (PAD). Patients were randomised to clopidogrel 75 mg/day or ASA 325 mg/day, and were followed for 1 to 3 years. In the myocardial infarction subgroup, most of the patients received ASA for the first few days following the acute myocardial infarction.

Clopidogrel significantly reduced the incidence of new ischaemic events (combined end point of myocardial infarction, ischaemic stroke and vascular death) when compared to ASA. In the intention to treat analysis, 939 events were observed in the clopidogrel group and 1,020 events with ASA (relative risk reduction (RRR) 8.7%, [95% CI: 0.2 to 16.4]; p=0.045), which corresponds, for every 1,000 patients treated for 2 years, to 10 [CI: 0 to 20] additional patients being prevented from experiencing a new ischaemic event. Analysis of total mortality as a secondary endpoint did not show any significant difference between clopidogrel (5.8%) and ASA (6.0%).

In a subgroup analysis by qualifying condition (myocardial infarction, ischaemic stroke, and PAD) the benefit appeared to be strongest (achieving statistical significance at p=0.003) in patients enrolled due to PAD (especially those who also had a history of myocardial infarction) (RRR = 23.7%; CI: 8.9 to 36.2) and weaker (not significantly different from ASA) in stroke patients (RRR = 7.3%; CI: -5.7 to 18.7 [p=0.258]). In patients who were enrolled in the trial on the sole basis of a recent myocardial infarction, clopidogrel was numerically inferior, but not statistically different from ASA (RRR = -4.0%; CI: -22.5 to 11.7 [p=0.639]). In addition, a subgroup analysis by age suggested that the benefit of clopidogrel in patients over 75 years was less than that observed in patients ≤75 years.

Since the CAPRIE trial was not powered to evaluate efficacy of individual subgroups, it is not clear whether the differences in relative risk reduction across qualifying conditions are real, or a result of chance.

Acute coronary syndrome
The CURE study included 12,562 patients with non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction), and presenting within 24 hours of onset of the most recent episode of chest pain or symptoms consistent with ischaemia. Patients were required to have either ECG changes compatible with new ischaemia or elevated cardiac enzymes or troponin I or T to at least twice the upper limit of normal. Patients were randomised to clopidogrel (300 mg loading dose followed by 75 mg/day, N=6,259) or placebo (N=6,303), both given in combination with ASA (75-325 mg once daily) and other standard therapies. Patients were treated for up to one year. In CURE, 823 (6.6%) patients received concomitant GPIIb/IIIa receptor antagonist therapy. Heparins were administered in more than 90% of the patients and the relative rate of bleeding between clopidogrel and placebo was not significantly affected by the concomitant heparin therapy.

The number of patients experiencing the primary endpoint [cardiovascular (CV) death, myocardial infarction (MI), or stroke] was 582 (9.3%) in the clopidogrel-treated group and 719 (11.4%) in the placebo-treated group, a 20% relative risk reduction (95% CI of 10%-28%; p=0.00009) for the clopidogrel-treated group (17% relative risk reduction when patients were treated conservatively, 29% when they underwent percutaneous transluminal coronary angioplasty (PTCA) with or without stent and 10% when they underwent coronary artery bypass graft (CABG)). New cardiovascular events (primary endpoint) were prevented, with relative risk reductions of 22% (CI: 8.6, 33.4), 32% (CI: 12.8, 46.4), 4% (CI: -26.9, 26.7), 6% (CI: -33.5, 34.3) and 14% (CI: -31.6, 44.2), during the 0-1, 1-3, 3-6, 6-9 and 9-12 month study intervals, respectively. Thus, beyond 3 months of treatment, the benefit observed in the clopidogrel + ASA group was not further increased, whereas the risk of haemorrhage persisted.

The use of clopidogrel in CURE was associated with a decrease in the need of thrombolytic therapy (RRR = 43.3%; CI: 24.3%, 57.5%) and GPIIb/IIIa inhibitors (RRR = 18.2%; CI: 6.5%, 28.3%).

The number of patients experiencing the co-primary endpoint (CV death, MI, stroke or refractory ischaemia) was 1,035 (16.5%) in the clopidogrel-treated group and 1,187 (18.8%) in the placebo-treated group, a 14% relative risk reduction (95% CI of 6%-21%, p=0.0005) for the clopidogrel-treated group. This benefit was mostly driven by the statistically significant reduction in the incidence of MI [287 (4.6%) in the clopidogrel treated group and 363 (5.8%) in the placebo treated group]. There was no observed effect on the rate of rehospitalisation for unstable angina.

The results obtained in populations with different characteristics (e.g. unstable angina or non-Q-wave MI, low to high risk levels, diabetes, need for revascularisation, age, gender, etc.) were consistent with the results of the primary analysis. In particular, in a post-hoc analysis in 2,172 patients (17% of the total CURE population) who underwent stent placement (Stent-CURE), the data showed that clopidogrel compared to placebo, demonstrated a significant RRR of 26.2% favouring clopidogrel for the co-primary endpoint (CV death, MI, stroke) and also a significant RRR of 23.9% for the second co-primary endpoint (CV death, MI, stroke or refractory ischaemia). Moreover, the safety profile of clopidogrel in this subgroup of patients did not raise any particular concern. Thus, the results from this subset are in line with the overall trial results.

The benefits observed with clopidogrel were independent of other acute and long-term cardiovascular therapies (such as heparin/LMWH, GPIIb/IIIa antagonists, lipid lowering medicinal products, beta blockers, and ACE-inhibitors). The efficacy of clopidogrel was observed independently of the dose of ASA (75-325 mg once daily).

In patients with acute ST-segment elevation MI, safety and efficacy of clopidogrel have been evaluated in 2 randomised, placebo-controlled, double-blind studies, CLARITY and COMMIT.

The CLARITY trial included 3,491 patients presenting within 12 hours of the onset of a ST elevation MI and planned for thrombolytic therapy. Patients received clopidogrel (300 mg loading dose, followed by 75 mg/day, n=1,752) or placebo (n=1,739), both in combination with ASA (150 to 325 mg as a loading dose, followed by 75 to 162 mg/day), a fibrinolytic agent and, when appropriate, heparin. The patients were followed for 30 days. The primary endpoint was the occurrence of the composite of an occluded infarct-related artery on the predischarge angiogram, or death or recurrent MI before coronary angiography. For patients who did not undergo angiography, the primary endpoint was death or recurrent myocardial infarction by Day 8 or by hospital discharge. The patient population included 19.7% women and 29.2% patients ≥ 65 years. A total of 99.7% of patients received fibrinolytics (fibrin specific: 68.7%, non-fibrin specific: 31.1%), 89.5% heparin, 78.7% beta blockers, 54.7% ACE inhibitors and 63% statins.

Fifteen percent (15.0%) of patients in the clopidogrel group and 21.7% in the placebo group reached the primary endpoint, representing an absolute reduction of 6.7% and a 36 % odds reduction in favor of clopidogrel (95% CI: 24, 47%; p < 0.001), mainly related to a reduction in occluded infarct-related arteries. This benefit was consistent across all prespecified subgroups including patients' age and gender, infarct location, and type of fibrinolytic or heparin used.

The 2x2 factorial design COMMIT trial included 45,852 patients presenting within 24 hours of the onset of the symptoms of suspected MI with supporting ECG abnormalities (i.e. ST elevation, ST depression or left bundle-branch block). Patients received clopidogrel (75 mg/day, n=22,961) or placebo (n=22,891), in combination with ASA (162 mg/day), for 28 days or until hospital discharge. The co-primary endpoints were death from any cause and the first occurrence of re-infarction, stroke or death. The population included 27.8% women, 58.4% patients ≥ 60 years (26% ≥ 70 years) and 54.5% patients who received fibrinolytics.

Clopidogrel significantly reduced the relative risk of death from any cause by 7% (p=0.029), and the relative risk of the combination of re-infarction, stroke or death by 9% (p=0.002), representing an absolute reduction of 0.5% and 0.9%, respectively. This benefit was consistent across age, gender and with or without fibrinolytics, and was observed as early as 24 hours.

De-escalationofP2Y12 Inhibitor Agents in ACS
Switching from a more potent P2Y12 receptor inhibitor to clopidogrel in association with aspirin after acute phase in ACS has been evaluated in two randomized investigator-sponsored studies (ISS) - TOPIC and TROPICAL-ACS - with clinical outcome data.

The clinical benefit provided by the more potent P2Y12 inhibitors, ticagrelor and prasugrel, in their pivotal studies is related to a significant reduction in recurrent ischaemic events (including acute and subacute stent thrombosis (ST), myocardial infarction (MI), and urgent revascularization). Although the ischaemic benefit was consistent throughout the first year, greater reduction in ischaemic recurrence after ACS was observed during the initial days following the treatment initiation. In contrast, post-hoc analyses demonstrated statistically significant increases in the bleeding risk with the more potent P2Y12 inhibitors, occurring predominantly during the maintenance phase, after the first month post- ACS. TOPIC and TROPICAL-ACS were designed to study how to mitigate the bleeding events while maintaining efficacy.

TOPIC (Timing Of Platelet Inhibition after acute Coronary syndrome)
This randomized, open-label trial included ACS patients requiring PCI. Patients on aspirin and a more potent P2Y12 blocker and without adverse event at one month were assigned to switch to fixed-dose aspirin plus clopidogrel (de- escalated dual antiplatelet therapy (DAPT)) or continuation of their drug regimen (unchanged DAPT).

Overall, 645 of 646 patients with STEMI or NSTEMI or unstable angina were analyzed (de-escalated DAPT (n=322); unchanged DAPT (n=323)). Follow-up at one year was performed for 316 patients (98.1%) in the de-escalated DAPT group and 318 patients (98.5%) in the unchanged DAPT group. The median follow-up for both groups was 359 days. The characteristics of the studied cohort were similar in the 2 groups.

The primary outcome, a composite of cardiovascular death, stroke, urgent revascularization, and BARC (Bleeding Academic Research Consortium) bleeding ≥2 at 1-year post ACS, occurred in 43 patients (13.4%) in the de-escalated DAPT group and in 85 patients (26.3%) in the unchanged DAPT group (p<0.01). This statistically significant difference was mainly driven by fewer bleeding events, with no difference reported in ischaemic endpoints (p=0.36), while BARC ≥2 bleeding occurred less frequently in the de-escalated DAPT group (4.0%) versus 14.9% in the unchanged DAPT group (p<0.01). Bleeding events defined as all BARC occurred in 30 patients (9.3%) in the de-escalated DAPT group and in 76 patients (23.5%) in the unchanged DAPT group (p<0.01).

TROPICAL-ACS (Testing Responsiveness to Platelet Inhibition on Chronic Antiplatelet Treatment for Acute Coronary Syndromes)
This randomized, open-label trial included 2,610 biomarker-positive ACS patients after successful PCI. Patients were randomized to receive either prasugrel 5 or 10 mg/d (Days 0-14) (n=1309), or prasugrel 5 or 10 mg/d (Days 0-7) then de- escalated to clopidogrel 75 mg/d (Days 8-14) (n=1309), in combination with ASA (<100 mg/day). At Day 14, platelet function testing (PFT) was performed. The prasugrel-only patients were continued on prasugrel for 11.5 months.

The de-escalated patients underwent high platelet reactivity (HPR) testing. If HPR≥46 units, the patients were escalated back to prasugrel 5 or 10 mg/d for 11.5 months; if HPR<46 units, the patients continued on clopidogrel 75 mg/d for 11.5 months. Therefore, the guided de-escalation arm had patients on either prasugrel (40%) or clopidogrel (60%). All patients were continued on aspirin and were followed for one year.

The primary endpoint (the combined incidence of CV death, MI, stroke and BARC bleeding grade ≥2 at 12 months) was met showing non-inferiority. Ninety-five patients (7%) in the guided de-escalation group and 118 patients (9%) in the control group (p non-inferiority=0.0004) had an event. The guided de-escalation did not result in an increased combined risk of ischemic events (2.5% in the de-escalation group vs 3.2% in the control group; p non-inferiority=0.0115), nor in the key secondary endpoint of BARC bleeding ≥2 ((5%) in the de-escalation group versus 6% in the control group (p=0.23)). The cumulative incidence of all bleeding events (BARC class 1 to 5) was 9% (114 events) in the guided de- escalation group versus 11% (137 events) in the control group (p=0.14).

Atrial fibrillation
The ACTIVE-W and ACTIVE-A studies, separate trials in the ACTIVE program, included patients with atrial fibrillation (AF) who had at least one risk factor for vascular events. Based on enrollment criteria, physicians enrolled patients in ACTIVE-W if they were candidates for vitamin K antagonist (VKA) therapy (such as warfarin). The ACTIVE-A study included patients who could not receive VKA therapy because they were unable or unwilling to receive the treatment.

The ACTIVE-W study demonstrated that anticoagulant treatment with vitamin K antagonists was more effective than with clopidogrel and ASA.

The ACTIVE-A study (N=7,554) was a multicenter, randomized, double-blind, placebo-controlled study which compared clopidogrel 75 mg/day + ASA (N=3,772) to placebo + ASA (N=3,782). The recommended dose for ASA was 75 to 100 mg/day. Patients were treated for up to 5 years.

Patients randomized in the ACTIVE program were those presenting with documented AF, i.e., either permanent AF or at least 2 episodes of intermittent AF in the past 6 months, and had at least one of the following risk factors: age ≥ 75 years or age 55 to 74 years and either diabetes mellitus requiring drug therapy, or documented previous MI or documented coronary artery disease; treated for systemic hypertension; prior stroke, transient ischaemic attack (TIA), or non-CNS systemic embolus; left ventricular dysfunction with left ventricular ejection fraction <45%; or documented peripheral vascular disease. The mean CHADS2 score was 2.0 (range 0 -6).

The major exclusion criteria for patients were documented peptic ulcer disease within the previous 6 months; prior intracerebral hemorrhage; significant thrombocytopenia (platelet count < 50 x 109/l); requirement for clopidogrel or oral anticoagulants (OAC); or intolerance to any of the two compounds.

Seventy-three percent (73%) of patients enrolled into the ACTIVE-A study were unable to take VKA due to physician assessment, inability to comply with INR (international normalised ratio) monitoring, predisposition to falling or head trauma, or specific risk of bleeding; for 26% of the patients, the physician's decision was based on the patient's unwillingness to take VKA.

The patient population included 41.8 % women. The mean age was 71 years, 41.6% of patients were ≥75 years. A total of 23.0% of patients received anti-arrhythmics, 52.1% beta-blockers, 54.6% ACE inhibitors, and 25.4% statins.

The number of patients who reached the primary endpoint (time to first occurrence of stroke, MI, non-CNS systemic embolism or vascular death) was 832 (22.1%) in the group treated with clopidogrel + ASA and 924 (24.4%) in the placebo + ASA group (relative risk reduction of 11.1%; 95% CI of 2.4% to 19.1%; p=0.013), primarily due to a large reduction in the incidence of strokes. Strokes occurred in 296 (7.8%) patients receiving clopidogrel + ASA and 408 (10.8%) patients receiving placebo + ASA (relative risk reduction, 28.4%; 95% CI, 16.8% to 38.3%; p=0.00001).

Paediatric population
In a dose escalation study of 86 neonates or infants up to 24 months of age at risk for thrombosis (PICOLO), clopidogrel was evaluated at consecutive doses of 0.01, 0.1 and 0.2 mg/kg in neonates and infants and 0.15 mg/kg only in neonates. The dose of 0.2 mg/kg achieved the mean percent inhibition of 49.3% (5 µM ADP-induced platelet aggregation) which was comparable to that of adults taking Plavix 75 mg/day.

In a randomised, double-blind, parallel-group study (CLARINET), 906 paediatric patients (neonates and infants) with cyanotic congenital heart disease palliated with a systemic-to-pulmonary arterial shunt were randomised to receive clopidogrel 0.2 mg/kg (n=467) or placebo (n=439) along with concomitant background therapy up to the time of second stage surgery. The mean time between shunt palliation and first administration of study medicinal product was 20 days. Approximately 88% of patients received concomitant ASA (range of 1 to 23 mg/kg/day). There was no significant difference between groups in the primary composite endpoint of death, shunt thrombosis or cardiac-related intervention prior to 120 days of age following an event considered of thrombotic nature (89 [19.1%] for the clopidogrel group and 90 [20.5%] for the placebo group). Bleeding was the most frequently reported adverse reaction in both clopidogrel and placebo groups; however, there was no significant difference in the bleeding rate between groups. In the long-term safety follow-up of this study, 26 patients with the shunt still in place at one year of age received clopidogrel up to 18 months of age. No new safety concerns were noted during this long-term follow-up.

The CLARINET and the PICOLO trials were conducted using a constituted solution of clopidogrel. In a relative bioavailability study in adults, the constituted solution of clopidogrel showed a similar extent and slightly higher rate of absorption of the main circulating (inactive) metabolite compared to the authorised tablet.

2. Pharmacokinetic properties

ROSUVASTATIN

Absorption: Maximum rosuvastatin plasma concentrations are achieved approximately 5 hours after oral administration. The absolute bioavailability is approximately 20%.

Distribution: Rosuvastatin is taken up extensively by the liver which is the primary site of cholesterol synthesis and LDL-C clearance. The volume of distribution of rosuvastatin is approximately 134 L. Approximately 90% of rosuvastatin is bound to plasma proteins, mainly to albumin.

Metabolism: Rosuvastatin undergoes limited metabolism (approximately 10%). In vitro metabolism studies using human hepatocytes indicate that rosuvastatin is a poor substrate for cytochrome P450-based metabolism. CYP2C9 was the principal isoenzyme involved, with 2C19, 3A4 and 2D6 involved to a lesser extent. The main metabolites identified are the N-desmethyl and lactone metabolites. The N-desmethyl metabolite is approximately 50% less active than rosuvastatin whereas the lactone form is considered clinically inactive. Rosuvastatin accounts for greater than 90% of the circulating HMG-CoA reductase inhibitor activity.

Excretion: Approximately 90% of the rosuvastatin dose is excreted unchanged in the faeces (consisting of absorbed and non-absorbed active substance) and the remaining part is excreted in urine. Approximately 5% is excreted unchanged in urine. The plasma elimination half-life is approximately 19 hours. The elimination half-life does not increase at higher doses. The geometric mean plasma clearance is approximately 50 litres/hour (coefficient of variation 21.7%). As with other HMG-CoA reductase inhibitors, the hepatic uptake of rosuvastatin involves the membrane transporter OATP-C. This transporter is important in the hepatic elimination of rosuvastatin.

Linearity: Systemic exposure of rosuvastatin increases in proportion to dose. There are no changes in pharmacokinetic parameters following multiple daily doses.

Special populations:
Age and sex: There was no clinically relevant effect of age or sex on the pharmacokinetics of rosuvastatin in adults. The exposure in children and adolescents with heterozygous familial hypercholesterolemia appears to be similar to or lower than that in adult patients with dyslipidaemia.

Race: Pharmacokinetic studies show an approximate 2-fold elevation in median AUC and Cmax in Asian subjects (Japanese, Chinese, Filipino, Vietnamese and Koreans) compared with Caucasians; Asian-Indians show an approximate 1.3-fold elevation in median AUC and Cmax. A population pharmacokinetic analysis revealed no clinically relevant differences in pharmacokinetics between Caucasian and Black groups.

Renal insufficiency: In a study in subjects with varying degrees of renal impairment, mild to moderate renal disease had no influence on plasma concentration of rosuvastatin or the N-desmethyl metabolite. Subjects with severe impairment (CrCl <30 ml/min) had a 3-fold increase in plasma concentration and a 9-fold increase in the N-desmethyl metabolite concentration compared to healthy volunteers. Steady-state plasma concentrations of rosuvastatin in subjects undergoing haemodialysis were approximately 50% greater compared to healthy volunteers.

Hepatic insufficiency: In a study with subjects with varying degrees of hepatic impairment, there was no evidence of increased exposure to rosuvastatin in subjects with Child-Pugh scores of 7 or below. However, two subjects with Child-Pugh scores of 8 and 9 showed an increase in systemic exposure of at least 2-fold compared to subjects with lower Child-Pugh scores. There is no experience in subjects with Child-Pugh scores above 9.

Genetic polymorphisms: Disposition of HMG-CoA reductase inhibitors, including rosuvastatin, involves OATP1B1 and BCRP transporter proteins. In patients with SLCO1B1 (OATP1B1) and/or ABCG2 (BCRP) genetic polymorphisms there is a risk of increased rosuvastatin exposure. Individual polymorphisms of SLCO1B1 c.521CC and ABCG2 c.421AA are associated with a higher rosuvastatin exposure (AUC) compared to the SLCO1B1 c.521TT or ABCG2 c.421CC genotypes. This specific genotyping is not established in clinical practice, but for patients who are known to have these types of polymorphisms, a lower daily dose of rosuvastatin is recommended.

ASPIRIN

Absorption
After oral administration, acetylsalicylic acid is rapidly absorbed from the gastrointestinal tract. However, a significant portion of the dosage is already hydrolysed to salicylic acid in the intestinal wall during the absorption process.

Distribution
Acetylsalicylic acid as well as the main metabolite salicylic acid, are extensively bound to plasma proteins, primarily albumin, and distributed rapidly into all parts of the body. Maximum plasma concentration is reached after 0.3 - 2 hours (total salicylate). The volume of distribution of acetylsalicylic acid is ca. 0.16 l/kg of body weight.

Biotransformation
Acetylsalicylic acid is rapidly metabolised to salicylic acid, with a half-life of 15-30 minutes. Salicylic acid is subsequently predominantly converted into glycine and glucuronic acid conjugates.

Elimination kinetics of salicylic acid is dose-dependent, because the metabolism is limited by liver enzyme capacity. Thus, elimination half-time varies and is 2-3 hours after low doses (75 mg – 160 mg).

Excretion
Salicylic acid and its metabolites are predominantly excreted via the kidneys.

CLOPIDOGREL

Absorption
After single and repeated oral doses of 75 mg per day, clopidogrel is rapidly absorbed. Mean peak plasma levels of unchanged clopidogrel (approximately 2.2-2.5 ng/ml after a single 75 mg oral dose) occurred approximately 45 minutes after dosing. Absorption is at least 50%, based on urinary excretion of clopidogrel metabolites.

Distribution
Clopidogrel and the main circulating (inactive) metabolite bind reversibly in vitro to human plasma proteins (98% and 94% respectively). The binding is non-saturable in vitro over a wide concentration range.

Biotransformation
Clopidogrel is extensively metabolised by the liver. In vitro and in vivo, clopidogrel is metabolised according to two main metabolic pathways: one mediated by esterases and leading to hydrolysis into its inactive carboxylic acid derivative (85% of circulating metabolites), and one mediated by multiple cytochromes P450. Clopidogrel is first metabolised to a 2-oxo-clopidogrel intermediate metabolite. Subsequent metabolism of the 2-oxo-clopidogrel intermediate metabolite results in formation of the active metabolite, a thiol derivative of clopidogrel. The active metabolite is formed mostly by CYP2C19 with contributions from several other CYP enzymes, including CYP1A2, CYP2B6 and CYP3A4. The active thiol metabolite which has been isolated in vitro, binds rapidly and irreversibly to platelet receptors, thus inhibiting platelet aggregation.

The C_max of the active metabolite is twice as high following a single 300-mg clopidogrel loading dose as it is after four days of 75-mg maintenance dose. C_max occurs approximately 30 to 60 minutes after dosing.

Elimination
Following an oral dose of 14C-labelled clopidogrel in man, approximately 50% was excreted in the urine and approximately 46% in the faeces in the 120-hour interval after dosing. After a single oral dose of 75 mg, clopidogrel has a half-life of approximately 6 hours. The elimination half-life of the main circulating (inactive) metabolite was 8 hours after single and repeated administration.

Pharmacogenetics
CYP2C19 is involved in the formation of both the active metabolite and the 2-oxo-clopidogrel intermediate metabolite. Clopidogrel active metabolite pharmacokinetics and antiplatelet effects, as measured by ex vivo platelet aggregation assays, differ according to CYP2C19 genotype.

The CYP2C19*1 allele corresponds to fully functional metabolism while the CYP2C19*2 and CYP2C19*3 alleles are nonfunctional. The CYP2C19*2 and CYP2C19*3 alleles account for the majority of reduced function alleles in Caucasian (85%) and Asian (99%) poor metabolisers. Other alleles associated with absent or reduced metabolism are less frequent and include CYP2C19*4, *5, *6, *7, and *8. A patient with poor metaboliser status will possess two loss-of-function alleles as defined above. Published frequencies for the poor CYP2C19 metaboliser genotypes are approximately 2% for Caucasians, 4% for Blacks and 14% for Chinese. Tests are available to determine a patient's CYP2C19 genotype.

A crossover study in 40 healthy subjects, 10 each in the four CYP2C19 metaboliser groups (ultrarapid, extensive, intermediate and poor), evaluated pharmacokinetic and antiplatelet responses using 300 mg followed by 75 mg/day and 600 mg followed by 150 mg/day, each for a total of 5 days (steady state). No substantial differences in active metabolite exposure and mean inhibition of platelet aggregation (IPA) were observed between ultrarapid, extensive and intermediate metabolisers. In poor metabolisers, active metabolite exposure was decreased by 63-71% compared to extensive metabolisers. After the 300 mg/75 mg dose regimen, antiplatelet responses were decreased in the poor metabolisers with mean IPA (5 μM ADP) of 24% (24 hours) and 37% (Day 5) as compared to IPA of 39% (24 hours) and 58% (Day 5) in the extensive metabolisers and 37% (24 hours) and 60% (Day 5) in the intermediate metabolisers. When poor metabolisers received the 600 mg/150 mg regimen, active metabolite exposure was greater than with the 300 mg/75 mg regimen. In addition, IPA was 32% (24 hours) and 61% (Day 5), which were greater than in the poor metabolisers receiving the 300 mg/75 mg regimen, and were similar to the other CYP2C19 metaboliser groups receiving the 300 mg/75 mg regimen. An appropriate dose regimen for this patient population has not been established in clinical outcome trials.

Consistent with the above results, in a meta-analysis including 6 studies of 335 clopidogrel-treated subjects at steady state, it was shown that active metabolite exposure was decreased by 28% for intermediate metabolisers, and 72% for poor metabolisers while platelet aggregation inhibition (5 μM ADP) was decreased with differences in IPA of 5.9% and 21.4%, respectively, when compared to extensive metabolisers.

The influence of CYP2C19 genotype on clinical outcomes in patients treated with clopidogrel has not been evaluated in prospective, randomised, controlled trials. There have been a number of retrospective analyses, however, to evaluate this effect in patients treated with clopidogrel for whom there are genotyping results: CURE (n=2721), CHARISMA (n=2428), CLARITY-TIMI 28 (n=227), TRITON-TIMI 38 (n=1477), and ACTIVE-A (n=601), as well as a number of published cohort studies.

In TRITON-TIMI 38 and 3 of the cohort studies (Collet, Sibbing, Giusti) the combined group of patients with either intermediate or poor metaboliser status had a higher rate of cardiovascular events (death, myocardial infarction, and stroke) or stent thrombosis compared to extensive metabolisers.

In CHARISMA and one cohort study (Simon), an increased event rate was observed only in poor metabolisers when compared to extensive metabolisers.

In CURE, CLARITY, ACTIVE-A and one of the cohort studies (Trenk), no increased event rate was observed based on metaboliser status.

None of these analyses were adequately sized to detect differences in outcome in poor metabolisers.

Special populations
The pharmacokinetics of the active metabolite of clopidogrel is not known in these special populations.

Renal impairment
After repeated doses of 75 mg clopidogrel per day in subjects with severe renal disease (creatinine clearance from 5 to 15 ml/min), inhibition of ADP-induced platelet aggregation was lower (25%) than that observed in healthy subjects, however, the prolongation of bleeding time was similar to that seen in healthy subjects receiving 75 mg of clopidogrel per day. In addition, clinical tolerance was good in all patients.

Hepatic impairment
After repeated doses of 75 mg clopidogrel per day for 10 days in patients with severe hepatic impairment, inhibition of ADP-induced platelet aggregation was similar to that observed in healthy subjects. The mean bleeding time prolongation was also similar in the two groups.

Race
The prevalence of CYP2C19 alleles that result in intermediate and poor CYP2C19 metabolism differs according to race/ethnicity (see Pharmacogenetics). From literature, limited data in Asian populations are available to assess the clinical implication of genotyping of this CYP on clinical outcome events.

ROSUVASTATIN
Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity and carcinogenicity potential. Specific tests for effects on hERG have not been evaluated. Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels were as follows: In repeated-dose toxicity studies histopathologic liver changes likely due to the pharmacologic action of rosuvastatin were observed in mouse, rat, and to a lesser extent with effects in the gall bladder in dogs, but not in monkeys. In addition, testicular toxicity was observed in monkeys and dogs at higher dosages. Reproductive toxicity was evident in rats, with reduced litter sizes, litter weight and pup survival observed at maternally toxic doses, where systemic exposures were several times above the therapeutic exposure level.

ASPIRIN
The nonclinical safety profile of acetylsalicylic acid is well documented.
In experimental animal studies, salicylates have shown no other organ injury than renal damage. In rat studies, fetotoxicity and teratogenic effects were observed with acetylsalicylic acid at maternotoxic doses. Clinical relevance is unknown as the doses used in non-clinical studies are much higher (7 times at least) than the maximal recommended doses in targeted cardiovascular indications. Acetylsalicylic acid was extensively investigated with regard to mutagenic and carcinogenic effects. The results as a whole show no relevant signs for any mutagenic or carcinogenic effects in mice and rat studies.

CLOPIDOGREL
During non-clinical studies in rat and baboon, the most frequently observed effects were liver changes. These occurred at doses representing at least 25 times the exposure seen in humans receiving the clinical dose of 75 mg/day and were a consequence of an effect on hepatic metabolising enzymes. No effect on hepatic metabolising enzymes was observed in humans receiving clopidogrel at the therapeutic dose.
At very high doses, a poor gastric tolerability (gastritis, gastric erosions and/or vomiting) of clopidogrel was also reported in rat and baboon.

There was no evidence of carcinogenic effect when clopidogrel was administered for 78 weeks to mice and 104 weeks to rats when given at doses up to 77 mg/kg per day (representing at least 25 times the exposure seen in humans receiving the clinical dose of 75 mg/day).

Clopidogrel has been tested in a range of in vitro and in vivo genotoxicity studies, and showed no genotoxic activity.

Clopidogrel was found to have no effect on the fertility of male and female rats and was not teratogenic in either rats or rabbits. When given to lactating rats, clopidogrel caused a slight delay in the development of the offspring. Specific pharmacokinetic studies performed with radiolabelled clopidogrel have shown that the parent compound or its metabolites are excreted in the milk. Consequently, a direct effect (slight toxicity), or an indirect effect (low palatability) cannot be excluded.
 

REVOSTAT GOLD® is a fixed dose combination of Rosuvastatin, Aspirin, and Clopidogrel. Rosuvastatin acts as a selective and competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor of cholesterol. Aspirin [acetylsalicylic acid (ASA)] inhibits prostaglandin synthesis resulting in inhibition of platelet aggregation. Clopidogrel is an inhibitor of platelet activation and aggregation through the irreversible binding of its active metabolite to the P2Y12 class of ADP receptors on platelets. Each hard gelatin capsule contains Rosuvastatin (10 mg) + Aspirin (75 mg) + Clopidogrel (75 mg) IP + Excipient (q.s).
 

Chemical structure of Rosuvastatin

Chemical structure of Aspirin

Chemical structure of Clopidogrel

1. Incompatibilities
None 

2. Shelf-life
Refer on pack

3. Packaging information
10 capsules per strip

4. Storage and handing instructions
Store below 300c. Protect from light. 
Keep out of reach of children.
 

ROSUVASTATIN

Skeletal Muscle Effects 
Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. 

Concomitant Use of Antacids 
When taking CRESTOR with an aluminum and magnesium hydroxide combination antacid, the antacid should be taken at least 2 hours after CRESTOR administration.

Pregnancy
If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus and the lack of known clinical benefit with continued use during pregnancy.

Liver Enzymes
It is recommended that liver enzymes be checked before and at 12 weeks following both the initiation of therapy and any elevation of dose, and periodically (e.g., semiannually) thereafter.

ASPIRIN
Bleeding
Inform patients that they may bruise or bleed more easily or that it may take longer to stop bleeding and to report to their physician any prolonged, unusual or excessive bleeding. Inform patients to notify their physician about blood in their stool or urine and the signs and symptoms of occult bleeding.

Inform patients about the signs and symptoms of GI side effects and seek medical advice when experiencing any of these signs and symptoms.

Hypersensitivity
Advise the patient to discontinue aspirin and seek immediate medical attention if any signs or symptoms of a hypersensitivity reaction occur.

Alcohol Consumption
Inform patients they should not take aspirin 2 hours before or 1 hour after consuming alcohol. Counsel patients who drink three or more alcoholic drinks every day about the risk of bleeding involved in chronic, heavy alcohol use while taking aspirin.

Administration Instructions
Advise patients to swallow aspirin capsules whole and not to chew or crush them.
Remind patients not to discontinue aspirin without first notifying and discussing with their physician. Advise patients not to use extra medicine to make up a missed dose. Advise patients not to take ibuprofen around the same time as aspirin.

Pregnancy and Lactation
Advise patients that ASA containing products such as aspirin cause harm to fetuses especially during the third trimester of pregnancy. Inform patients to notify their physician if they are pregnant, plan to become pregnant, breastfeed or are considering breastfeeding prior or during receiving treatment with aspirin.

CLOPIDOGREL
Benefits and Risks
Summarize the effectiveness features and potential side effects of Plavix.

Tell patients to take clopidogrel exactly as prescribed.

Remind patients not to discontinue clopidogrel without first discussing it with the physician who prescribed clopidogrel.

Bleeding
Inform patients that they:

• -will bruise and bleed more easily.
• -will take longer than usual to stop bleeding.
• -should report any unanticipated, prolonged, or excessive bleeding, or blood in their stool or urine.

Other Signs and Symptoms Requiring Medical Attention
Inform patients that TTP is a rare but serious condition that has been reported with clopidogrel and other drugs in this class of drugs.

Instruct patients to get prompt medical attention if they experience any of the following symptoms that cannot otherwise be explained: fever, weakness, extreme skin paleness, purple skin patches, yellowing of the skin or eyes, or neurological changes.

16th Jan 2025

Rosuvastatin & Fenofibrate Tablets IP (10 mg + 160 mg)

Each film coated tablet contains:
Rosuvastatin Calcium IP
equivalent to Rosuvastatin ………….. 10 mg
Fenofibrate (Micronised) IP………… 160 mg
Excipients……………………………. q.s.
Colours: Ferric Oxide Yellow USP-NF & Titanium Dioxide IP
 

Film-coated tablet 10mg/160mg

4.1 Therapeutic indication

For the treatment of combined hyperlipidemia in patients with normal hepatic and renal function.

4.2 Posology and method of administration

One Revostat®FB tablet once daily or as directed by the Physician.

4.3 Contraindications

• Patients who are hypersensitivity to any component of this product.
• Patients with active liver disease or renal impairment.
• Patients with preexisting gall bladder disease.
• Pregnancy and lactation.

4.4 Special warnings and precautions for use

Liver Dysfunction

It is recommended that liver enzyme tests be performed before the initiation of REVOSTAT®FB, and if signs or symptoms of liver injury occur.
Increases in serum transaminases [AST (SGOT) or ALT (SGPT)] have been reported with HMG-CoA reductase inhibitors, including REVOSTAT®FB. In most cases, the elevations were transient and resolved or improved on continued therapy or after a brief interruption in therapy. There were two cases of jaundice, for which a relationship to rosuvastatin therapy could not be determined, which resolved after discontinuation of therapy. There were no cases of liver failure or irreversible liver disease in these trials.

In a pooled analysis of placebo-controlled trials, increases in serum transaminases to greater than 3 times the upper limit of normal occurred in 1.1% of patients taking REVOSTAT®FB versus 0.5% of patients treated with placebo. There have been rare post-marketing reports of fatal and non-fatal hepatic failure in patients taking statins, including REVOSTAT®FB. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with REVOSTAT®FB, promptly interrupt therapy. If an alternate etiology is not found, do not restart REVOSTAT®FB. 

REVOSTAT®FB should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of chronic liver disease. Active liver disease, which may include unexplained persistent transaminase elevations, is a contraindication to the use of REVOSTAT®FB.

Hepatic insufficiency

In a study in subjects with varying degrees of hepatic impairment there was no evidence of increased exposure to REVOSTAT®FB other than in the 2 subjects with the most severe liver disease (Child-Pugh scores of 8 and 9). In these subjects, systemic exposure was increased by at least 2-fold compared with subjects with lower Child-Pugh scores. Its recommended that the liver enzyme tests be performed before and after 12 weeks following both the initiation of therapy and any elevation of dose thereafter. 

Renal effects

An assessment of renal function should be considered during routine follow-up of patients treated with higher dose.

Skeletal muscle

Effects on skeletal muscle e.g. uncomplicated myalgia, myopathy and rhabdomyolysis, have been reported in patients treated with REVOSTAT®FB. Patients who develop any signs or symptoms suggestive of myopathy should have their CK levels measured. REVOSTAT®FB therapy should be discontinued if myopathy is diagnosed or suspected. 

An increase in the incidence of myositis and myopathy has been seen in patients receiving other HMG-CoA reductase inhibitors together with cyclosporin, fibric acid derivatives, including gemfibrozil, nicotinic acid, azole antifungals and macrolide antibiotics. 

REVOSTAT®FB should be prescribed with caution in patients with pre-disposing factors for myopathy, such as renal impairment, advanced age and hypothyroidism, or situations where an increase in plasma levels may occur. 

REVOSTAT®FB should be temporarily withheld in any patient with an acute serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g. sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders; or uncontrolled seizures).

4.5 Drug Interaction 

Rosuvastatin:
Cyclosporin: Rosuvastatin steady state AUC increased up (0-t) to 7-fold over that seen in healthy volunteers administered the same dose.

Gemfibrozil: Concomitant use of Rosuvastatin and gemfibrozil resulted in a 2-fold increase in Rosuvastatin C and AUC.

Protease Inhibitor: Co-administration of Rosuvastatin with certain protease inhibitors given in combination with ritonavir has different effects on roasuvastatin exposure. The protease inhibitor combinations lopinavir/ritonavir and atazanavir/ritonavir increase Rosuvastatin exposure up to threefold. For these combination the dose of Rosuvastatin is restricted to low dose.

Coumarin Anticoagulants: Rosuvastatin significantly increased INR (International Normalized Ratio) in patients receiving coumarin anticoagulants. Therefore, caution should be excercised when coumarin anticoagulants are given in conjunction with Rosuvastatin. In patients taking coumarin anticoagulants and Rosuvastatin concomitantly INR should be determined before starting Rosuvastatin and frequently enough during early therapy to ensure that no significant alteration of INR occurs.

Niacin: The skeletal muscle effects may be enhanced with Rosuvastatin in used with combination Niacin; a reduction in Rosuvastatin dosage should be considered.

Fenofibrate:
Oral Anticoagulants: Caution should be exercised when coumarin anticoagulants are given along with fenofibrate. The dosage of anticoagulant should be reduced to maintain the prothrombin time/INR.

Cyclosporine: Because cyclosporine can produce nephrotoxicity with decreases in creatinine clearance and rises in serum creatinine and because renal excretion is the primary elimination route of fibrate drugs including Fenofibrate, there is a risk that an interaction will lead to deterioration.

4.6 Use in Special Population

Age and sex: There was no clinically relevant effect on age or sex by this combination.

Race: Population pharmacokinetic analysis revealed no clinically relevant differences in pharmacokinetics among Caucasian, Hispanic and Black or Afro-Caribbean groups. However, in asian patients there is 2 fold median exposure in AUC and C of rosuvatstatin.

Renal insufficiency: The lowest possible dose should be administered in renal insufficiency (mild, moderate and severe). As the drug concentration increases more than 2-fold raise in this case.

Pregnancy and Lactation: The safety of this combination, during pregnancy and breast-feeding has not been established. Women of childbearing potential should use appropriate contraceptive measures. 

4.7 Effects on ability to drive and use machines

No effect of Fenofibrate was noted. Studies to determine the effect of Rosuvastatin on the ability to drive and use machines have not been conducted. However, based on its pharmacodynamic properties, Rosuvastatin is unlikely to affect this ability.  When driving vehicles or operating machines, it should be taken into account that dizziness may occur during treatment.

4.8 Undesirable effects

Rosuvastatin 
Rosuvastatin is generally well tolerated. The adverse events seen with Rosuvastatin are generally mild and transient. In controlled clinical trials less than 4% of Rosuvastatin treated patients were withdrawn due to adverse events. The adverse reactions seen with Revostat are generally mild and transient. In controlled clinical trials, less than 4% of Revostat-treated patients were withdrawn due to adverse reactions.
The frequencies of adverse events are ranked according to the following:
Common (> 1/100, < 1/10); Uncommon (> 1/1000, < 1/100); Rare (> 1/10 000, < 1/1000).

Nervous system disorders: 

Common: headache, dizziness and memory loss

Gastrointestinal disorders: 

Common: constipation, nausea, abdominal pain 

Musculoskeletal, connective tissue and bone disorders: 

Common: myalgia 

Rare: myopathy, rhabdomyolysis 

General disorders: 

Common: asthenia Skin disorders: Uncommon: pruritis, rash, urticaria 

Rare: hypersensitivity reactions including angioedema.

The incidence of adverse drug reactions tends to increase with increasing dose. 

Skeletal muscle effects: Rhabdomyolysis, which may occasionally be associated with impairment of renal function, has been reported with Rosuvastatin. 

Renal effects: Proteinuria Laboratory effects: A dose-related increase in liver transaminases and CK has been observed in patients taking Rosuvastatin. Abnormal urinalysis testing (dipstick-positive proteinuria with haematuria) has been seen in patients taking Rosuvastatin. The protein detected was mostly tubular in origin. In most cases, proteinuria decreases or disappears spontaneously on reduction of dose.

Fenofibrate

Adverse events reported by 2% or more of patients treated with Fenofibrate during the double-blind, placebo-controlled trials, regardless of causality, are listed in the table below. Adverse events led to discontinuation of treatment in 5% of patients treated with Fenofibrate and in 3% treated with placebo. Increases in liver function tests were the most frequent events, causing discontinuation of Fenofibrate treatment in 1.6% of patients in double-blind trials.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zuventus.com

Website: Website: https://www.zuventus.co.in/drug-safety-reporting

By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

There is no specific treatment in the event of overdose. In the event of overdose, the patient should be treated symptomatically and supportive measures instituted as required. If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage; usual precautions should be observed to maintain the airway. Hemodialysis is unlikely to be of benefit.
 

5.1 Mechanism of action

Rosuvastatin 
Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor for cholesterol. The primary site of action of rosuvastatin is the liver, the target organ for cholesterol lowering. Rosuvastatin increases the number of hepatic LDL receptors on the cell-surface, enhancing uptake and catabolism of LDL and it inhibits the hepatic synthesis of VLDL, thereby reducing the total number of VLDL and LDL particles.

Fenofibrate
By activation of peroxisome proliferator activated receptor α (PPARα), Fenofibrate increases lipolysis and elimination of triglyceride rich particles from plasma by activating lipoprotein lipase and reducing production of apoprotein C-III (an inhibitor of lipoprotein lipase activity). 

5.2 Pharmacodynamic effects

Rosuvastatin 
Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase. Rosuvastatin increases the number of hepatic LDL receptors on the cell-surface, enhancing uptake and catabolism of LDL and it inhibits the hepatic synthesis of VLDL, thereby reducing the total number of VLDL and LDL particles.

Fenofibrate
By activation of peroxisome proliferator activated receptor α (PPARα), Fenofibrate increases lipolysis and elimination of triglyceride rich particles from plasma by activating lipoprotein lipase and reducing production of apoprotein C-III (an inhibitor of lipoprotein lipase activity). The resulting fall in triglycerides produces an alteration in the size and composition of LDL from small, dense particles (which are thought to be atherogenic due to their susceptibility to oxidation), to large buoyant particles. These larger particles have a greater affinity for cholesterol receptors and are catabolized rapidly. Activation of PPARα (Peroxisome proliferator activated receptor alpha) also induces an increase in the synthesis of apoproteins AI, AII and HDL-cholesterol.

5.3 Pharmacokinetic properties

Rosuvastatin
After oral administration peak plasma levels occur 5 hours after dosing. The half-life is 19 hours and does not increase with increasing dose. Rosuvastatin is approximately 90% bound to plasma proteins, mostly albumin. The parent compound, accounts for greater than 90% of the circulating active HMG-CoA reductase inhibitor activity. Rosuvastatin undergoes limited metabolism in humans (approximately 10%), mainly to the N-desmethyl form, and 90% is eliminated as unchanged drug in the faeces with the remainder being excreted in the urine.

Fenofibrate
Peak plasma levels of fenofibric acid occur within 6 to 8 hours after administration, the absorption is increased when administered with food. Serum protein binding was approximately 99%, it is rapidly hydrolyzed by esterases to the active metabolite fenofibric acid; no unchanged Fenofibrate is detected in plasma. Fenofibric acid is primarily conjugated with glucuronic acid and then excreted in urine and its half-life is 20 hours.
 

6.1 Animal Toxicology or Pharmacology

Rosuvastatin
In a 104-week carcinogenicity study in rats at dose levels of 2, 20, 60, or 80 mg/kg/day by oral gavage, the incidence of uterine stromal polyps was significantly increased in females at 80 mg/kg/day at systemic exposure 20 times the human exposure at 40 mg/day based on AUC. Increased incidence of polyps was not seen at lower doses. 

In a 107-week carcinogenicity study in mice given 10, 60, or 200 mg/kg/day by oral gavage, an increased incidence of hepatocellular adenoma/carcinoma was observed at 200 mg/kg/day at systemic exposures 20 times the human exposure at 40 mg/day based on AUC. An increased incidence of hepatocellular tumors was not seen at lower doses. 

Rosuvastatin was not mutagenic or clastogenic with or without metabolic activation in the Ames test with Salmonella typhimurium and Escherichia coli, the mouse lymphoma assay, and the chromosomal aberration assay in Chinese hamster lung cells. Rosuvastatin was negative in the in vivo mouse micronucleus test. 

In rat fertility studies with oral gavage doses of 5, 15, 50 mg/kg/day, males were treated for 9 weeks prior to and throughout mating and females were treated 2 weeks prior to mating and throughout mating until gestation day 7. No adverse effect on fertility was observed at 50 mg/kg/day (systemic exposures up to 10 times the human exposure at 40 mg/day based on AUC). In testicles of dogs treated with rosuvastatin at 30 mg/kg/day for one month, spermatidic giant cells were seen. Spermatidic giant cells were observed in monkeys after 6-month treatment at 30 mg/kg/day in addition to vacuolation of seminiferous tubular epithelium. Exposures in the dog were 20 times and in the monkey 10 times the human exposure at 40 mg/day based on body surface area. Similar findings have been seen with other drugs in this class. 

Fenofibrate
Carcinogenesis: Two dietary carcinogenicity studies have been conducted in rats with fenofibrate. In the first 24-month study, Wistar rats were dosed with fenofibrate at 10 mg/kg/day, 45 mg/kg/ day, and 200 mg/kg/day, approximately 0.3 times, 1 times, and 6 times the maximum recommended human dose (MRHD), based on body surface area comparisons (mg/m2). At a dose of 200 mg/kg/day (at 6 times the MRHD), the incidence of liver carcinoma was significantly increased in both sexes. A statistically significant increase in pancreatic carcinomas was observed in males at 1 and 6 times the MRHD; an increase in pancreatic adenomas and benign testicular interstitial cell tumors was observed in males at 6 times the MRHD. In a second 24-month study in a different strain of rats (Sprague-Dawley), doses of 10 mg/kg/day and 60 mg/kg/day (0.3 and 2 times the MRHD) produced significant increases in the incidence of pancreatic acinar adenomas in both sexes and increases in testicular interstitial cell tumors in males at 2 times the MRHD. 

A 117-week carcinogenicity study was conducted in rats comparing three drugs: fenofibrate 10 mg/kg/day and 60 mg/kg/day (0.3 and 2 times the MRHD), clofibrate (400 mg/kg/day; 2 times the human dose), and gemfibrozil (250 mg/kg/day; 2 times the human dose, based on mg/m2 surface area). Fenofibrate increased pancreatic acinar adenomas in both sexes. Clofibrate increased hepatocellular carcinomas in males and hepatic neoplastic nodules in females. Gemfibrozil increased hepatic neoplastic nodules in males and females, while all three drugs increased testicular interstitial cell tumors in males. 

In a 21-month study in CF-1 mice, fenofibrate 10 mg/kg/day, 45 mg/kg/day, and 200 mg/kg/day (approximately 0.2 times, 1 times, and 3 times the MRHD on the basis of mg/m2 surface area) significantly increased the liver carcinomas in both sexes at 3 times the MRHD. In a second 18-month study at 10 mg/kg/day, 60 mg/kg/day, and 200 mg/kg/day, fenofibrate significantly increased the liver carcinomas in male mice and liver adenomas in female mice at 3 times the MRHD. 

Electron microscopy studies have demonstrated peroxisomal proliferation following fenofibrate administration to the rat. An adequate study to test for peroxisome proliferation in humans has not been done, but changes in peroxisome morphology and numbers have been observed in humans after treatment with other members of the fibrate class when liver biopsies were compared before and after treatment in the same individual. 

Mutagenesis: Fenofibrate has been demonstrated to be devoid of mutagenic potential in the following tests: Ames, mouse lymphoma, chromosomal aberration and unscheduled DNA synthesis in primary rat hepatocytes. 

Impairment of Fertility: In fertility studies rats were given oral dietary doses of fenofibrate, males received 61 days prior to mating and females 15 days prior to mating through weaning which resulted in no adverse effect on fertility at doses up to 300 mg/kg/day (approximately 10 times the MRHD, based on mg/m2 surface area comparisons). 
 

REVOSTAT®FB is a combination of Rosuvastatin and Fenofibrate.

Rosuvastatin is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA)-reductase inhibitor. 

ChemicalName:bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid]

Molecular Formula: (C22H27FN3O6S)2Ca  Molecular Weight: 1,001.14.

Structure: 

Fenofibrate is a peroxisome proliferator-activated receptor (PPAR) alpha agonist.

Chemical Name: 2-[4-(4-chlorobenzoyl) phenoxy]-2-methyl-propanoic acid, l-methylethyl ester

Molecular Formula: C20H21O4Cl
 
Molecular Weight: 360.83

Structure: 
 

8.1 Incompatibilities
Not applicable.

8.2 Shelf-life
Refer on pack.

8.3 Packaging information
10 Blister strips of 10 tablets each

8.4 Storage and handing instructions
Store protected from moisture at a temperature below 30°C.
Keep out of reach of children.
 

Myopathy and Rhabdomyolysis 

Advise patients that REVOSTAT®FB may cause myopathy and rhabdomyolysis. Inform patients that the risk is also increased when taking certain types of medication and they should discuss all medication, both prescription and over-the-counter, with their healthcare provider. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever.

Hepatic Dysfunction 

Inform patients that REVOSTAT®FB may cause liver enzyme elevations and possibly liver failure. Advise patients to promptly report fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice.
 
Increases in HbA1c and Fasting Serum Glucose Levels 

Inform patients that increases in HbA1c and fasting serum glucose levels may occur with REVOSTAT®FB. Encourage patients to optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices. 

Hypersensitivity Reactions 

Inform patients that serious hypersensitivity reactions, such as anaphylaxis and angioedema, have been reported with fibrates. Advise patients to report immediately any signs or symptoms suggesting allergic reaction, and to discontinue drug until they have consulted prescribing physicians.

Pregnancy 

Advise pregnant patients and patients who can become pregnant of the potential risk to a fetus. Advise patients to inform their healthcare provider of a known or suspected pregnancy to discuss if REVOSTAT®FB should be discontinued.

Lactation 

Advise patients that breastfeeding during treatment with REVOSTAT®FB is not recommended. 

Concomitant Use of Antacids 
When taking REVOSTAT®FB with an aluminum and magnesium hydroxide combination antacid, administer REVOSTAT®FB at least 2 hours before the antacid.

Missed Doses 

If a dose is missed, advise patients not to take an extra dose. Just resume the treatment with the next dose. 
 

14th January 2025.

Saline Nasal Solution IP

Sodium Chloride IP…………………………. 0.9 % w/v

in Purified Water IP q.s.

Nasal Spray

Sodium Chloride (0.9%w/v)

4.1 Therapeutic Indication 

• Gently cleans the nasal cavities when nose is blocked during colds or in allergic conditions.
• Moisturises the nasal mucosa when dry or irritated.
• Thins and loosens nasal secretions and helps their removal.

4.2 Posology and method of administration

Method of administration: Nasal use

Infants and toddlers up to 2 years: 1 spray/ nostril or 1-2 drops/nostril.

Adults and children > 2 years: 1-2 spray/ nostril or 2-3 drops/ nostril as needed. The usual frequency of use is 2 to 4 times a day per nostril. I Rinse is suitable for infants, children and adults. Seek medical advice before using I Rinse in an infant less than 2 weeks old. For children below 11 years, I Rinse should be used under adult supervision. For hygienic reasons and to avoid contamination, the nasal spray should be used by one person.

Method of Administration

I-Rinse can be used in any position. Remove the protective cap. Delicately insert the nozzle into the nostril. Press the nozzle, spray as long as necessary and allow the excess solution to trickle down. Clear your nose after 30 secs to 1 min. Repeat the procedure if required. Wash the nozzle with soapy water, wipe dry and replace protective cap. For infants & children administer under supervision.

4.3 Contraindications

Hypersensitivity to the active substance.

4.4 Special warnings and precautions for use 

• Consult a doctor before use if you are using the product after nasal surgery or injury.
• Due to its cleansing properties, it should be used first when using another local nasal product (e.g. for cold or allergic rhinitis).
• Keep out of reach and sight of Children.
• Do not use a broken, expired or damaged product.

4.5 Drugs interactions

No known drug-drug interaction.

4.6 Use in special populations

I Rinse nasal spray may be used during pregnancy and breast-feeding.

4.7 Effects on ability to drive and use machines

None known.

4.8 Undesirable effects

Stinging, sneezing increased nasal discharge or salty taste may occur. If any of these effects persists or worsen, notify your doctor. Tell your doctor immediately if frequent nosebleeds occur. If you notice any other effects not listed above, contact your doctor. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zuventus.com

Website: https://www.zuventus.com/drug-safety-reporting

By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

Treatment should be supportive and systematic.

5.1 Mechanism of Action/Pharmacodynamic properties

The exact mechanism of action of saline nasal irrigation is unknown. One possibility is that the breakdown of the protective function of the nasal mucosa plays a role in upper respiratory conditions. Saline nasal irrigation may improve nasal mucosa function through several physiologic effects, including direct cleansing, removal of inflammatory mediators and improved mucociliary function, as suggested by increasing ciliary beat frequency.

5.2 Pharmacokinetic properties

Absorption

Sodium chloride distributes primarily to extracellular compartments, including plasma and interstitial fluid; sodium is maintained outside the cell via the Na+/K+-ATPase pump, which exchanges intracellular sodium for extracellular potassium. Penetration across the blood-brain barrier is low. Sodium chloride is excreted primarily in the urine, but it is also excreted in sweat and stool. In healthy patients at steady state with minimal sweat losses, sodium excreted in urine is roughly the same as dietary intake. Sweat sodium concentration is increased in children with cystic fibrosis, aldosterone deficiency, or pseudohypoaldosteronism.

6.1 Animal Toxicology or Pharmacology

Not available.

Sodium chloride, also known as salt, common salt, table salt or halite, is an ionic compound with the chemical formula NaCl, representing a 1:1 ratio of sodium and chloride ions. Molecular Weight : 58.44 g/mol.

8.1 Incompatibilities

None known.

8.2 Shelf-life

Refer on the pack.

8.3 Packaging information

8.4 Storage and handing instructions

• Pressurised container. Keep away from heat and sunlight.
• Do not puncture, break or burn even when apparently empty.
• For external use only.
• Shake well before each use.
• Keep away from eyes.

• Shake the bottle before using the medicine.
• Clean your nose thoroughly before using the medicine.
• Insert the bottle tip into one nostril and close the other nostril.
• Direct the spray towards the sides of your nostril, away from the cartilage dividing the two sides of your nose.
• Breathe out gently through your mouth and repeat the same process for the other nostril.
• Avoid deep breathing as it will cause medication to go back to the throat and make it less effective.
• Avoid deep breathing as it will cause the medication to go back to the throat and make it less effective.
• Do not share the bottle with anyone else so that you do not spread germs.

06.01.2025