Tukon

Chemical name and Molecular formula: Atorvastatin: [R-(R*,R*)]-2-(4-fluorophenyl)-b, d-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino) carbonyl]-[1H-pyrrole-1-heptanoic acid, calcium salt (2:1) trihydrate (C₃₃H₃₄FN₂O₅),C₃₃H₃₄FN₂O₅, Ca₃H, O₂.
Amlodipine: 3-Ethyl-5-methyl (±)-2-[2-(aminoethoxy) methyl]-4-(2-chlorophenyl)-1, 4-dibromo-6-methyl-3,5-pyridinedicarboxylate, monobenzenesulphonate C₂₀H₂₅ClN₂O₅SC₂₀H₂₅ClN₂O₅H₆O₃S.
Tukon 5 mg/10 mg: Amlodipine Besylate USP eq. to Amlodipine 5 mg; Atorvastatin Calcium USP eq. to Atorvastatin 10 mg.
Tukon 5 mg/20 mg: Amlodipine Besylate USP eq. to Amlodipine 5 mg; Atorvastatin Calcium USP eq. to Atorvastatin 20 mg.
Tukon 10 mg/10 mg: Amlodipine Besylate USP eq. to Amlodipine 10 mg; Atorvastatin Calcium USP eq. to Atorvastatin 10 mg.

Category: Atorvastatin: Atorvastatin calcium is a synthetic lipid-lowering agent.
Amlodipine: Amlodipine is a dihydropyridine calcium antagonist with long duration of action, used for treatment of hypertension and angina pectoris.
Pharmacology: Atorvastatin: Atorvastatin is a selective, competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme-A (HMG-CoA) reductase, the rate-limiting enzyme that converts HMG-CoA to mevalonate, a precursor of sterols, including cholesterol. Atorvastatin lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and by increasing the number of hepatic LDL receptors on the cell surface to enhance uptake and catabolism of LDL. It also reduces LDL production, number of LDL particles and LDL-C in some patients with homozygous familial hypercholesterolemia (FH). The drug reduces total-C, LDL-C, and apo B in patients with homozygous and heterozygous FH, nonfamilial forms of hyperlipidemia, and mixed dyslipidemia. It also reduces VLDL-C and TG and produces increases in HDL-C and apolipoprotein-A1.
Amlodipine: Amlodipine inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. It binds to both dihydropyridine and nondihydropyridine binding sites and inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.
Pharmacokinetics: Atorvastatin: Absorption: Atorvastatin is rapidly absorbed after oral administration; maximum plasma concentrations occur within 1-2 hours. Extent of absorption increases in proportion to atorvastatin dose. The absolute bioavailability of atorvastatin is approximately 14% and the systemic availability of HMG-CoA reductase inhibitor activity is approximately 30%. Although food decreases the rate and extent of drug absorption by approximately 25% and 9%, respectively, LDL-C reduction is similar whether atorvastatin is given with or without food.
Distribution: Atorvastatin is ≥98% bound to plasma proteins. Based on observations in rats, atorvastatin is likely to be secreted inhuman milk.
Metabolism: Atorvastatin is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites.
Excretion: Atorvastatin and its metabolites are eliminated primarily in bile following hepatic and/or extra hepatic metabolism; however, the drug does not appear to undergo enterohepatic recirculation. Mean plasma elimination half-life is approximately 14 hours, with the half-life of inhibitor activity for HMG-CoA reductase being 20-30 hours due to the contribution of active metabolites. Less than 2% of a dose of atorvastatin is recovered in urine following oral administration. In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin are markedly increased.
Amlodipine: Amlodipine is well absorbed after oral doses with peak blood concentration occurring after 6-12 hours. The bioavailability varies but is usually about 60-65% . Amlodipine is reported to be about 97.5% bound to plasma proteins. It has a prolonged terminal elimination half-life of 35-50 hours and steady-state plasma concentrations are not achieved until after 7-8 days of use. Amlodipine is extensively metabolized in the liver; metabolites are mostly excreted in urine together with less than 10% of a dose as unchanged drug.

Amlodipine is indicated in patients with essential hypertension: Prevention of cardiovascular disease in adult patients without clinically evident coronary heart disease, but with multiple risk factors for coronary heart disease such as age, smoking, hypertension, low HDL-C, or a family history of early coronary heart disease; Reduce the risk of myocardial infarction; Reduce the risk of stroke; Reduce the risk for revascularization procedures and angina in patients with type-2 diabetes, and without clinically evident coronary heart disease, but with multiple risk factors for coronary heart disease such as retinopathy, albuminuria, smoking, or hypertension.
Atorvastatin is indicated to: Reduce the risk of myocardial infarction; Reduce the risk of stroke in patients with clinically evident coronary heart disease; Reduce the risk of non-fatal myocardial infarction; Reduce the risk of fatal and non-fatal stroke; Reduce the risk for revascularization procedures; Reduce the risk of angina; Reduce the risk of hospitalization for CHF.
As adjunct therapy to diet for reducing elevated total-C, LDL-C, apo B, and TG levels and to increase HDL-C in patients with: Primary hypercholesterolemia (heterozygous familial and nonfamilial); Mixed dyslipidemia (Fredrickson Types IIa and IIb); Elevated serum triglyceride levels (Fredrickson Type IV); Primary dysbetalipoproteinemia (Fredrickson Type III).
To reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments.
As an adjunct to diet to reduce total-C, LDL-C, and apo B levels in boys and postmenarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia if after an adequate trial of diet therapy the following findings are present: LDL-C remain ≥190 mg/dL or LDL-C remain ≥160 mg/dL, and there is a positive family history of premature cardiovascular disease; or two or more other CVD risk factors are present in the pediatric patient therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia.

Adults: One tablet of amlodipine & atorvastatin combination once daily.
Route: Oral.

Atorvastatin: There is no specific treatment for atorvastatin overdosage. In the event of an overdose, the patient should be treated symptomatically, and supportive measures instituted as required.
Amlodipine: Symptoms of overdose might be excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia. If massive overdose should occur, active cardiac and respiratory monitoring should be instituted. Frequent blood pressure measurements are essential. Should hypotension occur, cardiovascular support including elevation of the extremities and the judicious administration of fluids should be initiated. If hypotension remains unresponsive to these conservative measures, administration of vasopressors (such as phenylephrine) should be considered with attention to circulating volume and urine output.

Atorvastatin: Active liver disease or unexplained persistent elevations in hepatic transaminases.
Hypersensitivity to any component of this drug.
Pregnancy and lactation.
Amlodipine: Hypersensitivity to dihydropyridine derivatives.

Atorvastatin: Liver Dysfunction: HMG-CoA reductase inhibitors have been associated with biochemical abnormalities of liver function. Therefore, liver function tests should be performed prior to and at 12 weeks following initiation of therapy or elevation in dose, and semiannually thereafter.
Atorvastatin should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease.
Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with other drugs in this class. A history of renal impairment may be a risk factor for the development of rhabdomyolysis. Therefore, Atorvastatin therapy should be temporarily withheld or discontinued in any patient with an acute, serious condition suggestive of a myopathy or having a risk factor predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders, and uncontrolled seizures).
Caution should be exercised when used in patients with recent stroke or TIA as higher incidence of hemorrhagic stroke was seen.
Caution should be exercised if an HMG-CoA reductase inhibitor is administered concomitantly with drugs that may decrease the levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone and cimetidine.
Amlodipine: In patients with severe obstructive coronary artery disease there is possibility of increased frequency; duration and/or severity of angina or acute myocardial infarction on starting calcium channel blocker therapy or at the time of dosage increase.
Acute hypotension have rarely been reported, hence caution should be exercised particularly in patients with severe aortic stenosis.
Amlodipine is extensively metabolized in the liver; hence caution should be exercised when administering to patients with severe hepatic impairment.

There are no adequate and well-controlled studies in pregnant women. Amlodipine atorvastatin combination should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing should be discontinued while amlodipine atorvastatin combination is administered.

Atorvastatin: The most frequent adverse events (occurring in >2%) are nasopharyngitis, arthralgia, diarrhea, pain in extremity, urinary tract infection, dyspepsia, nausea, muscle spasms, myalgia, insomnia and pharyngolaryngeal pain.
Other side effects rarely reported are: Body as a whole: malaise, pyrexia.
Digestive system: abdominal discomfort, eructation, flatulence, hepatitis, cholestasis.
Musculoskeletal system: musculoskeletal pain, muscle fatigue, neck pain, joint swelling.
Metabolic and nutritional system: transaminases increase, liver function test abnormal, blood alkaline phosphatase increase, creatine phosphokinase increase, hyperglycemia.
Nervous system: nightmare.
Respiratory system: epistaxis.
Skin and appendages: urticarial.
Special senses: vision blurred, tinnitus.
Urogenital system: white blood cells urine positive.
Amlodipine: Most adverse reactions reported during therapy with amlodipine are of mild or moderate severity and are as follows: dizziness, flushing, headache, edema, palpitation, fatigue, abdominal pain and somnolence.
Other rarely observed adverse effects are: Cardiovascular: arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, hypotension, peripheral ischemia, syncope, tachycardia, postural dizziness, postural hypotension, vasculitis.
Central and Peripheral Nervous System: hypoesthesia, peripheral neuropathy, paresthesia, tremor, vertigo.
Gastrointestinal: anorexia, constipation, dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gingival hyperplasia.
General: allergic reaction, asthenia, back pain, hot flushes, malaise, pain, rigors, weight gain, weight decrease.
Musculoskeletal System: arthralgia, arthrosis, myalgia.
Psychiatric: sexual dysfunction, insomnia, nervousness, depression, abnormal dreams, anxiety.
Skin and Appendages: angioedema, erythema multiforme, pruritus, erythematous or maculopapular rash.
Special Senses: abnormal vision, conjunctivitis, diplopia, tinnitus.
Urinary System: micturition frequency, micturition disordered, nocturia.
Autonomic Nervous System: dry mouth.
Metabolic: hyperlipidemia, thirst.
Hematologic: leukopenia, purpura, thrombocytopenia.

Atorvastatin: The risk of myopathy during treatment with other statins is increased with concurrent administration of cyclosporine, fibric acid derivatives (Gemfibrozil, Fenofibrate), lipid-modifying doses of niacin (nicotinic acid), or strong CYP3A4 inhibitors (e.g., clarithromycin, erythromycin, HIV protease inhibitors: ritonavir, lopinavir, and azole antifungals: itraconazole).
Atorvastatin is metabolized by cytochrome P450 3A4. Concomitant administration of atorvastatin with strong inhibitors of CYP3A4 can lead to increases in plasma concentrations of atorvastatin.
Plasma concentration of atorvastatin increase approximately 40% with co-administration of erythromycin, which is a known inhibitor of cytochrome P450 3A4.
Grapefruit juice contains one or more components that inhibit CYP3A4 and can increase plasma concentrations of atorvastatin, especially with excessive grapefruit juice consumption.
Atorvastatin and atorvastatin-metabolites are substrates of the OATP1B1 transporter. Inhibitors of the OATP1B1 (e.g., cyclosporine) can increase the bioavailability of atorvastatin. In cases where coadministration of atorvastatin with cyclosporine is necessary, the dose of atorvastatin should not exceed 10 mg.
Co-administration with antacid reduces plasma concentrations of atorvastatin by approximately 34%.
Plasma concentrations of atorvastatin decrease approximately 26% when co-administered with colestipol.
When multiple doses of atorvastatin and digoxin are coadministered, plasma digoxin concentrations increase by approximately 20%.
Co-administration of atorvastatin and an oral contraceptive increased AUC values for norethindrone and ethinyl estradiol.
Co-administration of atorvastatin with diltiazem resulted in a 51% increase in atorvastatin AUC.
Co-administration with cimetidine reduces plasma concentrations of atorvastatin by approximately 11%.
Concomitant administration of atorvastatin with inducers of cytochrome P450 3A4 (e.g. efavirenz, rifampin) can lead to variable reductions in plasma concentrations of atorvastatin.
Due to the dual interaction mechanism of rifampin, simultaneous co-administration of atorvastatin with rifampin is recommended, as delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations.
Co-administration with antipyrine reduces plasma concentrations of antipyrine by approximately 11%.
Co-administration of amlodipine with atorvastatin resulted in increase in AUC and decrease in Cmax.
Amlodipine: Strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, ritonavir) may increase the plasma concentrations of amlodipine to a greater extent. Symptoms of hypotension and edema should be monitored when amlodipine is co-administered with CYP3A4 inhibitors.
Blood pressure should be closely monitored when amlodipine is co-administered with CYP3A4 inducers.

Store at temperatures not exceeding 30°C. Protect from light.
Shelf life: 36 months from the date of manufacturing.

Calcium Antagonists / Dyslipidaemic Agents

C10BX03 - atorvastatin and amlodipine ; Belongs to the class of HMG CoA reductase inhibitors, other combinations.

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