Caduet, 5 mg+10 mg 30 pcs

A combined drug that combines two drugs: dihydropyridine calcium antagonist amlodipine and HMG-CoA reductase inhibitor atorvastatin. In this combination, amlodipine inhibits the transmembrane flux of calcium ions in vascular and cardiac smooth muscle fibers; atorvastatin is a selective potent inhibitor of HMG-CoA reductase, the key enzyme converting HMG-CoA to mevalonate, a substance that is a precursor of styrenes, including CHF.

The mechanism of antihypertensive action: amlodipine affects the relaxation of vascular smooth muscle fibers. The mechanism of antianginal action of amlodipine is poorly understood, it is believed that the drug:

• expands the peripheral arterioles and thereby reduces RPS (afterload). Since the heart rate is almost unchanged, the decrease in cardiac output reduces energy consumption and myocardial oxygen demand;
• dilates large coronary arteries and coronary arterioles in both unchanged and ischemic areas of the myocardium. This dilatation increases myocardial oxygen supply in patients with vasospastic angina (Prinzmetal’s angina or variant angina) and prevents coronary vasoconstriction.

In AH patients a single dose of amlodipine provides clinically significant BP reduction for 24 hours in both lying and standing position. Due to slow onset of action, amlodipine does not cause acute arterial hypotension. In patients with angina pectoris, amlodipine increases exercise tolerance, reduces the frequency of angina attacks and the need for nitroglycerin tablets.

Indications

Hypertension with three or more risk factors for cardiovascular events (fatal and non-fatal CHD, need for revascularization, fatal and non-fatal myocardial infarction, stroke and transient ischemic attack), with normal to moderately elevated CHD levels without clinically significant CHD.

The drug is used in cases where combination therapy with amlodipine and low-dose atorvastatin is recommended.

Caduet may be combined with other antihypertensive and/or antianginal agents.

Caduet is used in cases where hypolipidemic diet and other non-pharmacological methods of treatment of dyslipidemia prove to be little or ineffective.

Active ingredient

Composition

1 tablet contains

amlodipine 5 mg and atorvastatin 10 mg;

excipients:

calcium carbonate,

croscarmellose sodium,

microcrystalline cellulose,

Pregelatinized starch,

Polysorbate 80 (tween 80),

/p>

Hyprolose,

colloidal silicon dioxide,

magnesium stearate,

p> Opadray II white film jacket 85F28751 (polyvinyl alcohol, titanium dioxide, macrogol (PEG) 3000, talc).

How to take, the dosage

Caduet is taken orally 1 tablet once daily at any time, regardless of meals.

The starting and maintenance doses are adjusted individually, taking into account the efficacy and tolerability of both components in the treatment of arterial hypertension/stenocardia and dyslipidemia. Caduet may be administered to patients who are already taking one component of the drug in monotherapy.

Caduet is used in combination with nonmedicamental therapies including diet, exercise, weight loss in obese patients and smoking cessation.

Caduet should be started with 5/10 mg tablets (amlodipine/atorvastatin, respectively). In patients with arterial hypertension, BP should be monitored every 2-4 weeks and, if necessary, it is possible to transfer to 10/10 mg tablets (amlodipine/atorvastatin, respectively).

In CHD, the recommended dose of amlodipine is 5-10 mg once daily.

Interaction

The data regarding drug interactions of amlodipine and atorvastatin in healthy subjects indicate that pharmacokinetics of amlodipine is not altered when these drugs are used in combination. Amlodipine has no effect on Cmax for atorvastatin: 91% (90% confidence interval: 80-103%), but increases AUC of atorvastatin by 18% (90% CI: 109-127%).

There have been no studies of drug interactions between amlodipine/atorvastatin concentrations and other drugs, but there are studies regarding the effects of amlodipine and atorvastatin separately. These findings are summarized below.

Amlodipine can be safely used together with thiazide diuretics, β- and α-adrenoreceptor blockers, ACE inhibitors, long-acting nitrates, sublingual forms of nitroglycerin, NSAIDs, antibiotics and oral hypoglycemic agents. In vitro data from human plasma studies indicate that amlodipine does not affect the protein binding of digoxin, phenytoin, warfarin or indomethacin. Cimetidine – Combined use of amlodipine and cimetidine does not alter the pharmacokinetics of amlodipine.

Grapefruit juice – Combined use of 240 mL of grapefruit juice and a single oral dose of 10 mg amlodipine in 20 healthy volunteers had no effect on amlodipine pharmacokinetics.

Aluminum/magnesium (antacid) – Combined use of aluminum/magnesium (antacid) and a single dose of amlodipine had no effect on amlodipine pharmacokinetics.

Sildenafil – A single dose of 100 mg of sildenafil in subjects with essential hypertension had no effect on the pharmacokinetic parameters of amlodipine. When amlodipine and sildenafil are used in combination, each agent independently manifests its hypotensive effect.

Digoxin – Combined use of amlodipine and digoxin does not change the serum concentration and renal clearance of digoxin in healthy volunteers.

Ethyl alcohol (alcohol) – Single and multiple doses of 10 mg amlodipine do not affect the pharmacokinetics of ethyl alcohol.

Warfarin – Combined use of amlodipine and warfarin does not alter the warfarin-dependent prothrombin time.
Cyclosporine – Pharmacokinetic studies of cyclosporine indicate that amlodipine does not alter the pharmacokinetics of cyclosporine.

The effect on laboratory test values is not known.

The risk of myopathy during treatment with HMG-CoA reductase inhibitors (including atorvastatin) increases with concomitant use of cyclosporine, fibric acid derivatives, erythromycin, azole antifungals or nicotinic acid.

Antacids – combined use of atorvastatin and oral suspensions of antacids containing magnesium and aluminum hydroxides reduces plasma concentrations of atorvastatin by approximately 35%; however, the magnitude of decrease in LDL-C levels does not change.

Phenazone (antipyrine) – as atorvastatin does not affect pharmacokinetics of phenazone, interaction with other drugs that are metabolized by the same cytochrome isoenzymes is unlikely.
Colestipol – in concomitant use of colestipol and atorvastatin plasma concentration is reduced by about 25%. However, the effects on lipids are more pronounced when used in combination than when used separately.

Digoxin – When combined repeated use of digoxin and 10 mg atorvastatin, the equilibrium plasma concentration of digoxin is not changed. However, when combined use of digoxin and 80 mg atorvastatin per day, digoxin concentration is increased by almost 20%. Patients taking digoxin require appropriate monitoring.

Eritromycin/clarithromycin – Combined use of atorvastatin and erythromycin (500 mg 4 times daily) or clarithromycin (500 mg 2 times daily) – known cytochrome P450 WA4 inhibitors – increases the plasma concentration of atorvastatin.

Azithromycin – combined use of atorvastatin (10 mg once daily) and azithromycin (500 mg once daily) does not change the plasma concentration of atorvastatin.

Terfenadine – combined use of atorvastatin and terfenadine does not cause clinically significant changes in terfenadine pharmacokinetics.

Peroral contraceptives – combined use with oral contraceptives containing norethindrone and ethinylestradiol increases equal AUCs for norethindrone and ethinylestradiol by approximately 30 and 20%. This increase should be considered when choosing an oral contraceptive for women taking atorvastatin.
Warfarin – no clinically significant interaction was found in the study of atorvastatin and warfarin interaction when used in combination.

Cimetidine – no clinically significant interaction was found in the study of atorvastatin and cimetidine interaction in combined use.

Protease inhibitors – combined use of atorvastatin and protease inhibitors – known cytochrome P450 ZA4 inhibitors – leads to a decrease in plasma concentration of atorvastatin.

Attorvastatin has been used with antihypertensive agents and estrogen replacement therapy in clinical trials. No clinically significant adverse interactions have been identified. Studies of interaction with specific agents have not been conducted.

.

Special Instructions

Myalgia has been observed in patients receiving atorvastatin. The diagnosis of myopathy (pain or weakness in muscles combined with an increase in CPK activity of more than 10 times that of IGN) should be assumed in patients with widespread myalgia, muscle soreness or weakness and/or a marked increase in CPK activity. Patients should immediately consult a physician if unexplained muscle pain or weakness occurs, especially if accompanied by malaise or fever. Therapy with Kaduet should be discontinued if there is a marked increase in CPK activity or if there is confirmed or suspected myopathy.

The risk of myopathy during treatment with other drugs of this class increases with concomitant use of cyclosporine, fibric acid derivatives, erythromycin, nicotinic acid or azole antifungals. Many of these drugs inhibit CYP3A4-mediated metabolism and/or drug transport. CYP3A4 is known to be the main liver isoenzyme involved in the biotransformation of atorvastatin. When prescribing atorvastatin in hypolipidemic doses in combination with fibric acid derivatives, erythromycin, immunosuppressants, azole antifungal drugs or nicotinic acid, the expected benefits and risks of treatment should be carefully weighed and patients should be regularly observed to detect muscle pain or weakness, especially during the first months of treatment and during dose increases of any drug. Periodic determination of CPK activity may be recommended in such situations, although such monitoring does not prevent the development of severe myopathy.

The administration of Caduet may cause an increase in CPK activity. Rare cases of rhabdomyolysis with acute renal failure due to myoglobinuria have been described with atorvastatin and other drugs of this class. Therapy with Kaduet should be temporarily stopped or completely discontinued if there are signs of possible myopathy or if there are risk factors of renal failure due to rhabdomyolysis (such as severe acute infection, arterial hypotension, surgical intervention, trauma, metabolic, endocrine and electrolyte disorders and uncontrolled convulsions). Treatment with amlodipine at an adequate dose to control arterial hypertension may be continued.

Impact on driving and operating machinery

While available data on amlodipine and atorvastatin suggest that the combined drug should not impair the ability to drive and operate machinery, caution should be exercised when driving and operating machinery (given the possible development of excessive BP decrease, dizziness, fainting).

Contraindications

Known hypersensitivity to dihydropyridine, amlodipine, atorvastatin, or any component of the drug;

Liver disease in the active phase or elevated serum transaminase levels,

three times the normal values;

Pregnancy and breastfeeding or childbearing age in the absence of adequate contraception.

Side effects

The safety of amlodipine and atorvastatin has been studied in clinical trials in patients with a combination of arterial hypertension and dyslipidemia, and no unexpected adverse effects have been reported with combination therapy.

The undesirable effects were consistent with those previously identified during treatment with amlodipine and/or atorvastatin. In general, the tolerability of the combination therapy was good. Most of the adverse effects were mild to moderate. In controlled clinical trials, amlodipine and atorvastatin treatment was discontinued in 5.1% of patients and placebo in 4.0% due to adverse effects or abnormal laboratory parameters.

Amlodipine

The following refers to the frequency of adverse reactions: frequent (> 1%), infrequent (< 1%), rare (< 0.1%), very rare (< 0.01%).

Cardiovascular system disorders: frequent – peripheral edema (ankles and feet), palpitations; infrequent – excessive BP decrease, orthostatic hypotension, vasculitis; rare – development or aggravation of heart failure; very rare – heart rhythm disorders (including bradycardia, ventricular tachycardia and atrial fibrillation), myocardial infarction, chest pain, migraine.

Muscular system disorders: infrequent – arthralgia, muscle cramps, myalgia, back pain, arthrosis; rarely – myasthenia.

CNS and peripheral nervous system disorders: Feeling of heat and blood rush to the face, increased fatigue, dizziness, headache, drowsiness; infrequent – malaise, fainting, increased sweating, asthenia, hypoesthesia, paresthesia, peripheral neuropathy, tremor, insomnia, mood lability, unusual dreams, nervousness, depression, anxiety; rare – convulsions, apathy, agitation; very rare – ataxia, amnesia.

Digestive system disorders: frequent – abdominal pain, nausea; infrequent – vomiting, changes in defecation mode (including constipation, flatulence), dyspepsia, diarrhea, anorexia, dry mouth, thirst; rare – gum hyperplasia, increased appetite; very rare – gastritis, pancreatitis, hyperbilirubinemia, jaundice (usually cholestatic), increased liver transaminases activity, hepatitis.

Hematopoietic system: very rarely – thrombocytopenic purpura, leukopenia, thrombocytopenia.

Metabolic disorders: very rarely – hyperglycemia.

Respiratory system disorders: infrequent dyspnea and rhinitis; very rare – cough.

Perior urinary system disorders: infrequent frequent frequent urination, painful urination, nicturia, impotence; very rare – dysuria, polyuria.

An organ of vision: infrequent – visual disturbances, diplopia, accommodation disorders, xerophthalmia, conjunctivitis, pain in the eye.

Skin disorders: infrequent alopecia; rarely – dermatitis; very rare – xeroderma, impaired skin pigmentation.

Allergic reactions: infrequent – skin itching, rash; very rare – angioedema, erythema multiforme, urticaria.

Others: infrequent – tinnitus, gynecomastia, weight gain/decrease, perversion of taste, chills, nosebleed; very rare – parosmia, “cold” sweat.

Atorvastatin

It is usually well tolerated. Adverse reactions are usually mild and transient.

The most common adverse reactions (≥1%):

CNS side: insomnia, headache, asthenic syndrome.

Digestive system disorders: nausea, diarrhea, abdominal pain, dyspepsia, constipation, flatulence.

Muscular system disorders: myalgia.

Less frequent adverse reactions:

CNS and peripheral nervous system: malaise, dizziness, amnesia, paresthesia, peripheral neuropathy, hypoesthesia.

In the digestive system: vomiting, anorexia, hepatitis, pancreatitis, cholestatic jaundice.

Muscular system: back pain, muscle cramps, myositis, myopathy, arthralgia, rhabdomyolysis.

Allergic reactions: urticaria, pruritus, skin rash, anaphylaxis, bullous rash, erythema multiforme, toxic epidermal necrolysis (Lyell syndrome), erythema malignant exudative (Stevens-Johnson syndrome).

Metabolic disorders: hypoglycemia, hyperglycemia, increased serum CPK, weight gain.

Hematopoietic system: thrombocytopenia.

Others: impotence, peripheral edema, chest pain, secondary renal failure, alopecia, tinnitus, fatigue.

Overdose

There are no data on overdose of the drug.

Both amlodipine and atorvastatin actively bind to blood plasma proteins, therefore a significant increase in clearance of the combined drug in hemodialysis is unlikely.

The symptoms of amlodipine overdose: excessive peripheral vasodilation leading to reflex tachycardia, and pronounced and persistent decrease of BP, including with development of shock and lethal outcome.

The symptoms of atorvastatin overdose have not been described.

Treatment of amlodipine overdose: Administration of activated charcoal immediately or within 2 hours after taking amlodipine in dose of 10 mg leads to significant delay in absorption of the drug. In some cases gastric lavage may be effective. Clinically significant arterial hypotension caused by amlodipine overdose requires active measures aimed at maintaining cardiovascular function, including control of heart and lung function, elevation of extremities and control of CPR and diuresis. For restoration of vascular tone and BP it may be useful to use a vasoconstrictor, if there are no contraindications for its prescription, for elimination of the consequences of calcium channel blockade – IV administration of calcium gluconate.

There are no specific remedies for treatment of atorvastatin overdose. In case of overdose symptomatic and supportive treatment should be carried out as needed.

Pregnancy use

It is contraindicated in pregnant women and during lactation.