VYTORIN ® Ezetimibe + Simvastatin

VYTORIN ® is a drug based on Ezetimibe + Simvastatin

THERAPEUTIC GROUP: Hypolipidemic - Ezetimibe + HMG-CoA reductase inhibitor

IndicationsAction mechanismStudies and clinical effectiveness Usage and dosage instructionsWarnings Pregnancy and lactationInteractionsContraindicationsUndesirable effects

Indications VYTORIN ® Ezetimibe + Simvastatin

VYTORIN ® is indicated - in addition to diet therapy and a correct lifestyle - in the treatment of primary hypercholesterolemia and mixed dyslipidemia, in case of therapeutic failure following administration of statin alone.

VYTORIN ® is also effective in the treatment of familial hypercholesterolemia, both in the heterozygous form and in the homozygous variant.

Mechanism of action VYTORIN ® Ezetimibe + Simvastatin

The oral intake of VYTORIN ® provides in a single administration two different active ingredients, with different pharmacokinetic and pharmacodynamic characteristics.

In fact, while ezetimibe is absorbed in the intestine, mainly glucoronized by the liver and poured into the small intestine with timing that is optimized within the first two hours, simvastatin is activated at the liver level through a hydrolysis process that transforms it into the corresponding hydroxy acid, biologically active, on average after 4 hours.

The therapeutic action of VYTORIN ® is therefore given by the sum of the lipid-lowering properties of the two active principles, which act according to different and complete mechanisms. More precisely, the ezetimibe-glucoronide, once poured into the intestine through the bile, reduces the absorption of "food" cholesterol by inhibiting the relative intestinal transporter; simvastatin, on the other hand, acts at the hepatic level reducing the activity of the enzyme involved in the synthesis of mevalonate, therefore of cholesterol, and increasing the expression of hepatic receptors for LDL.

These biological effects translate into an improvement in lipid-lowering abilities, in a more marked reduction in blood concentrations of LDL cholesterol and triglycerides, in an increase in HDL cholesterolemia and in the reduction of cardiovascular risk. Simvastatin, however, appears to have a number of pleiotropic effects of which ezetimibe is free; these effects could support and enhance the preventive effect of VYTORIN ® against cardiovascular diseases.

In both cases, once the therapeutic action is over, albeit with different times, the active ingredients are eliminated mainly through the faeces.

Studies carried out and clinical efficacy

VYTARIN AND COENZIMA Q10

The decrease in coenzyme Q10 observed following statin therapy appears to be one of the main suspects in the onset of myopathies and rhabdomyolysis. This study verified the variation of this important cofactor in patients undergoing VYTARIN therapy. The presence of simvastatin in VYTARIN led to a significant decrease in coenzyme Q10 plasma levels, which was not observed in ezetimibe monotherapy. Furthermore, the reduction in concentrations of this cofactor appears to be related to the decline in LDL cholesterol.

2. THE EFFECTIVENESS OF COMBINED THERAPY IN DIABETIC PATIENTS

Combination therapy with 10 mg of ezetimibe and 20 mg of simvastatin for 6 weeks guaranteed a reduction in LDL cholesterol of about 30%; this was recorded in diabetic patients at high cardiovascular risk with hypercholesterolemia. The results obtained with the combined therapy were definitely higher than those observed following monotherapy with high-dose simvastatin alone.

3. EFFECTS OF VYTORIN ON THE HEALTH OF ARTERIES

This study allowed us to understand how the administration of VYTORIN in patients with high cardiovascular risk, in addition to significantly lowering the level of LDL cholesterol, can guarantee a reduction in average thickness and carotid stiffness. However, despite the positive results, a decrease in the most common inflammatory markers was not observed.

Method of use and dosage

VYTORIN ® 10 mg tablets of ezetimibe + 10/20/40/80 mg of simvastatin: the standard dosage used in the treatment of primary hypercholesterolemia is that of 10/10 - 10/20 - 10/40, in conjunction with a diet hypolipidic and healthy habits.

The 10/80 dosage is recommended in the treatment of homozygous familial hypercholesterolemia in the presence of a strong cardiovascular risk.

The different dosage formulation allows the physician to adapt the therapy to those that are the patient's needs, taking into account that dosage adjustments should be made only after at least 4 weeks from the beginning of the therapy (time frame necessary to reach the maximum therapeutic effect of simvastatin).

IN ANY CASE, BEFORE TAKING VYTORIN ® Ezetimibe + Simvastatin THE REQUIREMENT AND CHECK OF YOUR DOCTOR IS NECESSARY.

Warnings VYTORIN ® Ezetimibe + Simvastatin

The pharmacological intervention with VYTORIN ® should be preceded and accompanied by a hypolipid dietary regime and healthy lifestyle habits. The assumption of this drug should also be preceded by a careful anamnestic and laboratory check, useful for verifying the presence or predisposition to the development of muscular and liver disorders.

In order to reduce the possible development of these diseases, therapy with VYTORIN ® should be suspended or avoided in the case of: increased plasma levels of creatinkinase associated with myalgia, persistent muscle pain and fatigue, or an increase in transaminase values 3 times higher than to the normal range.

Furthermore, particular care should be used for the pharmacological treatment of patients suffering from gallbladder disease or interstitial lung disease.

VYTORIN ® contains lactose; therefore, the administration of this medicinal product in patients with glucose / galactose malabsorption or lactase enzyme deficiency could cause gastro-intestinal symptoms.

Although the drug does not act absolutely on the nervous system and on the patient's attention span, the presence of side effects such as dizziness and dizziness (more frequent in the starting phase of the treatment), could make driving cars and the use of machinery dangerous.

PREGNANCY AND BREASTFEEDING

Currently there are no experimental data and clinical trials demonstrating the safety of VYTORIN ® taken during pregnancy, on the health of the mother and the fetus.

For this reason, given the importance of lipids during the embryonic and fetal development phases, the use of this drug is not recommended during the whole period of pregnancy and lactation.

Interactions

The most important drug interactions observed for VYTORIN ® depend mainly on the presence of simvastatin and its hepatic metabolism induced by cytochrome CYP3A4.

More precisely, the intake of CYP3A4 inhibitors, such as grapefruit juice, itraconazole, ketoconazole, HIV protease inhibitors, erythromycin, clarithromycin, telithromycin and nefazodone, could result in a significant increase in drug exposure, increasing the incidence of even serious side effects.

VYTORIN ® could also interact with oral anticoagulants such as warfarin, causing it to enhance its therapeutic effects, resulting in increased bleeding episodes. In order to avoid the aforementioned side effects, it would therefore be advisable to monitor the prothrombin time and eventually adjust the dosage.

The same precaution should be taken in case of concurrent intake of cyclosporine.

Although ezetiemibe contained in VYTORIN ® does not appear to be responsible for serious interactions, it should be remembered that antacids, cholestyramine and ciclosporin may cause a change in exposure to this active ingredient.

The concomitant administration of fibrates, for which an increase in cholesterol in the bile of the gallbladder was observed, is contraindicated for the potential risk of cholelithiasis, whereas in the case of simultaneous intake of Diltiazem, the maximum doses of VYTORIN ® should not exceed the dosage 10/40, in order to avoid the incidence of myopathies and rhabdomyolysis.

Contraindications VYTORIN ® Ezetimibe + Simvastatin

VYTORIN ® is contraindicated in case of liver disease and increased transaminase blood levels, in case of concomitant administration of CYP3A4 inhibitors, and of hypersensitivity to ezetimibe, simvastatin or one of its excipients.

Undesirable effects - Side effects

The side effects associated with VYTORIN ® therapy seem to reflect those described for the two active ingredients taken individually, with headache, dizziness, vertigo, abdominal pain, meteorism and myalgia.

Particular categories of patients at risk showed a more frequent increase in plasma transaminase and creatinkinase values, without however a correlated symptomatology.

The incidence of myopathies, rhabdomyolysis and clinically relevant side effects remained almost the same as that observed for the individually administered active ingredients.

Only rare cases of hypersensitivity to the drug have been described, accompanied by dermatological reactions, angioedema, vasculitis, polymyalgia, thrombocytopenia and haematoclinic parameters alterations.