Active ingredients: Atorvastatin
ARKAS 10 mg film-coated tablets
ARKAS 20 mg film-coated tablets
ARKAS 40 mg film-coated tablets
Why is Arkas used? What is it for?
ARKAS belongs to a group of drugs known as statins, which regulate lipid (fat) levels.
ARKAS is used to reduce blood lipid levels, known as cholesterol and triglycerides, when a low-fat diet and lifestyle changes have not been successful. If you are at high risk of cardiovascular disease, ARKAS can also be used to reduce this risk, even if your cholesterol levels are normal. A standard diet to reduce cholesterol should be continued during treatment.
Contraindications When Arkas should not be used
Do not take ARKAS
- if you are allergic to atorvastatin, or similar medicines used to lower blood lipid levels, or to any of the other ingredients of this medicine
- listed in paragraph 6.
- If you have or have ever had liver disease.
- If the results of liver function tests have shown unexplainably altered values.
- If you are a woman of childbearing age and are not using a reliable method of contraception.
- If you are pregnant or planning to become pregnant.
- If you are breast-feeding.
Precautions for use What you need to know before taking Arkas
Talk to your doctor or pharmacist before taking ARKAS.
Below are the reasons why ARKAS may not be suitable for you:
- if you have had a history of stroke with brain haemorrhage, or have small pockets of fluid in the brain from a previous stroke.
- If you have kidney problems.
- If you have a poorly functioning thyroid gland (hypothyroidism).
- If you have had repeated or unexplained muscle pain, a personal or family history of muscle problems. Also, tell your doctor or pharmacist if you have constant muscle weakness. Additional tests and medicines may be needed to diagnose and treat this condition.
- If you have had previous muscle problems during treatment with other lipid-lowering medicines (e.g. other medicines of the statin or fibrate class).
- If you regularly drink large amounts of alcohol.
- If you have a history of liver disease in the medical history.
- If you are over 70 years old.
While you are taking this medicine your doctor will carefully check if you have diabetes or if you are at risk of developing diabetes.If you have high blood sugar and fat levels, are overweight and have high blood pressure you are likely at risk of developing diabetes.
Check with your doctor or pharmacist before taking ARKAS
- If you suffer from severe respiratory failure.
If any of these apply to you, your doctor will need to carry out a blood test before and possibly during treatment with ARKAS to predict the risk of muscle related side effects. The risk of muscle related side effects (eg rhabdiomyolysis) is known to increase when certain medicines are taken at the same time (see section 2 "Other medicines and ARKAS").
Interactions Which drugs or foods can modify the effect of Arkas
Other medicines and ARKAS
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
Some medicines can alter the effect of ARKAS or the effect of these medicines can be changed by ARKAS. This type of interaction may reduce the effect of one or both medicines. Alternatively, it may increase the risk or severity of side effects including a wasting muscle condition known as rhabdiomyolysis, described in Section 4.
- Medicines used to change the way the immune system works, e.g. cyclosporine.
- Some antibiotics or antifungals, eg. erythromycin, clarithromycin, telithromycin, ketoconazole, itraconazole, voriconazole, fluconazole, posaconazole, rifampicin, fusidic acid.
- Other medicines used to regulate lipid levels, eg. gemfibrozil, other fibrates, colestipol.
- Some calcium channel blockers used for angina or high blood pressure, eg amlodipine, diltiazem; medicines to regulate heart rhythm, eg digoxin, verapamil, amiodarone.
- Medicines used to treat HIV, eg ritonavir, lopinavir, atazanavir, indinavir, darunavir etc.
- Other medicines known to interact with ARKAS include ezetimibe (lowers cholesterol), warfarin (reduces the formation of blood clots), oral contraceptives, stiripentol (an anticonvulsant to treat epilepsy), cimetidine (for stomach acid and peptic ulcers), phenazone (a pain reliever) and antacids (indigestion products containing aluminum or magnesium).
- This also applies to medicines that you can buy without a prescription: St. John's wort.
ARKAS with food and drink
Please refer to section 3 for instructions on how to take ARKAS. Keep in mind the following:
Grapefruit juice
You should not drink more than one or two small glasses of grapefruit juice a day as large amounts of grapefruit juice can alter the effects of ARKAS.
Alcohol
Avoid drinking too much alcohol while taking this medicine. See Section 2. "Warnings and Precautions" for more details.
Warnings It is important to know that:
Pregnancy and breastfeeding
You should not use ARKAS if you are pregnant or planning to become pregnant. You should not use ARKAS if you think you may become pregnant unless you are using an effective method of contraception.
Do not take ARKAS if you are breastfeeding.
The safety of ARKAS during pregnancy and breastfeeding has not yet been proven. Consult your doctor or pharmacist before taking any medication.
Driving and using machines
The drug does not normally affect the ability to drive or use machines. However, do not drive a car if this medicine affects your ability to drive. Do not use tools or machines if your ability to use them is impaired by this medicine.
Dose, Method and Time of Administration How to use Arkas: Posology
Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.
Before starting treatment, your doctor will put you on a low cholesterol diet, which must be continued during treatment with ARKAS.
The usual dose of ARKAS is 10 mg once a day in adults and children from 10 years of age. If necessary, this dose can be increased by your doctor until the dose you need is reached. Your doctor will adjust the dosage at intervals of 4 or more weeks. The maximum dose of ARKAS is 80 mg once daily in adults and 20 mg once daily in children.
ARKAS tablets should be swallowed whole with a drink of water and can be taken at any time of the day, with or without food. However, try to take the tablets at the same time each day.
The duration of treatment with ARKAS is determined by the doctor.
Please consult your doctor if you feel that the effect of ARKAS is too strong or too weak.
Overdose What to do if you have taken too much Arkas
If you take more ARKAS than you should
If you accidentally take too many ARKAS tablets (more than your usual dose), contact your doctor or the nearest hospital for advice.
If you forget to take ARKAS
If you forget to take a dose, take your next dose at the correct time. Do not take a double dose to make up for a forgotten dose.
If you stop taking ARKAS
If you have any further questions about the use of this medicine or if you want to stop treatment, ask your doctor or pharmacist.
Side Effects What are the side effects of Arkas
Like all medicines, this medicine can cause side effects, although not everybody gets them.
If any of the following serious side effects occur, stop taking the tablets and contact your doctor immediately or go to the nearest emergency department.
Rare: affects 1 to 10 users in 10,000:
- Severe allergic reaction which causes swelling of the face, tongue and trachea with possible serious respiratory consequences.
- Severe condition characterized by severe peeling and swelling of the skin, blistering with involvement of the skin, mouth, eyes and genitals, and fever. Severe rash characterized by pink-red patches mainly on the palms of the hands or soles of the feet, with possible blistering.
- Muscle weakness, tenderness or pain, and particularly if you feel unwell or have a fever at the same time, possibly as a result of an abnormal potentially life-threatening muscle breakdown that can lead to kidney problems.
Very rare: affects less than 1 in 10,000 users:
- Unexpected or unusual bleeding or bruising may be indicative of a liver problem. Consult your doctor as soon as possible.
Other side effects reported with ARKAS are
Common side effects (affects 1 to 10 users in 100) are:
- Inflammation of the nasal passages, sore throat, nosebleeds
- Allergic reactions
- Increase in blood sugar levels (if you have diabetes keep close monitoring of blood sugar levels), increase in blood creatine kinase
- Headache
- Nausea, constipation, wind, indigestion, diarrhea
- Joint pain, muscle pain and back pain
- Blood test results showing possible liver malfunction
Uncommon side effects (affects 1 to 10 users in 1,000) are:
- Anorexia (loss of appetite), weight gain, low blood sugar levels (if you have diabetes keep close monitoring of your blood sugar levels).
- Nightmares, insomnia
- Dizziness, numbness or tingling in the toes and hands, decreased sensitivity to pain or touch, altered sense of taste, memory loss
- Blurred vision
- Ringing in my ears or head
- Vomiting, belching, upper and lower abdominal pain, pancreatitis (inflammation of the pancreas which can cause stomach pain)
- Hepatitis (inflammation of the liver)
- Rash, rash and itching, hives, hair loss
- Neck pain, muscle fatigue
- Fatigue, feeling unwell, weakness, chest pain, swelling especially in the ankles (edema), increased temperature
- Positive urine tests for white blood cells
Rare side effects (affects 1 to 10 users in 10,000) are:
- Changes in vision
- Unexpected bleeding or bruising
- Cholestasis (yellowing of the skin and whites of the eyes)
- Trauma to the tendons
Very rare side effects (affects less than 1 user in 10,000) are:
- Allergic reaction - symptoms may include sudden wheezing and chest pain or tightness in the chest, swelling of the eyelids, face, lips, mouth, tongue or throat, difficulty breathing, collapse
- Loss of hearing
- Gynecomastia (breast enlargement in men and women)
Undesirable effects of unknown frequency (frequency cannot be estimated from the available data):
- constant muscle weakness
Possible side effects reported with some statins (drugs of the same group):
- Difficulty in the sexual sphere
- Depression
- Breathing difficulties, including persistent cough and / or shortness of breath or fever.
- Diabetes. This is more likely if you have high blood sugar and fat levels, are overweight, and have high blood pressure. Your doctor will monitor you while you are taking this medicine.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse. By reporting side effects you can help provide more information on safety. of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Plastic bottle: Do not store above 25 ° C.
Al / Al blisters: Do not store above 30 ° C.
Do not use this medicine after the expiry date which is stated on the blister or outer carton after {exp.}. The expiry date refers to the last day of that month.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Composition and pharmaceutical form
What ARKAS
The active ingredient is atorvastatin.
ARKAS 10 mg film-coated tablets
Each tablet contains 10 mg of atorvastatin (as atorvastatin calcium).
ARKAS 20 mg film-coated tablets
Each tablet contains 20 mg of atorvastatin (as atorvastatin calcium).
ARKAS 40 mg film-coated tablets
Each tablet contains 40 mg of atorvastatin (as atorvastatin calcium).
The other ingredients are: mannitol, microcrystalline cellulose, crospovidone, sodium carbonate, povidone K30, methionine and magnesium stearate. The film-coated tablet coating of ARKAS contains hypromellose 6cP, titanium dioxide (E171) and macrogol 6000.
Description of the appearance of ARKAS and contents of the package
ARKAS 10 mg film-coated tablets
White, biconvex, oval, film-coated tablets debossed with 10 on one side and A on the other.
ARKAS 20 mg film-coated tablets
White, biconvex, oval, film-coated tablets with 20 debossed on one side and A on the other.
ARKAS 40 mg film-coated tablets
White, biconvex, oval, film-coated tablets with 40 debossed on one side and A on the other.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
ARKAS TABLETS COATED WITH FILM
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
ARKAS 10 mg film-coated tablets
Each film-coated tablet contains 10 mg of atorvastatin (as atorvastatin calcium).
ARKAS 20 mg film-coated tablets
Each film-coated tablet contains 20 mg of atorvastatin (as atorvastatin calcium).
ARKAS 40 mg film-coated tablets
Each film-coated tablet contains 40 mg of atorvastatin (as atorvastatin calcium). For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Film-coated tablet.
ARKAS 10 mg film-coated tablets
White, biconvex, oval, film-coated tablets debossed with 10 on one side and A on the other.
ARKAS 20 mg film-coated tablets
White, biconvex, oval, film-coated tablets with 20 debossed on one side and A on the other.
ARKAS 40 mg film-coated tablets
White, biconvex, oval, film-coated tablets with 40 debossed on one side and A on the other.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Hypercholesterolemia
ARKAS is indicated, in addition to the diet, for the reduction of high levels of total cholesterol (C-total),
low-density lipoprotein (LDL-C), apolipoprotein B and triglyceride cholesterol in adult, adolescent and child patients from 10 years of age with primary hypercholesterolaemia including familial hypercholesterolemia (heterozygous variant) or combined (mixed) hyperlipidemia (corresponding to Types IIa and IIb of the Fredrickson classification) when the response to diet and other non-pharmacological measures is inadequate.
ARKAS is also indicated to reduce total cholesterol and LDL cholesterol in adult patients with homozygous familial hypercholesterolaemia as an adjunct to other lipid-lowering treatments (e.g. LDL apheresis) or if such treatments are not available.
Prevention of cardiovascular disease
Prevention of cardiovascular events in adult patients believed to be at high risk for a first cardiovascular event (see section 5.1), as an adjunct to correction of other risk factors.
04.2 Posology and method of administration
Dosage
Before receiving ARKAS, the patient should be placed on a standard cholesterol-lowering diet
you must continue this diet during treatment with ARKAS.
Dosage should be individualized taking into account baseline LDL cholesterol levels, therapy goal and patient response.
The usual starting dose is 10 mg once a day. Dosage adjustments should be made at intervals of 4 weeks or more. The maximum dose is 80 mg once a day.
Primary hypercholesterolaemia and combined (mixed) hyperlipidaemia
Most patients are monitored with ARKAS at a dose of 10 mg once daily. Therapeutic response is evident within two weeks and maximum therapeutic response is usually achieved within 4 weeks. The therapeutic effect is maintained during chronic treatment.
Heterozygous familial hypercholesterolaemia
Patients should start treatment with ARKAS at a dose of 10 mg / day. The dosage should be individualized and adjusted every 4 weeks up to 40 mg per day. Thereafter, the dosage may be increased to a maximum of 80 mg per day or a bile acid sequestering agent may be given along with 40 mg of atorvastatin once daily.
Homozygous familial hypercholesterolaemia
Only limited data are available (see section 5.1).
The dosage of atorvastatin in patients with homozygous familial hypercholesterolaemia ranges from 10 to 80 mg / day (see section 5.1). Atorvastatin should be used as an adjunct to other lipid-lowering treatments (eg LDL apheresis) in these patients or if such treatments are unavailable.
Prevention of cardiovascular disease
The 10 mg / day dose was used in primary prevention studies. To achieve the cholesterol (LDL) levels required by current guidelines, higher dosages may be required.
Renal impairment
No dose adjustment is required (see section 4.4).
Hepatic impairment
ARKAS should be used with caution in patients with impaired hepatic function (see sections 4.4 and 5.2). ARKAS is contraindicated in patients with active liver disease (see section 4.3).
Use in the elderly
The efficacy and tolerability in patients over 70 years of age treated with the recommended doses are similar to those seen in the general population.
Pediatric use
Hypercholesterolemia: Pediatric use should be reserved for physicians who specialize in the treatment of pediatric hyperlipidaemia and patients should be re-evaluated on a regular basis to assess progress of care.
The recommended starting dose in patients from 10 years of age is atorvastatin 10 mg per day with an increase up to 20 mg / day. In pediatric patients the dose should be increased according to individual response and tolerability. Safety information for pediatric patients treated with doses above 20 mg, which is approximately 0.5 mg / kg, is limited.
Experience in children aged 6-10 years is limited (see section 5.1). Atorvastatin is not indicated for the treatment of patients less than 10 years of age.
For this patient population, other pharmaceutical formulations may be more suitable.
Method of administration
ARKAS is a drug to be administered orally. Each daily dose of atorvastatin is given as a single dose and can be given at any time of the day, regardless of meals.
04.3 Contraindications
ARKAS is contraindicated in patients:
- with hypersensitivity to the active substance or to any other component of the product,
- with active liver disease or unexplained and persistent elevations of serum transaminases, more than 3 times the upper limit of normal,
- in pregnancy, during lactation and in women of childbearing potential not using appropriate contraceptive measures (see section 4.6).
04.4 Special warnings and appropriate precautions for use
Hepatic effects
Liver function tests should be performed prior to initiation of treatment and periodically thereafter. Patients presenting with signs or symptoms suggestive of liver damage should be monitored for liver function. Patients with elevated transaminases should be monitored for to normalization of values.
If an increase in transaminases of more than 3 times the ULN persists, dose reduction or discontinuation of ARKAS is recommended (see section 4.8).
ARKAS should be used with caution in patients who consume large quantities of alcohol and / or who have a history of liver disease.
Prevention of Stroke by Aggressive Reduction of Cholesterol Levels (SPARCL study)
A "post-hoc analysis of stroke subtypes in patients without ischemic cardiomyopathy (CHD) who had had a stroke or a recent transient ischemic attack (TIA), found a" higher incidence of haemorrhagic stroke in patients who started treatment with atorvastatin 80 mg compared with the placebo group. The increased risk was particularly observed in patients with previous haemorrhagic stroke or lacunar infarction at study enrollment.
For patients with prior haemorrhagic stroke or lacunar infarction, the benefit / risk balance of using atorvastatin 80 mg is unclear and the potential risk of haemorrhagic stroke should be carefully considered before initiating treatment (see section 5.1).
Effects on skeletal muscles
Atorvastatin, like other HMG-CoA reductase inhibitors, can on rare occasions affect skeletal muscle and can cause myalgia, myositis and myopathy that can progress to rhabdomyolysis, a potentially fatal condition characterized by marked increases in creatine phosphokinase (CPK). (> 10 times the upper limit of normal), myoglobinemia and myoglobinuria which can lead to renal failure.
Before the treatment
Atorvastatin should be prescribed with caution in patients with predisposing factors for rhabdomyolysis. Creatine phosphokinase (CPK) level should be measured before starting treatment in the presence of the following clinical conditions:
- Impaired renal function
- Hypothyroidism
- Personal or family history of hereditary muscle diseases
- History of muscle toxicity with statins or fibrates
- History of liver disease and / or when large quantities of alcoholic beverages are consumed
- In old age (over 70 years of age), the need for such measurement should be considered in accordance with the presence of other predisposing factors for rhabdomyolysis
- Situations where increased drug plasma levels may occur, such as in the case of interactions (see section 4.5) and special populations, including genetic subpopulations (see section 5.2).
In such situations, the risk of treatment should be weighed against the possible benefits, and clinical monitoring of the patient is recommended.
If baseline CK levels are significantly elevated (> 5 times the upper limit of normal), treatment should not be initiated.
Measurement of creatine kinase
The creatine kinase (CK) level should not be measured after strenuous exercise or in the presence of any possible alternative causes of the increase in CK as this makes it difficult to interpret the value obtained. If the CK levels are significantly increased compared to at baseline (> 5 times ULN), CK levels should be re-measured within the next 5-7 days to confirm results.
During the treatment
- Patients should be advised to promptly report episodes of muscle pain, cramps or weakness, particularly if associated with malaise or fever.
- If these symptoms occur when a patient is being treated with atorvastatin, CK levels should be measured. If these levels are significantly increased (> 5 times the ULN), treatment should be stopped.
- If muscle symptoms are severe and cause daily discomfort, even if CK levels are ≤5 times ULN, treatment discontinuation should be considered.
- If symptoms resolve and CK levels normalize, restarting atorvastatin or another statin at the lower dose and careful monitoring may be considered.
- Atorvastatin treatment should be discontinued if clinically significant increases in CK (> 10 x ULN) occur or if rhabdomyolysis is diagnosed or suspected.
Concomitant treatment with other drugs
The risk of rhabdomyolysis is increased when atorvastatin is co-administered with certain medicinal products that may increase plasma concentrations of atorvastatin such as in the case of potent CYP3A4 inhibitors or transport proteins (e.g. cyclosporine, telithromycin, clarithromycin, delavirdine stiripentol, ketoconazole, voriconazole , itraconazole, posaconazole and HIV protease inhibitors, including ritonavir, lopinavir, atazanavir, indinavir, darunavir, etc). The risk of myopathy may also increase with the concomitant use of gemfibrozil and other fibric acid derivatives, erythromycin, niacin and ezetimibe. If possible, alternative (non-interacting) therapies should be considered as an alternative to these medicinal products. In cases where concomitant administration of these medicinal products and atorvastatin is necessary, the risks and benefits of treatment should be carefully weighed. If patients are taking medicinal products that increase the plasma concentration of atorvastatin, a lower maximum dose of atorvastatin is recommended. In case of concomitant treatment with potent CYP3A4 inhibitors, a lower starting dose of atorvastatin should be considered. and appropriate clinical monitoring of these patients is recommended (see section 4.5).
Concomitant use of atorvastatin and fusidic acid is not recommended; therefore, a temporary withdrawal of atorvastatin during treatment with fusidic acid should be considered (see section 4.5).
Diabetes mellitus
Some evidence suggests that the statin class increases blood glucose and in some patients, at high risk of developing diabetes, may produce a level of hyperglycemia that requires formal diabetes care. This risk, however, is offset by the reduction in vascular risk with statins and therefore should not be a reason for stopping treatment with statins. Patients at risk (fasting glucose 5.6-6.9 mmol / L, BMI> 30 kg / m2, increased triglycerides, hypertension) should be monitored both clinically and biochemically according to national guidelines.
Interstitial lung disease
Exceptional cases of interstitial lung disease have been reported following the use of some statins, especially in the context of long-term therapy (see section 4.8). Initial symptoms may include dyspnoea, non-productive cough, and deterioration of the general state of health (fatigue, weight loss and fever) If there is a suspicion of the patient developing interstitial lung disease, statin therapy should be discontinued.
Pediatric use
Developmental safety has not been established in the pediatric population (see section 4.8).
04.5 Interactions with other medicinal products and other forms of interaction
Effect of medicinal products on concomitantly administered atorvastatin
Atorvastatin is metabolised by cytochrome P450 3A4 (CYP3A4) and is a substrate of transport proteins, such as the transporter OATP1B1 involved in hepatic uptake. plasma concentrations of atorvastatin and increase the risk of myopathy. This risk may also increase following concomitant administration of atorvastatin with other medicinal products that have the potential to induce myopathy, such as fibric acid derivatives and ezetimibe (see section 4.4).
CYP3A4 inhibitors
Potent CYP3A4 inhibitors have been shown to cause markedly increased concentrations of atorvastatin (see Table 1 and specific information below). Concomitant administration of potent CYP3A4 inhibitors (eg cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole and HIV protease inhibitors, including ritonavir, lopinavir, indazanavir, etc.) should be avoided if possible.
In the event that concomitant treatment of these drugs and atorvastatin cannot be avoided, lower initial and maximum doses of atorvastatin should be considered and appropriate clinical monitoring of these patients is recommended (see table 1).
Moderate inhibitors of CYP3A4 (e.g. erythromycin, diltiazem, verapamil and fluconazole) may increase plasma concentrations of atorvastatin (see table 1). An increased risk of myopathy has been observed following concomitant use of erythromycin and statins. No interaction studies have been conducted to evaluate the effects of amiodarone or verapamil on atorvastatin. Both amiodarone and verapamil are known inhibitors of CYP3A4 activity and co-administration with atorvastatin may result in increased exposure to atorvastatin. A lower maximum dose of atorvastatin is therefore considered and appropriate clinical monitoring of these patients is recommended when treated concomitantly with moderate CYP3A4 inhibitors. Upon initiation of inhibitor treatment or following inhibitor dosage adjustments, appropriate clinical monitoring is advised.
CYP3A4 inducers
Concomitant administration of atorvastatin and inducers of cytochrome P450 3A4 (e.g. efavirenz, rifampicin, St. John's wort) may result in variable reductions in plasma concentrations of atorvastatin. Due to the dual mechanism of interaction of rifampicin (induction of cytochrome P450 3A and inhibition of the transporter OATP1B1 at the hepatocyte level), concomitant administration of atorvastatin and rifampicin is recommended, as delayed administration of atorvastatin following rifampicin administration is It has been associated with a significant decrease in plasma concentrations of atorvastatin. However, the effect of rifampicin on atorvastatin concentrations in hepatocytes is not known; if concomitant administration cannot be avoided, patients should be carefully monitored to verify the efficacy of the treatment.
Transport inhibitors
Transport inhibitors (eg cyclosporine) may increase the systemic exposure of atorvastatin (see Table 1). The inhibitory effect of transporters involved in hepatic uptake on atorvastatin concentrations in hepatocytes is unknown. In the event that concomitant treatment cannot be avoided, dose reduction and clinical monitoring are recommended for evaluation of efficacy.
Gemfibrozil / fibric acid derivatives
The use of fibrates alone is occasionally associated with muscle events, including rhabdomyolysis. This risk may be increased by concomitant administration of fibric acid derivatives and atorvastatin. If concomitant administration cannot be avoided, the lowest dose of atorvastatin necessary to achieve the therapeutic goal should be used; the patient should be adequately monitored (see section 4.4).
Ezetimibe
The use of ezetimibe alone has been associated with muscle events, including rhabdomyolysis.
This risk may therefore be increased when ezetimibe and atorvastatin are co-administered. Appropriate clinical monitoring of these patients is advised.
Colestipol
Plasma concentrations of atorvastatin and its active metabolites were reduced (approximately 25%) when colestipol was co-administered with ARKAS. However, the effects on lipids were greater when ARKAS and colestipol were administered simultaneously than when administered alone.
Fusidic acid
No interaction studies have been conducted with atorvastatin and fusidic acid. As with other statins, muscle-related events, including rhabdomyolysis, have been reported in the post-marketing period following co-administration of atorvastatin and fusidic acid. mechanism of this interaction is unknown.
Patients should be monitored very closely and a temporary suspension of atorvastatin treatment may be appropriate.
Effect of atorvastatin on concomitantly administered medicinal products
Digoxin
Co-administration of repeated doses of digoxin and atorvastatin 10 mg resulted in a slight increase in steady-state plasma digoxin concentrations. Patients taking digoxin should be monitored appropriately.
Oral contraceptives
Co-administration of ARKAS and an oral contraceptive resulted in increased plasma concentrations of norethindrone and ethinylestradiol.
Warfarin
In a clinical study in patients on chronic warfarin treatment, co-administration of atorvastatin 80 mg / day and warfarin resulted in a small decrease of approximately 1.7 seconds in prothrombin time during the first 4 days of therapy that normalized within 15 days of treatment with atorvastatin. Although clinically significant anticoagulant interactions have occurred only very rarely, prothrombin time should be determined before starting treatment with atorvastatin in patients taking coumarin anticoagulants and with sufficient frequency during early therapy to ensure that no significant alteration of the prothrombin time occurs.
Once a stable prothrombin time is documented, prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of atorvastatin is changed or discontinued, the same procedure must be repeated. Atorvastatin therapy has not been associated with bleeding or changes in prothrombin time in patients not on anticoagulant therapy.
Pediatric population
Interaction studies have only been conducted with adults. The extent of interactions in the pediatric population is unknown. The interactions noted above and observed for adults and warnings in the section
4.4 should be considered for the pediatric population.
Table 1: Effect of concomitantly administered medicinal products on the pharmacokinetics of atorvastatin
& data shown as x-fold alteration represent a simple relationship between combined administration and administration of atorvastatin alone (e.g. 1-time = no change). The data shown as percent change represent the percent difference relative to atorvastatin when given alone (for example: 0% = no change).
# See sections 4.4 and 4.5 for clinical significance.
* Contains one or more components that inhibit CYP3A4 and may increase plasma concentrations of drugs metabolised by CYP3A4. The intake of a quantity of grapefruit juice equal to
240 ml also resulted in a 20.4% reduction in the AUC of the active ortho-hydroxylated metabolite. Large quantities of grapefruit juice (over 1.2 L / day for 5 days) resulted in a 2.5-fold increase in the AUC of atorvastatin and an increase in the AUC of the active ingredient (atorvastatin and metabolites).
^ Total equivalent activity of atorvastatin
The "increase is indicated with the" ↑ "symbol, the decrease with the" ↓ "symbol
OD = once a day; SD = single dose; BID = twice a day; QID = four times a day.
Table 2: Effect of atorvastatin on the pharmacokinetics of concomitantly administered medicinal products
& the data shown as percent alteration represent the percent difference relative to atorvastatin
when given alone (for example: 0% = no change).
* Co-administration of multiple doses of atorvastatin and phenazone resulted in small or undetectable effects on phenazone clearance.
The "increase is indicated with the symbol" ↑ ", the decrease with the symbol" ↓ "OD = once daily; SD = single dose
04.6 Pregnancy and lactation
Women of childbearing age
Women of childbearing potential must use effective contraceptive methods during treatment (see section 4.3).
Pregnancy
ARKAS is contraindicated during pregnancy (see section 4.3). The safety of use of the drug in pregnant women has not been established. No controlled clinical studies have been performed with atorvastatin in pregnant women. There have been rare reports of congenital abnormalities following intrauterine exposure to HMG-CoA reductase inhibitors.
Animal studies have shown reproductive toxicity (see section 5.3).
Maternal treatment with atorvastatin can reduce fetal levels of mevalonate, a precursor of cholesterol biosynthesis. Atherosclerosis is a chronic process, and the usual discontinuation of cholesterol-lowering drugs during pregnancy should have a low impact on the long-term risk associated with primary hypercholesterolemia.
For these reasons, ARKAS should not be used in women who are pregnant or are trying or suspecting pregnancy. Treatment with ARKAS should be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant (see section 4.3).
Feeding time
It is unknown whether atorvastatin or its metabolites are excreted in human milk. In rats, plasma concentrations of atorvastatin and its active metabolites are similar to those found in human milk (see section 5.3).
Due to the possible occurrence of serious adverse reactions in infants, women receiving ARKAS should not breastfeed their child (see section 4.3). Atorvastatin is contraindicated during breastfeeding (see section 4.3).
Fertility
Animal studies have shown that atorvastatin has no effect on male or female fertility (see section 5.3).
04.7 Effects on ability to drive and use machines
ARKAS has no, if any, effect on the ability to drive and use machines.
04.8 Undesirable effects
From the analysis of data relating to the placebo-controlled clinical study on atorvastatin involving 16,066 patients (8,755 treated with Lipitor vs 7,311 treated with placebo) treated for a mean period of 53 weeks it was observed that 5.2% of patients treated with Atorvastatin had to discontinue therapy due to adverse reactions compared with 4.0% of patients treated with placebo.
The adverse reaction profile information for ARKAS presented in the table below is attributable to clinical studies performed and extensive post-marketing experience.
Frequency groupings are defined according to the following convention: common (≥1 / 100,
Infections and infestations:
Common: Nasopharyngitis
Disorders of the blood and lymphatic system
Rare: Thrombocytopenia
Disorders of the immune system
Common: Allergic reactions
Very rare: Anaphylaxis
Metabolism and nutrition disorders
Common: Hyperglycemia
Uncommon: Hypoglycaemia, weight gain, anorexia
Psychiatric disorders
Uncommon: Nightmares, insomnia
Nervous pathologies
Common: Headache
Uncommon: Dizziness, paraesthesia, hypoesthesia, dysgeusia, amnesia
Rare: Peripheral neuropathy.
Eye disorders
Uncommon: Vision blurred
Rare: Changes in vision
Ear and labyrinth disorders
Uncommon: Tinnitus
Very rare: Hearing loss
Respiratory, thoracic and mediastinal disorders
Common: Pharyngolaryngeal pain, epistaxis
Gastrointestinal disorders
Common: Constipation, flatulence, dyspepsia, nausea, diarrhea
Uncommon: Vomiting, pain in the lower and upper abdomen, belching, pancreatitis
Hepatobiliary disorders
Uncommon: Hepatitis
Rare: Cholestasis
Very rare: Hepatic failure
Skin and subcutaneous tissue disorders
Uncommon: Urticaria, rash, pruritus, alopecia
Rare: Angioneurotic edema, bullous dermatitis, including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis
Musculoskeletal and connective tissue disorders
Common: Myalgia, arthralgia, pain in extremity, muscle spasms, joint swelling, back pain
Uncommon: Neck pain, muscle fatigue
Rare: Myopathy, myositis, rhabdomyolysis, tendinopathy, sometimes complicated by rupture
Diseases of the reproductive system and breast
Very rare: Gynecomastia
General disorders and administration site conditions
Uncommon: Malaise, asthenia, chest pain, peripheral edema, fatigue, pyrexia
Diagnostic tests
Common: Abnormal liver function tests, increased blood creatine kinase levels
Uncommon: White blood cell positive urine.
As with other HMG-CoA reductase inhibitors, increases in serum transaminases have been reported in patients treated with ARKAS. These elevations were usually mild and transient and did not require treatment discontinuation. Clinically significant (> 3 times ULN) increases in serum transaminases were observed in 0.8% of ARKAS-treated patients. These increases were dose-dependent and reversible in all patients.
Elevated creatine kinase (CK) levels above 3 times the upper limit of normal have been observed in 2.5% of ARKAS-treated patients in clinical trials, similar to other HMG-CoA reductase inhibitors. Levels above 10 times the upper limit of normal were observed in 0.4% of ARKAS-treated patients (see section 4.4).
The following adverse events have been reported with some statins:
- sexual dysfunction
- depression
Exceptional cases of interstitial lung disease have been reported, especially in the context of long-term therapy (see section 4.4).
Diabetes Mellitus: Frequency will depend on the presence or absence of risk factors (fasting blood glucose ≥ 5.6 mmol / L, BMI> 30 kg / m2, increased triglycerides, history of hypertension).
Pediatric population
The clinical safety database includes safety data from 249 pediatric patients who received atorvastatin, of whom 7 were "less than 6 years old, 14 were" 6 to 9 years old, and 228 were " between 10 and 17 years.
Nervous pathologies
Common: Headache
Gastrointestinal disorders
Common: Abdominal pain
Diagnostic tests
Common: Alanine transferase levels increased, creatine phosphokinase blood levels increased.
Based on the available data it is considered that the frequency, type and severity of adverse reactions in children are comparable to those seen in adults. At present, the long-term safety experience in the pediatric population is limited.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
04.9 Overdose
There is no specific treatment available for ARKAS overdose. In this case, the patient should be treated symptomatically and with appropriate supportive measures. Liver function tests should be performed and serum CK levels monitored. Due to the high plasma protein binding of atorvastatin, hemodialysis is not expected to significantly increase the clearance of atorvastatin.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: Lipid modifying substances, HMG-CoA reductase inhibitors.
ATC code: C10AA05.
Atorvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme of conversion of 3-hydroxy-3-methyl-glutaryl Coenzyme A to mevalonic acid, a precursor of sterols, including cholesterol. The triglycerides and cholesterol synthesized in the liver are incorporated into very low density lipoproteins (VLDL) and released into the plasma for distribution to peripheral tissues. Low-density lipoproteins (LDL) are formed from VLDL and are mainly catabolized by the high-affinity LDL receptor (LDL receptor).
Atorvastatin lowers plasma cholesterol and serum concentrations of lipoproteins, inhibiting HMG-CoA reductase, and consequently the biosynthesis of hepatic cholesterol, and increases the number of hepatic LDL receptors present on the cell surface, with consequent increased uptake and catabolism of LDL.
Atorvastatin reduces the production of LDL and the number of LDL particles. Atorvastatin causes a conspicuous and prolonged increase in LDL receptor activity, together with a "useful modification of the quality of circulating LDL particles." Atorvastatin is effective. in lowering LDL cholesterol in patients with homozygous familial hypercholesterolemia, a population that usually does not respond to lipid-lowering drugs.
In a dose-response study, atorvastatin was shown to reduce concentrations of total cholesterol (30% - 46%), LDL cholesterol (41% - 61%), apolipoprotein B (34% - 50%) and triglycerides (14 % - 33%) causing simultaneously variable increases in HDL cholesterol and apolipoprotein A1.These results have been shown in patients with heterozygous familial hypercholesterolemia, non-familial forms of hypercholesterolemia and mixed hyperlipemia, including patients with non-insulin-dependent diabetes mellitus.
The reduction of total cholesterol, LDL cholesterol and apolipoprotein B has been shown to reduce the risk of cardiovascular events and cardiovascular mortality.
Homozygous familial hypercholesterolaemia
An 8-week open-label compassionate use multicenter study with an optional extension phase of variable length enrolled 335 patients, 89 of whom were identified as patients with homozygous familial hypercholesterolaemia. The mean percentage reduction in LDL cholesterol was approximately 20% in these 89 patients. Atorvastatin has been administered in doses up to 80 mg / day.
Arteriosclerosis
In the Reversing Atherosclerosis with Aggressive Lipid-Lowering Study (REVERSAL) the effect of an aggressive lipid-lowering treatment with atorvastatin 80 mg and of a standard treatment with pravastatin 40 mg on coronary atherosclerosis by intravascular ultrasound (IVUS) was evaluated, in course of angiography, in patients with coronary artery disease. In this randomized, double-blind, multicenter, controlled clinical trial, IVUS was performed in 502 patients at baseline and at 18 months. No progression of atherosclerosis was observed in the atorvastatin group (n = 253).
Median percentage changes in total atheroma volume (main study objective) from baseline were -0.4% (p = 0.98) for the atorvastatin group and + 2.7% (p = 0.001) for the pravastatin group (n = 249). Comparison of the effects of atorvastatin versus pravastatin was statistically significant (p = 0.02). The effect of aggressive lipid-lowering treatment on cardiovascular endpoints (eg, need for revascularization, non-fatal myocardial infarction, coronary death) was not evaluated in this study.
In the atorvastatin group, LDL cholesterol decreased to a mean of 2.04 mmol ± 0.8 (78.9 mg / dL ± 30) from a baseline of 3.89 mmol / L ± 0.7 (150 mg / dL ± 28) and in the pravastatin group LDL cholesterol decreased to a mean value of 2.85 mmol / L ± 0.7 (110 mg / dL ± 26) from a baseline of 3.89 mmol / L ± 0.7 (150 mg / dL ± 26) (pPCR equal to 36.4% in the atorvastatin group compared to the 5.2% reduction observed in the pravastatin group (p
The results of the study were obtained with the 80 mg dose and therefore cannot be extrapolated to the lower dosages.
The safety and tolerability profiles were comparable between the two treatment groups.
The effect of aggressive lipid-lowering treatment on major cardiovascular endpoints was not evaluated in this study. The clinical significance of these imaging findings for primary and secondary prevention of cardiovascular events is therefore unknown.
Acute coronary syndrome
In the MIRACL study, atorvastatin 80 mg was evaluated in 3,086 patients (atorvastatin n = 1,538; placebo n = 1,548) with acute coronary syndrome (non-Q myocardial infarction or unstable angina). Treatment was initiated during phase acute after hospital admission and lasted for a period of 16 weeks.Treatment with atorvastatin 80 mg / day increased the time to onset of the combined primary endpoint, defined as death from any cause, non-fatal myocardial infarction, cardiac arrest with resuscitation, or angina pectoris with evidence of myocardial ischaemia requiring hospitalization, indicating a 16% risk reduction (p = 0.048). This was mainly due to a 26% reduction in the risk of re-hospitalization for angina pectoris with evidence of myocardial ischaemia (p = 0.018). Other secondary endpoints did not meet individually a statistical significance (overall: Placebo: 22.2%; Atorvastatin: 22.4%).
The safety profile of atorvastatin in the MIRACL study was in line with that described in section 4.8.
Prevention of cardiovascular disease
The effect of atorvastatin on fatal and non-fatal coronary artery disease was evaluated in the lipid-lowering arm of the Anglo-Scandinavian Cardiac Outcomes Trial Lipid Lowering Arm (ASCOT-LLA), a randomized, double-blind, placebo-controlled study. Patients were hypertensive, aged aged 40 to 79 years, with no previous myocardial infarction or treatment for angina and with total cholesterol (CT) levels ≤ 6.5 mmol / l (251 mg / dl). All patients had at least 3 of the predefined risk factors cardiovascular: male, age = 55 years, smoking, diabetes, history of coronary heart disease in first degree relative, CT: HDL> 6, peripheral vascular disease, left ventricular hypertrophy, previous cerebrovascular events, specific ECG changes, proteinuria / albuminuria. Not all patients included were at high risk for a first cardiovascular event.
Patients were treated with antihypertensive therapy (amlodipine or atenolol-based regimen) and atorvastatin 10 mg / day (n = 5,168) or placebo (n = 5,137).
The effect of atorvastatin on absolute and relative risk reduction is as follows:
1 Based on difference in event frequencies that occurred over the median follow-up period of 3.3 years.
CHD = coronary artery disease, MI = myocardial infarction.
Total mortality and cardiovascular mortality did not significantly reduce (185 vs. 212 events, p = 0.17 and 74 vs. 82 events, p = 0.51). In the subgroup analyzes based on gender (81% men, 19% women), a positive effect of atorvastatin was found in men, but could not be established in women, possibly due to the low event rates in the subgroup of women. Total and cardiovascular mortality were numerically higher in women (38 vs. 30 and 17 vs. 12), but this was not statistically significant.
There was a significant treatment interaction due to antihypertensive therapy at baseline. The primary endpoint (fatal CHD and non-fatal MI) was significantly reduced by atorvastatin in amlodipine-treated patients (HR 0.47 (0.32-0.69) p = 0.00008), but not in those treated. with atenolol (HR 0.83 (0.59-1.17), p = 0.287).
The effect of atorvastatin on fatal and non-fatal heart disease was also evaluated in a multicentre, randomized, double-blind, placebo-controlled study, the Collaborative Atorvastatin Diabetes Study (CARDS) conducted in patients with type 2 diabetes of age. 40 - 75 years, with no previous history of cardiovascular disease and with LDL-C = 4.14 mmol / l (160 mg / dl) and TG = 6.78 mmol / l (600 mg / dl). All patients had at least 1 of the following risk factors: hypertension, ongoing smoking, retinopathy, microalbuminuria or macroalbuminuria. Patients were treated with atorvastatin 10 mg / day (n = 1,428) or placebo (n = 1,410) for a median follow-up period of 3.9 years.
The effect of atorvastatin on absolute and relative risk reduction is as follows:
1 Based on difference in event frequencies that occurred over the median follow-up period of 3.9 years.
AMI = acute myocardial infarction, CABG = coronary artery bypass surgery, CHD = coronary artery disease, MI = myocardial infarction; PTCA = percutaneous trans-luminal coronary angioplasty.
No differences in treatment effect were observed in relation to gender, age or baseline LDL-C level. A positive trend in mortality rate was observed (82 deaths in the placebo group vs. 61 deaths in the atorvastatin group, p = 0.0592).
Recurrent stroke
In the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study, the effects of atorvastatin 80 mg once daily or placebo on stroke were evaluated in 4,731 patients who had had stroke or transient ischemic attack (TIA) in 6 months prior and who had no history of heart disease (CHD). 60% of patients were male aged 21 to 92 years (mean age 63) with a mean baseline LDL of 133 mg / dL (3.4 mmol / L). The mean LDL-C value was 73 mg / dL (1.9 mmol / L) during treatment with atorvastatin and 129 mg / dL (3.3 mmol / L) during treatment with placebo .
The median follow-up was 4.9 years.
Atorvastatin 80 mg reduced the risk of the primary endpoint of fatal or non-fatal stroke by 15% (HR 0.85; 95% CI, 0.72-1.00; p = 0.05 or 0.84; 95% CI, 0.71-0.99; p = 0.03 after adjustment for baseline factors) versus placebo. All cause mortality was 9.1% (216/2365) for atorvastatin versus 8.9% (211/2366) for placebo.
A post-hoc analysis found that atorvastatin 80 mg reduced the incidence of ischemic stroke (218/2365, 9.2% versus 274/2366, 11.6%, p = 0.01) and increased the incidence of haemorrhagic stroke (55/2365, 2.3% versus 33/2366, 1.4%, 1.4%) versus placebo.
The risk of haemorrhagic stroke was increased in patients enrolled in the study with prior haemorrhagic stroke (7/45 atorvastatin versus 2/48 placebo; HR 4.06; 95% CI, 0.84 - 19.57) and the risk of ischemic stroke is similar for the two groups (3/45 atorvastatin versus 2/48 placebo; HR 1.64; 95% CI, 0.27 - 9.82).
The risk of haemorrhagic stroke was increased in patients enrolled in the study and with prior lacunar infarction (20/708 atorvastatin versus 4/701 placebo; HR 4.99; 95% CI, 1.71-14.61), but the risk was also reduced in these patients. of ischemic stroke (79/708 atorvastatin versus 102/701 placebo; HR 0.76; 95% CI, 0.57-1.02). It is possible that the net risk of stroke is higher in patients with prior lacunar infarction taking atorvastatin 80 mg / day. All cause mortality was 15.6% (7/45) in the atorvastatin group compared to 10.4% (5 / 48) in the subgroup of patients with prior haemorrhagic stroke. All cause mortality was 10.9% (77/708) for atorvastatin versus 9.1% (64/701) for placebo in the subgroup of patients with prior lacunar infarction .
Pediatric population
Heterozygous familial hypercholesterolaemia in pediatric patients aged 6-17 years.
An 8-week open-label study was conducted to evaluate the pharmacokinetics, pharmacodynamics, safety and tolerability of atorvastatin in children and adolescents with genetically confirmed heterozygous familial hypercholesterolemia and baseline LDL cholesterol of = 4 mmol / L A total of 39 children and adolescents between the ages of 6 and 17 were enrolled. Group A included 15 children aged 6-12 and Tanner Stage 1. Group B included 24 children aged 10-17 and Tanner Stage = 2.
The starting dose of atorvastatin was one 5 mg chewable tablet per day in group A and one 10 mg tablet per day in group B. If a subject did not reach the target LDL cholesterol level
Mean LDL cholesterol, total cholesterol, VLDL cholesterol, and apolipoprotein B values decreased at week 2 in all subjects. In subjects in whom the dose was doubled, further reductions were observed as early as the beginning of the 2nd week, first evaluation after dose increase. The mean percent reduction in lipid parameters was similar for both groups, regardless of whether subjects remained on the starting dose or doubled the starting dose. At week 8, the percent change from baseline for LDL and total cholesterol averaged 40% and 30%, respectively, across the drug exposure range.
Heterozygous familial hypercholesterolaemia in pediatric patients aged 10 to 17 years.
In a double-blind, placebo-controlled study followed by an open-label phase, 187 boys and girls (post-menarche phase), aged 10-17 years (mean age 14.1 years) with heterozygous familial hypercholesterolemia (FH) o severe hypercholesterolaemia were randomized to treatment with atorvastatin (n = 140) or placebo (n = 47) for 26 weeks and subsequently all treated with atorvastatin for 26 weeks. The dosage of atorvastatin (once daily) was 10 mg for the first 4 weeks and then gradually increased to 20 mg if the LDL cholesterol level was> 3.36 mmol / L. Atorvastatin significantly reduced plasma levels of total cholesterol, LDL cholesterol, triglycerides and apolipoprotein B in the 26-week double-blind phase. The mean achieved LDL cholesterol was 3.38 mmol / l (range: 1.81-6.26 mmol / l) in the atorvastatin treatment group compared to 5.91 mmol / l (range: 3.93-9.96 mmol / l) obtained in the placebo group in the 26-week double-blind phase.
Another pediatric study with atorvastaine versus colestipol in patients with hypercholesterolaemia aged 10-18 years showed that atorvastatin (N = 25) caused a significant reduction in LDL cholesterol at week 26 (p
A compassionate use study in patients with severe hypercholesterolaemia (including homozygous hypercholesterolaemia) included 46 patients treated with atorvastatin titrated based on response to treatment (some subjects were treated with 80 mg of atorvastatin daily). The study lasted. 3 years: LDL cholesterol was reduced by 36%.
The long-term efficacy of pediatric atorvastatin treatment in reducing adult morbidity and mortality has not been established.
The European Medicines Agency has waived the obligation to submit the results of studies with atorvastatin in children aged 0 and treatment of heterozygous hypercholesterolemia and in children aged 0 to
05.2 "Pharmacokinetic properties
Absorption
Atorvastatin is rapidly absorbed following oral administration; maximum plasma concentrations (Cmax) are reached within 1 to 2 hours.
The extent of absorption increases in proportion to the dose of atorvastatin. After oral administration, the bioavailability of the film-coated tablets is 95% - 99% relative to the oral atorvastatin solution. The absolute bioavailability of atorvastatin is approximately 12% and the systemic availability of HMG-CoA reductase inhibiting activity is approximately 30%. Low systemic availability is attributed to pre-systemic clearance in the gastrointestinal mucosa and / or first pass hepatic metabolism.
Distribution
The mean volume of distribution of atorvastatin is approximately 381 L. Atorvastatin is 98% or more bound to plasma proteins.
Biotransformation
Atorvastatin is metabolised by cytochrome P450 3A4 to ortho- and para-hydroxylated derivatives and various beta-oxidation products. In addition to other metabolic pathways, these products are also metabolised via glucuronication. In vitro inhibition of HMG-CoA reductase by ortho- and para-hydroxylated metabolites is equivalent to that of atorvastatin. Approximately 70% of the circulating inhibitory activity of HMG-CoA reductase is attributed to active metabolites.
Excretion
Atorvastatin is eliminated primarily in the bile following hepatic and / or extrahepatic metabolism. However, the drug does not appear to undergo significant enterohepatic recirculation. In humans, the mean plasma elimination half-life of atorvastatin is approximately 14 hours. The half-life of HMG-CoA reductase inhibiting activity is approximately 20 - 30 hours due to the contribution of active metabolites.
Special populations
Elderly patients: Plasma concentrations of atorvastatin and its active metabolites in the healthy elderly are higher than those in the young adult, while the effects on lipids are comparable to those observed in younger patient populations.
Pediatrics: In an 8-week open-label study, pediatric patients aged 6-17 years, Tanner Stage 1 (N = 15) and Tanner Stage ≥2 (N = 24), with heterozygous familial hypercholesterolaemia and baseline LDL cholesterol ≥ 4 mmol / L were treated with once daily atorvastatin 5 mg or 10 mg chewable tablets or atorvastatin 10 mg or 20 mg film-coated tablets, respectively. Body weight was the only significant covariant in the population pharmacokinetic model of atorvastatin. The apparent oral clearance of atorvastatin in pediatric subjects was similar to that in adults using allometric equations based on body weight. Significant reductions in LDL cholesterol and total cholesterol were observed over the dose range of exposure to atorvastatin and o-hydroxyiatorvastatin.
Sex: Concentrations of atorvastatin and its active metabolites in women differ from those in men (women: approximately 20% higher Cmax and approximately 10% lower AUC). These differences were not of clinical significance, resulting in no clinically significant differences. of the effects on lipids between men and women.
Kidney failure: renal disease does not affect the plasma concentration or the lipid-lowering effects of atorvastatin and its active metabolites.
Liver failure: Plasma concentrations of atorvastatin and its active metabolites are markedly increased (approximately 16 times the Cmax and approximately 11 times the AUC) in patients with chronic alcoholic liver disease (Child-Pugh B).
Polymorphism of SLCO1B1. Hepatic uptake of all HMG-CoA reductase inhibitors, including atorvastatin, involves the OATP1B1 transporter. Patients with SLCO1B1 polymorphism are at risk of increased exposure to atorvastatin, resulting in an increased risk of rhabdomyolysis (see paragraph 4.4). Polymorphism in the gene encoding OATP1B1 (SLCO1B1 c.521CC) is associated with a 2.4-fold greater increase in atorvastatin exposure (AUC) than in individuals without this genotype variant (c.521TT). Genetically impaired hepatic uptake of atorvastatin is possible. The possible consequences on efficacy are unknown.
05.3 Preclinical safety data
Atorvastatin did not reveal mutagenic and clastogenic potential in a series of 4 in vitro tests and one in vivo test. Atorvastatin was not carcinogenic in rats; administration of high doses in mice (with an AUC 0-24h 6-11 times higher than that achieved in humans at the maximum recommended dose), however, resulted in the appearance of hepatocellular adenomas. in males and hepatocellular carcinomas in females.
Experimental animal studies have provided evidence that HMG-CoA reductase inhibitors can affect the development of embryos or fetuses. Atorvastatin did not show any effect on fertility in rats, rabbits and dogs and did not show any teratogenic effects. However, fetal toxicity was observed in rats and rabbits after administration of maternally toxic doses. Rat pup development was delayed and postnatal survival reduced following exposure to high doses of atorvastatin. Evidence of placental transfer was found in rats.
In rats, plasma concentrations of atorvastatin are similar to those found in breast milk. It is unknown whether atorvastatin or its metabolites are excreted in human milk.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Core of the tablet:
Mannitol
Microcrystalline cellulose
Crospovidone
Sodium carbonate anhydrous
Povidone K30
Methionine
Magnesium stearate
Coating:
Hypromellose 6cP
Titanium dioxide (E 171)
Macrogol 6000
06.2 Incompatibility
Not relevant.
06.3 Period of validity
2 years.
06.4 Special precautions for storage
Plastic bottle: Do not store above 25 ° C.
Al / Al blisters: Do not store above 30 ° C.
06.5 Nature of the immediate packaging and contents of the package
Al / Al blister packs or bottles made of HDPE plastic and a round white plastic LDPE cap with tear-off opening and sealing ring and HDPE plastic container filled with silica gel as desiccant, containing:
Blister packs of 7 or 10 tablets: 7, 10, 14, 28, 30, 50, 56, 84, 100, 112, 126, 140, 168, 500
Bottles:
10 mg: 10, 28, 30, 100, 200 tablets
20 mg: 7, 10, 14, 28, 30, 100 tablets
40 mg: 10, 14, 28, 30, 50.56, 100 tablets
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
No special precautions.
07.0 MARKETING AUTHORIZATION HOLDER
CRINOS S.p.A., Via Pavia, 6 - 20136 Milan
08.0 MARKETING AUTHORIZATION NUMBER
ARKAS 10 mg film-coated tablets, 7 tablets Al / Al blister AIC n. 041460015
ARKAS 10 mg film-coated tablets, 10 tablets blister Al / Al AIC n. 041460027
ARKAS 10 mg film-coated tablets, 14 tabs Al / Al blister AIC n. 041460039
ARKAS 10 mg film-coated tablets, 28 tabs Al / Al blister AIC n. 041460041
ARKAS 10 mg film-coated tablets, 30 tabs Al / Al blisters AIC n. 041460054
ARKAS 10 mg film-coated tablets, 50 tablets Al / Al blister AIC n. 041460066
ARKAS 10 mg film-coated tablets, 56 tablets Al / Al blisters AIC n. 041460078
ARKAS 10 mg film-coated tablets, 84 tablets blister Al / Al AIC n. 041460080
ARKAS 10 mg film-coated tablets, 100 tabs Al / Al blisters AIC n. 041460092
ARKAS 10 mg film-coated tablets, 112 tablets Al / Al blisters AIC n. 041460104
ARKAS 10 mg film-coated tablets, 126 tablets blister Al / Al AIC n. 041460116
ARKAS 10 mg film-coated tablets, 140 cpr Al / Al blister AIC n. 041460128
ARKAS 10 mg film-coated tablets, 168 cpr Al / Al blister AIC n. 041460130
ARKAS 10 mg film-coated tablets, 500 tablets Al / Al blister AIC n. 041460142
ARKAS 10 mg film-coated tablets, 10 tablets HDPE bottle AIC n. 041460155
ARKAS 10 mg film-coated tablets, 28 tablets HDPE bottle AIC n. 041460167
ARKAS 10 mg film-coated tablets, 30 tablets HDPE bottle AIC n. 041460179
ARKAS 10 mg film-coated tablets, 100 tabs HDPE bottle AIC n. 041460181
ARKAS 10 mg film-coated tablets, 200 tablets HDPE bottle AIC n. 041460193
ARKAS 20 mg film-coated tablets, 7 tablets blister Al / Al AIC n. 041460205
ARKAS 20 mg film-coated tablets, 10 tablets Al / Al blisters AIC n. 041460217
ARKAS 20 mg film-coated tablets, 14 tabs Al / Al blister AIC n. 041460229
ARKAS 20 mg film-coated tablets, 28 tabs Al / Al blister AIC n. 041460231
ARKAS 20 mg film-coated tablets, 30 tabs Al / Al blisters AIC n. 041460243
ARKAS 20 mg film-coated tablets, 50 tablets Al / Al blister AIC n. 041460256
ARKAS 20 mg film-coated tablets, 56 tablets Al / Al blister AIC n. 041460268
ARKAS 20 mg film-coated tablets, 84 tablets blister Al / Al AIC n. 041460270
ARKAS 20 mg film-coated tablets, 100 tabs Al / Al blisters AIC n. 041460282
ARKAS 20 mg film-coated tablets, 112 tablets Al / Al blister AIC n. 041460294
ARKAS 20 mg film-coated tablets, 126 tablets Al / Al blisters AIC n. 041460306
ARKAS 20 mg film-coated tablets, 140 tabs Al / Al blister AIC n. 041460318
ARKAS 20 mg film-coated tablets, 168 tablets Al / Al blister AIC n. 041460320
ARKAS 20 mg film-coated tablets, 500 tablets Al / Al blister AIC n. 041460332
ARKAS 20 mg film-coated tablets, 7 tablets HDPE bottle AIC n. 041460344
ARKAS 20 mg film-coated tablets, 10 tablets HDPE bottle AIC n. 041460357
ARKAS 20 mg film-coated tablets, 14 tablets HDPE bottle AIC n. 041460369
ARKAS 20 mg film-coated tablets, 28 tablets HDPE bottle AIC n. 041460371
ARKAS 20 mg film-coated tablets, 30 tablets HDPE bottle AIC n. 041460383
ARKAS 20 mg film-coated tablets, 100 tabs HDPE bottle AIC n. 041460395
ARKAS 40 mg film-coated tablets, 7 tablets Al / Al blister AIC n. 041460407
ARKAS 40 mg film-coated tablets, 10 tablets Al / Al blisters AIC n. 041460419
ARKAS 40 mg film-coated tablets, 14 tabs Al / Al blister AIC n. 041460421
ARKAS 40 mg film-coated tablets, 28 tabs Al / Al blister AIC n. 041460433
ARKAS 40 mg film-coated tablets, 30 tabs Al / Al blisters AIC n. 041460445
ARKAS 40 mg film-coated tablets, 50 tablets Al / Al blister AIC n. 041460458
ARKAS 40 mg film-coated tablets, 56 tablets Al / Al blisters AIC n. 041460460
ARKAS 40 mg film-coated tablets, 84 tablets blister Al / Al AIC n. 041460472
ARKAS 40 mg film-coated tablets, 100 tabs Al / Al blisters AIC n. 041460484
ARKAS 40 mg film-coated tablets, 112 tablets Al / Al blisters AIC n. 041460496
ARKAS 40 mg film-coated tablets, 126 tablets Al / Al blisters AIC n. 041460508
ARKAS 40 mg film-coated tablets, 140 tablets Al / Al blister AIC n. 041460510
ARKAS 40 mg film-coated tablets, 168 tablets Al / Al blister AIC n. 041460522
ARKAS 40 mg film-coated tablets, 500 tablets Al / Al blister AIC n. 041460534
ARKAS 40 mg film-coated tablets, 10 tablets HDPE bottle AIC n. 041460546
ARKAS 40 mg film-coated tablets, 14 tablets HDPE bottle AIC n. 041460559
ARKAS 40 mg film-coated tablets, 28 tablets HDPE bottle AIC n. 041460561
ARKAS 40 mg film-coated tablets, 30 tablets HDPE bottle AIC n. 041460573
ARKAS 40 mg film-coated tablets, 50 tablets HDPE bottle AIC n. 041460585
ARKAS 40 mg film-coated tablets, 56 tablets HDPE bottle AIC n. 041460597
ARKAS 40 mg film-coated tablets, 100 tablets HDPE bottle AIC n. 041460609
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
22 March 2012
