REXTAT - PACKAGE LEAFLET - LEAFLETS

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Rextat - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Unwanted Effects Shelf Life and Storage Other Information

Active ingredients: Lovastatin

Rextat 10 mg tablets
Rextat 20 mg tablets
Rextat 40 mg tablets

Why is Rextat used? What is it for?

Rextat contains the active substance lovastatin. It belongs to a group of medicines called 'statins' which lower the levels of fats in the blood, such as cholesterol and triglycerides.

Rextat is used for:

reduce elevated blood cholesterol levels (primary hypercholesterolemia, including familial hypercholesterolemia) or elevated blood fat values (mixed hyperlipidemia) when diet, physical activity and weight reduction have not been satisfactory
reduce high blood cholesterol values when you have a high risk of severe cardiovascular disease and your diet has not been satisfactory
reduce high blood cholesterol values and decrease the risk of a heart attack when you have a disease of the blood vessels of the heart (ischemic heart disease) and the diet has not worked satisfactorily.

Contraindications When Rextat should not be used

Do not take Rextat

if you are allergic to the active substance or any of the other ingredients of this medicine (listed in section 6)
if you are allergic to other statins
if you currently have liver problems, elevated transaminases and cholestasis
if you have repeated or unexplained muscle aches or pains (myopathy)
if you are pregnant (or think you may be) or breastfeeding.

Precautions for use What you need to know before you take Rextat

Talk to your doctor or pharmacist before taking Rextat:

if you have severe respiratory failure (interstitial lung disease manifesting as difficulty in breathing, non-productive cough, tiredness, weight loss and fever). In this case, contact your doctor who will stop the treatment.
if you have or have ever had liver problems. Your doctor will order blood tests to check your liver before starting treatment with Rextat, 6 and 12 weeks after starting therapy, each time your dose is increased and at least twice a year regardless of the change. of dose.
if you regularly drink large amounts of alcohol
if you are taking or have taken within the last 7 days a medicine called fusidic acid (a medicine for bacterial infections) by mouth or by injection. Combining fusidic acid with Rextat can lead to severe muscle problems (rhabdomyolysis).

Rextat is not suitable for high triglyceride levels in the presence of impaired fat metabolism.

Rextat can change the effect of many medicines. Tell your doctor about all medicines you are using and plan to use, including those available without a prescription and herbal medicines.

While you are being treated with this medicine, your doctor will carefully check that you do not have diabetes or that you are not at risk of developing diabetes. You are at risk of developing diabetes if you have high blood sugar and fat levels, are overweight and have high blood pressure.

Interactions Which drugs or foods may change the effect of Rextat

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

The risk of muscle problems is greatly increased if you are taking Rextat or other medicines of the same type at the same time:

an amiodarone-based medicine to regulate the rhythm of the heart
a blood pressure lowering medicine based on verapamil.

The risk of muscle problems may also be increased if you are taking Rextat with:

clarithromycin, erythromycin, norfloxacin, telithromycin, troleandomycin (antibiotics)
cyclosporine (against rejection after organ transplants)
quinine (against malaria)
cimetidine, omeprazole (against excess stomach acid)
danazol (hormone)
delavirdine, HIV protease inhibitors, indinavir, nelfinavir, ritonavir, saquinavir (against viruses)
diltiazem, mibefradil, beta blockers, some diuretics that lower blood potassium (for heart and high blood pressure)
fluconazole, itraconazole, ketoconazole, metronidazole, miconazole (against diseases caused by fungi)
fluoxetine, fluvoxamine, St. John's wort, nefazodone, sertraline, barbiturates (against depression and anxiety)
propoxyphene (against inflammation)
zafirlukast, theophylline, terbutaline (against asthma)
colchicine (against gout)
coumarins (blood thinners)
lipid-lowering agents: gemfibrozil, other fibrates or high doses of niacin (medicines that reduce fat levels in the blood). These medicines, even when not combined with Rextat, can cause muscle problems
fusidic acid: if you need to take oral fusidic acid to treat a bacterial infection, you will need to temporarily stop taking this medicine. Your doctor will tell you when it is safe to restart Rextat. Taking Rextat with fusidic acid may, rarely, lead to muscle weakness, tenderness or pain (rhabdomyolysis). See section 4 for more information on rhabdomyolysis.

In the cases described above, your doctor will decide whether you should stop taking Rextat or continue taking it by defining the daily dosage.

Rextat with food, drink and alcohol

Do not take Rextat on an empty stomach (see section "How to take Rextat"). Avoid alcohol, grapefruit juice and chamomile tea as they can increase the risk of muscle problems.

Warnings It is important to know that:

Rextat can cause muscle problems (myopathy) manifested by muscle aches, soreness, tenderness, weakness related to the prescribed dose. Sometimes these problems can be serious (destruction of muscle cells) and cause kidney problems; they can rarely lead to death.

The risk of muscle problems is greatly increased when Rextat is taken with other medicines (see section "Other medicines and Rextat").

The risk of muscle problems may also be due to the simultaneous presence of:

alterations of mineral salts in the organism
convulsions
thyroid disease
drop in body temperature (hypothermia)
increase in the amount of acids in the blood (metabolic acidosis)
reduction of oxygen in the body (hypoxia)
virus infections
drugs and substances of abuse (cannabinoids, alcohol, amphetamine, cocaine, LSD, ecstasy, etc.)

The risk of muscle effects has also been observed after taking Rextat with grapefruit juice and chamomile.

In the cases described above, your doctor will decide whether you should stop taking Rextat or continue taking it by defining the daily dosage.

If you have started Rextat therapy or your dose has been increased, you have a higher risk of muscle problems (myopathy). Report any spontaneous or induced muscle pain (eg from palpation), tiredness, weakness, fever, dark urine and increased levels of creatine kinase (an enzyme produced mainly in muscles) to your doctor.

Your doctor may decide to stop treatment and have blood tests done.

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.

You are more likely to develop muscle problems if you have severe kidney disease resulting from long-lasting diabetes.

Before dental extractions you should advise your dentist that you are on Rextat therapy.

Tell your doctor a few days before undergoing surgery or other invasive medical intervention.

Always tell your doctor and healthcare professionals that you are taking Rextat.

Children and adolescents

Rextat is not recommended for use in children and adolescents below 18 years of age because safety and efficacy in children have not been established.

Pregnancy, breastfeeding and fertility

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Pregnancy

The use of Rextat is contraindicated during pregnancy. If you become pregnant while taking Rextat, your doctor will have you discontinue the medicine immediately.

Feeding time

The use of Rextat is contraindicated during breastfeeding.

Fertility

If you are a woman of childbearing age, your doctor will ask you to perform a pregnancy test before starting treatment with Rextat.

Driving and using machines

No known effects on the ability to drive and use machines.

Rextat contains lactose

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

Dose, Method and Time of Administration How to use Rextat: Posology

Always take this medicine exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist.

Take Rextat during dinner.

If your doctor has prescribed this medicine twice a day, take one tablet with breakfast and one with dinner.

Do not take Rextat on an empty stomach.

A standard low cholesterol (hypocholesterolemic) diet should be started before starting treatment with Rextat, to be continued during treatment.

High blood cholesterol values (hypercholesterolemia)

The starting dose for adults is 10 mg per day in the evening with a meal. Your doctor may adjust your daily dose at four-week intervals up to a maximum of 40 mg per day. Your doctor will reduce your dose if your cholesterol levels are too low (LDL cholesterol below 75 mg / 100 ml and total-cholesterol below 140 mg / 100 ml).

High blood cholesterol values not corrected by diet alone in the presence of a disease of the blood vessels of the heart (ischemic heart disease)

The starting dose for adults is 20 mg per day in the evening with a meal. Your doctor may adjust your daily dose at four-week intervals up to a maximum of 80 mg per day as a single dose in the evening with a meal or by taking two doses (one with breakfast and one with dinner). Your doctor will reduce your dose. dose in case of excessive lowering of cholesterol values (LDL-cholesterol below 75 mg / 100 ml and total-cholesterol below 140 mg / 100 ml).

Your doctor may find it necessary to adjust your doses, especially if you are taking some of the medicines listed above (see "Other medicines and Rextat"), if you are elderly, if you have kidney problems (severe kidney failure) or if you have diseases that increase the risk of muscle problems (untreated hyperthyroidism, hereditary myopathy or following treatment with other statins or fibrates, alcoholics).

Use in children and adolescents

Rextat is not recommended for use in children and adolescents below 18 years of age because safety and efficacy in children have not been established.

If you forget to take Rextat

Do not take a double dose to make up for a forgotten tablet and outside the normal time.

Failure to take a dose does not compromise the efficacy of therapy.

Resume taking according to the established therapeutic schemes without making up for the missed dose.

If you stop using Rextat

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

Overdose What to do if you have taken too much Rextat

If you accidentally take an overdose of Rextat, notify your doctor immediately or go to the nearest hospital.

Side Effects What are the side effects of Rextat

Like all medicines, this medicine can cause side effects, although not everybody gets them.

The reported side effects are usually mild and transient in nature:

muscle weakness (asthenia)
abdominal pain
constipation
diarrhea
stomach problems (dyspepsia)
leaking of intestinal gas (flatulence)
nausea
muscle cramps and pains (myalgia)
dizziness
headache
skin rash (rash)
impaired vision
chest pain
reflux of stomach acid into the mouth (esophageal reflux)
dry mouth
He retched
pain in the legs
shoulder pain
joint pain (arthralgia)
insomnia
change in sensitivity of the skin, tingling (paraesthesia)
hair loss (alopecia)
itch
eye irritation
tiredness
heartburn
taste disturbances.

The following side effects have been reported for medicines belonging to the same family as Rextat (statins):

Effects on the muscles and skeleton: muscle cramps, pains in the muscles (myalgia), changes in the muscles (myopathy), breakdown of muscle cells (rhabdomyolysis), pain in the joints (arthralgia). Undesirable effects of unknown frequency: constant muscle weakness
Effects on the nervous system: abnormal functioning of some nerves (dysfunction of some cranial nerves), tremors, dizziness, dizziness, memory loss, impaired sensitivity of the skin and pins and needles (paraesthesia), damage to peripheral nerves (peripheral neuropathy), mental disorders , anxiety, sleep disturbances including insomnia and nightmares, depression
Hypersensitivity reactions: severe and rapid general allergic reaction (anaphylaxis), rapid swelling of the legs, arms, face or tongue (angioedema), autoimmune diseases (lupus erythematosus, dermatomyositis), rheumatic diseases (polymyalgia rheumatica), inflammation of the blood vessels ( vasculitis), red spots on the body (purpura), decrease in some types of blood cells (thrombocytopenia and leukopenia), decrease in red blood cells (haemolytic anemia), increase in a type of white blood cells (eosinophilia), hives, muscle weakness (asthenia), abnormal and exaggerated reaction of the skin to light (photosensitivity), fever, difficulty in breathing (dyspnoea), skin diseases (epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome)
Effects on the stomach and intestines: inflammation of the pancreas (pancreatitis), inflammation of the liver (including chronic hepatitis), yellowing of the skin and eyes (cholestatic jaundice), accumulation of fat in the liver cells (fatty liver), severe impairment liver disease (cirrhosis), massive and rapid death of liver cells (fulminant hepatic necrosis), malignant liver tumor (hepatoma), loss of appetite (anorexia), vomiting
Effects on the skin: hair loss (alopecia), itching
Effects on the sexual organs: breast enlargement in men (gynecomastia), sexual problems (loss of libido, sexual difficulties, erectile dysfunction)
Effects on vision: progressive loss of transparency of the eye (cataract progression), paralysis of the eye muscles (ophthalmoplegia)
Changes in laboratory parameters: changes in liver function (transaminase, alkaline phosphatase, gammaglutamyltranspeptidase (gammaGT), bilirubin)
Internal organ alteration: abnormal thyroid function, lung problems (interstitial lung disease), diabetes mellitus (more likely if you have high blood sugar and fat levels, are overweight and have high blood pressure blood).

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 www.agenziafarmaco.gov.it/it/responsabili. By reporting side effects you can help provide more information on the safety of this medicine.

Expiry and Retention

Do not store above 30 ° C.

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton after "Expiry". 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.

Deadline "> Other information

What Rextat contains

The active ingredient is lovastatin. Each tablet contains 10 mg, 20 mg or 40 mg of lovastatin.
The other ingredients are lactose, microcrystalline cellulose, pregelatinised starch, magnesium stearate, sodium starch glycolate, butyl hydroxyanisole, hydrogenated castor oil (10 mg tablets only).

What Rextat looks like and contents of the pack

Rextat comes in tablet form for oral use.

It is available in the following packs:

10 mg: 20 tablets in blister packs.

20 mg: 20 and 30 tablets in blister packs.

40 mg: 10, 20 and 30 tablets in blister packs.

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.

Further information on Rextat can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT - 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION - 03.0 PHARMACEUTICAL FORM - 04.0 CLINICAL PARTICULARS - 04.1 Therapeutic indications - 04.2 Posology and method of administration - 04.3 Contraindications - 04.4 Special warnings and appropriate precautions for use - 04.5 Interactions with other medicinal products and other forms of interaction - 04.6 Pregnancy and lactation - 04.7 Effects on the ability to drive and use machines - 04.8 Undesirable effects - 04.9 Overdose - 05.0 PHARMACOLOGICAL PROPERTIES - 05.1 "Pharmacodynamic properties - 05.2 Pharmacokinetic properties" - 05.3 Preclinical safety data - 06.0 PHARMACEUTICAL PARTICULARS - 06.1 Excipients - 06.2 Incompatibility "- 06.3 Shelf life" - 06.4 Special precautions for storage - 06.5 Nature of the primary packaging and contents of the package - 06.6 Instructions for use and handling - 07.0 AUTHORIZATION HOLDER ALL "PLACING ON THE MARKET - 08.0 MARKETING AUTHORIZATION NUMBER - 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION - 10.0 DATE OF REVISION OF THE TEXT - 11.0 FOR RADIO DRUGS, COMPLETE DATA ON INTERNAL RADIATION DOSIMETRY - 12.0 INSTRUCTIONS FOR RADIOPHONES ON EXTEMPORARY PREPARATION AND QUALITY CONTROL -

01.0 NAME OF THE MEDICINAL PRODUCT -

REXTAT TABLETS

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -

Rextat 10 mg tablets

Each tablet contains 10 mg of lovastatin.

Excipient with known effects:

Each tablet contains 33.80 mg of lactose.

Rextat 20 mg tablets

Each tablet contains 20 mg of lovastatin.

Excipient with known effects:

Each tablet contains 67.60 mg of lactose.

Rextat 40 mg tablets

Each tablet contains 40 mg of lovastatin.

Excipient with known effects:

Each tablet contains 135.20 mg of lactose.

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM -

Tablets.

04.0 CLINICAL INFORMATION -

04.1 Therapeutic indications -

Primary hypercholesterolaemia including familial hypercholesterolaemia (heterozygous variant) or mixed hyperlipemia (type IIa and IIb) when the sole response to diet and other non-pharmacological measures (increased physical activity and, if indicated, decreased body weight) was inadequate .

Hypercholesterolemia not corrected by diet alone in subjects at high risk of a major cardiovascular event (subjects with a risk greater than 20%, total cholesterol greater than 190 mg / dl and LDL cholesterol greater than 115 mg / dl).

Hypercholesterolemia not corrected by diet alone in patients with ischemic heart disease, due to the reduction of the risk of myocardial infarction.

04.2 Posology and method of administration -

Dosage

Hypercholesterolemia.

The starting dosage is 10 mg / day as a single dose in the evening during a meal. The dosage can be adjusted at four-week intervals up to a maximum of 40 mg / day.

The dosage should be reduced in the case of lowering of the LDL-cholesterol below 75 mg / 100 ml and of the total-cholesterol below 140 mg / 100 ml.

Hypercholesterolemia not corrected by diet alone in patients with ischemic heart disease.

In ischemic heart disease, the initial dosage is 20 mg / day as a single dose in the evening during a meal. The dosage can be adjusted at four-week intervals up to a maximum of 80 mg / day as a single dose in the evening with a meal or in two doses (one for breakfast and the other for dinner).

Dosage should be reduced in case of lowering of LDL-cholesterol below 75 mg / 100 ml (1.94 mmol / l) and total-cholesterol below 140 mg / 100 ml (3.6 mmol / l).

In case of suspected or actual missed dose of lovastatin, do not take the drug outside the scheduled time or with the next dose. Failure to take a dose does not compromise the efficacy of therapy. Resume the intake according to the established therapeutic schemes without making up for the missed dose.

Pediatric population.

The safety and efficacy of Rextat in children have not yet been established. Currently available data are described in sections 4.8 and 5.1 but no recommendation on a posology can be made.

Concomitant therapy.

Lovastatin can be taken concomitantly with other cholesterol-lowering agents (biliary sequestrants), but in this case the dose of 20 mg / day should not be exceeded. Caution should be exercised in the therapeutic combination with gemfibrozil, other fibrates, niacin (nicotinic acid) (dose of 1 g / day or greater) (Do not exceed 20 mg / day see also section 4.5).

For patients taking concomitant amiodarone and verapamil, see section 4.4 "Effects on muscles".

In patients with severe renal insufficiency (creatinine clearance less than or equal to 30 ml / min) doses greater than 20 mg / day should be carefully considered.

Administration in patients over 65 must involve careful risk assessment and careful monitoring of possible adverse reactions.

Method of administration

Lovastatin is administered orally and should be taken with dinner. If the patient has been prescribed two intakes per day by the physician, these are to be considered one at breakfast and the other at dinner. Do not take lovastatin on an empty stomach.

Before starting treatment with lovastatin, the patient should be placed on a standard cholesterol-lowering diet, which should continue during treatment.

04.3 Contraindications -

Hypersensitivity to the active substance or to other statins or to any of the excipients listed in section 6.1.

Active liver disease, elevation of transaminases, cholestasis.

Myopathy.

Do not administer in cases of confirmed or presumed pregnancy and during lactation (see section 4.6).

04.4 Special warnings and appropriate precautions for use -

Precautions

Lovastatin can increase serum creatine kinase and transaminase levels.

Perform liver function tests prior to initiation of lovastatin treatment, 6 and 12 weeks after initiation of therapy, each time the dose is increased and at least twice a year regardless of dosage adjustments.

Lovastatin interacts with many medications, so the patient should be informed of the need to tell the doctor about all medications they are using and intend to use (including those available without a prescription and herbal remedies).

The patient should be informed of the need to report to the physician the occurrence of fever, weakness, muscle aches, spontaneous pain and palpation and the appearance of dark urine during treatment.

Lovastatin has only a moderate effect on triglycerides and is not indicated when hypertriglyceridemia is relevant in the presence of fat metabolic disturbances (eg Fredrickson Types I, IV and V hyperlipidemia).

There is insufficient experience for Type III hyperlipemia.

Lovastatin is less effective in patients with homozygous familial hypercholesterolaemia because these patients lack functional LDL receptors.

In patients with homozygous familial hypercholesterolaemia, lovastatin appears to increase transaminases more frequently.

Interstitial lung disease

Exceptional cases of interstitial lung disease have been reported with some statins, especially with long-term therapy (see section 4.8). Symptoms may include dyspnoea, non-productive cough, and deterioration in general health (fatigue, weight loss, and fever). If it is suspected that a patient has developed interstitial lung disease, statin therapy should be discontinued.

Diabetes mellitus

Some evidence suggests that statins, as a class effect, increase blood glucose and in some patients, at high risk of developing diabetes, may induce a level of hyperglycemia such that antidiabetic therapy is appropriate. This risk, however, is outweighed by the reduction in vascular risk with the use of statins and therefore should not be a reason for discontinuation of treatment. Patients at risk (fasting glucose 5.6-6.9 mmol / L, BMIhypertension) should be monitored both at a clinical and biochemical level in accordance with national guidelines.

Warnings

Rextat contains lactose as an excipients, therefore patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

Effects on musculature: Myopathy / Rhabdomyolysis (see also section 4.5)

Lovastatin like other 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) inhibitors may occasionally cause myopathy, manifesting as muscle pain, achiness, tenderness, weakness, and / or increased creatine kinase levels. (up to 10 times the maximum reference values).

Myopathy sometimes manifests as rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, rarely with a fatal outcome.

The risk of myopathy is dose related.

The risk of myopathy / rhabdomyolysis is greatly increased by the concomitant use of lovastatin with amiodarone and / or verapamil. The dose of lovastatin should not exceed 40 mg / day in patients receiving concomitant treatment of amiodarone or verapamil. Concomitant use lovastatin at doses above 40 mg / day and amiodarone or verapamil should be avoided unless the benefits outweigh the increased risk of myopathy.

The risk of potential or documented myopathy / rhabdomyolysis is also increased by:

• concomitant use of lovastatin with potent inhibitors of the CYP3A4 enzyme (lovastatin is a substrate of cytochrome P450 isoform 3A4 (CYP3A4): amiodarone, cannabinoids, clarithromycin, cyclosporine, quinine, cimetidine, danazole, delavic

fluoxetine, fluvoxamine, HIV protease inhibitors, indinavir, St.John's wort, itraconazole, ketoconazole, omeprazole, metronidazole, miconazole, nefazodone, nelfinavir, mibefradil, norfloxacin, propoxifene, ritonavir, verapirlicine, serum of serum grapefruit juice (0.20 l / day) and chamomile.

• concomitant use of lovastatin with lipid-lowering drugs which alone can cause myopathy: gemfibrozil, other fibrates, or high doses of niacin (nicotinic acid) (1 g / day or higher), particularly when combined with lovastatin doses greater than 20 mg / day.

• concomitant use of lovastatin with other non-cholesterol-lowering drugs, such as: beta-blockers, diuretics that cause hypokalaemia, cimetidine, theophylline, terbutaline, barbiturates and colchicine.

• electrolyte disturbances, convulsions, thyroid function disturbances, hypothermia, metabolic acidosis, hypoxia, viral infections (Epstein-Barr, flu, coksackie, etc.), drugs of abuse (alcohol, amphetamine, cocaine, LSD, ectasy, etc.). ).

Consequentially:

Concomitant use of lovastatin with itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, moderate amounts of grapefruit juice (0.20 l / day) and chamomile should be avoided. with these drugs indispensable, the administration of lovastatin should be suspended. The concomitant use of other drugs having a strong inhibitory effect on the CYP3A4 system should be avoided unless the expected benefits outweigh the possible risk.

The dose of lovastatin should not exceed 20 mg / day in patients receiving concomitant treatment with immunosuppressive drugs (e.g. cyclosporine), gemfibrozil, other fibrates, or high doses of niacin (nicotinic acid) (1 g / day or higher) .

The combined use of lovastatin and fibrates or niacin should be avoided unless the benefit of a further reduction in lipid levels justifies the increased risk of associated therapy. Adding these drugs to lovastatin induces a modest additional reduction in LDL cholesterol, but may further reduce triglycerides and increase HDL cholesterol.

The dose of lovastatin should not exceed 40 mg / day in patients receiving concomitant treatment with amiodarone or verapamil. Concomitant use of lovastatin at doses above 40 mg / day and amiodarone or verapamil should be avoided unless the benefits outweigh the increased risk of myopathy.

All patients who start therapy with lovastatin or whose dose is increased should be warned of the risk of myopathy and asked to report any spontaneous or induced muscle pain (e.g. from palpation), fatigue, weakness, fever, urine to the treating physician. dark.

Lovastatin therapy should be discontinued immediately if myopathy is diagnosed or suspected.

The presence of the above symptoms and / or elevation of CK (> 10 fold) are indicative of myopathy. In most cases where treatment is stopped, muscle pain disappears and CK levels tend to return to normal. Checks Periodic CKs should be performed in patients starting therapy or increasing their dosage, although there is no certainty that controls will prevent myopathy.

Many patients who developed rhabdomyolysis on lovastatin therapy had a complicated history, including renal failure resulting from long-standing diabetes mellitus.

The doctor should prescribe lovastatin paying attention to patients who have already presented myopathy following treatment with statins or fibrates or who suffer from diseases that increase the risk of rhabdomyolysis (untreated hyperthyroidism, hereditary myopathy, alcoholics).

There have been very rare reports of immune-mediated necrotizing myopathy (Immune-Mediated Necrotizing Myopathy, IMNM) during or after treatment with some statins. IMNM is clinically characterized by persistent proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment.

Rextat should not be administered with systemic formulations of fusidic acid or for 7 days after discontinuation of fusidic acid treatment. In patients in whom systemic use of fusidic acid is considered essential, statin treatment should be discontinued. for the duration of the fusidic acid treatment. Cases of rhabdomyolysis (including some fatal cases) have been reported in patients receiving fusidic acid in combination with statins (see section 4.5). Patients should be advised to consult their physician immediately if they experience symptoms of muscle weakness, pain or tenderness.

Statin therapy can be reintroduced 7 days after the last dose of fusidic acid.

In exceptional circumstances, where it is necessary to prolong systemic fusidic acid therapy, for example for the treatment of severe infections, the need for co-administration of Rextat and fusidic acid should only be considered on a case-by-case basis and under close medical supervision. .

Liver dysfunctions

An increase in serum transaminases of up to 3 times normal values has been reported in 1.9% of adult patients who have taken lovastatin for at least 1 year: in these cases, therapy should be discontinued. The increase usually appears after 3-12 months with no associated signs or symptoms. Withdrawal of treatment slowly returns the level of transaminases to normal. No signs of hypersensitivity have been observed.

In the 48-week Expanded Clinical Evaluation of Lovastatin (EXCEL) clinical trial, the incidence of persistent elevations in serum transaminases was 0.1% with placebo, 0.1% with 20 mg / day, 0.9% with 40 mg / day and 1.5% with 80 mg / day of lovastatin. In post-marketing surveillance, symptomatic liver disorders were rarely reported.

In a study with an average duration of over 5 years [Air Force / Texas Coronary Atherosclerosis Prevention Study, AFCAPS / TexCAPS] conducted on 6605 patients, of which 3304 treated with 20-40 mg / day of lovastatin, the incidence of patients increased (> 3 times the limit) of alanine transferase [ALT] and aspartate aminotransferase [AST] did not differ significantly from that observed with placebo.

Liver function tests (ALT, AST) are recommended before initiation of therapy and after 6 and 12 weeks of therapy or dose escalation, then every six months. Patients who develop elevated transaminases should be monitored for as long as possible. values are not within normal An increase in ALT or AST greater than 3 times the normal values should lead to discontinuation of therapy.

The drug should be administered with caution to alcoholic patients or patients with a history of liver disorders.

Before dental extractions, advise your dentist that you are on lovastatin therapy.

You may need to stop taking lovastatin a few days before undergoing surgery or other invasive medical intervention.

To this end, always inform healthcare professionals that you are undergoing lovastatin therapy.

Pediatric population

In a limited number of controlled studies (see sections 4.8 and 5.1), there was no detectable effect on sexual growth or maturation in adolescent boys or on menstrual cycle length in girls.

Adolescents should be advised to use adequate contraceptive methods during lovastatin therapy (see sections 4.3 and 4.6). Rextat has not been adequately studied in pre-pubertal children or pre-menarche girls, nor in patients of older age. less than 10 years.

04.5 Interactions with other medicinal products and other forms of interaction -

Interactions with CYP3A4 inhibitors

Lovastatin is metabolised primarily by the cytochrome P450 isoform CYP3A4, but does not inhibit the enzyme and therefore is not expected to affect the metabolism of other drugs that are metabolised by the CYP3A4 enzyme.

The following isoenzyme inhibitors may increase the risk of myopathy by reducing the plasma clearance of lovastatin: itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIVprotease inhibitors, nefazodone, cyclosporine, grapefruit juice (0.20 liters and more), chamomile (see also section 4.4).

Interactions with lipid-lowering agents

The risk of myopathy is increased by the following drugs, which alone can induce myopathy:

gemfibrozil, other fibrates, niacin (nicotinic acid) (> 1 g / day).

Other interactions

Amiodarone or verapamil: the risk of myopathy / rhabdomyolysis is increased by the concomitant use of these drugs with lovastatin and other HMG-CoA reductase inhibitors.

Coumarin anticoagulants: the intake of HMG-CoA reductase inhibitors can modify the prothrombin time, so the administration of lovastatin must be accompanied by periodic checks. After stabilization of the prothrombin time, the checks can be performed with the usual frequency of patients on anticoagulant therapy In cases of modification of the dose of lovastatin, the procedure should be repeated.

Propranolol: no pharmacodynamic interactions were found.

Digoxin: No pharmacokinetic interactions were found.

Oral hypoglycemic agents: no pharmacokinetic interactions were found.

ACE inhibitors, diuretics, non-steroidal anti-inflammatory drugs: no clinical interactions were found.

Endocrine function: Although HMG-CoA reductase inhibitors could theoretically reduce steroid production by the adrenal gland and gonads, lovastatin has been shown not to reduce basal plasma levels of cortisol and testosterone.

Thyroid function: be careful in case of hypothyroidism and hyperthyroidism.

Fusidic acid: The risk of myopathy including rhabdomyolysis may be increased by the concomitant use of systemic fusidic acid with statins. The mechanism of this interaction (whether it is a pharmacodynamic, pharmacokinetic or both) is still unknown. Cases of rhabdomyolysis (including some fatal cases) have been reported in patients receiving this combination.

If systemic fusidic acid treatment is necessary, lovastatin treatment should be discontinued for the duration of fusidic acid treatment. See also section 4.4.

04.6 Pregnancy and breastfeeding -

Pregnancy

Lovastatin is contraindicated in pregnancy.

Before prescribing to women of childbearing age it is recommended that a pregnancy test be performed.

If pregnancy is diagnosed during treatment with lovastatin, treatment should be stopped immediately.

Feeding time

Although its passage and / or that of its metabolites in breast milk has not been demonstrated, in order not to expose newborns to potential toxicity, administration should be avoided in breastfeeding women or, in the case of indispensable therapy, lactation should be discontinued.

04.7 Effects on ability to drive and use machines -

No known effects.

04.8 Undesirable effects -

Undesirable effects are usually mild and transient in nature.

The percentage of patients who discontinued therapy in the 48-week EXCEL study due to adverse events judged possibly, probably or definitely attributed to lovastatin is 4.6% versus 2.5% for placebo.

The events found in percentages greater than 0.5 and 1% are shown in the following table:

Adverse events Placebo% (n = 1663) Lovastatin% 20 mg (n = 1642) Lovastatin% 40 mg (n = 1645) Lovastatin% 20 mg x 2 (n = 1646) Lovastatin% 40 mg x 2 (n = 1649) Asthenia 1,4 1,7 1,4 1,5 1,2 Abdominal pain 1,6 2,0 2,0 2,2 2,5 Constipation 1,9 2,0 3,2 3,2 3,5 Diarrhea 2,3 2,6 2,4 2,2 2,6 Dyspepsia 1,9 1,3 1,3 1,0 1,6 Flatulence 4,2 3,7 4,3 3,9 4,5 Nausea 2,5 1,9 2,5 2,2 2,2 Muscle cramps 0,5 0,6 0,8 1,1 1,0 Myalgia 1,7 2,6 1,8 2,2 3,0 Dizziness 0,7 0,7 1,2 0,5 0,5 Headache 2,7 2,6 2,8 2,1 3,2 Skin rash 0,7 0,8 1,0 1,2 1,3 Impaired vision 0,8 1,1 0,9 0,9 1,2

Other adverse events reported in 0.5-1.0% of patients are: chest pain, oesophageal reflux, dry mouth, vomiting, leg pain, shoulder pain, arthralgia, insomnia, paraesthesia, alopecia, pruritus, eye irritation. Also: fatigue, heartburn, taste disturbances.

In the Air Force Coronary Atheriosclerosis Prevention Study (AFCAPS / TexCAPS), in 6605 patients treated with lovastatin 20-40 mg / day (n = 3304) and placebo (n = 3301) the adverse events reported were similar to those in the EXCEL study.

The following side effects have been reported for drugs in this class (statins) and not necessarily associated with lovastatin therapy:

musculoskeletal: muscle cramps, myalgia, myopathy, rhabdomyolysis, arthralgia. Frequency not known: immune-mediated necrotizing myopathy (see section 4.4).

neurological: dysfunction of some cranial nerves, tremors, vertigo, dizziness, memory loss, paraesthesia, peripheral neuropathy, mental disorders, anxiety, sleep disturbances including insomnia and nightmares, depression.

hypersensitivity reactions: anaphylaxis, angioedema, lupus erythematosus, rheumatic polymyalgia, dermatomyositis, vasculitis, purpura, thrombocytopenia, leukopenia, haemolytic anemia, eosinophilia, urticaria, asthenia, photosensitivity, fever, dyspnoea, epidermal necrolysis, erythema multiformens, including Stevens-Johnson syndrome.

gastrointestinal: pancreatitis, including chronic hepatitis, cholestatic jaundice, fatty liver, cirrhosis, fulminant hepatic necrosis, hepatoma, anorexia, vomiting.

cutaneous: alopecia, itching.

reproductive: gynecomastia, loss of libido, sexual dysfunction, erectile dysfunction.

view: progression of cataracts, ophthalmoplegia.

alterations of laboratory parameters: increased: transaminases, alkaline phosphatase, gammaglutamyltranspeptidase (gammaGT), bilirubin.

endocrine: abnormality of thyroid function.

Exceptional cases of interstitial lung disease, especially with long-term therapy (see section 4.4).

Diabetes mellitus: frequency depends on the presence or absence of risk factors (fasting glucose  5.6 mmol / L, BMI

Pediatric population

The safety and efficacy of lovastatin (10, 20 and 40 mg daily) were evaluated in 100 children aged 10 to 17 years with heterozygous familial hypercholesterolaemia, in controlled clinical trials lasting 48 weeks in adolescent boys and lasting 24 weeks in girls who were at least one year post menarche Doses greater than 40 mg have not been studied in this population.

The safety profile of Rextat obtained from this limited number of controlled studies was generally similar to that in adults, with the exception of a statistically significant reduction in LH levels in adolescent girls treated with lovastatin.

There was no detectable effect on sexual growth or maturation in adolescent boys or on menstrual cycle length in girls (see sections 4.4 and 5.1).

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 www.agenziafarmaco.gov.it/it/responsabili.

04.9 Overdose -

There have been rare reports of accidental overdose following ingestion of up to 5-6 g of lovastatin without significant clinical effects.

No specific antidote can be recommended.

Adopt appropriate general therapeutic measures.

Monitor vital functions.

Monitor liver function.

It is not known whether lovastatin and its metabolites are dialyzable.

05.0 PHARMACOLOGICAL PROPERTIES -

05.1 "Pharmacodynamic properties -

Pharmacotherapeutic group: Hypocholesterolemics and hypotiglyceridemics - HMG CoA reductase inhibitors - lovastatin, ATC code: C10AA02.

The empirical formula of lovastatin is C24H36O5 and its molecular weight is 404.55. It is a white, crystalline non-hygroscopic powder, insoluble in water and partially soluble in ethanol, methanol and acetonitrile.

The involvement of LDL-cholesterol (Low Density Lipoproteins) in atherogenesis is documented in many clinical studies. Epidemiological studies have shown that high LDL-cholesterol and low HDL-cholesterol (High Density Lipoproteins) levels are risk factors for coronary heart disease. Lovastatin reduces both normal and elevated LDL-cholesterol levels. LDLs are formed from VLDL (Very Low Density Lipoproteins) and are mainly catabolized by high affinity LDL receptors. The LDL-cholesterol reduction mechanism can affect both the reduction of VLDL-cholesterol and the induction of LDL receptors, i.e. it intervenes on the synthesis and / or catabolism of LDL-cholesterol.

Apoprotein B, which is contained in LDL, is significantly reduced during treatment with lovastatin, suggesting that lovastatin not only reduces the concentration of cholesterol bound to LDL lipoproteins, but also the amount of circulating LDL themselves.

It can also variably increase the amount of HDL-cholesterol and moderately reduce VLDL-cholesterol and plasma triglycerides.

Lovastatin was highly effective in reducing total and LDL cholesterol in familial and non-familial forms of primary hypercholesterolemia and mixed hyperlipidemia. A significant response is observed after two weeks of therapy and the maximum effect is achieved after 4-6 weeks.

The double-blind EXCEL study showed a statistically significant reduction compared to placebo in LDL-cholesterol (24-40%), total cholesterol (17-29%), triglycerides (10-19%) and an increase in triglycerides (10-19%) in hypercholesterolemic patients of HDL-cholesterol after 12-48 weeks of treatment.

The double-blind AFCAPS / TexCAPS study demonstrated a statistically significant 37% reduction versus placebo in the risk of a first acute coronary event (myocardial infarction, unstable angina, sudden death) in patients without symptoms of cardiovascular disease with a risk factor greater than 20% (LDL-cholesterol> 115 mg / dL) over a follow-up of more than 5 years. Treatment significantly reduced the risk of unstable angina by 32%, the risk of myocardial infarction by 40% and the risk of coronary revascularization (coronary bypass or percutaneous transluminal angioplasty) by 33%.

The double-blind Canadian Coronary Atherosclerosis Intervention Trial (CCAIT) measured the effect of lovastatin (20-80 mg / day) on minimum lumen diameter and stenosis diameter versus placebo with computed coronary angiography: after 2 years of treatment, the percentage of patients with progression of atherosclerosis was lower than placebo (33% vs. 50%) as was the percentage of patients with new lesions (16% vs. 32%).

The Monitored Atheriosclerosis Regression Study (MARS) demonstrated by scoring computed coronary angiography that lovastatin (80 mg / day) significantly slowed the progression of atherosclerosis in 23% of patients treated versus 11% of patients treated with placebo.

The Familial Atherosclerosis Treatment Study (FATS) demonstrated in hyperlipidemic patients after 2.5 years using computerized coronary angiography the efficacy of lovastatin, associated with a biliary sequestrant, in decreasing the frequency of progression and increasing the frequency of regression of atherosclerotic lesions of the coronary arteries.

The double-blind Asymptomatic Carotid Artery Progression Study (ACAPS) demonstrated by ultrasonography B in hyperlipidemic patients that lovastatin reduces the maximal intimal-medial thickness of 12 carotid segments after 3 years of therapy with 20-40 mg / day.

Pediatric population

In a randomized, double-blind, placebo-controlled study, 132 males aged 10-17 years with heterozygous familial hypercholesterolaemia (baseline LDL cholesterol 189-500 mg / dL) were randomized to lovastatin (n = 67 ) or placebo (n = 65) for 48 weeks. The once daily dosage of lovastatin in the evening was 10 mg for the first 8 weeks, 20 mg for the next 8 weeks and 40 mg thereafter. Lovastatin significantly reduced the mean baseline total-C by 19.3%, mean LDL-C by 24.2% and mean apolipoprotein B levels by 21%.

Similarly in another randomized, double-blind, placebo-controlled study, 54 girls aged 10 to 17 who were at least one year postmenarche with heterozygous familial hypercholesterolemia (baseline LDL cholesterol level 160-400 mg / dl) were randomized to lovastatin (n = 35) or placebo (n = 19) for 24 weeks. The once daily dosage of lovastatin in the evening was 20 mg for the first 4 weeks, and 40 mg thereafter. Lovastatin significantly reduced the mean baseline total-C by 22.4%, mean LDL-C by 29.2%, mean apolipoprotein B levels by 24.4%, and mean triglyceride levels by 22.7%.

The safety and efficacy of doses above 40 mg daily have not been studied in children. The long-term efficacy of lovastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established.

05.2 "Pharmacokinetic properties -

After oral ingestion lovastatin, which is an inactive lactone, is hydrolyzed into the corresponding β-hydroxy acid (β-hydroxy-lovastatin) form. This major metabolite is a 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA) inhibitor. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, the first step in the biosynthesis of cholesterol.

The absorption of lovastatin in animals from the oral route is about 30% compared to the intravenous route, with mainly faecal and small part urinary excretion; the drug concentrates in the liver, site of a metabolization process by cytochrome P450-CYP3A4, it is excreted with the metabolites in the bile and passes the blood brain and placental barrier.

In humans, its bioavailability is low and variable: in patients less than 5% of lovastatin taken as a single oral dose reaches the systemic route (calculated as enzymatic activity). After oral administration of lovastatin marked 83% of the radioactivity is found in the faeces and 10% in urine Fecal radioactivity is due to the sum of the drug and its metabolites excreted via the bile and the unabsorbed drug.

Lovastatin reaches a very high concentration in the liver where it undergoes a strong metabolism due to the first pass effect and with the metabolites it is excreted via the bile.

Plasma levels of radioactivity show a peak after two hours and an almost total disappearance in the following 24 hours. The plasma Tmax of the unchanged active substance and its active metabolites is 2-4 hours; the t½β is approximately 3-4 hours.

The pharmacokinetic parameters are highly variable: the most recent data, obtained with the most sensitive and accurate analytical method available, are summarized in the table below.

Single dose 80 mg (Bramer S.L. - Clin Pharmacokinnet 37: 69-77,1999)

Analyte Cmax (ng / ml) Tmax (hours) AUCt (ng / ml * h) T ½β (hours) Lovastatin 10,7 ± 4,1 1 55,6 ± 32,4 23,5 ± 16,1 β-hydroxy Lovastatin 7,4 ± 3,0 3 43,0 ± 18,0 15,4 ± 110,5

Single dose 40 mg (Rogers D.J - Clin Pharmacol The 66: 358-366,1999)

Analyte Cmax (ng / ml) Tmax (hours) AUCt (ng / ml * h) T ½β (hours) Lovastatin 4,3 ± 4,3 3,1 23,0 ± 12 3,5 β-hydroxy Lovastatin 6,0 ± 2,6 5,4 43,0 ± 21 --

Linearity of pharmacokinetics was established between doses of 60-120 mg / day and between 10-40 mg for single administration.

The main active metabolites are: lovastine in open form (β-hydroxy acid), 6 "β-hydroxy lovastatin, 6" -exomethylene-lovastatin, 3 "hydroxy-lovastatin and 3", 5 "-dihydroxy-3 ", 5" -diol- Δ4-lovastatin.

Lovastatin and β-hydroxy acid have a protein bond greater than 95%.

05.3 Preclinical safety data -

Acute toxicity

The DL50 p.o. of lovastatin in mice is greater than 20 g / kg.

Repeated dose toxicity

The toxic effects of lovastatin, common to other drugs of the same class (statins), have been studied in mice, rats, dogs and rabbits. In dogs at a dose of 180 mg / kg / day p.o. optic nerve degeneration, cataracts and vascular lesions, characterized by perivascular haemorrhage and edema, infiltration of mononuclear cells into the perivascular space, perivascular fibrin deposits and necrosis of the small vessels have been observed after 11-28 weeks.

Fertility and Teratogenesis.

No dose-related effects on fertility were observed in the rat; in dogs doses higher than 20 mg / kg / day produced testicular atrophy, decreased spermatogenesis, alteration of spermatocytes.

Lovastatin in high doses causes malformations of the skeleton during the period of organogenesis.

Mutagenesis and carcinogenesis.

Lovastatin was not mutagenic in various in vitro and in vivo tests.

In long-term toxicity studies (up to 2 years) hepatocellular carcinogenic effects were observed in rats at doses 2-7 times the maximum human dose; in mice, hepatocellular carcinomas and adenomas were observed at doses 3-4 times the maximum human dose and papillomas of the non-glandular mucosa of the stomach at doses 1-2 times the maximum human dose.