Aplactin - 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: Pravastatin (Pravastatin sodium salt)

APLACTIN 20 mg tablets
APLACTIN 40 mg tablets

Why is Aplactin used? What is it for?

APLACTIN contains pravastatin, a substance belonging to the group of statins, drugs capable of reducing the level of fat and cholesterol in the blood. This action is made possible by the blocking of an enzyme important in the synthesis of cholesterol itself, called HMG-CoA reductase.

APLACTIN is indicated in adults in the following cases:

  • Hypercholesterolemia (excess cholesterol in the blood)

Treatment of primary (familial) hypercholesterolaemia or mixed dyslipidaemia (changes in the amount of fat in the blood) as an adjunct to diet, when the response to diet or other non-drug treatments (e.g. exercise or weight reduction) has been inadequate .

  • Primary prevention

Reduction of mortality and the frequency of cardiovascular disease (affecting the heart and / or blood vessels) in patients with moderate to severe hypercholesterolemia and at high risk of a first cardiovascular event (heart attack, stroke), in addition to the diet.

  • Secondary prevention

Reduction in mortality and the frequency of cardiovascular disease in patients who have had a history of myocardial infarction (death of part of the heart tissue caused by the closure of a vessel that carries blood to the heart) or unstable angina pectoris (pain in the chest due to a temporary decrease in blood flow and oxygen to the heart) and who have normal or elevated cholesterol levels, in addition to correcting other risk factors.

  • Post-transplant

Reduction of hyperlipidemia (increase in blood fat levels) following transplantation in patients undergoing immunosuppressive therapy (therapy to avoid rejection of the transplanted organ) following transplantation of a solid organ (eg liver, pancreas, kidneys) (see section 3 "How to take APLACTIN" and "Other medicines and APLACTIN").

Contraindications When Aplactin should not be used

Do not take APLACTIN

  • If you are allergic to pravastatin or any of the other ingredients of this medicine (listed in section 6).
  • If you have active liver disease (liver disease) and if you have a marked and lasting increase in levels of transaminases in the blood (enzymes that indicate liver function), which exceed 3 times the maximum permitted limits (see "Warnings and precautions" ).
  • If you are pregnant or breastfeeding (see "Pregnancy and Breastfeeding").

Precautions for use What you need to know before taking Aplactin

Talk to your doctor or pharmacist before taking APLACTIN.

Before starting treatment with APLACTIN, tell your doctor:

  • if you suffer from kidney failure (impaired kidney function);
  • if you have hypothyroidism (decreased thyroid function);
  • if you have previously had problems with muscle toxicity from 'using statins and fibrates (see' Other medicines and APLACTIN ') or another cholesterol-lowering medicine, such as nicotinic acid (niacin);
  • if you or someone in your family have hereditary muscle disorders;
  • if you suffer from alcoholism (alcohol dependence);
  • if you are over 70, especially if you have other factors that could predispose you to muscle disorders;
  • if you are taking or have taken within the last 7 days a medicine called fusidic acid (used to treat bacterial infections) by mouth or by injection; the combination of fusidic acid with APLACTIN can cause severe muscle problems (rhabdomyolysis).

In these cases, the doctor will need to perform a blood test to assess creatine kinase (CK) levels before starting therapy.

Tell your doctor immediately if you experience symptoms such as pain, tension, weakness or muscle cramps of unknown nature during treatment, because blood tests are needed to evaluate creatine kinase (CK) levels, or it may be necessary to stop taking treatment. This medicine can cause muscle problems such as myalgia (muscle pain), myopathy (disease affecting muscles) Rhabdomyolysis (disease characterized by damage to muscle fibers), even fatal, may occur very rarely, which may be associated with secondary renal failure (alteration of function kidney resulting from other pathologies).

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.

Stop taking this medicine and see your doctor if you experience any of the following symptoms, especially if you are being treated with this medicine for a long time, as interstitial lung disease (lung problem) can occur:

  • dyspnoea (difficulty in breathing);
  • dry cough;
  • tiredness;
  • weight loss and fever.

While you are being treated with this medicine, your doctor will check the levels of enzymes produced by the liver (AST and ALT) and will tell you to stop taking APLACTIN if the levels are three times above normal and consistently.

Tell your doctor if you have suffered from liver disease (liver disease) in the past or if you regularly consume alcohol, as special caution should be used in these cases.

During therapy with this medicine, blood sugar (blood sugar concentration) may rise and, in some patients at high risk of developing diabetes, it may cause an excessive rise in blood sugar (hyperglycaemia) that may require diabetes therapy.

Your doctor will monitor you closely if you have high levels of blood sugar, triglycerides (fat) and high blood pressure.

APLACTIN is not suitable when hypercholesterolemia is due to high HDL cholesterol levels.

Children and adolescents

The use of APLACTIN in patients under 18 years of age is not recommended.

Interactions Which drugs or foods can change the effect of Aplactin

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

Tell your doctor if you are taking medicines called fibrates (eg gemfibrozil, fenofibrate) and used to lower the fat (cholesterol) content in the blood; concurrent use with APLACTIN is not recommended because it may increase the risk of muscle problems (see "Warnings and Precautions"). Your doctor will perform specific tests (control of creatine kinase, CK levels).

Take this medicine with caution and talk to your doctor if you are taking the following medicines:

  • Colestyramine or Colestipol (drugs used to lower cholesterol levels in the blood). When APLACTIN is taken simultaneously with these drugs it may decrease its therapeutic effect. APLACTIN should be taken 1 hour before or 4 hours after cholestyramine or 1 hour before colestipol. In order not to have a therapeutic decrease of pravastatin (see section 3 "How to take APLACTIN");
  • Cyclosporine. The simultaneous intake of cyclosporine (a drug used to prevent rejection reactions after organ transplantation) and APLACTIN increases the body's exposure to the drug by about 4 times or more;
  • Erythromycin and clarithromycin (antibiotics). These drugs can lead to an increase in the concentration of pravastatin in the blood.

If you are taking a medicine used to treat and prevent blood clots called a "vitamin K antagonist", please tell your doctor before taking APLACTIN as the use of vitamin K antagonists concomitantly with APLACTIN may alter the test results. blood used to monitor treatment with vitamin K antagonists.

If you need to take oral fusidic acid to treat a bacterial infection you should temporarily stop using this medicine. Your doctor will tell you when you can resume treatment with APLACTIN. Taking APLACTIN with fusidic acid may rarely cause muscle weakness, burning or pain (rhabdomyolysis). For more information on rhabdomyolysis, see section 4 "Possible side effects".

Warnings It is important to know that:

Pregnancy, breastfeeding and fertility

Pregnancy

Do not take APLACTIN during pregnancy (see "Do not take APLACTIN").

If during therapy with APLACTIN you realize that you are pregnant or are planning to become pregnant, please inform your doctor immediately and stop treatment due to the potential risk to the fetus.

Feeding time

Do not take APLACTIN while breastfeeding because a small amount of pravastatin is excreted in breast milk (see "Do not take APLACTIN").

Driving and using machines

APLACTIN has no or negligible influence on the ability to drive or use machines. However, you may feel dizzy after taking APLACTIN. If this happens to you, avoid driving or using machines.

APLACTIN contains lactose.

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

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

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

Before starting therapy with APLACTIN, the doctor will rule out secondary causes of hypercholesterolemia (eg hypothyroidism, diabetes mellitus, excessive fat intake with diet).

Before and during treatment with APLACTIN you must follow a diet to lower the levels of fat in the blood (standard lipid-lowering diet). Take APLACTIN by mouth once a day, preferably in the evening, with or without food.

The duration of treatment varies according to medical prescription.

The recommended dose varies in the following cases:

  • in the treatment of hypercholesterolemia (high blood fat levels) it is 10-40 mg once a day. Response is seen within one week and full effect is achieved within four weeks. Your doctor will check your blood fat levels and adjust the dose based on the results of the tests. The maximum daily dose is 40 mg.
  • in cardiovascular prevention (prevention of heart disorders) is 40 mg per day.
  • in therapy after organ transplantation the recommended starting dose is 20 mg per day if you are being treated with specific medicines (immunosuppressive therapy). Your doctor will adjust your dose up to a maximum of 40 mg per day.

Use in children and adolescents

The use of APLACTIN is not recommended.

Use in the elderly

Dosage adjustment is not necessary in the elderly unless there are predisposing risk factors (see "Warnings and precautions")

Use in patients with renal or hepatic insufficiency (kidney or liver problems)

If you have moderate or severe renal insufficiency or significant hepatic insufficiency the recommended starting dose is 10 mg per day. Your doctor will adjust the dosage based on your fat level.

Simultaneous therapy with other drugs

If you are taking a resin, ie a bile acid sequestering drug (such as cholestyramine and colestipol) at the same time, take APLACTIN one "hour before or at least four hours after the resin (see" Other medicines and APLACTIN ").

If you are taking cyclosporine (a medicine used in organ transplantation), with or without other immunosuppressive medicines, the recommended starting dose of APLACTIN is 20 mg per day.

Increasing the dose to 40 mg should be done with caution and under medical supervision (See "Other medicines and APLACTIN").

Overdose What to do if you have taken too much Aplactin

In case of accidental ingestion / intake of an overdose of APLACTIN, notify your doctor immediately or go to the nearest hospital.

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

Side Effects What are the side effects of Aplactin

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

Major side effects:

  • muscle pain (myalgia), joint pain (arthralgia), muscle cramps, muscle weakness, high levels of a substance produced by the muscles (creatine kinase, CK);
  • increased levels of liver enzymes (serum transaminases).

The following undesirable effects have also been reported during clinical trials and following marketing of APLACTIN:

Uncommon side effects (may affect up to 1 in 100 people)

  • dizziness, headache (headache);
  • sleep disturbances including insomnia and nightmares;
  • vision disturbances, including blurred vision and double vision;
  • digestive and burning disorders, abdominal pain, nausea, vomiting, constipation, diarrhea, bloating;
  • itching, rash, hives, scalp and hair changes, including hair loss;
  • difficulty urinating (dysuria), frequent passing of small amounts of urine (pollakiuria) and repeated urge to urinate during the night's rest (nocturia);
  • sexual dysfunctions;
  • fatigue.

Very rare side effects (may affect up to 1 in 10,000 patients)

  • peripheral polyneuropathy (disease affecting multiple nerves), especially with prolonged treatment, and paraesthesia (decreased sensitivity of a part of the body);
  • hypersensitivity reactions such as anaphylaxis, angioedema, lupus erythematosus-like syndrome;
  • pancreatitis (inflammation of the pancreas).
  • jaundice (yellowing of the skin), hepatitis (inflammation of the liver) and fulminant hepatic necrosis;
  • rhabdomyolysis (disease characterized by damage to muscle fibers) which may be associated with acute renal failure secondary to myoglobinuria (presence of myoglobin in the urine) and myopathy (muscle disorders) (see "Warnings and precautions").

Isolated side effects

  • tendon disorders, sometimes complicated by rupture.

Undesirable effects of unknown frequency (frequency of which cannot be determined from the available data)

  • constant muscle weakness (immune-mediated necrotizing myopathy).

Undesirable effects related to the class of statins

  • nightmares
  • memory loss;
  • depression;
  • interstitial lung disease (disease characterized by alteration of the tissue lining the pulmonary alveoli which can manifest itself with breathing problems such as persistent cough and / or shortness of breath), in exceptional cases especially in long-term therapy (see "Warnings and precautions ");
  • diabetes mellitus, frequency depends on the presence or absence of risk factors (fasting blood glucose ≥ 5.6 mmol / L, BMI> 30 kg / m2, elevated triglyceride levels, history of hypertension);
  • dermatomyositis (a condition characterized by "inflammation of the muscles and skin).

Compliance with the instructions contained in the package leaflet reduces the risk of undesirable effects.

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 http://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

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 package after "EXP".

The expiry date refers to the last day of that month and to the product in intact packaging, correctly stored.

Store the medicine below 30 ° C.

Store in the original packaging.

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 APLACTIN contains

APLACTIN 20 mg tablets

One 20 mg tablet contains:

the active ingredient is pravastatin sodium salt 20 mg.

The other ingredients are lactose monohydrate, polyvinylpyrrolidone, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, magnesium oxide, yellow iron oxide (E172).

APLACTIN 40 mg tablets

One 40 mg tablet contains:

the active ingredient is pravastatin sodium salt 40 mg.

The other ingredients are lactose monohydrate, polyvinylpyrrolidone, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, magnesium oxide, yellow iron oxide (E172).

Description of what APLACTIN looks like and contents of the pack

APLACTIN 20 mg tablets

Each pack contains 10 tablets of 20 mg

APLACTIN 40 mg tablets

Each pack contains 14 tablets of 40 mg

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 Aplactin 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 -

APLACTIN 20 MG TABLETS

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -

Each tablet contains 20 mg of pravastatin sodium salt.

Excipients with known effects: lactose monohydrate

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM -

Tablet.

04.0 CLINICAL INFORMATION -

04.1 Therapeutic indications -

APLACTIN is indicated in adults in the following cases:

Hypercholesterolemia

Treatment of primary hypercholesterolaemia or mixed dyslipidemia, in addition to diet, when the response to diet or other non-pharmacological treatments (e.g. exercise, weight reduction) has been inadequate.

Primary prevention

Reduction of cardiovascular mortality and morbidity in patients with moderate to severe hypercholesterolaemia and at high risk of a first cardiovascular event, in addition to diet (see section 5.1).

Secondary prevention

Reduction of cardiovascular mortality and morbidity in patients with a history of myocardial infarction or unstable angina pectoris and with normal or elevated cholesterol levels, as an adjunct to correction of other risk factors (see section 5.1).

Post-transplant

Reduction of post-transplant hyperlipidaemia in patients undergoing immunosuppressive therapy following solid organ transplantation (see sections 4.2, 4.5 and 5.1).

04.2 Posology and method of administration -

Before initiating therapy with APLACTIN, secondary causes of hypercholesterolaemia should be excluded and patients should be placed on a standard lipid-lowering diet to be continued during treatment.

APLACTIN is administered by mouth once a day, preferably in the evening, with or without food.

Hypercholesterolemia: the recommended dosage range is 10 & -; 40 mg in a single daily administration. The therapeutic response is evident within one week and the full effect of a certain dose is obtained within four weeks, therefore periodic evaluations of the lipid profile should be carried out. and the dosage should be adjusted accordingly.The maximum daily dose is 40 mg.

Cardiovascular prevention: In all morbidity and mortality prevention clinical trials, the only starting and maintenance dose studied was 40 mg daily.

Dosage after transplantation: In patients on immunosuppressive therapy following organ transplantation, a starting dose of 20 mg per day is recommended (see section 4.5).

Based on the response of lipid parameters, the dose can be adjusted up to 40 mg under close medical supervision (see section 4.5).

Children: Documentation on efficacy and safety in patients below 18 years of age is limited, therefore the use of APLACTIN is not recommended in these patients.

Elderly patients: No dosage adjustment is necessary in these patients unless there are predisposing risk factors (see section 4.4).

Renal or hepatic impairment: In patients with moderate or severe renal impairment or with significant hepatic impairment, a starting dose of 10 mg per day is recommended. Dosage should be adjusted according to the response of lipid parameters and under medical supervision.

Concomitant therapy: The lipid-lowering effects of APLACTIN on total cholesterol and LDL cholesterol are enhanced when administered in combination with a bile acid sequestering resin (eg, cholestyramine, colestipol). APLACTIN should be administered 1 hour before or at least 4 hours after the resin (see section 4.5).

For patients receiving ciclosporin, with or without other immunosuppressive medicinal products, treatment should start with pravastatin 20 mg once daily and dose escalation up to 40 mg should be implemented with caution (see section 4.5). .

04.3 Contraindications -

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

- Active hepatopathies including persistent undetermined elevations of serum transaminases exceeding 3 times the upper limit of normal (see section 4.4).

- Pregnancy and lactation (see section 4.6).

04.4 Special warnings and appropriate precautions for use -

Pravastatin has not been evaluated in patients with homozygous familial hypercholesterolaemia. Treatment is not suitable when hypercholesterolemia is due to elevated HDL cholesterol.

As with other HMG-CoA reductase inhibitors, the combination of pravastatin with fibrates is not recommended (see section 4.5).

Hepatic Disorders: As with other lipid-lowering drugs, moderate increases in hepatic transaminases have been reported. In most cases, liver transaminase levels returned to their baseline value without having to stop treatment. Particular care should be taken in patients who develop elevations in transaminase levels and therapy should be discontinued if elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) exceed 3 times the upper limits of the norm and are persistent.

Caution should be exercised when administering pravastatin to patients with a history of liver disease or alcoholism.

Muscle disorders: As with other HMG-CoA reductase inhibitors (statins), pravastatin has been associated with the onset of myalgia, myopathy and, very rarely, rhabdomyolysis. Myopathy should be considered in all patients on statin therapy who present with muscle symptoms of unknown nature such as pain or tension, muscle weakness or muscle cramps. In such cases, creatine kinase (CK) levels should be checked (see below). Statin therapy should be temporarily discontinued if CK levels are> 5 times the ULN or in the event of severe clinical symptoms. Very rarely (in approximately 1 case per 100,000 patient-years), rhabdomyolysis has occurred, with or without secondary renal insufficiency. Rhabdomyolysis is an acute, potentially fatal, skeletal muscle condition that can develop at any time during treatment and is characterized by massive muscle destruction associated with a substantial increase in CK (usually> 30 or 40 times the upper limit of normal ) which leads to myoglobinuria.

The risk of myopathy with statin use appears to be exposure dependent and therefore may vary with individual drug characteristics (due to differences in lipophilicity and pharmacokinetics), including dosage and drug interaction potential. Although there is no muscle contraindication to the prescription of a statin, some predisposing factors may increase the risk of muscle toxicity and therefore justify a "careful evaluation of the benefit / risk ratio and a particular clinical monitoring. In such patients, control of CK is indicated. before starting statin treatment (see below).

The risk and severity of muscle disorders during therapy with a statin are increased by the co-administration of interacting drugs. Occasionally the use of fibrates alone is associated with myopathy. The combined use of a statin with fibrates should generally be avoided. Co-administration of statins and nicotinic acid should be used with caution. An increase in the incidence of myopathy has also been described in patients receiving other statins in combination with cytochrome P450 metabolism inhibitors. This may result from pharmacokinetic interactions that have not been documented for pravastatin (see section 4.5). When combined with treatment. with statins, muscle symptoms generally resolve upon discontinuation of therapy.

Creatine kinase levels and their interpretation: Periodic monitoring of creatine kinase (CK) or other muscle enzymes is not recommended in asymptomatic patients on statin therapy. However, it is recommended that CK be monitored prior to initiating therapy with a statin in patients with specific predisposing factors and in patients who have developed muscular symptoms during statin therapy, as described below. If baseline CK levels are significantly elevated (> 5 times the upper limits of normal), these will need to be re-measured 5 to 7 days later to confirm the results.

Once measured, CK levels need to be interpreted in the context of other potential factors that can cause transient muscle damage, such as strenuous exercise or muscle trauma.

Before starting the treatment: Caution should be exercised in patients with predisposing factors such as renal failure, hypothyroidism, previous history of muscle toxicity with a statin or with fibrates, personal or family history of hereditary muscle disorders or alcoholism. In these cases the CK levels will need to be measured before starting therapy. Measurement of CK levels should also be considered before starting treatment in people over 70 years of age, especially in the presence of other predisposing factors in this population. If baseline CK levels are significantly elevated (> 5 times the upper limit of normal), treatment should not be initiated and levels should be re-measured after 5 & -; 7 days. Baseline CK levels may also be useful as a reference in the event of a subsequent increase during statin therapy.

During the treatment: Patients should be advised to promptly report the onset of muscle pain, tension, weakness or cramps of unknown nature. In these cases, CK levels should be measured. If a markedly elevated CK level (> 5 times the upper limit of normal) is detected, statin therapy should be discontinued. Also, discontinuation of treatment should be considered if muscle symptoms are severe and cause discomfort throughout the day, even if the CK rise remains? 5 times the upper limits of the norm. If symptoms resolve and CK levels return to normal, reintroduction of statin therapy at a lower dose and closely monitored may be considered. If an inherited muscle disorder is suspected in such patients, reintroduction of statin therapy is not recommended.

There have been very rare reports of 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.

Pravastatin should not be co-administered with systemic fusidic acid formulations or within 7 days of discontinuing fusidic acid treatment. In patients where systemic use of fusidic acid is considered essential, statin treatment should be discontinued. for the duration of the fusidic acid treatment. There have been reports of rhabdomyolysis (including some deaths) in patients treated with fusidic acid and statins in combination (see section 4.5). The patient should be advised to consult a physician immediately if he experiences symptoms of muscle weakness, pain or tenderness.

Statin therapy can be reintroduced seven days after the last dose of fusidic acid is given.

In exceptional circumstances, where prolonged systemic treatment with fusidic acid is required, for example in the case of severe infections, the need for co-administration of pravastatin and fusidic acid should only be considered on a case-by-case basis and under close medical supervision.

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, BMI> 30 kg / m² , elevated triglyceride levels, hypertension) should be monitored both clinically and biochemically in accordance with national guidelines.

Important information about some of the ingredients:

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

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

Fibrates: The use of fibrates alone is occasionally associated with myopathy. An increased risk of muscle adverse events, including rhabdomyolysis, has been found when given in combination with other statins. These adverse events cannot be excluded with the use of pravastatin, therefore the combined use of pravastatin and fibrates (eg, gemfibrozil, fenofibrate) should generally be avoided (see section 4.4). If this combination is considered necessary, careful clinical monitoring and control of CK levels is required for patients on this regimen.

Colestyramine / Colestipol: When administered concomitantly, approximately 40 to 50% decrease in the bioavailability of pravastatin was observed. Administration of pravastatin 1 hour before or 4 hours after cholestyramine or 1 hour before colestipol did not result in clinically significant decreases in the bioavailability or therapeutic effect of pravastatin (see section 4.2).

Ciclosporin: Co-administration of pravastatin and cyclosporine leads to an approximately 4-fold increase in systemic exposure to pravastatin. However, in some patients the increase in pravastatin exposure may be greater. Clinical and biochemical monitoring of patients is recommended. being treated with this combination (see section 4.2).

Vitamin K antagonists: As with other HMG-CoA reductase inhibitors, treatment initiation or dose increase of pravastatin in patients concomitantly treated with vitamin K inhibitors (eg warfarin or other coumarin anticoagulants) may result in increased of the International Normalized Ratio (or INR, International Normalized Ratio). On the other hand, interrupting or reducing the dosage of pravastatin may result in a reduction in INR. In these situations, adequate monitoring of the INR is necessary.

The steady state bioavailability parameters of pravastatin were not altered following administration of warfarin.

Drugs Metabolized by Cytochrome P450: Pravastatin is not metabolically significantly metabolised by the cytochrome P450 complex. This is why drugs that are metabolized by the cytochrome P450 system, or are inhibitors of it, can be added to a stable regimen of pravastatin without causing significant changes in the plasma levels of pravastatin, as has been observed with other statins. The absence of significant pharmacokinetic interaction with pravastatin has been specifically demonstrated for several substances, particularly those which are substrates / inhibitors of CYP3A4, such as diltiazem, verapamil, itraconazole, ketoconazole, protease inhibitors, grapefruit juice and CYP2C9 inhibitors ( eg: fluconazole).

A statistically significant increase in pravastatin AUC (70%) and Cmax (121%) was observed in one of the two interaction studies with pravastatin and erythromycin. A statistically significant increase in AUC (110%) and Cmax (127%) was observed in a similar study with clarithromycin. Although these are minor changes, care should be taken when combining pravastatin with erythromycin or clarithromycin.

Fusidic acid: The risk of myopathy, including rhabdomyolysis, may be increased by concomitant administration of systemic fusidic acid and statins. The mechanism of this interaction (whether it is pharmacodynamic, pharmacokinetic or both) is still unknown. There have been reports of rhabdomyolysis (including some deaths) in patients treated with this combination.

If systemic treatment with fusidic acid is required, pravastatin treatment should be suspended for the duration of fusidic acid treatment. See also section 4.4.

Other drugs: No statistically significant differences in bioavailability were noted in interaction studies when pravastatin is administered with acetylsalicylic acid, antacids (taken 1 hour before pravastatin), nicotinic acid or probucol.

04.6 Pregnancy and breastfeeding -

Pregnancy: Pravastatin is contraindicated during pregnancy and should only be given to women of childbearing potential when pregnancy is highly unlikely and when they have been advised of the potential risk. If pregnancy is planned or established, the physician should be informed immediately and pravastatin therapy discontinued due to the potential risk to the fetus.

Lactation: a small amount of pravastatin is excreted in human milk, therefore pravastatin is contraindicated during breastfeeding (see section 4.3).

04.7 Effects on ability to drive and use machines -

Pravastatin has no or negligible influence on the ability to drive or use machines. However, when driving vehicles or operating machines, it should be taken into account that dizziness may occur during treatment.

04.8 Undesirable effects -

The frequency of undesirable effects is classified according to the following convention: very common (≥1 / 10); common (≥1 / 100,

Clinical trials: APLACTIN was studied at a dose of 40 mg in seven randomized double-blind placebo-controlled clinical trials involving more than 21,000 patients treated with pravastatin (N = 10,764) or placebo (N = 10,719), representing more than 47,000 patient-years of pravastatin exposure. More than 19,000 patients were followed up for a median of 4.8 & -; 5.9 years.

The following adverse drug reactions have been reported; none occurred at a frequency in excess of 0.3% in the pravastatin group compared to the placebo group.

Nervous system disorders:

Uncommon: dizziness, headache, sleep disturbances including insomnia and nightmares

Eye disorders:

Uncommon: visual disturbances (including blurred vision and diplopia)

Gastrointestinal disorders:

Uncommon: dyspepsia / burning, abdominal pain, nausea / vomiting, constipation, diarrhea, flatulence

Skin and subcutaneous tissue disorders:

Uncommon: pruritus, rash, hives, scalp / hair changes (including alopecia)

Renal and urinary disorders:

Uncommon: Micturition disturbances (including dysuria, pollakiuria, nocturia)

Diseases of the reproductive system and breast:

Uncommon: sexual dysfunction

General disorders and administration site conditions:

Uncommon: fatigue

Events of special clinical interest

Musculoskeletal and connective tissue disordersEffects on skeletal muscle have been reported in clinical trials, eg: musculoskeletal pain including arthralgia, muscle cramps, myalgia, muscle weakness and elevated CK levels. The percentage of myalgia (1.4% pravastatin vs 1.4% placebo) and muscle weakness (0.1% pravastatin vs 3 times the ULN and> 10 times the ULN in CARE, WOSCOPS and LIPIDs are similar in the placebo groups (1.6% pravastatin vs 1.6% placebo and 1.0% pravastatin vs 1.0% placebo, respectively) (see section 4.4).

Hepatobiliary disorders: elevations of serum transaminases have been reported. In the three long-term, placebo-controlled clinical trials, CARE, WOSCOPS and LIPID, marked alterations in ALT and AST levels (> 3 times the ULN) occurred at a similar frequency (≤ 1.2%). in both treatment groups.

Post-marketing experience

In addition to the above, the following undesirable effects have been reported since the marketing of pravastatin:

Nervous system disorders

Very rare: peripheral polyneuropathy, particularly after long-term use, paraesthesia

Disorders of the immune system

Very rare: hypersensitivity reactions: anaphylaxis, angioedema, lupus erythematosus-like syndrome

Gastrointestinal disorders

Very rare: pancreatitis

Hepatobiliary disorders

Very rare: jaundice, hepatitis, fulminant hepatic necrosis

Skin and subcutaneous tissue disorders

Dermatomyositis

Musculoskeletal and connective tissue disorders

Very rare: rhabdomyolysis which may be associated with acute renal failure secondary to myoglobinuria, myopathy (see section 4.4)

Isolated cases of tendon disorders, sometimes complicated by rupture.

Frequency not known: immune-mediated necrotizing myopathy (see section 4.4).

The following side effects have also been reported with the use of statins:

Class effects

• Nightmares

• Loss of memory

• Depression

• exceptional cases of interstitial lung disease, especially in long-term therapy (see section 4.4)

• Diabetes mellitus: frequency depends on the presence or absence of risk factors (fasting blood glucose ≥ 5.6 mmol / L, BMI> 30 kg / m², elevated triglyceride levels, history of hypertension).

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 http / www.agenziafarmaco.gov.it / it / responsible

04.9 Overdose -

There is limited experience to date with pravastatin overdose. In case of overdose there is no specific treatment. In this case, the patient should be treated symptomatically and with appropriate supportive measures.

05.0 PHARMACOLOGICAL PROPERTIES -

05.1 "Pharmacodynamic properties -

Pharmacotherapeutic group: lipid-lowering agents, cholesterol and triglyceride reducing agents, HMG-CoA reductase inhibitors; ATC code: C10AA03

Mechanism of action

Pravastatin is a competitive inhibitor of 3-hydroxy-3-methyl-glutaryl Coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the early passage that limits the rate of cholesterol biosynthesis, and produces its lipid-lowering effect in two ways First, through a specific and reversible competitive inhibition of HMG-CoA reductase, pravastatin produces a modest reduction in intracellular cholesterol synthesis. This leads to an increase in the number of LDL receptors on the cell surface and increases receptor-mediated catabolism and elimination of circulating LDL cholesterol.

Second, pravastatin inhibits LDL production by inhibiting hepatic synthesis of VLDL cholesterol, the precursor of LDL cholesterol.

In both healthy subjects and in patients with hypercholesterolemia, pravastatin sodium salt lowered the following lipid values: total cholesterol, LDL cholesterol, apolipoprotein B, VLDL cholesterol and triglycerides; while HDL cholesterol and apolipoprotein A were elevated.

Clinical efficacy

Primary prevention

The West of Scotland Coronary Prevention Study (WOSCOPS) was a randomized, double-blind, placebo-controlled clinical study of 6,595 male patients aged 45 to 64 years with moderate to severe hypercholesterolemia (LDL cholesterol = 155 & -; 232 mg / dl [4.0 & -; 6.0 mmol / l]) and with no history of myocardial infarction, treated for a mean duration of 4.8 years at a dose of 40 mg once daily pravastatin or placebo in addition to the diet. In patients treated with pravastatin the results showed:

- a reduction in the risk of death from coronary heart disease and non-fatal myocardial infarction (the relative risk reduction RRR was 31%; p = 0.0001 with an absolute risk of 7.9% in the placebo group and 5, 5% in patients treated with pravastatin); the effects on the incidence of these cumulative cardiovascular events were already evident after six months of treatment;

- a reduction in the total number of deaths from a cardiovascular event (RRR 32%; p = 0.03);

- that taking into account the risk factors, an RRR of death from all causes of 24% (p = 0.039) is also observed among patients treated with pravastatin;

- a reduction in the relative risk of subjecting the patient to myocardial revascularization procedures (coronary artery bypass graft or coronary angioplasty) of 37% (p = 0.009) and of coronary angiography by 31% (p = 0.007).

The benefit of the treatment, according to the above criteria, is not known in patients over the age of 65, as it could not be included in the study.

Given the lack of data on patients with hypercholesterolaemia associated with triglyceride levels above 5.3 g / l (6 mmol / l) after an 8-week diet, the benefit of pravastatin treatment was not established in this study. type of patients.

Secondary prevention

The Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) was a multicenter, randomized, double-blind, placebo-controlled study comparing the effects of pravastatin (40 mg once daily) with placebo on 9,014 patients, between 31 and 75 years of age, for a mean duration of 5.6 years, with normal to high cholesterol (baseline total cholesterol = 155 & -; 271 mg / dl [4.0 & -; 7.0 mmol / l], mean total cholesterol = 219 mg / dl [5.66 mmol / l]) and with variable triglyceride levels up to 443 mg / dl [5.0 mmol / l] and with a history of myocardial infarction or unstable angina pectoris within the previous 3 & -; 36 months. Treatment with pravastatin significantly reduced the relative risk of death from coronary heart disease by 24% (p = 0.0004, with an absolute risk of 6.4% in the placebo group and 5.3% in patients treated with pravastatin), the relative risk of coronary events (death from coronary artery disease or non-fatal myocardial infarction) of 24% (p

- a reduction in the relative risk of death from all causes by 23% (cardiovascular p by 25% (p

- a reduction in the relative risk of using myocardial revascularization procedures (coronary artery bypass graft or percutaneous transluminal coronary angioplasty) of 20% (p

- a 19% reduction in the relative risk of stroke (p = 0.048).

The "Cholesterol and Recurrent Events" (CARE) study was a randomized, double-blind, placebo-controlled study that compared the effects of pravastatin (40 mg once daily) on death from coronary heart disease and myocardial infarction. non-fatal for a mean of 4.9 years out of 4,159 patients, aged 21 to 75 years, with normal total cholesterol (mean total baseline cholesterol

- the incidence of recurrent coronary events (death from coronary heart disease or non-fatal myocardial infarction) of 24% (p = 0.003, placebo 13.3%, pravastatin 10.4%);

- the relative risk of recourse to revascularization procedures (coronary artery bypass graft or percutaneous transluminal coronary angioplasty) of 27% (p

The relative risk of stroke was also reduced by 32% (p = 0.032) and the risk of stroke or transient ischemic attack (TIA) combined was reduced by 27% (p = 0.02).

The benefit of the treatment according to the above criteria is not known in patients over 75 years of age, as it could not be included in the CARE and LIPID studies.

In the absence of data on hypercholesterolemic patients with triglyceride levels greater than 3.5 g / l (4 mmol / l) or greater than 4.45 g / l (5 mmol / l) respectively in the CARE and LIPID studies, after a 4 or 8 week diet regimen, the benefit of pravastatin treatment in these patients has not been established.

In the CARE and LIPID clinical trials, approximately 80% of patients took acetylsalicylic acid as part of their treatment.

Heart and kidney transplant

The efficacy of pravastatin in patients treated with immunosuppressants following:

• heart transplant, was assessed in a prospective, randomized and controlled study (n = 97). Patients were treated simultaneously with pravastatin (20 & -; 40 mg) or less and a standard immunosuppressive regimen of cyclosporine, prednisone and azathioprine. Treatment with pravastatin significantly reduced the incidence of cardiac rejection with haemodynamic compromise at one year, increased survival to one year (p = 0.025), and lowered the risk of coronary vascular disease during transplantation as demonstrated by angiography and from the autopsy (p = 0.049).

• kidney transplant, was evaluated in a prospective, uncontrolled, non-randomized study (n = 48) of 4 months duration. Patients were treated simultaneously with pravastatin (20 mg) or less and a standard immunosuppressive regimen of cyclosporine and prednisone.

In renal transplant patients, pravastatin significantly reduced both the incidence of multiple rejection episodes, the incidence of biopsy-confirmed acute rejection episodes and the use of intermittent injections of both prednisolone and Muromonab-CD3.

05.2 "Pharmacokinetic properties -

Absorption

Pravastatin is administered by mouth in its active form. It is rapidly absorbed and peak serum levels are reached 1 & -; 1.5 hours after ingestion. On average 34% of the oral dose is absorbed, with an absolute bioavailability of 17%.

The presence of food in the gastrointestinal tract leads to a reduction in bioavailability, but the cholesterol-lowering effect of pravastatin is the same whether it is taken with or without food.

After absorption, 66% of pravastatin undergoes a first extraction from the circulation in the liver, which is the main site of its action and the main site of cholesterol synthesis and elimination of LDL cholesterol. Studies in vitro have shown that pravastatin is transported to hepatocytes and, to a substantially lesser extent, to other cells.

In light of this substantial first pass through the liver, the plasma concentrations of pravastatin have only limited value in predicting a lipid-lowering effect.

Plasma concentrations are proportional to the administered doses.

Distribution

About 50% of circulating pravastatin is bound to plasma proteins.

The volume of distribution is approximately 0.5 l / kg.

A small amount of pravastatin passes into human milk.

Metabolism and elimination

Pravastatin is not significantly metabolised by cytochrome P450 nor does it appear to be a substrate or inhibitor of P-glycoprotein but rather a substrate of other transport proteins.

After oral administration, 20% of the initial dose is eliminated in the urine and 70% in the faeces. The plasma elimination half-life of oral pravastatin is one and a half to two hours.

After intravenous administration, 47% of the dose is eliminated by renal excretion and 53% by biliary excretion and biotransformation. The major breakdown product of pravastatin is the 3-α-hydroxy isomeric metabolite. This metabolite possesses one-tenth to one-fortieth HMG-CoA reductase inhibiting activity of the parent compound.

The systemic clearance of pravastatin is 0.81 l / h / kg and the renal clearance is 0.38 l / h / kg indicating tubular secretion.

Populations at risk

Hepatic insufficiency: Systemic exposure to pravastatin and its metabolites in patients with alcoholic cirrhosis is increased by approximately 50% compared to patients with normal hepatic function.

Kidney failure: no significant changes were found in patients with mild renal insufficiency. However, severe and moderate renal insufficiency can lead to a two-fold increase in systemic exposure to pravastatin and its metabolites.

05.3 Preclinical safety data -

Based on conventional studies of safety pharmacology, repeated dose toxicity and reproductive toxicity, there are no other risks to the patient than those expected due to the pharmacological mechanism of action.

Repeated dose studies indicate that pravastatin can induce varying degrees of hepatotoxicity and myopathy; in general, substantial effects on these tissues were only evident at doses 50 times or more of the maximum human dose in mg / kg.

In the studies in vitro and in vivo of genetic toxicology, no evidence of mutagenic potential was found.

In a 2-year carcinogenicity study in mice using pravastatin at doses of 250 and 500 mg / kg / day (≥ 310 times the maximum human dose in mg / kg), statistically significant increases in the incidence of hepatocellular carcinomas in males and females and, only in females, of lung adenomas. In a 2-year carcinogenicity study in rats, at a dose of 100 mg / kg / day (125 times the maximum human dose in mg / kg), a statistically significant increase in the incidence of hepatocellular carcinomas was demonstrated. only in males.

06.0 PHARMACEUTICAL INFORMATION -

06.1 Excipients -

Lactose monohydrate, polyvinylpyrrolidone, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, magnesium oxide, yellow iron oxide (E172).

06.2 Incompatibility "-

Not relevant.

06.3 Period of validity "-

2 years.

06.4 Special precautions for storage -

Store at a temperature not exceeding 30 ° C.

Store in the original container

06.5 Nature of the immediate packaging and contents of the package -

Blister containing 10 tablets of 20 mg.

06.6 Instructions for use and handling -

No special instructions.

07.0 HOLDER OF THE "MARKETING AUTHORIZATION" -

SIGNATURE. S.p.A., Via di Scandicci 37 - Florence

08.0 MARKETING AUTHORIZATION NUMBER -

A.I.C. N ° 027786021

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION -

Date of first authorization: 1 March 1993

Date of most recent renewal: 1 March 2008

10.0 DATE OF REVISION OF THE TEXT -

May 2016

11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY -

12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL -

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