INSTRUCTION

for medical use of the preparation

LIMISTIN 10

LIMISTIN 20

LIMISTIN 40

Composition.

Active substance: atorvastatin;
1 tablet contains atorvastatin calcium equivalent to atorvastatin  10 mg or 20 mg or 40 mg;

Auxiliary substances: calcium carbonate, microcrystalline cellulose, lactose monohydrate, sodium croscarmellose, polysorbate 80, hydroxypropyl cellulose, magnesium stearate, propylene glycol, hydroxypropylmethyl cellulose, polyethyleneglycol-6000, talcum, titanium dioxide Е 171 (tablets 10 mg and 20 mg); 

calcium carbonate, microcrystalline cellulose, lactose monohydrate, sodium croscarmellose, polysorbate 80, hydroxypropyl cellulose, magnesium stearate, crosspovidone, sodium laurile sulfate, hypromellose, polyethyleneglycol, talcum, titanium dioxide Е 171 (tablets 40 mg). 

Medicinal form. Film coated tablets.

Pharmacotherapeutical group.  Hypolipidemic agents. HMG-CoA reductase inhibitors. АТС code С10А А05. 

Clinical characteristics. 
Indications.

As a supplement to the diet in order to reduce the increased level of total cholesterol, low-density lipoprotein cholesterol (LDL-C), apolipoprotein В, and triglycerides in order to increase high-density lipoprotein cholesterol (HDL-C) in patients with primary hypercholesterolemia (heterozygous familial and non-heritable hypercholesterolemia), combined (mixed) hyperlipidemia (Fredrickson type IV) and in patients with dysbetalipoproteinemia (Fredrickson type III) in those cases when diet does not provide the expected effect.
To reduce the increased level of total cholesterol and LDL-C in patients with homozygous familial hypercholesterolemia, in those cases when diet and other non-medicament methods do not provide the expected effect.
In patients without clinical manifestations of cardiovascular diseases, with presence or absence of dyslipidemia, but who have several risk factors of cardiovascular diseases, such as smoking, arterial hypertension, diabetes mellitus, low level of HDL-C or there is information in the family anamnesis on cardiovascular diseases in the young age, in order to:

• decrease the risk of fatal manifestations of ischaemic heart disease and non-fatal myocardial  infarction;

• decrease the risk of stroke development;

• decrease the risk of stenocardia development and the necessity of myocardial revasculization procedures.

Children (10-17 years old).
Limistin is indicated as a supplement to the diet in order to reduce the increased level of total cholesterol, LDL-C, and apolipoprotein В:

• in boys and girls in postmenarchial period, aged 10 - 17 years old із heterozygous familial hypercholesterolemia, if even under condition of following the adequate diet:

                          a) the level of LDL-C remains ≥ 190 mg/decilitre (1.90 g/l) or
                          b) the level of LDL-C remains ≥ 160 mg/decilitre (1.60 g/l);

• there is information in the family anamnesis on cardiovascular diseases in the young age;

• pediatric patients have two or more risk factors of the development of cardiovascular diseases (smoking, arterial hypertension, diabetes mellitus, low level of HDL-C or there is information in the family anamnesis on cardiovascular diseases in the young age).

Contraindications.

• hypersensitivity to any component of the preparation; 
• active hepatic diseases or unascertained genesis of persisting increase of transaminase activity that is three times higher than the norm; 
• pregnant women, nursing mothers or in case of probable pregnancy due to insufficient means of contraception. 

Way of introduction and doses. 
Before initiating therapy with Limistin it is necessary to determine the level of hypercholesterolemia against the background of appropriate diet, indicate physical exercises and activities to decrease weight in patients with obesity and carry out the treatment of other diseases. During treatment with Limistin patients should follow standard diet with low content of cholesterol. The preparation is indicated in dose of 10 – 80 mg once a day every day, at any time of the day irrespectively from meal intakes. Initial and supportive dose may be individualized according to the initial level of LDL-C, purpose of the therapy and its efficiency. In 2 – 4 weeks after initiation of the treatment and/or dose adjustment of Limistin, it is necessary to determine lipidogram and adjust the dose accordingly.

Primary hypercholesterolemia and combined (mixed) hyperlipidemia. In most cases it is enough to indicate 10 mg once a day. The result of the treatment becomes evident in 2 weeks, maximal effect is observed in 4 weeks. Positive changes are maintained via long-term use.

Homozygous familial hypercholesterolemia. In most cases in patients with homozygous familial hypercholesterolemia the result is achieved using 80 mg of Limistin once a day, which provides decrease of LDL-C level by over 15 % (18 – 45 %).

Heterozygous familial hypercholesterolemia in pediatric practice (10–17-year old patients). It is recommended to indicate Limistin in the initial dose of 10 mg once a day every day. Maximal recommended dose is 20 mg once a day every day (doses exceeding 20 mg have not been studied in patients of this age group). Doses may be individualized according to the purpose of the therapy; dose adjustment may be done with the interval of 4 weeks and more. 
Use for treatment of patients with renal insufficiency. Renal diseases do not influence the concentration of atorvastatin or decrease of plasma LDL-C level. So, there is no need to adjust the dose.

Use for treatment of elderly patients. There is no difference in safety, efficiency or achievement of the purpose in treatment of hypercholesterolemia in elderly patients and patients of other age groups.

Side effects.
Atorvastatin is usually well tolerated. The most frequent side effects are constipation, meteorism, dyspepsia, abdominal pain.

Most frequent side effects of atorvastatin were the following:

• general disorders: pain in the chest, face edema, fever, asthenia, rigid neck muscles, weakness, photosensitivity reactions, generalized edema.
• neurologic disorders: insomnia, dizziness, paresthesia, sleepiness, amnesia, sleep disorders, decreased libido, emotional lability, impared coordination, peripheral neuropathy, paesthesia, torticollis, facial paralysis, hyperkinesia, depression, hypesthesia, hypertension;
• gastro-intestinal disorders: gastroenteritis, hepatic disfunction, colitis, vomiting, gastritis, dry mouth, rectum hemorrhage, esophagitis, glossitis, ulcer of mouth cavity, anorexia, increase appetite, stomatitis, cheilitis, duodenal ulcer, dysphagia, enteritis, melena, gum bleeding, gastric ulcer, tenesmus, ulcer stomatitis, hepatitis, pancreatitis, cholestatic jaundice, diarrhea, abdominal pain, dyspepsia, constipation, meteorism;
• changes from the side of skin and subcutaneous cellular tissue: alopecia, itch, contact dermatitis, dry skin, sweating, acne, urticaria, eczema, seborrhea, skin ulcer, rash.
• disorders from the side of locomotor system and connective tissue: arthritis, myopathy, myalgia, myositis, muscular cramps, bursitis, tendosynovitis, myasthenia, tendon contracture.
• disorders from the side of urinary and reproductive systems: infection of urinary system, hematuria, albuminuria, frequent urination, cystitis, dysuria, renal calculus, nycturia, epididymitis, mastopathy, vaginal hemorrhage, metrorrhagia, enlarged mammary gland, metrorrhagia, nephritis, urinary incontinence, urinary retention, acute urinary retention, impotency, impaired ejaculation;
• sense organs: amblyopia, ear noise, xerophthalmus, impaired refraction, cataract, haemorrhage of the eye, deafness, glaucoma, parosmia, taste loss, taste alteration;
• disorders from the side of respiratory system: bronchitis, rhinitis, pneumonia, dyspnea, asthma, nasal hemorrhage;
• disorders from the side of cardio-vascular system: palpitation, vasodilation, syncopal state, migraine, postural hypotension, phlebitis, arrhythmia, stenocardia attack,  hypotension;
• disorders metabolism: peripheral edema, hyperglycemia, increased level of creatine phosphokinase, gout, increased body weight, hypoglycemia;
• disorders from the side of blood and lymphatic system: ecchymosis, anaemia, lymphadenopathy, thrombocytopenia, petechia.

Pediatric patients (10 – 17 years old). In patients, using atorvastatin, there have been noticed side effects similar to those of placebo patients. Most generalized side effect observed in both groups, not taking into consideration causal relationship, were infections.
During post-marketing period there have been the following side effects:thrombocytopenia;  allergic reactions (including anaphylaxis); angioneurotic edema, increased body weight; hypesthesia, amnesia, dizziness, ringing of the ears; Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, bullous rash, urticaria; rhabdomyolysis, tendon tear, arthralgia, backache;  pain in the chest, peripheral edema, malaise, fatigability.

Overdose.    

In case of overdose development of rhabdomyolysis and hepatic dysfunction are possible. There is no specific antidote. In case of overdose the treatment is symptomatic and supportive. Taking into consideration binding of the preparation to plasma proteins, hemodialysis is ineffective. 

Use during pregnancy and lactation.
Limistin is contraindicated during pregnancy. Women of childbearing age should use appropriate contraceptives. Limistin can be indicated to women of childbearing age only when they positively ignore this contraindication and are well-informed about possible risk for the fetus. If during treatment with the preparation the patient wants to become pregnant she should discontinue preparation intake not later than 1 month before planned pregnancy.Limistin  is contraindicated during lactation. It is unknown whether Limistin excretes with breast milk. As there is potential risk for infants receiving breast milk, breast-feeding should be discontinued during treatment with Limistin.

Children. 
The efficiency and safety of use of Limistin for treatment of children under 10 years old with heterozygous familial hypercholesterolemia has not been studied, so the preparation is not used for treatment patients of this age group.

Peculiarities of administration.
Influence on the liver. Similar to use of other hypolipoproteinemic agents of this class, during treatment with atorvastatin there may be moderate increase of serum transaminase activity (3 times higher than upper level of the norm - ULN). Liver function was controlled at pre- and post-marketing stages of the study of atorvastatin use in doses of 10, 20, 40 and 80mg. Persistent increase of transaminase activity (3 times higher than ULN in 2 or more cases) was observed in 0.7% of patients, receiving atorvastatin during the studies. Deviation limits were 0.2, 0.2, 0.6 and 2.3% at use of 10, 20, 40 and 80mg of the preparation, accordingly. Increase of transaminase activity was not accompanied with jaundice or other clinical manifestations. If the dose of atorvastatin was decreased, there was a break or discontinuation of the treatment, transaminase level normalized. The majority of patients continued the treatment with lesser doses of atorvastatin without unwanted sequences. 

Liver function should be determined before the initiation of the treatment and controlled periodically during the course of treatment. Patients having signs of hepatic dysfunction should determine indexes of liver function. Patients having increased transaminase activity should be supervised up to the normalization of indexes. In case of more than triple increase of SPGT or SGOT activity over the norm, atorvastatin dose should be decreased or treatment should be discontinued. Atorvastatin may cause increased transaminase activity.Limistin should be indicated with caution to the patients taking alcohol and/or have hepatic diseases in anamnesis. Hepatic diseases in active phase or increased transaminase activity because of unknown reason are contraindications for indication of Limistin.

Influence on skeletal muscles. Myopathy may be observed in patients during treatment with Limistin. Under myopathy one should understand muscle pain or muscle weakness in combination with increased level of creatine phosphokinase (CPK) 10 times over ULN. The possibility of this state should be hypothesized in patients with diffuse myalgia, painful or weak muscles and і/or significant increase of the creatine phosphokinase level. Patients should be warned about possible muscle pain or muscle weakness, sometimes with weakness or increased temperature. In cases of increased CPK level and clarified or possible diagnosis of myopathy treatment with Limistin should be discontinued. The risk of myopathy during treatment with preparations of this group increases at concomitant use of cyclosporine, fibrin acid derivatives, erythromycin, niacin or azole antifungal agents. The majority of these preparations inhibit metabolism of cytochrome Р450 3А4 and/or distribution of the preparation in the organism. Limistin biotransforms first of all with the help of liver enzyme CYP 3А4. Doctors, indicating Limistin in combination with fibrin acid derivatives, erythromycin, immunosuppressor or azole antifungal agents or hypolypoproteinemic doses of niacin, should consider possible positive results and harmful consequences and monitor the patients in order to detect such manifestations as muscle pain or muscle weakness, especially during first months of treatment and after dose increase of one of those preparations. With this purpose periodic determination of CPK is recommended, but it is necessary to remember, that this test is not enough for timely diagnostics of severe myopathy. Limistin may cause increase of CPK level.At treatment with Limistin, as using similar preparations of this group, there are seldom cases of rhabdomyolysis in combination with secondary renal insufficiency, caused by myoglobinuria. Therapy with Limistin should be discontinued or stopped in case of severe state of the patient in suspicion that these changes have been caused by myopathy, or at presence of risk factors as for development of secondary renal insufficiency at rhabdomyolysis (e.g., severe acute infection, hypotension, serious surgeries, trauma, severe endocrine, metabolic or electrolytic disorders and uncontrolled cramps).Sort-term discontinuation of Lipitin intake does not involve direct threat. 

If the treatment has been stopped for a prolonged period of time there may progress vascular disease due to fat accumulation in vascular walls (atherosclerosis) and there may develop recurrence risk of cardio-vascular disease. 

The preparation contains lactose, which should be considered by patients with inherited lactose intolerance.

Haemorrhagic stroke.

 Therapy with atorvastatin at the dose of 80 mg in patients without cardiovascular diseases, who had a stroke or transitory ischemic attack (TIA) 6 month or less prior the treatment, increases the frequency of haemorrhagic strokes. In patients, who had a haemorrhagic stroke at the beginning of the therapy, the risk of recurrent haemorrhagic stroke increases. Atorvastatin at the dose of 80 mg decreases general frequency of strokes and decreases general frequency of cardiovascular diseases.
 

The ability to influence the reaction time when driving and working with other mechanisms. 

At the use of the preparation there can be observed delayed responses, which impare the ability to drive and work with precise mechanisms, so it is recommended to avoid these actions during treatment with the preparation.

Interaction with other drugs and other forms of interaction.
The risk of myopathy during treatment with atorvastatin and similar preparations increases at concomitant use of cyclosporine, fibrin acid and its derivatives, erythromycin, antifungal agents of azole group and niacin. 
Antacids. Concomitant use of atorvastatin and suspensions of oral antacids containing aluminum hydroxide and magnesium hydroxide decreases plasma concentration of atorvastatin approximately by 35%, but it does not influence decreasing of LDL-C level.

Antipyrin. As atorvastatin does not change pharmacokinetics of antipyrin, interaction between these preparations metabolizing with the help of the same cytochrome (such as terfenadine, tolbutamide, triazolam, oral contraceptives), is unlikely. 

Colestipol. Plasma concentration of atorvastatin decreases by 25% at concomitant use of colestipol. But hypolipoprotein effect was more expressed at concomitant use of atorvastatin and colestipol, than at use of one of these preparations. 

Digoxin. At long0term use of digoxin and concomitant use of 10 mg of atorvastatin plasma level of digoxin does not change. But the concentration of digoxin increased approximately by 20% at concomitant use of 80 mg of atorvastatin a day. It is necessary to control appropriately the state of patient receiving digoxin. 

Erythromycin/clarithromycin. Concomitant use of atorvastatin and erythromycin (500 mg 4 times a day) or clarithromycin (500 mg twice a day), that inhibit cytochrome Р450 3А4, was accompanied by increased plasma level of atorvastatin (see «Peculiarities of administration. Influence on skeletal muscles»).

Azithromycin. Concomitant use of atorvastatin (10 mg every day) and azithromycin (500 mg every day) does not change plasma concentration of atorvastatin.

Terfenadine. Concomitant use of atorvastatin and terfenadine does not cause significant pharmacokinetic changes of terfenadine.

Intraconasole. Concomitant use of atorvastatin (20-40 mg) and intraconasole (200 mg) leads to increased level of atorvastatin in blood.

Diltiazem hydrochloride. Concomitant use of atorvastatin (40 mg) and diltiazem (240 mg) leads to increased plasma level of atorvastatin.

Oral contraceptives. Concomitant use with oral contraceptives, containing norethindrone and ethanylestradiol, increases AUC of both preparations approximately by 30 and 20%. This effect is to be considered when choosing contraceptives for women taking atorvastatin. 

Warfarin and cimetidine. No significant interaction effect between these preparations and atorvastatin has been established.

Amlodipine. At concomitant use of 80 mg of atorvastatin and 10 mg of amlodipine no pharmacokinetic change of atorvastatin has been established.

Protease inhibitors. Concomitant use of atorvastatin and protease inhibitors, inhibiting action of cytochrome Р450 3А4 (such as ritonavir or sacvinavir), is accompanied by increased plasma concentration of atorvastatin. 
Cytochrome Р450 3А4 inductors. Concomitant use of atorvastatin with cytochrome Р4503А4 inductors (Efavirenz, rifampicin) may lead to changeable decrease of plasma concentration of atorvastatin. Due to double mechanism of rifampicin action it is recommended to use concomitantly atorvastatin and rifampicin, later use of atorvastatin after use of rifampicin connected with determining of decreased plasma concentration of atorvastatin. 

Other concomitant therapy. During clinical studies atorvastatin was used concomitantly with antihypertensive agents and estrogen-substitute preparations without significant interaction effects. At interaction with cimetidine the level of atorvastatin does not change. Interaction with specific agents has not been studied.
Grapefruit juice causes inhibition of cytochrome Р450 3А4 and may lead to increased   atorvastatin, especially at excessive use of grapefruit juice (>1.2 l a day). 

Pharmacological properties. 
Pharmacodynamics. Selective competitive enzyme inhibitor 3-hydroxy-3-methylglytaryl coenzyme А-reductase, converting 3-hydroxy-3-methylglytaryl coenzyme А into mevalonic acid, which is sterol precursor, including cholesterol. Lipitin decreases cholesterol and lipoprotein level in plasma due to inhibition of 3-hydroxy-3-methylglytaryl coenzyme А reductase and cholesterol synthesis in liver, as well as increasing number of low-density lipoprotein receptors on hepatocyte surface, which leads to increased capture and catabolism of low-density lipoproteins. Lipitin decreases level of total cholesterol, low-density lipoproteins, apolipoprotein В and triglycerides, increases level of high-density lipoprotein cholesterol and apolipoprotein А. These results are registered in patients with heterozygous familial hypercholesterolemia and mixed hyperlipidemia, including patients with insulin-dependent diabetes.  
Pharmacokinetics. Atorvastatin absorbs quickly after internal intake; maximal plasma concentration is achieved in 1-2 h. The degree of absorption increases proportionally to the dose of atorvastatin. Bioavaliability of the preparation is 95-99%. Absolute bioavailability of atorvastatin is approximately 12%, and systemic availability of inhibiting activity towards 3-hydroxy-3-methylglytaryl coenzyme А-reductase is nearly 30%. Low systemic bioavailability is caused by presystemic clearance in mucus of gastro-intestinal tract and/or biotransformation at primary passage through liver. Mean distribution volume of atorvastatin is approximately 565 l. Atorvastatin is more than 98%bound to plasma proteins, it biotransforms under action of cytochrome Р450 3 А4 with formation of ortho- and parahydroxylated derivatives and different products of β-oxidation. Atorvastatin effect on 3-hydroxy-3-methylglytaryl coenzyme А reductase is approximately 70% determined by circulating metabolites activity. The preparation is excreted with bile after hepatic and/or extrahepatic biotransformation. The preparation does not undergo expressed enterohepatic recirculation. Mean half-life of atorvastatin is nearly 14 h. Inhibiting activity towards 3-hydroxy-3-methylglytaryl coenzyme А-reductase lasts for about 20-30 h due to the presence of active metabolites. There are no pharmacokinetic data of the preparation in children.  

Pharmaceutical characteristics.
Main physical and chemical properties:

• White or almost white capsule-like film-coated tablets, with a score on one side (tablets 10 mg and 20 mg); 
• White or almost white round biconvex film-coated tablets. (tablets 40 mg).

Shelf life: 2 years.
Storage conditions. 

Keep out of the reach of children.

Store in the original package at temperature below 30ºC. 

Packing. 10 tablets in a blister; 3 blisters in a carton.  

Applicant. Ananta Medicare Ltd.

Location. Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, Great Britain.

Manufacturer. Akums Drugs  & Pharmaceuticals Ltd.

Location. 

304, Mohan Place, LSC, Block-C, Saraswati Vihar, Delhi-110034 India

19, 20, 21, Sector-6A I.I.E SIDCUL, Ranipur, Haridwar -249403, Uttarakhand, India 

Category of dispensing. On prescription.