GENERAL CHARACTERISTICS:
General physico-chemical properties:
For Lolip 20 mg:
Pink, Circular, Biconvex, film-coated tablets embossed with ’20’ on one side and plain on other side of tablet
For Lolip 10 mg:
Pink, Circular, Biconvex, film-coated tablets embossed with ’10’ on one side and plain on other side of tablet
Composition:
Active substance:
Atorvastatin calcium Each film-coated tablet contains
Atorvastatin calcium equivalent to Atorvastatin…………10 mg/20 mg
Additional ingredients:
Lactose monohydrate, microcrystalline cellulose, calcium carbonate, povidone (K 30), croscarmellose sodium, colloidal anhydrous silica, magnesium stearate, opadry pink 03F84827, isopropyl alcohol and purified water.

INDICATIONS:
Hypercholesterolaemia:
Lolip is indicated as an adjunct to diet for reduction of elevated total cholesterol (total-C), LDL-cholesterol (LDL-C), apolipoprotein B, and triglycerides in adults, adolescents and children aged 10 years or older with primary hypercholesterolaemia including familial hypercholesterolaemia (heterozygous variant) or combined (mixed) hyperlipidaemia (Corresponding to Types IIa and IIb of the Fredrickson classification) when response to diet and other nonpharmacological measures is inadequate.
Lolip is also indicated to reduce total-C and LDL-C in adults with homozygous familial hypercholesterolaemia as an adjunct to other lipid-lowering treatments (e.g. LDL apheresis) or if such treatments are unavailable.
Prevention of cardiovascular disease:
Prevention of cardiovascular events in adult patients estimated to have a high risk for a first cardiovascular event, as an adjunct to correction of other risk factors.
POSOLOGY AND METHOD OF ADMINISTRATION:
Posology:The patient should be placed on a standard cholesterol-lowering diet before receiving Lolip and should continue on this diet during treatment with Lolip. The dose should be individualised according to baseline LDL-C levels, the goal of therapy, and patient response.
The usual starting dose is 10 mg once a day. Adjustment of dose should be made at intervals of 4 weeks or more. The maximum dose is 80 mg once a day.
Primary hypercholesterolaemia and combined (mixed) hyperlipidaemia:
The majority of patients are controlled with Atorvastatin 10 mg once a day. A therapeutic response is evident within 2 weeks, and the maximum therapeutic response is usually achieved within 4 weeks. The response is maintained during chronic therapy.
Heterozygous familial hypercholesterolaemia:
Patients should be started with Lipitor 10 mg daily. Doses should be individualized and adjusted every 4 weeks to 40 mg daily. Thereafter, either the dose may be increased to a maximum of 80 mg daily or a bile acid sequestrant may be combined with 40 mg atorvastatin once daily.
Homozygous familial hypercholesterolaemia:
The dose of atorvastatin in patients with homozygous familial hypercholesterolemia is 10 to 80 mg daily. Atorvastatin should be used as an adjunct to other lipidlowering treatments (e.g. LDL apheresis) in these patients or if such treatments are unavailable.
Prevention of cardiovascular disease:
In the primary prevention trials the dose was 10 mg/day. Higher doses may be necessary in order to attain (LDL) cholesterol levels according to current guidelines.
Patients with renal impairment:
No adjustment of dose is required.
Patients with hepatic impairment:
Atorvastatin should be used with caution in patients with hepatic impairment. Lolip is contraindicated in patients with active liver disease.
Use in the elderly:
Efficacy and safety in patients older than 70 using recommended doses are similar to those seen in the general population.
Paediatric use:
Hypercholesterolaemia:
Paediatric use should only be carried out by physicians experienced in the treatment of paediatric hyperlipidaemia and patients should be reevaluated on a regular basis to assess progress.
For patients aged 10 years and above, the recommended starting dose of atorvastatin is 10 mg per day with titration up to 20 mg per day. Titration should be conducted according to the individual response and tolerability in paediatric patients. Safety information for paediatric patients treated with doses above 20 mg, corresponding to about 0.5 mg/kg, is limited.
There is limited experience in children between 610 years of age (see section 5.1). Atorvastatin is not indicated in the treatment of patients below the age of 10 years. Other pharmaceutical forms/strengths may be more appropriate for this population.
Mode of administration:
Lolip is for oral administration. Each daily dose of atorvastatin is given all at once and may be given at any time of day with or without food.

UNDESIRABLE EFFECTS:
Estimated frequencies of reactions are ranked according to the following convention:
common ( 1/100, < 1/10); uncommon ( 1/1,000, < 1/100); rare ( 1/10,000, < 1/1,000); very rare ( 1/10,000).
Infections and infestation
Common:
nasopharyngitis
Blood and lymphatic system disorders
Rare:
thrombocytopenia Immune system disorders
Common:
allergic reactions
Very rare:
anaphylaxis
Metabolism and nutrition disorders Common: hyperglycaemia.
Uncommon:
hypoglycaemia, weight gain, anorexia
Psychiatric disorders
Uncommon:
nightmare, insomnia
Nervous system disorders
Common:
headache
Uncommon:
dizziness, paraesthesia, hypoesthesia, dysgeusia, amnesia Rare: peripheral neuropathy
Eye disorders
Uncommon:
vision blurred
Rare:
visual disturbance Ear and labyrinth disorders
Uncommon:
tinnitus
Very rare:
hearing loss
Respiratory, thoracic and mediastinal disorders
Common:
pharyngolaryngeal pain, epistaxis. Gastrointestinal disorders
Common:
constipation, flatulence, dyspepsia, nausea, diarrhoea
Uncommon:
vomiting, abdominal pain upper and lower, eructation, pancreatitis
Hepatobiliary disorders
Uncommon:
hepatitis
Rare:
cholestasis
Very rare:
hepatic failure
Skin and subcutaneous tissue disorders Uncommon:
urticaria, skin rash, pruritus, alopecia
Rare:
angioneurotic oedema, dermatitis bullous including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis
Musculoskeletal and connective tissue disorders
Common:
myalgia, arthralgia, pain in extremity, muscle spasms, joint swelling, back pain. Uncommon: neck pain, muscle fatigue
Rare:
myopathy, myositis, rhabdomyolysis, tendonopathy, sometimes complicated by rupture
Reproductive system and breast disorders
Very rare:
gynecomastia
General disorders and administration site conditions Uncommon:
malaise, asthenia, chest pain, peripheral oedema, fatigue, pyrexia
ADVERSE DRUG REACTION:
“Inform doctors about unexpected reactions after using drugs”.

INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF INTERACTION
Effect of co-administered medicinal products on Atorvastatin
Atorvastatin is metabolized by cytochrome P450 3A4 (CYP3A4) and is a substrate to transport proteins e.g. the hepatic uptake transporter OATP1B1. Concomitant administration of medicinal products that are inhibitors of CYP3A4 or transport proteins may lead to increased plasma concentrations of atorvastatin and an increased risk of myopathy. The risk might also be increased at concomitant administration of atorvastatin with other medicinal products that have a potential to induce myopathy, such as fibric acid derivates and ezetimibe.
CYP3A4 inhibitors
Potent CYP3A4 inhibitors have been shown to lead to markedly increased concentrations of atorvastatin. Co-administration of potent CYP3A4 inhibitors (e.g. ciclosporin, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole and HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir, etc.) should be avoided if possible. In cases where co-administration of these medicinal products with atorvastatin cannot be avoided lower starting and maximum doses of atorvastatin should be considered and appropriate clinical monitoring of the patient is recommended.
Moderate CYP3A4 inhibitors (e.g. erythromycin, diltiazem, verapamil and fluconazole) may increase plasma concentrations of atorvastatin. An increased risk of myopathy has been observed with the use of erythromycin in combination with statins. Interaction studies evaluating the effects of amiodarone or verapamil on atorvastatin have not been conducted. Both amiodarone and verapamil are known to inhibit CYP3A4 activity and co-administration with atorvastatin may result in increased exposure to atorvastatin. Therefore, a lower maximum dose of atorvastatin should be considered and appropriate clinical monitoring of the patient is recommended when concomitantly used with moderate CYP3A4 inhibitors. Appropriate clinical monitoring is recommended after initiation or following dose adjustments of the inhibitor.
CYP3A4 inducers
Concomitant administration of atorvastatin with inducers of cytochrome P450 3A (e.g. efavirenz, rifampin, St. John’s Wort) can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampin, (cytochrome P450 3A induction and inhibition of hepatocyte uptake transporter OATP1B1), simultaneous co-administration of atorvastatin with rifampin is recommended, as delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations. The effect of rifampin on atorvastatin concentrations in hepatocytes is, however, unknown and if concomitant administration cannot be avoided, patients should be carefully monitored for efficacy.
Transport protein inhibitors
Inhibitors of transport proteins (e.g. ciclosporin) can increase the systemic exposure of atorvastatin (see Table 1). The effect of inhibition of hepatic uptake transporters on atorvastatin concentrations in hepatocytes is unknown. If concomitant administration cannot be avoided, a dose reduction and clinical monitoring for efficacy is recommended.
Gemfibrozil / fibric acid derivatives
The use of fibrates alone is occasionally associated with muscle related events, including rhabdomyolysis. The risk of these events may be increased with the concomitant use of fibric acid derivatives and atorvastatin. If concomitant administration cannot be avoided, the lowest dose of atorvastatin to achieve the therapeutic objective should be used and the patients should be appropriately monitored.
Ezetimibe
The use of ezetimibe alone is associated with muscle related events, including rhabdomyolysis. The risk of these events may therefore be increased with concomitant use of ezetimibe and atorvastatin. Appropriate clinical monitoring of these patients is recommended.
Colestipol
Plasma concentrations of atorvastatin and its active metabolites were lower (by approx. 25%) when colestipol was co-administered with Lolip. However, lipid effects were greater when Lolip and colestipol were co-administered than when either medicinal product was given alone.

Fusidic acid
Interaction studies with atorvastatin and fusidic acid have not been conducted. As with other statins, muscle related events, including rhabdomyolysis, have been reported in post-marketing experience with atorvastatin and fusidic acid given concurrently. The mechanism of this interaction is not known. Patients should be closely monitored and temporary suspension of atorvastatin treatment may be appropriate.
Effect of atorvastatin on co-administered medicinal products
Digoxin
When multiple doses of digoxin and 10 mg atorvastatin were co-administered, steady-state digoxin concentrations increased slightly. Patients taking digoxin should be monitored appropriately.
Oral contraceptives
Co-administration of Lolip with an oral contraceptive produced increases in plasma concentrations of norethindrone and ethinyl oestradiol.
Warfarin In a clinical study in patients receiving chronic warfarin therapy, coadministration of atorvastatin 80 mg daily with warfarin caused a small decrease of about 1.7 seconds in prothrombin time during the first 4 days of dosing which returned to normal within 15 days of atorvastatin treatment. Although only very rare cases of clinically significant anticoagulant interactions have been reported, prothrombin time should be determined before starting atorvastatin in patients taking coumarin anticoagulants and frequently enough during early therapy to ensure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of atorvastatin is changed or discontinued, the same procedure should be repeated. Atorvastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants.
Paediatric population
Drug- drug interaction studies have only been performed in adults. The extent of interactions in the paediatric population is not known.
Fertility, pregnancy and lactation
Women of childbearing potential
Women of childbearing potential should use appropriate contraceptive measures during treatment.

Pregnancy
Lipitor is contraindicated during pregnancy . Safety in pregnant women has not been established. No controlled clinical trials with atorvastatin have been conducted in
pregnant women. Rare reports of congenital anomalies following intrauterine exposure to HMGCoA reductase inhibitors have been received. Animal studies have shown toxicity to reproduction. Maternal treatment with atorvastatin may reduce the fetal levels of mevalonate which is a precursor of cholesterol biosynthesis. Atherosclerosis is a chronic process, and ordinarily discontinuation of lipid lowering medicinal products during pregnancy should have little impact on the longterm risk associated with primary hypercholesterolaemia. For these reasons, Lipitor should not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant. Treatment with Lipitor should be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant.
Breast feeding
It is not known whether atorvastatin or its metabolites are excreted in human milk. In rats, plasma concentrations of atorvastatin and its active metabolites are similar to those in milk. Because of the potential for serious adverse reactions, women taking Lipitor should not breastfeed their infants. Atorvastatin is contraindicated during breastfeeding.
Fertility In animal studies atorvastatin had no effect on male or female fertility.
Effects on ability to drive and use machines
Lipitor has negligible influence on the ability to drive and use machines.

SPECIAL WARNINGS AND PRECAUTIONS FOR USE:
Liver effects
Liver function tests should be performed before the initiation of treatment and periodically thereafter. Patients who develop any signs or symptoms suggestive of liver injury should have liver function tests performed. Patients who develop increased transaminase levels should be monitored until the abnormalities resolve. Should an increase in transaminases of greater than 3 times the upper limit of normal (ULN) persist, reduction of dose or withdrawal of Lolip is recommended.
Lolip should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease.
Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL)
In a post-hoc analysis of stroke subtypes in patients without coronary heart disease (CHD) who had a recent stroke or transient ischemic attack (TIA) there was a higher incidence of hemorrhagic stroke in patients initiated on atorvastatin 80 mg compared to placebo. The increased risk was particularly noted in patients with prior hemorrhagic stroke or lacunar infarct at study entry. For patients with prior hemorrhagic stroke or lacunar infarct, the balance of risks and benefits of atorvastatin 80 mg is uncertain, and the potential risk of hemorrhagic stroke should be carefully considered before initiating treatment.
Skeletal muscle effects
Atorvastatin, like other HMG-CoA reductase inhibitors, may in rare occasions affect the skeletal muscle and cause myalgia, myositis, and myopathy that may progress to rhabdomyolysis, a potentially life- threatening condition characterised by markedly elevated creatine kinase (CK) levels (> 10 times ULN), myoglobinaemia and myoglobinuria which may lead to renal failure.
Before the treatment Atorvastatin should be prescribed with caution in patients with pre-disposing factors for rhabdomyolysis. A CK level should be measured before starting statin treatment in the following situations:
• Renal impairment
• Hypothyroidism
• Personal or familial history of hereditary muscular disorders
• Previous history of muscular toxicity with a statin or fibrate
• Previous history of liver disease and/or where substantial quantities of alcohol are consumed
• In elderly (age > 70 years), the necessity of such measurement should be considered, according to the presence of other predisposing factors for Rhabdomyolysis
• Situations where an increase in plasma levels may occur, such as interactions and special populations including genetic subpopulations.
• In such situations, the risk of treatment should be considered in relation to possible benefit, and clinical monitoring is recommended.
• If CK levels are significantly elevated (> 5 times ULN) at baseline, treatment should not be started.
Creatine kinase measurement
Creatine kinase (CK) should not be measured following strenuous exercise or in the presence of any plausible alternative cause of CK increase as this makes value interpretation difficult. If CK levels are significantly elevated at baseline (> 5 times ULN), levels should be remeasured within 5 to 7 days later to confirm the results.
Concomitant treatment with other medicinal products Risk of rhabdomyolysis is increased when atorvastatin is administered concomitantly with certain medicinal products that may increase the plasma concentration of atorvastatin such as potent inhibitors of CYP3A4 or transport proteins (e.g. ciclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole and HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir, etc). The risk of myopathy may also be increased with the concomitant use of gemfibrozil and other fibric acid derivates, erythromycin, niacin and ezetimibe. If possible, alternative (non-interacting) therapies should be considered instead of these medicinal products.
In cases where co-administration of these medicinal products with atorvastatin is necessary, the benefit and the risk of concurrent treatment should be carefully considered. When patients are receiving medicinal products that increase the plasma concentration of atorvastatin, a lower maximum dose of atorvastatin is recommended. In addition, in the case of potent CYP3A4 inhibitors, a lower starting dose of atorvastatin should be considered and appropriate clinical monitoring of these patients is recommended.
The concurrent use of atorvastatin and fusidic acid is not recommended, therefore, temporary suspension of atorvastatin may be considered during fusidic acid therapy.
Paediatric use
Developmental safety in the paediatric population has not been established.
Interstitial lung disease
Exceptional cases of interstitial lung disease have been reported with some statins, especially with long term therapy. Presenting features can include dyspnoea, non-productive cough and deterioration in general health (fatigue, weight loss and fever). If it is suspected a patient has developed interstitial lung disease, statin therapy should be discontinued.
Diabetes Mellitus
Some evidence suggests that statins as a class raise blood glucose and in some patients, at high risk of future diabetes, may produce a level of hyperglycaemia where formal diabetes care is appropriate. This risk, however, is outweighed by the reduction in vascular risk with statins and therefore should not be a reason for stopping statin treatment. Patients at risk (fasting glucose 5.6 to 6.9 mmol/L, BMI>30kg/m2, raised triglycerides, hypertension) should be monitored both clinically and biochemically according to national guidelines.
Excipients
Lipitor contains lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactose deficiency or glucosegalactose malabsorption should not take this medicine.
Fertility, pregnancy and lactation
Women of childbearing potential
Women of childbearing potential should use appropriate contraceptive measures during treatment.

Pregnancy
Lipitor is contraindicated during pregnancy . Safety in pregnant women has not been established. No controlled clinical trials with atorvastatin have been conducted in
pregnant women. Rare reports of congenital anomalies following intrauterine exposure to HMGCoA reductase inhibitors have been received. Animal studies have shown toxicity to reproduction. Maternal treatment with atorvastatin may reduce the fetal levels of mevalonate which is a precursor of cholesterol biosynthesis. Atherosclerosis is a chronic process, and ordinarily discontinuation of lipid lowering medicinal products during pregnancy should have little impact on the longterm risk associated with primary hypercholesterolaemia. For these reasons, Lipitor should not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant. Treatment with Lipitor should be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant.
Breast feeding
It is not known whether atorvastatin or its metabolites are excreted in human milk. In rats, plasma concentrations of atorvastatin and its active metabolites are similar to those in milk. Because of the potential for serious adverse reactions, women taking Lipitor should not breastfeed their infants. Atorvastatin is contraindicated during breastfeeding.

OVERDOSAGE:
Specific treatment is not available for Lolip overdose. Should an overdose occur, the patient should be treated symptomatically and supportive measures instituted, as required. Liver function tests should be performed and serum CK levels should be monitored. Due to extensive atorvastatin binding to plasma proteins, haemodialysis is not expected to significantly enhance atorvastatin clearance.
CONTRAINDICATIONS:
Lolip is contraindicated in patients:
• With hypersensitivity to the active substance or to any of the excipients of this medicinal product
• With active liver disease or unexplained persistent elevations of serum transaminases exceeding 3 times the upper limit of normal
• During pregnancy, while breast-feeding and in women of child-bearing potential not using appropriate contraceptive measures.

Pharmacodynamics:
Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme responsible for the conversion of 3-hydroxy-3-methyl-glutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. Triglycerides and cholesterol in the liver are incorporated into very low-density lipoproteins (VLDL) and released into the plasma for delivery to peripheral tissues. Low-density lipoprotein (LDL) is formed from VLDL and is catabolized primarily through the receptor with high affinity to LDL (LDL receptor).
Atorvastatin lowers plasma cholesterol and lipoprotein serum concentrations by inhibiting HMG-CoA reductase and subsequently cholesterol biosynthesis in the liver and increases the number of hepatic LDL receptors on the cell surface for enhanced uptake and catabolism of LDL.
Atorvastatin reduces LDL production and the number of LDL particles. Atorvastatin produces a profound and sustained increase in LDL receptor activity coupled with a beneficial change in the quality of circulating LDL particles. Atorvastatin is effective in reducing LDL-C in patients with homozygous familial hypercholesterolaemia, a population that has not usually responded to lipid-lowering medicinal products.
Reductions in total-C, LDL-C, and apolipoprotein B have been proven to reduce risk for cardiovascular events and cardiovascular mortality.

Pharmacokinetics:
Absorption:
Atorvastatin is rapidly absorbed after oral administration; maximum plasma concentrations (Cmax) occur within 1 to 2 hours. Extent of absorption increases in proportion to atorvastatin dose. After oral administration, atorvastatin film-coated tablets are 95% to 99% bioavailable compared to the oral solution. The absolute bioavailability of atorvastatin is
approximately 12% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability is attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism.
Distribution:
Mean volume of distribution of atorvastatin is approximately 381 l. Atorvastatin is 98% bound to plasma proteins.
Biotransformation:
Atorvastatin is metabolized by cytochrome P450 3A4 to ortho- and parahydroxylated derivatives and various beta-oxidation products. Apart from other pathways these products are further metabolized via glucuronidation. In vitro, inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of atorvastatin. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites.
Elimination:
Atorvastatin is eliminated primarily in bile following hepatic and/or extrahepatic metabolism. However, atorvastatin does not appear to undergo significant enterohepatic recirculation. Mean plasma elimination half-life of atorvastatin in humans is approximately 14 hours. The half-life of inhibitory activity for HMG-CoA reductase is approximately 20 to 30 hours due to the contribution of active metabolites.

STORAGE CONDITION:
Store below 30°C.
SHELF-LIFE:
2 years
DOSAGE FORM AND PACKING AVAILABLE:
Alu-Alu blister of 14 tablets and 2 or 10 blisters are packed in a carton along with pack insert.
NAME AND ADDRESS OF MANUFACTURER:
Kusum Healthcare Pvt. Ltd.
SP 289 (A), RIICO, Indl. Area,
Chopanki, Bhiwadi (Rajasthan), India
DATE OF REVISION OF PACKAGE INSERT
Not Applicable