Duvaztor-20/Duvaztor-40

Duvaztor-20: Lemon yellow coloured, circular, biconvex film-coated tablets having a break line mark on one side and plain on the other side.
Each film-coated tablet contains: Atorvastatin Calcium equivalent to Atorvastatin 20 mg, Excipients: q.s.
Duvaztor-40: White coloured, circular, biconvex film-coated scored tablet.
Each film-coated tablet contains: Atorvastatin Calcium equivalent to Atorvastatin 40 mg, Excipients q.s.

Pharmacotherapeutic group: Lipid modifying agents, HMG-CoA-reductase inhibitors.
Pharmacology: Pharmacodynamics: Atorvastatin (Duvaztor) 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 steroids, 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 high affinity LDL (LDL receptor).
Atorvastatin (Duvaztor) 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 (Duvaztor) reduces LDL production and the number of LDL particles. Atorvastatin (Duvaztor) produces a profound and sustained increase in LDL receptor activity coupled with a beneficial change in the quality of circulating LDL particles. Atorvastatin (Duvaztor) is effective in reducing LDL-C in patients with homozygous familial hypercholesterolaemia, a population that has not usually responded to lipid-lowering medicinal products.
Atorvastatin (Duvaztor) has been shown to reduce concentrations of total-C (30%-40%), LDL-C (41%-61%), apolipoprotein B (34%-50%), and triglycerides (14%-33%), while producing variable increases in HDL-C and apolipoprotein A1 in a dose response study. These results are consistent in patients with heterozygous familial hypercholesterolaemia, nonfamilial forms of hypercholesterolaemia, and mixed hyperlipidaemia, including patients with non-insulin-dependent diabetes mellitus.
Reductions in total-C, LDL-C, and apolipoprotein B have been proven to reduce risk for cardiovascular events and cardiovascular mortality.
Pharmacokinetics: Atorvastatin (Duvaztor) is rapidly absorbed after oral administration, maximum plasma levels occur within one to two hours. Although food reduces the rate and extent of absorption, LDL-C reduction is similar whether Atorvastatin (Duvaztor) is given with or without food. Atorvastatin (Duvaztor) is approximately 98% bound to plasma proteins. Atorvastatin is extensively metabolised and eliminated primarily in bile. The mean plasma elimination half-life of Atorvastatin in humans is approximately 14 hours, but the half life of inhibitory activity for HMG-CoA reductase is 20-30 hours.

It is used to reduce LDL-cholesterol, Apolipoprotein B, and triglycerides, and to increase HDL-cholesterol in the treatment of hyperlipidaemias, including hypercholesterolaemias and combined (mixed) hyperlipidaemia (Type IIa or IIb hyperlipoproteinaemias), hypertriglyceridaemia (Type IV), and dysbetalipoproteinaemia (Type III) and also can be effective as adjunct therapy in patients with homozygous familial hypercholesterolaemia who have some LDL-receptor function.

The usual dose is 10 mg to 20 mg of Atorvastatin once daily.
Initial dose of 40 mg daily may be used in patients who require a large reduction in LDL-cholesterol. The dose may be adjusted at intervals of 4 weeks up to a maximum of 80 mg daily.
Children and adolescents aged 10 to 17 with heterozygous familial hypercholesterolaemia may be given an initial dose of 10 mg once daily adjusted according to response to a maximum of 20 mg once daily. Or as prescribed by the physician.

Specific treatment is not available for Atorvastatin (Duvaztor) overdosage. Should an overdose occur, the patient should be treated symptomatically and supportive measures initiated, as required. Liver function tests and serum CK levels should be monitored. Due to extensive Atorvastatin (Duvaztor) binding to plasma proteins, haemodialysis is not expected to significantly enhance Atorvastatin (Duvaztor) clearance.

Atorvastatin (Duvaztor) is contraindicated in patients: With hypersensitivity to the active substance or to any of the excipients; 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; treated with the hepatitis C antivirals glecaprevir/pibrentasvir.

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 abnormality(ies) resolve. Should an increase in transaminases of greater than 3 times the upper limit of normal (ULN) persist, reduction of dose or withdrawal of Atorvastatin (Duvaztor) is recommended. Atorvastatin (Duvaztor) 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 haemorrhagic stroke in patients initiated on atorvastatin 80 mg compared to placebo. The increased risk was particularly noted in patients with prior haemorrhagic stroke or lacunar infarct at study entry. For patients with prior haemorrhagic stroke or lacunar infarct, the balance of risks and benefits of atorvastatin 80 mg is uncertain and the potential risk of haemorrhagic stroke should be carefully considered before initiating treatment.
Skeletal muscle effects: Atorvastatin (Duvaztor), 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 characterized by markedly elevated creatine kinase (CK) levels (>10 times ULN), myoglobinemia and myoglobinuria which may lead to renal failure.
Before the treatment: Atorvastatin (Duvaztor) 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.
Whilst on treatment: Patients must be asked to promptly report muscle pain, cramps, or weakness especially if accompanied by malaise or fever.
If such symptoms occur whilst a patient is receiving treatment with Atorvastatin (Duvaztor), their CK levels should be measured. If these levels are found to be significantly elevated (>5 times ULN), treatment should be stopped.
If muscular symptoms are severe and cause daily discomfort, even if the CK levels are elevated to less than 5 times ULN, treatment discontinuation should be considered.
If symptoms resolve and CK levels return to normal, then re-introduction of atorvastatin or introduction of an alternative statin may be considered at the lowest dose and with close monitoring.
Atorvastatin (Duvaztor) must be discontinued if clinically significant elevation of CK levels (>10 times ULN) occur, or if rhabdomyolysis is diagnosed or suspected.
Concomitant treatment with other medicinal products: Risk of rhabdomyolysis is increased when Atorvastatin (Duvaztor) is administered concomitantly with certain medicinal products that may increase the plasma concentration of Atorvastatin (Duvaztor) 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, tipranavir/ritonavir. The risk of myopathy may also be increased with the concomitant use of gemfibrozil and other fibric acid derivatives, antivirals for the treatment of hepatitis C (HCV) (boceprevir, telaprevir, elbasvir/grazoprevir), erythromycin, niacin or ezetimibe. If possible, alternative (non-interacting) therapies should be considered instead of these medicinal products.
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 persists despite discontinuation of statin treatment.
In cases where co-administration of these medicinal products with Atorvastatin (Duvaztor) 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 (Duvaztor) is recommended. In addition, in the case of potent CYP3A4 inhibitors, a lower starting dose of Atorvastatin (Duvaztor) should be considered and appropriate clinical monitoring of these patients is recommended.
Atorvastatin must not be co-administered with systemic formulations of fusidic acid or within 7 days of stopping fusidic acid treatment. In patients where the use of systemic fusidic acid is considered essential, statin treatment should be discontinued throughout the duration of fusidic acid treatment. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving fusidic acid and statins in combination. The patient should be advised to seek medical advice immediately if they experience any symptoms of muscle weakness, pain or tenderness.
Statin therapy may be re-introduced seven days after the last dose of fusidic acid.
In exceptional circumstances, where prolonged systemic fusidic acid is needed, e.g., for the treatment of severe infections, the need for co-administration of Atorvastatin (Duvaztor) and fusidic acid should only be considered on a case by case basis and under close medical supervision.

Pregnancy: Atorvastatin (Duvaztor) is contraindicated during pregnancy. Safety in pregnant women has not been established. No controlled clinical trials with Atorvastatin (Duvaztor) have been conducted in pregnant women. Rare reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase inhibitors have been received. Animal studies have shown toxicity to reproduction.
Maternal treatment with Atorvastatin (Duvaztor) 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 long-term risk associated with primary hypercholesterolaemia.
For these reasons, Atorvastatin (Duvaztor) should not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant. Treatment with Atorvastatin (Duvaztor) should be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant.
Lactation: It is not known whether Atorvastatin (Duvaztor) 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 atorvastatin should not breast feed their infants. Atorvastatin (Duvaztor) is contraindicated during breastfeeding.

Infections and infestations: 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, hypoaesthesia, 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, muscle rupture, tendinopathy; sometimes complicated by rupture.
Very rare: lupus-like syndrome. Not known: immune-mediated necrotizing myopathy.
Reproductive system and breast disorders: Very rare: gynecomastia.
General disorders and administration site conditions: Uncommon: malaise, asthenia, chest pain, peripheral oedema, fatigue, pyrexia.

Effect of co-administered medicinal products on atorvastatin: Atorvastatin (Duvaztor) is metabolised by cytochrome P450 3A4 (CYP3A4) and is a substrate of the hepatic transporters, organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) transporters. Metabolites of atorvastatin (Duvaztor) are substrates of OATP1B1. Atorvastatin (Duvaztor) is also identified as a substrate of the multi-drug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP), which may limit the intestinal absorption and biliary clearance of atorvastatin (Duvaztor). Concomitant administration of medicinal products that are inhibitors of CYP3A4 or transport proteins may lead to increased plasma concentrations of atorvastatin (Duvaztor) and an increased risk of myopathy. The risk might also be increased at concomitant administration of atorvastatin (Duvaztor) with other medicinal products that have a potential to induce myopathy, such as fibric acid derivatives and ezetimibe.
CYP3A4 inhibitors: Moderate CYP3A4 inhibitors (e.g. erythromycin, diltiazem, verapamil and fluconazole) may increase plasma concentrations of atorvastatin (Duvaztor). An increased risk of myopathy has been observed with the use of erythromycin in combination with statins. Interaction studies evaluating the effect of amiodarone or verapamil on atorvastatin (Duvaztor) have not been conducted. Both amiodarone and verapamil are known to inhibit CYP3A4 activity and co-administration with atorvastatin (Duvaztor) may result in increased exposure to atorvastatin (Duvaztor). 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 inhibitors.
CYP3A4 inducers: Concomitant administration of atorvastatin (Duvaztor) with inducers of cytochrome P450 3A4 (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 3A4 induction and inhibition of hepatocyte uptake transporter OATP1B1, simultaneous co-administration of atorvastatin (Duvaztor) with rifampin is recommended, as delayed administration of atorvastatin (Duvaztor) after administration of rifampin has been associated with a significant reduction in atorvastatin (Duvaztor) plasma concentrations. The effect of rifampin on atorvastatin (Duvaztor) concentrations in hepatocytes is, however, unknown and if concomitant administration cannot be avoided, patients should be carefully monitored for efficacy.
Transport inhibitors: Inhibitors of transport proteins (e.g., ciclosporin) can increase the systemic exposure of atorvastatin. The effect of inhibition of hepatic uptake transporters on atorvastatin (Duvaztor) 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 (Duvaztor). If concomitant administration cannot be avoided, the lowest dose of atorvastatin (Duvaztor) to achieve the therapeutic objective should be used and 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 (Duvaztor). Appropriate clinical monitoring of these patients is recommended.
Colestipol: Plasma concentrations of atorvastatin (Duvaztor) and its active metabolites were lower (by approx. 25%) when colestipol was co-administered with atorvastatin (Duvaztor). However, lipid effects were greater when atorvastatin (Duvaztor) and colestipol were co-administered than when either medicinal product was given alone.
Fusidic acid: The risk of myopathy including rhabdomyolysis may be increased by the concomitant administration of systemic fusidic acid with statins. The mechanism of this interaction (whether it is pharmacodynamic or pharmacokinetic, or both) is yet unknown. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving this combination.
If treatment with systemic fusidic acid is necessary, atorvastatin treatment should be discontinued throughout the duration of the fusidic acid treatment.
Colchicine: Although interaction studies with atorvastatin (Duvaztor) and colchicine have not been conducted, cases of myopathy have been reported with atorvastatin (Duvaztor) co-administered with colchicine, and caution should be exercised when prescribing atorvastatin (Duvaztor) with colchicine.

Store at temperatures not exceeding 30°C.

Dyslipidaemic Agents

C10AA05 - atorvastatin ; Belongs to the class of HMG CoA reductase inhibitors. Used in the treatment of hyperlipidemia.

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