Atchol 40

Atchol 40 is approved for use in the following clinical indications

Heterozygous familial hypercholesterolemia: To reduce elevated total cholesterol (Total-C), LDL cholesterol (LDL-C), Apo lipoprotein B (Apo B), and triglyceride levels, and to increase HDL cholesterol in patients with primary hypercholesterolemia.

Heterozygous familial hypercholesterolemia (pediatrics): To reduce Total-C, LDL-C, and apo B levels in pediatric patients 10 to 17 years of age with heterozygous familial hypercholesterolemia with LDL-C ≥190 mg/dl, LDL-C ≥160 mg/dl with a positive family history of premature cardiovascular disease (CVD), or LDL-C ≥160 mg/dl with two or more other CVD risk factors.

Homozygous familial hypercholesterolemia: To reduce Total-C and LDL-C in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable.

Prevention of atherosclerotic cardiovascular disease:

Primary Prevention of atherosclerotic cardiovascular disease (ASCVD): To reduce the risk of myocardial infarction (MI), stroke, revascularization procedures, and angina in adult patients without a history of coronary heart disease (CHD) but who have multiple CHD risk factors.

• Although not approved, there have been certain off label use documented for Atchol 40 which include: -

Transplantation, post heart; Transplantation, post kidney.

Atchol 40 contains 40 mg of Atorvastatin and is available in the form of Oral Tablet.

Dosage Adjustment in Kidney Patient

• Altered kidney function: Mild to severe impairment: No dosage adjustment necessary.

• Hemodialysis, intermittent (thrice weekly): Poorly dialyzed: No supplemental dose or dosage adjustment necessary.

• Peritoneal dialysis: No dosage adjustment is necessary.

• CRRT: No dosage adjustment necessary.

• PIRRT (e.g., sustained, low-efficiency diafiltration): No dosage adjustment necessary (Ref).

Dosage Adjustment in Hepatic Impairment Patient

Contraindicated in active liver disease or in patients with unexplained persistent elevations of serum transaminases.

Dosage Adjustment for Pediatric Patients: -

Heterozygous familial and nonfamilial hypercholesterolemia:

• Note: Begin treatment if, after adequate trial (6 to 12 months) of intensive lifestyle modification emphasizing body weight normalization and diet, the following are present
• LDL-C ≥190 mg/dl.

• LDL-C remains ≥160 mg/dl and 2 or more cardiovascular risk factors: family history of premature atherosclerotic cardiovascular disease (<55 years of age); overweight; obesity; or other elements of insulin resistance syndrome.

• LDL-C ≥130 mg/dl and diabetes mellitus.

• Children 6 to <10 years of age (Tanner stage I): Limited data available: Oral: Initial: 40 mg once daily; if target LDL-C not achieved after 4 weeks, may increase incrementally by doubling dose (10 mg/day, 20 mg/day) at monthly intervals until target LDL-C; usual maximum daily dose: 40 mg/day; however, in some cases doses up to 80 mg/day have been used; dosing based on a long-term trial (3 years) of 272 patients (age range: 6 to 15 years); doses of 80 mg/day were used in 12 patients <10 years of age; over the 3 year study duration, similar efficacy was observed without growth or maturation impairment.

• Children and Adolescents 10 to 17 years: Oral: Initial: 40 mg once daily; if target LDL-C not achieved after 4 weeks, may increase incrementally by doubling dose (20 mg/day, 40 mg/day) at monthly intervals until target LDL-C up to a maximum daily dose: 80 mg/day.

Hyperlipidemia

• Children and Adolescents 10 to 17 years (males and postmenarchal females): Oral: Initial: 20 mg once daily; if LDL-C target not achieved after 1 to 3 months, may increase to meet target LDL-C; in pediatric patients with heterozygous familial hypercholesterolemia, a maximum titrated dose based upon LDL response: 80 mg/day was used

Transplantation post-heart; Prevention of cardiac allograft vasculopathy (CAV):

• Note: Initiate following heart transplantation regardless of baseline cholesterol levels in children and adolescents with high risk for rejection and CAV (eg, re-transplantation, elevated panel reactive antibodies). Significant drug interactions between statins and immunosuppressant drugs are frequent; many interactions can increase statin serum concentrations and risk of toxicity (eg, myopathy).

• Children and Adolescents: Oral: 0.2 mg/kg/day rounded to nearest 2.5 mg increment; maximum daily dose: 40 mg/day.

Atchol 40 should be used in the treatment of (approved indications) along with appropriate dietary restrictions.

Hypercholesterolemia:

• Before initiation of therapy, patients should be placed on a standard cholesterol lowering diet for 3 to 6 months and the diet should be continued during drug therapy. Atorvastatin serum concentration may be increased when taken with grapefruit juice; avoid concurrent intake of large quantities (>1.2 liters/day).

• Red yeast rice contains variable amounts of several compounds that are structurally similar to HMG-CoA reductase inhibitors, primarily monacolin K (or mevinolin) which is structurally identical to lovastatin; concurrent use of red yeast rice with HMG-CoA reductase inhibitors may increase the incidence of adverse and toxic effects.

The dietary restriction should be individualized as per patient requirements.

Atchol 40 contains Atorvastatin should be used with certain warnings and precautions. The treating physician must closely monitor the patient and keep pharmacovigilance as follows

HDL Cholesterol

A paradoxical, severe, and reversible decrease in HDL-C (as low as 2 mg/dl) with a simultaneous decrease in apolipoprotein A1 has been reported within 2 weeks to years after initiation of fibrate therapy; clinical significance unknown.

● Venous thromboembolism

Use has been associated with pulmonary embolism and deep vein thrombosis. Use with caution in patients with risk factors for venous thromboembolism.

● Serum Creatinine

Elevations in serum creatinine have been reported in patients on Atchol 40. These elevations tend to return to baseline following discontinuation of Atorvastatin. The clinical significance of these observations is unknown. Monitor renal function in patients with renal impairment taking Atorvastatin. Renal monitoring should also be considered for patients taking Atorvastatin and are at risk for renal insufficiency, such as the elderly and patients with diabetes.

● Cholelithiasis

Atorvastatin, like clofibrate and gemfibrozil, may increase cholesterol excretion into the bile, leading to cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated. Atchol 40 therapy should be discontinued if gallstones are found.

● Coumarin Anticoagulants

Caution should be exercised when Atorvastatin is given in conjunction with coumarin anticoagulants. Atorvastatin may potentiate the anticoagulant effects of these agents resulting in prolongation of the Prothrombin Time/International Normalized Ratio (PT/INR). To prevent bleeding complications, frequent monitoring of PT/INR and dose adjustment of the anticoagulant are recommended until PT/INR has stabilized.

● Pancreatitis

Pancreatitis has been reported in patients taking Atorvastatin, gemfibrozil, and clofibrate. This occurrence may represent a failure of efficacy in patients with severe hypertriglyceridemia, a direct drug effect, or a secondary phenomenon mediated through biliary tract stone or sludge formation with obstruction of the common bile duct.

● Hematologic Changes

Mild to moderate decreases in hemoglobin, hematocrit, and white blood cell decreases have been observed in patients following initiation of Atorvastatin therapy. However, these levels stabilize during long term administration. Thrombocytopenia and agranulocytosis have been reported in individuals treated with Atorvastatin. Periodic monitoring of red and white blood cell counts is recommended during the first 12 months of Atorvastatin administration.

● Hypersensitivity Reactions

Acute hypersensitivity reactions including severe skin rashes such as Steven-Johnson syndrome and toxic epidermal necrolysis requiring patient hospitalization and treatment with steroids have been reported in individuals treated with Atorvastatin. Urticaria was seen in 1.1 vs. 0% and rash in 1.4 vs. 0.8% of Atorvastatin and placebo patients respectively in controlled trials.

The adverse reactions related to Atchol 40 can be categorized as

• Common Adverse effects

Myopathy, myalgia, diabetes mellitus, persistent serum transaminase elevations. Rarely, immune-mediated necrotising myopathy (IMNM), interstitial lung disease, Myopathy, myalgia, diabetes mellitus, persistent serum transaminase elevations. Rarely, immune-mediated necrotising myopathy (IMNM), interstitial lung disease.

• Less Common Adverse effects:

Malaise, asthenia, fatigue, pyrexia. Hepatobiliary disorders: Cholestasis, Headache, dizziness, paresthesia, amnesia. Psychiatric disorders: Insomnia, nightmares

• Rare Adverse effects

Gynecomastia. Respiratory, thoracic and mediastinal disorders: Nasopharyngitis, pharyngolaryngeal pain. Skin and subcutaneous tissue disorders: Alopecia, skin rash, pruritus, urticaria. Vascular disorders: Epistaxis.

The common side effects of Atchol 40 which contain 40 gm of salt Atorvastatin include the following

Common

● Constipation, diarrhea, Heartburn, pain in the back, arm, or legs, Headache, joint pain.

Geriatric Use

Atchol 40 is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Atchol 40 exposure is not influenced by age. Since elderly patients have a higher incidence of renal impairment, dose selection for the elderly should be made based on renal function. Elderly patients with normal renal function should require no dose modifications. Consider monitoring renal function in elderly patients taking Atorvastatin.

Atchol 40 contains Atorvastatin.

Pharmacodynamics

Atorvastatin, as well as some of its metabolites, are pharmacologically active in humans. The liver is the primary site of action and the Principal site of cholesterol synthesis and LDL clearance. Drug dosage, rather than systemic drug concentration, correlates better with LDL-C reduction. Individualization of drug dosage should be based on therapeutic response

Pharmacokinetics

• Absorption

Atorvastatin is rapidly absorbed after oral administration; maximum plasma concentrations occur within 1 to 2 hours. Extent of absorption increases in proportion to Atorvastatin dose. The absolute bioavailability of Atorvastatin (parent drug) is approximately 14% 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. Although food decreases the rate and extent of drug absorption by approximately 25% and 9%, respectively, as assessed by Cmax and AUC, LDL-c reduction is similar whether Atorvastatin is given with or without food. Plasma Atorvastatin concentrations are lower (approximately 30% for Cmax and AUC) following evening drug administration compared with morning. However, LDL-c reduction is the same regardless of the time of day of drug administration

• Distribution

Mean Volume of distribution of Atorvastatin is approximately 381 liters. Atorvastatin is ≥98% bound to plasma proteins. A blood/plasma ratio of approximately 0.25 indicates poor drug penetration into red blood cells. Based on observations in rats, Atorvastatin is likely to be secreted in human milk

• Metabolism

Atorvastatin is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products. 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. In vitro studies suggest the importance of Atorvastatin metabolism by cytochrome p450 3a4, consistent with increased plasma concentrations of Atorvastatin in humans following co-administration with erythromycin, a known inhibitor of this isozyme. In animals, the ortho-hydroxy metabolite undergoes further glucuronidation.

• Excretion

Atchol 40 and its metabolites are eliminated primarily in bile following hepatic and/or extra-hepatic metabolism; however, the drug does not appear to undergo enterohepatic recirculation. Mean plasma elimination half-life of Atchol 40 in humans is approximately 14 hours, but the half-life of inhibitory activity for HMG-CoA reductase is 20 to 30 hours due to the contribution of active metabolites. Less than 2% of a dose of Atchol 40 is recovered in urine following oral administration.