Rozavel 40

Rozavel 40 contains 40 mg of the statin called Rosuvastatin is approved for use in the following clinical indications-

Adult indication

• Heterozygous familial hypercholesterolemia
• Homozygous familial hypercholesterolemia
• Prevention of atherosclerotic cardiovascular disease
• Transplantation

Pediatric indication

• Heterozygous familial hypercholesterolemia
• Homozygous familial hypercholesterolemia

Adult Dose

• Heterozygous familial hypercholesterolemia

High-intensity therapy: Oral: Initial: recommended start dose is 5 or 10 mg orally once daily. If well-tolerated increase the dose to 20 or 40mg

Homozygous familial hypercholesterolemia

High-intensity therapy: Oral: 40 mg once daily.

• Prevention of atherosclerotic cardiovascular disease
• Primary prevention:

Patients without diabetes, 40 to 75 years of age, and with LDL-C 70 to 189 mg/dL:

ASCVD 10-year risk 5% to <7.5%:

Moderate-intensity therapy: Oral: 5 to 10 mg once daily to reduce LDL-C by 30% to 49%.

ASCVD 10-year risk ≥7.5% to <20%:

Moderate-intensity therapy: Oral: 5 to 10 mg once daily to reduce LDL-C by 30% to 49%; higher risk patients with multiple risk-enhancing factors may benefit from higher doses to reduce LDL-C by ≥50%.

ASCVD 10-year risk ≥20%:

High-intensity therapy: Oral: 20 to 40 mg once daily to reduce LDL-C by ≥50%; if unable to tolerate due to adverse effects, may reduce dose to maximum tolerated.

• Patients with diabetes:

40-75 years of age without additional ASCVD risk factors:

Moderate-intensity therapy: Oral: 5 to 10 mg once daily to reduce LDL-C by 30% to 49%.

ASCVD risk ≥20% or multiple ASCVD risk factors:

High-intensity therapy: Oral: 20 to 40 mg once daily to reduce LDL-C by ≥50%; if unable to tolerate due to adverse effects, may reduce dose to maximum tolerated.

Patients with LDL-C ≥190 mg/dL and 20 to 75 years of age:

High-intensity therapy: Oral: 20 to 40 mg once daily to reduce LDL-C by ≥50%; if unable to tolerate due to adverse effects, may reduce dose to maximum tolerated.

Secondary prevention in patients with established ASCVD (eg, coronary heart disease, cerebrovascular disease [ischemic stroke or transient ischemic attack], peripheral arterial disease)

High-intensity therapy: Oral: 20 to 40 mg once daily to reduce LDL-C by ≥50%; if unable to tolerate due to adverse effects, may reduce dose to maximum tolerated

• Transplantation

Transplantation, post heart (off-label use)

Oral: Initial: 5 mg once daily starting 1 to 2 weeks after transplant, regardless of baseline cholesterol levels; increase dose based on response, tolerability, and use of concomitant medications up to 20 to 40 mg once daily.

Transplantation, post kidney (off-label use)

Oral: Initial: 5 mg once daily; increase dose based on response, tolerability, and use of concomitant medications up to 10 mg once daily.

Pediatric Dose

• Heterozygous familial hypercholesterolemia

Children 8 to <10 years (females >1year postmenarche):

Oral: 5 to 10 mg once daily; maximum daily dose: 10 mg/day.

Children ≥10 years and Adolescents (females >1year postmenarche):

Oral: 5 to 20 mg once daily; maximum daily dose: 20 mg/day.

• Homozygous familial hypercholesterolemia

Children ≥7 years and Adolescents: Oral:

Initial dose: 20 mg once daily. Maximum daily dose in adults is 40 mg/day. Although higher doses have been used (ie, 80 mg/day), additional benefit has not been reported.

Rozavel 40 contains 40 mg of the statin called Rosuvastatin is available in the form of Oral Tablets and Oral Capsule.

• Dosage Adjustment in Kidney Patient

CrCl ≥30 mL/minute/1.73 m²: No dosage adjustment necessary.

CrCl <30 mL/minute/1.73 m²: 5 to 10 mg once daily.

• Dosage Adjustment in Hepatic impairment Patient

There are no specific dosage adjustments provided.

Rozavel 40 contains 40 mg of the statin called Rosuvastatin and is contraindicated in patients with-

• Patients with a known hypersensitivity to any component of this product. Hypersensitivity reactions including rash, pruritus, urticaria, and angioedema have been reported with Rosuvastatin.
• Patients with active liver disease may include unexplained persistent elevations of hepatic transaminase levels.
• Pregnancy.
• Lactation. Limited data indicate that Rozavel 40 is present in human milk. Because statins have the potential for serious adverse reactions in nursing infants, women who require Rozavel 40 treatment should not breastfeed their infants.

• Diabetes mellitus

Small increases in HbA_1c (mean: ~0.1%) and fasting blood glucose have been reported with rosuvastatin; however, the benefits of statin therapy far outweigh the risk of dysglycemia.

• Skeletal Muscle Effects

Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with HMG-CoA reductase inhibitors, including Rosuvastatin. These risks can occur at any dose level but are increased at the highest dose (40 mg). Rozavel 40 should be prescribed with caution in patients with predisposing factors for myopathy (e.g., age ≥65 years, inadequately treated hypothyroidism, renal impairment). The risk of myopathy during treatment with Rozavel 40 may be increased with concurrent administration of some other lipid-lowering therapies (fibrates or niacin), gemfibrozil, cyclosporine, atazanavir/ritonavir, lopinavir/ritonavir, or simeprevir. Cases of myopathy, including rhabdomyolysis, have been reported with HMG-CoA reductase inhibitors, including rosuvastatin, coadministered with colchicine, and caution should be exercised when prescribing Rozavel 40 with colchicines. Rozavel 40 therapy should be discontinued if markedly elevated creatine kinase (CK-enzyme) levels occur, or myopathy is diagnosed or suspected.

• Hematuria/proteinuria

Hematuria (microscopic) and proteinuria have been observed; more commonly reported in adults receiving Rosuvastatin 40 mg daily. Typically, transient and not associated with a decrease in renal function. Consider dosage reduction if unexplained hematuria and proteinuria persist.

• Myasthenia gravis

May rarely worsen or precipitate myasthenia gravis (MG); monitor for worsening MG if treatment is initiated.

• Proteinuria And Hematuria

In the Rozavel 40 clinical trial program, dipstick-positive proteinuria and microscopic hematuria were observed among Rosuvastatin-treated patients. These findings were more frequent in patients taking Rosuvastatin 40 mg or comparator HMG-CoA reductase inhibitors, though it was generally transient and was not associated with worsening renal function. Although the clinical significance of this finding is unknown, a dose reduction should be considered for patients on Rozavel 40 therapy with unexplained persistent proteinuria and/or hematuria during routine urinalysis testing.

• Concomitant Coumarin Anticoagulants

Caution should be exercised when anticoagulants are given in conjunction with Rozavel 40 because of its potentiation of the effect of coumarin-type anticoagulants in prolonging the prothrombin time/INR. In patients taking coumarin anticoagulants and Rozavel 40 concomitantly, INR should be determined before starting Rozavel 40 and frequently enough during early therapy to ensure that no significant alteration of INR occurs.

Common Adverse effects

• Myalgia, diabetes mellitus, constipation, nausea, cystitis, increased serum alanine aminotransferase, increased serum transaminases (including increased serum alkaline phosphatase, increased serum bilirubin), dizziness, headache, arthralgia, asthenia, increased creatine phosphokinase in blood specimen, Abnormal thyroid function test, increased gamma-glutamyl transferase, increased serum glucose, Abdominal pain, Hematuria, proteinuria, Elevated glycosylated hemoglobin (HbA_1c), Hypersensitivity reaction.

Rare Adverse effects

• Gynecomastia, Pancreatitis, Thrombocytopenia, Autoimmune hepatitis, hepatic failure, hepatitis, jaundice, Angioedema, Drug reaction with eosinophilia and systemic symptoms, immune-mediated necrotizing myopathy, Cognitive dysfunction (reversible; includes amnesia, confusion, memory impairment), depression, peripheral neuropathy, sleep disorder (including insomnia, nightmares), Myoglobinuria, myopathy, myositis, rhabdomyolysis, Renal failure syndrome, Interstitial pulmonary disease.

• Cyclosporine

Cyclosporine increased Rozavel 40 exposure and may result in an increased risk of myopathy. Therefore, in patients taking cyclosporine, the dose of Rozavel 40 should not exceed 5 mg once daily.

• Gemfibrozil

Gemfibrozil significantly increased Rozavel 40 exposure. Due to an observed increased risk of myopathy/rhabdomyolysis, combination therapy with Rozavel 40 and gemfibrozil should be avoided. If used together, the dose of Rozavel 40 should not exceed 10 mg once daily.

• Protease Inhibitors

Coadministration of Rozavel 40 with certain protease inhibitors has differing effects on Rozavel 40 exposure and may increase the risk of myopathy. Simeprevir, which is a hepatitis C virus (HCV) protease inhibitor, or combinations of atazanavir/ritonavir or lopinavir/ritonavir, which are HIV-1 protease inhibitors, increase Rozavel 40 exposure. For these protease inhibitors, the dose of Rozavel 40 should not exceed 10 mg once daily. The combinations of fosamprenavir/ritonavir or tipranavir/ritonavir, which are HIV-1 protease inhibitors, produce little or no change in Rozavel 40 exposure. Caution should be exercised when Rozavel 40 is coadministered with protease inhibitors.

• Coumarin Anticoagulants

Rozavel 40 significantly increased INR in patients receiving coumarin anticoagulants. Therefore, caution should be exercised when coumarin anticoagulants are given in conjunction with Rosuvastatin. In patients taking coumarin anticoagulants and Rozavel 40 concomitantly, INR should be determined before starting Rozavel 40 and frequently enough during early therapy to ensure that no significant alteration of INR occurs.

• Niacin

The risk of skeletal muscle effects may be enhanced when Rozavel 40 is used in combination with lipid-modifying doses (≥1 g/day) of niacin; caution should be used when prescribing with Rosuvastatin.

• Fenofibrate

When Rozavel 40 was coadministered with fenofibrate, no clinically significant increase in the AUC of Rozavel 40 or fenofibrate was observed. Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concomitant use of fenofibrates, caution should be used when prescribing fenofibrates with Rosuvastatin.

• Colchicine

Cases of myopathy, including rhabdomyolysis, have been reported with HMG-CoA reductase inhibitors, including rosuvastatin, coadministered with colchicine, and caution should be exercised when prescribing Rozavel 40 with colchicine.

The common side effects of Rozavel 40 which contains 40 mg of a statin called Rosuvastatin include the following-

Common

● Constipation, stomach pain, Dizziness, difficulty falling asleep or staying asleep, Depression, joint pain, Headache, memory loss or forgetfulness, confusion.

Rare

● Muscle pain, tenderness, or weakness (or if these symptoms continue after stopping rosuvastatin), lack of energy, fever, chest pain, dark, reddish urine; decreased amount of urine; weakness; and muscle aches, yellowing of the skin or eyes, dark colored urine, pain in the upper right part of the abdomen, nausea, extreme tiredness, weakness, unusual bleeding or bruising, loss of appetite, flu-like symptoms, rash, hives, itching, difficulty breathing or swallowing, swelling of the face, throat, tongue, lips, eyes, hands, feet, ankles, or lower legs, hoarseness.

• Pregnancy

Pregnancy Category X

Teratogenic effects: Rozavel 40 is contraindicated in women who are or may become pregnant. Serum cholesterol and triglycerides increase during normal pregnancy and cholesterol products are essential for fetal development. Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during pregnancy should have little impact on the long-term outcomes of primary hyperlipidemia therapy. There are no adequate and well-controlled studies of Rozavel 40 in pregnant women. There have been rare reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase inhibitors. In a review of about 100 prospectively followed pregnancies in women exposed to other HMG-CoA reductase inhibitors, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed the rate expected in the general population. However, this study was only able to exclude a three-to-fourfold increased risk of congenital anomalies over background incidence. In 89% of these cases, drug treatment started before pregnancy and stopped during the first trimester when pregnancy was identified. Rozavel 40 crosses the placenta in rats and rabbits. In rats, Rozavel 40 was not teratogenic at systemic exposures equivalent to a human therapeutic dose of 40 mg/day. At 10-12 times the human dose of 40 mg/day, there was decreased pup survival, decreased fetal body weight among female pups, and delayed ossification. In rabbits, pup viability decreased, and maternal mortality increased at doses equivalent to the human dose of 40 mg/day. Rozavel 40 may cause fetal harm when administered to a pregnant woman. If the patient becomes pregnant while taking Rosuvastatin, the patient should be apprised of the potential risks to the fetus and the lack of known clinical benefits with continued use during pregnancy.

• Nursing Mothers

It is not known whether Rozavel 40 is excreted in human milk, but a small amount of another drug in this class does pass into breast milk. In rats, breast milk concentrations of Rozavel 40 are three times higher than plasma levels; however, animal breast milk drug levels may not accurately reflect human breast milk levels. Because another drug in this class passes into human milk and because HMG-CoA reductase inhibitors have the potential to cause serious adverse reactions in nursing infants, women who require Rozavel 40 treatment should be advised not to nurse their infants.

• Pediatric Use

The safety and effectiveness of Rozavel 40 in patients 10 to 17 years of age with heterozygous familial hypercholesterolemia were evaluated in a controlled clinical trial of 12 weeks duration followed by 40 weeks of open-label exposure. Patients treated with 5 mg, 10 mg, and 20 mg daily Rozavel 40 had an adverse experience profile generally similar to that of patients treated with a placebo. Although not all adverse reactions identified in the adult population have been observed in clinical trials of children and adolescent patients, the same warnings and precautions for adults should be considered for children and adolescents. There was no detectable effect of Rozavel 40 on growth, weight, BMI (body mass index), or sexual maturation in pediatric patients (10 to 17 years of age). Adolescent females should be counseled on appropriate contraceptive methods while on Rozavel 10therapy. Rozavel 40 has not been studied in controlled clinical trials involving prepubertal patients or patients younger than 10 years of age. Doses of Rozavel 40 greater than 20 mg have not been studied in the pediatric population. In children and adolescents with homozygous familial hypercholesterolemia, experience is limited to eight patients (aged 8 years and above). In a pharmacokinetic study, 18 patients (9 boys and 9 girls) 10 to 17 years of age with heterozygous FH received single and multiple oral doses of Rosuvastatin. Both Cmax and AUC of Rozavel 40 were like values observed in adult subjects administered the same doses.

• Geriatric Use

Of the 10,275 patients in clinical studies with Rosuvastatin, 3159 (31%) were 65 years and older, and 698 (6.8%) were 75 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Elderly patients are at higher risk of myopathy and Rozavel 40 should be prescribed with caution in the elderly.

Pharmacodynamic

Rozavel 40 dose-dependently reduces elevated LDL cholesterol and reduces total cholesterol and triglycerides and increases HDL cholesterol. A therapeutic response to Rozavel 40 is evident within 1 week of commencing therapy and 90% of the maximum response is usually achieved in 2 weeks. The maximum response is usually achieved within 4 weeks and is maintained after that. Individualization of drug dosage should be based on the therapeutic response.

Pharmacokinetics

• Absorption

In clinical pharmacology studies in men, peak plasma concentrations of Rozavel 40 were reached 3 to 5 hours following oral dosing. Both Cmax and AUC increased in approximate proportion to the Rozavel 40 dose. The absolute bioavailability of Rozavel 10is approximately 20%. Administration of Rozavel 40 with food did not affect the AUC of rosuvastatin. The AUC of Rozavel 40 does not differ following evening or morning drug administration.

• Distribution

The mean volume of distribution at the steady state of Rozavel 40 is approximately 134 liters. Rozavel 40 is 88% bound to plasma proteins, mostly albumin. This binding is reversible and independent of plasma concentrations.

• Metabolism

Rozavel 40 is not extensively metabolized; approximately 10% of a radiolabeled dose is recovered as a metabolite. The major metabolite is N-desmethyl rosuvastatin, which is formed principally by cytochrome P450 2C9, and in vitro studies have demonstrated that N-desmethyl Rozavel 10has approximately one-sixth to one-half the HMG-CoA reductase inhibitory activity of the parent compound. Overall, greater than 90% of active plasma HMG-CoA reductase inhibitory activity is accounted for by the parent compound.

• Excretion

Following oral administration, Rozavel 40 and its metabolites are primarily excreted in the feces (90%). The elimination half-life (t1/2) of Rozavel 40 is approximately 19 hours. After an intravenous dose, approximately 28% of total body clearance was via the renal route, and 72% by the hepatic route.