Revostat FB

Rosuvastatin & Fenofibrate Tablets IP (10 mg + 160 mg)

Each film coated tablet contains:
Rosuvastatin Calcium IP
equivalent to Rosuvastatin ………….. 10 mg
Fenofibrate (Micronised) IP………… 160 mg
Excipients……………………………. q.s.
Colours: Ferric Oxide Yellow USP-NF & Titanium Dioxide IP
 

Film-coated tablet 10mg/160mg

4.1 Therapeutic indication

For the treatment of combined hyperlipidemia in patients with normal hepatic and renal function.

4.2 Posology and method of administration

One Revostat®FB tablet once daily or as directed by the Physician.

4.3 Contraindications

• Patients who are hypersensitivity to any component of this product.
• Patients with active liver disease or renal impairment.
• Patients with preexisting gall bladder disease.
• Pregnancy and lactation.

4.4 Special warnings and precautions for use

Liver Dysfunction

It is recommended that liver enzyme tests be performed before the initiation of REVOSTAT®FB, and if signs or symptoms of liver injury occur.
Increases in serum transaminases [AST (SGOT) or ALT (SGPT)] have been reported with HMG-CoA reductase inhibitors, including REVOSTAT®FB. In most cases, the elevations were transient and resolved or improved on continued therapy or after a brief interruption in therapy. There were two cases of jaundice, for which a relationship to rosuvastatin therapy could not be determined, which resolved after discontinuation of therapy. There were no cases of liver failure or irreversible liver disease in these trials.

In a pooled analysis of placebo-controlled trials, increases in serum transaminases to greater than 3 times the upper limit of normal occurred in 1.1% of patients taking REVOSTAT®FB versus 0.5% of patients treated with placebo. There have been rare post-marketing reports of fatal and non-fatal hepatic failure in patients taking statins, including REVOSTAT®FB. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with REVOSTAT®FB, promptly interrupt therapy. If an alternate etiology is not found, do not restart REVOSTAT®FB. 

REVOSTAT®FB should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of chronic liver disease. Active liver disease, which may include unexplained persistent transaminase elevations, is a contraindication to the use of REVOSTAT®FB.

Hepatic insufficiency

In a study in subjects with varying degrees of hepatic impairment there was no evidence of increased exposure to REVOSTAT®FB other than in the 2 subjects with the most severe liver disease (Child-Pugh scores of 8 and 9). In these subjects, systemic exposure was increased by at least 2-fold compared with subjects with lower Child-Pugh scores. Its recommended that the liver enzyme tests be performed before and after 12 weeks following both the initiation of therapy and any elevation of dose thereafter. 

Renal effects

An assessment of renal function should be considered during routine follow-up of patients treated with higher dose.

Skeletal muscle

Effects on skeletal muscle e.g. uncomplicated myalgia, myopathy and rhabdomyolysis, have been reported in patients treated with REVOSTAT®FB. Patients who develop any signs or symptoms suggestive of myopathy should have their CK levels measured. REVOSTAT®FB therapy should be discontinued if myopathy is diagnosed or suspected. 

An increase in the incidence of myositis and myopathy has been seen in patients receiving other HMG-CoA reductase inhibitors together with cyclosporin, fibric acid derivatives, including gemfibrozil, nicotinic acid, azole antifungals and macrolide antibiotics. 

REVOSTAT®FB should be prescribed with caution in patients with pre-disposing factors for myopathy, such as renal impairment, advanced age and hypothyroidism, or situations where an increase in plasma levels may occur. 

REVOSTAT®FB should be temporarily withheld in any patient with an acute serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g. sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders; or uncontrolled seizures).

4.5 Drug Interaction 

Rosuvastatin:
Cyclosporin: Rosuvastatin steady state AUC increased up (0-t) to 7-fold over that seen in healthy volunteers administered the same dose.

Gemfibrozil: Concomitant use of Rosuvastatin and gemfibrozil resulted in a 2-fold increase in Rosuvastatin C and AUC.

Protease Inhibitor: Co-administration of Rosuvastatin with certain protease inhibitors given in combination with ritonavir has different effects on roasuvastatin exposure. The protease inhibitor combinations lopinavir/ritonavir and atazanavir/ritonavir increase Rosuvastatin exposure up to threefold. For these combination the dose of Rosuvastatin is restricted to low dose.

Coumarin Anticoagulants: Rosuvastatin significantly increased INR (International Normalized Ratio) in patients receiving coumarin anticoagulants. Therefore, caution should be excercised when coumarin anticoagulants are given in conjunction with Rosuvastatin. In patients taking coumarin anticoagulants and Rosuvastatin concomitantly INR should be determined before starting Rosuvastatin and frequently enough during early therapy to ensure that no significant alteration of INR occurs.

Niacin: The skeletal muscle effects may be enhanced with Rosuvastatin in used with combination Niacin; a reduction in Rosuvastatin dosage should be considered.

Fenofibrate:
Oral Anticoagulants: Caution should be exercised when coumarin anticoagulants are given along with fenofibrate. The dosage of anticoagulant should be reduced to maintain the prothrombin time/INR.

Cyclosporine: Because cyclosporine can produce nephrotoxicity with decreases in creatinine clearance and rises in serum creatinine and because renal excretion is the primary elimination route of fibrate drugs including Fenofibrate, there is a risk that an interaction will lead to deterioration.

4.6 Use in Special Population

Age and sex: There was no clinically relevant effect on age or sex by this combination.

Race: Population pharmacokinetic analysis revealed no clinically relevant differences in pharmacokinetics among Caucasian, Hispanic and Black or Afro-Caribbean groups. However, in asian patients there is 2 fold median exposure in AUC and C of rosuvatstatin.

Renal insufficiency: The lowest possible dose should be administered in renal insufficiency (mild, moderate and severe). As the drug concentration increases more than 2-fold raise in this case.

Pregnancy and Lactation: The safety of this combination, during pregnancy and breast-feeding has not been established. Women of childbearing potential should use appropriate contraceptive measures. 

4.7 Effects on ability to drive and use machines

No effect of Fenofibrate was noted. Studies to determine the effect of Rosuvastatin on the ability to drive and use machines have not been conducted. However, based on its pharmacodynamic properties, Rosuvastatin is unlikely to affect this ability.  When driving vehicles or operating machines, it should be taken into account that dizziness may occur during treatment.

4.8 Undesirable effects

Rosuvastatin 
Rosuvastatin is generally well tolerated. The adverse events seen with Rosuvastatin are generally mild and transient. In controlled clinical trials less than 4% of Rosuvastatin treated patients were withdrawn due to adverse events. The adverse reactions seen with Revostat are generally mild and transient. In controlled clinical trials, less than 4% of Revostat-treated patients were withdrawn due to adverse reactions.
The frequencies of adverse events are ranked according to the following:
Common (> 1/100, < 1/10); Uncommon (> 1/1000, < 1/100); Rare (> 1/10 000, < 1/1000).

Nervous system disorders: 

Common: headache, dizziness and memory loss

Gastrointestinal disorders: 

Common: constipation, nausea, abdominal pain 

Musculoskeletal, connective tissue and bone disorders: 

Common: myalgia 

Rare: myopathy, rhabdomyolysis 

General disorders: 

Common: asthenia Skin disorders: Uncommon: pruritis, rash, urticaria 

Rare: hypersensitivity reactions including angioedema.

The incidence of adverse drug reactions tends to increase with increasing dose. 

Skeletal muscle effects: Rhabdomyolysis, which may occasionally be associated with impairment of renal function, has been reported with Rosuvastatin. 

Renal effects: Proteinuria Laboratory effects: A dose-related increase in liver transaminases and CK has been observed in patients taking Rosuvastatin. Abnormal urinalysis testing (dipstick-positive proteinuria with haematuria) has been seen in patients taking Rosuvastatin. The protein detected was mostly tubular in origin. In most cases, proteinuria decreases or disappears spontaneously on reduction of dose.

Fenofibrate

Adverse events reported by 2% or more of patients treated with Fenofibrate during the double-blind, placebo-controlled trials, regardless of causality, are listed in the table below. Adverse events led to discontinuation of treatment in 5% of patients treated with Fenofibrate and in 3% treated with placebo. Increases in liver function tests were the most frequent events, causing discontinuation of Fenofibrate treatment in 1.6% of patients in double-blind trials.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zuventus.com

Website: Website: https://www.zuventus.co.in/drug-safety-reporting

By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

There is no specific treatment in the event of overdose. In the event of overdose, the patient should be treated symptomatically and supportive measures instituted as required. If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage; usual precautions should be observed to maintain the airway. Hemodialysis is unlikely to be of benefit.
 

5.1 Mechanism of action

Rosuvastatin 
Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor for cholesterol. The primary site of action of rosuvastatin is the liver, the target organ for cholesterol lowering. Rosuvastatin increases the number of hepatic LDL receptors on the cell-surface, enhancing uptake and catabolism of LDL and it inhibits the hepatic synthesis of VLDL, thereby reducing the total number of VLDL and LDL particles.

Fenofibrate
By activation of peroxisome proliferator activated receptor α (PPARα), Fenofibrate increases lipolysis and elimination of triglyceride rich particles from plasma by activating lipoprotein lipase and reducing production of apoprotein C-III (an inhibitor of lipoprotein lipase activity). 

5.2 Pharmacodynamic effects

Rosuvastatin 
Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase. Rosuvastatin increases the number of hepatic LDL receptors on the cell-surface, enhancing uptake and catabolism of LDL and it inhibits the hepatic synthesis of VLDL, thereby reducing the total number of VLDL and LDL particles.

Fenofibrate
By activation of peroxisome proliferator activated receptor α (PPARα), Fenofibrate increases lipolysis and elimination of triglyceride rich particles from plasma by activating lipoprotein lipase and reducing production of apoprotein C-III (an inhibitor of lipoprotein lipase activity). The resulting fall in triglycerides produces an alteration in the size and composition of LDL from small, dense particles (which are thought to be atherogenic due to their susceptibility to oxidation), to large buoyant particles. These larger particles have a greater affinity for cholesterol receptors and are catabolized rapidly. Activation of PPARα (Peroxisome proliferator activated receptor alpha) also induces an increase in the synthesis of apoproteins AI, AII and HDL-cholesterol.

5.3 Pharmacokinetic properties

Rosuvastatin
After oral administration peak plasma levels occur 5 hours after dosing. The half-life is 19 hours and does not increase with increasing dose. Rosuvastatin is approximately 90% bound to plasma proteins, mostly albumin. The parent compound, accounts for greater than 90% of the circulating active HMG-CoA reductase inhibitor activity. Rosuvastatin undergoes limited metabolism in humans (approximately 10%), mainly to the N-desmethyl form, and 90% is eliminated as unchanged drug in the faeces with the remainder being excreted in the urine.

Fenofibrate
Peak plasma levels of fenofibric acid occur within 6 to 8 hours after administration, the absorption is increased when administered with food. Serum protein binding was approximately 99%, it is rapidly hydrolyzed by esterases to the active metabolite fenofibric acid; no unchanged Fenofibrate is detected in plasma. Fenofibric acid is primarily conjugated with glucuronic acid and then excreted in urine and its half-life is 20 hours.
 

6.1 Animal Toxicology or Pharmacology

Rosuvastatin
In a 104-week carcinogenicity study in rats at dose levels of 2, 20, 60, or 80 mg/kg/day by oral gavage, the incidence of uterine stromal polyps was significantly increased in females at 80 mg/kg/day at systemic exposure 20 times the human exposure at 40 mg/day based on AUC. Increased incidence of polyps was not seen at lower doses. 

In a 107-week carcinogenicity study in mice given 10, 60, or 200 mg/kg/day by oral gavage, an increased incidence of hepatocellular adenoma/carcinoma was observed at 200 mg/kg/day at systemic exposures 20 times the human exposure at 40 mg/day based on AUC. An increased incidence of hepatocellular tumors was not seen at lower doses. 

Rosuvastatin was not mutagenic or clastogenic with or without metabolic activation in the Ames test with Salmonella typhimurium and Escherichia coli, the mouse lymphoma assay, and the chromosomal aberration assay in Chinese hamster lung cells. Rosuvastatin was negative in the in vivo mouse micronucleus test. 

In rat fertility studies with oral gavage doses of 5, 15, 50 mg/kg/day, males were treated for 9 weeks prior to and throughout mating and females were treated 2 weeks prior to mating and throughout mating until gestation day 7. No adverse effect on fertility was observed at 50 mg/kg/day (systemic exposures up to 10 times the human exposure at 40 mg/day based on AUC). In testicles of dogs treated with rosuvastatin at 30 mg/kg/day for one month, spermatidic giant cells were seen. Spermatidic giant cells were observed in monkeys after 6-month treatment at 30 mg/kg/day in addition to vacuolation of seminiferous tubular epithelium. Exposures in the dog were 20 times and in the monkey 10 times the human exposure at 40 mg/day based on body surface area. Similar findings have been seen with other drugs in this class. 

Fenofibrate
Carcinogenesis: Two dietary carcinogenicity studies have been conducted in rats with fenofibrate. In the first 24-month study, Wistar rats were dosed with fenofibrate at 10 mg/kg/day, 45 mg/kg/ day, and 200 mg/kg/day, approximately 0.3 times, 1 times, and 6 times the maximum recommended human dose (MRHD), based on body surface area comparisons (mg/m2). At a dose of 200 mg/kg/day (at 6 times the MRHD), the incidence of liver carcinoma was significantly increased in both sexes. A statistically significant increase in pancreatic carcinomas was observed in males at 1 and 6 times the MRHD; an increase in pancreatic adenomas and benign testicular interstitial cell tumors was observed in males at 6 times the MRHD. In a second 24-month study in a different strain of rats (Sprague-Dawley), doses of 10 mg/kg/day and 60 mg/kg/day (0.3 and 2 times the MRHD) produced significant increases in the incidence of pancreatic acinar adenomas in both sexes and increases in testicular interstitial cell tumors in males at 2 times the MRHD. 

A 117-week carcinogenicity study was conducted in rats comparing three drugs: fenofibrate 10 mg/kg/day and 60 mg/kg/day (0.3 and 2 times the MRHD), clofibrate (400 mg/kg/day; 2 times the human dose), and gemfibrozil (250 mg/kg/day; 2 times the human dose, based on mg/m2 surface area). Fenofibrate increased pancreatic acinar adenomas in both sexes. Clofibrate increased hepatocellular carcinomas in males and hepatic neoplastic nodules in females. Gemfibrozil increased hepatic neoplastic nodules in males and females, while all three drugs increased testicular interstitial cell tumors in males. 

In a 21-month study in CF-1 mice, fenofibrate 10 mg/kg/day, 45 mg/kg/day, and 200 mg/kg/day (approximately 0.2 times, 1 times, and 3 times the MRHD on the basis of mg/m2 surface area) significantly increased the liver carcinomas in both sexes at 3 times the MRHD. In a second 18-month study at 10 mg/kg/day, 60 mg/kg/day, and 200 mg/kg/day, fenofibrate significantly increased the liver carcinomas in male mice and liver adenomas in female mice at 3 times the MRHD. 

Electron microscopy studies have demonstrated peroxisomal proliferation following fenofibrate administration to the rat. An adequate study to test for peroxisome proliferation in humans has not been done, but changes in peroxisome morphology and numbers have been observed in humans after treatment with other members of the fibrate class when liver biopsies were compared before and after treatment in the same individual. 

Mutagenesis: Fenofibrate has been demonstrated to be devoid of mutagenic potential in the following tests: Ames, mouse lymphoma, chromosomal aberration and unscheduled DNA synthesis in primary rat hepatocytes. 

Impairment of Fertility: In fertility studies rats were given oral dietary doses of fenofibrate, males received 61 days prior to mating and females 15 days prior to mating through weaning which resulted in no adverse effect on fertility at doses up to 300 mg/kg/day (approximately 10 times the MRHD, based on mg/m2 surface area comparisons). 
 

REVOSTAT®FB is a combination of Rosuvastatin and Fenofibrate.

Rosuvastatin is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA)-reductase inhibitor. 

ChemicalName:bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid]

Molecular Formula: (C22H27FN3O6S)2Ca  Molecular Weight: 1,001.14.

Structure: 

Fenofibrate is a peroxisome proliferator-activated receptor (PPAR) alpha agonist.

Chemical Name: 2-[4-(4-chlorobenzoyl) phenoxy]-2-methyl-propanoic acid, l-methylethyl ester

Molecular Formula: C20H21O4Cl
 
Molecular Weight: 360.83

Structure: 
 

8.1 Incompatibilities
Not applicable.

8.2 Shelf-life
Refer on pack.

8.3 Packaging information
10 Blister strips of 10 tablets each

8.4 Storage and handing instructions
Store protected from moisture at a temperature below 30°C.
Keep out of reach of children.
 

Myopathy and Rhabdomyolysis 

Advise patients that REVOSTAT®FB may cause myopathy and rhabdomyolysis. Inform patients that the risk is also increased when taking certain types of medication and they should discuss all medication, both prescription and over-the-counter, with their healthcare provider. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever.

Hepatic Dysfunction 

Inform patients that REVOSTAT®FB may cause liver enzyme elevations and possibly liver failure. Advise patients to promptly report fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice.
 
Increases in HbA1c and Fasting Serum Glucose Levels 

Inform patients that increases in HbA1c and fasting serum glucose levels may occur with REVOSTAT®FB. Encourage patients to optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices. 

Hypersensitivity Reactions 

Inform patients that serious hypersensitivity reactions, such as anaphylaxis and angioedema, have been reported with fibrates. Advise patients to report immediately any signs or symptoms suggesting allergic reaction, and to discontinue drug until they have consulted prescribing physicians.

Pregnancy 

Advise pregnant patients and patients who can become pregnant of the potential risk to a fetus. Advise patients to inform their healthcare provider of a known or suspected pregnancy to discuss if REVOSTAT®FB should be discontinued.

Lactation 

Advise patients that breastfeeding during treatment with REVOSTAT®FB is not recommended. 

Concomitant Use of Antacids 
When taking REVOSTAT®FB with an aluminum and magnesium hydroxide combination antacid, administer REVOSTAT®FB at least 2 hours before the antacid.

Missed Doses 

If a dose is missed, advise patients not to take an extra dose. Just resume the treatment with the next dose. 
 

14th January 2025.