Atorsam-F

Red coloured, round shaped, biconvex film-coated tablets plain on both sides.

HMG-CoA Reductase Inhibitor/Lipid Modifying Agent.

The fixed dose combination of Atorvastatin and Fenofibrate is indicated as an adjunct to diet to reduce elevated total-C, LDL-C, apo B, and TG levels and to increase HDL-C in patients with mixed hyperlipidemia.

Patients should be placed on appropriate lipid-lowering diet before receiving the fixed dose combination of Atorvastatin and Fenofibrate, and should continue this diet during treatment. The fixed dose combination of Atorvastatin and Fenofibrate should be given with meals, thereby optimizing the bioavailability of the medication.
Adults and Elderly: Start with Atorvastatin 10 mg plus Fenofibrate 160 mg (or Atorvastatin 10 mg plus Fenofibrate 200 mg) once daily. The dosage can be titrated upwards depending on the patients' response and tolerability to treatment to a maximum of Atorvastatin 40 mg plus Fenofibrate 160 mg (or Atorvastatin 40 mg plus Fenofibrate 200 mg). Or as prescribed by the physician.
Patients with Renal and Hepatic Impairment: The fixed dose combination of Atorvastatin plus Fenofibrate is contraindicated in patients with severe renal and hepatic impairment.
Children and Adolescents: No data is available on the use of the fixed dose combination of Atorvastatin and Fenofibrate in patients under the age of 18 years. Therefore, the use of the fixed dose combination of Atorvastatin and Fenofibrate in this age group is not recommended.

The fixed dose combination of Atorvastatin and Fenofibrate is contraindicated in patients with: hypersensitivity of either component; severe hepatic or renal dysfunction, including primary biliary cirrhosis, and patients with unexplained persistent liver function abnormality, unexplained persistent elevations of serum transaminases exceeding three times the upper limit of normal; pre-existing gallbladder disease. Pregnancy and Lactation.

Liver Function: The two drugs, given individually, have been associated with biochemical abnormalities of liver function. Persistent elevations (>3 times the upper limit of normal [ULN]) occurring on two or more occasions in serum transaminases occurred in 0.7% of patients who received atorvastatin in clinical trials. Specifically, the incidence of these abnormalities was 0.2% for atorvastatin 10 mg. In a pooled analysis of 10 placebo-controlled trials, increases in serum transaminases to >3 ULN to occurred in 5.3% of patients taking fenofibrate versus 1.1% of patients treated with placebo.
It is recommended that liver function tests be performed prior to and at 12 weeks following initiation of therapy and periodically thereafter (e.g. semiannually). Patients who develop increased transaminase levels should be monitored until the abnormalities resolve. Should an increase in ALT or AST of >3 times ULN persist, withdrawal of the fixed dose combination of atorvastatin and fenofibrate is recommended. The fixed dose combination of atorvastatin and fenofibrate should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease.
Skeletal Muscle: The use of the fixed dose combination of atorvastatin and fenofibrate may occasionally be associated with myopathy since the two drugs, individually, have been shown to cause myopathy in a small percentage of patients (<1%) in international trials. Treatment with atorvastatin as well as fenofibrate has been associated on rare occasions with rhabdomyolysis, usually in patients with impaired renal function. Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevations of CPK levels. The risk of myopathy during treatment may be increased with concurrent administration of cyclosporine, erythromycin, and niacin or azole anti-fungals. Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. The CPK levels should be assessed in patients reporting these symptoms and the fixed dose combination of atorvastatin and fenofibrate should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed. The fixed dose combination of Atorvastatin and Fenofibrate should be temporarily withheld or discontinued in any patient with an acute, serious condition suggestive of a myopathy or having a risk factor predisposing to the development of renal failure secondary to rhabdomyolysis (eg, severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders, and uncontrolled seizures).
Endocrine Functions: Statins interfere with cholesterol synthesis and theoretically might blunt adrenal and/or gonadal steroid production. Clinical studies have shown that Atorvastatin does not reduce basal plasma cortisol concentration or impair adrenal reserve. The effects of statins on male fertility have not been studied in adequate numbers of patients. The effects, if any, on the pituitary-gonadal axis in premenopausal women are unknown. Caution should be exercised if the fixed dose combination of Atorvastatin and Fenofibrate is administered concomitantly with drugs that may decrease the levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone, and cimetidine.
Cholelithiasis: Fenofibrate, like clofibrate and gemfibrozil, may increase cholesterol excretion into the bile, leading to cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated. Fenofibrate therapy should be discontinued if gallstones are found.
Pancreatitis: Pancreatitis has been reported in patients taking Fenofibrate, 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.
Hypersensitivity Reactions: Acute hypersensitivity reactions including severe skin rashes requiring patient hospitalization and treatment with steroids have occurred very rarely during treatment with Fenofibrate, including rare spontaneous reports of Stevens-Johnson syndrome, and toxic epidermal necrolysis. Urticaria was seen in 1.1 vs. 0%, and rash in 1.4 vs. 0.8% of Fenofibrate and placebo patients respectively in controlled trials.
Hematologic Changes: Mild to moderate hemoglobin, hematocrit, and white blood cell decreases have been observed in patients following initiation of fenofibrate therapy. However, these levels stabilize during long-term administration. Extremely rare spontaneous reports of thrombocytopenia and agranulocytosis have been received during post-marketing surveillance outside of the U.S. Periodic blood counts are recommended during the first 12 months of fenofibrate administration.

HMG CoA Reductase Inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol and may cause fetal harm when administered to the pregnant woman. Furthermore, the safety of Fenofibrate in pregnant women has not been established. Because of the potential for adverse reactions, the fixed dose combination of Atorvastatin and Fenofibrate is contraindicated during pregnancy in women and in nursing mothers.

Atorvastatin: Adverse reactions following treatment with Atorvastatin are generally mild and transient with less than 2% of patients discontinuing treatment due to side effects. The most frequent (1% or more) adverse effects associated with Atorvastatin treatment, in patients participating in controlled clinical studies were: Psychiatric Disorders: insomnia.
Nervous System Disorders: headache.
Gastrointestinal Disorders: abdominal pain, dyspepsia, nausea, flatulence, constipation, diarrhea.
Musculoskeletal and Connective Tissue Disorders: myalgia.
General Disorders and Administration Site Conditions: asthenia.
Elevated serum ALT levels have been reported in 1.3% of patients receiving Atorvastatin. Elevations in ALT >3 times upper normal occurred 0.8% of patients treated with Atorvastatin. Elevated serum CPK levels >3 times upper normal limit occurred in 2.5% of atorvastatin treated. Levels above 10 times the normal upper range occurred in only 0.4% of patients. Adverse events that have been reported in Atorvastatin clinical trials and in post marketing experience are categorized as follows according to system organ class and frequency. Frequencies are defined as: very common (≥10%), common (≥1% and <10%), uncommon (≥0.1% and <1%), rare (≥0.01% and <0.1%) and very rare (<0.01%).
Gastrointestinal Disorders: Common: constipation, flatulence, dyspepsia, nausea, and diarrhea. Uncommon: anorexia, vomiting, pancreatitis.
Blood and Lymphatic System Disorders: Uncommon: thrombocytopenia.
Immune System Disorders: Common: allergic reactions (including anaphylaxis).
Endocrine Disorders: Uncommon: alopecia, hyperglycemia, hypoglycemia.
Psychiatric: Common: insomnia. Uncommon: amnesia.
Nervous System Disorders: Common: headache, dizziness, paraesthesia, hypoesthesia. Uncommon: peripheral neuropathy. Very rare: dysgeusia.
Eye Disorders: Very rare: visual disturbance.
Hepato-Biliary Disorders: Rare: hepatitis, cholestatic jaundice. Very rare: hepatic failure.
Skin/Appendages: Common: Skin rash, pruritus. Uncommon: urticaria, alopecia. Very rare: angioneurotic edema, bullous rashes (including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis).
Ear and Labyrinth Disorders: Uncommon: tinnitus. Very rare: hearing loss.
Musculoskeletal Disorders: Common: myalgia, arthralgia. Uncommon: myopathy, muscle cramps. Rare: myositis, rhabdomyolysis. Very rare: tendon rupture.
Reproductive System and Breast Disorders: Uncommon: impotence. Very rare: gynecomastia.
General Disorders: Common: asthenia, chest pain, back pain, fatigue. Uncommon: malaise, weight gain. Rare: peripheral edema.
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 as follows. Adverse events led to discontinuation of treatment in 5.0% of patients treated with fenofibrate and in 3.0% in patients 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.
Body as a Whole: abdominal pain (4.6%), back pain (3.4%), headache (3.2%), asthenia (2.1%), flu syndrome (2.1%).
Digestive: liver function tests abnormal (7.5%, significantly different from placebo), diarrhea (2.3%), nausea (2.3%), constipation (2.1%).
Metabolic and Nutritional Disorders: SGPT increased (3.0%), creatine phosphokinase increased (3.0%), SGOT increased (3.4%, significantly different from placebo).
Respiratory: respiratory disorder (6.2%), rhinitis (2.3%).
Additional adverse events reported during post-marketing surveillance or by three or more patients in placebo-controlled trials or reported in other controlled or open trials, regardless of causality are listed as follows.
Body as a Whole: accidental injury, allergic reaction, chest pain, cyst, fever, hernia, infection, malaise and pain (unspecified).
Cardiovascular System: angina pectoris, arrhythmia, atrial fibrillation, cardiovascular disorder, coronary artery disorder, electrocardiogram abnormal, extrasystoles, hypertension, hypotension, migraine, myocardial infarct, palpitation, peripheral vascular disorder, phlebitis, tachycardia, varicose vein, vascular disorder, vasodilatation, venous thromboembolic events (deep vein thrombosis, pulmonary embolus) and ventricular extrasystoles.
Digestive System: anorexia, cholecystitis, cholelithiasis, colitis, diarrhea, duodenal ulcer, dyspepsia, eructation, esophagitis, flatulence, gastritis, gastroenteritis, gastrointestinal disorder, increased appetite, jaundice, liver fatty deposit, nausea, pancreatitis, peptic ulcer, rectal disorder, rectal hemorrhage, tooth disorder and vomiting.
Endocrine System: diabetes mellitus.
Hemic and Lymphatic System: Anemia, ecchymosis, eosinophilia, leukopenia, lymphadenopathy, and thrombocytopenia.
Laboratory Investigations: Alkaline phosphatase increased, bilirubin increased, blood urea nitrogen increased, serum creatinine increased, gamma glutamyl transpeptidase increased, lactate dehydrogenase increased, SGOT and SGPT increased.
Metabolic and Nutritional Disorders: edema, gout, hyperuricemia, hypoglycemia, peripheral edema, weight gain, and weight loss.
Musculoskeletal System: Arthralgia, arthritis, arthrosis, bursitis, joint disorder, leg cramps, myalgia, myasthenia, myositis, rhabdomyolysis and tenosynovitis.
Nervous System: Anxiety or nervousness, depression, dizziness, dry mouth, hypertonia, insomnia, libido decreased, neuralgia, paresthesia, somnolence and vertigo.
Respiratory System: Allergic pulmonary alveolitis, asthma, bronchitis, cough increased, dyspnea, laryngitis, pharyngitis, pneumonia and sinusitis.
Skin and Appendages: Acne, alopecia, contact dermatitis, eczema, fungal dermatitis, herpes simplex, herpes zoster, maculopapular rash, nail disorder, photosensitivity reaction, pruritus, rash, sweating, skin disorder, skin ulcer and urticaria.
Special Senses: Abnormal vision, amblyopia, cataract specified, conjunctivitis, ear pain, eye disorder, otitis media and refraction disorder.
Urogenital System: Abnormal kidney function, cystitis, dysuria, gynecomastia, prostatic disorder, unintended pregnancy, urinary frequency, urolithiasis and vaginal moniliasis.

Co-administration of Fenofibrate with Atorvastatin does not significantly affect Atorvastatin AUC.
Atorvastatin: Colestipol: Plasma concentrations of Atorvastatin decreased approximately 25% when colestipol and atorvastatin were co-administered. However, LDL-C reduction was greater when atorvastatin and colestipol were co-administered than when either drug was given alone. Since bile acid sequestrants may bind other drugs given concurrently, patients should take the fixed dose combination of Atorvastatin and Fenofibrate at least 1 hour before or 4-6 hours after a bile acid binding resin to avoid impeding its absorption.
Digoxin: Administration of multiple doses of Atorvastatin with digoxin increases the steady-state plasma digoxin concentrations by approximately 20%. Patients taking digoxin and fixed dose combination of Atorvastatin and Fenofibrate concomitantly should be monitored appropriately.
Erythromycin: In healthy individuals, plasma concentrations of atorvastatin increased by approximately 40% with co-administration of Atorvastatin and erythromycin, a known inhibitor of cytochrome P450 3A4. The risk of myopathy is increased when statins and erythromycin are concurrently administered. Caution should be exercised when co-administering the fixed dose combination of Atorvastatin and Fenofibrate with erythromycin.
Oral Contraceptives: Co-administration of Atorvastatin and an oral contraceptive containing norethindrone and ethinyl estradiol produces increased plasma concentrations of norethindrone and ethinyl estradiol. These increases should be considered when selecting an oral contraceptive for a woman taking the fixed dose combination of Atorvastatin and Fenofibrate.
Oral Anticoagulants: If coumarin anticoagulants and fixed dose combination of Atorvastatin and Fenofibrate are co-administered, the dosage of the anticoagulant should be reduced to maintain the prothrombin time/INR at the desired level to prevent bleeding complications. Frequent prothrombin time/INR determinations are advisable until it has been definitely determined that the prothrombin time/INR has stabilized.
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. The benefits and risks of using the fixed dose combination of Atorvastatin and Fenofibrate with immunosuppressants and other potentially nephrotoxic agents should be carefully considered. Also, the risk of myopathy during treatment with statins is increased with concurrent administration of cyclosporine. Hence, caution should be exercised when co-administering fixed dose combination of Atorvastatin and Fenofibrate with cyclosporine.
Azole antifungals/Niacin: The risk of myopathy during treatment with statins is increased with concurrent administration of these agents. Hence caution should be exercised when these drugs are co-administered with the fixed dose combination of Atorvastatin and Fenofibrate.
Fenofibrate: In vitro studies using human liver microsomes indicate that Fenofibrate and fenofibric acid is not an inhibitor of cytochrome (CYP) P450 isoforms; CYP3A4, CYP2D6, CYP2E1, or CYP1A2. They are weak inhibitors of CYP2C8, CYP2C19 and CYP2A6, and mild-to-moderate inhibitors of CYP2C9 at therapeutic concentrations.
Oral Anti-coagulants: Potentiation of coumarin-type anticoagulants has been observed with prolongation of the prothrombin time/INR. The dosage of the anticoagulant should be reduced to maintain the prothrombin time/INR at the desired level to prevent bleeding complications. Frequent prothrombin time/INR determinations are advisable until it has been definitely determined that the prothrombin time/INR has stabilized.
Bile acid sequestrants: Bile acid sequestrants have been shown to bind to other drugs given concurrently. Therefore, fenofibrate should be taken at least 1 hour before, or 4-6 hours after, a bile acid binding resin to avoid impeding its absorption.
Glimepiride: Concomitant administration of Fenofibrate once daily for 10 days with glimepiride (1 mg tablet) single dose simultaneously with the last dose of Fenofibrate resulted in a 35% increase in mean AUC of glimepiride in healthy subjects. Glimepiride Cmax was not significantly affected by Fenofibrate co-administration. There was no statistically significant effect of multiple doses of Fenofibrate on glucose nadir or AUC with the baseline glucose concentration as the covariate after glimepiride administration in healthy volunteers. However, glucose concentrations at 24 hours remained statistically significantly lower after pretreatment with Fenofibrate than with glimepiride alone. Glimepiride had no significant effect on the pharmacokinetics of fenofibric acid.
Ezetimibe: Concomitant administration of Fenofibrate with ezetimibe (10 mg) once daily for 10 days in 18 healthy adults resulted in increases in total ezetimibe AUC, Cmax and Cmin of approximately 43%, 33% and 56%, respectively, and increases in ezetimibe glucuronide AUC, Cmax and Cmin of approximately 49%, 34% and 62%, respectively. The pharmacokinetics of fenofibric acid was not significantly affected by ezetimibe and the multiple-dose pharmacokinetics of free (unconjugated) ezetimibe was not significantly affected by Fenofibrate.

Store at temperatures not exceeding 30°C.
Shelf Life: 36 months.

Dyslipidaemic Agents

C10AB05 - fenofibrate ; Belongs to the class of fibrates. Used in the treatment of hyperlipidemia.
C10AA05 - atorvastatin ; Belongs to the class of HMG CoA reductase inhibitors. Used in the treatment of hyperlipidemia.

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