Each film coated tablet contains:

• Atorvastatin ( As  Atorvastatin Calcium trihydrate)        10 mg        
• Ezetimibe       10 mg
   

¤ Atorium plus® is indicated as an adjunct to diet for reduction elevated cholesterol and triglyceride values, when response to diet and other non pharmacological measures (such as physical exercises, weight loss) is inadequate in patient with :
- Primary Hyperlipidemia:

• Atorium plus® is indicated for the reduction of elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB), triglycerides (TG), and non-high-density lipoprotein cholesterol (non-HDL-C), and to increase high-density lipoprotein cholesterol (HDL-C) in patients with primary (heterozygous familial and non-familial) hyperlipidemia or mixed hyperlipidemia.

-Homozygous Familial Hypercholesterolemia (HoFH):

• Atorium plus® is indicated for the reduction of elevated 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.

Atorium®plus is Contraindicated in patients with :

• Hypersensitivity to any component of this medication.
• Liver disease or unexplained elevations, of hepatic function test values (Serum transaminases).
• Skeletal muscle disease .

• Concurrent use of Atorvastatin and digoxin may increase digoxin Serum Concentrations in large dose .
• Concurrent use of Atorvastatin and Colestipol decrease plasma   Concentration of Atorvastatin .
• Coadministration of Atorvastatin with oral Contraceptives produce increases in plasma concentrations of norethindrone and ethinyloestradiol.
• Coadministration of Atorvastatin with an oral antacid Suspension containing magnesium and aluminium hydroxides decreased plasma concentrations of Atorvastatin.
• Concurrents use of Atorvastatin with grapefruit juice Can increase plasma Concentrations of Atorvastatin Since grapefruit juice contains one or more components that inhibit CYP3A4 concomitant intake of large quantities of grapefruit juice and Atorvastatin is therefore not recommended .
• Inhibitors of cytochrom P450  3A4: (e.g : ciclosporn, macrolide antibiotics including erythromycin and Clarithromycin, nefazodone,azole antifungals including itraconazole and HIV protease inhibitors),concomitant administration can lead to increased plasma concentration of Atorvastatin.
• Inhibitors of P-glycoprotein :( e.g : ciclosporn) can increased the bioavailability of Atorvastatin.
• Protease inhibitors: coadministration of Atorvastatin with protease inhibitors was associated with increase the bioavailability of Atorvastatin.
• Gemfibrozil/ fibric acid derivatives: the risk of Atorvastatin - induced myopathy may be increased.
• Warfarin: coadministration of Atorvastatin and warfarin caused a small decrease in brothrompin time in the first days and become normal within 15 days of Atorium®plus treatment.
• phenazone: coadministration of multiple doses of Atorium®plus and phenazone should little or no detectable effect in the clearance of phenazone.
• Cyclosporine: caution Should be exercised when Ezetimibe and Cyclosporine used together due to increase exposure to both Ezetimibe and Cyclosporine.
• Fenofibrates: the risk of myopathy during treatment with HMG-CoA reductase inhibitor is increased with concurrent administration of fenofibrates (e.g., fenofibrate and fenofibric acid).
• Niacin: The risk of skeletal muscle effects may be enhanced when Atorium plus® is used in combination with niacin.
• Rifampin or Other Inducers of Cytochrome P450 3A4: Concomitant administration of atorvastatin with inducers of cytochrome P450 3A4 (e.g., efavirenz, rifampin) can lead to variable reductions in plasma concentrations of atorvastatin.
• Colchicine: Cases of myopathy, including rhabdomyolysis, have been reported with atorvastatin coadministered with colchicine.
• Cholestyramine: Concomitant cholestyramine administration decreased the mean area under the curve (AUC) of total ezetimibe approximately 55%.
• Elbasvir and Grazoprevir: concomitant administration of lebasvir and grazoprevir may lead to increased plasma concentrations of atorvastatin and an increased risk of myopathy; therefore, a dose adjustment of atorvastatin may be necessary.

• Atorium®plus is Contraindicated in Pregnancy and while breast Feeding:Women of child – bearing potential should use appropriate contraceptive measures.
• It is unknown whether this drug or its metabolites are excreted in human milk.

¤ Atorvastatin is generally well tolerated , the adverse effects observed are usually mild and transient
• Gastrointestinal disorders:

• Common: constipation, flatulence, dyspepsia, nausea, diarrhea.
•  Uncommon: anorexia, vomiting.

• Eye disorders :

• Rare: Conjunctivitis , Visual disturbances including blurred  vision .

• Cardiac disorders :

• Uncommon: Palpitations. 

• Blood and lymphatic system disorders:

• Uncommon: thrombocytopenia.

• Immune system disorders:

• Common: allergic reaction.
• Very rare: anaphylaxis.

• Endocrine disorders:

• Uncommon: alopecia, hypoglycemia, pancreatitis.

• Psychiatric:

• Common: insomnia.
• Uncommon: amnesia.

• Nervous system disorders:

• Common: headache, dizziness, paraesthaesia, hypoesthesia.
• Uncommon: peripheral neuropathy.

• Hepato-biliary disorders:

• Rare: hepatitis, cholestatic jaundice.

• Skin/appendages:

• Common: skin rash, pruritus.
• Uncommon: urticaria.
• Very rare: angioneurotic oedema, bullous rashes (including erthema multiforme, stevens-Johnson syndrome and toxic epidermal necrolysis).

• Ear and labyrinth disorders:

• Uncommon: tinnitus.

• Musculoskeletal disorders:

• Common: myalgia, erthralgia.
• Uncommon: myopathy.
• Rare: myositis, rhabdomyolysis.

• Reproductive system disorders:

• Uncommon: impotence.

• General disorders:

• Common: asthenia, chest pain, peripheral oedema.
• Uncommon: malaise, weight gain. Urine discoloration may occur due to Ezetimibe.

The must common adverse reaction in the group of patients treated with Ezetimibe & Atorvastatin that  lead to treatment discontinuation and occur at a rate greater than Atorvastatin alon were:

• Alanine aminotransferase increase (0.6%).
• Myalgia (0.5%).
• Fatigue, aspartate aminotransferase increase headache. 

Over dose:

• No specific treatment is available for Atorium®plus over dosage. When overdose occurs, the patient should be treated symptomatically and supportive measures instated as required. Liver function tests should be performed and serum CPK levels should be monitor

¤ The patient should be placed on standared cholesterol lowering diet before receiving Atorium plus® and should continue on this diet during treatment with Atorium®plus.

The recommended dose:

• The dosage range of Atorium plus® is 10 / 10 mg/day to 10 / 80 mg/day.
• The recommended starting dose of Atorium plus® is 10 / 10 mg/day or 10 / 20 mg/day.
• Atorium plus® can be administered as a single dose at any time of the day, with or without food.
• The recommended starting dose for patients who require a larger reduction in LDL-C (greater than 55%) is 10 / 40mg/day.
• After initiation and/or upon titration of  Atorium plus®, lipid levels should be analyzed within 2 or more weeks and dosage adjusted accordingly.

Patients with Homozygous Familial Hypercholesterolemia:

• The dosage of Atorium plus® in patients with homozygous familial hypercholesterolemia is 10 / 40 mg/day or 10 / 80 mg/day. Atorium plus® should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable.

Patients with renal insufficiency: 

• No dosage adjustment are required in patient with renal impairment; However, a history of renal impairment may be a risk factor for statin-associated myopathy. 

Patients with hepatic insufficiency:

• Atorium plus® is contraindicated in patients with active liver disease or unexpected persistent elevations in hepatic transaminase levels.

Geriatric Patients:

• No dosage adjustment is necessary in geriatric patients. 

¤ liver effects:

• liver function Should be tested prior the initiation of therapy and at 12 weak  following initiation of therapy.
• Patients who develop increased transaminase  levels  should be monitored until  the abnormalities resolve. If the liver function values should increase to more than triple the normal level and persist over longer period , dose reduction or withdrawal of Atrovastatin  is recommended .

¤Skeletal muscle effects :

• Atorvastatin may in rare occasion affect the skeletal muscel and cause myalgia , myositis and myopthy .
• The increasea of muscle enzyme (CPK) in blood Should be examined if it remains clearly elevated over a longer period the dose should be reduced or withdrawn.

¤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 patients is receiving treatment with Atorvastatin, their CPK levels should be measured. If these level are found to be significantly elevated (>5 times ULN), treatment should be  stopped.
• If muscular symptoms are severe and cause dialy discomfort, even if the CPK levels are elevated to ≤ 5 × ULN,treatment discontinuation should be considered.
• If symptoms resolve and CPK levels return to normal, than re-introduction of Atorvastatin or introduction of an alternative statin may be considered at the lowest dose and with close monitoring.
• Atorvastatin must be discontinued if cilincally significant elevation of CPK levels (> 10 × ULN ) occur, or if rhabdomyolysis is diagnosed or suspected.

• Atorium®plus film coated tablet  (Blister of 10 tablets, pack of 3 blisters.) 

• Store in a dry place  at a temperature below 25ºC.