Mayanmar Product

Flusum Tablets

Sampine A Tablets

Sampine A Tablets

Why you have been prescribed this medicine?

You have been prescribed this medicine if you have any of the following:

Sampine-A is indicated in patients for whom treatment with both S (-) Amlodipine and atorvastatin is appropriate.
S (-) Amlodipine
1. Hypertension: It is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents.
2. Coronary Artery Disease (CAD)
Chronic Stable Angina: It is indicated for the treatment of chronic stable angina. It may be used alone or in combination with other antianginal or antihypertensive agents; Vasospastic Angina (Prinzmetal's or Variant Angina): It is indicated for the treatment of confirmed or suspected vasospastic angina. It may be used as monotherapy or in combination with other antianginal drugs. Angiographically Documented CAD: In patients with recently documented CAD by angiography and without heart failure or an ejection fraction <40%, It is indicated to reduce the risk of hospitalization due to angina and to reduce the risk of a coronary revascularization procedure.
Atorvastatin
Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is recommended as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate. In patients with CHD or multiple risk factors for CHD, the atorvastatin component of S (-) Amlodipine/Atorvastatin tablets can be started simultaneously with diet restriction.
1. Prevention of Cardiovascular Disease: In adult patients without clinically evident coronary heart disease, but with multiple risk factors for coronary heart disease such as age, smoking, hypertension, low HDL-C, or a family history of early coronary heart disease, atorvastatin is indicated to:
Reduce the risk of myocardial infarction
Reduce the risk of stroke
Reduce the risk for revascularization procedures and angina
In patients with type 2 diabetes, and without clinically evident coronary heart disease, but with multiple risk factors for coronary heart disease such as retinopathy, albuminuria, smoking, or hypertension, atorvastatin calcium tablets are indicated to:
Reduce the risk of myocardial infarction
Reduce the risk of stroke;
In patients with clinically evident coronary heart disease, atorvastatin calcium tablets are indicated to: Reduce the risk of non-fatal myocardial infarction
Reduce the risk of fatal and non-fatal stroke Reduce the risk for revascularization procedures Reduce the risk of hospitalization for CHF Reduce the risk of angina
2. Heterozygous Familial and Nonfamilial Hyperlipidemia: It 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 primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Fredrickson Types IIa and Iib);
3. Elevated Serum TG Levels: It is indicated as an adjunct to diet for the treatment of patients with elevated serum TG levels (Fredrickson Type IV);
4. Primary Dysbetalipoproteinemia: It is indicated for the treatment of patients with primary dysbetalipoproteinemia (Fredrickson Type III) who do not respond adequately to diet;
5. Homozygous Familial Hypercholesterolemia: It is indicated 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;
6. Pediatric Patients: It is indicated as an adjunct to diet to reduce total-C, LDL-C, and apo B levels in boys and postmenarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia if after an adequate trial of diet therapy the following findings are present:
³LDL-C remains 190 mg/dL or LDL-C remains ³ 160 mg/dL and:
There is a positive family history of premature cardiovascular disease or two or more other CVD risk factors are present in the pediatric patients. The antidyslipidemic component of S (-) Amlodipine/Atorvastatin tablets has not been studied in conditions where the major lipoprotein abnormality is elevation of chylomicrons (Fredrickson Types I and V).

When you should consult your doctor?

You should consult your doctor if you experience any of the following:
S (-) Amlodipine & Atorvastatin Tablets have been evaluated for safety in 1092 patients in double blind placebo controlled studies treated for concomitant hypertension and dyslipidaemia. In clinical trials with Sampine-A, no adverse events peculiar to this combination have been observed. Adverse events have been limited to those that were reported previously with S (-) Amlodipine and/or atorvastatin (please see respective adverse event tables below).
In controlled clinical trials, discontinuation of therapy due to clinical adverse events or laboratory abnormalities was only required in 5.1% of patients treated with both S (-) Amlodipine and atorvastatin compared to 4.0% of patients given placebo.
The following adverse events, listed according to the MedDRA system organ class and frequencies, are for S-amlodipine and atorvastatin individually. Very common: = 1/10, common: = 1/100 and < 1/10, Uncommon: = 1/1000 and < 1/100, Rare: = 1/10,000 and < 1/1000, Very Rare: < 1/10,000.

Med DRA System Organ Class

Undesirable Effects

Frequency

 

 

 

 

S (-) Amlodipine

Atorvastatin

Blood and the lymphatic system disorders

Leucopenia

Very rare

-

 

 

Thrombocytopenia

Very Rare

Uncommon

Immune system disorders

Allergic reactions; urticaria

Very Rare

Uncommon

 

 

 

 

 

Metabolism and Nutrition disorders

Hyperglycemia

Very Rare

Uncommon

 

Weight gain

Uncommon

Uncommon

 

 

 

 

 

 

Weight decrease

Uncommon

-

 

 

Hypoglycemia

-

Uncommon

 

 

 

 

 

 

Anorexia

-

Uncommon

Psychiatric Disorders

Insomnia

Uncommon

common

 

Mood changes

Uncommon

-

 

Nervous system disorders

Somnolence

common

-

 

 

Dizziness

Common

Common

 

Headache

Common

Common

 

Tremor

Uncommon

-

 

 

Hypoesthesia, paresthesia

Uncommon

Common

 

Hypertonia

Very rare

-

 

 

Peripheral neuropathy

Very rare

Uncommon

 

Amnesia

-

Uncommon

Eye disorders

Visual disturbances

Uncommon

-

 

Ear and labyrinth disorders

Tinnitus

Uncommon

Uncommon

Cardiac disorders

Palpitations

Common

-

 

 

Syncope

Uncommon

-

 

 

Angina pain

Rare

-

 

 

Myocardial infraction

Very rare

-

 

 

Arrhythmia (including

Very rare

-

 

 

bradychardia, ventricular

 

 

 

 

tachycardia and atrial fibrillation)

 

 

 

Vascular disorders

Flushing

Common

-

 

 

Hypotension

Uncommon

-

 

 

Vasculitis

Very rare

-

 

Respiratory, thoracic and mediastinal disorders

Dyspnoea

Uncommon

-

 

 

Rhinitis

Uncommon

-

 

 

Coughing

Very rare

-

 

Gastrointestinal disorders

Gingival hyperplasia

Very rare

-

 

 

Abdominal pain, nausea

Common

Common

 

Vomiting

Uncommon

Uncommon

 

Dyspepsia

Uncommon

Common

 

Altered bowel habits

Uncommon

-

 

 

Dry mouth

Uncommon

-

 

 

Taste perversion

uncommon

-

 

 

Diarrohea, constipation, flatulence

-

Common

 

Pancreatitis

Very rare

Rare

Hepato-biliary disorders

Hepatitis, cholestatic jaundice

Very rare

Rare

Skin and subcutaneous tissue disorders

Quincke's oedema

Very rare

Very rare

 

Erythema multiforme

Very rare

-

 

 

 

 

 

 

Alopecia

Uncommon

Uncommon

 

Purpura

Uncommon

-

 

 

Skin discoloration

Uncommon

-

 

 

Increase sweating

Uncommon

-

 

 

 

 

 

 

Pruritus

Uncommon

Common

 

Rash

Uncommon

Common

 

Bullous rashes

-

Rare

 

Stevens-johnson syndrome

Very rare

Very rare

 

 

 

 

 

(Lyells's syndrome)

-

Very rare

Musculoskeletal and connective tissue disorders

Arthralgia, myalgia

Uncommon

Common

 

Muscle cramps

Uncommon

Rare

 

Back pain

Uncommon

Common

 

Myositis

-

Rare

 

 

 

 

 

 

Rhabdomyolysis, myopathy

-

Very rare

 

 

 

 

 

 

Tendinopathy, sometimes

 

Very rare

 

complicated by rupture

 

 

 

Renal and urinary disorders

Micturition disorders, nocturia,

Uncommon

-

 

 

increased urinary frequency

 

 

 

Reproductive system and breast disorders

Impotence

Uncommon

Uncommon

 

Gynaecomastia

Uncommon

-

 

 

 

 

 

General disorders and administration site conditions

Oedema, peripheral oedema

common

Rare

 

Fatigue

Common

-

 

 

 

 

 

 

Chest pain

Uncommon

Common

 

Asthenia

Uncommon

Common

 

 

 

 

 

 

Pain

Uncommon

-

 

 

Malaise

Uncommon

Uncommon

Investigations

Hepatic  enzyme elevations ALT,

Very rare

Common

 

AST (mostly consistent

 

 

 

 

with cholestasis)

 

 

 

 

CPK increased levels

-

common

 

 

 

 

 

ADVERSE DRUG REACTIONS

 

 

 

 

What to do if you miss a dose?

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to. Otherwise take it as soon as you remember and then go back to taking it as you would normally.

Things you MUST NOT DO while on this medicine?

CONTRAINDICATIONS
S (-) Amlodipine/Atorvastatin tablets contain atorvastatin and are therefore contraindicated in patients with active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels, pregnancy and breast-feeding, In combination with itraconazole, ketoconazole and telithromycin.
S (-)Amlodipine/Atorvastatin tablets are contraindicated in patients with known hypersensitivity to any component of this medication.

What to do if you accidentally take too much (overdose) of the medicine?

OVERDOSE AND TREATMENT
There is no information on overdosage with S (-) Amlodipine/Atorvastatin tablets in humans.
Information on S (-) Amlodipine
Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia. In humans, experience with intentional overdosage of S (-) Amlodipine is limited.
Single oral doses of S (-) Amlodipine maleate equivalent to 40 mg S (-) Amlodipine/kg and 100 mg S (-) Amlodipine/kg in mice and rats, respectively, caused deaths. Single oral S (-) Amlodipine maleate doses equivalent to 4 or more mg S (-) Amlodipine/kg in dogs (11 or more times the maximum recommended clinical dose on a mg/m2 basis) caused a marked peripheral vasodilation and hypotension.
If overdose should occur, initiate active cardiac and respiratory monitoring. Perform frequent blood pressure measurements. Should hypotension occur, provide cardiovascular support including elevation of the extremities and administration of fluids. If hypotension remains unresponsive to these conservative measures, consider administration of vasopressors (such as phenylephrine) with specific attention to circulating volume and urine output. As S (-) Amlodipine is highly protein bound, hemodialysis is not likely to be of benefit.
Information on Atorvastatin
There is no specific treatment for atorvastatin overdosage. In the event of an overdose, the patient should be treated symptomatically, and supportive measures instituted as required. Due to extensive drug binding to plasma proteins, hemodialysis is not expected to significantly enhance atorvastatin clearance.

Is it safe in pregnancy and breast-feeding?

Tell your doctor immediately if you become pregnant while taking this medication.
For safety of any drug during pregnancy or breastfeeding – please consult your doctor.

Storage Conditions:

Store below 30°C.
Keep all medicines out of reach of children.

Drug Description

COMPOSITION
Each film-coated tablet contains:
S (-) Amlodipine besylate equivalent to S (-) Amlodipine ............................. 2.5 mg
Atorvastatin calcium equivalent to Atorvastatin ............................................ 10 mg
ADDITIONAL INGREDIENTS
Excipients:
Microcrystalline cellulose, lactose monohydrate, hypromellose, calcium carbonate, croscarmellose sodium, colloidal anhydrous silica, magnesium stearate, opadry yellow 04F82783 and purified water.

Indications and dosage.

THERAPEUTIC INDICATIONS
Sampine-A is indicated in patients for whom treatment with both S (-) Amlodipine and atorvastatin is appropriate.
S (-) Amlodipine
1. Hypertension: It is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents.
2. Coronary Artery Disease (CAD)
Chronic Stable Angina: It is indicated for the treatment of chronic stable angina. It may be used alone or in combination with other antianginal or antihypertensive agents; Vasospastic Angina (Prinzmetal's or Variant Angina): It is indicated for the treatment of confirmed or suspected vasospastic angina. It may be used as monotherapy or in combination with other antianginal drugs. Angiographically Documented CAD: In patients with recently documented CAD by angiography and without heart failure or an ejection fraction <40%, It is indicated to reduce the risk of hospitalization due to angina and to reduce the risk of a coronary revascularization procedure.
Atorvastatin
Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is recommended as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate. In patients with CHD or multiple risk factors for CHD, the atorvastatin component of S (-) Amlodipine/Atorvastatin tablets can be started simultaneously with diet restriction.
1. Prevention of Cardiovascular Disease: In adult patients without clinically evident coronary heart disease, but with multiple risk factors for coronary heart disease such as age, smoking, hypertension, low HDL-C, or a family history of early coronary heart disease, atorvastatin is indicated to:
Reduce the risk of myocardial infarction
Reduce the risk of stroke
Reduce the risk for revascularization procedures and angina
In patients with type 2 diabetes, and without clinically evident coronary heart disease, but with multiple risk factors for coronary heart disease such as retinopathy, albuminuria, smoking, or hypertension, atorvastatin calcium tablets are indicated to:

Reduce the risk of myocardial infarction
Reduce the risk of stroke;
In patients with clinically evident coronary heart disease, atorvastatin calcium tablets are indicated to: Reduce the risk of non-fatal myocardial infarction
Reduce the risk of fatal and non-fatal stroke Reduce the risk for revascularization procedures
Reduce the risk of hospitalization for CHF Reduce the risk of angina
2. Heterozygous Familial and Nonfamilial Hyperlipidemia: It 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 primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Fredrickson Types IIa and Iib);
3. Elevated Serum TG Levels: It is indicated as an adjunct to diet for the treatment of patients with elevated serum TG levels (Fredrickson Type IV);
4. Primary Dysbetalipoproteinemia: It is indicated for the treatment of patients with primary dysbetalipoproteinemia (Fredrickson Type III) who do not respond adequately to diet;
5. Homozygous Familial Hypercholesterolemia: It is indicated 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;
6. Pediatric Patients: It is indicated as an adjunct to diet to reduce total-C, LDL-C, and apo B levels in boys and postmenarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia if after an adequate trial of diet therapy the following findings are present:
³LDL-C remains 190 mg/dL or LDL-C remains ³ 160 mg/dL and:
There is a positive family history of premature cardiovascular disease or two or more other CVD risk factors are present in the pediatric patients. The antidyslipidemic component of S (-) Amlodipine/Atorvastatin tablets has not been studied in conditions where the major lipoprotein abnormality is elevation of chylomicrons (Fredrickson Types I and V).
DOSAGE AND ADMINISTRATION
The usual starting dose is 2.5 mg/10 mg once daily.
S (-) Amlodipine/Atorvastatin tablets may be used to initiate treatment in patients with hyperlipidemia and either hypertension or angina. The recommended starting dose of S (-) Amlodipine/Atorvastatin tablets should be based on the appropriate combination of recommendations for the monotherapies. The maximum dose of the S (-) Amlodipine component of S (-) Amlodipine/Atorvastatin tablets is 10 mg once daily. The maximum dose of the atorvastatin component of S (-) Amlodipine/Atorvastatin tablets is 80 mg once daily.
MODE OF ADMINISTRATION
Doses may be taken at any time of day with or without food.

Side effects and drug interactions.

UNDESIRABLE EFFECTS
S (-) Amlodipine & Atorvastatin Tablets have been evaluated for safety in 1092 patients in double blind placebo controlled studies treated for concomitant hypertension and dyslipidaemia. In clinical trials with Sampine-A, no adverse events peculiar to this combination have been observed. Adverse events have been limited to those that were reported previously with S (-) Amlodipine and/or atorvastatin (please see respective adverse event tables below).
In controlled clinical trials, discontinuation of therapy due to clinical adverse events or laboratory abnormalities was only required in 5.1% of patients treated with both S (-) Amlodipine and atorvastatin compared to 4.0% of patients given placebo.
The following adverse events, listed according to the MedDRA system organ class and frequencies, are for S-amlodipine and atorvastatin individually. Very common: = 1/10, common: = 1/100 and < 1/10, Uncommon: = 1/1000 and < 1/100, Rare: = 1/10,000 and < 1/1000, Very Rare: < 1/10,000.

Med DRA System Organ Class

Undesirable Effects

Frequency

 

 

 

 

S (-) Amlodipine

Atorvastatin

Blood and the lymphatic system disorders

Leucopenia

Very rare

-

 

 

Thrombocytopenia

Very Rare

Uncommon

Immune system disorders

Allergic reactions; urticaria

Very Rare

Uncommon

 

 

 

 

 

Metabolism and Nutrition disorders

Hyperglycemia

Very Rare

Uncommon

 

Weight gain

Uncommon

Uncommon

 

 

 

 

 

 

Weight decrease

Uncommon

-

 

 

Hypoglycemia

-

Uncommon

 

 

 

 

 

 

Anorexia

-

Uncommon

Psychiatric Disorders

Insomnia

Uncommon

common

 

Mood changes

Uncommon

-

 

Nervous system disorders

Somnolence

common

-

 

 

Dizziness

Common

Common

 

Headache

Common

Common

 

Tremor

Uncommon

-

 

 

Hypoesthesia, paresthesia

Uncommon

Common

 

Hypertonia

Very rare

-

 

 

Peripheral neuropathy

Very rare

Uncommon

 

Amnesia

-

Uncommon

Eye disorders

Visual disturbances

Uncommon

-

 

Ear and labyrinth disorders

Tinnitus

Uncommon

Uncommon

Cardiac disorders

Palpitations

Common

-

 

 

Syncope

Uncommon

-

 

 

Angina pain

Rare

-

 

 

Myocardial infraction

Very rare

-

 

 

Arrhythmia (including

Very rare

-

 

 

bradychardia, ventricular

 

 

 

 

tachycardia and atrial fibrillation)

 

 

 

Vascular disorders

Flushing

Common

-

 

 

Hypotension

Uncommon

-

 

 

Vasculitis

Very rare

-

 

Respiratory, thoracic and mediastinal disorders

Dyspnoea

Uncommon

-

 

 

Rhinitis

Uncommon

-

 

 

Coughing

Very rare

-

 

Gastrointestinal disorders

Gingival hyperplasia

Very rare

-

 

 

Abdominal pain, nausea

Common

Common

 

Vomiting

Uncommon

Uncommon

 

Dyspepsia

Uncommon

Common

 

Altered bowel habits

Uncommon

-

 

 

Dry mouth

Uncommon

-

 

 

Taste perversion

uncommon

-

 

 

Diarrohea, constipation, flatulence

-

Common

 

Pancreatitis

Very rare

Rare

Hepato-biliary disorders

Hepatitis, cholestatic jaundice

Very rare

Rare

Skin and subcutaneous tissue disorders

Quincke's oedema

Very rare

Very rare

 

Erythema multiforme

Very rare

-

 

 

 

 

 

 

Alopecia

Uncommon

Uncommon

 

Purpura

Uncommon

-

 

 

Skin discoloration

Uncommon

-

 

 

Increase sweating

Uncommon

-

 

 

 

 

 

 

Pruritus

Uncommon

Common

 

Rash

Uncommon

Common

 

Bullous rashes

-

Rare

 

Stevens-johnson syndrome

Very rare

Very rare

 

 

 

 

 

(Lyells's syndrome)

-

Very rare

Musculoskeletal and connective tissue disorders

Arthralgia, myalgia

Uncommon

Common

 

Muscle cramps

Uncommon

Rare

 

Back pain

Uncommon

Common

 

Myositis

-

Rare

 

 

 

 

 

 

Rhabdomyolysis, myopathy

-

Very rare

 

 

 

 

 

 

Tendinopathy, sometimes

 

Very rare

 

complicated by rupture

 

 

 

Renal and urinary disorders

Micturition disorders, nocturia,

Uncommon

-

 

 

increased urinary frequency

 

 

 

Reproductive system and breast disorders

Impotence

Uncommon

Uncommon

 

Gynaecomastia

Uncommon

-

 

 

 

 

 

General disorders and administration site conditions

Oedema, peripheral oedema

common

Rare

 

Fatigue

Common

-

 

 

 

 

 

 

Chest pain

Uncommon

Common

 

Asthenia

Uncommon

Common

 

 

 

 

 

 

Pain

Uncommon

-

 

 

Malaise

Uncommon

Uncommon

Investigations

Hepatic  enzyme elevations ALT,

Very rare

Common

 

AST (mostly consistent

 

 

 

 

with cholestasis)

 

 

 

 

CPK increased levels

-

common

 

 

 

 

 

ADVERSE DRUG REACTIONS

 

 

 

 

INTERACTIONS WITH OTHER MEDICINAL PRODUCTS
Data from a drug-drug interaction study involving 10 mg of S (-) Amlodipine and 80 mg of atorvastatin in healthy subjects indicate that the pharmacokinetics of S (-) Amlodipine is not altered when the drugs are co-administered. The effect of S (-) Amlodipine on the pharmacokinetics of atorvastatin showed no effect on the Cmax: 91% (90% confidence interval: 80 to 103%), but the AUC of atorvastatin increased by 18% (90% confidence interval: 109 to 127%) in the presence of S (-) Amlodipine, which was not clinically meaningful.
No drug interaction studies have been conducted with S (-) Amlodipine/Atorvastatin tablets and other drugs, although studies have been conducted in the individual S (-) Amlodipine and atorvastatin components, as described below:
STUDIES WITH S (-) AMLODIPINE
In vitro data in human plasma indicate that S (-) Amlodipine has no effect on the protein binding of drugs tested (digoxin, phenytoin, warfarin, and indomethacin).
Cimetidine
Co-administration of S (-) Amlodipine with cimetidine did not alter the pharmacokinetics of S (-) Amlodipine.
Magnesium and Aluminum Hydroxide Antacid
Co-administration of magnesium and aluminum hydroxide antacid with a single dose of S (-) Amlodipine had no significant effect on the pharmacokinetics of S (-) Amlodipine.
Sildenafil
A single 100 mg dose of sildenafil in subjects with essential hypertension had no effect on the pharmacokinetic parameters of S (-) Amlodipine. When S (-) Amlodipine and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect.
Digoxin
Co-administration of S (-) Amlodipine with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers.
Ethanol (Alcohol)
Single and multiple 10 mg doses of S (-) Amlodipine had no significant effect on the pharmacokinetics of ethanol.
Warfarin
Co-administration of S (-) Amlodipine with warfarin did not change the warfarin prothrombin response time.
CYP3A4 Inhibitors
Co-administration of a 180 mg daily dose of diltiazem with 5 mg S (-) Amlodipine in elderly hypertensive patients resulted in a 60% increase in S (-) Amlodipine systemic exposure. Erythromycin co-administration in healthy volunteers did not significantly change S (-) Amlodipine systemic exposure. However, strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, ritonavir) may increase the plasma concentrations of S (-) Amlodipine to a greater extent. Monitor for symptoms of hypotension and edema when S (-) Amlodipine is co-administered with CYP3A4 inhibitors.
CYP3A4 Inducers
No information is available on the quantitative effects of CYP3A4 inducers on S (-) Amlodipine. Blood pressure should be closely monitored when S (-) Amlodipine is co-administered with CYP3A4 inducers.
STUDIES WITH ATORVASTATIN
The risk of myopathy during treatment with statins is increased with concurrent administration of fibric acid derivatives, lipid-modifying doses of niacin, cyclosporine, or strong CYP 3A4 inhibitors (e.g., clarithromycin, HIV protease inhibitors, and itraconazole)
Strong Inhibitors of CYP 3A4
Atorvastatin is metabolized by cytochrome P450 3A4. Concomitant administration of atorvastatin with strong inhibitors of CYP 3A4 can lead to increases in plasma concentrations of atorvastatin. The extent of interaction and potentiation of effects depends on the variability of effect on CYP 3A4.
Clarithromycin
Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin 80 mg with clarithromycin (500 mg twice daily) compared to that of atorvastatin alone. Therefore, in patients taking clarithromycin, use caution when administering atorvastatin doses >20 mg.
Combination of Protease Inhibitors
Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin 40 mg with ritonavir plus saquinavir (400 mg twice daily) or atorvastatin 20 mg with lopinavir plus ritonavir (400 mg + 100 mg twice daily) compared to that of atorvastatin alone. Therefore, in patients taking HIV protease inhibitors, use caution when administering atorvastatin doses >20 mg
Itraconazole
Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin 40 mg and itraconazole 200 mg. Therefore, in patients taking itraconazole, use caution when administering atorvastatin doses >20 mg.
Grapefruit juice
Contains one or more components that inhibit CYP 3A4 and can increase plasma concentrations of atorvastatin, especially with excessive grapefruit juice consumption (>1.2 liters per day).
Cyclosporine
Atorvastatin and atorvastatin-metabolites are substrates of the OATP1B1 transporter. Inhibitors of the OATP1B1 (e.g., cyclosporine) can increase the bioavailability of atorvastatin. Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin 10 mg and cyclosporine 5.2 mg/kg/day compared to that of atorvastatin alone in cases where co-administration of atorvastatin with cyclosporine is necessary, the dose of atorvastatin should not exceed 10 mg.
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. Due to the dual interaction mechanism of rifampin, simultaneous co-administration of atorvastatin with rifampin is recommended, as delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations.
Digoxin
When multiple doses of atorvastatin and digoxin were co-administered, steady-state plasma digoxin concentrations increased by approximately 20%. Patients taking digoxin should be monitored appropriately.
Oral Contraceptives
Co-administration of atorvastatin and an oral contraceptive increased AUC values for norethindrone and ethinyl estradiol. These increases should be considered when selecting an oral contraceptive for a woman taking S (-) Amlodipine/Atorvastatin tablets.
Warfarin
Atorvastatin had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin treatment.

Warnings and precautions

PREGNANCY AND LACTATION
S(-)Amlodipine/Atorvastatin tablets contain atorvastatin and are therefore contraindicated in women who are pregnant or may become pregnant. The atorvastatin component of S(-) Amlodipine/ Atorvastatin tablets may cause fetal harm when administered to a pregnant woman. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development.
There are no adequate and well-controlled studies of atorvastatin use during pregnancy; however in rare reports congenital anomalies were observed following intrauterine exposure to statins. S (-) Amlodipine/Atorvastatin tablets, which include atorvastatin, should be administered to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the potential hazards. If the patient becomes pregnant while taking this drug, therapy should be discontinued immediately and the patient apprised of the potential hazard to the fetus.
It is not known whether atorvastatin or S (-) Amlodipine are excreted into human milk; however a small amount of another statin does pass into breast milk. Because statins have the potential for serious adverse reactions in nursing infants, women taking S (-) Amlodipine/Atorvastatin tablets should not breastfeed their infants.

SPECIAL WARNINGS AND PRECAUTIONS FOR USE Skeletal Muscle
Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with the atorvastatin component of S (-) Amlodipine/Atorvastatin tablets and with other statins. A history of renal impairment may be a risk factor for the development of rhabdomyolysis. Such patients merit closer monitoring for skeletal muscle effects.

Interacting agents

Prescribing recommendations

Cyclosporine

Do not exceed 10 mg atorvastatin daily

Clarithromycin, itraconazole, HIV protease inhibitors

Caution when exceeding doses> 20 mg atorvastatin daily.

(ritonavir plus sapuniavir or lopinavir plus ritonacir)

The lowest dose necessary should be used.


In patients taking S (-) Amlodipine/Atorvastatin tablets, therapy 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 (e.g., severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders, and uncontrolled seizures).
Liver dysfunctioning
Statins, like the atorvastatin component of S (-) Amlodipine/Atorvastatin tablets and like some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver function. Persistent elevations (>3 times the upper limit of normal [ULN] occurring on 2 or more occasions) in serum transaminases occurred in 0.7% of patients who received atorvastatin in clinical trials. The incidence of these abnormalities was 0.2%, 0.2%, 0.6%, and 2.3% for 10, 20, 40, and 80 mg, respectively.
It is recommended that liver function tests be performed prior to and at 12 weeks following both the initiation of therapy and any elevation of dose, and periodically (e.g., semiannually) thereafter. Liver enzyme changes generally occur in the first 3 months of treatment with the atorvastatin component of S (-) Amlodipine/Atorvastatin tablets. Patients who develop increased transaminase levels should be monitored until the abnormalities resolve.
Increased Angina and/or Myocardial Infarction
Worsening angina and acute myocardial infarction can develop after starting or increasing the dose of S (-) Amlodipine, particularly in patients with severe obstructive coronary artery disease.
SPECIAL WARNINGS AND PRECAUTIONS FOR USE
Hypotension


Symptomatic hypotension is possible, particularly in patients with severe aortic stenosis. Because of the gradual onset of action, acute hypotension is unlikely.
Beta-Blocker Withdrawal
The S (-) Amlodipine component of S (-) Amlodipine/Atorvastatin tablets is not a beta-blocker and therefore gives no protection against the dangers of abrupt beta-blocker withdrawal; any such withdrawal should be by gradual reduction of the dose of beta-blocker.
Endocrine Function
Statins, such as the atorvastatin component of S (-) Amlodipine/Atorvastatin tablets, 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. Use caution when administering a statin with drugs that may decrease the levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone, and cimetidine.
Use in Patients with Recent Stroke or TIA
In a post-hoc analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study where atorvastatin 80 mg vs. placebo was administered in 4,731 subjects without CHD who had a stroke or TIA within the preceding 6 months, a higher incidence of hemorrhagic stroke was seen in the atorvastatin 80 mg group compared to placebo (55, 2.3% atorvastatin vs. 33, 1.4% placebo; HR: 1.68, 95% CI: 1.09, 2.59; p=0.0168). The incidence of fatal hemorrhagic stroke was similar across treatment groups (17 vs. 18 for the atorvastatin and placebo groups, respectively). The incidence of nonfatal hemorrhagic stroke was significantly higher in the atorvastatin group (38, 1.6%) as compared to the placebo group (16, 0.7%). Some baseline characteristics, including hemorrhagic and lacunar stroke on study entry, were associated with a higher incidence of hemorrhagic stroke in the atorvastatin group.
CNS Toxicity
Brain hemorrhage was seen in a female dog treated with atorvastatin calcium for 3 months at a dose equivalent to 120 mg atorvastatin/kg/day. Brain hemorrhage and optic nerve vacuolation were seen in another female dog that was sacrificed in moribund condition after 11 weeks of escalating doses of atorvastatin calcium equivalent to up to 280 mg atorvastatin/kg/day. The 120 mg/kg dose of atorvastatin resulted in a systemic exposure approximately 16 times the human plasma area-under-the-curve (AUC, 0–24 hours) based on the maximum human dose of 80 mg/day. A single tonic convulsion was seen in each of 2 male dogs (one treated with atorvastatin calcium at a dose equivalent to 10 mg atorvastatin/kg/day and one at a dose equivalent to 120 mg atorvastatin/kg/day) in a 2-year study. No CNS lesions have been observed in mice after chronic treatment for up to 2 years at doses of atorvastatin calcium equivalent to up to 400 mg atorvastatin/kg/day or in rats at doses equivalent to up to 100 mg atorvastatin/kg/day. These doses were 6 to 11 times (mouse) and 8 to 16 times (rat) the human AUC (0–24) based on the maximum recommended human dose of 80 mg atorvastatin/day.
CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell infiltration of perivascular spaces, have been observed in dogs treated with other statins. A chemically similar drug in this class produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion at a dose that produced plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose.

Overdosage and Contraindications

OVERDOSE AND TREATMENT
There is no information on overdosage with S (-) Amlodipine/Atorvastatin tablets in humans.
Information on S (-) Amlodipine
Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia. In humans, experience with intentional overdosage of S (-) Amlodipine is limited.
Single oral doses of S (-) Amlodipine maleate equivalent to 40 mg S (-) Amlodipine/kg and 100 mg S (-) Amlodipine/kg in mice and rats, respectively, caused deaths. Single oral S (-) Amlodipine maleate doses equivalent to 4 or more mg S (-) Amlodipine/kg in dogs (11 or more times the maximum recommended clinical dose on a mg/m2 basis) caused a marked peripheral vasodilation and hypotension.
If overdose should occur, initiate active cardiac and respiratory monitoring. Perform frequent blood pressure measurements. Should hypotension occur, provide cardiovascular support including elevation of the extremities and administration of fluids. If hypotension remains unresponsive to these conservative measures, consider administration of vasopressors (such as phenylephrine) with specific attention to circulating volume and urine output. As S (-) Amlodipine is highly protein bound, hemodialysis is not likely to be of benefit.
Information on Atorvastatin
There is no specific treatment for atorvastatin overdosage. In the event of an overdose, the patient should be treated symptomatically, and supportive measures instituted as required. Due to extensive drug binding to plasma proteins, hemodialysis is not expected to significantly enhance atorvastatin clearance.

CONTRAINDICATIONS
S (-) Amlodipine/Atorvastatin tablets contain atorvastatin and are therefore contraindicated in patients with active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels, pregnancy and breast-feeding, In combination with itraconazole, ketoconazole and telithromycin.
S (-)Amlodipine/Atorvastatin tablets are contraindicated in patients with known hypersensitivity to any component of this medication.

Clinical pharmacology.

PHARMACEUTICAL FORM
Film Coated Tablets
PHARMACOTHERAPEUTIC GROUP:
Antihypertensive and Antihyperlipidemic
ATC CODE: C10BX03
PHARMACOLOGICAL PROPERTIES
PHARMACODYNAMIC PROPERTIES: This is a combined medicine; the action of which is caused by its active components.
Mechanism of action:
S (-) Amlodipine/Atorvastatin tablets are a combination of two drugs, a dihydropyridine calcium channel blocker S (-) Amlodipine and an HMG-CoA reductase inhibitor atorvastatin. The S (-) Amlodipine component of S (-) Amlodipine/Atorvastatin tablets inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. The atorvastatin component of S (-) Amlodipine/Atorvastatin tablets is a selective, competitive inhibitor of HMG-CoA reductase (statin), the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol.

PHARMACOKINETIC PROPERTIES Absorption

Following oral administration of S (-) Amlodipine/Atorvastatin tablets, peak plasma concentrations of S (-) Amlodipine and atorvastatin are seen at 6 to 12 hours and 1 to 2 hours post dosing, respectively. The rate and extent of absorption (bioavailability) of S (-) Amlodipine and atorvastatin from S (-) Amlodipine/Atorvastatin tablets are not significantly different from the bioavailability of S (-) Amlodipine and atorvastatin administered separately.
The bioavailability of S (-) Amlodipine from S (-) Amlodipine/Atorvastatin tablets was not affected by food. Food decreases the rate and extent of absorption of atorvastatin from S (-) Amlodipine/Atorvastatin tablets by approximately 32% and 11%, respectively, as it does with atorvastatin when given alone. LDL-C reduction is similar whether atorvastatin is given with or without food.
Distribution
Ex vivo studies have shown that approximately 93% of the circulating S (-) Amlodipine drug is bound to plasma proteins in hypertensive patients. Steady-state plasma levels of S (-) Amlodipine are reached after 7 to 8 days of consecutive daily dosing.
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 calcium is likely to be secreted in human milk.
Metabolism
S (-) Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic 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
Elimination of S (-) Amlodipine from the plasma is biphasic with a terminal elimination half-life of about 30–50 hours. Ten percent of the parent S(-)Amlodipine compound and 60% of the metabolites of S (-) Amlodipine are excreted in the urine.
Atorvastatin 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 atorvastatin 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 atorvastatin is recovered in urine following oral administration.
THERAPEUTIC INDICATIONS
Sampine-A is indicated in patients for whom treatment with both S (-) Amlodipine and atorvastatin is appropriate.
S (-) Amlodipine
1. Hypertension: It is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents.
2. Coronary Artery Disease (CAD)
Chronic Stable Angina: It is indicated for the treatment of chronic stable angina. It may be used alone or in combination with other antianginal or antihypertensive agents; Vasospastic Angina (Prinzmetal's or Variant Angina): It is indicated for the treatment of confirmed or suspected vasospastic angina. It may be used as monotherapy or in combination with other antianginal drugs.
Angiographically Documented CAD: In patients with recently documented CAD by angiography and without heart failure or an ejection fraction <40%, It is indicated to reduce the risk of hospitalization due to angina and to reduce the risk of a coronary revascularization procedure.
Atorvastatin
Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is recommended as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate. In patients with CHD or multiple risk factors for CHD, the atorvastatin component of S (-) Amlodipine/Atorvastatin tablets can be started simultaneously with diet restriction.
1. Prevention of Cardiovascular Disease: In adult patients without clinically evident coronary heart disease, but with multiple risk factors for coronary heart disease such as age, smoking, hypertension, low HDL-C, or a family history of early coronary heart disease, atorvastatin is indicated to:

Reduce the risk of myocardial infarction
Reduce the risk of stroke
Reduce the risk for revascularization procedures and angina
In patients with type 2 diabetes, and without clinically evident coronary heart disease, but with multiple risk factors for coronary heart disease such as retinopathy, albuminuria, smoking, or hypertension, atorvastatin calcium tablets are indicated to:

Reduce the risk of myocardial infarction
Reduce the risk of stroke;
In patients with clinically evident coronary heart disease, atorvastatin calcium tablets are indicated to:

Reduce the risk of non-fatal myocardial infarction Reduce the risk of fatal and non-fatal stroke
Reduce the risk for revascularization procedures Reduce the risk of hospitalization for CHF Reduce the risk of angina
2. Heterozygous Familial and Nonfamilial Hyperlipidemia: It 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 primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Fredrickson Types IIa and Iib);
3. Elevated Serum TG Levels: It is indicated as an adjunct to diet for the treatment of patients with elevated serum TG levels (Fredrickson Type IV);
4. Primary Dysbetalipoproteinemia: It is indicated for the treatment of patients with primary dysbetalipoproteinemia (Fredrickson Type III) who do not respond adequately to diet;
5. Homozygous Familial Hypercholesterolemia: It is indicated 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;
6. Pediatric Patients: It is indicated as an adjunct to diet to reduce total-C, LDL-C, and apo B levels in boys and postmenarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia if after an adequate trial of diet therapy the following findings are present:
³LDL-C remains 190 mg/dL or LDL-C remains ³ 160 mg/dL and:
There is a positive family history of premature cardiovascular disease or two or more other CVD risk factors are present in the pediatric patients.
The antidyslipidemic component of S (-) Amlodipine/Atorvastatin tablets has not been studied in conditions where the major lipoprotein abnormality is elevation of chylomicrons (Fredrickson Types I and V).
DOSAGE AND ADMINISTRATION
The usual starting dose is 2.5 mg/10 mg once daily.
S (-) Amlodipine/Atorvastatin tablets may be used to initiate treatment in patients with hyperlipidemia and either hypertension or angina. The recommended starting dose of S (-) Amlodipine/Atorvastatin tablets should be based on the appropriate combination of recommendations for the monotherapies. The maximum dose of the S (-) Amlodipine component of S (-) Amlodipine/Atorvastatin tablets is 10 mg once daily. The maximum dose of the atorvastatin component of S (-) Amlodipine/Atorvastatin tablets is 80 mg once daily.
MODE OF ADMINISTRATION
Doses may be taken at any time of day with or without food.

STORAGE CONDITION
Store below 30°C.
Keep all medicines out of reach of children.
NAME AND ADDRESS OF MANUFACTURER
DOSAGE FORMS AND PACKAGING AVAILABLE
Alu-Alu blister of 14 tablets. 2 or 10 blisters are in a carton.
SHELF LIFE
36 months
Kusum Healthcare Pvt. Ltd. A
SP 289(A), RIICO Industrial Area, Chopanki, Bhiwadi (Rajasthan), India
DATE OF REVISION OF PACKAGE INSERT: Not Applicable
MM Reg. No.: 1812AA 7077

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