Polycap, Atenolol 50 mg/ Thiazide 12·5 mg/ Ramipril 5 mg/ Simvastatin 20 mg/ Aspirin 100 mg Patient Information Sheet
For the use of Cardiologist onlySimvastatin, Ramipril, Atenolol, Hydrochlorothiazide and Aspirin (Enteric coated Tablet) Capsules
"POLYCAP"
Each hard gelatin capsule contains: Simvastatin BP 20 mg
Ramipril IP 5 mg
Atenolol IP 50 mg
Hydrochlorothiazide IP 12.5 mg
Aspirin IP (Enteric coated tablet) 100 mg
Excipients q.s.
Colour: Titanium Dioxide IP Approved colours used in capsule shell
POLYCAP™ is a fixed-dose combination of three blood pressure lowering drugs (atenolol, ramipril, hydrochlorothiazide), a lipid lowering drug (simvastatin) and an anti-platelet drug (aspirin). Atenolol component is a synthetic, beta 1-selective adrenoreceptor blocking agent, may be chemically described as 2-[4-[2-hydroxy-3-(propan-2-ylamino)propoxy]phenyl]acetamide. Ramipril component is a 2-aza-bicyclo [3.3.0]-octane-3-carboxylic acid derivative. Ramipril's chemical name is (2S,3aS,6aS)-1 [(S)-N-((S)-1-Carboxy-3-phenylpropyl] alanyl] octahydrocyclopenta (b]pyrrole-2-carboxylic acid, 1-ethyl ester. Simvastatin component is butanoic acid, 2,2-dimethyl-,1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4hydroxy-6-oxo-2H-pyran-2-yl)-ethyl]-1-naphthalenyl ester, (1S-[1a,3a,7B,8B(2S',4S*),-8a33)]. Hydrochlorothiazide component is a diuretic and antihypertensive. It is the 3,4-dihydro derivative of chlorothiazide. Its chemical name is 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7- sulfonamide 1,1-dioxide. Aspirin (acetylsalicylic acid) component is chemically known as 2- acetyloxy benzoic acid.
CLINICAL PHARMACOLOGY
Mechanism of Action
POLYCAP™ reduces the risk factors of CHD and Stroke like B.P., LDL and Platelet
aggregability and thus reduces the overall CHD and Stroke events.
Atenolol: Atenolol is a beta 1 -selective beta-adrenoceptor blocking agent without membrane stabilizing or intrinsic sympathomimetic (partial agonist) activities.
Ramipril: Ramipril and its active metabolite, ramiprilat, inhibit angiotensin-converting
enzyme (ACE).
Hydrochlorothiazide: Hydrochlorothiazide is a diuretic/ antihypertensive that blocks the reabsorption of sodium and chloride ions in the distal convoluted tubule of the kidney, and thereby increases the quantity of sodium traversing the distal tubule and the volume of water excreted. The exact mechanism of the antihypertensive effect of hydrochlorothiazide is not known.
Simvastatin: Simvastatin lowers plasma cholesterol and lipoprotein levels by inhibiting HMG CoA reductase and cholesterol synthesis in the liver and by increasing the number of hepatic LDL receptors on the cell-surface.
Aspirin: Aspirin is a non-steroidal anti-inflammatory drug which affects platelet aggregation by irreversibly inhibiting prostaglandin cyclo-oxygenase. It thus inhibits the generation of thromboxane A,, a powerful inducer of platelet aggregation and vasoconstriction
Pharmacokinetics
All the drugs in the POLYCAP™ are well absorbed orally and show no major deviation from their respective individual pharmacokinetics.
Absorption
Atenolol: Atenolol is not completely absorbed from the gastrointestinal tract, its oral bioavailability being of the order 50-60%. It is approximately 5% bound to plasma proteins.
Ramipril: Ramipril is hydrolyzed in the liver to form the active angiotensin converting enzyme (ACE) inhibitor. Ramiprilat that is a potent and long acting ACE inhibitor. Following oral administration ramipril is rapidly absorbed from the gastrointestinal tract: peak plasma concentrations of ramipril are reached within one hour. Peak plasma concentrations of the active metabolite, ramiprilat, are reached within 2-4 hours
Simvastatin: After an oral dose, approximately 60-85% of simvastatin is absorbed and undergoes extensive first-pass extraction in the liver, its primary site of action. Hydrochlorothiazide: Hydrochlorothiazide is well absorbed (65%-757o) following oral administration. Absoipiion of hydrochlorothiazide is reduced in patients with congestive heart failure Peak plasma concentrations are observed within 1-5 hours of dosing, and range from 70490 ng/mL following oral doses of 12.5-100 mg. Plasma concentrations are linearly related to the administered dose.
Aspirin: Aspirin is rapidly absorbed from the gastrointestinal tract if given in aqueous solution. Its absorption rate from capsules and tablets depends on the release characteristics of these dosage forms and isa function of the drug's rate of dissolution. Distribution and Metabolism
Atenolol: Atenolol is eliminated virtually entirely as unchanged drug in the urine and dosage needs to be reduced in patients with moderate to severely impaired renal function (glomerular filtration rate less than 30 ml/min). There is no need for modification of dosage of atenolol in liver disease.
Ramipril: Ramipril is almost completely metabolized and the metabolites are excreted mainly via the kidneys. In addition to the bioactive metabolite, Ramiprilat, other, inactive metabolites have been identified, including diketopiperazine ester, diketopiperazine acid and conjugates Simvastatin: Simvastatin is metabolized by cytochrome P450 (CYP) 3A4 but it is no* an inhibitor of this isoform. Therefore, it is not expected to affect tne plasma levels of other drugs metabolized by CYP3A4.
Hydrochlorothiazide: Concentrations of hydrochlorothiazide are 1.6-1.8 times higher in whole blood than in plasma. Binding to serum proteins has been reported to be approximately 40% to 68%.
Aspirin: Aspirin (acetylsalicylic acid) is hydrolyzed in the body to salicylic acid, a process which probably occurs mainly in the liver and has a biologic half-life of about 15 min. Aspirin and salicylic acid have analgesic, antipyretic and anti-inflammatory activity. Elimination
Atenolol: The plasma half-life of atenolol is about 6 hours However, the duration of therapeutic effect is much longer than this, allowing once daily dosing. Ramipril: Plasma concentrations of Ramiprilat decline in a polyphasic manner. The effective half-life of Ramiprilat after multiple once daily administration of ramipril is 13-17 hours for 5-10 mg ramipril and markedly longer for lower doses, 1.25-2.5 mg ramipril. Steady-state plasma concentrations of Ramiprilat after once dailv dosing with the usual doses of ramipril are reached by about the fourth day of treatment
Simvastatin: Following an oral dose of simvastatin in man, 13% of the dose was excreted in urine and 60% in feces. Plasma concentrations declined rapidly to about 10% of peak by 12 hours post-dose.
Hydrochlorothiazide: The plasma elimination half-life has been reported to be 6-15 hours. Hydrochlorothiazide is eliminated primarily by renal pathways. Plasma concentrations of hydrochlorothiazide are increased and the elimination half-life is prolonged in patients with renal disease
Aspirin: Following absorption of aspirin and its conversion in the body to salicylic acid, the latter is eliminated by five parallel and competing pathways: renal excretion.
CLINICAL STUDY DATA The Indian POLYCAP™ Study
The effect of POLYCAP™ on biood pressure, lipids, heart rate, and urinary thromboxane B2 levels and its tolerability was assessed in a randomized, double-blind, active-comparator controlled clinical trial conducted in 56 centres in India, The Indian POLYCAP" Study (TIPS) 2053 individuals without cardiovascular disease, aged 45-80 years, and wilh one risk factor were selected and randomly assigned, by a central secure website, to the POLYCAP"' (n=412), or to eight other groups, each with about 200 individuals, of aspirin alone, simvastatin alone, hydrochlorothiazide alone, three combinations of the two blood-pressure-lowering drugs, three blood-pressure-lowering drugs alone, or three blood-pressure-lowering drugs plus aspirin. The primary outcomes were changes in LDL for the effect of lipids, blood pressure for antihypertensive drugs, heart rate for the effects of atenolol, urinan/ 11-dehydrothromboxane B2 for the anti-platelet effects of aspirin. and rates of discontinuation of drugs for safety.Compared with groups not receiving Dlood-pressure-lowering drugs, the POLYCAP * reduced systolic blood pressure by 7 4 mm Hg (95% CI 6-1-8-1) and diastolic blood pressure by 5-6 mm Hg (4 7-6 4), which was similar when three blood-pressure-lowenng drugs were used, with or without aspirin. POLYCAP" reduced LDL cholesterol by 0 70 mmol/L (95% CI 0 62-0 78), which was less than that with simvastatin alone (0 83 mmol/L. 0'72-0-93; p=0 04): both reductions were greater than for groups without simvastatin (p<00001) The reductions in heart rate with POLYCAP™ and other groups using atenolol were similar (7 0 beats per min), and both were significantly greater than that in groups without atenolol (p<0 0001). The reductions in 11-dehydrothromboxane B2 were similar with the POLYCAP™ (283-1 ng/mmol creatinine, 95% CI 229 1-337 0) and aspirin alone (348 8 ng/mmoi creatinine, 277 6-419 9). From the study results, it was postulated that regular use of POLYCAP™ can reduce the risk of coronary heart disease by 62% and of stroke by 48%. Reference Effects of a polypill (POLYCAP™) on risk factors in middle-aged individuals without cardiovascular disease- The Indian POLYCAP™ Study (TIPS). Lancet 20C9 Mar 30 [Epub ahead of pnntl PMID: 19339045
INDICATIONS and USAGE
POLYCAP™ is indicated for Secondary prevention of Coronary Heart Disease / Stroke in patients with multiple risk factors where use of this combination is appropriate
CONTRAINDICATIONS
POLYCAP™ is contraindicated in anyone who is hypersensitive to any of the components of this drug. All the respective contraindications to the individual drugs in the POLYCAP™ apply lo POLYCAP™ also. POLYCAP" is contraindicated in anyone in whom atenolol, ramipril hydrochlorthiazide, simvastatin or aspirin alone or in combination are contraindicated. Atenolol is contraindicated in sinus bradycardia, heart block greater than first degree, cardiogenic shock, and overt cardiac failure Simvastatin is contraindicated in active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels
WARNINGS and PRECAUTIONS
All the warnings and precautions applicable about the individual drugs apply to POLYCAP". Atenolol
Cardiac Failure: Renal and Hepatic Disease and Electrolyte Disturbances: Ischemic Heart Disease: Concomitant Use of Calcium Channel Blockers: Bronchospastic Diseases Anesthesia and Major Surgery, Untreated Pheochromocytoma Ramipril
Anaphylactoid and Possibly Related Reactions: Head and Neck Angioedema: Intestinal Angioedema- Anaphylactoid reactions auring membrane exposure: Hypotension: Hepatic Failure: Neutropenia/Agranulocytosis Simvastatin
Myopathy/ Rhabdomyolysis: Liver Dysfunction: Aspirin
Coagulation Abnormalities: Gastrointestinal (Gl) Side Effects: Peptic Ulcer Disease
DRUG INTERACTIONS
No major drug-drug interactions are seen when ail the drugs are used in the fixed-dose combination as POLYCAP™ However individual drug interactions with each component should be considered while prescribing POLYCAP 1.
USE in PREGNANCY
POLYCAP" should not be taken during pregnancy. When pregnancy is detected.
POLYCAP" should be discontinued as soon as possible
USE in NURSING MOTHERS
POLYCAP" should not be taken bv breast feeding mothers.
PAEDIATRIC USE
Safety of POLYCAP™ has not been tested in this group of population.
GERIATRIC USE
Unless any other co-existing factors are present, POLYCAP™ has been found to be safe in all age groups from 45-80 years. Individual discretion regarding risk vs. benefits and clinical judgment needs to be exercised while prescribing POLYCAP™ in geriatric patients.
TERATOGENIC EFFECTS
The administration of ramipril to female rats during the fetal penod and lactation produced irreversible renal damage (dilatation of the renal pelvis) in the offspring at daily doses of 50 mg/kg body weight and higher. In therapeutic doses, angiotensin converting enzymes (ACE) inhibitor drugs can cause fetal and neonatal morbidity and mortality when administered to pregnant women.
ADVERSE REACTIONS
The rates of discontinuing medications were similar across study arms during 'The Indian POLYCAP™ Study'. Elevated creatinine (an increase by >50%) was seen in 7.8%, elevated K+ (>5.5 mmol/l) was seen in 3.9%, or elevated liver enzymes (doubling of SGPT) was seen in 2.9% and were not significantly different between study arms.
Majority of adverse events observed in the trial were mild to moderate, except for three serious adverse events including one stroke and two hospitalizations one due to stroke/TIA and one due to other cardiac reasons. The rate of adverse events in POLYCAP'" group, was comparable (p<0.05) to all other treatment arms. Commonly observed adverse events irrespective of causal relationship with POLYCAP'" included dyspepsia and related disorders (10%), cough (15%), vertigo/dizziness (13%), musculoskeletal complaints (8%), fatigue/weakness (10%).
Other adverse events seen with POLYCAP'" were abdominal discomfort/pain, allergic reactions, headache, chest pain, diarrhea, URTI, fever and related symptoms, Nausea and vomiting and anxiety disorder.
Reference: Effects of a polypill (POLYCAP™) on risk factors in middle-aged individuals without cardiovascular disease: The Indian POLYCAP'" Study (TIPS). Lancet. 2009 Mar 30. [Epubahead of print] PMID: 19339045
OVERDOSAGE
No reports on overdosage with POLYCAP™ are available. However overdosage recommendations of the individual drugs need to be followed in the event of an overdosage Gastric lavage needs to be done promptly and patient should be put on supportive therapy and monitored for fluid and electrolyte imbalance, hypotension, Gl bleed etc. Signs of electrolyte imbalance include dry mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain and cramps, seizures, oliguria, hypotension, and gastrointestinal disturbances
DOSAGE and ADMINISTRATION
As directed by the Cardiologist. One capsule of POLYCAP™ should be taken once daily, preferably at one fixed easy-to-remembertime, such as in the morning.
Storage: Store in a cool dry place, Protect from light.
Keep all medicines out of reach of children.
Manufactured by:
@ CADI LAs
- PHARMACEUTICALSg
1389, Dholka - 387810, Dist.: Ahmedabad.