COMPOSITION
Each film-coated tablet contains: Amlodipine (as besylate) U.S.P. 5mg & Valsartan U.S.P. 80mg.
Each film-coated tablet contains: Amlodipine (as besylate) U.S.P. 5mg & Valsartan U.S.P. 160mg.
Each film-coated tablet contains: Amlodipine (as besylate) U.S.P. 10mg & Valsartan U.S.P. 160mg.

DESCRIPTION
Caloc-V is a fixed combination of amlodipine and valsartan.

Caloc-V contains the besylate salt of amlodipine, a dihydropyridine calcium-channel blocker (CCB). Amlodipine besylate is a white to pale yellow crystalline powder, slightly soluble in water and sparingly soluble in ethanol. Amlodipine besylate’s chemical name is 3-Ethyl-5-methyl(4RS)-2-[(2-aminoethoxy) methyl]-4-(2 chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate benzenesulphonate; its structural formula is

Valsartan is a nonpeptide, orally active, and specific angiotensin II antagonist acting on the AT¹ receptor subtype. Valsartan is a white to partially white fine powder, soluble in ethanol and methanol and slightly soluble in water. Valsartan’s chemical name is N-(1-oxopentyl)-N-[[2’- (1H-tetrazol-5-yl) [1,1’-biphenyl]-4 yl]methyl]-L-valine; its structural formula is

Caloc-V tablets are formulated in three strengths for oral administration with a combination of amlodipine besylate, equivalent to 5 mg or 10 mg of amlodipine free-base, with 80 mg, or 160 mg of valsartan providing for the following available combinations: 5/80 mg, 5/160 mg and 10/160 mg.

The inactive ingredients for all strengths of the tablets are colloidal silicon dioxide, crospovidone, magnesium stearate and microcrystalline cellulose. The film coating contains hypromellose, iron oxides, polyethylene glycol, talc and titanium dioxide.

INDICATIONS
Treatment of essential hypertension.

Posology and method of administration
Posology
The recommended dose of Caloc-V is one tablet per day.
Caloc-V can be used with or without food. Individual dose titration with the components (i.e. amlodipine and valsartan) is recommended before changing to the fixed dose combination. When clinically appropriate, direct change from monotherapy to the fixed-dose combination may be considered. For convenience, patients receiving valsartan and amlodipine from separate tablets/capsules may be switched to Caloc-V containing the same component doses.

Renal impairment
There are no available clinical data in severely renally impaired patients. No dosage adjustment is required for patients with mild to moderate renal impairment. Monitoring of potassium levels and creatinine is advised in moderate renal impairment.

Hepatic impairment
Caloc-V is contraindicated in patients with severe hepatic impairment. Caution should be exercised when administering Caloc-V to patients with hepatic impairment or biliary obstructive disorders. In patients with mild to moderate hepatic impairment without cholestasis, the maximum recommended dose is 80 mg valsartan. Amlodipine dosage recommendations have not been established in patients with mild to moderate hepatic impairment. When switching eligible hypertensive patients with hepatic impairment to amlodipine or Caloc-V, the lowest available dose of amlodipine monotherapy or of the amlodipine component, respectively, should be used.

Elderly (age 65 years or over)
In elderly patients, caution is required when increasing the dosage. When switching eligible elderly hypertensive patients to amlodipine or Caloc-V, the lowest available dose of amlodipine monotherapy or of the amlodipine component, respectively, should be used.

Paediatric population
The safety and efficacy of Caloc-V in children aged below 18 years have not been established. No data are available.

Method of administration
Oral use.
It is recommended to take Caloc-V with some water.

Contraindications

• Hypersensitivity to the active substances, to dihydropyridine derivatives, or to any of the excipients listedin description.
• Severe hepatic impairment, biliary cirrhosis or cholestasis.
• Concomitant use of Caloc-V with aliskiren-containing products in patients with diabetes mellitus or renal impairment (GFR <60 ml/min/1.73 m²).
• Second and third trimesters of pregnancy.
• Severe hypotension.
• Shock (including cardiogenic shock).
• Obstruction of the outflow tract of the left ventricle (e.g. hypertrophic obstructive cardiomyopathy and high grade aortic stenosis).
• Haemodynamically unstable heart failure after acute myocardial infarction.

Special warnings and precautions for use
The safety and efficacy of amlodipine in hypertensive crisis have not been established.

Pregnancy
Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started.

Sodium- and/or volume-depleted patients
Excessive hypotension was seen in 0.4% of patients with uncomplicated hypertension treated with Caloc-V in placebo-controlled studies. In patients with an activated renin-angiotensin system (such as volume-and/or salt-depleted patients receiving high doses of diuretics) who are receiving angiotensin receptor blockers, symptomatic hypotension may occur. Correction of this condition prior to administration of Caloc-V or close medical supervision at the start of treatment is recommended. If hypotension occurs with Caloc-V, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. Treatment can be continued once blood pressure has been stabilised.

Hyperkalaemia
Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium, or other medicinal products that may increase potassium levels (heparin, etc.) should be undertaken with caution and with frequent monitoring of potassium levels.

Renal artery stenosis
Caloc-V should be used with caution to treat hypertension in patients with unilateral or bilateral renal artery stenosis or stenosis to a solitary kidney since blood urea and serum creatinine may increase in such patients.

Kidney transplantation
To date there is no experience of the safe use of Caloc-V in patients who have had a recent kidney
transplantation.

Hepatic impairment
Valsartan is mostly eliminated unchanged via the bile. The half life of amlodipine is prolonged and AUC values are higher in patients with impaired liver function; dosage recommendations have not been established. Particular caution should be exercised when administering Caloc-V to patients with mild to moderate hepatic impairment or biliary obstructive disorders. In patients with mild to moderate hepatic impairment without cholestasis, the maximum recommended dose is 80 mg valsartan.

Renal impairment
No dosage adjustment of Caloc-V is required for patients with mild to moderate renal impairment (GFR >30 ml/min/1.73 m²). Monitoring of potassium levels and creatinine is advised in moderate renal impairment.

Angioedema
Angioedema, including swelling of the larynx and glottis, causing airway obstruction and/or swelling of the face, lips, pharynx and/or tongue, has been reported in patients treated with valsartan. Some of  these patients previously experienced angioedema with other medicinal products, including ACE inhibitors. Caloc-V should be discontinued immediately in patients who develop angioedema and should not be re-administered.

Heart failure/post-myocardial infarction
As a consequence of the inhibition of the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with ACE inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotaemia and (rarely) with acute renal failure and/or death. Similar outcomes have been reported with valsartan. Evaluation of patients with heart failure or post-myocardial infarction should always include assessment of renalfunction.

In a long-term, placebo-controlled study (PRAISE-2) of amlodipine in patients with NYHA (New York Heart Association Classification) III and IV heart failure of non-ischaemic aetiology, amlodipine was associated with increased reports of pulmonary oedema despite no significant difference in the incidence of worsening heart failure as compared to placebo.

Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as they may increase the risk of future cardiovascular events and mortality.

Aortic and mitral valve stenosis
As with all other vasodilators, special caution is indicated in patients suffering from mitral stenosis or significant aortic stenosis that is not high grade.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
There is evidence that the concomitant use of ACE inhibitors, ARBs or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE inhibitors, ARBs or aliskiren is therefore not recommended. If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure. ACE inhibitors and ARBs should not be used concomitantly in patients with diabetic nephropathy. Caloc-V has not been studied in any patient population other than hypertension.

INTERACTION

Amlodipine
In monotherapy, amlodipine has been safely administered with thiazide diuretics,beta-blockers,angiotensin converting enzyme inhibitors,long-acting nitrates, sub lingual nitroglycerin,digoxin,warfarin, atorvastatin,sildenafil,maalox(Aluminium hydroxide gel,magnesium hydroxide and simeticone), cimetidine,non-steroidal anti-inflammatory drugs,antibiotics and oral hypoglycemic drugs.

Valsartan
In monotherapy with valsartan, no drug interactions of clinical significance have been found with the following drugs: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, glibenclamide, concomitant use with potassium suppliments,potassium-sparing diuretics.

Salt substitutes containing potassium or other drugs that may increase potassium levels (heparin etc) requires caution and frequent monitoring of potassium levels Fertility, pregnancy and lactation

Pregnancy
Amlodipine
The safety of amlodipine in human pregnancy has not been established. In animal studies, reproductive toxicity was observed at high doses. Use in pregnancy is only recommended when there is no safer alternative and when the disease itself carries greater risk for the mother and foetus.

Valsartan
The use of Angiotensin II Receptor Antagonists (AIIRAs) is not recommended during the first trimester of pregnancy. The use of AIIRAs is contraindicated during the second and third trimesters of pregnancy. Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however, a small increase in risk cannot be excluded.

Whilst there is no controlled epidemiological data on the risk with Angiotensin II Receptor Antagonists (AIIRAs), similar risks may exist for this class of drugs. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started.

Exposure to AIIRA therapy during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia).

Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken AIIRAs should be closely observed for hypotension.

Breast-feeding
Amlodipine is excreted in human milk . The proportion of the maternal dose received by the infant has been estimated with an interquartile range of 3-7%, with a maximum of 15%. The effect of amlodipine on infants is unknown. No information is available regarding the use of Caloc-V during breast-feeding, therefore Caloc-V is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

Fertility
There are no clinical studies on fertility with Caloc-V.

Valsartan

Valsartan had no adverse effects on the reproductive performance of male or female rats at oral doses up to 200 mg/kg/day. This dose is 6 times the maximum recommended human dose on a mg/m² basis (calculations assume an oral dose of 320 mg/day and a 60-kg patient).

Amlodipine
Reversible biochemical changes in the head of spermatozoa have been reported in some patients treated by calcium channel blockers. Clinical data are insufficient regarding the potential effect of amlodipine on fertility. In one rat study, adverse effects were found on male fertility.

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES
Patients taking Caloc-V and driving vehicles or using machines should take into account that dizziness or weariness may occasionally occur.

Amlodipine can have mild or moderate influence on the ability to drive and use machines. If patients taking amlodipine suffer from dizziness, headache, fatigue or nausea the ability to react may be impaired.

Undesirable Effect

Adverse reactions have been ranked under headings of frequency using the following convention:
very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to  <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).

MedDRA System organ class	Adverse reactions		Frequency
		Caloc-V	Amlodipine	Valsartan
Infections and infestations	Nasopharyngitis	Common	—	—
	Influenza	Common	—	—
Blood and lymphatic system disorders	Haemoglobin and haematocrit decreased	—	—	Not known
	Leukopenia	—	Very rare	—
	Neutropenia	—	—	Not known
	Thrombocytopenia, sometimes with purpura	—	Very rare	Not known
Immune system disorders	Hypersensitivity	Rare	Very rare	Not known
Metabolism and nutrition disorders	Anorexia	Uncommon	—	—
	Hypercalcaemia	Uncommon	—	—
	Hyperglycaemia	—	Very rare	—
	Hyperlipidaemia	Uncommon	—	—
	Hyperuricaemia	Uncommon	—	—
	Hypokalaemia	Common	—	—
	Hyponatraemia	Uncommon	—	—
Psychiatric disorders	Depression	—	Uncommon	—
	Anxiety	Rare	—	—
	Insomnia/sleep disorders	—	Uncommon	—
	Mood swings	—	Uncommon	—
	Confusion	—	Rare	—
Nervous system disorders	Coordination abnormal	Uncommon	—	—
	Dizziness	Uncommon	Common	—
	Dizziness postural	Uncommon	—	—
	Dysgeusia	—	Uncommon	—
	Extrapyramidal syndrome	—	Not known	—
	Headache	Common	Common	—
	Hypertonia	—	Very rare	—
	Paraesthesia	Uncommon	Uncommon	—
	Peripheral neuropathy, neuropathy	—	Very rare	—
	Somnolence	Uncommon	Common	—
	Syncope	—	Uncommon	—
	Tremor	—	Uncommon	—
	Hypoesthesia	—	Uncommon	—
Eye disorders	Visual disturbance	Rare	Uncommon	—
	Visual impairment	Uncommon	Uncommon	—
Ear and labyrinth disorders Cardiac disorders	Tinnitus	Rare	Uncommon	—
	Vertigo	Uncommon	—	Uncommon
	Palpitations	Uncommon	Common	—
	Syncope	Rare	—	—
	Tachycardia	Uncommon	—	—
	Arrhythmias (including bradycardia, ventricular	—	Very rare	—
	tachycardia, and atrial fibrillation)
	Myocardial infarction	—	Very rare	—
Vascular disorders	Flushing	—	Common	—
	Hypotension	Rare	Uncommon	—
	Orthostatic hypotension	Uncommon	—	—
	Vasculitis	—	Very rare	Not known
Respiratory, thoracic and mediastinal disorders	Cough	Uncommon	Very rare	Uncommon
	Dyspnoea	—	Uncommon	—
	Pharyngolaryngeal pain	Uncommon	—	—
	Rhinitis	—	Uncommon	—
Gastrointestinal disorders	Abdominal discomfort, abdominal pain upper	Uncommon	Common	Uncommon
	Change of bowel habit	—	Uncommon	—
	Constipation	Uncommon	—	—
	Diarrhoea	Uncommon	Uncommon	—
	Dry mouth	Uncommon	Uncommon	—
	Dyspepsia	—	Uncommon	—
	Gastritis	—	Very rare	—
	Gingival hyperplasia	—	Very rare	—
	Nausea	Uncommon	Common	—
	Pancreatitis	—	Very rare	—
	Vomiting	—	Uncommon	—
Hepatobiliary disorders	Liver function test abnormal, including blood	—	Very rare*	Not known
	bilirubin increase
	Hepatitis	—	Very rare	—
	Intrahepatic cholestasis, jaundice	—	Very rare	—
Skin and subcutaneous tissue disorders	Alopecia	—	Uncommon	—
	Angioedema	—	Very rare	Not known
	Dermatitis bullous	—	—	Not known
	Erythema	Uncommon	—	—
	Erythema multiforme	—	Very rare	—
	Exanthema	Rare	Uncommon	—
	Hyperhidrosis	Rare	Uncommon	—
	Photosensitivity reaction	—	Uncommon	—
	Pruritus	Rare	Uncommon	Not known
	Purpura	—	Uncommon	—
	Rash	Uncommon	Uncommon	Not known
	Skin discolouration	—	Uncommon	—
	Urticaria and other forms of rash	—	Very rare	—
	Exfoliative dermatitis	—	Very rare	—
	Stevens-Johnson syndrome	—	Very rare	—
	Quincke oedema	—	Very rare	—
	Toxic Epidermal Necrolysis	—	Not known	—
Musculoskeletal and connective tissue disorders	Arthralgia	Uncommon	Uncommon	—
	Back pain	Uncommon	Uncommon	—
	Joint swelling	Uncommon	—	—
	Muscle spasm	Rare	Uncommon	—
	Myalgia	—	Uncommon	Not known
	Ankle swelling	—	Common	—
	Sensation of heaviness	Rare	—	—
Renal and urinary disorders	Blood creatinine increased	—	—	Not known
	Micturition disorder	—	Uncommon	—
	Nocturia	—	Uncommon	—
	Pollakiuria	Rare	Uncommon	—
	Polyuria	Rare	—	—
	Renal failure and impairment	—	—	Not known
Reproductive system and breast disorders	Impotence	—	Uncommon	—
	Erectile dysfunction	Rare	—	—
	Gynaecomastia	—	Uncommon	—
General disorders and administration site conditions	Asthenia	Common	Uncommon	—
	Discomfort, malaise	—	Uncommon	—
	Fatigue	Common	Common	Uncommon
	Facial oedema	Common	—	—
	Flushing, hot flush	Common	—	—
	Non cardiac chest pain	—	Uncommon	—
	Oedema	Common	Common	—
	Oedema peripheral	Common	—	—
	Pain	—	Uncommon	—
	Pitting oedema	Common	—	—
Investigations	Blood potassium increased	—	—	Not known
	Weight increase	—	Uncommon	—
	Weight decrease	—	Uncommon	—

*Mostly consistent with cholestasis

Overdose
Symptoms
There is no experience of overdose with Caloc-V. The major symptom of overdose with valsartan is possibly pronounced hypotension with dizziness. Overdose with amlodipine may result in excessive peripheral vasodilation and, possibly, reflex tachycardia. Marked and potentially prolonged systemic hypotension up to and including shock with fatal outcome have been reported.

Treatment
If ingestion is recent, induction of vomiting or gastric lavage may be considered. Administration of activated charcoal to healthy volunteers immediately or up to two hours after ingestion of amlodipine has been shown to significantly decrease amlodipine absorption. Clinically significant hypotension due to Caloc-V overdose calls for active cardiovascular support, including frequent monitoring of cardiac and respiratory function, elevation of extremities, and attention to circulating fluid volume and urine output.

A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided that there is no contraindication to its use. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade.

Both valsartan and amlodipine are unlikely to be removed by haemodialysis.

Pharmacodynamic properties
Caloc-V combines two antihypertensive compounds with complementary mechanisms to control blood pressure in patients with essential hypertension: amlodipine belongs to the calcium antagonist class and valsartan to the angiotensin II antagonist class of medicines. The combination of these substances has an additive antihypertensive effect, reducing blood pressure to a greater degree than either component alone.

Amlodipine/Valsartan

The combination of amlodipine and valsartan produces dose-related additive reduction in blood pressure across its therapeutic dose range. The antihypertensive effect of a single dose of the combination persisted for 24 hours.

Over 1,400 hypertensive patients received Caloc-V once daily in two placebo-controlled trials. A multicentre, randomised, double-blind, active-controlled, parallel-group trial showed normalisation of blood pressure (trough sitting diastolic blood pressure <90 mmHg at the end of the trial) in patients not adequately controlled on valsartan 160 mg in 75% of patients treated with amlodipine/valsartan 10 mg/160 mg and 62% of patients treated with amlodipine/valsartan 5 mg/160 mg, compared to 53% of patients remaining on valsartan 160 mg. The addition of amlodipine 10 mg and 5 mg produced an additional reduction in systolic/diastolic blood pressure of 6.0/4.8 mmHg and 3.9/2.9 mmHg, respectively, compared to patients who remained on valsartan 160 mg only. A multicentre, randomised, double-blind, active-controlled, parallel-group trial showed normalisation of blood pressure (trough sitting diastolic blood pressure <90 mmHg at the end of the trial) in patients not adequately controlled on amlodipine 10 mg in 78% of patients treated with amlodipine/valsartan 10 mg/160 mg, compared to 67% of patients remaining on amlodipine 10 mg. The addition of valsartan 160 mg produced an additional reduction in systolic/diastolic blood pressure of 2.9/2.1 mmHg compared to patients who remained on amlodipine 10 mg only. Caloc-V was also studied in an active-controlled study of 130 hypertensive patients with mean sitting diastolic blood pressure ≥110 mmHg and <120 mmHg. In this study (baseline blood pressure 171/113 mmHg), a Caloc-V regimen of 5 mg/160 mg titrated to 10 mg/160 mg reduced sitting blood pressure by 36/29 mmHg as compared to 32/28 mmHg with a regimen of lisinopril/hydrochlorothiazide 10 mg/12.5 mg titrated to 20 mg/12.5 mg. In two long-term follow-up studies the effect of Caloc-V was maintained for over one year.  Abrupt withdrawal of Caloc-V has not been associated with a rapid increase in blood pressure. Age, gender, race or body mass index (≥30 kg/m², <30 kg/m²) did not influence the response to Caloc-V. Caloc-V has not been studied in any patient population other than hypertension. Valsartan has been studied in patients with post myocardial infarction and heart failure. Amlodipine has been studied in patients with chronic stable angina, vasospastic angina and angiographically documented coronary artery disease.

Amlodipine
The amlodipine component of Caloc-V inhibits the transmembrane entry of calcium ions into cardiac and vascular smooth muscle. The mechanism of the antihypertensive action of amlodipine is due to a direct relaxant effect on vascular smooth muscle, causing reductions in peripheral vascular resistance and in blood pressure. Experimental data suggest that amlodipine binds to both dihydropyridine and
non-dihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilation, resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing. Plasma concentrations correlate with effect in both young and elderly patients. In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow, without change in filtration fraction or proteinuria. As with other calcium channel blockers, haemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In haemodynamic studies, amlodipine has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and humans, even when co-administered with beta blockers to humans. Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals or humans. In clinical studies in which amlodipine was administered in combination with beta blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic parameters were observed.

Valsartan
Valsartan is an orally active, potent and specific angiotensin II receptor antagonist. It acts selectively on the receptor subtype AT¹, which is responsible for the known actions of angiotensin II. The increased plasma levels of angiotensin II following AT¹ receptor blockade with valsartan may stimulate the unblocked receptor subtype AT², which appears to counterbalance the effect of the AT¹ receptor. Valsartan does not exhibit any partial agonist activity at the AT¹ receptor and has much (about 20,000-fold) greater affinity for the AT¹ receptor than for the AT² receptor.

Valsartan does not inhibit ACE, also known as kininase II, which converts angiotensin I to angiotensin II and degrades bradykinin. Since there is no effect on ACE and no potentiation of bradykinin or substance P, angiotensin II antagonists are unlikely to be associated with coughing. In clinical trials where valsartan was compared with an ACE inhibitor, the incidence of dry cough was significantly (p <0.05) lower in patients treated with valsartan than in those treated with an ACE inhibitor (2.6% versus 7.9%, respectively). In a clinical trial of patients with a history of dry cough during ACE inhibitor therapy, 19.5% of trial subjects receiving valsartan and 19.0% of those receiving a thiazide diuretic experienced coughing, compared to 68.5% of those treated with an ACE inhibitor (p <0.05). Valsartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.

Administration of valsartan to patients with hypertension results in a drop in blood pressure without
affecting pulse rate. In most patients, after administration of a single oral dose, onset of antihypertensive activity occurs within 2 hours, and the peak drop in blood pressure is achieved within 4–6 hours. The antihypertensive effect persists over 24 hours after administration. During repeated administration, the maximum reduction in blood pressure with any dose is generally attained within 2–4 weeks and is sustained during long-term therapy. Abrupt withdrawal of valsartan has not been associated with rebound hypertension or other adverse clinical events.

PHARMACOKINETIC PROPERTIES
Linearity
Amlodipine and valsartan exhibit linear pharmacokinetics.

Amlodipine/Valsartan
Following oral administration of Caloc-V, peak plasma concentrations of valsartan and amlodipine are reached in 3 and 6–8 hours, respectively. The rate and extent of absorption of Caloc-V are equivalent to the bioavailability of valsartan and amlodipine when administered as individual tablets.

Amlodipine
Absorption: After oral administration of therapeutic doses of amlodipine alone, peak plasma concentrations of amlodipine are reached in 6–12 hours. Absolute bioavailability has been calculated as between 64% and 80%. Amlodipine bioavailability is unaffected by food ingestion.

Distribution: Volume of distribution is approximately 21 l/kg. In vitro studies with amlodipine have shown that approximately 97.5% of circulating drug is bound to plasma proteins.

Biotransformation: Amlodipine is extensively (approximately 90%) metabolised in the liver to inactive metabolites.

Elimination: Amlodipine elimination from plasma is biphasic, with a terminal elimination half-life of approximately 30 to 50 hours. Steady-state plasma levels are reached after continuous administration for 7–8 days. 10% of original amlodipine and 60% of amlodipine metabolites are excreted in urine.

Valsartan
Absorption: Following oral administration of valsartan alone, peak plasma concentrations of valsartan are reached in 2–4 hours. Mean absolute bioavailability is 23%. Food decreases exposure (as measured by AUC) to valsartan by about 40% and peak plasma concentration (Cmax) by about 50%, although from about 8 h post dosing plasma valsartan concentrations are similar for the fed and fasted groups. This reduction in AUC is not, however, accompanied by a clinically significant reduction in the therapeutic effect, and valsartan can therefore be given either with or without food.

Distribution: The steady-state volume of distribution of valsartan after intravenous administration is about 17 litres, indicating that valsartan does not distribute into tissues extensively. Valsartan is highly bound to serum proteins (94–97%), mainly serum albumin.

Biotransformation: Valsartan is not transformed to a high extent as only about 20% of dose is recovered as metabolites. A hydroxy metabolite has been identified in plasma at low concentrations (less than 10% of the valsartan AUC). This metabolite is pharmacologically inactive.

Elimination: Valsartan shows multiexponential decay kinetics (t½α <1 h and t½ß about 9 h). Valsartan is primarily eliminated in faeces (about 83% of dose) and urine (about 13% of dose), mainly as unchanged drug. Following intravenous administration, plasma clearance of valsartan is about 2 l/h and its renal clearance is 0.62 l/h (about 30% of total clearance). The half-life of valsartan is 6 hours.

Special populations

Paediatric
Paediatric population (age below 18 years)
No pharmacokinetic data are available in the paediatric population.

Elderly (age 65 years or over)
Time to peak plasma amlodipine concentrations is similar in young and elderly patients. In elderly patients, amlodipine clearance tends to decline, causing increases in the area under the curve (AUC) and elimination half-life. Mean systemic AUC of valsartan is higher by 70% in the elderly than in the young, therefore caution is required when increasing the dosage.

Renal impairment
The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. As expected for a compound where renal clearance accounts for only 30% of total plasma clearance, no correlation was seen between renal function and systemic exposure to valsartan. Patients with mild to moderate renal impairment may receive the usual initial dose.

Hepatic impairment
Very limited clinical data are available regarding amlodipine administration in patients with hepatic impairment. Patients with hepatic impairment have decreased clearance of amlodipine with resulting increase of approximately 40–60% in AUC. On average, in patients with mild to moderate chronic liver disease exposure (measured by AUC values) to valsartan is twice that found in healthy volunteers (matched by age, sex and weight). Caution should be exercised in patients with liver disease.

Availability
Caloc-V Tablet 5mg/80mg: Pack of 14’s tablets in Cold Form & Cold Seal (Alu Alu) Blister packing.
Caloc-V 5mg/160mg: Pack of 14’s tablets in Cold Form & Cold Seal (Alu Alu) Blister packing.
Caloc-V 10mg/160mg: Pack of 14’s tablets in Cold Form & Cold Seal (Alu Alu) Blister packing.

Storage
Protect from light & moisture, Store below 30°C.
Keep out of the reach of children.

Dosage:
As prescribed by the physician.

Warning
To be sold on prescription of a registered medical practitioner only.