Calsar Co Tablets

Treatment of essential hypertension in patients stabilised on the individual components given at the same doses. CALSAR CO is not indicated for the initial therapy of hypertension (see section 4.2).

Posology
The recommended dose is one tablet per day (of either of the 5 strengths listed under section 2). If a tablet shows signs of cracking, the tablet should not be taken. Patients stabilised with valsartan, amlodipine and hydrochlorothiazide (HCTZ) from separate tablets may be switched to CALSAR CO containing the same component doses. The maximum antihypertensive effect of CALSAR CO is reached within two weeks after a change in dose. The maximum recommended dose of CALSAR CO is one 10/320/25 mg daily.

Special populations
Elderly
No adjustment of the initial dose is required for elderly patients (see section 5.2).
Renal impairment
No dosage adjustment is required for patients with mild to moderate renal impairment. Due to the hydrochlorothiazide component, CALSAR CO is not recommended in patients with severe renal impairment (creatinine clearance <30 ml/min) (see section 4.3 and 5.2).
Hepatic Impairment
Caution should be exercised when administering CALSAR CO to in patients with hepatic impairment or biliary obstructive disorders (see section 4.4). Due to the hydrochlorothiazide component, CALSAR CO is not recommended in patients with severe hepatic impairment (see section 4.3 and 5.2)
Paediatric population
CALSAR CO is not recommended for use in patients aged below 18 years due to a lack of data on safety and efficacy (see section 4.3).

Method of administration
For oral use. CALSAR CO can be taken with or without food. It is recommended to take CALSAR CO with some water.

• hypersensitivity to amlodipine, valsartan, hydrochlorothiazide and other sulphonamides, dihydropyridine derivatives, or to any of the CALSAR CO excipients listed in section 6.1
• history of angioedema related to previous therapy with angiotensin receptor blockers (ARBs): These patients must never again be given these medicines
• concomitant use of fluroquinolones with ACE inhibitors/angiotensin receptor blockers is contraindicated in patients with moderate (creatinine clearance <60 ml/min) to severe renal function impairment (creatinine clearance less than 30 ml/min) and in the elderly
• concomitant use of CALSAR CO with aliskiren-containing medicines in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1,73 m2) (see sections 4.5 and 5.1)
• lithium therapy: concomitant administration with CALSAR CO may lead to toxic blood concentrations of lithium (see section 4.5)
• concomitant therapy with potassium sparing diuretics such as spironolactone, triamterene, amiloride
• hereditary or idiopathic angioedema
• severe hepatic impairment (Child-Pugh C)
• CALSAR CO should not be given to patients with Addison's disease
• anuria, severe renal impairment (creatinine clearance less than 30 mL/min) and patients undergoing dialysis
• refractory hypokalaemia, hyponatraemia, hypercalcaemia and symptomatic hyperuricaemia
• obstruction of the outflow tract of the left ventricle (e.g. hypertrophic obstructive cardiomyopathy (HOCM) and high-grade aortic stenosis and mitral valve stenosis)
• bilateral renal artery stenosis, renal artery stenosis in patients with a single kidney
• pregnancy and lactation. CALSAR CO should be discontinued as soon as possible when pregnancy is suspected (see section 4.6)
• porphyria
• children under 18 years of age, as safety and efficacy have not been established
• patients with a history of previous and/or current basal cell carcinomas and/or squamous cell carcinomas of the skin and lip.

The safety and efficacy of amlodipine in hypertensive crisis have not been established.

Pregnancy
Renal Impairment
Due to the hydrochlorothiazide component, CALSAR CO is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min, anuria or undergoing dialysis) (see section 4.3). Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. Should a woman become pregnant while receiving CALSAR CO, the treatment should be stopped promptly and switched to a different class of antihypertensive medicine (see sections 4.3 and 4.6)

Thiazide diuretics may precipitate uraemia in patients with chronic kidney disease. When CALSAR CO is used in patients with renal impairment periodic monitoring of serum electrolytes (including potassium), creatinine and uric acid serum levels is recommended.

Renal artery stenosis
CALSAR CO should not be used in bilateral renal artery stenosis and renal artery stenosis in patients with a single kidney since blood urea and serum creatinine may increase in such patients (see section 4.3).

Kidney transplantation
There is no experience with the use of CALSAR CO in patients with a recent kidney transplant.

Hepatic Impairment
Valsartan is mostly eliminated unchanged via the bile, whereas amlodipine is extensively metabolised by the liver. The half-life of amlodipine is prolonged and AUC values are higher in patients with impaired liver function but dose recommendations have not been established. Particular caution should be exercised when administering CALSAR CO to patients with hepatic impairment or biliary obstructive disorders. CALSAR CO is contraindicated in patients with severe hepatic impairment, because of the hydrochlorothiazide component (see section 4.3).

Sodium- and/or volume depleted patients
Excessive hypotension, including orthostatic hypotension was seen in 1,7 % of patients treated with the maximum dose of amlodipine/valsartan/HCTZ (10/320/25 mg) compared to 1,8 % of valsartan/HCTZ (320/25 mg) patients, 0,4 % of amlodipine/valsartan (10/320 mg) patients, and 0,2 % of HCTZ/amlodipine (25/10 mg) patients in a controlled trial in patients with moderate to severe uncomplicated hypertension.

In patients with an activated renin-angiotensin system, such as volume-and/or salt-depleted patients receiving high doses of diuretics, symptomatic hypotension may occur in patients receiving angiotensin receptor blockers. This condition should be corrected prior to administration of CALSAR CO, or the treatment should start under close medical supervision. If excessive hypotension occurs with CALSAR CO, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of 0,9 % sodium chloride solution. Treatment can be continued once blood pressure has been stabilised.

Serum electrolyte changes
Amlodipine/valsartan/hydrochlorothiazide: A controlled trial indicates, the counteracting effects of valsartan 320 mg and hydrochlorothiazide 25 mg on serum potassium approximately balanced each other in many patients. In other patients, one or the other effect may be dominant. Periodic determination of serum electrolytes and potassium in particular should be performed at appropriate intervals to detect possible electrolyte imbalance, especially in patients with other risk factors such as impaired renal function, treatment with other medicines or history of prior electrolyte imbalances.

Valsartan: Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium, or other medicines that may increase potassium levels (heparin, etc.) contraindicated (see section 4.3). Monitoring of potassium should be undertaken as appropriate.

Hydrochlorothiazide: Concomitant use with potassium supplements, potassium sparing diuretics, salt substitutes containing potassium, or other medicines that may increase potassium levels (heparin, etc.) could lead to hyperkalaemia and should be used with caution. Hypokalaemia has been reported under treatment with thiazide diuretics including hydrochlorothiazide. Frequent monitoring of potassium is recommended (see section 4.3).

Treatment with CALSAR CO should only start after correction of hypokalaemia and any co-existing hypomagnesaemia. Thiazide diuretics can precipitate new onset hypokalaemia or exacerbate pre-existing hypokalaemia. Thiazide diuretics should be administered with caution in patients with conditions involving enhanced potassium loss, for example salt-losing nephropathies and prerenal (cardiogenic) impairment of kidney function. If hypokalaemia develops during hydrochlorothiazide therapy, CALSAR CO should be discontinued until stable correction of the potassium balance.

Thiazide diuretics can precipitate new onset hyponatraemia and hypochloraemic alkalosis or exacerbate pre-existing hyponatraemia. Thiazides, including hydrochlorothiazide increase the urinary excretion of magnesium, which may result in hypomagnesaemia. Hyponatraemia, accompanied by neurological symptoms (nausea, progressive disorientation, apathy) has been observed. Treatment with hydrochlorothiazide should only be started after correction of pre-existing hyponatraemia. In case severe or rapid hyponatraemia develops during CALSAR CO therapy, the treatment should be discontinued until normalisation of natremia.

All patients receiving thiazide diuretics should be periodically monitored for imbalances in electrolytes, particularly potassium, sodium and magnesium.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy
Special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy (see section 4.3).

Systemic lupus erythematosus
Thiazide diuretics, including hydrochlorothiazide, have been reported to exacerbate or activate systemic lupus erythematosus.

Other metabolic disturbances
Thiazide diuretics, including hydrochlorothiazide, may alter glucose tolerance and raise serum levels of cholesterol, triglycerides, and uric acid. In diabetic patients, dosage adjustments of insulin or oral hypoglycaemic medicines may be required. Due to the hydrochlorothiazide component, CALSAR CO is contraindicated in symptomatic hyperuricemia. Hydrochlorothiazide may raise the serum uric acid level due to reduced clearance of uric acid and may cause or exacerbate hyperuricemia as well as precipitate gout in susceptible patients. Thiazides reduce urinary calcium excretion and may cause intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. CALSAR CO is contraindicated in patients with hypercalcaemia and should only be used after correction of any pre-existing hypercalcaemia (see section 4.3). CALSAR CO should be discontinued if hypercalcaemia develops during treatment. Serum levels of calcium should be periodically monitored during treatment with thiazides. Marked hypercalcaemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.

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 medicines including ACE inhibitors.

CALSAR CO should be discontinued immediately in patients who develop angioedema and should not be re-administered.

Heart failure and coronary artery disease/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 renal function.

In a long-term, placebo-controlled study 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. Caution is advised in patients with heart failure and coronary artery disease, particularly at the maximum dose of CALSAR CO, 10 mg/320 mg/25 mg, since available data in these patient populations is limited.

Concomitant use of fluoroquinolones and ACE inhibitors /Angiotensin receptor blockers
Concomitant use of fluoroquinolones and ACE inhibitors/Angiotensin receptor blockers may precipitate acute kidney injury in patients, especially those with moderate to severe renal impairment and elderly patients (see section 4.3). Renal function should be assessed before initiating treatment and monitored during treatment with fluoroquinolones or ACE inhibitors/angiotensin receptor blockers, whether used separately and/or concomitantly.

Primary hyperaldosteronism
Patients with primary hyperaldosteronism should not be treated with the angiotensin II antagonist valsartan as their renin-angiotensin system is not activated. Therefore, CALSAR CO is not recommended in this population.

Photosensitivity
Cases of photosensitivity reactions have been reported with thiazide diuretics (see section 4.8). If photosensitivity reaction occurs during treatment with CALSAR CO, it is recommended to stop the treatment. If a re-administration of the diuretic is deemed necessary, it is recommended to protect exposed areas to the sun or to artificial UVA.

Acute angle-closure glaucoma
Hydrochlorothiazide, a sulphonamide, has been associated with an idiosyncratic reaction resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to a week of treatment initiation. Untreated acute-angle closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatment may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle closure glaucoma may include a history of sulphonamide or penicillin allergy.

General
Caution should be exercised in patients who have shown prior hypersensitivity to other angiotensin II receptor antagonists. Hypersensitivity reactions to hydrochlorothiazide are more likely in patients with allergy and asthma.

Elderly
Caution, including more frequent monitoring of blood pressure, is recommended in elderly patients, particularly at the maximum dose of CALSAR CO, 10 mg/320 mg/25 mg, since available data in this patient population are limited.

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 decreases renal function (including acute renal failure). Dual blockade of RAAS through the combined use of CALSAR CO and aliskiren is therefore contraindicated (see sections 4.5 and 5.1). 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.

Non-melanoma skin cancer
An increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] with increasing cumulative dose of hydrochlorothiazide exposure has been observed in Pharmaco-epidemiological studies. The risk for NMSC appears to increase with long-term use. Photosensitising actions of hydrochlorothiazide could act as a possible mechanism for NMSC.

Patients taking hydrochlorothiazide, alone or in combination, should be informed of the risk of NMSC and advised to regularly check their skin for any new lesions, as well as changes to existing ones, and promptly report any suspicious skin lesions. Suspicious skin lesions should be promptly examined potentially including histological examinations of biopsies. Possible preventive measures such as limited exposure to sunlight and UV rays and, in case of exposure, adequate protection should be advised to the patients in order to minimise the risk of skin cancer. The use of hydrochlorothiazide is contraindicated in patients who have experienced previous NMSC (see also section 4.8).

Paediatric population
Safety and efficacy of CALSAR CO in patients aged below 18 years has not been established (see section 4.3).

No formal interaction studies with other medicines have been performed with CALSAR CO. Thus, only information on interactions with other medicines that are known for the individual active substances is provided in this section. However, it is important to take into account that CALSAR CO may increase the hypotensive effect of other antihypertensive medicines.

Concomitant use not recommended
Dual blockade of the RAAS with ARBs, ACE Inhibitors or Aliskiren: Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (see sections 4.3 and 4.4).

Fluoroquinolones: Concomitant use of fluoroquinolones and ACE inhibitors/angiotensin receptor blockers may precipitate acute kidney injury. The mechanism of the possible interaction between the different classes of medicines, over and above different mechanisms of kidney damage, is unknown (see section 4.3).

Lithium: Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors, angiotensin II receptor antagonists including valsartan or thiazides. Since renal clearance of lithium is reduced by thiazides, the risk of lithium toxicity may presumably be increased further with CALSAR CO. Therefore, the concomitant use of CALSAR CO with lithium is contraindicated (see section 4.3).

Valsartan
Potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium and other substances that may increase potassium levels: If a medicine that affects potassium levels (e.g. heparin) is considered necessary in combination with valsartan, frequent monitoring of potassium plasma levels is advised.

Amlodipine
Grapefruit or grapefruit juice: Administration of amlodipine with grapefruit or grapefruit juice is not recommended as bioavailability may be increased in some patients, resulting in increased blood pressure lowering effects.

Caution required with concomitant use:
Amlodipine CYP3A4 inhibitors (i.e. ketoconazole, itraconazole, ritonavir): Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides like erythromycin or clarithromycin, verapamil or diltiazem) may give rise to significant increase in amlodipine exposure. The clinical translation of these pharmacokinetic variations may be more pronounced in the elderly. Clinical monitoring and dose adjustment may thus be required.

CYP3A4 inducers: (anticonvulsant agents [e.g. carbamazepine, phenobarbitone, phenytoin, fosphenytoin, primidone], rifampicin, Hypericum perforatum): Upon co-administration of known inducers of the CYP3A4, the plasma concentration of amlodipine may vary. Therefore, blood pressure should be monitored, and dose regulation considered both during and after concomitant therapy, particularly with strong CYP3A 4 inducers (e.g. rifampicin, St. Johnu2019s Wort (Hypericum perforatum)).

Simvastatin: Co-administration of multiple doses of 10 mg amlodipine with 80 mg simvastatin resulted in a 77 % increase in exposure to simvastatin compared to simvastatin alone. It is recommended to limit the dose of simvastatin to 20 mg daily in patients on amlodipine.

Dantrolene (infusion): In animals, lethal ventricular fibrillation and cardiovascular collapse are observed in association with hyperkalaemia after administration of verapamil and intravenous dantrolene. Due to risk of hyperkalaemia, it is recommended that the co-administration of calcium channel blockers such as amlodipine be avoided in patients susceptible to malignant hyperthermia and in the management of malignant hyperthermia.

Valsartan
Inhibitors of the uptake transporter (rifampicin, ciclosporin) or efflux transporter (ritonavir): The results of an in vitro study with human liver tissue indicate that valsartan is a substrate of the hepatic uptake transporter OATP1B1 and of the hepatic efflux transporter MRP2. Co-administration of inhibitors of the uptake transporter (rifampicin, ciclosporin) or efflux transporter (ritonavir) may increase the systemic exposure to valsartan.

Valsartan and Hydrochlorothiazide
Non-steroidal anti-inflammatory medicines (NSAIDs), including selective COX-2 inhibitors, acetylsalicylic acid (>3 g/day), and non-selective NSAIDs: NSAIDs can attenuate the antihypertensive effect of both angiotensin II antagonists and hydrochlorothiazide when administered simultaneously. Furthermore, concomitant use of CALSAR CO and NSAIDs may lead to an increased risk of worsening of renal function and an increase in serum potassium. Therefore, monitoring of renal function at the beginning of the treatment is recommended, as well as adequate hydration of the patient.

Hydrochlorothiazide
Alcohol, barbiturates or narcotics: Concomitant administration of thiazide diuretics with substances that also have a blood pressure lowering effect (e.g. by reducing sympathetic central nervous system activity or direct vasodilatation) may potentiate orthostatic hypotension.

Amantadine: Thiazides, including hydrochlorothiazide, may increase the risk of adverse reactions caused by amantadine.

Anticholinergic medicines: The bioavailability of thiazide-type diuretics may be increased by anticholinergic medicines (e.g. atropine, biperiden), apparently due to a decrease in gastrointestinal motility and the stomach emptying rate. Conversely, it is anticipated that prokinetic substances such as cisapride may decrease the bioavailability of thiazide-type diuretics.

Antidiabetic medicines: It may prove necessary to readjust the dosage of insulin and of oral antidiabetic medicines. Metformin should be used with caution because of the risk of lactic acidosis induced by possible functional renal failure linked to hydrochlorothiazide.

Beta blockers and diazoxide: Concomitant use of thiazide diuretics, including hydrochlorothiazide, with beta blockers may increase the risk of hyperglycaemia. Thiazide diuretics may enhance the hyperglycaemic effect of diazoxide.

Carbamazepine: Patients receiving hydrochlorothiazide concomitantly with carbamazepine may develop hyponatraemia. Such patients should therefore be advised about the possibility of hyponatraemic reactions, and should be monitored accordingly.

Ciclosporin: Concomitant treatment with ciclosporin may increase the risk of hyperuricaemia and gout-type complications.

Cytotoxic medicines: Thiazides, including hydrochlorothiazide, may reduce the renal excretion of cytotoxic medicines (e.g. cyclophosphamide, methotrexate) and potentiate their myelosuppressive effects.

Digitalis glycosides: Thiazide-induced hypokalaemia or hypomagnesaemia may occur as unwanted effects, favouring the onset of digoxin-induced cardiac dysrhythmias.

Iodine contrasting medicines: In case of diuretic-induced dehydration, there is an increased risk of acute renal failure, especially with high doses of iodine products. Patients should be re-hydrated before the administration.

Ion-exchange resins: Absorption of thiazide diuretics, including hydrochlorothiazide, is decreased by cholestyramine or colestipol. This could result in sub-therapeutic effects of thiazide diuretics. However, staggering the dosage of hydrochlorothiazide and resin such that hydrochlorothiazide is administered at least 4 hours before or 4-6 hours after the administration of resins would potentially minimise the interaction.

Medicines affecting potassium: The hypokalaemic effect of diuretics may be increased by kaliuretic diuretics, corticosteroids, laxatives, adrenocorticotropic hormone (ACTH), amphotericin, amphotericin, carbenoxolone, penicillin G, salicylic acid derivatives or anti-dysrhythmics. If these medicines are to be prescribed with CALSAR CO, monitoring of potassium plasma levels is advised.

Medicines affecting serum sodium level: The hyponatraemic effect of diuretics may be intensified by concomitant administration of medicines such as antidepressants, antipsychotics, antiepileptics, etc. Caution is indicated in long-term administration of these medicines.

Medicines that could induce torsades de pointes: Due to the risk of hypokalaemia, hydrochlorothiazide should be administered with caution when associated with medicines that could induce torsades de pointes, in particular Class Ia and Class III anti-dysrhythmics and some antipsychotics.

Medicines used in the treatment of gout: (probenecid, sulphinpyrazone and allopurinol). Dose adjustment of uricosuric medicines may be necessary as hydrochlorothiazide may raise the level of serum uric acid. An increase of the dose of probenecid or sulphinpyrazone may be necessary. Co-administration of thiazide diuretics, including hydrochlorothiazide, may increase the incidence of hypersensitivity reactions to allopurinol.

Methyldopa: There have been reports in the literature of haemolytic anaemia occurring with concomitant use of hydrochlorothiazide and methyldopa.

Non-depolarising muscle relaxants: Thiazides, including hydrochlorothiazide, potentiate the action of non-depolarising muscle relaxants.

Other anti-hypertensive medicines: Thiazides potentiate the antihypertensive action of other antihypertensive medicines (e.g. guanethidine, methyldopa, beta-blockers, vasodilators, calcium channel blockers, ACE inhibitors, ARBs and Direct Renin Inhibitors (DRIS).

Pressor amines (e.g. noradrenaline, adrenaline): Hydrochlorothiazide may reduce the response to pressor amines such as noradrenaline. The clinical significance of this effect is uncertain and not sufficient to preclude their use.

Vitamin D and calcium salts: Administration of thiazide diuretics, including hydrochlorothiazide, with vitamin D or with calcium salts may potentiate the rise in serum calcium. Concomitant use of thiazide type diuretics may lead to hypercalcaemia in patients pre-disposed for hypercalcaemia (e.g. hyperparathyroidism, malignancy or vitamin-D-mediated conditions) by increasing tubular calcium reabsorption.

Monotherapy
In monotherapy, amlodipine has been safely administered with thiazide diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, long-acting nitrates, sublingual nitroglycerin, digoxin, warfarin, atorvastatin, sildenafil, aluminium hydroxide gel, magnesium hydroxide and simeticone, cimetidine, non-steroidal anti-inflammatory medicines, antibiotics, and oral hypoglycaemic medicines. In monotherapy with valsartan, no medicine interactions of clinical significance have been found with the following medicines: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, glibenclamide.

Women of childbearing potential / Contraception in males and females
Women of childbearing age should use effective contraception.

Pregnancy
CALSAR CO is contraindicated in pregnancy as teratogenicity has been shown in experimental animals (see section 4.3). Medicines affecting the renin-angiotensin system, such as CALSAR CO, can cause embryonal toxicity, foetal and neonatal morbidity and mortality when administered to pregnant women. When pregnancy is detected, CALSAR CO should be discontinued as soon as possible. Pregnant women should be informed of the potential hazards to the foetus and must not take CALSAR CO during pregnancy (see section 4.3). Patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with CALSAR CO should be stopped immediately and if appropriate, alternative therapy should be started. Foetal exposure to ACE inhibitors during the first trimester of pregnancy has been reported to be associated with an increased risk of malformations of the cardiovascular (atrial and/or ventricular septal defect, pulmonic stenosis, patent ductus arteriosus) and central nervous system (microcephaly spina bifida) and of kidney malformations. CALSAR CO passes through the placenta and can be presumed to cause disturbance in foetal blood pressure regulatory mechanisms. Oligohydramnios as well as hypotension, oliguria and anuria in new-borns, have been reported after administration of CALSAR CO during the second and third trimester. Cases of defective skull ossification have been observed. Prematurity and low birth mass can occur (see section 4.3).

Breastfeeding
It is not known whether valsartan and/or amlodipine are excreted in human milk. Valsartan was excreted in the milk of lactating rats. Hydrochlorothiazide is excreted into breast milk. CALSAR CO is contraindicated in women who are breastfeeding (see section 4.3).

Fertility
There is no data on fertility with CALSAR CO.

CALSAR CO can lead to dizziness or weariness, patients should be advised not to drive, operate machinery or perform hazardous tasks until they know how CALSAR CO affects them.

a) Summary of the safety profile
Adverse reactions were generally mild and transient in nature and only infrequently required discontinuation of therapy. The most common reasons for discontinuation of therapy were dizziness and hypotension.

b) Tabulated summary of adverse reactions
Side effects for CALSAR CO
System Organ Class Frequency Side effects Blood and lymphatic system disorders Frequency unknown Thrombocytopenia Immune system disorders Frequency unknown Angioedema Metabolism and nutrition disorders Frequent Less frequent Frequency unknown Hypokalaemia Anorexia, hypercalcaemia, hyperlipidaemia, hyperuricaemia, hyponatraemia Blood potassium increased Psychiatric disorders Less frequent Insomnia/sleep disorders Nervous system disorders Frequent Less frequent Frequency unknown Dizziness, headache Abnormal coordination Dysgeusia, lethargy, paraesthesia, peripheral neuropathy, somnolence, syncope, dizziness postural, dizziness exertional Eye disorders Less frequent Visual impairment Ear and labyrinth disorders Less frequent Vertigo Cardiac disorders Less frequent Tachycardia Vascular disorders Frequent Less frequent Frequency unknown Hypotension Orthostatic hypotension, phlebitis, thrombophlebitis Vasculitis Respiratory, thoracic and mediastinal disorders Less frequent Cough, dyspnoea, throat irritation Gastrointestinal disorders Frequent Less frequent Dyspepsia Abdominal discomfort and pain, breath odour, diarrhoea, dry mouth, nausea, vomiting Hepato-biliary disorders Frequency unknown Elevation of liver function values including serum bilirubin Skin and subcutaneous tissue disorders Less frequent Hyperhidrosis, pruritus Musculoskeletal, connective tissue and bone disorders Less frequent Back pain, joint swelling, muscle spasm, muscular weakness, myalgia, pain in extremity Renal and urinary disorders Frequent Less frequent Pollakiuria Blood creatinine increased, renal impairment acute renal failure Reproductive system and breast disorders Less frequent Impotence General disorders and administrative site conditions Frequent Less frequent Fatigue, oedema Asthenia, discomfort, malaise, non-cardiac chest pain, abasia, gait disturbance Investigations Less frequent Blood urea nitrogen increased, blood uric acid increased, blood potassium decreased, weight increase

Signs and symptoms
There is no experience of overdose with CALSAR CO. Overdose with amlodipine may result in excessive peripheral vasodilatation and possibly reflex tachycardia. Marked and potentially prolonged systemic hypotension up to, and including, shock with fatal outcome have been reported. The major symptom of overdose with valsartan is possibly pronounced hypotension with dizziness. Available data for amlodipine suggest that gross overdosage could result in excessive peripheral vasodilatation and possibly reflex tachycardia. Marked and probably prolonged systemic hypotension up to and including shock with fatal outcome have been reported. Non-cardiogenic pulmonary oedema has rarely been reported as a consequence of amlodipine overdose that may manifest with a delayed onset (24 - 48 hours post-ingestion) and require ventilatory support. Early resuscitative measures (including fluid overload) to maintain perfusion and cardiac output may be precipitating factors.

Management of overdose
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 CALSAR CO 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 whereas clearance of HCTZ will be achieved by dialysis.