1 Name of Medicine
Candesartan cilexetil/ hydrochlorothiazide.
2 Qualitative and Quantitative Composition
BTC Candesartan HCT 16 mg/12.5 mg contains candesartan cilexetil 16 mg and hydrochlorothiazide 12.5 mg.
BTC Candesartan HCT 32 mg/12.5 mg contains candesartan cilexetil 32 mg and hydrochlorothiazide 12.5 mg.
BTC Candesartan HCT 32 mg/25 mg contains candesartan cilexetil 32 mg and hydrochlorothiazide 25 mg.
Candesartan cilexetil is a white to off white powder and is practically insoluble in water.
Excipients with known effect.
Sugars as lactose.
For the full list of excipients, see Section 6.1 List of Excipients.3 Pharmaceutical Form
BTC Candesartan HCT 16 mg/12.5 mg tablets are apricot, mottled, oval biconvex tablets, scored on both sides.
BTC Candesartan HCT 32 mg/12.5 mg tablets are light brown, mottled, oblong, biconvex tablets, debossed with 32 on one side and with score line on both sides.
BTC Candesartan HCT 32 mg/25 mg tablets are reddish brown, mottled, oblong, biconvex tablets, debossed with H 32 on one side and with score line on both sides.
4.1 Therapeutic Indications
The treatment of hypertension. Treatment should not be initiated with this fixed dose combination.
4.2 Dose and Method of Administration
Dosage.
The dose of BTC Candesartan HCT must be determined by careful titration of the dose of each of the individual components.
Method of administration.
The recommended dose of BTC Candesartan HCT is one tablet once daily, taken with or without food. BTC Candesartan HCT tablets should not be divided.
BTC Candesartan HCT 16 mg/12.5 mg may be administered in patients whose blood pressure is not optimally controlled with hydrochlorothiazide alone or with candesartan 16 mg monotherapy.
BTC Candesartan HCT 32 mg/12.5 mg or 32 mg/25 mg may be administered in patients whose blood pressure is not optimally controlled with hydrochlorothiazide alone or candesartan 32 mg monotherapy, or at a lower dose of BTC Candesartan HCT. Dose titration of candesartan cilexetil is recommended when adding on to hydrochlorothiazide monotherapy.
Most of the antihypertensive effect is usually attained within four weeks of initiation of treatment.
BTC Candesartan HCT should not be used to initiate treatment.
Dosage adjustment.
Infants and children.
The safety and efficacy of BTC Candesartan HCT have not been established in children.
Elderly.
Dose titration of candesartan cilexetil is recommended before treatment with BTC Candesartan HCT.
Hepatic impairment.
Dose titration of candesartan cilexetil is recommended before treatment with BTC Candesartan HCT in patients with mild to moderate hepatic impairment.
BTC Candesartan HCT should not be used in patients with severe hepatic impairment and/or cholestasis (see Section 4.3 Contraindications).
Renal impairment.
Loop diuretics are preferred to thiazides in this population. Dose titration of candesartan cilexetil is recommended before treatment with BTC Candesartan HCT in patients with renal impairment whose creatinine clearance is greater than or equal to 30 mL/minute/1.73 m2 body surface area (BSA). BTC Candesartan HCT should not be used in patients with severe renal impairment (creatinine clearance < 30 mL/minute/1.73 m2 BSA).
Intravascular volume depletion.
Patients who are severely volume and/or sodium depleted should have this corrected before being treated with BTC Candesartan HCT.4.3 Contraindications
Hypersensitivity to any component of BTC Candesartan HCT or to sulfonamide derived medicines.
Pregnancy and lactation.
Severe renal impairment (creatinine clearance < 30 mL/minute/1.73 m2 body surface area).
Severe hepatic impairment and/or cholestasis.
Gout.
The use of candesartan/HCT in combination with aliskiren-containing medicines in patients with diabetes mellitus (type I or II) or with moderate to severe renal impairment (GFR < 60 mL/min/1.73 m2).
4.4 Special Warnings and Precautions for Use
General.
In patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensin-aldosterone system (RAAS) (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with medicines that affect this system has been associated with acute hypotension, azotaemia, oliguria or, rarely, acute renal failure. As with any antihypertensive agent, excessive blood pressure decrease in patients with ischaemic heart disease or atherosclerotic cerebrovascular disease could result in a myocardial infarction or stroke.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS).
There is evidence that the concomitant use of angiotensin converting enzyme (ACE)-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of the RAAS through the combined use of candesartan/HCT with ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
If dual blockade therapy is considered necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.
ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy. The use of candesartan/HCT with aliskiren is contraindicated in patients with diabetes mellitus (type I or II) or moderate to severe renal impairment (GFR < 60 mL/min/1.73 m2) (see Section 4.3 Contraindications).
Renal artery stenosis.
Other medicines that affect the RAAS, i.e. ACE-inhibitors, may increase blood urea and serum creatinine in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney. A similar effect may be anticipated with angiotensin II receptor antagonists.
Aortic and mitral valve stenosis (obstructive hypertrophic cardiomyopathy).
As with other vasodilators, special caution is indicated in patients suffering from haemodynamically relevant aortic or mitral valve stenosis, or obstructive hypertrophic cardiomyopathy.
Primary hyperaldosteronism.
Patients with primary hyperaldosteronism will not generally respond to antihypertensive medicines acting through inhibition of the renin-angiotensin-aldosterone system. Therefore, the use of candesartan/HCT in these patients is not recommended.
Fluid and electrolyte imbalance.
As for any patient receiving diuretic therapy, periodic determination of serum electrolytes should be performed at appropriate intervals.
Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (hypercalcaemia, hypokalaemia, hyponatraemia, hypomagnesaemia and hypochloraemic alkalosis).
Hydrochlorothiazide dose-dependently increases urinary potassium excretion which may result in hypokalaemia. This effect of hydrochlorothiazide seems to be less evident when combined with candesartan cilexetil. The risk of hypokalaemia may be increased in patients with cirrhosis of the liver, in patients experiencing brisk diuresis, in patients with an inadequate oral intake of electrolytes and in patients receiving concomitant therapy with corticosteroids or adrenocorticotropic hormone (ACTH).
Based on experience with the use of other medicines that affect the RAAS, concomitant use of BTC Candesartan HCT and ACE-inhibitors, aliskiren, potassium sparing diuretics, potassium supplements or salt substitutes or other medicines that may increase serum potassium levels may lead to increases in serum potassium.
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 two epidemiological studies based on Danish National Cancer Registry (see Clinical trials). Photosensitizing actions of hydrochlorothiazide could act as a possible mechanism for NMSC.
Patients taking hydrochlorothiazide should be informed of the risk of NMSC and advised to regularly check their skin for any new lesions and promptly report any suspicious skin lesions. 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 minimize the risk of skin cancer. Suspicious skin lesions should be promptly examined potentially including histological examinations of biopsies. The use of hydrochlorothiazide may also need to be reconsidered in patients who have experienced previous NMSC (see Section 4.8 Adverse Effects (Undesirable Effects)).
Acute respiratory toxicity.
Very rare severe cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS) have been reported after taking hydrochlorothiazide. Pulmonary oedema typically develops within minutes to hours after hydrochlorothiazide intake. At the onset, symptoms include dyspnoea, fever, pulmonary deterioration, and hypotension. If diagnosis of ARDS is suspected, candesartan/HCT should be withdrawn, and appropriate treatment given. Hydrochlorothiazide should not be administered to patients who previously experienced ARDS following hydrochlorothiazide intake.
Metabolic and endocrine effects.
Treatment with a thiazide diuretic may impair glucose tolerance. Dosage adjustment of antidiabetic medicines, including insulin, may be required. Metformin should be used with caution because of the risk of lactic acidosis induced by possible functional renal failure linked to hydrochlorothiazide.
Latent diabetes mellitus may become manifest during thiazide therapy. Increases in cholesterol and triglyceride levels have been associated with thiazide diuretic therapy. However, at the doses contained in BTC Candesartan HCT, only minimal effects were observed. Thiazide diuretics increase serum uric acid concentration and may precipitate gout in susceptible patients.
Hypotension, volume depleted patients.
Candesartan/HCT like all antihypertensive agents may cause symptomatic hypotension in some patients. Symptomatic hypotension may be expected to occur more frequently in patients who have been sodium and/or volume depleted by vigorous diuretic therapy and/or dietary salt restrictions, or vomiting and/or diarrhoea or haemodialysis. Sodium and/or volume depletion should be corrected prior to administration of BTC Candesartan HCT.
Postsympathectomy.
The antihypertensive effects of thiazide diuretics may be increased in the postsympathectomy patient.
Systemic lupus erythematosus.
Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazide diuretics.
Anaesthesia and surgery.
Hypotension may occur during anaesthesia and surgery in patients treated with angiotensin II antagonists due to blockade of the RAAS. Very rarely, hypotension may be severe such that it may warrant the use of intravenous fluids and/or vasopressors.
Combination use of ACE-inhibitors or angiotensin receptor antagonists, anti-inflammatory medicines and thiazide diuretics.
The use of an ACE inhibiting medicine (ACE-inhibitor or angiotensin receptor antagonist), an anti-inflammatory medicine (NSAID or COX-2 inhibitor) and a thiazide diuretic at the same time increases the risk of renal impairment. This includes use in fixed combination products containing more than one class of medicine. Combined use of these medications should be accompanied by increased monitoring of serum creatinine, particularly at the institution of the combination. The combination of medicines from these three classes should be used with caution particularly in elderly patients or those with pre-existing renal impairment.
Choroidal effusion, acute myopia and secondary angle-closure glaucoma.
Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction resulting in choroidal effusion with visual field defect, 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 weeks of drug 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 treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.
Use in hepatic impairment.
Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma. There is no clinical experience with BTC Candesartan HCT in patients with hepatic impairment. Use in patients with severe hepatic impairment is contraindicated. Caution is advised in patients with mild to moderate hepatic impairment.
Use in renal impairment.
When BTC Candesartan HCT is used in patients with renal impairment, periodic monitoring of serum potassium, creatinine and uric acid levels is recommended. Loop diuretics are preferred to thiazides in this population. As with other agents inhibiting the RAAS, changes in renal function may be anticipated in susceptible patients treated with candesartan/HCT (see Section 4.3 Contraindications).
Kidney transplantation.
There is limited clinical experience regarding the administration of BTC Candesartan HCT in patients who have undergone kidney transplantation.
Use in the elderly.
For dosage recommendations for use of BTC Candesartan HCT in elderly patients please (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use, Combination use of ACE inhibitors or angiotensin receptor antagonists, anti-inflammatory medicines and thiazide diuretics; Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in special populations).
Paediatric use.
Safety and efficacy have not been established in children.
Effects on laboratory tests.
In general, there were no clinically important influences of candesartan cilexetil/hydrochlorothiazide on routine laboratory variables. Increases in creatinine, urea, potassium, uric acid, glucose and ALAT (SGPT) and decreases in sodium have been observed. Minor decreases in haemoglobin and increases in ASAT (SGOT) have been observed in single patients.4.5 Interactions with Other Medicines and Other Forms of Interactions
The antihypertensive effect of BTC Candesartan HCT may be enhanced by other antihypertensives.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS).
Clinical trial data has shown that dual blockade of the 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 (including acute renal failure) compared to the use of a single RAAS-acting agent (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).
Candesartan cilexetil.
No medicine interactions of clinical significance have been identified with candesartan cilexetil. Compounds which have been investigated include hydrochlorothiazide, warfarin, digoxin (see Hydrochlorothiazide below), oral contraceptives (i.e. ethinyloestradiol/levonorgestrel), glibenclamide and nifedipine.
The antihypertensive effect of angiotensin II receptor antagonists, including candesartan, may be attenuated by NSAIDs, including COX-2 inhibitors and acetylsalicylic acid.
As with ACE-inhibitors, concomitant use of AIIRAs and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure, and an increase in serum potassium, especially in patients with poor pre-existing renal function. The combination should be administered with caution, especially in older patients and in volume depleted patients. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy and periodically thereafter.
Candesartan is eliminated only to a minor extent by hepatic metabolism (CYP2C9).
Interaction studies performed to date show no effect of candesartan on the metabolising capacity of CYP2C9 and CYP3A4. Based on in vitro data, no interaction would be expected to occur in vivo with medicines whose metabolism is dependent upon cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4.
Hydrochlorothiazide.
Alcohol, barbiturates, opioids and anaesthetics.
Potentiation of thiazide diuretic induced orthostatic hypotension may occur.
Anti-diabetic agents (oral and insulin).
Thiazides may increase blood glucose concentration and adjustment of anti-diabetic medication may be required.
Cardiac glycosides and other anti-arrhythmics.
Thiazide induced hypokalaemia and hypomagnesaemia predisposes to the potential cardiotoxic effects of digitalis glycosides and antiarrhythmics.
Periodic monitoring of serum potassium is recommended when BTC Candesartan HCT is administered with such active substances, and with the following active substances that could induce torsade de pointes:
Class Ia antiarrhythmics (e.g. quinidine, hydroquinidine, disopyramide);
Class III antiarrhythmics (e.g. amiodarone, sotalol, dofetilide, ibutilide);
Some antipsychotics (e.g. thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamenmazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol);
Others (e.g. bepridil, cisapride, diphemanil, erythromycin IV, halofantrin, ketanserin, mizolastin, pentamidine, sparfloxacin, terfenadine, vincamine IV).
Calcium salts and vitamin D.
Thiazide diuretics may increase the serum calcium concentration due to decreased excretion. If calcium or vitamin D is prescribed, serum calcium levels should be monitored and calcium dosage adjusted accordingly.
Cholestyramine resin and colestipol hydrochloride.
The absorption of thiazide may be delayed or decreased in the presence of bile acids sequestrants. BTC Candesartan HCT should be taken at least one hour before or after such medicines.
Lithium.
Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE-inhibitors or hydrochlorothiazide. A similar effect may occur with angiotensin II receptor antagonists (AIIRAs) and careful monitoring of serum lithium levels is recommended during concomitant use.
Non-steroidal anti-inflammatory medicines (NSAIDs).
The diuretic, natriuretic and antihypertensive effect of hydrochlorothiazide is blunted by NSAIDs.
Hypokalaemic agents.
The potassium depleting effect of hydrochlorothiazide could be expected to be potentiated by other medicines associated with potassium loss and hypokalaemia (e.g. other kaliuretic diuretics, laxatives, amphotericin, carbenoxolone, salicylic acid derivatives).
Potassium sparing agents.
Based on experience with the use of other medicines that affect the renin-angiotensin-aldosterone system, concomitant use of BTC Candesartan HCT and potassium sparing diuretics, potassium supplements or salt substitutes or other medicines that may increase serum potassium levels (e.g. heparin sodium, trimethoprim/sulfamethoxazole) may lead to increases in serum potassium.
Nondepolarising muscle relaxants (e.g. tubocurarine).
The effect of nondepolarising skeletal muscle relaxants (e.g. tubocurarine) may be potentiated by hydrochlorothiazide.
Pressor amines.
Hydrochlorothiazide may cause the arterial response to pressor amines to decrease but not enough to exclude a pressor effect.
Iodinated contrast media.
Hydrochlorothiazide may increase the risk of acute renal insufficiency especially with high doses of iodinated contrast media.
Corticosteroids, ACTH.
The risk for hypokalaemia may be increased during concomitant use of steroids or ACTH.
Amantadine.
Thiazides may increase the risk of adverse effects caused by amantadine.
Beta-blockers and diazoxide.
The hyperglycaemic effect of beta-blockers and diazoxide may be enhanced by thiazides.
Anticholinergic agents (e.g. atropine).
Anticholinergic agents (e.g. atropine, biperiden) may increase the bioavailability of thiazide diuretics by decreasing gastrointestinal motility and stomach emptying rate.
Cytotoxic medicines (e.g. cyclophosphamide, methotrexate).
Thiazides may reduce the renal excretion of cytotoxic medicines (e.g. cyclophosphamide, methotrexate) and potentiate their myelosuppressive effects.
Ciclosporin.
Concomitant treatment with ciclosporin may increase the risk of hyperuricaemia and gout-type complications.
Baclofen, amifostin, tricyclic antidepressants or neuroleptics.
Concomitant treatment may lead to enhancement of the antihypertensive effect and may induce hypotension.4.6 Fertility, Pregnancy and Lactation
Effects on fertility.
The effects of hydrochlorothiazide alone or in combination with candesartan cilexetil on fertility have not been evaluated in animal studies. However, candesartan cilexetil alone had no adverse effects on the reproductive performance of male or female rats at oral doses up to 300 mg/kg/day.
(Category D)
Medicines which have caused, are suspected to have caused or may be expected to cause an increased incidence of human fetal malformations or irreversible damage. These medicines may also have adverse pharmacological effects. Accompanying texts should be consulted for further details.
The use of BTC Candesartan HCT is contraindicated in pregnancy (see Section 4.3 Contraindications). Patients receiving BTC Candesartan HCT should be made aware of that before contemplating a possibility of becoming pregnant so that they can discuss appropriate options with their treating physician. When pregnancy is diagnosed, treatment with BTC Candesartan HCT must be stopped immediately and if appropriate, alternative therapy should be started.
The use of medicines that act directly on the RAAS during the second and third trimesters of human pregnancy has been associated with fetal and neonatal injury, including hypotension, hyperkalaemia, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation and hypoplastic lung development. Prematurity, intrauterine growth retardation, skull ossification retardation and patent ductus arteriosus have also been reported. Exposure to angiotensin II receptor antagonist therapy is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia).
There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta. Hydrochlorothiazide can reduce the plasma volume as well as the uteroplacental blood flow. Based on the pharmacological mechanism of action of hydrochlorothiazide, its use during pregnancy may compromise feto-placental perfusion and may cause fetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia.
In retrospective data, first trimester use of ACE-inhibitors has been associated with a potential risk of birth defects. There have been reports of spontaneous abortion, oligohydramnios and newborn renal dysfunction, when pregnant women have inadvertently taken the angiotensin II antagonist valsartan. As for any medicine that also acts directly on the RAAS, candesartan cilexetil should not be used during pregnancy (see Section 4.3 Contraindications) or in women planning to become pregnant.
Healthcare professionals prescribing any agents acting on the RAAS should counsel women of childbearing potential about the potential risk of these agents during pregnancy.
If pregnancy is detected during therapy, candesartan cilexetil should be discontinued as soon as possible, and if appropriate, alternative therapy should be started.
It is not known whether candesartan is excreted in human milk. However, candesartan is excreted in the milk of lactating rats. Hydrochlorothiazide passes into human milk. Because of the potential for adverse effects on the breastfed infant, breastfeeding should be discontinued if the use of BTC Candesartan HCT is considered essential.4.7 Effects on Ability to Drive and Use Machines
When driving vehicles or operating machines, it should be taken into account that dizziness or weariness may occur during treatment of hypertension.
4.8 Adverse Effects (Undesirable Effects)
Adverse events were mild and transient and comparable to placebo in controlled clinical studies with various doses of candesartan cilexetil/hydrochlorothiazide (candesartan cilexetil up to 32 mg and hydrochlorothiazide up to 25 mg). The overall incidence of adverse events showed no association with age or gender. Withdrawals from treatment due to adverse events were similar with candesartan cilexetil/ hydrochlorothiazide (2.3%-3.3%) and placebo (2.7%-4.3%).
Clinical adverse events, regardless of causal relationship, with a cumulative eight week incidence rate of greater than or equal to 1% during treatment with candesartan cilexetil/ hydrochlorothiazide up to 16 mg/12.5 mg in the double blind, placebo-controlled trials are presented in Table 1.
The following clinical adverse events occurred with a frequency of 0.5% to < 1% with no occurrence in the placebo group: AV-block, vomiting.
Clinical adverse events, regardless of causal relationship, occurring in ≥ 1% of the patients during 8-week randomised treatment with candesartan cilexetil/hydrochlorothiazide 32/12.5 mg and 32/25 mg in double-blind clinical trials are presented in Table 2.
Adverse events on individual components.
Candesartan cilexetil.
The following clinical adverse events, regardless of whether attributed to therapy, have been reported to occur with a cumulative eight week incidence rate of ≥ 1% in placebo-controlled clinical trials with candesartan cilexetil monotherapy: cough, diarrhoea, peripheral oedema and rhinitis. Angioedema, urticaria, pruritus and rash have been reported very rarely in patients treated with candesartan cilexetil. Very rare cases of increased liver enzymes, abnormal hepatic function or hepatitis have also been reported. Very rare adverse reactions include hyponatraemia, hyperkalaemia and renal impairment, including renal failure in susceptible patients (see Section 4.4 Special Warnings and Precautions for Use). Other adverse events reported for candesartan cilexetil where a causal relationship could not be established include very rare cases of leukopenia, neutropenia and agranulocytosis.
Hydrochlorothiazide.
The following clinical adverse events have been reported to occur with hydrochlorothiazide monotherapy: anorexia, loss of appetite, gastric irritation, diarrhoea, constipation, jaundice (intrahepatic cholestatic jaundice), pancreatitis, leucopenia, neutropenia/agranulocytosis, thrombocytopenia, aplastic anaemia, haemolytic anaemia, bone marrow depression, photosensitivity reactions, fever, rash, cutaneous lupus erythematosus-like reactions, reactivation of cutaneous lupus erythematosus, urticaria, necrotising angiitis (vasculitis, cutaneous vasculitis), anaphylactic reactions, toxic epidermal necrolysis, respiratory distress (including pneumonitis and pulmonary oedema and acute respiratory distress syndrome (very rare) - see Section 4.4 Special Warnings and Precautions for Use), hyperglycaemia, glycosuria, hyperuricaemia, electrolyte imbalance (including hyponatraemia and hypokalaemia), increases in cholesterol and triglycerides, increases in blood urea nitrogen (BUN) and serum creatinine, renal dysfunction, interstitial nephritis, muscle spasm, weakness, restlessness, transient blurred vision, light-headedness, postural hypotension, vertigo, paraesthesia, cardiac arrhythmias, sleep disturbances, depression, choroidal effusion*, acute myopia, acute angle-closure glaucoma.
* Cases of choroidal effusion with visual field defect have been reported after the use of thiazide diuretics.
Laboratory findings.
In general, there were no clinically important influences of candesartan cilexetil/hydrochlorothiazide on routine laboratory variables. Increases in creatinine, urea, potassium, uric acid, glucose and ALAT (SGPT) and decreases in sodium have been observed. Minor decreases in haemoglobin and increases in ASAT (SGOT) have been observed in single patients.
Postmarketing.
The following adverse reactions have been reported very rarely (< 0.01%) in postmarketing experience.
Musculoskeletal, connective tissue and bone disorders.
Myalgia.
Respiratory, thoracic and mediastinal disorders.
Cough.
Rare reports of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.
Although causality to candesartan has not been established, the following neuropsychiatric and cardiovascular adverse reactions have been very rarely reported during postmarketing surveillance. These were agitation, anxiety, depression, insomnia, somnolence, nervousness, nightmare, sleep disorder and palpitations.
The following adverse reactions have been reported post-marketing with hydrochlorothiazide, regardless of causality:
Neoplasms benign, malignant and unspecified (including cysts and polyps).
Frequency "not known": Non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma) (see Section 4.4 Special Warnings and Precautions for Use; Section 5.1 Pharmacodynamic Properties, Clinical trials).
Reporting suspected adverse effects.
Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.4.9 Overdose
Symptoms.
Based on pharmacological considerations, the main manifestation of an overdose of candesartan cilexetil is likely to be symptomatic hypotension and dizziness. In two case reports of overdose (candesartan cilexetil 160 and 432 mg) patient recovery was uneventful.
The main manifestation of an overdose of hydrochlorothiazide is acute loss of fluid and electrolytes. Symptoms such as dizziness, hypotension, thirst, tachycardia, ventricular arrhythmias, sedation/ impairment of consciousness and muscle cramps can also be observed.
Treatment.
No specific information is available on the treatment of overdosage with BTC Candesartan HCT. The following measures are however suggested in case of overdosage.
Administration of activated charcoal with or without gastric lavage. If symptomatic hypotension should occur, symptomatic treatment should be instituted and vital signs monitored. The patient should be placed supine with the legs elevated. If this is not sufficient, plasma volume should be increased by infusion of isotonic saline solution. Serum electrolyte and acid balance should be checked and corrected if needed. Sympathomimetic medicines may be administered if the abovementioned measures are not sufficient.
Activated charcoal may reduce absorption of the medicine if given within one or two hours after ingestion. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via a nasogastric tube, once the airway is protected.
Candesartan cannot be removed by haemodialysis. It is not known to what extent hydrochlorothiazide is removed by haemodialysis.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).5 Pharmacological Properties
5.1 Pharmacodynamic Properties
Mechanism of action.
Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system and plays a significant role in the pathophysiology of hypertension and other cardiovascular disorders. It also has an important role in the pathogenesis of end organ hypertrophy and damage. The major physiological effects of angiotensin II, such as vasoconstriction, aldosterone stimulation, regulation of salt and water homeostasis and stimulation of cell growth, are mediated via the type 1 (AT1) receptor.
Candesartan cilexetil is a prodrug suitable for oral use. It is rapidly converted to the active medicine, candesartan, by ester hydrolysis during absorption from the gastrointestinal tract. Candesartan is an angiotensin II receptor antagonist, selective for AT1 receptors, with tight binding to and slow dissociation from the receptor. It has no agonist activity.
Candesartan does not inhibit ACE, 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 receptor antagonists are unlikely to be associated with cough. This has been confirmed in controlled clinical studies with candesartan. Candesartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.
Hydrochlorothiazide inhibits the active reabsorption of sodium, mainly in the distal kidney tubules, and promotes the excretion of sodium, chloride and water. The renal excretion of potassium and magnesium increases dose-dependently, while calcium is reabsorbed to a greater extent. Hydrochlorothiazide decreases plasma volume and extracellular fluid and reduces cardiac output and blood pressure. During long-term therapy, reduced peripheral resistance contributes to the blood pressure reduction.
Candesartan and hydrochlorothiazide have additive antihypertensive effects. In hypertensive patients, candesartan/HCT causes an effective and long lasting reduction in arterial blood pressure without reflex increase in heart rate. There is no indication of serious or exaggerated first dose hypotension or rebound effect after cessation of treatment.
After administration of a single dose of candesartan/HCT, onset of the antihypertensive effect generally occurs within two hours. With continuous treatment, most of the reduction in blood pressure is attained within four weeks and is sustained during long-term treatment.
Candesartan/HCT once daily provides effective and smooth blood pressure reduction over 24 hours, with little difference between maximum and trough effects during the dosing interval. In double-blind, randomised studies, the incidence of cough was lower during treatment with candesartan cilexetil/ hydrochlorothiazide than during treatment with combinations of ACE-inhibitors and hydrochlorothiazide.
Age and gender have no influence on the efficacy of candesartan/HCT.
Epidemiological studies have shown that long-term treatment with hydrochlorothiazide reduces the risk for cardiovascular morbidity and mortality. There are no data regarding the effects of candesartan cilexetil and candesartan cilexetil/hydrochlorothiazide on morbidity and mortality in hypertensive patients.
In a variety of preclinical safety studies conducted in several species, expected exaggerated pharmacological effects (e.g. renal changes leading to juxtaglomerular cell hypertrophy, adrenal gland zona glomerulosa atrophy and reduced heart weight related to reduced afterload), due to modification of the renin-angiotensin-aldosterone system homeostasis, have been observed. The incidence and severity of the effects induced were dose and time related and have been shown to be reversible in adult animals. Addition of hydrochlorothiazide caused a potentiation of the nephrotoxicity seen with candesartan alone, however, without any qualitatively new findings.
Clinical trials.
In a randomised, double-blind, parallel group, 8 week clinical study, including 1975 randomised patients not adequately controlled on 32 mg candesartan cilexetil once daily, the addition of 12.5 mg or 25 mg hydrochlorothiazide resulted in additional blood pressure reductions of 7/3 mmHg and 9/4 mmHg, respectively over 32 mg monotherapy. The candesartan cilexetil/hydrochlorothiazide 32/12.5 mg and 32/25 mg combinations produced overall mean blood pressure reductions of 13/9 mmHg and 16/10 mmHg, respectively. This study also demonstrated that the 32/25 mg combination was significantly more effective than the 32/12.5 mg combination.
In two 8 week clinical studies (randomised, double-blind, placebo-controlled, parallel group) including 275 and 1524 randomised patients, respectively, the candesartan cilexetil/hydrochlorothiazide combinations 32/12.5 mg and 32/25 mg resulted in blood pressure reductions of 21/14 mmHg for the highest dose, and were significantly more effective than the respective monotherapy components.
Epidemiological studies have shown that long term treatment with hydrochlorothiazide reduces the risk for cardiovascular morbidity and mortality. There are no data regarding the effects of candesartan cilexetil and candesartan cilexetil/hydrochlorothiazide on morbidity and mortality in hypertensive patients.
Non-melanoma skin cancer (NMSC).
Based on available data from epidemiological studies, cumulative dose-dependent association between hydrochlorothiazide and NMSC has been observed. One study included a population comprised of 71,553 cases of BCC and of 8,629 cases of SCC matched to 1,430,883 and 172,462 population controls, respectively. High hydrochlorothiazide use (≥ 50,000 mg cumulative) was associated with an adjusted OR of 1.29 (95% CI: 1.23-1.35) for BCC and 3.98 (95% CI: 3.68-4.31) for SCC. A clear cumulative dose response relationship was observed for both BCC and SCC. Another study showed a possible association between lip cancer (SCC) and exposure to hydrochlorothiazide: 633 cases of lip-cancer were matched with 63,067 population controls, using a risk-set sampling strategy. A cumulative dose-response relationship was demonstrated with an adjusted OR 2.1 (95% CI: 1.7-2.6) increasing to OR 3.9 (3.0-4.9) for high use (~25,000 mg) and OR 7.7 (5.7-10.5) for the highest cumulative dose (~100,000 mg) (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).
5.2 Pharmacokinetic Properties
The individual pharmacokinetic profiles of candesartan and hydrochlorothiazide were not clinically significantly affected when given in combination.
Absorption.
Candesartan cilexetil.
Following oral administration, candesartan cilexetil is converted to the active medicine candesartan. The absolute bioavailability of candesartan is approximately 40% after an oral solution of candesartan cilexetil. The relative bioavailability of the tablet formulation compared with the same oral solution is approximately 34%, with little variability. The absolute bioavailability of candesartan following administration of the tablet is approximately 14%. The mean peak plasma concentration (Cmax) is reached three to four hours after taking a tablet. The candesartan plasma concentrations increase linearly with increasing doses in the therapeutic dose range.
The area under the plasma concentration versus time curve (AUC) of candesartan is not significantly affected by food. The peak concentration (Cmax) is increased by 26% and the rate of absorption is increased when taken with food. These changes are unlikely to result in clinically significant effects.
Hydrochlorothiazide.
Hydrochlorothiazide is rapidly absorbed from the gastrointestinal tract with an absolute bioavailability of approximately 70%. Concomitant intake of food increases the absorption by approximately 15%. The bioavailability may decrease in patients with cardiac failure and pronounced oedema.
Distribution.
Candesartan cilexetil.
Candesartan is highly bound to plasma protein (more than 99%). The apparent volume of distribution (Vss) of candesartan is 0.1 L/kg.
Following oral administration of a single-dose of BTC Candesartan HCT 16 mg/12.5 mg to healthy male subjects under fasting conditions, a mean peak plasma concentration (Cmax) of candesartan cilexetil compared to the reference product was 119.93% (confidence interval 111.67%-128.79%) which was achieved within approximately 3.94 hours (Tmax). The ratios of the areas under the plasma concentration versus time curve (AUC) of candesartan cilexetil compared to the reference product was 103.96% (confidence interval 99.53%-108.59%).
Hydrochlorothiazide.
The plasma protein binding of hydrochlorothiazide is approximately 60%. The apparent volume of distribution is approximately 0.81 L/kg.
Following oral administration of a single-dose of BTC Candesartan HCT 16 mg/12.5 mg to healthy male subjects under fasting conditions, a mean peak plasma concentration (Cmax) of hydrochlorothiazide compared to the reference product was 99.23% (confidence interval 96.61%-102.11%) which was achieved within approximately 1.90 hours (Tmax). The ratios of the areas under the plasma concentration versus time curve (AUC) for hydrochlorothiazide compared to the reference product was 99.32% (confidence interval 94.05%-104.71%).
Metabolism.
Candesartan cilexetil.
The half-life of candesartan remains unchanged (approximately nine hours) after administration of candesartan cilexetil in combination with hydrochlorothiazide. There is a clinically nonsignificant increase in AUC (15 to 18%) and Cmax (23 to 24%) of candesartan when given together with hydrochlorothiazide. No accumulation of candesartan occurs after repeated doses of the combination compared to monotherapy.
Excretion.
Candesartan cilexetil.
Candesartan cilexetil is mainly eliminated unchanged via urine and bile and is eliminated by hepatic metabolism only to a minor extent (CYP2C9). The terminal half-life of candesartan is approximately nine hours. There is no accumulation following multiple doses.
Total plasma clearance of candesartan is about 0.37 mL/minute/kg, with a renal clearance of about 0.19 mL/minute/kg. The renal elimination of candesartan is both by glomerular filtration and active tubular secretion. Following an oral dose of 14C-labelled candesartan cilexetil about 30 and 70% of the total radioactivity is recovered in the urine and faeces, respectively.
Hydrochlorothiazide.
Hydrochlorothiazide is not metabolised and is excreted almost entirely as unchanged drug by glomerular filtration and active tubular secretion. The terminal t1/2 of hydrochlorothiazide is approximately eight hours. Approximately 70% of an oral dose is eliminated in the urine within 48 hours. The half-life of hydrochlorothiazide remains unchanged (approximately eight hours) after administration of hydrochlorothiazide in combination with candesartan cilexetil. No accumulation of hydrochlorothiazide occurs after repeated doses of the combination compared to monotherapy.
Pharmacokinetics in special populations.
Candesartan cilexetil. Elderly.
In the elderly (over 65 years) both Cmax and AUC of candesartan are increased by approximately 50 and 80%, respectively, in comparison to young subjects. However, the blood pressure response and the incidence of adverse events are similar after a given dose of candesartan/HCT 16 mg/12.5 mg in young and elderly patients.
Renal impairment.
In patients with mild to moderate renal impairment, Cmax and AUC of candesartan increased during repeated dosing by approximately 50 and 70%, respectively, but t1/2 was not altered compared to patients with normal renal function. The corresponding changes in patients with severe renal impairment were approximately 50 and 110%, respectively. The terminal t1/2 of candesartan was approximately doubled in patients with severe renal impairment. The pharmacokinetics in patients undergoing haemodialysis were similar to those in patients with severe renal impairment.
Hydrochlorothiazide. The terminal t1/2 of hydrochlorothiazide is prolonged in patients with renal impairment.
Hepatic impairment.
In patients with mild to moderate hepatic impairment, there was a 23% increase in the AUC of candesartan. No initial dosage adjustment is necessary in these patients.
5.3 Preclinical Safety Data
Genotoxicity.
Candesartan cilexetil alone or in combination with hydrochlorothiazide showed no evidence of genotoxic potential in a series of assays for gene mutations (Salmonella typhimurium and Escherichia coli), chromosomal aberrations (mouse micronucleus assay) and DNA damage (unscheduled DNA synthesis in rat liver). In addition, candesartan cilexetil alone showed no evidence of genotoxic potential in further assays for gene mutations (mouse L5178Y cells and Chinese hamster ovary cells). The active metabolite, candesartan, caused an increase in chromosomal aberrations in vitro (Chinese hamster lung cells) but not in vivo (mouse micronucleus test and chromosomal aberrations in rat bone marrow). However, hydrochlorothiazide had mutagenic activity in a mammalian cell assay (mouse L5178Y cells) and caused an increase in chromosomal aberrations in vitro (Chinese hamster lung cells). Candesartan at subclastogenic concentration did not modify these effects of hydrochlorothiazide. Hydrochlorothiazide also had a genotoxic activity in the sister chromatid exchange assay in Chinese hamster ovary cells and a nondisjunction assay in Aspergillus nidulans.
Carcinogenicity.
The carcinogenic potential of candesartan cilexetil in combination with hydrochlorothiazide has not been evaluated in animal studies.
Candesartan cilexetil alone was not carcinogenic when administered orally to rats and mice for 2 years at doses up to 100 and 1000 mg/kg/day corresponding to ca. 7 times and 260 times the clinical exposure at the maximum recommended daily dose of 32 mg (based on AUC, respectively).
Hydrochlorothiazide alone was not carcinogenic in female mice in doses ca. 600 mg/kg/day, or in male and female rats at doses up to ca. 100 mg/kg/day in two-year feeding studies. These doses correspond to ca. 110 times (female mice) or 40 times (male and female rats) the clinical exposure at the maximum recommended daily human dose of 25 mg (based on BSA). However, there was equivocal evidence for hepatocarcinogenicity in male mice that received ca. 600 mg/kg/day.6 Pharmaceutical Particulars
6.1 List of Excipients
BTC Candesartan HCT 16 mg/12.5 mg tablets also contain the following excipients ingredients: lactose monohydrate, iron oxide red, iron oxide yellow, maize starch, povidone, carrageenan, croscarmellose sodium and magnesium stearate.
BTC Candesartan HCT 32 mg/12.5 mg tablets also contain the following excipients ingredients: lactose monohydrate, iron oxide red, iron oxide yellow, iron oxide black, maize starch, povidone, carrageenan, croscarmellose sodium and magnesium stearate.
BTC Candesartan HCT 32 mg/25 mg tablets also contain the following excipients ingredients: lactose monohydrate, iron oxide red, iron oxide black, titanium dioxide, maize starch, povidone, carrageenan, croscarmellose sodium and magnesium stearate.
6.2 Incompatibilities
Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
For information on interactions with other medicines and other forms of interactions, see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.
6.3 Shelf Life
In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.
6.4 Special Precautions for Storage
Store below 25°C. Store in the original package.
6.5 Nature and Contents of Container
BTC Candesartan HCT tablets (all strengths) are available in blister packs of 30 tablets.
6.6 Special Precautions for Disposal
In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.
6.7 Physicochemical Properties
Hydrochlorothiazide (HCT) is a sulfonamide derived medicine. It is a white or almost white crystalline powder and is very slightly soluble in water.
Chemical structure.
Candesartan cilexetil.
The chemical name of candesartan cliexetil is (+/-)-1-(cyclohexyloxycarbonyl-oxy) ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl]-1H-benzimidazole-7-carboxylate. Its empirical formula is C33H34N6O6 (MW: 610.7) and its chemical structure is:
Hydrochlorothiazide.
The chemical name of hydrochlorothiazide is 6-chloro- 3,4-dihydro- 2H-1,2,4-benzo-thiadiazine -7-sulfonamide 1,1-dioxide. Its empirical formula is C7H8ClN3O4S2 (MW: 297.7) and its chemical structure is:
CAS number.
Candesartan cilexetil.
145040-37-5.
Hydrochlorothiazide.
58-93-5.7 Medicine Schedule (Poisons Standard)
S4 - Prescription Only Medicine.
Summary Table of Changes
