clinical overview candesartan cilexetil hct 8+12.5/16+12.5

Clinical Overview

Candesartan Cilexetil HCT 8+12.5/16+12.5/32+12.5/32+25 mg Tablets

Expert: Dr. med. Raija Duesing, MD, FFPM, Dipl. Pharm. Med. Frohmestrasse 78d D-22459 Hamburg Phone: +49-(0)40-57003561 Fax: +49-(0)40-57003562 Mobile: +49-(0)173-2347213 E-Mail: [email protected]

Candesartan Cilexetil HCT Tablets

Clinical Overview I

TABLE OF CONTENTS 2.5.1 PRODUCT DEVELOPMENT RATIONALE ............................................1 2.5.2 OVERVIEW OF BIOPHARMACEUTICS................................................3

2.5.2.1 Bioavailability ...................................................................................3 2.5.2.2 Bioequivalence.................................................................................3

2.5.3 OVERVIEW OF CLINICAL PHARMACOLOGY .....................................9 2.5.3.1 Pharmacokinetics of Candesartan ...................................................9

2.5.3.1.1 Absorption ...................................................................................9 2.5.3.1.2 Distribution, Protein Binding ........................................................9 2.5.3.1.3 Metabolism ..................................................................................9 2.5.3.1.4 Excretion....................................................................................10 2.5.3.1.5 Pharmacokinetics in Special Populations..................................10

2.5.3.2 Pharmacokinetics of Hydrochlorothiazide ......................................11 2.5.3.3 Pharmacokinetics of the Combination............................................12 2.5.3.4 Drug Interactions............................................................................12 2.5.3.5 Pharmacodynamics of Candesartan ..............................................12

2.5.3.5.1 Mechanism of Action ..................................................................12 2.5.3.5.2 Pharmacodynamics in Healthy Volunteers.................................13 2.5.3.5.3 Pharmacodynamics in Patients ..................................................14

2.5.3.6 Pharmacodynamics of Hydrochlorothiazide...................................15 2.5.3.6.1 Effect of Hydrochlorothiazide on Blood Pressure .......................15 2.5.3.6.2 Effects of Hydrochlorothiazide on Diuresis and Electrolytes ......16 2.5.3.6.3 Effects of Hydrochlorothiazide on Plasma Lipids .......................17

2.5.3.7 Pharmacodynamics of the Combination ........................................17 2.5.4 OVERVIEW OF EFFICACY .................................................................18

2.5.4.1 Clinical Studies and Study Population of Candesartan..................18 2.5.4.1.1 Placebo-Controlled Dose-Response Studies ............................18 2.5.4.1.2 Reference-Controlled Studies ...................................................18

2.5.4.2 Clinical Studies on Hydrochlorothiazide.........................................23 2.5.4.3 Clinical Studies of the Combination ...............................................24

2.5.4.3.1 Dose-response Study .................................................................24 2.5.4.3.2 Studies of Combination Therapy versus Monotherapy...............24 2.5.4.3.3 Reference Controlled Studies.....................................................25

2.5.4.4 Dosage and Duration of Treatment................................................28 2.5.5 OVERVIEW OF SAFETY.....................................................................29

2.5.5.1 Global Safety Information...............................................................29 2.5.5.1.1 Contraindications........................................................................29 2.5.5.1.2 Special Warnings and Precautions for Use ................................29 2.5.5.1.3 Pregnancy and Lactation............................................................31 2.5.5.1.4 Effects on Ability to Drive and Use Machines.............................32 2.5.5.1.5 Undesirable Effects ....................................................................32 2.5.5.1.6 Overdose ....................................................................................35

2.5.5.2 Post-Marketing Experience ............................................................35 2.5.6 BENEFITS AND RISKS CONCLUSIONS ............................................36 2.5.7 REFERENCES.....................................................................................37 2.5.8 APPENDIX ...........................................................................................43


Clinical Overview II

Abbreviations Used in this Document ACE angiotensin-converting enzyme AE adverse event AMD amlodipine ANOVA analysis of variance AUC area under the plasma concentration-time curve BL baseline BMI body mass index BP blood pressure Cmax maximum plasma concentration CDS candesartan cilexetil CHMP Committee for Medicinal Products for Human Use CI confidence interval CL clearance CO cardiac output COX cyclooxygenase CT combination therapy CV coefficient of variation DB double blind DBP diastolic blood pressure ECG electrocardiogram ENL enalapril ESRD end-stage renal disease EU European Union F female FBF forearm blood flow GCP Good Clinical Practice GFR glomerular filtration rate h hour HA hypertension arterialis HCT hydrochlorothiazide HDL high density lipoprotein HPLC high-pressure liquide chromatography HR heart rate, hazard ratio IC50 50% inhibitory concentration ITT intention to treat kg kilogram Ke elimination constant Ki inhibition constant LDL low-density lipoprotein L-NMMA N-monomethyl-L-arginine LOS losartan M male MAP mean arterial pressure MC multicentre mg milligram min minute ml millilitre mmHg millimetre mercury MRT mean residence time MS mass spectrometry MT monotherapy NA not applicable ng nanogram


Clinical Overview III

nmol nanomol NS not significant NSAID non-steroidal anti-inflammatory drug PC placebo-controlled PG parallel groups PLA placebo PM previous medication PRA plasma renin activity R randomised RAS renin-angiotensin system RR responder rate RVR renal vascular resistance SBP systolic blood pressure SD standard deviation; single dose SPC Summary of Product Characteristics SS steady state SSA Subjective Symptom Assessment SV stroke volume Tmax time to peak concentration T1/2 elimination half-life TC total cholesterol TG triglycerides UK United Kingdom Vd volume of distribution µg microgram


Clinical Overview 1

2.5.1 PRODUCT DEVELOPMENT RATIONALE Candesartan Cilexetil 8+12.5/16+12.5/32+12.5/32+25 mg Tablets (containing candesartan cilexetil and hydrochlorothiazide as pharmacologically active agents) is the subject of this Marketing Authorisation Application on Article 10(2)(b) of Directive 2001/83/EC. Article 10 of European Directive 2001/83/EC states that the applicant shall not be required to provide the results of toxicological and pharmacological tests if he can demonstrate that the medicinal product is a generic of a reference medicinal product, which has been authorized within the European Union (EU) for 6-10 years (depending on the territory). The generic medicinal product shall mean a medicinal product, which have the same qualitative and quantitative composition in active substances and the same pharmaceutical form as the reference medicinal product, and whose bioequivalence with the reference medicinal product has been demonstrated by appropriate bioavailability studies. In accordance with these provisions, the Applicant has not conducted clinical efficacy and safety studies on Candesartan Cilexetil HCT tablets. Instead appropriate data are provided to support the claim that Candesartan Cilexetil HCT tablets proposed for marketing is generic of Atacand® Plus, AstraZeneca. The in-vitro dissolution profiles have been adjusted to be similar to those of the brand leader and the Applicant’s Summary of Product Characteristics (SPC) is overall compliant with the SPC1 for the existing brand, with no novel claims or dose recommendations. Two appropriate single-dose studies confirm the equality of the biological availability of the Applicant’s formulation to the corresponding strengths of the brand leader. The studies were performed in accordance with current CHMP guidelines and the principles of the Declaration of Helsinki. Candesartan is an angiotensin II receptor antagonist (ATC Code: C09CA06) and hydrochlorothiazide is a thiazide diuretic (ATC-Code: C03AA03).2 The combination of candesartan cilexetil and hxdrochlorothiazide (ATC Code: C09DA06) is proposed for the treatment of essential hypertension in adult patients, whose blood pressures are not sufficiently controlled with candesartan cilexetil or hydrochlorothiazide monotherapy.1 Hypertension (HA), particularly essential or primary hypertension, is widespread and although usually asymptomatic, is a major risk factor for stroke and to some extent ischaemic heart disease. Control of hypertension is therefore a major aspect of cardiovascular risk reduction. Blood pressure above 140 mmHg systolic (SBP), and/or 90 mmHg diastolic (DBP) is generally considered to represent hypertension. Classifications of mild, moderate, and severe hypertension are widely used.2;3 The development of angiotensin-converting enzyme (ACE) inhibitors, which block the conversion of angiotensin I to angiotensin II, was the major breakthrough in the inhibition of the renin-angiotensin system (RAS). However, the inhibition of this pathway is incomplete due to conversion being possible through alternate pathways (e.g. chymase). Angiotensin II receptor antagonists have potential advantages over ACE inhibitors because they act by specifically blocking the binding of angiotensin II to the receptor on the cell surface.3;4


Clinical Overview 2

Diuretics are the drugs of first choice for the treatment of hypertension, either alone or in combination with other antihypertensive agents, e.g. AIIRAs, such as candesartan. The fixed combination of hydrochlorothiazide and cacndesartan has been developed in response to promising results reported for combination therapy with both agents as individual tablets. It is a valuable alternative for patients who are likely to need multiple drugs to achieve their blood pressure goals.5 This application is made on the basis of essential similarity of Candesartan Cilexetil HCT tablets to the brand leader Atacand® Plus Tablets. The clinical documentation has been obtained using standard text and reference books as well as computer-based searches of the scientific literature have been performed using the following databases:

• MEDLINE • BIOSIS PREVIEWS • EMBASE • DERWENT DRUG FILE • SCI REARCH.


Clinical Overview 3

2.5.2 OVERVIEW OF BIOPHARMACEUTICS 2.5.2.1 Bioavailability The absolute bioavailability of candesartan cilexetil approximately 40% after administration as oral solution.6 The relative bioavailability of the tablet formulation compared with the same oral solution is approximately 34% with very little variability. The estimated absolute bioavailability of the tablet is therefore 14%.1 The candesartan serum concentrations increased linearly with increasing doses in the therapeutic dose range.7 Hydrochlorothiazide exhibits linear kinetics after single oral doses 12.5-100 mg.8;9 Combination of hydrochlorothiazide and candesartan did not relevantly influence the kinetics of either substance1 2.5.2.2 Bioequivalence Candesartan Cilexetil HCT 8+12.5/16+12.5/32+12.5/32+25 mg tablets were developed to be generic medicinal products of the brand leader Atacand® Plus. After conduction of an explorative pilot study using the 32+25-mg strength, two bioequivalence studies using the 8+12.5-mg and 32+25-mg strengths were conducted by the Institutia Medico-Sanitaria Publica, Clinical Hospital of the Ministry of Health of the Republic of Moldova. The reference products were Atacand® Plus 8+12.5 mg tablets / Atacand® Plus Forte 32+25 mg tablets, manufactured by AstraZeneca GmbH, Germany. The studies adhered to the CHMP/ICH guidelines “Note for Guidance on Good Clinical Practice” (CPMP/ICH/135/95) and “Note for Guidance on the Investigation of Bioavailability and Bioequivalence” (CPMP/EWP/QWP/1401/98 Rev.1/corr.**) and have been approved by Ethical Committee to ensure compliance with the Declaration of Helsinki. A quality assurance certificate is included in the final study report. Detailed summaries of the relevant bioequivalence studies are in the Appendix of this documentation. The strengths (8+12.5 mg and 32+25 mg) used for the bioequivalence studies cover the whole range of the product strengths. According to the above mentioned guidelines, a biowaiver for a lower strengths may be claimed, since candesartan and hydrochlorothiazide have been shown to have linear kinetics over the therapeutic dose range, the compositions of the different strengths are proportional. The Pilot Study In a single-centre, single-dose, two-period crossover study, 10 healthy male and female subjects received either the test (Candesartan Cilexetil HCT 32+25 mg; batch no.: 92010902; use by date: 05/2010) or reference product (Atacand® Plus Forte 32+25 mg; AstraZeneca, Germany; batch no.: LF135A3; exp. date: 05/2012) in randomised order after controlled fasting. Study periods were separated by a washout of 20 days. The primary variables for the assessment of bioequivalence were AUC0-t, and Cmax. Blood samples were collected and adverse events recorded at appropriate intervals up to 48 hours after drug administration. Candesartan plasma


Clinical Overview 4

concentrations were analysed using a validated HPLC/MS/MS method. Bioequvalence was confirmed when the point estimates and 90% confidence intervals of the primary parameters were within the generally accepted limits of 80% to 125%. Point estimates and 90% confidence intervals for the ln-transformed primary parameters were: Candesartan cilexetil: Cmax: T/R 115.446 90% CIs 91.708 to 145.328 AUC0-t : T/R 102.488 90% CIs 85.527 to 122.812 Hydrochlorothiazide : Cmax: T/R 103.342 90% CIs 92.349 to 115.643 AUC0-t : T/R 101.768 90% CIs 92.850 to 111.543 Conclusions: Statistical analysis of the primary target parameters demonstrated that the two products were bioequivalent regarding the extent of absorption for both candesartan and hydrochlorothiazide and regarding the rate of absorption only for hydrochlorothiazide but not for candesartan. Both formulations were well tolerated. The 8+12.5 mg Pivotal Study In a two-stage, two-period, single-centre, single dose crossover study, 24 healthy male and female subjects received either test or reference product in randomised order after controlled fasting. Study periods were separated by a washout of 14 days. Primary variables for the assessment of bioequivalence were AUC0-t, and Cmax. Secondary pharmacokinetic parameter was Tmax and AUC0-inf, MRT and T1/2 were evaluated as further parameters. Blood samples were collected and adverse events recorded at appropriate intervals up to 48 hours after drug administration. Candesartan plasma concentrations were analysed using a validated HPLC/MS/MS method. Bioequvalence was confirmed when the point estimates and 94.12% confidence intervals (two-stage approach) of the primary parameters were within the generally accepted limits of 80% to 125%. The study was planned in two-stage design, but bioequivalence was already confirmed after the first stage and the second stage could be waived. Pharmacokinetic parameters for candesartan and hydrochlorothiazide as well as bioequivalence assessments are given in tables 1-4.


Clinical Overview 5

Table 1: Pharmacokinetic parameters for candesartan

N = 24

Cmax (ng/ml)

Tmax (hours)

AUC0-t (ng/ml*h)

AUC0-inf (ng/ml*h)

AUC%extrap(%)

T1/2 (hours)

MRT (hours)

Reference

Mean 72.600 4.146 944.438 984.029 3.867 10.229 14.488

SD 15.788 1.156 189.720 204.034 2.821 2.229 2.833

CV 21.747 27.885 20.088 20.735 72.954 21.791 19.558

Test

Mean 67.607 4.438 886.313 935.753 4.743 10.694 15.136

SD 18.110 1.477 264.841 305.903 2.895 2.327 3.426

CV 26.788 33.278 29.881 32.691 61.039 21.757 22.635

Table 2: Pharmacokinetic parameters for hydrochlorothiazide

N = 24

Cmax (ng/ml)

Tmax (hours)

AUC0-t (ng/ml*h)

AUC0-inf (ng/ml*h)

AUC%extrap(%)

T1/2 (hours)

MRT (hours)

Reference

Mean 86.531 1.806 577.821 597.486 3.402 8.676 9.968

SD 25.746 0.856 99.371 97.615 1.097 1.374 1.287

CV 29.753 47.434 17.198 16.338 32.251 15.841 12.910

Test

Mean 77.260 2.090 570.711 589.743 3.370 8.649 10.013

SD 13.961 0.707 123.345 121.821 1.395 1.474 1.496

CV 18.071 33.827 21.612 20.657 41.392 17.045 14.936 No significant differences in the pharmacokinetic parameters of either active component were observed between the formulations. The percentages for residual AUC were below 20%, indicating that the blood collection time period was correctly chosen. Table 3: Bioequivalence assessment for candesartan

94.12% confidence intervals

N = 24

Ratio T/R% Lower limit

Upper limit

Cmax

92.102

81.492

104.094

AUC0-t

91.650

83.161

101.005


Clinical Overview 6

Table 4: Bioequivalence assessment for hydrochlorothiazide


N = 24


Upper limit

Cmax

90.940

81.291

101.734

AUC0-t

98.073

93.264

103.131

The tables show that the point estimates and classical 94.12% confidence intervals for candesartan and hydrochlotohiazide were all within the in the protocol defined equivalence range of 80% to 125%. Both formulations were well tolerated. No deaths or serious adverse events occurred during the study period. Four subjects reported four adverse experiences that all were mild and completely resolved at the end of the study period. No clinically relevant changes were observed in vital signs, laboratory values or ECGs of any subject at the end of the study. Conclusions: Statistical analysis of the primary target parameters demonstrated bioequivalence for both rate and extent of absorption of both candesartan and hydrochlorothiazide according to the current generally accepted concepts of bioequivalence testing. Both formulations were well tolerated. The 32+25 mg Study In a two-stage, two-period, single-centre, single dose crossover study, 44 (43 analysed for bioequivalence) healthy male and female subjects received either test or reference product in randomised order after controlled fasting. Study periods were separated by a washout of 10 days in stage I and by a washout of 14 days in stage II. Primary variables for the assessment of bioequivalence were AUC0-t, and Cmax. Secondary pharmacokinetic parameter was Tmax, and AUC0-inf, MRT and T1/2 were evaluated as further parameters. Blood samples were collected and adverse events recorded at appropriate intervals up to 48 hours after drug administration. Candesartan and hydrochlorothiazide plasma concentrations were analysed using a validated HPLC/MS/MS method. Bioequvalence was confirmed when the point estimates and 94.12% confidence intervals of the primary parameters for candesartan and 90% confidence intervals for hydrochlorothiazide were within the generally accepted limits of 80% to 125%. No significant differences in the pharmacokinetic parameters were observed between the formulations. The percentages for residual AUC were below 20%, indicating that the blood collection time period was correctly chosen. Pharmacokinetic parameters for candesartan and hydrochlorothiazide as well as bioequivalence assessments are given in tables 5-8.


Clinical Overview 7

Table 5: Pharmacokinetic parameters for candesartan

N = 43

Cmax (ng/ml)

Tmax (hours)

AUC0-t (ng/ml*h)

AUC0-inf (ng/ml*h)

AUC%extrap(%)

T1/2 (hours)

MRT (hours)

Reference

Mean 252.879 4.140 3648.497 3949.205 7.074 11.976 17.619

SD 97.458 1.794 1040.609 1171.941 5.179 3.794 5.649

CV 38.539 43.336 28.522 29.675 73.210 31.683 32.064

Test

Mean 241.493 4.488 3436.087 3716.080 7.075 12.302 17.554

SD 85.273 1.692 939.251 1050.268 5.775 4.086 5.904

CV 35.311 37.698 27.335 28.263 81.616 33.212 33.635

Table 6: Pharmacokinetic parameters for hydrochlorothiazide

N = 18

Cmax (ng/ml)

Tmax (hours)

AUC0-t (ng/ml*h)

AUC0-inf (ng/ml*h)

AUC%extrap(%)

T1/2 (hours)

MRT (hours)

Reference

Mean 173.890 1.861 1218.968 1238.886 1.709 8.682 9.614

SD 47.560 0.890 294.754 294.674 0.768 1.259 1.127

CV 27.351 47.808 24.181 23.785 44.933 14.495 11.721

Test

Mean 177.209 1.750 1201.271 1224.723 1.989 8.928 9.671

SD 47.582 0.489 263.143 263.853 0.861 1.169 1.167

CV 26.850 27.958 21.905 21.544 43.286 13.096 12.067

No significant differences in the pharmacokinetic parameters of either active component were observed between the formulations. The percentages for residual AUC were below 20%, indicating that the blood collection time period was correctly chosen. Table 7: Bioequivalence assessment for candesartan (combined stage I and

stage II)


N = 43


Upper limit

Cmax

95.125

85.817

105.442

AUC0-t

94.924

89.696

100.457


Clinical Overview 8

Table 8: Bioequivalence assessment for hydrochlorothiazide (stage I)

90% confidence intervals

N = 18


Upper limit

Cmax

102.201

96.119

108.668

AUC0-t

99.241

93.858

104.934

The tables show that the point estimates and classical 94.12% confidence intervals for candesartan and classical 90% confidence intervals for hydrochlotohiazide were all within the in the protocol defined equivalence range of 80% to 125%. Both formulations were well tolerated. No deaths, serious adverse events or clinically relevant adverse events occurred during the study period. Nine adverse events were reported by seven subjects. Eight of them were mild and one moderate in intensity and all were resolved before the end of study. No clinically relevant changes were observed in vital signs, laboratory values or ECGs of any subject at the end of the study. Conclusions: Statistical analysis of the primary target parameters demonstrated bioequivalence for both rate and extent of absorption of both candesartan and hydrochlorothiazide according to the current generally accepted concepts of bioequivalence testing. Both formulations were well tolerated.


Clinical Overview 9

2.5.3 OVERVIEW OF CLINICAL PHARMACOLOGY 2.5.3.1 Pharmacokinetics of Candesartan 2.5.3.1.1 Absorption Following oral administration, candesartan cilexetil is converted to the active substance candesartan. The absolute bioavailability of candesartan is approximately 40% after an oral solution of candesartan cilexetil.6 The relative bioavailability of the tablet formulation compared with the same oral solution is approximately 34% with very little variability. The estimated absolute bioavailability of the tablet is therefore 14%.1 The mean peak serum concentration (Cmax) is reached 3-4 hours following tablet intake. The candesartan serum concentrations increase linearly with increasing doses in the therapeutic dose range (table 9).7;10 Table 9: Pharmacokinetics of candesartan after single and multiple doses of

2-16 mg candesartan cilexetil in healthy young subjects

Cmax

(ng/ml)

Tmax (h)

T1/2 (h)

Dose (mg)

N

SD

SS

SD

SS

SD

2

4

8

12

16

18

18

17

12

12

17.3 ± 6.5

27.6 ± 10.1

55.0 ± 21.7

64.0 ± 20.5

107.5 ± 39.9

17.1 ± 6.7

28.3 ± 13.0

60.5 ± 22.3

60.7 ± 27.5

119.2 42.8

3.9 ± 0.8

3.8 ± 1.0

4.3 ± 1.2

3.8 ± 0.3

3.6 ± 0.6

4.0 ± 1.6

3.6 ± 1.1

3.8 ± 1.0

3.7 ± 1.0

4.0 ± 1.3

7.70 ± 4.03

9.23 ± 3.69

9.05 ± 1.98

12.85 ± 3.37

9.09 ± 1.69

Cmax = peak plasma concentration; h = hour; N = number of subjects; SD = single dose; SS = steady state; Tmax = time to Cmax; T1/2 = elimination half-life No accumulation was observed after multiple doses of candesartan cilexetil (table 5). No gender related differences in the pharmacokinetics of candesartan have been observed.10 The area under the serum concentration versus time curve (AUC) of candesartan is not significantly affected by food.11 2.5.3.1.2 Distribution, Protein Binding The volume of distribution of candesartan was relatively low (0.13 l/kg) after intravenous administration of 4 mg in eight healthy volunteers.6 Candesartan is highly bound to plasma proteins (> 99%).6 2.5.3.1.3 Metabolism The esterified prodrug candesartan cilexetil is presumed to be completely metabolised to candesartan during absorption from the gastrointestinal tract as


Clinical Overview 10

no candesartan cilexetil is detectable in human plasma.7 Candesartan did not display affinity to any of clinically relevant CYP enzymes in vitro, but undergoes minor hepatic metabolism by demethylation to an inactive metabolite.12 2.5.3.1.4 Excretion Candesartan is mainly eliminated unchanged via urine and bile and only to a minor extent eliminated by hepatic metabolism.6 The terminal half-life (T1/2) of candesartan was approximately 9 hours in healthy volunteers.6 There is no accumulation following multiple doses.12 After intravenous administration of 4 mg candesartan cilexetil in healthy volunteers, total plasma clearance of candesartan was about 0.37 ml/min/kg, with a renal clearance of about 0.19 ml/min/kg.6 The renal elimination of candesartan is both by glomerular filtration and active tubular secretion. Following an oral dose of [14C]-labelled candesartan cilexetil to healthy volunteers, approximately 26% of the dose is excreted in the urine as candesartan and 7% as an inactive metabolite while approximately 56% of the dose is recovered in the faeces as candesartan and 10% as the inactive metabolite. More than 90% of total radioactivity was excreted within 72 hours after administration.6 2.5.3.1.5 Pharmacokinetics in Special Populations 2.5.3.1.5.1 Elderly Patients In healthy elderly volunteers (aged 65 to 78 years) receiving a single dose or repeated daily dosages of candesartan cilexetil 4 to 16 mg, the Cmax and AUC were greater than that of healthy younger volunteers aged 19 to 40 years, but no accumulation occurred.10 The T1/2 was only minimally longer (9 to 12 hours) in the elderly population than in younger volunteers (9 hours).10 Therefore, no dose adjustment is necessary for elderly patients. 2.5.3.1.5.2 Renal Impairment The AUC and T1/2 were significantly higher in patients with hypertension and impaired renal function receiving a single 8-mg dose of candesartan cilexetil compared with patients with normal renal function.13 This difference became more significant after repeated daily administrations (p < 0.01). Cmax was also significantly higher with increasing severity of renal impairment in patients receiving 12 mg/day candesartan cilexetil (p < 0.05).14 Haemodialysis did not contribute significantly to the elimination of candesartan in patients with end-stage renal disease (ESRD). The plasma concentrations of candesartan in patients receiving haemodialysis were approximately twice as high as those observed in subjects with normal renal function, but the plasma concentrations remained stable 7 and 14 days after dose titration to 4 –8 mg/day.15 Linear pharmacokinetics of candesartan were observed after doses of 4, 8 and 16 mg/day candesartan cilexetil also in patients with haemodialysis.16



2.5.3.1.5.3 Hepatic Impairment Since candesartan is mainly excreted unchanged through renal and biliary routes there were no significant pharmacokinetic difference between healthy individuals and patients with mild to moderate liver impairment after a single dose or multiple doses of candesartan 12 mg/day for 7 days. On day 7 the Cmax was almost identical and AUC was approximately 23% higher and the T1/2 was prolonged by 20% in patients with impaired hepatic function.17 2.5.3.2 Pharmacokinetics of Hydrochlorothiazide Hydrochlorothiazide is rapidly absorbed from the gastrointestinal tract. It has been reported to have a bioavailability of 65 to 70%.2 Hydrochlorothiazide was demonstrated to exhibit linear kinetics following oral administration in the dose range of 12.5-100 mg.8;9 Cmax and AUC0-9 increased dose-dependently in eight healthy volunteers (table 10)8. Table 10: Mean (± SD) pharmacokinetics of hydrochlorothiazide following

single administration of different doses

Dose of hydrochlorothiazide (mg)

Parameter

12.5

25

50

75

Cmax (ng/ml) AUC0-9 (ng/ml x h) T1/2 (h)* CLR0-9 (ml/min)

70 ± 19

351 ± 133

1.19-3.75

345 ± 123

142 ± 50

613 ± 276

1.47-14.81

332 ± 139

260 ± 88

1275 ± 526

3.44-12.39

340 ± 121

376 ± 70

1923 ± 295

3.52-10.42

319 ± 86

* range AUC0-9 = area under the plasma concentration curve during 9 hours; Cmax = peak plasma concentration; CLR0-9 = renal clearance during 9 hours; SD = standard deviation; T1/2 = elimination half-life Hydrochlorothiazide is excreted in human milk. After a dose 50 mg, the maximum concentration of hydrochlorothiazide in the breast milk of a young mother was approximately120 ng/ml while the blood concentration was about 420 ng/ml. No hydrochlorothiazide was detectable in the blood of the child.18 Hydrochlorothiazide is mainly eliminated unchanged via the kidneys. After administration of 12.5-75 mg, the urinary recovery of hydrochlorothiazide averaged between 65 and 72%, suggesting mean gastrointestinal absorption of 70%.8;9 The renal clearance varied substantially between and within individuals, although the mean clearance was almost the same for all doses (table 10).



2.5.3.3 Pharmacokinetics of the Combination A randomised, double blind, crossover placebo controlled study in healthy subjects receiving candesartan 12 mg and hydrochlorothiazide 25 mg investigated potential pharmacokinetic interaction of candesartan and hydrochlorothiazide. Coadministration of candesartan had no effect on hydrochlorothiazide Cmax, Tmax or T1/2, although it induced a slight but significant decrease in AUC values of hydrochlorothiazide (752 vs. 877 ng xh/ml; p < 0.01).19 Coadministration of hydrochlorothiazide increased the bioavailability of candesartan by approximately 20% and Cmax by 23%, but Tmax, T1/2 and MRT were not affected.19 Unpublished data indicated that the fixed combination and the combination of separate components were bioequivalent. Most least squares estimates of ratio and 90% confidence intervals for AUC and Cmax were within the acceptance limits for bioequivalence 0f 80 to 125%, with exception of those for Cmax of candesartan.5 2.5.3.4 Drug Interactions Randomised, crossover studies in healthy volunteers aged 18 to 45 years found that coadministration of candesartan cilexetil 8 to 16 mg/day had no clinically significant effects on the pharmacokinetic parameters of hydrochlorothiazide, nifedipine, glibenclamide, digoxin, warfarin, oral contraceptives (i.e. ethinylestradiol/ levonorgestrel) or enalapril.19 The bioavailability and Cmax of candesartan were increased by about 20% when coadministered with hydrochlorothiazide. However, these increases were not considered to be clinically relevant.3 Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors. A similar effect may occur with angiotensin II receptor antagonists.1 When angiotensin II receptor antagonists are administered simultaneously with non-steroidal anti-inflammatory drugs (i.e. selective COX-2 inhibitors, acetylsalicylic acid (> 3g/day) and non-selective NSAIDs), attenuation of the antihypertensive effect may occur.1 As with ACE inhibitors, concomitant use of angiotensin II receptor antagonists 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 the elderly. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy, and periodically thereafter.1 2.5.3.5 Pharmacodynamics of Candesartan 2.5.3.5.1 Mechanism of Action Angiotensin II is the key effector peptide of the renin-angiotensin system (RAS), which is central to the development of hypertension. Arterial blood pressure (BP)



and the maintenance of fluid and electrolyte homeostasis are regulated, in part, through binding of angiotensin II to receptors located in cardiac and vascular tissue but also in lung, liver, kidney, adrenal gland, prostate gland, platelets, adipocytes, placenta and brain. RAS plays a pivotal role in the pathogenesis of hypertension, congestive heart failure and diabetic nephropathy. Angiotensin II receptors exist as subtype 1 (AT1) and subtype 2 (AT2), with AT1 being responsible for the angiotensin II-mediated effects described above.3;4 Candesartan has demonstrated to have specific binding to the AT1 receptor in a monophasic and concentration-dependent manner. Candesartan showed a selective AT1 receptor antagonism in rabbit aortic membranes, with an inhibition constant (Ki) of 0.64 nmol/l.20 Candesartan depressed the angiotensin II concentration-response curve and inhibited the angiotensin II-induced contraction of isolated rabbit aortic strips.20;21 Candesartan inhibited the angiotensin II-induced contractile response of rabbit aorta at very low concentrations. Candesartan at 1 nmol/l almost completely inhibited the angiotensin II-induced contractile response of the strip.22 When compared with other angiotensin II receptor antagonists, candesartan was a more potent inhibitor of angiotensin II binding to human AT1 receptors expressed in COS-7 cells than other angiotensin II receptor antagonists (table 11). Table 11: Inhibitory effects of various angiotensin II receptor antagonists

on the specific binding of [125]angiotensin II to the human AT1 receptor

Compound

Inhibition IC50 mol/l

Candesartan EXP3175 Eprosartan Irbesartan Valsartan

3.0 x 10-9 9.2 x 10-9 5.3 x 10-8 8.0 x 10-9 6.0 x 10-8

The inhibition potencies were in the following order: candesartan ≥ irbesartan and EXP3175 (active metabolite of losartan) > eprosartan and valsartan.22 Binding studies with [3H]candesartan revealed a high affinity and selective binding of candesartan to the human AT1 receptors in Chinese hamster ovary cells expressing the cloned human AT1 receptor. Angiotensin II-induced accumulation of inositol triphosphate in the cells was inhibited by 94% when the cells were preincubated with candesartan, and recovery of inositol triphosphate in the cells was directly linked to the rate of dissociation of the angiotensin II antagonist from the AT1 receptor.23 2.5.3.5.2 Pharmacodynamics in Healthy Volunteers The response to exogenous angiotensin II was attenuated after oral administration of 4-16 mg of candesartan cilexetil in healthy male volunteers.3;7;24 The tight and long-lasting effects of candesartan at the AT1 receptor found during in vitro studies has been confirmed in human subjects. In 27 healthy, male



volunteers, candesartan cilexetil (1, 2, 4, or 8 once daily) produced a dose-dependent reduction in the rise of SBP in response to an intravenous infusion of angiotensin II. The reduction in BP was found to maintain throughout the 24-hour dosing interval, despite of fall of candesartan plasma concentration.7 Approximately 25 to 30 times the amount of angiotensin II was required to achieve the same DBP increase after treatment with a therapeutic oral dose of candesartan cilexetil (4-16 mg) in healthy volunteers.24 The apparent Ki (dose required for a 2-fold shift in the angiotensin II dose-response curve) was 1.94 mg 24 hours after administration in 12 volunteers;24 however, the 24-hour Ki was 6 mg in another trial, which is within the therapeutic oral dose range.3 BP responses to IV angiotensin II were completely suppressed by candesartan 16 mg for 24 hours compared to placebo (p < 0.001). Forearm blood flow (FBF) response to angiotensin II was also significantly suppressed by candesartan at 2 hours (p = 0.0326) after administration but not after 24 hours. FBF response to IV norepinephrine was also suppressed by candesartan while the BP responses were not altered.25 2.5.3.5.3 Pharmacodynamics in Patients 2.5.3.5.3.1 Effects on Hypertension A single dose of candesartan cilexetil 16 mg reduced mean arterial pressure (-8.8 mmHg; p < 0.001) 4 hours after drug administration in 17 patients with mild to moderate hypertension. The effect was due to reduction in total peripheral resistance (- 1.2 mmHg/l/min; p = 0.08), while heart rate (HR), stroke volume (SV) and cardiac output (CO) remained unchanged. There was also a marked reduction in renal vascular resistance (RVR) of 0.0273 mmHg/ml/min (16%), resulting in an increased renal plasma flow.26 A second study using the same dose showed that the reduction in systemic and forearm vascular resistance maintained during 6 weeks treatment. There was a significant reduction in SBP (p < 0.001), DBP (p = 0.018) and mean arterial pressure (MAP; p < 0.005) compared with placebo. Angiotensin II concentration and plasma renin activity (PRA) increased during the candesartan cilexetil therapy.27 Compared to healthy subjects, patients with essential hypertension have a reduced vasoconstrictor response to N-monomethyl-L-arginine (L-NMMA; FBF decrease –46% vs. –28%; p < 0.001). Candesartan cilexetil significantly enhanced vasoconstriction to L-NMMA after 2 and 12 months (maximal FBF decrease by 37% and 42%, respectively; p < 0.05 and p < 0.001, respectively).28 Treatment with candesartan cilexetil significantly lowered BP values and increased PRA and plasma angiotensin II levels (table 12).



Table 12: Haemodynamic and humoral parameters in patients with

hypertension during treatment with candesartan cilexetil Parameter

Baseline

Candesartan

2 months

Candesartan 12 months

SBP (mmHg) DBP (mmHg) HR (beats/min) PRA# Angiotensin II (pg/ml)

152.3 ± 7.1 102.6 ± 4.1 77.9 ± 4.4

0.74 ± 0.53 5.02 ± 2.02

135.2 ± 4.8* 85.3 ± 3.6* 74.7 ± 4.4* 1.27 ± 1.13 6.65 ± 2.82

131.1 ± 6.7* 82.6 ± 4.9* 70.7 ± 5.5* 1.50 ± 1.93 8.96 ± 2.53*

* p < 0.01 vs. baseline # as measured by ng of angiotensin I/ml/hour. DBP = diastolic blood pressure; HR = heart rate; PRA = plasma renin activity; SBP = systolic blood pressure A meta-analysis of 6 European placebo-controlled studies involving 1482 evaluable patients with mild to moderate hypertension showed that candesartan cilexetil (2 to 16 mg/day for 4 to 12 weeks) produced a significant, dose-dependent reduction in BP, but had no effects on heart rate and did not cause postural hypotension. There was no indication of any influence of gender or age on the reductions in BP.29 2.5.3.5.3.2 Renal Effects In healthy volunteers, candesartan cilexetil in 4-, 8-, 16-, and 32-mg doses produced a dose-related increase in renal plasma flow, with the maximum vasodilator response at 14 mg occurring during the first 14 hours after administration. Further, candesartan cilexetil caused a dose-related increase in plasma renin activity (PRA), with 32 mg producing the greatest response at 4 and 24 hours after administration.30 Candesartan cilexetil preserves or improves renal function in patients with hypertension. Candesartan cilexetil reduced renal vascular resistance (RVR) in patients with hypertension given a single oral dose26 or treated for 6 weeks.27 A single oral dose of candesartan cilexetil 16 mg in 16 patients with hypertension significantly reduced BP within 4 hours and was accompanied by a reduction in renal vascular resistance (-0.027 mmHg/ml/min; p < 0.001 vs. baseline) and increases in glomerular filtration rate (GFR) (+0.47 l/h; p < 0.05 vs. baseline), renal plasma flow (+3.89 l/h; p< 0.02 vs. baseline) and renal blood flow (+6.74 l/h; p < 0.05 vs. baseline).26 A reduction in renal vascular resistance (mean difference of –0.03 mmHg/ml/min vs. placebo; p < 0.01) was also seen after 6 week’s treatment with candesartan cilexetil in 19 patients with hypertension. However, GFR and renal blood and plasma flow were not significantly changed.27 2.5.3.6 Pharmacodynamics of Hydrochlorothiazide 2.5.3.6.1 Effect of Hydrochlorothiazide on Blood Pressure The effect of hydrochlorothiazide on blood pressure is discussed in detail in section 2.5.4.2 (Clinical Efficacy).



The average systolic and diastolic blood pressure responses to hydrochlorothiazide for a group of patients (n = 22) were reproducible in two settings mean 26.6 months apart. However, the responses for individual subjects are unpredictable.31 2.5.3.6.2 Effects of Hydrochlorothiazide on Diuresis and Electrolytes The mechanism of antihypertensive action of diuretics is not completely elucidated. The initial fall in arterial pressure produced by diuretics at the beginning of treatment is mainly due to reduction in blood volume. During this period, cardiac output falls, presumably due to reduction in venous return and total peripheral resistance remains unchanged or slightly increased. Chronic treatment results in maintenance of reduction, while cardiac output increases, vascular resistance reduces, and plasma volume returns to pre-treatment level.32 Hydrochlorothiazide is a thiazide diuretic. It exerts its antihypertensive effect by inhibiting Na+/Cl- reabsorption from the distal tubules in the kidney. By reducing osmotic pressure, hydrochlorothiazide reduces the reabsorption of water in the distal convoluted tubules and thereby reduces plasma volume and cardiac output.32 A diuretic effect of hydrochlorothiazide becomes evident during the third hour and persists until 6-12 hours.8 In healthy volunteers, diuresis was significantly (p < 0.001) higher after any hydrochlorothiazide dose than after placebo (table 13). The diuretic effect of hydrochlorothiazide reached the maximum already after 12.5 mg, with no significant differences between the doses.8 Table 13: Renal excretion of water and electrolytes after oral

administration of placebo and various doses of hydrochloro-thiazide to healthy volunteers

Dose

Water (ml)

Na+ (mmol)

K+ (mmol)

Ca++ (mmol)

Mg++ (mmol)

Placebo 12.5 mg 25 mg 50 mg 75 mg

1208 ± 284

2009 ± 320*** 2005 ± 379*** 1962 ± 391*** 2040 ± 440***

36.9 ± 14.0

136.7 ± 22.9*** 144.6 ± 41.4*** 160.1 ± 18.5*** 157.4 ± 50.0***

29.5 ± 7.7

35.6 ± 14.9 46.7 ± 15.1*

50.8 ± 13.7*** 55.7 ± 16.4**

1.19 ± 0.26 1.31 ± 0.55 1.48 ± 0.61 1.75 ± 0.73* 1.42 ± 0.62

1.51 ± 0.62 1.93 ± 0.62

2.05 ± 0.92** 1.98 ± 0.63* 1.68 ± 0.72

* p < 0.05; ** p < 0.01; *** p < 0.001 vs. placebo The natriuretic effect of hydrochlorothiazide was significantly (p < 0.001) greater than that of placebo, without differences between the doses. The effects on potassium, calcium and magnesium excretion were more variable than those on sodium, but at higher doses, potassium excretion was significantly greater than that after placebo.8 Administration of 3-6-12.5-25 mg/day hydrochlorothiazide for 6 weeks did not significantly change from baseline sodium, magnesium, or glucose levels at any dose level.33 Plasma potassium decreased and urate increased significantly after the doses of 12.5 and 25 mg (p < 0.05 and p < 0.01, respectively). The increase in urate after 25 mg/day was significantly (p < 0.05) greater as after placebo, and the decrease in potassium in the 25-mg treatment group was significantly greater



than those in the placebo or in the hydrochlorothiazide 3- and 6-mg groups (p < 0.05)33. Plasma renin activity increased after 25 mg/day significantly more than with placebo (p < 0.01) or in the 6-mg group (p < 0.005).33 2.5.3.6.3 Effects of Hydrochlorothiazide on Plasma Lipids Thiazide diuretics have been associated with increases in plasma cholesterol. Meta-analyses have indicated that these effects are dose-dependent. Ott et al. (2003)34 examined the effect of hydrochlorothiazide on the lipid parameters of 320 elderly healthy subjects during three years of treatment followed by one-year observation period without medication. Table 14: Change in cholesterol levels from baseline to 30 months of

treatment

Men

Women

Cholesterol (mg/dl)

PLA

(n = 35)

HCT 12.5 mg (n = 38)

HCT 25 mg

(n = 35)

PLA

(n = 64)

HCT 12.5 mg (n = 64)

HCT 25 mg

(n = 67) TC HDLC LDLC TG

-4.5 ± 4.7 -2.3 ± 1.4 -5.2 ± 3.9 -3.3 ± 9.4

-2.3 ± 4.5 -1.7 ± 1.4 -4.6 ± 3.7 0.8 ± 8.9

5.0 ± 4.6

-0.05 ± 1.4 1.1 ± 3.8 2.6 ± 9.2

1.4 ± 3.3 -3.1 ± 1.3 1.3 ± 2.8 8.7 ± 6.2

0.1 ± 3.4 -4.0 ± 1.4 -1.1 ± 2.8 11.6 ± 6.3

-3.9 ± 3.3 -0.8 ± 1.3 -6.8 ± 2.8 0.8 ± 6.1

Data given as mean ± SD HCT = hydrochlorothiazide; HDLD = high-density lipoprotein cholesterol; LDLD = low-density lipoprotein cholesterol; PLA = placebo; TC = total cholesterol; TG = triglycerides

No significant differences in the change of plasma lipids were observed between placebo and dose of hydrochlorothiazide (table 12). Women taking hydrochlorothiazide had a more favourable lipid profile than those taking placebo, but these changes were not statistically significant (table 12). During the fourth year (without medication) there were no significant changes in plasma lipid levels and no significant differences between the former treatment groups.34 No significant changes in plasma lipid profile were observed after a 6-week treatment with hydrochlorothiazide 3-6-12.5-25 mg/day, except an increase in HDL-cholesterol after 25 mg.33 2.5.3.7 Pharmacodynamics of the Combination The pharmacodynamics of both active agents, candesartan and hydrochlorothiazide, have been investigated extensively. For the combination no special studies have been published.



2.5.4 OVERVIEW OF EFFICACY 2.5.4.1 Clinical Studies and Study Population of Candesartan 2.5.4.1.1 Placebo-Controlled Dose-Response Studies The antihypertensive efficacy of candesartan cilexetil has been well established in placebo-controlled dose ranging studies. A meta-analysis involving 1482 evaluable included a six placebo controlled studies in hypertonic patients receiving up to 16 mg/day for 4 to 12 weeks. Response rates increased from 35% with candesartan cilexetil 2 mg to 55% with the 16 mg daily dose.29 The efficacy of higher doses has been evaluated in two more recent randomised studies.35;36 360 patients received placebo or candesartan cilexetil 2, 4, 8, 16, or 32 mg/day for 8 weeks. At the end of treatment, all dosages of candesartan cilexetil produced greater reductions in trough seated DBP, with increasing efficacy of increasing dosages (p = 0.0004). Similarly, reductions in seated SBP were significantly greater in candesartan cilexetil recipients than in placebo recipients at all dosages (p < 0.001).35 In a randomised, double-blind, placebo controlled study in 133 patients with hypertension, candesartan cilexetil at all dosages (16-64 mg/day) was significantly superior to placebo in reducing through sitting DBP (p < 0.01) and SBP (p < 0.001). Maximum reductions in DBP and SBP were obtained with 32 mg/day, an increase of the dose to 64 mg/day did not reduce BP significantly more than 32 mg/day.36 In a placebo controlled, double blind comparison of candasartan cilexetil 4, 8, 12 mg/day with enalapril 10 mg/day in 335 patients with hypertension for 12 weeks, DBP was significantly decreased after candesartan cilexetil 8, 12 mg/day and enalapril 10 mg/day compared to placebo (table 15). Table 15: Mean changes in diastolic blood pressure after different doses

of candesartan cilexetil, enalapril and placebo

Treatment group

N

Mean changes in DBP

(mmHg)

p

vs. PLA Placebo Candesartan cilexetil 4 mg Candesartan cilexetil 8 mg Candesartan cilexetil 12 mg Enalapril 10 mg

65 66 68 65 71

-5.3 ± 11.1 -8.4 ± 10.5 -10.5 ± 9.9

-10.0 ± 10.0 -10.6 ± 9.8

NA

0.074 < 0.01 < 0.01 < 0.01

DBP = diastolic blood pressure; NA = not applicable; PLA = placebo Corresponding reductions in SBP were also seen in all active treatment groups.37 2.5.4.1.2 Reference-Controlled Studies Nine reference-controlled, double blind trials of candesartan cilexetil are presented in tables 16-18 (3 studies vs. enalapril, 3 studies vs. losartan and 3 studies vs. other antihypertensiva).



The studies versus enalapril38;39;40 were all randomised, double blind trials with parallel groups in more than 1000 patients (candesartan cilexetil 408, enalapril 407, hydrochlorothiazide 143, placebo 39) with mild to moderate hypertension. The mean efficacy parameter in all studies was change in BP. In one placebo controlled study, both candesartan cilexetil and enalapril reduced BP significantly more effective than placebo. There was no difference in efficacy between the groups.38 In the two other studies, the efficacy of candesartan cilexetil was significantly greater than that of enalapril (SBP p < 0.032 and p < 0.01; DBP p < 0.008 and p < 0.01) and caused less discomfort. None of the drugs significantly influenced heart rate of the patients.39;40 The studies versus losartan41;42;43 were all randomised, double blind trials with parallel groups in more than 1300 patients (candesartan cilexetil 660, losartan 575, placebo 85) with mild to moderate hypertension. Candesartan cilexetil was significantly more effective in reducing BP than losartan in all three studies,41;42;43 and there were markedly more patients controlled with candesartan cilexetil than with losartan.43 Candesartan cilexetil was equally effective in reducing BP as hydrochlorothiazide44 in one and amlodipine in two randomised, double blind studies.45;46 A combination therapy with candesartan cilexetil and amlodipine was more effective in reducing BP than either single agent alone.46



Table 16: Reference-controlled studies of candesartan cilexetil vs. enalapril in patients with hypertension

Reference

Design

Criteria for evaluation

Number of

patients

Gender

Age

(years)

Dose of drug

(mg/day)

Observation

period

Results

Zanchetti et al. 200138

MC, DB, R, PC,

PG

Change in sitting DBP

227 (178)

CDS 72 / ENL 67 / PLA 39

M 104 / F

74

18-70

CDS 4-8 / ENL 10-20

8 weeks

Both active medications reduced BP significantly vs. PLA; DBP: -10, -10 and –7, respectively (p < 0.01); SBP: -13, -14 and –6 for CDS, ENL and PLA, respectively (p < 0.01); No significant effect on HR, no significant difference between CDS and ENL

Himmelmann et al. 200139

MC, DB, R, PG

Change in

mean DBP and SBP

395 (ITT 390)

CDS 196 / ENL 194

M 232 / F

194

20-80

CDS 8-16 / ENL 10-20

8 weeks

CDS was more effective at 22-24 h post dose; difference –3.5 (p < 0.032) and –3.0 (p < 0.008) in SBP and DBP, respectively, and in mean adjusted BP 24-36 h post dose of -4.2 (p < 0.002) and –3.5 (p < 0.001)

Malmqvist et al. 200040

MC, DB, R, PG

SSA (QOL); dry

cough; dizziness;

change in BP

429 ITT

CDS 140 / ENL 146 / HCT 143

All F

40-74

CDS 8-16 / ENL 10-20 / HCT 12.5-25

12 weeks

SSA scores revealed that ENL caused much more discomfort then either CDS or HCT; both CDS and HCT caused significantly (p < 0.0001) less dry cough than ENL; no significant differences in the occurrence of dizziness; CDS lowered seated SBP and DBP significantly more than ENL (p < 0.01) or HCT (p < 0.01) at 6 and 12 weeks: -17/-11 and –19/-11 mmHg, respectively, for CC and –12/-8 and –13/-9 mmHg, respectively, for ENL and –12/-7 and –13/-8 mmHg, respectively, for HCT

BP = blood pressure; CDS = candesartan cilexetil; DB = double blind; DBP = diastolic blood pressure; ENL = enalapril; HCT = hydrochlorothiazide; ITT = intention to treat analysis; MC = multicentre; PC = placebo controlled; PG = parallel groups; PLA = placebo; QOL = quality of life; R = randomised; SBP = systolic blood pressure; SSA = Subjective Symptom Assessment



Table 17: Reference-controlled studies of candesartan cilexetil vs. losartan in patients with hypertension

Reference

Design


Number of

patients

Gender

Age

(years)

Dose of drug

(mg/day)

Observation

period

Results

Andersson et al. 199841

MC, DB, R, PC,

PG

Change in BP

334

CDS8 82 / CDS16 84 /

LOS 83 / PLA 85

M 188 / F

146

Mean 59-

60

CDS 8-16 /

LOS 50

8 weeks

Both CDS doses reduced DBP significantly more than PLA (p < 0.001 both); CDS 16 mg reduced trough DBP significantly more than LOS (difference -3.7 mmHg; p = 0.013); CDS 8 mg was equally effective with LOS in reducing DBP

Gradman et al. 199942

MC, DB, R, PG

Change in BP

332 (329)

CDS 162 / LOS 170

M 191 / F

141

Mean 54-

57

CDS 16-32 / LOS 50-100

8 weeks

CDS lowered trough DBP significantly more than LOS ( difference –2.1 mmHg; p = 0.016); 64% of the CDS patients and 54% with LOS responded to tha treatment; 54% and 43% of patients, respectively, were controlled with the medication

Bakris et al. 200143

MC, DB, R, PG

Change in BP

654

CDS 332 / LOS 322

M 380 / F

274

Mean 54.1

CDS 16 / LOS 50

8 weeks

CDSlowered trough SBP/DBP significantly more than LOS: -13.3/-10.9 vs. –9.8/-8.7 mmHg, respectively (p < 0.001) and peak SBP/DBP -15.2/-11.6 vs. –12.6/-10.1 mmHg, respectively (p < 0.05); there were significantly (p < 0.05) more responders and controlled patients with CDS than LOS

BP = blood pressure; CDS = candesartan cilexetil; DB = double blind; DBP = diastolic blood pressure; ITT = intention to treat analysis; LOS = losartan; MC = multicentre; PC = placebo controlled; PG = parallel groups; PLA = placebo; R = randomised; SBP = systolic blood pressure



Table 18: Reference-controlled studies of candesartan cilexetil vs. other antihypertensiva in patients with hypertension

Reference

Design


Number of

patients

Gender

Age

(years)

Dose of drug

(mg/day)

Observation

period

Results

Neldam et al. 200144

MC, DB, R, PG

vs. HCT

% patients with

AE; change in BP

185

CDS 123 / HCT 62

M 69 / F

116

≥ 75

CDS 8-16 /

HCT 12.5-25

24 weeks

No significant difference between the groups in occurrence of AEs (64.2% vs. 62.9% for CC and HCTZ, respectively; Mean changes in sitting DBP: -12.0 and –11.4 mmHg for CC and HCTZ, respectively; NS

Kloner et al. 200145

MC, DB, R, PG

vs. AMD

Change in

mean trough DBP

251

CDS 123 / AMD 128

M 137 / F

114

Mean 53-

54

CDS 16-32 / AMD 5-10

8 weeks

Reductions in mean DBP were –10.2 and –11.3 mmHg after CC and AMD, respectively; NS and in mean SBP –15.2 and –15.4 mmHg, respectively; NS

Farsang et al. 200146

MC, DB, R, PC,

PG

vs. AMD and CT with CDS +

AMD

Change in sitting DBP

341

CDS 85 / AMD 84 / CDS +

AMD 89 / PLA 83

M 231 / F

110

Mean 51-

54

CDS 8 / AMD 5 / CDS 8 +

AMD 5

8 weeks

All active treatments were significantly (p < 0.001) more effective than PLA; CT was more effective than either single agent, except for sitting DBP: difference in the adjusted mean reductions: -5.8/-0.8 mmHg CT vs. CC (p < 0.05/NS and –5.6/-2.0 mmHg CT vs. AMD (p < 0.05 both)

AE = adverse event; AMD = amlodipine; BP = blood pressure; CDS = candesartan cilexetil; CT = combination therapy; DB = double blind; DBP = diastolic blood pressure; F = female; HCT = hydrochlorothiazide; ITT = intention to treat analysis; M = male; MC = multicentre; NS = not significant; PC = placebo controlled; PG = parallel groups; PLA = placebo; R = randomised; SBP = systolic blood presseure



2.5.4.2 Clinical Studies on Hydrochlorothiazide Thiazide diuretics have been the drugs of first choice for the treatment of hypertension, either in monotherapy or in combination with other antihypertensive drugs, for more than four decades. Only a few studies have been conducted especially on hydrochlorothiazide but it has been part of large comparative studies initiated by various national councils47 and reviews comparing diuretics.32;48 Medical Research Council of UK47 organised a large (n = 4396) placebo-controlled clinical comparison of standard antihypertensive treatments including older (65-74 years) patients with previously untreated hypertension. Patients were randomised to beta-blocker (atenolol, n = 1102), diuretic (hydrochlorothiazide or amiloride, n = 1081), or placebo (n = 2213). Decreases in blood pressure were similar in both active treatment groups, but only the diuretic group had significantly reduced risks of stroke (31%, p = 0.04), coronary events (44%, p = 0.0009), and all cardiovascular events (35%, p = 0.0005). The antihypertensive effect of hydrochlorothiazide was demonstrated to be dose related in a placebo-controlled study (table 19)33. Table 19: Mean (SD) supine blood pressure values and heart rate at

baseline and after 6 week of treatment

Hydrochlorothiazide (mg/day)

Parameter

PLA (n = 22)

3 (n = 22)

6 (n = 22)

12.5 (n = 22)

25 (n = 23)

SBP mmHg BL 6 weeks change

152.5 150.4

-2.1 (13.2)

147.4 143.7

-3.8 (10.4)

152.7 146.3

-6.4 (7.4)**

152.8 146.4

-6.5 (11.7)*

147.0 134.9

-12.1 (12.4)**

DBP mmHg BL 6 weeks change

99.8 94.3

-5.5 (8.5)**

99.0 94.0

-5.0 (8.6)*

99.9 93.0

-6.9 (5.2)**

99.3 92.0

-7.3 (6.1)**

97.6 85.4

-12.2 (7.3)**

HR bpm BL 6 weeks change

72.7 70.4

-2.3 (9.8)

70.1 69.2

-0.9 (5.2)

67.2 66.5

-0.7 (4.6)

71.4 72.4

1.0 (7.8)

73.0 72.2

-0.8 (7.5)

* p < 0.05; ** p < 0.01 BL = baseline; bpm = beats per minute; DBP = diastolic blood pressure; HR = heart rate; SBP = systolic blood pressure Heart rate did not differ significantly from the baseline or between the treatment groups.33 Ernst et al. (2006)49 compared the antihypertensive effects of hydrochlorothiazide 25-50 mg/day) and chlorthalidone (12.5-25 mg/day) in a randomised, single blind crossover study with 30 previously untreated patients. Medications were administered for 8 weeks each, with a washout of 4 weeks. The efficacy of chlorthalidone appeared to be greater when it was administered first but was not



the case when given after hydrochlorothiazide. Week 8 ambulatory BP indicated a greater reduction from baseline in systolic blood pressure with chlorthalidone compared with hydrochlorothiazide (24-hour mean: -12.4 ± 1.8 mmHg vs. –7.4 ± 1.7 mmHg; p = 0.054; night-time mean –13.5 ± 1.9 mmHg vs. –6.4 ± 1.8; p = 0.009). The reductions in mean daytime SBP were similar for both drugs. No significant differences in the antihypertensive effects of the agents were observed in the office blood pressure.49 2.5.4.3 Clinical Studies of the Combination 2.5.4.3.1 Dose-response Study Karlson et al. (2009)50 performed a meta-analysis of all avilable RCTs on BP lowering effect of combinations of candesartan hydrochlorothiazide of different strengths. Eight studies enrolled a total of 4632 patients (1561 on differnt strengts of the combination, 1274 on candesartan monotherapy, 1123 on hydrochlorothiazide monotherapy and 674 on placebo). Table 20: Effects of differnt doses of the combination on blood pressure

Candesartan (mg)

HCT (mg)

0

2

4

8

16

32 SBP 0 6.25 12.5 25

0.0 2.7 4.5 6.8

2.9 5.9 7.9

10.5

4.5 7.7 9.8

12.4

6.2 9.5

11.7 14.5

7.6 11.0 13.3 16.2

8.5 12.1 14.4 17.4

DBP 0 6.25 12.5 25

0.0 1.2 2.1 3.5

1.5 2.8 3.8 5.3

2.5 3.8 4.9 6.4

3.6 5.0 6.2 7.8

4.8 6.2 7.4 9.1

5.6 7.2 8.4

10.2

The placebo-adjusted reductions with the combination therapy ranged from 5.9 to 17.4 mmHg for SBP and from 2.8 to 10.2 mmHg for DBP. The reduction in both SBP and DBP increased with increasing doses of candesartan and hydrochlorothiazide alone and in combination. Candesartan hydrochlorothiazide combination therapy using moderate doses was more effective in reducing BP than high doses of either monotherapy. The reduction with candesartan hydrochlorothiazide represented fully additive contributions of the components over the entire dose range (table 20).50 2.5.4.3.2 Studies of Combination Therapy versus Monotherapy Three trials (including a total of 3827 patients with hypertension) compared the clinical efficacy of candesartan hydrochlorothiazide combination with candesartan monotherapy or hydrochlorothiazide monotherapy or placebo (table 21). Combination therapy with 16+12.5 mg was significantly (p = 0.010 for SBP and p = 0.037 for DBP) more effective than candesartan 16 mg monotherapy.51 Candesartan hydrochlorothiazide 32+12.5 mg and 32+25 mg were significantly (p



< 0.001 all) more effective in reducing BP than candesartan 32 mg alone. Further, the higher dose combination reduced BP significantly more than the combination of candesartan hydrochlorothiazide 32+12.5 (p < 0.001 for SBP and p < 0.01 for DBP).52 In the third study, candesartan hydrochlorothiazide 32+25 mg and both individual components at the same dose level were significantly more effective in reducing BP than placebo and the combination was signficantly (p < 0.001) more effective than either monotherapy.53 2.5.4.3.3 Reference Controlled Studies Two trials compared candesartan hydrochlorothiazide combination with other combination therapies (table 22). Candesartan hydrochlorothiazide 16+12.5 mg was significantly more effective than previous antihypertensive therapy (calcium antagonist, betablocker, other angiotensin II antagonist or ACE inhibitor) plus hydrochlorothiazide 12.5 mg in normalising BP (82% vs. 72.6%; p < 0.05).54 Candesartan hydrochlorothiazide 16+12.5 mg reduced BP significantly more than losartan hydrochlorothiazide 50+12.5 mg and, significantly greater percentage of patients on candesartan hydrochlorothiazide had normalised BP after 12 weeks of treatment (60.9% vs. 49.3%; p = 0.044).55 Combination of candesartan hydrochlorothiazide 16+12.5 mg and candesartan 32 mg monotherapy reduced significantly (p < 0.001 both) BP in 4527 (3337 on combination, 1263 on monotherapy) patients with hypertension and additional cardiovascular risk. Also reduction of cardiovascular risks was similar in both treatment groups.56



Table 21: Controlled studies of candesartan cilexetil plus hydrochlorothiazide in patients with hypertension

Reference

Design


Number of

patients

Gender

Age

(years)

Dose of drug

(mg/day)

Median

observationperiod

Results

Campbell et al. 200151

MC, R, DB, PC,

PG

SBP, DBP, RR

328

CDS HCT 164 / CDS PLA 164

M 190 / F

138

Mean 52.8

CDS HCT 16+12.5 / CDS PLA 16+PLA

8 weeks

CDS HCT reduced SBP significantly more than CDS PLA (- 12.0 vs. -7.5; p = 0.010), CDS HCT reduced DBP significantly more than CDS PLA (- 7.5 vs. – 5.5; p = 0.037); significantly more patients responded to CDS HCT (61.0% vs. 47.6%; p = 0.015)

Bonner et al. 200852

MC, R, DB, PG

SBP, DBP

1975 (1945) CDS HCT

32+12.5 648 / 32+25 659 / CDS 32 638

M 1131 / F

814

Mean

54.6-54.9

CDS HCT 32+12.5 /

32+25 / CDS 32

8 weeks

CDS HCT 32+12.5 reduced both SBP and DBP significantly more than MT (p < 0.001 both), CDS HCT 32+25 reduced oth SBP and DBP significantly more than MT (p < 0.001 both) and reduced SBP and DBP significantly more than CDS HCT 32+12.5 (p < 0.001 and p < 0.01, respectively)

Edes et al. 200953

MC, R, DB, PC,

PG

SBP, DBP

1524 (1499)

CDS HCT 486 / CDS 457 / HCT

464 / PLA 92

M 631 / F

868

20-80

CDS HCT

32+25 / CDS 32 / HCT 25 /

PLA

8 weeks

All active medications reduced both SBP and DBP significantly more than PLA (p < 0.001 all), CDS HCT reduced SBP and DBP signifiacntly more than either MT (p < 0.001 both)

CDS = candesartan cilexetil; CI = confidence intervals; DB = double blind; DBP = diastolic blood pressure; F = female; HCT = hydrochlorothiazide; M = male; MC = multicentre; MT = montherapy; PC = placebo controlled; PG = parallel groups; PLA = placebo; R = randomised; RR = responder rate; SBP = systolic blood pressure



Table 22: Reference-controlled studies of candesartan cilexetil plus hydrochlorothiazide

Reference

Design


Number of

patients

Gender

Age

(years)

Dose of drug

(mg/day)

Observation

period

Results

Mancia et al. 200454

MC, R, DB, PG

MC, R, DB, PG

409 (396)

CDS HCT 202 / PM HCT 207

M 261 / F

148

Mean 55-

56

CDS HCT 16+12.5 / PM* HCT

12.5

8 weeks

At weeks 4 and 8, SBP and DBP were decreased from BL in both medication groups, no signifiacnt between-group difference was observed; in the CDS HCT group, signifiacntly more patienten showed a normalised BP than in the PM HCT group (82% vs. 72.6%; p < 0.05)

Ohman et al. 200055

MC, R, DB, PG

MC, R, DB, PG

299

CDS HCT 151 / LOS HCT 148

M 155 / F

144

20-80

CDS HCT 16+12.5 / LOS HCT 50+12.5

12 weeks

CDS HCT reduced both SBP and DBP significantly more than LOS HCT (p = 0.004 and p = 0.016, respectively); percentage of patients with normalised BP was significantly higher with CDS HCT than with LOS HCT (60.9% vs. 49.3%; p = 0.044)

* PM = calcium antagonist, betablocker, angiotneisn II antagonist or ACE inhibitor BL = baseline; BP = blood pressure; CDS = candesartan cilexetil; CT = combination therapy; DB = double blind; DBP = diastolic blood pressure; F = female; HCT = hydrochlorothiazide; ITT = intention to treat analysis; LOS = losartan; M = male; MC = multicentre; PG = parallel groups; PM = previous medication; R = randomised; SBP = systolic blood presseure



2.5.4.4 Dosage and Duration of Treatment The usual maintenance dose is one tablet once daily. The initial dose of should be titrated using the single components. In patients with a previous hydrochlorothiazide monotherapy, a titration of the candesartan cilexetil dose is recommended. Use in the elderly No initial dosage adjustment is necessary in elderly patients. Use in patients with intravascular volume depletion An initial dose of candesartan 4 mg may be considered in patients at risk for hypotension, such as patients with possible volume depletion. The candesartan dose should be uptitrated in these patients before starting the combination. Use in impaired renal function The starting dose of candesartan is 4 mg in patients with mild to moderate renal impairment. The candesartan dose should be titrated according to response before starting the combination. Candesartan HCT is not recommended for patients with severe or end-stage renal impairment (CLCR < 30 ml/min/1.73 m2). Use in impaired hepatic function An initial dose of candesartan 4 mg once daily is recommended in patients with mild to moderate hepatic impairment. The candesartan dose may be adjusted according to response before starting the combination. Candesartan HCT is contraindicated in patients with severe hepatic impairment. Administration Candesartan cilexetil tablets should be taken once daily with or without food. Use in children and adolescents The safety and efficacy of the combination have not been established in children and adolescents (< 18 years).



2.5.5 OVERVIEW OF SAFETY 2.5.5.1 Global Safety Information The Summary of Product Characteristics of Atacand® Plus confirmed by EU medical authorities mirrors the results from clinical trials as well as the experience from clinical use in practice. Therefore, the discussion in the following section is based on the information given in SPC1. 2.5.5.1.1 Contraindications

- Hypersensitivity to candesartan cilexetil, hydrochlorothiazide or to any of the excipients.

- Second and third trimester of pregnancy and lactation. - Severe renal impairment (CLCR < 30 ml/min/1.73 m2). - Severe hepatic impairment and/or cholestasis. - Treatment-resistant hypokaliaemia or hypercalcaemia. - Gout.

2.5.5.1.2 Special Warnings and Precautions for Use Renal impairment When candesartan hydrochlorothiazide is used in patients with impaired renal function, plasma potassium, creatinine and uric acid concentrations should be monitored regularly. Renal artery stenosis Medicinal products that affect the RAAS, including angiotensin II receptor antagonists, may increase blood urea and serum creatinine in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney. Kidney transplantation There is no experience regarding the administration of candesartan hydrochlorothiazide in patients with recent kidney transplantation. Hypotension Hypotension may occur during treatment with candesartan cilexetil in heart failure patients. As described for other agents acting on the RAAS, it may also occur in hypertensive patients with intravascular volume depletion such as those receiving high dose diuretics. Caution should be observed when initiating therapy and correction of hypovolemia should be attempted. Anaesthesia and surgery Hypotension may occur during anaesthesia and surgery in patients treated with angiotensin II antagonists due to blockade of the RAS. Very rarely, hypotension may be severe such that it may warrant the use of intravenous fluids and/or vasopressors. 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 medicinal products acting through inhibition of the RAAS. Therefore, the use of candesartan is not recommended. Changes in serum electrolytes Serum electrolytes should be monitored regularly in patients receiving candesartan hydrochlorothiazide. Thiazides may reduce renal calcium excretion and lead to increased calcium levels. Thiazides should be stopped before tests on function of the parathyroid gland. Hydrochlorothiazide increases the renal excretion of potassium dose-dependently that may lead to hypokaliaemia. This effect appears to be reduced in combination with candesartan. The risk of hypokalaemia may be increased in patients with liver cirrhosis, with laboured diuresis, with reduced oral intake of electrolytes, or concomitant treatment with corticosteroids or ACTH. Concomitant use of candesartan with potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, or other medicinal products that may increase potassium levels (e.g. heparin) may lead to increases in serum potassium in hypertensive patients. Monitoring of potassium should be undertaken as appropriate. In heart failure patients treated with candesartan, hyperkalaemia may occur. During treatment with candesartan in patients with heart failure, periodic monitoring of serum potassium is recommended, especially when taken concomitantly with ACE inhibitors and potassium-sparing diuretics such as spironolactone. Thiazides may increase the renal excretion of magnesium. Metabolic and endocrine effects Treatment with thiazides may affect glucose tolerance. A dose adjustment of antidiabetics or insulin may become necessary. A latent diabetes mellitus may become apparent. Increases in cholesterol and triglyceride levels have been reported. Thiazide diuretics may increase serum uric acid concentrations and may elicit gout in predisposed patients. Photosensitivity Cases of photosensitivity have been reported with thiazides. In case of photosensitivity, the treatment with thiazides should be stopped. General In patients whose vascular tone and renal function depend predominantly on the activity of the RAAS (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with other medicinal products that affect this system has been associated with acute hypotension, azotaemia, oliguria or, rarely, acute renal failure. The possibility of similar effects cannot be excluded with angiotensin II receptor antagonists. As with any antihypertensive agent, excessive blood pressure decrease in patients with ischaemic cardiopathy or ischaemic cerebrovascular disease could result in a myocardial infarction or stroke.



Hypersensitivity to hydrochlorothiazide may occur also in patients without history of hypersensitivity. Worsening of a systemic Lupus erythematodes have been reported. 2.5.5.1.3 Pregnancy and Lactation Use in pregnancy Candesartan cilexetil: The use of angiotensin II receptor antagonists in not recommended during the first trimester of pregnancy. The use of angiotensin II receptor antagonists in contraindicated during the second and third trimester 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, similar risks may exist for this class of drugs. Unless continued angiotensin II receptor antagonist 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 angiotensin II receptor antagonists should be stopped immediately, and if appropriate, alternative therapy should be started. Exposure to angiotensin II receptor antagonist therapy during the second or 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 angiotensin II receptor antagonists have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have been taken angiotensin II receptor antagonists should be closely observed for hypotension. Hydrochlorothiazide: There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide its use during the second and third trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia.1 Use in lactation Because no information is available regarding the use of candesartan during breastfeeding, the combination is not recommended and alternative treatments with better established safety profiles during breastfeeding are preferable, especially while nursing a newborn or preterm infant.



2.5.5.1.4 Effects on Ability to Drive and Use Machines No studies on the effect of the combination on the ability to drive and use machines have been performed. However, it should be taken into account that occasionally dizziness or weariness may occur during treatment.1 2.5.5.1.5 Undesirable Effects 2.5.5.1.5.1 Candesartan Candesartan cilexetil has been generally well tolerated. Discontinuations due to adverse events varied between 1.8 to 10.6%; corresponding withdrawal rates with the comparator agents in the reference controlled, double blind studies varied between 1.6 to 9.4%.38;42;43;44 Compared to hydrochlorothiazide, Candesartan was similarly well-tolerated as hydrochlorothiazide and better tolerated than enalapril in women.39 In another comparison to hydrochlorothiazide in 234 patients with mild to moderate hypertension, 64.2% of the candesartan and 62.9% of the hydrochlorothiazide patients experienced adverse events during the double blind treatment of 24 weeks. Severe adverse events were reported in 5.7 and 9.7% of candesartan and hydrochlorothiazide recipients, respectively.43 The most common adverse events were dizziness/vertigo and headache (table 23). Table 23: Adverse events reported with an incidence of > 4% in at least

one group during 24 weeks

Incidence (%)

Adverse event

Candesartan

Hydrochlorothiazide

Dizziness/vertigo Headache Bronchitis /aggravated bronchitis Back pain Hypokalaemia Respiratory infection Fatigue Hyperuricaemia Cystitis Pain

14.6 8.9

7.3 4.1 0

3.3 1.6 0

2.4 1.6

16.1 11.3

4.8 4.8 8.1 8.1 6.5 6.5 4.8 4.8

Although the profile of adverse events was generally similar in both treatment groups, hypokalaemia and hyperuricaemia were recorded only with hydrochlorothiazide (by 8.1 and 6.5% of patients, respectively).43 Candesartan 8-16 mg/day was well tolerated as compared with placebo or losartan 50-100 mg/day in a randomised, double blind comparison in hypertensive patients (table 24).



Table 24: Percentage of patients with new adverse events with

candesartan, losartan or placebo Symptom

PLA

CDS 8 mg

(n = 82)

CDS 16 mg

(n = 84)

LOS

(n = 83) Any adverse event

48.2%

37.8%

38.1%

49.4%

Headache Albuminuria Fatigue Respiratory infection Coughing Dizziness/vertigo Viral infection Palpitation Abdominal pain Gastroenteritis Myalgia Vasospasm Arthralgia

14.1 4.7 4.7 4.7 3.5 3.5 3.5 3.5 - - - - -

6.1 - -

7.3 -

3.7 - -

3.7 3.7 3.7 3.7 -

4.8 -

4.8 4.8 4.8 3.6 3.6 - - - - -

6.0

3.6 - -

7.2 -

7.2 3.6 - -

4.8 - - -

CDS = candesartan cilexetil; LOS = losartan; PLA = placebo 2.5.5.1.5.2 Hydrochlorothiazide There is only limited information from clinical studies on adverse events of hydrochlorothiazide alone, but there is much experience from the long clinical practice of more than four decades that is summarised in the SPC:1



Table 25: Adverse events reported with the use of hydrochlorothiazide

Cardiac disorders

Cardiac arrhythmias

Blood and lymphatic system

Aplastic anaemia, bone marrow depression, neutropenia/agranulocytosis, haemolytic anaemia, leucopenia, thrombocytopenia

Nervous system

Vertigo, paraesthesia, light-headedness, restlessness

Eye disorders

Transient blurred vision, xanthopsia

Respiratory, thoracic and mediastinal disorders

Respiratory distress (including pneumonitis and pulmonary oedema)

Gastrointestinal disorders

Pancreatitis, anorexia, diarrhoea, constipation, gastric irritation, sialadeniitis, loss of appetite

Renal and urinary disorders

Interstitial nephritis, renal dysfunction

Skin and subcutaneous tissue

Anaphylactic reactions, toxic epidermal necrolysis, necrotizing angitis (vasculitis, cutabeous vasculitits), cutaneous lupus erythematosus-like reactions, reactivation of cutaneous lupus erythematosus, photosensitivity reactions, rash, urticaria

Musculoskeletal and connective tissue

Weakness, muscle spasms

Vascular disorders

Postural hypotension

General disorders and administration site conditions

Fever

Hepatobiliary disorders

Jaundice (intrahepatic cholestatic jaundice)

Psychiatric disorders

Depression, sleep disturbances

2.5.5.1.5.3 Combination The combination of candesartan cilexetil plus hydrochlorothiazide was generally well tolerated in clinical trials. The most common adverse events were dyslipidaemia, headache and dizziness. (bonner08) In a comparative study, the frequency of adverse events of the combination was similar to those of placebo, candesartan alone or hydrochlorothiazide alone (table 26). Table 25: Proportion of patients with at least one adverse event (AE)

CDS HCT 32+25 mg (n = 491)

CDS 32 mg

(n = 463)

HCT 25 mg

(n = 468)

PLA

(n = 97)

Any AE Serious AE Discontinuation due to AE

24.6% 0.2% 1.8%

23.1% 1.3% 2.4%

22.9% 0.2% 2.1%

23.7% 3.1% 2.1%

AE = adverse event; CDS = candesartan; HCT = hydrochlorothiazide; PLA = placebo



2.5.5.1.6 Overdose Symptoms Based on pharmacological considerations, the main manifestation of an overdose is likely to be symptomatic hypotension and dizziness. In individual case reports of overdose (of up to 672 mg candesartan cilexetil), patient recovery was uneventful.1 Overdose with hydrochlorothiazide is associated with electrolyte depletion (hypokalaemia, hypochloremia, hyponatraemia) and dehydration resulting from excessive diuresis. The most common signs and symptoms of overdose are nausea and somnolence. Hypokalaemia may result in muscle spasms and/or accentuate cardiac arrhythmias associated with the concomitant use of digitalis glycosides or certain anti-arrhythmic medicinal products.1 Management 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, for example, isotonic saline solution. Sympathomimetic medicinal products may be administered if the above-mentioned measures are not sufficient. Candesartan is not removed by haemodialysis.1 There is no information whether hydrochlorothiazide can be removed by haemodialysis.1 2.5.5.2 Post-Marketing Experience No relevant post marketing experience is available for Candesartan Cilexetil HCT 8+12.5/16+12.5/32+12.5/32+25 mg tablets at the present time. The post-marketing experience available for the reference formulation has been considered in the SPC1.



2.5.6 BENEFITS AND RISKS CONCLUSIONS This Clinical Overview assesses the clinical documentation on Candesartan Cilexetil HCT 8+12.5/16+12.5/32+12.5/32+25 mg tablets with candesartan cilexetil and hydrochlorothiazide as pharmacologically active agents. Candesartan Cilexetil HCT is indicated for the treatment of essential hypertension in adult patients, whose blood pressures are not sufficiently controlled with candesartan cilexetil or hydrochlorothiazide monotherapy. Candesartan Cilexetil HCT tablets have been developed to be generic of the brand leader Atacand® Plus. The essential similarity was demonstrated in two appropriate bioequivalence studies using the 8+12.5-mg and 32+25-mg tablet strengths. Candesartan is a selective angiotensin II AT1 receptor antagonist, with a potent binding to the receptor. In healthy subjects Candesartan is a selective angiotensin II AT1 receptor antagonist, with a potent binding to the receptor. Candesartan antagonised the angiotensin II-induced rise in blood pressure and reduced blood pressure significantly more than placebo in patients with mild to moderate essential hypertension. No special risk profile was revealed by the pharmacological investigations of candesartan. Hydrochlorothiazide is a thiazide diuretic with well-known activity and has been the drug of first choice for the treatment of hypertension for more than four decades. The combination of both compounds was demonstrated to be more effective than either single agent. The development of the fixed combination was based on the promising results of the combined treatment of hypertension with the single agents. Pharmacokinetics of both drugs is linear in the therapeutic dose range. No special risk potential is expected from the pharmacological activity of the combination. Clinical efficacy of candesartan was demonstrated in controlled studies including sufficient numbers of patients in hypertension and congestive heart failure. Candesartan was at least equally effective as enalapril and more effective than losartan in reducing blood pressure. The efficacy of hydrochlorothiazide monotherapy is well known from more than 40 years of experience being the drug of first choice. The combination was demonstrated to be more effective than either agent alone in thousands of patients in controlled clinical studies. Candesartan was generally well tolerated in clinical trials, with a comparable frequency and profile of adverse events as reference drugs. At dose levels currently used, hydrochlorothiazide is also generally well tolerated. The frequency and profile of adverse events of the combination did not significantly differ from those of the single compounds. There is no evidence of other risks of the combination for human use from clinical data. In conclusion, Candesartan Cilexetil HCT 8+12.5/16+12.5/32+12.5/32+25 mg tablets can be regarded to be an effective and safety remedy when used appropriately for the recommended indications and in the recommended dose range in humans. The evaluation of risks and benefits yields clear positive benefits with only negligible risks.



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28. Ghiadoni L; Virdis A; Magagna A; Taddei S; Salvetti A

Effect of the angiotensin II type 1 receptor blocker candesartan on endothelial function in patients with essential hypertension Hypertension 2000; 35(1Pt2): 501-506

29. Elmfeldt D; George M; Hubner R; Olofsson B

Candesartan cilexetil, a new generation angiotensin II antagonist, provides dose-dependent antihypertensive effect J Hum Hypertens 1997; 11(suppl 2): S49-53

30. Lansang MC; Osei SY; Price DA; Fisher ND; Hollenberg NK

Renal hemodynamic and hormonal responses to the angiotensin II antagonist candesartan Hypertension 2000; 36 (5): 834-838

31. Finkielman JD; Schwartz GL; Chapman AB; Boerwinkle E; Turner ST Reproducibility of blood pressure response to hydrochlorothiazide J Clin Hypertens 2002; 4 (6): 408-412

32. Padilla MC; Armas-Hernández MJ; Hernández RH; Israili ZH; Valasco M

Update of diuretics in the treatment of hypertension Am J Therap 2007; 14 (2): 154-160

33. Jounela AJ; Liljy M; Lumme J; Morlin C; Hoyem A; Wessel-Aas T;

Borrild NJ Relation between low dose of hydrochlorothiazide, antihypertensive effect and adverse effects Blood Press 1994; 3: 231-235



34. Ott SM; LaCroix AZ; Ichikawa LE; Scholes D; Barlow WE Effect of low-dose thiazide diuretics on plasma lipids: results from a double-blind, randomized clinical trial in older men and women J Am Ger Soc 2003; 51 (3): 340-347

35. Reif M; White WB; Fagan TC; Oparil S; Flanagan TL; Edwards DT;

Cushing DJ; Michelson EL; for the Candesartan Cilexetil Study Investigators Effects of candesartan cilexetil on patients with systemic hypertension. Candesartan Cilexetil Study Investigators Am J Cardiol 1998; 82(8): 961-965

36. Bell TP; De Quattro V; Lasseter KC; Ruff D; Hardison JD; Cushing D;

Kezer AE; Michelson EL; for the Candesartan Cilexetil Study Investigators Effective dose range of candesartan cilexetil for systemic hypertension. Candesartan Cilexetil Study Investigators Am J Cardiol 1999; 83(2): 272-275

37. Franke H

Antihypertensive effects of candesartan cilexetil, enalapril and placebo J Hum Hypertens 1997; 11(suppl 2): S61-62

38. Zanchetti A; Omboni S

Comparison of candesartan versus enalapril in essential hypertension. Italian Candesartan Study Group. Am J Hypertens 2001; 14 (2): 129-134

39. Himmelmann A; Keinanen-Kiukaanniemi S; Wester A; Redon J; Asmar R;

Hedner T; for the Effect Study Group The effect duration of candesartan cilexetil once daily, in comparison with enalapril once daily, in patients with mild to moderate hypertension Blood Press 2001; 10(1): 43-51

40. Malmqvist K; Kahan T; Dahl M

Angiotensin II type 1 (AT1) receptor blockade in hypertensive women: benefits of candesartan cilexetil versus enalapril or hydrochlorothiazide Am J Hypertens 2000; 13 (5 Pt 1): 504-511

41. Andersson OK; Neldam S

The antihypertensive effect and tolerability of candesartan cilexetil, a new generation angiotensin II antagonist, in comparison with losartan Blood Pressure 1998; 7: 53-59

42. Gradman AH; Lewin A; Bowling BT; Tonkon M; Deedwania PC;

Kezer AE; Hardison JD; Cushing DJ; Michelson EL; for the Candesartan versus Losartan Efficacy Comparison (CANDLE) Study Group Comparative effects of candesartan cilexetil and losartan in patients with systemic hypertension Heart Dis 1999; 1: 52-57

43. Bakris G; Gradman A; Reif M; Wofford M; Munger M; Harris S; Vendetti J;

Michelson EL; Wang R; for CLAIM Study Investigators Antihypertensive efficacy of candesartan in comparison to losartan: the CLAIM study J Clin Hypertens 2001; 3 (1): 16-21



44. Neldam S; Forsen B

Antihypertensive treatment in elderly patients aged 75 years or older: a 24-week study of the tolerability of candesartan cilexetil in relation to hydrochlorothiazide Drugs Aging 2001; 18(3): 225-232

45. Kloner RA; Weinberger M; Pool JL; Chrysant SG; Prasad R; Harris SM;

Zyczynski TM; Leidy NK; Michelson EL; for the Comparison of Candesartan and Amlodipine for Safety, Tolerability and Efficacy Study Investigators Comparative effects of candesartan cilexetil and amlodipine in patients with mild systemic hypertension. Comparison of Candesartan and Amlodipine for Safety, Tolerability and Efficacy (CASTLE) Study Investigators Am J Cardiol 2001; 87(6): 727-731

46. Farsang C; Kaweck-Jaszcz K; Langan J; Maritz F; Zannad F; for the

Multicentre Study Group Antihypertensive effects and tolerability of candesartan cilexetil alone and in combination with amlodipine Clin Drug Invest 2001; 21(1): 17-23

47. MRC Working Party Medical Research Council trial of treatment of hypertension in older adults: principal results BMJ 1992; 304: 405-412

48. Carter BL; Ernst ME; Cohen JD

Hydrochlorothiazide versus chlorthalidone: evidence supporting their interchangeability Hypertension 2004; 43 (1): 4-9

49. Ernst ME; Carter BL; Goerdt CJ; Steffensmeier JJ; Phillips BB;

Zimmerman MB; Bergus GR Comparative antihypertensive effects of hydrochlorothiazide and chlorthalidone on ambulatory and office blood pressure Hypertension 2006; 47 (3): 352-358

50. Karlson BW; Zetterstrand S; Olofsson B; Elmfeldt D A dose-response analysis of candesartan-hydrochlorothiazide combination therapy in patients with hypertension Blood Press 2009; 18(3): 149-156

51. Campbell M; Sonkodi S; Soucek M; Wiecek A

A candesartan cilexetil/hydrochlorothiazide combination tablet provides effective blood pressure control in hypertensive patients inadequately controlled on monotherapy Clin Exp Hypertens 2001; 23 (4): 345-355

52. Bönner G for the Multicentre Study Group Antihypertensive efficacy and tolerability of candesartan-hydrochlorothiazide 32/12.5 mg and 32/25 mg in patients not optimally controlled with candesartan monotherapy Blood Press 2008; 2 (Suppl 2): 22-30



53. Edes I CA: Multicentre Study Group

Combination therapy with candesartan cilexetil 32 mg and hydrochlorothiazide 25 mg provides the full additive antihypertensive effect of the components: A randomized, double-blind, parallel-group study in primary care Clin Drug Invest 2009; 29 (5): 293-304

54. Mancia G; Omboni S; for the CARDIO (CAndesaRtan combined with DIuretic in hypertensiOn) Study Group Candesartan plus hydrochlorothiazide fixed combination vs previous monotherapy plus diuretic in poorly controlled essential hypertensive patients Blood Pressure 2004; 2(Supplement) : 11-17

55. Öhman KP; Milon H; Valnes K Efficacy and tolerability of a combination tablet of candesartan cilexetil and hydrochlorothiazide in insufficiently controlled primary hypertension--comparison with a combination of losartan and hydrochlorothiazide Blood Press 2000; 9 (4): 214-220

56. Bönner G; Landers B; Bramlage P Candesartan cilexetil/hydrochlorothiazide combination treatment versus high-dose candesartan cilexetil monotherapy in patients with mild to moderate cardiovascular risk (CHILI Triple T) Vasc Health Risk Manag 2011; 7: 81-95



2.5.8 APPENDIX Synopsis of the 8+12.5-mg Bioequivalence Study Synopsis of the 32+25-mg Bioequivalence Study

Synopsis of the 8+12.5 mg Bioequivalence Study

Name of Company: A. E. Tiefenbacher GmbH & Co. KG Name of Finished Product: Candesartan Cilexetil HCT 8+12.5 mg tablets Name of Active Substance: candesartan cilexetil and hydrochlorothiazide

TABULAR FORMAT REFERRING TO MODULE 5 OF THE DOSSIER Volume: Page:

(For National Authority use only)

Title of the study: Open label, two-period, two sequences, controlled, randomised, single dose, bioequivalence study of Candesartan Cilexetil HCT 8+12.5 mg (test formulation) vs. equal dose of Atacand® Plus 8+12.5 mg tablets (reference formulation) in healthy male and female volunteers under fasting conditions Investigators: Dr. Vasile Parasca and Dr. Tamara Staris, Clinical Hospital of the Ministry of Health of the Republic of Moldova, Chisinau, Moldova Study centre: Institutia Medico-Sanitaria Publica, Clinical Hospital of the Ministry of Health of the Republic of Moldova, Chisinau, Moldova Publication (reference): Not published Studied period (years): 2011-03-03 to 2011-04-06

Clinical Phase: I

Objectives: to compare the extent and rate of absorption of the formulation of Candesartan Cilexetil HCT tablet 8+12.5 mg (Test), manufactured by Zhejiang Huahai Pharmaceutical Co. Ltd., China, following a single oral dose versus an equal dose of Atacand® Plus 32+25 mg tablets (Reference), AstraZeneca, Germany, administered as a single oral dose to healthy, human subjects under fasting conditions Safety: To monitor the safety and tolerability of a single dose of 8+12.5 mg in healthy human subjects. Methodology: Two-stage, two-period, two-sequence, crossover, block randomised bioavailability study in healthy human subjects under fasting conditions. Hospitalisation of subjects until 24 hours post administration, washout period between the drug administration was 14 days. Complete physical examination, ECG, haematology, biochemistry, urinalysis, vital signs and adverse events were evaluated. Plasma concentrations of candesartan and hydrochlorothiazide were determined using a validated LC/MS/MS method. Number of subjects (total and for each treatment): 24 Diagnosis and criteria for inclusion: healthy male volunteers, age 18-55 years; BMI 18.5-30 kg/m2

Page 1 of 4





Test product, dose, mode of administration, batch no.: Candesartan Cilexetil HCT 8+12.5 mg tablet; manufactured by Zhejiang Huahai Pharmaceutical Co. Ltd; batch no: 06910001; manufacturing date 10/2010; use by date: 03/2011; one was ingested with 240 ml tap water after an overnight fast Duration of treatment: single application; washout between the applications 14 days Reference therapy, dose, mode of administration, batch no.: Atacand® Plus; containing candesartan cilexetil 8 mg and hydrochlorothiazide 12.5 mg; manufactured by AstraZeneca GmbH, Germany; batch no: MB847A2; expiry date 01/2013; dosing as above Criteria for evaluation: A total of 21 blood samples were taken at pre-dose and at 0.33, 0.67, 1.0, 1.33, 1.67, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 8.0, 10.0, 12.0, 24.0, 36.0, and 48 hours post dose. Primary equivalence parameters: Primary parameters: Cmax, AUC0-t; secondary parameter: Tmax; AUC0-

inf,% AUC extrapolated, T1/2, and MRT as further parameters. Ratios and 94.12% (a two-stage design was planned, but the second stage was not needed) confidence intervals for the primary equivalence criteria of the ln-transformed data should be within 80% to 125%. Safety parameters: any kind of an adverse event, clinical examination, vital signs, ECG and laboratory screening and follow up Statistical methods: A two-stage design was planned, but the evaluation after the first 24 subjects proved already bioeguivalence and thus, the second stage was not performed. Summary statistics were calculated by formulation including mean values, standard deviations, coefficient of variations, medians, and geometric means for primary endpoints. Analysis of variance (ANOVA) with sequence, subject within sequence, period, and formulation effects has been performed for on the untransformed and ln-transformed pharmacokinetic parameters Cmax, AUC0-t, AUC0-inf. Ratios and 94.12% confidence intervals were calculated for the primary equivalence parameters.

Page 2 of 4





SUMMARY – CONCLUSIONS: The study was planned as a two-stage, randomised, two-way, single dose, crossover bioavailability study in 24 healthy male and female human subjects under fasting conditions. Since bioequivalence was already confirmed after the first stage, the second stage could be waived. The subjects were confined to the clinic from at least 10 hours prior to drug administration until after the 24-hour post-dose blood collection, in each period. Blood samples were collected according to the protocol up to 48 hours post dose and analysed for candesartan and hydrochlorothiazide using a validated LC/MS/MS method. The pharmacokinetic parameters for candesartan are given below:

N = 24

Cmax (ng/ml)

Tmax (hours)

AUC0-t (ng/ml*h)

AUC0-inf (ng/ml*h)

AUC%extrap(%)

T1/2 (hours)

MRT (hours)

Reference

Mean 72.600 4.146 944.438 984.029 3.867 10.229 14.488

SD 15.788 1.156 189.720 204.034 2.821 2.229 2.833

CV 21.747 27.885 20.088 20.735 72.954 21.791 19.558

Test

Mean 67.607 4.438 886.313 935.753 4.743 10.694 15.136

SD 18.110 1.477 264.841 305.903 2.895 2.327 3.426

CV 26.788 33.278 29.881 32.691 61.039 21.757 22.635

The pharmacokinetic parameters for hydrochlorothiazide are given below:

N = 24

Cmax (ng/ml)

Tmax (hours)

AUC0-t (ng/ml*h)

AUC0-inf (ng/ml*h)

AUC%extrap(%)

T1/2 (hours)

MRT (hours)

Reference

Mean 86.531 1.806 577.821 597.486 3.402 8.676 9.968

SD 25.746 0.856 99.371 97.615 1.097 1.374 1.287

CV 29.753 47.434 17.198 16.338 32.251 15.841 12.910

Test

Mean 77.260 2.090 570.711 589.743 3.370 8.649 10.013

SD 13.961 0.707 123.345 121.821 1.395 1.474 1.496

CV 18.071 33.827 21.612 20.657 41.392 17.045 14.936 No significant differences in the pharmacokinetic parameters of either active component were observed between the formulations. The percentages for residual AUC were below 20%, indicating that the blood collection time period was correctly chosen.

Page 3 of 4





SUMMARY – CONCLUSIONS (continued): The bioequivalence assessments for both candesartan and hydrochlorothiazide are given in tables below. Candesartan


N = 24


Upper limit

Cmax

92.102

81.492

104.094

AUC0-t

91.650

83.161

101.005

Hydrochlorothiazide


N = 24


Upper limit

Cmax

90.940

81.291

101.734

AUC0-t

98.073

93.264

103.131

The tables show that the point estimates and classical 94.12% confidence intervals for candesartan and hydrochlotohiazide were all within the in the protocol defined equivalence range of 80% to 125%. Both formulations were well tolerated. No deaths, serious adverse events or clinically relevant adverse events occurred during the study period. Four adverse events of mild intensity were reported by four subjects. All subjects were completely recovered before the end of study. No clinically relevant changes were observed in vital signs, laboratory values or ECGs of any subject at the end of the study. Conclusions: Statistical analysis of the primary target parameters demonstrated bioequivalence for both the rate and extent of absorption of both candesartan and hydrochlorothiazide according to the current generally accepted concepts of bioequivalence testing. Both formulations were well tolerated. Date of report: April 12, 2011

Page 4 of 4

Synopsis of the 32+25 mg Bioequivalence Study

Name of Company: A. E. Tiefenbacher GmbH & Co. KG Name of Finished Product: Candesartan Cilexetil HCT 32+25 mg tablets Name of Active Substance: candesartan cilexetil and hydrochlorothiazide



Title of the study: Open label, two-period, two sequences, controlled, randomised, single dose, bioequivalence study of Candesartan Cilexetil HCT 32+25 mg (test formulation) vs. equal dose of Atacand® Plus forte 32+25 mg tablets (reference formulation) in healthy male and female volunteers under fasting conditions Investigators: Dr. Vasile Parasca and Dr. Tamara Staris, Clinical Hospital of the Ministry of Health of the Republic of Moldova, Chisinau, Moldova Study centre: Institutia Medico-Sanitaria Publica, Clinical Hospital of the Ministry of Health of the Republic of Moldova, Chisinau, Moldova Publication (reference): Not published Studied period (years): 2011-01-18 to 2011-05-11

Clinical Phase: I

Objectives: to compare the extent and rate of absorption of the formulation of Candesartan Cilexetil HCT tablet 32+25 mg (Test), manufactured by Zhejiang Huahai Pharmaceutical Co. Ltd., China, following a single oral dose versus an equal dose of Atacand® Plus Forte 32+25 mg tablets (Reference), AstraZeneca, Germany, administered as a single oral dose to healthy, human subjects under fasting conditions Safety: To monitor the safety and tolerability of a single dose of 32+25 mg in healthy human subjects. Methodology: Two-stage, two-period, two-sequence, crossover, block randomised bioavailability study in healthy human subjects under fasting conditions. Hospitalisation of subjects until 24 hours post administration, washout periods between the drug administration were 10 days for stage I and 14 days for stage II. Complete physical examination, ECG, haematology, biochemistry, urinalysis, vital signs and adverse events were evaluated. Plasma concentrations of candesartan and hydrochlorothiazide were determined using a validated LC/MS/MS method. Number of subjects (total and for each treatment): 18 subjects in stage I, 26 subjects in stage II, 43 were analysed for bioequivalence Diagnosis and criteria for inclusion: healthy male and female volunteers, mean age 18-55 years; BMI 19-29 kg/m2

Page 1 of 4





Test product, dose, mode of administration, batch no.: Candesartan Cilexetil HCT 32+25 mg tablet; manufactured by Zhejiang Huahai Pharmaceutical Co. Ltd., China; batch no: 20110003; manufacturing date: 10/2010; use by date 03/2011?? For the medication used in the first stage and 06/2011 for the medication in second stage; one tablet was ingested with 240 ml still bottled water after an overnight fast Duration of treatment: single application; washout 10 days in stage I and 14 days in stage II Reference therapy, dose, mode of administration, batch no.: Atacand® Plus forte 32+25 mg tablet; containing candesartan cilexetil 32 mg and hydrochlorothiazide 25 mg; manufactured by AstraZeneca GmbH, Germany; batch no: LF135A3; expiry date 05/2012; dosing as above Criteria for evaluation: A total of 21 blood samples were taken at pre-dose and at 0.33, 0.67, 1.0, 1.33, 1.67, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 8.0, 10.0, 12.0, 24.0, 36.0, and 48 hours post dose. Primary parameters: Cmax, AUC0-t; secondary parameter: Tmax; AUC0-inf,% AUC extrapolated, T1/2, and MRT as further parameters. Due to the two-stage design, ratios and 94.12% confidence intervals for candesartan and for hydrochlorothiazide, ratios and 90% confidence intervals for the primary equivalence criteria of the ln- transformed data should be within 80% to 125%. Safety parameters: any kind of an adverse event, clinical examination, vital signs, ECG and laboratory screening and follow up Statistical methods: A statistical analysis was performed for the 18 subjects at the end of stage I. For candesartan, additional 26 subjects were needed for the second stage. For hydrochlorothiazide, bioequivalence was concluded already after the first stage and no further analyses were performed. Summary statistics were calculated by formulation including mean values, standard deviations, coefficient of variations, medians, and geometric means for primary endpoints. Analysis of variance (ANOVA) with sequence, subject within sequence, period, and formulation effects has been performed for on the untransformed and ln-transformed pharmacokinetic parameters Cmax, AUC0-t, AUC0-inf. Ratios and 94.12% (candesartan) and 90% (hydrochlorothiazide) confidence intervals were calculated for the primary equivalence parameters.

Page 2 of 4





SUMMARY – CONCLUSIONS: The study was conducted as a two-stage, randomised, two-way, single dose, crossover bioavailability study in 43 (18 for hydrochlorothiazide) healthy male and female human subjects under fasting conditions. The subjects were confined to the clinic from at least 10 hours prior to drug administration until after the 24-hour post-dose blood collection, in each period. Blood samples were collected according to the protocol up to 48 hours post dose and analysed for candesartan and hydrochlorothiazide using a validated LC/MS/MS method. The pharmacokinetic parameters for candesartan are given below:

N = 43

Cmax (ng/ml)

Tmax (hours)

AUC0-t (ng/ml*h)

AUC0-inf (ng/ml*h)

AUC%extrap(%)

T1/2 (hours)

MRT (hours)

Reference

Mean 252.879 4.140 3648.497 3949.205 7.074 11.976 17.619

SD 97.458 1.794 1040.609 1171.941 5.179 3.794 5.649

CV 38.539 43.336 28.522 29.675 73.210 31.683 32.064

Test

Mean 241.493 4.488 3436.087 3716.080 7.075 12.302 17.554

SD 85.273 1.692 939.251 1050.268 5.775 4.086 5.904

CV 35.311 37.698 27.335 28.263 81.616 33.212 33.635

The pharmacokinetic parameters for hydrochlorothiazide are given below:

N = 18

Cmax (ng/ml)

Tmax (hours)

AUC0-t (ng/ml*h)

AUC0-inf (ng/ml*h)

AUC%extrap(%)

T1/2 (hours)

MRT (hours)

Reference

Mean 173.890 1.861 1218.968 1238.886 1.709 8.682 9.614

SD 47.560 0.890 294.754 294.674 0.768 1.259 1.127

CV 27.351 47.808 24.181 23.785 44.933 14.495 11.721

Test

Mean 177.209 1.750 1201.271 1224.723 1.989 8.928 9.671

SD 47.582 0.489 263.143 263.853 0.861 1.169 1.167

CV 26.850 27.958 21.905 21.544 43.286 13.096 12.067 No significant differences in the pharmacokinetic parameters of either active component were observed between the formulations. The percentages for residual AUC were below 20%, indicating that the blood collection time period was correctly chosen.

Page 3 of 4





SUMMARY – CONCLUSIONS (continued): The bioequivalence assessments for both candesartan (n = 43) and hydrochlorothiazide are given in tables below. Candesartan (combined stages I and II)


N = 43


Upper limit

Cmax

95.125

85.817

105.442

AUC0-t

94.924

89.696

100.457

Hydrochlorothiazide

90% confidence intervals

N = 18


Upper limit

Cmax

102.201

96.119

108.668

AUC0-t

99.241

93.858

104.934

The tables show that the point estimates and classical 94.12% confidence intervals for candesartan and 90% confidence intervals for hydrochlotohiazide were all within the in the protocol defined equivalence range of 80% to 125%. Both formulations were well tolerated. No deaths, serious adverse events or clinically relevant adverse events occurred during the study period. Nine adverse events (8 of mild and one of moderate intensity) were reported by seven subjects. All subjects were completely recovered before the end of study. No clinically relevant changes were observed in vital signs, laboratory values or ECGs of any subject at the end of the study. Conclusions: Statistical analysis of the primary target parameters demonstrated bioequivalence for both the rate and extent of absorption of both candesartan and hydrochlorothiazide according to the current generally accepted concepts of bioequivalence testing. Both formulations were well tolerated. Date of report: May 18, 2011

Page 4 of 4

clinical overview candesartan cilexetil hct 8+12.5/16+12.5

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