Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Noden Pharma DAC, DOlier Chambers, 16A DOlier Street, Dublin 2, Ireland
Pharmacotherapeutic group: Agents acting on the renin-angiotensin system; renin inhibitor
ATC code: C09XA52
Rasilez HCT combines two antihypertensive active substances to control blood pressure in patients with essential hypertension: Aliskiren belongs to the class of direct renin inhibitors and hydrochlorothiazide to the class of thiazide diuretics. The combination of these substances with complementary mechanisms of action provides an additive antihypertensive effect, reducing blood pressure to a greater degree than either component alone.
Aliskiren is an orally active, non-peptide, potent and selective direct inhibitor of human renin.
By inhibiting the enzyme renin, aliskiren inhibits the RAAS at the point of activation, blocking the conversion of angiotensinogen to angiotensin I and decreasing levels of angiotensin I and angiotensin II. Whereas other agents that inhibit the RAAS (angiotensin converting enzyme inhibitors (ACEI) and angiotension II receptor blockers (ARB)) cause a compensatory rise in plasma renin activity (PRA), treatment with aliskiren decreases PRA in hypertensive patients by approximately 50 to 80%. Similar reductions were found when aliskiren was combined with other antihypertensive agents. The clinical implications of the effects on PRA are not known at the present time.
In hypertensive patients, once-daily administration of aliskiren at doses of 150 mg and 300 mg provided dose-dependent reductions in both systolic and diastolic blood pressure that were maintained over the entire 24-hour dose interval (maintaining benefit in the early morning) with a mean peak to trough ratio for diastolic response of up to 98% for the 300 mg dose. 85 to 90% of the maximal bloodpressure-lowering effect was observed after 2 weeks. The blood-pressure-lowering effect was sustained during long-term treatment (12 months), and was independent of age, gender, body mass index and ethnicity.
Combination therapy studies are available for aliskiren added to the diuretic hydrochlorothiazide, the calcium channel blocker amlodipine and the beta blocker atenolol. These combinations were efficacious and well tolerated.
The efficacy and safety of aliskiren-based therapy were compared to ramipril-based therapy in a 9-month non-inferiority study in 901 elderly patients (≥65 years) with essential systolic hypertension. Aliskiren 150 mg or 300 mg per day or ramipril 5 mg or 10 mg per day were administered for 36 weeks with optional add-on therapy of hydrochlorothiazide (12.5 mg or 25 mg) at week 12, and amlodipine (5 mg or 10 mg) at week 22. Over the 12 week period, aliskiren monotherapy lowered systolic/diastolic blood pressure by 14.0/5.1 mmHg, compared to 11.6/3.6 mmHg for ramipril, consistent with aliskiren being non-inferior to ramipril at the doses chosen and the differences in systolic and diastolic blood pressure were statistically significant. Tolerability was comparable in both treatment arms, however cough was more often reported with the ramipril regimen than the aliskiren regimen (14.2% vs. 4.4%), whilst diarrhoea was more common with the aliskiren regimen than for the ramipril regimen (6.6% vs. 5.0%).
In a 8-week study in 754 hypertensive elderly (≥65 years) and very elderly patients (30% ≥75 years) aliskiren at doses of 75 mg, 150 mg and 300 mg provided statistically significant superior reduction in blood pressure (both systolic and diastolic) when compared to placebo. No additional blood pressure lowering effect was detected with 300 mg aliskiren compared to 150 mg aliskiren. All three doses were well tolerated in both elderly and very elderly patients. In a pooled analysis of efficacy and safety data from clinical study up to 12 months duration, there was no statistically significant difference in blood pressure reduction between aliskiren 300 mg and aliskiren 150 mg in elderly patients (≥65 years).
There has been no evidence of first-dose hypotension and no effect on pulse rate in patients treated in controlled clinical studies. With cessation of treatment, blood pressure gradually returned towards baseline levels over a period of several weeks, with no evidence of a rebound effect for blood pressure or PRA.
In a 36-week study involving 820 patients with ischaemic left ventricular dysfunction, no changes in ventricular remodelling as assessed by left ventricular end systolic volume were detected with aliskiren compared to placebo on top of background therapy.
The combined rates of cardiovascular death, hospitalisation for heart failure, recurrent heart attack, stroke and resuscitated sudden death were similar in the aliskiren group and the placebo group. However, in patients receiving aliskiren there was a significantly higher rate of hyperkalaemia, hypotension and kidney dysfunction when compared to the placebo group.
Aliskiren was evaluated for cardiovascular and/or renal benefit in a double-blind placebo controlled randomised trial in 8,606 patients with type 2 diabetes and chronic kidney disease (evidenced by proteinuria and/or GFR <60 ml/min/1.73 m²) with or without cardiovascular disease. In most patients arterial blood pressure was well controlled at baseline. The primary endpoint was a composite of cardiovascular and renal complications.
In this study, aliskiren 300 mg was compared to placebo when added to standard of care which included either an angiotensin converting enzyme inhibitor or an angiotensin receptor blocker. The study was discontinued prematurely because the participants were unlikely to benefit from aliskiren. The final study results indicated a hazard ratio for the primary endpoint of 1.097 in favour of placebo (95.4% Confidence Interval: 0.987, 1.218, 2-sided p=0.0787). In addition, an increased incidence of adverse events was observed with aliskiren compared to placebo (38.2% versus 30.3%). In particular there was an increased incidence of renal dysfunction (14.5% versus 12.4%), hyperkalaemia (39.1% versus 29.0%), hypotension-related events (19.9% versus 16.3%) and adjudicated stroke endpoints (3.4% versus 2.7%). The increased incidence of stroke was greater in patients with renal insufficiency.
Aliskiren 150 mg (increased to 300 mg if tolerated) added to conventional therapy was evaluated in a double-blind placebo-controlled randomised trial in 1,639 patients with reduced ejection fraction hospitalised for an episode of acute heart failure (NYHA Class III–IV) who were haemodynamically stable at baseline. The primary endpoint was cardiovascular death or heart failure rehospitalisation within 6 months; secondary endpoints were assessed within 12 months.
The study showed no benefit of aliskiren when administered on top of standard therapy for acute heart failure and an increased risk of cardiovascular events in patients with diabetes mellitus. Study results indicated a non-significant effect of aliskiren with a hazard ratio of 0.92 (95% Confidence Interval: 0.76-1.12; p=0.41, aliskiren vs. placebo). Different treatment effects of aliskiren were reported for overall mortality within 12 months dependent on diabetes mellitus status. In the subgroup of patients with diabetes mellitus the hazard ratio was 1.64 in favour of placebo (95% Confidence Interval: 1.15-2.33), whereas the hazard ratio in the subgroup of patients without diabetes was 0.69 in favour of aliskiren (95% Confidence Interval: 0.50-0.94); p-value for interaction = 0.0003. An increased incidence of hyperkalaemia (20.9% versus 17.5%), renal impairment/renal failure (16.6% versus 12.1%) and hypotension (17.1% versus 12.6%) was observed in the aliskiren group compared with placebo and was greater in patients with diabetes.
Aliskiren was evaluated for cardiovascular mortality and morbidity benefit in a double-blind active controlled randomised study in 7,064 patients with chronic heart failure and reduced left ventricular ejection fraction, of which 62% had a history of hypertension. The primary endpoint was a composite of cardiovascular death and first hospitalisation for heart failure.
In this study, aliskiren at a target dose of 300 mg was compared to enalapril at a target dose of 20 mg when added to standard of care which included a beta blocker (and a mineralocorticoid receptor antagonist in 37% of patients) and a diuretic as needed. The study also evaluated the combination of aliskiren and enalapril. Mean duration of follow-up was 3.5 years. The final results of the study did not demonstrate statistically that aliskiren was non-inferior to enalapril on the primary endpoint, however there was essentially no difference in the observed incidence rates between aliskiren and enalapril (hazard ratio of 0.99 with 95% Confidence Interval: 0.90-1.10). There was no significant benefit of adding aliskiren to enalapril (primary endpoint: hazard ratio of 0.93 with 95% Confidence Interval: 0.85-1.03; p=0.1724, combination versus enalapril). Treatment effects were similar in patients with diabetes and with renal insufficiency. The incidence of adjudicated stroke was not significantly different between the aliskiren and enalapril groups (4.4% versus 4.0%; HR 1.12, 95% CI 0.848, 1.485) or between the combination and enalapril groups (3.7% versus 4.0%; HR 0.93, 95% CI 0.697, 1.251). The incidence of adverse events tended to be higher in patients with diabetes, or with GFR <60 ml/min/1.73 m², or with age ≥65 years; however, there was no difference between patients treated with aliskiren and those treated with enalapril.
The incidence of certain adverse events was similar between aliskiren and enalapril groups while there was an increased incidence of adverse events with the combination of aliskiren and enalapril: hyperkalaemia (21.4%, 13.2%, and 15.9% for combination, aliskiren and enalapril respectively); renal impairment/renal failure (23.2%, 17.4% and 18.7%) and hypotension related events (27.0%, 22.3% and 22.4%).
There was a statistically significant increased incidence of syncope with the combination of aliskiren and enalapril compared to enalapril in the overall population (4.2% versus 2.8%; RR 1.51, 95% CI 1.11-2.05) and in the subgroups NYHA I/II overall (4.8% versus 3.0%; RR 1.62, 95% CI 1.14-2.29).
The incidence of atrial fibrillation was 11.1%, 13.3%, and 11.0% in the combination, aliskiren, and enalapril groups, respectively.
Statistically significantly higher incidences in the occurrence of cardiac failure and ischaemic stroke were also found for aliskiren compared to enalapril in patients with NYHA I/II with hypertension, and in the occurrence of chronic cardiac failure and ventricular extrasystole in patients with NYHA III/IV with hypertension. For the combination of aliskiren and enalapril there were statistically significant differences in the rate of angina unstable compared to enalapril.
No clinically relevant differences in efficacy or safety results were observed in the subpopulation of elderly patients with a history of hypertension and chronic heart failure Class I-II compared to the overall study population.
The site of action of thiazide diuretics is primarily in the renal distal convoluted tubule. It has been shown that there is a high-affinity receptor in the renal cortex as the primary binding site for the thiazide diuretic action and inhibition of NaCl transport in the distal convoluted tubule. The mode of action of thiazides is through inhibition of the Na+Cl- symporter by competing for the Cl- site, thereby affecting electrolyte reabsorption mechanisms: directly increasing sodium and chloride excretion to an approximately equal extent, and indirectly by this diuretic action reducing plasma volume, with consequent increases in plasma renin activity, aldosterone secretion and urinary potassium loss, and a decrease in serum potassium.
Non-melanoma skin cancer: Based on available data from epidemiological studies, cumulative dosedependent association between HCTZ and NMSC has been observed. One study included a population comprised of 71,533 cases of BCC and of 8,629 cases of SCC matched to 1,430,833 and 172,462 population controls, respectively. High HCTZ use (≥50,000 mg cumulative) was associated with an adjusted OR of 1.29 (95% CI: 1.23-1.35) for BCC and 3.98 (95% CI: 3.68-4.31) for SCC. A clear cumulative dose response relationship was observed for both BCC and SCC. Another study showed a possible association between lip cancer (SCC) and exposure to HCTZ: 633 cases of lip-cancer were matched with 63,067 population controls, using a risk-set sampling strategy. A cumulative doseresponse relationship was demonstrated with an adjusted OR 2.1 (95% CI: 1.7-2.6) increasing to OR 3.9 (3.0-4.9) for high use (~25,000 mg) and OR 7.7 (5.7-10.5) for the highest cumulative dose (~100,000 mg) (see also section 4.4).
Over 3,900 hypertensive patients received Rasilez HCT once daily in clinical study.
In hypertensive patients, once-daily administration of Rasilez HCT provided dose-dependent reductions in both systolic and diastolic blood pressure that were maintained over the entire 24-hour dose interval. The antihypertensive effect is largely manifested within 1 week and the maximum effect is generally seen within 4 weeks. The blood-pressure-lowering effect was sustained during long-term treatment, and was independent of age, gender, body mass index and ethnicity. The antihypertensive effect of a single dose of the combination persisted for 24 hours. Upon withdrawal of the aliskiren treatment (aliskiren with or without hydrochlorothiazide add-on), the return of blood pressure towards baseline was gradual (3-4 weeks) with no evidence of the rebound effect.
Rasilez HCT was studied in a placebo-controlled trial including 2,762 hypertensive patients with diastolic blood pressure ≥95 mmHg and <110 mmHg (mean baseline blood pressure of 153.6/99.2 mmHg). In this study, Rasilez HCT in doses from 150 mg/12.5 mg to 300 mg/25 mg produced dose-dependent blood pressure reductions (systolic/diastolic) from 17.6/11.9 mmHg to 21.2/14.3 mmHg, respectively, compared to 7.5/6.9 mmHg with placebo. The greater blood pressure reductions with these combination doses were also significantly greater than the respective doses of aliskiren and hydrochlorothiazide when used alone. The combination of aliskiren and hydrochlorothiazide neutralised the reactive increase of PRA caused by hydrochlorothiazide.
When administered in hypertensive patients with markedly elevated blood pressure (systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg), Rasilez HCT in doses from 150 mg/12.5 mg to 300 mg/25 mg administered without up-titration from monotherapy demonstrated significantly greater systolic/diastolic blood pressure control rates (<140/90 mmHg) as compared to the respective monotherapies. In this population, Rasilez HCT 150 mg/12.5 mg to 300 mg/25 mg provided dose-dependent systolic/diastolic blood pressure reduction from 20.6/12.4 mmHg to 24.8/14.5 mmHg, which were significantly superior to the respective monotherapies. The safety of the combination therapy was similar to the respective monotherapies regardless of severity of hypertension or of the presence or absence of additional cardiovascular risk. Hypotension and related adverse events were uncommon with the combination treatment, with no increased incidence in elderly patients.
In a study in 880 randomised patients not adequately responsive to aliskiren 300 mg treatment, the combination of aliskiren/hydrochlorothiazide 300 mg/25 mg produced systolic/diastolic blood pressure reductions of 15.8/11.0 mmHg, which were significantly greater than aliskiren 300 mg monotherapy. In a study in 722 randomised patients not adequately responsive to hydrochlorothiazide 25 mg treatment, the combination of aliskiren/hydrochlorothiazide 300 mg/25 mg produced systolic/diastolic blood pressure reductions of 16.78/10.7 mmHg, which were significantly greater than hydrochlorothiazide 25 mg monotherapy.
In another clinical studies, the efficacy and safety of Rasilez HCT were also assessed in 489 obese hypertensive patients who did not respond to hydrochlorothiazide 25 mg (baseline systolic/diastolic blood pressure 149.4/96.8 mmHg). In this difficult-to-treat population, Rasilez HCT provided a blood pressure reduction (systolic/diastolic) of 15.8/11.9 mmHg compared to 15.4/11.3 mmHg for irbesartan/hydrochlorothiazide, 13.6/10.3 mmHg for amlodipine/hydrochlorothiazide and 8.6/7.9 mmHg for hydrochlorothiazide monotherapy, with similar safety to hydrochlorothiazide monotherapy.
In a study in 183 randomised patients with severe hypertension (mean sitting diastolic blood pressure ≥105 and <120 mmHg), aliskiren treatment regimen with optional addition of hydrochlorothiazide 25 mg was shown to be safe and efficacious in reducing blood pressure.
In a multicentre, randomised, double-blind, 8-week study with aliskiren monotherapy (3 dose groups by weight category [≥20 kg to <50 kg; ≥50 kg to <80 kg; ≥80 kg to ≤150 kg]: low 6.25/12.5/25 mg [0.13-0.31 mg/kg]; mid 37.5/75/150 mg [0.75-1.88 mg/kg]; and high dose 150/300/600 mg [3.0-7.5 mg/kg], with a wide dose ratio between the low, mid and high dose groups [1:6:24]) in 267 paediatric hypertensive patients aged 6 to 17 years, mostly overweight/obese, aliskiren lowered office and ambulatory blood pressure in a dose-dependent manner during the initial 4 week dose-finding phase of the study (Phase 1). However, in the subsequent 4 week randomised withdrawal phase of the study (Phase 2), the effect of aliskiren overlapped with the effects observed in patients switched to placebo in all dose groups (low, p=0.8894; mid, p=0.9511; high, p=0.0563). The average differences between aliskiren and placebo for the low and mid dose groups were <0.2 mmHg. The treatment with aliskiren was well tolerated in this study.
This study was extended with a 52-week double-blind, randomised study to evaluate the safety, tolerability and efficacy of aliskiren compared to enalapril in 208 paediatric hypertensive patients aged 6 to 17 years (at baseline in the previous study). The starting dose in each group was assigned depending on weight with three groups: ≥20 to <50 kg, ≥50 to <80 kg, and ≥80 to ≤150 kg. The starting doses for aliskiren were 37.5/75/150 mg in the low, mid and high weight groups, respectively. The starting doses for enalapril were 2.5/5/10 mg in the low, mid and high weight groups, respectively. Optional titration of the respective study drug doses to the next highest weight-based dose level was available by doubling the dose with each of the two allowed dose titrations, up to 600 mg (highest studied dose in adults) for aliskiren and 40 mg for enalapril in the ≥80 to ≤150 kg weight group, if medically necessary to control the mean sitting systolic blood pressure (i.e. msSBP should be less than the 90th percentile for age, gender and height). Overall, the mean age of the patients was 11.8 years with 48.6% of patients being in the 6-11 years age group and 51.4% in the 12-17 years age group. Mean weight was 68.0 kg with 57.7% of patients having BMI greater than or equal to the 95th percentile for age and gender. At the end of this extension study, changes in msSBP from baseline were similar with aliskiren compared to enalapril (-7.63 mmHg vs. -7.94 mmHg) in the full analysis set. However, the significance of the non-inferiority testing was not maintained when the analysis was performed on the per-protocol set in which the least square mean change in msSBP from baseline was -7.84 mmHg with aliskiren and -9.04 mmHg with enalapril. In addition, due to the possibility of up-titration if medically necessary to control the msSBP, no conclusion can be drawn on the appropriate posology of aliskiren in patients aged 6 to 17 years.
After the first 52 week extension study, eligible male and female paediatric patients aged 6 to 17 years with primary or secondary hypertension, were enrolled in a 52 to 104 week off-therapy noninterventional observational extension study designed to evaluate the LT growth and development, through height and weight measurement, with added neurocognitive and renal function evaluations as follow-up measures performed only in patients with secondary hypertension (19 patients: 9 previously treated with aliskiren and 10 previously treated with enalapril).
There were no statistically significant differences in the mean changes in weight, height, or BMI between the treatment groups from Baseline to LT Visit 18 (Week 104) (primary analysis).
In patients after 104 weeks (at LT Visit 19 [Week 156]), there were LS mean decreases from Baseline in weight and BMI in both treatment groups, with a slightly larger decrease in the aliskiren compared to the enalapril treatment group.
There was a greater LS mean increase from Baseline in height after 104 weeks (at LT Visit 19 [Week 156], secondary hypertension patients) compared to the increase observed after 52 weeks (at LT Visit 18 [Week 104], primary hypertension patients), which is expected in these growing paediatric patients.
Results of the neurocognitive assessments showed some improvements in most of the test scores, with no meaningful difference between the treatment groups.
The European Medicines Agency has waived the obligation to submit results of studies with Rasilez HCT in all subsets of the paediatric population in essential hypertension (see section 4.2 for information on paediatric use).
Following oral absorption, peak plasma concentrations of aliskiren are reached after 1-3 hours. The absolute bioavailability of aliskiren is approximately 2-3%. Meals with a high fat content reduce Cmax by 85% and AUC by 70%. At steady state meals with low fat content reduce Cmax by 76% and AUC0-tau by 67% in hypertensive patients. However the efficacy of aliskiren was similar when taken with a light meal or under fasted state. Steady-state-plasma concentrations are reached within 5-7 days following once-daily administration and steady-state levels are approximately 2-fold greater than with the initial dose.
MDR1/Mdr1a/1b (P-gp) was found to be the major efflux system involved in intestinal absorption and biliary excretion of aliskiren in pre-clinical studies.
Following intravenous administration, the mean volume of distribution at steady state is approximately 135 litres, indicating that aliskiren distributes extensively into the extravascular space. Aliskiren plasma protein binding is moderate (47-51%) and independent of the concentration.
The mean half-life is about 40 hours (range 34-41 hours). Aliskiren is mainly eliminated as unchanged compound in the faeces (oral radioactive dose recovery = 91%). Approximately 1.4% of the total oral dose is metabolised. The enzyme responsible for this metabolism is CYP3A4. Approximately 0.6% of the dose is recovered in urine following oral administration. Following intravenous administration, the mean plasma clearance is approximately 9 l/h.
Exposure to aliskiren increased slightly more than in proportion to the increase in dose. After single dose administration in the dose range of 75 to 600 mg, a 2-fold increase in dose results in a ~2.3 and 2.6-fold increase in AUC and Cmax, respectively. Mechanisms responsible for the deviation from dose proportionality have not been identified. A possible mechanism is saturation of transporters at the absorption site or at the hepatobiliary clearance route.
In a pharmacokinetic study of aliskiren treatment in 39 paediatric hypertensive patients aged 6 to 17 years given daily doses of 2 mg/kg or 6 mg/kg aliskiren administered as granules (3.125 mg/tablet), pharmacokinetic parameters were similar to those in adults. The results of this study did not suggest that age, body weight or gender have any significant effect on aliskiren systemic exposure (see section 4.2).
In an 8-week randomised, double-blind study with aliskiren monotherapy in 267 paediatric hypertensive patients aged 6 to 17 years, mostly overweight/obese, fasting trough aliskiren concentrations at day 28 were comparable to those observed in other studies in both adults and children using similar aliskiren doses.
Results from an in vitro MDR1 human tissue study suggested an age and tissue dependent pattern of MDR1 (P-gp) transporter maturation. A high inter-individual variability of mRNA expression levels was observed (up to 600-fold). Hepatic MDR1 mRNA expression was statistically significantly lower in samples from foetuses, neonates and infants up to 23 months.
The age at which the transporter system is mature cannot be determined. There is a potential for aliskiren overexposure in children with an immature MDR1 (P-gp) system (see section “Transporters” above and sections 4.2, 4.4 and 5.3).
The absorption of hydrochlorothiazide, after an oral dose, is rapid (Tmax about 2 h). The increase in mean AUC is linear and dose proportional in the therapeutic range.
The effect of food on hydrochlorothiazide absorption, if any, has little clinical significance. Absolute bioavailability of hydrochlorothiazide is 70% after oral administration.
The apparent volume of distribution is 4-8 l/kg. Circulating hydrochlorothiazide is bound to serum proteins (40-70%), mainly serum albumin. Hydrochlorothiazide also accumulates in erythrocytes at approximately 3 times the level in plasma.
Hydrochlorothiazide is eliminated predominantly as unchanged compound. Hydrochlorothiazide is eliminated from plasma with a half-life averaging 6 to 15 hours in the terminal elimination phase. There is no change in the kinetics of hydrochlorothiazide on repeated dosing, and accumulation is minimal when dosed once daily. There is more than 95% of the absorbed dose being excreted as unchanged compound in the urine. The renal clearance is composed of passive filtration and active secretion into the renal tubule.
Following oral administration of Rasilez HCT tablets, the median peak plasma concentration time is within 1 hour for aliskiren and 2.5 hours for hydrochlorothiazide.
The rate and extent of absorption of Rasilez HCT are equivalent to the bioavailability of aliskiren and hydrochlorothiazide when administered as individual monotherapies. Similar food effect was observed for Rasilez HCT as for the individual monotherapies.
Rasilez HCT has been shown to be effective as a once-a-day antihypertensive treatment in adult patients, regardless of gender, age, body mass index and ethnicity.
The pharmacokinetics of aliskiren are not significantly affected in patients with mild to moderate liver disease. Consequently, no initial dose adjustment of Rasilez HCT is required in patients with mild to moderate hepatic impairment. No data are available on patients with severe hepatic impairment treated by Rasilez HCT. Rasilez HCT is contraindicated in patients with severe hepatic impairment (see section 4.3).
No adjustment of the initial dose is required for patients with mild to moderate renal impairment (see sections 4.2 and 4.4). In the presence of renal impairment, mean peak plasma levels and AUC values of hydrochlorothiazide are increased and the urinary excretion rate is reduced. In patients with mild to moderate renal impairment, a 3-fold increase in hydrochlorothiazide AUC has been observed. In patients with severe renal impairment an 8-fold increase in AUC has been observed.
The pharmacokinetics of aliskiren were evaluated in patients with end stage renal disease receiving haemodialysis. Administration of a single oral dose of 300 mg aliskiren was associated with very minor changes in the pharmacokinetics of aliskiren (change in Cmax of less than 1.2 fold; increase in AUC of up to 1.6 fold) compared to matched healthy subjects. Timing of haemodialysis did not significantly alter the pharmacokinetics of aliskiren in ESRD patients. Therefore, if administration of aliskiren in ESRD patients receiving haemodialysis is considered necessary, no dose adjustment is warranted in these patients. However, the use of aliskiren is not recommended in patients with severe renal impairment (see section 4.4).
No initial dose adjustment of Rasilez HCT is required in elderly patients. Limited data suggest that the systemic clearance of hydrochlorothiazide is reduced in both healthy and hypertensive elderly subjects compared to young healthy volunteers.
No pharmacokinetic data on Rasilez HCT are available in the paediatric population.
Safety pharmacology studies with aliskiren did not reveal any adverse effects on central nervous, respiratory or cardiovascular function. Findings during repeat-dose toxicity studies in animals were consistent with the known local (gastrointestinal tract) irritation potential or the expected pharmacological effects of aliskiren.
No carcinogenic potential for aliskiren was detected in a 2-year rat study and a 6-month transgenic mouse study. One colonic adenoma and one caecal adenocarcinoma recorded in rats at the dose of 1500 mg/kg/day were not statistically significant.
Although aliskiren has known local (gastrointestinal tract) irritation potential, safety margins obtained in humans at the dose of 300 mg during a study in healthy volunteers were considered to be appropriate at 9-11-fold based on faecal concentrations or 6-fold based on mucosa concentrations in comparison with 250 mg/kg/day in the rat carcinogenicity study.
Aliskiren was devoid of any mutagenic potential in the in vitro and in vivo mutagenicity studies.
Reproductive toxicity studies with aliskiren did not reveal any evidence of embryofoetal toxicity or teratogenicity at doses up to 600 mg/kg/day in rats or 100 mg/kg/day in rabbits. Fertility, pre-natal development and post-natal development were unaffected in rats at doses up to 250 mg/kg/day. The doses in rats and rabbits provided systemic exposures of 1 to 4 and 5 times higher, respectively, than the maximum recommended human dose (300 mg).
Preclinical evaluations to support the administration of hydrochlorothiazide in humans included in vitro genotoxicity assays and reproductive toxicity and carcinogenicity studies in rodents. Extensive clinical data are available for hydrochlorothiazide and these are reflected in the relevant sections.
The findings observed in the 2-week and 13-week toxicity studies were consistent with those observed previously with aliskiren or hydrochlorothiazide monotherapies. There were no new or unexpected findings observed of relevance to human use. Increased cellular vacuolation of the adrenal gland zona glomerulosa was observed during the 13-week toxicity study in rats. The finding was observed in animals treated with hydrochlorothiazide but not in those animals receiving aliskiren alone or vehicle. There was no evidence that this finding was enhanced in the aliskiren/hydrochlorothiazide combination as it was only apparent at a minimal severity in all animals.
In a juvenile toxicity study in 8-day-old rats, aliskiren administration at 100 mg/kg/day and 300 mg/kg/day (2.3- and 6.8-fold the maximum recommended human dose) was associated with high mortality and severe morbidity. In another juvenile toxicity study in 14-day old rats, aliskiren administration at 300 mg/kg/day (8.5-fold the maximum recommended human dose) was associated with delayed mortality. The systemic exposure to aliskiren in 8-day old rats was >400-fold higher than in adult rats. Results from a mechanistic study showed that the MDR1 (P-gp) gene expression in juvenile rats was significantly lower when compared to adult rats. The increased aliskiren exposure in juvenile rats appears to be attributed mainly to lack of maturation of P-gp in the gastrointestinal tract. There is therefore a potential for aliskiren overexposure in paediatric patients with immature MDR1 efflux system (see sections 4.2, 4.3 and 5.2).
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