Summary of medicine characteristics - Riprazo HCT
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 150 mg aliskiren (as hemifumarate) and 25 mg hydrochlorothiazide.
Excipients: Each tablet contains 50 mg lactose monohydrate and 49 mg wheat starch.
For a full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Film-coated tablet
Pale yellow, biconvex, ovaloid film-coated tablet imprinted with “CLL” on one side and “NVR” on the other.
4. CLINICAL PARTICULARS4.1 Therapeutic indications
Treatment of essential hypertension in adults.
Riprazo HCT is indicated in patients whose blood pressure is not adequately controlled on aliskiren or hydrochlorothiazide used alone.
Riprazo HCT is indicated as substitution therapy in patients adequately controlled with aliskiren and hydrochlorothiazide, given concurrently, at the same dose level as in the combination.
4.2 Posology and method of administration
The recommended dose of Riprazo HCT is one tablet per day. Riprazo HCT should be taken with a light meal once a day, preferably at the same time each day. Grapefruit juice should not be taken together with Riprazo HCT.
The antihypertensive effect is largely manifested within 1 week and the maximum effect is generally seen within 4 weeks.
Posology in patients not adequately controlled with aliskiren or hydrochlorothiazide monotherapy Individual dose titration with each of the two components may be recommended before changing to the fixed combination. When clinically appropriate, direct change from monotherapy to the fixed combination may be considered.
Riprazo HCT 150 mg /25 mg may be administered in patients whose blood pressure is not adequately controlled with aliskiren 150 mg or hydrochlorothiazide 25 mg alone or by Riprazo HCT 150 mg/12.5 mg.
If blood pressure remains uncontrolled after 2–4 weeks of therapy, the dose may be titrated up to a maximum of Riprazo HCT 300 mg/25 mg daily. Dosing should be individualised and adjusted according to the patient’s clinical response.
Posology as substitution therapy
For convenience, patients receiving aliskiren and hydrochlorothiazide from separate tablets may be switched to a fixed combination tablet of Riprazo HCT containing the same component doses.
Renal impairment
No adjustment of the initial dose is required for patients with mild to moderate renal impairment (see sections 4.4 and 5.2). Due to the hydrochlorothiazide component, Riprazo HCT is contraindicated for use in patients with anuria and in patients with severe renal impairment (glomerular filtration rate (GFR) < 30 ml/min/1.73 m2). The concomitant use of Riprazo HCT with angiotensin II receptor blockers (ARB) or angiotensin converting enzyme inhibitors (ACEI) is contraindicated in patients with renal impairment (GFR < 60 ml/min/1.73 m2) (see sections 4.3, 4.4 and 5.2).
Hepatic impairment
No adjustment of the initial dose is required for patients with mild to moderate hepatic impairment (see section 5.2). Riprazo HCT is contraindicated in patients with severe hepatic impairment (see sections 4.3 and 4.4).
Elderly patients (over 65 years)
The recommended starting dose of aliskiren in elderly patients is 150 mg. No clinically meaningful additional blood pressure reduction is observed by increasing the dose to 300 mg in the majority of elderly patients.
Paediatric patients
s below age 18 due to a lack of
Riprazo HCT is not recommended for use in children and a data on safety and efficacy (see section 5.2).
4.3
Hypersensitivity to the active substances or to any of the excipients (see section 6.1), or to other sulphonamide-derived substances.
History of angioedema with aliskiren.
Hereditary or idiopathic angioedema.
Second and third trimesters of pregnancy (see section 4.6).
Anuria.
Severe renal impairment (GFR < 30 ml/min/1.73 m2).
Refractory hypokalaemia, hyponatraemia, hypercalcaemia and symptomatic hyperuricaemia.
Severe hepatic impairment.
The concomitant use of aliskiren with ciclosporin and itraconazole, two highly potent P-glycoprotein (P-gp) inhibitors, and other potent P-gp inhibitors (e.g. quinidine), is contraindicated (see section 4.5).
The concomitant use of aliskiren with ARBs or ACEIs is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) (see sections 4.2, 4.4, 4.5 and 5.1).
4.4 Special warnings and precautions for use
4.4 Special warnings and precautions for useDual blockade of the renin-angiotensin-aldosterone system (RAAS)
Hypotension, syncope, stroke, hyperkalaemia, and changes in renal function (including acute renal failure) have been reported in susceptible individuals, especially if combining medicinal products that affect this system (see section 5.1). Dual blockade of the renin-angiotensin-aldosterone system by combining aliskiren with an angiotensin converting enzyme inhibitor (ACEI) or an angiotensin II receptor blocker (ARB) is therefore not recommended.
The use of aliskiren in combination with ARBs or ACEIs is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) (see section 4.3).
Heart failure
Aliskiren should be used with caution in patients with serious congestive heart failure (New York Heart Association (NYHA) functional class III-IV). Riprazo HCT should be used with caution in patients with heart failure due to limited clinical efficacy and safety data.
Angioedema
As with other agents acting on the renin-angiotensin system, angioedema or symptoms suggestive of angioedema (swelling of the face, lips, throat and/or tongue) have been reported in patients treated with aliskiren.
A number of these patients had a history of angioedema or symptoms suggestive of angioedema, which in some cases followed use of other medicines that can cause angioedema, including RAAS blockers (angiotensin converting enzyme inhibitors or angiotensin receptor blockers) (see section 4.8).
Patients with a history of angioedema may be at increased risk of experiencing angioedema during treatment with aliskiren (see sections 4.3 and 4.8). Caution should therefore be exercised when prescribing aliskiren to patients with a history of angioedema, and such patients should be closely monitored during treatment (see section 4.8) especially at the beginning of the treatment.
If angioedema occurs, Riprazo HCT should be promptly discontinued and appropriate therapy and monitoring provided until complete and sustained resolution of signs and symptoms has occurred. Where there is involvement of the tongue, glottis or larynx adrenaline should be administered. In addition, measures necessary to maintain patent airways should be provided.
Sodium- and/or volume-depleted patients
In sodium-depleted and/or volume-depleted patients, such as those receiving high doses of diuretics, symptomatic hypotension may occur after initiation of treatment with Riprazo HCT. Riprazo HCT should be used only after correction of any pre-existing sodium and/or volume depletion.
Electrolyte imbalance
Treatment with Riprazo HCT should only start after correction of hypokalaemia and any coexisting hypomagnesaemia. Thiazide diuretics can precipitate new onset hypokalaemia or exacerbate preexisting hypokalaemia. Thiazide diuretics should be administered with caution in patients with conditions involving enhanced potassium loss, for example salt-losing nephropathies and prerenal (cardiogenic) impairment of kidney function. If hypokalaemia develops during hydrochlorothiazide therapy Riprazo HCT should be discontinued until stable correction of the potassium balance. Although hypokalaemia may develop with the use of thiazide diuretics, concurrent therapy with aliskiren may reduce diuretic-induced hypokalaemia. The risk of hypokalaemia is greater in patients with cirrhosis of the liver, patients experiencing brisk diuresis, patients with inadequate oral electrolyte intake and patients receiving concomitant therapy with corticosteroids or adrenocorticotropic hormone (ACTH) (see sections 4.5 and 4.8).
Conversely, increases in serum potassium have been observed with aliskiren in post-marketing experience and these may be exacerbated by concomitant use of other agents acting on the RAAS or by non-steroidal anti-inflammatory drugs (NSAIDs). Consistent with standard medical practice, periodic determination of renal function including serum electrolytes is advised if co-administration is considered necessary. The concomitant use of aliskiren and ACEIs or ARBs is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) (see sections 4.3, 4.5 and 4.8).
Thiazide diuretics can precipitate new onset hyponatraemia and hypochloroaemic alkalosis or exacerbate pre-existing hyponatraemia. Hyponatraemia, accompanied by neurological symptoms (nausea, progressive disorientation, apathy) has been observed. Treatment with hydrochlorothiazide should only be started after correction of pre-existing hyponatraemia. In case severe or rapid hyponatraemia develops during Riprazo HCT therapy, the treatment should be discontinued until normalisation of natraemia.
There is no evidence that Riprazo HCT would reduce or prevent diuretic-induced hyponatraemia.
Chloride deficit is generally mild and usually does not require treatment.
All patients receiving thiazide diuretics should be periodically monitored for imbalances in electrolytes, particularly potassium, sodium and magnesium.
Thiazides reduce urinary calcium excretion and may cause an intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Riprazo HCT is contraindicated in patients with hypercalcaemia and should only be used after correction of any preexisting hypercalcaemia. Riprazo HCT should be discontinued if hypercalcaemia develops during treatment. Serum levels of calcium should be periodically monitored during treatment with thiazides. Marked hypercalcaemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.
Renal impairment and kidney transplantation
Thiazide diuretics may precipitate azotaemia in patients with chronic kidney disease. When Riprazo HCT is used in patients with renal impairment, periodic monitoring of serum electrolytes including potassium, creatinine and uric acid serum levels is recommended. Riprazo HCT is contraindicated in patients with severe renal impairment or anuria (see section 4.3).
No dosage adjustment is necessary in patients with mild to moderate renal impairment (GFR > 30 ml/min/1.73 m2).
There is no experience regarding the administration of Riprazo HCT in patients who have recently undergone kidney transplantation.
As for other agents acting on the renin-angiotensin system, caution should be exercised when aliskiren is given in the presence of conditions pre-disposing to kidney dysfunction such as hypovolaemia (e.g. due to blood loss, severe or prolonged diarrhoea, prolonged vomiting, etc.), heart disease, liver disease, diabetes mellitus or kidney disease. The concomitant use of aliskiren and ACEIs or ARBs is contraindicated in patients with renal impairment (GFR < 60 ml/min/1.73 m2). Acute renal failure, reversible upon discontinuation of treatment, has been reported in at-risk patients receiving aliskiren in post-marketing experience. In the event that any signs of renal failure occur, aliskiren should be promptly discontinued.
Hepatic impairment K x
Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma. No adjustment of the initial dose is required for patients with mild to moderate hepatic impairment. No data are available for the use of Riprazo HCT in patients with severe hepatic impairment. Due to the hydrochlorothiazide component, Riprazo HCT is contraindicated in patients with severe hepatic impairment (see sections 4.3 and 5.2).
There is no clinical experience with Riprazo HCT in patients with hepatic impairment.
Moderate P-gp inhibitors
Co-administration of aliskiren 300 mg with ketoconazole 200 mg or verapamil 240 mg resulted in a 76% or 97% increase in aliskiren AUC, respectively. Therefore caution should be exercised when aliskiren is administered with moderate P-gp inhibitors such as ketoconazole or verapamil (see section 4.5).
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy
As with other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy.
Renal artery stenosis and renovascular hypertension
No controlled clinical data are available on the use of Riprazo HCT in patients with unilateral or bilateral renal artery stenosis, or stenosis to a solitary kidney. However, as with other agents acting on the renin-angiotensin system, there is an increased risk of renal insufficiency, including acute renal failure, when patients with renal artery stenosis are treated with aliskiren. Therefore caution should be exercised in these patients. If renal failure occurs, treatment should be discontinued.
Systemic lupus erythematosus
Thiazide diuretics, including hydrochlorothiazide, have been reported to exacerbate or activate systemic lupus erythematosus.
Metabolic and endocrine effects
Thiazide diuretics, including hydrochlorothiazide, may alter glucose tolerance and raise serum levels of cholesterol and triglycerides, and uric acid. In diabetic patients dosage adjustments of insulin or oral hypoglycaemic agents may be required. Concomitant use of Riprazo HCT with ARBs or ACEIs is contraindicated in patients with diabetes mellitus (see section 4.3).
z-0
z-0Due to the hydrochlorothiazide component, Riprazo HCT is contraindicated in symptomatic hyperuricaemia (see section 4.3). Hydrochlorothiazide may raise the serum uric acid level due to reduced clearance of uric acid and may cause or exacerbate hyperuricaemia as well as precipitate gout in susceptible patients.
Thiazides reduce urinary calcium excretion and may cause an intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Riprazo HCT is contraindicated in patients with hypercalcaemia and should only be used after correction of any preexisting hypercalcaemia. Riprazo HCT should be discontinued if hypercalcaemia develops during treatment. Serum levels of calcium should be periodically monitored during treatment with thiazides. Marked hypercalcaemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.
Photosensitivity
Cases of photosensitivity reactions have been reported with thiazide diuretics (see section 4.8). If photosensitivity reaction occurs during treatment with Riprazo HCT, it is recommended to stop the treatment. If a re-administration of the diuretic is deemed necessary, it is recommended to protect exposed areas to the sun or to artificial UVA.
Acute angle-closure glauco ma^S
Hydrochlorothiazide, a sulphonamide, has been associated with an idiosyncratic reaction resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of treatment initiation.
Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatment may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulphonamide or penicillin allergy.
General
In the event of severe and persistent diarrhoea, Riprazo HCT therapy should be stopped.
As with any antihypertensive agent, excessive reduction of blood pressure in patients with ischaemic cardiopathy or ischaemic cardiovascular disease could result in a myocardial infarction or stroke.
Hypersensitivity reactions to hydrochlorothiazide may occur in patients, but are more likely in patients with allergy and asthma.
Excipients
Riprazo HCT contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Riprazo HCT contains wheat starch. It is suitable for people with coeliac disease. Patients with wheat allergy (different from coeliac disease) should not take this medicine.
4.5 Interaction with other medicinal products and other forms of interaction
4.6 Fertility, pregnancy and lactation
4.7 Effects on ability to drive and use machines
No studies on the effect on the ability to drive and use machines have been performed. Riprazo HCT is unlikely to affect the ability to drive and use machines. However, when driving vehicles or operating machinery it must be borne in mind that dizziness or drowsiness may occasionally occur when taking antihypertensive therapy.
4.8 Undesirable effects
4.9 Overdose
No information is available on the treatment of overdose with Riprazo HCT. The most likely manifestation of overdose would be hypotension, related to the antihypertensive effect of aliskiren.
Overdose with hydrochlorothiazide is associated with electrolyte depletion (hypokalaemia, hypochloraemia, 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 antiarrhythmic medicinal products. If symptomatic hypotension should occur, supportive treatment should be initiated.
ialysis, dialysis
In a study conducted in patients with end stage renal disease (ESRD) receiving haemod
clearance of aliskiren was low (< 2% of oral clearance). Therefore dialysis is not adequate to treat aliskiren over-exposure.
5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties
5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic propertiesPharmacotherapeutic group: Renin inhibitor (aliskiren) combinations with diuretics (hydrochlorothiazide), ATC code: C09XA52
Riprazo HCT combines two antihypertensive compounds 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
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 dosages 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.
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. Preliminary study results indicated a hazard ratio for the primary endpoint of 1.09 in favour of placebo (95% Confidence Interval: 0.97, 1.22, 2-sided p=0.17). In addition, an increased incidence of serious adverse outcomes was observed with aliskiren compared to placebo for renal complications (4.7% versus 3.3%), hyperkalaemia (36.9% versus 27.1%), hypotension (18.4% versus 14.6%) and stroke (2.7% versus 2.0%). The increased incidence of non-fatal stroke was greater in patients with renal insufficiency.
Hydrochlorothiazide
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.
Aliskiren/hydrochlorothiazide
Over 3,900 hypertensive patients received Riprazo HCT once daily in clinical trials.
In hypertensive patients, once-daily administration of Riprazo 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.
Riprazo 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, Riprazo 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), Riprazo 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, Riprazo 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 trial, the efficacy and safety of Riprazo 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, Riprazo 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.
5.2 Pharmacokinetic properties
Aliskiren
Absorption
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%. 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.
Distribution
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.
Metabolism and elimination
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.
Linearity
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.
Hydrochlorothiazide
Absorption
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.
Distribution
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.
Metabolism and elimination
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.
Aliskiren/hydrochlorothiazide
Following oral administration of Riprazo 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 Riprazo HCT are equivalent to the bioavailability of aliskiren and hydrochlorothiazide when administered as individual monotherapies. Similar food effect was observed for Riprazo HCT as for the individual monotherapies.
Characteristics in patients
Riprazo 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 Riprazo HCT is required in patients with mild to moderate hepatic impairment. No data are available on patients with severe hepatic impairment treated by Riprazo HCT. Riprazo 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. Riprazo HCT is contraindicated in patients with anuria or severe renal impairment (GFR < 30 ml/min/1.73 m2) and the concomitant use of Riprazo HCT with ARBs or ACEIs is contraindicated in patients with renal impairment (GFR < 60 ml/min/1.73 m2) (see section 4.3).
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 Riprazo 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 are available in the paediatric population.
5.3 Preclinical safety data
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 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 1,500 mg/kg/day were not statistically significant. Aliskiren was devoid of any mutagenic potential, embryo-foetal toxicity or teratogenicity. Fertility, prenatal development and postnatal development were unaffected in rats.
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.
6. PHARMACEUTICAL PARTICULARS6.1 List of excipients
Tablet core :
Cellulose microcrystalline Crospovidone
Lactose monohydrate
Wheat starch
Povidone
Magnesium stearate Silica colloidal anhydrous Talc
Coating :
Talc
Hypromellose
Macrogol
Titanium dioxide (E171)
Red iron oxide (E172)
Yellow iron oxide (E172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
24 months 6.4 Special precautions for sDo not store above 30°C.
Store in the original package
r to protect from moisture.
6.5 Nature and contents of container
PA/Alu/PVC – Alu b’isters:
Single-packs containing 7, 14, 28, 30, 50 or 56 tablets.
Multi-packs containing 90, 98 or 280 tablets.
PVC/polychlorotrifluoroethylene (PCTFE) – Alu blisters:
Single-packs containing 7, 14, 28, 30, 50, 56, 90 or 98 tablets.
Single-packs (perforated unit dose blister) containing 56 × 1 tablets.
Multi-packs containing 280 tablets.
Multi-packs (perforated unit dose blister) containing 98 × 1 tablets.
Not all pack sizes or strengths may be marketed.
6.6 Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
7. MARKETING AUTHORISATION HOLDER
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
8. MARKETING AUTHORISATION NUMBER(S)
EU/1/11/680/021–040