Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Noden Pharma DAC, DOlier Chambers, 16A DOlier Street, Dublin 2, Ireland
An increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] with increasing cumulative dose of hydrochlorothiazide (HCTZ) exposure has been observed in two epidemiological studies based on the Danish National Cancer Registry. Photosensitizing actions of HCTZ could act as a possible mechanism for NMSC.
Patients taking HCTZ should be informed of the risk of NMSC and advised to regularly check their skin for any new lesions and promptly report any suspicious skin lesions. Possible preventive measures such as limited exposure to sunlight and UV rays and, in case of exposure, adequate protection should be advised to the patients in order to minimize the risk of skin cancer. Suspicious skin lesions should be promptly examined potentially including histological examinations of biopsies. The use of HCTZ may also need to be reconsidered in patients who have experienced previous NMSC (see also section 4.8).
In the event of severe and perisistent diarrhoea, Rasilez HCT therapy should be stopped (see section 4.8).
Hypotension, syncope, stroke, hyperkalaemia, and decreased 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 RAAS by combining aliskiren with an ACEI or an ARB is therefore not recommended. If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.
Aliskiren should be used with caution in patients with serious congestive heart failure (New York Heart Association (NYHA) functional class III-IV) (see section 5.1). Rasilez HCT should be used with caution in patients with heart failure due to limited clinical efficacy and safety data.
Symptomatic hypotension could occur after initiation of treatment with Rasilez HCT in the following cases:
• Patients with marked volume depletion or patients with salt depletion (e.g. those receiving high doses of diuretics) or
• Combined use of aliskiren with other agents acting on the RAAS.
The volume or salt depletion should be corrected prior to administration of Rasilez HCT, or the treatment should start under close medical supervision.
Treatment with Rasilez 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 Rasilez 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 (see sections 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 Rasilez HCT therapy, the treatment should be discontinued until normalisation of natraemia.
There is no evidence that Rasilez 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. Rasilez HCT is contraindicated in patients with hypercalcaemia and should only be used after correction of any preexisting hypercalcaemia. Rasilez 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.
Thiazide diuretics may precipitate azotaemia in patients with chronic kidney disease. When Rasilez HCT is used in patients with renal impairment, periodic monitoring of serum electrolytes including potassium, creatinine and uric acid serum levels is recommended. Rasilez HCT is contraindicated in patients with severe renal impairment or anuria (see section 4.2 and 4.3) There is no experience regarding the administration of Rasilez HCT in patients who have recently undergone kidney transplantation. Rasilez HCT should be used with caution in patients who have recently undergone kidney transplantation due to limited clinical efficacy and safety data.
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. 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.
There are no data with Rasilez HCT in patients with hepatic impairment. Rasilez HCT is contraindicated in patients with severe hepatic impairment and should be used with caution in patients with mild to moderate hepatic impairment or progressive liver disease. No adjustment of the initial dose is required for patients with mild to moderate hepatic impairment (see sections 4.2, 4.3 and 5.2).
Special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy.
No controlled clinical data are available on the use of Rasilez HCT in patients with unilateral or bilateral renal artery stenosis, or stenosis to a solitary kidney. However, 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.
Anaphylactic reactions have been observed during treatment with aliskiren from post-marketing experience (see section 4.8). 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 medicinal product that can cause angioedema, including RAAS blockers (angiotensin converting enzyme inhibitors or angiotensin receptor blockers) (see section 4.8).
In post-marketing experience, angioedema or angioedema-like reactions have been reported when aliskiren was co-administered with ACEIs and/or ARBs (see section 4.8).
In a post-authorisation observational study, the co-administration of aliskiren with ACEIs or ARBs has been associated with an increased risk of angioedema. The mechanism of this effect has not been established. In general, dual blockade of the RAAS by combining aliskiren with an ACEI or an ARB is not recommended (see section “Dual blockade of the renin-angiotensin-aldosterone system (RAAS)” above and also sections 4.5 and 4.8).
Special caution is necessary in patients with a hypersensitivity predisposition.
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 anaphylactic reactions or angioedema occur, Rasilez HCT should be promptly discontinued and appropriate therapy and monitoring provided until complete and sustained resolution of signs and symptoms has occurred. Patients should be informed to report to the physician any signs suggestive of allergic reactions, in particular difficulties in breathing or swallowing, swelling of face, extremities, eyes, lips or tongue. 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.
Thiazide diuretics, including hydrochlorothiazide, have been reported to exacerbate or activate systemic lupus erythematosus. In the event that any signs or clinical suspicion of systematic lupus erythematosus (SLE), Rasilez HCT should be promptly discontinued and appropriate therapy and monitoring provided until complete and sustained resolution of signs and symptoms has occurred.
Thiazide diuretics, including hydrochlorothiazide, may alter glucose tolerance and raise serum levels of cholesterol and triglycerides, and uric acid. In diabetic patients dose adjustments of insulin or oral hypoglycaemic agents may be required.
Due to the hydrochlorothiazide component, Rasilez 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. Rasilez HCT is contraindicated in patients with hypercalcaemia and should only be used after correction of any preexisting hypercalcaemia. Rasilez 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.
Cases of photosensitivity reactions have been reported with thiazide diuretics (see section 4.8). If photosensitivity reaction occurs during treatment with Rasilez 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.
Sulfonamide or sulfonamide derivative drugs can cause an idiosyncratic reaction resulting in choroidal effusion with visual field defect, transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue drug intake as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.
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.
Rasilez HCT contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Rasilez HCT contains wheat starch. Wheat starch in this medicine contains only very low levels of gluten (less than 100ppm) and is very unlikely to cause problems if you have coeliac disease. One dosage unit contains no more than 100 micrograms of gluten. If you have wheat allergy (different from coeliac disease) you should not take this medicine. You should consult your doctor prior to taking this medicine.
Aliskiren is a P-glycoprotein (P-gp) substrate, and there is a potential for aliskiren overexposure in children with an immature P-gp drug transporter system. The age at which the transporter system is mature cannot be determined (see sections 5.2 and 5.3). Therefore, Rasilez HCT is contraindicated in children from birth to less than 2 years and should not be used in children aged 2 to less than 6 years (see section 4.2 and 4.3). The safety and efficacy of aliskiren in children aged 6 to 17 years have not yet been established. Currently available data are described in sections 4.8, 5.1, and 5.2.
The potassium-depleting effect of hydrochlorothiazide is attenuated by the potassium-sparing effect of aliskiren. However, this effect of hydrochlorothiazide on serum potassium would be expected to be potentiated by other medicinal products associated with potassium loss and hypokalaemia (e.g. other kaliuretic diuretics, corticosteroids, laxatives, adrenocorticotropic hormone (ACTH), amphotericin, carbenoxolone, penicillin G, salicylic acid derivatives). Conversely, concomitant use of other agents affecting the RAAS, of NSAIDs or of agents that increase serum potassium levels (e.g. potassiumsparing diuretics, potassium supplements, salt substitutes containing potassium, heparin) may lead to increases in serum potassium. If co-administration with an agent affecting the level of serum potassium is considered necessary, caution is advisable (see sections 4.4 and 5.1).
Periodic monitoring of serum potassium is recommended when Rasilez HCT is administered with medicinal products affected by serum potassium disturbances (e.g. digitalis glycosides, antiarrhythmics).
NSAIDs may reduce the anti-hypertensive effect of aliskiren. NSAIDs may also weaken the diuretic and antihypertensive activity of hydrochlorothiazide. In some patients with compromised renal function (dehydrated patients or elderly patients) aliskiren and hydrochlorothiazide given concomitantly with NSAIDs may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore, the use of Rasilez HCT with an NSAID requires caution, especially in elderly patients.
The antihypertensive effect of Rasilez HCT may be increased with the concomitant use of other antihypertensive agents. Therefore, caution should be used if coadmnistering with any other hypertensive agents.
A single dose interaction study in healthy subjects has shown that ciclosporin (200 and 600 mg) increases Cmax of aliskiren 75 mg approximately 2.5-fold and AUC approximately 5-fold. The increase may be higher with higher aliskiren doses. In healthy subjects, itraconazole (100 mg) increases AUC and Cmax of aliskiren (150 mg) by 6.5-fold and 5.8-fold, respectively. Therefore, concomitant use of aliskiren and P-gp potent inhibitors is contraindicated (see section 4.3).
Administration of fruit juice with aliskiren resulted in a decrease in AUC and Cmax of aliskiren. Coadministration of grapefruit juice with aliskiren 150 mg resulted in a 61% decrease in aliskiren AUC and co-administration with aliskiren 300 mg resulted in a 38% decrease in aliskiren AUC. Coadministration of orange or apple juice with aliskiren 150 mg resulted in a 62% decrease in aliskiren AUC or in a 63% decrease in aliskiren AUC, respectively. This decrease is likely due to an inhibition of organic anion transporting polypeptide-mediated uptake of aliskiren by components of fruit juice in the gastrointestinal tract. Therefore, because of the risk of therapeutic failure, fruit juice should not be taken together with Rasilez HCT. The effect of drinks containing plant extracts (including herbal teas) on the absorption of aliskiren has not been investigated. However, compounds potentially inhibiting organic anion transporting polypeptide-mediated uptake of aliskiren are widely present in fruits, vegetables, and many other plant products. Therefore, drinks containing plant extracts, including herbal teas, should not be taken together with Rasilez HCT.
Clinical study data has shown that dual blockade of the RAAS through the combined use of ACEIs, ARBs or aliskiren is associated with a higher frequency of adverse events such as hypotension, stroke, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1).
MDR1/Mdr1a/1b (P-gp) was found to be the major efflux system involved in intestinal absorption and biliary excretion of aliskiren in preclinical studies (see section 5.2). Rifampicin, which is an inducer of P-gp, reduced aliskiren bioavailability by approximately 50% in a clinical study. Other inducers of Pgp (St. John’s wort) might decrease the bioavailability of aliskiren. Although this has not been investigated for aliskiren, it is known that P-gp also controls tissue uptake of a variety of substrates and P-gp inhibitors can increase the tissue-to-plasma concentration ratios. Therefore, P-gp inhibitors may increase tissue levels more than plasma levels. The potential for drug interactions at the P-gp site will likely depend on the degree of inhibition of this transporter.
Co-administration of ketoconazole (200 mg) or verapamil (240 mg) with aliskiren (300 mg) resulted in a 76% or 97% increase in aliskiren AUC, respectively. The change in plasma levels of aliskiren in the presence of ketoconazole or verapamil is expected to be within the range that would be achieved if the dose of aliskiren were doubled; aliskiren doses of up to 600 mg, or twice the highest recommended therapeutic dose, have been found to be well tolerated in controlled clinical studies. Preclinical studies indicate that aliskiren and ketoconazole co-administration enhances aliskiren gastrointestinal absorption and decreases biliary excretion. Therefore, caution should be exercised when aliskiren is administered with ketoconazole, verapamil or other moderate P-gp inhibitors (clarithromycin, telithromycin, erythromycin, amiodarone).
Concomitant use of other agents affecting the RAAS, of NSAIDs or of agents that increase serum potassium levels (e.g. potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, heparin) may lead to increases in serum potassium. If co-medication with an agent affecting the level of serum potassium is considered necessary, routine monitoring of potassium levels would be advisable.
NSAIDs may reduce the anti-hypertensive effect of aliskiren. In some patients with compromised renal function (dehydrated patients or elderly patients) aliskiren given concomitantly with NSAIDs may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore, the combination of aliskiren with an NSAID requires caution, especially in elderly patients.
Oral co-administration of aliskiren and furosemide had no effect on the pharmacokinetics of aliskiren but reduced exposure to furosemide by 20-30% (the effect of aliskiren on furosemide administered intramuscularly or intravenously has not been investigated). After multiple doses of furosemide (60 mg/day) co-administered with aliskiren (300 mg/day) to patients with heart failure the urinary sodium excretion and the urine volume were reduced during the first 4 hours by 31% and 24%, respectively, as compared to furosemide alone. The mean weight of patients concomitantly treated with furosemide and 300 mg aliskiren (84.6 kg) was higher than the weight of patients treated with furosemide alone (83.4 kg). Smaller changes in furosemide pharmacokinetics and efficacy were observed with aliskiren 150 mg/day.
The available clinical data did not indicate that higher doses of torasemide were used after coadministration with aliskiren. Torasemide renal excretion is known to be mediated by organic anion transporters (OATs). Aliskiren is minimally excreted via the renal route, and only 0.6% of the aliskiren dose is recovered in urine following oral administration (see section 5.2). However, since aliskiren has been shown to be a substrate for the organic anion-transporting polypeptide 1A2 (OATP1A2) (see section ‘Organic anion transporting polypeptide (OATP’ below) inhibitors), there is a potential for aliskiren to reduce plasma torasemide exposure by an interference with the absorption process.
In patients treated with both aliskiren and oral furosemide or torasemide, it is therefore recommended that the effects of furosemide or torasemide be monitored when initiating and adjusting furosemide, torasemide or aliskiren therapy to avoid changes in extracellular fluid volume and possible situations of volume overload (see section 4.4).
The effects of aliskiren on warfarin pharmacokinetics have not been evaluated.
Although meals (low or high fat content) have been shown to reduce the absorption of aliskiren substantially, the efficacy of aliskiren was shown to be similar when taken either with a light meal or without a meal (see section 4.2). The available clinical data do not suggest an additive effect of different types of foods and/or drinks, however the potential for decreased aliskiren bioavailability due to this additive effect has not been studied and therefore cannot be excluded. Concomitant administration of aliskiren with fruit juice or drinks containing plant extracts, including herbal teas, should be avoided.
Compounds that have been investigated in clinical pharmacokinetic studies include acenocoumarol, atenolol, celecoxib, pioglitazone, allopurinol, isosorbide-5-mononitrate and hydrochlorothiazide. No interactions have been identified.
Co-administration of aliskiren with either metformin (↓28%), amlodipine (↑29%) or cimetidine (↑19%) resulted in between 20% and 30% change in Cmax or AUC of aliskiren. When administered with atorvastatin, steady-state aliskiren AUC and Cmax increased by 50%. Co-administration of aliskiren had no significant impact on atorvastatin, metformin or amlodipine pharmacokinetics. As a result no dose adjustment for aliskiren or these co-administered medicinal products is necessary.
Digoxin and verapamil bioavailability may be slightly decreased by aliskiren.
Aliskiren does not inhibit the CYP450 isoenzymes (CYP1A2, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A). Aliskiren does not induce CYP3A4. Therefore, aliskiren is not expected to affect the systemic exposure of substances that inhibit, induce or are metabolised by these enzymes. Aliskiren is metabolised minimally by the cytochrome P450 enzymes. Hence, interactions due to inhibition or induction of CYP450 isoenzymes are not expected. However, CYP3A4 inhibitors often also affect Pgp. Increased aliskiren exposure during co-administration of CYP3A4 inhibitors that also inhibit P-gp can therefore be expected (see other P-gp references in section 4.5).
No relevant interactions with atenolol, digoxin, amlodipine or cimetidine have been observed. When administered with atorvastatin (80 mg), steady-state aliskiren (300 mg) AUC and Cmax increased by 50%. In experimental animals, it has been shown that P-gp is a major determinant of aliskiren bioavailability. Inducers of P-gp (St. John’s wort, rifampicin) might therefore decrease the bioavailability of aliskiren.
Preclinical studies indicate that aliskiren might be a substrate of organic anion transporting polypeptides. Therefore, the potential exists for interactions between OATP inhibitors and aliskiren when administered concomitantly (see section “Fruit juice and drinks containing plant extracts” above).).
When administered concurrently, the following medicinal products may interact with thiazide diuretics.
Renal clearance of lithium is reduced by thiazides, therefore the risk of lithium toxicity may be increased with hydrochlorothiazide. Co-administration of lithium and hydrochlorothiazide is not recommended. If this combination proves essential, careful monitoring of serum lithium level is recommended during concomitant use.
Due to the risk of hypokalaemia, hydrochlorothiazide should be administered with caution when associated with medicinal products that could induce torsades de pointes, in particular Class Ia and Class III antiarrhythmics and some antipsychotics.
The hyponatraemic effect of diuretics may be intensified by concomitant administration of medicinal products such as antidepressants, antipsychotics, antiepileptics, etc. Caution is indicated in long-term administration of these medicinal products.
Hydrochlorothiazide may reduce the response to pressor amines such as noradrenaline. The clinical significance of this effect is uncertain and not sufficient to preclude their use.
Thiazide-induced hypokalaemia or hypomagnesaemia may occur as undesirable effects, favouring the onset of digitalis-induced cardiac arrhythmias.
Administration of thiazide diuretics, including hydrochlorothiazide, with vitamin D or with calcium salts may potentiate the rise in serum calcium. Concomitant use of thiazide type diuretics may lead to hypercalcaemia in patients pre-disposed for hypercalcaemia (e.g. hyperparathyroidism, malignancy, or vitamin-D-mediated conditions) by increasing tubular calcium reabsorption.
Thiazides may alter glucose tolerance. Dose adjustment of the antidiabetic medicinal product may be necessary (see section 4.4). Metformin should be used with caution because of the risk of lactic acidosis induced by possible functional renal failure linked to hydrochlorothiazide.
Concomitant use of thiazide diuretics, including hydrochlorothiazide, with beta blockers may increase the risk of hyperglycaemia. Thiazide diuretics, including hydrochlorothiazide, may enhance the hyperglycaemic effect of diazoxide.
Dose adjustment of uricosuric medicinal products may be necessary as hydrochlorothiazide may raise the level of serum uric acid. Increase of dose of probenecid or sulfinpyrazone may be necessary. Coadministration of thiazide diuretics, including hydrochlorothiazide, may increase the incidence of hypersensitivity reactions to allopurinol.
The bioavailability of thiazide-type diuretics may be increased by anticholinergic agents (e.g. atropine, biperiden), apparently due to a decrease in gastrointestinal motility and the stomach emptying rate. Conversely, it is anticipated that prokinetic substances such as cisapride may decrease the bioavailability of thiazide-type diuretics.
Thiazides, including hydrochlorothiazide, may increase the risk of adverse reactions caused by amantadine.
Absorption of thiazide diuretics, including hydrochlorothiazide, is decreased by cholestyramine or colestipol. This could result in sub-therapeutic effects of thiazide diuretics. However, staggering the dose of hydrochlorothiazide and resin such that hydrochlorothiazide is administered at least 4 hours before or 4-6 hours after the administration of resins would potentially minimise the interaction.
Thiazides, including hydrochlorothiazide, may reduce the renal excretion of cytotoxic agents (e.g. cyclophosphamide, methotrexate) and potentiate their myelosuppressive effects.
Thiazides, including hydrochlorothiazide, potentiate the action of skeletal muscle relaxants such as curare derivatives.
Concomitant administration of thiazide diuretics with subtances that also have a blood pressure lowering effect (e.g. by reducing sympathetic central nervous system activity or direct vasodilatation) may potentiate orthostatic hypotension.
There have been isolated reports of haemolytic anaemia occurring with concomitant use of hydrochlorothiazide and methyldopa.
In case of diuretic-induced dehydration, there is an increased risk of acute renal failure, especially with high doses of iodine products. Patients should be rehydrated before administration.
There are no data on the use of aliskiren in pregnant women. Aliskiren was not teratogenic in rats or rabbits (see section 5.3). Other substances that act directly on the RAAS have been associated with serious foetal malformations and neonatal death when used during second and third trimesters. 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.
Hydrochlorothiazide should not be used for gestational oedema, gestational hypertension or pre-eclampsia due to the risk of decreased plasma volume and placental hypoperfusion, without a beneficial effect on the course of the disease.
Hydrochlorothiazide should not be used for essential hypertension in pregnant women except in rare situations where no other treatment could be used.
No specific clinical studies have been performed with this combination, therefore Rasilez HCT should not be used during the first trimester of pregnancy or in women planning to become pregnant and is contraindicated during the second and third trimesters (see section 4.3). A switch to a suitable alternative treatment should be carried out in advance of a planned pregnancy. If pregnancy is detected during therapy, Rasilez HCT should be discontinued as soon as possible.
It is not known whether aliskiren is excreted in human milk. Aliskiren was secreted in the milk of lactating rats.
Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causing intense diuresis can inhibit milk production.
The use of Rasilez HCT during breast-feeding is not recommended. If Rasilez HCT is used during breast-feeding, doses should be kept as low as possible.
There are no clinical data on fertility.
Rasilez HCT has minor influence on the ability to drive and use machines. When driving vehicles or using machines, it must be borne in mind that dizziness or drowsiness may occasionally occur when taking Rasilez HCT.
The safety of Rasilez HCT has been evaluated in more than 3,900 patients, including over 700 treated for over 6 months, and 190 for over 1 year. The incidence of adverse reactions showed no association with gender, age, body mass index, race or ethnicity. Treatment with Rasilez HCT had an overall incidence of adverse experiences at doses up to 300 mg/25 mg similar to placebo. The most common adverse reaction observed with Rasilez HCT is diarrhoea. The adverse reactions previously reported with one of the individual components of Rasilez HCT (aliskiren and hydrochlorothiazide) and included in the tabulated list of adverse reactions may occur with Rasilez HCT.
The frequency of adverse reactions listed below is defined using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. The adverse reactions observed with Rasilez HCT or with monotherapy with one or both of the two components are included in the table below. For adverse reactions observed with more than one component of a fixed-dose combination, the highest frequency is listed in the table below.
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | |
| Not known | Non-melanoma skin cancer (Basal cell carcinoma and Squamous cell carcinoma) |
| Blood and lymphatic system disorders | |
| Rare | Thrombocytopenia sometimes with purpurah |
| Very rare | Agranulocytosish, bone marrow depressionh, haemolytic anaemiah, leucopeniah |
| Not known | Aplastic anaemiah |
| Immune system disorders | |
| Rare | Anaphylactic reactionsa, hypersensitivity reactionsa,h |
| Metabolism and nutrition disorders | |
| Very common | Hypokalaemiah |
| Common | Hyperuricaemiah, hypomagnesaemiah |
| Rare | Hypercalcaemiah, hyperglycaemiah, worsening of diabetic metabolic stateh |
| Very rare | Hypochloraemic alkalosish |
| Psychiatric disorders | |
| Rare | Depressionh, sleep disturbancesh |
| Nervous system disorders | |
| Rare | Headacheh, paraesthesiah |
| Eye disorders | |
| Rare | Visual impairmenth |
| Not known | Acute angle-closure glaucomah, choroidal effusionh |
| Ear and labyrinth disorders | |
| Not known | Vertigoa |
| Cardiac disorders | |
| Common | Dizzinessa,h |
| Uncommon | Palpitationsa, oedema peripherala |
| Rare | Cardiac arrhythmiash |
| Vascular disorders | |
| Common | Orthostatic hypotensionh |
| Uncommon | Hypotensionc,a |
| Respiratory, thoracic and mediastinal disorders | |
| Uncommon | Cougha |
| Very rare | Respiratory distress (including pneumonitis and pulmonary oedema)h |
| Not known | Dyspnoeaa |
| Gastrointestinal disorders | |
| Common | Diarrhoeac,a,h, decreased appetiteh, nausea and vomitinga,h |
| Rare | Abdominal discomforth, constipationh |
| Very rare | Pancreatitish |
| Hepatobiliary disorders | |
| Rare | Intrahepatic cholestasish, jaundicea,h |
| Not known | Liver disordera,, hepatitisa, liver failurea,* |
| Skin and subcutaneous tissue disorders | |
| Common | Urticaria and other forms of rasha,h |
| Uncommon | Severe cutaneous adverse reactions (SCARs) including Stevens Johnson syndromea, toxic epidermal necrolysis (TEN)a, oral mucosal reactionsa, pruritusa |
| Rare | Angioedemaa, erythemaa, photosensitivity reactionsh |
| Very rare | Cutaneous lupus erythematosus-like reactionsh, reactivation of cutaneous lupus erythematosush, vasculitis necrotising and toxic epidermal necrolysish |
| Not known | Erythema multiformeh |
| Musculoskeletal and connective tissue disorders | |
| Common | Arthralgiaa |
| Not known | Muscle spasmh |
| Renal and urinary disorders | |
| Uncommon | Acute renal failurea,h, renal impairmenta |
| Not known | Renal dysfunctionh |
| Reproductive system and breast disorders | |
| Common | Impotenceh |
| General disorders and administration site conditions | |
| Not known | Astheniah, pyrexiah |
| Investigations | |
| Very common | Increases in cholesterol and triglyceridesh |
| Common | Hyperkalaemiaa, hyponatraemiac,a,h |
| Uncommon | Liver enzyme increaseda |
| Rare | Haemoglobin decreaseda, haematocrit decreaseda, blood creatinine increaseda, glycosuriah |
c Adverse reaction observed with Rasilez HCT
a Adverse reaction observed with monotherapy with aliskiren
h Adverse reaction observed with monotherapy with hydrochlorothiazide
* Isolated cases of liver disorder with clinical symptoms and laboratory evidence of more marked hepatic dysfunction.
** Including one case of “liver failure fulminant” reported in the post-marketing experience, for which a causal relationship with aliskiren cannot be excluded.
Diarrhoea is a dose-related adverse reaction for aliskiren. In controlled clinical study, the incidence of diarrhoea in Rasilez HCT-treated patients was 1.3% compared to 1.4% for aliskiren- or 1.9% for hydrochlorothiazide-treated patients.
In a large placebo-controlled clinical study, the opposite effects of aliskiren (150 mg or 300 mg) and hydrochlorothiazide (12.5 mg or 25 mg) on serum potassium approximately balanced each other in many patients. In other patients, one or the other effect may be dominant. Periodic determinations of serum potassium to detect possible electrolyte imbalance should be performed in patients at risk at appropriate intervals (see sections 4.4 and 4.5).
Adverse reactions previously reported with one of the individual components may occur with Rasilez HCT even if not observed in clinical study.
Hypersensitivity reactions including anaphylactic reactions and angioedema have occurred during treatment with aliskiren.
In controlled clinical study, angioedema and hypersensitivity reactions occurred rarely during treatment with aliskiren with rates comparable to treatment with placebo or comparators.
Cases of angioedema or symptoms suggestive of angioedema (swelling of the face, lips, throat and/or tongue) have also been reported in post-marketing experience. A number of these patients had a history of angioedema or symptoms suggestive of angioedema which in some cases was associated with the administration of other medicinal products known to cause angioedema, including RAAS blockers (ACEIs or ARBs).
In post-marketing experience, cases of angioedema or angioedema-like reactions have been reported when aliskiren was co-administered with ACEIs and/or ARBs.
Hypersensitivity reactions including anaphylactic reactions have also been reported in post-marketing experience (see section 4.4).
In the event of any signs suggesting a hypersensitivity reaction/angioedema (in particular difficulties in breathing or swallowing, rash, itching, hives or swelling of the face, extremities, eyes, lips and/or tongue, dizziness) patients should discontinue treatment and contact the physician (see section 4.4).
Arthralgia has been reported in post-marketing experience. In some cases this occurred as part of a hypersensitivity reaction.
In post-marketing experience, renal dysfunction, and cases of acute renal failure have been reported in patients at risk (see section 4.4).
Small decreases in haemoglobin and haematocrit (mean decreases of approximately 0.05 mmol/l and 0.16 volume percent, respectively) were observed. No patients discontinued therapy due to anaemia. This effect is also seen with other agents acting on the renin-angiotensin system, such as ACEIs and ARBs.
Increases in serum potassium have been observed with aliskiren and these may be exacerbated by concomitant use of other agents acting on the RAAS or by NSAIDs. Consistent with standard medical practice, periodic determination of renal function including serum electrolytes is advised if coadministration is considered necessary.
Aliskiren has been evaluated for safety in a randomised, double-blind, 8-week study in 267 hypertensive patients aged 6 to 17 years, mostly overweight/obese, followed by an extension
study including 208 patients treated for 52 weeks. An additional 52 to 104 weeks non-interventional observational extension study in 106 patients (no study treatment administered) was conducted with the objective to evaluate the long-term safety in terms of growth and development of children 6-17 years of age with hypertension (primary or secondary) at baseline in the core study, previously treated with aliskiren.
The frequency, type and severity of adverse reactions in children were generally similar to those seen in hypertensive adults. No overall clinically relevant adverse impact in paediatric patients aged 6 to 17 years was observed after treatment with aliskiren for up to one year based on physical development, assessed in patients with primary or secondary hypertension, and neurocognitive development assessed only in patients with secondary hypertension (19 patients: 9 previously treated with aliskiren and 10 previously treated with enalapril). See section 4.2, 4.8, 5.1 and 5.2 for information on paediatric use.
Hydrochlorothiazide has been extensively prescribed for many years, frequently in higher doses than those contained in Rasilez HCT. The adverse reactions listed in the table above, which are marked with the reference “h”, have been reported in patients treated with thiazide diuretics alone, including hydrochlorothiazide.
Based on available data from epidemiological studies, cumulative dose-dependent association between HCTZ and NMSC has been observed (see also sections 4.4 and 5.1).
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
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