Aliskiren and Hydrochlorothiazide interacts in the following cases:
Aliskiren/hydrochlorothiazide combination 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.
There are no data on the use of aliskiren in pregnant women. Aliskiren was not teratogenic in rats or rabbits. 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 aliskiren/hydrochlorothiazide 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. A switch to a suitable alternative treatment should be carried out in advance of a planned pregnancy. If pregnancy is detected during therapy, aliskiren/hydrochlorothiazide 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 aliskiren/hydrochlorothiazide during breast-feeding is not recommended. If aliskiren/hydrochlorothiazide is used during breast-feeding, doses should be kept as low as possible.
There are no clinical data on fertility.
Aliskiren/hydrochlorothiazide combination 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 aliskiren/hydrochlorothiazide.
The safety of aliskiren/hydrochlorothiazide fixed-dose combination 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 aliskiren/hydrochlorothiazide 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 aliskiren/hydrochlorothiazide is diarrhoea. The adverse reactions previously reported with one of the individual components of the fixed-dose combination (aliskiren and hydrochlorothiazide) and included in the tabulated list of adverse reactions may occur with aliskiren/hydrochlorothiazide combination.
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 aliskiren/hydrochlorothiazide fixed-dose combination 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 aliskiren/hydrochlorothiazide
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 aliskiren/hydrochlorothiazide-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.
Adverse reactions previously reported with one of the individual components may occur with aliskiren/hydrochlorothiazide 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.
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.
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.
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).
Hydrochlorothiazide has been extensively prescribed for many years, frequently in higher doses than those contained in aliskiren/hydrochlorothiazide. 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.
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