Aliskiren

As with other agents acting on the renin-angiotensin system, 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.

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.

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 P-gp. Increased aliskiren exposure during co-administration of CYP3A4 inhibitors that also inhibit P-gp can therefore be expected.

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.

Aliskiren is not recommended in patients with severe renal impairment (GFR <30 ml/min/1.73 m²).

Aliskiren should be used with caution in patients with serious congestive heart failure (New York Heart Association (NYHA) functional class III-IV).

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-administration with an agent affecting the level of serum potassium is considered necessary, routine monitoring of potassium levels would be advisable.

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. 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. 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.

When administered with atorvastatin (80 mg), steady-state aliskiren (300 mg) AUC and C_max increased by 50%.

Digoxin and verapamil bioavailability may be slightly decreased by aliskiren.

Aliskiren should be used with caution in patients with heart failure treated with furosemide or torasemide.

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 co-administration 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. However, since aliskiren has been shown to be a substrate for the organic anion-transporting polypeptide 1A2 (OATP1A2), 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.

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).

No controlled clinical data are available on the use of aliskiren 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.

As for other medicinal products 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 prolonged diarrhoea, prolonged vomiting, etc.), heart disease, liver disease, diabetes mellitus or kidney disease.

The volume or salt depletion should be corrected prior to administration of aliskiren, or the treatment should start under close medical supervision.

Administration of fruit juice with aliskiren resulted in a decrease in AUC and C_max of aliskiren. Co-administration 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. Co-administration 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 aliskiren.

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 aliskiren.

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. As for any medicine that acts directly on the RAAS, alsikiren 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. Healthcare professionals prescribing any agents acting on the RAAS should counsel women of childbearing potential about the potential risk of these agents during pregnancy. If pregnancy is detected during therapy, treatment should be discontinued accordingly.

It is unknown whether aliskiren/metabolites are excreted in human milk. Aliskiren was secreted in the milk of lactating rats. A risk to the newborns/infants cannot be excluded. Aliskiren should not be used during breast-feeding.

Fertility

There are no clinical data on fertility.

Aliskiren 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.

Summary of the safety profile

Serious adverse reactions include anaphylactic reaction and angioedema which have been reported in post-marketing experience and may occur rarely (less than 1 case per 1,000 patients). The most common adverse reaction is diarrhoea.

Tabulated list of adverse reactions

Aliskiren has been evaluated for safety in more than 7,800 patients, including over 2,300 treated for over 6 months, and more than 1,200 for over 1 year. The adverse reactions are ranked under heading of frequency, the most frequent first, 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).

^* 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.

Description of selected adverse reactions

Hypersensitivity reactions including anaphylactic reactions and angioedema

In controlled clinical trials, 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 medicines 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.

Renal dysfunction

In post-marketing experience, renal dysfunction and cases of acute renal failure have been reported in patients at risk.

Laboratory findings

In controlled clinical trials, clinically relevant changes in standard laboratory parameters were uncommonly associated with the administration of aliskiren. In clinical studies in hypertensive patients, aliskiren had no clinically important effects on total cholesterol, high density lipoprotein cholesterol (HDL-C), fasting triglycerides, fasting glucose or uric acid.

Haemoglobin and haematocrit

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.

Serum potassium

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 co-administration is considered necessary.

Paediatric population

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 week 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 on 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).