Chemical formula: C₂₄H₂₉N₅O₃ Molecular mass: 435.519 g/mol PubChem compound: 60846
Valsartan interacts in the following cases:
In vitro data indicates that valsartan is a substrate of the hepatic uptake transporter OATP1B1/OATP1B3 and the hepatic efflux transporter MRP2. The clinical relevance of this finding is unknown. Co-administration of inhibitors of the uptake transporter or efflux transporter may increase the systemic exposure to valsartan. Exercise appropriate care when initiating or ending concomitant treatment with such drugs.
In patients with mild to moderate hepatic impairment without cholestasis, the dose of valsartan should not exceed 80 mg.
Potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium and other substances that may increase potassium levels. If a medicinal product that affects potassium levels is considered necessary in combination with valsartan, monitoring of potassium plasma levels is advised.
Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent.
When angiotensin II antagonists are administered simultaneously with NSAIDs, attenuation of the antihypertensive effect may occur. Furthermore, concomitant use of angiotensin II antagonists and NSAIDs may lead to an increased risk of worsening of renal function and an increase in serum potassium. Therefore, monitoring of renal function at the beginning of the treatment is recommended, as well as adequate hydration of the patient.
Reversible increases in serum lithium concentrations and toxicity have been reported during concurrent use of ACE inhibitors. Due to the lack of experience with concomitant use of valsartan and lithium, this combination is not recommended. If the combination proves necessary, careful monitoring of serum lithium levels is recommended.
In patients with bilateral renal artery stenosis or stenosis to a solitary kidney, the safe use of valsartan has not been established.
Short-term administration of valsartan to twelve patients with renovascular hypertension secondary to unilateral renal artery stenosis did not induce any significant changes in renal haemodynamics, serum creatinine, or blood urea nitrogen (BUN). However, other agents that affect the renin-angiotensin system may increase blood urea and serum creatinine in patients with unilateral renal artery stenosis, therefore monitoring of renal function is recommended when patients are treated with valsartan.
Valsartan should be used with caution in patients suffering from aortic or mitral stenosis or obstructive hypertrophic cardiomyopathy.
In severely sodium-depleted and/or volume-depleted patients, such as those receiving high doses of diuretics, symptomatic hypotension may occur in rare cases after initiation of therapy with valsartan. Sodium and/or volume depletion should be corrected before starting treatment with valsartan, for example by reducing the diuretic dose.
Population group: only minors (0 - 18 years old)
Use in paediatric patients with a creatinine clearance <30 ml/min and paediatric patients undergoing dialysis has not been studied, therefore valsartan is not recommended in these patients. No dose adjustment is required for paediatric patients with a creatinine clearance >30 ml/min. Renal function and serum potassium should be closely monitored.
The use of Angiotensin II Receptor Antagonists (AIIRAs) is not recommended during the first trimester of pregnancy. The use of AIIRAs is contra-indicated during the second and third trimester of pregnancy.
Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however, a small increase in risk cannot be excluded. Whilst there is no controlled epidemiological data on the risk with AIIRAs, similar risks may exist for this class of drugs. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started.
AIIRAs therapy exposure during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia).
Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended.
Infants whose mothers have taken AIIRAs should be closely observed for hypotension.
Because no information is available regarding the use of valsartan during breastfeeding, Valsartan is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.
Valsartan had no adverse effects on the reproductive performance of male or female rats at oral doses up to 200 mg/kg/day. This dose is 6 times the maximum recommended human dose on a mg/m² basis (calculations assume an oral dose of 320 mg/day and a 60-kg patient).
No studies on the effects on the ability to drive have been performed. When driving vehicles or operating machines it should be taken into account that occasionally dizziness or weariness may occur when taking valsartan.
In controlled clinical studies in adult patients with hypertension, the overall incidence of adverse reactions (ADRs) was comparable with placebo and is consistent with the pharmacology of valsartan. The incidence of ADRs did not appear to be related to dose or treatment duration and also showed no association with gender, age or race.
The ADRs reported from clinical studies, post-marketing experience and laboratory findings are listed below according to system organ class.
Adverse reactions are ranked by 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), including isolated reports.
Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness.
For all the ADRs reported from post-marketing experience and laboratory findings, it is not possible to apply any ADR frequency and therefore they are mentioned with a ‘not known’ frequency.
Hypertension:
Not known: Decrease in haemoglobin, Decrease in haematocrit, Neutropenia, Thrombocytopenia
Not known: Hypersensitivity including serum sickness
Not known: Increase of serum potassium, hyponatraemia
Uncommon: Vertigo
Not known: Vasculitis
Uncommon: Cough
Uncommon: Abdominal pain
Not known: Elevation of liver function values including increase of serum bilirubin
Not known: Angioedema, Rash, Pruritus
Not known: Myalgia
Not known: Renal failure and impairment, Elevation of serum creatinine
Uncommon: Fatigue
The antihypertensive effect of valsartan has been evaluated in two randomised, double-blind clinical studies (each followed by an extension period or study) and one open-label study. These studies include 771 paediatric patients from 6 to less than 18 years of age with and without chronic kidney disease (CKD), of which 560 patients received valsartan. With the exception of isolated gastrointestinal disorders (such as abdominal pain, nausea, vomiting) and dizziness, no relevant differences in terms of type, frequency and severity of adverse reactions were identified between the safety profile for paediatric patients aged 6 to less than 18 years and that previously reported for adult patients.
A pooled analysis of 560 paediatric hypertensive patients (aged 6-17 years) receiving either valsartan monotherapy [n=483] or combination antihypertensive therapy including valsartan [n=77] was conducted. Of the 560 patients, 85 (15.2%) had CKD (baseline GFR <90 mL/min/1.73m²). Overall, 45 (8.0%) patients discontinued a study due to adverse events. Overall 111 (19.8%) patients experienced an adverse drug reaction (ADR), with headache (5.4%), dizziness (2.3%) and hyperkalaemia (2.3%) being the most frequent. In patients with CKD, the most frequent ADRs were hyperkalaemia (12.9%), headache (7.1%), blood creatinine increased (5.9%) and hypotension (4.7%). In patients without CKD, the most frequent ADRs were headache (5.1%) and dizziness (2.7%). ADRs were observed more frequently in patients receiving valsartan in combination with other antihypertensive medications than valsartan alone.
Neurocognitive and developmental assessment of paediatric patients aged 6 to 16 years of age revealed no overall clinically relevant adverse impact after treatment with Valsartan for up to one year.
In a double-blind randomized study in 90 children aged 1 to 6 years, which was followed by a one-year open-label extension, two deaths and isolated cases of marked liver transaminases elevations were observed. These cases occurred in a population who had significant comorbidities. A causal relationship to Valsartan has not been established. In a second study in which 75 children aged 1 to 6 years were randomised, no significant liver transaminase elevations or death occurred with valsartan treatment.
Hyperkalaemia was more frequently observed in children and adolescents aged 6 to 18 years with underlying chronic kidney disease.
The safety profile seen in controlled-clinical studies in adult patients with post-myocardial infarction and/or heart failure varies from the overall safety profile seen in hypertensive patients. This may relate to the patients underlying disease. ADRs that occurred in adult patients with post-myocardial infarction and/or heart failure patients are listed below.
Post-myocardial infarction and/or heart failure (studied in adult patients only):
Not known: Thrombocytopenia
Not known: Hypersensitivity including serum sickness
Uncommon: Hyperkalaemia
Not known: Increase of serum potassium, hyponatraemia
Common: Dizziness, Postural dizziness
Uncommon: Syncope, Headache
Uncommon: Vertigo
Uncommon: Cardiac failure
Common: Hypotension, Orthostatic hypotension
Not known: Vasculitis
Uncommon: Cough
Uncommon: Nausea, Diarrhoea
Not known: Elevation of liver function values
Uncommon: Angioedema
Not known: Rash, Pruritus
Not known: Myalgia
Common: Renal failure and impairment
Uncommon: Acute renal failure, Elevation of serum creatinine
Not known: Increase in Blood Urea Nitrogen
Uncommon: Asthenia, Fatigue
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