1. Name Of The Medicinal Product
Valsartan 40 mg Film-Coated Tablets
2. Qualitative And Quantitative Composition
Each film-coated tablet contains valsartan 40mg.
Excipients: Each Valsartan 40 mg Film-Coated Tablet contains 21.11 mg lactose monohydrate and 0.126 mg lecithin (contains soya oil)
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Film-coated tablet
Yellow, oval, biconvex, film-coated tablets, 9 x 4.5 mm, with a scoreline on one side and marked with a "V" on the other.
The tablet can be divided into equal halves.
4. Clinical Particulars
4.1 Therapeutic Indications
Recent myocardial infarction
Treatment of clinically stable patients with symptomatic heart failure or asymptomatic left ventricular systolic dysfunction after a recent (12 hours
Heart failure
Treatment of symptomatic heart failure when Angiotensin Converting Enzyme (ACE) inhibitors cannot be used, or as add-on therapy to ACE inhibitors when beta blockers cannot be used (see sections 4.4 and 5.1).
4.2 Posology And Method Of Administration
Recent-myocardial infarction
In clinically stable patients, therapy may be initiated as early as 12 hours after a myocardial infarction. After an initial dose of 20mg twice daily, valsartan should be titrated to 40mg, 80mg, and 160mg twice daily over the next few weeks. The starting dose is provided by the 40mg divisible tablet.
The target maximum dose is 160mg twice a day. In general, it is recommended that patients achieve a dose level of 80mg dose twice a day, two weeks after the treatment initiation and that the target maximum dose, 160mg twice a day be achieved by three months, based on the patient's tolerability. If symptomatic hypotension or renal dysfunction occur, consideration should be given to a dosage reduction.
Valsartan may be used in patients treated with other post-myocardial infarction therapies, e.g. thrombolytics, acetylsalicylic acid, beta blockers, statins and diuretics. The combination with ACE inhibitors is not recommended (see sections 4.4 and 5.1).
Evaluation of post-myocardial infarction patients should always include assessment of renal function.
Heart failure
The recommended starting dose of valsartan is 40mg twice daily. Uptitration to 80mg and 160mg twice daily should be done at intervals of at least two weeks to the highest dose, as tolerated by the patient. Consideration should be given to reducing the dose of concomitant diuretics. The maximum daily dose administered in clinical trials is 320mg in divided doses.
Valsartan may be administered with other heart failure therapies. However, the triple combination of an ACE inhibitor, a beta blocker and valsartan is not recommended (see sections 4.4 and 5.1).
Evaluation of patients with heart failure should always include assessment of renal function.
Method of administration
Valsartan may be taken independently of a meal and should be administered with water.
Additional information on special populations
Elderly
No dose adjustment is required in elderly patients.
Renal impairment
No dosage adjustment is required for patients with a creatinine clearance >10 ml/min (see sections 4.4 and 5.2)
Hepatic impairment
In patients with mild to moderate hepatic impairment without cholestasis, the dose of valsartan should not exceed 80mg. Valsartan is contraindicated in patients with severe hepatic impairment and in patients with cholestasis (see sections 4.3, 4.4 and 5.2).
Paediatric patients
Valsartan is not recommended for use in children below the age of 18 years due to a lack of data on safety and efficacy.
4.3 Contraindications
Hypersensitivity to valsartan, soya oil, peanut oil or to any of the excipients (see section 6.1).
Severe hepatic impairment, biliary cirrhosis and cholestasis.
Second and third trimester of pregnancy (see section 4.4 and 4.6)
4.4 Special Warnings And Precautions For Use
Hyperkalaemia
Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium, or other agents that may increase potassium levels (heparin, etc.) is not recommended. Monitoring of potassium should be undertaken as appropriate.
Sodium and/or volume depleted patients
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 shall be corrected prior to initiation of treatment with valsartan, e.g. by diuretic dose reduction.
Renal artery stenosis
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.
Kidney transplantation
There is currently no experience on the safe use of valsartan in patients who have recently undergone kidney transplantation.
Primary hyperaldosteronism
Patients with primary hyperaldosteronism should not be treated with valsartan as their renin-angiotensin system is not activated.
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy
As with all other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or hypertrophic obstructive cardiomyopathy (HOCM).
Impaired renal function
No dosage adjustment is required for patients with a creatinine clearance >10 ml/min. There is currently no experience on the safe use in patients with a creatinine clearance <10 ml/min and patients undergoing dialysis, therefore valsartan should be used with caution in these patients (see sections 4.2 and 5.2).
Hepatic impairment
In patients with mild to moderate hepatic impairment without cholestasis, valsartan should be used with caution (see sections 4.2 and 5.2).
Pregnancy
Angiotensin II Receptor Inhibitors (AIIRAs) should not be initiated during pregnancy. Unless continued AIIRAs 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.(see sections 4.3 and 4.6).
Recent myocardial infarction
The combination of captopril and valsartan has shown no additional clinical benefit, instead the risk for adverse events increased compared to treatment with the respective therapies (see sections 4.2 and 5.1). Therefore, the combination of valsartan with an ACE inhibitor is not recommended.
Caution should be observed when initiating therapy in post-myocardial infarction patients. Evaluation of post-myocardial infarction patients should always include assessment of renal function (see section 4.2).
Use of valsartan in post-myocardial infarction patients commonly results in some reduction in blood pressure, but discontinuation of therapy because of continuing symptomatic hypotension is not usually necessary provided dosing instructions are followed (see section 4.2).
Heart failure
In patients with heart failure, the triple combination of an ACE inhibitor, a beta blocker and valsartan has not shown any clinical benefit (see section 5.1). This combination apparently increases the risk for adverse events and is therefore not recommended.
Caution should be observed when initiating therapy in patients with heart failure. Evaluation of patients with heart failure should always include assessment of renal function (see section 4.2). Use of valsartan in patients with heart failure commonly results in some reduction in blood pressure, but discontinuation of therapy because of continuing symptomatic hypotension is not usually necessary provided dosing instructions are followed (see section 4.2).
In patients whose renal function may depend on the activity of the renin-angiotensin system (e.g. patients with severe congestive heart failure), treatment with ACE-inhibitors has been associated with oliguria and/or progressive azotemia and in rare cases with acute renal failure and/or death. As valsartan is an angiotensin II antagonist, it cannot be excluded that the use of valsartan may be associated with impairment of the renal function.
Galactose intolerance, Lapp lactase deficiency, glucose-galactose malabsorbtion
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Lecithin
If a patient is hypersensitive to peanut or soya, this medicine should not be used.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Concomitant use not recommended
Lithium
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.
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.
Caution required with concomitant use
Non-steroidal anti-inflammatory medicines (NSAIDs), including selective COX-2 inhibitors, acetylsalicylic acid >3 g/day), and non-selective NSAIDs
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.
Others
In drug interaction studies with valsartan, no interactions of clinical significance have been found with valsartan or any of the following substances: cimetidine, warfarin, furosemide, digoxin, atenolol, indometacin, hydrochlorothiazide, amlodipine, glibenclamide.
4.6 Pregnancy And Lactation
Pregnancy:
The use of Angiotensin II Receptor Inhibitors is not recommended during the first trimester of pregnancy (see section 4.4).The use of Angiotensin II Receptor Inhibitors is contra-indicated during the second and third trimester of pregnancy (see section 4.3 and 4.4)
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 Angiotensin II Receptor Inhibitors (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.
Exposure to AIIRA therapy during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). (See also 5.3)
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 (see also section 4.3 and 4.4).
Lactation:
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.
4.7 Effects On Ability To Drive And Use Machines
No studies on the effects on the ability to drive and use machines have been performed. When driving and using machines it should be considered that orthostatic hypotension, dizziness or weariness may occur.
4.8 Undesirable Effects
In controlled clinical studies in 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 (
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
| |
|
|
| |
|
|
| |
|
|
| |
|
|
| |
|
|
| |
|
|
| |
|
|
| |
|
|
| |
|
|
| |
|
|
| |
|
|
| |
|
|
The safety profile seen in controlled-clinical studies in 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 post-myocardial infarction and/or heart failure patients are listed below:
• Post-myocardial infarction and/or heart failure
| |
|
|
| |
|
|
| |
|
|
|
|
| |
|
|
|
|
| |
|
|
| |
|
|
| |
|
|
|
|
| |
|
|
| |
|
|
| |
|
|
| |
|
|
|
|
| |
|
|
| |
|
|
|
|
|
|
| |
|
|
4.9 Overdose
Symptoms
Overdose with valsartan may result in marked hypotension, which could lead to depressed level of consciousness, circulatory collapse and/or shock.
Treatment
The therapeutic measures depend on the time of ingestion and the type and severity of the symptoms; stabilisation of the circulatory condition is of prime importance.
If hypotension occurs, the patient should be placed in a supine position and blood volume correction should be undertaken.
Valsartan is unlikely to be removed by haemodialysis.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Angiotensin II antagonists, plain, ATC code: C09CA03
Valsartan is an orally active, potent, and specific angiotensin II (Ang II) receptor antagonist. It acts selectively on the AT1 receptor subtype, which is responsible for the known actions of angiotensin II. The increased plasma levels of Ang II following AT1 receptor blockade with valsartan may stimulate the unblocked AT2 receptor, which appears to counterbalance the effect of the AT1 receptor.
Valsartan does not exhibit any partial agonist activity at the AT1 receptor and has much (about 20,000 fold) greater affinity for the AT1 receptor than for the AT2 receptor. Valsartan is not known to bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation. Valsartan does not inhibit ACE (also known as kininase II) which converts Ang I to Ang II and degrades bradykinin. Since there is no effect on ACE and no potentiation of bradykinin or substance P, angiotensin II antagonists are unlikely to be associated with coughing. In clinical trials where valsartan was compared with an ACE inhibitor, the incidence of dry cough was significantly (P<0.05) less in patients treated with valsartan than in those treated with an ACE inhibitor (2.6 % versus 7.9 % respectively). In a clinical trial of patients with a history of dry cough during ACE inhibitor therapy, 19.5 % of trial subjects receiving valsartan and 19.0 % of those receiving a thiazide diuretic experienced cough compared to 68.5 % of those treated with an ACE inhibitor (P < 0.05).
Recent myocardial infarction
The VALsartan In Acute myocardial iNfarcTion trial (VALIANT) was a randomised, controlled, multinational, double-blind study in 14,703 patients with acute myocardial infarction and signs, symptoms or radiological evidence of congestive heart failure and/or evidence of left ventricular systolic dysfunction (manifested as an ejection fraction
Valsartan was as effective as captopril in reducing all-cause mortality after myocardial infarction. All-cause mortality was similar in the valsartan (19.9 %), captopril (19.5 %), and valsartan + captopril (19.3 %) groups. Combining valsartan with captopril did not add further benefit over captopril alone.
There was no difference between valsartan and captopril in all-cause mortality based on age, gender, race, baseline therapies or underlying disease. Valsartan was also effective in prolonging the time to and reducing cardiovascular mortality, hospitalisation for heart failure, recurrent myocardial infarction, resuscitated cardiac arrest, and non-fatal stroke (secondary composite endpoint).
The safety profile of valsartan was consistent with the clinical course of patients treated in the post-myocardial infarction setting. Regarding renal function, doubling of serum creatinine was observed in 4.2 % of valsartan-treated patients, 4.8 % of valsartan+captopril-treated patients, and 3.4 % of captopril-treated patients. Discontinuations due to various types of renal dysfunction occurred in 1.1 % of valsartan-treated patients, 1.3 % in valsartan+captopril patients, and 0.8 % of captopril patients. An assessment of renal function should be included in the evaluation of patients post-myocardial infarction.
There was no difference in all-cause mortality, cardiovascular mortality or morbidity when beta blockers were administered together with the combination of valsartan + captopril, valsartan alone, or captopril alone. Irrespective of treatment, mortality was lower in the group of patients treated with a beta blocker, suggesting that the known beta blocker benefit in this population was maintained in this trial.
Heart failure
Val-HeFT was a randomised, controlled, multinational clinical trial of valsartan compared with placebo on morbidity and mortality in 5,010 NYHA class II (62 %), III (36 %) and IV (2 %) heart failure patients receiving usual therapy with LVEF <40 % and left ventricular internal diastolic diameter (LVIDD)>2.9cm/m2. Baseline therapy included ACE inhibitors (93 %), diuretics (86 %), digoxin (67 %) and beta blockers (36 %). The mean duration of follow-up was nearly two years. The mean daily dose of valsartan in Val-HeFT was 254mg. The study had two primary endpoints: all cause mortality (time to death) and composite mortality and heart failure morbidity (time to first morbid event) defined as death, sudden death with resuscitation, hospitalisation for heart failure, or administration of intravenous inotropic or vasodilator agents for four hours or more without hospitalisation.
All cause mortality was similar (p=NS) in the valsartan (19.7 %) and placebo (19.4 %) groups. The primary benefit was a 27.5 % (95 % CI: 17 to 37 %) reduction in risk for time to first heart failure hospitalisation (13.9 % vs. 18.5 %). Results appearing to favour placebo (composite mortality and morbidity was 21.9 % in placebo vs. 25.4 % in valsartan group) were observed for those patients receiving the triple combination of an ACE inhibitor, a beta blocker and valsartan.
In a subgroup of patients not receiving an ACE inhibitor (n=366), the morbidity benefits were greatest. In this subgroup all-cause mortality was significantly reduced with valsartan compared to placebo by 33 % (95 % CI: –6 % to 58 %) (17.3 % valsartan vs. 27.1 % placebo) and the composite mortality and morbidity risk was significantly reduced by 44 % (24.9 % valsartan vs. 42.5 % placebo).
In patients receiving an ACE inhibitor without a beta-blocker, all cause mortality was similar (p=NS) in the valsartan (21.8 %) and placebo (22.5 %) groups. Composite mortality and morbidity risk was significantly reduced by 18.3 % (95 % CI: 8 % to 28 %) with valsartan compared with placebo (31.0 % vs. 36.3 %).
In the overall Val-HeFT population, valsartan treated patients showed significant improvement in NYHA class, and heart failure signs and symptoms, including dyspnoea, fatigue, oedema and ralescompared to placebo. Patients treated with valsartan had a better quality of life as demonstrated by change in the Minnesota Living with Heart Failure Quality of Life score from baseline at endpoint than placebo. Ejection fraction in valsartan treated patients was significantly increased and LVIDD significantly reduced from baseline at endpoint compared to placebo.
5.2 Pharmacokinetic Properties
Absorption:
Following oral administration of valsartan alone, peak plasma concentrations of valsartan are reached in 2–4 hours. Mean absolute bioavailability is 23 %. Food decreases exposure (as measured by AUC) to valsartan by about 40 % and peak plasma concentration (Cmax) by about 50 %, although from about 8 h post dosing plasma valsartan concentrations are similar for the fed and fasted groups. This reduction in AUC is not, however, accompanied by a clinically significant reduction in the therapeutic effect, and valsartan can therefore be given either with or without food.
Distribution:
The steady-state volume of distribution of valsartan after intravenous administration is about 17 litres, indicating that valsartan does not distribute into tissues extensively. Valsartan is highly bound to serum proteins (94–97 %), mainly serum albumin.
Biotransformation:
Valsartan is not biotransformed to a high extent as only about 20 % of dose is recovered as metabolites. A hydroxy metabolite has been identified in plasma at low concentrations (less than 10 % of the valsartan AUC). This metabolite is pharmacologically inactive.
Excretion:
Valsartan shows multiexponential decay kinetics (t½α <1 h and t½ß about 9 h). Valsartan is primarily eliminated by biliary excretion in faeces (about 83 % of dose) and renally in urine (about 13 % of dose), mainly as unchanged drug. Following intravenous administration, plasma clearance of valsartan is about 2 l/h and its renal clearance is 0.62 l/h (about 30 % of total clearance). The half-life of valsartan is 6 hours.
In Heart failure patients:
The average time to peak concentration and elimination half-life of valsartan in heart failure patients are similar to that observed in healthy volunteers. AUC and Cmax values of valsartan are almost proportional with increasing dose over the clinical dosing range (40 to 160mg twice a day). The average accumulation factor is about 1.7. The apparent clearance of valsartan following oral administration is approximately 4.5l/h. Age does not affect the apparent clearance in heart failure patients.
Special populations
Elderly
A somewhat higher systemic exposure to valsartan was observed in some elderly subjects than in young subjects; however, this has not been shown to have any clinical significance.
Impaired renal function
As expected for a compound where renal clearance accounts for only 30 % of total plasma clearance, no correlation was seen between renal function and systemic exposure to valsartan. Dose adjustment is therefore not required in patients with renal impairment (creatinine clearance >10 ml/min). There is currently no experience on the safe use in patients with a creatinine clearance <10 ml/min and patients undergoing dialysis, therefore valsartan should be used with caution in these patients (see sections 4.2 and 4.4). Valsartan is highly bound to plasma protein and is unlikely to be removed by dialysis.
Hepatic impairment
Approximately 70 % of the dose absorbed is eliminated in the bile, essentially in the unchanged form. Valsartan does not undergo any noteworthy biotransformation. A doubling of exposure (AUC) was observed in patients with mild to moderate hepatic impairment compared to healthy subjects. However, no correlation was observed between plasma valsartan concentration versus degree of hepatic dysfunction. Valsartan has not been studied in patients with severe hepatic dysfunction (see sections 4.2, 4.3 and 4.4).
5.3 Preclinical Safety Data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential.
In rats, maternally toxic doses (600mg/kg/day) during the last days of gestation and lactation led to lower survival, lower weight gain and delayed development (pinna detachment and ear-canal opening) in the offspring (see section 4.6). These doses in rats (600mg/kg/day) are approximately 18 times the maximum recommended human dose on a mg/m2 basis (calculations assume an oral dose of 320mg/day and a 60-kg patient).
In non-clinical safety studies, high doses of valsartan (200 to 600mg/kg body weight) caused in rats a reduction of red blood cell parameters (erythrocytes, haemoglobin, haematocrit) and evidence of changes in renal haemodynamics (slightly raised plasma urea, and renal tubular hyperplasia and basophilia in males). These doses in rats (200 and 600mg/kg/day) are approximately 6 and 18 times the maximum recommended human dose on a mg/m2 basis (calculations assume an oral dose of 320mg/day and a 60-kg patient).
In marmosets at similar doses, the changes were similar though more severe, particularly in the kidney where the changes developed to a nephropathy which included raised urea and creatinine.
Hypertrophy of the renal juxtaglomerular cells was also seen in both species. All changes were considered to be caused by the pharmacological action of valsartan which produces prolonged hypotension, particularly in marmosets. For therapeutic doses of valsartan in humans, the hypertrophy of the renal juxtaglomerular cells does not seem to have any relevance.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Tablet core
Lactose monohydrate
Cellulose, microcrystalline
Croscarmellose sodium
Povidone K29-K32
Talc
Magnesium Stearate
Colloidal anhydrous silica
Film-coat
Polyvinyl alcohol
Macrogol 3350
Talc
Lecithin (contains soya oil) (E322)
Titanium dioxide (E171)
Yellow iron oxide (E172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf Life
3 years for tablets packed in PVC/PE/PVDC-Al blisters
3 years for tablets packed in polyethylene tablet containers
6.4 Special Precautions For Storage
PVC/PE/PVDC-Al blisters: Do not store above 30°C.
Polyethylene tablet containers: This medicinal product does not require any special storage conditions.
6.5 Nature And Contents Of Container
PVC/PE/PVDC-Al blister.
Pack sizes: 7, 14, 28, 30, 56, 98 and 280 film-coated tablets
Polyethylene tablet container (securitainer, PE).
Pack sizes: 7, 14, 28, 30, 56, 98 and 280 film-coated tablets
Not all pack sizes may be marketed.
6.6 Special Precautions For Disposal And Other Handling
No special requirements.
Any unused product or waste material should be disposed of in accordance with local requirements
7. Marketing Authorisation Holder
Actavis Group PTC ehf.
Reykjavíkurvegur 76-78,
220 Hafnarfjöròur
Iceland
8. Marketing Authorisation Number(S)
PL 30306/0109
9. Date Of First Authorisation/Renewal Of The Authorisation
14.07.08
10. Date Of Revision Of The Text
01/02/11
11 DOSIMETRY (IF APPLICABLE)
Not applicable.
12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS (IF APPLICABLE)
Not applicable.
