Valsartan Teva

Valsartan.

Each film-coated tablet contains valsartan 80 mg or 160 mg.
The tablet can be divided into equal halves.
Excipients/Inactive Ingredients: Tablet core: Colloidal anhydrous silicon dioxide (Aerosil 200), Sodium starch glycolate (Type A), Crospovidone (Kollidon CL), Microcrystalline cellulose (Avicel PH 101), Maize Starch, Magnesium Stearate.
Film-coat: 80-mg: Opadry 03F24040 Pink: Hypromellose 2910 6cP (E464), Macrogol 8000, Titanium dioxide (E171), Talc, Red iron oxide (E172).
160-mg: Opadry 03F32185 Yellow: Hypromellose 2910 6cP (E464), Macrogol 8000, Titanium dioxide (E171), Talc, Yellow iron oxide (E172), Red iron oxide (E172).

Pharmacotherapeutic group: Angiotensin II antagonists, plain. ATC Code: C09CA03.
Pharmacology: Pharmacodynamics: The active hormone of the RAAS (renin-angiotensin-aldosterone system) is angiotensin II, which is formed from angiotensin I through ACE. Angiotensin II binds to specific receptors located in the cell membranes of various tissues. It has a wide variety of physiological effects, including in particular both direct and indirect involvement in the regulation of blood pressure. As a potent vasoconstrictor, angiotensin II exerts a direct pressor response. In addition it reduces the excretion of sodium and stimulates secretion of aldosterone.
Valsartan is an orally active 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. It is possible that increased plasma levels of angiotensin II following AT1 receptor blockade by valsartan induces the unblocked AT2 receptor, which seems to balance the effects 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 does not inhibit ACE, also known as kininase II, which converts Ang I to Ang II and degrades bradykinin. No potentiation of bradykinin related side effects should be expected. In clinical studies where valsartan was compared with an ACE-inhibitor the incidence of dry cough was significantly lower (P<0.05) in patients treated with valsartan than in patients treated with an ACE-inhibitor (2.6% versus 7.9%, respectively). In a clinical study of patients with a history of dry cough during ACE-inhibitor treatment, 19.5% of those receiving valsartan and 19% of those receiving a thiazide diuretic experienced cough compared to 68.5% of those treated with an ACE-inhibitor (P<0.05). Valsartan does neither bind to nor block other hormone receptors or ion channels known to be important in cardiovascular regulation.
Hypertension: Administration of valsartan to patients with hypertension results in reduction of blood pressure without affecting pulse rate.
In most patients antihypertensive activity is detectable within 2 hours and maximum reduction of blood pressure is reached within 4-6 hours following a single dose. The antihypertensive effects persist for over 24 hours after dosing. During repeated dosing the maximum reduction in blood pressure with any dose is generally attained within 2-4 weeks and is sustained during long-term treatment. Combined with hydrochlorthiazide, a significant additional reduction in blood pressure is achieved.
Abrupt withdrawal of valsartan has not been associated with rebound hypertension or other adverse clinical events.
Recent myocardial infarction: The VALIANT study (VALsartan In Acute myocardial iNfarcTion trial) was a randomized, controlled, multinational, double blind study in 14,703 patients with acute myocardial infarction and signs, symptoms or radiological evidence of congestive and/or evidence of left ventricular systolic dysfunction (manifested as ejection fraction ≤ 40% according to radionuclide ventriculography or ≤ 35% according to echocardiography or ventricular contrast angiography). Within 12 hours to 10 days from the onset of symptoms of myocardial infarction the patients were randomized into groups receiving valsartan, captopril or both. Duration of treatment was on average two years.
Valsartan was equally 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. Concurrent use of captopril and valsartan did not provide additional benefits compared to use of captopril alone. There was no difference between valsartan and captopril with respect to all-cause mortality, based on gender, age, race, treatments received upon onset of myocardial infarction or underlying disease. Valsartan also delayed and reduced cardiovascular mortality, hospitalization due to heart failure, recurrent myocardial infarction, resuscitation due to cardiac arrest and a non-fatal stroke.
There was no difference in all-cause mortality, cardiovascular mortality or morbidity during concurrent administration of beta-blockers and valsartan + captopril, valsartan alone or captopril alone. Irrespective of the study drug treatment, the mortality was lower in the group of patients receiving beta-blockers, which indicated that known benefits of beta-blockers in this population have remained through the study.
Pharmacokinetics: Absorption of valsartan after oral administration is rapid, although the amount absorbed varies widely. Mean absolute bioavailability for valsartan is 23%. Valsartan shows multi-exponential decay kinetics (t_1/2α<1 hour and t_1/2β about 9 hours).
The pharmacokinetics of valsartan are linear in the dose range tested. There is no change in the kinetics of valsartan on repeated administration, and little accumulation when dosed once daily. Plasma concentrations were observed to be similar in males and females.
Valsartan is highly bound to serum protein (94-97%), mainly serum albumin. Steady state volume of distribution is about 17 liters. Plasma clearance is relatively slow (about 2 l/hour) compared with hepatic blood flow (about 30 l/hour). Elimination of valsartan is mainly in bile and urine, as unchanged compound. At normal glomerular filtration rate (120 ml/min) the renal clearance is about 30% of total plasma clearance. A hydroxy metabolite has been identified in plasma at low levels (less than 10% of valsartan AUC). This metabolite is pharmacologically inactive. After oral administration 83% is excreted in the faeces and 13% in the urine, mainly as unchanged compound.
When valsartan is given with food, AUC of valsartan is reduced by 48%, although from about 8 hours post dosing plasma level of valsartan are similar for the fed and fasted group. This reduction of AUC is however not associated with a clinically significant reduction in therapeutic effect.
Mean values for time to peak concentration and elimination half life of valsartan in patients with heart failure are similar to that observed in healthy volunteers. AUC and C_max values for valsartan are almost proportional with increasing dose over the clinical dosing range (40 to 160 mg twice a day). The average accumulation factor is about 1.7. Apparent clearance of valsartan following oral administration is about 4.5 l/hour. Age does not affect the apparent clearance in patients with heart failure.
Special populations: Elderly: A somewhat higher systemic exposure to valsartan was observed in some elderly subjects compared with young subjects; and a lower starting dose (40 mg) is recommended for the elderly.
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 mild renal impairment (creatinine clearance 20-50 ml/min). Limited data are available in patients with moderate-severe impairment of renal function and a starting dose of 40 mg is recommended for these patients. No studies have been performed in patients undergoing dialysis. However valsartan is highly bound to protein and is unlikely to be removed by dialysis.
Impaired hepatic function: About 70% of the absorbed dose is excreted in the bile mainly as unchanged compound. Valsartan does not undergo extensive biotransformation, and as expected, systemic exposure to valsartan is not correlated with the degree of liver dysfunction. No dose adjustment for valsartan is therefore necessary in patients with hepatic insufficiency of non-biliary origin and without cholestasis. The AUC with valsartan has been observed to approximately double in patients with biliary cirrhosis or biliary obstruction (see Precautions).
Toxicology: Preclinical safety data: Non-clinical data reveal no special hazard for human based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.
In non-clinical safety studies, high doses of valsartan (200 to 600 mg/kg body weight) in rats caused reduction in red blood cell parameters (erythrocytes, haemoglobin, haematocrit) and evidence of changes in renal haemodynamics (minor increase of urea in plasma, and renal tubular hyperplasia and basophilia in males). In marmosets similar doses resulted in similar alterations, though more severe, especially in the kidneys, where alterations evolved into nephropathy, which led to elevation of urea and creatinine.
Hypertrophy of renal juxtaglomerular cells was also seen in both species. All alterations were considered resulting from pharmacological action of valsartan which produces prolonged hypotension, especially in marmosets. Hypertrophy of renal juxtaglomerular cells does not seem to be of relevance in humans receiving recommended doses of valsartan.
There was no evidence of mutagenicity, clastogenicity or carcinogenicity.

Hypertension: Treatment of essential hypertension.
Recent-myocardial infarction: Treatment of clinically stable patients with symptomatic heart failure or asymptomatic left ventricular systolic dysfunction after a recent (12 hours - 10 days) myocardial infarction (see Precautions and Pharmacology: Pharmacodynamics under Actions).

Hypertension: The recommended dose of Valsartan Teva is 80 mg once daily for most patients. The antihypertensive effect is substantially present within 2 weeks and maximal effects are seen after 4 weeks. In some patients whose blood pressure is not adequately controlled, the dose can be increased to 160 mg and to a maximum of 320 mg. Further blood pressure reduction may be achieved by adding in a thiazide diuretic.
Valsartan Teva may also be administered with other antihypertensive agents.
Recent-myocardial infarction: Therapy may be initiated as early as 12 hours after a myocardial infarction in clinically stable patients. After an initial dose of 20 mg twice daily, valsartan therapy should be titrated to 40 mg, 80 mg, and 160 mg twice daily over the next few weeks. The starting dose is provided by the 40 mg divisible tablet.
The target maximum dose is 160 mg twice a day. It is generally recommended that patients have reached an 80 mg dose twice a day, two weeks after the treatment was initiated and that a maximum dose, 160 mg twice a day has been reached after 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. Concurrent use of ACE-inhibitors is not recommended (see Precautions, Adverse Reactions and Pharmacology: Pharmacodynamics under Actions).
Evaluation of post-myocardial infarction patients should always include evaluation of renal function.
Additional information on special populations: Elderly: No dose adjustment is required in elderly patients.
Use in renal impairment: No dosage adjustment is required for patients with a creatinine clearance >10 ml/min (see Precautions and Pharmacology: Pharmacokinetics under Actions).
For patients with severe renal impairment valsartan is contraindicated (see Contraindications).
Use in patients with mild to moderate hepatic impairment: In patients with mild to moderate hepatic impairment without cholestasis the dose of valsartan should not exceed 80 mg (see Precautions). Patients with severe hepatic impairment, cirrhosis or biliary obstruction should not use Valsartan Teva (see Contraindications).
Use in children and adolescents: Valsartan is not recommended for use in children below 18 years due to a lack of data on safety and efficacy.
Method of administration: The tablets should be swallowed with a sufficient amount of fluid (e. g. one glass of water). The tablet can be taken with or without food.

Symptoms: Overdose with valsartan may result in marked hypotension, which could lead to depressed level of consciousness, circulatory collapse and/or shock.
Treatment: Treatment is based on the time of ingestion and the type and severity of symptoms, stabilisation of the circulatory condition being of prime importance.
The patient should always be given a sufficient amount of activated charcoal.
If hypotension occurs, the patient should be positioned in a supine position and salt and volume supplementation should be given rapidly.
Valsartan can not be removed by dialysis due to strong plasma protein binding.

Hypersensitivity to valsartan or to any of the excipients (see Description).
Severe hepatic impairment, biliary chirrosis and cholestasis.
Severe renal impairment (creatinine clearance <10 ml/min) and patients undergoing dialysis.
Pregnancy (see Precautions and Use in Pregnancy & Lactation).
Lactation (see Use in Pregnancy & Lactation).
The concomitant use of Valsartan Teva with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m²).

Hyperkalemia: Caution should be exercised during concurrent use of potassium supplements, potassium sparing diuretics, salt substitutes containing potassium or other medicinal products that may increase potassium levels (heparin, etc.) and frequent monitoring of potassium levels should be performed.
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.
If hypotension occurs, the patient should be placed in the supine position and, if necessary, give an i.v. infusion of normal saline. Treatment can be continued once blood pressure had been stabilized.
Renal artery stenosis: Safety of valsartan use in patients with bilateral renal artery stenosis or stenosis to a solitary kidney has not been demonstrated.
Short-term use of valsartan in twelve patients with renovascular hypertension secondary to unilateral renal artery stenosis did not induce any significant changes in renal hemodynamics, serum creatinine, or blood urea nitrogen (BUN). However, since other drugs that affect the renin-angiotensin-aldosterone system may increase blood urea and serum creatinine in patients with unilateral renal artery stenosis, monitoring is recommended as a safety measure.
Kidney transplantation: No experience with respect to safety of the use of valsartan in patients after recent kidney transplantation is yet available.
Primary hyperaldosteronism: Valsartan should not be used in patients with primary hyperaldosteronism since the disease affects the renin-angiotensin-aldosterone system.
Aortic and mitral stenosis, obstructive hypertrophic cardiomyopathy: As with other vasodilators, special caution should be exercised in patients with aortic and mitral stenosis, or obstructive hypertrophic cardiomyopathy.
Renal impairment: No dose adjustment is necessary in patients with impaired renal function with creatinine clearance >10 ml/min.
As a consequence of inhibiting the rennin angiotensin aldosterone system, increase of blood urea and serum creatinine and changes in renal function including renal failure (very rarely) have been reported particularly in patients with pre-existing renal dysfunction or those with severe cardiac insufficiency.
Hepatic impairment: Caution should be exercised when valsartan is used in patients with mild to moderate non-cholestatic hepatic impairment. The dose of valsartan should not exceed 80 mg.
Recent myocardial infarction: Increased clinical benefits of concurrent use of captopril and valsartan has not been confirmed, and instead the risk of adverse effects was increased compared to treatment with the products separately (see Pharmacology: Pharmacodynamics under Actions and Adverse Reactions). Concomitant use of these products is therefore not recommended.
Caution should be exercised when initiating treatment in post-myocardial infarction patients. Evaluation of post-myocardial infarction patients should always include evaluation of renal function (see Dosage & Administration).
Use of valsartan in post-myocardial infarction patients is commonly accompanied by some blood pressure reduction but usually treatment does not need to be discontinued due to continued symptomatic hypotension, provided that dose recommendations are being followed.
Heart failure: Clinical benefits of a triple combination with ACE-inhibitor, beta-blocker and valsartan have not been confirmed for patients with heart failure (see Pharmacology: Pharmacodynamics under Actions). This combination seems to increase the risk of adverse events and is therefore not recommended.
The use of valsartan in patients with heart failure commonly causes some blood pressure reduction, but usually treatment does not need to be discontinued due to continued symptomatic hypotension, provided that dose recommendations are being followed. Caution should be observed when initiating therapy in patients with heart failure.
In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone 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 acute renal failure. Since valsartan is an angiotensin II receptor antagonist it has an inhibitory effect on the renin-angiotensin-aldosterone system and therefore it cannot be excluded that the use of valsartan may be associated with impairment of the renal function.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS): There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren 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.
ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.
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.
Use in 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 Contraindications and Use in Pregnancy & Lactation).

The use of Angiotensin II Receptor Inhibitors is not recommended during the first trimester of pregnancy (see Precautions).The use of Angiotensin II Receptor Inhibitors is contra-indicated during the 2nd and 3rd trimester of pregnancy (see Contraindications and Precautions).
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 ARB therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive 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 fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). (See also Pharmacology: Toxicology: Preclinical safety data under Actions.)
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 Contraindications and Precautions).
It is not known whether valsartan is excreted into human milk. Valsartan was excreted into the milk of rats. Lactating mothers should not breastfeed while taking valsartan.

In controlled clinical trials 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 as follows in Table 1 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.
Hypertension: See Table 1.

Click on icon to see table/diagram/image

The following events have also been observed during clinical trials in hypertensive patients irrespective of their causal association with the study drug: Arthralgia, asthenia, back pain, diarrhea, dizziness, headache, insomnia, libido decrease, nausea, oedema, pharyngitis, rhinitis, sinusitis, upper respiratory tract infection, viral infections.
Post-myocardial infarction and/or heart failure: 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 as follows in Table 2: See Table 2.

Click on icon to see table/diagram/image

The following events have also been observed during clinical trials in patients with post-myocardial infarction and/or heart failure irrespective of their causal association with the study drug: Arthralgia, abdominal pain, back pain, insomnia, libido decrease, neutropenia, oedema, pharyngitis, rhinitis, sinusitis, upper respiratory tract infection, viral infections.

Caution should be exercised during concurrent use of potassium supplements, potassium sparing diuretics, salt substitutes containing potassium or other drugs that may increase the level of potassium (heparin, etc.) and frequent measurements of potassium levels should be performed.
Other antihypertensive agents can increase the antihypertensive effects of valsartan.
Combination with NSAIDs: When Angiotensin II antagonists are administered simultaneously with non-steroidal anti-inflammatory drugs (i.e. selective COX-2 inhibitors, acetylsalicylic acid (>3g/day) and non-selective NSAIDs), attenuation of the antihypertensive effect may occur.
As with ACE inhibitors, concomitant use of Angiotensin II antagonists and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure, and an increase in serum potassium, especially in patients with poor pre-existing renal function. The combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy, and periodically thereafter.
Clinical trial data has shown that dual blockade of the 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.
Reversible increases in lithium serum concentration and toxic effects have been reported during concomitant use of ACE-inhibitors. There is only limited experience with the concurrent use of valsartan and lithium. In case of concurrent use, monitoring serum levels of lithium is recommended.
No interactions of clinical relevance have been seen in association with the use of the following products commonly used for the treatment of patients with hypertension: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, and glibenclamide.
Interaction studies have only been performed in adults.

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.
Incompatibilities: Not applicable.

Angiotensin II Antagonists

C09CA03 - valsartan ; Belongs to the class of angiotensin II receptor blockers (ARBs). Used in the treatment of cardiovascular disease.

P₁S₁S₃