Valsartan a-teva
Ukraine
Table of Contents
INSTRUCTION FOR MEDICINAL USE OF THE MEDICINAL PRODUCT Valsartan A-Teva (Valsartan A-Teva)
Composition:
Active substances: amlodipine in the form of amlodipine besylate, valsartan;
One tablet contains amlodipine 5 mg in the form of amlodipine besylate and valsartan 80 mg, or amlodipine 5 mg in the form of amlodipine besylate and valsartan 160 mg, or amlodipine 10 mg in the form of amlodipine besylate and valsartan 160 mg;
Excipients: microcrystalline cellulose (Type 101), povidone (K30), sodium croscarmellose, microcrystalline cellulose (Type 102), talc, magnesium stearate;
coating for dosage 5 mg/80 mg and 5 mg/160 mg (Opadry Yellow 03B220017): hypromellose, titanium dioxide (E 171), yellow iron oxide (E 172), macrogol (polyethylene glycol) (400);
coating for dosage 10 mg/160 mg (Opadry White 03B28796): hypromellose, titanium dioxide (E 171), macrogol (polyethylene glycol) (400).
Pharmaceutical form. Film-coated tablets.
Main physico-chemical properties:
tablets 5 mg/80 mg: yellow, round, biconvex, film-coated tablets with marking «1» on one side and «LD» on the other;
tablets 5 mg/160 mg: yellow, oval, biconvex, film-coated tablets with marking «2» on one side and «LD» on the other;
tablets 10 mg/160 mg: white, oval, biconvex, film-coated tablets with marking «3» on one side and «LD» on the other.
Pharmacotherapeutic group. Agents acting on the cardiovascular system. Agents acting on the renin-angiotensin system. Angiotensin II receptor blockers (ARBs), combinations. Angiotensin II receptor blockers (ARBs) and calcium channel blockers. Valsartan and amlodipine. ATC code C09D B01.
Pharmacological Properties.
Pharmacodynamics.
Valsartan A-Teva contains two antihypertensive components with complementary mechanisms of blood pressure control in patients with essential hypertension: valsartan belongs to the class of angiotensin II antagonists; amlodipine belongs to the class of calcium channel blockers. The combination of these ingredients provides an additive antihypertensive effect, reducing blood pressure to a greater extent than either component alone.
The combination of amlodipine and valsartan provides dose-dependent additive reduction of blood pressure within their therapeutic dose ranges. The antihypertensive effect of a single dose of the combined medicinal product persists for 24 hours.
Amlodipine
Amlodipine inhibits transmembrane influx of calcium ions into vascular and cardiac smooth muscle. The antihypertensive mechanism of amlodipine is due to direct vasodilatory action on vascular smooth muscle, resulting in reduced peripheral vascular resistance and decreased arterial blood pressure. Experimental data confirm that amlodipine binds at both dihydropyridine and non-dihydropyridine binding sites. Contraction of cardiac and vascular smooth muscle depends on the influx of extracellular calcium into these cells through specific ion channels.
After administration of therapeutic doses to patients with arterial hypertension, amlodipine induces vasodilation, leading to reduced arterial blood pressure in both supine and standing positions. This reduction in blood pressure is not accompanied by significant changes in heart rate or plasma catecholamine levels during long-term treatment.
The effect correlates with plasma concentrations in both young and elderly patients.
In patients with arterial hypertension and normal renal function, therapeutic doses of amlodipine lead to reduced renal vascular resistance and increased glomerular filtration rate, as well as effective renal plasma flow, without changes in filtration fraction or proteinuria.
As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or walking) in patients with normal ventricular function treated with amlodipine generally show a slight increase in cardiac index without significant effects on dP/dt, left ventricular end-diastolic pressure, or volume. Hemodynamic studies have shown that amlodipine does not exhibit a negative inotropic effect when used at therapeutic doses in intact animals and humans, even when co-administered with β-blockers.
Amlodipine does not alter sinus node function or atrioventricular conduction in healthy animals or humans. In clinical studies where amlodipine was used in combination with β-blockers in patients with arterial hypertension or angina, no changes in electrocardiographic parameters were observed.
Positive clinical effects of amlodipine have been observed in patients with chronic stable angina, vasospastic angina, and angiographically confirmed ischemic heart disease.
Valsartan
Valsartan is an active, potent, and specific oral angiotensin II receptor antagonist. It acts selectively on AT1 receptors, which mediate the known effects of angiotensin II. Elevated plasma angiotensin II levels following AT1 receptor blockade by valsartan may stimulate unblocked AT2 receptors, counterbalancing the effects of AT1 receptor activation. Valsartan exhibits no partial agonist activity at AT1 receptors and has a much greater (approximately 20,000 times) affinity for AT1 receptors than for AT2 receptors. Valsartan does not bind to or block receptors of other hormones or ion channels that play a significant role in cardiovascular regulation.
Valsartan does not inhibit angiotensin-converting enzyme (ACE), also known as kininase II, which converts angiotensin I to angiotensin II and degrades bradykinin. Angiotensin II antagonists do not cause cough, as they do not affect ACE activity or increase bradykinin and substance P production.
Administration of the drug to patients with arterial hypertension results in reduced blood pressure without affecting pulse rate.
In most patients, after a single oral dose, onset of antihypertensive activity occurs within 2 hours, and maximum reduction in blood pressure is achieved within 4–6 hours.
The antihypertensive effect persists for more than 24 hours after a single dose. With regular administration, the maximum therapeutic effect is usually achieved within 2–4 weeks and is maintained at this level during long-term therapy. Abrupt discontinuation of the drug does not lead to withdrawal syndrome or other adverse clinical effects.
Pharmacokinetics.
Linearity. Valsartan and amlodipine exhibit linear pharmacokinetics.
Amlodipine/Valsartan
After oral administration of amlodipine/valsartan, Cmax in plasma is reached at 3 hours for valsartan and 6–8 hours for amlodipine, respectively. The rate and extent of absorption of amlodipine/valsartan are equivalent to the bioavailability of valsartan and amlodipine when administered as separate tablets.
Valsartan
Absorption. After oral administration, Cmax of valsartan in plasma is achieved within 2–4 hours. The mean absolute bioavailability of the drug is approximately 23%. Food intake reduces valsartan exposure by approximately 40% (based on AUC) and maximum plasma concentration (Cmax) by nearly 50%, although valsartan plasma concentrations are similar 8 hours after dosing in both fasting and postprandial groups. The reduction in AUC does not result in clinically significant reduction in therapeutic effect; therefore, valsartan can be administered independently of food intake.
Distribution. The steady-state volume of distribution of valsartan after intravenous administration is approximately 17 L, indicating that valsartan does not extensively distribute into tissues. Valsartan is highly bound to plasma proteins (94–97%), primarily to serum albumin.
Metabolism. Valsartan undergoes minimal biotransformation, with only 20% of the dose converted to metabolites. A hydroxymetabolite, identified in plasma at low concentrations (less than 10% of valsartan AUC), is pharmacologically inactive.
Elimination. Valsartan exhibits multi-exponential elimination kinetics (elimination half-life T1/2α < 1 hour and T1/2β approximately 9 hours). Valsartan is primarily excreted unchanged in feces (approximately 83% of dose) and urine (approximately 13% of dose). After intravenous administration, plasma clearance of valsartan is approximately 2 L/h, and renal clearance is approximately 0.62 L/h (about 30% of total clearance). The elimination half-life of valsartan is 6 hours.
Amlodipine
Absorption. After oral administration of therapeutic doses of amlodipine alone, maximum plasma concentration (Cmax) is reached within 6–12 hours. Calculated absolute bioavailability ranges from 64% to 80%. Food does not affect the bioavailability of amlodipine.
Distribution. The volume of distribution is approximately 21 L/kg. In vitro studies have shown that approximately 97.5% of circulating amlodipine is protein-bound.
Metabolism. Amlodipine is extensively metabolized (approximately 90%) in the liver to inactive metabolites.
Elimination. Elimination of amlodipine from plasma is biphasic, with an elimination half-life of approximately 30–50 hours. Steady-state plasma levels are achieved after 7–8 days of continuous administration. Approximately 10% of amlodipine is excreted unchanged in urine and 60% as metabolites.
Pharmacokinetics in Specific Patient Populations
Children (under 18 years of age)
Pharmacokinetic data in children are not available.
Elderly patients (aged 65 years and older)
Time to reach Cmax of amlodipine in plasma is approximately the same in younger and older patients. In elderly patients, clearance of amlodipine tends to be reduced, leading to increased AUC and prolonged elimination half-life. Mean systemic AUC of valsartan in elderly individuals is 70% higher than in younger patients; therefore, caution is required when increasing the dose.
Renal impairment
Renal impairment does not significantly affect the pharmacokinetics of amlodipine. As expected for a compound with renal clearance accounting for only 30% of total plasma clearance, no correlation was observed between renal function status and systemic exposure to valsartan.
Hepatic impairment
Very limited clinical data are available regarding amlodipine use in patients with hepatic impairment. In patients with hepatic insufficiency, clearance of amlodipine is reduced, leading to an increase in AUC by approximately 40–60%. In patients with mild to moderate chronic liver disease, exposure to valsartan (as measured by AUC) is on average twice that observed in healthy volunteers (matched for age, sex, and body weight). Caution should be exercised when administering the drug to patients with liver disease.
Clinical characteristics.
Indications.
Essential hypertension in adult patients whose blood pressure is not controlled by monotherapy with amlodipine or valsartan.
Contraindications.
Hypersensitivity to the active substances, dihydropyridine derivatives, or to any of the excipients of the medicinal product.
Severe hepatic impairment, biliary cirrhosis, or cholestasis.
Concomitant use of amlodipine/valsartan with medicinal products containing aliskiren in patients with diabetes mellitus or renal impairment (glomerular filtration rate (GFR) < 60 mL/min/1.73 m²).
Pregnancy or women planning to become pregnant (see section "Use during pregnancy or breastfeeding").
Severe hypotension.
Shock (including cardiogenic shock).
Left ventricular outflow tract obstruction (e.g., hypertrophic obstructive cardiomyopathy and severe aortic stenosis).
Hemodynamically unstable heart failure following acute myocardial infarction.
Interaction with other medicinal products and other forms of interaction.
Studies on drug interactions with other medicinal products have not been conducted.
Medicinal products requiring caution when co-administered
Other antihypertensive agents
Commonly used antihypertensive agents (e.g., alpha-blockers, diuretics) and other medicinal products whose adverse effect may include arterial hypotension (e.g., tricyclic antidepressants, alpha-blockers used for the treatment of benign prostatic hyperplasia) may enhance the hypotensive effect of the combination.
Interactions related to valsartan
Not recommended concomitant use
Lithium
When lithium is used concomitantly with ACE inhibitors or angiotensin II receptor antagonists, including valsartan, reversible increases in serum lithium concentrations and lithium toxicity have been reported. Careful monitoring of serum lithium levels is recommended if these agents are used concomitantly. The risk of increased lithium toxicity may be further elevated when co-administering the combination of valsartan and amlodipine with diuretics.
Potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other medicinal products that may increase potassium levels
If co-administration of a medicinal product affecting potassium levels with valsartan is necessary, frequent monitoring of plasma potassium levels is recommended.
Necessary safety measures during concomitant use
Non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors, acetylsalicylic acid (>3 g/day), and non-selective NSAIDs
Concomitant use of angiotensin II receptor antagonists with NSAIDs may reduce the antihypertensive effect of the drug. In addition, concomitant use of angiotensin II receptor antagonists and NSAIDs may increase the risk of worsening renal function and elevated serum potassium levels. Therefore, monitoring of renal function and ensuring adequate hydration at the beginning of treatment is recommended.
Inhibitors of uptake transporters (rifampicin, cyclosporine) or efflux transporters (ritonavir)
Valsartan is a substrate of the hepatic uptake transporter OATP1B1 and the hepatic efflux transporter MRP2. Concomitant use of inhibitors of uptake transporters (rifampicin, cyclosporine) or efflux transporters (ritonavir) may increase systemic exposure to valsartan.
Dual blockade of the RAAS with ARBs, ACE inhibitors, or aliskiren
Clinical trial data indicate that dual blockade of the RAAS by combining ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with an increased incidence of adverse events such as arterial hypotension, hyperkalemia, and reduced renal function (including acute renal failure), compared to using a single agent affecting the RAAS. Therefore, concomitant use of ARBs—including valsartan—or ACE inhibitors with aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m²).
Others
No clinically significant interactions with the following medicinal products were observed during monotherapy with valsartan: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, glipizide.
Interactions related to amlodipine
Not recommended concomitant use
Grapefruit or grapefruit juice
The concomitant use of amlodipine with grapefruit or grapefruit juice is not recommended due to the potential for increased bioavailability in some patients, leading to an enhanced hypotensive effect.
Necessary safety measures during concomitant use
CYP3A4 inhibitors
Concomitant use of amlodipine with strong and moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil, or diltiazem) may lead to a significant increase in amlodipine exposure. Clinical manifestations of such pharmacokinetic changes may be more pronounced in elderly patients. Therefore, clinical monitoring and dose adjustment may be necessary.
Clarithromycin is a CYP3A4 inhibitor. In patients receiving clarithromycin with amlodipine, there is an increased risk of developing arterial hypotension. Close monitoring of patients is recommended when amlodipine is co-administered with clarithromycin.
When amlodipine is co-administered with tacrolimus, there is a risk of increased blood levels of tacrolimus. To avoid tacrolimus toxicity, blood levels of tacrolimus should be monitored and doses adjusted as necessary when amlodipine is prescribed to a patient taking tacrolimus.
CYP3A4 inducers (anticonvulsants [e.g., carbamazepine, phenobarbital, phenytoin, fosphenytoin, primidone], rifampicin, St. John's wort (Hypericum perforatum))
When known CYP3A4 inducers are co-administered, plasma concentrations of amlodipine may change. Therefore, blood pressure should be monitored and dosage adjusted during and after co-administration, especially when potent CYP3A4 inducers (e.g., rifampicin, Hypericum perforatum) are used.
Simvastatin
Repeated co-administration of amlodipine 10 mg with simvastatin 80 mg increases simvastatin exposure by 77% compared to simvastatin monotherapy. For patients taking amlodipine, the dose of simvastatin should be limited to 20 mg daily.
Dantrolene (infusion)
In animals, fatal cases of ventricular fibrillation and cardiovascular collapse associated with hyperkalemia have been observed after intravenous administration of verapamil and dantrolene. Due to the risk of hyperkalemia, concomitant use of calcium channel blockers such as amlodipine should be avoided in patients predisposed to malignant hyperthermia or during treatment of malignant hyperthermia.
Consider the following when used concomitantly
Other medicinal products
According to clinical interaction studies, amlodipine does not affect the pharmacokinetics of atorvastatin, digoxin, warfarin, or cyclosporine.
Special precautions for use.
The safety and efficacy of amlodipine during hypertensive crisis have not been established.
Patients with sodium and/or circulating blood volume depletion
Excessive hypotension occurred in 0.4% of patients with uncomplicated arterial hypertension treated with Valsartan A-Teva. Symptomatic hypotension may occur in patients with activated renin-angiotensin system (such as in the case of sodium and/or circulating blood volume deficiency due to high-dose diuretic therapy) who are receiving angiotensin receptor blockers. It is recommended to correct this condition prior to initiating treatment with Valsartan A-Teva or to ensure close medical supervision at the beginning of therapy.
In case of arterial hypotension developing during treatment with Valsartan A-Teva, the patient should be placed in a supine position and, if necessary, receive intravenous infusion of physiological saline. Treatment may be resumed after stabilization of blood pressure.
Hyperkalemia
Concomitant use with potassium supplements, potassium-sparing diuretics, potassium-containing salt substitutes, or other medicinal products capable of increasing potassium levels (e.g., heparin) should be performed with caution and with frequent monitoring of serum potassium levels.
Renal artery stenosis
Amlodipine/valsartan should be used with caution in the treatment of hypertension in patients with unilateral or bilateral renal artery stenosis or stenosis of the artery of a single kidney, as increased blood urea and serum creatinine levels may occur in such patients.
Kidney transplantation
There is currently no experience regarding the safe use of amlodipine/valsartan in patients who have recently undergone kidney transplantation.
Hepatic impairment
Valsartan is primarily excreted unchanged in bile. The elimination half-life of amlodipine is prolonged and the AUC is increased in patients with hepatic impairment; however, no dosage recommendations have been established. Particular caution should be exercised when prescribing Valsartan A-Teva to patients with mild to moderate hepatic impairment or obstructive biliary disorders.
The maximum recommended dose for patients with mild to moderate hepatic impairment without cholestasis is 80 mg of valsartan.
Renal impairment
Dosage adjustment of Valsartan A-Teva is not required in patients with mild to moderate renal insufficiency (eGFR > 30 mL/min/1.73 m²). In moderate renal impairment, monitoring of potassium and creatinine levels is recommended. Concomitant use of angiotensin receptor antagonists, including valsartan, or ACE inhibitors with aliskiren is contraindicated in patients with renal dysfunction (eGFR < 60 mL/min/1.73 m²).
Primary hyperaldosteronism
Patients with primary hyperaldosteronism should not be treated with the angiotensin II receptor antagonist valsartan due to the underlying disease affecting the renin-angiotensin system.
Angioedema
Angioedema, including laryngeal and vocal cord edema with airway obstruction and/or facial, lip, pharyngeal, and/or tongue swelling, has been reported in patients taking valsartan. Some of these patients had a history of angioedema with other medicinal products, including ACE inhibitors.
Patients who develop angioedema should immediately discontinue amlodipine/valsartan and must not be rechallenged with the drug.
Heart failure/post-myocardial infarction state
Due to suppression of the RAAS, renal function may change in susceptible individuals. In patients with severe heart failure, in whom renal function depends on RAAS activity, treatment with ACE inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotemia, and (rarely) acute renal failure and/or death. Similar outcomes have been reported with valsartan. Evaluation of patients with heart failure or post-myocardial infarction should always include assessment of renal function.
It is known that amlodipine use in patients with NYHA (New York Heart Association) Class III and IV non-ischemic heart failure has been associated with an increased incidence of pulmonary edema, despite no significant differences in the rate of worsening heart failure compared to placebo.
Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure due to their potential to increase the risk of future cardiovascular events and mortality.
Aortic and mitral valve stenosis
As with any vasodilating agents, the drug should be used with particular caution in patients with mitral valve stenosis or mild to moderate aortic stenosis.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
Evidence indicates that concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of hypotension, hyperkalemia, and decreased renal function (including acute renal failure). Therefore, dual blockade of the RAAS by combining ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended.
If dual blockade is absolutely necessary, it should be performed only under specialist supervision and with frequent and careful 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.
The use of Valsartan A-Teva has not been studied in patients with conditions other than arterial hypertension.
Use during pregnancy or breastfeeding.
Pregnancy
The medicinal product is contraindicated in pregnant women or women planning to become pregnant.
If pregnancy is confirmed during treatment with this medicinal product, its use must be immediately discontinued and replaced with another medicinal product approved for use during pregnancy.
Amlodipine
The safety of amlodipine use in pregnant women has not been established. Reproductive toxicity has been observed in animal studies at high doses. Amlodipine should be used during pregnancy only if no safer alternative exists and if the risk associated with the underlying disease exceeds the potential harm of treatment to the mother and fetus.
Valsartan
The use of angiotensin II receptor antagonists (ARBs) is not recommended during the first trimester of pregnancy. ARBs are contraindicated during the second and third trimesters of pregnancy.
Epidemiological data suggesting teratogenic risk following ACE inhibitor use in the first trimester of pregnancy are not conclusive. However, a small increased risk cannot be ruled out. In the absence of controlled epidemiological data on the risk of angiotensin II receptor antagonists, similar risks may exist for this class of drugs. Even if continued use of angiotensin II receptor antagonists is necessary in women planning pregnancy, they should be switched to alternative antihypertensive agents with an established safety profile during pregnancy. If pregnancy is detected, ARBs must be discontinued immediately and, if necessary, alternative therapy initiated.
It is known that ARB use during the second and third trimesters causes fetal toxicity (reduced renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia).
If ARBs were used during the second trimester of pregnancy, ultrasound monitoring of fetal renal function and skull development is recommended.
Infants whose mothers took ARBs require careful monitoring for arterial hypotension.
Period of breastfeeding
Amlodipine is excreted in human breast milk. The infant dose relative to the maternal dose has been estimated at an interquartile range of 3–7%, with a maximum of 15%. The effect of amlodipine on the infant is unknown.
Valsartan A-Teva is not recommended during breastfeeding due to lack of information on its use during this period. Instead, alternative treatments with a better-established safety profile during breastfeeding should be considered, especially in the case of newborns or preterm infants.
Fertility
No clinical studies have been conducted to evaluate the effect of Valsartan A-Teva on fertility.
Valsartan
Valsartan did not cause adverse effects on reproductive performance in male and female rats following oral administration at doses up to 200 mg/kg/day. This dose is 6 times the maximum recommended human dose based on mg/m² (calculations include oral dose of 320 mg/day and patient body weight of 60 kg).
Amlodipine
Reversible biochemical changes in sperm heads have been reported in some patients receiving calcium channel blockers. There is insufficient clinical data on the potential effect of amlodipine on fertility. Adverse effects on male fertility were observed in one rat study.
Ability to influence reaction speed when driving or operating machinery.
Patients taking Valsartan A-Teva and driving or operating machinery should be aware that dizziness or fatigue may occasionally occur.
Amlodipine may have a mild to moderate effect on the ability to drive or operate machinery. If patients taking amlodipine experience dizziness, headache, fatigue, or nausea, their reaction speed may be impaired.
Method of Administration and Dosage.
For patients whose blood pressure is not adequately controlled with amlodipine or valsartan monotherapy, combination therapy with the medicinal product Valsartan A-Teva may be used.
The recommended dose is 1 tablet daily. Valsartan A-Teva tablets can be taken independently of food, swallowed with a small amount of water.
Before switching to the fixed-dose combination, it is recommended to titrate individual doses of the components (i.e., amlodipine and valsartan). If clinically appropriate, direct transition from monotherapy to the fixed-dose combination may be considered.
For the convenience of patients previously receiving valsartan and amlodipine as separate tablets/capsules, they may be switched to Valsartan A-Teva tablets containing the same component doses.
Maximum daily dose — 1 tablet of 5 mg/80 mg, or 1 tablet of 5 mg/160 mg, or 1 tablet of 10 mg/160 mg (maximum permitted doses of the components in the product — 10 mg amlodipine, 320 mg valsartan).
Renal Impairment
Clinical data in patients with severe renal impairment are lacking. Dose adjustment is not required in patients with mild to moderate renal impairment. In moderate renal impairment, monitoring of potassium and creatinine levels is recommended.
Hepatic Impairment
Valsartan A-Teva is contraindicated in patients with severe hepatic impairment.
Caution should be exercised when prescribing Valsartan A-Teva to patients with hepatic impairment or biliary obstruction. In patients with mild to moderate hepatic impairment without cholestasis, the maximum recommended dose of valsartan is 80 mg. Dose recommendations for amlodipine in patients with mild to moderate hepatic impairment have not been established. When switching such patients with arterial hypertension (see section "Indications") to amlodipine or Valsartan A-Teva, the lowest available dose of amlodipine should be used, either as monotherapy or as a component of a combination medicinal product.
Elderly Patients (≥ 65 years)
Dosage should be increased with caution in elderly patients. When switching such patients with arterial hypertension (see section "Indications") to amlodipine or Valsartan A-Teva, the lowest available dose of amlodipine should be used, either as monotherapy or as a component of a combination medicinal product.
Children.
The safety and efficacy of Valsartan A-Teva in children and adolescents under 18 years of age have not been established. Data on the use of the medicinal product in this patient group are lacking.
Overdose.
Symptoms
Cases of overdose with Valsartan A-Teva have not been reported. The main symptom of valsartan overdose may be marked hypotension with dizziness. Amlodipine overdose may lead to progressive peripheral vasodilation and possibly reflex tachycardia. Cases of marked and potentially prolonged systemic hypotension, including shock and fatal outcomes, have been reported.
Rare cases of non-cardiogenic pulmonary edema following amlodipine overdose have been reported, which may present with delayed onset (24–48 hours after ingestion) and may require mechanical ventilation. Early resuscitative measures (including fluid loading) to support perfusion and cardiac output may act as triggering factors.
Treatment
If the drug has been recently ingested, induction of emesis or gastric lavage should be considered. Absorption of amlodipine is significantly reduced by activated charcoal administered immediately or within two hours after amlodipine intake. Clinically significant hypotension caused by overdose of Valsartan A-Teva requires active cardiovascular support, including frequent monitoring of cardiac and respiratory function, elevation of the limbs, and control of circulating fluid volume and diuresis. A vasoconstrictor agent may be used to restore vascular tone and blood pressure, provided there are no contraindications to its use. Intravenous calcium gluconate may be beneficial in counteracting the effects of calcium channel blockade.
Valsartan and amlodipine are not removed from the body by hemodialysis.
Adverse Reactions
The safety of amlodipine/valsartan was evaluated in five controlled clinical studies. The most commonly observed or significant and serious adverse reactions were: nasopharyngitis, influenza, hypersensitivity, headache, dizziness, orthostatic hypotension, edema, soft tissue swelling, facial swelling, peripheral edema, fatigue, flushing, asthenia, and hot flushes.
Adverse effects that may occur during treatment are classified by frequency as follows: 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); not known (frequency cannot be estimated from the available data).
| MedDRA System Organ Class |
Adverse Reaction |
Frequency |
||
| Amlodipine/valsartan |
Amlodipine |
Valvalsartan |
||
| Infections and infestations |
Nasopharyngitis |
Common |
-- |
-- |
| Influenza |
Common |
-- |
-- |
|
| Blood and lymphatic system disorders |
Decreased hemoglobin and hematocrit levels |
-- |
-- |
Unknown |
| Leukopenia |
-- |
Very rare |
-- |
|
| Neutropenia |
-- |
-- |
Unknown |
|
| Thrombocytopenia, sometimes with purpura |
-- |
Very rare |
Unknown |
|
| Immune system disorders |
Hypersensitivity |
Uncommon |
Very rare |
Unknown |
| Nutritional and metabolic disorders |
Anorexia |
Uncommon |
-- |
-- |
| Hypercalcemia |
Uncommon |
-- |
-- |
|
| Hyperglycemia |
-- |
Very rare |
-- |
|
| Hyperlipidemia |
Uncommon |
-- |
-- |
|
| Hyperuricemia |
Uncommon |
-- |
-- |
|
| Hypokalemia |
Common |
-- |
-- |
|
| Hyponatremia |
Uncommon |
-- |
-- |
|
| Psychiatric disorders |
Depression |
-- |
Uncommon |
-- |
| Anxiety |
Uncommon |
-- |
-- |
|
| Insomnia/sleep disorders |
-- |
Uncommon |
-- |
|
| Mood swings |
-- |
Uncommon |
-- |
|
| Confusion |
-- |
Uncommon |
-- |
|
| Nervous system disorders |
Coordination disturbance |
Uncommon |
-- |
-- |
| Dizziness |
Uncommon |
Common |
-- |
|
| Postural dizziness |
Uncommon |
-- |
-- |
|
| Dysgeusia |
-- |
Uncommon |
-- |
|
| Extrapyramidal syndrome |
-- |
Unknown |
-- |
|
| Extrapyramidal disorder |
-- |
Unknown |
-- |
|
| Headache |
Common |
Common |
-- |
|
| Hypertonia |
-- |
Very rare |
-- |
|
| Paraesthesia |
Uncommon |
Uncommon |
-- |
|
| Peripheral neuropathy, neuropathy |
-- |
Very rare |
-- |
|
| Somnolence |
Uncommon |
Common |
-- |
|
| Fainting |
-- |
Uncommon |
-- |
|
| Tremor |
-- |
Uncommon |
-- |
|
| Hypoesthesia |
-- |
Uncommon |
-- |
|
| Eye disorders |
Visual disturbance |
Uncommon |
Uncommon |
-- |
| Blurred vision |
Uncommon |
Uncommon |
-- |
|
| Ear and labyrinth disorders |
Tinnitus |
Uncommon |
Uncommon |
-- |
| Vertigo |
Uncommon |
-- |
Uncommon |
|
| Cardiac disorders |
Palpitations |
Uncommon |
Common |
-- |
| Fainting |
Uncommon |
-- |
-- |
|
| Tachycardia |
Uncommon |
-- |
-- |
|
| Arrhythmia (including bradycardia, ventricular tachycardia, atrial fibrillation) |
-- |
Very rare |
-- |
|
| Myocardial infarction |
-- |
Very rare |
-- |
|
| Vascular disorders |
Flushing |
-- |
Common |
-- |
| Arterial hypotension |
Uncommon |
Uncommon |
-- |
|
| Orthostatic hypotension |
Uncommon |
-- |
-- |
|
| Vasculitis |
-- |
Very rare |
Unknown |
|
| Respiratory, thoracic and mediastinal disorders |
Cough |
Uncommon |
Very rare |
Uncommon |
| Dyspnea |
-- |
Uncommon |
-- |
|
| Pharyngolaryngeal pain |
Uncommon |
-- |
-- |
|
| Rhinitis |
-- |
Uncommon |
-- |
|
| Gastrointestinal disorders |
Abdominal discomfort and upper abdominal pain |
Uncommon |
Common |
Uncommon |
| Change in defecation rhythm |
-- |
Uncommon |
-- |
|
| Constipation |
Uncommon |
-- |
-- |
|
| Diarrhea |
Uncommon |
Uncommon |
-- |
|
| Dry mouth |
Uncommon |
Uncommon |
-- |
|
| Dyspepsia |
-- |
Uncommon |
-- |
|
| Gastritis |
-- |
Very rare |
-- |
|
| Gingival hyperplasia |
-- |
Very rare |
-- |
|
| Nausea |
Uncommon |
Common |
-- |
|
| Pancreatitis |
-- |
Very rare |
-- |
|
| Vomiting |
-- |
Uncommon |
-- |
|
| Hepatobiliary disorders |
Atypical liver function tests, including increased blood bilirubin levels |
-- |
Very rare* |
Unknown |
| Hepatitis |
-- |
Very rare |
-- |
|
| Intrahepatic cholestasis, jaundice |
-- |
Very rare |
-- |
|
| Skin and subcutaneous tissue disorders |
Alopecia |
-- |
Uncommon |
-- |
| Angioedema |
-- |
Very rare |
Unknown |
|
| Bullous dermatitis |
-- |
-- |
Unknown |
|
| Erythema |
Uncommon |
-- |
-- |
|
| Multiform erythema |
-- |
Very rare |
-- |
|
| Exanthema |
Uncommon |
Uncommon |
-- |
|
| Hyperhidrosis |
Uncommon |
Uncommon |
-- |
|
| Photosensitivity reaction |
-- |
Uncommon |
-- |
|
| Pruritus |
Uncommon |
Uncommon |
Unknown |
|
| Purpura |
-- |
Uncommon |
-- |
|
| Rash |
Uncommon |
Uncommon |
Unknown |
|
| Skin discoloration |
-- |
Uncommon |
-- |
|
| Urticaria and other forms of rash |
-- |
Very rare |
-- |
|
| Exfoliative dermatitis |
-- |
Very rare |
-- |
|
| Stevens-Johnson syndrome |
-- |
Very rare |
-- |
|
| Quincke's edema |
-- |
Very rare |
-- |
|
| Toxic epidermal necrolysis |
-- |
Unknown |
-- |
|
| Musculoskeletal and connective tissue disorders |
Arthralgia |
Uncommon |
Uncommon |
-- |
| Back pain |
Uncommon |
Uncommon |
-- |
|
| Joint swelling |
Uncommon |
-- |
-- |
|
| Muscle cramps |
Uncommon |
Uncommon |
-- |
|
| Muscle pain |
-- |
Uncommon |
Unknown |
|
| Ankle swelling |
-- |
Common |
-- |
|
| Heaviness sensation |
Uncommon |
-- |
-- |
|
| Renal and urinary disorders |
Increased blood creatinine levels |
-- |
-- |
Unknown |
| Urination disorder |
-- |
Uncommon |
-- |
|
| Nocturia |
-- |
Uncommon |
-- |
|
| Frequency of urination |
Uncommon |
Uncommon |
-- |
|
| Polyuria |
Uncommon |
-- |
-- |
|
| Renal failure and impaired kidney function |
-- |
-- |
Unknown |
|
| Reproductive system and breast disorders |
Impotence |
-- |
Uncommon |
-- |
| Erectile dysfunction |
Uncommon |
-- |
-- |
|
| Gynecomastia |
-- |
Uncommon |
-- |
|
| General disorders |
Asthenia |
Common |
Uncommon |
-- |
| Discomfort, malaise |
-- |
Uncommon |
-- |
|
| Increased fatigue |
Common |
Common |
Uncommon |
|
| Facial swelling |
Common |
-- |
-- |
|
| Flushing, hot flushes |
Common |
-- |
-- |
|
| Chest pain, non-cardiac |
-- |
Uncommon |
-- |
|
| Edema |
Common |
Common |
-- |
|
| Peripheral edema |
Common |
-- |
-- |
|
| Pain |
-- |
Uncommon |
-- |
|
| Soft tissue swelling |
Common |
-- |
-- |
|
| Investigations |
Increased blood potassium levels |
-- |
-- |
Unknown |
| Increased body weight |
-- |
Uncommon |
-- |
|
| Decreased body weight |
-- |
Uncommon |
-- |
|
Mainly associated with cholestasis.
Additional information on the combination
Peripheral edema, a known side effect of amlodipine, was generally reported less frequently in patients treated with Valsartan A-Teva than with amlodipine alone. In double-blind controlled clinical trials, the average incidence of peripheral edema, evenly distributed across the entire dose range, was 5.1% with amlodipine/valsartan combination therapy.
Additional information on the components of the medicinal product
Adverse reactions previously observed with either component of the drug (amlodipine or valsartan) may also occur with Valsartan A-Teva, even if they were not reported during clinical trials or in the post-marketing period.
Amlodipine
Common: somnolence, dizziness, palpitations, abdominal pain, nausea, ankle swelling.
Uncommon: insomnia, mood changes (including anxiety), depression, tremor, dysgeusia, syncope, hypesthesia, visual disturbances (including diplopia), tinnitus, arterial hypotension, dyspnea, rhinitis, vomiting, dyspepsia, alopecia, purpura, skin discoloration, increased sweating, pruritus, exanthema, muscle pain, muscle spasms, pain, urinary disorders, increased frequency of urination, impotence, gynecomastia, breast pain, malaise, weight gain, weight loss.
Rare: confusion.
Very rare: leukopenia, thrombocytopenia, allergic reactions, hyperglycemia, hypertension, peripheral neuropathy, myocardial infarction, arrhythmia (including bradycardia, ventricular tachycardia, and atrial fibrillation), vasculitis, pancreatitis, gastritis, gingival hyperplasia, hepatitis, jaundice, elevated liver enzymes (mainly associated with cholestasis), angioedema, erythema multiforme, urticaria, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke's edema, photosensitivity.
Exceptional cases of extrapyramidal syndrome have been reported.
Valsartan
Not known: decreased hemoglobin, decreased hematocrit, neutropenia, thrombocytopenia, increased serum potassium levels, elevated liver function tests, including serum bilirubin, renal failure and impaired kidney function, increased serum creatinine levels, angioedema, myalgia, vasculitis, hypersensitivity, including serum sickness.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after medicinal product authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report all suspected adverse reactions and lack of efficacy to the State Expert Center of the Ministry of Health of Ukraine via the following link: https://aisf.dec.gov.ua/.
Shelf life. 3 years.
Storage conditions. Store at temperatures not exceeding 30 °C. Keep out of reach of children.
Packaging.
7 tablets per blister, 2 or 4 blisters per carton;
10 tablets per blister, 3 or 9 blisters per carton.
Prescription status. Prescription only.
Manufacturer. Balkanpharma-Dupnitsa AD.
Manufacturer's address and location of operations.
3 Samokovsko Shose Str., Dupnitsa, 2600, Bulgaria.