Diovan
Ukraine
Table of Contents
- INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DIOVAN® (DIOVAN®)
- Composition:
- Pharmacological properties.
- Clinical characteristics.
- Special precautions for use.
- Method of Administration and Dosage
- Adverse Reactions
- reported by patients with heart failure
- reported more frequently by patients with heart failure (frequent: dizziness, renal dysfunction, hypotension; infrequent: headache, nausea)
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DIOVAN® (DIOVAN®)
Composition:
Active substance: valsartan;
1 tablet contains 80 mg or 160 mg of valsartan;
Excipients: microcrystalline cellulose, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate, hypromellose, titanium dioxide (E 171), macrogol 8000, iron oxide red (E 172), iron oxide yellow (E 172), iron oxide black (E 172) – only for 160 mg tablets.
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties:
Diovan® 80 mg: pale red, round, film-coated tablets with bevelled edges, with a score line on one side, marked (imprinted) with "D" on one side of the score line and "V" on the other, and the marking (imprint) "NVR" on the reverse side of the tablet.
Diovan® 160 mg: grey-orange, oval, film-coated tablets, slightly convex in shape, with a score line on one side, marked (imprinted) with "DX" on one side of the score line and "DX" on the other, and the marking (imprint) "NVR" on the reverse side of the tablet.
Pharmacotherapeutic group. Simple angiotensin II antagonists.
ATC code C09CA03.
Pharmacological properties.
Pharmacodynamics.
Valsartan is an active specific angiotensin II receptor antagonist intended for oral administration. It acts selectively on AT1 receptors, which are responsible for the known effects of angiotensin II. Increased plasma levels of angiotensin II following blockade of AT1 receptors by valsartan may stimulate unblocked AT2 receptors, which counterbalance the effect of AT1 receptors. Valsartan exhibits no partial agonist activity at the AT1 receptor, but has much greater (approximately 20,000 times) affinity for the AT1 receptor than for the AT2 receptor.
Valsartan does not inhibit ACE (angiotensin-converting enzyme), also known as kininase II, which converts angiotensin I to angiotensin II and degrades bradykinin. Administration of the drug to patients with arterial hypertension leads to a reduction in arterial blood pressure without affecting pulse rate.
The onset of antihypertensive effect occurs within 2 hours, reaching maximum effect within 4–6 hours after oral administration; duration of action lasts more than 24 hours. Maximum therapeutic effect develops within 4 weeks of starting treatment and is maintained during long-term therapy. When used in combination with hydrochlorothiazide, a significant additional reduction in arterial blood pressure is achieved.
Sudden discontinuation of the drug does not lead to withdrawal syndrome.
Long-term administration of the drug to patients with arterial hypertension has shown no significant effect on total cholesterol levels, uric acid, or on fasting serum concentrations of triglycerides and glucose.
Administration of the drug reduces hospitalization due to heart failure, slows progression of heart failure, improves functional class according to NYHA classification, increases ejection fraction, and reduces symptoms of heart failure as well as improves quality of life compared to placebo.
The VALIANT trial demonstrated that valsartan, like captopril, reduces overall mortality after myocardial infarction. Valsartan was also effective in reducing cardiovascular mortality and hospitalizations due to heart failure, as well as recurrent myocardial infarction. Valsartan positively influenced the time period from the acute myocardial infarction to the first occurrence of cardiovascular events leading to fatal outcomes.
Children
The antihypertensive effect of valsartan was evaluated in 4 randomized, double-blind clinical trials involving 561 children aged 6 to 18 years and 165 children aged 1 to 6 years. Renal and urinary tract disorders and obesity were the most common underlying medical conditions causing arterial hypertension in children included in these studies.
Clinical experience in children aged 6 years and older
In a clinical study involving 261 children with arterial hypertension aged 6 to 16 years, patients with body weight < 35 kg received 10, 40, or 80 mg of valsartan per day (low, medium, and high doses), while patients with body weight ≥ 35 kg received 20, 80, and 160 mg of valsartan per day (low, medium, and high doses). At the end of 2 weeks, valsartan reduced systolic and diastolic blood pressure in a dose-dependent manner. Overall, the three dose levels of valsartan (low, medium, and high) significantly reduced systolic blood pressure by 8, 10, and 12 mm Hg from baseline, respectively.
Clinical experience in children under 6 years of age
Valsartan is not recommended for use in this age group.
Pharmacokinetics.
Absorption
After oral administration of valsartan, maximum plasma concentrations (Cmax) are reached within 2–4 hours; when administered as a solution, within 1–2 hours. The mean absolute bioavailability of the tablet and solution formulations is 23% and 39%, respectively.
Food reduces exposure (as defined by AUC) to valsartan by approximately 40% and maximum plasma concentration (Cmax) by approximately 50%, although plasma concentrations of valsartan starting at approximately 8 hours after dosing are similar between fasting and fed conditions. However, the reduction in AUC is not clinically associated with a significant reduction in therapeutic effect; therefore, valsartan can be administered with or without food.
Distribution
The volume of distribution of valsartan at steady state 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.
Biological transformation
Valsartan is not significantly metabolized, as only about 20% of the dose is excreted as metabolites. A hydroxymetabolite has been identified in plasma at low concentrations (less than 10% of the AUC of valsartan). This metabolite is pharmacologically inactive.
Elimination
The pharmacokinetic curve of valsartan is multiphasic (T½α <1 hour and T½ß approximately 9 hours). Valsartan is primarily eliminated via bile into feces (approximately 83% of the dose) and via kidneys into urine (approximately 13% of the dose), mainly in unchanged form. After intravenous administration, the plasma clearance of valsartan is approximately 2 L/h, and renal clearance is 0.62 L/h (about 30% of total clearance). The elimination half-life of valsartan is 6 hours.
Patients with heart failure (80 mg and 160 mg tablets)
The mean time to reach Cmax and elimination half-life of valsartan in patients with heart failure are similar to those in healthy volunteers. AUC and Cmax values of valsartan are nearly proportional to dose increases above the clinical dose range (from 40 to 160 mg twice daily). The mean accumulation ratio is approximately 1.7. Predicted clearance of valsartan after oral administration is approximately 4.5 L/h. Age does not affect predicted clearance in patients with heart failure.
Pharmacokinetics in specific patient populations
Elderly patients. In some elderly patients, systemic exposure to valsartan was slightly higher than in younger patients, although no clinical significance of this has been demonstrated.
Patients with renal impairment. No correlation was observed between renal function and systemic exposure to valsartan. Therefore, dose adjustment is not required in patients with impaired renal function (creatinine clearance > 10 mL/min). Currently, there are no data on the safety of valsartan in patients with creatinine clearance < 10 mL/min or in patients undergoing dialysis; thus, valsartan should be used with caution in these patients. Valsartan is highly bound to plasma proteins, and removal by hemodialysis is unlikely.
Patients with hepatic impairment. Approximately 70% of the absorbed dose is excreted via bile, primarily in unchanged form. Valsartan undergoes no significant biotransformation, and systemic exposure to valsartan is not expected to correlate with the degree of hepatic dysfunction. Therefore, dose adjustment of valsartan is not required in patients with non-biliary liver insufficiency and in the absence of cholestasis. It has been shown that in patients with biliary cirrhosis or biliary obstruction, the AUC of valsartan increases approximately twofold.
Children
In a study involving 26 children with arterial hypertension (aged 1 to 16 years) who received a single dose of valsartan suspension (mean dose 0.9–2 mg/kg, maximum dose 80 mg), clearance (L/h/kg) of valsartan was comparable across the entire age range of 1 to 16 years to that observed in adults receiving the same drug.
Patients with renal impairment
The use of valsartan in children with creatinine clearance < 30 mL/min and in children undergoing dialysis has not been studied; therefore, valsartan is not recommended for such patients. Dose adjustment is not required in children with creatinine clearance > 30 mL/min. Renal function and serum potassium levels should be carefully monitored.
Clinical characteristics.
Indications.
Arterial hypertension.
Treatment of arterial hypertension in adults and children aged 6 to 18 years.
Post-infarction state.
Treatment of clinically stable adult patients with symptomatic heart failure or asymptomatic left ventricular systolic dysfunction following a recent (12 hours – 10 days) myocardial infarction.
Heart failure.
Treatment of symptomatic heart failure in adult patients when angiotensin-converting enzyme (ACE) inhibitors cannot be used, or as adjunctive therapy with ACE inhibitors when beta-blockers cannot be used.
Contraindications.
- Hypersensitivity to valsartan or to any excipient.
- Pregnancy or planned pregnancy (see "Use during pregnancy or breastfeeding").
- Hereditary or ACE inhibitor- or angiotensin II receptor antagonist-induced angioedema.
- Concomitant use of angiotensin receptor antagonists, including Diovan®, or ACE inhibitors with aliskiren in patients with diabetes (type 1 or type 2) or renal impairment (glomerular filtration rate (GFR) < 60 mL/min).
- No data are available in patients with severe renal impairment (creatinine clearance less than 10 mL/min).
Interaction with other medicinal products and other forms of interaction.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS) with ARB, ACE inhibitors or aliskiren
Concomitant use of ARB agents, including Diovan®, with other drugs acting on the RAAS is associated with an increased incidence of hypotension, syncope, hyperkalaemia, and changes in renal function (including acute renal failure) compared to monotherapy. Dual blockade of the RAAS by combining ACE inhibitors, ARBs, or aliskiren is therefore not recommended. If dual RAAS blockade therapy is considered absolutely necessary, it should be undertaken only under specialist supervision with close monitoring of renal function, electrolyte levels, and blood pressure.
Concomitant use of angiotensin receptor antagonists, including Diovan®, or ACE inhibitors with aliskiren in patients with diabetes or renal impairment (glomerular filtration rate (GFR) < 60 mL/min) is contraindicated.
Concomitant use of ARBs, including Diovan®, or ACE inhibitors with aliskiren is contraindicated in patients with type 1 or type 2 diabetes.
ACE inhibitors, including Diovan®, and ARBs should not be used concomitantly in patients with diabetic nephropathy.
Concomitant use not recommended
Lithium
Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant 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 is considered necessary, careful monitoring of serum lithium levels is recommended.
Potassium
Potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, potassium-containing salt substitutes, and other medicinal products that may increase potassium levels (e.g., heparin, etc.) may lead to increased serum potassium levels, and in patients with heart failure, to increased creatinine levels.
If concomitant use of a medicinal product affecting potassium levels is considered necessary with valsartan, monitoring of plasma potassium levels is recommended.
Caution required 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 antagonists with NSAIDs may attenuate the antihypertensive effect. Furthermore, concomitant use of angiotensin II antagonists and NSAIDs may increase the risk of worsening renal function and elevated serum potassium levels. Therefore, monitoring of renal function and adequate patient hydration are recommended at the start of treatment.
Transporters
In vitro studies indicate that valsartan is a substrate of the hepatic uptake transporters OATP1B1/OATP1B3 and the hepatic efflux transporter MRP2. The clinical relevance of these findings is unknown. Concomitant use with inhibitors of OATP1B1 transporters (e.g., rifampicin, cyclosporine) or MRP2 (e.g., ritonavir) may increase systemic exposure to valsartan. Appropriate precautions should be taken at the initiation and discontinuation of concomitant use of these medicinal products.
Other
No clinically relevant interactions with valsartan or any of the following substances were observed in drug interaction studies: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, glyburide.
Children
Caution is recommended when administering valsartan concomitantly with other drugs that inhibit the renin-angiotensin-aldosterone system in children and adolescents with arterial hypertension, as this may increase serum potassium levels. Renal function and serum potassium levels should be carefully monitored.
Special precautions for use.
Hyperkalemia
Concomitant use of potassium supplements, potassium-sparing diuretics, potassium-containing salt substitutes, or other agents that may increase potassium levels (e.g., heparin, etc.) is not recommended. If necessary, potassium levels should be monitored.
Renal impairment. There are no safety data available on the use of the drug in patients with creatinine clearance < 10 mL/min or in patients undergoing dialysis; therefore, valsartan should be used with caution in such patients. Dose adjustment is not required in adult patients with creatinine clearance > 10 mL/min.
Concomitant use of angiotensin II receptor antagonists, including Diovan®, or angiotensin-converting enzyme (ACE) inhibitors with aliskiren in patients with impaired renal function (glomerular filtration rate (GFR) < 60 mL/min/1.73 m²) is contraindicated.
Hepatic impairment. Diovan® should be used with caution in patients with mild to moderate hepatic impairment without cholestasis.
Patients with sodium and/or circulating blood volume (CBV) depletion. In patients with severe sodium and/or circulating blood volume depletion, e.g., those receiving high doses of diuretics, symptomatic arterial hypotension may occur after initiation of therapy with Diovan®. Prior to starting Diovan® therapy, correction of sodium and/or circulating blood volume should be performed, for example, by reducing the diuretic dose.
Renal artery stenosis. The safety of using Diovan® in patients with bilateral renal artery stenosis or stenosis of the artery of a solitary kidney has not been established. Short-term use of Diovan® in 12 patients with renovascular hypertension secondary to unilateral renal artery stenosis did not cause any significant changes in renal hemodynamic parameters, serum creatinine, or blood urea nitrogen. Since other medicinal products affecting the renin-angiotensin-aldosterone system (RAAS) may increase blood urea and serum creatinine in patients with unilateral renal artery stenosis, monitoring of renal function is recommended as a safety measure during treatment with valsartan.
Kidney transplantation
Currently, there are no data on the safety of using Diovan® in patients who have recently undergone kidney transplantation.
Primary hyperaldosteronism
Diovan® should not be used in patients with primary hyperaldosteronism, as the renin-angiotensin system is not activated in these patients.
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy
As with other vasodilators, the drug should be administered with particular caution in patients with aortic or mitral valve stenosis or obstructive hypertrophic cardiomyopathy.
Pregnancy
Angiotensin II receptor antagonists are contraindicated during pregnancy. If continued treatment with the drug is considered necessary, women planning pregnancy should switch to alternative antihypertensive agents with an established safety profile for use during pregnancy. If pregnancy is confirmed, treatment should be discontinued immediately and, if necessary, alternative therapy should be initiated.
Recent myocardial infarction
The combination of captopril and valsartan did not demonstrate additional clinical benefit, while the risk of adverse reactions increased compared to monotherapy with the respective drugs. Therefore, combination of valsartan with an ACE inhibitor is not recommended.
Caution should be exercised in patients after myocardial infarction. Evaluation of patients after myocardial infarction should always include assessment of renal function.
Use of Diovan® in patients after myocardial infarction often leads to some reduction in blood pressure, which usually results in the need to discontinue therapy due to persistent symptomatic arterial hypotension, despite adherence to dosing instructions.
Heart failure
In patients with heart failure, triple combination therapy with an ACE inhibitor, beta-blocker, and Diovan® did not show any clinical benefit. This combination is likely to increase the risk of adverse effects and therefore is not recommended. Triple combination of ACE inhibitors, mineralocorticoid receptor antagonists, and valsartan is also not recommended.
Such combinations may be used only under specialist supervision and with careful monitoring of renal function, electrolyte levels, and blood pressure.
Safety and efficacy of Diovan® in children have not been studied.
History of angioedema
Angioedema, including laryngeal and glottis edema leading to airway obstruction and/or facial, lip, pharyngeal, and/or tongue swelling, has been reported in patients receiving valsartan. Some of these patients had previously experienced angioedema during treatment with other drugs, including ACE inhibitors. Angioedema requires immediate discontinuation of Diovan®; re-administration of Diovan® to such patients is not recommended.
Other conditions involving stimulation of the renin-angiotensin system
In patients in whom 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 some cases, acute renal failure and/or fatal outcomes. Since valsartan is an angiotensin II antagonist, renal function impairment cannot be ruled out with the use of Diovan®.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
Concomitant use of ARBs, including Diovan®, with other drugs acting on the RAAS is associated with increased incidence of arterial hypotension, hyperkalemia, and renal function changes compared to monotherapy. Monitoring of blood pressure, renal function, and electrolyte levels is recommended in patients receiving Diovan® and other RAAS-affecting drugs.
Children
Renal impairment
Use in children with creatinine clearance < 30 mL/min or in children undergoing dialysis has not been studied; therefore, valsartan is not recommended for such patients. Dose adjustment is not required in children with creatinine clearance > 30 mL/min. Renal function and serum potassium levels should be carefully monitored during treatment with valsartan, particularly in cases where valsartan is used in the presence of other conditions (e.g., high fever, dehydration) that may impair renal function.
Concomitant use of angiotensin receptor antagonists, including Diovan®, or ACE inhibitors with aliskiren in patients with impaired renal function (glomerular filtration rate (GFR) < 60 mL/min/1.73 m²) is contraindicated.
Hepatic impairment
As in adults, Diovan® is contraindicated in children with severe hepatic impairment, biliary cirrhosis, or cholestasis. Clinical experience with Diovan® in children with mild to moderate hepatic impairment is limited. The dose of valsartan should not exceed 80 mg in such patients.
Use during pregnancy or breastfeeding
Use of angiotensin II receptor antagonists (ARBs) is contraindicated in pregnant women or women planning pregnancy.
Epidemiological data on the teratogenic risk associated with ACE inhibitor use during the first trimester of pregnancy are inconclusive, but a small increased risk cannot be excluded. Since there are no controlled epidemiological data on the risk of angiotensin II receptor antagonists, a teratogenic risk may also exist for this class of drugs. Except when continuation of therapy is considered necessary, women planning pregnancy should be switched to alternative antihypertensive therapy with an established safety profile during pregnancy. If pregnancy is diagnosed, treatment with angiotensin II receptor antagonists should be discontinued immediately and, if necessary, replaced with a drug approved for use in pregnant women.
It is known that use of angiotensin II receptor antagonists during the second and third trimesters of pregnancy induces human fetotoxicity (impaired renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia).
If ARBs have been used from the second trimester of pregnancy, ultrasound examination is recommended to assess renal function and skull condition.
Newborns of mothers who used ARBs should be carefully monitored for the development of arterial hypotension.
Due to lack of information on valsartan use during breastfeeding, Diovan® is not recommended for use in breastfeeding women.
Fertility
Valsartan at doses up to 200 mg/kg/day did not cause adverse effects on reproductive function in rats. The dose of 200 mg/kg/day is 6 times higher than the maximum recommended human dose, adjusted by mg/m² (based on oral dose of 320 mg/day in a 60 kg patient).
Ability to affect reaction rate while driving or operating machinery
Studies on the effect on the ability to drive vehicles or operate machinery have not been conducted. It should be borne in mind that dizziness or weakness may occur during treatment with the drug.
Method of Administration and Dosage
Method of Administration
Diovan® can be administered regardless of food intake; tablets should be taken with water.
Dosage
Arterial Hypertension
The recommended initial dose of Diovan® is 80 mg once daily. Antihypertensive effect is achieved within 2 weeks, and maximum effect within 4 weeks. For some patients with inadequately controlled blood pressure, the dose may be increased to 160 mg and up to the maximum dose of 320 mg.
Diovan® may also be used in combination with other antihypertensive agents. Concomitant use of diuretics, such as hydrochlorothiazide, will further reduce blood pressure in these patients.
Recent Myocardial Infarction
Treatment may be initiated in clinically stable patients as early as 12 hours after myocardial infarction. After an initial dose of valsartan 20 mg (tablets must not be split into equal doses; dosage forms with appropriate strengths should be taken) twice daily, the dose should be increased to 40 mg (tablets must not be split into equal doses; dosage forms with appropriate strengths should be taken), 80 mg, and then 160 mg twice daily over the following weeks.
The target maintenance dose is 160 mg twice daily. It is generally recommended that the dose of 80 mg twice daily be reached within 2 weeks of starting treatment, and the maximum dose of 160 mg twice daily be achieved within 3 months, depending on patient tolerance. If symptomatic arterial hypotension or renal dysfunction occurs, dose reduction should be considered.
Valsartan may be used in patients who have been treated with other post-myocardial infarction therapies, such as thrombolytics, acetylsalicylic acid, beta-blockers, statins, and diuretics. Combination with ACE inhibitors is not recommended.
Patients after myocardial infarction require regular monitoring of renal function.
Heart Failure
The recommended initial dose of valsartan is 40 mg (tablets must not be split into equal doses; dosage forms with appropriate strengths should be taken) twice daily. Gradual dose escalation to 80 mg and then to 160 mg twice daily should be performed at intervals of at least 2 weeks, depending on patient tolerance, up to the highest tolerated dose. Consideration should be given to reducing the dose of concomitant diuretics. The maximum daily dose used in clinical trials was 320 mg, divided into multiple doses.
Valsartan may be used in combination with other heart failure medications. However, triple combination of an ACE inhibitor, a beta-blocker, and valsartan is not recommended.
Patients with heart failure require monitoring of renal function.
Use in Specific Patient Populations
Elderly Patients
No dose adjustment is required for elderly patients.
Renal Impairment
No dose adjustment is required for adult patients with creatinine clearance > 10 mL/min. Concomitant use of Diovan® with aliskiren in patients with impaired renal function (glomerular filtration rate (GFR) < 60 mL/min/1.73 m²) is contraindicated.
Diabetes Mellitus
Concomitant use of Diovan® with aliskiren in patients with diabetes mellitus is contraindicated.
Hepatic Impairment
Diovan® is contraindicated in patients with severe hepatic impairment, biliary cirrhosis, and in patients with cholestasis. For patients with mild to moderate hepatic impairment without cholestasis, the dose of valsartan should not exceed 80 mg.
Children
Diovan® is used for the treatment of arterial hypertension in children aged 6 to 18 years. Safety and efficacy of Diovan® in children aged 1 to 6 years have not been established. The drug is not recommended for the treatment of heart failure or post-myocardial infarction conditions in children due to lack of safety and efficacy data.
Arterial Hypertension in Children
Children and adolescents aged 6 to 18 years
The initial dose is 40 mg (tablets must not be split into equal doses; dosage forms with appropriate strengths should be taken) once daily for children with body weight below 35 kg, and 80 mg once daily for children with body weight of 35 kg or more. Dose should be adjusted according to blood pressure response. Maximum doses studied in clinical trials are shown in Table 1.
Doses higher than those specified have not been studied and are therefore not recommended.
Table 1
| Patient body weight |
Maximum dose of Deuvant® investigated in clinical trials |
||
| From ≥ 18 kg to < 35 kg |
80 mg |
||
| From ≥ 35 kg to < 80 kg |
160 mg |
||
| From ≥ 80 kg to ≤ 160 kg |
320 mg |
Children under 6 years of age
The safety and efficacy of Diovan® in children aged 1 to 6 years have not been established.
Children aged 6 to 18 years with renal impairment
Use in children with creatinine clearance < 30 mL/min and in children undergoing dialysis has not been studied; therefore, valsartan is not recommended for such patients. Dose adjustment is not required in children with creatinine clearance > 30 mL/min. Renal function and serum potassium levels should be closely monitored.
Children aged 6 to 18 years with hepatic impairment
As with adults, Diovan® is contraindicated in children with severe hepatic impairment, biliary cirrhosis, and in patients with cholestasis. Clinical experience with Diovan® in children with mild to moderate hepatic impairment is limited. The dose of valsartan should not exceed 80 mg in such patients.
Heart failure and recent myocardial infarction in children
Diovan® is not recommended for the treatment of heart failure or recent myocardial infarction in children due to lack of data on safety and efficacy.
Overdose.
Following an overdose of Diovan®, marked hypotension may develop, which could lead to decreased level of consciousness, circulatory collapse, and/or shock. Therapeutic measures depend on the time of ingestion and the type and severity of symptoms; primary importance is given to stabilization of circulation. If hypotension occurs, the patient should be placed in a supine position and blood volume should be corrected.
It is unlikely that valsartan can be removed from the body by hemodialysis.
Adverse Reactions
Arterial hypertension/heart failure/myocardial infarction
During controlled clinical trials in adult patients with arterial hypertension, the incidence of adverse reactions was similar between those receiving placebo and those receiving valsartan. The incidence of adverse reactions was found to be unrelated to dose or duration of treatment, and was independent of patient's sex, age, or race.
Adverse reactions identified during clinical, post-marketing, and laboratory studies are listed below by system organ classes.
With regard to adverse reactions categorized as "very rare," "rare," and "uncommon," which were not detected during clinical trials, a cumulative search was conducted in the safety database.
The frequency of adverse reactions is defined as follows: very common (> 1/10),
common (> 1/100, < 1/10), uncommon (> 1/1000, < 1/100), rare (> 1/10000, < 1/1000),
very rare (< 1/100000), including isolated case reports. Within each frequency group, adverse reactions are listed in order of decreasing severity.
Adverse reactions identified during post-marketing and laboratory studies, for which frequency cannot be estimated reliably, are listed as "not known."
Table 2
| Infections |
||||
| Common |
Viral infections |
|||
| Uncommon |
Upper respiratory tract infections, pharyngitis, sinusitis |
|||
| Very rare |
Rhinitis |
|||
| Blood and lymphatic system disorders |
||||
| Uncommon |
Neutropenia |
|||
| Very rare |
Thrombocytopenia |
|||
| Immune system disorders |
||||
| Very rare |
Hypersensitivity reactions, including serum sickness |
|||
| Metabolism and nutrition disorders |
||||
| Uncommon |
Hyperkalemia*# |
|||
| Psychiatric disorders |
||||
| Uncommon |
Insomnia, decreased libido |
|||
| Nervous system disorders |
||||
| Common |
Dizziness##, Postural dizziness# |
|||
| Uncommon |
Syncope* |
|||
| Very rare |
Headache## |
|||
| Ear and labyrinth disorders |
||||
| Uncommon |
Vertigo |
|||
| Cardiac disorders |
||||
| Uncommon |
Heart failure* |
|||
| Very rare |
Cardiac rhythm disorders |
|||
| Vascular disorders |
||||
| Common |
Orthostatic hypotension# |
|||
| Uncommon |
Hypotension*## |
|||
| Very rare |
Vasculitis |
|||
| Respiratory system disorders |
||||
| Uncommon |
Cough |
|||
| Gastrointestinal disorders |
||||
| Uncommon |
Diarrhea, abdominal pain |
|||
| Very rare |
Nausea##, vomiting |
|||
| Hepatobiliary disorders |
||||
| Not known |
Increased liver function tests, including increased serum bilirubin levels |
|||
| Skin and subcutaneous tissue disorders |
||||
| Very rare |
Angioedema**, rash, pruritus, exanthema |
|||
| Not known |
Bullous dermatitis |
|||
| Musculoskeletal and connective tissue disorders |
||||
| Uncommon |
Back pain |
|||
| Very rare |
Arthralgia, myalgia |
|||
| Renal and urinary disorders |
||||
| Very rare |
Renal failure**##, acute renal failure**, renal dysfunction** |
|||
| Pregnancy and perinatal conditions |
||||
| Very rare |
Fetal developmental complications |
|||
| General disorders |
||||
| Uncommon |
Fatigue, asthenia, edema |
|||
| Investigations |
||||
| Common |
Increased serum creatinine levels, increased blood urea levels |
|||
| Very rare |
Elevated serum bilirubin levels, decreased hemoglobin/hematocrit levels, liver function parameters outside normal range. |
|||
* reported by patients in post-infarction condition
reported by patients with heart failure
** infrequently reported by patients in post-infarction condition
reported more frequently by patients with heart failure (frequent: dizziness, renal dysfunction, hypotension; infrequent: headache, nausea)
Laboratory findings
In isolated cases, valsartan caused a decrease in hemoglobin levels and hematocrit count. In controlled clinical trials, significant reduction (> 20%) in hematocrit count and hemoglobin level was observed in 0.8% and 0.4% of patients receiving Diovan®, respectively. In comparison, reduction in both parameters – hematocrit count and hemoglobin level – was noted in 0.1% of placebo-treated patients.
Neutropenia was observed in 1.9% of patients treated with valsartan and in 1.6% of patients treated with an ACE inhibitor in controlled clinical trials.
In controlled clinical trials involving patients with arterial hypertension, significant increases in serum creatinine, potassium, and total bilirubin levels were observed in 0.8%, 4.4%, and 6% of patients treated with valsartan, respectively, compared to 1.6%, 6.4%, and 12.9% of patients treated with an ACE inhibitor.
Isolated cases of increased liver function parameters have been reported in patients treated with valsartan.
Patients with arterial hypertension receiving valsartan therapy do not require any specific laboratory monitoring.
In cases of heart failure, serum creatinine levels increased by more than 50% in 3.9% of patients taking valsartan, compared to 0.9% of patients taking placebo; and serum potassium levels increased by more than 20% in 10% of patients taking valsartan, compared to 5.1% of patients taking placebo.
In heart failure studies, increased blood urea nitrogen levels were observed in 16.6% of patients taking valsartan, compared to 6.3% of patients taking placebo.
Serum creatinine levels doubled in 4.2% of patients receiving valsartan, in 4.8% of patients treated with a combination of valsartan and captopril, and in 3.4% of patients treated with captopril during the post-infarction period.
The number of cases of discontinuation of the drug due to adverse reactions was lower in the valsartan-treated group compared to the captopril group (5.8% vs. 7.7%, respectively).
Pediatric population
Arterial hypertension
The antihypertensive effect of valsartan was evaluated in two randomized, double-blind clinical trials involving 561 children aged 6 to 18 years. Except for isolated gastrointestinal disorders (such as abdominal pain, nausea, vomiting) and dizziness, no significant differences were observed in the type, frequency, and severity of adverse reactions between the safety profile in children aged 6 to 18 years and the previously established safety profile in adult patients.
Neurocognitive assessment and evaluation of development in children aged 6 to 16 years did not reveal any clinically significant overall negative consequences after treatment with Diovan® for up to 1 year.
In a double-blind, randomized study involving 90 children aged 1 to 6 years, followed by an open-label extension study lasting one year, two fatal cases and isolated cases of marked elevation of liver transaminases were recorded. These cases occurred in a population with significant comorbidities. A causal relationship with Diovan® has not been established. In a second study involving 75 children aged 1 to 6 years, no significant elevations in liver transaminases or fatal cases were observed during valsartan treatment.
Hyperkalemia was more frequently observed in children aged 6 to 18 years with underlying chronic kidney disease.
The safety profile observed in controlled clinical trials in adult patients after myocardial infarction and/or with heart failure differs from the general safety profile observed in patients with arterial hypertension. This may be related to the underlying disease. Adverse reactions observed in adult patients after myocardial infarction and/or with heart failure are listed in Table 2.
Shelf life. 3 years.
Storage conditions.
Store in a place inaccessible to children, at a temperature not exceeding 30 °C. Protect from moisture.
Packaging. Film-coated tablets, 80 mg or 160 mg, pack size: 14, 28.
14 tablets per blister. 1 or 2 blisters per cardboard packaging.
Prescription status. Prescription only.
Manufacturer.
Novartis Pharma S.p.A.
Manufacturer's address and location of operations.
Via Provinciale Scafa 131, 80058 Torre Annunziata (Naples), Italy.