Valni 20 delayed-release tablets - Summary of product characteristics (SmPC) (2023)

One tablet contains 20 mg nifedipine.

Excipient with known effect: One tablet contains 11,980 mg lactose (as monohydrate)

For the full list of excipients, see section 6.1.

A modified version of the tablet.

Light red, round, biconvex tablets, marked NTF 20 on one side.

Valni 20 Retard tablets are indicated in the following cases:

(I) hypertension

(ii) Prevention of chronic stable angina pectoris

Dose

It is recommended to swallow the tablets with a glass of water. These tablets should be swallowed whole and should not be broken or chewed.

grown ups: The recommended dose is one tablet (20 mg) every 12 hours. The dose can be increased to 40 mg every 12 hours to achieve the desired effect.

Pediatric population

The safety and efficacy of nifedipine in children under 18 years of age have not been established. Currently available data on the use of nifedipine in the treatment of hypertension are described in section 5.1.

Old people

There are no special dosage requirements for the elderly; however, the pharmacokinetics of nifedipine are altered in the elderly and lower maintenance doses of nifedipine may be required compared to younger patients.

Patients with liver damage should be carefully monitored at the start of treatment because nifedipine is mainly metabolized in the liver. If liver function is impaired, it is necessary to determine the necessary dose of nifedipine before applying Valnija 20 Retard.

In patients with renal insufficiency it is not necessary to adjust the dose.

Treatment with Valni 20 Retard can be continued long term.

Application Method

Oral administration.

Hypersensitivity to nifedipine, to any of the excipients listed in section 6.1.

or other dihydropyridines due to the theoretical risk of cross-reactivity.

Nifedipine should not be used in cardiogenic shock, clinically significant aortic stenosis, unstable angina, or during or within a month after a myocardial infarction.

Nifedipine should not be used to treat acute attacks of angina.

The safety of nifedipine for the treatment of malignant hypertension has not been established.

Nifedipine should not be used for the secondary prevention of myocardial infarction.

Due to the long-term effects of the preparation, nifedipine should not be administered to patients with hepatic impairment.

Nifedipine should not be administered to patients with a history of gastrointestinal obstruction, esophageal obstruction, or any degree of reduced lumen diameter of the gastrointestinal tract.

Nifedipine should not be used in patients with Kock's pouch (ileostomy after proctocolectomy).

Nifedipine is contraindicated in patients with inflammatory bowel disease or Crohn's disease.

Nifedipine should not be co-administered with rifampicin as effective nifedipine plasma concentrations cannot be achieved by enzyme induction (see section 4.5).

Nifedipine should be used with caution in patients with severe hypotension and in patients with reduced cardiac reserve. Occasionally exacerbation of heart failure has been observed with the use of nifedipine.

Nifedipine can potentiate the effects of other antihypertensive drugs, such as beta-blockers (although this combination is well tolerated), causing orthostatic hypotension. Nifedipine will not prevent rebound effects after discontinuation of other antihypertensive drugs.

Caution is required in patients with hypotension as there is a risk of further lowering of blood pressure, and caution is also required in patients with very low blood pressure (severe hypotension with systolic blood pressure less than 90 mm Hg).

Ischemic cardiac pain has been reported in some patients within 1 to 4 hours after receiving nifedipine. In such cases, treatment should be discontinued.

When nifedipine is used with intravenous therapy, careful monitoring of blood pressure is necessary. magnesium sulfate because it can cause an excessive drop in blood pressure, which can harm both the mother and the fetus.

Caution should be exercised when nifedipine is administered to diabetic patients, as nifedipine may impair glucose tolerance and may require adjustment of antidiabetic therapy.

In patients with malignant hypertension and hypovolemia who are on dialysis, a significant drop in blood pressure may occur.

Nifedipine is metabolized by the cytochrome P450 3A4 system. Therefore, drugs that inhibit or induce this enzyme system may alter the first pass or clearance of nifedipine (see section 4.5).

Medicinal products known to be inhibitors of the cytochrome P450 3A4 system and therefore may increase the plasma concentration of nifedipine include:

- macrolide antibiotics (for example, erythromycin)

- HIV protease inhibitors (for example, ritonavir)

- azole antifungals (for example, ketoconazole)

- antidepressants, nefazodone and fluoxetine

- chinuprystyna/dalfopristyna

- valproic acid

- cimetidine

When used simultaneously with these drugs, it is necessary to monitor blood pressure and, if necessary, consider reducing the dose of nifedipine.

Nifedipine should not be used during pregnancy unless the clinical condition of the woman requires treatment with nifedipine. Nifedipine should be used in women with severe hypertension unresponsive to standard therapy (see section 4.6).

The use of nifedipine during lactation is not recommended as nifedipine has been reported to pass into breast milk and the effects of oral absorption of small amounts of nifedipine are unknown (see section 4.6).

For use in special patient groups, see section 4.2.

Patients with rare hereditary problems of galactose intolerance, Lapland lactase deficiency or glucose-galactose malabsorption should not take this medicine because it contains lactose.

Drugs that affect nifedipine.

Nifedipine is metabolized by the cytochrome P450 3A4 system, which is found both in the intestinal mucosa and in the liver. Therefore, drugs that inhibit or induce this enzyme system may alter the first pass (oral) or clearance of nifedipine (see section 4.4).

When nifedipine is used with the following medications, the extent and duration of the interaction should be taken into account:

Ryfampicyna

Rifampin strongly induces the cytochrome P450 3A4 system. When used concurrently with rifampicin, the bioavailability of nifedipine is significantly reduced and therefore its efficacy. Therefore, the use of nifedipine in combination with rifampicin is contraindicated (see section 4.3).

It is necessary to monitor blood pressure during concurrent use of the following weak or moderate inhibitors of the cytochrome P450 3A4 system and, if necessary, consider reducing the dose of nifedipine.

In most of these cases, formal studies on interactions between nifedipine and the mentioned drugs have not been performed to date.

Macrolide antibiotics (eg, erythromycin)

No interaction studies between nifedipine and macrolide antibiotics have been performed. Some macrolide antibiotics are known to inhibit cytochrome P450 3A4-mediated metabolism of other drugs. Therefore, the possibility of an increased nifedipine plasma concentration when the two drugs are administered concurrently cannot be excluded (see section 4.4).

Azithromycin, although structurally related to the macrolide class of antibiotics, does not inhibit CYP3A4.

HIV protease inhibitors (for example, ritonavir)

A clinical study evaluating the potential for interactions between nifedipine and certain HIV protease inhibitors has not yet been performed. Drugs in this class are known to inhibit the cytochrome P450 3A4 system. In addition, drugs in this class have been shown to be inhibitory.in vitroMetabolism of nifedipine mediated by cytochrome P450 3A4. With simultaneous use with nifedipine, a significant increase in nifedipine plasma concentration as a result of reduced first-pass metabolism and reduced elimination cannot be excluded (see section 4.4).

Azolni antifungals (for example, ketoconazole)

A formal interaction study evaluating the potential for interaction between nifedipine and some azole antifungals has not yet been performed. Drugs in this class are known to inhibit the cytochrome P450 3A4 system. When administered orally with nifedipine, a significant increase in the systemic bioavailability of nifedipine as a result of reduced first-pass metabolism cannot be excluded (see section 4.4).

fluoxetine

No clinical study has yet been performed to evaluate the possibility of interaction between nifedipine and fluoxetine. Fluoxetine has been shown to inhibit cytochrome P450 3A4-mediated metabolism of nifedipine in vitro. Therefore, an increase in nifedipine plasma concentrations cannot be excluded when the two drugs are administered concomitantly (see section 4.4).

nefazodon

No clinical study has yet been performed to assess the possibility of interaction between nifedipine and nefazodone. Nefazodone is known to inhibit the cytochrome P450 3A4-mediated metabolism of other drugs. Therefore, an increase in nifedipine plasma concentrations cannot be excluded when the two drugs are administered concomitantly (see section 4.4).

Chinuprystyna/Dalfoprystyna

Co-administration of quinupristin/dalfopristin and nifedipine may result in increased nifedipine plasma concentrations (see section 4.4).

Valproic acid

No formal studies have been performed to investigate the possible interaction between nifedipine and valproic acid. Since valproic acid has been shown to increase the plasma concentration of the structurally similar calcium channel blocker nimodipine by inhibiting the enzyme, an increase in the plasma concentration of nifedipine and thus an increase in its efficacy cannot be excluded. (see section 4.4).

Cimetidine

Due to the inhibition of cytochrome P450 3A4, cimetidine increases the plasma concentration of nifedipine and may potentiate the antihypertensive effect (see section 4.4).

When inducers of the cytochrome P450 3A4 system are co-administered, the clinical response to nifedipine should be monitored and, if necessary, an increase in nifedipine dose should be considered. If the nifedipine dose is increased during concurrent use of both drugs, consideration should be given to reducing the nifedipine dose after stopping treatment.

cizaprida

Concomitant use of cisapride and nifedipine may cause an increase in nifedipine plasma concentration.

Cytochrome P450 3A4 system for the induction of antiepileptic drugs such as phenytoin, carbamazepine, and phenobarbitone.

Phenytoin induces the cytochrome P450 3A4 system. When used concurrently with phenytoin, the bioavailability of nifedipine and therefore its efficacy is reduced. If both drugs are administered concurrently, the clinical response to nifedipine should be monitored and, if necessary, an increase in the nifedipine dose should be considered. If the nifedipine dose is increased during concomitant administration of both drugs, consideration should be given to reducing the nifedipine dose after stopping phenytoin treatment.

No formal studies have been performed to investigate the possible interaction between nifedipine and carbamazepine or phenobarbitone. Since both drugs have been shown to reduce plasma concentrations of the structurally similar calcium channel blocker nimodipine by enzyme induction, a reduction in nifedipine plasma concentration and therefore a reduction in its efficacy cannot be excluded.

Effect of nifedipine on other drugs.

Medicines to lower blood pressure.

Nifedipine may potentiate the blood pressure lowering effect of concomitantly administered antihypertensive drugs. as:

- diuretics,

- β-blocking,

- ACE inhibitors,

- angiotensin 1 (AT1) receptor antagonists,

- other calcium antagonists,

- drugs that block alpha-adrenergic receptors,

- PDE5 inhibitors,

- α-methylodopa

In the case of simultaneous administration of nifedipine with beta-blockers, the patient should be carefully monitored, since worsening of heart failure is also known in isolated cases. Discontinuation of any previously used antihypertensive drug should be gradual, as nifedipine does not compensate for possible rebound effects.

Quinidine

A decrease in quinidine serum concentration has been reported when used in combination with nifedipine, and in isolated cases a significant increase in quinidine plasma concentration may be observed after discontinuation of nifedipine treatment. Therefore, when nifedipine is added or discontinued, it is recommended to monitor the plasma concentration of quinidine and, if necessary, adjust the quinidine dose. Some authors reported an increase in nifedipine plasma concentrations after simultaneous administration of both drugs, while others observed no changes in nifedipine pharmacokinetics.

Therefore, blood pressure should be carefully monitored if quinidine is added to existing nifedipine therapy. The dose of nifedipine should be reduced if necessary.

tacrolimus

Tacrolimus is metabolized by the cytochrome P450 3A4 system. Published data show that the dose of tacrolimus co-administered with nifedipine can be reduced in individual cases. When both drugs are co-administered, tacrolimus plasma concentrations should be monitored and, if necessary, a reduction in the tacrolimus dose should be considered.

Co-administration of nifedipine with theophylline and phenytoin will increase plasma concentrations of theophylline and phenytoin. and enhanced effects of nonpolarizing muscle relaxants such as tubocurarine.

digoxin

Co-administration of nifedipine and digoxin may result in decreased digoxin clearance and therefore increased digoxin plasma concentrations. . Therefore, the patient should be examined as a precautionary measure for signs of digoxin overdose and, if necessary, the dose of the glycoside should be reduced, taking into account digoxin plasma concentrations.

Food-Drug Interactions

Grape juice

Like other dihydropyridines, nifedipine should not be taken with grapefruit juice as it increases bioavailability.

Grapefruit juice inhibits the cytochrome P450 3A4 system, leading to increased nifedipine plasma concentrations and prolonged action of nifedipine due to reduced metabolism or first-pass clearance. As a consequence, the blood pressure lowering effect of nifedipine may be potentiated. With regular consumption of grapefruit juice, this effect can last for at least three days after the last consumption of grapefruit juice.

Therefore, consumption of grapefruit/grapefruit juice should be avoided while taking nifedipine.

Other forms of interaction

Nifedipine may falsely increase the spectrophotometric values ​​of vanillylmandelic acid in urine. However, this does not affect HPLC measurements.

The pregnancy

Nifedipine should not be used during pregnancy unless the clinical condition of the woman requires treatment with nifedipine. Nifedipine should be reserved for women with severe hypertension unresponsive to standard therapy (see section 4.4).

There are no adequate and well-controlled studies in pregnant women.

In animal studies, nifedipine has been shown to cause embryotoxicity, fetotoxicity, and teratogenicity.

No specific prenatal risk has been identified based on the available clinical evidence, although an increased incidence of perinatal asphyxia, cesarean delivery, prematurity, and intrauterine growth retardation have been reported. It is not clear whether these reports are due to the underlying disease, the treatment of hypertension, or the effect of a specific drug.

Available data are insufficient to exclude harmful effects to the fetus and newborn.

Acute pulmonary edema has been observed with calcium channel blockers, including nifedipine as a tocolytic during pregnancy (see section 4.8), especially in multiple pregnancies (twins or multiples), administered intravenously and/or with concomitant beta-2 agonists. .

Breast-feeding

Nifedipine passes into breast milk. The concentration of nifedipine in breast milk is almost comparable to that in maternal serum. For immediate-release formulations, it is suggested to delay breastfeeding or expressing milk for 3 to 4 hours after administration to reduce the exposure of the infant to nifedipine (see section 4.4).

Fertility

In individual casesin vitroAt the time of conception, the use of calcium channel blockers such as nifedipine is associated with reversible biochemical changes in the sperm head that can cause sperm dysfunction. For those men who have repeatedly failed to conceive a child.in vitroconception, and if no other explanation can be found, calcium antagonists such as nifedipine should be considered as a possible cause.

Reactions to medications, the intensity of which varies from person to person, can affect the ability to drive vehicles and machines. This applies especially at the start of treatment, change of medication and combination with alcohol.

Nausea, headache, lethargy, and dizziness have been reported, and the patient should be warned of possible symptoms.

Adverse Drug Reactions (ADRs) Based on Placebo-Controlled Studies of Nifedipine, Classified by CIOMS Frequency Category III (Clinical Trials Database: Nifedipine n=2661; Placebo n=1486; Accessed February 22, 2006, and ACTION study: nifedipine n=3825; placebo n=3840) are listed below: Adverse events listed under “common” were reported in less than 3%, except edema (9.9%) and headache (3.9%). %). Side effects were printed from post-marketing reports, the frequency of which could not be estimated.bold italic.

* = can be life threatening

**Cases of use of tocolytics during pregnancy have been reported (see section 4.6.)

At the beginning of treatment with short-acting forms of nifedipine, an exacerbation of angina pectoris can usually occur. Myocardial infarction has been reported, although this event cannot be distinguished from the natural course of ischemic heart disease.

Gingival hyperplasia and, in older men, gynecomastia have been reported, but these symptoms usually resolve after stopping the drug. Hypersensitivity reactions such as skin rashes and liver function disorders have occurred. These symptoms disappear after stopping treatment with nifedipine.

In patients with malignant hypertension and hypovolemia on dialysis, a pronounced fall in blood pressure may occur as a consequence of vasodilatation.

Report suspected side effects

It is important to report suspected side effects after the drug has been approved. It allows continuous monitoring of the benefit-risk ratio of the drug. Healthcare professionals are requested to report any suspected side effects via the Yellow Card scheme at www.mhra.gov.uk/amarillocard or by searching for MHRA Yellow Card on Google Play or the Apple App Store.

This may be associated with severe hypotension, tachycardia or bradycardia, and unconsciousness, although there are few reports and symptoms are not necessarily dose related.

Metabolic abnormalities that can occur include hyperglycemia and metabolic acidosis. Cardiac effects that can occur include heart block, atrioventricular dissociation and asystole, and cardiogenic shock with pulmonary edema.

Other effects include drowsiness, dizziness, disorientation, nausea, vomiting, lethargy, flushing, hypoxia, altered consciousness up to coma.

Treatment-

In treatment, the priority is the elimination of nifedipine and the establishment of a stable cardiovascular condition. After oral administration, a thorough gastric lavage is indicated, if necessary in combination with small intestinal lavage. Especially in case of poisoning by slow-release forms of nifedipine, such as Nifedipine Retard, it is necessary to perform a complete elimination, if possible including the small intestine, to avoid the inevitable subsequent absorption of the active substance.

The benefits of gastric decontamination are uncertain.

1. Consider the use of activated charcoal (50 g for adults, 1 g/kg for children) if the patient develops a potentially toxic amount within 1 hour of ingestion.

2. Alternatively, consider gastric lavage in adults within 1 hour of a life-threatening overdose.

3. Additional doses of activated charcoal (or ipecacone) every 4 hours should be considered if a clinically significant amount of an extended-release preparation is ingested with a single dose of an osmotic laxative (eg, sorbitol, lactulose, or sodium sulfate). magnesium).

4. Asymptomatic patients should be observed for at least 4 hours after ingestion.

Hemodialysis is not helpful because nifedipine cannot be dialyzed, but plasmapheresis (high plasma protein binding, relatively small volume of distribution) is recommended.

Hypotension resulting from cardiogenic shock and arterial vasodilation can be treated with calcium (10-20 mL of 10% calcium gluconate solution given slowly intravenously and repeated if necessary). As a result, the serum calcium concentration may reach the slightly elevated upper range of normal levels. If a sufficient increase in blood pressure is not achieved after calcium administration, additional vasoconstrictor sympathomimetics such as dopamine or norepinephrine are used. The dosage of these drugs depends solely on the effect achieved. Bradycardia arrhythmias can be treated symptomatically with beta-sympathomimetics, and for life-threatening bradycardia arrhythmias, installation of a temporary pacemaker is indicated. Metaraminol has also been reported to be beneficial in combination with calcium salts. Care must be taken to avoid cardiac overload when additional fluids or volumes are administered.

ATK Code: C08

Nifedipine is a dihydropyridine and is a potent antagonist of calcium flux through the slow channel in the cell membrane of cardiac cells and smooth muscle. Nifedipine also binds to intracellular calcium-binding proteins.

Calcium is normally released intracellularly from the sarcoplasmic reticulum, which, combined with an influx of extracellular calcium, results in increased calcium binding to calmodulin. Calcium channel blockers, such as nifedipine, work to widen the arteries, preventing calcium from entering the channel. The effect is most pronounced in vascular smooth muscles, since myocardial cell depolarization depends on both sodium ion influx and calcium ion influx, and nifedipine has little effect on recovery rate. of the free calcium channel.

Nifedipine is known to be an effective and relatively well tolerated drug for angina pectoris and mild to severe hypertension.

The antihypertensive effect of nifedipine is achieved by peripheral vasodilation, resulting in decreased peripheral resistance. Nifedipine lowers blood pressure in the treatment of hypertension, but has little or no effect in people with normal blood pressure.

Nifedipine has an effect in the treatment of angina pectoris by reducing peripheral and coronary vascular resistance, leading to an increase in coronary blood flow, cardiac output, and stroke volume, and a reduction in afterload.

Pediatric population:

Limited information is available comparing nifedipine with other antihypertensive agents for acute and long-term hypertension, for different formulations and at different doses. Nifedipine has been shown to have an antihypertensive effect, but dosing recommendations, long-term safety, and impact on cardiovascular outcomes have not yet been established. There is no pharmaceutical form for children.

Following oral administration, nifedipine is rapidly and almost completely absorbed from the gastrointestinal tract; however, due to extensive first-pass metabolism in the liver, the resulting bioavailability ranges from 45% to 75%. Administration with food slightly changes the early rate of absorption, but does not affect the degree of availability.

The final elimination half-life of conventional formulations (nifedipine capsules) ranges from 1.7 to 3.4 hours. The terminal half-life after administration of the retarder nifedipine is not a significant parameter because the plasma concentration remains stable during tablet dissolution and absorption. After the release and absorption of the last dose, plasma concentrations eventually decline and elimination half-lives are observed with conventional formulations.

Nifedipine is approximately 92-98% bound to plasma proteins (albumin). The distribution half-life after intravenous administration was 5 to 6 minutes.

Following oral administration, nifedipine is metabolized in the intestinal wall and in the liver, mainly by oxidative processes. These metabolites do not have pharmacodynamic activity. Nifedipine is excreted in the form of metabolites, mainly via the kidneys, with approximately 5% to 15% being excreted in the bile and feces. Unmetabolized nifedipine can only be detected in traces (less than 0.1%) in urine.

There are no significant differences in the pharmacokinetics of nifedipine between healthy volunteers and patients with renal failure. Therefore, no dose adjustment is necessary in these patients.

In patients with hepatic impairment, the elimination half-life is significantly prolonged and the total clearance is reduced. Due to the duration of action of the drug, the retardant drug nifedipine should not be used in these patients.

The standard nifedipine capsule dosage regimen is 10 mg three times daily, leading to a maximum dose of 20 mg three times daily. The nifedipine tablet is designed as a modified-release product and provides a 20 mg twice daily dose, which can be increased to 40 mg twice daily if necessary.

Adalat Retard is a modified release formulation currently available on the UK market. A comparative bioavailability study was carried out comparing this formulation with Valni 20 Retard. The results of the study are presented below and show that the two formulations are bioequivalent.

Below are the average data from the comparative bioavailability study:

Preclinical data reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity, genotoxicity and carcinogenic potential.

Following acute oral and intravenous administration of nifedipine to various animal species, the following LDs may occur₅₀(mg/kg) values ​​obtained:

In subacute and subchronic toxicity studies in rats and dogs, nifedipine was tolerated without impairment at doses up to 50 mg/kg (rats) and 100 mg/kg (dogs) orally. thirteen and four weeks respectively. Following intravenous administration, dogs tolerated nifedipine up to 0.1 mg/kg for six days without injury. Rats tolerated daily intravenous administration of 2.5 mg/kg nifedipine for three weeks without injury.

In chronic toxicity studies in dogs treated for up to one year, nifedipine was tolerated without deterioration at doses up to 100 mg/kg orally. In rats, toxicity occurred at concentrations greater than 100 ppm in food (approximately 5-7 mg/kg body weight).

In a rat carcinogenicity study (two years) there was no evidence of carcinogenicity of nifedipine.

Nifedipine has been shown to cause teratogenic effects in rats, mice, and rabbits, including digit abnormalities, limb malformations, cleft palate, cleft sternum, and rib malformations.

The digit abnormalities and limb malformations are probably the result of impaired blood flow in utero, but were also observed in animals treated with nifedipine only after the end of the period of organogenesis.

The use of nifedipine has been associated with a variety of embryotoxic, placental, and fetotoxic effects, including fetal stunting (rats, mice, rabbits), small placentas and underdeveloped chorionic villi (monkeys), embryofoetal death (rats, mice, rabbits). and prolonged pregnancy. /decreased neonatal survival (rats; not evaluated in other species). A risk to humans cannot be excluded with a sufficiently high systemic exposure; however, all doses associated with teratogenic, embryotoxic, or fetotoxic effects in animals were maternally toxic, many times the highest recommended human dose.

W.in vitroyLiveStudies have shown that nifedipine does not have mutagenic properties.

Blister strips composed of: PVC foil 250 µm ± 5%, PVdC 25 µm ± 5%, aluminum foil 25 µm ± 8%, PVdC 20GSM ± 10%.

Pack size: 28, 30, 56, 60, 84, 100, 250, 500, 1000.

Not all pack sizes may be commercially available.

There are no special removal requirements

Any unused medication or waste material must be disposed of in accordance with local regulations.

Tillomed Laboratories Ltd

220 Butterfield, Grandes Marlings

London

LU2 8DL

Britain

First approval date: 10/10/1995

Renewal date: 20.08.2001