Nifedipress MR 10 - Summary of product characteristics (Technical Data Sheet) (2023)

One tablet contains 10 mg nifedipine.

Excipient with known effect: lde acetic monohydrate

For the full list of excipients, see section 6.1.

modified-release tablets

Round, pinkish-brown, film-coated tablets.

NIFEDIPRESS MR tablets are indicated in adults for the treatment of hypertension and the prevention of chronic stable angina pectoris.

Dose

The recommended starting dose of NIFEDIPRESS MR is 10 mg every 12 hours, to be swallowed with water and then gradually increased based on your response. NIFEDIPRESS MR is a titrated starting dose that can be increased to 40 mg every 12 hours up to a maximum daily dose of 80 mg.

Concomitant use with CYP 3A4 inhibitors or inducers of CYP 3A4 may result in a recommendation for dose adjustment of nifedipine or complete discontinuation of nifedipine treatment (see section 4.5).

Treatment duration

Treatment can be continued indefinitely.

Additional information on special populations

Pediatric population

The safety and efficacy of NIFEDIPRESS MR 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.

Elderly (>65 years)

The pharmacokinetics of NIFEDIPRESS MR in the elderly are altered and lower maintenance doses of nifedipine may be required.

Patients with liver damage.

Nifedipine is mainly metabolized in the liver, therefore patients with mild, moderate, or severe hepatic impairment should be carefully monitored and a dose reduction may be necessary.

The pharmacokinetics of nifedipine have not been studied in patients with severe hepatic impairment (see sections 4.4 and 5.2).

Patients with kidney damage.

Based on pharmacokinetic data, no dose adjustment is necessary in patients with renal impairment (see section 5.2).

Application Method

Oral administration.

As a general rule, the tablets should be swallowed whole with a small amount of liquid, regardless of food. NIFEDIPRESS MR tablets should not be taken with grapefruit juice (see section 4.5).

The tablets should not be crushed, chewed, divided or dissolved.

NIFEDIPRESS MR is contraindicated in patients with a known hypersensitivity to nifedipine or other dihydropyridines due to the theoretical risk of cross-reactivity. They should also not be used in case of known hypersensitivity to any of the excipients listed in sections 4.4 and 6.1.

They should not be used in women who are or may become pregnant (see section 4.6).

Do not use NIFEDIPRESS TM in case of clinically significant aortic stenosis, unstable angina, or during or within a month after a myocardial infarction. They should not be used in patients with cardiogenic shock.

NIFEDIPRESS MR should not be used for the treatment of acute anginal attacks or in patients who have experienced ischemic pain after previous administration.

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

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

NIFEDIPRESS MR is contraindicated in patients with acute porphyria.

NIFEDIPRESS MR should not be used in patients with Kock syndrome (ileostomy after proctocolectomy).

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

NIFEDIPRESS MR is not a beta-blocker and therefore does not offer protection against the dangers of abruptly stopping beta-blockers. Discontinuation of any previously prescribed beta-blocker should be gradual, preferably over 8 to 10 days.

NIFEDIPRESS MR can be used in combination with beta-blockers and other antihypertensives, but the possibility of an additive effect leading to orthostatic hypotension and/or heart failure should be taken into account. NIFEDIPRESS MR will not prevent possible rebound effects after discontinuation of other antihypertensive drugs.

Nifedipine should be used with caution in hypotensive patients (severe hypotension with systolic blood pressure less than 90 mmHg).

Excessive drops in blood pressure can lead to temporary blindness. If these symptoms occur, the patient should not attempt to drive or use machinery (see section 4.8).

NIFEDIPRESS MR should be used with caution in patients with poor cardiac reserve; in patients with heart failure or significantly weakened left ventricular function. Occasionally exacerbation of heart failure has been observed with the use of nifedipine.

The use of NIFEDIPRESS MR in diabetics may require adjustment of antidiabetic therapy.

In patients with malignant hypertension on dialysis with irreversible hypovolemic renal failure, a significant drop in blood pressure may occur due to the vasodilatory effect of nifedipine.

Although the steal effect has not been demonstrated, patients experiencing this effect should discontinue nifedipine treatment.

The use of NIFEDIPRESS TM is not recommended during lactation as nifedipine has been reported to be excreted in breast milk and the effects of exposure to nifedipine on the nursing infant are unknown (see section 4.6).

Careful monitoring and dose reduction may be necessary in patients with mild, moderate, or severe hepatic impairment. The pharmacokinetics of nifedipine have not been studied in patients with severe hepatic impairment (see sections 4.2 and 5.2). Therefore, nifedipine should be used with caution in patients with severe hepatic impairment.

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 that are inhibitors of the cytochrome P450 3A4 system and therefore may increase the plasma concentration of nifedipine include:

• macrolide antibiotics (eg erythromycin)

• HIV protease inhibitors (for example, ritonavir)

• azole antifungals (eg ketoconazole)

• antidepressants nefazodone and fluoxetine

• chinuprystyna/dalfopristyna

• valproic acid

• cimetidine

so that-Blood pressure should be monitored and a dose reduction of nifedipine should be considered if necessary (see section 4.5).

Because this medicine contains lactose, patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

For use in special populations, see section 4.2.

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:

Rifampicin: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).

Blood pressure should be monitored during co-administration of known inhibitors of the cytochrome P450 3A4 system and, if necessary, a dose reduction of nifedipine should be considered (see sections 4.2 and 4.4). In most of these cases, formal studies on interactions between nifedipine and the mentioned drugs have not been performed to date.

Drugs that increase exposure to nifedipine:

•macrolide antibiotics (for example, erythromycin)

• HIV protease inhibitors (for example, ritonavir)

• azole antifungals (eg ketoconazole)

• fluoxetine

• nefazodon

• chinuprystyna/dalfopristyna

• cizaprida

• valproic acid

• cimetidine

• diltiazem

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.

Elevated concentrations of nifedipine in plasma were recorded with the simultaneous use of alcohol, cyclosporine, ginkgo biloba, and ginseng.

Potentiated hypotensive effects of nifedipine may occur with: aldesleukin, alprostadil, anesthetics, antipsychotics, diuretics, phenothiazides, prazosin, and intravenous x-ray ion contrast agents. Cases of profound hypotension have been reported with the use of nifedipine and intravenous magnesium sulphate for the treatment of pre-eclampsia.

Drugs that reduce exposure to nifedipine:

• rifampicin (see above)

• kao phenytoin

• carbamazepine

• phenobarbital

A decrease in nifedipine plasma concentrations has also been reported with concomitant administration of St. John's wort.

Effect of nifedipine on other drugs.

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

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.

The risk of excessive hypotension, bradycardia, and heart failure is increased with the use of beta-blockers.

digoxin:Co-administration of nifedipine and digoxin may cause decreased digoxin clearance and therefore increased digoxin plasma concentration. Therefore, the patient should be monitored prophylactically for signs of digoxin overdose and, if necessary, the glycoside dose reduced.

Quinidine:Concomitant use of nifedipine with quinidine may result in decreased quinidine plasma concentration 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. It is necessary to carefully monitor blood pressure and, if necessary, reduce the dose of nifedipine.

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.

Plasma concentrations of phenytoin, theophylline, and nondepolarizing muscle relaxants (eg, tubocurarine) are increased when used in combination with nifedipine.

Nifedipine may cause increased mizolastine levels due to CYP3A4 inhibition.

Nifedipine may potentiate the neuromuscular blocking effect of vecuronium.

Food-Drug Interactions

Grapefruit juice inhibits the cytochrome P450 3A4 system. Therefore, co-administration of nifedipine with grapefruit juice results in increased nifedipine plasma concentrations and prolonged effects of nifedipine due to reduced first-pass metabolism or reduced elimination. 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 (see section 4.2).

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

Since animal studies have shown embryotoxicity and teratogenicity (see section 5.3 Preclinical safety data), the use of NIFEDIPRESS TM is contraindicated during pregnancy (see section 4.3). Embryotoxicity was observed with 6 to 20 times the recommended dose of NIFEDIPRESS TM in rats, mice, and rabbits, and teratogenicity was observed in rabbits given 20 times the highest recommended dose of NIFEDIPRESS TM.

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

Increased rates of perinatal asphyxia, cesarean delivery, and intrauterine growth retardation and prematurity have been reported, but it is unclear whether these reports are due to hypertension, its treatment, or a specific drug effect.

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 is excreted in breast milk, therefore the use of NIFEDIPRESS MR during lactation is not recommended (see section 4.4).

Fertility

In individual casesin vitroFertilization The use of calcium channel blockers such as nifedipine is associated with reversible biochemical changes in the sperm head that can cause sperm dysfunction. If there is no other explanation for the failed parenthood, nifedipine should be considered as a possible cause.

Reactions to medicinal products, the intensity of which varies from person to person, may affect the ability to drive and use machines (see section 4.8). This applies especially at the start of treatment, change of medication and combination with alcohol.

Possible side effects include dizziness and lethargy. If these symptoms occur, do not try to drive or use machines (see section 4.8).

An excessive drop in blood pressure can cause temporary blindness. If these symptoms occur, do not try to drive or use machines (see section 4.8).

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, 2015). 2006 and ACTION study: nifedipine n=3825; placebo, n=3840) are listed below: Side effects listed under "common" were seen in less than 3%, with the exception of edema (9.9%) and pain head (3.9%). Most of the side effects are due to the vasodilator effect of nifedipine.

Frequencies of adverse reactions reported with nifedipine-containing products are summarized in the table below. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Frequencies are defined as common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), and rare (≥1/10,000 to <1/1000). Side effects that have been identified only during continuous post-marketing surveillance and whose frequency could not be estimated are listed under 'Unknown'.

1 = may be life threatening

2 = Myocardial infarction has been reported, but cannot be distinguished from the natural course of coronary disease.

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

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 website: www.mhra.gov.uk/amarillocard or by searching for MHRA Yellow Card on Google Play or the Apple App Store.

Symptoms

Reports of nifedipine overdose are limited and symptoms are not necessarily dose related. In case of overdose, it is most likely to be manifested by severe hypotension due to vasodilatation and tachycardia or bradycardia.

Metabolic disturbances include hyperglycemia, metabolic acidosis, and hypo- or hyperkalemia.

Cardiac effects may include heart block, atrioventricular dissociation and asystole, and cardiogenic shock with pulmonary edema.

Other toxic effects include nausea, vomiting, drowsiness, disorientation, lethargy, flushing, hypoxia, unconsciousness, and coma.

Treatment

In treatment, the priority is the elimination of nifedipine and the establishment of a stable cardiovascular condition.

After oral administration, if necessary, gastric lavage combined with small bowel lavage is indicated. Ipecacuanha should be given to children.

Elimination should be as complete as possible, including the small intestine, to avoid 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.

Although it may seem reasonable to assume that delayed application of activated charcoal could be beneficial for sustained release (SR, MR) formulations, there is no evidence for this.

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

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

4. Asymptomatic patients should be observed for at least 4 hours after ingestion and 12 hours when a sustained release preparation is used.

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

It is necessary to monitor blood pressure, ECG, central arterial pressure, pulmonary wedge pressure, urea and electrolytes.

Hypotension secondary to cardiogenic shock and arterial vasodilation can be treated by elevating the feet and draining the plasma. If these measures are not effective, hypotension can be treated with calcium (10-20 ml of 10% calcium gluconate solution given intravenously over 5-10 minutes). If the effects are insufficient, treatment with ECG monitoring can be continued. In addition, beta-sympathomimetics can be used, for example, isoprenaline 0.2 mg slowly i.v. or as a continuous infusion of 5 µg/min. If a sufficient increase in blood pressure is not achieved with calcium and isoprenaline, it is necessary to apply vasoconstrictor sympathomimetics such as dopamine or norepinephrine. The dose of these drugs should be based on the patient's response.

If necessary, bradycardia can be treated with atropine, beta-sympathomimetics, or a temporary pacemaker.

Additional fluids must be administered carefully to avoid overloading the heart.

Pharmacotherapeutic group: Selective calcium channel blocker (dihydropyridine derivative), mainly vasoactive (ATC code: C08CA05).

Nifedipine is a specific and potent 1,4-dihydropyridine calcium antagonist. Calcium antagonists reduce the transmembrane flux of calcium ions into the cell through slow calcium channels. Nifedipine acts specifically on myocardial cells and smooth muscle cells of coronary arteries and peripheral resistance vessels.

In hypertension, the main action of NIFEDIPRESS MR is peripheral vasodilatation and, therefore, the reduction of peripheral resistance.

For angina, NIFEDIPRESS MR reduces peripheral and coronary vascular resistance, thereby increasing coronary blood flow, cardiac output, and stroke volume, while reducing afterload.

In addition, submaximal nifedipine dilates clear and atherosclerotic coronary arteries, thus protecting the heart from coronary artery spasm and improving perfusion of the ischemic myocardium.

Nifedipine reduces the frequency of painful attacks and ischemic ECG changes, regardless of the relative contribution of coronary artery spasm or atherosclerosis.

NIFEDIPRESS MR administered twice a day guarantees high blood pressure control for 24 hours. NIFEDIPRESS MR reduces blood pressure in such a way that the percentage reduction is directly related to its initial level. In people with normal blood pressure, NIFEDIPRESS MR has little or no effect on blood pressure.

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.

Absorption

After oral administration, nifedipine is rapidly and almost completely absorbed. The systemic availability of orally administered nifedipine is 45-56% due to the first-pass effect. Peak plasma and serum concentrations are reached between 1.5 and 4.2 hours after administration of NIFEDIPRESS MR (20 mg tablets). Simultaneous food intake causes delayed, but not reduced absorption.

Distribution

Nifedipine is approximately 95% bound to plasma proteins (albumin). The distribution half-life after intravenous administration is estimated to be 5 to 6 minutes.

biotransformation

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 through the kidneys and about 5-15% through the bile in the feces. Unchanged substance is detected only in traces (less than 0.1%) in urine.

Elimination

The final elimination half-life is 6 to 11 hours (Nifedipress MR 20 mg) due to delayed absorption. During prolonged treatment there was no accumulation of substances after the usual dose. In the case of kidney damage, no significant changes were found compared to healthy volunteers. In a study comparing the pharmacokinetics of nifedipine in patients with mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment with patients with normal hepatic function, oral clearance of nifedipine was reduced by an average of 48% (Child Pugh A) and 72% (Pugh's baby B). As a result, nifedipine AUC and Cmax were increased on average by 93% and 64% (Child Pugh A) and 253% and 171% (Child Pugh B), respectively, compared to patients with normal hepatic function. The pharmacokinetics of nifedipine have not been studied in patients with severe hepatic impairment (see section 4.4).

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

reproductive toxicology

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 foetotoxic effects in animals were maternally toxic and several times the highest recommended human dose (see section 4.6).

Silicon colloidal anhydrous, lactose monohydrate, microcrystalline cellulose, polysorbate 80, pregelatinized starch, magnesium stearate, hypromellose 2910, macrogol 6000, titanium dioxide (E171), purified talc, red iron oxide (E172), purified water, carnauba wax .

Does not apply

Red PVC/aluminium vials

28 pills

30 tablets

56 pills

Not all pack sizes may be commercially available.

dexcel^®-Pharmaceutical Limited Liability Company

7 Sopwith method

Drayton Fields and Daventry

Northamptonshire NN11 8PB

Britain

PL 14017/0013

Date of first approval: August 26, 1997;

Date of last renewal - October 30, 2002

16.02.2023