Nicardipine 10 mg/10 ml, solution for injection

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NIKARDIPINE 10 mg/10 ml, injectable solution

Composition:

Active substance: nicardipine hydrochloride;

1 ml of solution contains 1 mg of nicardipine hydrochloride;

one 10 ml ampoule contains 10 mg of nicardipine hydrochloride;

Excipients: sorbitol, citric acid monohydrate, sodium citrate, hydrochloric acid or sodium hydroxide, water for injections, nitrogen (should ensure an inert atmosphere in the ampoule).

Pharmaceutical form. Injectable solution.

Main physicochemical properties: clear yellow-colored solution.

Pharmacotherapeutic group. Calcium antagonists. Selective calcium antagonists with predominant vascular action.

ATC code C08CA04.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Nicardipine is a second-generation slow calcium channel inhibitor belonging to the group of phenyl dihydropyridines. Nicardipine has greater selectivity for L-type calcium channels in vascular smooth muscle than in cardiac myocytes. At very low concentrations, it inhibits calcium influx into the cell. It primarily acts on the smooth muscle of arteries. This manifests as relatively pronounced and rapid changes in arterial pressure with minimal inotropic changes in cardiac function (baroreflex effect).

Pharmacodynamic effects

When administered systemically, nicardipine is a potent vasodilator that reduces total peripheral resistance and lowers arterial pressure. Heart rate increases temporarily; as a result of reduced afterload, cardiac output increases significantly and persistently.

In humans, the vasodilatory effect is observed both after acute dose administration and during prolonged administration in both large and small arteries, increasing blood flow and improving arterial compliance. Renal vascular resistance decreases.

Pharmacokinetics.

Distribution

Nicardipine is extensively bound to plasma proteins over a wide concentration range.

Biotransformation

Nicardipine is metabolized via cytochrome P450 3A4. Studies involving either single-dose administration or dosing three times daily for three days showed that less than 0.03% of unchanged nicardipine is excreted in human urine after oral or intravenous administration. The most common metabolite in human urine is the hydroxy glucuronide form, formed through oxidative cleavage of the N-methylbenzyl fragment and oxidation of the pyridine ring.

Elimination

After simultaneous administration of a radiolabeled intravenous dose of nicardipine and an oral dose of 30 mg every 8 hours, 49% of the radioactive dose was excreted in urine and 43% in feces within 96 hours. No unchanged nicardipine was detected in urine. The elimination profile of the drug after intravenous administration consists of three phases with corresponding elimination half-lives: alpha – 6.4 min, beta – 1.5 hours, gamma – 7.9 hours.

Renal impairment

The pharmacokinetics of intravenously administered nicardipine were studied in patients with severe renal impairment requiring hemodialysis (creatinine clearance < 10 mL/min), mild-to-moderate renal impairment (creatinine clearance 10–50 mL/min), and normal renal function (creatinine clearance > 50 mL/min). At steady state, Cmax and AUC were significantly higher, and clearance significantly lower in patients with mild-to-moderate renal impairment compared to patients with normal renal function. No significant differences were observed in major pharmacokinetic parameters between patients with severe renal impairment and those with normal renal function.

Clinical characteristics.

Indications.

Intravenous nicardipine is indicated for the treatment of life-threatening acute arterial hypertension, particularly in cases of:

• malignant arterial hypertension/hypertensive encephalopathy;
• aortic dissection, when short-acting beta-blocker therapy is not suitable, or in combination with a beta-blocker when beta-blocker monotherapy is ineffective;
• severe pre-eclampsia, when other intravenous antihypertensive agents are not recommended or are contraindicated.

Nicardipine is also indicated for the treatment of postoperative arterial hypertension.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients.

Severe aortic stenosis.

Compensatory arterial hypertension in the presence of an arteriovenous shunt or coarctation of the aorta.

Unstable angina.

Within 8 days following myocardial infarction.

Special precautions.

Warning

Nicardipine should be administered with caution to avoid excessive reduction in blood pressure. Rapid pharmacological lowering of arterial pressure may lead to systemic hypotension and reflex tachycardia. If either of these events occurs during nicardipine administration, consideration should be given to reducing the dose by half or discontinuing the infusion.

Bolus or intravenous administration without electronic syringe pump or volumetric infusion pump control is not recommended, as this may increase the risk of severe arterial hypotension, particularly in elderly patients, children, patients with renal or hepatic impairment, and pregnant women.

Heart failure

Nicardipine should be used with caution in patients with congestive heart failure or pulmonary edema, especially if these patients are receiving concomitant beta-blockers, as heart failure may be exacerbated.

Ischemic cardiovascular disease

Nicardipine is contraindicated in unstable angina and immediately following myocardial infarction.

Nicardipine should be used with caution in patients with suspected coronary ischemia. Rarely, an increase in frequency, duration, or severity of angina has been observed at the beginning of nicardipine therapy, during dose escalation, or during the course of treatment.

Pregnancy

Due to the risk of severe maternal hypotension and potentially fatal fetal hypoxia, blood pressure reduction should be gradual and always performed under close monitoring. Caution should be exercised when magnesium sulfate is used concomitantly due to the potential risk of pulmonary edema or excessive reduction in arterial pressure.

Since cases of acute pulmonary edema during pregnancy have been reported, nicardipine should be administered with caution in pregnant women, who should be closely monitored for the possible development of acute pulmonary edema. If acute pulmonary edema occurs, nicardipine treatment should be immediately discontinued and appropriate therapy initiated.

Patients with history of hepatic dysfunction or hepatic impairment

Rare cases of hepatic dysfunction possibly related to nicardipine administration have been reported. Patients with a history of hepatic dysfunction and those with hepatic impairment at the start of nicardipine therapy are considered at potential risk. Nicardipine should be used with particular caution in patients with hepatic impairment.

Renal impairment

Nicardipine should be used with caution in patients with renal impairment.

Patients with portal hypertension

Intravenous nicardipine administered at high doses has been reported to worsen portal hypertension and the portosystemic collateral blood flow index in patients with liver cirrhosis.

Patients with pre-existing intracranial hypertension

Nicardipine should be used with caution in patients at risk of increased intracranial pressure. Intracranial pressure should be monitored to allow calculation of cerebral perfusion pressure.

Patients with stroke

Nicardipine should be used with caution in patients with acute cerebral infarction. Hypertensive episodes, which often accompany stroke, are not an indication for immediate (emergency) antihypertensive therapy. Antihypertensive agents are not recommended in patients with ischemic stroke, except when acute arterial hypertension interferes with appropriate treatment (e.g., thrombolysis) or when there is another life-threatening end-organ damage in the short term.

Interaction with other medicinal products and other forms of interaction.

Undesirable combinations

Dantrolene

Infusion of dantrolene. In animal studies, intravenous administration of verapamil and dantrolene consistently resulted in fatal ventricular fibrillation. Therefore, the combination of a calcium channel inhibitor and dantrolene is potentially hazardous.

However, several patients receiving a combination of nifedipine and dantrolene experienced no problems.

Combinations requiring precautions in use

Idelalisib

Enhanced adverse effects of nicardipine, such as orthostatic hypotension, particularly in elderly patients. Clinical monitoring and dose adjustment of nicardipine should be performed during and after treatment with idelalisib.

Immunosuppressants (cyclosporine, everolimus, sirolimus, tacrolimus, and temsirolimus)

Increased blood levels of immunosuppressants due to inhibition of their metabolism. Renal function, blood levels of immunosuppressants, and dose adjustments should be monitored during and after treatment.

Inducers and inhibitors of CYP3A4

Nicardipine is metabolized by cytochrome P450 3A4. Concomitant use of drugs that induce CYP3A4 enzyme activity (e.g., carbamazepine, phenobarbital, phenytoin, fosphenytoin, primidone, and rifampicin) may result in decreased plasma concentrations of nicardipine due to enhanced hepatic metabolism.

Clinical monitoring and possible dose adjustment of nicardipine should be performed during and after treatment with these anticonvulsants.

Concomitant use of potent inhibitors of CYP3A4 enzyme (e.g., cimetidine, clarithromycin, cobicistat, erythromycin, itraconazole, grapefruit juice, ketoconazole, nelfinavir, posaconazole, ritonavir, telaprevir, telithromycin, voriconazole) may lead to increased plasma concentrations of nicardipine.

Enhanced adverse effects of nicardipine, particularly orthostatic hypotension, especially in elderly patients. Concomitant use of calcium channel blockers with itraconazole has demonstrated an increased risk of adverse effects, including edema, due to reduced hepatic metabolism of the calcium channel blocker.

Clinical monitoring and dose adjustment of nicardipine should be performed during and after treatment with a potent CYP3A4 inhibitor.

Combinations to be taken into account

Potential additive antihypertensive effect

Medicinal products that may enhance the antihypertensive effect of nicardipine when used concomitantly and increase the risk of orthostatic hypotension include baclofen, urological alpha-blockers (alfuzosin, doxazosin, prazosin, silodosin, tamsulosin, terazosin), alpha-blocking antihypertensives (doxazosin, prazosin, urapidil), tricyclic antidepressants, imipramine-type antidepressants, neuroleptics, opioids, and amifostine.

Nitrates and related substances

Increased risk of hypotension, particularly orthostatic hypotension.

Medicinal products causing orthostatic hypotension

Increased risk of arterial hypotension, particularly orthostatic hypotension.

Inhalational anesthetics

Concomitant use of nicardipine with inhalational anesthetics may result in a potential additive or synergistic hypotensive effect, and anesthetic-induced suppression of baroreflex-mediated increases in heart rate in response to peripheral vasodilators. Limited clinical data suggest that the effect of inhalational anesthetics (e.g., isoflurane, sevoflurane, and enflurane) on nicardipine is moderate.

Enhanced negative inotropic effect

Nicardipine may potentiate the negative inotropic effect of beta-blockers (except esmolol) and may cause arterial hypotension and heart failure in patients with latent or uncontrolled heart failure (additive negative inotropic effects). Additionally, beta-blockers may minimize the reflex sympathetic response triggered by excessive hemodynamic effects.

Magnesium

Caution should be exercised when magnesium sulfate is used concomitantly due to the potential risk of pulmonary edema or excessive reduction in arterial pressure.

Digoxin

Pharmacokinetic studies have reported that nicardipine increases plasma digoxin levels. Digoxin levels should be monitored at the initiation of concomitant nicardipine therapy.

Reduced antihypertensive effect

Nicardipine in combination with intravenous corticosteroids (glucocorticoids and mineralocorticoids) and tetracosactide (except hydrocortisone used as replacement therapy in Addison’s disease) may lead to reduced antihypertensive effect.

Competitive neuromuscular blockers

Limited data suggest that nicardipine, like other calcium channel blockers, may enhance neuromuscular blockade, possibly by affecting the postsynaptic site. The required infusion dose of vecuronium may be reduced when nicardipine is used concomitantly. Nicardipine infusion appears not to affect reversal of neuromuscular blockade by neostigmine. No additional monitoring is required.

Special precautions for use.

Combination with beta-blockers

Caution should be exercised when administering nicardipine in combination with a beta-blocker to patients with impaired cardiac function. In such cases, the dosage of the beta-blocker should be individually adjusted according to the clinical situation.

Reactions at the site of administration

Reactions at the infusion site may occur, particularly during prolonged administration and when administered into peripheral veins. The infusion site should be changed at the first sign of irritation. The use of a central venous catheter or greater dilution of the solution may reduce the risk of infusion site reactions.

Excipients

1 ml of the injection solution contains 50 mg of sorbitol; one 10 ml ampoule contains 500 mg of sorbitol. If you have been diagnosed with intolerance to certain sugars, consult your doctor before using this medicinal product. This medicinal product must not be administered to patients with hereditary fructose intolerance unless clearly necessary.

1 ml of the injection solution contains 0.039 mg (equivalent to 0.0017 mmol) of sodium; one 10 ml ampoule contains 0.39 mg (equivalent to 0.017 mmol) of sodium. This medicinal product contains less than 1 mmol (23 mg) of sodium per dose, i.e. it is practically sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy

Animal studies have not revealed teratogenic effects. Given the absence of teratogenic effects in animals, developmental abnormalities in humans are not expected. Substances known to cause developmental abnormalities in humans have invariably demonstrated teratogenic effects in animals during studies conducted on two animal species. Nicardipine should be used only when the benefit outweighs the risk, as reduced birth weight in newborns has been reported when it is used in combination with calcium channel blockers.

Limited pharmacokinetic data have shown that intravenously administered nicardipine does not accumulate and has low placental penetration.

To date, clinical experience with the use of nicardipine during the first two trimesters in a limited number of pregnancies has not revealed any developmental abnormalities or specific fetotoxic effects.

The use of nicardipine in severe pre-eclampsia during the third trimester of pregnancy may potentially cause an undesirable tocolytic effect, which could interfere with spontaneous labor induction.

Acute pulmonary edema has been observed when nicardipine is used as a tocolytic agent during pregnancy, particularly in cases of multiple pregnancies (twins or more), with intravenous administration and/or concomitant use of beta-2 agonists. Nicardipine should not be used in multiple pregnancies or in pregnant women with cardiovascular disorders, except when no suitable alternative is available.

Breastfeeding

Nicardipine should not be used during breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

Adverse reactions to the medicinal product, which vary between patients, may impair the ability to drive vehicles or operate machinery, particularly at the beginning of treatment or when the dosage is changed, and especially when combined with alcohol. Precautions should be taken, as the hypotensive effect of this medicinal product may cause dizziness.

Method of Administration and Dosage.

Dosage

The antihypertensive effect depends on the administered dose. The dosage required to achieve the desired blood pressure may vary depending on the target blood pressure, patient response, and patient's age or general condition.

If administration is via a central venous catheter, the drug should be diluted to a concentration of 0.1–0.2 mg/mL prior to use (see section "Incompatibility").

Administration in Adults

Initial dose: Treatment should be initiated with continuous infusion of nicardipine at a rate of 3–5 mg/hour for 15 minutes. The rate may be increased by increments of 0.5 or 1 mg every 15 minutes. The infusion rate should not exceed 15 mg/hour.

Maintenance dose: Once the target blood pressure is achieved, the dose should be gradually reduced, usually to 2–4 mg/hour, to maintain therapeutic efficacy.

Transition to Oral Antihypertensive Therapy: Discontinue nicardipine infusion or reduce the infusion rate when initiating appropriate oral therapy. When initiating oral antihypertensive therapy, the time to onset of action of the oral agent should be considered. Blood pressure monitoring should continue until the desired effect is achieved.

Alternatively, transition to oral nicardipine capsules 20 mg at a dose of 60 mg/day in three divided doses, or to extended-release nicardipine tablets 50 mg at a dose of 100 mg/day in two divided doses, may be considered.

Elderly Patients

Clinical studies of nicardipine did not include sufficient numbers of patients aged 65 years and older to determine whether their responses differ from those of younger patients.

Elderly patients may be more sensitive to the effects of nicardipine due to impaired renal and/or hepatic function. It is recommended to initiate continuous nicardipine infusion at an initial rate of 1 mg/hour to 5 mg/hour, depending on blood pressure and clinical condition. After 30 minutes, depending on the observed effect, the infusion rate may be increased or decreased in increments of 0.5 mg/hour. The infusion rate should not exceed 15 mg/hour.

Pregnancy

It is recommended to initiate continuous nicardipine infusion at an initial rate of 1 mg/hour to 5 mg/hour, depending on blood pressure and clinical condition. After 30 minutes, depending on the observed effect, the infusion rate may be increased or decreased in increments of 0.5 mg/hour.

In the treatment of pre-eclampsia, doses usually do not exceed 4 mg/hour. The infusion rate should not exceed 15 mg/hour.

Hepatic Impairment

Nicardipine should be used with particular caution in these patients. Since nicardipine is metabolized in the liver, patients with hepatic impairment or reduced hepatic blood flow should be administered the same dosage regimens as recommended for elderly patients.

Renal Impairment

Nicardipine should be used with particular caution in these patients. In some patients with moderate renal impairment, significantly lower systemic clearance and higher area under the curve (AUC) have been observed. Therefore, patients with renal impairment should be administered the same dosage regimens as recommended for elderly patients.

Use in Children

The safety and efficacy of nicardipine in low-birth-weight infants, neonates, breastfed infants, infants, and young children have not been established.

Nicardipine should be used only in life-threatening arterial hypertension in pediatric intensive care units or for the treatment of postoperative arterial hypertension.

Initial dose: In emergency situations, the recommended initial dose is 0.5 to 5 mcg/kg/min.

Maintenance dose: The recommended maintenance dose is 1 to 4 mcg/kg/min.

Nicardipine should be used with caution in children with renal impairment. In such cases, only the lowest dose should be used.

Method of Administration

Nicardipine should be administered only by continuous intravenous infusion.

Nicardipine must be administered only by healthcare professionals in well-controlled medical settings, such as hospitals and intensive care units, with continuous blood pressure monitoring. The infusion rate should be precisely controlled using an electronic syringe pump or volumetric infusion pump. Blood pressure and heart rate should be monitored at least every 5 minutes during infusion, until vital signs stabilize, and for at least 12 hours after discontinuation of nicardipine infusion.

Children.

Safety and efficacy of intravenous nicardipine in infants or children have not been studied in controlled clinical trials; therefore, particular caution is required in this population.

Overdose.

Overdose of nicardipine hydrochloride may potentially lead to the following symptoms: marked arterial hypotension, bradycardia, tachycardia, flushing, drowsiness, collapse, peripheral edema, confusion, dysarthria, and hyperglycemia. In animals, overdose also led to reversible liver function disturbances, sporadic focal hepatic necrosis, and progressive atrioventricular conduction block.

In case of overdose, standard supportive measures are recommended, including monitoring of cardiac and respiratory function. In addition to general supportive measures, intravenous administration of calcium preparations and vasopressors is clinically indicated in patients exhibiting effects of calcium influx blockade. Marked arterial hypotension may be treated by intravenous infusion of any plasma volume-expanding agent. During infusion, the patient should remain in a supine position with legs elevated.

Nicardipine is not dialyzable.

Adverse reactions.

Most adverse effects are consequences of the vasodilatory action of nicardipine. The most common effects are headache, dizziness, peripheral edema, palpitations, and flushing.

The adverse reactions listed below were observed during clinical trials and/or following market release and are based on clinical trial data, classified according to the MedDRA System Organ Class. Frequency categories are defined 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); and not known (cannot be estimated from the available data).

System organ class	Frequency
Blood and lymphatic system disorders	Unknown – thrombocytopenia
Immune system disorders	Unknown – anaphylactic reaction
Nervous system disorders	Very common – headache
	Common – dizziness
Cardiac disorders	Common – lower limb edema, palpitations
	Common – arterial hypotension, tachycardia
	Unknown – atrioventricular block, angina pectoris
Vascular disorders	Common – orthostatic hypotension
	Unknown – flushing
Respiratory, thoracic and mediastinal disorders	Unknown – pulmonary edema*
Gastrointestinal disorders	Common – nausea, vomiting
	Unknown – paralytic ileus
Skin and subcutaneous tissue disorders	Unknown – erythema, rash
General disorders and administration site conditions	Unknown – phlebitis
Investigations	Unknown – increased levels of liver enzymes

* Cases of use as a tocolytic agent during pregnancy have also been reported.

Reporting of suspected adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, patients, or their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

Shelf life. 2 years.

Shelf life after opening the ampoule: the physicochemical stability of the undiluted solution or diluted in 5% glucose solution in a polypropylene syringe has been demonstrated for 24 hours when stored at 25 °C in a light-protected environment. However, from a microbiological standpoint, the product should be used immediately.

Storage conditions

Store in the original packaging, protected from light, at a temperature not exceeding 25 °C. Keep out of the reach of children.

Incompatibilities.

There is a risk of precipitate formation when mixed with solutions having a pH greater than 6 (e.g., bicarbonate solution, Ringer's solution, diazepam, furosemide, methohexital sodium, thiopental).

In the presence of saline solutions, there is a risk of nicardipine adsorption onto plastic materials of infusion devices.

Packaging.

10 ml in a glass ampoule; 10 ampoules per cardboard box.

The ampoules are equipped with an OPC (One Point Cut) break system.

Instructions for opening ampoules

1. Hold the ampoule with the colored dot facing upwards. If liquid is present in the upper part of the ampoule, tap it gently to allow the liquid to flow back into the main body of the ampoule.
2. Then grasp the top portion of the ampoule (above the tip) and press to break the ampoule.

Any unused medicinal product or waste material should be disposed of properly.

Prescription status.

Prescription only. For hospital use only.

Manufacturer.

Laboratoire Agetan, France.

Manufacturer's address and location of operations.

1, rue Alexander Fleming, Lyon, 69007, France