Naropin, solution for injection 7.5mg/ml ampoules polyprop

Composition

Active ingredient:

ropivacaine hydrochloride 7.5 mg;

Auxiliary substances:  

sodium chloride;

hydrochloric acid or sodium hydroxide (up to pH 4-6);

water for injection;

Pharmacological action

A long-acting local anaesthetic of the amide type. Reversibly blocks voltage-dependent sodium channels and, thus, prevents the generation of impulses in the endings of sensitive nerves and the conduction of impulses along nerve fibers.

The duration of action depends on the route of use and dose of the drug.

Pharmacokinetics

Suction

After use, ropivacaine is completely absorbed from the epidural space. Absorption is biphasic. The concentration of ropivacaine in blood plasma depends on the dose, route of use and vascularization of the injection site. The pharmacokinetics of ropivacaine are linear, Cmax is proportional to the administered dose.

The pKa distribution of ropivacaine is 8.1; the partition coefficient is 141 (n-octanol / phosphate buffer pH 7.4).

Vd is 47 liters. The average hepatic extraction rate obtained in the experiment is 0.4. Ropivacaine binds mainly to α1-acid glycoproteins in blood plasma, the unbound fraction is about 6%.

Prolonged epidural use of ropivacaine leads to an increase in the total content of ropivacaine in blood plasma, which is due to a postoperative increase in the level of α1-acid glycoproteins in the blood. At the same time, the concentration of an unbound, pharmacologically active form of ropivacaine in blood plasma changes to a much lesser extent than the total concentration.

Ropivacaine passes well through the placental barrier. Fetal plasma protein binding is lower than that of the mother.

Metabolism

It is actively biotransformed in the body, mainly by hydroxylation. The main metabolite is 3-hydroxy-ropivacaine.

T1/2 elimination is biphasic and lasts 14 minutes (alpha phase) and 4 hours (beta phase). Total plasma clearance is 440 ml/min. After intravenous use, about 86% of the dose is excreted in the urine, mainly as metabolites, and only about 1% of the dose is excreted unchanged in the urine. About 37% of 3-hydroxy-ropivacaine is excreted in the urine mainly in conjugated form.

Indications

Anesthesia during surgical procedures:

• epidural blockage for surgical procedures, including Caesarean section;
• blockage of major nerves and nerve plexuses;
• blockage of individual nerves and infiltration anesthesia.

Relief of acute pain syndrome:

• prolonged epidural infusion or periodic bolus use, for example, to eliminate postoperative pain or analgesia of labor;
• blockage of individual nerves and infiltration anesthesia;
• prolonged blockage of peripheral nerves;
• intra-articular injection.

Acute pain management in pediatrics:

• caudal epidural block in newborns and children up to 12 years of age inclusive;
• extended epidural infusion in newborns and children up to 12 years of age inclusive.

Use during pregnancy and lactation

Pregnancy

No effect of ropivacaine on fertility and reproductive function, as well as teratogenic effects, was found. No studies have been conducted to assess the possible effect of ropivacaine on fetal development in women.

Naropin® can be used during pregnancy only if it is justified by the clinical situation (in obstetrics, the use of the drug for anesthesia or analgesia is well justified).

Studies of the effect of the drug on reproductive function were conducted on animals. In rat studies, ropivacaine had no effect on fertility and reproduction in two generations. When maximum doses of the drug were administered to pregnant rats, an increase in the mortality of offspring was observed in the first three days after delivery, which may be due to the toxic effect of ropivacaine on the mother, leading to a violation of maternal instinct.

Teratogenicity studies in rabbits and rats did not reveal any side effects of ropivacaine on organogenesis or fetal development in the early stages. Also, during perinatal and postnatal studies on rats receiving the maximum tolerated dose of the drug, there were no side effects on the late stages of fetal development, labor, lactation, viability or growth of offspring. In the course of perinatal and postnatal comparative studies of ropivacaine with bupivacaine, it was shown that, in contrast to ropivacaine, the toxic effect of bupivacaine was observed at significantly lower doses of the drug and at lower concentrations of unbound bupivacaine in the blood.

Lactation

The excretion of ropivacaine or its metabolites in breast milk has not been studied. Based on experimental data, the dose of the drug received by the newborn is estimated to be 4% of the dose administered to the mother (concentration of the drug in milk/ concentration of the drug in plasma). The total dose of ropivacaine that affects the baby during breastfeeding is significantly less than the dose that can enter the fetus when the mother’s anesthetic is administered during childbirth.

If it is necessary to use the drug during breastfeeding, the ratio of the potential benefit to the mother and the possible risk to the children should be considered.

Contraindicated in children under 12 years of age.

Contraindications

• hypersensitivity to the components of the drug;
• known hypersensitivity to local anesthetics of the amide type.

With caution:  the drug should be administered to debilitated elderly patients or patients with severe concomitant diseases, such as grade II and III intracardiac conduction blockages (sinoatrial, atrioventricular, intraventricular), progressive liver diseases, severe hepatic insufficiency, severe chronic renal failure, in the treatment of hypovolemic shock. For these groups of patients, regional anesthesia is often preferred. When performing “large” blockades in order to reduce the risk of severe adverse events, it is recommended to pre-optimize the patient’s condition, as well as adjust the dose of anesthetic.

Caution should be exercised when injecting local anesthetics in the head and neck area due to the possible increased frequency of serious side effects.

When intra-articular use of the drug, caution should be exercised if the presence of a recent extensive joint injury or surgery with opening of extensive joint surfaces is suspected due to the possibility of increased absorption of the drug and a higher concentration of the drug in plasma.

Special attention should be paid when using the drug in children under 6 months of age due to immaturity of organs and functions.

Patients on a sodium-restricted diet should take into account the sodium content of the drug.

Side effects

Adverse reactions to Naropin® are similar to those to other local anesthetics of the amide type. They should be distinguished from the physiological effects that occur due to sympathetic nerve blockage during epidural anesthesia, such as a decrease in blood pressure. Blood pressure, bradycardia, or effects related to the technique of drug use, such as local nerve damage, meningitis, post-puncture headache, or epidural abscess.

Side effects of local anesthetics

Central and peripheral nervous system disorders

Possible neuropathy and spinal cord dysfunction (anterior spinal artery syndrome, arachnoiditis, ponytail syndrome), usually associated with the technique of regional anesthesia, and not with the effect of the drug.

Complete spinal block may occur as a result of accidental intrathecal use of an epidural dose.

Serious complications are possible with systemic overdose and unintentional intravascular use of the drug (see the section “Overdose”).

Acute systemic toxicity

Naropin can cause acute systemic toxic reactions when used at high doses or with a rapid increase in its concentration in the blood with accidental intravascular use of the drug or its overdose (see the section “Overdose”).

Most common side effects

Various side effects of the drug were reported, the vast majority of which were related not to the effect of the anesthetic used, but to the technique of regional anesthesia.

The most common side effects (>1%) were the following, which were considered to be of clinical significance regardless of whether a causal relationship was established with the use of an anesthetic: decreased blood pressure*, nausea, bradycardia, vomiting, paresthesia, fever, headache, urinary retention, dizziness, chills, increased blood pressure. Blood pressure, tachycardia, hypesthesia, anxiety.

Very often

From the side of the cardiovascular system: a decrease in blood pressure.

From the gastrointestinal tract:  nausea.

Often

Nervous system disorders:  paresthesia, dizziness, headache.

From the CCC side:  bradycardia, tachycardia, hypertension.

From the gastrointestinal tract:  vomiting.

From the genitourinary system:  delayed urination.

Common:  back pain, chills, fever.

Infrequently

Nervous system disorders:  anxiety, symptoms of central nervous system toxicity (seizures, large seizures, paresthesia in the perioral zone, dysarthria, numbness of the tongue, visual disturbances, tinnitus, tremor, muscle cramps), hypesthesia.

From the vascular system: fainting.

Respiratory system disorders: shortness of breath, difficulty breathing.

Common: hypothermia.

Rarely

From the CCC side: arrhythmia, cardiac arrest.

Common: allergic reactions (anaphylactic reactions, angioedema, urticaria).

Interaction

Increases the toxic effect of other local anesthetics and drugs that are structurally similar to local anesthetics of the amide type.

How to take, course of use and dosage

• the relief of acute pain: epidural at the lumbar level as a bolus of 10-20 ml (20-40 mg);
• intermittent introduction (pain during childbirth) 10-15 ml (20-30 mg) with a minimum interval of 30 min;
• continuous infusion for labor analgesia — 6-10 ml/h (12-20 mg/h);
• postoperative introduction — 6-14 ml/h (12-28 mg/h);
• thoracic epidural analgesia, continuous infusion after surgery — 6-14 ml/h (12-28 mg/h),
• conduction and infiltration anesthesia,1-100 ml (2-200 mg).

Overdose

Acute systemic toxicity

Seizures have been reported with accidental intravascular use during nerve plexus blockades or other peripheral blockades.

If the epidural dose of an anesthetic is administered incorrectly intrathecally, a complete spinal block may occur.

Accidental intravascular injection of an anesthetic may cause an immediate toxic reaction.

In case of overdose during regional anesthesia, symptoms of a systemic toxic reaction appear in a delayed order 15-60 minutes after injection due to a slow increase in the concentration of local anesthetic in the blood plasma. Systemic toxicity is primarily manifested by symptoms from the central nervous system and CVS. These reactions are caused by high concentrations of local anesthetic in the blood, which can occur due to (accidental) intravascular use, overdose, or exceptionally high adsorption from highly vascularized areas. Reactions from the central nervous system are similar for all local anesthetics of the amide type, while reactions from the CVS are more dependent on the drug administered and its dose.

Central nervous system

Manifestations of systemic toxicity from the central nervous system develop gradually: first there are visual disturbances, numbness around the mouth, numbness of the tongue, hyperacusis, ringing in the ears, dizziness. Dysarthria, tremor and muscle twitching are more serious manifestations of systemic toxicity and may precede the appearance of generalized seizures (these signs should not be taken as neurotic behavior of the patient). With the progression of intoxication, there may be loss of consciousness, seizures lasting from several seconds to several minutes, accompanied by respiratory disorders, rapid development of hypoxia and hypercapnia due to increased muscle activity and inadequate ventilation. In severe cases, respiratory arrest may even occur. The resulting acidosis, hyperkalemia, and hypocalcemia increase the toxic effects of the anesthetic.

Subsequently, due to the redistribution of the anesthetic from the central nervous system and its subsequent metabolism and excretion, a fairly rapid recovery of functions occurs, unless a large dose of the drug has been administered.

Cardiovascular system

Disorders of the cardiovascular system are signs of more serious complications. Decline Blood pressure, bradycardia, arrhythmia and, in some cases, even cardiac arrest may occur due to high systemic concentrations of local anesthetics. In rare cases, cardiac arrest is not accompanied by previous symptoms from the central nervous system. In studies on volunteers, intravenous infusion of ropivacaine resulted in inhibition of conduction and contractility of the heart muscle. External symptoms CVS is usually preceded by manifestations of CNS toxicity, which may not be noticed if the patient is under sedation (benzodiazepines or barbiturates) or under general anesthesia.

In children, early signs of systemic toxicity of local anesthetics are sometimes more difficult to detect due to the difficulties experienced by children in describing symptoms, or when regional anesthesia is used in combination with general anesthesia.

Treatment of acute toxicity

When the first signs of acute systemic toxicity appear, the drug should be discontinued immediately.

When seizures and symptoms of CNS depression appear, the patient needs adequate treatment, the purpose of which is to maintain oxygenation, stop seizures, and maintain the activity of the CVS. Oxygenation with oxygen should be provided, and if necessary, switching to mechanical ventilation. If convulsions do not stop after 15-20 seconds, anticonvulsants should be used: thiopental sodium 1-3 mg / kg IV (provides rapid relief of seizures) or diazepam 0.1 mg / kg IV (the effect develops more slowly compared to the effect of thiopental sodium). Suxamethonium 1 mg / kg quickly stops seizures, but its use requires intubation and mechanical ventilation.

When the activity of the CCC is suppressed (decrease Blood pressure, bradycardia) should be intravenously administered 5-10 mg of ephedrine, if necessary, repeat the use after 2-3 minutes. If circulatory failure or cardiac arrest develops, standard resuscitation measures should be initiated immediately. It is vital to maintain optimal oxygenation, ventilation, and blood circulation, as well as correct acidosis. In case of cardiac arrest, longer resuscitation measures may be required.

When treating systemic toxicity in children, it is necessary to adjust the dose according to the patient’s age and body weight.

Special instructions

Anesthesia should be performed by experienced specialists. It is mandatory to have equipment and medicines for resuscitation. An intravenous catheter should be inserted before major blockages are performed.

Anaesthetic personnel should be appropriately trained and familiar with the diagnosis and treatment of possible side effects, systemic toxic reactions and other possible complications (see section “Overdose”).

A complication of unintentional subarachnoid injection may be spinal block with respiratory arrest and a decrease in blood pressure. Convulsions develop more frequently with brachial plexus block and epidural block, probably due to accidental intravascular use or rapid absorption at the injection site.

Performing peripheral nerve blockages may require the use of a large volume of local anesthetic to areas with a large number of vessels, often near large vessels, which increases the risk of intravascular use and/or rapid systemic absorption, which can lead to a high concentration of the drug in plasma.

Some procedures involving the use of local anesthetics, such as injections in the head and neck area, may be accompanied by an increased frequency of serious side effects, regardless of the type of local anesthetic used. Care must be taken to prevent injection into the inflamed area.

Caution should be exercised when administering the drug to patients with grade II and III intracardiac conduction block, patients with severe renal insufficiency, elderly and debilitated patients.

Rare cases of cardiac arrest have been reported with the use of Naropin® for epidural anesthesia or peripheral nerve block, especially after accidental intravascular use of the drug, in elderly patients and in patients with concomitant cardiovascular diseases.

In some cases, resuscitation measures were difficult. Cardiac arrest, as a rule, requires longer resuscitation measures.

Since Naropin® is metabolized in the liver, caution should be exercised when using the drug in patients with severe liver diseases; in some cases, due to delayed elimination, it may be necessary to reduce the repeatedly administered doses of the anesthetic.

Usually, in patients with renal insufficiency, when the drug is administered once or when the drug is used for a short period of time, it is not necessary to adjust the dose. However, acidosis and a decrease in the concentration of proteins in blood plasma, often developing in patients with chronic renal failure, may increase the risk of systemic toxic effects of the drug (see the section “Dosage and use”). The risk of systemic toxicity is also increased when using the drug in patients with low body weight and patients with hypovolemic shock.

Epidural anesthesia can lead to a decrease in Blood pressure and bradycardia. The introduction of vasoconstrictor drugs or an increase in BCC may reduce the risk of such side effects. The decline should be corrected in a timely manner Blood pressure by intravenous use of 5-10 mg of ephedrine, repeated if necessary.

When intra-articular use of the drug, caution should be exercised if the presence of a recent extensive joint injury or surgical operation with opening of extensive joint surfaces is suspected, due to the possibility of increased absorption of the drug and a higher concentration of the drug in plasma.

Patients receiving therapy with class III antiarrhythmic drugs (for example, amiodarone) should be carefully monitored, it is recommended ECG monitoring due to the risk of increased cardiovascular effects.

Long-term use of Naropin® should be avoided in patients taking strong P4501a2 inhibitors (such as fluvoxamine and enoxacin).

The possibility of cross-hypersensitivity should be considered when using Naropin® concomitantly with other local anesthetics of the amide type.

Patients on a sodium-restricted diet should take into account the sodium content of the drug.

The use of the drug in newborns requires taking into account the possible immaturity of organs and physiological functions of newborns. Clearance of the unbound fraction of ropivacaine and pipeloxylidine (PPK) depends on the child’s body weight and age in the first years of life. The effect of age is expressed in the development and maturity of liver function; clearance reaches its maximum value at the age of about 1-3 years. T_1/2 of ropivacaine is 5-6 hours in newborns and children aged 1 month, compared with 3 hours in older children. Due to the insufficient development of liver functions, the systemic exposure of ropivacaine is higher in newborns, moderately higher in children from 1 to 6 months compared to older children. Significant differences in the plasma concentrations of ropivacaine in newborns, identified in clinical studies, suggest an increased risk of systemic toxicity in this group of patients, especially with prolonged epidural infusion.

Recommended doses for newborns are based on limited clinical data.

When using ropivacaine in newborns, it is necessary to monitor systemic toxicity (monitoring signs of toxicity from the central nervous system, ECG, monitoring of blood oxygenation) and local neurotoxicity, which should be continued after the end of the infusion due to the slow elimination of the drug in newborns.

The use of the drug in concentrations above 5 mg/ml, as well as the intrathecal use of Naropin® in children, has not been studied.

Naropin ® has the potential to cause porphyria and can only be used in patients diagnosed with acute porphyria if there is no safer alternative. In case of hypersensitivity of patients, the necessary precautions should be taken.

Cases of chondrolysis have been reported with postoperative prolonged intra-articular infusion of local anesthetics. In most of the cases described, an infusion was performed in the shoulder joint. A causal relationship with the use of anesthetics has not been established. Naropin®should not be used for prolonged intra-articular infusion.

Influence on the ability to drive vehicles and other mechanisms. In addition to the analgesic effect, Naropin® may have a weak transient effect on motor function and coordination. Given the side effect profile of the drug, caution should be exercised when driving vehicles and performing other potentially dangerous activities that require increased concentration of attention and speed of psychomotor reactions.

Form of production

Solution for injection

Storage conditions

At temperatures below 30 °C (do not freeze)

Shelf life

3 years

Active ingredient

Ropivacaine

Conditions of release from pharmacies

By prescription

Dosage form

solution for injection

Purpose

Adult Doctor’s prescription