Active ingredients: Ropivacaine (Ropivacaine hydrochloride)
Naropin 2 mg / ml, 7.5 mg / ml, 10 mg / ml solution for injection
Naropin 2 mg / ml solution for infusion
Naropin package inserts are available for pack sizes: - Naropin 2 mg / ml, 7.5 mg / ml, 10 mg / ml solution for injection, Naropin 2 mg / ml solution for infusion
- Naropin 5 mg / ml solution for injection
Indications Why is Naropin used? What is it for?
The name of the medicine is "Naropin solution for injection" or "Naropin solution for infusion".
- It contains a medicine called ropivacaine hydrochloride.
- It belongs to a group of medicines called local anesthetics.
- It will be given to you either as an injection or as an infusion, depending on how it is used. Naropin 7.5 mg / ml is used in adults and children over 12 years of age to numb (numb) parts of the body. It is used to prevent pain from appearing or to provide pain relief.
It can be used for:
- Anesthetize parts of the body during surgery, including caesarean delivery.
- Relieve pain during childbirth, after surgery or after an injury.
Naropin 2 mg / ml is used in adults and children of all ages for the treatment of acute pain.It numbs (anesthetizes) parts of the body, eg. after surgery.
Contraindications When Naropin should not be used
You should not be given Naropin:
- If you are allergic (hypersensitive) to ropivacaine hydrochloride or any of the other ingredients of Naropin (see section 6: Further information).
- If you are allergic to any other local anesthetic of the same class (e.g. lidocaine or bupivacaine).
- If you have been told that you have decreased blood volume (hypovolaemia).
- In a blood vessel to numb a specific area of the body or in the cervix to relieve pain during childbirth.
If you are not sure whether any of the above apply to you, consult your doctor before receiving Naropin.
Precautions for use What you need to know before taking Naropin
before receiving Naropina. Take special care with Naropin:
- Tell your doctor if you have heart, liver or kidney problems as your doctor may need to adjust the dose of Naropin.
- Tell your doctor if you have been told that you or a member of your family have a rare blood disorder called "porphyria", in which case the doctor may give you a different anesthetic.
- Inform your doctor of all previous illnesses or medical conditions prior to treatment.
- In newborn babies as they are more sensitive to Naropin.
- In children up to and including 12 years of age, as some injections to numb areas of the body have not been evaluated in younger children.
- In children up to and including 12 years of age, since the use of Naropin 7.5 mg / ml and 10 mg / ml injections to numb areas of the body have not been evaluated. Dosages of Naropin 2 mg / ml and 5 mg / ml may be more suitable.
Interactions Which drugs or foods can modify the effect of Naropin
Tell your doctor if you are taking or have recently taken any other medicines, including those without a prescription and herbal medicines. Naropin can affect the mechanism of action of other drugs and some medicines can have an effect on Naropin.
In particular, tell your doctor if you are taking any of the following medicines:
- Other local anesthetics
- Strong pain relievers, such as morphine or codeine.
- Medicines used to treat irregular heartbeat (arrhythmia), such as lidocaine and mexiletine. Your doctor should be informed that you are taking these medicines in order to determine the correct dose of Naropin.
Also tell your doctor if you are taking any of the following medicines:
- Medicines for depression (such as fluvoxamine).
- Antibiotics to treat infections caused by bacteria (such as enoxacin). It takes the body longer to eliminate Naropin if you take these medicines. If you are taking any of these medicines, prolonged use of Naropin should be avoided.
Warnings It is important to know that:
Pregnancy and breastfeeding
Before receiving Naropin, tell your doctor if you are pregnant, planning to become pregnant or breastfeeding. It is not known whether ropivacaine hydrochloride affects pregnancy or passes into breast milk.
Ask your doctor or pharmacist for advice before taking any medicine if you are pregnant or breastfeeding.
Driving and using machines
Naropin may make you feel drowsy and affect the reaction rate. After receiving Naropin, you should not drive or use any tools or machines until the next day.
Important information about some of the ingredients of Naropin
Naropin contains up to 3.7 milligrams (mg) of sodium in each milliliter (ml) of solution. If you are on a controlled sodium diet, you will need to take this into account.
Dose, Method and Time of Administration How to use Naropin: Posology
Naropin will be given to you by a doctor. The dose your doctor gives will depend on the type of pain relief you need. It will also depend on your size, age and physical condition.
Naropin will be given to you as an injection or infusion. The part of the body where it will be given will depend on why Naropin is given. Your doctor will administer Naropin in one of the following places:
- The part of the body that needs to be anesthetized.
- The area near the part of the body that needs to be anesthetized.
- An area away from the part of the body that needs to be anesthetized. This is when an "epidural or infusional injection (in an" area around the spinal cord) is given.
When Naropin is used in any of the above ways, it stops the nerves from transmitting pain messages to the brain. He will not feel the sensation of pain, heat or cold, but he may have other sensations such as pressure or touch.
Your doctor will know the correct way to give the medicine.
Overdose What to do if you have taken an overdose of Naropin
Serious side effects from taking too much Naropin need special treatment and your doctor can handle these situations. The first signs of a Naropin overdose are usually the following:
- Feeling dizzy or lightheaded.
- Numbness of the lips and around the mouth.
- Numbness of the tongue.
- Hearing problems.
- Problems with sight (vision).
To reduce the risk of serious side effects, your doctor will stop taking Naropin as soon as these signs appear.
This means that if any of the above occur, or if you think you have received too much Naropin, you should inform your doctor immediately.
The more serious side effects resulting from an overdose of Naropin include speech problems, muscle spasms, tremors, tremors, seizures (fits) and loss of consciousness.
Side Effects What are the side effects of Naropin
Like all medicines, Naropin can cause side effects, although not everybody gets them.
Important side effects to watch out for:
Sudden and life-threatening allergic reactions (such as anaphylaxis) are rare, affecting 1 to 10 patients in 10,000. Possible symptoms include sudden onset of rash, itching or lumpy rash (hives); swelling of the face, lips, tongue or other parts of the body; wheezing, wheezing or difficulty breathing.
If you think Naropin is causing an allergic reaction, tell your doctor right away.
Other possible side effects:
Very common (affects more than 1 in 10 patients)
- Low blood pressure (hypotension). It can cause dizziness or mental confusion.
- Feeling sick (nausea).
Common (affects 1 to 10 users in 100)
- Paresthesia.
- Dizziness
- Headache.
- Slow or rapid heartbeat (bradycardia, tachycardia).
- High blood pressure (hypertension).
- He retched.
- Difficulty urinating.
- High temperature (fever) or tremors (chills).
- Back pain.
Uncommon (affects 1 to 10 users in 1,000)
- Anxiety.
- Reduced skin sensitivity.
- Fainting.
- Difficult breathing.
- Low body temperature (hypothermia).
- Some symptoms may occur if you have been injected into a blood vessel by mistake or if you have been given an overdose of Naropin (see also "If you are given more Naropin than you should"). These include seizures (fits), dizziness o mental confusion, numbness of the lips and around the mouth, numbness of the tongue, hearing problems, sight (vision) problems, speech problems, muscle stiffness and tremor.
Rare (affects 1 to 10 users in 10,000)
- Heart attack (cardiac arrest).
- Irregular heartbeat (arrhythmia).
Other possible side effects include:
- Numbness, due to nerve irritation caused by the needle or injection. It usually doesn't last long.
- Involuntary muscle movements (dyskinesia).
Possible side effects seen with other local anesthetics, which could also be caused by Naropin, are:
- They hurt the nerves. Rarely (affects 1 to 10 users in 10,000), this can cause permanent problems.
- If an overdose of Naropin is given into the spinal fluid, the whole body may become numb (anesthetized).
Children
In children, the side effects are the same as in adults, with the exception of blood pressure lowering which affects children less frequently (affects 1 to 10 children in 100) and vomiting which occurs more often in children (affects more than 1 child). child on 10).
Reporting of side effects
If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system at www.agenziafarmaco.gov.it/it. / responsible. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
- Keep out of the reach and sight of children.
- Do not use Naropin after the expiry date which is stated on the package, after EXP. The expiry date refers to the last day of the month.
- Do not store above 30ºC. Do not freeze.
- Naropin will normally be kept by your doctor or hospital, who are also responsible for the quality of the product if it is not used immediately after opening. The medicinal product should be visually inspected prior to use. The solution should only be used if clear, substantially free of particles and if the container is intact.
- They are also responsible for the proper disposal of any unused Naropin.
Deadline "> Other information
What Naropin contains
The active ingredient is ropivacaine hydrochloride.
Naropin is provided in the following strengths: 2 mg, 7.5 mg or 10 mg of ropivacaine hydrochloride per ml of solution.
The other ingredients are sodium chloride, hydrochloric acid and / or sodium hydroxide and water for injections.
What Naropin looks like and contents of the pack
Naropin is a clear and colorless solution for injection or infusion.
Naropin solution for injection 2 mg / ml, 7.5 mg / ml and 10 mg / ml is available in:
- 10 ml polypropylene vials (Polyamp) in packs of 5 or 10.
- 20 ml polypropylene vials (Polyamp) in packs of 5 or 10.
Naropin solution for infusion 2 mg / ml is available in:
- 100 ml polypropylene bags (Polybag) in packs of 5.
- 200 ml polypropylene bags (Polybag) in packs of 5.
Not all types of pack sizes may be marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT -
NAROPINE
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -
Naropin 2 mg / ml:
1 ml of solution for injection contains ropivacaine hydrochloride monohydrate equivalent to 2 mg of ropivacaine hydrochloride.
1 ampoule of 10 ml or 20 ml of solution for injection contains ropivacaine hydrochloride monohydrate equivalent to 20 mg and 40 mg of ropivacaine hydrochloride respectively.
1 bag of 100 ml solution for infusion contains ropivacaine hydrochloride monohydrate equivalent to 200 mg ropivacaine hydrochloride.
Naropin 7.5 mg / ml:
1 ml of solution for injection contains ropivacaine hydrochloride monohydrate equivalent to 7.5 mg of ropivacaine hydrochloride.
1 ampoule of 10 ml or 20 ml of solution for injection contains ropivacaine hydrochloride monohydrate equivalent to 75 mg and 150 mg of ropivacaine hydrochloride respectively.
Naropin 10 mg / ml:
1 ml of solution for injection contains ropivacaine hydrochloride monohydrate equivalent to 10 mg of ropivacaine hydrochloride.
1 ampoule of 10 ml or 20 ml of solution for injection contains ropivacaine hydrochloride monohydrate equivalent to 100 mg and 200 mg of ropivacaine hydrochloride respectively.
Excipients:
2 mg / ml:
Each 10 ml vial contains 1.48 mmol (34 mg) of sodium
Each 20 ml vial contains 2.96 mmol (68 mg) of sodium
Each 100 ml bag contains 14.8 mmol (340 mg) of sodium
7.5 mg / ml:
Each 10 ml vial contains 1.3 mmol (29.9 mg) of sodium
Each 20 ml vial contains 2.6 mmol (59.8 mg) of sodium
10 mg / ml:
Each 10 ml vial contains 1.2 mmol (28 mg) of sodium
Each 20 ml vial contains 2.4 mmol (56 mg) of sodium
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM -
Injectable solution.
Solution for infusion.
Clear and colorless solution.
04.0 CLINICAL INFORMATION -
04.1 Therapeutic indications -
Naropin 7.5 mg / ml and 10 mg / ml is indicated in adults and adolescents over 12 years for:
Surgical anesthesia:
- epidural blocks in surgery, including caesarean section
- major nerve blocks
- blocks of the surgical field
Naropin 2 mg / ml is indicated for the treatment of acute pain:
In adults and adolescents over 12 years for:
- continuous epidural infusion or intermittent bolus administration for post-operative pain and in the analgesia of childbirth
- blocks of the surgical field
- continuous block of peripheral nerves by continuous infusion or by intermittent bolus injections, for example for the treatment of post-operative pain
In infants from 1 year and children up to and including 12 years (peri and postoperative):
- single and continuous block of peripheral nerves
In newborns, infants and children up to and including 12 years of age (peri and postoperative):
- caudal epidural block
- continuous epidural infusion
04.2 Posology and method of administration -
Naropin should only be used by physicians experienced in regional anesthesia or under their supervision.
Dosage
Adults and adolescents over 12 years of age
The table below is a guide to recommended dosages in the most common block types. The dose to be used should be the lowest required for effective blockade. The dose to be administered should be chosen based on the physician's experience and knowledge of the patient's clinical status.
Table 1 Adults and adolescents over 12 years of age
The doses shown in the table are those considered necessary to produce adequate blockade and should be considered as a guide for use in adults. However, individual variations in onset of activity and duration may occur. The "dose" column shows the intervals. of average dose needed Reference texts should be consulted both on aspects that affect specific blocking techniques and on the individual needs of the patient.
* With respect to major nerve block, a dose for brachial plexus block only may be recommended.
For other types of major nerve blocks, lower doses may be required.However, there is currently no experience of specific recommended doses for other types of blockade.
1) Increasing doses should be administered starting from a dose of approximately 100 mg (97.5 mg = 13 ml; 105 mg = 14 ml) over 3-5 minutes. If necessary, two additional doses can be used up to a total of 50 mg.
2) n / a = not applicable.
3) The dose for major nerve block should be adjusted according to the site of administration and the patient's condition.
Blockages of the interscalenic and supraclavicular brachial plexuses may be associated with a higher frequency of serious adverse reactions, regardless of the local anesthetic used (see section 4.4).
In general, surgical anesthesia (eg for epidural administration) requires the use of higher concentrations and dosages. The use of Naropin 10 mg / ml is recommended for epidural anesthesia in surgery where complete motor block is required. Lower concentrations and dosages are recommended for analgesia (eg for epidural administration for the treatment of acute pain). .
Method of administration
To avoid intravascular injection, careful aspiration before and during injection is recommended. When a high dose is to be injected it is recommended that a test dose of 3 - 5 ml lidocaine with adrenaline (epinephrine) be performed. An "accidental intravascular injection can be recognized by the temporary increase in heart rate, while an" accidental intrathecal injection can be recognized by the signs of spinal block.
Aspiration must be performed before and during the administration of the drug, which must be injected slowly or in divided doses, at a rate of 25-50 mg / minute, keeping the patient's vital signs under close observation and maintaining verbal contact. symptoms of toxicity should be discontinued immediately.
In epidural block surgery, single doses of up to 250 mg of ropivacaine have been used and well tolerated.
In brachial plexus block a single dose of 300 mg was administered in a limited number of patients and was well tolerated.
When prolonged blocks are performed, either by continuous epidural infusion or by repeated bolus administration, the possible risk of reaching toxic plasma concentrations or inducing local neuronal damage should be considered. Cumulative doses of up to 675 mg of ropivacaine administered over 24 hours for surgical anesthesia and analgesia in the postoperative period were well tolerated in adults, as were continuous epidural infusions of up to 28 mg / h for 72 hours in the post-operative period. In a limited number of patients, higher doses up to 800 mg / day have been administered with a relatively low number of adverse reactions.
For the treatment of post-operative pain, the following technique is recommended: unless it has already been induced before surgery, epidural block is performed with Naropin 7.5 mg / ml administered via an epidural catheter. Analgesia is then performed. maintained with infusion of Naropin 2 mg / ml: in most cases of moderate to severe post-operative pain the infusion of 6 - 14 ml (12 - 28 mg / h) maintains adequate analgesia, only with a mild and non-progressive motor block. The maximum duration of epidural block is 3 days. In any case, careful monitoring of the analgesic effect should be carried out in order to remove the catheter as soon as the intensity of the pain permits. A significant reduction in the need to use opioids was observed with this technique.
In clinical studies, an epidural infusion of Naropin 2 mg / ml, alone or mixed with fentanyl 1-4 mcg / ml, was administered for up to 72 hours for post-operative pain control.
The combination of Naropin with fentanyl allowed for further pain control but caused side effects due to opioid administration.
The combination of Naropin and fentanyl has only been studied for Naropin 2 mg / ml.
When prolonged peripheral nerve blocks are performed, either through continuous infusion or through repeated injections, the risks of reaching a toxic plasma concentration or causing local neuronal damage should be considered. In clinical trials, femoral nerve block was achieved with 300 mg Naropin 7.5 mg / mL and interscalenic block with 225 mg Naropin 7.5 mg / mL, respectively, prior to surgery. L " analgesia was then maintained with Naropin 2 mg / ml. Infusion rates or intermittent injections of 10 - 20 mg every hour for 48 hours provided adequate analgesia and were well tolerated.
The use of Naropin at concentrations higher than 7.5 mg / ml is not documented in caesarean section.
Pediatric population
Table 2 Epidural Block: Pediatric Patients 0 (full-term infants) to 12 years
The dose indicated in the table should be considered as a guide for use in pediatrics. Individual variations may be necessary. In pediatric patients with high body weight, a gradual reduction in dosage is often necessary and should be based on ideal weight. epidural caudal block and the volume for epidural bolus doses should not exceed 25 ml for each patient Reference texts should be consulted both with regard to aspects that affect specific blocking techniques, as well as the individual needs of the patient.
a) In the reported dose range, lower doses are recommended for thoracic epidural blocks, while higher doses are recommended for lumbar or caudal epidural blocks.
b) Recommended for lumbar epidural blocks. It is good practice to reduce the bolus dose for epidural thoracic analgesia.
The use of ropivacaine 7.5 mg / ml and 10 mg / ml may be associated with systemic and central toxic events in children. Lower concentrations (2 mg / ml and 5 mg are more appropriate for administration in this population). / ml).
The use of ropivacaine in preterm infants has not been documented.
Table 3 Peripheral Nerve Blocks: Infants and Children 1 to 12 Years Old
The dose indicated in the table should be considered as a guide for use in pediatrics. Individual variations may be necessary. In pediatric patients with high body weight, a gradual reduction in dosage is often necessary and should be based on ideal weight. they should be consulted both about aspects that affect specific blocking techniques and about the individual needs of the patient.
Single injections for peripheral nerve block (e.g. ilioinguinal nerve block, brachial plexus block, iliac fascia compartment block) should not exceed 2.5 - 3.0 mg / kg.
Doses for peripheral block in infants and children provide guidelines for use in children without severe disease. More conservative doses and careful monitoring are recommended for children with severe disease.
Method of administration
Careful aspiration before and during injection is recommended to avoid intravascular administration. The patient's vital signs should be closely observed during the injection. If signs of toxicity occur, administration should be discontinued immediately.
In the majority of patients, a single caudal epidural injection of ropivacaine 2 mg / ml below the T12 level produces "adequate postoperative analgesia when a dose of 2 mg / kg in a volume of 1 ml / kg is used. "Caudal epidural injection can be adapted to achieve a different distribution of sensory block, as indicated in the reference texts. Doses up to 3 mg / kg for a ropivacaine concentration of 3 mg / ml have been evaluated in children over 4 years of age. However, a "high incidence of motor block is associated with this concentration."
Gradual administration of the calculated dose of local anesthetic is recommended, whatever the route of administration.
04.3 Contraindications -
Hypersensitivity to ropivacaine or to other local anesthetics of the amide type.
The typical contraindications of epidural anesthesia must be taken into consideration, regardless of the local anesthetic used.
Regional intravenous anesthesia.
Obstetric paracervical anesthesia.
Hypovolemia.
04.4 Special warnings and appropriate precautions for use -
Regional anesthesia procedures must always be performed in adequately equipped areas and by qualified personnel. In addition, the tools and drugs necessary for monitoring and emergency resuscitation must be immediately available.
Patients undergoing major blockade must be in optimal condition and have an intravenous catheter inserted prior to the blocking procedure.
The responsible anesthetist must take adequate precautions to avoid an intravascular injection (see section 4.2) and must have adequate experience and knowledge regarding the diagnosis and treatment of side effects, systemic toxicity and other complications (see sections 4.8 and 4.9). such as an accidental subarachnoid injection which can lead to a high spinal block with apnea and hypotension. Convulsions occurred more frequently after brachial plexus block and epidural block. This is likely to result from either accidental intravascular injection or rapid absorption from the injection site.
Use caution to avoid giving injections into inflamed areas.
Cardiovascular
Patients treated with class III antiarrhythmic drugs (e.g. amiodarone) should be closely monitored and ECG monitoring should be considered, as cardiac effects can be additive.
Rare cases of cardiac arrest have been reported during use of Naropin under epidural anesthesia or in peripheral nerve block, especially following accidental intravascular administration in elderly patients and in patients with concomitant heart disease. In some cases resuscitation has been In the event of cardiac arrest, a sustained resuscitation effort may be required to increase the chances of success.
Blockage in the cervical and head
Some local anesthesia procedures, such as injections to the head and neck regions, may be associated with a higher frequency of serious adverse reactions, regardless of the local anesthetic used.
Blockage in the major peripheral nerves
Blockade of the peripheral major nerves may result in the administration of a larger volume of local anesthetic in a highly vascularized area, often in the vicinity of large blood vessels, where there is an increased risk of intravascular injection and / or rapid systemic absorption, which can lead to high plasma concentrations.
Hypersensitivity
The possibility of cross-hypersensitivity with other local anesthetics of the amide type should be considered.
Hypovolemia
Patients with hypovolaemia, due to any cause, may be subject to sudden and severe hypotension during epidural anesthesia, regardless of the local anesthetic used.
Patients in poor general conditions
Patients in poor general conditions, due to age or other compromising factors such as partial or complete block of cardiac conduction, advanced liver disease or severe renal impairment, require special attention, nevertheless regional anesthesia it is frequently indicated in these patients.
Patients with impaired hepatic and renal function
Ropivacaine is metabolised by the liver and therefore should be used with caution in patients with severe hepatic impairment; repeated dose administration should be reduced due to delayed elimination. When Naropin is used as a single dose or for short-term treatment in patients with impaired renal function, no dose adjustment is normally required. Acidosis and decreased plasma protein concentrations, frequently observed in patients with chronic renal failure, may increase the risk of systemic toxicity.
Acute porphyria
Naropin solution for injection and infusion is probably porphyrinogenic and should only be prescribed in patients with acute porphyria when no safer alternatives are available. Appropriate precautions must be taken in cases of vulnerable patients, in accordance with what is reported in the standard reference texts and / or in consultation with experts in this disease.
Chondrolysis
There have been post-marketing reports of chondrolysis in patients who received a continuous postoperative intra-articular infusion of local anesthetics, including ropivacaine. Most of the reported cases of chondrolysis involved the shoulder joint. Continuous intra-articular infusion is not an approved indication for Naropin. Continuous intra-articular infusion with Naropin should be avoided as efficacy and safety have not been established.
Excipients with known actions / effects
The medicinal product contains a maximum of 3.7 mg of sodium per ml, this should be taken into consideration in patients on a controlled sodium diet.
Prolonged administration
Prolonged administration of ropivacaine should be avoided in patients concomitantly treated with strong CYP1A2 inhibitors, such as fluvoxamine and enoxacin (see section 4.5).
Pediatric population
Particular attention should be paid to neonates due to the immaturity of the metabolic pathways. The wide variations in plasma concentrations of ropivacaine observed in clinical studies conducted in neonates suggest that there may be an increased risk of systemic toxicity in this age group, especially during the epidural infusion continues.
The recommended doses in neonates are based on limited clinical data.
When ropivacaine is used in this patient group, regular monitoring of systemic toxicity (e.g. signs of central nervous system toxicity, ECG, SpO2) and local neurotoxicity (e.g. protracted recovery) is required. Following the slow elimination of the product in neonates, the control should continue even after the end of the infusion.
- The safety and efficacy of ropivacaine 7.5 mg / ml and 10 mg / ml in children up to and including 12 years have not yet been established.
- The safety and efficacy of ropivacaine 2 mg / ml for surgical field blockade have not been established for children below 12 years.
- The safety and efficacy of ropivacaine 2 mg / ml for peripheral nerve block have not been established for infants less than 1 year of age.
04.5 Interactions with other medicinal products and other forms of interaction -
Naropin should be used with caution in patients being treated with other local anesthetics or substances structurally related to local amide-type anesthetics, for example certain antiarrhythmics, such as lidocaine and mexiletine, as the systemic toxic effects are additive.
The concomitant use of Naropin with general anesthetics or opiates may result in a reciprocal enhancement of the respective (adverse) effects.
No specific interaction studies have been performed with ropivacaine and class III antiarrhythmic drugs (e.g. amiodarone), but caution is recommended in these cases (see also section 4.4).
Cytochrome P450 (CYP) 1A2 is involved in the formation of the major metabolite of ropivacaine, 3-hydroxy ropivacaine. In vivo, the plasma clearance of ropivacaine is reduced by up to 77% during co-administration with fluvoxamine, a selective and potent inhibitor of CYP1A2. Consequently, strong inhibitors of CYP1A2, such as fluvoxamine and enoxacin, may interact with Naropin when given concomitantly with its prolonged administration. Prolonged administration of ropivacaine should be avoided in patients concomitantly treated with strong CYP1A2 inhibitors, see also section 4.4.
In vivo, the plasma clearance of ropivacaine is reduced by 15% during concomitant administration of ketoconazole, a selective and potent inhibitor of CYP3A4. However, inhibition of this isoenzyme does not appear to have clinical relevance.
In vitro ropivacaine is a competitive inhibitor of CYP2D6, but does not appear to inhibit this isoenzyme at clinical plasma concentrations.
04.6 Pregnancy and breastfeeding -
Pregnancy
Except for epidural administration in obstetrics, there are insufficient data on the use of ropivacaine in pregnant women.Experimental studies in animals do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal / fetal development, parturition or postnatal development (see section 5.3).
Feeding time
No data are available on the excretion of ropivacaine in human milk.
04.7 Effects on ability to drive and use machines -
There is no data available on this. In relation to the dose, local anesthetics may have less influence on mental function and coordination, even in the absence of obvious central nervous system toxicity, and may temporarily adversely affect locomotion and alertness.
04.8 Undesirable effects -
General
The adverse reaction profile of Naropin is similar to that of other long-acting amide-type local anesthetics. Adverse drug reactions must be distinguished from physiological effects of nerve block such as decreased blood pressure and bradycardia. during spinal / epidural block.
Table 4. Table of adverse reactions
The frequencies used in the table in section 4.8 are: very common (≥1 / 10), common (≥1 / 100,
to) Hypotension is less common in children (> 1/100).
b) Vomiting is more common in children (> 1/10).
* these symptoms usually occur following accidental intravascular administration, overdose or rapidly absorbed, see section 4.9.
Class-related adverse drug reactions
Neurological complications
Regardless of the local anesthetic used, neuropathies and spinal cord alterations (eg anterior spinal artery syndrome, arachnoiditis, cauda equina syndrome) have been associated with regional anesthesia, which in rare cases can cause permanent sequelae.
Total spinal block
Total spinal block can occur when an epidural dose is accidentally administered intrathecally.
Acute systemic toxicity
Systemic toxic reactions primarily involve the central nervous system (CNS) and the cardiovascular system (CVS). These reactions are caused by a "high blood concentration of local anesthetic which may be triggered by" accidental intravascular injection, overdose or exceptionally rapid absorption from a highly vascularized area, see section 4.4. CNS reactions are similar in terms of all local anesthetics of the amide type, while cardiac reactions are more dependent on the drug, both in quantitative and qualitative terms.
Central nervous system toxicity
Central nervous system toxicity occurs gradually with symptoms and signs of increasing severity. Initially, symptoms such as: visual or auditory disturbances, perioral hypoesthesia, dizziness, mental confusion, vellichio and paraesthesia are noted. The most serious effects are dysarthria, muscle stiffness and muscle spasm and may precede the onset of generalized convulsions. These symptoms should not be confused with neurotic behavior. Unconsciousness and seizures (grand mal) may follow which can last from a few seconds to several minutes During seizures due to increased muscle activity and interference with breathing, hypoxia and hypercapnia can rapidly develop. In severe cases, apnea can also occur. Respiratory and metabolic acidosis increases and prolongs the toxic effects of local anesthetics.
The patient's return to initial clinical conditions results from the redistribution of local anesthetics in the central nervous system and subsequent metabolism and excretion. Recovery can be quick if large amounts of the drug have not been administered.
Cardiovascular system toxicity
Cardiovascular toxicity indicates a more serious situation. As a result of high systemic concentrations of local anesthetics, hypotension, bradycardia, arrhythmia and even cardiac arrest can be generated. In volunteers, intravenous infusion of ropivacaine induced a decrease in conductivity and contractility.
Cardiovascular toxic effects are generally preceded by signs of central nervous system toxicity, unless the patient has received a general anesthetic or has been heavily sedated with benzodiazepines or barbiturates.
In children, early signs of local anesthetic toxicity may be difficult to detect as they may not be able to express themselves verbally. See section 4.4.
Pediatric population
Frequency, type and severity of adverse reactions in children are assumed to be the same as in adults with the exception of hypotension which occurs less often in children (1 in 10).
In children, early signs of local anesthetic toxicity may be difficult to detect as they may not be able to express it verbally (see also section 4.4).
Treatment of acute systemic toxicity
See section 4.9.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address www.agenziafarmaco.gov.it/it/responsabili.
04.9 Overdose -
Symptoms
Accidental intravascular injection of local anesthetics can cause immediate systemic toxic effects (within seconds to minutes). In overdose cases the peak plasma concentration may not be reached between the first and second hour, depending on the injection site and therefore signs of toxicity may be delayed (see section 4.8).
Treatment
Administration of local anesthetics should be discontinued immediately if symptoms of acute systemic toxicity appear and CNS symptoms (CNS convulsions and depression) should be rapidly treated with appropriate airway / respiratory support and administration of anticonvulsant drugs.
Should circulatory arrest occur, cardiopulmonary resuscitation should be performed immediately. It is vital to ensure optimal oxygenation, support ventilation and circulation, and treat acidosis.
In case of cardiovascular depression (hypotension, bradycardia) appropriate treatment with intravenous fluids, vasoconstrictors and or inotropic drugs should be considered. Children should be given an age- and weight-appropriate dosage.
In the event of cardiac arrest, protracted resuscitation may be required to increase the chances of success.
05.0 PHARMACOLOGICAL PROPERTIES -
05.1 "Pharmacodynamic properties -
Pharmacotherapeutic group: local anesthetics, starches.
ATC code: N01B B09.
Ropivacaine is a long-acting local anesthetic of the amide type with both anesthetic and analgesic effects. At high doses Naropin produces surgical anesthesia, while lower doses induce a sensory block with limited and non-progressive motor block.
The mechanism of action is ascribable to a reversible reduction in the permeability of the membrane of the nerve fibers to sodium ions. This results in a decrease in the depolarization rate and an increase in the excitability threshold which result in the blocking of nerve impulses at a local level.
The most characteristic property of ropivacaine is its long duration of action. The onset of activity and the duration of local anesthetic efficacy depend on the site of administration and dosage and are not influenced by the presence of a vasoconstrictor (eg . adrenaline (epinephrine)). For details regarding the initiation of activity and the duration of action, please refer to Table 1 reported in the "Posology and method of administration".
In healthy volunteers, ropivacaine administered as an intravenous infusion was well tolerated at low doses. At high dosages (maximum tolerated dose) the expected symptoms of the Central Nervous System occurred. Clinical studies with this drug indicate a good tolerance margin when used adequately at recommended doses.
05.2 "Pharmacokinetic properties -
Ropivacaine has a chiral center and is available as a pure left-handed enantiomer form. It is highly fat soluble. All its metabolites have a local anesthetic effect but of considerably less potency and shorter duration than ropivacaine.
The plasma concentration of ropivacaine depends on the dosage, the route of administration and the vascularity of the injection site.
Ropivacaine follows linear kinetics and Cmax is dose proportional.
Ropivacaine shows, in the adult, a complete and biphasic absorption from the epidural space, with half-life of the two phases of the order of 14 minutes and 4 hours, respectively. Slow absorption is the limiting factor in the elimination of ropivacaine; this explains why the apparent elimination half-life after epidural administration is longer than that after intravenous administration.
Ropivacaine exhibits biphasic absorption from the caudal epidural space even in children.
Ropivacaine exhibits a mean total plasma clearance of the order of 440 ml / minute, a renal clearance of 1 ml / minute, a steady-state volume of distribution of 47 liters and a terminal half-life of 1.8 hours after iv administration. Ropivacaine has an intermediate hepatic extraction ratio of 0.4 and is mainly bound to a1-acid glycoprotein in plasma, with an unbound fraction of approximately 6%.
During continuous and interscalenic epidural infusion, an increase in total plasma concentration was detected which can be correlated with a post-operative increase in a1-acid glycoprotein. The changes in the concentration of the unbound, pharmacologically active fraction were less than those of the plasma concentration. total.
Since ropivacaine has an intermediate to low hepatic extraction ratio, its elimination rate depends on the unbound plasma concentration.
In clinical studies conducted in children and adults, a post-operative increase in AAG was observed leading to a reduction in the unbound fraction, due to increased protein binding resulting in a decrease in total clearance and an increase in plasma concentration. total.
Unbound ropivacaine clearance remains unchanged, as demonstrated by stable concentrations observed during postoperative infusion.
It is the unbound plasma concentration that correlates with toxicity and systemic pharmacodynamic effects.
Ropivacaine crosses the placenta rapidly and equilibrium between the bound and free fractions is readily achieved. The degree of plasma protein binding in the fetus is less than that seen in the mother, resulting in a lower total plasma concentration in the fetus than in the mother.
Ropivacaine is extensively metabolised mainly by aromatic hydroxylation. After intravenous administration 86% of the dose is eliminated in the urine and of this only 1% relates to the unchanged drug. The major metabolite is 3 - hydroxy-ropivacaine which approximately 37% is excreted in the urine, mainly as a conjugate. The urinary excretion of 4 - hydroxy-ropivacaine, the N - dealkylated metabolite (PPX) and 4 - hydroxy-dealkylated is 1 - 3%. Conjugated and unconjugated 3-hydroxy- ropivacaine exhibits determinable concentrations only in plasma.
The metabolic picture was similar in children over 1 year.
Impaired renal function has little or no influence on the pharmacokinetics of ropivacaine. Renal clearance of PPX is significantly correlated with creatinine clearance. The lack of correlation between total exposure, expressed as AUC, with creatinine clearance indicates that total PPX clearance includes non-renal elimination in addition to renal excretion. Some patients with renal impairment may exhibit increased exposure to PPX resulting from low non-renal clearance. Due to the reduced CNS toxicity of PPX compared to ropivacaine, the clinical consequences are considered negligible in short-term treatment. Patients with end stage renal disease undergoing dialysis have not been studied.
There is no evidence of an in vivo racemization of ropivacaine.
Pediatrics
The pharmacokinetics of ropivacaine were characterized by analyzing the pharmacokinetic data of a population consisting of 192 children between 0 and 12 years of age.
The clearance of the unbound ropivacaine fraction, the PPX metabolite and the volume of distribution of unbound ropivacaine are a function of both body weight and age, until liver function reaches maturity, thereafter are primarily a function of Full functional clearance of the unbound fraction of ropivacaine appears to be complete by 3 years of age, that of the metabolite PPX by 1 year, and the volume of distribution of unbound ropivacaine by 2 years of life.
The volume of distribution of the unbound PPX metabolite depends solely on body weight. Since PPX has a longer half-life and lower clearance, it can accumulate during epidural infusion.
The clearance of unbound ropivacaine (Clu), for ages above 6 months, reached values within the adult range. The total clearance values of ropivacaine (CL), reported in Table 5, are those not affected by the " post-operative increase in AAG.
Table 5 Estimation of pharmacokinetic parameters derived from the analysis of a pediatric population
to median body weight by age group -WHO database.
b clearance of unbound ropivacaine
c volume of distribution of unbound ropivacaine
d total clearance of ropivacaine
and terminal half-life of ropivacaine
f terminal half-life of PPX
The mean simulated maximum unbound plasma concentration (Cumax) after a single caudal block tends to be higher in neonates and the time to maximum unbound plasma concentration (tmax) decreases with increasing age (Table 6). The mean simulated unbound plasma concentrations at the end of 72 hours of continuous epidural infusion at the recommended dose showed higher levels in neonates than in infants and children. See section 4.4.
Table 6 Mean and range of simulated unbound Cumax after a single caudal block
a Maximum unbound plasma concentration
b Time to maximum unbound plasma concentration
c Maximum observed unbound plasma concentration and normalized dose
At 6 months of life, break point for changing the recommended dose for continuous epidural infusion, the clearance of unbound ropivacaine and the unbound metabolite PPX reaches 34% and 71% of the mature values, respectively. Systemic exposure it is higher in infants and even more in infants from 1 to 6 months of age than in older children, this is related to the immaturity of liver functions. However, this is partially offset by the 50% reduction in the recommended dose for infusion continues in children under 6 months of age.
Simulations of the sum of the plasma concentrations of unbound ropivacaine and the metabolite PPX, based on the pharmacokinetic parameters and their variability in the population analysis, indicate that for a single caudal block the recommended dose should be increased by a factor of 2.7. in the younger group and by a factor of 7.4 in the 1 to 10-year-old group, so that the predictivity of the upper 90% confidence interval reaches the systemic toxicity threshold.
The matching factors for continuous epidural infusion are 1.8 and 3.8, respectively.
Simulations of the sum of the plasma concentrations of unbound ropivacaine and the metabolite PPX, based on the pharmacokinetic parameters and their variability in population analyzes, indicate that for children 1 year to 12 years of age with single peripheral nerve block ( ilioinguinal) with a dose of 3 mg / kg, the median peak free plasma concentration, reached after 0.8 hours is 0.0347 mg / L, one-tenth of the toxicity threshold (0.34 mg / L). The greater than 90% confidence interval for the maximum free plasma concentration is 0.074 mg / L, one fifth of the toxicity threshold. Similarly for continuous peripheral nerve block (0.6 mg ropivacaine / kg for 72 hours ) preceded by a single 3 mg / kg peripheral nerve block, the median peak free plasma concentration is 0.053 mg / L. The greater than 90% confidence interval for maximum free plasma concentration is 0.088 mg / L, a quarter of the toxicity threshold.
05.3 Preclinical safety data -
On the basis of conventional pharmacological studies of tolerability, single and repeated dose toxicity, reproductive toxicity, mutagenic potential and local toxicity, no risks for humans were highlighted, apart from those expected based on the pharmacodynamic action of high doses of ropivacaine (such as CNS signs, including convulsions and cardiotoxicity).
06.0 PHARMACEUTICAL INFORMATION -
06.1 Excipients -
Sodium chloride
Hydrochloric acid
Sodium hydroxide
Water for injections.
06.2 Incompatibility "-
Compatibility with other solutions other than those indicated in section 6.6 has not been studied.
Precipitation may occur in alkaline solutions as ropivacaine is poorly soluble at pH above 6.0.
06.3 Period of validity "-
Vials (Polyamp):
3 years.
Infusion bags (Polybag):
2 years.
Validity after first opening:
from a microbiological point of view, the product must be used immediately.
If this is not the case, in-use storage conditions and times prior to use are the responsibility of the user and these, in any case, should not exceed 24 hours at 2 - 8 ° C.
For mixtures see section 6.6.
06.4 Special precautions for storage -
Do not store above 30 ° C. Do not freeze.
For storage after opening see section 6.3.
06.5 Nature of the immediate packaging and contents of the package -
Naropin 2 mg / ml
10 ml polypropylene vials (Polyamp) in packs of 5 and 10
sterile polypropylene vials (Polyamp) of 10 ml in sterile blister packs of 5 and 10
20 ml polypropylene vials (Polyamp) in packs of 5 and 10
20 ml sterile polypropylene vials (Polyamp) in sterile blister packs of 5 and 10
100 ml sterile polypropylene bags (Polybag) in sterile blister packs of 5
Naropin 7.5 mg / ml
10 ml polypropylene vials (Polyamp) in packs of 5 and 10
sterile polypropylene vials (Polyamp) of 10 ml in sterile blister packs of 5 and 10
20 ml polypropylene vials (Polyamp) in packs of 5 and 10
sterile 20 ml polypropylene vials (Polyamp) in sterile blister packs of 5 and 10.
Naropin 10 mg / ml
10 ml polypropylene vials (Polyamp) in packs of 5 and 10
sterile polypropylene vials (Polyamp) of 10 ml in sterile blister packs of 5 and 10
20 ml polypropylene vials (Polyamp) in packs of 5 and 10
sterile 20 ml polypropylene vials (Polyamp) in sterile blister packs of 5 and 10.
Not all pack sizes may be marketed.
Polypropylene (Polyamp) vials are specifically designed to fit Luer Lock and Luer fit syringes.
06.6 Instructions for use and handling -
Naropin is preservative-free and is for single use only. Any residual solution must be eliminated.
The unopened primary container must not be resterilized. Sterile blister packaging should be chosen in cases where sterility of the outer surface of the vial is also required.
The Naropin infusion solution contained in polypropylene bags (Polybag) is chemically and physically compatible with the following drugs:
* The range of concentration values shown in the table is wider than that used in clinical practice. Epidural infusions of Naropin / sufentanil citrate, Naropin / morphine sulfate and Naropin / clonidine hydrochloride have not been evaluated in clinical studies.
The medicinal product should be visually inspected prior to use. The solution should only be used if clear, substantially free of particles and if the container is intact.
The mixtures are chemically and physically stable for 30 days when stored between 20 and 30 ° C, but from a microbiological point of view, the mixtures should be used immediately. If this is not the case, in-use storage conditions and times prior to use are the responsibility of the user and these, in any case, should not exceed 24 hours at a temperature between 2 - 8 ° C.
07.0 HOLDER OF THE "MARKETING AUTHORIZATION" -
AstraZeneca S.p.A. - Palazzo Ferraris - Via Ludovico il Moro 6 / C - Basiglio (MI) 20080
08.0 MARKETING AUTHORIZATION NUMBER -
AIC n. 032248015 "2 mg / ml solution for injection / infusion" 5 polypropylene ampoules (Polyamp) of 10 ml
AIC n. 032248027 "2 mg / ml solution for injection / infusion" 5 sterile polypropylene vials (Polyamp) of 10 ml in sterile blister
AIC n. 032248041 "2 mg / ml solution for injection / infusion" 5 polypropylene ampoules (Polyamp) of 20 ml
AIC n. 032248054 "2 mg / ml solution for injection / infusion" 5 sterile polypropylene vials (Polyamp) of 20 ml in sterile blister
AIC n.032248078 "2 mg / ml solution for injection / infusion" 5 sterile polypropylene bags (Polybag) of 100 ml in sterile blister
AIC n. 032248092 "7.5 mg / ml solution for injection" 5 polypropylene ampoules (Polyamp) of 10 ml
AIC n. 032248104 "7.5 mg / ml solution for injection" 5 sterile polypropylene vials (Polyamp) of 10 ml in sterile blister
AIC n. 032248128 "7.5 mg / ml solution for injection" 5 polypropylene ampoules (Polyamp) of 20 ml
AIC n. 032248130 "7.5 mg / ml solution for injection" 5 sterile polypropylene vials (Polyamp) of 20 ml in sterile blister
AIC n. 032248155 "10 mg / ml solution for injection" 5 polypropylene ampoules (Polyamp) of 10 ml
AIC n. 032248167 "10 mg / ml solution for injection" 5 sterile polypropylene vials (Polyamp) of 10 ml in sterile blister
AIC n. 032248181 "10 mg / ml solution for injection" 5 polypropylene ampoules (Polyamp) of 20 ml
AIC n. 032248193 "10 mg / ml solution for injection" 5 sterile polypropylene vials (Polyamp) of 20 ml in sterile blister
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION -
Date of first authorization: 30.10.1996
Date of last renewal: 13.11.2009
10.0 DATE OF REVISION OF THE TEXT -
08 September 2016
