Naropin 2 mg / ml solution for injection

1. Name Of The Medicinal Product

Naropin^®2 mg/ml solution for injection

2. Qualitative And Quantitative Composition

Naropin^® 2 mg/ml:

1 ml solution for injection contains ropivacaine hydrochloride monohydrate equivalent to 2 mg ropivacaine hydrochloride.

1 ampoule of 10 ml or 20 ml solution for injection contains ropivacaine hydrochloride monohydrate equivalent to 20 mg and 40 mg ropivacaine hydrochloride respectively.

For excipients, see section 6.1.

3. Pharmaceutical Form

Solution for injection for perineural and epidural administration (10–20 ml).

Clear, colourless solution.

4. Clinical Particulars

4.1 Therapeutic Indications

Naropin is indicated for:

1. Surgical anaesthesia

2. Acute pain management

Continuous peripheral nerve block via a continuous infusion or intermittent bolus injections, e.g. postoperative pain management

3. Acute pain management in paediatrics

(per- and postoperative)

- Caudal epidural block in neonates, infants and children up to and including 12 years.

- Continuous epidural infusion in neonates, infants and children up to and including 12 years.

4.2 Posology And Method Of Administration

Naropin should only be used by, or under the supervision of, clinicians experienced in regional anaesthesia.

Posology

Adults and children above 12 years of age:

The following table is a guide to dosage for the more commonly used blocks. The smallest dose required to produce an effective block should be used. The clinician's experience and knowledge of the patient's physical status are of importance when deciding the dose.

	Conc.	Volume	Dose	Onset	Duration
	mg/ml	ml	mg	minutes	hours
Surgical anaesthesia
Lumbar Epidural Administration
Surgery	7.5	15–25	113–188	10–20	3–5
	10	15–20	150–200	10–20	4–6
Caesarean section	7.5	15–20	113–150(1)	10–20	3–5
Thoracic Epidural Administration
To establish block for postoperative pain relief	7.5	5–15 (depending on the level of injection)	38–113	10–20	n/a(2)
Major Nerve Block *
Brachial plexus block	7.5	30–40	225–300(3)	10–25	6–10
Field Block	7.5	1–30	7.5–225	1–15	2–6
(e.g. minor nerve blocks and infiltration)
Acute pain management
Lumbar Epidural Administration
Bolus	2	10–20	20–40	10–15	0.5–1.5
Intermittent injections (top up) (e.g. labour pain management)	2	10–15 (minimum interval 30 minutes)	20–30
Continuous infusion e.g. labour pain	2	6–10 ml/h	12–20 mg/h	n/a(2)	n/a(2)
Postoperative pain management	2	6–14 ml/h	12–28 mg/h	n/a(2)	n/a(2)
Thoracic Epidural Administration
Continuous infusion (postoperative pain management)	2	6–14 ml/h	12–28 mg/h	n/a(2)	n/a(2)
Field Block
(e.g. minor nerve blocks and infiltration)	2	1–100	2–200	1–5	2–6
Peripheral nerve block (Femoral or interscalene block)
Continuous infusion or intermittent injections (e.g. postoperative pain management)	2	5–10 ml/h	10–20 mg/h	n/a	n/a
The doses in the table are those considered to be necessary to produce a successful block and should be regarded as guidelines for use in adults. Individual variations in onset and duration occur. The figures in the column 'Dose' reflect the expected average dose range needed. Standard textbooks should be consulted for both factors affecting specific block techniques and individual patient requirements.
* With regard to major nerve block, only for brachial plexus block a dose recommendation can be given. For other major nerve blocks lower doses may be required. However, there is presently no experience of specific dose recommendations for other blocks.
(1) Incremental dosing should be applied, the starting dose of about 100 mg (97.5 mg = 13 ml; 105 mg = 14 ml) to be given over 3–5 minutes. Two extra doses, in total an additional 50mg, may be administered as needed. (2) n/a = not applicable (3) The dose for a major nerve block must be adjusted according to site of administration and patient status. Interscalene and supraclavicular brachial plexus blocks may be associated with a higher frequency of serious adverse reactions, regardless of the local anaesthetic used, (see section 4.4. Special warnings and special precautions for use).

In general, surgical anaesthesia (e.g. epidural administration) requires the use of the higher concentrations and doses. The Naropin 10 mg/ml formulation is recommended for epidural anaesthesia in which a complete motor block is essential for surgery. For analgesia (e.g. epidural administration for acute pain management) the lower concentrations and doses are recommended.

Method of administration

Careful aspiration before and during injection is recommended to prevent intravascular injection. When a large dose is to be injected, a test dose of 3–5 ml lidocaine (lignocaine) with adrenaline (epinephrine) (Xylocaine^® 2% with Adrenaline (epinephrine) 1:200,000) is recommended. An inadvertent intravascular injection may be recognised by a temporary increase in heart rate and an accidental intrathecal injection by signs of a spinal block.

Aspiration should be performed prior to and during administration of the main dose, which should be injected slowly or in incremental doses, at a rate of 25–50 mg/min, while closely observing the patient's vital functions and maintaining verbal contact. If toxic symptoms occur, the injection should be stopped immediately.

In epidural block for surgery, single doses of up to 250 mg ropivacaine have been used and well tolerated.

In brachial plexus block a single dose of 300 mg has been used in a limited number of patients and was well tolerated.

When prolonged blocks are used, either through continuous infusion or through repeated bolus administration, the risks of reaching a toxic plasma concentration or inducing local neural injury must be considered. Cumulative doses up to 675 mg ropivacaine for surgery and postoperative analgesia administered over 24 hours were well tolerated in adults, as were postoperative continuous epidural infusions at rates up to 28 mg/hour for 72 hours. In a limited number of patients, higher doses of up to 800 mg/day have been administered with relatively few adverse reactions.

For treatment of postoperative pain, the following technique can be recommended: Unless preoperatively instituted, an epidural block with Naropin 7.5 mg/ml is induced via an epidural catheter. Analgesia is maintained with Naropin 2 mg/ml infusion. Infusion rates of 6–14 ml (12–28 mg) per hour provide adequate analgesia with only slight and non-progressive motor block in most cases of moderate to severe postoperative pain. The maximum duration of epidural block is 3 days. However, close monitoring of analgesic effect should be performed in order to remove the catheter as soon as the pain condition allows it. With this technique a significant reduction in the need for opioids has been observed.

In clinical studies an epidural infusion of Naropin 2 mg/ml alone or mixed with fentanyl 1-4 μg/ml has been given for postoperative pain management for up to 72 hours. The combination of Naropin and fentanyl provided improved pain relief but caused opioid side effects. The combination of Naropin and fentanyl has been investigated only for Naropin 2 mg/ml.

When prolonged peripheral nerve blocks are applied, either through continuous infusion or through repeated injections, the risks of reaching a toxic plasma concentration or inducing local neural injury must be considered. In clinical studies, femoral nerve block was established with 300 mg Naropin 7.5 mg/ml and interscalene block with 225 mg Naropin 7.5 mg/ml, respectively, before surgery. Analgesia was then maintained with Naropin 2 mg/ml. Infusion rates or intermittent injections of 10–20 mg per hour for 48 hours provided adequate analgesia and were well tolerated.

Concentrations above 7.5 mg/ml Naropin have not been documented for Caesarean section.

Paediatric patients 0 up to and including 12 years of age:

	Conc.	Volume	Dose
	mg/ml	ml/kg	mg/kg
ACUTE PAIN MANAGEMENT
(per and postoperative)
Single Caudal Epidural Block Blocks below T12, in children with a body weight up to 25 kg	2.0	1	2
Continuous Epidural Infusion In children with a body weight up to 25 kg
0 up to 6 months Bolus dosea Infusion up to 72 hours	2.0 2.0	0.5–1 0.1 mL/kg/h	1–2 0.2 mg/kg/h
6 up to 12 months Bolus dosea Infusion up to 72 hours	2.0 2.0	0.5–1 0.2 mL/kg/h	1–2 0.4 mg/kg/h
1 to 12 years Bolus doseb Infusion up to 72 hours	2.0 2.0	1 0.2 mL/kg/h	2 0.4 mg/kg/h
The dose in the table should be regarded as guidelines for use in paediatrics. Individual variations occur. In children with a high body weight, a gradual reduction of the dosage is often necessary and should be based on the ideal body weight. The volume for single caudal epidural block and the volume for epidural bolus doses should not exceed 25 mL in any patient. Standard textbooks should be consulted for factors affecting specific block techniques and for individual patient requirements. a Doses in the low end of the dose interval are recommended for thoracic epidural blocks while doses in the high end are recommended for lumbar or caudal epidural blocks. b Recommended for lumbar epidural blocks. It is good practice to reduce the bolus dose for thoracic epidural analgesia.

Method of Administration

Careful aspiration before and during injection is recommended to prevent intravascular injection. The patient's vital functions should be observed closely during the injection. If toxic symptoms occur, the injection should be stopped immediately.

A single caudal epidural injection of ropivacaine 2 mg/ml produces adequate postoperative analgesia below T12 in the majority of patients when a dose of 2 mg/kg is used in a volume of 1 ml/kg. The volume of the caudal epidural injection may be adjusted to achieve a different distribution of sensory block, as recommended in standard textbooks. In children above 4 years of age, doses up to 3 mg/kg of a concentration of ropivacaine 3 mg/ml have been studied. However, this concentration is associated with a higher incidence of motor block.

Fractionation of the calculated local anaesthetic dose is recommended, whatever the route of administration.

The use of ropivacaine in premature children has not been documented.

4.3 Contraindications

Hypersensitivity to ropivacaine or to other local anaesthetics of the amide type.

General contraindications related to epidural anaesthesia, regardless of the local anaesthetic used, should be taken into account.

Intravenous regional anaesthesia.

Obstetric paracervical anaesthesia.

Hypovolaemia.

4.4 Special Warnings And Precautions For Use

Regional anaesthetic procedures should always be performed in a properly equipped and staffed area. Equipment and drugs necessary for monitoring and emergency resuscitation should be immediately available. Patients receiving major blocks should be in an optimal condition and have an intravenous line inserted before the blocking procedure. The clinician responsible should take the necessary precautions to avoid intravascular injection (see section 4.2 Posology and method of administration) and be appropriately trained and familiar with diagnosis and treatment of side effects, systemic toxicity and other complications (see section 4.8 Undesirable effects and 4.9 Overdose) such as inadvertent subarachnoid injection, which may produce a high spinal block with apnoea and hypotension. Convulsions have occurred most often after brachial plexus block and epidural block. This is likely to be the result of either accidental intravascular injection or rapid absorption from the injection site.

Caution is required to prevent injections in inflamed areas.

Cardiovascular

Patients treated with anti-arrhythmic drugs class III (eg, amiodarone) should be under close surveillance and ECG monitoring considered, since cardiac effects may be additive.

There have been rare reports of cardiac arrest during the use of Naropin for epidural anaesthesia or peripheral nerve blockade, especially after unintentional accidental intravascular administration in elderly patients and in patients with concomitant heart disease. In some instances, resuscitation has been difficult. Should cardiac arrest occur, prolonged resuscitative efforts may be required to improve the possibility of a successful outcome.

Head and neck blocks

Certain local anaesthetic procedures, such as injections in the head and neck regions, may be associated with a higher frequency of serious adverse reactions, regardless of the local anaesthetic used.

Major peripheral nerve blocks

Major peripheral nerve blocks may imply the administration of a large volume of local anaesthetic in highly vascularized areas, often close to large vessels where there is an increased risk of intravascular injection and/or rapid systemic absorption, which can lead to high plasma concentrations.

Hypersensitivity

A possible cross–hypersensitivity with other amide–type local anaesthetics should be taken into account.

Hypovolaemia

Patients with hypovolaemia due to any cause can develop sudden and severe hypotension during epidural anaesthesia, regardless of the local anaesthetic used.

Patients in poor general health

Patients in poor general condition due to ageing or other compromising factors such as partial or complete heart conduction block, advanced liver disease or severe renal dysfunction require special attention, although regional anaesthesia is frequently indicated in these patients.

Patients with hepatic and renal impairment

Ropivacaine is metabolised in the liver and should therefore be used with caution in patients with severe liver disease; repeated doses may need to be reduced due to delayed elimination. Normally there is no need to modify the dose in patients with impaired renal function when used for single dose or short-term treatment. Acidosis and reduced plasma protein concentration, frequently seen in patients with chronic renal failure, may increase the risk of systemic toxicity.

Acute porphyria

Naropin^® solution for injection and infusion is possibly porphyrinogenic and should only be prescribed to patients with acute porphyria when no safer alternative is available. Appropriate precautions should be taken in the case of vulnerable patients, according to standard textbooks and/or in consultation with disease area experts.

Excipients with recognised action/effect

This medicinal product contains maximum 3.7 mg sodium per ml. To be taken into consideration by 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.

Paediatric patients

Neonates may need special attention due to immaturity of metabolic pathways. The larger variations in plasma concentrations of ropivacaine observed in clinical trials in neonates suggest that there may be an increased risk of systemic toxicity in this age group, especially during continuous epidural infusion. 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. by signs of CNS toxicity, ECG, SpO₂) and local neurotoxicity (e.g. prolonged recovery) is required, which should be continued after ending infusion, due to a slow elimination in neonates.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Naropin should be used with caution in patients receiving other local anaesthetics or agents structurally related to amide-type local anaesthetics, e.g. certain antiarrhythmics, such as lidocaine and mexiletine, since the systemic toxic effects are additive. Simultaneous use of Naropin with general anaesthetics or opioids may potentiate each others (adverse) effects. Specific interaction studies with ropivacaine and anti-arrhythmic drugs class III (e.g. amiodarone) have not been performed, but caution is advised (see also section 4.4 Special warnings and precautions for use).

Cytochrome P450 (CYP) 1A2 is involved in the formation of 3-hydroxy-ropivacaine, the major metabolite. In vivo, the plasma clearance of ropivacaine was reduced by up to 77% during co

In vivo, the plasma clearance of ropivacaine was reduced by 15% during co

In vitro, ropivacaine is a competitive inhibitor of CYP2D6 but does not seem to inhibit this isozyme at clinically attained plasma concentrations.

4.6 Pregnancy And Lactation

Pregnancy

Apart from epidural administration for obstetrical use, there are no adequate data on the use of ropivacaine in human pregnancy. Experimental animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/fœtal development, parturition or postnatal development (see section 5.3 Preclinical safety data).

Lactation

There are no data available concerning the excretion of ropivacaine into human milk.

4.7 Effects On Ability To Drive And Use Machines

No data are available. Depending on the dose, local anaesthetics may have a minor influence on mental function and co-ordination even in the absence of overt CNS toxicity and may temporarily impair locomotion and alertness.

4.8 Undesirable Effects

General

The adverse reaction profile for Naropin is similar to those for other long acting local anaesthetics of the amide type. Adverse drug reactions should be distinguished from the physiological effects of the nerve block itself e.g. a decrease in blood pressure and bradycardia during spinal/epidural block.

Table of adverse drug reactions

Within each system organ class, the ADRs have been ranked under the headings of frequency, most frequent reactions first.

Very common (>1/10)	Vascular Disorders	Hypotensiona
	Gastrointestinal Disorders	Nausea
Common (>1/100)	Nervous System Disorders	Headache, paraesthesia, dizziness
	Cardiac Disorders	Bradycardia, tachycardia
	Vascular Disorders	Hypertension
	Gastrointestinal Disorders	Vomitingb
	Renal and Urinary Disorders	Urinary retention
	General Disorder and Administration Site Conditions	Temperature elevation, rigor, back pain
Uncommon (>1/1,000)	Psychiatric Disorders	Anxiety
	Nervous System Disorders	Symptoms of CNS toxicity (convulsions, grand mal convulsions, seizures, light headedness, circumoral paraesthesia, numbness of the tongue, hyperacusis, tinnitus, visual disturbances, dysarthria, muscular twitching, tremor)* , Hypoaesthesia.
	Vascular Disorders	Syncope
	Respiratory, Thoracic and Mediastinal Disorders	Dyspnoea
	General Disorders and Administration Site Conditions	Hypothermia
Rare (>1/10,000)	Cardiac Disorders	Cardiac arrest, cardiac arrhythmias
	General Disorder and Administration Site Conditions	Allergic reactions (anaphylactic reactions, angioneurotic oedema and urticaria)

^a Hypotension is less frequent in children (>1/100).

^b Vomiting is more frequent in children (>1/10).

^* These symptoms usually occur because of inadvertent intravascular injection, overdose or rapid absorption, see section 4.9

Class-related adverse drug reactions:

Neurological complications

Neuropathy and spinal cord dysfunction (e.g. anterior spinal artery syndrome, arachnoiditis, cauda equina), which may result in rare cases of permanent sequelae, have been associated with regional anaesthesia, regardless of the local anaesthetic used.

Total spinal block

Total spinal block may occur if an epidural dose is inadvertently administered intrathecally.

Acute systemic toxicity

Systemic toxic reactions primarily involve the central nervous system (CNS) and the cardiovascular system (CVS). Such reactions are caused by high blood concentration of a local anaesthetic, which may appear due to (accidental) intravascular injection, overdose or exceptionally rapid absorption from highly vascularized areas, see also section 4.4. CNS reactions are similar for all amide local anaesthetics, while cardiac reactions are more dependent on the drug, both quantitatively and qualitatively.

Central nervous system toxicity

Central nervous system toxicity is a graded response with symptoms and signs of escalating severity. Initially symptoms such as visual or hearing disturbances, perioral numbness, dizziness, light-headedness, tingling and paraesthesia are seen. Dysarthria, muscular rigidity and muscular twitching are more serious and may precede the onset of generalised convulsions. These signs must not be mistaken for neurotic behaviour. Unconsciousness and grand mal convulsions may follow, which may last from a few seconds to several minutes. Hypoxia and hypercarbia occur rapidly during convulsions due to the increased muscular activity, together with the interference with respiration. In severe cases even apnoea may occur. The respiratory and metabolic acidosis increases and extends the toxic effects of local anaesthetics.

Recovery follows the redistribution of the local anaesthetic drug from the central nervous system and subsequent metabolism and excretion. Recovery may be rapid unless large amounts of the drug have been injected.

Cardiovascular system toxicity

Cardiovascular toxicity indicates a more severe situation. Hypotension, bradycardia, arrhythmia and even cardiac arrest may occur as a result of high systemic concentrations of local anaesthetics. In volunteers the intravenous infusion of ropivacaine resulted in signs of depression of conductivity and contractility.

Cardiovascular toxic effects are generally preceded by signs of toxicity in the central nervous system, unless the patient is receiving a general anaesthetic or is heavily sedated with drugs such as benzodiazepines or barbiturates.

In children, early signs of local anaesthetic toxicity may be difficult to detect since they may not be able to verbally express them. See also section 4.4.

Treatment of acute systemic toxicity

See section 4.9 Overdose.

4.9 Overdose

Symptoms:

Accidental intravascular injections of local anaesthetics may cause immediate (within seconds to a few minutes) systemi