Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Sintetica Limited, 30<sup>th</sup> Floor, 40 Bank Street, Canary Wharf, London, E14 5NR, United Kingdom
Regional anaesthetic procedures should always be performed in a properly equipped and staffed area. Equipment and medicinal products necessary for monitoring and emergency resuscitation should be immediately available.
The clinician responsible should take the necessary precautions to avoid intravascular injection (see section 4.2) and be appropriately trained and familiar with diagnosis and treatment of undesirable effects, systemic toxicity and other complications (see section 4.8 and 4.9) 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.
Patients treated with anti-arrhythmic drugs class III (e.g. amiodarone) should be under close surveillance and ECG monitoring considered, since cardiac effects may be additive (see section 4.5).
There have been rare reports of cardiac arrest during the use of ropivacaine hydrochloride for epidural anaesthesia or peripheral nerve blockade, especially after 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.
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 may imply the administration of a large volume of local anaesthetic in highly vascularised 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.
A possible cross – hypersensitivity with other amide – type local anaesthetics should be taken into account (see section 4.3).
Patients with hypovolaemia due to any cause can develop sudden and severe hypotension during epidural anaesthesia, regardless of the local anaesthetic used (see section 4.3).
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, however, regional anaesthesia is frequently indicated in these patients.
Ropivacaine hydrochloride 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.
Ropivacaine solution for 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 text books and/or in consultation with disease area experts.
There have been post-marketing reports of chondrolysis in patients receiving post-operative intraarticular continuous infusion of local anaesthetics, including ropivacaine. The majority of reported cases of chondrolysis have involved the shoulder joint. Intra-articular continuous infusion is not an approved indication for ropivacaine. Intra-articular continuous infusion with ropivacaine should be avoided, as the efficacy and safety has not been established.
Prolonged administration of ropivacaine hydrochloride should be avoided in patients concomitantly treated with strong CYP1A2 inhibitors, such as fluvoxamine and enoxacin (see section 4.5).
Neonates may need special attention due to immaturity of metabolic pathways. The larger variations in plasma concentrations of ropivacaine hydrochloride 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 hydrochloride 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.
The safety and efficacy of ropivacaine 2mg/ml for peripheral nerve blocks in infants below 1 year have not been established.
The safety and efficacy of ropivacaine 2mg/ml for field block in children up to and including 12 years has not been established.
This medicinal product contains 3.39 mg sodium per ml, equivalent to 0.2% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
Ropivacaine hydrochloride 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 Ropivacaine with general anaesthetics or opioids may potentiate each other’s (adverse) effects. Specific interaction studies with ropivacaine hydrochloride and anti-arrhythmic drugs class III (e.g. amiodarone) have not been performed, but caution is advised (see section 4.4).
Cytochrome P450 (CYP) 1A2 is involved in the formation of 3-hydroxy ropivacaine, the major metabolite.
In vivo the plasma clearance of ropivacaine hydrochloride was reduced by up to 77% during coadministration of fluvoxamine, a selective and potent CYP1A2 inhibitor. Thus strong inhibitors of CYP1A2, such as fluvoxamine and enoxacin, given concomitantly during prolonged administration of Ropivacaine, can interact with ropivacaine hydrochloride. Prolonged administration of ropivacaine hydrochloride should be avoided in patients concomitantly treated with strong CYP1A2 inhibitors (see section 4.4).
In vivo the plasma clearance of ropivacaine hydrochloride was reduced by 15% during coadministration of ketoconazole, a selective and potent inhibitor of CYP3A4. However the inhibition of this isozyme is not likely to have clinical relevance.
In vitro, ropivacaine hydrochloride is a competitive inhibitor of CYP2D6 but does not seem to inhibit this isozyme at clinically attained plasma concentrations.
There are no data available concerning the fertility.
Apart from epidural administration for obstetrical use, there are no adequate data on the use of ropivacaine hydrochloride in human pregnancy. Experimental animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3).
There is no data available concerning the excretion of ropivacaine hydrochloride into human breast milk.
No studies on the effects on the ability to drive and use machines have been performed. Depending on the dose, local anaesthetics may have a minor influence on mental function and coordination even in the absence of overt CNS toxicity and may temporarily impair locomotion and alertness.
The adverse reaction profile for Ropivacaine 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. hypotension and bradycardia during spinal/epidural block, and events caused by needle puncture (e.g., spinal haematoma, postdural puncture headache, meningitis and epidural abscess).
The most frequently reported adverse reactions, nausea, vomiting and hypotension, are very frequent during anaesthesia and surgery in general and it is not possible to distinguish those caused by the clinical situation from those caused by the medicinal product or the block.
The percentage of patients that can be expected to experience adverse reactions varies with the route of administration of Ropivacaine. Systemic and localised adverse reactions of Ropivacaine usually occur because of excessive dosage, rapid absorption, or inadvertent intravascular injection.
The frequency of undesirable effects listed below is defined using the following convention: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100), Rare (≥1/10,000 to <1/1,000), Very rare (<1/10,000), Not known (cannot be estimated from the available data).
Uncommon: Anxiety
Common: Headache, paraesthesia, dizziness
Uncommon: 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
Not known: Dyskinesia
Common: Bradycardia, tachycardia
Rare: Cardiac arrest, cardiac arrhythmias
Very common: Hypotensiona
Common: Hypertension
Uncommon: Syncope
Uncommon: Dyspnoea
Very common: Nausea
Common: Vomitingb
Common: Urinary retention
Common: Chills
Uncommon: Hypothermia
Rare: Allergic reactions (anaphylactic reactions, angioneurotic oedema and urticaria)
Common: Back pain
* These symptoms usually occur because of inadvertent intravascular injection, overdose or rapid absorption (see section 4.9).
a Hypotension is less frequent in children (>1/100).
b Vomiting is more frequent in children. (>1/10).
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 may occur if an epidural dose is inadvertently administered intrathecally.
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 vascularised areas (see section 4.4). CNS reactions are similar for all amide local anaesthetics, while cardiac reactions are more dependent on the active substance, both quantitatively and qualitatively.
Central nervous system toxicity is a graded response with symptoms and signs of escalating severity. Initially symptoms such as visual or auditory 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 an underlying neurological disease. Unconsciousness and tonic-clonic (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 active substance from the central nervous system and subsequent metabolism and excretion. Recovery may be rapid unless large amounts of the medicinal product have been injected.
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 hydrochloride 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 medicinal products such as benzodiazepines or barbiturates.
Frequency, type and severity of adverse reactions in children are expected to be the same as in adults except for hypotension which happens less often in children (<1 in 10) and vomiting which happens more often in children (>1 in 10).
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)
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
Compatibilities with other solutions than those mentioned in section 6.6 have not been investigated.
In alkaline solutions precipitation may occur as ropivacaine hydrochloride shows poor solubility at pH>6.0.
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