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ROPIVACAINE HYDROCHLORIDE 2 MG/ML SOLUTION FOR INFUSION

Active substance(s): ROPIVACAINE HYDROCHLORIDE MONOHYDRATE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Ropivacaine Hydrochloride 2 mg/ml Solution for Infusion

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of solution for infusion contains 2 mg Ropivacaine Hydrochloride (as
monohydrate)
Each 100 ml bag of solution for infusion contains 200 mg of ropivacaine
hydrochloride (as monohydrate)
Each 200 ml bag of solution for infusion contains 400 mg of ropivacaine
hydrochloride (as monohydrate)
Excipient (s) with known effect:
Each ml of solution for infusion contains 0.15 mmol (3.4 mg) sodium
100 ml solution for infusion contains 15 mmol (340 mg) sodium
200 ml solution for infusion contains 30 mmol (680 mg) sodium
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Solution for infusion
Clear, colourless solution
pH: 5.4 to 5.8
Osmolality: 270-310 mOsmol/kg

4

CLINICAL PARTICULARS

4.1

Therapeutic indications

Ropivacaine Hydrochloride 2 mg/ml solution for infusion is indicated for acute pain
management
In adults and adolescents above 12 years of age for
• Continuous epidural infusion or intermittent bolus administration during
postoperative

or labour pain
• Field blocks
• Continuous peripheral nerve block via a continuous infusion or intermittent
bolus injections, e.g. postoperative pain management.
In infants from 1 year and children up to and including 12 years of age for (per- and
postoperative):
• Single and continuous peripheral nerve block
In neonates, infants and children up to and including 12 years of age for (per- and
postoperative):
• Caudal epidural block
• Continuous epidural infusion
4.2
Posology and method of administration
Ropivacaine hydrochloride should only be used by, or under the supervision of,
clinicians experienced in regional anaesthesia.
For surgical anaesthesia (e.g. epidural administration, caesarean section) and for
epidural anaesthesia in which a complete motor block is essential for surgery, higher
concentrations and doses are required. For those indications, other strengths of
ropivacaine hydrochloride solution for injection are available (7.5 mg/ml and 10
mg/ml). For analgesia (e.g epidural administration for acute pain management) the
lower concentration and doses are recommended.
Posology
Adults and adolescents 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.
(mg/ml)
Lumbar Epidural Administration
Bolus
2.0
Intermittent injections (top
2.0
up)
(e.g. labour pain
management)

Continuous infusion e.g.
2.0
Labour pain
Postoperative pain
2.0
management
Thoracic Epidural Administration

Volume
(ml)

Dose
(mg)

Onset
minutes

Duration
hours

10-20
10-15
(minimu
m
interval
30
minutes)
6-10
ml/h
6-14
ml/h

20-40
20-30

10-15

0.5-1.5

12-20
mg/h
12-28
mg/h

n/a

n/a

n/a

n/a

Continuous infusion
2.0
(postoperative pain
management)
Field Block
(e.g. minor nerve blocks
2.0
and infiltration)
Peripheral nerve block
(Femoral or interscalene block)
Continuous infusion or
2.0
intermittent injections (e.g.
postoperative pain
management)
n/a = not applicable.

6-14
ml/h

12-28
mg/h

n/a

n/a

1-100

2.0-200

1-5

2-6

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.
Method of administration

For perineural and epidural use only.
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) is recommended. An inadvertent
intravascular injection may be recognised by a temporary increase in heart rate and
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.
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 hydrochloride 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 Ropivacaine Hydrochloride
solution for infusion 7.5 mg/ml is induced via an epidural catheter. Analgesia is
maintained with Ropivacaine Hydrochloride 2 mg/ml solution for 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 Ropivacaine hydrochloride 2 mg/ml solution
for infusion alone or mixed with fentanyl 1-4 μg/ml has been given for postoperative
pain management for up to 72 hours. The combination of Ropivacaine hydrochloride
and fentanyl provided improved pain relief but caused opioid side effects. The
combination of ropivacaine hydrochloride and fentanyl has been investigated only for
Ropivacaine hydrochloride 2 mg/ml solution for infusion.
When prolonged peripheral nerve blocks are applied, either through continuous
infusion 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 Ropivacaine
hydrochloride 7.5 mg/ml and interscalene block with 225 mg Ropivacaine
hydrochloride 7.5 mg/ml, respectively before surgery. Analgesia was then maintained
with Ropivacaine hydrochloride 2 mg/ml solution for infusion. Infusion rates or
intermittent injections of 10-20 mg per hour for 48 hours provided adequate analgesia
and were well tolerated.
Paediatric patients 0 up to and including 12 years of age:

Single Caudal Epidural Block
Blocks below T12, in children
with a body weight up to 25 kg
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
6 up to 12 months
Bolus dosea
Infusion up to 72 hours
1 to 12 years
Bolus doseb
Infusion up to 72 hours

Concentration of Volume
ropivacaine
hydrochloride
mg/ml
ml/kg
2.0
1

Dose

mg/kg
2

2.0
2.0

0.5-1
0.1 ml/kg/h

1-2
0.2 mg/kg/h

2.0
2.0

0.5-1
0.2 ml/kg/h

1-2
0.4 mg/kg/h

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.
Infants and children aged 1-12 years:
The proposed ropivacaine doses for peripheral block in infants and children provide
guidance for use in children without severe disease. More conservative doses and
close monitoring are recommended for children with severe diseases.
Single injections for peripheral nerve block (e.g. ilioinguinal nerve block, brachial
plexus block, fascia iliaca compartment block) should not exceed 2,5-3,0 mg/kg.
Continuous infusion for peripheral nerve block are recommended at 0,2-0,6 mg/kg/h
(0,1-0,3 ml/kg/h) up to 72 h.
The use of ropivacaine in premature children has not been documented.
Method of administration
For perineural and epidural use only.
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 hydrochloride 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 hydrochloride 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.
4.3

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1
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 medicinal products 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) and be appropriately
trained and familiar with diagnosis and treatment of side 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.
Cardiovascular
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.
There have been rare reports of cardiac arrest during the use of Ropivacaine
hydrochloride 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 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.
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 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.
Acute porphyria
Ropivacaine 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.
Chondrolysis
There have been post-marketing reports of chondrolysis in patients receiving postoperative intra-articular 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 hydrochloride. Intra-articular continuous infusion with Ropivacaine
hydrochloride should be avoided, as the efficacy and safety has not been established.

Prolonged administration
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).
Excipients with recognised action/effect
This medicinal product contains maximum 3.4 mg sodium per ml. To be taken into
consideration by patients on a controlled sodium diet.
Paediatric population
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.
The safety and efficacy of ropivacaine 2 mg/ml for peripheral nerve blocks has not
been established for infants < 1 year.
The safety and efficacy of ropivacaine 2 mg/ml for field blocks has not been
established for children up to and including 12 years.
4.5

Interaction with other medicinal products and other forms of interaction
Ropivacaine hydrochloride 2 mg/ml should be used with caution in patients
receiving other local anaesthetics or agents structurally related to amide-type
local anaesthetics, e.g. certain anti-arrhythmics, such as lidocaine and
mexiletine, since the systemic toxic effects are additive. Simultaneous use of
Ropivacaine hydrochloride 2 mg/ml with general anaesthetics or opioids may
potentiate each others (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 also section
4.4).
Cytochrome P450 (CYP) 1A2 is involved in the formation of 3-hydroxyropivacaine, the major metabolite. In vivo, the plasma clearance of ropivacaine
hydrochloride was reduced by up to 77% during co-administration 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 hydrochloride solution for infusion,
can interact with Ropivacaine hydrochloride solution for infusion. Prolonged
administration of Ropivacaine hydrochloride should be avoided in patients
concomitantly treated with strong CYP1A2 inhibitors, see also section 4.4.
In vivo, the plasma clearance of ropivacaine hydrochloride was reduced by
15% during co-administration 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.

4.6

Fertility, pregnancy and lactation

Pregnancy
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).
Breastfeeding
There are no data available concerning the excretion of ropivacaine hydrochloride 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 Ropivacaine hydrochloride 2 mg/ml is similar to
those for other long acting local anaesthetics of the amide type. Adverse 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.
The percentage of patients that can be expected to experience adverse reactions varies
with the route of administration of Ropivacaine hydrochloride. Systemic and localised
adverse reactions of Ropivacaine hydrochloride usually occur because of excessive
dosage, rapid absorption, or inadvertent intravascular injection. The most frequently
reported adverse reactions, nausea 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.
Tablutated list of adverse reactions
The frequencies of adverse events are ranked according to the following: 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 established
from the available data).
System organ class
Psychiatric disorders
Nervous system disorders

Frequency
Uncommon
Anxiety
Common
Paraesthesia, Dizziness, Headache
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
Cardiac disorders
Common
Bradycardia, Tachycardia
Rare
Cardiac arrest, Cardiac arrhythmias
Vascular disorders
Very Common
Hypotension
Common
Hypotension (in children), Hypertension
Uncommon
Syncope
Respiratory, thoracic and
Uncommon
mediastinal disorders
Dyspnoea
Gastrointestinal disorders
Very Common
Nausea, Vomiting (in children)
Common
Vomiting
Renal and urinary disorders
Common
Urinary retention
General disorders and
Common
administration site conditions
Temperature elevation, Back pain, Rigor
Uncommon
Hypothermia
Rare
Allergic reactions (Anaphylactic reactions,
Angioneurotic oedema and Urticaria)
*
These symptoms usually occur because of inadvertent intravascular injection,
overdose or rapid absorption, see section 4.9.
Class-related adverse 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 vascularised areas, see also
section 4.4. CNS reactions are similar for all amide local anaesthetics, while cardiac
reactions are more dependent on the medicinal product, 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 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 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 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 drugs such as benzodiazepines or barbiturates.
Paediatric population:
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).
Treatment of acute systemic toxicity
See section 4.9.
Reporting of suspected adverse reactions
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

4.9

Overdose

Symptoms

Accidental intravascular injections of local anaesthetics may cause immediate (within
seconds to a few minutes) systemic toxic reactions. In the event of overdose, peak
plasma concentrations may not be reached for one to two hours, depending on the site
of the injection, and signs of toxicity may thus be delayed.(See section 4.8).
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 system toxicity
If signs of acute systemic toxicity appear, injection of the local anaesthetic should be
stopped immediately and CNS symptoms (convulsions, CNS depression) must
promptly be treated with appropriate airway/respiratory support and the
administration of anticonvulsant drugs.
If circulatory arrest should occur, immediate cardiopulmonary resuscitation should be
instituted. Optimal oxygenation and ventilation and circulatory support as well as
treatment of acidosis are of vital importance.
If cardiovascular depression occurs (hypotension, bradycardia), appropriate treatment
with intravenous fluids, vasopressor, and or inotropic agents should be considered.
Children should be given doses commensurate with age and weight.
Should cardiac arrest occur, a successful outcome may require prolonged resuscitative
efforts.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Anaesthetics, local, Amides
ATC code: N01B B09
Ropivacaine hydrochloride is a long-acting, amide-type local anaesthetic with
both anaesthetic and analgesic effects. At high doses it produces surgical
anaesthesia, while at lower doses it produces sensory block with limited and
non-progressive motor block.
The mechanism is a reversible reduction of the membrane permeability of the
nerve fibre to sodium ions. Consequently the depolarisation velocity is
decreased and the excitable threshold increased, resulting in a local blockade
of nerve impulses.
The most characteristic property of ropivacaine hydrochloride is the long
duration of action. Onset and duration of the local anaesthetic efficacy are
dependent upon the administration site and dose, but are not influenced by the
presence of a vasoconstrictor (e.g. adrenaline (epinephrine)).

For details concerning the onset and duration of action, see table under
posology and method of administration.
Healthy volunteers exposed to intravenous infusions tolerated ropivacaine
hydrochloride well at low doses and with expected CNS symptoms at the
maximum tolerated dose. The clinical experience with this medicinal product
indicates a good margin of safety when adequately used in recommended
doses.

5.2

Pharmacokinetic properties

Ropivacaine has a chiral centre and is available as the pure S-(-)-enantiomer. It is
highly lipid-soluble. All metabolites have a local anaesthetic effect but of
considerably lower potency and shorter duration than that of ropivacaine.
The plasma concentration of ropivacaine hydrochloride depends upon the dose, the
route of administration and the vascularity of the injection site. Ropivacaine
hydrochloride follows linear pharmacokinetics and the Cmax is proportional to the
dose.
Ropivacaine hydrochloride shows complete and biphasic absorption from the epidural
space with half-lives of the two phases of the order of 14 min and 4 h in adults. The
slow absorption is the rate-limiting factor in the elimination of ropivacaine
hydrochloride, which explains why the apparent elimination half-life is longer after
epidural than after intravenous administration. Ropivacaine hydrochloride shows a
biphasic absorption from the caudal epidural space also in children.
Ropivacaine hydrochloride has a mean total plasma clearance in the order of 440
ml/min, a renal clearance of 1 ml/min, a volume of distribution at steady state of 47
litres and a terminal half-life of 1.8 h after i.v. administration. Ropivacaine
hydrochloride has an intermediate hepatic extraction ratio of about 0.4. It is mainly
bound to α1-acid glycoprotein in plasma with an unbound fraction of about 6%.
An increase in total plasma concentrations during continuous epidural and
interscalene infusion has been observed, related to a postoperative increase of α1-acid
glycoprotein.
Variations in unbound, i.e. pharmacologically active, concentration have been much
less than in total plasma concentration.
Since ropivacaine hydrochloride has an intermediate to low hepatic extraction ratio,
its rate of elimination should depend on the unbound plasma concentration. A
postoperative increase in AAG will decrease the unbound fraction due to increased
protein binding, which will decrease the total clearance and result in an increase in
total plasma concentrations, as seen in the paediatric and adult studies. The unbound
clearance of ropivacaine hydrochloride remains unchanged as illustrated by the stable
unbound concentrations during postoperative infusion. It is the unbound plasma
concentration that is related to systemic pharmacodynamic effects and toxicity.

Ropivacaine hydrochloride readily crosses the placenta and equilibrium in regard to
unbound concentration will be rapidly reached. The degree of plasma protein binding
in the foetus is less than in the mother, which results in lower total plasma
concentrations in the foetus than in the mother.
Ropivacaine hydrochloride is extensively metabolised, predominantly by aromatic
hydroxylation. In total, 86% of the dose is excreted in the urine after intravenous
administration, of which only about 1% relates to unchanged medicinal product. The
major metabolite is 3-hydroxy-ropivacaine, about 37% of which is excreted in the
urine, mainly conjugated. Urinary excretion of 4-hydroxy-ropivacaine, the Ndealkylated metabolite (PPX) and the 4-hydroxy-dealkylated product accounts for 1–
3%. Conjugated and unconjugated 3-hydroxy-ropivacaine shows only detectable
concentrations in plasma.
A similar pattern of metabolites has been found in children above one year.
Impaired renal function has little or no influence on ropivacaine pharmacokinetics.
The renal clearance of PPX is significantly correlated with creatinine clearance. A
lack of correlation between total exposure, expressed as AUC, with creatinine
clearance indicates that the total clearance of PPX includes a non-renal elimination in
addition to renal excreation. Some patients with impaired renal function may show an
increased exposure to PPX resulting from a low non-renal clearance. Due to the
reduced CNS toxicity of PPX as 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 in vivo racemisation of ropivacaine hydrochloride.
Paediatrics population:
The pharmacokinetics of ropivacaine was characterized in a pooled population PK
analysis on data in 192 children between 0 and 12 years. Unbound ropivacaine and
PPX clearance and ropivacaine unbound volume of distribution depend on both body
weight and age up to the maturity of liver function, after which they depend largely on
body weight. The maturation of unbound ropivacaine clearance appears to be
complete by the age of 3 years, that of PPX by the age of 1 year and unbound
ropivacaine volume of distribution by the age of 2 years. The PPX unbound volume of
distribution only depends on body weight. As PPX has a longer half-life and a lower
clearance, it may accumulate during epidural infusion.
Unbound ropivacaine clearance (Clu) for ages above 6 months has reached values
within the range of those in adults. Total ropivacaine hydrochloride clearance (CL)
values displayed in the table below are those not affected by the postoperative
increase in AAG.
Estimates of pharmacokinetic parameters derived from the pooled paediatric
population PK analysis
Age
Group
Newborn

BWa
kg
3.27

Club
L/h/kg
2.40

Vuc
L/kg
21.86

CLd
L/k/kg
0.096

t½e
h
6.3

t½ppxf
h
43.3

4.29
3.60
25.94
0.143
1m
7.85
8.03
41.71
0.320
6m
10.15
11.32
52.60
0.451
1y
16.69
15.91
65.24
0.633
4y
32.19
13.94
65.57
0.555
10 y
a
Median bodyweight for respective age from WHO database
b
Unbound ropivacaine clearance
c
Ropivacaine unbound volume of distribution
d
Total ropivacaine clearance
e
Ropivacaine terminal half life
f
PPX terminal half life

5.0
3.6
3.2
2.8
3.3

25.7
14.5
13.6
15.1
17.8

The simulated mean unbound maximal plasma concentration (Cumax) after a single
caudal block tended to be higher in neonates and the time to Cumax (tmax) decreased
with an increase in age. Simulated mean unbound plasma concentrations at the end of
a 72 h continuous epidural infusion at recommended dose rates also showed higher
levels in neonates as compared to those in infants and children. See also section 4.4.
Simulated mean and observed range of unbound Cumax after a single caudal
block
tmaxb
Age
Dose
Cumaxa
Cumaxc
Group
(mg/kg)
(mg/L)
(mg/L)
(h)
2.00
0.0582
2.00
0.05-0.08 (n=5)
0-1 m
2.00
0.0375
1.50
0.02-0.09 (n=18)
1-6m
2.00
0.0283
1.00
0.01-0.05 (n=9)
6-12m
2.00
0.0221
0.50
0.01-0.05 (n=60)
1-10y
a
Unbound maximal plasma concentration
b
Time to unbound maximal plasma concentration
c
Observed and dose-normalised unbound maximal plasma concentration
At 6 months, the breakpoint for change in the recommended dose rate for continuous
epidural infusion, unbound ropivacaine hydrochloride clearance has reached 34% and
unbound PPX 71% of its mature value. The systemic exposure is higher in neonates
and also somewhat higher in infants between 1 and 6 months compared to older
children, which is related to the immaturity of their liver function. However, this is
partly compensated for by the recommended 50% lower dose rate for continuous
infusion in infants below 6 months.
Simulations on the sum of unbound plasma concentrations of ropivacaine
hydrochloride and PPX, based on the PK parameters and their variance in the
population analysis, indicate that for a single caudal block the recommended dose
must be increased by a factor of 2.7 in the youngest group and a factor of 7.4 in the 1
to 10 year group in order for the upper prediction 90% confidence interval limit to
touch the threshold for systemic toxicity. Corresponding factors for the continuous
epidural infusion are 1.8 and 3.8 respectively.
Simulations on the sum of unbound plasma concentrations of ropivacaine and PPX,
based on the PK parameters and their variance in the population analysis, indicate that
for 1- to 12- year-old infants and children receiving 3 mg/kg single peripheral
(ilioinguinal) nerve block the median unbound peak concentration reached after 0.8 h

is 0.0347 mg/L, one-tenth of the toxicity threshold (0.34 mg/L). The upper 90%
confidence interval for the maximum unbound plasma concentration is 0.074 mg/L,
one-fifth of the toxicity threshold. Similarly, for continuous peripheral block (0.6 mg
ropivacaine/kg for 72 h) preceded by a 3 mg/kg single peripheral nerve block, the
median unbound peak concentration is 0.053 mg/L. The upper 90% confidence
interval for the maximum unbound plasma concentration is 0.088 mg/L, one-quarter
of the toxicity threshold.

5.3

Preclinical safety data
Based on conventional studies of safety pharmacology, single and repeated
dose toxicity, reproduction toxicity, mutagenic potential and local toxicity, no
hazards for humans were identified other than those which can be expected on
the basis of the pharmacodynamic action of high doses of ropivacaine
hydrochloride (e.g. CNS signs, including convulsions, and cardiotoxicity).

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Sodium chloride
Sodium hydroxide (for pH adjustment)
Hydrochloric acid (for pH adjustment)
Water for injections

6.2

Incompatibilities
This medicinal product must not be mixed with other medicinal products
except those mentioned in section 6.6. In alkaline solutions precipitation may
occur as ropivacaine hydrochloride shows poor solubility at pH> 6.

6.3

Shelf life
2 years.
Shelf life after first opening:
From a microbiological point of view, the product should be used
immediately. If not used immediately, in-use storage times and conditions
prior to use are the responsibility of the user and would normally not be longer
than 24 hours at 2–8°C.
For mixtures, see section 6.6.

6.4

Special precautions for storage
Do not store above 30°C.
Do not refrigerate or freeze.
For storage after opening, see section 6.3.

6.5

Nature and contents of container
100 ml, - 1 plastic infusion bag with an inner layer of polyolefin and styreneethylene-butylene (SEB) containing 2 polypropropylene infusion ports closed
with isoprene rubber stoppers and snap caps with plastic over-pouch. Packs of
1, 5 and 10 bags are available.
200 ml, - 1 plastic infusion bag with an inner layer of polyolefin and styreneethylene-butylene (SEB) containing 2 polypropropylene infusion ports closed
with isoprene rubber stoppers and snap caps with plastic over-pouch. Packs of
1, 5 and 10 bags are available.
Not all pack sizes may be marketed.

6.6

Special precautions for disposal and other handling
For single use only. Discard any unused solution.
The product should be visually inspected for particles and discoloration prior
to administration. The solution should only be used if it is clear, free from
particles and if the bag is undamaged.
The intact container must not be re-autoclaved. A blistered container should be
chosen when a sterile outside is required.
Ropivacaine hydrochloride 2 mg/ml is chemically and physically compatible
with the following medicinal products:
Concentration of Ropivacaine hydrochloride: 1–2 mg/ml
Additive
Concentration*
Fentanyl citrate
1–10 microgram/ml
Sufentanil citrate
0.4–4 microgram/ml
Morphine sulphate
20–100 microgram/ml
Clonidine hydrochloride
5–50 microgram/ml
The concentration ranges stated in the table are wider than those used in
clinical practice.
Epidural infusions of Ropivacaine hydrochloride/sufentanil citrate,
Ropivacaine
hydrochloride/morphine
sulphate
and
Ropivacaine
hydrochloride/clonidine hydrochloride have not been evaluated in clinical
studies.
The mixtures are chemically and physically stable for 30 days at 20-30°C.

The solution should be used immediately. Any unused product or waste
material should be disposed of in accordance with local requirements.

7

MARKETING AUTHORISATION HOLDER
Teva UK Limited
Brampton Road
Hampden Park
Eastbourne
East Sussex
BN22 9AG
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 00289/1304

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
31/05/2013

10

DATE OF REVISION OF THE TEXT
15/12/2014

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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