Ropivacaine Hydrochloride Injection for Epidural Infusion 2 mg/mL Ropivacaine Hydrochloride Injection 5 and 10 mg/mL Local Anaesthetic

PRODUCT MONOGRAPH 1 TABLE OF CONTENTS 2 PART I: HEALTH PROFESSIONAL INFORMATION 3 SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 5 ADVERSE REACTIONS 11 DRUG INTERACTIONS. 20 DOSAGE AND ADMINISTRATION 21 OVERDOSAGE 24 ACTION AND CLINICAL PHARMACOLOGY 27 STORAGE AND STABILITY 29 SPECIAL HANDLING INSTRUCTIONS 29 DOSAGE FORMS, COMPOSITION AND PACKAGING 30 PART II: SCIENTIFIC INFORMATION 31 PHARMACEUTICAL INFORMATION 31 CLINICAL TRIALS 31 DETAILED PHARMACOLOGY 33 TOXICOLOGY 34 REFERENCES 37 PART III: CONSUMER INFORMATION 40

NAROPIN(r)

Ropivacaine Hydrochloride Injection for Epidural Infusion Ropivacaine Hydrochloride Injection

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

Route of Administration

Dosage Form / Strength Clinically Relevant Nonmedicinal Ingredients

CONTRAINDICATIONS

NAROPIN (ropivacaine hydrochloride) is contraindicated: in patients with a hypersensitivity to ropivacaine or any other local anaesthetic agent of the amide type. for intravenous regional anaesthesia (Bier block). in obstetric paracervical block anaesthesia. Use of other local anaesthetics in this technique has resulted in foetal bradycardia and death.

WARNINGS AND PRECAUTIONS

IN PERFORMING NAROPIN BLOCKS, UNINTENDED INTRAVASCULAR OR SUBARACHNOID INJECTION IS POSSIBLE AND MAY RESULT IN CARDIAC ARRHYTHMIA OR CARDIAC ARREST. THE POTENTIAL FOR SUCCESSFUL RESUSCITATION HAS NOT BEEN STUDIED IN HUMANS.

LOCAL ANAESTHETICS SHOULD ONLY BE EMPLOYED BY CLINICIANS WHO ARE WELL VERSED IN THE DIAGNOSIS AND MANAGEMENT OF DOSE- RELATED TOXICITY AND OTHER ACUTE EMERGENCIES WHICH MIGHT ARISE FROM THE BLOCK TO BE EMPLOYED. FOR MANAGEMENT OF TOXIC REACTIONS AND RELATED EMERGENCIES, CARDIOPULMONARY RESUSCITATIVE EQUIPMENT, OXYGEN, RESUSCITATIVE DRUGS, AND PERSONNEL RESOURCES SHOULD BE IMMEDIATELY AVAILABLE WHEN ANY LOCAL ANAESTHETIC IS USED. DELAY IN PROPER MANAGEMENT OF DOSE-RELATED TOXICITY, UNDERVENTILATION FROM ANY CAUSE AND/OR ALTERED SENSITIVITY MAY LEAD TO THE DEVELOPMENT OF ACIDOSIS, CARDIAC ARREST AND, POSSIBLY, DEATH (see ADVERSE REACTIONS and OVERDOSAGE).

PRIOR TO RECEIVING MAJOR BLOCKS THE GENERAL CONDITION OF THE PATIENT SHOULD BE OPTIMIZED AND THE PATIENT SHOULD HAVE AN I.V. LINE INSERTED. ALL NECESSARY PRECAUTIONS SHOULD BE TAKEN TO AVOID INTRAVASCULAR INJECTION.

NAROPIN SHOULD BE ADMINISTERED IN INCREMENTAL DOSES. IT IS NOT RECOMMENDED FOR EMERGENCY SITUATIONS, WHERE A FAST ONSET OF SURGICAL ANAESTHESIA IS NECESSARY.

IT IS ESSENTIAL THAT ASPIRATION FOR BLOOD AND CEREBROSPINAL FLUID BE DONE PRIOR TO INJECTING ANY LOCAL ANAESTHETIC, BOTH FOR THE ORIGINAL DOSE AND ALL SUBSEQUENT DOSES, TO AVOID INTRAVASCULAR OR SUBARACHNOID INJECTION. HOWEVER, A NEGATIVE ASPIRATION DOES NOT ENSURE AGAINST AN INTRAVASCULAR OR SUBARACHNOID INJECTION.

SOLUTIONS OF NAROPIN (ROPIVACAINE HYDROCHLORIDE) SHOULD NOT BE USED FOR THE PRODUCTION OF RETROBULBAR BLOCK OR SPINAL ANAESTHESIA (SUBARACHNOID BLOCK) DUE TO INSUFFICIENT DATA TO SUPPORT SUCH USE.

For Caesarean section, the 5 mg/mL NAROPIN solution in doses up to 150 mg is recommended. The 10 mg/mL solution should not be used for this indication. Historically, pregnant patients were reported to have a high risk for cardiac arrhythmias, cardiac/circulatory arrest and death when 0.75% bupivacaine (another member of the amino amide class of local anaesthetics) was inadvertently rapidly injected intravenously.

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 increased risk of intravascular injection and/or rapid systemic absorption, which can lead to high plasma concentrations and serious adverse reactions (see ADVERSE REACTIONS). Local anaesthetic procedures should be performed with care in inflamed regions. Injections should not be performed through inflamed tissue nor when there is sepsis at or near the injection site. NAROPIN should be used with caution in patients receiving other local anaesthetics or agents structurally related to amide-type local anaesthetics, since the toxic effects are additive (see DRUG INTERACTIONS). Patients treated with class III antiarrhythmic drugs (e.g., amiodarone) should be under close surveillance and ECG monitoring, since cardiac effects may be additive (see DRUG INTERACTIONS).

Local anaesthetics should be used with caution in patients in poor general condition due to advanced age, debilitation, or other compromising factors such as partial or complete heart conduction block, advanced liver disease, or severe renal dysfunction (see DOSAGE AND ADMINISTRATION). Patients treated with class III anti-arrhythmic drugs (e.g. amiodarone) should be under close surveillance and ECG monitoring. 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 or 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 likelihood of a successful outcome. NAROPIN 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.

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 patients with concomitant heart disease (see WARNINGS AND PRECAUTIONS, High Risk Populations). Local anaesthetics should be used with caution in patients with impaired cardiovascular function who may be less able to compensate for functional changes associated with prolongation of AV conduction produced by these drugs. Hypotension, hypovolemia, or partial or complete heart block represent risk factors.

The safe and effective use of local anaesthetics depends on proper dosage, correct technique, adequate precautions and readiness for emergencies. Resuscitative equipment, oxygen and resuscitative drugs should be available for immediate use (see ADVERSE REACTIONS and OVERDOSAGE). During major regional nerve blocks, the patients should be in an optimal condition and have i.v. fluids running via an indwelling catheter to assure a functioning intravenous pathway. The clinician responsible should take the necessary precautions to avoid intravascular injection (see DOSAGE AND ADMINISTRATION) and be trained, and familiar with, the diagnosis and treatment of side effects, systemic toxicity, and other complications. The lowest dosage of local anaesthetics that results in effective anaesthesia should be used. Injections should be made slowly and incrementally. When a continuous catheter technique is used, syringe aspirations should be performed before and during each supplemental injection. If blood is aspirated, relocate the needle. Inadvertent intravascular injection may cause serious consequences. Absorption is more rapid when injections are made into highly vascular tissues. Administration of higher than recommended doses of NAROPIN to achieve greater motor blockade or increased duration of sensory blockade may pose a particular risk in the event that an inadvertent intravascular injection occurs. In epidural administration, the procedure should be discontinued and re-initiated if the subarachnoid space has been entered, as shown by aspiration of spinal fluid. Careful and constant monitoring of cardiovascular and respiratory vital signs (adequacy of ventilation) and the patient's state of consciousness should be performed during the anaesthetic procedure. It should be kept in mind at such times that restlessness, anxiety, incoherent speech, lightheadedness, numbness and tingling of the mouth and lips, metallic taste, tinnitus, dizziness, blurred vision, tremors, twitching, depression, or drowsiness may be early warning signs of central nervous system toxicity. Ropivacaine plasma concentrations may approach the threshold for central nervous system toxicity after the administration of 300 mg of ropivacaine for brachial plexus block. Caution should be exercised when using the 300 mg dose.

A well known risk of epidural anaesthesia is unintentional subarachnoid injection of the local anaesthetic. Two clinical studies have been performed to verify the safety of NAROPIN injected into the subarachnoid space at a volume of 3 mL, selected to be representative of an incremental epidural volume that could be unintentionally injected. The 15 and 22.5 mg doses injected resulted in sensory block levels as high as T5 and T4, respectively. Sensory block started in the sacral dermatomes in 2-3 minutes, extended to the T10 level in 10-13 minutes and lasted for approximately 2 hours. The results of these two clinical studies showed that a 3 mL dose did not produce any serious adverse events when spinal anaesthesia was achieved. Epidural anaesthesia or analgesia may lead to hypotension and bradycardia. This risk can be reduced either by preloading the circulation or by injecting a vasopressor such as ephedrine 20-40 mg i.m.. Hypotension should be treated promptly with e.g. ephedrine 5-10 mg intravenously and repeated as necessary. During epidural administration, it is recommended that a test dose of a local anaesthetic with a fast onset of action be administered initially. The patient should be monitored for central nervous system and cardiovascular toxicity, as well as for signs of unintended intrathecal administration, before proceeding. When clinical conditions permit, test doses of local anaesthetic solutions which contain epinephrine should be considered because circulatory changes compatible with epinephrine may also serve as a warning sign of unintended intravascular injection. If injected into a blood vessel, this amount of epinephrine is likely to produce a transient "epinephrine response" within 45 seconds, consisting of an increase in heart rate and systolic blood pressure, circumoral pallor, palpitations and nervousness in the unsedated patient. The sedated patient may exhibit only a pulse rate increase of 20 or more beats per minute for 15 or more seconds. Therefore, following the test dose, the heart rate should be continuously monitored. Patients on beta-blockers may not manifest changes in heart rate, but blood pressure monitoring can detect a rise in systolic blood pressure. A test dose of a short-acting amide anaesthetic such as lidocaine (30-40 mg) is recommended to detect an unintentional intrathecal administration. This will be manifested within a few minutes by signs of spinal block (e.g., decreased sensation of the buttocks, paresis of the legs, or, in the sedated patient, absent knee jerk). An intravascular or subarachnoid injection is still possible even if results of the test dose are negative. The test dose itself may produce a systemic toxic reaction, high spinal or epinephrine-induced cardiovascular effects. During epidural administration, ropivacaine should be administered in incremental doses of 3 to 5 mL with sufficient time between doses to detect toxic manifestations of unintentional intravascular or subarachnoid injection. Frequent aspirations for blood or cerebrospinal fluid (where applicable, i.e. when using a "continuous" intermittent catheter technique) should be performed before and during each supplemental injection because plastic tubing in the epidural space can migrate into a blood vessel or through the dura. A negative aspiration, however, does not ensure against an intravascular or intrathecal injection.

Small doses of local anaesthetics injected into the head and neck area, including dental and stellate ganglion blocks, may produce adverse reactions as a result of inadvertent intra-arterial injection and subsequent retrograde flow to the cerebral circulation. These adverse reactions may be similar to systemic toxicity seen with unintentional intravascular injections of larger doses. Confusion, convulsions, respiratory depression, and/or respiratory arrest, and cardiovascular stimulation or depression have been reported. Patients receiving these blocks should have their circulation and respiration monitored and be constantly observed. Resuscitative equipment and personnel for treating adverse reactions should be immediately available. Dosage recommendations should not be exceeded.

Because amide-type local anaesthetics such as ropivacaine are metabolized by the liver, these drugs, especially repeat doses, should be used cautiously in patients with hepatic disease. Patients with severe hepatic disease, because of their inability to metabolize local anaesthetics normally, are at an increased risk of developing toxic plasma concentrations (see WARNINGS AND PRECAUTIONS, High Risk Populations, and DOSAGE AND ADMINISTRATION, Special Populations).

Local anaesthetics may have a dose-dependent effect on mental function and coordination, causing temporary impairment of locomotion and alertness, even in the absence of overt CNS toxicity.

Solutions of NAROPIN should not be used for the production of retrobulbar block due to insufficient data to support such use.

Until appropriate experience is gained, the use of NAROPIN for such surgery is not recommended.

Local anaesthetics should be used with caution in patients in poor general condition due to severe renal dysfunction (see DOSAGE AND ADMINISTRATION). Normally there is no need to modify the dose of NAROPIN when used for single dose or short term treatment in patients with impaired renal function. Acidosis and reduced plasma protein concentration, frequently seen in patients with chronic renal failure, may increase the risk of systemic toxicity.

No effects on fertility and general reproductive performance were seen in rats over two generations. At the highest dose level, increased pup loss was seen during the first three days post partum, which was considered to be secondary to impaired maternal care of the newborn, due to maternal toxicity. Teratogenicity studies in rats and rabbits did not show evidence of any adverse effects of ropivacaine on organogenesis or early foetal development. There were no treatment-related effects on late foetal development, parturition, lactation, neonatal viability or growth of the offspring in a perinatal and postnatal study in rats using the maximum tolerated dose. An additional perinatal and postnatal study in rats, in which ropivacaine was compared with bupivacaine, showed that maternal toxicity was observed at much lower dose levels and at lower unbound plasma concentrations of bupivacaine than of ropivacaine. There are no clinical studies in preterm pregnant women on the effects of ropivacaine on the developing foetus. Ropivacaine should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus. The use of ropivacaine at term for obstetric anaesthesia or analgesia is well documented.

Local anaesthetics, including NAROPIN, rapidly cross the placenta, and when used for an epidural block, can cause varying degrees of maternal, foetal and neonatal toxicity. The incidence and degree of toxicity depend upon the procedure performed, the type and amount of drug used, and the technique of drug administration. Adverse reactions in the parturient, foetus and neonate involve alterations of the central nervous system, peripheral vascular tone and cardiac function.

Maternal hypotension has resulted from epidural analgesia with NAROPIN for obstetrical pain relief. Elevating the patient's legs and positioning her on her left side will help prevent decreases in blood pressure. The foetal heart rate also should be monitored continuously, and electronic foetal monitoring is highly advisable. It is extremely important to avoid aorto-caval compression by the gravid uterus during administration of regional block to parturients. The patient should be maintained in the left lateral decubitus position if possible, or manual displacement of the uterus off the great vessels be accomplished. Nursing Women: The excretion of ropivacaine or its metabolites in human milk has not been studied. Based on the milk/plasma concentration ratio in rats, the estimated daily dose to a pup will be about 4% of the dose given to the mother. Caution should be exercised when NAROPIN is administered to a nursing woman. Assuming that the milk/plasma concentration ratio in humans is of the same order, the total ropivacaine dose to which the baby is exposed by breast-feeding is far lower than by exposure in utero in pregnant women at term.

The safety and efficacy of NAROPIN have not been investigated in children under 18 years of age. In children early signs of local anaesthetic toxicity may be difficult to detect in cases where the block is given during general anaesthesia (OVERDOSE). NAROPIN is not indicated for use in patients below the age of 18 years.

Elderly patients should be given reduced doses of ropivacaine, commensurate with their age and physical condition (DOSAGE AND ADMINISTRATION, Special Populations). The risk of hypotension and bradycardia in patients receiving epidural anaesthesia with NAROPIN increases in an age-dependent manner (see Table 5 in ADVERSE REACTIONS).

ADVERSE REACTIONS

Reactions to NAROPIN (ropivacaine hydrochloride) are characteristic of those associated with other long-acting local anaesthetics of the amide type.

Clinical Trial Adverse Drug Reactions

In clinical trials, the great majority of adverse events reported with ropivacaine were related to the expected effects of the block and to the clinical situation, rather than reactions to the drug. When all clinical studies were pooled (total n=3056), hypotension and nausea were registered in 41.2% (n=1259) and 28.4% (n=867) of the patients, respectively. Similar incidences were reported for bupivacaine in the double-blind comparisons. Adverse reactions to local anaesthetics are very rare in the absence of overdose or inadvertent intravascular injection. The effects of systemic overdose and unintentional intravascular injections can be serious, but should be distinguished from the physiological effects of the nerve block itself e.g. a decrease in blood pressure, bradycardia, urinary retention after epidural and intrathecal block, and events caused directly by needle puncture (e.g. spinal haematoma, postdural puncture, headache), or indirectly by introduction of micro-organisms (e.g. meningitis and epidural abscess). Acute systemic toxicity from local anaesthetics is generally dose-related and due to high plasma levels which may result from overdosage (see OVERDOSAGE), rapid absorption from the injection site, diminished tolerance, or from inadvertent intravascular injection. Most commonly, the acute adverse experiences originate from the central nervous and cardiovascular systems.

Table 1 Adverse Events Reported In >= 1% Of Adult Patients Receiving Regional Or Local Anaesthesia (Surgery, Labour, Caesarean Section, Peripheral Nerve Block, Local Infiltration And Post-Operative Pain Management)

Adverse Reaction	Total Number of Patients=2867
	2 mg/mL		5 mg/mL		7.5 mg/mL		10 mg/mL
	Total n=1360		Total n=740		Total n=540		Total n=222
	n	%	n	%	n	%	n	%
Hypotension	641	47.1	224	30.1	174	32.2	116	52.3
Nausea	550	40.4	84	11.3	98	18.1	41	18.5
Fever	281	20.7	11	1.5	6	1.1	6	2.7
Vomiting	272	20.0	41	5.5	43	8.0	16	7.2
Postoperative complications	204	15.0	21	2.8	3	0.6	3	1.4
Anaemia	188	13.8	4	0.5	1	0.2	1	0.5
Bradycardia	140	10.3	48	6.4	82	15.2	35	15.8
Pain	140	10.3	42	5.6	15	2.8	2	0.9
Oliguria	139	10.2
Dizziness	136	10.0	20	2.7	11	2.0	4	1.8
Pruritus	123	9.0	10	1.3	16	3.0	2	0.9
Hypertension	113	8.3	4	0.5	3	0.6
unexpected therapeutic effect	108	7.9
Paraesthesia	107	7.9	51	6.8	14	2.6	3	1.4
Hypoxia	86	6.3			2	0.4
rigors (chills)	84	6.2	11	1.5	10	1.9	12	5.4
hypokalaemia	79	5.8	2	0.3
Headache	74	5.4	21	2.8	30	5.6	18	8.1
back pain	74	5.4	31	4.2	33	6.1	24	10.8
hypoproteinaemia	74	5.4
Diarrhoea	66	4.9	1	0.1	1	0.2	1	0.5
bradycardia foetal	66	4.9	2	0.3
Haematuria	63	4.6					2	0.9
urinary retention	62	4.6	7	0.9	8	1.5	5	2.3
Hypothermia	62	4.6	1	0.1
Tachycardia	60	4.4	7	0.9			1	0.5

Adverse Reaction	Total Number of Patients=2867
	2 mg/mL		5 mg/mL		7.5 mg/mL		10 mg/mL
	Total n=1360		Total n=740		Total n=540		Total n=222
	n	%	n	%	n	%	n	%
Constipation	59	4.3	1	0.1	1	0.2
abdominal pain	59	4.3	8	1.1
urinary tract infection	48	3.5	1	0.1
creatine phosphokinase increased	46	3.4
hypoaesthesia	45	3.3	7	0.9	6	1.1	5	2.3
Leukocytosis	44	3.2
Dyspepsia	42	3.1	1	0.1
hypocalcaemia	41	3.0
urine abnormal	40	2.9
chest pain	39	2.9	4	0.5	3	0.6	1	0.5
Anxiety	36	2.6	7	0.9	1	0.2	1	0.5
Dyspnoea	35	2.6	3	0.4	1	0.2	2	0.9
hypotension postural	34	2.5
abdomen enlarged	34	2.5	1	0.1
oedema peripheral	33	2.4			3	0.6
phosphatase alkaline increased	29	2.1
injection site reaction	28	2.1			1	0.2
Insomnia	27	2.0
thrombocytopenia	27	2.0
Infection	27	2.0			6	1.1	1	0.5
pleural effusion	26	1.9
thrombocythaemia	26	1.9
Rash	25	1.8	4	0.5	3	0.6
SGOT increased	25	1.8
Pyuria	25	1.8
Confusion	24	1.8	2	0.3	1	0.2

Adverse Reaction	Total Number of Patients=2867
	2 mg/mL		5 mg/mL		7.5 mg/mL		10 mg/mL
	Total n=1360		Total n=740		Total n=540		Total n=222
	n	%	n	%	n	%	n	%
faecal incontinence	24	1.8
hyperglycaemia	23	1.7
Arthralgia	22	1.6	4	0.5			1	0.5
Atelectasis	22	1.6
bronchospasm	21	1.5	1	0.1
Rales	21	1.5
Albuminuria	20	1.5
progression of labour poor/failed	20	1.5
BUN decreased	19	1.4
sweating increased	18	1.3			2	0.4	1	0.5
urinary incontinence	18	1.3	4	0.5	4	0.7	1	0.5
Agitation	18	1.3			1	0.2
Somnolence	18	1.3			3	0.6
SGPT increased	18	1.3			1	0.2
Coughing	18	1.3
respiratory disorder	18	1.3
respiratory insufficiency	18	1.3
Paresis	17	1.3	1	0.1
injection site inflammation	16	1.2
prothrombin decreased	16	1.2
Tremor	15	1.1	5	0.7	1	0.2	2	0.9
Purpura	15	1.1	3	0.4			1	0.5
application site reaction	14	1.0
Myalgia	14	1.0	1	0.1
hepatic function abnormal	14	1.0
Arrhythmia	14	1.0			1	0.2	1	0.5

Adverse Reaction	Total Number of Patients=2867
	2 mg/mL		5 mg/mL		7.5 mg/mL		10 mg/mL
	Total n=1360		Total n=740		Total n=540		Total n=222
	n	%	n	%	n	%	n	%
micturition disorder	14	1.0			1	0.2	1	0.5
Dysuria	8	0.6	2	0.3	2	0.4	3	1.4
jaundice neonatal	3	0.2	9	1.2

Table 2A Adverse Events Reported In >= 1% of Women who Received NAROPIN 5 mg/mL During Caesarean Section

Adverse Reaction	Total Number of Patients=173 *
Adverse Reaction	n	%
hypotension	101	58.4
paraesthesia	44	25.4
pain	29	16.8
nausea	27	15.6
vomiting	10	5.8
dizziness	7	4.0
anxiety	7	4.0
abdominal pain	7	4.0
pruritus	5	2.9
bradycardia	5	2.9
back pain	5	2.9
dyskinesia	4	2.3
headache	4	2.3
tachycardia	4	2.3
hypoaesthesia	3	1.7
tremor	2	1.2
anaemia	2	1.2
rigors (chills)	2	1.2
postoperative complications	2	1.2
postpartum haemorrhage	2	1.2

some patients experienced more than one adverse event

Table 2B Adverse Events Reported In >= 1% of Foetuses or Neonates of Mothers who Received NAROPIN 5 mg/mL During Caesarean Section

Adverse Reaction	Total Number of Patients=173 *
Adverse Reaction	n	%
Jaundice neonatal	9	5.2
tachypnoea neonatal	6	3.5
respiratory disorder neonatal	3	1.7
bradycardia foetal	2	1.2

*some patients experienced more than one adverse event.

Table 2C Adverse Events Reported In >= 1% of Women who Received NAROPIN 2 mg/mL During Labour

Adverse Reaction	Total Number of Patients=231 *
Adverse Reaction	n	%
hypotension	35	15.2
progression of labour poor/failed	20	8.7
paraesthesia	15	6.5
fever	15	6.5
back pain	13	5.6
nausea	9	3.9
pain	7	3.0
vomiting	6	2.6
rigors (chills)	6	2.6
bradycardia	5	2.2
urinary tract infection	4	1.7
dystocia	4	1.7
urinary retention	3	1.3
tachycardia	3	1.3
jaundice	3	1.3

*some patients experienced more than one adverse event.

Table 2D Adverse Events Reported In >= 1% of Foetuses or Neonates of Mothers Who Received NAROPIN 2 mg/mL During Labour

Adverse Reaction	Total Number of Patients=231 *
Adverse Reaction	n	%
bradycardia foetal	66	28.6
foetal distress	10	4.3
tachycardia foetal	7	3.0
fever neonatal	6	2.6
vomiting neonatal	4	1.7
apgar score low	4	1.7
jaundice neonatal	3	1.3
hypoglycaemia neonatal	3	1.3
neonatal complication (Not Other Specified)	3	1.3
tachypnoea neonatal	3	1.3
respiratory disorder neonatal	3	1.3

*some patients experienced more than one adverse event.

Table 3 Common Events (Epidural Administration)

Adverse Reaction	NAROPIN
	5 mg/mLTotal n=256		7.5 mg/mLTotal n=297		10 mg/mLTotal n=207
	n	(%)	n	(%)	n	(%)
hypotension	99	(38.7)	146	(49.2)	113	(54.6)
nausea	34	(13.3)	68	(22.9)	-	-
bradycardia	29	(11.3)	58	(19.5)	40	(19.3)
back pain	18	(7.0)	23	(7.7)	34	(16.4)
vomiting	18	(7.0)	33	(11.1)	23	(11.1)
headache	12	(4.7)	20	(6.7)	16	(7.7)
fever	8	(3.1)	5	(1.7)	18	(8.7)

Table 4 Most common adverse events by gender (epidural administration) Total n: female=405, males=355

Adverse Reaction	Female		Male
Adverse Reaction	n	(%)	n	(%)
hypotension	220	(54.3)	138	(38.9)
nausea	119	(29.4)	23	(6.5)
bradycardia	65	(16.0)	56	(15.8)
vomiting	59	(14.6)	8	(2.3)
back pain	41	(10.1)	23	(6.5)
headache	33	(8.1)	17	(4.8)
chills	18	(4.4)	5	(1.4)
fever	16	(4.0)	3	(0.8)
pruritus	16	(4.0)	1	(0.3)

Table 5 Incidence Of Hypotension In Relation To Age (Epidural Administration) Total N: NAROPIN=760

Age	NAROPIN
	5 mg/mL		7.5 mg/mL		10 mg/mL
	n	(%)	n	n	(%)	n
< 65	68	(32.2)	99	(43.2)	87	(51.5)
>= 65	31	(68.9)	47	(69.1)	26	(68.4)

Central Nervous System:

These are characterized by excitation and/or depression. Restlessness, anxiety, dizziness, tinnitus, blurred vision or tremors may occur, possibly proceeding to convulsions. However, excitement may be transient or absent, with depression being the first manifestation of an adverse reaction. This may quickly be followed by drowsiness merging into unconsciousness and respiratory arrest. Other central nervous system effects may be nausea, vomiting, chills, and constriction of the pupils.

The incidence of convulsions associated with the use of local anaesthetics varies with the procedure used and the total dose administered. For a detailed description of Central Nervous System toxicity, please refer to 'OVERDOSAGE'.

Cardiovascular System:

High doses or unintentional intravascular injection may lead to high plasma levels and related depression of the myocardium, decreased cardiac output, heart block, hypotension, bradycardia, ventricular arrhythmias, including ventricular tachycardia and ventricular fibrillation, and cardiac arrest. Reactions due to systemic absorption may be either slow or rapid in onset. Cardiovascular collapse and cardiac arrest can occur rapidly (see WARNINGS AND PRECAUTIONS, General and OVERDOSAGE).

Allergic:

Allergic type reactions are rare and may occur as a result of sensitivity to local anaesthetics of the amide-type. These reactions are characterized by signs such as urticaria, pruritus, erythema, angioneurotic oedema (including laryngeal oedema), tachycardia, sneezing, nausea, vomiting, dizziness, syncope, excessive sweating, elevated temperature, and in the most severe instances, anaphylactic shock.

Neurologic:

The incidence of adverse neurologic reactions may be related to the total dose of local anaesthetic administered but is also dependent upon the particular drug used, the route of administration and the physical status of the patient. Neuropathy and spinal cord dysfunction

(e.g. anterior spinal artery syndrome, arachnoiditis, cauda equina syndrome), have been associated with regional anaesthesia. Neurological effects may be related to local anaesthetic techniques, with or without a contribution from the drug. During epidural block, occasional unintentional penetration of the subarachnoid space by the catheter or needle may occur. Neurologic effects following unintentional subarachnoid administration during epidural anaesthesia may include spinal block of varying magnitude (including total or high spinal block) and hypotension secondary to spinal block. A high spinal block is characterized by limb paralysis, loss of consciousness, respiratory paralysis and bradycardia. Other neurological effects following unintentional subarachnoid administration during epidural anaesthesia may include persistent anaesthesia, paraesthesia, weakness, paralysis of the extremities and loss of sphincter control, all of which may have slow, incomplete or no recovery. Urinary retention, loss of bladder and bowel control (faecal and urinary incontinence), and loss of perineal sensation and sexual functions are extremely rare but possible neurotoxic complications. Headache, septic meningitis, meningismus, slowing of labour, increased incidence of forceps delivery, or cranial nerve palsies due to traction on nerves from loss of cerebrospinal fluid have been reported.

Elevation of Body Temperature:

Epidural infusion of NAROPIN has, in some cases, been associated with transient elevations in body temperature to >38.5degC. This has occurred more frequently at doses greater than 16 mg/hour. The pyrexia seen in connection with postoperative epidural infusion of ropivacaine is similar to that seen with bupivacaine. Body temperature is not affected by systemic concentrations of ropivacaine.

DRUG INTERACTIONS

Local anaesthetics and agents structurally related to amide-type local anaesthetics

NAROPIN (ropivacaine hydrochloride) should be used with caution in patients receiving other amide-type local anaesthetics such as lidocaine, bupivacaine, mepivacaine and prilocaine since toxic effects are additive.

NAROPIN should also be used with caution with structurally related agents such as the antiarrhythmics procainamide, disopyramide, tocainide, mexiletine and flecainide.

Specific interactions studies with ropivacaine and class III anti-arrhythmic drugs (e.g. amiodarone) have not been performed. Caution is advised when using Class III antiarrhythmic drugs concomitantly with ropivacaine due to potential pharmacodynamic or pharmacokinetic interactions, or both (see WARNINGS AND PRECAUTIONS - High Risk Populations). Patients treated with class III antiarrhythmic drugs should be under close surveillance and ECG monitoring, since cardiac effects may be additive.

If sedatives are employed to reduce patient apprehension, they should be used in reduced doses, since local anaesthetic agents, like sedatives, are central nervous system depressants which in combination may have an additive effect.

studies indicate that the cytochrome P4501A2 is involved in the formation of 3- hydroxy ropivacaine, the major metabolite.

In healthy volunteers, the plasma clearance of ropivacaine was reduced by up to 77% during co-administration of fluvoxamine, a selective and potent P4501A2 inhibitor. Thus strong inhibitors of cytochrome P4501A2, such as fluvoxamine, and enoxacin, given concomitantly during repeated administration of NAROPIN, can interact with NAROPIN. Prolonged administration should be avoided in patients treated with such strong inhibitors of P4501A2.

Possible interactions with drugs known to be metabolized by P4501A2 via competitive inhibition, such as theophylline and imipramine will occur, but should be of less importance.

DOSAGE AND ADMINISTRATION

NAROPIN (ropivacaine hydrochloride) should only be used by or under the supervision of clinicians experienced in regional anaesthesia. It is recommended that hospitals using local anaesthetic infusions have a treatment protocol in place for nursing to follow in order to safely monitor the level of the block and for the proper management of complications and/or toxic reactions. If toxic reactions occur, the infusion should be stopped immediately. NAROPIN should be administered at the smallest dose and the lowest concentration which are consistent with the necessary degree of anaesthesia or analgesia. The rapid injection of a large volume of local anaesthetic solution should be avoided and fractional doses should always be used. In general, surgical anaesthesia, e.g. epidural administration, requires the use of higher concentrations and doses. For analgesia, e.g. epidural administration for acute pain management, lower concentrations and doses are recommended. The dose of any local anaesthetic administered varies with the anaesthetic procedure, the area to be anaesthetized, the vascularity of the tissues, the number of neuronal segments to be blocked, the depth of anaesthesia and degree of muscle relaxation required, the duration of anaesthesia desired, individual tolerance, and the physical condition of the patient. Patients in poor general condition due to advanced age 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. To reduce the risk of potentially serious adverse reactions, attempts should be made to optimize the patient's condition before major blocks are performed, and the dosage should be adjusted accordingly. Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration, whenever solution and container permit. Solutions which are discoloured or which contain particulate matter should not be administered. For specific techniques and procedures, refer to standard contemporary textbooks.

Local anaesthetics should be used with caution in patients in poor general condition due to advanced age, debilitation, or other compromising factors such as partial or complete heart conduction block, advanced liver disease, or severe renal dysfunction. Elderly and acutely ill patients should be given reduced doses of ropivacaine, commensurate with their age and physical condition.

The dosages in Table 6 are recommended as a guide for use in the average adult for the more commonly used blocks. The clinician's experience and knowledge of the patient's physical status are of importance in calculating the required dose.

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. The figures reflect the expected average dose range needed. For other local anaesthetic techniques standard textbooks should be consulted.

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 anaesthetic used.

Careful aspiration before and during injection is recommended to prevent intravascular injection. When employing an epidural block, a test dose of 3-5 mL lidocaine (Xylocaine(r) 1- 2%) with epinephrine is recommended. An inadvertent intravascular injection may be recognized by a temporary increase in heart rate and an accidental subarachnoid injection by signs of a spinal block. Aspiration should be repeated 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. The test dose should be repeated if the patient is moved in such a fashion as to have displaced the epidural catheter. In epidural block for surgery (excluding Caesarean section), single doses of up to 250 mg ropivacaine have been used and are well tolerated. In epidural block for Caesarean section, an initial epidural dose of up to 150 mg (25 mL NAROPIN 5 mg/mL) injected over 5 minutes is well tolerated (see WARNINGS AND PRECAUTIONS, Peri-Operative Considerations). For treatment of postoperative pain, the following technique is recommended: Unless preoperatively instituted, an initial epidural block with NAROPIN 5 mg/mL is induced via an epidural catheter. Analgesia is maintained with NAROPIN 2 mg/mL infusion. Clinical studies have demonstrated that 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. With this technique, a significant reduction in the need for narcotics has been observed. Clinical experience supports the use of NAROPIN epidural infusions at rates up to 28 mg/h for 72 hours. 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. Clinical experience to date indicates that a cumulative dose of up to 770 mg ropivacaine administered over 24 hours and continuous epidural infusion at rates up to 28 mg/h for 72 hours have been well tolerated in adults when used for postoperative pain management (i.e., >=2000 mg). The duration and intensity of ropivacaine block are not improved by the addition of epinephrine.

The safety and efficacy of NAROPIN have not been investigated in children under 18 years of age. NAROPIN is not indicated for use in patients below the age of 18 years.

OVERDOSAGE

Systemic toxic reactions primarily involve the central nervous system and cardiovascular system. Such reactions are caused by high plasma levels encountered during therapeutic use, overdose, or to unintended intravascular or subarachnoid injection (see ADVERSE REACTIONS and WARNINGS AND PRECAUTIONS). CNS reactions are similar for all amide local anaesthetics, while cardiac reactions are more dependent on the drug, both quantitatively and qualitatively.

Accidental intravascular injections may cause immediate (within seconds to a few minutes) toxic effects. In the event of overdose, peak plasma concentrations may not be reached for 1 to 2 hours, depending on the site of injection, with signs of toxicity thus being delayed.

toxicity is a graded response with symptoms and signs of escalating severity. First symptoms are usually light-headedness, circumoral paraesthesia, numbness of the tongue, hyperacusis, tinnitus and visual disturbances. Dysarthria, muscular rigidity and muscular twitching are more serious and may precede the onset of generalized convulsions. These signs must not be mistaken for a neurotic behaviour. Unconsciousness and grand mal convulsions may follow which may last from a few seconds to several minutes. Hypoxia and hypercarbia occur rapidly following convulsions due to the increased muscular activity, together with the interference with normal respiration and loss of the airway. In severe cases apnoea may occur. Acidosis, hyperkalaemia, hypocalcaemia and hypoxia increase and extend the toxic effects of local anaesthetics.

Recovery is due to redistribution and metabolism of the local anaesthetic drug. Recovery may be rapid unless large amounts of the drug have been administered.

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

In children early signs of local anaesthetic toxicity may be difficult to detect in cases where the block is given during general anaesthesia. It should be noted that NAROPIN (ropivacaine hydrochloride) is not approved for use in paediatric patients.

The first consideration is prevention, best accomplished by incremental injection of NAROPIN, careful and constant monitoring of cardiovascular and respiratory vital signs and the patient's state of consciousness after each local anaesthetic injection and during continuous infusion. At the first sign of change, oxygen should be administered. If signs of acute systemic toxicity appear, injection of the local anaesthetic should be immediately stopped.

The first step in the management of systemic toxic reactions, as well as underventilation or apnoea due to unintentional subarachnoid injection of drug solution, consists of immediate attention to the establishment and maintenance of a patent airway and assisted or controlled ventilation with oxygen and a delivery system capable of permitting immediate positive airway pressure by mask and bag or tracheal intubation

If necessary, use drugs to control the convulsions. An anticonvulsant should be given i.v. if the convulsions do not stop spontaneously in 15-20 seconds. Thiopental 1-3 mg/kg i.v. will abort the convulsions rapidly. Alternatively diazepam 0.1 mg/kg i.v. may be used, although its action will be slow. Both these drugs, however, depress the central nervous system, respiratory and cardiac function, add to postictal depression, and may result in apnoea. Prolonged convulsions may jeopardize the patient's ventilation and oxygenation. If so, injection of a muscle relaxant such as succinylcholine (1 mg/kg) will stop the muscle convulsions rapidly, so that ventilation and oxygenation can be controlled. Endo-tracheal intubation must be considered in such situations. If cardiovascular depression is evident (hypotension, bradycardia) administration of intravenous fluids or a vasopressor such as ephedrine or epinephrine may be required. Should circulatory arrest occur, immediate cardiopulmonary resuscitation should be instituted. Optimal oxygenation and ventilation and circulatory support as well as treatment of acidosis are of vital importance. Should cardiac arrest occur, prolonged resuscitative efforts may be required to improve the likelihood of a successful outcome. Clinical data from patients experiencing local anaesthetic-induced convulsions demonstrated rapid development of hypoxia, hypercarbia, and acidosis within a minute of the onset of convulsions. These observations suggest that oxygen consumption and carbon dioxide production are greatly increased during local anaesthetic convulsions and emphasize the importance of immediate and effective ventilation with oxygen which may avoid cardiac arrest. The supine position is dangerous in pregnant women at term because of aorto-caval compression by the gravid uterus. Therefore, during treatment of systemic toxicity, maternal hypotension or foetal bradycardia following regional block, the parturient should be maintained in the left lateral decubitus position if possible, or manual displacement of the uterus off the great vessels should be accomplished. Resuscitation of obstetrical patients may take longer than resuscitation of non-pregnant patients and closed-chest cardiac compression may be ineffective. Rapid delivery of the foetus may improve the response to resuscitative efforts. In human volunteers given intravenous NAROPIN, the mean maximum tolerated total and free arterial plasma concentrations were 4.3 and 0.6 ug/mL respectively, at which time moderate CNS symptoms (muscle twitching) were noted.

ACTION AND CLINICAL PHARMACOLOGY

NAROPIN (ropivacaine hydrochloride), a local anaesthetic of the amino amide class, is supplied as the pure S-(-)-enantiomer. NAROPIN has both local anaesthetic and analgesic effects. At high doses, surgical anaesthesia is achieved. At lower doses, NAROPIN produces sensory block (analgesia) with limited and non-progressive motor block.

NAROPIN, like other local anaesthetics, causes reversible blockade of impulse propagation along nerve fibres by preventing the inward movement of sodium ions through the cell membrane of the nerve fibres.

The duration of action of local anaesthetics depends on the injection site, the route of administration, and the concentration and volume of the drug. The duration and intensity of ropivacaine block are not improved by the addition of epinephrine. After epidural infusion of ropivacaine, the spread of sensory block and the degree of motor block, as well as their subsequent regression, are dose-dependent.

Ropivacaine, like other local anaesthetics, can also have effects on the central nervous and cardiovascular systems. If excessive amounts of drug reach the systemic circulation, symptoms and signs of central nervous system toxicity and cardiotoxicity may appear. Signs and symptoms of central nervous system toxicity (see OVERDOSAGE) generally occur at lower plasma concentrations than do those of cardiotoxicity. Following systemic absorption, local anaesthetics can produce central nervous system stimulation, depression or both. Apparent central stimulation is usually manifested as restlessness, tremors, and shivering, progressing to convulsions, followed by depression and coma, leading ultimately to respiratory arrest. However, the local anaesthetics have a primary depressant effect on the medulla and on higher centres. The depressed stage may occur without a prior excited stage. High blood concentrations of local anaesthetics resulting from systemic absorption or intravascular injection can depress cardiac conduction and excitability. At toxic levels, atrioventricular block, ventricular arrhythmias, cardiac arrest, and death are possibilities. Indirect cardiovascular effects (hypotension, bradycardia) may occur after epidural administration, depending on the extent of the concomitant sympathetic block. In two clinical pharmacology studies (total N=24) ropivacaine and bupivacaine were infused (10 mg/min) in human volunteers until the appearance of CNS symptoms, e.g., visual or hearing disturbances, perioral numbness, tingling and others. Similar symptoms were seen with both drugs. In one study, the mean +- SD maximum tolerated intravenous dose of ropivacaine infused (124 +- 38 mg) was significantly higher than that of bupivacaine (99 +- 30 mg), while in the other study the doses were not different (115 +- 29 mg of ropivacaine and 103 +- 30 mg of bupivacaine). In the latter study, the number of subjects reporting each symptom was similar for both drugs with the exception of muscle twitching, which was reported by more subjects with bupivacaine than ropivacaine at comparable intravenous doses. At the end of the infusion, ropivacaine in both studies caused significantly less depression of cardiac conductivity (less QRS widening) than bupivacaine. Ropivacaine and bupivacaine caused evidence of depression of cardiac contractility, but there were no changes in cardiac output.

The systemic concentration of local anaesthetics is dependent upon the total dose and the concentration administered, the route of administration, the patient's hemodynamic/ circulatory condition, and the vascularity of the injection site. Ropivacaine follows linear pharmacokinetics and the maximum plasma concentration is proportional to the dose.

Ropivacaine shows complete and biphasic absorption from the epidural space. The mean half-lives of the two phases are in the order of 14 min and 4 h. The slow absorption is the rate-limiting factor in the elimination of ropivacaine, which explains why the apparent elimination half-life is longer after epidural than after intravenous administration. Ropivacaine shows dose proportionality at epidural doses up to 250 mg and intravenous doses up to 80 mg.

Following intravenous administration, the volume of distribution of NAROPIN is approximately 40 L. NAROPIN is extensively bound to alpha1-acid glycoprotein in plasma with an unbound, i.e. pharmacologically active, fraction of about 6%. An increase in total plasma concentration during continuous epidural infusion has been observed in postoperative patients and is related to the postoperative increase of alpha1-acid glycoprotein. Variations in unbound concentration have been much less than in total plasma concentration.

Ropivacaine readily crosses the placenta and equilibrium, in regard to unbound concentration, is 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. The ratios of umbilical vein to maternal vein total and free concentrations are 0.31 and 0.74, respectively.

Ropivacaine is extensively metabolized in the liver predominantly to 3- hydroxy-ropivacaine by an aromatic hydroxylation process mediated by cytochrome P4501A2 and N-dealkylation to PPX mediated by CYP3A4. Conjugated and unconjugated 3-hydroxy- ropivacaine represent the major urinary metabolites. Urinary excretion of 4-hydroxy ropivacaine, N-dealkylated pipecoloxylidide (S-PPX) and both the 3-hydroxy and 4-hydroxy N-dealkylated metabolites account for less than 3% of the dose. An additional metabolite, 2- hydroxy-methyl-ropivacaine has been identified, but not quantified in urine. S-PPX and 3- hydroxy ropivacaine are the major metabolites excreted in the urine during epidural infusion. A total S-PPX concentration in the plasma was about half that of total ropivacaine however, mean unbound concentrations of S-PPX were about 7 - 9 times higher than that of unbound ropivacaine following continuous epidural infusion up to 72 hours. The threshold for CNS toxicity in rats due to unbound plasma concentrations of PPX is approximately 12 times higher than that of unbound ropivacaine. S-PPX, 3-hydroxy ropivacaine, and 4-hydroxy ropivacaine have a pharmacological activity in animal models less than that of ropivacaine.

After intravascular administration, 86% of the total dose of ropivacaine is excreted in the urine of which approximately 1% is the parent compound and 36% is 3- hydroxy- ropivacaine. Ropivacaine has a mean total plasma clearance in the order of 440 mL/min, an unbound plasma clearance of 8 L/min, a renal clearance of 1 mL/min, and a volume of distribution at steady state of 47 L. Ropivacaine has an intermediate hepatic extraction ratio of about 0.4. The terminal elimination half-life is 1.6 to 1.8 hours after intravenous administration, 4.1-6.5 hours after epidural administration, and 5.7-8.0 hours after brachial plexus block. The total and unbound clearance of epidural ropivacaine at term in pregnancy (223-256 mL/min and 2.8-3.3 L/min, respectively), are lower than that observed in non-pregnant patients.

STORAGE AND STABILITY

SPECIAL HANDLING INSTRUCTIONS

Do not freeze. Due to the nature of the Polyamp(r) and the Polybag(r) systems, the containers must not be re-autoclaved. NAROPIN (ropivacaine hydrochloride) solutions are sterile, without preservative and are for single use only. Discard unused portion.

NAROPIN for infusion in polypropylene infusion bags (Polybag(r)) is chemically and physically compatible with the following drugs:

The mixtures should be used immediately. As with all parenteral products, intravenous admixtures should be visually inspected for clarity, particulate matter, precipitate, discoloration and leakage prior to administration, whenever solution and container permit. Solutions showing haziness, particulate matter, precipitate, discoloration or leakage should not be used. Discard unused portions.

Alkalinization may lead to precipitation since ropivacaine is poorly soluble above pH 6.0

DOSAGE FORMS, COMPOSITION AND PACKAGING

NAROPIN (ropivacaine hydrochloride) presentations are sterile isotonic solutions.

ropivacaine hydrochloride 2 5 10 mg/mL sodium chloride water for injection sodium hydroxide and/or hydrochloric acid to adjust pH to 4.0 - 6.0

NAROPIN 2 mg/mL for infusion (epidural) is available in a 100 and 200 mL Polybag(r) (polypropylene infusion bag), packed in a sterile blister pack. NAROPIN for injection (perineural and epidural) is available in 5 mg/mL (20 mL) and 10 mg/mL (10 and 20 mL) Polyamp(r) Duofit(r) (polypropylene ampoules suitable for Luer lock and Luer fit syringes), packed in a sterile blister pack.

TYPE OF BLOCK	CONC. (mg/mL)	VOLUME (mL)	DOSE (mg)
ACUTE PAIN MANAGEMENT
Lumbar Epidural	2	10-20	20-40
Bolus (initial dose)	2	10-20	20-40
Intermittent injections (top-up)	2	10-15	20-30
e.g. labour pain management		(minimum
		interval 30
		minutes)
Lumbar Epidural
Continuous infusion	2	6-14 mL/h	12-28
e.g. labour pain and postoperative pain management	2	6-14 mL/h	mg/h
Thoracic Epidural Continuous infusion e.g. postoperative pain management	2	6-14 mL/h	12-28 mg/h
Field Block	2	1-100	2-200
e.g. infiltration	2	1-100	2-200
e.g. infiltration	5	1-40	5-200
SURGICAL ANAESTHESIA
Lumbar Epidural	5	15-30	75-150
Surgery	5	15-30	75-150
	10	15-20	150-200
Caesarean Section	5	20-30	100-150
Thoracic Epidural To establish block for postoperative pain management.	5	5-15	25-75
Major Nerve Block e.g. brachial plexus block	5	35-50	175-250 1
Field Block e.g. infiltration	5	1-40	5-200

Concentration of NAROPIN: 1-2 mg/mL
Additive	Concentration
Fentanyl citrate	1.0 - 10.0 mg/mL
Sufentanil citrate	0.4 - 4.0 mg/mL
Morphine sulphate	20.0 - 100.0 mg/mL
Clonidine hydrochloride	5.0 - 50.0 mg/mL