Consumer medicine information

Naropin with Fentanyl

Ropivacaine hydrochloride; Fentanyl

BRAND INFORMATION

Brand name

Naropin 0.2% with Fentanyl

Active ingredient

Ropivacaine hydrochloride; Fentanyl

Schedule

S8

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Naropin with Fentanyl.

What is in this leaflet?

This leaflet answers some of the common questions people ask about Naropin with Fentanyl. It does not contain all the information that is known about Naropin with Fentanyl.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor will have weighed the risks of you being given Naropin with Fentanyl against the benefits they expect it will have for you.

If you have any concerns about being given this medicine, ask your doctor or pharmacist.

Keep this leaflet. You may need to read it again.

What Naropin with Fentanyl is for

Naropin with Fentanyl is used after surgery to treat post-operative pain.

NAROPIN is a local anaesthetic (an-a-set-ik). When injected, it makes the nerves nearby unable to pass messages to the brain and will therefore prevent or relieve pain.

FENTANYL belongs to a group of medicines called narcotic analgesics. It is a powerful drug used to relieve pain. It works by changing the way your brain receives pain messages.

Naropin with Fentanyl is a combination of the two drugs and produces anaesthesia (loss of feeling) and analgesia (pain relief).

Your doctor will have explained why you are being treated with Naropin with Fentanyl and told you what dose you will be given.

Follow all directions given to you by your doctor carefully. They may differ from the information contained in this leaflet.

Your doctor may prescribe this medicine for another use. Ask your doctor if you want more information.

As it contains fentanyl, Naropin with Fentanyl can be addictive, but when it is used only to relieve or prevent pain it is unlikely to become habit forming.

Before you are given Naropin with Fentanyl

Before you are given it

You must tell your doctor if:

  1. you have previously been given Naropin or fentanyl and had problems with them.
  2. you have any allergies to
  • other local anaesthetics eg. lignocaine
  • other strong pain killers eg. morphine or pethidine
  • any ingredients listed at the end of this leaflet
  1. you have any of these medical conditions
  • problems with your blood pressure or circulation
  • blood poisoning
  • problems with the clotting of your blood
  • acidosis, or too much acid in the blood
  • head injury
  • muscle disease or weakness (e.g. myasthenia gravis)
  • nerve problems
  • heart, liver or kidney problems
  • diseases of the brain or spine
  • problems with your breathing
  • diabetes
  • bronchial asthma
  • had an operation in the biliary tract
  1. you are pregnant, are breast-feeding or intend to breast-feed.
Your doctor will discuss the possible risks and benefits of using Naropin with fentanyl during pregnancy and breast-feeding.

It may not be safe for you to be given Naropin with Fentanyl if you have any of these conditions.

Naropin is not recommended for children under 12 years of age.

Naropin with fentanyl will only be used if the solution is clear, the package is undamaged and the use by (expiry) date marked on the pack has not been passed.

Taking other medicines

Tell your doctor if you are taking any other medicines, including

  • medicines that control your heart beat
  • sedatives, medicines to help you sleep
  • pain killers
  • fluvoxamine, a medicine used to treat depression.
  • ketoconazole, a medicine used to treat fungal infections
  • medicines for depression or mental illness
  • medicine used to thin your blood, including aspirin
  • low molecular weight heparin or other medicines used to prevent blood clots.
  • monoamine oxidase inhibitors (medicines used for treating depression) taken within the last 14 days.
  • medicines that you buy at the chemist, supermarket or health food shop.

These medicines may affect the way Naropin with Fentanyl works.

Your doctor or pharmacist can tell you what to do if you are taking any of these medicines.

If you have not told your doctor about any of these things, tell them before you are given any Naropin with Fentanyl.

How Naropin with Fentanyl is given

Naropin with Fentanyl will be injected by your doctor into the epidural space, near your spinal cord, through a space between the bones in your lower back. A thin tube will be inserted so a dose can be given over a period of time.

This is called an epidural infusion and it will result in a feeling of numbness in your lower body, in an area that may seem unrelated to the injection.

Naropin with Fentanyl is not injected directly into the blood.

The dosage you will be given will depend on your body size, age and the type of pain relief required.

Your doctor will have had a lot of experience injecting Naropin with Fentanyl or other similar drugs and will choose the best dose for you.They will be willing to discuss this decision with you.

Overdose

The doctor giving you Naropin with Fentanyl will be experienced in the use of this type of medicine, so it is unlikely that you will be given too much. However, if you are particularly sensitive to Naropin with Fentanyl, or the dose is accidently injected directly into your blood, you may develop problems for a short time with your sight or hearing.

You may get a numb feeling in or around the mouth, feel dizzy or stiff, or have twitchy muscles.

In rare cases, these effects may be followed by drowsiness and fits. In extreme cases you may have problems with your breathing or your heart and you may become unconscious.

Whenever you are given Naropin with Fentanyl, equipment will be available to care for you if you are given too much.

While you are being given it

Things to be careful of

Be careful driving or operating machinery after you have been given Naropin with Fentanyl. You may be drowsy and your reflexes may be slow.

Do not stand up or walk unless somebody is there to help you. Naropin with fentanyl can make your legs numb and you might fall.

Do not drink alcohol while you are being given Naropin with Fentanyl. If you drink alcohol while you are being given Naropin with Fentanyl your blood pressure may drop making you feel dizzy and faint.

Please talk to your doctor or pharmacist about these possibilities if you think they may bother you.

Side effects

Tell your doctor or nurse as soon as possible if you do not feel well while you are being given Naropin with Fentanyl.

Naropin with Fentanyl will prevent or relieve pain in most people, but it may have unwanted side-effects. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Ask your doctor, nurse or pharmacist to answer any questions you may have.

Tell your doctor or nurse if you notice any of the following and they worry you:

  • headache
  • irregular or slow heart beat
  • nervousness
  • dizziness
  • fever or shivering
  • blurred vision
  • excessive sweating
  • drowsiness
  • ringing in the ears
  • numbness or tingling (pins and needles)
  • feeling strange (disoriented)
  • nausea (feeling sick), vomiting
  • itching
  • cough
  • constipation
  • unable to pass urine

These are all mild side effects of Naropin with Fentanyl.

Tell your doctor or nurse immediately if you notice any of the following:

  • extreme dizziness
  • slow heart beat
  • fits
  • chest pain
  • breathing problems
  • slow heart beat
  • stiff or twitching muscles
  • painful joints
  • seizures

On rare occasions you may lose consciousness.

These are all serious side effects. You may need urgent medical attention

Serious side effects are rare.

Tell your doctor or nurse if you notice anything else that is making you feel unwell. Some people may get other side effects while taking Naropin with Fentanyl.

After using it

Storage

Naropin with Fentanyl will be stored by your doctor or pharmacist under the recommended conditions.

It should be kept in a cool dry place where the temperature stays below 30 °C.

Disposal

Any Naropin with Fentanyl which is not used will be disposed of in a safe manner by your doctor or pharmacist.

Product description

Naropin with Fentanyl contains ropivacaine hydrochloride plus fentanyl citrate as the active ingredients.

It is available in 2 strengths:

  • ropivacaine hydrochloride 2mg/mL with fentanyl 2microgram/mL (as citrate).
  • ropivacaine hydrochloride 2mg/mL with fentanyl 4 microgram /mL (as citrate).

Naropin with Fentanyl also contains

  • sodium chloride
  • sodium hydroxide 2M or hydrochloric acid 2M for pH adjustment
  • water for injections

Naropin with Fentanyl is available in 100mL or 200mL Polybag in sterile theatre packs.

Sponsor

Aspen Pharmacare Australia Pty Ltd
34-36 Chandos St
St Leonards NSW 2065
Australia

NAROPIN (2mg/mL) with FENTANYL (2 microgram/mL)
100mL Polybag Aust R 72874
200mL Polybag Aust R 72873

NAROPIN (2mg/mL) with FENTANYL (4 microgram /mL)
100mL Polybag Aust R 72876
200mL Polybag Aust R 72875

This leaflet was revised in August 2018.

Published by MIMS December 2018

BRAND INFORMATION

Brand name

Naropin 0.2% with Fentanyl

Active ingredient

Ropivacaine hydrochloride; Fentanyl

Schedule

S8

 

1 Name of Medicine

Ropivacaine hydrochloride with fentanyl citrate.

2 Qualitative and Quantitative Composition

The active ingredients in Naropin 0.2% with Fentanyl are ropivacaine hydrochloride and fentanyl citrate.
Naropin 0.2% with Fentanyl solution is available in two strengths; ropivacaine 2 mg/mL with fentanyl (as citrate) 2 microgram/mL and ropivacaine 2 mg/mL with fentanyl (as citrate) 4 microgram/mL. Naropin 0.2% with Fentanyl is a sterile, isotonic solution with nominal osmolality of 288 mOsmol/kg.
The injection solutions also contain sodium chloride, hydrochloric acid, sodium hydroxide and water for injections. The pH of the solution is adjusted with sodium hydroxide or hydrochloric acid to remain between 4.0-6.0 during the approved shelf-life.

3 Pharmaceutical Form

Naropin 0.2% with Fentanyl 200 microgram/100 mL and Naropin 0.2% with Fentanyl 400 microgram/200 mL are sterile, clear, colourless, particle free, isotonic solutions in 100 mL, 200 mL Polybag infusion bags.
Naropin 0.2% with Fentanyl 400 microgram/100 mL and Naropin 0.2% with Fentanyl 800 microgram/200 mL are sterile, clear, colourless, particle free, isotonic solutions in 100 mL, 200 mL Polybag infusion bags.
Naropin 0.2% with Fentanyl Polybag presentations are in a sterile Theatre Pack.

4 Clinical Particulars

4.1 Therapeutic Indications

For the management of post-operative pain by epidural infusion for up to 72 hours.

4.2 Dose and Method of Administration

Naropin 0.2% with Fentanyl should not be mixed with other solutions as no compatibility studies have been conducted. The solubility of ropivacaine is limited at pH > 6.0 and precipitation may occur if mixed with alkaline solutions.
Naropin 0.2% with Fentanyl should only be used by or under the supervision of clinicians experienced in epidural anaesthesia.
Naropin 0.2% with Fentanyl Polybags do not contain a preservative and are intended for single use only. Any solution remaining after 24 hours should be discarded.
Tolerability varies between patients. The lowest dosage that results in effective analgesia should be used and should be based on the status of the patient and the analgesia required. Careful observation of the patient must be maintained during the infusion.
Table 1 is a guide to dosage. The clinician's experience and knowledge of the patient's physical status are of importance when deciding the dose. No data are available for infusion rates greater than 14 mL/hour or infusion times longer than 72 hours.

Adults.

See Table 1.

Note.

Careful aspiration before and during injection is recommended to avoid intravascular injection.

1. Test dose.

For epidural analgesia, a 3-5 mL test dose of a local anaesthetic solution, preferably containing 5 microgram/mL of adrenaline (e.g. Xylocaine 2% with adrenaline 1:200,000) should be administered. Verbal contact and repeated monitoring of heart rate and blood pressure should be maintained for 5 minutes following the test dose after which, in the absence of signs of intravascular or intrathecal injection, the main dose may be administered.
An inadvertent intravascular injection may be recognised by a temporary increase in heart rate and an accidental intrathecal injection by signs of a spinal block.
If toxic symptoms or signs occur, the infusion should be stopped immediately.

2. Analgesia.

When calculating the dosage for postoperative analgesia, the use of intraoperative local anaesthetics and opioids should be taken into account.
When prolonged blocks are used, either by continuous infusion or repeated bolus administration, the risks of reaching a toxic plasma concentration or inducing local neural injury must be considered. Cumulative doses of up to 800 mg ropivacaine for surgery and postoperative analgesia administered over 24 hours were well tolerated, as were postoperative continuous epidural infusions of ropivacaine with 2 microgram or 4 microgram fentanyl at rates up to 14 mL/hour for 72 hours.

Use in children.

Until further experience has been gained, Naropin 0.2% with Fentanyl is contraindicated for use in children below the age of 12 years (see Section 4.3 Contraindications).

Use in debilitated or elderly patients.

Debilitated or elderly patients, including those with partial or complete heart conduction block, advanced liver disease or severe renal dysfunction, should be given reduced dosage commensurate with their physical condition. Clinical studies with this group of patients have not been performed (see Section 4.4 Special Warnings and Precautions for Use).

4.3 Contraindications

1. Allergy or hypersensitivity to amide type local anaesthetics, fentanyl or other ingredients contained in Naropin 0.2% with Fentanyl solution (see Section 2 Qualitative and Quantitative Composition).
2. Intravenous administration.
3. Epidural anaesthesia is contraindicated in patients with uncorrected hypotension.
4. Local anaesthetic techniques must not be used when there is infection in the region of the proposed injection and/or in the presence of septicaemia.
5. As with all ropivacaine solutions, ropivacaine is contraindicated in obstetric paracervical block, intravenous regional anaesthesia (Bier's block) and all intravenous infusions.
6. Fentanyl should not be administered to patients who are taking or have taken a monoamine oxidase inhibitor (including selegiline) within the previous fourteen days.
7. Fentanyl should not be used in patients susceptible to respiratory depression or in patients whom respiratory reserve is significantly depleted (e.g. comatose patients who may have head injuries or a brain tumour). Fentanyl may obscure the clinical course of patients with head injury.
8. Local anaesthetics are contraindicated for epidural and spinal anaesthesia in patients with uncorrected hypotension.
9. General contraindications related to epidural anaesthesia, regardless of the local anaesthetic used, should be taken into account.
10. Bronchial asthma is contraindicated.
11. Fentanyl may cause muscle rigidity upon IV administration. Therefore, the need for reversal and muscle relaxants contraindicates its used in patient with a history of myasthenia gravis.
12. Use in patient after operative interventions in the biliary tract.
13. Until further experience has been gained, Naropin 0.2% with Fentanyl is contraindicated in children below the age of 12 years.

4.4 Special Warnings and Precautions for Use

1. When Naropin 0.2% with Fentanyl is used, resuscitative equipment and drugs, including oxygen and an opioid antagonist, should be immediately available in order to manage possible adverse reactions involving the cardiovascular, respiratory or central nervous systems. Because of the possibility of hypotension and bradycardia following major blocks, an intravenous cannula should be inserted before the solution is injected.
2. Injection should always be made slowly with frequent aspirations to avoid inadvertent intravascular injection which can produce toxic effects.
3. Although intra-articular continuous infusions of local anaesthetics following arthroscopic and other surgical procedures is an unapproved use, there have been postmarketing reports of chondrolysis in patients receiving such infusions. The majority of reported cases of chondrolysis have involved the shoulder joint; cases of glenohumeral chondrolysis have been described in paediatric and adult patients following intra-articular continuous infusions of local anaesthetics with and without adrenaline for periods of 48 to 72 hours. There is insufficient information to determine whether shorter infusion periods are not associated with these findings. The time of onset of symptoms, such as joint pain, stiffness and loss of motion can be variable, but may begin as early as the second month after surgery. Currently, there is no effective treatment for chondrolysis; patients who experienced chondrolysis have required additional diagnostic and therapeutic procedures and some required arthroplasty or shoulder replacement. Therefore, Naropin 0.2% with Fentanyl should not be used for postoperative intra-articular continuous infusion.
4. Low molecular weight heparins and heparinoids (spinal/epidural haematomas). When neuraxial anaesthesia (epidural/spinal anaesthesia) is employed, patients anticoagulated or scheduled to be anticoagulated with low molecular weight heparins or heparinoids are at risk of developing an epidural or spinal haematoma which can result in long-term or permanent paralysis. The risk of these events is increased by the use of indwelling epidural catheters, traumatic or repeated epidural/spinal puncture, and the concomitant use of drugs affecting haemostasis, such as NSAIDs, platelet inhibitors or other anticoagulants. Patients should be frequently monitored for signs and symptoms of neurological impairment.
5. The safety and efficacy of Naropin 0.2% with Fentanyl depends on proper dosage, correct technique and adequate precautions. Standard textbooks should be consulted regarding specific techniques and precautions for epidural analgesia.
6. The lowest dosage that results in efficacious analgesia should be used (see Section 4.2 Dose and Method of Administration).
Elderly, young or debilitated patients, including those with partial or complete heart conduction block, advanced liver disease or severe renal dysfunction, should be given reduced doses commensurate with their age and physical condition.
7. The possibility of hypotension and bradycardia following epidural and intrathecal blockade should be anticipated and precautions taken, including the prior establishment of an intravenous line and the availability of vasopressor drugs, vagolytic drugs and oxygen.
8. Local anaesthetics should be given with caution (if at all) to patients with pre-existing neurological disease.
9. Ropivacaine should be used with caution in patients with known drug sensitivities.
10. Naropin 0.2% with Fentanyl should be used with caution in patients with severe impairment of respiratory function. In such patients, opioid agonists, such as fentanyl, may further decrease respiratory drive. Patients should be monitored for signs of respiratory depression and appropriate countermeasures taken as necessary.
11. Fentanyl may cause spasm of the sphincter of Oddi.
12. Fentanyl has abuse potential. Psychological and physical dependence may occur with repeated or prolonged dosing.
13. Hyperglycaemia has been reported with opioid agonists. This should be considered when diabetics require treatment with these agents.
14. Naropin 0.2% with Fentanyl may cause drowsiness and lower limb weakness. Patients should be supervised with initial ambulation to provide assistance where required.
15. Careful and constant monitoring of cardiovascular and respiratory vital signs and the patient's state of consciousness should be accomplished after each local anaesthetic injection. It should be kept in mind that at such times restlessness, anxiety, tinnitus, dizziness, blurred vision, tremors, depression or drowsiness may be early warning signs of CNS toxicity.
16. Local anaesthetics should be given with great caution (if at all) to patients with pre-existing abnormal neurological pathology, e.g. myasthenia gravis. Use with extreme caution in epidural, caudal and spinal anaesthesia when there are serious diseases of the CNS or of the spinal cord, e.g. meningitis, spinal fluid block, cranial or spinal haemorrhage, tumours, poliomyelitis, syphilis, tuberculosis or metastatic lesions of the spinal cord.
17. Patients treated with class III antiarrhythmic drugs (e.g. amiodarone) should be under close surveillance. ECG monitoring should also be considered, since cardiac effects may be additive.
18. There have been reports of cardiac arrest during the use of Naropin 0.2% with Fentanyl 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.
19. Naropin 0.2% with Fentanyl 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.
20. If fentanyl is administered with neuroleptics, the user should be familiar with the special properties of each medicine, particularly with regard to durations of action. In addition, when such a combination is used, fluids and other countermeasures to manage hypotension should be available.
21. Fentanyl can produce drug dependence of the morphine type and therefore has the potential for being abused.
22. Depression of respiration is the most marked and dangerous side effect of fentanyl.
In the post-operative period, patients may exhibit delayed depression of respiration. Patients should be monitored for this possibility and appropriate countermeasures taken as necessary. (See impaired respiration below.)
23. Fentanyl should be used with caution in patients with severe impairment of pulmonary function because of the possibility of respiratory depression (e.g. chronic obstructive pulmonary disease, patients with decreased respiratory reserve, or any patient with potentially compromised respiration). In such patients, opioids may further decrease respiratory drive and increase airway resistance.
24. Vital signs should be monitored routinely.
25. Caution is advised when fentanyl is coadministered with drugs that affect the serotonergic neurotransmitter systems. The development of a potentially life threatening serotonin syndrome may occur with the concomitant use of serotonergic drugs such as Selective Serotonin Re-uptake Inhibitors (SSRIs) and Serotonin Norepinephrine Reuptake Inhibitors (SNRIs), and with drugs which impair metabolism of serotonin (including Monoamine Oxidase Inhibitors [MAOIs]). This may occur within the recommended dose. Serotonin syndrome may include mental status changes (e.g. agitation, hallucinations, coma), autonomic instability (e.g. tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g. hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g. nausea, vomiting, diarrhoea). If serotonin syndrome is suspected, rapid discontinuation of fentanyl should be considered.
26. 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.

Use in hepatic impairment.

Elderly, young or debilitated patients, including those with partial or complete heart conduction block, advanced liver disease or severe renal dysfunction, should be given reduced doses commensurate with their age and physical condition.
Ropivacaine is eliminated primarily by hepatic metabolism and changes in hepatic function may have significant consequences. Ropivacaine has an intermediate to low clearance, which depends on its unbound fraction and intrinsic metabolic clearance. Naropin 0.2% with Fentanyl should therefore be used with caution in patients with severe hepatic disease.

Use in renal impairment.

Elderly, young or debilitated patients, including those with partial or complete heart conduction block, advanced liver disease or severe renal dysfunction, should be given reduced doses commensurate with their age and physical condition.
Acidosis and reduced plasma protein concentration, frequently seen in patients with chronic renal dysfunction, may increase the risk of systemic toxicity (see Section 4.2 Dose and Method of Administration). Normally there is no need to modify the dose of ropivacaine in patients with impaired renal function when used for single dose or short term treatment. However these patients may be more sensitive to the effects of fentanyl and the possibility of fentanyl accumulation should be kept in mind. Dosage reduction may be necessary in patients with impaired renal function, particularly towards the end of the infusion.

Use in the elderly.

Elderly, young or debilitated patients, including those with partial or complete heart conduction block, advanced liver disease or severe renal dysfunction, should be given reduced doses commensurate with their age and physical condition.

Paediatric use.

Until further experience has been gained, Naropin 0.2% with Fentanyl is contraindicated in children below the age of 12 years (see Section 4.3 Contraindications).
Elderly, young or debilitated patients, including those with partial or complete heart conduction block, advanced liver disease or severe renal dysfunction, should be given reduced doses commensurate with their age and physical condition.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Local anaesthetics and antiarrhythmic drugs.

Naropin 0.2% with Fentanyl should be used with caution in patients receiving other local anaesthetics, agents structurally related to amide type local anaesthetics or other opioids since the toxic effects may be additive.

Adrenaline.

The duration and intensity of ropivacaine sensory block is not improved by the addition of adrenaline.

CNS depressants.

The depressant effects of fentanyl are potentiated by other CNS depressant drugs, such as alcohol, tranquilizers, benzodiazepines, barbiturates, neuroleptics, opioids and general anaesthetics.
Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including barbiturates, tranquilizers, alcohol, neuroleptics, opioids and general anaesthetics increases the risk of respiratory depression, profound sedation, coma and death. Reserve concomitant prescribing of these medicines for use in patients for whom alternative treatment options are inadequate. When patients have received such medicines, the dose of fentanyl required will be less than usual. Likewise, following the administration of fentanyl the dose of other CNS depressant medicines should be reduced. Follow patients closely for signs of respiratory depression and sedation.

Alkaline solutions.

The solubility of ropivacaine is limited at pH values above 6.0. This must be taken into consideration if adding an alkaline solution since precipitation might occur at higher pH values.

Cytochrome P450 interactions.

Fluvoxamine.

There is a potential risk for metabolic interaction when Naropin is used in combination with a potent cytochrome P450 (CYP1A2) inhibitor, e.g. fluvoxamine. Oral fluvoxamine treatment caused a 70% decrease in ropivacaine clearance and a 3-fold higher AUC in healthy volunteers. Single administrations of ropivacaine should be used with care in patients who are concomitantly receiving a potent CYP1A2 inhibitor. Repeated administration or long-term infusion should be avoided in such patients.

Ketoconazole.

Coadministration with ketoconazole, a potent inhibitor of CYP3A4, has been shown to cause a marginal (15%) decrease in ropivacaine clearance in healthy volunteers.

Theoretical interactions.

Cimetidine, an inhibitor of CYP2E1, did not inhibit the formation of 3-hydroxy-ropivacaine but inhibited some formation of minor metabolites in vitro.
A theoretical possibility of metabolic drug interactions with potent inhibitors of CYP1A2, such as enoxacin, may exist.
A theoretical possibility of metabolic ropivacaine drug interactions with other substances known to be metabolised by CYP1A2 such as theophylline, imipramine (also by CYP2D6, CYP2C19) and oestrogens may exist, as with potent inhibitors such as verapamil.

Neuroleptics.

When a neuroleptic such as droperidol is used with fentanyl, pulmonary arterial pressure may be decreased. Hypotension can occur and, possibly, hypovolaemia (which should be managed with appropriate parenteral fluids). The following adverse reactions have also been reported: chills, shivering, restlessness, hypertension, postoperative hallucinatory episodes and transient periods of mental depression. Extrapyramidal symptoms (dystonia, akathisia and oculogyric crisis) have been observed up to 24 hours postoperatively. When they occur, extrapyramidal symptoms can usually be controlled with antiparkinson agents.

MAO inhibitors.

Severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics. Since the safety of Naropin 0.2% with Fentanyl in this regard has not been established, the use of fentanyl in patients who have received monoamine oxidase inhibitors within 14 days is not recommended (see Section 4.3 Contraindications).

Nitrous oxide.

Nitrous oxide has been reported to produce cardiovascular depression when given with high doses of fentanyl.

Amiodarone.

Profound bradycardia, sinus arrest and hypotension have occurred when patients receiving amiodarone have been given fentanyl.

Beta-adrenergic blockers and calcium channel blockers.

The combination of calcium channel blockers and beta-adrenergic blockers during fentanyl anaesthesia should be used with caution since severe hypotension has been reported to occur.

Serotonin syndrome.

Opioids can interact with antidepressants and migraine medicines to cause a serious central nervous system reaction called serotonin syndrome, in which high levels of the chemical serotonin build up in the brain and cause toxicity.
Coadministration of the following drugs may enhance or prolong the effects of fentanyl: azole antifungals, macrolide antibiotics and protease inhibitors such as ritonavir.
Coadministration of the following drugs may decrease the plasma concentration of fentanyl: phenytoin.
Coadministration of sibutramine hydrochloride with fentanyl may increase the risk of serotonin syndrome (hypertension, hypothermia, myoclonus and mental status changes).
The concurrent administration of fentanyl and naltrexone precipitates opioid withdrawal symptoms.

Metabolic interactions.

With the low to intermediate hepatic extraction ratio of ropivacaine (mean 0.4), a fall in the liver blood flow is not expected to have a significant influence on ropivacaine clearance (see Section 4.4 Special Warnings and Precautions for Use).
There was no metabolic interactions between ropivacaine and fentanyl when given in a fixed combination as a continuous epidural infusion for one month in dogs.

Clinical relevance of interactions.

Patients in clinical studies usually received Naropin 0.2% with Fentanyl in combination with several other therapies. The safety evaluation of Naropin 0.2% with Fentanyl is therefore based upon its use in combination with various concomitant treatments. The review of safety data in these studies show that Naropin 0.2% with Fentanyl has a safety profile comparable to other local anaesthetics used for epidural anaesthesia. Furthermore, drugs metabolised by CYP1A2, e.g. paracetamol, have also been used in combination with Naropin 0.2% with Fentanyl in the clinical program, without clinical evidence of metabolic interactions.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No adverse effects on fertility and reproductive performance were seen in rats over 2 generations following daily subcutaneous administration of ropivacaine from prior to mating through weaning, with estimated systemic exposure (plasma AUC) twice the clinical exposure following a 200 mg epidural dose. Increased pup loss in the first 3 days postpartum was attributed to reduced maternal care.
Animal studies have not been done to assess the potential for impairment of fertility when ropivacaine is given in combination with fentanyl.
(Category C)

Ropivacaine (Category B1).

There was no evidence of teratogenicity following daily subcutaneous administration of ropivacaine to rats and rabbits during the period of organogenesis, with estimated systemic exposure (plasma AUC) twice the clinical exposure following a 200 mg epidural dose. In rats treated similarly with ropivacaine daily from late gestation to weaning, there were no treatment related effects on late foetal development, parturition, lactation, neonatal viability, or offspring growth. In rats treated from late gestation to weaning, maternal toxicity was elicited at a lower dose and lower unbound plasma concentration with bupivacaine than with ropivacaine.
There are no clinical studies in preterm pregnant women on the effects of ropivacaine on the developing fetus. Ropivacaine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
The use of ropivacaine in obstetrics is well documented and no negative effects have been observed.

Fentanyl (Category C).

Fentanyl crosses the placenta in humans and has been found in fetal blood at concentrations approximately 40% of those found in maternal blood. The safe use of fentanyl in pregnant women has not been established with respect to possible adverse effects on the fetus or on fetal development. Opioid analgesics used during labour may cause respiratory depression in the newborn infant and should be used only after weighing the needs of the mother against the risk to the fetus. Withdrawal symptoms in newborn infants have been reported with prolonged use of this class of drugs.
Therefore it should be used in women of childbearing potential only when in the judgement of the physician the potential benefits outweigh the possible hazards.

Ropivacaine and fentanyl.

Animal studies have not been done to assess the potential for adverse effects on pregnancy or on the fetus when ropivacaine and fentanyl are given in combination.
 Subcutaneous administration of ropivacaine to rats from late gestation to weaning, with estimated systemic exposure (plasma AUC) twice the clinical exposure following a 200 mg epidural dose, did not affect late fetal development, parturition, lactation, neonatal viability or offspring growth. Ropivacaine and/or its metabolites are excreted into milk in rats, but excretion into human milk has not been investigated.
Small amounts of fentanyl have been detected in breast milk.

4.7 Effects on Ability to Drive and Use Machines

Naropin 0.2% with Fentanyl may have an effect on mental function and coordination even in the absence of overt CNS toxicity and may impair locomotion and alertness.

4.8 Adverse Effects (Undesirable Effects)

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at "http://www.tga.gov.au/reporting-problems" and "[email protected]".
Adverse reactions to ropivacaine are rare in the absence of overdosage or inadvertent intravascular injection. Adverse reactions to fentanyl are similar to those observed with other opioid agonist analgesics. The adverse reactions to Naropin 0.2% with Fentanyl are similar to those observed with the individual agents.
These adverse reactions are, in general, dose related and may result from high plasma levels caused by excessive dosage, rapid absorption or may result from a hypersensitivity, idiosyncrasy or diminished tolerance on the part of the patient. They should be distinguished from the physiological effects of the nerve block itself, e.g. a decrease in blood pressure and bradycardia during epidural anaesthesia.
Pronounced acidosis, hyperkalaemia or hypoxia in the patient may increase the risk and severity of toxic reactions.
The effects of systemic overdose and unintentional intravascular injection may involve the central nervous system and/or the cardiovascular system (see Section 4.9 Overdose). Inadvertent subarachnoid injection may lead to CNS depression, respiratory arrest and cardiovascular collapse.
The following list of adverse events is based upon experience with the monotherapies in their usual dosage range. These events are considered to be of clinical importance, regardless of causal relationship.

Very common events (> 10%).

Cardiovascular.

Hypotensionc.

Gastrointestinal.

Nausea.

Common events (> 1%).

Cardiovascular.

Bradycardiaa, hypertension and tachycardia.

Nervous system.

Paraesthesia, temperature elevation, rigors (chills), headachea and dizziness.

Gastrointestinal.

Vomitinga.

Other.

Urinary retentiona, back pain, insomnia, chest pain and oliguria.

Uncommon events (< 1%).

Acute systemic toxicity.

More serious but less common reactions that reflect acute systemic toxicityb, include dysarthria, muscular rigidity, muscle twitching, myoclonic movements, muscle rigidity with laryngospasm or bronchospasm, unconsciousness, convulsions, hypoxia, hypercapnia, apnoea, respiratory depression, severe hypotension and bradycardia, arrhythmias, cardiac arrest. Indirect cardiovascular effects (hypotension, bradycardia) may occur after epidural administration, depending on the extent of the concomitant sympathetic block.

Psychiatric.

Anxiety.

Nervous system.

Hypoaesthesiaa, symptoms of CNS toxicity (grand mal convulsions, seizures, light headedness, circumoral paraesthesia, numbness of the tongue, hyperacusis, tinnitus, visual disturbances, dysarthria, tremor).

Vascular.

Syncopea.

Respiratory, thoracic and mediastinal.

Dyspnoeaa.

General disorders and administration site conditions.

Hypothermiaa.

Rare (≤ 0.1%).

Cardiac disorders.

Cardiac arrest, cardiac arrhythmias.

General disorders and administration site conditions.

Allergic reactions (anaphylactoid reactions, angioneurotic oedema and urticaria).

Unknown.

Cough, constipation.
a These reactions are more frequent after spinal anaesthesia.
b These symptoms usually occur because of inadvertent intravascular injection, overdose or rapid absorption.

Class related adverse drug reactions.

This section includes complications related to anaesthetic technique regardless of the local anaesthetic used.

Neurological complications.

Neuropathy and spinal cord dysfunctions (e.g. anterior spinal artery syndrome, arachnoiditis, cauda equina syndrome) have been associated with intrathecal and epidural anaesthesia.

Total spinal block.

Total spinal block may occur if an epidural dose is inadvertently administered intrathecally or if a too large intrathecal dose is administered.

Allergic reactions.

Allergic reactions (in the most severe instances anaphylactic shock) to local anaesthetics of the amide type or to fentanyl are rare.

Neurological.

Neuropathy and spinal cord dysfunction (e.g. anterior spinal artery syndrome, arachnoiditis, cauda equina syndrome) have been associated with regional anaesthesia, regardless of the local anaesthetic drug used. Convulsions have been observed following unintended intravascular injection of ropivacaine.

Other.

Blurred vision, miosis, diaphoresis, postoperative mental depression, paradoxical CNS excitation, delirium and spasm of the sphincter of Oddi.

Clinical trials using Naropin 2 mg/mL with fentanyl 2 microgram/mL.

Clinical trials in patients undergoing epidural infusion for postoperative pain show that the following events were more common in patients receiving Naropin 0.2% with Fentanyl than in the group receiving Naropin alone: pruritus, ileus, hypomagnesaemia, hypoglycaemia, atelectasis, urine abnormal, laboratory test abnormal.
The following events were less common in the Naropin 0.2% with Fentanyl group than in the plain Naropin group: hypothermia, chest pain, vasospasm, coughing.

4.9 Overdose

For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).
Acute emergencies associated with the use of local anaesthetics are generally related to high plasma levels or to unintended subarachnoid injection of the solution (see Section 4.8 Adverse Effects (Undesirable Effects)).
Accidental intravascular injections of local anaesthetics may cause immediate toxic effects. Toxic effects may also arise from exceptionally rapid absorption from highly vascularised areas. 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. Systemic toxic reactions may involve the central nervous system and the cardiovascular system. CNS reactions are similar for all amide local anaesthetics, while cardiac reactions are more dependent on the drug, both quantitatively and qualitatively.

Symptoms.

There have been no reports of overdosage in patients receiving Naropin 0.2% with Fentanyl. The symptoms of Naropin 0.2% with Fentanyl overdosage are expected to reflect those seen with overdosage of the individual drugs. Systemic toxic reactions of ropivacaine may involve the central nervous system and the cardiovascular system.
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, lightheadedness, tingling and paraesthesia are seen. Dysarthria, muscular rigidity and muscular twitching are more serious and may precede the onset of generalised convulsions.
Unconsciousness and grand mal convulsions may follow which can last from a few seconds to several minutes. Hypoxia and hypercapnia occur rapidly during convulsions due to the increased muscular activity, together with disruption to respiration and possible loss of functional airways. In severe cases apnoea may occur. Respiratory and metabolic acidosis, hyperkalaemia, hypocalcaemia and hypoxia increase and extend the toxic effects of local anaesthetics.
Recovery follows the redistribution of the local anaesthetic drug from the central nervous system and subsequent metabolism and excretion. Recovery should be rapid unless large amounts of the drug have been injected.
Cardiovascular toxicity indicates a more severe situation. Hypotension, bradycardia, arrhythmia and even cardiac arrest may occur as a result of high systemic concentrations of local anaesthetics. In volunteers, the intravenous infusion of Naropin 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. However, in rare cases, cardiac arrest has occurred without prodromal CNS effects.
Large doses of fentanyl can cause respiratory depression.

Treatment.

If signs of acute toxicity appear, injection of the infusion solution should be immediately stopped.
Treatment consists of ensuring adequate ventilation and arresting convulsions. In the presence of hypoventilation or apnoea, oxygen should be administered and respiration assisted or controlled as necessary. A patent airway must be maintained.
Respiratory depression due to fentanyl can be managed by assisted or controlled respiration or where appropriate by the administration of an opioid antagonist such as naloxone. The duration of respiratory depression of doses of fentanyl employed during anaesthesia is usually longer than the duration of opioid antagonist action. Consult the individual product information before administering opioid antagonists.
If convulsions occur and do not spontaneously stop within 15-20 seconds, an anticonvulsant should be given intravenously, e.g. diazepam 5-10 mg i.v. or, where indicated, sodium thiopentone (5 mg/kg). If convulsions interfere with breathing and/or are not rapidly controlled by specific anticonvulsant medication, suxamethonium (1-2 mg/kg) may be used to paralyse the patient. Artificial ventilation must then be instituted.
If cardiovascular depression is evident (hypotension, bradycardia), appropriate treatment with intravenous fluids, vasopressor and/or inotropic agents should be considered.
If ventricular fibrillation, cardiac arrest or circulatory arrest occur, cardiopulmonary resuscitation must be instituted and maintained for a prolonged period if necessary. 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 possibility of a successful outcome.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Ropivacaine.

Ropivacaine has both anaesthetic and analgesic effects. At higher doses it produces surgical anaesthesia with motor block, while at lower doses it produces a sensory block including analgesia with little motor block.
The duration and intensity of ropivacaine sensory block is not improved by the addition of adrenaline.
Ropivacaine, 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. It is the first long acting amide local anaesthetic developed as a pure enantiomer. There is no evidence of in vivo racemisation of ropivacaine.
The local anaesthetic effect of ropivacaine and its R-(+) enantiomer was evaluated for sciatic block, spinal anaesthesia and infiltration anaesthesia over a wide concentration range (0.25-1.0%) in a number of animal species and a concentration (dose) response relationship was ascertained. These studies supported the selection of the enantiomerically pure drug ropivacaine and are consistent with the observations with other local anaesthetics that the S-(-) form is less toxic and/or has a longer duration of action than the R-(+) form.
In vitro testing of ropivacaine conduction anaesthesia indicate that ropivacaine is comparable to, or slightly more potent than, bupivacaine in blocking sensory fibres and is less active in blocking motor fibres.
The anaesthetic effects of ropivacaine were evaluated in peripheral (sciatic nerve and brachial plexus) and central (spinal and epidural) neural blocks, as well as in infiltration and topical anaesthesia in a large number of studies using multiple animal species including mouse, rat, guinea pig, dog, sheep and Rhesus monkey.
For central neural blockade, for all species studied, it appeared that onset times of epidural anaesthesia with ropivacaine and bupivacaine were similar. The concentration required to consistently produce complete motor blockade with epidural block appeared to be 0.75-1.0% for ropivacaine. Duration of sensory anaesthesia appeared to be comparable for equal concentrations of ropivacaine and bupivacaine.
For analgesia, the potency of ropivacaine is similar to that of bupivacaine. For motor block, the potency was found to be around 80% of bupivacaine.
Cardiovascular effects measured in vivo in animal studies showed that ropivacaine is consistently well tolerated and that ropivacaine is less likely than bupivacaine to produce ventricular arrhythmias. Resuscitative measures were highly successful in dogs given large overdoses (9.8 mg/kg given intravenously) of ropivacaine. In most preclinical studies of the cardiovascular effects, comparisons were also made with lignocaine. In general all results were consistent with the observation that a given dose of lignocaine was less toxic than an equivalent dose of ropivacaine or bupivacaine.
Ropivacaine and bupivacaine are equipotent in producing seizures in rats and dogs. In both pregnant and nonpregnant sheep, ropivacaine was less toxic than bupivacaine.
Comparisons with the short acting local anaesthetic lignocaine shows that the doses needed to produce seizures are 2 (in sheep) to 4 (in rats and dogs) times the dose of ropivacaine. In studies in sheep ropivacaine appears to have less central nervous system and cardiovascular toxicity than bupivacaine, and pregnancy does not appear to enhance sensitivity in either the central nervous system or in cardiac membranes as has been reported in some studies with bupivacaine.
In vitro heart studies indicate that the effects of ropivacaine on conduction and contractility are less compared to bupivacaine. The risk of ventricular tachycardia is less with ropivacaine than bupivacaine. Atrial and ventricular pacing were more successful during exposure to high concentrations of ropivacaine compared to bupivacaine. The in vitro electrophysiological studies are consistent with the findings in the in vitro heart preparation.
In man, ropivacaine is less toxic regarding the CNS and cardiovascular systems than bupivacaine. In two tolerability studies in volunteers given i.v. infusions, CNS symptoms appeared at higher doses and higher free plasma concentrations of ropivacaine compared to bupivacaine. The ropivacaine dose response and concentration response curves for CNS symptoms, e.g. muscular twitching, dysarthria, were consistently shifted to the right compared with those of bupivacaine. A threshold for CNS toxicity was apparent at mean free plasma concentrations in the order of 0.6 mg/L ropivacaine and 0.3 mg/L bupivacaine. Ropivacaine caused a smaller increase in the QRS width and less pronounced reduction in diastolic and systolic function of the left ventricle as compared to bupivacaine.
Factors which may increase the relative systemic toxicity of local anaesthetics are acidosis and severe hepatic dysfunction.
Ropivacaine, like bupivacaine and other local anaesthetics, produces vasoconstriction at lower concentrations and vasodilation at higher concentrations. These findings appear to be consistent both in vivo and in vitro.
Pharmacodynamic drug interactions between ropivacaine and other agents used in conjunction with epidural anaesthesia are similar to those seen with bupivacaine and lignocaine. These probably depend more on the physiological effects of the block, such as hypotension and bradycardia, than on circulating blood levels of the local anaesthetic.

Fentanyl.

Fentanyl is an opioid analgesic with pharmacologic effects similar to morphine and pethidine. It is 50 to 100 times more potent than morphine on a weight basis. Fentanyl citrate 157 microgram is approximately equivalent to 100 microgram of fentanyl. A dose of 100 microgram fentanyl is approximately equivalent in analgesic activity to 10 mg of morphine or 75 mg of pethidine. The principal actions of therapeutic value are analgesia and sedation. When given epidurally, opioids produce selective analgesia by blocking opioid receptors in the dorsal horn. Opioids may produce dose related respiratory depression. Alterations in respiratory rate and alveolar ventilation may last longer than the analgesic effect. As the dose of opioid is increased, the decrease in pulmonary exchange becomes greater. Large doses may produce apnoea.
Histamine assays and skin wheal testing in man indicate that clinically significant histamine release rarely occurs with fentanyl. Fentanyl appears to have less emetic activity than either morphine or pethidine. Fentanyl preserves cardiac stability and blunts stress related hormonal changes at higher doses. Fentanyl produces minimal cortical depression and may act by filling receptor sites located in the thalamus, midbrain and spinal cord.
A specific opioid antagonist (e.g. nalorphine) produces reversal of respiratory, cardiovascular, miotic and motor incoordination effects and also produces reversal of analgesia, euphoria and sedation. Cholinergic effects such as bradycardia are reversed by atropine.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Ropivacaine.

The plasma concentration of ropivacaine depends upon the dose, the route of administration and the vascularity of the injection site. Ropivacaine has linear pharmacokinetics and the maximum plasma concentration is proportional to the dose.
The pharmacokinetic profile of ropivacaine following experimental i.v. administration is summarised in Table 2.

Absorption.

Ropivacaine shows complete and biphasic absorption from the epidural space with half-lives of the two phases in the order of 14 minutes and 4 hours. 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.

Distribution.

Ropivacaine is mainly bound to α1-acid glycoprotein in plasma with an unbound pharmacologically active fraction of about 6%. An increase in total plasma concentrations during continuous postoperative epidural infusion has been observed. This increase is related to a postoperative increase of α1-acid glycoprotein. Variations in unbound concentration of ropivacaine have been much less than in total plasma concentration.

Metabolism.

Ropivacaine 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% is unchanged drug. Approximately 9% is excreted in faeces.
Both the dealkylation (N-depropylated or PPX) and the hydroxylation pathways in the metabolism of ropivacaine are detoxification reactions. PPX is considered to have no or very little pharmacological activity. The hydroxylated metabolites of ropivacaine have some local anaesthetic activity (ropivacaine > 3-hydroxy-ropivacaine > > 4-hydroxy-ropivacaine). The hydroxylated metabolites are rapidly conjugated in human plasma and are very unlikely to have any pharmacological or toxicological activities.
The major metabolite is 3-hydroxy-ropivacaine. This metabolite accounts for about 37% of urinary excretion, mainly as a glucuronide conjugate. The only metabolite which reaches detectable concentrations in plasma is 3-hydroxy-ropivacaine (conjugated and unconjugated). Urinary excretion of 4-hydroxy-ropivacaine, the N-dealkylated metabolite and the 4-hydroxy-dealkylated metabolite accounts for 1-3% of a given dose.
The NADPH dependent metabolism of ropivacaine to 3-hydroxy-ropivacaine is catalysed by CYP1A2. The formation of minor metabolites in vivo is catalysed by CYP3A4. The apparent Km (affinity constant) for 3-hydroxy-ropivacaine is 16 micromolar and about 400 micromolar for the other metabolites. Of the two members in the CYP1A family, CYP1A1 is expressed only after exposure to inducers, while CYP1A2 accounts for about 10% of total P450 in the liver.

Excretion.

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 nonrenal elimination in addition to renal excretion. Some patients with impaired renal function may show an increased exposure to PPX resulting from a low nonrenal clearance. The potential for toxicity in these patients is dependent on the total dose, dose route and duration of exposure to ropivacaine.

Fentanyl.

The pharmacokinetics of fentanyl can be described by a three compartment model, with a distribution time of 1.7 minutes, redistribution of 13 minutes and a terminal elimination half-life of 219 minutes. The volume of distribution for fentanyl is 4 L/kg. Fentanyl accumulates in skeletal muscle and fat and is released slowly into the blood.
Fentanyl plasma protein binding capacity increases with increasing ionisation of the drug. Alterations in pH may affect its distribution between plasma and the central nervous system.
Fentanyl is primarily transformed in the liver, catalysed by CYP3A4 and demonstrates a high first pass clearance with approximately 75% of an intravenous dose excreted in urine, primarily as inactive metabolites with less than 10% representing the unchanged drug. Approximately 9% of the dose is recovered in the faeces, primarily as metabolites.

5.3 Preclinical Safety Data

Genotoxicity.

Ropivacaine hydrochloride was negative in the Ames salmonella/mammalian microsome mutagenicity test, human lymphocyte chromosome aberration test, mouse micronucleus test, E. coli differential DNA repair test, E. coli host-mediated DNA repair test in mice, and the somatic mutation and recombination test in Drosophila melanogaster (fruit fly), and weakly mutagenic in the mouse lymphoma test. The clinical use of ropivacaine is unlikely to pose any risk of genotoxicity.
Fentanyl showed no evidence of genotoxic potential in standard assays for gene mutations, chromosomal damage and other genotoxic effects.
Animal studies have not been done to assess the potential for mutagenic activity when ropivacaine is given in combination with fentanyl.

Carcinogenicity.

Long term animal assays of carcinogenic potential have not been performed with ropivacaine hydrochloride.
The carcinogenic potential of fentanyl has not been investigated.
Animal studies have not been done to assess the potential for carcinogenic activity when ropivacaine is given in combination with fentanyl.

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

Naropin 0.2% with Fentanyl should not be mixed with other solutions as no compatibility studies have been conducted. The solubility of ropivacaine is limited at pH > 6.0 and precipitation may occur if mixed with alkaline solutions.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging. Naropin with Fentanyl Polybag presentations have a shelf-life of 24 months when stored below 30°C.

6.4 Special Precautions for Storage

Store below 30°C. Do not freeze.
Polybag must not be re-autoclaved.
Naropin 0.2% with Fentanyl injection solutions do not contain a preservative. Each Polybag is intended for single use only, not exceeding 24 hours. Any solution remaining from an opened Polybag should be discarded.

6.5 Nature and Contents of Container

Container type: polypropylene bag.
Pack size: 5 x 100 mL bags; 5 x 200 mL bags.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with the local requirements.

6.7 Physicochemical Properties

Naropin 0.2% with Fentanyl is a sterile, isotonic solution with nominal osmolality of 288 mOsmol/kg.
The pH of the solution is adjusted with sodium hydroxide or hydrochloric acid to remain between 4.0-6.0 during the approved shelf-life.
The active ingredients in Naropin 0.2% with Fentanyl are ropivacaine hydrochloride and fentanyl citrate.
The chemical formula of ropivacaine hydrochloride is C17H26N2O.HCl.H2O. MW 328.89. The chemical formula for fentanyl citrate is C22H28N2O,C6H8O7. MW 528.61.
The chemical name for ropivacaine hydrochloride is (S)-(-)- propyl- piperidine -2-carboxylic acid (2,6-dimethyl -phenyl)- amide hydrochloride monohydrate. It is a white crystalline powder and has a water solubility of about 50 mg/mL. Ropivacaine hydrochloride was developed as the pure S-(-)-isomer and has an enantiomeric purity of > 99%. It has a pKa of 8.1 (at 25°C). The Australian approved name is ropivacaine hydrochloride.
The chemical name for fentanyl citrate is N-(1-phenethyl-4-piperidyl) propionanilide citrate. It is a white crystalline powder sparingly soluble in water.

Chemical structure.


CAS number.

The CAS number for the free base ropivacaine is 84057-95-4. The CAS number for fentanyl citrate is 990-73-8.

7 Medicine Schedule (Poisons Standard)

S8.

Summary Table of Changes