'Global Leaders in Anaesthesia'

1. NAME OF THE MEDICINAL PRODUCT
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
3. PHARMACEUTICAL FORM
4. CLINICAL PARTICULARS
5. PHARMACOLOGICAL PROPERTIES
6. PHARMACEUTICAL PARTICULARS

Please consult full local prescribing information before using Naropin.

1. NAME OF THE MEDICINAL PRODUCT

Naropi® 2 mg/mL solution for injection/infusion
Naropin® 5 mg/mL solution for injection
Naropin® 7.5 mg/mL solution for injection
Naropin® 10 mg/mL solution for injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Table 1    Qualitative and quantitative composition- ampoule

Table 2   Qualitative and quantitative composition- bag

For excipients, see 6.1.

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3. PHARMACEUTICAL FORM

Solution for injection for perineural and epidural administration
(10 and 20 mL).
Solution for infusion for perineural and epidural administration
(100 and 200 mL).

Naropin solution for injection/infusion is a sterile, isotonic, isobaric, aqueous solution. The pH of the solution is adjusted to 4.0-6.0 with sodium hydroxide or hydrochloric acid and the solution is free from preservatives. The solutions are intended for single use only.
 

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4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Surgical anaesthesia
- Epidural block for surgery, including Caesarean section
- Intrathecal block
- Major nerve block
- Field block

Acute pain management
- Continuous epidural infusion or intermittent bolus administration e.g.
postoperative or labour pain
- Field block
- Intra-articular injection
- Continuous peripheral nerve block infusion or intermittent injections, e.g.
postoperative pain management

Acute pain management in paediatrics
(per- and postoperative)
- Caudal epidural block in neonates, infants and children up to and including 12 years.
- Peripheral nerve block in children aged 1 up to and including 12 years.
- Continuouis epidural infusion in neonates, infants and children up to and including 12 years.

4.2 Posology and method of administration

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

Adults and children above 12 years of age:
The following table is a guide to dosage for the more commonly used blocks. The clinician's experience and knowledge of the patient's physical status are of importance when deciding the dose.

In general, surgical anaesthesia (e.g. epidural administration) requires the use of the higher concentrations and doses. For analgesia the 2 mg/ml concentration of Naropin is generally recommended, except for intra-articular injection where the 7.5 mg/ml concentration is recommended.

DOSAGE RECOMMENDATIONS FOR NAROPIN IN ADULTS

The doses in the table are those considered to be necessary to produce a successful block and should be regarded as guidelines for use in adults. Individual variations in onset and duration occur. The figures reflect the expected average dose range needed. Standard textbooks should be consulted for factors affecting specific block techniques and for individual patient requirements.
n/a = not applicable
1) The dose for a major nerve block must be adjusted according to site of administration and patient status. Interscalene and supraclavicular brachial plexus blocks may be associated with a higher frequency of serious adverse reactions, regardless of the local anaesthetic used, see also section 4.4.

2) If additional ropivacaine is used by any other techniques in the same patient an overall dose limit of 225 mg should not be exceeded.

In order to avoid intravascular injection, 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. When a epidural dose is to be injected, a preceding test dose of 3-5 ml lidocaine (Xylocaine 1-2%) with adrenaline is recommended. An inadvertent intravascular injection may be recognized by a temporary increase in heart rate and an accidental intrathecal injection by signs of a spinal block. If toxic symptoms occur, the injection should be stopped immediately.

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

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

For the treatment of postoperative pain, the following technique can be recommended: Unless preoperatively instituted, an epidural block with Naropin 7.5 mg/ml is induced via an epidural catheter. Analgesia is maintained with Naropin 2 mg/ml infusion. 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 opioids has been observed.

In clinical studies an epidural infusion of Naropin 2 mg/ml alone or mixed with fentanyl 1-4 microgram/ml has been given for postoperative pain management for up to 72 hours. Naropin 2mg/ml (6-14 ml/hour) provided adequate pain relief for the majority of patients. The combination of Naropin and fentanyl provided improved pain relief but caused opioid side effects.

For Caesarean section, neither intrathecal administration nor the use of the ropivacaine concentration 10 mg/ml for epidural administration, have been documented.

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

Paediatrics:

Table 4 - DOSAGE RECOMMENDATIONS FOR PAEDIATRIC PATIENTS 1 TO 12 YEARS OF AGE

The doses in the table should be regarded as guidelines for use in paediatrics. Individual variations occur. In children with a high body weight a gradual reduction of the dosage is often necessary and should be based on the ideal body weight. The volume for single caudal epidural block and the volume for epidural bolus doses should not exceed 25 mL in any patient. Standard textbooks should be consulted for factors affecting specific block techniques and for individual patient requirements.

(a)    Doses in the low end of the dose interval are recommended for thoracic epidural blocks while doses in the high end are recommended for lumbar or caudal epidural blocks.

(b)    Recommended for lumbar epidural blocks. It is good practice to reduce the bolus dose for thoracic epidural analgesia.

*       Including children 12 years of age.

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

A single caudal epidural injection of ropivacaine 2 mg/ml produces adequate postoperative analgesia below T12 in the majority of patients when a dose of 2 mg/kg is used in a volume of 1 mL/kg. Doses up to 3 mg/kg have been used safely. The volume of the caudal epidural injection may be adjusted to achieve a different distribution of sensory block, as recommended in standard textbooks.

For ilioinguinal block, a single injection of ropivacaine 5 mg/mL produces effective analgesia when a dose of 3 mg/kg in a volume of 0.6 mL/kg is used.

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

Concentration above 5 mg/mL have not been documented for children.

Intrathecal administration has not been documented for use in children.

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

4.3 Contraindications

Naropin solutions are contraindicated in patients with hypersensitivity to local anaesthetics of the amide-type.

4.4 Special warnings and special precautions for use

Regional anaesthetic procedures should always be performed in a properly equipped and staffed area. Equipment and drugs necessary for monitoring and emergency resuscitation should be immediately available. Patients receiving major blocks should be in an optimal condition and have an i.v. line inserted before the blocking procedure. The clinician responsible should take the necessary precautions to avoid intravascular injection (see section 4.2) and be appropriately trained and familiar with the diagnosis and treatment of side effects, systemic toxicity and other complications. (see section 4.9.)

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

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

Patients in poor general condition due to aging 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 the optimal anaesthetic technique in these patients. Patients treated with anti-arrhythmic drugs class III (eg, emiodarone) should be under close surveillance and ECG monitoring considered, since cardiac effects may be additive.

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

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

Epidural and intrathecal anaesthesia may lead to hypotension and bradycardia. The risk of such effects can be reduced, e.g. by pre-loading the circulation or by injecting a vasopressor. Hypotension should be treated promptly with, for example, ephedrine 5-10 mg intravenously, repeated as necessary. Children should be given ephedrine doses commensurate with their age and weight.

Neonates need special attention due to immaturity of some organs and functions. This is especially important during continuous epidural infusion.

When Naropin is administered as intra-articular injection, caution is advised when recent major intra-articular trauma is suspected or extensive raw surfaces within the joint have been created by the surgical procedure, as that may accelerate absorption and result in higher plasma concentrations.

Prolonged administration of ropivacaine should be avoided in patients treated with strong inhibitors of CYP1A2, such as fluvoxamine and enoxacin, see section 4.5.

Naropin solution for injection and infusion is possibly porphyrinogenic and should not be prescribed to patients with acute porphyria when no safer alternative is available. Appropriate precautions should be taken in the case of vulnerable patients.

4.5 Interaction with other medicinal products and other forms of interaction

Naropin should be used with caution in patients receiving other local anaesthetics or agents structurally related to amide-type local anaesthetics, eg, certain antiarrhythmics, such as lidocaine and mexiletin since the systemic toxic effects are additive. Specific interactions studies with ropivacaine and anti-arrhythmic drugs class III (eg, amiodarone) have not been performed, but caution is advised. (See also section 4.4.)

In healthy volunteers ropivacaine clearance was reduced by up to 77% during co-administration of fluvoxamine, a potent competitive inhibitor of P4501A2.
CYP1A2 is involved in the formation of 3-hydroxy-ropivacaine, a major metabolite. Thus strong inhibitors of CYP1A2, such as fluvoxamine and enoxacin, given concomitantly with Naropin can cause a metabolic interaction leading to an increased ropivacaine plasma concentration . Prolonged administration of ropivacaine should therefore be avoided in patients treated with strong inhibitors of CYP1A2 such as fluvoxamine and enoxacin, see also section 4.4.

4.6 Pregnancy and lactation

Pregnancy
Apart from obstetrical use, there are no adequate data on the use of ropivacaine in pregnancy. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3).

Intrathecal administration has not been documented for Caesarean section.

Lactation
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. 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.

4.7 Effects on ability to drive and use machines

Besides the direct anaesthetic effect, local anaesthetics may have a very mild effect on mental function and coordination even in the absence of overt CNS toxicity and may temporarily impair locomotion and alertness.

4.8 Undesirable effects

General

The adverse reaction profile for Naropin® is similar to those of other amide local anaesthetics.
Adverse reactions caused by the drug per se are difficult to distinguish from the physiological effects of the nerve block (eg, decrease in blood pressure, bradycardia), events caused directly (eg, nerve trauma) or indirectly (eg, epidural abscess) by the needle puncture.

Table 5- Table of adverse drug reactions
(Pooled data from all types of blocks)

(a) These reactions are more frequent after spinal anaesthesia.

(b)  These symptoms usually occur because of inadvertent intravascular injection, overdose or rapid absorption, see section 4.9

(c)   Hypotension is less frequent in children (>1/100)

(d)    Vomiting is more frequent in children (>1/10)

Class-related adverse drug reactions

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

Neurological complications
Neuropathy and spinal cord dysfunctions (e.g. anterior spinal artery syndrome, arachnoiditis, cauda equina), 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.

4.8.1 Acute systemic toxicity

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

Central nervous system toxicity is a graded response with symptoms and signs of escalating severity. The first symptoms are usually light-headedness, circumoral paraesthesia, numbness of the tongue, hyperacusis, tinnitus and visual disturbances. Dysarthria, muscular twitching or tremors are more serious and precede the onset of generalised 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
respiration and possible loss of functional airways. 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 of the local anaesthetic drug from the central nervous system and subsequent metabolism and excretion. Recovery may be rapid unless large amounts of the drug have been injected.

Cardiovascular system toxicity may be seen in severe cases and is generally preceded by signs of toxicity in the central nervous system. In patients under heavy sedation or receiving a general anaesthetic, prodromal CNS symptoms may be absent. Hypotension, bradycardia, arrythmia and
even cardiac arrest may occur as a result of high systemic concentrations of local anaesthetics, but in rare cases cardiac arrest has occurred without prodromal CNS effects.

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

4.8.2 Treatment of acute systemic toxicity

If signs of acute systemic toxicity appear, injection of the local anaesthetic should be stopped immediately and CNS symptoms (convulsion, CNS depression) must promptly be treated with appropriate airway/respiratory support and the administration of anticonvulsant drugs.

If circulatory arrest should occur, immediate cardiopulmonary resuscitation should be instituted. Optimal oxygenation and ventilation and circulatory support as well as treatment of acidosis are of vital importance.

If cardiovascular depression occurs (hypotension, bradycardia), appropriate treatment with intravenous fluids, vasopressor, and or inotropic agents should be considered. Children should be given doses commensurate with age and weight.

Should cardiac arrest occur, a successful outcome may require prolonged resuscitative efforts.

4.9 Overdose

Accidental intravascular injections of local anaesthetics may cause immediate (within seconds to a few minutes) systemic toxic reactions. In the event of overdose, systemic toxicity appears later (15-60 minutes after injection) due to the slower increase in local anaesthetic blood concentration. (See section 4.8.1 Acute systemic toxicity and 4.8.2 Treatment of acute systemic toxicity.)

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5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group (ATC code): N01B B09
Ropivacaine is a long acting, amide-type local anaesthetic with both anaesthetic and analgesic effects. At high doses it produces surgical anaesthesia, while at lower doses it produces sensory block (analgesia) with limited and non-progressive motor block.

Onset and duration of the local anaesthetic effect of Naropin depend on the dose and site of administration, while presence of a vasoconstrictor (eg, adrenaline) has little, if any influence.

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.

Local anaesthetics may have similar effects on other excitable membranes eg, in the brain and myocardium. If excessive amounts of drug reach the systemic circulation, symptoms and signs of toxicity may appear, emanating from the central nervous and cardiovascular systems.

Cardiac effects measured in vivo in animal studies showed that ropivacaine has a lower cardiac toxicity than bupivacaine.

Pregnant ewes showed no greater sensitivity to systemic toxic effects of ropivacaine than nonpregnant ewes.

Healthy volunteers exposed to intravenous infusions of CNS toxic doses showed significantly less cardiac effects after ropivacaine than after bupivacaine.

Indirect cardiovascular effects (hypotension, bradycardia) may occur after epidural administration, depending on the extent of the concomitant sympathetic block, but is less commonly seen in children.

5.2 Pharmacokinetic properties

Ropivacaine has a chiral centre and is the pure S-(-)- enantiomer. Ropivacaine has a pKa of 8.1 and a distribution ratio of 141 (25°C n-octanol/ phosphate buffer pH 7.4). The metabolites have a pharmacological activity that is less than that of ropivacaine.

The plasma concentration of ropivacaine depends on the dose, the route of administration 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, with half-lives of the two phases of 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 a biphasic absorption from the caudal epidural space also in children.

 
Ropivacaine has a mean total plasma clearance of the order of 440 mL/min, an unbound plasma clearance of 8 L/min, a renal clearance of 1 mL/min, a volume of distribution at steady state of 47 L and a terminal half-life of 1.8 h after iv administration. Ropivacaine has an intermediate hepatic extraction ratio of about 0.4. It is mainly bound to α-acid glycoprotein in plasma with
an unbound fraction of about 6%.

An increase in total plasma concentrations during continuous epidural and interscalene infusion has been observed, related to a postoperative increase of α1-acid glycoprotein. Variations in unbound, ie, pharmacologically active, 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.

Ropivacaine is extensively metabolised in the liver, predominantly by aromatic hydroxylation to 3-hydroxy-ropivacaine mediated by cytochrome P4501A2, and N-dealkylation to PPX mediated by CYP3A4. After single iv administration approximately 37% of the total dose is excreted in the urine as both free and conjugated 3-hydroxy-ropivacaine, the major metabolite. Low concentrations of 3-hydroxy-ropivacaine have been found in the plasma. Urinary excretion of the PPX and other metabolites account for less than 3% of the dose.

During epidural infusion, both PPX and 3-hydroxy-ropivacaine are the major metabolites excreted in the urine. Total PPX concentration in the plasma was about half of that of total ropivacaine, however, mean unbound concentrations of PPX was about 7 to 9 times higher than that of unbound ropivacaine following continuous epidural infusion up to 72 hours. Thethreshold for CNS-toxic unbound plasma concentrations of PPX in rats is about twelve times
higher than that of unbound ropivacaine.

There is no evidence of in vivo racemization of ropivacaine.

Paediatrics

The pharmacokinetics of ropivacaine was characterized in a pooled population PK analysis on data in 192 children between 0 and 12 years from six studies. Unbound ropivacaine and PPX clearance and ropivacaine unbound volume of distribution depend on both body weight and age
up to the maturity of liver function, after which they depend largely on body weight. The maturation of unbound ropivacaine clearance appears to be complete by the age of 3 years, that of PPX by the age of 1 year and unbound ropivacaine volume of distribution by the age of 2 years. The PPX unbound volume of distribution only depends on body weight.

Unbound ropivacaine clearance increases from 2.4 and 3.6 L/h/kg in the newborn and the 1- month neonate to about 8-16 L/h/kg for ages above 6 months, values within the range of those in adults. Total ropivacaine clearance values per kg body weight increase from about 0.10 and 0.15
L/h/kg in the newborn and the 1-month neonate to about 0.3 - 0.6 L/h/kg beyond the age of 6 months. Unbound ropivacaine volume of distribution per kg body weight increases from 22 and 26 L/kg in the newborn and the 1-month neonate to 42 - 66 L/kg above 6 months. Total ropivacaine volume of distribution per kg body weight increases from 0.9 and 1.0 L/kg for the
newborn and the 1-month neonate to 1.7 - 2.6 L/kg beyond the age of 6 months. The terminal half-life of ropivacaine is longer, 6 to 5 h in the newborn and the 1-month neonate compared to about 3 h in older children. The terminal half-life of PPX is also longer, from 43 and 26 h in the
newborn and the 1-month old neonate to about 15 h in older children.

At 6 months, the breakpoint for change in the recommended dose rate for continuous epidural infusion, unbound ropivacaine clearance has reached 34% and unbound PPX 71% of its mature value. The systemic exposure is higher in neonates and also somewhat higher in infants between 1 to 6 months compared to older children, which is related to the immaturity of their liver function. However, this is partly compensated for by the recommended 50% lower dose rate for continuous infusion in infants below 6 months.

Simulations on the sum of unbound plasma concentrations of ropivacaine and PPX, based on the PK parameters and their variance in the population analysis, indicate that for a single caudal block the recommended dose must be increased by a factor of 2.7 in the youngest group and a factor of 7.4 in the 1 to 10 year group in order for the upper prediction 90% confidence interval limit to touch the threshold for systemic toxicity. Corresponding factors for the continuous epidural infusion are 1.8 and 3.8 respectively.

5.3 Preclinical Safety Data

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

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6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium chloride
Hydrochloric acid
Sodium hydroxide
Water for injections

6.2 Incompatibilities

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

6.3 Shelf-life

Polypropylene ampoules 10 ml, 20 ml
Naropin 2.0 mg/ml 36 months
Naropin 5.0 mg/ml
Naropin 7.5 mg/ml
Naropin 10.0 mg/ml

Polypropylene infusion bags 100 ml, 200 ml
Naropin 2.0 mg/ml 24 months

6.4 Special precautions for storage

Do not store above 30°C. Do not freeze

6.5 Nature and contents of container

Polypropylene ampoules of 10 and 20 ml (Polyamp®)
Polypropylene ampoules of 10 and 20 ml in blister packs (Polyamp®)
Polypropylene infusion bags of 100 and 200 ml (Polybag®)
Polypropylene infusion bags of 100 and 200 ml in blister packs (Polybag®)

The ampoules are designed to fit Luer lock and Luer fit syringes.

6.6 Instructions for use, handling and disposal

The products are free from preservatives and are intended for single use only. Any solution remaining from an opened container should be discarded.

The intact container must not be re-autoclaved. A blister container should be chosen when a sterile exterior is required.

Naropin solution for infusion in plastic infusion bags (Polybag) is chemically and physically compatible with the following drugs:

The mixtures are chemically and physically stable for 30 days at up to 30°C.

From a microbiological point of view, the mixtures should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.
 

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Date of text: April 2007