When a pharmaceutical company changes an SPC or PIL, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.
Section 4.8
Additional text (2nd paragraph)
The adverse reaction profile for Xylocaine with adrenaline 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 (e.g. decrease in blood pressure, bradycardia), events caused directly (e.g. nerve trauma) or indirectly by the needle puncture.
Section 10 Revision date of text: 10th May 2011
Section 10
Revision date of text: 10th May 2011
Section 4.2
Additional text:
Xylocaine with adrenaline solution for injection contains methyl parahydroxybenzoate (methylparaben) as a preservative and should not be used for anaesthesia by the intrathecal, intracisternal or intra- or retro-bulbar routes.
Deletion of text:
Preservative containing solutions, i.e. those supplied in multidose vials, should not be used when:
–The volume to be injected in a single dose exceeds 15 ml, unless otherwise justified.
–The preparation is intended for administration by routes where, for medical reasons, an antimicrobial preservative is not acceptable, such as intracisternally, epidurally, intrathecally or by any route giving access to the cerebrospinal fluid, or intra- or retro-bulbary.
Section 4.4
Deletion of text
Section 6.3 Deleted text: Use within 3 days of first opening. Additional text: Chemical and physical in-use stability has been demonstrated for 3 days at room temperature, 20–23°C. From a microbiological point of view, once opened, the product may be stored as long as the chemical-physical stability allows, i.e. 3 days at room temperature, 20–23°C. Other in-use storage times and conditions are the responsibility of the user. Section 6.4 Additional text: For storage of product that has been opened please refer to section 6.3. Section 10 Date of revision of text: 16 November 2010
Section 6.3
Deleted text:
Use within 3 days of first opening.
Chemical and physical in-use stability has been demonstrated for 3 days at room temperature, 20–23°C. From a microbiological point of view, once opened, the product may be stored as long as the chemical-physical stability allows, i.e. 3 days at room temperature, 20–23°C. Other in-use storage times and conditions are the responsibility of the user.
Section 6.4
For storage of product that has been opened please refer to section 6.3.
Date of revision of text: 16 November 2010
SPC Changes – Xylocaine
Additional text in second paragraph, now reads,
“The dosage is adjusted according to the response of the patient and the site of administration. The lowest concentration and smallest dose producing the required effect should be given (see section 4.4). Individual variations in onset and duration occur. Solutions containing adrenaline may be used to prolong anaesthesia and reduce systemic absorption (see section 5.2). The risk of systemic effects of adrenaline with large volumes of adrenaline-containing solutions should be considered.”
Paragraph before table removed.
Deleted and additional text to paragraphs after table, now reads,
“Preservative containing solutions, i.e. those supplied in multidose vials, should not be used when:
– The volume to be injected in a single dose exceeds 15 ml, unless otherwise justified.
– The preparation is intended for administration by routes where, for medical reasons, an antimicrobial preservative is not acceptable, such as intracisternally, epidurally, intrathecally or by any route giving access to the cerebrospinal fluid, or intra- or retro-bulbary.
In general, surgical anaesthesia requires the use of higher concentrations and doses. When blocking smaller nerves, or when a less intense block is required, the use of a lower concentration is indicated. The volume of drug used will affect the extent and spread of anaesthesia.
Care should be taken to prevent acute toxic reactions by avoiding intravascular injection. Careful aspiration before and during the injection is recommended. An accidental intravascular injection may be recognised by a temporary increase in heart rate. The main dose should be injected slowly, at a rate of 100–200 mg/min, or in incremental doses, while closely observing the patient’s vital functions and maintaining verbal contact. If toxic symptoms occur, the injection should be stopped immediately.”
Deletions and additional text throughout section, now reads,
“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. When performing major blocks, or using large doses, an IV cannula should be inserted before the local anaesthetic is injected. Clinicians should have received adequate and appropriate training in the procedure to be performed and should be familiar with the diagnosis and treatment of side effects, systemic toxicity or other complications (see sections 4.8 and 4.9).
Care should be taken to prevent acute toxic reactions by avoiding intravascular injection. Careful aspiration before and during the injection is recommended. An accidental intravascular injection may be recognised by a temporary increase in heart rate. The main dose should be injected slowly at a rate of 100–200 mg/min, or in incremental doses, while keeping in constant verbal contact with the patient. If toxic symptoms occur, the injection should be stopped immediately.
The effect of local anaesthetics may be reduced if an injection is made into an inflamed or infected area, absorption from these areas is also increased.
Attempts should be made to optimise the patient’s condition before major blocks.
Although regional anaesthesia is frequently the optimal anaesthetic technique, some patients require special attention in order to reduce the risk of dangerous side effects:
– Patients with epilepsy.
– The elderly and patients in poor general condition.
– Patients with partial or complete heart conduction block - due to the fact that local anaesthetics may depress myocardial conduction.
– Patients with advanced liver disease or severe renal dysfunction.
– Patients treated with anti-arrhythmic drugs class III (e.g. amiodarone) should be under close surveillance and ECG monitoring considered, since cardiac effects may be additive (see section 4.5).
– Patients with acute porphyria. Xylocaine with adrenaline is probably porphyrinogenic and should only be prescribed to patients with acute porphyria on strong or urgent indications. Appropriate precautions should be taken for all porphyric patients.
Certain local anaesthetic procedures may be associated with serious adverse reactions, regardless of the local anaesthetic drug used, e.g.
– Injections in the head and neck regions may be made inadvertently into an artery, causing cerebral symptoms even at low doses.
– Paracervical block can sometimes cause foetal bradycardia/tachycardia, and careful monitoring of the foetal heart rate is necessary.
– There have been post-marketing reports of chondrolysis in patients receiving post-operative intra-articular continuous infusion of local anaesthetics. The majority of reported cases of chondrolysis have involved the shoulder joint. Due to multiple contributing factors and inconsistency in the scientific literature regarding mechanism of action, causality has not been established. Intra-articular continuous infusion is not an approved indication for Xylocaine.
Solutions containing adrenaline should be used with caution in patients with hypertension, cardiac disease, cerebrovascular insufficiency, hyperthyroidosis, advanced diabetes and any other pathological condition that may be aggravated by the effects of adrenaline.
Xylocaine with adrenaline contains sodium metabisulphite, which may cause allergic reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulphite sensitivity in the general population is unknown and probably low. Sulphite sensitivity is seen more frequently in asthmatic than non-asthmatic people.
Xylocaine with adrenaline contains methyl parahydroxybenzoate, which may cause allergic reactions (possibly delayed) and exceptionally, bronchospasm.
– The preparation is intended for administration by routes where, for medical reasons, an antimicrobial preservative is not acceptable, such as intracisternally, epidurally, intrathecally or by any route giving access to the cerebrospinal fluid, or intra- or retro-bulbary.”
Section 10 Revision of text: 21st July 2010
SPC changes - Xylocaine adrenaline
Section 2
New second paragraph,
“Each ml of solution also contains 0.5 mg sodium metabisulphite (E223), 1 mg methyl parahydroxybenzoate (E218) and 2.49 mg of sodium.”
Last paragraph now reads,
“For a full list of excipients, see section 6.1.”
New fifth paragraph,
“The risk of systemic effects of adrenaline with large volumes of Xylocaine 2% with adrenaline should be considered.”
New final paragraph,
“Solutions containing adrenaline may be used to prolong anaesthesia and reduce systemic absorption (see section 5.2).”
Wording deleted in 7th paragraph, text now reads,
“Solutions containing adrenaline should be used with caution in patients with hypertension, cardiac disease, cerebrovascular insufficiency, hyperthyroidosis, advanced diabetes and any other pathological condition that may be aggravated by the effects of adrenaline.”
New 9th paragraph,
“Xylocaine with adrenaline contains methyl parahydroxybenzoate, which may cause allergic reactions (possibly delayed) and exceptionally, bronchospasm.”
Section 5.1
First paragraph, now reads,
” ATC code: N01B B52”
Section 6.1
Now reads,
“Sodium chloride
Sodium metabisulphite (E223)
Methyl parahydroxybenzoate (E218)
Water for injections
Sodium hydroxide (for pH-adjustment)
Hydrochloric acid (for pH-adjustment)”
Section 6.2 Now reads,
“In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.”
The words, “in order to protect from light” added to end of final paragraph.
Section 9
“Date of first authorisation: 1st April 1980
Date of last renewal: 1st April 2010”
9th April 2010”
The dosages in the following table are recommended asis a guide to dosage for the more commonly used techniques used in the average adult. 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.
Section 4.3
Known hHypersensitivity to local anaesthetics of the amide type, or to any of the excipientsother components of the solution, e.g. methyl parahydroxybenzoate or sodium metabisulphite.
Hypersensitivity to methyl and/or propyl parahydroxybenzoate (methyl-/propyl paraben), or to their metabolite para amino benzoic acid (PABA). Formulations of lidocaine containing parabens should be avoided in patients allergic to ester local anaesthetics or their metabolite PABA.
Hypersensitivity to sodium metabisulphite.
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. When performing major blocks, or using large doses, an IV cannula should be inserted before the local anaesthetic is injected. Clinicians should have received adequate and appropriate training in the procedure to be performed and should be familiar with the diagnosis and treatment of side effects, systemic toxicity or other complications (see sections 4.8 and 4.9).
In common with other local anaesthetics, Xylocaine with adrenaline should be used cautiously in patients with epilepsy, impaired cardiac conduction, impaired respiratory function, and in patients with impaired hepatic function, if the dose or site of administration is likely to result in high blood levels. Patients with severe renal dysfunction, the elderly and patients in poor general condition also require special attention. Attempts should also be made to optimise the patient’s condition before major blocks. Patients treated with anti-arrhythmic drugs class III (e.g. amiodarone) should be under close surveillance and ECG monitoring considered, since cardiac effects may be additive (see section 4.5 Interaction with other medicinal products and other forms of interaction).
Facilities for resuscitation should be available when local anaesthetics are administered.
Section 4.5
Drugs that reduce the clearance of lidocaine (e.g. cimetidine or betablockers) may cause potentially toxic plasma concentrations when lidocaine is given in repeated high doses over a long time period. Such interactions should be of no clinical importance following short term treatment with lidocaine at recommended doses.
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 concentrations of a local anaesthetic, which may appear due to (accidental) intravascular injection, overdose or exceptionally rapid absorption from highly vascularised areas (see section 4.9). CNS reactions are similar for all amide local anaesthetics, while cardiac reactions are more dependent on the drug, both quantitatively and qualitatively. Signs of toxicity in the central nervous system generally precede cardiovascular toxic effects, unless the patient is receiving a general anaesthetic or is heavily sedated with drugs such as benzodiazepine or barbiturate.
Central nervous system toxicity is a graded response with symptoms and signs of escalating severity. The first symptoms are usually, circumoral paraesthesia, numbness of the tongue, light-headedness, 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, arrhythmia 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 in cases where the block is given during general anaesthesia.
4.8.2 Treatment of acute 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, chronotropic and or inotropic agents should be considered. Children should be given doses commensurate with age and weight.
Section 4.9
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 and 4.8.2).
Acute systemic toxicity
Overdosage or accidental "intravascular" injection can produce systemic toxicity which is dose-related. In increasing order of severity: numbness of the mouth and tongue; light headedness; tinnitus; visual disturbance; irrational behaviour and speech; muscle twitching; unconsciousness; convulsions; coma and apnoea may occur. CNS toxicity is enhanced by the acidosis and hypoxia which result from convulsions. Cardiovascular effects are usually secondary to the hypoxia which results from apnoea, but slowing of intracardiac conduction, myocardial depression and peripheral vasodilatation can also occur as a direct effect of the drug itself.
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 a benzodiazepine or barbiturate.
Recovery is due to redistribution of the local anaesthetic drug from the central nervous system and metabolism. Recovery may be rapid unless large amounts of the drug have been injected.
Treatment of acute toxicity
Treatment of a patient with systemic toxicity consists of arresting convulsions and ensuring adequate ventilation with oxygen, if necessary by assisted or controlled ventilation (respiration). If convulsions occur they must be treated promptly by intravenous injection of thiopentone 1‑3 mg/kg or diazepam 0.1 mg/kg.
Prolonged convulsions may jeopardise the patient’s ventilation and oxygenation. If so, injection of a muscle relaxant (e.g. succinylcholine 1 mg/kg) will facilitate ventilation, and oxygenation can be controlled. Early endotracheal intubation must be considered in such situations. If cardiovascular depression is evident (hypotension, bradycardia) ephedrine 5–10 mg i.v. should be given and repeated, if necessary, after 2–3 min.
Should circulatory arrest occur, immediate cardiopulmonary resuscitation should be instituted. Continual optimal oxygenation and ventilation and circulatory support as well as treatment of acidosis are of vital importance. Adrenaline (epinephrine) (0.1–0.2 mg intravenous or intracardiac) should be given as soon as possible and repeated, if necessary.
Central nervous system toxicity (see "Overdose") usually precedes the cardiovascular effects since it occurs at lower plasma concentrations (see section 4.8.1), and usually precedes the cardiovascular effects. Direct effects of local anaesthetics on the heart include slow conduction, negative inotropism and eventually cardiac arrest.
Section 5.2
Only 2% of lidocaine is excreted unchanged. Most is metabolised first to monoethylglycinexylidide (MEGX) and then to glycinexylidide (GX) and 2,6-dimethylanilinexylidine. Up to 70% appears in the urine as 4-hydroxy-2,6-dimethylanilinexylidine.
Section 5.3
Genotoxicity tests with lidocaine showed no evidence of mutagenic potential. A metabolite of lidocaine, 2,6-dimethylanilinexylidine, showed weak evidence of activity in some genotoxicity tests. The metabolite 2,6-dimethylanilinexylidine has been shown to have carcinogenicity potential in preclinical toxicological studies evaluating chronic exposure. Risk assessments comparing the calculated maximum human exposure from intermittent use of lidocaine, with the exposure used in preclinical studies, indicate a wide margin of safety for clinical use.
Date of revision of text: 14th July 2008