Lidocaine Tchaikapharma

Lidocaine Tchaikapharmae is a local anaesthetic of the amide group. Lidocaine Tchaikapharmae solution for injection is indicated for use in infiltration anaesthesia, intravenous regional anaesthesia and nerve blocks.

Lidocaine Tchaikapharma is indicated for the symptomatic relief of neuropathic pain associated with previous herpes zoster infection (post-herpetic neuralgia, PHN) in adults.

The method of administration of Lidocaine Tchaikapharmae varies according to the procedure (infiltration anaesthesia, intravenous regional anaesthesia or nerve block).

The dosage should be 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. The maximum dose for healthy adults should not exceed 200 mg.

Children and elderly or debilitated patients require smaller doses, commensurate with age and physical status.

Adults and elderly patients

The painful area should be covered with the plaster once daily for up to 12 hours within a 24 hours period. Only the number of plasters that are needed for an effective treatment should be used. When needed, the plasters may be cut into smaller sizes with scissors prior to removal of the release liner. In total, not more than three plasters should be used at the same time.

The plaster must be applied to intact, dry, non-irritated skin (after healing of the shingles).

Each plaster must be worn no longer than 12 hours. The subsequent plaster-free interval must be at least 12 hours. The plaster can be applied during the day or during the night.

The plaster must be applied to the skin immediately after removal from the sachet and following removal of the release liner from the gel surface. Hairs in the affected area must be cut off with a pair of scissors (not shaved).

Treatment outcome should be re-evaluated after 2-4 weeks. If there has been no response to Lidocaine Tchaikapharma after this period (during the wearing time and/or during the plaster-free interval), treatment must be discontinued as potential risks may outweigh benefits in this context. Long-term use of Lidocaine Tchaikapharma in clinical studies showed that the number of plasters used decreased over time. Therefore treatment should be reassessed at regular intervals to decide whether the amount of plasters needed to cover the painful area can be reduced, or if the plaster-free period can be extended.

Renal impairment

In patients with mild or moderate renal impairment a dosage adjustment is not required.

Lidocaine Tchaikapharma should be used with caution in patients with severe renal impairment.

Hepatic impairment

In patients with mild or moderate hepatic impairment a dosage adjustment is not required.

Lidocaine Tchaikapharma should be used with caution in patients with severe hepatic impairment.

Paediatric population

The safety and efficacy of Lidocaine Tchaikapharma in children below 18 years has not been established. No data are available.

Known hypersensitivity to anaesthetics of the amide type

Complete heart block

Hypovolaemia

The plaster is also contraindicated in patients with known hypersensitivity to other local anaesthetics of the amide type e.g. bupivacaine, etidocaine, mepivacaine and prilocaine.

The plaster must not be applied to inflamed or injured skin, such as active herpes zoster lesions, atopic dermatitis or wounds.

Lidocaine Tchaikapharmae should be administered by persons with resuscitative skills and equipment.

Facilities for resuscitation should be available when administering local anaesthetics.

As with other local anaesthetics, Lidocaine Tchaikapharmae should be used with caution in patients with epilepsy, myasthenia gravis, impaired cardiac conduction, congestive cardiac failure, bradycardia or impaired respiratory function, including where agents are known to interact with Lidocaine Tchaikapharmae either to increase its availability or additive effects e.g. phenytoin or prolong its elimination e.g. hepatic or end renal insufficiency where the metabolites of Lidocaine Tchaikapharmae may accumulate, or if the dose or site of administration is likely to produce high blood levels. Lidocaine Tchaikapharmae is metabolised in the liver and it should be used with caution in patients with impaired hepatic function.

The effect of local anaesthetics may be reduced if the injection is made into an inflamed or infected area.

Intramuscular Lidocaine Tchaikapharmae may increase creatinine phosphokinase concentrations which can interfere with the diagnosis of acute myocardial infarction. Lidocaine Tchaikapharmae has been shown to be porphyrinogenic in animals and should be avoided in persons suffering from porphyria.

Hypokalaemia, hypoxia and disorder of acid-base balance should be corrected before treatment with intravenous Lidocaine Tchaikapharmae begins.

Certain local anaesthetic procedures may be associated with serious adverse reactions, regardless of the local anaesthetic drug used, e.g.:

- Central nerve blocks may cause cardiovascular depression, especially in the presence of hypovolaemia, and therefore epidural anaesthesia should be used with caution in patients with impaired cardiovascular function.

- Retrobulbar injections may rarely reach the cranial subarachnoid space, causing serious / severe reactions, including cardiovascular collapse, apnoea, convulsions and temporary blindness.

- Retro- and peribulbar injections of local anaesthetics carry a low risk of persistent ocular muscle dysfunction. The primary causes include trauma and/or local toxic effects on muscles and/or nerves.

The severity of such tissue reactions is related to the degree of trauma, the concentration of the local anaesthetic and the duration of exposure of the tissue to the local anaesthetic. For this reason, as with all local anaesthetics, the lowest effective concentration and dose of local anaesthetic should be used.

- 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.

Epidural anaesthesia may lead to hypotension and bradycardia. This risk can be reduced by preloading the circulation with crystalloidal or colloidal solutions. Hypotension should be treated promptly

Lidocaine Tchaikapharmae Injection is not recommended for use in neonates. The optimum serum concentration of Lidocaine Tchaikapharmae required to avoid toxicity, such as convulsions and cardiac arrhythmias, in this age group is not known.

Each 5 ml of Lidocaine Tchaikapharmae 1% w/v solution for injection contains approximately 13.57 mg (0.59 mmol) sodium.

Each 10 ml of Lidocaine Tchaikapharmae 1% w/v solution for injection contains approximately 27.14 mg (1.18 mmol) sodium.

The plaster should not be applied to mucous membranes. Eye contact with the plaster should be avoided.

The plaster contains propylene glycol (E1520) which may cause skin irritation. It also contains methyl parahydroxybenzoate (E218) and propyl parahydroxybenzoate (E216) which may cause allergic reactions (possibly delayed).

The plaster should be used with caution in patients with severe cardiac impairment, severe renal impairment or severe hepatic impairment.

One of the lidocaine metabolites, 2,6 xylidine, has been shown to be genotoxic and carcinogenic in rats. Secondary metabolites have been shown to be mutagenic. The clinical significance of this finding is unknown. Consequently long term treatment with Lidocaine Tchaikapharma is only justified if there is a therapeutic benefit for the patient.

Where outpatient anaesthesia affects areas of the body involved in driving or operating machinery, patients should be advised to avoid these activities until normal function is fully restored. Where major motor nerve block occurs e.g. Brachial plexus, epidural, spinal block. Where there is a loss of sensation resulting from nerve block to areas of muscle co-ordination or balance. Advice is that for general anaesthesia as sedative/hypnotic drugs are often used during nerve blockade.

No studies on the effects on the ability to drive and use machines have been performed. An effect on the ability to drive and use machines is unlikely because systemic absorption is minimal

Blood and Lymphatic System Disorders

Lidocaine Tchaikapharmae may also produce methaemoglobinaemia.

Immune system disorders

Hypersensitivity reactions (allergic or anaphylactoid reactions, anaphylactic shock) - see also Skin & subcutaneous tissue disorders) are rare. They may be characterised by cutaneous lesions,

Skin testing for allergy to Lidocaine Tchaikapharmae is not considered to be reliable.

Localised nerve damage at the site of injection (very rare).

Nervous & Psychiatric disorders

Neurological signs of systemic toxicity include dizziness or light-headedness, nervousness, tremor, circumoral paraesthesia, tongue numbness, drowsiness, convulsions, coma.

Nervous system reactions may be excitatory and or depressant. Signs of CNS stimulation may be brief, or may not occur at all, so that the first signs of toxicity may be confusion and drowsiness, followed by coma and respiratory failure.

CNS (central nervous system) reactions may be excitatory and/or depressant.. Signs of CNS stimulation may be brief or may not occur at all, so that the first signs of toxicity may be confusion and drowsiness, followed by coma and respiratory failure.

Neurological complications of spinal anaesthesia include transient neurological symptoms such as pain of the lower back, buttock and legs. These symptoms usually develop within twenty-four hours of anaesthesia and resolve within a few days. Isolated cases of arachnoiditis or cauda equina syndrome, with persistent paraesthesia, bowel and urinary dysfunction, or lower limb paralysis have been reported following spinal anaesthesia with Lidocaine Tchaikapharmae and other similar agents. The majority of cases have been associated with hyperbaric concentrations of Lidocaine Tchaikapharmae or prolonged spinal infusion.

Psychotic reactions have been reported following infusion for the control of arrhythmia.

Eye disorders

Blurred vision, diplopia and transient amaurosis may be signs of Lidocaine Tchaikapharmae toxicity.

Bilateral amaurosis may also be a consequence of accidental injection of the optic nerve sheath during ocular procedures. Orbital inflammation and diplopia have been reported following retro or peribulbar anaesthesia

Ear and labyrinth disorders

Tinnitus, hyperacusis

Cardiac and vascular disorders

Cardiovascular reactions are depressant and may manifest as hypotension, bradycardia, myocardial depression, cardiac arrhythmias and possibly cardiac arrest or circulatory collapse.

Hypotension may accompany spinal and epidural anesthesia. Isolated cases of bradycardia and cardiac arrest have also been reported.

Profound hypotension may be associated with B blockade, widespread sympathetic block from spinal or epidural block, intercostal nerve block administration or supine hypotension in pregnancy.

The major adverse effects on the CNS and CVS are primarily due to the absorption of Lidocaine Tchaikapharmae into the systemic circulation.

Ventricular fibrillation occurs less frequently than that seen with bupivacaine.

Respiratory, thoracic or mediastinal disorders

Dyspnoea, bronchospasm and respiratory depression

Gastrointestinal

Nausea, vomiting.

Skin and subcutaneous tissue disorders

Rash, urticaria, oedema (including angioedema, face oedema)

Prolonged neural blockade following epidural may be due to delayed spread. Permanent neural blockade may be more likely associated with hypotension and cord ischaemia.

Following regional blockade as when Lidocaine Tchaikapharmae is injected intrathecally or extradurally, hypotension, hypoventilation, Horners Syndrome and hypoglycaemia may be seen. The degree of these effects will depend on the dose and the height of the block. Urinary retention may occur following sacral or lumbar epidural block. It should not outlast the duration of the block. Apnoea and coma followed by aphasia and hemiparesis may occur following stellate ganglion block. The probable cause is a direct injection of Lidocaine Tchaikapharmae into the vertebral or carotid arteries.

Profound lethargy and death have been reported following the injection of only 10 - 32 mg of Lidocaine Tchaikapharmae for dental blocks.

The initial CNS toxic effects are demonstrated by a gradual onset of drowsiness or inebriation similar to alcoholic intoxication. Balance is disturbed, dizziness or light-headedness, nervousness, circumoral pins and needles (circumoral paraesthesia), tongue numbness, tinnitus, hyperacusis, visual disturbances, restlessness and twitching may occur. Severe intoxication of rapid onset may immediately lead to convulsions followed by circulatory depression. Major overdosage may depress all systems simultaneously.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Approximately 16% of patients can be expected to experience adverse reactions. These are localised reactions due to the nature of the medicinal product.

The most commonly reported adverse reactions were administration site reactions (such as burning, dermatitis, erythema, pruritus, rash, skin irritation, and vesicles).

The table below lists adverse reactions that have been reported in studies of post herpetic neuralgia patients receiving the plaster. They are listed by system organ class and frequency. Frequencies are defined as very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).

The following reactions have been observed in patients receiving the plaster under post-marketing conditions:

All adverse reactions were predominantly of mild and moderate intensity. Of those less than 5% lead to treatment discontinuation.

Systemic adverse reactions following the appropriate use of the plaster are unlikely since the systemic concentration of lidocaine is very low. Systemic adverse reactions to lidocaine are similar in nature to those observed with other amide local anaesthetic agents.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Symptoms of acute systemic toxicity

Central nervous system toxicity presents with symptoms of increasing severity. Patients may present initially with circumoral paraesthesia, numbness of the tongue, light-headedness, hyperacusis and tinnitus. Visual disturbance and muscular tremors or muscle twitching are more serious and precede the onset of generalised convulsions. These signs must not be mistaken for neurotic behaviour. Unconsciousness and grand mal convulsions may follow, which may last from a few seconds to several minutes. Hypoxia and hypercapnia occur rapidly following convulsions due to increased muscular activity, together with the interference with normal respiration and loss of the airway. In severe cases, apnoea may occur. Acidosis increases the toxic effects of local anaesthetics.

Effects on the cardiovascular system may be seen in severe cases. Hypotension, bradycardia, arrhythmia and cardiac arrest may occur as a result of high systemic concentrations, with potentially fatal outcome.

Recovery occurs as a consequence of redistribution of the local anaesthetic drug from the central nervous system and metabolism and may be rapid unless large amounts of the drug have been injected.

Treatment of acute toxicity

If signs of acute systemic toxicity appear, injection of the anaesthetic should be stopped immediately.

Treatment will be required if convulsions and CNS depression occurs. The objectives of treatment are to maintain oxygenation, stop the convulsions and support the circulation. A patent airway should be established and oxygen should be administered, together with assisted ventilation (mask and bag) if necessary. The circulation should be maintained with infusions of plasma or intravenous fluids. Where further supportive treatment of circulatory depression is required, use of a vasopressor agent may be considered although this involves a risk of CNS excitation. Convulsions may be controlled by the intravenous administration of Diazepam or Thiopentone Sodium, bearing in mind that anti-convulsant drugs may also depress respiration and the circulation. Prolonged convulsions may jeopardize the patient's ventilation and oxygenation and early endotracheal intubation should be considered. If cardiac arrest should occur, standard cardiopulmonary resuscitation procedures should be instituted. Continual optimal oxygenation and ventilation and circulatory support as well as treatment of acidosis are of vital importance.

Dialysis is of negligible value in the treatment of acute overdosage with Lidocaine Tchaikapharmae.

Overdose with the plaster is unlikely but it cannot be excluded that inappropriate use, such as use of a higher number of plasters at the same time, with prolonged application period, or using the plaster on broken skin might result in higher than normal plasma concentrations. Possible signs of systemic toxicity will be similar in nature to those observed after administration of lidocaine as a local anaesthetic agent, and may include the following signs and symptoms:

dizziness, vomiting, drowsiness, seizures, mydriasis, bradycardia, arrhythmia, and shock.

In addition, known drug interactions related to systemic lidocaine concentrations with beta-blockers, CYP3A4 inhibitors (e.g. imidazole derivatives, macrolides) and antiarrhythmic agents might become relevant with overdose.

In case of suspected overdose the plaster should be removed and supportive measures taken as clinically needed. There is no antidote to lidocaine.

ATC Code:N01BB02

Lidocaine Tchaikapharmae is a local anaesthetic of the amide type. It is used to provide local anaesthesia by nerve blockade at various sites in the body and in the control of dysrhythmias. It acts by inhibiting the ionic refluxes required for the initiation and conduction of impulses, thereby stabilising the neuronal membrane. In addition to blocking conduction in nerve axons in the peripheral nervous system, Lidocaine Tchaikapharmae has important effects on the central nervous system and cardiovascular system. After absorption, Lidocaine Tchaikapharmae may cause stimulation of the CNS followed by depression and in the cardiovascular system, it acts primarily on the myocardium where it may produce decreases in electrical excitability, conduction rate and force of contraction. It has a rapid onset of action (about one minute following intravenous injection and fifteen minutes following intramuscular injection) and rapidly spreads through the surrounding tissues. The effect lasts about ten to twenty minutes and about sixty to ninety minutes following intravenous and intramuscular injection respectively.

Pharmacotherapeutic group: local anaesthetics, amides

ATC code: N01 BB02

Mechanism of action

Lidocaine Tchaikapharma has a dual mode of action: the pharmacological action of lidocaine diffusion and the mechanical action of the hydrogel plaster that protects the hypersensitive area.

The lidocaine contained in the Lidocaine Tchaikapharma plaster diffuses continuously into the skin, providing a local analgesic effect. The mechanism by which this occurs is due to stabilisation of neuronal membranes, which is thought to cause down regulation of sodium channels resulting in pain reduction.

Clinical efficacy

Pain management in PHN is difficult. There is evidence of efficacy with Lidocaine Tchaikapharma in the symptomatic relief from the allodynic component of PHN in some cases.

Efficacy of Lidocaine Tchaikapharma has been shown in post-herpetic neuralgia studies.

There were two main controlled studies carried out to assess the efficacy of the lidocaine 700 mg medicated plaster.

In the first study, patients were recruited from a population who were already considered to respond to the product. It was a cross over design of 14 days treatment with lidocaine 700 mg medicated plaster followed by placebo, or vice versa. The primary endpoint was the time to exit, where patients withdrew because their pain relief was two points lower than their normal response on a six point scale (ranging from worse to complete relief). There were 32 patients, of whom 30 completed. The median time to exit for placebo was 4 days and for active was 14 days (p value < 0.001); none of those on active discontinued during the two week treatment period.

In the second study 265 patients with post-herpetic neuralgia were recruited and allocated eight weeks of open label active treatment with lidocaine 700 mg medicated plaster. In this uncontrolled setting approximately 50% of patients responded to treatment as measured by at least four points on a six point scale (ranging from worse to complete relief). A total of 71 patients were randomised to receive either placebo or lidocaine 700 mg medicated plaster given for 2-14 days. The primary endpoint was defined as lack of efficacy on two consecutive days because their pain relief was two points lower than their normal response on a six point scale (ranging from worse to complete relief) leading to withdrawal of treatment. There were 9/36 patients on active and 16/35 patients on placebo who withdrew because of lack of treatment benefit.

Post hoc analyses of the second study showed that the initial response was independent of the duration of pre-existing PHN. However, the notion that patients with longer duration of PHN (> 12 months) do benefit more from active treatment is supported by the finding that this group of patients was more likely to drop out due to lack of efficacy when switched to placebo during the double-blind withdrawal part of this study.

In a controlled open-label study Lidocaine Tchaikapharma suggested comparable efficacy to pregabalin in 98 patients with PHN with a favourable safety profile.

The concentration of Lidocaine Tchaikapharmae in the blood will be determined by its rate of absorption from the site of injection, the rate of tissue distribution and the rate of metabolism and excretion.

The systemic absorption of Lidocaine Tchaikapharmae is determined by the site of injection, the dosage and its pharmacological profile. The maximum blood concentration occurs following intercostal nerve blockade followed in order of decreasing concentration, the lumbar epidural space, brachial plexus site and subcutaneous tissue. The total dose injected regardless of the site is the primary determinant of the absorption rate and blood levels achieved. There is a linear relationship between the amount of Lidocaine Tchaikapharmae injected and the resultant peak anaesthetic blood levels.

The lipid solubility and vasodilator activity will also influence its rate of absorption. This is seen in the epidural space where Lidocaine Tchaikapharmae is absorbed more rapidly than prilocaine.

Lidocaine Tchaikapharmae is distributed throughout the total body water. Its rate of disappearance from the blood can be described by a two or three compartment model. There is a rapid disappearance (alpha) phase which is believed to be related to uptake by rapidly equilibrating tissues (i.e. tissues with a high vascular perfusion). The slower phase is related to distribution, to slowly equilibrating tissues (Betaphase) and to its metabolism and excretion (Gamma phase).

Lidocaine Tchaikapharmae is distributed less rapidly than prilocaine (an amide drug of similar potency and duration of action) but equally as with mepivacaine. Its distribution is throughout all body tissues. In general, the more highly perfused organs will show higher concentrations of Lidocaine Tchaikapharmae. The highest percentage of this drug will be found in skeletal muscle. This is because of the mass of muscle rather than an affinity.

Lidocaine Tchaikapharmae undergoes enzymatic degradation primarily in the liver. Some degradation may take in tissues other than liver. The main pathway involves oxidative de-ethylation to monoethylglycinexylidide followed by a subsequent hydrolysis to xylidine.

The excretion occurs via the kidney with less than 5% in the unchanged form appearing in the urine. The renal clearance is inversely related to its protein binding affinity and the pH of the urine. This suggests by the latter that excretion of Lidocaine Tchaikapharmae occurs by non-ionic diffusion..

Absorption

When lidocaine 700 mg medicated plaster is used according to the maximum recommended dose (3 plasters applied simultaneously for 12 h) about 3 ± 2% of the total applied lidocaine dose is systemically available and similar for single and multiple administrations.

A population kinetics analysis of the clinical efficacy studies in patients suffering from PHN revealed a mean maximum concentration for lidocaine of 45 ng/ml after application of 3 plasters simultaneously 12 h per day after repeated application for up to one year. This concentration is in accordance with the observation in pharmacokinetic studies in PHN patients (52 ng/ml) and in healthy volunteers (85 ng/ml and 125 ng/ml).

For lidocaine and its metabolites MEGX, GX, and 2,6-xylidine no tendency for accumulation was found, steady state concentrations were reached within the first four days.

The population kinetic analysis indicated that when increasing the number from 1 to 3 plasters worn simultaneously, the systemic exposure increased less than proportionally to the number of used plasters.

Distribution

After intravenous administration of lidocaine to healthy volunteers, the volume of distribution was found to be 1.3 ± 0.4 l/kg (mean ± S.D., n = 15). The lidocaine distribution volume showed no age-dependency, it is decreased in patients with congestive heart failure and increased in patients with liver disease. At plasma concentrations produced by application of the plaster approximately 70 % of lidocaine is bound to plasma proteins. Lidocaine crosses the placental and blood brain barriers presumably by passive diffusion.

Biotransformation

Lidocaine is metabolised rapidly in the liver to a number of metabolites. The primary metabolic route for lidocaine is N-dealkylation to monoethylglycinexylidide (MEGX) and glycinexylidide (GX), both of which are less active than lidocaine and available in low concentrations. These are hydrolyzed to 2,6-xylidine, which is converted to conjugated 4-hydroxy-2,6-xylidine.

The metabolite, 2,6-xylidine, has unknown pharmacological activity but shows carcinogenic potential in rats. A population kinetics analysis revealed a mean maximum concentration for 2,6-xylidine of 9 ng/ml after repeated daily applications for up to one year. This finding is confirmed by a phase I pharmacokinetic study. Data on lidocaine metabolism in the skin are not available.

Elimination

Lidocaine and its metabolites are excreted by the kidneys. More than 85 % of the dose is found in the urine in the form of metabolites or active substance. Less than 10 % of the lidocaine dose is excreted unchanged. The main metabolite in urine is a conjugate of 4-hydroxy-2,6-xylidine, accounting for about 70 to 80% of the dose excreted in the urine. 2,6-xylidine is excreted in the urine in man at a concentration of less than 1% of the dose. The elimination half-life of lidocaine after plaster application in healthy volunteers is 7.6 hours. The excretion of lidocaine and its metabolites may be delayed in cardiac, renal or hepatic insufficiency.

No further relevant information other than that which is included in other sections of the Summary of Product Characteristics.

Effects in non-clinical general toxicity studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.

Lidocaine HCl has shown no genotoxicity when investigated in vitro or in vivo. Its hydrolysis product and metabolite, 2,6-xylidine, showed mixed genotoxic activity in several assays particularly after metabolic activation.

Carcinogenicity studies have not been performed with lidocaine. Studies performed with the metabolite 2,6-xylidine mixed in the diet of male and female rats resulted in treatment-related cytotoxicity and hyperplasia of the nasal olfactory epithelium and carcinomas and adenomas in the nasal cavity were observed. Tumorigenic changes were also found in the liver and subcutis. Because the risk to humans is unclear, long-term treatment with high doses of lidocaine should be avoided.

Lidocaine had no effect on general reproductive performance, female fertility or embryo-foetal development/teratogenicity in rats at plasma concentrations up to more than 50-fold those observed in patients.

Animal studies are incomplete with respect to male fertility, parturition or postnatal development.

Lidocaine Tchaikapharmae solution for injection should not be mixed with other preparations unless compatibility is known.

Not applicable.

For single use only.

Use immediately after opening.

If only part of an ampoule is used, discard the remaining solution.

The injection should not be used if particles are present.

After use the plaster still contains active substance. After removal, the used plasters should be folded in half, adhesive side inwards so that the self-adhesive layer is not exposed, and the plaster should be discarded.

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