LIORESAL Solution for intrathecal injection / infusion Ref.[6373] Active ingredients: Baclofen

Intrathecal administration of Lioresal through an implanted delivery system should only be undertaken by physicians with the necessary knowledge and experience. Specific instructions for implantation, programming and/or refilling of the implantable pump are given by the pump manufacturers, and must be strictly adhered to.

Lioresal Intrathecal 50 micrograms/1ml is intended for administration in single bolus test doses (via spinal catheter or lumbar puncture) and, for chronic use, in implantable pumps suitable for continuous administration of Lioresal Intrathecal 10mg/20ml and 10mg/5ml into the intrathecal space (EU certified pumps). Establishment of the optimum dose schedule requires that each patient undergoes an initial screening phase with intrathecal bolus, followed by a very careful individual dose titration prior to maintenance therapy.

Respiratory function should be monitored and appropriate resuscitation facilities should be available during the introduction of treatment with Lioresal Intrathecal. Intrathecal administration using an implanted delivery system should only be undertaken by physicians with appropriate knowledge and experience. Specific instructions for using the implantable pump should be obtained from the pump manufacturers. Only pumps constructed of material known to be compatible with the product and incorporating an in-line bacterial retentive filter should be used.

Adult Screening Phase

Prior to initiation of a chronic infusion, the patient’s response to intrathecal bolus doses administered via a catheter or lumbar puncture must be assessed. Low concentration ampoules containing 50 micrograms baclofen in 1ml are available for the purpose. Patients should be infection-free prior to screening, as the presence of a systemic infection may prevent an accurate assessment of the response.

The usual initial test dose in adults is 25 or 50 micrograms, increasing step-wise by 25 microgram increments at intervals of not less than 24 hours until a response of approximately 4 to 8 hours duration is observed. Each dose should be given slowly (over at least one minute). In order to be considered a responder the patient must demonstrate a significant decrease in muscle tone and/or frequency and/or severity of muscle spasms.

The variability in sensitivity to intrathecal baclofen between patients is emphasised. Signs of severe overdose (coma) have been observed in an adult after a single test dose of 25 micrograms. It is recommended that the initial test dose is administered with resuscitative equipment on hand.

Patients who do not respond to a 100 micrograms test dose should not be given further dose increments or considered for continuous intrathecal infusion.

Monitoring of respiratory and cardiac function is essential during this phase, especially in patients with cardiopulmonary disease and respiratory muscle weakness or those being treated with benzodiazepine-type preparations or opiates, who are at higher risk of respiratory depression.

Paediatric population Screening Phase

The initial lumbar puncture test dose for patients 4 to <18 years of age should be 25-50 micrograms/day based upon age and size of the child. Patients who do not experience a response may receive a 25 microgram/day dose escalation every 24 hours. The maximum screening dose should not exceed 100 micrograms/day in paediatric patients.

Dose-Titration Phase

Once the patient’s responsiveness to Lioresal Intrathecal has been established, an intrathecal infusion may be introduced. Lioresal Intrathecal is most often administered using an infusion pump which is implanted in the chest wall or abdominal wall tissues. Implantation of pumps should only be performed in experienced centres to minimise risks during the perioperative phase.

Infection may increase the risk of surgical complications and complicate attempts to adjust the dose.

The initial total daily infused dose is determined by doubling the bolus dose which gave a significant response in the initial screening phase and administering it over a 24 hour period.

However, if a prolonged effect (i.e. lasting more than 12 hours) is observed during screening the starting dose should be the unchanged screening dose delivered over 24 hours. No dose increases should be attempted during the first 24 hours.

After the initial 24 hour period dosage should be adjusted slowly to achieve the desired clinical effect. If a programmable pump is used the dose should be increased only once every 24 hours; for non-programmable multi-dose reservoir pumps intervals of 48 hours between dose adjustments are recommended. In either case increments should be limited as follows to avoid possible overdosage:

Patients with spasticity of spinal origin: 10-30% of the previous daily dose

Patients with spasticity of cerebral origin: 5-15% of the previous daily dose.

If the dose has been significantly increased without apparent clinical effect pump function and catheter patency should be investigated.

There is limited clinical experience using doses greater than 1000 micrograms/day.

It is important that patients are monitored closely in an appropriately equipped and staffed environment during screening and immediately following pump implantation. Resuscitative equipment should be available for immediate use in case of life-threatening adverse reactions.

Adult Maintenance Therapy

The clinical goal is to maintain as normal a muscle tone as possible, and to minimise the frequency and severity of spasms without inducing intolerable side effects. The lowest dose producing an adequate response should be used. The retention of some spasticity is desirable to avoid a sensation of “paralysis” on the part of the patient. In addition, a degree of muscle tone and occasional spasms may help support circulatory function and possibly prevent the formation of deep vein thrombosis.

In patients with spasticity of spinal origin maintenance dosing for long-term continuous infusions of intrathecal baclofen has been found to range from 12 to 2003 micrograms/day, with most patients being adequately maintained on 300 to 800 micrograms/day.

In patients with spasticity of cerebral origin maintenance dosage has been found to range from 22 to 1400 micrograms/day, with a mean daily dosage of 276 micrograms per day at 12 months and 307 micrograms per day at 24 months.

Paediatric population Maintenance Therapy

In children aged 4 to <18 years with spasticity of cerebral and spinal origin, the initial maintenance dosage for long-term continuous infusion of Lioresal Intrathecal ranges from 25 to 200 micrograms/day (median dose: 100 micrograms/day). The total daily dose tends to increase over the first year of therapy, therefore the maintenance dose needs to be adjusted based on individual clinical response. There is limited experience with doses greater than 1,000 micrograms/day.

The safety and efficacy of Lioresal Intrathecal for the treatment of severe spasticity of cerebral or spinal origin in children younger than 4 years of age have not been established (also see section 4.4).

Delivery specifications

Lioresal Intrathecal ampoules of 20ml containing 500 micrograms/ml and 5ml containing 2mg (2000micrograms)/ml are intended for use with infusion pumps. The concentration to be used depends on the dose requirements and size of pump reservoir. Use of the more concentrated solution obviates the need for frequent re-filling in patients with high dosage requirements.

Delivery regimen

Lioresal Intrathecal is most often administered in a continuous infusion mode immediately following implant. After the patient has stabilised with regard to daily dose and functional status, and provided the pump allows it, a more complex mode of delivery may be started to optimise control of spasticity at different times of the day. For example, patients who have increased spasm at night may require a 20% increase in their hourly infusion rate. Changes in flow rate should be programmed to start two hours before the desired onset of clinical effect.

Most patients require gradual dose increases to maintain optimum response during chronic therapy due to decreased responsiveness or disease progression. In patients with spasticity of spinal origin the daily dose may be increased gradually by 10-30% to maintain adequate symptom control. Where the spasticity is of cerebral origin any increase in dose should be limited to 20% (range: 5-20%). In both cases the daily dose may also be reduced by 10-20% if patients suffer side effects.

A sudden requirement for substantial dose escalation is indicative of a catheter complication (i.e. a kink or dislodgement) or pump malfunction.

In order to prevent excessive weakness the dosage of Lioresal Intrathecal should be adjusted with caution whenever spasticity is required to maintain function.

During long-term treatment approximately 5% of patients become refractory to increasing doses due to tolerance or drug delivery failure (see Section 4.4 – Special Warnings and Precautions for Use “Treatment Withdrawal” section). This “tolerance” may be treated by gradually reducing Lioresal Intrathecal dose over 2 to 4 week period and switching to alternative methods of spasticity management (e.g. Intrathecal preservative-free morphine sulphate). Lioresal Intrathecal should be resumed at the initial continuous infusion dose. Caution should be exercised when switching from Lioresal Intrathecal to morphine and vice versa (see section 4.5).

Discontinuation

Except in overdose-related emergencies, the treatment with Lioresal Intrathecal should always be gradually discontinued by successively reducing the dosage. Lioresal Intrathecal should not be discontinued suddenly (see section 4.4).

Special populations

Renal impairment

No studies have been performed in patients with renal impairment receiving Lioresal Intrathecal therapy. Because baclofen is primarily excreted unchanged by the kidneys (see section 5.2) it should be given with special care and caution in patients with impaired renal function (see section 4.4).

Hepatic impairment

No studies have been performed in patients with hepatic impairment receiving Lioresal Intrathecal therapy. No dosage adjustment is recommended as the liver does not play any significant role in the metabolism of baclofen after intrathecal administration of Lioresal. Therefore, hepatic impairment is not expected to impact the drug systemic exposure (see section 5.2).

Elderly population

Several patients over the age of 65 years have been treated with Lioresal Intrathecal during the clinical trials without increased risks compared to younger patients. Problems specific to this age group are not expected as doses are individually titrated.

Special attention should be given to recognising the signs and symptoms of overdosage at all times, but especially during the initial “screening” and “dose-titration” phases and also during reintroduction of Lioresal Intrathecal after an interruption of therapy.

Signs of overdose may appear suddenly or (more usually) insidiously.

Symptoms of overdose: excessive muscular hypotonia, drowsiness, light-headedness, dizziness, somnolence, seizures, loss of consciousness, hypothermia, excessive salivation, nausea, vomiting, tachycardia and tinnitus.

Respiratory depression, apnoea, and coma result from serious overdosage. Seizures may occur with increasing dosage or, more commonly, during recovery from an overdose. Serious overdose may occur through the inadvertent delivery of the catheter contents, errors in pump programming, excessively rapid dose increases or concomitant treatment with oral baclofen. Possible pump malfunction should also be investigated.

Treatment

There is no specific antidote for treating overdoses of intrathecal baclofen. Any instructions provided by the pump manufacturer should be followed, and the following steps should generally be undertaken:

• Where a programmable continuous infusion pump is used further delivery of baclofen should be halted immediately by removal of residual drug solution from the reservoir.
• If it is possible to do so without surgical intervention the intrathecal catheter should be disconnected from the pump as soon as possible, and infusion fluid allowed to drain back together with some CSF (up to 30-40ml is suggested).
• Patients with respiratory depression should be intubated if necessary, and ventilated artificially if required. Cardiovascular functions should be supported and in the event of convulsions, iv diazepam cautiously administered.
• Blood pressure, pulse, body temperature, cardiac rhythm and respiratory rate should be monitored.

Lioresal Intrathecal Injection 50micrograms/1ml: 3 years.

Lioresal Intrathecal Infusion 10mg/20ml: 3 years.

Lioresal Intrathecal Infusion 10mg/5ml: 3 years.

Store below 30°C.

Colourless glass ampoules, glass type I, according to Ph. Eur.

Each ampoule is intended for single use only, and any unused solution should be discarded. Ampoules should not be either frozen or autoclaved.