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

Intrathecal baclofen therapy is valuable but hazardous. Careful pre-operative assessment is mandatory.

The patient must be given adequate information regarding the risks of this mode of treatment, and be physically and psychologically able to cope with the pump. It is essential that the responsible physicians and all those involved in the care of the patient receive adequate instruction on the signs and symptoms of overdose, procedures to be followed in the event of an overdose and the proper home care of the pump and insertion site.

Inflammatory mass at the tip of the implanted catheter: cases of inflammatory mass at the tip of the implanted catheter that can result in serious neurological impairment, including paralysis, have been reported. Although they have been reported with Lioresal intrathecal, they have not been confirmed by contrast MRI or histopathology. The most frequent symptoms associated with inflammatory mass are: 1) decreased therapeutic response (worsening spasticity, return of spasticity when previously well controlled, withdrawal symptoms, poor response to escalating doses, or frequent or large dosage increases), 2) pain, 3) neurological deficit/dysfunction. Clinicians should monitor patients on intraspinal therapy carefully for any new neurological signs or symptoms. Clinicians should use their medical judgement regarding the most appropriate monitoring specific to their patients' medical needs to identify prodromal signs and symptoms for inflammatory mass especially if using pharmacy compounded drugs or admixtures that include opioids. In patients with new neurological signs or symptoms suggestive of an inflammatory mass, consider a neurosurgical consultation since many of the symptoms of inflammatory mass are not unlike the symptoms experienced by patients with severe spasticity from their disease. In some cases, performance of an imaging procedure may be appropriate to confirm or rule-out the diagnosis of an inflammatory mass.

Pump Implantation

Patients should be infection-free prior to pump implantation because the presence of infection may increase the risk of surgical complications. Moreover, a systemic infection may complicate attempts to adjust the dose. A local infection or catheter malplacement can also lead to drug delivery failure, which may result in sudden Lioresal Intrathecal withdrawal and its related symptoms (see Section 4.4 – Special Precautions for Use “Treatment Withdrawal” section).

Reservoir refilling

Reservoir refilling must be performed by trained and qualified personnel in accordance with the instructions provided by the pump manufacturer. Refills should be timed to avoid excessive depletion of the reservoir, as this would result in the return of spasticity or potentially life-threatening symptoms of Lioresal Intrathecal withdrawal (see Section 4.4 – Special Precautions for Use “Treatment Withdrawal” section).

When refilling the pump care should be taken to avoid discharging the contents of the catheter into the intrathecal space.

Strict asepsis is required to avoid microbial contamination and infection.

Extreme caution must be taken when filling a pump equipped with an injection port that allows direct access to the intrathecal catheter as a direct injection into the catheter through the access port could cause a life-threatening overdose.

Precautions in paediatric patients

For patients with spasticity due to head injury, it is recommended not to proceed to long-term Lioresal Intrathecal therapy until the symptoms of spasticity are stable (i.e. at least one year after the injury).

Children should be of sufficient body mass to accommodate the implantable pump for chronic infusion. Use of Lioresal Intrathecal in the paediatric population should be only prescribed by medical specialists with the necessary knowledge and experience. There is very limited clinical data regarding the safety and efficacy of the use of Lioresal Intrathecal in children under the age of four years

Precautions in special patient populations

In patients with abnormal CSF flow the circulation of drug and hence antispastic activity may be inadequate.

Psychotic disorders, schizophrenia, confusional states or Parkinson’s disease may be exacerbated by treatment with oral Lioresal. Patients suffering from these conditions should therefore be treated cautiously and kept under close surveillance.

Close supervision of patients with additional risk factors for suicide should accompany therapy with Lioresal. Patients (and caregivers of patients) should be alerted about the need to monitor for clinical worsening, suicidal behavior or thoughts or unusual changes in behavior and to seek medical advice immediately if these symptoms present (see section 4.8 – Psychiatric disorders).

Special attention should be given to patients known to suffer from epilepsy as seizures have occasionally been reported during overdose with, and withdrawal from, Lioresal Intrathecal as well as in patients maintained on therapeutic doses.

Lioresal Intrathecal should be used with caution in patients with a history of autonomic dysreflexia. The presence of nociceptive stimuli or abrupt withdrawal of Lioresal Intrathecal may precipitate an autonomic dysreflexic episode.

Lioresal should be used with caution in patients with cerebrovascular or respiratory insufficiency.

An effect of Lioresal Intrathecal on underlying, non-CNS related diseases is unlikely because its systemic availability is substantially lower than after oral administration. Caution should be exercised in patients with history of peptic ulcers and based on observations after oral baclofen therapy, in those with pre-existing sphincter hypertonia.

Renal impairment

After oral Lioresal dosing severe neurological outcomes have been reported in patients with renal impairment. Thus caution should be exercised while administering Lioresal Intrathecal in patients with renal impairment.

In rare instances elevated SGOT, alkaline phosphatase and glucose levels in the serum have been recorded when using oral Lioresal.

Treatment withdrawal (including associated with catheter or device malfunction)

Abrupt discontinuation of Lioresal Intrathecal, regardless of cause, manifested by increased spasticity, pruritus, paraesthesia and hypotension, has resulted in sequelae including a hyperactive state with rapid uncontrolled spasms, hyperthermia, tachycardia and symptoms consistent with neuroleptic malignant syndrome, e.g. altered mental status and muscle rigidity. In rare cases this has advanced to seizures/status epilepticus, rhabdomyolysis, coagulopathy, multiple organ failure and death. All patients receiving intrathecal baclofen therapy are potentially at risk for withdrawal.

Some clinical characteristics associated with intrathecal baclofen withdrawal may resemble autonomic dysreflexia, infection (sepsis), malignant hyperthermia, neuroleptic-malignant syndrome, or other conditions associated with a hypermetabolic state or widespread rhabdomyolysis.

Patients and caregivers should be advised of the importance of keeping scheduled refill visits and should be educated on the signs and symptoms of baclofen withdrawal particularly those seen early in the withdrawal syndrome (e.g. priapism).

In most cases, symptoms of withdrawal appeared within hours to a few days following interruption of baclofen therapy. Common reasons for abrupt interruption of intrathecal baclofen therapy included malfunction of the catheter (especially disconnection), low volume in the pump reservoir, end of pump battery life and device malfunction. Device malfunction resulting in altered drug delivery leading to withdrawal symptoms including death has been reported.

Prevention of abrupt discontinuation of intrathecal baclofen requires careful attention to programming and monitoring of the infusion system, refill scheduling and procedures, and pump alarms. The suggested treatment for intrathecal Lioresal withdrawal is the restoration of intrathecal Lioresal at or near the same dosage as before therapy was interrupted. However, if restoration of intrathecal delivery is delayed, treatment with GABA-ergic agonist drugs such asoral or enteral Lioresal, or oral, enteral, or intravenous benzodiazepines may prevent potentially fatal sequelae. Oral or enteral Lioresal alone should not be relied upon to halt the progression of intrathecal baclofen withdrawal.

Scoliosis

The onset of scoliosis or worsening of a pre-existing scoliosis has been reported in patients treated with Lioresal Intrathecal. Signs of scoliosis should be monitored during treatment with Lioresal Intrathecal.

Excipients

Lioresal 0.05 mcg/1mL Intrathecal Injection contains less than 1 mmol sodium (23 mg) in 1mL, that is to say essentially ‘sodium-free’.

Lioresal 10 mg/5mL Intrathecal Infusion contains less than 1 mmol sodium (23 mg) in 5mL, that is to say essentially ‘sodium-free’.

Lioresal 10 mg/20mL Intrathecal Infusion contains 70.81mg sodium per dose. equivalent to 3.5% of the WHO recommended maximum daily intake of 2g sodium for an adult.

This medicinal product may be diluted with sodium-containing solutions (see section 6.2); this should be considered in relation to the total sodium from all sources that will be administered to the patient.

The co-administration of other intrathecal agents with Lioresal Intrathecal is not recommended.

An attempt should be made to reduce or discontinue concomitant oral antispastic medications, preferably before initiating baclofen infusion. However, abrupt reduction or discontinuation during chronic intrathecal baclofen therapy should be avoided.

There is little experience with the use of Lioresal Intrathecal in combination with systemic medications to be able to predict specific drug-drug interactions, although it is suggested that the low baclofen systemic exposure after intrathecal administration could reduce the potential for pharmacokinetic interactions (see section 5.2). Experience with oral baclofen would suggest that:

• Alcohol and other compounds affecting the CNS: There may be increased sedation where Lioresal is taken concomitantly with other drugs acting on the CNS (e.g. analgesics, neuroleptics, barbiturates, benzodiazepines, anxiolytics) or with alcohol.
• Tricyclic antidepressants: During concurrent treatment with tricyclic antidepressants, the effect of Lioresal may be potentiated, resulting in muscular hypotonia.
• Antihypertensives and other drugs known to lower blood pressure: Since concomitant treatment with drugs that lower blood pressure is likely to increase the fall in blood pressure, dosage of concomitant medications should be adjusted accordingly
• Levodopa: Concomitant use of oral Lioresal and levodopa/dopa-decarboxylase (DDC) inhibitor resulted in increased risk of adverse events like visual hallucinations, confusional state, headache and nausea. Worsening of the symptoms of Parkinsonism has also been reported. Thus, caution should be exercised when intrathecal Lioresal is administered to patients receiving levodopa/DDC inhibitor therapy.

Morphine

The combined use of morphine and intrathecal baclofen has been responsible for hypotension in one patient; the potential for this combination to cause dyspnoea or other CNS symptoms cannot be excluded.

Anaesthetics

Concomitant use of intrathecal baclofen and general anaesthetics (e.g. fentanyl, propofol) may increase the risk of cardiac disturbances and seizures. Thus, caution should be exercised when anaesthetics are administered to patients receiving intrathecal Lioresal.

Women of child bearing potential

Preconceptual counselling before programmable baclofen pump placement and in women with intrathecal baclofen pumps already implanted is recommended to ensure proper preparation and management throughout pregnancy and the peripartum period.

Pregnancy

There are limited data on the use of Lioresal Intrathecal in pregnant women.

Reproductive toxicity has been observed at high oral doses of baclofen (see section 5.3). After intrathecal administration of Lioresal small amounts of baclofen can be detected in maternal plasma (see section 5.2). Animal data show that baclofen can cross the placental barrier. Therefore, Lioresal Intrathecal should not be used during pregnancy unless the expected benefit outweighs the potential risk to the foetus.

Breast-feeding

After oral administration of Lioresal at therapeutic doses, baclofen passes into the breast milk, but in quantities so small that no undesirable effects on the infant are to be expected.

After intrathecal administration of Lioresal small amounts of baclofen can be detected in maternal plasma (see section 5.2). Therefore, no baclofen is expected to be found in the milk of the mother receiving Lioresal Intrathecal therapy and no special recommendations are given.

Fertility

Animal studies have shown that intrathecal baclofen is unlikely to have an adverse effect on fertility under clinically-relevant conditions (see section 5.3).

Central nervous system (CNS) depressant effects such as somnolence and sedation have been reported in some patients receiving intrathecal baclofen, and patients should be advised to exercise due caution. Other listed events include ataxia, hallucinations, vision blurred, diplopia and withdrawal symptoms. Operating equipment or machinery may be hazardous.

Some of the adverse reactions listed below have been reported in patients with spasticity of spinal origin but could also occur in patients with spasticity of cerebral origin. Adverse reactions that are more frequent in either population are indicated below.

Adverse drug reactions (Table 1) are listed according to system organ classes in MedDRA. Within each system organ class, the adverse drug reactions are ranked under headings of frequency, the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category using the following convention (CIOMS III) is also provided for each adverse drug reaction: 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), and Not known (cannot be estimated from available data).

Table 1. Adverse drug reactions:

Adverse events associated with the delivery system

Adverse events associated with the delivery system (inflammatory mass at the tip of the catheter, catheter dislocation with possible complications, pocket infection, meningitis, overdose due to wrong manipulation of the device) have been reported. Device malfunction resulting in altered drug delivery leading to withdrawal symptoms including death has been reported.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization 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.

If alternative baclofen concentrations are required Lioresal Intrathecal may be diluted under aseptic conditions with sterile preservative-free sodium chloride for injections. The ampoules should not be mixed with other solutions for injection or infusion (dextrose has proved to be incompatible due to a chemical reaction with baclofen).

The compatibility of Lioresal Intrathecal with the components of the infusion pump (including the chemical stability of baclofen in the reservoir) and the presence of an in-line bacterial retentive filter should be confirmed with the pump manufacturer prior to use.