Lioresal Intrathecal (baclofen injection)

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Intrathecal baclofen therapy (ITB therapy) is delivered by the Medtronic SynchroMed^® II Drug Infusion System, which consists of an implantable, programmable pump and an intrathecal catheter. Lioresal^® Intrathecal (baclofen injection) is administered directly to the intrathecal space surrounding the spinal cord. This allows effective drug concentrations to reach the cerebrospinal fluid (CSF), while the plasma remains relatively unaffected compared with oral administration.^1-3

The use of ITB therapy has gained widespread use over the last several decades due to the advantages of targeted drug delivery with Lioresal^® Intrathecal as well as innovations in infusion and pump technologies. The origin of this type of therapy can be traced to the turn of the 20th century (1898), first used by Bier for spinal anesthesia with intrathecal cocaine, after which the approach became a mainstay in anesthesiology. It took nearly 8 decades of use to transition from short-term use to applying this therapy to treat chronic conditions. ITB therapy was first used in spasticity in 1984 when Penn and Kroin described use of continuous intrathecal baclofen infusion for the reduction of spasticity following spinal cord injury.^3,4 ITB Therapy℠ with Lioresal^® Intrathecal has been commercially available in the U.S. since 1992 for severe spasticity of spinal origin and since 1996 for severe spasticity of cerebral origin.³ Thus, there is a long history of the safety and efficacy of ITB Therapy℠ with Lioresal^® Intrathecal.

Prior to implantation of a device for chronic intrathecal infusion of Lioresal^® Intrathecal, patients must show a response to Lioresal^® Intrathecal in a screening trial. Implantation of the infusion system is contraindicated if the patient is of insufficient body size, requires a pump implant deeper than 2.5 cm, or, in the presence of spinal anomalies or active infection.

Following pump implantation, and for each adjustment of the dosing rate of the pump and/or concentration of Lioresal^® Intrathecal, the patient should be monitored closely until it is certain the patient’s response to the infusion is acceptable and reasonably stable. Reservoir refilling must be performed by fully trained and qualified personnel following the directions provided by the pump manufacturer. Extreme caution must be used when filling an FDA approved implantable pump, following strict aseptic technique and ensuring refill directly into the reservoir and not the catheter access port.

Lioresal^® Intrathecal (baclofen injection) for intrathecal injection [prescribing information]. Amneal Pharmaceuticals LLC, Bridgewater, Jersey; January 2022..
Muller H, Zierski J, Dralle D, Krauss D, Mutschler E. Pharmacokinetics of intrathecal baclofen. Local-spinal therapy of spasticity. 1988:223-226.
Francisco GE, Saulino M. Chapter 19: Intrathecal baclofen for spasticity. In: Brashear A, Elovic E, eds. Spasticity: Diagnosis and Management. 2nd ed. New York, NY: Demos Medical Publishing, LLC, 2016.
Penn RD. Intrathecal baclofen for spasticity of spinal origin: seven years experience. J Neurosurg. 1992;77:236-240.
Coffey RJ, Cahill D, Steers W, et al. Intrathecal baclofen for intractable spasticity of spinal origin: results of a long-term multi-center study. J Neurosurg. 1993;78:226-232.

Event^a	% (n=7459)
Catheter occlusion^b	3.45
Catheter dislodgement	3.16
Catheter break/cut	2.27
Pump motor stall	1.50
Catheter kink	1.51
Catheter-related complication^c	0.70
Device malfunction^d	0.55
Catheter disconnection at pump	0.55
Catheter leakage	0.51
Pump reservoir volume discrepancy	0.38
Corrosion and/or gear wear	0.38
Pump unable to enter/withdraw from catheter access port	0.25
Pump underinfusion	0.23
Overinfusion^e	0.16
Pump connector break/cut	0.21
Medical device complication^f	0.13
Deformed pump tube	0.12
Device breakage	0.08
Catheter access port issue	0.07
Device use error	0.05
Catheter disconnection between catheter segments	0.05
Device alarm issue	0.04
Motor feedthrough anomaly	0.04
Pump not infusing	0.04
Reservoir access issues due to residue	0.04
Catheter damage	0.03
Device connection issue	0.03
Device difficult to use	0.03
Device issue	0.01
Alarm and/or resonator anomaly	0.01
Coil shorted to case	0.01
Concave pump shield	0.01
Connector block problem	0.01
Cracked rotor magnet holder	0.01
Device component issue^g	0.01
Device development issue	0.01
Device infusion issue^h	0.01
Device telemetry issue	0.01
Gear or bridging residue	0.01
Leaky capacitor	0.01
Product sedimentation present	0.01
Pump inversion	0.01
Not codedⁱ	0.01

Adapted from Reference 5: 2016 Product Performance Report. Medtronic HCP Website. https://professional.medtronic.com/wcm/groups/mdtcom_sg/@mdt/@neuro/documents/documents/mdt_product_performance_2016.pdf

^aMedical Dictionary for Regulatory Activities (MedDRA) Preferred Term or Medtronic’s coding system term for events that do not exist in the MedDRA dictionary.

^bIncludes events reported as catheter occlusion and catheter kink/occlusion.

^cIncludes 18 catheter malfunctions, 15 inability to aspirate from catheter, 4 suspected catheter malfunctions, 4 coiled catheters, 2 difficulty aspirating catheter, 2 nonfunctioning distal catheter, 1 inability to aspirate CSF, 1 poor CSF flow, 1 aneurysm in catheter, 1 catheter wrapped in coils and knots, 1 catheter wrapped around pump, 1 evidence of catheter wear, 1 catheter failure, 1 no free flow of CSF from spinal segment of catheter, 1 patency issues of catheter, 1 slight loop in catheter, and 1 catheter occlusion.

^dIncludes 25 PTM malfunctions, 8 suspected catheter malfunctions, 6 pump malfunctions, 1 clinician programmer malfunction, 1 catheter dysfunction, 1 possible pump malfunction, 1 suspected rotor problem, and 1 catheter anchor malfunction.

^eThere were a total of 24 pumps with overinfusion (physician reported or confirmed by returned product analysis). The events for 15 of these pumps are reported in the table above. The remaining 9 pumps had no reported events associated with explant but had returned product analysis confirmed overinfusion (not reflected in the table above but included in the occurrence rate of overinfusion indicated in the Pump Events section of this report). The 15 pumps represented in the above table had 21 events; 18 events for overinfusion, and 3 events for pump motor stall.

^fIncludes 1 pump connector appeared somewhat worn, 1 pump unable to interrogate, 1 sutureless connector failure, 1 roller arm seized to ball bearing, 1 pump beeped, 1 pump in safe state, 1 possible corrosion of pump due to concentration of drug, 1 possible corrosion of catheter due to concetration of drug, 1 worn catheter connector, 1 metal clips on sutureless connector bent, 1 prescription table corruption, and 1 pump absorption of drug.

^gIncludes 1 event reported as broken anchor.

^hIncludes 1 event reported as slow dosing at refills.

ⁱEvent that had not been MedDRA-coded at the time of the report cutoff.

Important Safety Information for Lioresal^® Intrathecal (baclofen injection)

Abrupt discontinuation of intrathecal baclofen, regardless of the cause, has resulted in sequelae that include high fever, altered mental status, exaggerated rebound spasticity, and muscle rigidity, that in rare cases has advanced to rhabdomyolysis, multiple organ-system failure and death.

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. Patients and caregivers should be advised of the importance of keeping scheduled refill visits and should be educated on the early symptoms of baclofen withdrawal. Special attention should be given to patients at apparent risk (e.g. spinal cord injuries at T-6 or above, communication difficulties, history of withdrawal symptoms from oral or intrathecal baclofen). Consult the technical manual of the implantable infusion system for additional postimplant clinician and patient information (see WARNINGS).

Important Safety Information for Lioresal^® Intrathecal (baclofen injection)

Indications and Usage

Lioresal^® Intrathecal (baclofen injection) is a muscle relaxant and antispastic that is indicated for use in the management of severe spasticity of cerebral or spinal origin.
Lioresal^® Intrathecal is intended for use by the intrathecal route in single bolus test doses (via spinal catheter or lumbar puncture) and, for chronic use, only in implantable pumps approved by the FDA specifically for the administration of Lioresal^® Intrathecal into the intrathecal space.
Lioresal^® Intrathecal via an implantable pump should be reserved for patients unresponsive to oral baclofen therapy or those who experience intolerable CNS side effects at effective doses.
Patients with spasticity due to traumatic brain injury should wait at least one year after the injury before consideration of long term intrathecal baclofen therapy.
Prior to implantation of a device for chronic intrathecal infusion of Lioresal^® Intrathecal, patients must show a response to Lioresal^® Intrathecal in a screening trial.
Please review the dosing and administration section of the Lioresal^® Intrathecal prescribing information for further details.

Contraindications

Hypersensitivity to baclofen.
Lioresal^® Intrathecal is not recommended for intravenous, intramuscular, subcutaneous or epidural administration.

Select Warnings and Precautions

It is mandatory that all patients, caregivers, and treating physicians receive adequate information regarding the risks of the mode of treatment. Instruction should be given on signs and symptoms of overdose, procedures to be followed in the event of an overdose, and proper home care of the pump and insertion site.
Due to the possibility of life-threatening CNS depression, cardiovascular collapse, and/or respiratory failure, physicians must be adequately trained and educated in chronic intrathecal infusion therapy.
Patients should be infection-free prior to both a screening trial and a pump implantation. The presence of infection may interfere with an assessment of the patient’s response to bolus Lioresal^® Intrathecal, increase the risk of surgical complications and complicate dosing.
Reservoir refilling must be performed by fully trained and qualified personnel following the directions provided by the pump manufacturer. Extreme caution must be used when filling an FDA approved implantable pump, following strict aseptic technique and ensuring refill directly into the reservoir and not the catheter access port.
An attempt should be made to discontinue concomitant oral antispasticity medication to avoid possible overdose or adverse drug interactions, either prior to screening or following implant and initiation of chronic Lioresal^® Intrathecal infusion.
Following pump implantation, and for each adjustment of the dosing rate of the pump and/or concentration of Lioresal^® Intrathecal, the patient should be monitored closely until it is certain the patient’s response to the infusion is acceptable and reasonably stable.
Early symptoms of baclofen withdrawal may include return of baseline spasticity, pruritus, hypotension and paresthesias.
Priapism may develop or recur if treatment with intrathecal baclofen is interrupted.
Signs of overdose may appear suddenly or insidiously, and a massive overdose may present as coma. Less sudden and/or less severe forms of overdose may present with signs of drowsiness, lightheadedness, dizziness, somnolence, respiratory depression, seizures, rostral progression of hypotonia and loss of consciousness progressing to coma.
Should overdose appear likely, the patient should be taken immediately to a hospital for assessment and emptying of pump reservoir.
Except in overdose related emergencies, the dose of Lioresal^® Intrathecal should ordinarily be reduced slowly if the drug is discontinued for any reason.

Adverse Reactions

Common Adverse Reactions

The most frequent drug adverse events vary by indication but include: hypotonia (34.7%), somnolence (20.9%), headache (10.7%), convulsion (10.0%), dizziness (8.0%), urinary retention (8.0%), nausea (7.3%), and paresthesia (6.7%). Dosing and programming errors may result in clinically significant overdose or withdrawal. Acute massive overdose may result in coma and may be life threatening.
Drowsiness has been reported in patients on Lioresal^® Intrathecal. Patients should be cautioned regarding the operation of automobiles or other dangerous machinery and activities made hazardous by decreased alertness. Patients should also be cautioned that the central nervous system depressant effects of Lioresal^® Intrathecal may be additive to those of alcohol and other CNS depressants.

Serious Adverse Reactions

Seizures have been reported during overdose and with withdrawal from Lioresal^® Intrathecal as well as in patients maintained on therapeutic doses of Lioresal^® Intrathecal.
Fatalities have been reported with Lioresal^® Intrathecal use.

Postmarketing Experience

The following adverse events have been reported during post-approval use of Lioresal^® Intrathecal.
- Musculoskeletal – The onset of scoliosis or worsening of a pre-existing scoliosis has been reported.
- Urogenital – Sexual dysfunction in men and women including decreased libido and orgasm dysfunction have been reported.

Use in Specific Populations

There are no adequate and well controlled studies in pregnant women. Lioresal^® Intrathecal should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing mothers should exercise caution, as oral baclofen has been shown to pass into milk at therapeutic doses.
Safety and effectiveness in pediatric patients below the age of 4 have not been established.
Patients suffering from psychotic disorders, schizophrenia, or confusional states should be treated cautiously with Lioresal^® Intrathecal and kept under careful surveillance.
Lioresal^® Intrathecal should be given with caution in patients with impaired renal function. Dose reduction may be necessary.
Lioresal^® Intrathecal should be used with caution in patients with a history of autonomic dysreflexia.

For more information, including BOXED WARNING, refer to Lioresal^® Intrathecal (baclofen injection) prescribing information.

Event	n (%) (n=62)
Pump motor stall	25 (40.3)
Pump reservoir volume discrepancy	8 (12.9)
Device malfunction^a	4 (6.5)
Overinfusion	4 (6.5)
Pump unable to enter/withdraw from catheter access port	3 (4.8)
Medical device complication^b	3 (4.8)
Motor feedthrough anomaly	2 (3.2)
Reduced battery performance	2 (3.2)
Alarm and/or resonator anomaly	2 (3.2)
Catheter occlusion	1 (1.6)
Deformed pump tube	1 (1.6)
Device alarm issue	1 (1.6)
Device telemetry issue	1 (1.6)
Pump connector break/cut	1 (1.6)
Pump not infusing	1 (1.6)
Pump underinfusion	1 (1.6)
Reservoir access issues due to residue	1 (1.6)

ITB Therapy℠ With Lioresal® Intrathecal

Important Safety Information for Lioresal® Intrathecal (baclofen injection)

Indications and Usage

Contraindications

Select Warnings and Precautions

Adverse Reactions

Use in Specific Populations

ITB Therapy^℠ With Lioresal^® Intrathecal

Important Safety Information for Lioresal^® Intrathecal (baclofen injection)