Baclofen Injection

Baclofen Injection (Intrathecal) is packaged in single use ampules of 0.05 mg/mL (50 mcg/mL), 10 mg/20 mL (500 mcg/mL) or 40 mg/20 mL (2000 mcg/mL) supplied as follow:

Screening dose: Baclofen Injection (Intrathecal) 0.05 mg/mL (50 mcg/mL) in shelf carton of 10 ampules

Baclofen Injection (Intrathecal) 10 mg/20 mL (500 mcg/mL) in individual packaging of 1 ampule

Baclofen Injection (Intrathecal) 40 mg/20 mL (2000 mcg/mL) in individual packaging of 1 ampule

Storage

Does not require refrigeration.

Store at 20° to 25°C (68° to 77°F) [See USP controlled room temperature].

Do not freeze.

Do not heat sterilize.

Manufactured by Sintetica SA, Mendrisio, Switzerland. Revised: May 2016

LIORESAL Intrathecal (baclofen injection) is indicated for the management of patients with severe spasticity due to spinal cord injury or multiple sclerosis who are unresponsive to oral baclofen or who experience unacceptable side effects at effective oral doses.

LIORESAL Intrathecal therapy may be considered as an alternative to destructive neurosurgical procedures.

Prior to implantation of a device for chronic intrathecal infusion, patients must demonstrate a positive clinical response to a LIORESAL Intrathecal screening trial (see DOSAGE AND ADMINISTRATION).

LIORESAL Intrathecal has been used in patients with other spasticity of cerebral origin, e.g. spasticity following hypoxic encephalopathy, head injury, or stroke; however, clinical experience is limited.

Baclofen Injection (Intrathecal) is for use in single bolus intrathecal injections (via a catheter placed in the lumbar intrathecal space or injection by lumbar puncture) and in implantable pumps approved by the FDA specifically for the intrathecal administration of baclofen. Because of the possibility of potentially life- threatening CNS depression, cardiovascular collapse, and/ or respiratory failure, physicians must be adequately trained and educated in chronic intrathecal infusion therapy. The pump system should not be implanted until the patient's response to bolus Baclofen Injection (Intrathecal) is adequately evaluated. Evaluation (consisting of a screening procedure: see Dosage and Administration) requires that Baclofen Injection (Intrathecal) be administered into the intrathecal space via a catheter or lumbar puncture. Because of the risks associated with the screening procedure and the adjustment of dosage following pump implantation, these phases must be conducted in a medically supervised and adequately equipped environment following the instructions outlined in the Dosage and Administration section.

Resuscitative equipment should be available.

Following surgical implantation of the pump, particularly during the initial phases of pump use, the patient should be monitored closely until it is certain that the patient's response to the infusion is acceptable and reasonably stable. On each occasion that the dosing rate of the pump and/ or the concentration of Baclofen Injection (Intrathecal) in the reservoir is adjusted, close medical monitoring is required until it is certain that the patient's response to the infusion is acceptable and reasonably stable. It is mandatory that the patient, all patient caregivers, and the physicians responsible for the patient receive adequate information regarding the risks of this mode of treatment. All medical personnel and caregivers should be instructed in 1) the signs and symptoms of overdose, 2) procedures to be followed in the event of overdose and 3) proper home care of the pump and insertion site.

Overdose: Signs of overdose may appear suddenly or insidiously. Acute 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 pro- gression 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 the pump reservoir. In cases reported to date, overdose has generally been related to pump malfunction, inadvertent subcutaneous injection, or dosing error. (See Drug Overdose Symptoms and Treatment.) Extreme caution must be used when filling an FDA approved implantable pump. Such pumps should only be refilled through the reservoir refill septum. Inadvertent injection into the subcutaneous tissue can occur if the reservoir refill septum is not properly accessed. Some pumps are also equipped with a catheter access port that allows direct access to the intrathecal catheter. Direct injection into this catheter access port or inadvertent injection into the subcutaneous tissue may cause a life-threatening overdose.

Withdrawal: Abrupt withdrawal of intrathecal baclofen, regardless of the cause, has resulted in sequelae that included high fever, altered mental status, exaggerated rebound spasticity and muscle rigidity that in rare cases progressed to rhabdomyolysis, multiple organ-system failure, and death. In the first 9 years of post-marketing experience, 27 cases of withdrawal temporally related to the cessation of baclofen therapy were reported; six patients died. 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, and end of pump battery life; human error may have played a causal or contributing role in some cases. Cases of intrathecal mass at the tip of the implanted catheter leading to withdrawal symptoms have also been reported, most of them involving pharmacy compounded analgesic admixtures (see PRECAUTIONS). 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. All patients receiving intrathecal baclofen therapy are potentially at risk for withdrawal. Early symptoms of baclofen withdrawal may include return of baseline spasticity, pruritus, hypotension, and paresthesias. Some clinical characteristics of the advanced intrathecal baclofen withdrawal syndrome may resemble autonomic dysreflexia, infection (sepsis), malignant hyperthermia, neuroleptic- malignant syndrome, or other conditions associated with a hypermetabolic state or widespread rhabdomyolysis. Rapid, accurate diagnosis and treatment in an emergency-room or intensive- care setting are important in order to prevent the potentially life-threatening central nervous system and systemic effects of intrathecal baclofen withdrawal. The suggested treatment for intrathecal baclofen withdrawal is the restoration of intrathecal baclofen 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 as oral or enteral baclofen, or oral, enteral, or intravenous benzodiazepines may prevent potentially fatal sequelae. Oral or enteral baclofen alone should not be relied upon to halt the progression of intrathecal baclofen withdrawal. Seizures have been reported during overdose and with withdrawal from intrathecal baclofen as well as in patients maintained on therapeutic doses of intrathecal baclofen.

Fatalities:

Spasticity of Spinal Cord Origin: There were 16 deaths reported among the 576 U.S. patients treated with intrathecal baclofen in pre- and post- marketing studies evaluated as of December 1992. Because these patients were treated under uncontrolled clinical settings, it is impossible to determine definitively what role, if any, intrathecal baclofen played in their deaths. As a group, the patients who died were relatively young (mean age was 47 with a range from 25 to 63), but the majority suffered from severe spasticity of many years duration, were nonambulatory, had various medical complications such as pneumonia, urinary tract infections, and decubiti, and/ or had received multiple concomitant medications. A case- by- case review of the clinical course of the 16 patients who died failed to reveal any unique signs, symptoms, or laboratory results that would suggest that treatment with intrathecal baclofen caused their deaths. Two patients, however, did suffer sudden and unexpected death within 2 weeks of pump implantation and one patient died unexpectedly after screening. One patient, a 44 year-old male with MS, died in hospital on the second day following pump implantation. An autopsy demonstrated severe fibrosis of the coronary conduction system. A second patient, a 52 year-old woman with MS and a history of an inferior wall myocardial infarction, was found dead in bed 12 days after pump implantation, 2 hours after having had documented normal vital signs. An autopsy revealed pulmonary congestion and bilateral pleural effusions. It is impossible to determine whether intrathecal baclofen contributed to these deaths. The third patient underwent three baclofen screening trials. His medical history included SCI, aspiration pneumonia, septic shock, disseminated intravascular coagulopathy, severe metabolic acidosis, hepatic toxicity, and status epilepticus. Twelve days after screening (he was not implanted), he again experienced status epilepticus with subsequent significant neurological deterioration. Based upon prior instruction, extraordinary resuscitative measures were not pursued and the patient died.

Spasticity of Cerebral Origin: There were three deaths occurring among the 211 patients treated with intrathecal baclofen in pre- marketing studies as of March 1996. These deaths were not attributed to the therapy.

No specific laboratory tests are deemed essential for the management of patients on Baclofen Injection (Intrathecal).

There is inadequate systematic experience with the use of Baclofen Injection (Intrathecal) in combination with other medications to predict specific drug-drug interactions. Interactions attributed to the combined use of Baclofen Injection (Intrathecal) and epidural morphine include hypotension and dyspnea.

Children should be of sufficient body mass to accommodate the implantable pump for chronic infusion. Please consult pump manufacturer's manual for specific recommendations. Safety and effectiveness in pediatric patients below the age of 4 have not been established. Considerations based on experience with oral baclofen (baclofen USP) A dose-related increase in incidence of ovarian cysts was observed in female rats treated chronically with oral baclofen. Ovarian cysts have been found by palpation in about 4% of the multiple sclerosis patients who were treated with oral baclofen for up to one year. In most cases these cysts disappeared spontaneously while patients continued to receive the drug. Ovarian cysts are estimated to occur spontaneously in approximately 1% to 5% of the normal female population.

Refer to the manufacturer's manual for the implantable pump approved for intrathecal infusion for specific instructions and precautions for programming the pump and/ or refilling the reservoir. There are various pumps with varying reservoir volumes and there are various refill kits available. It is important to be familiar with all of these products in order to select the appropriate refill kit for the particular pump in use.

Screening Phase:

Prior to pump implantation and initiation of chronic infusion of Baclofen Injection (Intrathecal), patients must demonstrate a positive clinical response to a Baclofen Injection (Intrathecal) bolus dose administered intrathecally in a screening trial. The screening trial employs Baclofen Injection (Intrathecal) at a concentration of 50 mcg/mL. A 1 mL ampule (50 mcg/mL) is available for use in the screening trial. The screening procedure is as follows. An initial bolus containing 50 micrograms in a volume of 1 milliliter is administered into the intrathecal space by barbotage over a period of not less than one minute. The patient is observed over the ensuing 4 to 8 hours. A positive response consists of a significant decrease in muscle tone and/or frequency and/or severity of spasms. If the initial response is less than desired, a second bolus injection may be administered 24 hours after the first. The second screening bolus dose consists of 75 micrograms in 1.5 milliliters. Again, the patient should be observed for an interval of 4 to 8 hours. If the response is still inadequate, a final bolus screening dose of 100 micrograms in 2 milliliters may be administered 24 hours later.

Pediatric Patients: The starting screening dose for pediatric patients is the same as in adult patients, i.e., 50 mcg. However, for very small patients, a screening dose of 25 mcg may be tried first. Patients who do not respond to a 100 mcg intrathecal bolus should not be considered candidates for an implanted pump for chronic infusion.

Post-Implant Dose Titration Period: To determine the initial total daily dose of Baclofen Injection (Intrathecal) following implant, the screening dose that gave a positive effect should be doubled and administered over a 24-hour period, unless the efficacy of the bolus dose was maintained for more than 8 hours, in which case the starting daily dose should be the screening dose delivered over a 24-hour period. No dose increases should be given in the first 24 hours (i.e., until the steady state is achieved).

Adult Patients with Spasticity of Spinal Cord Origin: After the first 24 hours, for adult patients, the daily dosage should be increased slowly by 10 to 30% increments and only once every 24 hours, until the desired clinical effect is achieved.

Adult Patients with Spasticity of Cerebral Origin: After the first 24 hours, the daily dose should be increased slowly by 5 to 15% only once every 24 hours, until the desired clinical effect is achieved.

Pediatric Patients: After the first 24 hours, the daily dose should be increased slowly by 5 to 15% only once every 24 hours, until the desired clinical effect is achieved. If there is not a substantive clinical response to increases in the daily dose, check for proper pump function and catheter patency. Patients must be monitored closely in a fully equipped and staffed environment during the screening phase and dose- titration period immediately following implant. Resuscitative equipment should be immediately available for use in case of life- threatening or intolerable side effects.

Maintenance Therapy:

Spasticity of Spinal Cord Origin Patients: The clinical goal is to maintain muscle tone as close to normal as possible, and to minimize the frequency and severity of spasms to the extent possible, without inducing intolerable side effects. Very often, the maintenance dose needs to be adjusted during the first few months of therapy while patients adjust to changes in life style due to the alleviation of spasticity. During periodic refills of the pump, the daily dose may be increased by 10 to 40%, but no more than 40%, to maintain adequate symptom control. The daily dose may be reduced by 10 to 20% if patients experience side effects. Most patients require gradual increases in dose over time to maintain optimal response during chronic therapy. A sudden large requirement for dose escalation suggests a catheter complication (i.e., catheter kink or dislodgement). Maintenance dosage for long term continuous infusion of Baclofen Injection (Intrathecal) has ranged from 12 mcg/day to 2003 mcg/day, with most patients adequately maintained on 300 micrograms to 800 micrograms per day. There is limited experience with daily doses greater than 1000 mcg/day. Determination of the optimal Baclofen Injection (Intrathecal) dose requires individual titration. The lowest dose with an optimal response should be used.

Spasticity of Cerebral Origin Patients: The clinical goal is to maintain muscle tone as close to nor- mal as possible and to minimize the frequency and severity of spasms to the extent possible, without inducing intolerable side effects, or to titrate the dose to the desired degree of muscle tone for optimal functions. Very often the maintenance dose needs to be adjusted during the first few months of therapy while patients adjust to changes in life style due to the alleviation of spasticity. During periodic refills of the pump, the daily dose may be increased by 5 to 20%, but no more than 20%, to maintain adequate symptom control. The daily dose may be reduced by 10 to 20% if patients experience side effects. Many patients require gradual increases in dose over time to maintain optimal response during chronic therapy. A sudden large requirement for dose escalation suggests a catheter complication (i.e., catheter kink or dislodgement). Maintenance dosage for long term continuous infusion of Baclofen Injection (Intrathecal) has ranged from 22 mcg/day to 1400 mcg/day, with most patients adequately maintained on 90 micrograms to 703 micrograms per day. In clinical trials, only 3 of 150 patients required daily doses greater than 1000 mcg/day.

Pediatric Patients: Use same dosing recommendations for patients with spasticity of cerebral origin. Pediatric patients under 12 years seemed to require a lower daily dose in clinical trials. Average daily dose for patients under 12 years was 274 mcg/day, with a range of 24 to 1199 mcg/day. Dosage requirement for pediatric patients over 12 years does not seem to be different from that of adult patients. Determination of the optimal Baclofen Injection (Intrathecal) dose requires individual titration. The lowest dose with an optimal response should be used.

Potential need for dose adjustments in chronic use: During long term treatment, approximately 5% (28/627) of patients become refractory to increasing doses. There is not sufficient experience to make firm recommendations for tolerance treatment; however, this "tolerance" has been treated on occasion, in hospital, by a "drug holiday" consisting of the gradual reduction of Baclofen Injection (Intrathecal) over a 2 to 4 week period and switching to alternative methods of spasticity management. After the "drug holiday", Baclofen Injection (Intrathecal) may be restarted at the initial continuous infusion dose.

Stability

Parenteral drug products should be inspected for particulate matter and discoloration prior to administration, whenever solution and container permit.

Delivery Specifications

The specific concentration that should be used depends upon the total daily dose required as well as the delivery rate of the pump. Baclofen Injection (Intrathecal) may require dilution when used with certain implantable pumps. Please consult manufacturer's manual for specific recommendations.

Preparation Instruction:

Screening

Use the 1 mL screening ampule only (50 mcg/mL) for bolus injection into the subarachnoid space. For a 50 mcg bolus dose, use 1 mL of the screening ampule. Use 1.5 mL of 50 mcg/mL Baclofen Injection for a 75 mcg bolus dose. For the maximum screening dose of 100 mcg, use 2 mL of 50 mcg/mL Baclofen Injection (2 screening ampules).

Maintenance

For patients who require concentrations other than 500 mcg/mL or 2000 mcg/mL, Baclofen Injection (Intrathecal) must be diluted. Baclofen Injection (Intrathecal) must be diluted with sterile preservative free Sodium Chloride for Injection, U.S.P.

Delivery Regimen:

Baclofen Injection (Intrathecal) is most often administered in a continuous infusion mode immediately following implant. For those patients implanted with programmable pumps who have achieved relatively satisfactory control on continuous infusion, further benefit may be attained using more complex schedules of Baclofen Injection (Intrathecal) delivery. For example, patients who have increased spasms 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 time of desired clinical effect.

Baclofen Injection (Intrathecal) is packaged in single use ampules of 0.05 mg/mL (50 mcg/mL), 10 mg/20 mL (500 mcg/mL) or 40 mg/20 mL (2000 mcg/mL) supplied as follow:

Screening dose: Baclofen Injection (Intrathecal) 0.05 mg/mL (50 mcg/mL) in shelf carton of 10 ampules

Baclofen Injection (Intrathecal) 10 mg/20 mL (500 mcg/mL) in individual packaging of 1 ampule

Baclofen Injection (Intrathecal) 40 mg/20 mL (2000 mcg/mL) in individual packaging of 1 ampule

Baclofen has been shown to have general CNS depressant properties, causing sedation, somnolence, and respiratory and cardiovascular depression.

The most commonly reported adverse events with LIORESAL Intrathecal (baclofen injection) in clinical trials were drowsiness, weakness in the lower extremities, dizziness and seizures.

Adverse drug reactions from clinical trials are listed in the table below 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, < 1/10); uncommon ( ≥ 1/1,000, < 1/100); rare ( ≥ 1/10,000, < 1/1,000); very rare ( < 1/10,000), including isolated reports.

Adverse events associated with the delivery system (e.g. 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, whereby in some cases a causal relationship with baclofen cannot be excluded (see WARNINGS). These are in addition to those listed below. In a fatal case of a child (causality with baclofen uncertain), inflammatory signs in the posterior horns and signs of arachnoiditis in proximity of the catheter tip were observed. This corresponds to observations in dogs, where chronic inflammatory reactions to the foreign body of the catheter were observed, independently of baclofen concentration.

Incidence of Most Frequent Adverse Events in US Clinical Trials

In addition to the more common adverse events reported above, the following adverse events were observed during clinical trials elsewhere or reported by clinicians.

Uncommon: Dehydration, weight loss, albuminuria and hyperglycemia

Common: Depression, anxiety, agitation

Uncommon: Suicide ideation and suicide attempt, hallucinations, paranoia, euphoric mood

Common: Confusional state, disorientation, insomnia, sedation, paresthesia, fatigue, lethargy

Uncommon: nystagmus, ataxia, memory impairment.

Common: Accommodation disorder, diplopia

Uncommon: Bradycardia

Rare: pulmonary embolism.

Uncommon: Deep vein thrombosis, flushing, pallor

Common: Dry mouth, diarrhea, decreased appetite, increased salivation

Uncommon: Ileus, hypogeusia, dysphagia

Common: Respiratory depression, pneumonia,

Common: urinary incontinence, urinary retention.

Common: Sexual dysfunction

Common: Urticaria, pruritus, facial and/or peripheral edema

Uncommon: Alopecia, hyperhidrosis

Common: Hypertonia

Common: Asthenia, pyrexia, chills, pain

Uncommon: Hypothermia

Adverse Drug Reactions From Spontaneous Reports And Literature Cases (frequency not known)

The following adverse drug reactions have been derived from post-marketing experience with LIORESAL Intrathecal via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorized as not known. Adverse reactions are listed according to system organ classes in MedDRA. Within each system organ class, ADRs are presented in order of decreasing seriousness.

Nervous system disorders: dysphoria

Respiratory, thoracic and mediastinal disorders: bradypnea

Read the entire FDA prescribing information for Lioresal Intrathecal (Baclofen Injection)