Baclofen injection is indicated for use in the management of severe spasticity in adult and pediatric patients age 4 years and above. Patients should first respond to a screening dose of intrathecal baclofen prior to consideration for long term infusion via an implantable pump. For spasticity of spinal cord origin, chronic infusion of baclofen injection 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.

{ "type": "p", "children": [], "text": "Baclofen injection is indicated for use in the management of severe spasticity in adult and pediatric patients age 4 years and above. Patients should first respond to a screening dose of intrathecal baclofen prior to consideration for long term infusion via an implantable pump. For spasticity of spinal cord origin, chronic infusion of baclofen injection 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. Baclofen injection is intended for use by the intrathecal route in single bolus test doses (via spinal catheter or lumbar puncture) and, for chronic use, only with the Medtronic SynchroMed® II Programmable Pump or other pumps labeled for intrathecal administration of baclofen injection [see Clinical Studies(14)] .

{ "type": "p", "children": [], "text": "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. Baclofen injection is intended for use by the intrathecal route in single bolus test doses (via spinal catheter or lumbar puncture) and, for chronic use, only with the Medtronic SynchroMed® II Programmable Pump or other pumps labeled for intrathecal administration of baclofen injection\n \n [see\n \n Clinical Studies(14)]\n \n .\n\n " }

Prior to implantation of a device for chronic intrathecal infusion of baclofen injection, patients must show a response to baclofen injection in a screening trial [see Dosage and Administration(2.2)] .

{ "type": "p", "children": [], "text": "Prior to implantation of a device for chronic intrathecal infusion of baclofen injection, patients must show a response to baclofen injection in a screening trial\n \n [see\n \n Dosage and Administration(2.2)]\n \n .\n\n " }

2.1 Use Only in Medtronic SynchroMed® II Programmable Pump (or other pumps labeled for intrathecal administration of baclofen injection)

Baclofen injection is approved only for use with the Medtronic SynchroMed ®II Programmable Pump or other pumps labeled for intrathecal administration of baclofen injection. Refer to the manufacturer’s manual for specific instructions and precautions for programming the pump and/or refilling the reservoir. It is important to select the appropriate refill kit for the pump used to administer baclofen injection. Baclofen injection is not to be compounded with other medications.

2.2 Screening Phase

Prior to pump implantation and initiation of chronic infusion of baclofen injection, patients must demonstrate a positive clinical response to a baclofen injection bolus dose administered intrathecally in a screening trial. The screening trial employs baclofen injection at a concentration of 50 mcg/mL. A 1 mL syringe (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.

2.3 Preparation Information

Screening

Use the 1 mL screening syringe only (50 mcg/mL) for bolus injection into the subarachnoid space. For a 50 mcg bolus dose, use 1 mL of the screening syringe. 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 syringes).

Maintenance

The specific concentration that should be used depends upon the total daily dose required as well as the delivery rate of the pump. For patients who require concentrations other than 500 mcg/mL, 1,000 mcg/mL, or 2,000 mcg/mL, baclofen injection must be diluted with sterile preservative free Sodium Chloride for Injection, USP.

2.4 Administration Information

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

The external surface of baclofen injection prefilled syringes (all strengths, including the 50 mcg/mL strength) are non-sterile. The use of baclofen injection prefilled syringe in an aseptic setting (i.e., operating room) to fill sterile intrathecal pumps prior to implantation in patients is not recommended. For outpatient use, modify aseptic procedures to avoid contamination of sterile surfaces through contact with the non-sterile exterior of the baclofen injection prefilled syringe when filling the pump reservoir [see Warnings and Precautions (5.2)] .

Delivery Regimen

Baclofen injection 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 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.

2.5 Dose Titration

Post-Implant Dose Titration Period To determine the initial total daily dose of baclofen injection 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). In most patients, it will be necessary to increase the dose gradually over time to maintain effectiveness; a sudden requirement for substantial dose escalation typically indicates a catheter complication (i.e., catheter kink or dislodgement).

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.

Additional Considerations Pertaining to Dosage Adjustment Careful dose titration of baclofen injection is needed when spasticity is necessary to sustain upright posture and balance in locomotion or whenever spasticity is used to obtain optimal function and care. It may be important to titrate the dose to maintain some degree of muscle tone and allow occasional spasms to: 1) help support circulatory function, 2) possibly prevent the formation of deep vein thrombosis, 3) optimize activities of daily living and ease of care.

Except in overdose related emergencies, the dose of baclofen injection should ordinarily be reduced slowly if the drug is discontinued for any reason.

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 baclofen injection infusion. Reduction and discontinuation of oral anti-spasmotics should be done slowly and with careful monitoring by the physician. Abrupt reduction or discontinuation of concomitant antispastics should be avoided.

2.6 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 lifestyle 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 intrathecal baclofen has ranged from 12 mcg/day to 2,003 mcg/day, with most patients adequately maintained on 300 micrograms to 800 micrograms per day. There is limited experience with daily doses greater than 1,000 mcg/day. Determination of the optimal baclofen injection 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 normal 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 lifestyle 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 intrathecal baclofen has ranged from 22 mcg/day to 1,400 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 1,000 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 mcg/day to 1,199 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 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 intrathecal baclofen over a 2 to 4 week period and switching to alternative methods of spasticity management. After the “drug holiday,” intrathecal baclofen may be restarted at the initial continuous infusion dose.

Baclofen injection is available, for intrathecal use only, in:

{ "type": "p", "children": [], "text": "Baclofen injection is available, for intrathecal use only, in:" }

{ "type": "ul", "children": [ "Single-dose vials of 10,000 mcg per 20 mL (500 mcg/mL)", "Single-dose vials of 20,000 mcg per 20 mL (1,000 mcg/mL)", "Single-dose vials of 40,000 mcg per 20 mL (2,000 mcg/mL)" ], "text": "" }

Baclofen injection is contraindicated in patients with a hypersensitivity to baclofen. Do not use baclofen injection for intravenous, intramuscular, subcutaneous or epidural administration.

{ "type": "p", "children": [], "text": "Baclofen injection is contraindicated in patients with a hypersensitivity to baclofen. Do not use baclofen injection for intravenous, intramuscular, subcutaneous or epidural administration." }

5.1 Risk of Life-Threatening Overdose During Pump Refills

Use extreme caution when filling the Medtronic SynchroMed ®II Programmable Pump which is equipped with an injection port that allows direct access to the intrathecal catheter. Direct injection into the catheter through the catheter access port may cause a life-threatening overdose.

Reservoir refilling must be performed by fully trained and qualified personnel following the directions provided by the pump manufacturer. Carefully calculate refill intervals to prevent depletion of the reservoir, as this would result in the return of severe spasticity and possibly symptoms of withdrawal.

Strict aseptic technique in filling is required to avoid bacterial contamination and serious infection. A period of observation appropriate to the clinical situation should follow each refill or manipulation of the drug reservoir.

5.2 Potential for Contamination due to Non-sterile External Surface of Prefilled Syringe

Although the drug solution and pathway in the baclofen injection prefilled syringes are sterile, the external surface of the prefilled syringes (all strengths, including the 50 mcg/mL strength) are non-sterile. This has the potential to lead to contamination and consequent adverse reactions. The use of baclofen injection prefilled syringe in an aseptic setting (e.g., operating room) to fill sterile intrathecal pumps prior to implantation in patients is not recommended, unless the external surface of the prefilled syringe is treated to ensure sterility. Baclofen injection supplied in vials may be used with conventional aseptic technique to fill intrathecal pumps prior to implantation. Procedures should also be put in place while refilling implantable intrathecal pumps in an outpatient setting to avoid contamination of sterile surfaces through contact with the non-sterile exterior of the baclofen injection prefilled syringe.

5.3 Prescriber, Caregiver and Patient Training and Screening Procedure/Post- Implantation Environment

Baclofen injection is for use in single bolus intrathecal injections (via a catheter placed in the lumbar intrathecal space or injection by lumbar puncture) and in the implantable Medtronic SynchroMed® II Programmable Pump or other pumps labeled for intrathecal administration of baclofen injection. 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 injection is adequately evaluated. Evaluation (consisting of a screening procedure) requires that baclofen injection be administered into the intrathecal space via a catheter or lumbar puncture [see Dosage and Administration (2.2)] . 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 [see Dosage and Administration( 2.2and 2.5)] .

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 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.

5.4 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 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 the pump reservoir. In cases reported to date, overdose has generally been related to pump malfunction or dosing error [see Overdosage (10)] .

Extreme caution must be used when filling the implantable pump.

Medtronic SynchroMed® II Programmable Pump should only be refilled through the reservoir refill septum. The Medtronic SynchroMed® II Programmable Pump is also equipped with a catheter access port that allows direct access to the intrathecal catheter. Direct injection into this catheter access port may cause a life-threatening overdose.

5.5 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 Warnings and Precautions (5.10)] .

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.

5.6 Possible Exacerbation of Psychotic Disorders, Schizophrenia, or Confusional States

Patients suffering from psychotic disorders, schizophrenia, or confusional states should be treated cautiously with baclofen injection and kept under careful surveillance, because exacerbations of these conditions have been observed with oral administration.

5.7 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 Multiple Sclerosis, 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 spinal cord injury, 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.

5.8 Use with Caution in Patients with a History of Autonomic Dysreflexia

Baclofen injection should be used with caution in patients with a history of autonomic dysreflexia. The presence of nociceptive stimuli or abrupt withdrawal of baclofen injection may cause an autonomic dysreflexic episode.

5.9 Infections

Patients should be infection-free prior to the screening trial with baclofen injection because the presence of a systemic infection may interfere with an assessment of the patient's response to bolus baclofen injection. Patients should be infection-free prior to implantation of the pump because the presence of infection may increase the risk of surgical complications. Moreover, a systemic infection may complicate dosing.

5.10 Drowsiness

Drowsiness has been reported in patients on intrathecal baclofen. 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 intrathecal baclofen may be additive to those of alcohol and other CNS depressants.

5.11 Intrathecal Mass Formation

Cases of intrathecal mass at the tip of the implanted catheter have been reported, most of them involving pharmacy compounded analgesic admixtures. The most frequent symptoms associated with intrathecal 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. In patients with new neurological signs or symptoms suggestive of an intrathecal 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 intrathecal mass.

5.12 Ovarian Cysts

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.

6.1 Spasticity of Spinal Cord Origin

Most Common Adverse Reactions in Patients with Spasticity of Spinal Origin

In pre- and post-marketing clinical trials, the most common adverse reactions associated with use of intrathecal baclofen which were not seen at an equivalent incidence among placebo-treated patients were: somnolence, dizziness, nausea, hypotension, headache, convulsions and hypotonia.

Adverse Reactions Associated with Discontinuation of Treatment

8/474 patients with spasticity of spinal cord origin receiving long term infusion of intrathecal baclofen in pre- and post-marketing clinical studies in the U.S. discontinued treatment due to adverse reactions. These include: pump pocket infections (3), meningitis (2), wound dehiscence (1), gynecological fibroids (1) and pump overpressurization (1) with unknown, if any, sequela. Eleven patients who developed coma secondary to overdose had their treatment temporarily suspended, but all were subsequently re-started and were not, therefore, considered to be true discontinuations.

Fatalities - [see Warnings and Precautions(5.6)] .

Incidence in Controlled Trials

Experience with intrathecal baclofen obtained in parallel, placebo-controlled, randomized studies provides only a limited basis for estimating the incidence of adverse reactions because the studies were of very brief duration (up to three days of infusion) and involved only a total of 63 patients. The following events occurred among the 31 patients receiving intrathecal baclofen in two randomized, placebo-controlled trials: hypotension (2), dizziness (2), headache (2), dyspnea (1). No adverse reactions were reported among the 32 patients receiving placebo in these studies.

Events Observed during the Pre- and Post-marketing Evaluation of Intrathecal Baclofen

Adverse events associated with the use of intrathecal baclofen reflect experience gained with 576 patients followed prospectively in the United States. They received intrathecal baclofen for periods of one day (screening) (N=576) to over eight years (maintenance) (N=10). The usual screening bolus dose administered prior to pump implantation in these studies was typically 50 mcg. The maintenance dose ranged from 12 mcg to 2,003 mcg per day. Because of the open, uncontrolled nature of the experience, a causal linkage between events observed and the administration of intrathecal baclofen cannot be reliably assessed in many cases and many of the adverse reactions reported are known to occur in association with the underlying conditions being treated. Nonetheless, many of the more commonly reported reactions — hypotonia, somnolence, dizziness, paresthesia, nausea/vomiting and headache — appear clearly drug-related.

Adverse experiences reported during all U.S. studies (both controlled and uncontrolled) are shown in Table 1. Eight of 474 patients who received chronic infusion via implanted pumps had adverse experiences which led to a discontinuation of long term treatment in the pre- and post-marketing studies.

Table 1: Most Common (≥1%) Adverse Reactions in Patients with Spasticity of Spinal Origin in Prospectively Monitored Clinical Trials

<div class="scrollingtable"><table cellpadding="0" cellspacing="0" width="621.775"> <col width="24.9946524064171%"/> <col width="24.9946524064171%"/> <col width="25.0053475935829%"/> <col width="25.0053475935829%"/> <tbody class="Headless"> <tr class="Botrule First First"> <td class="Lrule Rrule" valign="top"><span class="Bold">Adverse Reaction</span></td><td class="Rrule" valign="top"><span class="Bold">Percent</span> <br/> <br/> N=576 <br/> <br/> Screening* </td><td class="Rrule" valign="top"><span class="Bold">Percent</span> <br/> <br/> N=474 <br/> <br/> Titration† </td><td class="Rrule" valign="top"><span class="Bold">Percent</span> <br/> <br/> N=430 <br/> <br/> Maintenance <span class="Sup">‡</span></td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Hypotonia</td><td class="Rrule" valign="top">5.4</td><td class="Rrule" valign="top">13.5</td><td class="Rrule" valign="top">25.3</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Somnolence</td><td class="Rrule" valign="top">5.7</td><td class="Rrule" valign="top">5.9</td><td class="Rrule" valign="top">20.9</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Dizziness</td><td class="Rrule" valign="top">1.7</td><td class="Rrule" valign="top">1.9</td><td class="Rrule" valign="top">7.9</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Paresthesia</td><td class="Rrule" valign="top">2.4</td><td class="Rrule" valign="top">2.1</td><td class="Rrule" valign="top">6.7</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Nausea and Vomiting</td><td class="Rrule" valign="top">1.6</td><td class="Rrule" valign="top">2.3</td><td class="Rrule" valign="top">5.6</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Headache</td><td class="Rrule" valign="top">1.6</td><td class="Rrule" valign="top">2.5</td><td class="Rrule" valign="top">5.1</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Constipation</td><td class="Rrule" valign="top">0.2</td><td class="Rrule" valign="top">1.5</td><td class="Rrule" valign="top">5.1</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Convulsion</td><td class="Rrule" valign="top">0.5</td><td class="Rrule" valign="top">1.3</td><td class="Rrule" valign="top">4.7</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Urinary Retention</td><td class="Rrule" valign="top">0.7</td><td class="Rrule" valign="top">1.7</td><td class="Rrule" valign="top">1.9</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Dry Mouth</td><td class="Rrule" valign="top">0.2</td><td class="Rrule" valign="top">0.4</td><td class="Rrule" valign="top">3.3</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Accidental Injury</td><td class="Rrule" valign="top">0.0</td><td class="Rrule" valign="top">0.2</td><td class="Rrule" valign="top">3.5</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Asthenia</td><td class="Rrule" valign="top">0.7</td><td class="Rrule" valign="top">1.3</td><td class="Rrule" valign="top">1.4</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Confusion</td><td class="Rrule" valign="top">0.5</td><td class="Rrule" valign="top">0.6</td><td class="Rrule" valign="top">2.3</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Death</td><td class="Rrule" valign="top">0.2</td><td class="Rrule" valign="top">0.4</td><td class="Rrule" valign="top">3.0</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Pain</td><td class="Rrule" valign="top">0.0</td><td class="Rrule" valign="top">0.6</td><td class="Rrule" valign="top">3.0</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Speech Disorder</td><td class="Rrule" valign="top">0.0</td><td class="Rrule" valign="top">0.2</td><td class="Rrule" valign="top">3.5</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Hypotension</td><td class="Rrule" valign="top">1.0</td><td class="Rrule" valign="top">0.2</td><td class="Rrule" valign="top">1.9</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Ambylopia</td><td class="Rrule" valign="top">0.5</td><td class="Rrule" valign="top">0.2</td><td class="Rrule" valign="top">2.3</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Diarrhea</td><td class="Rrule" valign="top">0.0</td><td class="Rrule" valign="top">0.8</td><td class="Rrule" valign="top">2.3</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Hypoventilation</td><td class="Rrule" valign="top">0.2</td><td class="Rrule" valign="top">0.8</td><td class="Rrule" valign="top">2.1</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Coma</td><td class="Rrule" valign="top">0.0</td><td class="Rrule" valign="top">1.5</td><td class="Rrule" valign="top">0.9</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Impotence</td><td class="Rrule" valign="top">0.2</td><td class="Rrule" valign="top">0.4</td><td class="Rrule" valign="top">1.6</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Peripheral Edema</td><td class="Rrule" valign="top">0.0</td><td class="Rrule" valign="top">0.0</td><td class="Rrule" valign="top">2.3</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Urinary Incontinence</td><td class="Rrule" valign="top">0.0</td><td class="Rrule" valign="top">0.8</td><td class="Rrule" valign="top">1.4</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Insomnia</td><td class="Rrule" valign="top">0.0</td><td class="Rrule" valign="top">0.4</td><td class="Rrule" valign="top">1.6</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Anxiety</td><td class="Rrule" valign="top">0.2</td><td class="Rrule" valign="top">0.4</td><td class="Rrule" valign="top">0.9</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Depression</td><td class="Rrule" valign="top">0.0</td><td class="Rrule" valign="top">0.0</td><td class="Rrule" valign="top">1.6</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Dyspnea</td><td class="Rrule" valign="top">0.3</td><td class="Rrule" valign="top">0.0</td><td class="Rrule" valign="top">1.2</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Fever</td><td class="Rrule" valign="top">0.5</td><td class="Rrule" valign="top">0.2</td><td class="Rrule" valign="top">0.7</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Pneumonia</td><td class="Rrule" valign="top">0.2</td><td class="Rrule" valign="top">0.2</td><td class="Rrule" valign="top">1.2</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Urinary Frequency</td><td class="Rrule" valign="top">0.0</td><td class="Rrule" valign="top">0.6</td><td class="Rrule" valign="top">0.9</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Urticaria</td><td class="Rrule" valign="top">0.2</td><td class="Rrule" valign="top">0.2</td><td class="Rrule" valign="top">1.2</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Anorexia</td><td class="Rrule" valign="top">0.0</td><td class="Rrule" valign="top">0.4</td><td class="Rrule" valign="top">0.9</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Diplopia</td><td class="Rrule" valign="top">0.0</td><td class="Rrule" valign="top">0.4</td><td class="Rrule" valign="top">0.9</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Dysautonomia</td><td class="Rrule" valign="top">0.2</td><td class="Rrule" valign="top">0.2</td><td class="Rrule" valign="top">0.9</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Hallucinations</td><td class="Rrule" valign="top">0.3</td><td class="Rrule" valign="top">0.4</td><td class="Rrule" valign="top">0.5</td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="top">Hypertension</td><td class="Rrule" valign="top">0.2</td><td class="Rrule" valign="top">0.6</td><td class="Rrule" valign="top">0.5</td> </tr> </tbody> </table></div>

*Following administration of test bolus

† Two month period following implant

‡ Beyond two months following implant

N=Total number of patients entering each period

%=% of patients evaluated

In addition to the more common (1% or more) adverse reactions reported in the prospectively followed 576 domestic patients in pre- and post-marketing studies, experience from an additional 194 patients exposed to intrathecal baclofen from foreign studies has been reported. The following adverse reactions, not described in the table, and arranged in decreasing order of frequency, and classified by body system, were reported:

Nervous System: Abnormal gait, thinking abnormal, tremor, amnesia, twitching, vasodilatation, cerebrovascular accident, nystagmus, personality disorder, psychotic depression, cerebral ischemia, emotional lability, euphoria, hypertonia, ileus, drug dependence, incoordination, paranoid reaction and ptosis.

Digestive System: Flatulence, dysphagia, dyspepsia and gastroenteritis.

Cardiovascular: Postural hypotension, bradycardia, palpitations, syncope, arrhythmia ventricular, deep thrombophlebitis, pallor and tachycardia.

Respiratory: Respiratory disorder, aspiration pneumonia, hyperventilation, pulmonary embolus and rhinitis.

Urogenital: Hematuria and kidney failure.

Skin and Appendages: Alopecia and sweating.

Metabolic and Nutritional Disorders: Weight loss, albuminuria, dehydration and hyperglycemia.

Special Senses: Abnormal vision, abnormality of accommodation, photophobia, taste loss and tinnitus.

Body as a Whole: Suicide, lack of drug effect, abdominal pain, hypothermia, neck rigidity, chest pain, chills, face edema, flu syndrome and overdose.

Hemic and Lymphatic System: Anemia.

6.2 Spasticity of Cerebral Origin

Most Common Adverse Reactions

In pre-marketing clinical trials, the most common adverse reactions associated with use of intrathecal baclofen which were not seen at an equivalent incidence among placebo- treated patients included: agitation, constipation, somnolence, leukocytosis, chills, urinary retention and hypotonia.

Adverse Reactions Associated with Discontinuation of Treatment

Nine of 211 patients receiving intrathecal baclofen in pre-marketing clinical studies in the U.S. discontinued long-term infusion due to adverse reactions associated with intrathecal therapy.

The nine adverse reactions leading to discontinuation were: infection (3), CSF leaks (2), meningitis (2), drainage (1), and unmanageable trunk control (1).

Fatalities

Three deaths, none of which were attributed to intrathecal baclofen, were reported in patients in clinical trials involving patients with spasticity of cerebral origin. See Warnings on other deaths reported in spinal spasticity patients.

Incidence in Controlled Trials

Experience with intrathecal baclofen obtained in parallel, placebo-controlled, randomized studies provides only a limited basis for estimating the incidence of adverse reactions because the studies involved a total of 62 patients exposed to a single 50 mcg intrathecal bolus. The following adverse reactions occurred among the 62 patients receiving intrathecal baclofen in two randomized, placebo-controlled trials involving cerebral palsy and head injury patients, respectively: agitation, constipation, somnolence, leukocytosis, nausea, vomiting, nystagmus, chills, urinary retention, and hypotonia.

Events Observed during the Pre-marketing Evaluation of Intrathecal Baclofen

Adverse events associated with the use of intrathecal baclofen reflect experience gained with a total of 211 U.S. patients with spasticity of cerebral origin, of whom 112 were pediatric patients (under age 16 at enrollment). They received intrathecal baclofen for periods of one day (screening) (N=211) to 84 months (maintenance) (N=1). The usual screening bolus dose administered prior to pump implantation in these studies was 50 mcg to 75 mcg. The maintenance dose ranged from 22 mcg to 1,400 mcg per day. Doses used in this patient population for long-term infusion are generally lower than those required for patients with spasticity of spinal cord origin.

Because of the open, uncontrolled nature of the experience, a causal linkage between events observed and the administration of intrathecal baclofen cannot be reliably assessed in many cases. Nonetheless, many of the more commonly reported reactions— somnolence, dizziness, headache, nausea, hypotension, hypotonia and coma — appear clearly drug-related.

The most frequent (≥1%) adverse reactions reported during all clinical trials are shown in Table 2. Nine patients discontinued long term treatment due to adverse reactions.

Table 2: Most Common (≥1%) Adverse Reactions in Patients with Spasticity of Cerebral Origin

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0" width="50%"> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule" valign="top"><span class="Bold">Adverse Reaction</span></td><td class="Botrule Lrule Rrule" valign="top"><span class="Bold">Percent</span> <p class="First TableParagraph">N=211</p> <p class="TableParagraph">Screening <span class="Bold">*</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph"> <span class="Bold">Percent</span> </p> <p class="TableParagraph">N=153</p> <p class="TableParagraph">Titration <span class="Sup">†</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph"> <span class="Bold">Percent</span> </p> <p class="TableParagraph">N=150</p> <p class="TableParagraph">Maintenance <span class="Sup">‡</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">Hypotonia</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">2.4</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">14.4</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">34.7</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">Somnolence</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">7.6</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">10.5</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">18.7</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">Headache</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">6.6</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">7.8</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">10.7</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">Nausea and Vomiting</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">6.6</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">10.5</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">4.0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">Vomiting</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">6.2</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">8.5</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">4.0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">Urinary Retention</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">0.9</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">6.5</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">8.0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">Convulsion</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">0.9</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">3.3</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">10.0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">Dizziness</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">2.4</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">2.6</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">8.0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">Nausea</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">1.4</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">3.3</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">7.3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">Hypoventilation</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">1.4</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">1.3</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">4.0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">Hypertonia</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">0.0</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">0.7</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">6.0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">Paresthesia</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">1.9</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">0.7</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">3.3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">Hypotension</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">1.9</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">0.7</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">2.0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">Increased Salivation</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">0.0</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">2.6</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">2.7</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">Back Pain</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">0.9</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">0.7</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">2.0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">Constipation</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">0.5</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">1.3</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">2.0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">Pain</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">0.0</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">0.0</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">4.0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">Pruritus</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">0.0</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">0.0</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">4.0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">Diarrhea</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">0.5</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">0.7</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">2.0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">Peripheral Edema</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">0.0</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">0.0</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">3.3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">Thinking Abnormal</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">0.5</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">1.3</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">0.7</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">Agitation</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">0.5</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">0.0</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">1.3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">Asthenia</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">0.0</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">0.0</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">2.0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">Chills</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">0.5</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">0.0</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">1.3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">Coma</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">0.5</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">0.0</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">1.3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">Dry Mouth</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">0.5</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">0.0</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">1.3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">Pneumonia</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">0.0</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">0.0</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">2.0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">Speech Disorder</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">0.5</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">0.7</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">0.7</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">Tremor</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">0.5</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">0.0</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">1.3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">Urinary Incontinence</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">0.0</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">0.0</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">2.0</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">Urination Impaired</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">0.0</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">0.0</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First TableParagraph">2.0</p> </td> </tr> </tbody> </table></div>

         *Following administration of test bolus

         † Two month period following implant

         ‡ Beyond two months following implant

         N=Total number of patients enteringeach period. 211 patients received drug; (1 of 212) received placebo only

The more common (1% or more) adverse reactions reported in the prospectively followed 211 patients exposed to intrathecal baclofen have been reported. In the total cohort, the following adverse reactions, not described in Table 2, and arranged in decreasing order of frequency, and classified by body system, were reported:

Nervous System: Akathisia, ataxia, confusion, depression, opisthotonos, amnesia, anxiety, hallucinations, hysteria, insomnia, nystagmus, personality disorder, reflexes decreased, and vasodilitation.

Digestive System: Dysphagia, fecal incontinence, gastrointestinal hemorrhage and tongue disorder.

Cardiovascular: Bradycardia.

Respiratory: Apnea, dyspnea and hyperventilation.

Urogenital: Abnormal ejaculation, kidney calculus, oliguria and vaginitis.

Skin and Appendages: Rash, sweating, alopecia, contact dermatitis and skin ulcer.

Special Senses: Abnormality of accommodation.

Body as a Whole: Death, fever, abdominal pain, carcinoma, malaise and hypothermia.

Hemic and Lymphatic System: Leukocytosis and petechial rash.

There is inadequate systematic experience with the use of intrathecal baclofen in combination with other medications to predict specific drug-drug interactions. Interactions attributed to the combined use of baclofen injection and epidural morphine include hypotension and dyspnea.

{ "type": "p", "children": [], "text": "There is inadequate systematic experience with the use of intrathecal baclofen in combination with other medications to predict specific drug-drug interactions. Interactions attributed to the combined use of baclofen injection and epidural morphine include hypotension and dyspnea." }

Risk Summary

There are no adequate data on the developmental risk associated with the use of baclofen injection in pregnant women.

In animal studies, oral administration of baclofen to pregnant rats produced an increase in fetal malformations (see Data). There are no animal data on developmental risk associated with baclofen administered via continuous intrathecal infusion.

The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Animal Data

Baclofen given orally to pregnant rats has been shown to increase the incidence of omphaloceles (ventral hernias) in fetuses at a dose associated with maternal toxicity. This abnormality was not seen in mice or rabbits.

Risk Summary There is insufficient information regarding levels of baclofen in milk of nursing mothers receiving baclofen injection. There are no adequate data on the effects of baclofen injection on the breastfed infant or on milk production. At recommended oral doses, baclofen is present in human milk and withdrawal symptoms can occur in breastfed infants when maternal administration of baclofen is stopped or when breastfeeding is stopped.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for baclofen injection and any potential adverse effects on the breastfed infant from baclofen injection or from the underlying maternal condition.

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.

Special attention must be given to recognizing the signs and symptoms of overdosage, especially during the initial screening and dose-titration phase of treatment, but also during re-introduction of baclofen injection after a period of interruption in therapy.

{ "type": "p", "children": [], "text": "Special attention must be given to recognizing the signs and symptoms of overdosage, especially during the initial screening and dose-titration phase of treatment, but also during re-introduction of baclofen injection after a period of interruption in therapy." }

Symptoms of Intrathecal Baclofen Overdose

{ "type": "p", "children": [], "text": "\nSymptoms of Intrathecal Baclofen Overdose\n" }

Drowsiness, lightheadedness, dizziness, somnolence, respiratory depression, seizures, rostral progression of hypotonia and loss of consciousness progressing to coma of up to 72 hours duration. In most cases reported, coma was reversible without sequelae after drug was discontinued. Symptoms of intrathecal baclofen overdose were reported in a sensitive adult patient after receiving a 25 mcg intrathecal bolus.

{ "type": "p", "children": [], "text": "Drowsiness, lightheadedness, dizziness, somnolence, respiratory depression, seizures, rostral progression of hypotonia and loss of consciousness progressing to coma of up to 72 hours duration. In most cases reported, coma was reversible without sequelae after drug was discontinued. Symptoms of intrathecal baclofen overdose were reported in a sensitive adult patient after receiving a 25 mcg intrathecal bolus." }

Treatment Suggestions for Overdose

{ "type": "p", "children": [], "text": "\nTreatment Suggestions for Overdose\n" }

There is no specific antidote for treating overdoses of baclofen injection; however, the following steps should ordinarily be undertaken:

{ "type": "p", "children": [], "text": "There is no specific antidote for treating overdoses of baclofen injection; however, the following steps should ordinarily be undertaken:" }

1) Residual intrathecal baclofen solution should be removed from the pump as soon as possible.

{ "type": "p", "children": [], "text": "1) Residual intrathecal baclofen solution should be removed from the pump as soon as possible." }

2) Patients with respiratory depression should be intubated if necessary, until the drug is eliminated.

{ "type": "p", "children": [], "text": "2) Patients with respiratory depression should be intubated if necessary, until the drug is eliminated." }

Anecdotal reports suggest that intravenous physostigmine may reverse central side effects, notably drowsiness and respiratory depression. Caution in administering physostigmine is advised, however, because its use has been associated with the induction of seizures and bradycardia.

{ "type": "p", "children": [], "text": "Anecdotal reports suggest that intravenous physostigmine may reverse central side effects, notably drowsiness and respiratory depression. Caution in administering physostigmine is advised, however, because its use has been associated with the induction of seizures and bradycardia." }

Physostigmine Doses for Adult Patients

{ "type": "p", "children": [], "text": "\nPhysostigmine Doses for Adult Patients\n" }

Administer 2 mg of physostigmine intramuscularly or intravenously at a slow controlled rate of no more than 1 mg per minute. Dosage may be repeated if life-threatening signs, such as arrhythmia, convulsions or coma occur.

{ "type": "p", "children": [], "text": "Administer 2 mg of physostigmine intramuscularly or intravenously at a slow controlled rate of no more than 1 mg per minute. Dosage may be repeated if life-threatening signs, such as arrhythmia, convulsions or coma occur." }

Physostigmine Doses for Pediatric Patients

{ "type": "p", "children": [], "text": "\nPhysostigmine Doses for Pediatric Patients\n" }

Administer 0.02 mg/kg physostigmine intramuscularly or intravenously, do not give more than 0.5 mg per minute. The dosage may be repeated at 5 to 10 minute intervals until a therapeutic effect is obtained or a maximum dose of 2 mg is attained.

{ "type": "p", "children": [], "text": "Administer 0.02 mg/kg physostigmine intramuscularly or intravenously, do not give more than 0.5 mg per minute. The dosage may be repeated at 5 to 10 minute intervals until a therapeutic effect is obtained or a maximum dose of 2 mg is attained." }

Physostigmine may not be effective in reversing large overdoses and patients may need to be maintained with respiratory support.

{ "type": "p", "children": [], "text": "Physostigmine may not be effective in reversing large overdoses and patients may need to be maintained with respiratory support." }

If lumbar puncture is not contraindicated, consideration should be given to withdrawing 30 to 40 mL of CSF to reduce CSF baclofen concentration.

{ "type": "p", "children": [], "text": "If lumbar puncture is not contraindicated, consideration should be given to withdrawing 30 to 40 mL of CSF to reduce CSF baclofen concentration." }

Baclofen injection is a muscle relaxant and antispastic. Baclofen's pharmacological class is a gamma-aminobutyric acid (GABA)ergic agonist. Baclofen's chemical name is 4-amino- 3-(4-chlorophenyl) butanoic acid, and its structural formula is:

{ "type": "p", "children": [], "text": "Baclofen injection is a muscle relaxant and antispastic. Baclofen's pharmacological class is a gamma-aminobutyric acid (GABA)ergic agonist. Baclofen's chemical name is 4-amino- 3-(4-chlorophenyl) butanoic acid, and its structural formula is:" }

Baclofen is a white to off-white powder, with a molecular weight of 213.66. It is slightly soluble in water, very slightly soluble in methanol and ethanol, practically insoluble in acetone and ether, soluble in 0.1N hydrochloric acid, 0.1N sodium hydroxide, and insoluble in chloroform.

{ "type": "p", "children": [], "text": "Baclofen is a white to off-white powder, with a molecular weight of 213.66. It is slightly soluble in water, very slightly soluble in methanol and ethanol, practically insoluble in acetone and ether, soluble in 0.1N hydrochloric acid, 0.1N sodium hydroxide, and insoluble in chloroform." }

Baclofen injection is a sterile, pyrogen-free, isotonic solution free of antioxidants, preservatives or other potentially neurotoxic additives indicated only for intrathecal administration. The drug is stable in solution at 37°C and compatible with CSF. Each mL of baclofen injection contains baclofen USP 500 mcg, 1,000 mcg or 2,000 mcg and sodium chloride 9 mg in Water for Injection; pH range is 5.5 to 7.5.

{ "type": "p", "children": [], "text": "Baclofen injection is a sterile, pyrogen-free, isotonic solution free of antioxidants, preservatives or other potentially neurotoxic additives indicated only for intrathecal administration. The drug is stable in solution at 37°C and compatible with CSF. Each mL of baclofen injection contains baclofen USP 500 mcg, 1,000 mcg or 2,000 mcg and sodium chloride 9 mg in Water for Injection; pH range is 5.5 to 7.5." }

The precise mechanism of action of baclofen as a muscle relaxant and antispasticity agent is not fully understood. Baclofen inhibits both monosynaptic and polysynaptic reflexes at the spinal level, possibly by decreasing excitatory neurotransmitter release from primary afferent terminals, although actions at supraspinal sites may also occur and contribute to its clinical effect. Baclofen is a structural analog of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), and may exert its effects by stimulation of the GABAB receptor subtype. 

Baclofen when introduced directly into the intrathecal space permits effective CSF concentrations to be achieved with resultant plasma concentrations 100 times less than those occurring with oral administration. In people, as well as in animals, baclofen has been shown to have general CNS depressant properties as indicated by the production of sedation with tolerance, somnolence, ataxia, and respiratory and cardiovascular depression. 

Intrathecal Bolus

Adult Patients  The onset of action is generally one-half hour to one hour after an intrathecal bolus. Peak spasmolytic effect is seen at approximately four hours after dosing and effects may last four to eight hours. Onset, peak response, and duration of action may vary with individual patients depending on the dose and severity of symptoms. 

Pediatric Patients  The onset, peak response and duration of action are similar to those seen in adult patients. 

Continuous Infusion

Adult Patients  Intrathecal baclofen's antispastic action is first seen at 6 to 8 hours after initiation of continuous infusion. Maximum activity is observed in 24 to 48 hours. 

Pediatric Patients  No additional information on continuous infusions is available for pediatric patients. 

The pharmacokinetics of cerebrospinal fluid (CSF) clearance of intrathecal baclofen calculated from intrathecal bolus or continuous infusion studies approximates CSF turnover, suggesting elimination is by bulk-flow removal of CSF. 

Intrathecal Bolus  After a bolus lumbar injection of 50 mcg or 100 mcg intrathecal baclofen in seven patients, the average CSF elimination half-life was 1.51 hours over the first four hours and the average CSF clearance was approximately 30 mL/hour. 

Continuous Infusion  The mean CSF clearance for intrathecal baclofen was approximately 30 mL/hour in a study involving ten patients on continuous intrathecal infusion. Concurrent plasma concentrations of baclofen during intrathecal administration are expected to be low (0 to 5 ng/mL). Limited pharmacokinetic data suggest that a lumbar-cisternal concentration gradient of about 4:1 is established along the neuroaxis during baclofen infusion. This is based upon simultaneous CSF sampling via cisternal and lumbar tap in 5 patients receiving continuous baclofen infusion at the lumbar level at doses associated with therapeutic efficacy; the interpatient variability was great. The gradient was not altered by position. Six pediatric patients (age 8 to 18 years) receiving continuous intrathecal baclofen infusion at doses of 77 to 400 mcg/day had plasma baclofen levels near or below 10 ng/mL. 

Carcinogenesis

No increase in tumors was seen in rats receiving baclofen orally for two years.

Mutagenesis

Mutagenicity assays with baclofen have not been performed.

Impairment of Fertility

Studies to assess the potential for adverse effects of baclofen on fertility have not been conducted.

Spasticity of Spinal Cord Origin  Evidence supporting the efficacy of intrathecal baclofen was obtained in randomized, controlled investigations that compared the effects of either a single intrathecal dose or a three day intrathecal infusion of intrathecal baclofen to placebo in patients with severe spasticity and spasms due to either spinal cord trauma or multiple sclerosis. Intrathecal baclofen was superior to placebo on both principal outcome measures employed: change from baseline in the Ashworth rating of spasticity and the frequency of spasms. 

{ "type": "p", "children": [], "text": "\nSpasticity of Spinal Cord Origin \n Evidence supporting the efficacy of intrathecal baclofen was obtained in randomized, controlled investigations that compared the effects of either a single intrathecal dose or a three day intrathecal infusion of intrathecal baclofen to placebo in patients with severe spasticity and spasms due to either spinal cord trauma or multiple sclerosis. Intrathecal baclofen was superior to placebo on both principal outcome measures employed: change from baseline in the Ashworth rating of spasticity and the frequency of spasms. \n\n " }

Spasticity of Cerebral Origin  The efficacy of intrathecal baclofen was investigated in three controlled clinical trials; two enrolled patients with cerebral palsy and one enrolled patients with spasticity due to previous brain injury.

{ "type": "p", "children": [], "text": "\nSpasticity of Cerebral Origin \n The efficacy of intrathecal baclofen was investigated in three controlled clinical trials; two enrolled patients with cerebral palsy and one enrolled patients with spasticity due to previous brain injury.\n\n " }

The first study, a randomized controlled cross-over trial of 51 patients with cerebral palsy, provided strong, statistically significant results; intrathecal baclofen was superior to placebo in reducing spasticity as measured by the Ashworth Scale. A second cross-over study was conducted in 11 patients with spasticity arising from brain injury. Despite the small sample size, the study yielded a nearly significant test statistic (p=0.066) and provided directionally favorable results. The last study, however, did not provide data that could be reliably analyzed. 

{ "type": "p", "children": [], "text": "The first study, a randomized controlled cross-over trial of 51 patients with cerebral palsy, provided strong, statistically significant results; intrathecal baclofen was superior to placebo in reducing spasticity as measured by the Ashworth Scale. A second cross-over study was conducted in 11 patients with spasticity arising from brain injury. Despite the small sample size, the study yielded a nearly significant test statistic (p=0.066) and provided directionally favorable results. The last study, however, did not provide data that could be reliably analyzed. " }

Baclofen injection, USP is a sterile, pyrogen-free, isotonic solution available in single-dose vials of 40,000 mcg per 20 mL for intrathecal administration only.

{ "type": "p", "children": [], "text": "Baclofen injection, USP is a sterile, pyrogen-free, isotonic solution available in single-dose vials of 40,000 mcg per 20 mL for intrathecal administration only." }

2,000 mcg per mL

{ "type": "p", "children": [], "text": "\n2,000 mcg per mL\n" }

NDC 14789-161-05: 20 mL Vial – 40,000 mcg per 20 mL.

{ "type": "p", "children": [], "text": "NDC 14789-161-05: 20 mL Vial – 40,000 mcg per 20 mL." }

Baclofen injection does not contain any antioxidants, preservatives or other potentially neurotoxic additives. Each single-dose vial is intended for single use only.

{ "type": "p", "children": [], "text": "Baclofen injection does not contain any antioxidants, preservatives or other potentially neurotoxic additives. Each single-dose vial is intended for single use only." }

Discard any unused portion.

{ "type": "p", "children": [], "text": "Discard any unused portion." }

Does not require refrigeration.

{ "type": "p", "children": [], "text": "Does not require refrigeration." }

Do not store above 86°F (30°C).

{ "type": "p", "children": [], "text": "Do not store above 86°F (30°C)." }

Do not freeze.

{ "type": "p", "children": [], "text": "Do not freeze." }

Do not heat sterilize.

{ "type": "p", "children": [], "text": "Do not heat sterilize." }

Risks Related to Sudden Withdrawal of Baclofen Injection

{ "type": "p", "children": [], "text": "\nRisks Related to Sudden Withdrawal of Baclofen Injection\n" }

Advise patients and caregivers that sudden withdrawal of baclofen injection, regardless of the cause, can result in serious complications that include high fever, confusion, muscle stiffness, multiple organ-system failure, and death. Inform patients that early symptoms of baclofen injection withdrawal may include increased spasticity, itching, and tingling of extremities. If baclofen injection withdrawal or a pump malfunction is suspected, patients should be brought immediately to a hospital for assessment and treatment.

{ "type": "p", "children": [], "text": "Advise patients and caregivers that sudden withdrawal of baclofen injection, regardless of the cause, can result in serious complications that include high fever, confusion, muscle stiffness, multiple organ-system failure, and death. Inform patients that early symptoms of baclofen injection withdrawal may include increased spasticity, itching, and tingling of extremities. If baclofen injection withdrawal or a pump malfunction is suspected, patients should be brought immediately to a hospital for assessment and treatment." }

Inform patients and caregivers that sudden withdrawal occurs most frequently due to a delivery problem with the catheter or the pump, or failure to refill the pump on schedule. Advise patients and their caregivers to pay careful attention to infusion system alarms. Instruct patients and caregivers that if they miss their scheduled pump refill, they should immediately contact their physician to reschedule the refill before the pump runs out of drug.

{ "type": "p", "children": [], "text": "Inform patients and caregivers that sudden withdrawal occurs most frequently due to a delivery problem with the catheter or the pump, or failure to refill the pump on schedule. Advise patients and their caregivers to pay careful attention to infusion system alarms. Instruct patients and caregivers that if they miss their scheduled pump refill, they should immediately contact their physician to reschedule the refill before the pump runs out of drug." }

Baclofen Injection Overdose

{ "type": "p", "children": [], "text": "\nBaclofen Injection Overdose\n" }

Inform patients and their caregivers that baclofen injection overdose may occur suddenly or insidiously, and that symptoms may include confusion, drowsiness, lightheadedness, dizziness, slow or shallow breathing, seizures, loss of muscle tone, loss of consciousness, and coma. If an overdose appears likely, patients should be brought immediately to a hospital for assessment and possible emptying of the pump.

{ "type": "p", "children": [], "text": "Inform patients and their caregivers that baclofen injection overdose may occur suddenly or insidiously, and that symptoms may include confusion, drowsiness, lightheadedness, dizziness, slow or shallow breathing, seizures, loss of muscle tone, loss of consciousness, and coma. If an overdose appears likely, patients should be brought immediately to a hospital for assessment and possible emptying of the pump." }

Operation of Automobiles and Other Dangerous Machinery

{ "type": "p", "children": [], "text": "\nOperation of Automobiles and Other Dangerous Machinery\n" }

Advise patients that baclofen injection may cause drowsiness, and that they should exercise caution regarding the operation of automobiles or other dangerous machinery, or activities made hazardous by decreased alertness. Increased Risk of Drowsiness with Alcohol and Other CNS Depressants Inform patients and their caregivers that the drowsiness associated with baclofen injection use can be worsened by alcohol and other CNS depressants. Advise patients to read all medicine labels carefully, and to tell their physician about all prescription and nonprescription drugs they may use.

{ "type": "p", "children": [], "text": "Advise patients that baclofen injection may cause drowsiness, and that they should exercise caution regarding the operation of automobiles or other dangerous machinery, or activities made hazardous by decreased alertness. Increased Risk of Drowsiness with Alcohol and Other CNS Depressants Inform patients and their caregivers that the drowsiness associated with baclofen injection use can be worsened by alcohol and other CNS depressants. Advise patients to read all medicine labels carefully, and to tell their physician about all prescription and nonprescription drugs they may use." }

Distributed by:

{ "type": "p", "children": [], "text": "Distributed by:" }

Nexus Pharmaceuticals, LLC

{ "type": "p", "children": [], "text": "Nexus Pharmaceuticals, LLC" }

Lincolnshire, IL 60069

{ "type": "p", "children": [], "text": "Lincolnshire, IL 60069" }

Made in India

{ "type": "p", "children": [], "text": "Made in India" }

Revision: 12/2024

{ "type": "p", "children": [], "text": "Revision: 12/2024" }

BACPI01INR02

{ "type": "p", "children": [], "text": "BACPI01INR02" }

Baclofen Injection 4,000 mcg per mL - NDC 14789-161-05 - Single-Dose Vial Carton

{ "type": "p", "children": [], "text": "\nBaclofen Injection 4,000 mcg per mL - NDC 14789-161-05 - Single-Dose Vial Carton\n" }

Baclofen Injection 4,000 mcg per mL - NDC 14789-161-07 - Single-Dose Vial Label

{ "type": "p", "children": [], "text": "\nBaclofen Injection 4,000 mcg per mL - NDC 14789-161-07 - Single-Dose Vial Label\n" }

Baclofen is indicated for the treatment of spasticity resulting from multiple sclerosis, particularly for the relief of flexor spasms and concomitant pain, clonus, and muscular rigidity.

{ "type": "p", "children": [], "text": "Baclofen is indicated for the treatment of spasticity resulting from multiple sclerosis, particularly for the relief of flexor spasms and concomitant pain, clonus, and muscular rigidity." }

Baclofen may also be of some value in patients with spinal cord injuries and other spinal cord diseases.

{ "type": "p", "children": [], "text": "Baclofen may also be of some value in patients with spinal cord injuries and other spinal cord diseases." }

Limitations of Use

{ "type": "p", "children": [], "text": "\nLimitations of Use\n" }

Baclofen is not indicated in the treatment of skeletal muscle spasm resulting from rheumatic disorders.

{ "type": "p", "children": [], "text": "Baclofen is not indicated in the treatment of skeletal muscle spasm resulting from rheumatic disorders." }

Baclofen is a concentrated formulation. Verify the strength and the dose of the product prior to prescribing, dispensing, and administering.

Initiate baclofen with a low dosage, preferably in divided doses, administered orally. The following gradually increasing dosage regimen is suggested, but should be adjusted based on clinical response and tolerability:

1 mL (5 mg) three times a day for three days 2 mL (10 mg) three times a day for three days 3 mL (15 mg) three times a day for three days 4 mL (20 mg) three times a day for three days

Additional increases may be necessary up to the maximum recommended dosage of 80 mg daily [4 mL (20 mg) four times a day].

Shake well baclofen oral suspension before administration. Discard unused portion 2 months after first opening.

A calibrated measuring device is recommended to measure and deliver the prescribed dose accurately. A household teaspoon or tablespoon is not an adequate measuring device.

Nasogastric Tube Administration

Baclofen oral suspension can be administered via a nasogastric (NG) tube at sizes 8 French or larger using the following steps:

When discontinuing baclofen, reduce the dosage slowly and avoid abrupt withdrawn from the drug to help minimize the risk of adverse reactions [see Warnings and Precautions ( 5.1)] .

Oral Suspension: 25 mg per 5 mL (5 mg/mL) baclofen as a concentrated orange to yellow- colored, grape-flavored suspension.

{ "type": "p", "children": [], "text": "Oral Suspension: 25 mg per 5 mL (5 mg/mL) baclofen as a concentrated orange to yellow- colored, grape-flavored suspension." }

Baclofen oral suspension is contraindicated in patients with hypersensitivity to baclofen.

{ "type": "p", "children": [], "text": "Baclofen oral suspension is contraindicated in patients with hypersensitivity to baclofen." }

Abrupt discontinuation of baclofen, regardless of the cause, has resulted in adverse reactions that include hallucinations, seizures, 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. Therefore, reduce the dosage slowly when baclofen is discontinued, unless the clinical situation justifies a rapid withdrawal.

Withdrawal symptoms in neonates whose mothers were treated with oral baclofen throughout pregnancy have been reported starting hours to days after delivery. The symptoms of withdrawal in these infants have included increased muscle tone, tremor, jitteriness, and seizure. If the potential benefit justifies the potential risk to the fetus and baclofen is continued during pregnancy, gradually reduce the dosage and discontinue baclofen before delivery. If slow withdrawal is not feasible, advise the parents or caregivers of the exposed neonate of the potential for neonatal withdrawal.

Drowsiness and sedation have been reported in up to 63% of patients taking baclofen, the active ingredient in baclofen [see Adverse Reactions ( 6.1)] . Patients should avoid operation of automobiles or other dangerous machinery and activities made hazardous by decreased alertness when starting baclofen or increasing the dose until they know how the drug affects them. Advise patients that the central nervous system depressant effects of baclofen may be additive to those of alcohol and other CNS depressants.

Baclofen should be used with caution in patients who have had a stroke. Baclofen has not significantly benefited patients with stroke. These patients have also shown poor tolerability to the drug.

Baclofen should be used with caution in patients suffering from psychotic disorders, schizophrenia, or confusional states. If treated with baclofen, these patients should be kept under careful surveillance because exacerbations of these conditions have been observed with oral baclofen administration.

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

Baclofen should be used with caution in patients with epilepsy. Deterioration in seizure control has been reported in patients taking baclofen.

Baclofen should be used with caution in patients where spasticity is utilized to sustain upright posture and balance in locomotion or whenever spasticity is utilized to obtain increased function.

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.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The most common adverse reaction is transient drowsiness. In one controlled study of 175 patients, transient drowsiness was observed in 63% of those receiving baclofen compared to 36% of those in the placebo group. Other common adverse reactions (up to 15%) are dizziness and weakness. Adverse reactions with a frequency of ≥1% are listed in Table 1.

<div class="scrollingtable"><table cellpadding="3.6pt" width="50%"> <caption> <span>Table 1. Common (≥1%) Adverse Reactions in Patients Treated with Baclofen for Spasticity</span> </caption> <col width="28%"/> <col width="28%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule" valign="top"> <p class="First"> <span class="Bold">ADVERSE REACTION</span> </p> </td><td class="Botrule" valign="top"> <p class="First"> <span class="Bold">PERCENT</span> </p> </td> </tr> <tr> <td class="Toprule" valign="top"> <p class="First">Drowsiness</p> </td><td class="Toprule" valign="top"> <p class="First">10-63%</p> </td> </tr> <tr> <td valign="top"> <p class="First">Dizziness</p> </td><td valign="top"> <p class="First">5-15%</p> </td> </tr> <tr> <td valign="top"> <p class="First">Weakness</p> </td><td valign="top"> <p class="First">5-15%</p> </td> </tr> <tr> <td valign="top"> <p class="First">Nausea</p> </td><td valign="top"> <p class="First">4-12%</p> </td> </tr> <tr> <td valign="top"> <p class="First">Confusion</p> </td><td valign="top"> <p class="First">1-11%</p> </td> </tr> <tr> <td valign="top"> <p class="First">Hypotension</p> </td><td valign="top"> <p class="First">0-9%</p> </td> </tr> <tr> <td valign="top"> <p class="First">Headache</p> </td><td valign="top"> <p class="First">4-8%</p> </td> </tr> <tr> <td valign="top"> <p class="First">Insomnia</p> </td><td valign="top"> <p class="First">2-7%</p> </td> </tr> <tr> <td valign="top"> <p class="First">Constipation</p> </td><td valign="top"> <p class="First">2-6%</p> </td> </tr> <tr> <td valign="top"> <p class="First">Urinary Frequency</p> </td><td valign="top"> <p class="First">2-6%</p> </td> </tr> <tr class="Last"> <td valign="top"> <p class="First">Fatigue</p> </td><td valign="top"> <p class="First">2-4%</p> </td> </tr> </tbody> </table></div>

The following adverse reactions not included in Table 1, classified by body system, were also reported:

Neuropsychiatric:euphoria, excitement, depression, hallucinations, paresthesia, muscle pain, tinnitus, slurred speech, coordination disorder, tremor, rigidity, dystonia, ataxia, blurred vision, nystagmus, strabismus, miosis, mydriasis, diplopia, dysarthria, epileptic seizure

Cardiovascular:dyspnea, palpitation, chest pain, syncope

Gastrointestinal:dry mouth, anorexia, taste disorder, abdominal pain, vomiting, diarrhea, and positive test for occult blood in stool

Genitourinary:enuresis, urinary retention, dysuria, impotence, inability to ejaculate, nocturia, hematuria

Other:rash, pruritus, ankle edema, excessive perspiration, weight gain, nasal congestion

The following laboratory tests have been found to be abnormal in patients receiving baclofen: increased SGOT, elevated alkaline phosphatase, and elevation of blood sugar.

Baclofen can cause CNS depression, including drowsiness and sedation, which may be additive when used concomitantly with other CNS depressants or alcohol [see Warnings and Precautions ( 5.3)] .

There are no adequate data on the risk of major birth defects, miscarriages, or other maternal adverse outcomes associated with the use of baclofen in pregnant women. There are adverse effects on fetal outcomes associated with withdrawal from baclofen after delivery (see Clinical Considerations) . Oral administration of baclofen to pregnant rats resulted in an increased incidence of fetal structural abnormalities at a dose that was also associated with maternal toxicity. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Fetal/Neonatal Adverse Reactions

Baclofen may increase the risk of late-onset neonatal withdrawal symptoms [see Warnings and Precautions ( 5.2)] .

Animal Data

Baclofen given orally has been shown to increase the incidence of omphaloceles (ventral hernias) in fetuses of rats given approximately 13 times on a mg/kg basis, or 3 times on a mg/m 2basis, the maximum oral dose recommended for human use; this dose also caused reductions in food intake and weight gain in the dams. This abnormality was not seen in mice or rabbits.

At recommended oral doses, baclofen is present in human milk. There are no human data on the effects of baclofen on milk production. Withdrawal symptoms can occur in breastfed infants when maternal administration of baclofen is stopped, or when breastfeeding is stopped [see Warnings and Precautions ( 5.2)] . There are no adequate data on other effects of baclofen on the breastfed infant.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for baclofen and any potential adverse effects on the breastfed infant from baclofen or from the underlying maternal condition.

Safety and effectiveness in pediatric patients below the age of 12 have not been established.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Use in Specific Populations ( 8.6)] .

Because baclofen is primarily excreted unchanged through the kidneys, baclofen should be given with caution to patients with renal impairment, and it may be necessary to reduce the dosage.

With overdose of baclofen, patients may present in coma or with progressive drowsiness, lightheadedness, dizziness, somnolence, accommodation disorders, respiratory depression, seizures, or hypotonia progressing to loss of consciousness.

The treatment of baclofen overdose includes gastric decontamination, maintaining an adequate airway and respirations.

Baclofen oral suspension is a gamma-aminobutyric acid (GABA-ergic) agonist available as 25 mg per 5 mL (5 mg/mL) suspension for oral administration. Its chemical name is 4-amino-3-(4-chlorophenyl)-butanoic acid, and its structural formula is:

{ "type": "p", "children": [], "text": "Baclofen oral suspension is a gamma-aminobutyric acid (GABA-ergic) agonist available as 25 mg per 5 mL (5 mg/mL) suspension for oral administration. Its chemical name is 4-amino-3-(4-chlorophenyl)-butanoic acid, and its structural formula is:" }

Molecular formula is C 10H 12C1NO 2. Molecular Weight is 213.66 g/mol.

{ "type": "p", "children": [], "text": "Molecular formula is C\n \n 10H\n \n 12C1NO\n \n 2. \n Molecular Weight is 213.66 g/mol.\n\n " }

Baclofen USP is a white to off-white, odorless or practically odorless crystalline powder. It is slightly soluble in water, very slightly soluble in methanol, and insoluble in chloroform.

{ "type": "p", "children": [], "text": "Baclofen USP is a white to off-white, odorless or practically odorless crystalline powder. It is slightly soluble in water, very slightly soluble in methanol, and insoluble in chloroform." }

The baclofen oral suspension inactive ingredients are: artificial grape flavor, citric acid anhydrous, D&C yellow No. 10, FD&C red No. 40, hydroxyethyl cellulose, propylene glycol, purified water, simethicone emulsion, sodium benzoate, and sucralose.

{ "type": "p", "children": [], "text": "The baclofen oral suspension inactive ingredients are: artificial grape flavor, citric acid anhydrous, D&C yellow No. 10, FD&C red No. 40, hydroxyethyl cellulose, propylene glycol, purified water, simethicone emulsion, sodium benzoate, and sucralose." }

The precise mechanism of action of baclofen is not fully understood. Baclofen inhibits both monosynaptic and polysynaptic reflexes at the spinal level, possibly by decreasing excitatory neurotransmitter release from afferent terminals, although actions at supraspinal sites may also occur and contribute to its clinical effect. Baclofen is a structural analog of the inhibitory neurotransmitter gamma- aminobutyric acid (GABA) and may exert its effects by stimulation of the GABA Breceptor subtype.

Baclofen has been shown to have general CNS depressant properties, as indicated by the production of sedation with tolerance, somnolence, ataxia, and respiratory and cardiovascular depression [see Warnings and Precautions ( 5.3), Adverse Reactions ( 6.1), and Overdosage ( 10.1)] .

A pharmacokinetic study in heathy adult male and female subjects under fasting conditions at 20 mg dose level demonstrated similar bioavailability for baclofen oral suspension and oral tablets.

Absorption

The peak plasma concentrations of baclofen were achieved in about 1 hour from administration of baclofen oral suspension in the fasted state, and the apparent elimination half-life is about 5.6 hours.

Effect of Food

Administration of baclofen with a high-fat meal resulted in 9% decrease in AUC and 33% decrease in C maxcompared to the fasted state.

Elimination

Baclofen is excreted primarily by the kidney in unchanged form, and there is relatively large intersubject variation in absorption and/or elimination.

Carcinogenesis

No increase in tumors was seen in rats receiving baclofen orally for two years at approximately 30 to 60 times on a mg/kg basis, or 10 to 20 times on a mg/m 2basis, the maximum oral dose recommended for human use.

Mutagenesis

Genetic toxicology assays have not been conducted for baclofen.

Impairment of Fertility

Studies to evaluate the effects of baclofen on fertility have not been conducted.

The efficacy of baclofen is based upon a bioavailability study in healthy adults comparing baclofen oral tablets to baclofen [see Clinical Pharmacology ( 12.3)] .

{ "type": "p", "children": [], "text": "The efficacy of baclofen is based upon a bioavailability study in healthy adults comparing baclofen oral tablets to baclofen\n \n [see Clinical Pharmacology (\n \n 12.3)]\n \n .\n\n " }

16.1 How Supplied Baclofen oral suspension contains 25 mg per 5 mL (5 mg/mL) baclofen. It is a concentrated orange to yellow-colored, grape-flavored suspension and is supplied in high-density polyethylene (HDPE) bottles with white, polypropylene, child-resistant closures with a foam liner and heat induction layered inner seal.

{ "type": "p", "children": [], "text": "\n16.1 How Supplied\nBaclofen oral suspension contains 25 mg per 5 mL (5 mg/mL) baclofen. It is a concentrated orange to yellow-colored, grape-flavored suspension and is supplied in high-density polyethylene (HDPE) bottles with white, polypropylene, child-resistant closures with a foam liner and heat induction layered inner seal." }

{ "type": "ul", "children": [ "NDC 72162-2342-2: 120 mL in a BOTTLE", "NDC 72162-2342-4: 300 mL in a BOTTLE" ], "text": "" }

16.2 Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15° and 30° (59° and 86° F) (see USP Controlled Room Temperature).

{ "type": "p", "children": [], "text": "\n16.2 Storage and Handling\nStore at 20°C to 25°C (68°F to 77°F); excursions permitted between 15° and 30° (59° and 86° F) (see USP Controlled Room Temperature)." }

Discard unused portion 2 months after first opening.

{ "type": "p", "children": [], "text": "Discard unused portion 2 months after first opening." }

Repackaged/Relabeled by:Bryant Ranch Prepack, Inc.Burbank, CA 91504

{ "type": "p", "children": [], "text": "Repackaged/Relabeled by:Bryant Ranch Prepack, Inc.Burbank, CA 91504" }

Administration Instructions

{ "type": "p", "children": [], "text": "\nAdministration Instructions\n" }

Inform patients that baclofen is a concentrated formulation. Instruct patients or caregivers to use an oral dosing syringe and not to use a household teaspoon to correctly measure the prescribed amount of medication. Inform patients that oral dosing syringes may be obtained from their pharmacy. Instruct patients to shake before using [see Dosage and Administration ( 2.1, 2.3)] .

{ "type": "p", "children": [], "text": "Inform patients that baclofen is a concentrated formulation. Instruct patients or caregivers to use an oral dosing syringe and not to use a household teaspoon to correctly measure the prescribed amount of medication. Inform patients that oral dosing syringes may be obtained from their pharmacy. Instruct patients to shake before using\n \n [see Dosage and Administration (\n \n 2.1,\n \n 2.3)]\n \n .\n\n " }

Risks Related to Sudden Withdrawal of Baclofen

{ "type": "p", "children": [], "text": "\nRisks Related to Sudden Withdrawal of Baclofen\n" }

Advise patients and caregivers not to discontinue use of baclofen without consulting with their healthcare provider because sudden withdrawal of baclofen can result in serious complications that include hallucinations, seizures, high fever, confusion, muscle stiffness, multiple organ-system failure, and death [see Warnings and Precautions ( 5.1)] . Inform patients that early symptoms of baclofen withdrawal may include increased spasticity, itching, and tingling of extremities.

{ "type": "p", "children": [], "text": "Advise patients and caregivers not to discontinue use of baclofen without consulting with their healthcare provider because sudden withdrawal of baclofen can result in serious complications that include hallucinations, seizures, high fever, confusion, muscle stiffness, multiple organ-system failure, and death\n \n [see Warnings and Precautions (\n \n 5.1)]\n \n . Inform patients that early symptoms of baclofen withdrawal may include increased spasticity, itching, and tingling of extremities.\n\n " }

Neonatal Withdrawal Symptoms

{ "type": "p", "children": [], "text": "\nNeonatal Withdrawal Symptoms\n" }

Advise patients to notify their healthcare provider if they are pregnant, plan to become pregnant, or plan to breastfeed [see Warnings and Precautions ( 5.2) and Use in Specific Populations ( 8.2)] .

{ "type": "p", "children": [], "text": "Advise patients to notify their healthcare provider if they are pregnant, plan to become pregnant, or plan to breastfeed\n \n [see Warnings and Precautions (\n \n 5.2) and Use in Specific Populations (\n \n 8.2)]\n \n .\n\n " }

Increased Risk of Drowsiness with Alcohol and Other CNS Depressants

{ "type": "p", "children": [], "text": "\nIncreased Risk of Drowsiness with Alcohol and Other CNS Depressants\n" }

Advise patients that baclofen may cause drowsiness, and that they should avoid the operation of automobiles or other dangerous machinery, or activities made hazardous by decreased alertness when starting baclofen or increasing the dose until they know how the drug affects them [see Warnings and Precautions ( 5.3)] . Inform patients and their caregivers that the drowsiness associated with baclofen use can be worsened by alcohol and other CNS depressants. Advise patients to read all medicine labels carefully, and to tell their healthcare provider about all prescription and nonprescription drugs they may use.

{ "type": "p", "children": [], "text": "Advise patients that baclofen may cause drowsiness, and that they should avoid the operation of automobiles or other dangerous machinery, or activities made hazardous by decreased alertness when starting baclofen or increasing the dose until they know how the drug affects them\n \n [see Warnings and Precautions (\n \n 5.3)]\n \n . Inform patients and their caregivers that the drowsiness associated with baclofen use can be worsened by alcohol and other CNS depressants. Advise patients to read all medicine labels carefully, and to tell their healthcare provider about all prescription and nonprescription drugs they may use.\n\n " }

Storage

{ "type": "p", "children": [], "text": "\nStorage\n" }

Instruct patients to store baclofen at room temperature and to discard unused portion 2 months after first opening [see How Supplied/Storage and Handling ( 16.2)] .

{ "type": "p", "children": [], "text": "Instruct patients to store baclofen at room temperature and to discard unused portion 2 months after first opening\n \n [see How Supplied/Storage and Handling (\n \n 16.2)]\n \n .\n\n " }

Manufactured for:

{ "type": "p", "children": [], "text": "\nManufactured for:\n" }

Wilshire Pharmaceuticals, Inc. Atlanta, GA 30328 USA

{ "type": "p", "children": [], "text": "Wilshire Pharmaceuticals, Inc. \n Atlanta, GA 30328 USA\n " }

PN: PI-00729

{ "type": "p", "children": [], "text": "PN: PI-00729" }

REV: 01

{ "type": "p", "children": [], "text": "REV: 01" }

Baclofen Oral Suspension 25 mg per 5 mL (5 mg/mL)

{ "type": "p", "children": [], "text": "\nBaclofen Oral Suspension 25 mg per 5 mL (5 mg/mL)\n" }

{ "type": "", "children": [], "text": "" }

Baclofen oral solution is indicated for the treatment of spasticity resulting from multiple sclerosis, particularly for the relief of flexor spasms and concomitant pain, clonus, and muscular rigidity.

{ "type": "p", "children": [], "text": "Baclofen oral solution is indicated for the treatment of spasticity resulting from multiple sclerosis, particularly for the relief of flexor spasms and concomitant pain, clonus, and muscular rigidity." }

Baclofen oral solution may also be of some value in patients with spinal cord injuries and other spinal cord diseases.

{ "type": "p", "children": [], "text": "Baclofen oral solution may also be of some value in patients with spinal cord injuries and other spinal cord diseases." }

Limitations of Use Baclofen oral solution is not indicated in the treatment of skeletal muscle spasm resulting from rheumatic disorders.

{ "type": "p", "children": [], "text": "\nLimitations of Use\n Baclofen oral solution is not indicated in the treatment of skeletal muscle spasm resulting from rheumatic disorders.\n\n " }

Initiate baclofen oral solution with a low dosage, preferably in divided doses, administered orally. The following gradually increasing dosage regimen is suggested, but should be adjusted based on clinical response and tolerability:

5 mL (5 mg) three times a day for three days

10 mL (10 mg) three times a day for three days

15 mL (15 mg) three times a day for three days

20 mL (20 mg) three times a day for three days

Additional increases may be necessary up to the maximum recommended dosage of 80 mg daily (20 mg four times a day).

When discontinuing baclofen oral solution, reduce the dosage slowly and avoid abrupt withdrawn from the drug to help minimize the risk of adverse reactions [see Warnings and Precautions ( 5.1)].

Oral Solution:5 mg/5 mL baclofen,USP as a clear, colorless solution with a grape flavor.

{ "type": "p", "children": [], "text": "\nOral Solution:5 mg/5 mL baclofen,USP as a clear, colorless solution with a grape flavor.\n\n " }

Baclofen oral solution is contraindicated in patients with hypersensitivity to baclofen.

{ "type": "p", "children": [], "text": "Baclofen oral solution is contraindicated in patients with hypersensitivity to baclofen." }

Abrupt discontinuation of baclofen, regardless of the cause, has resulted in adverse reactions that include hallucinations, seizures, 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. Therefore, reduce the dosage slowly when baclofen oral solution is discontinued, unless the clinical situation justifies a rapid withdrawal.

Withdrawal symptoms in neonates whose mothers were treated with oral baclofen throughout pregnancy have been reported starting hours to days after delivery. The symptoms of withdrawal in these infants have included increased muscle tone, tremor, jitteriness, and seizure. If the potential benefit justifies the potential risk to the fetus and baclofen is continued during pregnancy, gradually reduce the dosage and discontinue baclofen before delivery. If slow withdrawal is not feasible, advise the parents or caregivers of the exposed neonate of the potential for neonatal withdrawal.

Drowsiness and sedation have been reported in up to 63% of patients taking baclofen, the active ingredient in baclofen oral solution [see Adverse Reactions ( 6.1)] . Patients should avoid operation of automobiles or other dangerous machinery and activities made hazardous by decreased alertness when starting baclofen or increasing the dose until they know how the drug affects them. Advise patients that the central nervous system depressant effects of baclofen may be additive to those of alcohol and other CNS depressants.

Baclofen should be used with caution in patients who have had a stroke. Baclofen has not significantly benefited patients with stroke. These patients have also shown poor tolerability to the drug.

Baclofen should be used with caution in patients suffering from psychotic disorders, schizophrenia, or confusional states. If treated with baclofen, these patients should be kept under careful surveillance because exacerbations of these conditions have been observed with oral baclofen administration.

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

Baclofen should be used with caution in patients with epilepsy. Deterioration in seizure control has been reported in patients taking baclofen.

Baclofen should be used with caution in patients where spasticity is utilized to sustain upright posture and balance in locomotion or whenever spasticity is utilized to obtain increased function.

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.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The most common adverse reaction is transient drowsiness. In one controlled study of 175 patients, transient drowsiness was observed in 63% of those receiving baclofen compared to 36% of those in the placebo group. Other common adverse reactions (up to 15%) are dizziness and weakness. Adverse reactions with a frequency of ≥1% are listed in Table 1.

<div class="scrollingtable"><table cellpadding="5" width="60%"> <caption> <span>Table 1. Common (≥1%) Adverse Reactions in Patients Treated with Baclofen for Spasticity</span> </caption> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">ADVERSE REACTION</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">PERCENT</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Drowsiness</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">10-63%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Dizziness</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">5-15%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Weakness</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">5-15%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Nausea</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4-12%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Confusion</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1-11%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Hypotension</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0-9%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Headache</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4-8%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Insomnia</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2-7%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Constipation</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2-6%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Urinary Frequency</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2-6%</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Fatigue</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2-4%</p> </td> </tr> </tbody> </table></div>

The following adverse reactions not included in Table 1, classified by body system, were also reported:

Neuropsychiatric:euphoria, excitement, depression, hallucinations, paresthesia, muscle pain, tinnitus, slurred speech, coordination disorder, tremor, rigidity, dystonia, ataxia, blurred vision, nystagmus, strabismus, miosis, mydriasis, diplopia, dysarthria, epileptic seizure

Cardiovascular:dyspnea, palpitation, chest pain, syncope

Gastrointestinal:dry mouth, anorexia, taste disorder, abdominal pain, vomiting, diarrhea, and positive test for occult blood in stool

Genitourinary:enuresis, urinary retention, dysuria, impotence, inability to ejaculate, nocturia, hematuria

Other:rash, pruritus, ankle edema, excessive perspiration, weight gain, nasal congestion

The following laboratory tests have been found to be abnormal in patients receiving baclofen: increased SGOT, elevated alkaline phosphatase, and elevation of blood sugar.

Baclofen can cause CNS depression, including drowsiness and sedation, which may be additive when used concomitantly with other CNS depressants or alcohol [see Warnings and Precautions ( 5.3)].

Risk Summary There are no adequate data on the developmental risk associated with the use of baclofen in pregnant women. Oral administration of baclofen to pregnant rats resulted in an increased incidence of fetal structural abnormalities at a dose which was also associated with maternal toxicity. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations Fetal/Neonatal adverse reactions Baclofen oral solution may increase the risk of late-onset neonatal withdrawal symptoms [see Warnings and Precautions ( 5.2)] .

Data

Animal Data Baclofen given orally has been shown to increase the incidence of omphaloceles (ventral hernias) in fetuses of rats given approximately 13 times on a mg/kg basis, or 3 times on a mg/m 2basis, the maximum oral dose recommended for human use; this dose also caused reductions in food intake and weight gain in the dams. This abnormality was not seen in mice or rabbits.

Risk Summary At recommended oral doses, baclofen is present in human milk. There are no human data on the effects of baclofen on milk production. There are no adequate data on the effects of baclofen on the breastfed infant. Withdrawal symptoms can occur in breastfed infants when maternal administration of baclofen is stopped, or when breastfeeding is stopped [see Warnings and Precautions ( 5.2)] .

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for baclofen and any potential adverse effects on the breastfed infant from baclofen or from the underlying maternal condition.

Safety and effectiveness in pediatric patients below the age of 12 have not been established.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Because baclofen is primarily excreted unchanged through the kidneys, baclofen should be given with caution to patients with renal impairment, and it may be necessary to reduce the dosage.

Patients may present in coma or with progressive drowsiness, lightheadedness, dizziness, somnolence, accommodation disorders, respiratory depression, seizures, or hypotonia progressing to loss of consciousness.

The treatment of baclofen overdose includes gastric decontamination, maintaining an adequate airway and respirations.

Baclofen is a gamma-aminobutyric acid (GABA-ergic) agonist available as 5 mg/5 mL solution for oral administration. Its chemical name is 4-amino-3-(4-chlorophenyl)-butanoic acid, and its structural formula is:

{ "type": "p", "children": [], "text": "Baclofen is a gamma-aminobutyric acid (GABA-ergic) agonist available as 5 mg/5 mL solution for oral administration. Its chemical name is 4-amino-3-(4-chlorophenyl)-butanoic acid, and its structural formula is:" }

Molecular formula is C 10H 12CINO 2.

{ "type": "p", "children": [], "text": "Molecular formula is C\n \n 10H\n \n 12CINO\n \n 2.\n\n " }

Molecular Weight is 213.66.

{ "type": "p", "children": [], "text": "Molecular Weight is 213.66." }

Baclofen, USP is a white to off-white, odorless or practically odorless crystalline powder. It is slightly soluble in water, very slightly soluble in methanol, and insoluble in chloroform.

{ "type": "p", "children": [], "text": "Baclofen, USP is a white to off-white, odorless or practically odorless crystalline powder. It is slightly soluble in water, very slightly soluble in methanol, and insoluble in chloroform." }

The inactive ingredients of baclofen oral solution are: carboxymethyl cellulose sodium, glycerin, grape flavor NAT & ART, methylparaben, propylparaben, purified water, and sucralose. May also contain sodium hydroxide or hydrochloric acid for pH adjustment.

{ "type": "p", "children": [], "text": "The inactive ingredients of baclofen oral solution are: carboxymethyl cellulose sodium, glycerin, grape flavor NAT & ART, methylparaben, propylparaben, purified water, and sucralose. May also contain sodium hydroxide or hydrochloric acid for pH adjustment." }

The precise mechanism of action of baclofen is not fully understood. Baclofen inhibits both monosynaptic and polysynaptic reflexes at the spinal level, possibly by decreasing excitatory neurotransmitter release from afferent terminals, although actions at supraspinal sites may also occur and contribute to its clinical effect. Baclofen is a structural analog of the inhibitory neurotransmitter gamma- aminobutyric acid (GABA), and may exert its effects by stimulation of the GABA Breceptor subtype.

Baclofen has been shown to have general CNS depressant properties, as indicated by the production of sedation with tolerance, somnolence, ataxia, and respiratory and cardiovascular depression [see Warnings and Precautions ( 5.3), Adverse Reactions ( 6.1), and Overdosage ( 10.1)].

A pharmacokinetic study in heathy adult male subjects under fasting conditions at 20 mg dose level demonstrated similar bioavailability for baclofen oral solution and oral tablets. The peak plasma concentrations were achieved in about 0.75 hours from oral solution and the apparent elimination half-life is about 5.7 hours. Baclofen is excreted primarily by the kidney in unchanged form, and there is relatively large intersubject variation in absorption and/or elimination.

Carcinogenesis

No increase in tumors was seen in rats receiving baclofen orally for two years at approximately 30 to 60 times on a mg/kg basis, or 10 to 20 times on a mg/m 2basis, the maximum oral dose recommended for human use.

Mutagenesis

Genetic toxicology assays have not been conducted for baclofen.

Impairment of Fertility

Studies to evaluate the effects of baclofen on fertility have not been conducted.

The efficacy of baclofen is based upon a bioavailability study in healthy adults comparing baclofen oral tablets to baclofen oral solution [see Clinical Pharmacology ( 12.3)].

{ "type": "p", "children": [], "text": "The efficacy of baclofen is based upon a bioavailability study in healthy adults comparing baclofen oral tablets to baclofen oral solution\n \n [see Clinical Pharmacology (\n \n 12.3)].\n \n \n" }

Baclofen Oral Solution contains 5 mg/5 mL baclofen, USP. It is a clear, colorless solution with a grape flavor and is supplied in bottles of 473 mL, NDC 72888-103-24.

Store at 20º to 25ºC (68º to 77ºF); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Product can also be stored at 2°C to 8°C (36°F to 46°F).

Dispense in a tight, light-resistant container with a child-resistant closure.

Administration Instructions

{ "type": "p", "children": [], "text": "\nAdministration Instructions\n" }

Instruct patients or caregivers to use an oral dosing syringe to correctly measure the prescribed amount of medication. Inform patients that oral dosing syringes may be obtained from their pharmacy.

{ "type": "p", "children": [], "text": "Instruct patients or caregivers to use an oral dosing syringe to correctly measure the prescribed amount of medication. Inform patients that oral dosing syringes may be obtained from their pharmacy." }

Risks Related to Sudden Withdrawal of Baclofen Oral Solution

{ "type": "p", "children": [], "text": "\nRisks Related to Sudden Withdrawal of Baclofen Oral Solution\n" }

Advise patients and caregivers not to discontinue use of baclofen oral solution without consulting with their healthcare provider because sudden withdrawal of baclofen oral solution can result in serious complications that include hallucinations, seizures, high fever, confusion, muscle stiffness, multiple organ-system failure, and death [see Warnings and Precautions ( 5.1)]. Inform patients that early symptoms of baclofen oral solution withdrawal may include increased spasticity, itching, and tingling of extremities.

{ "type": "p", "children": [], "text": "Advise patients and caregivers not to discontinue use of baclofen oral solution without consulting with their healthcare provider because sudden withdrawal of baclofen oral solution can result in serious complications that include hallucinations, seizures, high fever, confusion, muscle stiffness, multiple organ-system failure, and death\n \n [see Warnings and Precautions (\n \n 5.1)].\n \n Inform patients that early symptoms of baclofen oral solution withdrawal may include increased spasticity, itching, and tingling of extremities.\n\n " }

Neonatal Withdrawal Symptoms

{ "type": "p", "children": [], "text": "\nNeonatal Withdrawal Symptoms\n" }

Advise patients to notify their healthcare provider if they are pregnant, plan to become pregnant, or plan to breastfeed [see Warnings and Precautions ( 5.2) and Use in Specific Populations ( 8.2)].

{ "type": "p", "children": [], "text": "Advise patients to notify their healthcare provider if they are pregnant, plan to become pregnant, or plan to breastfeed\n \n [see Warnings and Precautions (\n \n 5.2) and Use in Specific Populations (\n \n 8.2)].\n \n \n" }

Increased Risk of Drowsiness with Alcohol and Other CNS Depressants

{ "type": "p", "children": [], "text": "\nIncreased Risk of Drowsiness with Alcohol and Other CNS Depressants\n" }

Advise patients that baclofen oral solution may cause drowsiness, and that they should avoid the operation of automobiles or other dangerous machinery, or activities made hazardous by decreased alertness when starting baclofen oral solution or increasing the dose until they know how the drug affects them [see Warnings and Precautions ( 5.3)]. Inform patients and their caregivers that the drowsiness associated with baclofen use can be worsened by alcohol and other CNS depressants. Advise patients to read all medicine labels carefully, and to tell their healthcare provider about all prescription and nonprescription drugs they may use.

{ "type": "p", "children": [], "text": "Advise patients that baclofen oral solution may cause drowsiness, and that they should avoid the operation of automobiles or other dangerous machinery, or activities made hazardous by decreased alertness when starting baclofen oral solution or increasing the dose until they know how the drug affects them\n \n [see Warnings and Precautions (\n \n 5.3)].\n \n Inform patients and their caregivers that the drowsiness associated with baclofen use can be worsened by alcohol and other CNS depressants. Advise patients to read all medicine labels carefully, and to tell their healthcare provider about all prescription and nonprescription drugs they may use.\n\n " }

Storage

{ "type": "p", "children": [], "text": "\nStorage\n" }

Instruct patients to store baclofen oral solution at room temperature. Product can also be stored in the refrigerator. [see How Supplied/Storage and Handling ( 16.2)].

{ "type": "p", "children": [], "text": "Instruct patients to store baclofen oral solution at room temperature. Product can also be stored in the refrigerator.\n \n [see How Supplied/Storage and Handling (\n \n 16.2)].\n \n \n" }

All trademarks are the property of their respective owners.

{ "type": "p", "children": [], "text": "All trademarks are the property of their respective owners." }

Distributed by:

{ "type": "p", "children": [], "text": "\nDistributed by:\n" }

Advagen Pharma Ltd.,

{ "type": "p", "children": [], "text": "Advagen Pharma Ltd.," }

East Windsor, NJ 08520, USA

{ "type": "p", "children": [], "text": "East Windsor, NJ 08520, USA" }

Revision: 06/2025

{ "type": "p", "children": [], "text": "Revision: 06/2025" }

BACLOFEN ORAL SOLUTION 16 FL.OZ. (473ml) - NDC 72888-103-24 - Label

{ "type": "p", "children": [], "text": "\nBACLOFEN ORAL SOLUTION 16 FL.OZ. (473ml) - NDC 72888-103-24 - Label\n" }