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UPSHER SMITH LA
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00832102400

baclofen 10 mg tablet

Generic
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Uses

Spasticity

Baclofen is used orally in the management of spasticity and its sequelae secondary to severe chronic disorders such as multiple sclerosis and other types of spinal cord lesions. For the drug to be beneficial, patients must have presumably reversible spasticity where relief of spasticity will aid in restoring residual function. In these patients, baclofen decreases the number and severity of spasms (particularly flexor spasms); alleviates associated pain, clonus, and muscle rigidity; and improves mobility to a greater extent than does placebo. In patients with multiple sclerosis, the drug produces little improvement in residual muscle function, but patient comfort is improved when the painful spasms are reversible. In one uncontrolled study, less than one-third of multiple sclerosis patients with urinary retention caused by bladder spasm showed decrease in urinary retention.

In studies comparing doses of about 60 mg of baclofen daily to 30 mg of diazepam daily in patients with multiple sclerosis or spinal cord lesions, the drugs were equally effective in reducing the number and severity of muscle spasms; however, baclofen produced a lower incidence of sedation than did diazepam. There are no published studies comparing the efficacy of baclofen and dantrolene; baclofen may cause less severe adverse effects than does dantrolene. Some clinicians consider baclofen to be the treatment of choice for muscle spasm in patients with multiple sclerosis or spinal cord lesions and diazepam to be the drug of second choice. Either drug usually is preferable to intrathecal injection of sclerosing agents (e.g., phenol, dilute alcohol), rhizotomy, or chordotomy.

Baclofen crosses the blood-brain barrier in only small amounts following oral administration. It has been suggested that administration of the drug at the spinal cord level (i.e., intrathecally) would increase drug efficacy while decreasing the dosage required and possibly the toxicity profile in patients with spasticity of spinal cord origin. While baclofen may be effective at relatively high oral dosages in some patients with spasticity of spinal cord origin, many other patients, particularly those with severe spasticity, do not respond adequately to and/or do not tolerate such therapy. Therefore, intrathecal baclofen may be a suitable alternative to ablative surgical or chemical procedures in patients who do not tolerate or respond adequately to oral therapy with the drug. (See Uses: Severe Spasticity.)

Severe Spasticity

Baclofen usually is used intrathecally in the management of severe spasticity of spinal cord origin in patients who do not tolerate or respond adequately to oral therapy with the drug. Baclofen also is used intrathecally in the management of intractable spasticity secondary to severe chronic disorders such as multiple sclerosis and other types of spinal diseases such as spinal ischemia, spinal tumor, transverse myelitis, cervical spondylosis, and degenerative myelopathy. Baclofen is designated an orphan drug by the FDA for use in these conditions. The clinical goal of such therapy is to maintain muscle tone as close to normal as possible and to minimize the frequency and severity of spasms without inducing intolerable adverse effects. In controlled studies in patients with severe spasticity and spasms secondary to spinal cord injury or multiple sclerosis, single doses or 3-day continuous infusions of intrathecal baclofen were more effective than placebo in improving the Ashworth (rigidity) rating of spasticity and in reducing the frequency of spasms. During chronic intrathecal baclofen therapy, many patients experience improvement in activities associated with daily living, especially in self-care, transferring, bowel function, and urinary continence.

Baclofen also is used intrathecally in patients with spasticity of cerebral origin, including those with cerebral palsy and acquired brain injury. Baclofen injection is designated an orphan drug by the FDA for the management of spasticity in patients with cerebral palsy. The clinical goal of such therapy is to maintain muscle tone as close to normal as possible and to minimize the frequency and severity of spasms without inducing intolerable adverse effects or to titrate dosage of baclofen to the desired degree of muscle tone for optimal function. Results of one randomized, controlled, crossover study in patients with cerebral palsy indicate that intrathecal baclofen was more effective than placebo in reducing spasticity as measured by the Ashworth scale. In addition, results of a small (11 patients) controlled study in patients with brain injury indicate that intrathecal baclofen was more effective than placebo in reducing spasticity.

Patients with spasticity secondary to brain injury should wait at least one year after the injury before considering long-term intrathecal baclofen therapy.

Other Uses

Baclofen has been used orally to reduce choreiform movements in patients with Huntington's chorea, to reduce rigidity in patients with parkinsonian syndrome, and to reduce spasticity in patients with cerebral lesions, cerebral palsy, or rheumatic disorders; however, the drug has not been shown to produce a substantial degree of improvement in these patients. Oral baclofen also has been used to reduce spasticity in patients with cerebrovascular stroke; however, therapy with the drug generally did not provide substantial improvement and was poorly tolerated. The manufacturer states oral baclofen is not indicated for use in patients with rheumatic disorders; use of oral baclofen also is not recommended in patients with stroke, cerebral palsy, or Parkinson's disease.

Although in one study oral baclofen reportedly improved behavior in patients with schizophrenic disorder receiving other drugs concomitantly (e.g., phenothiazines), schizophrenic behavior worsened in other patients when baclofen was used alone. Preliminary data indicate that oral baclofen has beneficial effects in the treatment of trigeminal neuralgia and may be synergistic with carbamazepine and phenytoin.

Dosage and Administration

Administration

Baclofen is administered orally or intrathecally. Abrupt discontinuance of the drug, including inadvertent discontinuance of the intrathecal infusion, should be avoided because of the risk of precipitating withdrawal. (See Cautions: Precautions and Contraindications.) For intrathecal use, baclofen is administered as an additive-free injection by direct intrathecal injection (via lumbar puncture or catheter) over a period of at least 1 minute employing barbotage or by continuous intrathecal infusion into a lumbar intrathecal space via an implantable controlled-infusion device (pump). The manufacturer's labeling should be consulted for specialized administration techniques.

In the preparation of test doses of the drug for the purposes of drug-response screening prior to initiation of chronic intrathecal baclofen therapy, 1-mL ampuls containing 50 mcg of baclofen should be used without further dilution. For maintenance therapy in patients receiving concentrations of the drug other than the commercially available strengths (i.e., 0.5 or 2 mg/mL), baclofen for injection concentrate for intrathecal administration must be diluted. The concentrate must only be diluted with sterile, preservative-free 0.9% sodium chloride injection. The specific concentration that should be used depends on the total daily dosage required and the delivery rate of the pump. The manufacturer's manual should be consulted for specific recommendations.

As with other parenteral drug products, baclofen for injection concentrate and diluted solutions of the drug should be inspected visually for particulate matter and/or discoloration prior to administration, whenever solution and container permit.

Patients receiving intrathecal baclofen therapy must be monitored closely in a fully equipped and staffed environment during the initial test for responsiveness and dosage-titration period immediately following implantation of the pump. Resuscitative equipment should be immediately available for use in case of life-threatening or intolerable adverse effects.

Dosage

Spasticity

Oral Dosage

Oral dosage of baclofen should be individualized according to the patient's requirements and response using the lowest dosage that produces optimum response. Initially, low oral dosages of the drug should be administered.

For the management of spasticity, the initial oral dosage of baclofen is 5 mg 3 times daily. Oral daily dosage may be increased by 15 mg at 3-day intervals (i.e., 5 mg 3 times daily for 3 days, then 10 mg 3 times daily for 3 days, then 15 mg 3 times daily for 3 days, then 20 mg 3 times daily for 3 days) until optimum effect is achieved (usually at dosages of 40-80 mg daily). In patients with psychiatric or brain disorders and in geriatric patients, oral dosage should be increased more gradually. In some patients, a smoother antispastic effect is obtained by administering the oral daily dosage in 4 divided doses. Some clinicians suggest that daily oral dosages of up to 150 mg are well tolerated and provide additional therapeutic benefit in some patients; however, the manufacturers state that total dosage should not exceed 80 mg daily (i.e., 20 mg 4 times daily). Some patients require 1-2 months of treatment for full benefit; however, the length of baclofen trial should be determined by the clinical state of the patient. If benefits are not evident after a reasonable trial, baclofen therapy should be discontinued by slowly reducing the daily dosage.

Severe Spasticity

Intrathecal Dosage

Prior to implantation of the controlled-infusion device (e.g., Medtronic SynchroMed pump) and initiation of chronic intrathecal baclofen therapy, the patient must exhibit a positive response (defined as a clinically important decrease in muscle tone and/or frequency and/or severity of spasms over a 4- to 8-hour observation period) to initial intrathecal baclofen test dose(s). Initially, a dose containing 50 mcg (1 mL of a 50-mcg/mL solution) of baclofen is administered into the intrathecal space by barbotage over a period of at least 1 minute. If response observed at 4-8 hours after the initial test dose is less than desired, a second injection containing 75 mcg (1.5 mL of a 50-mcg/mL solution) of baclofen may be administered 24 hours after the first dose. If response observed at 4-8 hours after the second test dose remains inadequate, a final injection containing 100 mcg (2 mL of a 50-mcg/mL solution) of baclofen may be administered 24 hours after the second dose. In pediatric patients, the initial test dose is the same as in adults (i.e., 50 mcg); however, in very small children, an initial dose of 25 mcg may be considered. Patients not responding to the 100-mcg intrathecal test dose of the drug are not considered candidates for chronic intrathecal baclofen therapy.

Following establishment of responsiveness to intrathecal baclofen and implantation of a compatible pump (e.g., SynchroMed infusion system), the initial intrathecal dose of baclofen for the management of spasticity is twice the test dose that produced a positive response with a duration not exceeding 8 hours; this dose is infused intrathecally over 24 hours. For patients in whom a positive response to the test dose persisted for longer than 8 hours, the initial intrathecal dose is the same as the test dose that produced a positive response; this dose also is infused intrathecally over 24 hours. Dosage should not be increased within 24 hours after the initial intrathecal dose (i.e., until steady state is achieved). Following the initial infusion dose in adults with spasticity of spinal cord origin, the daily dose can be increased slowly by 10-30% increments at 24-hour intervals until the desired clinical response is achieved; in pediatric patients with spasticity of spinal cord origin and adult and pediatric patients with spasticity of cerebral origin, the daily dose can be increased slowly by 5-15% increments at 24-hour intervals until the desired clinical response is achieved. If no substantive increase in response is observed with upward titration of intrathecal baclofen dosage, the function of the pump and patency of the catheter should be checked.

Adjustment of maintenance dosage often is needed during the initial months of intrathecal baclofen therapy as the patient adjusts to changes in life-style secondary to relief of spasticity. During periodic refills of the pump, the 24-hour dose may be increased by up to 10-40% or up to 5-20% in patients with spasticity of spinal cord origin or those with spasticity of cerebral origin, respectively, as necessary to maintain adequate control of symptoms. In patients who develop intolerable adverse effects, the 24-hour maintenance dose can be decreased by 10-20%. During chronic therapy, gradual increases in dosage will be required in most patients to maintain optimal response. A sudden increase in dosage requirement should suggest the possibility of pump and/or catheter malfunction (i.e., catheter kink or dislodgement). In patients with spasticity of spinal cord origin, maintenance dosage during chronic intrathecal therapy has ranged from 12-2003 mcg daily, with most patients responding adequately to 300-800 mcg daily. There is only limited experience with intrathecal baclofen dosages of 1000 mcg daily or greater in these patients. In patients with spasticity of cerebral origin, maintenance dosage during chronic intrathecal therapy has ranged from 22-1400 mcg daily, with most patients responding adequately to 90-703 mcg daily. In clinical studies in patients with spasticity of cerebral origin, only about 2% of patients required daily dosages exceeding 1000 mcg daily.

Maintenance dosage recommendations for pediatric patients are similar to those for patients with spasticity of cerebral origin. Pediatric patients younger than 12 years of age may require lower daily dosages; in clinical trials, the maintenance daily dosage averaged 274 mcg daily (range: 24-1199 mcg daily). Dosage requirements for pediatric patients older than 12 years of age does not appear to be different from that for adult patients. Determination of optimum therapy requires individual titration. The lowest possible dosage that produces optimum response should be employed.

During prolonged intrathecal baclofen therapy for spasticity, approximately 5% of patients become refractory to increasing dosages of the drug. While experience currently is insufficient to make firm recommendations regarding amelioration of such tolerance, patients occasionally have been hospitalized and subjected to a ''drug holiday'' in which intrathecal dosage was decreased gradually over a 2- to 4-week period, during which baclofen therapy was alternated with other methods of spasticity management. After a few days, sensitivity to baclofen may return and continuous intrathecal baclofen therapy may be resumed at the previously effective initial dosage.

For patients achieving relatively satisfactory relief via continuous intrathecal infusion employing an implantable pump, further benefit may be possible with more complex dosing schedules. For example, patients who commonly experience an exacerbation of spasticity at night that disrupts sleep may require a 20% increase in the hourly infusion rate; such changes should be programmed to begin approximately 2 hours before the time of desired clinical benefit.

The manual provided by the manufacturer of the implantable infusion device (i.e., pump) must be consulted for additional information, including specific instructions and precautions for programming the pump and/or refilling the reservoir. Various pumps (with different reservoir volumes) and refill kits are available; clinicians must be familiar with these products in order to select the appropriate refill kit for the particular pump in use.

Dosage in Renal Impairment

Because baclofen is excreted principally in urine as unchanged drug, it may be necessary to reduce either oral or intrathecal dosage in patients with impaired renal function.(See Cautions: Precautions and Contraindications.)

Cautions

Adverse Effects

The most common adverse effect of oral baclofen therapy is transient drowsiness (10-63%); other common adverse effects of oral baclofen therapy include dizziness (5-15%), weakness (5-15%), and fatigue (2-4%).

The most common adverse effects of intrathecal baclofen therapy in patients with spasticity of spinal cord origin include somnolence, dizziness, nausea, hypotension, headache, seizures, and hypotonia. The most common adverse effects of intrathecal baclofen therapy in patients with spasticity of cerebral origin include agitation, constipation, somnolence, leukocytosis, chills, urinary retention, and hypotonia.

The incidence of adverse effects during oral administration of baclofen can be minimized by slowly increasing dosage to therapeutic levels. If adverse effects occur, they can be reduced by decreasing dosage. Psychiatric disturbances, including hallucinations, euphoria, mental excitation, depression, confusion or anxiety, occur most commonly in patients with psychiatric or brain disorders, including stroke, and in geriatric patients; any increase in oral dosage should be made slowly in these patients. Many adverse CNS and genitourinary effects also are symptoms of the underlying disease (i.e., multiple sclerosis, spinal cord lesions) and may not be related to baclofen therapy.

CNS Effects

Neuropsychiatric disturbances reported during oral baclofen treatment include confusion, headache, insomnia, and, rarely, euphoria, excitement, depression, hallucinations, paresthesia, muscle pain, tinnitus, slurred speech, coordination disorder, tremor, rigidity, dystonia, ataxia, blurred vision, nystagmus, strabismus, miosis, mydriasis, diplopia, dysarthria, and seizures. Neuropsychiatric disturbances or adverse CNS effects reported during intrathecal baclofen treatment include hypotonia, somnolence, dizziness, paresthesia, hypertonia, headache, seizures, asthenia, confusion, speech disorder, coma, insomnia, anxiety, depression, abnormal thinking, tremor, agitation, dysautonomia, hallucinations, abnormal gait, amnesia, twitching, vasodilation, cerebrovascular accident, nystagmus, personality disorder, psychotic depression, cerebral ischemia, emotional lability, euphoria, ileus, drug dependence, incoordination, paranoid reaction, ptosis, akathisia, ataxia, opisthotonos, hysteria, insomnia, decreased reflexes, and vasodilation.

Genitourinary Effects

Urinary frequency and, rarely, enuresis, urinary retention, dysuria, impotence, inability to ejaculate, nocturia, and hematuria have occurred during oral baclofen therapy. During intrathecal baclofen therapy, urinary retention or incontinence, impotence, urinary frequency, impaired urination, hematuria, kidney failure, abnormal ejaculation, kidney calculus, oliguria, and vaginitis have been reported.

In female rats, chronic administration of oral baclofen has caused a dose-related increase in the incidence of ovarian cysts and a less marked increase in enlarged or hemorrhagic adrenal glands. Ovarian cysts have been found by palpation in about 4% of multiple sclerosis patients receiving oral baclofen for up to 1 year, but these cysts spontaneously disappeared despite continued use of the drug in most patients. It should be noted, however, that ovarian cysts are estimated to occur spontaneously in approximately 1-5% of healthy females.

Cardiovascular Effects

Adverse cardiovascular effects such as hypotension and, rarely, dyspnea, palpitation, chest pain, and syncope have occurred during oral baclofen therapy. Hypotension (including orthostatic hypotension), hypertension, dyspnea, bradycardia, palpitations, syncope, ventricular arrhythmia, deep thrombophlebitis, pallor, and tachycardia have been reported during intrathecal baclofen therapy.

GI Effects

Adverse GI effects of oral baclofen therapy include nausea and constipation and, rarely, dry mouth, anorexia, taste disorders, abdominal pain, vomiting, diarrhea, and positive tests for occult blood in the stool. Nausea, vomiting, constipation, dry mouth, diarrhea, anorexia, increased salivation, flatulence, dysphagia, dyspepsia, gastroenteritis, fecal incontinence, GI hemorrhage, tongue disorder, and abdominal pain have been reported during intrathecal baclofen therapy.

Abrupt Withdrawal

Abrupt discontinuance of oral baclofen therapy, regardless of the cause, has resulted in hallucinations and seizures. Abrupt discontinuance of intrathecal baclofen therapy has resulted in high fever, altered mental status, exaggerated rebound spasticity, and muscle rigidity that, in rare cases, have progressed to rhabdomyolysis, multisystem organ failure, and death. In most cases, manifestations of withdrawal appeared within hours to a few days following discontinuance of baclofen therapy. All patients receiving intrathecal baclofen therapy are potentially at risk for withdrawal. Early manifestations of intrathecal baclofen withdrawal may include return of baseline spasticity, pruritus, hypotension, and paresthesias. Clinical presentation of advanced intrathecal baclofen withdrawal syndrome may resemble autonomic dysreflexia, infection (sepsis), malignant hyperthermia, neuroleptic malignant syndrome (NMS), or other conditions associated with a hypermetabolic state or widespread rhabdomyolysis.(See Cautions: Precautions and Contraindications.) Baclofen therapy should be slowly discontinued to minimize the risk of withdrawal.

Death

Although fatalities, including one case of unexpected death after administration of 3 test doses and 2 cases of sudden and unexpected death occurring within 2 weeks of pump implantation, have been reported rarely during the use of intrathecal baclofen therapy, the manufacturer states that a causal relationship to the drug could not be established.

Other Adverse Effects

Rash, pruritus, ankle edema, excessive perspiration, weight gain, and nasal congestion have been reported during oral baclofen therapy. Increases in blood glucose concentration and serum AST (SGOT) and alkaline phosphatase concentrations also have been reported during oral therapy. During intrathecal baclofen therapy, accidental injury, death, pain, amblyopia, hypoventilation, peripheral edema, fever, pneumonia, urticaria, diplopia, back pain, pruritus, rash, sweating, alopecia, contact dermatitis, skin ulcer, chills, respiratory disorder, aspiration pneumonia, hyperventilation, apnea, pulmonary embolus, rhinitis, weight loss, albuminuria, dehydration, hyperglycemia, abnormal vision, abnormality of accommodation, photophobia, taste loss, tinnitus, suicide, hypothermia, neck rigidity, chest pain, chills, face edema, flu syndrome, anemia, carcinoma, malaise, leukocytosis, and petechial rash have been reported.

Precautions and Contraindications

Deteriorations in seizure control and EEG occasionally have been noted in epileptic patients receiving the drug; the epileptic patient's clinical state and EEG should be monitored at regular intervals during baclofen treatment.

Because baclofen may cause sedation and/or drowsiness, patients should be warned that therapy with the drug may impair their ability to perform hazardous activities requiring mental alertness or physical coordination such as operating machinery or driving a motor vehicle. In addition, additive CNS depression may occur when the drug is administered concomitantly with other CNS depressants, including alcohol. Oral or intrathecal baclofen should be used with caution, and it may be necessary to reduce dosage in patients with impaired renal function. The drug should be used with caution, with careful dosage titration, in patients who must use spasticity to maintain upright posture and balance in moving or when spasticity is used to obtain increased or optimal body function.

Patients with psychotic disorders, schizophrenia, or confusional states should be treated cautiously and kept under careful surveillance during intrathecal baclofen therapy, as exacerbations of these conditions have been reported following oral administration of the drug.

Intrathecal baclofen therapy should be instituted with caution in patients with a history of autonomic dysreflexia, since the presence of nociceptive stimuli or the abrupt withdrawal of therapy may precipitate an episode of dysreflexia.

The clinical goal of baclofen therapy is to maintain muscle tone as close to normal as possible and to minimize the frequency and severity of spasms without inducing intolerable adverse effects. It may be important to maintain some degree of muscle tone and allow occasional spasms to help support circulatory function, minimize the risk of development of deep-vein thrombosis, and optimize activities of daily living and ease of care.

If intrathecal baclofen therapy is to be employed, an attempt should be made to discontinue concomitant oral antispasmodic drugs, including oral baclofen, to avoid possible overdose and drug interactions, either prior to the screening phase or following implantation of the infusion device. Dosage reduction and discontinuance of concomitant oral antispasmodics should be employed slowly, and the patient should be monitored carefully; abrupt dosage reduction or discontinuance of concomitant antispasmodics should be avoided.

Patients undergoing pump implantation for the initiation of intrathecal baclofen therapy should be without concurrent infection, as the presence of infection may interfere with assessment of the patient's response to the baclofen test dose(s), increase surgical complications after pump implantation, and complicate attempts to adjust dosage.

Development of intrathecal mass at the tip of the implanted catheter, usually involving pharmacy compounded analgesic admixtures, has been reported in patients receiving long-term intrathecal baclofen therapy. The most common sequelae or manifestations associated with intrathecal mass include decreased therapeutic response (i.e., worsening spasticity, return of spasticity despite previous response, withdrawal symptoms, poor response to escalating doses, frequent or large dosage increases), pain, and neurologic deficit or dysfunction. Patients receiving intraspinal therapy should be carefully monitored for any new neurologic manifestations. If new neurologic manifestations suggestive of an intrathecal mass occur, a neurosurgical consultation should be considered, since many of the symptoms of inflammatory mass are similar to those observed in patients with severe spasticity. In some cases, performance of an imaging procedure may be appropriate to confirm or rule out the diagnosis of an intrathecal mass.

Because of the possibility of potentially life-threatening CNS depression, cardiovascular collapse, and/or respiratory failure, baclofen should be administered intrathecally only by qualified individuals familiar with the techniques of administration and patient management problems. When an implantable pump is used, familiarization with the device is essential, including specific instructions and precautions for programming the pump and refilling the reservoir. The patient, their caregivers, and health-care providers must receive adequate information regarding the risks of such therapy, including information on recognition and management of potential overdosage and proper care of the pump and catheter insertion site. Because of the risks involved, the initial test for responsiveness to intrathecal baclofen, implantation of the pump, and subsequent periods of dosage titration must be performed in a medically supervised setting that is adequately equipped for the management of potential complications; resuscitative equipment should be readily available. Filling of the drug reservoir of the device should be performed under aseptic conditions (to avoid bacterial contamination and serious infection) and only by fully trained and qualified personnel, following the directions provided by the device's manufacturer. The pump should be filled with extreme caution and should be refilled only through the reservoir refill septum of the device. If the reservoir refill septum is not properly accessed, inadvertent injection into the subcutaneous tissue can occur, possibly resulting in life-threatening overdosage or early depletion of the reservoir. Some pumps also are equipped with a catheter access port that allows direct access to the intrathecal catheter; direct injection into this catheter may cause life-threatening overdosage of the drug. During chronic therapy, care should be taken in employing the proper refill frequency so that depletion of the drug reservoir during use is avoided; symptoms of spasticity (e.g., rigidity) usually return within a few days if dosing is discontinued, and manifestations of withdrawal (e.g., hallucinations, seizures) could emerge. Careful patient monitoring is particularly important during the initial phase of pump use, dosage titration, and reservoir refilling so that an acceptable, reasonably stable response is ensured.

Abrupt discontinuance of oral baclofen therapy, regardless of the cause, has resulted in hallucinations and seizures. Abrupt discontinuance of intrathecal baclofen therapy has resulted in high fever, altered mental status, exaggerated rebound spasticity, and muscle rigidity that, in rare cases, have progressed to rhabdomyolysis, multisystem organ failure, and death. Common reasons for abrupt interruption of intrathecal baclofen therapy include malfunction of the catheter (particularly disconnection), low volume in the pump reservoir, end of pump battery life, and, possibly, human error. Cases of intrathecal mass at the tip of the implanted catheter (most of which involved pharmacy compounded analgesic admixtures) also have reportedly resulted in withdrawal symptoms. Therefore, the manufacturer states that careful attention to programming and monitoring of the infusion system, refill scheduling and procedures, and pump alarms is necessary to prevent abrupt discontinuance of intrathecal baclofen therapy. Patients and caregivers should be advised of the importance of keeping scheduled refill visits and should be informed of the early signs and symptoms of baclofen withdrawal.(See Abrupt Withdrawal under Cautions: Adverse Effects.) Special attention should be given to patients at apparent risk for withdrawal (e.g., spinal cord injury at the T6 level or above, communication difficulties, history of withdrawal symptoms from oral or intrathecal baclofen). Rapid, accurate diagnosis and treatment in an emergency room or intensive care setting are important in order to prevent the potentially life-threatening CNS and systemic effects of intrathecal baclofen withdrawal. Treatment of intrathecal baclofen withdrawal includes restoration of intrathecal baclofen at or near the dosage used prior to interruption of therapy. However, if reinstitution of intrathecal delivery is delayed, therapy with drugs that enhance GABA effects (e.g., oral or enteral baclofen; oral, enteral, or IV benzodiazepines) may prevent potentially fatal sequelae. However, the manufacturer states that oral or enteral baclofen alone should not be relied upon to halt the progression of intrathecal baclofen withdrawal.

Oral and intrathecal baclofen are contraindicated in patients with a history of hypersensitivity to the drug. Baclofen injection for intrathecal administration is not recommended or intended for IV, IM, subcutaneous, or epidural administration.

Pediatric Precautions

The manufacturers state that safety of oral or intrathecal baclofen therapy in pediatric patients younger than 12 or 4 years of age, respectively, has not been established. Pediatric patients undergoing pump implantation for the initiation of intrathecal baclofen therapy should have sufficient body mass to accommodate the pump. Directions provided by the device's manufacturer should be consulted.

Pregnancy and Lactation

Pregnancy

Reproduction studies in rats receiving oral baclofen at a dosage approximately 13 or 3 times the maximum recommended human oral dosage on a mg/kg or mg/m basis, respectively, demonstrated an increased incidence of omphaloceles (ventral hernias) in the fetuses; substantial reductions in food intake and weight gain occurred in pregnant rats receiving this dosage. An increased incidence of omphaloceles did not occur in mice or rabbit fetuses. An increased incidence of incomplete sternebral ossification occurred in the fetuses of rats receiving approximately 13 times the maximum recommended human dosage, and an increased incidence of unossified phalangeal nuclei of the forelimbs and hindlimbs occurred in the fetuses of rabbits receiving approximately 7 times the maximum recommended dosage. No teratogenic effects occurred in mice, although reduction in mean fetal weight with consequent delay in skeletal ossification occurred in offspring of mice receiving 17 or 34 times the human daily dosage of baclofen. There are no adequate and controlled studies using baclofen in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.

Lactation

Baclofen is distributed into milk following oral administration; it not known whether the drug distributes into milk following intrathecal administration. At least one manufacturer states that nursing should not be undertaken by women receiving oral baclofen. Nursing should be undertaken by women receiving intrathecal baclofen only if the potential benefit justifies the potential risks to the infant.

Drug Interactions

Experience with concomitant use of intrathecal baclofen with other drugs is insufficient to predict specific drug-drug interactions.

CNS Depressants

Concomitant use of baclofen with other CNS depressants (e.g., alcohol) may result in additive CNS depression.

Morphine

Concomitant use of intrathecal baclofen with epidural morphine reportedly has resulted in hypotension and dyspnea.

Pharmacokinetics

Absorption

Studies with radiolabeled baclofen have shown oral doses of 40 mg to be rapidly and almost completely absorbed from the GI tract, but there is relatively large intersubject variation in absorption and/or elimination. GI absorption of baclofen is reduced as dosage is increased. Serum concentrations required for therapeutic effects reportedly range from 80-395 ng/mL. Following oral administration of 40 mg of baclofen to healthy patients, peak blood concentrations of 500-600 ng/mL are reached in 2-3 hours and concentrations remain above 200 ng/mL for 8 hours. Beneficial effects of oral baclofen may not be immediately apparent; onset of therapeutic effect may vary from hours to weeks.

Following intrathecal administration of the drug, concurrent plasma baclofen concentrations are expected to be low (0-5 ng/mL); plasma concentrations of baclofen following intrathecal administration are 100 times lower than those achieved following oral administration. In pediatric patients 8-18 years of age who were receiving a continuous intrathecal infusion of baclofen at dosages of 77-400 mcg daily, plasma baclofen concentrations were near or below 10 mg/mL.

When baclofen is administered via intrathecal injection, the onset of action in adult patients generally is 0.5-1 hour following injection; peak spasmolytic effect is seen approximately 4 hours after dosing and effects may last 4-8 hours, although onset, peak, and duration of action are subject to interindividual variation, depending on the dose and severity of symptoms. Onset and duration of action and peak effects of baclofen in pediatric patients are similar to those reported in adult patients.

Following continuous intrathecal infusions of the drug, initial spasmolytic action is seen within 6-8 hours in adult patients; peak spasmolytic effect is observed within 24-48 hours. Pharmacokinetic data following continuous intrathecal infusion in pediatric patients currently are not available.

Distribution

In animals, orally administered baclofen is widely distributed throughout the body, but only small amounts of the drug cross the blood-brain barrier.

Limited data suggest that a lumbar-cisternal gradient of approximately 4:1 is established along the neuroaxis during infusion of baclofen injection, based on simultaneous CSF sampling via lumbar and cisternal taps in a limited number of patients receiving continuous lumbar infusion of the drug at doses associated with therapeutic efficacy; however, there was wide interindividual variation. This gradient was not affected by patient position.

Baclofen crosses the placenta. Baclofen is distributed into milk following oral administration; it is not known whether the drug is distributed into milk following intrathecal administration.

At blood concentrations of 10 ng to 300 mcg/mL, 30% of baclofen is bound to serum proteins.

Elimination

Baclofen has a serum half-life of 2.5-4 hours.

CSF clearance of baclofen following intrathecal administration via injection or continuous infusion approximates CSF turnover, suggesting that elimination of the drug occurs via bulk-flow removal of CSF. Following lumbar injection of the drug in doses of 50 or 100 mcg in a limited number of patients, the mean CSF elimination half-life was 1.51 hours for the first 4 hours following injection; mean CSF clearance of the drug was 30 mL/hour. Mean CSF clearance of the drug also was 30 mL/hour in a limited number of patients receiving the drug via continuous intrathecal infusion.

Only about 15% of a dose of the drug is metabolized in the liver, mostly by deamination. Baclofen is almost completely excreted within 72 hours following oral administration; 70-80% of the drug is excreted in urine unchanged or as metabolites and the remainder is excreted in the feces.

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