Mulax

Mulax is a gamma-amino-butyric acid (GABA) derivative used as a skeletal muscle relaxant. Mulax stimulates GABA-B receptors leading to decreased frequency and amplitude of muscle spasms. It is especially useful in treating muscle spasticity associated with spinal cord injury. It appears to act primarily at the spinal cord level by inhibiting spinal polysynaptic afferent pathways and, to a lesser extent, monosynaptic afferent pathways.

Mulax Injection (Intrathecal) is indicated for use in the management of severe spasticity. Patients should first respond to a screening dose of intrathecal Mulax prior to consideration for long term infusion via an implantable pump. For spasticity of spinal cord origin, chronic infusion of Mulax Injection (Intrathecal) via an implantable pump should be reserved for patients unresponsive to oral Mulax 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 Mulax therapy. Mulax Injection (Intrathecal) is intended for use by the intrathecal route in single bolus test doses (via spinal catheter or lumbar puncture) and, for chronic use, only in implantable pumps approved by the FDA specifically for the administration of Mulax Injection (Intrathecal) into the intrathecal space.

Spasticity of Spinal Cord Origin

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

Spasticity of Cerebral Origin

The efficacy of intrathecal Mulax was investigated in three controlled clinical trials; two enrolled patients with cerebral palsy and one enrolled patients with spasticity due to previous brain injury. The first study, a randomized controlled cross-over trial of 51 patients with cerebral palsy, provided strong, statistically significant results; intrathecal Mulax 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. Mulax Injection (Intrathecal) therapy may be considered an alternative to destructive neurosurgical procedures. Prior to implantation of a device for chronic intrathecal infusion of Mulax Injection (Intrathecal), patients must show a response to Mulax Injection (Intrathecal) in a screening trial.

FIRST Mulax is a muscle relaxer and an antispastic agent.

FIRST Mulax is used to treat muscle symptoms caused by multiple sclerosis, including spasm, pain, and stiffness.

FIRST Mulax is sometimes used to treat muscle spasms and other symptoms in people with injury or disease of the spinal cord.

FIRST Mulax may also be used for purposes not listed in this medication guide.

Use Only With Medtronic SynchroMed® II Programmable Pump (Or Other Pumps Labeled For Intrathecal Administration Of Mulax)

Mulax is approved only for use with the Medtronic SynchroMed® II Programmable Pump or other pumps labeled for intrathecal administration of Mulax. 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 Mulax. Mulax is not to be compounded with other medications.

Screening Phase

Prior to pump implantation and initiation of chronic infusion of Mulax, patients must demonstrate a positive clinical response to a Mulax bolus dose administered intrathecally in a screening trial. The screening trial employs Mulax 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.

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 Mulax injection for a 75 mcg bolus dose. For the maximum screening dose of 100 mcg, use 2 mL of 50 mcg/mL Mulax 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, Mulax must be diluted with sterile preservative free Sodium Chloride for Injection, USP.

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 Mulax prefilled syringes (all strengths, including the 50 mcg/mL strength) are non-sterile. The use of Mulax 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 Mulax prefilled syringe when filling the pump reservoir.

Delivery Regimen

Mulax 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 Mulax 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.

Dose Titration

Post-Implant Dose Titration Period

To determine the initial total daily dose of Mulax 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 Mulax 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 Mulax 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 Mulax infusion. Reduction and discontinuation of oral antispasmotics should be done slowly and with careful monitoring by the physician. Abrupt reduction or discontinuation of concomitant antispastics should be avoided.

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 Mulax 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 Mulax 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 Mulax 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 Mulax 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 Mulax over a 2 to 4 week period and switching to alternative methods of spasticity management. After the “drug holiday,” intrathecal Mulax may be restarted at the initial continuous infusion dose.

How supplied

Dosage Forms And Strengths

Mulax 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 milliliter of Mulax contains Baclofen USP 50 mcg, 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. Each vial or syringe is intended for single use only. Discard any unused portion. Do not autoclave.

Storage And Handling

Mulax (Mulax injection) is available in a single use syringe of 1 mL containing 50 mcg (50 mcg/mL) and in single use syringes and vials of 10,000 mcg per 20 mL (500 mcg/mL), 20,000 mcg per 20 mL (1,000 mcg/mL), and 40,000 mcg per 20 mL (2,000 mcg/mL) for intrathecal administration only.

50 mcg per mL

NDC 45945-151-01: 1 mL Syringe – 50 mcg per 1 mL

500 mcg per mL

NDC 45945-155-01: 20 mL Syringe – 10,000 mcg per 20 mL

NDC 45945-155-02: 20 mL Vial – 10,000 mcg per 20 mL

1,000 mcg per mL

NDC 45945-156-01: 20 mL Syringe – 20,000 mcg per 20 mL

NDC 45945-156-02: 20 mL Vial – 20,000 mcg per 20 mL

2,000 mcg per mL

NDC 45945-157-01: 20 mL Syringe – 40,000 mcg per 20 mL

NDC 45945-157-02: 20 mL Vial – 40,000 mcg per 20 mL

Does not require refrigeration.

Do not store above 86°F (30°C).

Do not freeze.

Do not heat sterilize.

Distributed by: Mallinckrodt Brand Pharmaceuticals, Inc. Hazelwood, MO 63042 USA. Issued 02/2015

See also:
What is the most important information I should know about Mulax?

Tablets and Injection

Hypersensitivity to Mulax.

Injection

Hypersensitivity to Mulax. Novo-Mulax injection is not recommended for intravenous, intramuscular, or epidural administration

OVERDOSAGE for Kemsto

Signs and Symptoms

Treatment

CONTRAINDICATIONS for Kemsto

KEMSTRO is contraindicated in patients who are hypersensitive to any component of this product.

Active ingredient matches for Mulax:

Baclofen in Taiwan.

Psyllium in Indonesia.

Psyllium hydrophilic mucilloid in Indonesia.

Ibuprofen/Paracetamol in Philippines.

Use Mulax as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Mulax is administered into the spinal canal as an injection or through an implantable infusion pump at your doctor's office, hospital, or clinic. Discuss any questions or concerns with your doctor.
• Do not use Mulax if it contains particles, is cloudy or discolored, or if the vial is cracked or damaged.
• Keep this product, as well as syringes and needles, out of the reach of children and pets. Do not reuse needles, syringes, or other materials. Ask your health care provider how to dispose of these materials after use. Follow all local rules for disposal.
• If you miss a dose of Mulax, contact your doctor right away.

Ask your health care provider any questions you may have about how to use Mulax.

Mulax is used to treat muscle spasms caused by certain conditions (such as multiple sclerosis, cerebral palsy, spinal cord injury/disease). It works by helping to relax the muscles.

Mulax injection is used by patients who do not respond to or who cannot tolerate the side effects of Mulax taken by mouth.

How to use Mulax

This medication is given by injection into the space around the spinal cord (intrathecally). It is usually given using a drug pump implanted under your skin. A health care professional will fill and refill the pump with medication.

The dosage is based on your medical condition and response to treatment.

If you are giving this medication to yourself at home, learn all preparation and usage instructions from your health care professional. Before using, check this product visually for particles or discoloration. If either is present, do not use the liquid. Learn how to store and discard medical supplies safely.

Do not stop treatment with this drug without consulting your doctor because serious withdrawal symptoms may occur. See also Warning section. To prevent withdrawal reactions, your doctor may reduce your dose gradually. Consult your doctor or pharmacist for more details, and report any withdrawal reactions right away.

When this medication is used for a long time, it may not work as well. Talk with your doctor if this medication stops working well.

Tell your doctor if your condition does not improve or if it worsens, or if you have any signs of infection (such as fever, chills, redness/swelling/pain/warmth at the pump site).

See also:
What other drugs will affect Mulax?

There is little experience with the use of Mulax in combination with systemic medications to predict specific drug-drug interactions, although it is suggested that the low Mulax systemic exposure observed after intrathecal administration could reduce the potential for pharmacokinetic interactions.

Drug-Drug Interactions

Levodopa/ Dopa Decarboxylase (DDC) inhibitor (carbidopa)

Concomitant use of oral LIORESAL and levodopa (alone or in combination with a DDC inhibitor, carbidopa) resulted in increased risk of adverse events such as visual hallucinations, confusional state, headache and nausea. Worsening of the symptoms of Parkinsonism has also been reported. Thus, similar interaction can be anticipated for intrathecal LIORESAL.

Anesthetics

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

Morphine

The combined use of morphine and intrathecal Mulax was responsible for hypotension in one patient. The potential for this combination to cause dyspnea or other CNS symptoms cannot be excluded.

The co-administration of other intrathecal agents with Mulax has not been tested and the safety of these combinations is unknown.

Alcohol and other compounds affecting CNS

The central nervous system depressant effects of alcohol and other compounds affecting the CNS (e.g. analgesics, neuroleptics, barbiturates, benzodiazepines, anxiolytics) may be additive to the effects of Mulax. Increased sedation may occur when Mulax is taken concomitantly with other drugs causing CNS depression, including other muscle relaxants (such as tizanidine), synthetic opiates, hypnotics, anxiolytics or alcohol. The risk of respiratory depression is also increased. Careful monitoring of respiratory and cardiovascular functions is essential, especially in patients with cardiopulmonary disease and respiratory muscle weakness.

Tricyclic antidepressants

When using oral Mulax, concurrent treatment with tricyclic antidepressants may potentiate the effect of LIORESAL, resulting in pronounced muscular hypotonia. In addition, concomitant use of tricyclic antidepressants can cause sedation, drowsiness and potentiate the effects of LIORESAL resulting in pronounced muscular hypotonia. Therefore, caution is advised when using Mulax in this combination.

Lithium

Concomitant use of oral Mulax and lithium resulted in aggravated hyperkinetic symptoms. Caution should be exercised when Mulax is used concomitantly with lithium.

Antihypertensives

Since concomitant treatment with oral LIORESAL and antihypertensives is likely to increase antihypertensive effects, it is recommended that blood pressure is checked and if necessary, the dosage of antihypertensive medication adjusted accordingly.

See also:
What are the possible side effects of Mulax?

Adverse Drug Events

Spasticity Of Spinal Cord Origin

Commonly Observed in Patients with Spasticity of Spinal Origin: In pre- and post-marketing clinical trials, the most commonly observed adverse events associated with use of intrathecal Mulax which were not seen at an equivalent incidence among placebo-treated patients were: somnolence, dizziness, nausea, hypotension, headache, convulsions and hypotonia.

Associated with Discontinuation of Treatment: 8/474 patients with spasticity of spinal cord origin receiving long term infusion of intrathecal Mulax in pre- and post-marketing clinical studies in the U.S. discontinued treatment due to adverse events. 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

Incidence in Controlled Trials: Experience with intrathecal Mulax obtained in parallel, placebocontrolled, randomized studies provides only a limited basis for estimating the incidence of adverse events 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 Mulax in two randomized, placebo-controlled trials: hypotension (2), dizziness (2), headache (2), dyspnea (1). No adverse events were reported among the 32 patients receiving placebo in these studies. Events Observed during the Pre- and Post- marketing Evaluation of Intrathecal Mulax: Adverse events associated with the use of intrathecal Mulax reflect experience gained with 576 patients followed prospectively in the United States. They received intrathecal Mulax 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 2003 mcg per day. Because of the open, uncontrolled nature of the experience, a causal linkage between events observed and the administration of intrathecal Mulax cannot be reliably assessed in many cases and many of the adverse events 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 drugrelated. Adverse experiences reported during all U.S. studies (both controlled and uncontrolled) are shown in the following table. 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 postmarketing studies.

INCIDENCE OF MOST FREQUENT ( ≥ 1%) ADVERSE EVENTS IN PATIENTS WITH SPASTICITY OF SPINAL ORIGIN IN PROSPECTIVELY MONITORED CLINICAL TRIALS

The more common (1% or more) adverse events reported in the prospectively followed 211 patients exposed to intrathecal Mulax have been reported. In the total cohort, the following adverse events, not described in the table, 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.