Fleqsuvy (Baclofen) OTC

(British Approved Name, US Adopted Name, rINN)

Pharmacokinetics

After an oral dose, Baclofen is rapidly and almost completely absorbed from the gastrointestinal tract. Peak plasma concentrations occur about 0.5 to 3 hours after ingestion, but the rate and extent of absorption vary between patients and may vary inversely with the dose. After oral doses, some baclofen crosses the blood-brain barrier, with concentrations in CSF about 12% of those in the plasma. About 30% of Baclofen is bound to plasma proteins. About 70 to 80% of a dose is excreted in the urine, mainly as an unchanged drug; about 15% is metabolized in the liver. The elimination half-life of Baclofen is about 3 to 4 hours in plasma and about 1 to 5 hours in the CSF. Baclofen crosses the placenta and is distributed into breast milk.

Absorption

A crossover study of 5 healthy subjects given Baclofen 20 mg orally after an overnight fast or a standardized breakfast showed that Baclofen was rapidly absorbed in both cases, and the presence of food did not significantly alter the rate and extent of absorption. There is no need to modify the current practice of giving Baclofen with food to minimize gastrointestinal adverse effects.

Uses and Administration

Baclofen, an analog of gamma-aminobutyric acid, is a centrally-acting skeletal muscle relaxant. It interferes with the release of excitatory neurotransmitters and inhibits monosynaptic and polysynaptic transmission at the spinal cord level. It may also act at supraspinal sites, producing CNS depression. Baclofen is one of the drugs commonly used for the symptomatic relief of severe chronic spasticity associated with a variety of conditions.

Baclofen is given orally in divided doses, preferably with or after food or milk. The initial dose of Baclofen is 5 mg three times daily for three days, increased to 10 mg three times daily for three days, then in similar increments and intervals until either a dose of 20 mg three times daily is reached or until the desired therapeutic effect is obtained. Higher doses have been used. Doses of more than 80 to 100 mg daily are not generally recommended, although doses of up to 150 mg daily have been given to carefully supervised patients.

In the UK, a dosage range of 0.75 to 2 mg/kg daily has been used for children; a maximum daily dosage of 2.5 mg/kg may be given to children over ten years. It is usual to start with a low dose of 2.5 mg given four times daily, increasing cautiously every three days until the desired therapeutic effect is obtained. The recommended daily maintenance doses are 12 months to 2 years, 10 to 20 mg; 2 to 6 years, 20 to 30 mg; 6 to 10 years, 30 to 60 mg.

Elderly patients should receive lower initial doses, although final maintenance doses may be in the same range as younger adults. For dosage in renal impairment, see below.

Therapy should be gradually withdrawn if no benefit is apparent within six weeks of achieving the maximum dosage.

Baclofen is also given by continuous intrathecal infusion in treating spasticity in patients intolerant of, or unresponsive to, oral Baclofen. Before beginning the intrathecal regimen, any existing antispastic therapy should be gradually withdrawn to avoid overdosage or drug interactions. Intrathecal test doses are given initially to determine if there will be any benefit before implanting a controlled infusion pump. It is essential that patients are monitored closely in experienced centers during screening and immediately after implantation of the infusion pump and that resuscitation equipment is available for immediate use.

Test doses start at 25 or 50 micrograms given over at least 1 minute and are increased by 25 micrograms every 24 hours until a dose of 100 micrograms is reached or a positive response of about 4 to 8 hours is obtained. Patients who fail to respond to a test dose of up to 100 micrograms are considered to be unsuitable for intrathecal treatment. For children aged 4 to 18 years with spasticity of cerebral origin, an initial test dose of 25 micrograms is recommended. However, the manufacturers do not recommend using intrathecal Baclofen in patients in this age group with spasticity of spinal origin.

For patients showing a positive response lasting for longer than 8 to 12 hours, the test dose that was required to produce the response can then be given as a 24-hour infusion; if the response to the test dose lasted 8 to 12 hours or less, then a dose equivalent to twice the test dose is given. Daily dosage can then be adjusted as required. Maintenance doses range from about ten micrograms to 2 mg daily, depending on the cause of spasticity, with most patients being adequately maintained with 300 to 800 micrograms daily.

Administration in Renal Impairment

Doses of Baclofen should be reduced in renal impairment or patients undergoing chronic hemodialysis; 5 mg daily by mouth has been suggested (but see also under Precautions, above).

Dystonias

There have been reports of improvement in patients with various forms of dystonia treated with Baclofen. However, there has also been a report of a patient whose condition deteriorated during baclofen therapy.

Gastro-Oesophageal Reflux Disease

Baclofen has been tried in the treatment of gastro-oesophageal reflux disease. It may control gastro-oesophageal reflux by inhibiting transient sphincter relaxation. Although both studies reported a reduction in reflux episodes, there was no effect on acid reflux symptoms. However, a subsequent study has shown a positive effect on the symptoms of acid reflux. Although Baclofen may be of benefit, its adverse CNS effects mean that new oral selective GABA-B agonists should be developed for this indication.

Hiccup

Baclofen has been given orally in daily divided doses ranging from 10 to 80 mg for the management of intractable hiccups poorly controlled by other drugs. It has also been combined with gabapentin. 

Migraine and Cluster Headache

The efficacy of Baclofen in conditions such as trigeminal neuralgia or various types of neuropathic pain suggested that it may be helpful in migraine or cluster headaches. Pilot studies confirmed these hypotheses, with Baclofen proving useful for migraine prevention and cluster headache treatment.

Pain

Like other muscle relaxants, Baclofen manages painful conditions associated with muscle spasms or spasticity (see below). The use of muscle relaxants for conditions such as acute low back pain is referred to on-site. Baclofen does not appear to possess conventional analgesic activity. Still, it may potentiate the analgesia produced by opioid analgesics and has been used as an adjuvant in neuropathic pain, notably trigeminal neuralgia.

Spasticity

Baclofen is one of the primary drugs used in the management of spasticity. It is used to reduce muscle spasms and pain, especially in spinal cord lesions in conditions such as multiple sclerosis or paraplegia. Baclofen is also used for spasticity of cerebral origin.

Oral doses of 30 to 80 mg daily are well tolerated. Still, patients with severe spasticity often require high doses of Baclofen before a response occurs, and consequently, some may fail to respond because adverse effects limit increases in dosage. Intrathecal Baclofen is, therefore, sometimes tried as this produces much higher concentrations in the CNS than oral doses.

It may be given intrathecally by bolus injection or continuous infusion; the infusion is preferred to minimize the risk of over-dosage. Results are generally good because patients are screened for response before beginning continuous infusion. There is a significant interindividual variation in the dose required to produce improvement in spasticity:

• In patients with spasticity of spinal origin, maintenance doses have ranged from 12 micrograms to about 2 mg daily, with most adequately managed on 300 to 800 micrograms daily.
• In patients with spasticity of cerebral origin, maintenance doses have ranged from 22 micrograms to 1.4 mg daily, with an average daily dose of 276 micrograms after 12 months and 307 micrograms after 24 months.
• For children under the age of 12 years with spasticity of cerebral origin, maintenance doses have ranged from 24 micrograms to about 1.2 mg daily, with an average daily dose of 274 micrograms.

An increased dose of Baclofen may be given at night to prevent spasms that interfere with sleep.

Although reports of tolerance to the effect of intrathecal Baclofen have raised doubt over whether long-term benefits can be maintained, several people have achieved long-term efficacy. It has been reported that some patients receiving long-term intrathecal baclofen treatment have been able to stop their therapy without symptoms of spasticity reappearing, and others have been able to reduce the dosage required.

Stiff-man Syndrome

There have been anecdotal case reports of the benefit of intrathecal Baclofen in a patient with stiff-man syndrome (see under Muscle Spasm) inadequately controlled with other drugs or oral Baclofen. However, in a double-blind placebo-controlled study, clinical improvement was evident in only 1 of 3 patients given intrathecal Baclofen.

Tardive Dyskinesia

Baclofen is one of many drugs that have been tried for antipsychotic-induced tardive dyskinesia, but its efficacy is unclear. A systematic review found the effects of Baclofen and other gamma-aminobutyric acid agonists to be inconclusive and unconvincing in the management of antipsychotic-induced tardive dyskinesia. The review also pointed out that the adverse effects caused by the use of these drugs might outweigh any benefits.

Tetanus

The management of tetanus is described on-site. Beneficial responses have been seen with Baclofen by continuous intrathecal infusion, usually in doses of 1 to 2 mg daily. However, the therapeutic range of intrathecal Baclofen in severe tetanus may be very narrow, and deep coma with loss of spontaneous respiration and reflexes has been reported after an increase in dosage from 1.2 mg to 2 mg daily. This adverse effect could be fatal in the absence of ventilatory support. Intermittent intrathecal Baclofen has also been used to avoid the risk of secondary infection from an indwelling intraspinal catheter.

Tourette’s Syndrome

Improvement was noted in children with Tourette’s syndrome (see Tics) treated with Baclofen compared with placebo in a small study.

Urinary Incontinence

Baclofen has been used with some benefit in the management of urinary incontinence and retention secondary to lesions of the spinal cord.

Adverse Effects

Adverse effects associated with Baclofen are often transient and dose-related. They may be minimized by increasing doses gradually or controlled by a reduction in dosage.

The most common adverse effects include drowsiness, nausea, dizziness, lassitude, lightheadedness, confusion, fatigue, muscular pain and weakness, and hypotension. Other adverse effects include euphoria, hallucinations, depression, headache, tinnitus, convulsions, paraesthesias, slurred speech, dry mouth, taste alterations, vomiting, diarrhea or constipation, ataxia, nystagmus, tremors, insomnia, visual disturbances, skin rashes, pruritus, increased sweating, urinary disturbances, respiratory or cardiovascular depression, blood sugar changes, alterations in liver function values, and a paradoxical increase in spasticity. Problems with erection and ejaculation have also been reported with intrathecal Baclofen; these are usually reversible on withdrawal of therapy.

Overdosage may lead to muscular hypotonia, hypothermia, drowsiness, respiratory depression, coma, and convulsions (see also below).

Stopping Baclofen abruptly may result in withdrawal syndrome (see Precautions section).

Effects on the Nervous System

Epilepsy, progressing to status epilepticus, has been associated with the use of Baclofen in a patient who had no history of seizures. Baclofen had been given in a dose of 80 mg daily, and symptoms had resolved after gradual withdrawal and the use of antiepileptics.

Treatment of Adverse Effects

Treatment of baclofen overdosage is symptomatic. Consideration should be given to the use of activated charcoal in adults who have ingested more than 100 mg and children who have taken more than 5 mg/kg within an hour of presentation.

Alternatively, gastric lavage may be considered in adults within an hour of ingesting a life-threatening overdose. Hemodialysis should be considered in severe cases. Observation should continue for at least 6 hours after ingestion. For physostigmine salicylate to treat intrathecal baclofen overdosage, see below.

Overdosage

Atropine sulfate 600 micrograms intravenously was used to treat a patient who had ingested 420 mg of Baclofen and had failed to improve after gastric lavage and induced diuresis. Bradycardia, hypotension, hypothermia, and respiratory depression all improved, and no further treatment was needed. The clinical course and management of acute intoxication in 8 adolescents who ingested estimated amounts of Baclofen, ranging from 60 to more than 600 mg, has also been described.

Accidental intrathecal overdosage has caused respiratory depression, decreased alertness, coma, muscle weakness, and vomiting. Mild intrathecal bolus overdoses of Baclofen in patients without cardiac compromise have been treated using physostigmine. However, the use of physostigmine in poisoning is now generally considered hazardous (see Antimuscarinic Poisoning).

Physostigmine salicylate was given intravenously in a 1 to 2mg dose over 5 minutes and repeated if necessary at 30 to 60-minute intervals. Physostigmine was ineffective in a patient who accidentally received 10 mg of Baclofen intrathecally; in such severe overdosage, respiratory support and time to recover are needed. A lumbar tap to remove about 30 to 50 mL of CSF may help to reduce the intrathecal concentration of Baclofen if implemented soon after the overdose.

Precautions

Baclofen stimulates gastric acid secretion and should be used with caution in patients with a history of peptic ulcer and avoided in those with active peptic ulcer disease. It should also be used with caution in patients with severe psychiatric disorders, epilepsy, or convulsive disorders since Baclofen may exacerbate these disorders. Liver function should be monitored in patients with liver disease; patients with renal impairment need a reduced dose. Baclofen should be used with caution in patients with respiratory impairment.

Observations of increased blood sugar concentrations suggest caution in patients with diabetes mellitus. Care is also required in seniors, in whom adverse effects may be more common, and in patients with cerebrovascular disease (who tolerate Baclofen poorly). It should be used cautiously in patients with spasticity to maintain posture or increase function. Urine retention may be exacerbated in patients with hypertonic bladder sphincters. Baclofen may cause drowsiness; patients affected should not drive or operate machinery.

Abrupt withdrawal of Baclofen may result in a withdrawal syndrome and worsening of spasticity; dosage should be reduced gradually over at least 1 to 2 weeks, or longer if symptoms occur.

Anesthesia

Acute bradycardia and hypotension occurred after rib retraction in 3 patients given Baclofen 30 mg orally 90 minutes before thoracic surgery under general anesthesia, but not in a further three patients given placebo. Giving atropine and ephedrine relieved bradycardia and hypotension in 2 patients, but a brief cardiac arrest occurred in 1. Baclofen may disturb auto-nomic control of the circulation during general anesthesia and surgery.

Breastfeeding

The concentrations of Baclofen found in breast milk are small, and UK-licensed product information states that no undesirable effects are expected in breastfed infants. The American Academy of Pediatrics also considers that Baclofen is usually compatible with breastfeeding; no adverse effects have been seen in breastfeeding infants whose mothers were receiving Baclofen.

Peptic Ulcer

Results of a study of baclofen-stimulated gastric acid secretion in 10 healthy subjects given 600 micrograms/kg intravenously suggested that patients on Baclofen might be at risk from baclofen-induced hyperacidity.

Porphyria

Baclofen is considered to be unsafe in patients with porphyria because it is porphyrinogenic in in-vitro systems.

Pregnancy and the Neonate

Two successful pregnancies have been reported in a woman receiving intrathecal Baclofen; there was no evidence of teratogenicity, and neurodevelopmental outcomes in the children seemed normal. However, convulsions were seen in a week-old infant whose mother had taken oral Baclofen during pregnancy. The convulsions, which were refractory to antiepileptics, lidocaine, and pyridoxine, ceased within 30 minutes of giving Baclofen to the infant.

Renal Impairment

Reports of baclofen toxicity in patients with severe renal impairment. Most patients had received 15 mg or more of Baclofen daily. However, one patient who had received the manufacturer’s suggested dose of 5 mg daily still developed toxic symptoms after only four days of treatment.

Respiratory Disorders

Baclofen might precipitate bronchoconstriction in susceptible individuals. A patient with asthma developed symptomatic bronchoconstriction after taking Baclofen on two separate occasions. Another patient who had a history of exercise-induced dyspnoea and wheezing was found to have bronchial hyperresponsiveness to methacholine only after taking Baclofen.

Withdrawal

Psychiatric reactions, including hallucinations, paranoia, delusions, psychosis, anxiety, confusion, and agitation, have been reported on abrupt withdrawal of oral Baclofen; symptoms generally resolved on restarting. Convulsions have also been reported. The abrupt withdrawal of intrathecal Baclofen may also result in high fever, altered mental status, exaggerated rebound spasticity, and muscle rigidity, which in rare cases has advanced to rhabdomyolysis, multiple organ failure, and death.

Except for severe adverse reactions, oral Baclofen should be gradually reduced: the UK CSM recommends reduction over at least 1 to 2 weeks or longer if symptoms occur. Similarly, the FDA has advised against the abrupt withdrawal of intrathecal Baclofen.

Interactions

Alcohol and other CNS depressants may exacerbate the CNS effects of Baclofen and should be avoided; severe aggravation of hyperkinetic symptoms may occur in patients taking lithium. There may be increased weakness if Baclofen is given to patients taking a tricyclic antidepressant, and there may be an increased hypotensive effect if it is given to patients receiving antihypertensive therapy. Ibuprofen (see below) and other drugs that produce renal insufficiency may reduce baclofen excretion, leading to toxicity.

Dopaminergic

For reports of patients with Parkinson’s disease taking Levodopa who have had adverse effects when given Baclofen, see under Levodopa.

NSAIDs

There has been a report of an elderly patient who developed baclofen toxicity after ibuprofen therapy was also started. It appeared that acute renal insufficiency caused by ibuprofen had impaired baclofen excretion.

Drug Nomenclature

International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):

Synonyms: Aminomethyl Chlorohydrocinnamic Acid; Ba-34647; Baclofeno; Baclofenum; Baklofén; Baklofeeni; Baklofen; Baklofenas

BAN: Baclofen

USAN: Baclofen

INN: Baclofen [rINN (en)]

INN: Baclofeno [rINN (es)]

INN: Baclofène [rINN (fr)]

INN: Baclofenum [rINN (la)]

INN: Баклофен [rINN (ru)]

Chemical name: β-Aminomethyl-p-chlorohydrocinnamic acid; (RS)-Amino-3-(4-chlorophenyl)butyric acid

Molecular formula: C10H12ClNO2 =213.7

CAS: 1134-47-0

ATC code: M03BX01

Read code: y031e

Pharmacopoeias. In Europe, Japan, and the US.

European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 6.2 (Baclofen). A white or almost white powder. It exhibits polymorphism. Slightly soluble in water; very slightly soluble in alcohol; practically insoluble in acetone; dissolves in dilute mineral acids and dilute solutions of alkali hydroxides.

The United States Pharmacopeia 31, 2008, and Supplements 1 and 2 (Baclofen). A white to off-white, odorless or practically odorless, crystalline powder. Slightly soluble in water, very slightly soluble in methyl alcohol, insoluble in chloroform. Store in airtight containers.

Preparations

British Pharmacopoeia 2008; Baclofen Oral Solution; Baclofen Tablets;

The United States Pharmacopeia 31, 2008, and Supplements 1 and 2: Baclofen Oral Suspension; Baclofen Tablets.

Proprietary Preparations

Argentina: Baclodox; Lioresal;

Australia: Baclo; Baclohexal ; Clofen; Lioresal; Stelax;

Austria; Lioresal;

Belgium: Lioresal;

Brazil: Baclon; Lioresal;

Canada: Lioresal; Liotec ; Nu-Baclo;

Chile: Cetril; Lioresyl;

Denmark: Lioresal;

Finland: Baclon; Baclopar; Lioresal;

France: Lioresal;

Germany; Lebic; Lioresal;

Greece: Jofen ; Lioresal; Miorel; Vioridon;

Hong Kong; Lioresal; Stelax;

Hungary: Lioresal;

India: Lioresal;

Indonesia: Lioresal;

Ireland: Baclopar; Lioresal;

Israel: Baclosal; Lioresal;

Italy: Lioresal;

Malaysia: Clofen; Lioresal;

The Netherlands: Lioresal;

Norway: Lioresal;

New Zealand: Pacifen;

Philippines: Lioresal; Onelaxant-R;

Portugal: Lioresal;

Russia: Baclosan;

Singapore: Lioresal-L;

Spain: Lioresal;

Sweden: Lioresal;

Switzerland: Lioresal;

Thailand: Baclosal; Fenisal; Liobac; Lioresal;

Turkey: Lioresal;

United Kingdom (UK): Baclospas ; Lioresal; Lyflex;

United States of America (US and USA): Kemstro; Lioresal;

Venezuela: Lioresal.