THERAPEUTIC CLASSIFICATION

Muscle Relaxant-Antispastic

ACTION AND CLINICAL PHARMACOLOGY

The precise mechanisms of action of baclofen are not fully known. It inhibits both monosynaptic and polysynaptic reflexes at the spinal level, probably by hyperpolarization of afferent terminals, although actions at supraspinal sites may also occur and contribute to its clinical effect. Although baclofen is an analog of the putative inhibitory neurotransmitter gamma-aminobutyric acid (GABA), there is no conclusive evidence that actions on GABA systems are involved in the production of its clinical effects. Peak plasma concentrations of baclofen are achieved within 2 hours and the plasma half-life is approximately 2.5-4 hours.

PHARMACOKINETICS AND METABOLISM

Results of studies with radio-labelled baclofen in healthy subjects indicate that it is well absorbed after oral administration, is metabolised to only a limited extent and is excreted largely in the urine.

Absorption/Excretion

Since 90% of baclofen is excreted in urine of rats, it was apparent this percentage must have been absorbed to be excreted in urine; the rest of the dose was excreted in feces. The same ratio was found when the drug was administered i.v.. Similar behavior was observed in dog and man. Evidence of absorption in man was derived from bioavailability studies employing analysis of unchanged baclofen in urine. In a study of experimental formulation, five subjects ingested 20 mg of baclofen as tablets on two occasions. Renal excretion of unchanged baclofen ranged from 49.5 to 82.8% of dose in 24 hours, based on G.C.. analysis, with 21.7 - 37.5% excreting within four hours after dosage. Maximum plasma concentrations were observed at 1-2 hours after dosage. No statistically significant difference was found as a result of fasting, either in the extent or the rate of excretion.

Blood Plasma Concentrations

Plasma samples from five subjects ingesting a 10 mg to 40 mg oral dose of 14C labelled baclofen showed maximum concentrations ranging from 0.1 to 0.8 :g/mL, by inverse isotope dilution method, two hours after dosing. The concentrations decreased to less than 0.2 :g/mL at the eighth hour, with a half-life of approximately 2.5 - 4.0 hours. Gas chromatographic analysis of plasma and cerebrospinal fluid samples from two multiple sclerosis patients on the fifth day of baclofen therapy (10 mg t.i.d.) showed plasma concentrations of 203 - 278 ng/mL for one patient and 91 - 179 ng/mL for the other. The concentrations in cerebrospinal fluid were 11 - 13 ng/mL and 8 - 25 ng/mL, respectively.

Elimination

Baclofen is readily eliminated by renal excretion, e.g. 55 - 92% radioactivity was excreted in urine by five subjects receiving a 10 mg to 40 mg oral dose of 14C-labelled baclofen. The unchanged drug in urine, as measured by an inverse isotope dilution method, comprised 94 - 96% of the total radioactivity in the urine.

Transformation

The concentration of metabolites was at a maximum between 2 and 4 hours after oral dosage, followed by a decrease to less than 0.05 :g/mL at 24 hours. Analysis of urine from these subjects showed that only 3 - 6% of the dose was excreted renally as metabolites, with the major portion being excreted in urine as unchanged baclofen. A bioavailability study was performed to compare the plasma levels produced after a single oral dose administration of two different formulations of baclofen 20 mg to healthy volunteers in order to test their bioequivalency. The results of the investigation show that the pharmacokinetic profile of the Pharmel Inc. baclofen formulation is almost superimposable to the one of the reference formulation, thus proving its bioequivalency.

Pharmacokinetic profile of two different formulations of baclofen (20 mg)

For the Tmax and T1/2el parameters these are the arithmetic means with standard deviation in parenthesis.

CONTRAINDICATIONS

WARNINGS

: Following abrupt withdrawal of baclofen, visual and auditory hallucinations, confusion, anxiety with tachycardia and sweating, insomnia, and worsening of spasticity have occurred.

Therefore, except for serious adverse reactions, the dose should be reduced slowly when the drug is discontinued.

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

: Baclofen has not significantly benefited patients with stroke. These patients have also shown poor tolerability to the drug.

: Safe use of baclofen during pregnancy or lactation has not been established. High doses are associated with a increased incidence of abdominal hernias in the fetuses of rats and of ossification defects in those of rats and rabbits. Therefore, the drug should be administered to pregnant patients, or women of child-bearing potential only when, in the judgment of the physician,

PRECAUTIONS

Safe use of baclofen in children under age 12 has not been established and it is, therefore, not recommended for use in children. Because of the possibility of sedation, patients should be cautioned regarding the operation of automobiles or dangerous machinery, and activities made hazardous by decreased alertness. Patients should also be cautioned that the central nervous system effects of baclofen may be additive to those of alcohol and other CNS depressants. Baclofen should be used with caution where spasticity is utilized to sustain upright posture and balance in locomotion, or whenever spasticity is utilized to obtain increased function. Extreme caution should be exercised in patients with epilepsy or a history of convulsive disorders. In such patients, the clinical state and electroencephalogram should be monitored at regular intervals during therapy, as deterioration in seizure control and EEG has been reported occasionally in patients taking baclofen. Caution should be used in treating patients with peptic ulceration, severe psychiatric disorders, elderly patients with cerebrovascular disorders, and in patients receiving antihypertensive therapy. It is not known whether baclofen is excreted in human milk. As a general rule, nursing should not be undertaken while a patient is on a drug since many drugs are excreted in human milk.

ADVERSE REACTIONS

The most common adverse reactions associated with baclofen are transient drowsiness, dizziness, weakness and fatigue. Others reported:

Neuropsychatric

: Headache (<10%), insomnia (<10%), and rarely euphoria, excitement, depression, confusion, hallucinations, paresthesia, muscle pain, tinnitus, slurred speech, coordination disorder, tremor, rigidity, dystonia, ataxia, blurred vision, nystagmus, strabismus, miosis, mydriasis, diplopia, dysarthria, epileptic seizures.

Cardiovascular

: Hypotension (<10%), rare instances of dyspnea, palpitation, chest pain, syncope.

Gastrointestinal

: Nausea (approx. 10%), constipation (<10%) and rarely, dry mouth, anorexia, taste disorder, abdominal pain, vomiting, diarrhea, and positive test for occult blood in stool.

Genitourinary

: Urinary frequency (<10%), and rarely, enuresis, urinary retention, dysuria, impotence, inabililty to ejaculate, nocturia, hematuria.

Other

: Instances of rash, pruritus, ankle edema, excessive perspiration, weight gain, nasal congestion.

Some of the CNS and genitourinary symptoms reported may be related to the underlying disease rather than to drug therapy. The following laboratory tests have been found to be abnormal in a few patients receiving baclofen: SGOT, alkaline phosphatase and blood sugar (all elevated).

SYMPTOMS AND TREATMENT OF OVERDOSAGE

Vomiting, muscular hypotonia, hypotension, drowsiness, accomodation disorders, coma, respiratory depression and seizures. The signs and symptoms may be further aggravated by co-administration of a variety of other agents including alcohol, diazepam, and tricyclic anti-depressants.

The treatment is symptomatic. In the alert patient, empty the stomach promptly by induced emesis followed by lavage. In the obtunded patient, secure the airway with a cuffed endotracheal tube before beginning lavage (do not induce emesis). Maintain adequate respiratory exchange; do not use respiratory stimulants. Muscular hypotonia may involve the respiratory muscles and require assisted respiration. A high urinary output should be maintained since baclofen (baclofen) is excreted mainly by the kidneys. Dialysis is indicated in severe poisoning associated with renal failure.

DOSAGE AND ADMINISTRATION

The determination of optimal dosage of phl-BACLOFEN (baclofen) requires individual titration. Start therapy at a low dosage and increase gradually until optimum effect is achieved (usually between 40-80 mg daily). The following dosage schedule is suggested: 5 mg three times daily for 3 days 10 mg three times daily for 3 days 15 mg three times daily for 3 days 20 mg three times daily for 3 days Thereafter additional increases may be necessary but the total daily dose should not exceed a maximum of 80 mg daily (20 mg four times daily). The lowest dose compatible with an optimal response is recommended. If benefits are not evident after a reasonable trial period, patients should be slowly withdrawn form the drug (see WARNINGS).

PHARMACEUTICAL INFORMATION

Molecular Formula: C10H12ClNO2 Molecular Weight: 213.67 Description: Baclofen is a white to off-white, virtually odorless, crystalline powder with slightly bitter taste. The melting range (192-193/C) of baclofen can vary due to lactam formation with a concomitant loss of water. Baclofen is slightly soluble in water, poorly soluble in organic solvents. The pKa values in water (5.0x10-3 moles/1) at 20/C are as follows: pKa1 = 3.87 + 0.1 (carboxyl group) pKa2 = 9.62 + 0.1 (amino group)

Stability and Storage Recommendations

AVAILABILITY OF DOSAGE FORMS

A white, oval, flat, bevelled edge bisected tablet inscribed "pms" on one side of line and "10" on the other. Reverse side inscribed "Baclofen". Available in bottles of 100, 500 and 1000. phl-BACLOFEN 20 mg tablet: A white capsule shaped tablet inscribed "pms" on one side of the score line and "20" on the other. Reverse side inscribed "Baclofen". Available in bottles of 100, 500 and 1000.

PHARMACOLOGY

Baclofen exerted a pronounced muscle-relaxant effect in the non-anesthetized mouse, rabbit, cat and dog. Doses of up to 10 mg/Kg p.o. did not affect coordination in mice. Intravenous doses of 1 or 2 mg/Kg decreased polysynaptic (flexor) spinal reflexes in anesthetized rabbits or cats respectively by 50%. A similar reduction was found in decerebrated or spinal cats. The monosynaptic (extensor) spinal reflex was reduced 50% by a dose of 0.5 mg/Kg i.v. in spinalized, decerebrate, or anesthetized cats. Baclofen had no direct effect on the alpha-motor nerve fibres, neuromuscular transmission, or contraction of extrafusal muscle fibres in anesthetized cats. An intravenous dose of 0.8 mg/Kg diminished to tonic activity of gamma motoneurons in decerebrate cats by 50%. Baclofen diminished or abolished decerebrate rigidity in cats in doses of 1-3 mg/Kg. It had no effect on the de-efferented muscle spindle or the slowly-adapting pulmonary stretch receptors in anesthetized cats. Baclofen had anticonvulsive effects against thiosemicarbazide and pentetrazole-induced convulsions in mice but had no effect against electroshock or strychnine-induced convulsions. An intravenous dose of 3-6 mg/Kg exerted a hypnotic effect in the unanesthetized dog. Large doses impaired respiration in mice, rabbits, and dogs. Doses of 1 mg/kg i.v. produced a fall in the blood pressure of anesthetized rabbits or cats, but 3 mg/kg i.v. had no effect on the blood pressure, heart rate, ECG, or respiration of unanesthetized dogs. In man, a single oral dose of 10 mg of baclofen is rapidly and almost completely absorbed whereas absorption of 20 mg and 40 mg doses is less complete. Animal studies indicate rapid distribution throughout the body except the CNS where concentrations are lower than average. The decay in CNS concentration is, however, slower than the decay from other tissues. About 85% of a single oral dose is excreted unchanged in the urine. The remaining 15% is mainly deaminated to ss-p-chlorophenyl)-J-hydroxybutyric acid within 24 hours.

TOXICOLOGY

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Mouse		i.v.	26 +- 6
Mouse		p.o.	75 +- 22
Rat	i.v.		112 +- 14
Rat	p.o.		150 +- 18
Rat	s.c.		137 +- 17

The toxic symptoms in mice and rats included ataxia, clonic-tonic convulsions and respiratory paralysis.

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TERATOLOGY AND REPRODUCTION

incidence of ovarian cysts.
Dog	12 12	4	3 M	0, 2-4, 3-8	p.o.	1 Y	Transient emesis,
			3 F	4-12			sedation,
	convulsions
and cardiovascular
collapse (single
animal) possible
slight adrenal
enlargement
hind limb weakness
paralysis.

: Two groups of pregnant rats were given 5 and 20 mg/kg baclofen daily by gavage on days 6 to 15 of gestation. In the high dose groups a significant number of fetuses (4/160) developed abdominal hernias, as did 6 out of 293 high dose (20 mg/kg) and 1 out of 229 control fetuses in a similar study. A comparable experiment in mice produced no such abnormalities.

Also in the 20 mg/kg group of pregnant rats, there was a significantly lower average neonatal weight. The control and active treatment groups showed no significant difference in the average number of viable or stillborn offspring. Doses of 4.5-5 and 17.7-21.3 mg/Kg/day were administered orally to two groups of female rats during pre-mating, mating, gestation, and lactation. The only significant effect was a reduction in litter size and survivability of offspring (possibly due to agalactia) in the high-dose group. In another study performed during the last trimester and throughout lactation, rats were given 5 and 10 mg/kg/day doses by gavage. Of the 31 females receiving 10 mg/kg 5 had agalactia, marked weight loss from days 15 to 21 of gestation, and by the second day after giving birth all their offspring had died.

: Doses of 1, 5 and 10 mg/kg/day were administered by gavage to groups of rabbits from the 6th to 18th day of gestation. There was an increased incidence of unossified phalangeal nuclei of forelimbs and hind-limbs in the fetuses from the high-dose group.

Parameter	Geometric Mean Arithmetic Mean (C.V.)		Ratio of Means (%)
Parameter	TEST	REFERENCE	Ratio of Means (%)
AUC t	1727.36	1643.22	105.1
(ng.h./mL)	1750.80 (16.9)	1662.59 (15.4)	105.1
AUC "	1932.48	1864.46	103.7
(ng.h./mL)	1955.94 (16.0)	1888.63 (16.4)
C max			105.8
(ng/mL)	348.73	329.64
	354.99 (18.9)	334.98 (18.0)
T max			---
(hours)	1.57 (0.70)	1.22 (0.75)
T 1 /2 el			---
(hours)	4.24 (1.09)	4.47 (1.23)	---

Rat	10 10	5	2 M	Baclofen +	p.o.	30 D	None
			2 F	diazepam; 0 + 0
				4 + 2, 20 + 10
				0 + 10, 20 + 0

Dog	8 8	4	2 M	0, 1, 2, 4-8	p.o.	30 D	Emesis at all
			2 F	(double in last			dose levels,
				last week)			anorexia,
							salivation,
							ataxia,
							sedation,
							weight loss.

Rat	80 80	4	20 M	0, 5, 20-160 p.o.	1 Y	Weight loss,
			20 F	40-500		mild alepecia
						urinary
						incontinence
						at intermediate
						and high doses.
						Elevated mean
						neutrophil/
						lymphocyte
						ratios and
						SGPT at
						intermediate
						and high doses

PRODUCT MONOGRAPH

Muscle Relaxant Antispastic Agent

PHARMEL INC

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