Baclofen (Page 2 of 3)

7 DRUG INTERACTIONS

7.1 CNS Depressants and Alcohol

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

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

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

Clinical Considerations

Fetal/Neonatal Adverse Reactions

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

Data

Animal Data

Baclofen given orally has been shown to increase the incidence of omphaloceles (ventral hernias) in fetuses of rats given approximately 13 times on a mg/kg basis, or 3 times on a mg/m2 basis, the maximum oral dose recommended for human use; this dose also caused reductions in food intake and weight gain in the dams. This abnormality was not seen in mice or rabbits.

8.2 Lactation

Risk Summary

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

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

8.4 Pediatric Use

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

8.5 Geriatric Use

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

8.6 Renal Impairment

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

10 OVERDOSAGE

10.1 Symptoms of Baclofen Overdose

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

10.2 Treatment for Overdose

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

11 DESCRIPTION

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

Structure

Molecular formula is C10 H12 C1NO2 .
Molecular Weight is 213.66 g/mol.

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

The baclofen oral suspension inactive ingredients are artificial grape flavor, hydrochloric acid, hypromellose, methyl paraben, propyl paraben, purified water, simethicone emulsion, sodium hydroxide, sucralose, and xanthan gum.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

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

12.3 Pharmacokinetics

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

Absorption

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

Effect of Food

Administration of baclofen oral suspension with a high-fat meal resulted in 9% decrease in AUC and 33% decrease in Cmax compared to the fasted state.

Elimination

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

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

No increase in tumors was seen in rats receiving baclofen orally for two years at approximately 30 to 60 times on a mg/kg basis, or 10 to 20 times on a mg/m2 basis, the maximum oral dose recommended for human use.

Mutagenesis

Genetic toxicology assays have not been conducted for baclofen.

Impairment of Fertility

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

14 CLINICAL STUDIES

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

16 HOW SUPPLIED/STORAGE AND HANDLING

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