Baclofen

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Adverse Reactions from Abrupt Withdrawal of Baclofen [see Warnings and Precautions ( 5.1 )] • Neonatal Withdrawal Symptoms [see Warnings and Precautions ( 5.2 )] • Drowsiness and Sedation [see Warnings and Precautions ( 5.3 )] • Poor Tolerability in Stroke Patients [see Warnings and Precautions ( 5.4 )] • Exacerbation of Psychotic Disorders, Schizophrenia, or Confusional States [see Warnings and Precautions ( 5.5 )] • Exacerbation of Autonomic Dysreflexia [see Warnings and Precautions ( 5.6 )] • Exacerbation of Epilepsy [see Warnings and Precautions ( 5.7 )] • Posture and Balance Effects [see Warnings and Precautions ( 5.8 )] • Ovarian Cysts [see Warnings and Precautions ( 5.9 )] • The most common (up to 15% or more) adverse reactions in patients were drowsiness, dizziness, and weakness. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Wilshire Pharmaceuticals at 1-877-495-6856 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most common adverse reaction is transient drowsiness. In one controlled study of 175 patients, transient drowsiness was observed in 63% of those receiving baclofen compared to 36% of those in the placebo group. Other common adverse reactions (up to 15%) are dizziness and weakness. Adverse reactions with a frequency of ≥1% are listed in Table 1 . Table 1. Common (≥1%) Adverse Reactions in Patients Treated with Baclofen for Spasticity ADVERSE REACTION PERCENT Drowsiness 10-63% Dizziness 5-15% Weakness 5-15% Nausea 4-12% Confusion 1-11% Hypotension 0-9% Headache 4-8% Insomnia 2-7% Constipation 2-6% Urinary Frequency 2-6% Fatigue 2-4% The following adverse reactions not included in Table 1, classified by body system, were also reported: Neuropsychiatric: euphoria, excitement, depression, hallucinations, paresthesia, muscle pain, tinnitus, slurred speech, coordination disorder, tremor, rigidity, dystonia, ataxia, blurred vision, nystagmus, strabismus, miosis, mydriasis, diplopia, dysarthria, epileptic seizure Cardiovascular: dyspnea, palpitation, chest pain, syncope Gastrointestinal: dry mouth, anorexia, taste disorder, abdominal pain, vomiting, diarrhea, and positive test for occult blood in stool Genitourinary: enuresis, urinary retention, dysuria, impotence, inability to ejaculate, nocturia, hematuria Other: rash, pruritus, ankle edema, excessive perspiration, weight gain, nasal congestion The following laboratory tests have been found to be abnormal in patients receiving baclofen: increased SGOT, elevated alkaline phosphatase, and elevation of blood sugar.

4 CONTRAINDICATIONS Baclofen oral suspension is contraindicated in patients with hypersensitivity to baclofen. • Hypersensitivity to baclofen ( 4 )

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: Molecular formula is C 10 H 12 C1NO 2 . 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, citric acid anhydrous, D&C yellow No. 10, FD&C red No. 40, hydroxyethyl cellulose, propylene glycol, purified water, simethicone emulsion, sodium benzoate, and sucralose. Structural Formula

2 DOSAGE AND ADMINISTRATION • Baclofen is a concentrated formulation. Verify the dose of the product prior to dispensing. ( 2.1 ) • Initiate baclofen with a low dosage, preferably in divided doses, administered orally. Increase gradually based on clinical response and tolerability. ( 2.2 ) • The maximum dosage is 80 mg daily (20 mg four times a day). ( 2.2 ) • When discontinuing, reduce the dosage slowly. ( 2.3 ) 2.1 Important Information Baclofen is a concentrated formulation. Verify the strength and the dose of the product prior to prescribing, dispensing, and administering. 2.2 Recommended Dosage Initiate baclofen with a low dosage, preferably in divided doses, administered orally. The following gradually increasing dosage regimen is suggested, but should be adjusted based on clinical response and tolerability: 1 mL (5 mg) three times a day for three days 2 mL (10 mg) three times a day for three days 3 mL (15 mg) three times a day for three days 4 mL (20 mg) three times a day for three days Additional increases may be necessary up to the maximum recommended dosage of 80 mg daily [4 mL (20 mg) four times a day]. 2.3 Administration Instructions Shake well baclofen oral suspension before administration. Discard unused portion 2 months after first opening. A calibrated measuring device is recommended to measure and deliver the prescribed dose accurately. A household teaspoon or tablespoon is not an adequate measuring device. 2.4 Discontinuation of Baclofen When discontinuing baclofen, reduce the dosage slowly and avoid abrupt withdrawn from the drug to help minimize the risk of adverse reactions [see Warnings and Precautions ( 5.1 )] .

1 INDICATIONS AND USAGE Baclofen is indicated for the treatment of spasticity resulting from multiple sclerosis, particularly for the relief of flexor spasms and concomitant pain, clonus, and muscular rigidity. Baclofen may also be of some value in patients with spinal cord injuries and other spinal cord diseases. Limitations of Use Baclofen is not indicated in the treatment of skeletal muscle spasm resulting from rheumatic disorders. • Baclofen is a gamma-aminobutyric acid (GABA-ergic) agonist indicated for the treatment of spasticity resulting from multiple sclerosis, particularly for the relief of flexor spasms and concomitant pain, clonus, and muscular rigidity. ( 1 ) • Baclofen may also be of some value in patients with spinal cord injuries and other spinal cord diseases. ( 1 ) Limitations of Use Baclofen is not indicated in the treatment of skeletal muscle spasm resulting from rheumatic disorders. ( 1 )

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.

7 DRUG INTERACTIONS 7.1 CNS Depressants and Alcohol Baclofen 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 )] .

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 GABA B 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 with a high-fat meal resulted in 9% decrease in AUC and 33% decrease in C max 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.

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 GABA B 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 with a high-fat meal resulted in 9% decrease in AUC and 33% decrease in C max 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.

20230222

1

3 DOSAGE FORMS AND STRENGTHS Oral Suspension: 25 mg per 5 mL (5 mg/mL) baclofen as a concentrated orange to yellow- colored, grape-flavored suspension. Oral Suspension: 25 mg per 5 mL (5 mg/mL) ( 3 )

Baclofen baclofen BACLOFEN BACLOFEN ANHYDROUS CITRIC ACID D&C YELLOW NO. 10 FD&C RED NO. 40 HYDROXYETHYL CELLULOSE, UNSPECIFIED PROPYLENE GLYCOL WATER DIMETHICONE SILICON DIOXIDE SODIUM BENZOATE SUCRALOSE

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/m 2 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.

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/m 2 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.

NDA215602

Baclofen

baclofen

52536-600

HUMAN PRESCRIPTION DRUG

ORAL

PRINCIPAL DISPLAY PANEL - Bottle Label Bottle Label NDC 52536-600-11 Rx Only Baclofen Oral Suspension 25 mg per 5 mL (5 mg/mL) Concentrated Formulation ATTENTION: This is a concentrated baclofen formulation of 25 mg/5 mL (5 mg/mL). Manufactured for: WILSHIRE ® PHARMACEUTICALS, INC. Atlanta,GA 30328 USA 120 mL KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN Each mL contains 5 mg of baclofen USP Recommended Dosage: See prescribing information. Store at 20°C to 25°C (68°F to 77°F) excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature] . Ensure tamper evident seal on the bottle is present and intact before using. Date of first opening _______ / _______ / _______ Discard unused portion 2 months after first opening. Part #: ASSY00721 REV 01 02/23 SHAKE BEFORE USING Principal Display Panel - Bottle Label

Manufactured for: Wilshire Pharmaceuticals, Inc. Atlanta, GA 30328 USA PN: PI-00729 REV: 01

17 PATIENT COUNSELING INFORMATION Administration Instructions Inform patients that baclofen is a concentrated formulation. Instruct patients or caregivers to use an oral dosing syringe and not to use a household teaspoon to correctly measure the prescribed amount of medication. Inform patients that oral dosing syringes may be obtained from their pharmacy. Instruct patients to shake before using [see Dosage and Administration ( 2.1 , 2.3 )] . Risks Related to Sudden Withdrawal of Baclofen Advise patients and caregivers not to discontinue use of baclofen without consulting with their healthcare provider because sudden withdrawal of baclofen can result in serious complications that include hallucinations, seizures, high fever, confusion, muscle stiffness, multiple organ-system failure, and death [see Warnings and Precautions ( 5.1 )] . Inform patients that early symptoms of baclofen withdrawal may include increased spasticity, itching, and tingling of extremities. Neonatal Withdrawal Symptoms Advise patients to notify their healthcare provider if they are pregnant, plan to become pregnant, or plan to breastfeed [see Warnings and Precautions ( 5.2 ) and Use in Specific Populations ( 8.2 )] . Increased Risk of Drowsiness with Alcohol and Other CNS Depressants Advise patients that baclofen may cause drowsiness, and that they should avoid the operation of automobiles or other dangerous machinery, or activities made hazardous by decreased alertness when starting baclofen or increasing the dose until they know how the drug affects them [see Warnings and Precautions ( 5.3 )] . Inform patients and their caregivers that the drowsiness associated with baclofen use can be worsened by alcohol and other CNS depressants. Advise patients to read all medicine labels carefully, and to tell their healthcare provider about all prescription and nonprescription drugs they may use. Storage Instruct patients to store baclofen at room temperature and to discard unused portion 2 months after first opening [see How Supplied/Storage and Handling ( 16.2 )] .

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

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 )] .

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

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 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 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/m 2 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 USE IN SPECIFIC POPULATIONS • Pregnancy: Based on animal data, may cause fetal harm. ( 8.1 ) • Because baclofen is excreted unchanged through the kidneys it may be necessary to reduce the dosage in patients with impaired renal function. ( 8.6 ) 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 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 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/m 2 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 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 and any potential adverse effects on the breastfed infant from baclofen 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 should be given with caution to patients with renal impairment, and it may be necessary to reduce the dosage.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Baclofen oral suspension contains 25 mg per 5 mL (5 mg/mL) baclofen. It is a concentrated orange to yellow-colored, grape-flavored suspension and is supplied in high-density polyethylene (HDPE) bottles with white, polypropylene, child-resistant closures with a foam liner and heat induction layered inner seal. 120 mL, NDC 52536-600-11 300 mL, NDC 52536-600-12 16.2 Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15° and 30° (59° and 86° F) (see USP Controlled Room Temperature). Discard unused portion 2 months after first opening.

16.2 Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15° and 30° (59° and 86° F) (see USP Controlled Room Temperature). Discard unused portion 2 months after first opening.