CREXONT

RECENT MAJOR CHANGES Dosage and Administration ( 2.1 ) 3/2026 Dosage and Administration ( 2.5 ) 5/2026 Warnings and Precautions ( 5.7 ) 3/2026

1 INDICATIONS AND USAGE CREXONT is indicated for the treatment of Parkinson's disease, post-encephalitic parkinsonism, and parkinsonism that may follow carbon monoxide intoxication or manganese intoxication in adults. CREXONT is a combination of carbidopa (an aromatic amino acid decarboxylation inhibitor) and levodopa (an aromatic amino acid) indicated for the treatment of Parkinson’s disease, post-encephalitic parkinsonism, and parkinsonism that may follow carbon monoxide intoxication or manganese intoxication in adults. ( 1 )

2 DOSAGE AND ADMINISTRATION Evaluate vitamin B6 levels prior to starting treatment with carbidopa/levodopa therapies. ( 2.1 ) Levodopa-naïve patients: Starting dose is 35 mg carbidopa / 140 mg levodopa taken orally twice daily for the first 3 days; on the fourth day of treatment, dosage may be increased gradually as needed. ( 2.2 ) Patients converting from immediate-release carbidopa/levodopa: See Table 1 for instructions; dosages are not substitutable on a 1:1 basis. ( 2.3 ) The maximum recommended daily dosage of CREXONT is 525 mg carbidopa / 2100 mg levodopa. ( 2.2 , 2.3 ) CREXONT may be taken with or without food; do not chew, divide, or crush. ( 2.5 , 12.3 ) CREXONT should not be taken with alcohol. ( 2.5 , 12.3 ) 2.1 Management of Vitamin B6 Levels Evaluate vitamin B6 levels prior to initiating carbidopa/levodopa therapies, including CREXONT, periodically during treatment, and as clinically indicated [see Warnings and Precautions (5.7) ]. If vitamin B6 levels are low, supplement to sufficient levels per standard of care. Patients may initiate and continue treatment with CREXONT while supplementing vitamin B6. 2.2 Dosage in Patients Naïve to Levodopa Therapy The recommended starting dosage of CREXONT in levodopa-naïve patients is 35 mg carbidopa / 140 mg levodopa taken orally twice daily for the first three days. Thereafter, dosage may be increased gradually as needed to a maximum daily dosage of 525 mg carbidopa / 2100 mg levodopa divided up to four times daily. 2.3 Dosage in Patients Converting from Immediate-Release Carbidopa-Levodopa to CREXONT The dosages of immediate-release carbidopa-levodopa products are not substitutable on a 1:1 basis with the dosages of CREXONT. To convert patients from immediate-release carbidopa-levodopa to CREXONT, follow these steps: Step 1: Determine the patient’s total daily dosage of immediate-release levodopa. Step 2: Determine the patient’s most frequent single dose of immediate-release levodopa. If more than one dose corresponds to the most frequent, use the highest of the doses. Step 3: Find the values from Step 1 and Step 2 in Table 1 (below) to determine the recommended starting CREXONT dosage of levodopa and dosing frequency. Step 4: After one to three days, adjust the dose or frequency as needed based on the patient’s clinical response and tolerability. Dosage may be increased gradually as needed to a maximum daily dosage of 525 mg carbidopa / 2100 mg levodopa divided up to four times daily. Table 1: Conversion from Immediate-Release Carbidopa-Levodopa to CREXONT Total Daily Immediate-Release Levodopa Dosage Most Frequent Immediate-Release Levodopa Single Dose Recommended Starting CREXONT Dosage of Levodopa Less than 500 mg daily 100 mg 280 mg twice daily 150 mg 420 mg twice daily 200 mg 560 mg twice daily Equal to or greater than 500 mg daily 100 mg 280 mg three times daily 150 mg 420 mg three times daily 200 mg 560 mg three times daily Greater than 200 mg 700 mg three times daily For patients currently treated with carbidopa and levodopa plus a catechol-O-methyl transferase (COMT) inhibitor (e.g., entacapone or opicapone), the initial total daily dose of levodopa in CREXONT may need to be increased if the COMT inhibitor is discontinued. Use of CREXONT in combination with other levodopa products has not been studied. 2.4 Dosage for Patients Converting from Extended-Release Carbidopa-Levodopa (Rytary) to CREXONT For patients converting from RYTARY (extended-release carbidopa-levodopa), initiate CREXONT on an approximately 1:1 mg basis using the levodopa component for conversion. 2.5 Administration Information Swallow CREXONT whole with or without food. CREXONT should not be taken with alcohol. A high-fat, high-calorie meal may delay the absorption of levodopa to reach the peak plasma concentration by about 2 hours [see Clinical Pharmacology (12.3) ]. Do not chew, divide, or crush CREXONT capsules. For patients who have difficulty swallowing intact capsules, administer CREXONT by …

3 DOSAGE FORMS AND STRENGTHS CREXONT extended-release capsules contain white to off-white granules and pellets and are available in the following strengths: 35 mg carbidopa and 140 mg levodopa: Capsules with white opaque body and yellow opaque cap. Body imprinted with “140” in black ink and cap imprinted with “IPX203” in white ink. 52.5 mg carbidopa and 210 mg levodopa: Capsules with white opaque body and green opaque cap. Body imprinted with “210” in black ink and cap imprinted with “IPX203” in white ink. 70 mg carbidopa and 280 mg levodopa: Capsules with white opaque body and purple opaque cap. Body imprinted with “280” in black ink and cap imprinted with “IPX203” in white ink. 87.5 mg carbidopa and 350 mg levodopa: Capsules with white opaque body and medium orange opaque cap. Body imprinted with “350” in black ink and cap imprinted with “IPX203” in white ink. Extended-Release Capsules: Carbidopa and Levodopa 35 mg / 140 mg, 52.5 mg / 210 mg, 70 mg / 280 mg, 87. 5 mg / 350 mg ( 3 )

4 CONTRAINDICATIONS CREXONT is contraindicated in patients currently taking a nonselective monoamine oxidase (MAO) inhibitor or have recently (within 2 weeks) taken a nonselective MAO inhibitor. Hypertension can occur if these drugs are used concurrently [see Drug Interactions (7.1) ] . Nonselective MAO inhibitors (4)

6 ADVERSE REACTIONS The following serious adverse reactions are discussed below and elsewhere in the labeling: Falling Asleep During Activities of Daily Living and Somnolence [see Warnings and Precautions (5.1) ] Withdrawal-Emergent Hyperpyrexia and Confusion [see Warnings and Precautions (5.2) ] Cardiovascular Ischemic Events [see Warnings and Precautions (5.3) ] Hallucinations/Psychosis [see Warnings and Precautions (5.4) ] Impulse Control/Compulsive Behaviors [see Warnings and Precautions (5.5) ] Dyskinesia [see Warnings and Precautions (5.6) ] Vitamin B6 Deficiency and Seizures [see Warnings and Precautions (5.7) ] P eptic Ulcer Disease [see Warnings and Precautions (5.8) ] Glaucoma [see Warnings and Precautions (5.9) ] The most common adverse reactions (incidence ≥ 3% and greater than immediate-release CD-LD) are nausea and anxiety. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 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 clinical practice. The safety population consisted of 589 patients with Parkinson’s disease who received CREXONT for up to 76 weeks and had an average duration of exposure of 35 weeks. Study 1 in patients with Parkinson’s Disease consisted of a dose adjustment period of immediate-release carbidopa-levodopa treatment prior to a 4-week dose conversion period to CREXONT, which was then followed by a 13-week, double-blind, randomized period comparing CREXONT to immediate-release carbidopa-levodopa [see Clinical Studies (14) ]. In Study 1 , the most common adverse reactions (in at least 3% of patients treated with CREXONT and more frequently than with immediate-release carbidopa-levodopa) that occurred during the double-blind maintenance period were nausea and anxiety. Table 2 lists adverse reactions occurring in at least 2% of CREXONT-treated patients while converting from immediate-release carbidopa-levodopa and at a higher rate than immediate-release carbidopa-levodopa in the double-blind maintenance period. Table 2. Adverse Reactions that Occurred in at Least 2% of Patients with Parkinson’s Disease who Received CREXONT and at a Higher Rate than Patients who Received Immediate-Release Carbidopa-Levodopa (Study 1) Adverse Reaction Dose Conversion Period Double-Blind Period CREXONT CREXONT Immediate-Release Carbidopa-Levodopa (N=589) % (N=256) % (N= 250) % Nausea 5 4 1 Anxiety 2 3 0 Dizziness 3 2 1 Dyskinesia 7 2 0.4 Constipation 2 2 0.4 Headache 2 1 0 Vomiting 2 1 0 Insomnia 2 1 0.4 Adverse Reactions Leading to Discontinuation In Study 1, 6% of patients discontinued treatment because of adverse reactions during conversion to CREXONT. During the double-blind treatment period of Study 1, 5% of patients taking CREXONT and 1% of patients taking immediate-release carbidopa-levodopa discontinued treatment because of adverse events. The common adverse reactions leading to drug discontinuation during dose conversion were dyskinesia, dizziness, and nausea.

7 DRUG INTERACTIONS Iron salts and dopamine D2 antagonists, including metoclopramide, may reduce the effectiveness of CREXONT. ( 7.2 , 7.3 ) 7.1 Monoamine Oxidase (MAO) Inhibitors Nonselective MAO Inhibitors The use of nonselective MAO inhibitors (e.g., phenelzine and tranylcypromine) with CREXONT is contraindicated [see Contraindications (4) ] . Discontinue use of any nonselective MAO inhibitors at least two weeks prior to initiating CREXONT. Selective MAO Inhibitors The use of selective MAO-B inhibitors (e.g., rasagiline and selegiline) with CREXONT may be associated with orthostatic hypotension. Monitor patients who are taking these drugs concurrently. 7.2 Dopamine D2 Receptor Antagonists and Isoniazid Dopamine D2 receptor antagonists (e.g., phenothiazines, butyrophenones, risperidone, metoclopramide) and isoniazid may reduce the effectiveness of levodopa. Monitor patients for worsening Parkinson’s symptoms. 7.3 Iron Salts Iron salts or multivitamins containing iron salts can form chelates with levodopa and carbidopa and can cause a reduction in the bioavailability of CREXONT. If iron salts or multivitamins containing iron salts are co-administered with CREXONT, monitor patients for worsening Parkinson’s symptoms.

8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm. (8.1) 8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of CREXONT (carbidopa and levodopa) in pregnant women. In animal studies, carbidopa-levodopa has been shown to be developmentally toxic (including teratogenic effects) at clinically relevant doses (see Data) . The estimated background risk of major birth defects and miscarriage in 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% to 4% and 15% to 20%, respectively. Data Animal Data When administered to pregnant rabbits throughout organogenesis, carbidopa-levodopa caused both visceral and skeletal malformation in fetuses at all doses and ratios of carbidopa-levodopa tested. No teratogenic effects were observed when carbidopa-levodopa was administered to pregnant mice throughout organogenesis. There was a decrease in the number of live pups delivered by rats receiving carbidopa-levodopa during organogenesis. 8.2 Lactation Risk Summary CREXONT is a combination of carbidopa and levodopa. Carbidopa There are no adequate data on the presence of carbidopa in human milk, the effects on the breastfed infant, or the effects on milk production. Carbidopa is excreted in rat milk. Levodopa Levodopa has been detected in human milk after administration of carbidopa-levodopa. Levodopa decreases secretion of prolactin in humans, which may inhibit lactation. There are no adequate data on the effects of levodopa on the breastfed infant. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CREXONT and any potential adverse effects on the breastfed infant from CREXONT or from the underlying maternal condition. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use There were 282 (45%) patients 65 to less than 74 years of age and 112 (18%) patients 75 years of age and older treated with CREXONT in an active-controlled study for Parkinson’s disease (Study 1) [see Clinical Studies (14) ] . There were no differences in safety outcomes between patients less than 65 years of age, 65 to less than 75 years of age, or 75 years and older.

12.1 Mechanism of Action Carbidopa When levodopa is administered orally, it is rapidly decarboxylated to dopamine in extracerebral tissues so that only a small portion of a given dose is transported unchanged to the central nervous system. Carbidopa inhibits the decarboxylation of peripheral levodopa, making more levodopa available for delivery to the brain. Levodopa Levodopa is the metabolic precursor of dopamine, does cross the blood-brain barrier, and presumably is converted to dopamine in the brain. This is thought to be the mechanism whereby levodopa treats symptoms of Parkinson's disease.

11 DESCRIPTION CREXONT is a combination of carbidopa, an inhibitor of aromatic amino acid decarboxylation, and levodopa, an aromatic amino acid, in extended-release capsules for oral use. CREXONT contains immediate-release granules consisting of carbidopa and levodopa and extended-release pellets consisting of levodopa. Carbidopa is a white to off-white powder, crystalline compound, slightly soluble in water, with a molecular weight of 244.24. It is designated chemically as (–)-L-α-hydrazino-α-methyl-β-(3,4-dihydroxy-benzene) propanoic acid monohydrate. Its molecular formula is C 10 H 14 N 2 O 4 •H 2 O and its structural formula is: Capsule content is expressed in terms of anhydrous carbidopa, which has a molecular weight of 226.3. Levodopa is a white, crystalline compound, slightly soluble in water, with a molecular weight of 197.2. It is designated chemically as (–)-L-α-amino-β-(3,4-dihydroxy-benzene) propanoic acid. Its molecular formula is C 9 H 11 NO 4 and its structural formula is: Each CREXONT extended-release capsule contains 35 mg carbidopa and 140 mg levodopa, 52.5 mg carbidopa and 210 mg levodopa, 70 mg carbidopa and 280 mg levodopa, or 87.5 mg carbidopa and 350 mg levodopa. The inactive ingredients are amino methacrylate copolymer, cellulose acetate, copovidone, croscarmellose sodium, magnesium stearate, mannitol, methacrylic acid and methyl methacrylate copolymer, microcrystalline cellulose, povidone, sodium lauryl sulfate, talc, and triethyl citrate. The 35mg/140 mg capsule shell contains D&C yellow #10, gelatin, Red Iron Oxide, and titanium dioxide. The 52.5 mg/210 mg capsule shell contains FD&C Blue #1, gelatin, titanium dioxide, and yellow iron oxide. The 70 mg/280 mg capsule shell contains FD&C Blue #1, FD&C Red #3, gelatin, and titanium dioxide. The 87.5 mg/350 mg capsule shell contains gelatin, Red Iron Oxide, titanium dioxide, and yellow iron oxide. The black imprinting ink contains ammonium hydroxide, ethanol, ferrosoferric oxide/black iron oxide, isopropyl alcohol, n-butyl alcohol, propylene glycol, and shellac glaze. The white imprinting ink contains ethanol, isopropyl alcohol, n-butyl alcohol, povidone, propylene glycol, shellac glaze, sodium hydroxide, and titanium dioxide. CD Structural Formula LD Structural Formula

10 OVERDOSAGE Based on the limited available information, the acute symptoms of levodopa/carbidopa overdosage can be expected to arise from dopaminergic overstimulation. Doses of a few grams may result in CNS disturbances, with an increasing likelihood of cardiovascular disturbance (e.g., hypotension, tachycardia) and more severe psychiatric problems at higher doses. An isolated report of rhabdomyolysis and another of transient renal insufficiency suggest that levodopa overdosage may give rise to systemic complications, secondary to dopaminergic overstimulation. In the event of CREXONT overdosage, monitor patients and provide supportive care. Patients should receive electrocardiographic monitoring for the development of arrhythmias; if needed, appropriate antiarrhythmic therapy should be given. The possibility that the patient may have taken other drugs, increasing the risk of drug interactions (especially catechol-structured drugs) should be taken into consideration.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied CREXONT capsules contain white to off-white granules and pellets and are available in bottles of 120 capsules as follows: Capsule Strength Description NDC Number 35 mg Carbidopa and 140 mg Levodopa Capsules with white opaque body and yellow opaque cap. Body imprinted with “140” in black ink and cap imprinted with “IPX203” in white ink. 64896-967-16 52.5 mg Carbidopa and 210 mg Levodopa Capsules with white opaque body and green opaque cap. Body imprinted with “210” in black ink and cap imprinted with “IPX203” in white ink. 64896-968-16 70 mg Carbidopa and 280 mg Levodopa Capsules with white opaque body and purple opaque cap. Body imprinted with “280” in black ink and cap imprinted with “IPX203” in white ink. 64896-969-16 87.5 mg Carbidopa and 350 mg Levodopa Capsules with white opaque body and medium orange opaque cap. Body imprinted with “350” in black ink and cap imprinted with “IPX203” in white ink. 64896-970-16 16.2 Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Store in a tightly closed container, protected from light and moisture. Dispense in a tightly closed, light-resistant container.