Drug Facts
Composition & Profile
Identifiers & Packaging
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.; PRINCIPAL DISPLAY PANEL 35-140 ifc; 52-5-210 ifc; 70-280 ifc; 87-5-350 ifc
- 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.
- PRINCIPAL DISPLAY PANEL 35-140 ifc
- 52-5-210 ifc
- 70-280 ifc
- 87-5-350 ifc
Overview
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
Indications & 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 )
Dosage & Administration
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. ( 2.1 ) Patients converting from immediate-release carbidopa/levodopa: See Table 1 for instructions; dosages are not substitutable on a 1:1 basis. ( 2.2 ) The maximum recommended daily dosage of CREXONT is 525 mg carbidopa / 2100 mg levodopa. ( 2.1 , 2.2 ) CREXONT may be taken with or without food; do not chew, divide, or crush. ( 2.4 , 12.3 ) CREXONT should not be taken with alcohol. ( 2.4 , 12.3 ) 2.1 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. 2.2 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. 2.3 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. 2.4 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. 2.5 Discontinuation of CREXONT Avoid sudden discontinuation or rapid dose reduction of CREXONT. The daily dose of CREXONT should be tapered at the time of treatment discontinuation [see Warnings and Precautions (5.2) ] .
Warnings & Precautions
May cause falling asleep during activities of daily living. ( 5.1 ) Avoid sudden discontinuation or rapid dose reduction to reduce the risk of withdrawal-emergent hyperpyrexia and confusion. ( 5.2 ) Cardiovascular Events: Monitor patients with a history of cardiovascular disease. ( 5.3 ) Hallucinations/Psychosis may occur. ( 5.4 ) Impulse Control Disorders: Consider dose reduction or stopping CREXONT if occurs. ( 5.5 ) May cause or exacerbate dyskinesia: Consider dose reduction. ( 5.6 ) 5.1 Falling Asleep During Activities of Daily Living and Somnolence Patients treated with levodopa, a component of CREXONT, have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles, which sometimes resulted in accidents. Although many of these patients reported somnolence while on levodopa, some perceived that they had no warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event (sleep attack). Some of these events have been reported more than 1 year after initiation of treatment. Falling asleep while engaged in activities of daily living usually occurs in patients experiencing preexisting somnolence, although patients may not give such a history. For this reason, prescribers should reassess for drowsiness or sleepiness in CREXONT-treated patients, especially since some of the events occur well after the start of treatment. Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities. Before initiating treatment with CREXONT, advise patients of the potential to develop drowsiness and specifically ask about factors that may increase the risk for somnolence with CREXONT, such as concomitant sedating medications or the presence of a sleep disorder. Consider discontinuing CREXONT in patients who report significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.). If a decision is made to continue CREXONT, patients should be advised not to drive and to avoid other potentially dangerous activities that might result in harm if the patients become somnolent. There is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living. 5.2 Withdrawal-Emergent Hyperpyrexia and Confusion A symptom complex that resembles neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in dopaminergic therapy. Avoid sudden discontinuation or rapid dose reduction in patients taking CREXONT. If the decision is made to discontinue CREXONT, the dose should be tapered to reduce the risk of hyperpyrexia and confusion [see Dosage and Administration (2.5) ] . 5.3 Cardiovascular Ischemic Events Cardiovascular ischemic events have occurred in patients taking CREXONT. In Study 1 [see Clinical Studies (14) ], 4/589 (0.7%) of CREXONT-treated patients experienced cardiovascular ischemic adverse reactions compared to 2/630 (0.3%) of oral immediate-release carbidopa-levodopa-treated patients. These patients all had a previous history of ischemic heart disease or risk factors for ischemic heart disease. In patients with a history of myocardial infarction who have residual atrial, nodal, or ventricular arrhythmias, cardiac function should be monitored in an intensive cardiac care facility during the period of initial dosage adjustment. 5.4 Hallucinations/Psychosis There is an increased risk for hallucinations in patients taking CREXONT. In Study 1, 17/589 (3%) of CREXONT-treated patients reported hallucinations compared to 2/630 (0.3%) of oral immediate-release carbidopa-levodopa-treated patients. Hallucinations present shortly after the initiation of therapy and may be responsive to dose reduction in levodopa. Hallucinations may be accompanied by confusion, insomnia, and excessive dreaming. Abnormal thinking and behavior may present with one or more symptoms, including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium. Because of the risk of exacerbating psychosis, patients with a major psychotic disorder should not be treated with CREXONT. In addition, medications that antagonize the effects of dopamine used to treat psychosis may exacerbate the symptoms of Parkinson’s disease and may decrease the effectiveness of CREXONT [see Drug Interactions (7.2) ] . 5.5 Impulse Control/Compulsive Behaviors Case reports suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including CREXONT, that increase central dopaminergic tone and that are generally used for the treatment of Parkinson’s disease. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending, or other urges while being treated with CREXONT. Consider a dose reduction or stopping the medication if a patient develops such urges while taking CREXONT. 5.6 Dyskinesia CREXONT can cause dyskinesias that may require a dosage reduction of CREXONT or other medications used for the treatment of Parkinson’s disease. 5.7 Peptic Ulcer Disease Treatment with CREXONT may increase the possibility of upper gastrointestinal hemorrhage in patients with a history of peptic ulcer. 5.8 Glaucoma CREXONT may cause increased intraocular pressure in patients with glaucoma. Monitor intraocular pressure in patients with glaucoma after starting CREXONT.
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)
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) ] Peptic Ulcer Disease [see Warnings and Precautions (5.7) ] Glaucoma [see Warnings and Precautions (5.8) ] 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.
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.
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