Crexont Prescribing Information

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

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)].

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.

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 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.

7.1 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.

8.1 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.

12.2 Pharmacodynamics

Because its decarboxylase inhibiting activity is limited to extracerebral tissues, administration of carbidopa with levodopa makes more levodopa available to the brain. The addition of carbidopa to levodopa reduces the peripheral effects (nausea, vomiting) due to decarboxylation of levodopa; however, carbidopa does not decrease the adverse reactions due to the central effects of levodopa.

Patients treated with levodopa therapy for Parkinson's disease may develop motor fluctuations characterized by end-of-dose failure, peak dose dyskinesia, ‘on-off’ phenomenon, and akinesia.

Cardiac Electrophysiology

At exposures corresponding to the maximum recommended dose of carbidopa in CREXONT, clinically significant QTc interval prolongation was not observed.

12.3 Pharmacokinetics

The pharmacokinetics of CREXONT were evaluated following single doses in healthy subjects and following single and multiple doses in patients with Parkinson’s disease.

CREXONT shows dose proportional pharmacokinetics for both carbidopa and levodopa over the carbidopa/levodopa dosage strength range of 35 mg/140 mg to 87.5 mg/350 mg.

Absorption

Carbidopa

Following oral dosing of CREXONT, the maximum concentration occurred at approximately 2.5 hours. The bioavailability of carbidopa from CREXONT relative to immediate-release carbidopa-levodopa tablets was approximately 103% to 123%.

Levodopa

The bioavailability of levodopa from CREXONT was approximately 88% to 99% relative to immediate-release carbidopa-levodopa.

For comparable doses, CREXONT results in a levodopa peak concentration (Cmax) that is 38% that of immediate-release carbidopa-levodopa. Following an initial peak at about one hour, plasma concentrations were maintained for about 6 to 7 hours before declining.

In patients with Parkinson’s disease, multiple-dose pharmacokinetics was comparable to single-dose pharmacokinetics, i.e., there was minimal accumulation of levodopa. Variation in levodopa peak to trough plasma concentrations at steady-state defined as (Cmax-Cmin)/Cavg was approximately 1.7 for CREXONT compared to approximately 2.7 for immediate-release carbidopa-levodopa.

Effect of Food

Carbidopa

In healthy adults, oral administration of CREXONT after a high-fat, high-calorie meal decreased both Cmax and AUC by approximately 64% for carbidopa compared to administration in the fasted state. The peak plasma concentrations of carbidopa were observed approximately one hour later when CREXONT is taken with a high-fat high-calorie meal.

Levodopa

In healthy adults, oral administration of CREXONT after a high-fat, high-calorie meal increased Cmax approximately 19% and AUC0-∞ approximately 18% for levodopa compared to administration in the fasted state [see Dosage and Administration (2.4)]. The peak plasma concentrations of levodopa were observed approximately two hours later when CREXONT is taken with a high-fat, high-calorie meal. In addition, absorption of levodopa may be decreased by a high protein meal.

Distribution

Approximately 36% of carbidopa binds to plasma proteins. Approximately 10% to 30% of levodopa binds to plasma proteins.

Metabolism and Elimination

Carbidopa

The terminal phase elimination half-life of carbidopa is approximately 2 hours.

Carbidopa is metabolized to two main metabolites: α-methyl-3-methoxy-4-hydroxyphenylpropionic acid and α-methyl-3,4-dihydroxy-phenylpropionic acid. These two metabolites are primarily eliminated in the urine unchanged or as a glucuronide. Unchanged carbidopa accounts for 30% of the total urinary excretion.

Peripheral dopa-decarboxylase may be saturated by carbidopa in immediate release carbidopa-levodopa products at 70 mg per day to 100 mg per day, which produces similar exposure to 62.5 mg to 89.3 mg per day of carbidopa provided by CREXONT.

Levodopa

The terminal phase elimination half-life of levodopa, the active moiety of antiparkinsonian activity, is approximately 2 hours in the presence of carbidopa.

Levodopa is extensively metabolized to various metabolites. The two major metabolic pathways are decarboxylation by dopa decarboxylase (DDC) and O-methylation by catechol-O-methyltransferase (COMT).

Specific Populations

Geriatric Patients

In pharmacokinetic studies following a single dose of CREXONT, the peak concentrations of carbidopa and levodopa are generally similar between younger (45 to 60 years) and older (60 to 75 years) subjects.

Drug Interaction Studies

In Vitro Studies

Effect of Ethanol

Ethanol-induced dose dumping of CREXONT was observed in the presence of 40% ethanol (80 proof) solution in a dissolution study [see Dosage and Administration (2.4)]; however, dose dumping was not observed in the presence of lower ethanol concentrations. The clinical significance of this dose dumping was not fully characterized in humans.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

In rats, oral administration of carbidopa-levodopa for two years resulted in no evidence of carcinogenicity.

Mutagenesis

Carbidopa was mutagenic in the in vitro Ames test and in the in vitro mouse lymphoma tk assay but was negative in the in vivo mouse micronucleus assay.

Impairment of Fertility

In reproduction studies, no effects on fertility were observed in rats receiving carbidopa-levodopa.

16.1 How Supplied

CREXONT capsules contain white to off-white granules and pellets and are available in bottles of 120 capsules as follows:

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.