Crexont Drug Information
Generic name: CARBIDOPA AND LEVODOPA
Aromatic Amino Acid [EPC]
Uses of Crexont
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.
Dosage & Administration of Crexont
Management of Vitamin B6 Levels
Evaluate vitamin B6 levels prior to initiating carbidopa/levodopa therapies, including CREXONT, periodically during treatment, and as clinically indicated. 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.
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.
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 4: After one to three days, adjust the dose or frequency as needed based on the patient’s clinical response and tolerability. 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.
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.
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.
Do not chew, divide, or crush CREXONT capsules. For patients who have difficulty swallowing intact capsules, administer CREXONT by carefully opening the capsule and sprinkling the entire contents on a small amount of applesauce (1 to 2 tablespoons). Swallow the mixture immediately without chewing.
Do not save or store the drug/food mixture for future use.
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.
| 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 |
Side Effects of Crexont
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.
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 s 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.
| 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 |
Warnings & Cautions for Crexont
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.
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.
Cardiovascular Ischemic Events
Cardiovascular ischemic events have occurred in patients taking CREXONT. 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.
Hallucinations/Psychosis There is an increased risk for hallucinations in patients taking CREXONT. 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.
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.
Dyskinesia CREXONT can cause dyskinesias that may require a dosage reduction of CREXONT or other medications used for the treatment of Parkinson’s disease.
Vitamin B6 Deficiency and Seizures Treatment with carbidopa-levodopa, including CREXONT, may contribute to reduced vitamin B6 levels. Higher doses of carbidopa/levodopa may increase the risk of vitamin B6 deficiency. Seizures associated with vitamin B6 deficiency have been reported in the postmarketing setting in patients taking carbidopa/levodopa.
In these reported cases, seizures were refractory to traditional anti-seizure medications and only resolved after vitamin B6 administration. Other symptoms of vitamin B6 deficiency may occur, including depression, confusion, cheilosis, glossitis, dermatitis, anemia, and/or neuropathy. Evaluate vitamin B6 levels prior to initiation of CREXONT and periodically while on treatment or if symptoms associated with vitamin B6 deficiency are identified.
Supplement with vitamin B6 as necessary.
Peptic Ulcer Disease Treatment with CREXONT may increase the possibility of upper gastrointestinal hemorrhage in patients with a history of peptic ulcer.
Glaucoma CREXONT may cause increased intraocular pressure in patients with glaucoma. Monitor intraocular pressure in patients with glaucoma after starting CREXONT.
Drug Interactions with Crexont
Monoamine Oxidase (MAO) Inhibitors Nonselective MAO Inhibitors The use of nonselective MAO inhibitors (e.g., phenelzine and tranylcypromine) with CREXONT is contraindicated. 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.
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.
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.
Pregnancy Safety for Crexont
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 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.
Pediatric Use of Crexont
Pediatric Use Safety and effectiveness in pediatric patients have not been established.
Contraindications for Crexont
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. Nonselective MAO inhibitors
Overdosage Information for Crexont
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.
Clinical Studies of Crexont
The effectiveness of CREXONT for the treatment of Parkinson’s disease was established in an active-controlled, multicenter, 20-week clinical trial (Study 1; NCT03670953). Study 1 consisted of a 3-week dose adjustment period of immediate-release carbidopa-levodopa treatment prior to a 4-week conversion period to CREXONT, which was followed by a 13-week, double-blind, double-dummy, randomized, parallel group period comparing CREXONT to immediate-release carbidopa-levodopa. Study 1 enrolled 630 (506 randomized) patients (Hoehn & Yahr Stages I-IV) who had been maintained on a stable regimen of at least 400 mg per day of levodopa prior to entry into the trial and who experienced a minimum of 2.5 hours of “Off” time per day while awake.
At baseline, approximately 73% of patients in the CREXONT group and 63% of patients in the oral IR carbidopa-levodopa group were taking at least 1 or more classes of PD medications other than carbidopa-levodopa. Patients were randomized to receive either immediate-release carbidopa-levodopa or CREXONT at the dose determined during the adjustment or conversion phases. Patients were not allowed to receive supplemental carbidopa-levodopa products or additional carbidopa, any catechol-O-methyl transferase (COMT) inhibitor products, non-selective monoamine oxidase (MAO) inhibitors, selective MAO-A inhibitors, apomorphine, or antidopaminergic agents (including antiemetics) during the trial.
In Study 1, 75% of patients required 2 or fewer titration steps to reach a stable total daily dose of CREXONT. The mean daily dosage of the levodopa component of CREXONT was 1487 mg. The primary efficacy measure in Study 1 was the mean change from baseline in “On” time without troublesome dyskinesia in hours per day at the end of the study (Week 20 or at early termination), as assessed by the patient’s Parkinson’s disease diary. “On” time without troublesome dyskinesia was defined as the sum of “On” time without dyskinesia and “On” time with non-troublesome dyskinesia.
Patients reported an improvement in “On” time without troublesome dyskinesia with CREXONT compared to immediate-release carbidopa-levodopa which was statistically significant (p=0.019) (Table 3). CREXONT-treated patients also reported less “Off” time compared to immediate-release carbidopa-levodopa, which was statistically significant (p=0.025) (Table 3). Table 3.
Efficacy Results in Patients with Parkinson’s Disease: based on change from Week 7 (Baseline) to Week 20 (End of Study or Early Termination)
| Week 0 Enrollment | Week 7 Baseline (Randomization) | Week 20 End of Study (or Early Termination) | p-value | |
|---|---|---|---|---|
| Mean “On” time without troublesome dyskinesia (hours) | ||||
| CREXONT | 9.46 | 11.67 | 11.35 | 0.019* |
| Immediate-release carbidopa-levodopa | 9.61 | 11.72 | 10.77 | |
| Mean “Off” time (hours) | ||||
| CREXONT | 6.15 | 3.95 | 4.18 | 0.025* |
| Immediate-release carbidopa-levodopa | 6.05 | 4.02 | 4.75 | |
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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