Brand name: Vyalev(https://www.vyalev.com)
Drug class: Dopamine Precursors

Introduction

Fixed combination of foscarbidopa (an aromatic amino acid decarboxylation inhibitor) and foslevodopa (an aromatic amino acid); foscarbidopa is a prodrug of carbidopa and foslevodopa is a prodrug of levodopa.

Uses for Foscarbidopa and Foslevodopa

Parkinson Disease

Treatment of motor fluctuations in adults with advanced Parkinson disease.

Designated an orphan drug by FDA for treatment of late stage Parkinson disease.

Levodopa remains the most effective treatment for managing the motor symptoms of Parkinson disease, particularly bradykinesia and rigidity, with variable effects on tremor.

The International Parkinson and Movement Disorder Society provides guidelines for the treatment of motor fluctuations in patients with Parkinson disease; foscarbidopa/foslevodopa is not included because the guidelines predate drug approval.

Foscarbidopa and Foslevodopa Dosage and Administration

General

Pretreatment Screening

• Select patients for treatment who are capable of understanding and using the delivery system.

• Before initiating treatment, evaluate risk factors for drowsiness, such as sedating medications or sleep disorders.

Patient Monitoring

• Monitor for drowsiness and excessive sleepiness.

Administration

Sub-Q Administration

Administer by sub-Q injection only using the Vyafuser pump.

Train patients on proper use of foscarbidopa/foslevodopa and the delivery system prior to initiating treatment.

Available as a 10 mL single-dose vial containing 120 mg of foscarbidopa and 2400 mg of foslevodopa.

Use aseptic technique and sterile, single-use components to prepare the foscarbidopa/foslevodopa solution for use with the infusion pump. Do not dilute or mix. Transfer the full vial contents into a syringe; do not withdraw partial doses.

Administer sub-Q, preferably in the abdomen, avoiding the 2-inch area around the navel. Change the site and infusion set every 3 days; select a new site at least 1 inch from prior sites used in the past 12 days. Avoid swollen, discolored, tender, or firm areas.

Discard the vial after transferring medication. Dispose of the syringe and any unused drug after 24 hours.

Dosage

Adults

Parkinson Disease

Sub-Q

Dosage is based on total levodopa dosage (TLD).

Calculate continuous infusion rate using the following formula and instructions below. Treatment may be administered over the patient's awake hours or over 24 hours.

Infusion rate (mL/hr) = ([TLD × 1.3] / 240) / (number of typical awake hours)

Step 1: To determine the base infusion rate, calculate the TLD for levodopa-containing medications that foscarbidopa/foslevodopa will replace. Convert all levodopa doses to their immediate-release levodopa equivalent. If the patient is using a COMT inhibitor, adjust the TLD accordingly, referencing the prescribing information for specific dose conversions. Do not include rescue doses, as-needed levodopa, or other anti-parkinsonian medication or therapy, including drugs taken outside of waking hours.

Step 2: Determine the total daily dosage (mg) of the foslevodopa component by multiplying the TLD by a factor of 1.3 to account for differences in molecular weight and bioavailability between foslevodopa and levodopa.

Step 3: Calculate the total daily volume (mL) of foscarbidopa/foslevodopa by dividing the total daily dosage (mg) of foslevodopa by 240, as each mL contains 240 mg of foslevodopa.

Step 4: Determine the hourly continuous infusion rate by dividing the total daily volume (mL) of foslevodopa by the number of hours the patient is typically awake (e.g., 16 hours). The infusion may be administered continuously during waking hours or over a full 24 hour period. Adjustments may be needed for overnight dosing based on clinical needs.

Maximum recommended daily dosage of foscarbidopa/foslevodopa is 3,525 mg of the foslevodopa component, which is equivalent to approximately 2,500 mg levodopa.

If infusion is missed for ≥3 hours or the patient is in an "Off" state, a loading dose can be administered before starting or restarting foscarbidopa/foslevodopa. Use either foscarbidopa/foslevodopa or oral immediate-release carbidopa/levodopa for the loading dose. Calculate the loading dose based on the patient’s first morning dose of oral immediate-release carbidopa/levodopa taken before starting treatment with foscarbidopa/foslevodopa. If foscarbidopa/foslevodopa is used for the loading dose, multiply the first morning dose of oral immediate-release levodopa dose by 1.3 to account for differences in bioavailability and divide by 240 to determine the volume for the loading dose. Set the pump to deliver a loading dose between 0.1 mL and 3 mL, with available increments of 0.1 mL.

If an extra dose is required, program the extra dose as needed (one per hour). If ≥2 extra doses are used in 24 hours, reassess the infusion rate. Available extra doses are 0.1 mL (to obtain an approximate equivalent 17 mg levodopa dose), 0.15 mL (to obtain an approximate equivalent 25.5 mg levodopa dose), 0.2 mL (to obtain an approximate equivalent 34 mg levodopa dose), 0.25 mL (to obtain an approximate equivalent 42.5 mg levodopa dose), and 0.3 mL (to obtain an approximate equivalent 51 mg levodopa dose).

If foscarbidopa/foslevodopa is interrupted, underdosing may occur. Avoid sudden discontinuation without availability of alternative dopaminergic therapy. For interruptions >1 hour, use a new infusion set and rotate sites. If interruption >3 hours, the patient may also self-administer a loading dose, if enabled by their healthcare provider.

Special Populations

Hepatic Impairment

No specific dosage recommendations.

Renal Impairment

No specific dosage recommendations.

Geriatric Patients

No specific dosage recommendations.

Cautions for Foscarbidopa and Foslevodopa

Contraindications

• Patients currently taking or who have recently discontinued (within 2 weeks) a non-selective monoamine oxidase (MAO) inhibitor.

Warnings/Precautions

Falling Asleep During Activities of Daily Living and Somnolence

Levodopa users have reported sudden sleep episodes, even after long-term use; assess for drowsiness regularly.

Consider discontinuing if significant daytime sleepiness or sleep attacks occur. Advise patients against driving and hazardous activities if therapy is continued, as dosage reduction may not prevent episodes.

Hallucinations/Psychosis

Increased risk of hallucinations and psychosis, which may appear early after initiation of therapy and respond to dosage adjustments of the combination drug or other concomitantly administered drugs. Avoid use in major psychotic disorders, as it may worsen symptoms. Dopamine antagonists can reduce efficacy and exacerbate symptoms of Parkinson disease.

Impulse Control/Compulsive Behaviors

Intense urges and compulsive behaviors (e.g., urge to gamble, increased sexual urges, binge eating, uncontrolled spending, other intense urges) and inability to control these urges reported in some patients receiving dopaminergic agents. In some cases, urges stopped when dosage was reduced or drug was discontinued.

Consider dosage reduction or discontinuation if these behaviors develop.

Infusion Site Reactions and Infections

May cause infusion site reactions (erythema, pain, edema, nodules, bruising, inflammation) and infusion site infections, including cellulitis.

If infection is suspected at infusion site, remove the cannula. Insert a new cannula at a different site or if an extended interruption occurs, switch to oral carbidopa/levodopa until foscarbidopa/foslevodopa can be resumed.

Withdrawal-Emergent Hyperpyrexia and Confusion

Avoid abrupt withdrawal or rapid dosage reduction to prevent a neuroleptic malignant syndrome-like reaction (fever, rigidity, altered consciousness, autonomic instability). Taper gradually if discontinuation is needed.

Dyskinesia

May cause or worsen dyskinesias; consider reducing dosage or adjusting other parkinson medications.

Cardiovascular Ischemic Events

Monitor for MI and arrhythmias, especially in patients with cardiac history; assess for ischemic and arrhythmic symptoms.

Glaucoma

May increase intraocular pressure in glaucoma; monitor pressure after starting treatment.

Specific Populations

Pregnancy

Developmental risk in pregnancy is unknown; animal studies show potential toxicity and teratogenic effects.

Lactation

Presence in human milk and effects on infants or lactation are unknown. Levodopa is excreted in human milk and may reduce prolactin. Weigh breastfeeding benefits against maternal need and infant risk.

Pediatric Use

Safety and effectiveness not established.

Geriatric Use

Insufficient data on patients ≥65 years of age. Dose cautiously, considering reduced organ function, comorbidities, and concurrent medications.

Common Adverse Effects

Most common adverse reactions (≥10% and greater than carbidopa/levodopa): infusion/catheter site reactions, infusion/catheter site infections, hallucinations, dyskinesia.

Drug Interactions

Specific Drugs

Foscarbidopa and Foslevodopa Pharmacokinetics

Absorption

Plasma Concentrations

Plasma levels detectable within 30 minutes and steady-state levels achieved within 2 hours.

Distribution

Extent

Levodopa distributes equally between erythrocytes and plasma (<10% protein-bound) and crosses the blood-brain barrier via amino acid transporters. Carbidopa (36% protein-bound) does not cross the blood-brain barrier.

Plasma Protein Binding

24-26%

Elimination

Metabolism

Levodopa is primarily metabolized by aromatic amino acid decarboxylase (AAAD) into dopamine and by COMT into 3-O-methyldopa. Carbidopa inhibits AAAD, reducing peripheral dopamine conversion.

Elimination Route

Carbidopa is metabolized into 2 primary metabolites and excreted in urine, mainly unchanged or as glucuronide conjugates.

Half-life

Carbidopa: 2 hours; Levodopa (when administered with carbidopa): 1.5 hours.

Stability

Storage

Parenteral

Injection

Store refrigerated at 2-8°C in original carton.

May store at room temperature (≤30°C) for a single period of up to 28 days. Do not refrigerate after removal; discard after 28 days.

Do not freeze or shake.

Actions

• Combination of foscarbidopa (an aromatic amino acid decarboxylation inhibitor) and foslevodopa (an aromatic amino acid); both are prodrugs that are converted by alkaline phosphatase to pharmacologically active carbidopa and levodopa.

• Manifestations of parkinsonian syndrome are related to depletion of striatal dopamine in the corpus striatum; levodopa is believed to act principally by increasing dopamine concentrations in the brain.

• Carbidopa inhibits peripheral decarboxylation of levodopa, allowing more levodopa to cross the blood-brain barrier to be converted to dopamine in the brain.

Advice to Patients

• Advise patients to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

• Refer patients to the Instructions for Use for complete administration instructions. Inform patients of aseptic technique and of sub-Q administration site selection and rotation. Instruct patients to record the date when foscarbidopa/foslevodopa is first removed from the refrigerator in the space provided on the carton.

• Inform patients that if they disconnect the pump for <1 hour (e.g., to shower or for a short medical procedure), a new infusion set (tubing and cannula) or rotation of the infusion site is not needed before resuming infusion, unless medically indicated. Instruct the patient to stop the pump and disconnect the tubing. The syringe can remain attached to the pump until the tubing is reconnected. Refer the patient to the Instructions for Use for additional information.

• Inform patients that if they have a prolonged interruption of therapy lasting >1 hour, a new infusion set (tubing and cannula) should be used, and rotation to a different infusion site is required before resuming infusion. In addition, if foscarbidopa/foslevodopa is interrupted for >3 hours, advise patients to administer a loading dose with either foscarbidopa/foslevodopa or oral immediate-release carbidopa and levodopa. Instruct patients to have oral carbidopa/levodopa available in case treatment with foscarbidopa/foslevodopa is interrupted for 1 hour or longer.

• Alert patients to the potential sedating effects caused by foscarbidopa/foslevodopa, including somnolence and the possibility of falling asleep while engaged in activities of daily living. Because somnolence is a common adverse reaction with potentially serious consequences, patients should not drive a car, operate machinery, or engage in other potentially dangerous activities until they have gained sufficient experience with foscarbidopa/foslevodopa to gauge whether it affects their mental and/or motor performance adversely. Advise patients that if increased somnolence or episodes of falling asleep during activities of daily living (e.g., conversations, eating, driving a motor vehicle) are experienced at any time during treatment, they should not drive or participate in potentially dangerous activities until they have contacted their healthcare professional.

• Advise patients of possible additive effects when patients are taking other sedating medications, alcohol, or other CNS depressants (e.g., benzodiazepines, antipsychotics, antidepressants) in combination with foscarbidopa/foslevodopa or when taking a concomitant medication that increases plasma levels of levodopa.

• Inform patients that they may experience hallucinations (unreal visions, sounds, or sensations) and other symptoms of psychosis while taking foscarbidopa/foslevodopa. Tell patients to report hallucinations, abnormal thinking, psychotic behavior, or confusion to their healthcare professional promptly.

• Advise patients that they may experience impulse control and/or compulsive behaviors while taking foscarbidopa/foslevodopa. Advise patients to inform their healthcare professional if they develop new or increased gambling urges, sexual urges, uncontrolled spending, binge or compulsive eating, or other urges.

• Advise patients to contact their healthcare professional if they notice signs of inflammation or infection at the infusion site, such as local spreading of redness, swelling, warmth, pain, discoloration when they apply pressure to the area, and/or fever. Tell patients to follow aseptic techniques while using foscarbidopa/foslevodopa and to regularly change the infusion site (at least every third day), using a new infusion set. Advise patients to make sure the new infusion site is at least 1 inch (2.5 cm) from a site used in the last 12 days. Instruct patients to remove the cannula if an infection at the infusion site occurs and to contact their healthcare provider. Inform patients that they may need to change the infusion site more often than every third day if they notice any of the above mentioned signs of infection.

• Advise patients to contact their healthcare professional before stopping foscarbidopa/foslevodopa. Tell patients to inform their healthcare professional if they develop withdrawal symptoms such as fever, confusion, or severe muscle stiffness.

• Inform patients that foscarbidopa/foslevodopa may cause or exacerbate pre-existing dyskinesias.

• Advise patients to notify their healthcare provider if they become pregnant during treatment or plan to become pregnant during treatment.

• Advise patients to notify their healthcare provider if they are breastfeeding or plan to breastfeed.

• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Foscarbidopa/foslevodopa is available through designated specialty pharmacies. Contact manufacturer or consult the foscarbidopa/foslevodopa website ([Web]) for specific information.

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