AHFS Class:

• Dopamine Precursors 28:36.16

Brands:

• Vyalev^®

Generic Name(s):

• Foscarbidopa and Foslevodopa

Foscarbidopa and foslevodopa (foscarbidopa/foslevodopa) is a fixed combination of foscarbidopa (an aromatic amino acid decarboxylation inhibitor) and foslevodopa (an aromatic amino acid).1 Foscarbidopa and foslevodopa are prodrugs that undergo enzymatic bioconversion to carbidopa and levodopa, respectively.1

Foscarbidopa/foslevodopa has the following uses:

Foscarbidopa/foslevodopa is indicated for the treatment of motor fluctuations in adults with advanced Parkinson's disease. 1

General

Foscarbidopa/foslevodopa is available in the following dosage form(s) and strength(s):

Injection: 120 mg foscarbidopa and 2,400 mg foslevodopa per 10 mL (12 mg foscarbidopa and 240 mg foslevodopa per mL) for subcutaneous use.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

• For subcutaneous administration only; administer by subcutaneous infusion, preferably in the abdomen, via the VYAFUSER pump.1
• Do not dilute or mix with other products.1 Transfer entire contents of a foscarbidopa/foslevodopa vial into a syringe for administration.1 Infusion set may remain in place for up to 3 days when foscarbidopa/foslevodopa is infused continuously.1
• Rotate the infusion site and use a new infusion set at least every 3 days.1
• See the Full Prescribing Information for calculation of the base continuous dosage, hourly infusion rate, optional loading dose, and extra dose.1
• The maximum recommended daily dosage of foscarbidopa/foslevodopa is 3,525 mg of foslevodopa (equivalent to approximately 2,500 mg levodopa). 1
• Prescribing a backup oral carbidopa and levodopa product is recommended in the event that delivery of foscarbidopa/foslevodopa is interrupted, which may result in underdosing.1 Sudden discontinuation or rapid dose reduction of foscarbidopa/foslevodopa, without administration of alternative dopaminergic therapy, should be generally avoided.1
• See Full Prescribing Information for additional preparation, administration, and dosage instructions.1

Contraindications

Foscarbidopa/foslevodopa is contraindicated in patients who are currently taking a nonselective monoamine oxidase (MAO) inhibitor or have recently (within 2 weeks) taken a nonselective MAO inhibitor.1

Warnings/Precautions

Falling Asleep During Activities of Daily Living and Somnolence

Patients treated with levodopa (the active metabolite of foscarbidopa and foslevodopa) have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles, which sometimes resulted in accidents.1 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).1 Some of these events have been reported more than one year after initiation of treatment. 1

Falling asleep while engaged in activities of daily living usually occurs in patients experiencing preexisting somnolence, although patients may not give such a history.1 For this reason, prescribers should reassess patients for drowsiness or sleepiness while using foscarbidopa/foslevodopa, especially since some of the events occur well after the start of treatment.1 Prescribers should be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities.1 Patients who have already experienced somnolence or an episode of sudden sleep onset should not participate in these activities while taking foscarbidopa/foslevodopa. 1

Before initiating treatment with foscarbidopa/foslevodopa, advise patients about the potential to develop drowsiness and specifically ask about factors that may increase the risk for somnolence with foscarbidopa/foslevodopa such as the use of concomitant sedating medications or the presence of sleep disorders.1 Consider discontinuing foscarbidopa/foslevodopa in patients who report significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating).1 If foscarbidopa/foslevodopa is continued, patients should be advised not to drive and to avoid other potentially dangerous activities that might result in harm if the patient becomes somnolent.1 There is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.1

Hallucinations/Psychosis

There is an increased risk for hallucinations and psychosis in patients taking foscarbidopa/foslevodopa.1 In the principal efficacy study, hallucinations occurred in 12.2% of patients treated with foscarbidopa/foslevodopa compared to 1.5% of patients treated with oral immediate-release carbidopa-levodopa.1 Psychosis occurred in 4.1% of patients treated with foscarbidopa/foslevodopa compared to 1.5% of patients treated with oral immediate-release carbidopa-levodopa.1 Treatment with foscarbidopa/foslevodopa was discontinued in 1 (1.4%) patient because of hallucinations.1

Hallucinations associated with levodopa may present shortly after the initiation of therapy and may be responsive to dose reduction of foscarbidopa/foslevodopa or other concomitantly administered medications.1 Confusion, insomnia, and excessive dreaming may accompany hallucinations.1 Abnormal thinking and behavior may present with one or more symptoms, including paranoid ideation, delusions, hallucinations, confusion, psychosis, disorientation, aggressive behavior, agitation, and delirium.1 Review of treatment is recommended if these symptoms develop.1

Because of the risk of exacerbating psychosis, patients with a major psychotic disorder should not be treated with foscarbidopa/foslevodopa.1 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 foscarbidopa/foslevodopa.1

Impulse Control/Compulsive Behaviors

Patients may experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge or compulsive eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including foscarbidopa/foslevodopa, that increase central dopaminergic tone and that are generally used for the treatment of parkinson's disease.1 In some cases, although not all, these urges were reported to have stopped when the dose was reduced, or the medication was discontinued. 1

Because patients may not recognize these behaviors as abnormal, it is important for prescribers to ask patients or their caregivers specifically about the development of new or increased gambling urges, sexual urges, uncontrolled spending, binge or compulsive eating, or other urges while being treated with foscarbidopa/foslevodopa.1 Consider reducing the dose or discontinuing foscarbidopa/foslevodopa if a patient develops such urges. 1

Infusion Site Reactions and Infections

Foscarbidopa/foslevodopa can cause infusion site reactions and infections.1

In the principal efficacy study, one or more infusion site reactions were reported in 62% of patients treated with foscarbidopa/foslevodopa and 8% of patients who received placebo subcutaneous infusion.1 Various types of reactions at the infusion site have been reported including erythema, pain, edema, nodule, bruising, hemorrhage, induration, pruritus, extravasation, inflammation, mass, warmth, hematoma, pallor, rash, and swelling.1 In the study, 8% of patients treated with foscarbidopa/foslevodopa and no patient who received placebo withdrew from treatment because of an infusion site reaction. 1

Infusion site infections occurred in 28% of patients treated with foscarbidopa/foslevodopa compared to 3% of patients who received placebo subcutaneous infusion; 5% of patients treated with foscarbidopa/foslevodopa and 2% who received placebo withdrew from treatment because of an infusion site infection.1 The most frequent infusion site infection reported was cellulitis.1 If an infection is suspected at the infusion site, the cannula should be removed from the infusion site.1 If the cannula is removed for an infection, either a new canula should be placed at a new infusion site or, in the event of a prolonged interruption, the patient should be prescribed an oral carbidopa and levodopa product until they are able to resume foscarbidopa/foslevodopa. 1

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.1 Avoid sudden discontinuation or rapid dose reduction in patients taking foscarbidopa/foslevodopa.1 If foscarbidopa/foslevodopa is discontinued, the dose should be tapered to reduce the risk of hyperpyrexia and confusion.1

Dyskinesia

Foscarbidopa/foslevodopa may cause or exacerbate dyskinesias.1 In the principal efficacy study, dyskinesia occurred in 11% of patients treated with foscarbidopa/foslevodopa compared to 6% of patients treated with oral immediate-release carbidopa-levodopa.1 The occurrence of dyskinesias may require a dosage reduction of foscarbidopa/foslevodopa or other medications used to treat parkinsons disease. 1

Cardiovascular Ischemic Events

In clinical studies, myocardial infarction and arrhythmia were reported in patients taking carbidopa-levodopa (the active metabolites of foscarbidopa/foslevodopa).1 Ask patients about symptoms of ischemic heart disease and arrhythmia, especially those with a history of myocardial infarction or cardiac arrhythmias. 1

Glaucoma

Carbidopa-levodopa (the active metabolites of foscarbidopa/foslevodopa) may cause increased intraocular pressure in patients with glaucoma.1 Monitor intraocular pressure in patients with glaucoma after starting foscarbidopa/foslevodopa.1

Specific Populations

Pregnancy

There are no data on the developmental risk associated with the use of foscarbidopa/foslevodopa in pregnant women.1 Foscarbidopa is a prodrug of carbidopa, and foslevodopa is a prodrug of levodopa.1 In animal studies, carbidopa-levodopa has been shown to be developmentally toxic (including teratogenic effects) at clinically relevant doses.1

The estimated background risk of major birth defects and miscarriage in the indicated population is unknown.1 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.1

Lactation

There are no adequate data on the presence of foscarbidopa/foslevodopa in human milk, the effects of the combination drug on milk production or on the breastfed infant.1

Foscarbidopa is a prodrug of carbidopa, and foslevodopa is a prodrug of levodopa.1

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.1 Carbidopa is excreted in rat milk.1

Levodopa has been detected in human milk after administration of carbidopa-levodopa.1 Levodopa decreases secretion of prolactin in humans, which may inhibit lactation.1 There are no adequate data on the effects of levodopa on the breastfed infant.1

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for foscarbidopa/foslevodopa and any potential adverse effects on the breastfed infant from the combination drug or from the underlying maternal condition.1

Pediatric Use

Safety and effectiveness in pediatric patients have not been established. 1

Geriatric Use

Clinical studies of foscarbidopa/foslevodopa did not include sufficient numbers of subjects 65 years of age and older to determine whether they respond differently from younger subjects.1 Other reported clinical experience has not identified differences in responses between the elderly and younger patients.1 In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.1

Common Adverse Effects

Most common adverse reactions for foscarbidopa/foslevodopa (incidence at least 10% and greater than oral carbidopa-levodopa incidence) were infusion/catheter site reactions, infusion/catheter site infections, hallucinations, and dyskinesia.1

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

• Selective MAO-B inhibitors: May cause orthostatic hypotension. 1
• Antihypertensive drugs: May cause symptomatic postural hypotension.1 Dosage adjustment of the antihypertensive drug may be needed. 1
• Dopamine D2 receptor antagonists and isoniazid may reduce the effectiveness of foscarbidopa/foslevodopa.1

Actions

Mechanism of Action

Foscarbidopa/foslevodopa is a prodrug combination of foscarbidopa (carbidopa-4´-monophosphate) and foslevodopa (levodopa-4´-monophosphate).1 Foscarbidopa and foslevodopa are converted in vivo to carbidopa and levodopa. 1

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 CNS.1 Carbidopa inhibits the decarboxylation of peripheral levodopa, making more levodopa available for delivery to the brain.1

Levodopa is the metabolic precursor of dopamine, does cross the blood-brain barrier, and presumably is converted to dopamine in the brain.1 This is thought to be the mechanism whereby levodopa treats symptoms of Parkinson's disease.1

Advice to Patients

• Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).1
• Refer patients to the Instructions for Use for complete administration instructions.1 Inform patients of aseptic technique and of subcutaneous administration site selection and rotation.1 Instruct the patient to record the date when foscarbidopa/foslevodopa is first removed from the refrigerator in the space provided on the carton.1
• Inform patients that if they disconnect the pump for less than 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.1 Instruct the patient to stop the pump and disconnect the tubing.1 The syringe can remain attached to the pump until the tubing is reconnected.1 Refer the patient to the Instructions for Use for additional information. 1
• Inform patients that if they have a prolonged interruption of therapy lasting more than 1 hour, a new infusion set (tubing and cannula) should be used, and rotation to a different infusion site is required before resuming infusion.1 In addition, if foscarbidopa/foslevodopa is interrupted for more than 3 hours, advise patients to administer a loading dose with either foscarbidopa/foslevodopa or oral immediate-release carbidopa and levodopa.1 Instruct patients to have oral carbidopa and levodopa available in case treatment with foscarbidopa/foslevodopa is interrupted for 1 hour or longer.1
• 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.1 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.1 Advise patients that if increased somnolence or episodes of falling asleep during activities of daily living (e.g., conversations, eating, driving a motor vehicle, etc.) are experienced at any time during treatment, they should not drive or participate in potentially dangerous activities until they have contacted their healthcare professional. 1
• 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.1
• Inform patients that they may experience hallucinations (unreal visions, sounds, or sensations) and other symptoms of psychosis while taking foscarbidopa/foslevodopa.1 Tell patients to report hallucinations, abnormal thinking, psychotic behavior, or confusion to their healthcare professional promptly should they develop.1
• Advise patients that they may experience impulse control and/or compulsive behaviors while taking foscarbidopa/foslevodopa.1 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 while being treated with foscarbidopa/foslevodopa.1
• 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.1 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.1 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.1 Instruct patients to remove the cannula if an infection at the infusion site occurs and to contact their healthcare provider.1 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. 1
• Advise patients to contact their healthcare professional before stopping foscarbidopa/foslevodopa.1 Tell patients to inform their healthcare professional if they develop withdrawal symptoms such as fever, confusion, or severe muscle stiffness.1
• Inform patients that foscarbidopa/foslevodopa may cause or exacerbate pre-existing dyskinesias.1
• Advise patients to notify their healthcare provider if they become pregnant during treatment or plan to become pregnant during treatment.1
• Advise patients to notify their healthcare provider if they are breastfeeding or plan to breastfeed.1

Additional Information

AHFS first Release^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. AbbVie Inc.. Vyalev^® (foscarbidopa/foslevodopa) SUBCUTANEOUS prescribing information. 2024 Oct. [Web]