2.1       Important Information

For subcutaneous administration only.

Patients selected for treatment with VYALEV should be capable of understanding and using the delivery system [see Healthcare Professional Instructions for Use of VYAFUSER Pump, and Patient Instructions for Use of VYAFUSER Pump] themselves or with assistance from a caregiver.

Patients should be trained on the proper use of VYALEV and the delivery system prior to initiating.

2.2       Recommended Dosage

VYALEV (foscarbidopa and foslevodopa) is administered as a subcutaneous infusion with the VYAFUSER pump [see Dosage and Administration (2.3), Healthcare Professional Instructions for Use of VYAFUSER Pump, and Patient Instructions for Use of VYAFUSER Pump].

VYALEV Base Continuous Dosage and Hourly Infusion Rate

The continuous infusion rate is based on total levodopa dosage (TLD). The hourly base continuous infusion rate (mL/hr) = [(TLD x 1.3) / 240] / [number of hours the patient is typically awake (e.g., 16 hours)], as shown in the steps below.

Step 1: Calculate the TLD for the levodopa-containing medications that VYALEV is replacing. All dosages should be converted to the equivalent dosage of immediate-release levodopa to obtain the TLD. Prescribers should adjust the total dose of levodopa-containing products for COMT inhibitor use. See the Prescribing Information for the respective drugs for conversions or adjustments. Do not include rescue or as needed levodopa or any other anti-Parkinsonian medication or therapy, including medications taken outside of awake time (e.g., night-time dosing) in this calculation.

Step 2: Determine the total daily dosage (mg) of VYALEV foslevodopa component by multiplying the TLD by 1.3. The conversion factor takes into account the molecular weight and bioavailability of foslevodopa compared to levodopa.

Step 3: Determine the total daily volume (mL) of VYALEV by dividing the total daily dosage (mg) of VYALEV by 240. Each 1 mL of VYALEV contains 240 mg of foslevodopa.

Step 4: Determine the hourly base continuous infusion rate of VYALEV by dividing the total daily volume (mL) of VYALEV by the number of hours the patient is typically awake (e.g., 16 hours). VYALEV may be administered over the patient’s waking hours or may be administered for 24 hours. See Dosage and Administration (2.3) for adjustment of and alternate infusion rates for lower overnight dosages.

Maximum Dosage

The maximum recommended daily dosage of VYALEV is 3,525 mg of the foslevodopa component (equivalent to approximately 2,500 mg levodopa).

Optional Loading Dose

If VYALEV therapy is being initiated in an “Off” state or the patient has not been receiving their base continuous infusion for more than 3 hours, a loading dose can be administered immediately prior to starting or re-starting the base continuous hourly infusion. Loading doses can be administered either with VYALEV or patients can continue using oral immediate-release carbidopa/levodopa tablets. The loading dose should be calculated from the first morning dose of oral immediate release carbidopa/levodopa the patient took before starting treatment with VYALEV. If VYALEV is used for the loading dose, multiply the first morning dose of oral immediate release levodopa by 1.3 and divide by 240 to determine the loading dose of VYALEV.

The pump is capable of delivering a loading dose ranging from 0.1 mL to a maximum of 3 mL, in increments of 0.1 mL.

Extra Dose

An extra dose volume can be programmed to 1 of 5 options (see Table 1). The “extra dose” feature is limited to no more than 1 extra dose per hour. If 2 or more extra doses are used by the patient during the 24-hour/day treatment period, a revision of the base continuous infusion rate should be considered (refer to the Healthcare Professional Instructions for Use of VYAFUSER Pump details).

*See Step 1

2.3       Preparation and Administration Instructions

Patients should be trained on the proper use of VYALEV and the delivery system prior to initiating treatment with VYALEV and, as necessary, thereafter [see Dosage and Administration (2.2) and the Patient Instructions for Use of VYAFUSER Pump].

Preparation

• Use aseptic technique.
  
• Use sterile, single-patient-use infusion components (syringe, infusion set, and vial adapter) qualified for use with the pump to infuse VYALEV.
  
• Do not dilute.
  
• Do not mix VYALEV with other products.
  
• The medication vials are for single dose only. The entire contents of a VYALEV vial should be transferred into a syringe for administration. Do not withdraw a partial portion of the vial contents.
  
• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit [see Dosage Forms and Strengths (3)].
  
• The infusion set (cannula) can remain in place for up to 3 days when VYALEV is infused continuously.

Administration

Site Selection

• Administer VYALEV subcutaneously, preferably in the abdomen, avoiding the area with a 2-inch radius from the navel.
  
• Rotate the infusion site and use a new infusion set at least every 3 days.
  
• Select new infusion sites at least 1 inch from sites used within the previous 12 days.
  
• Do not infuse VYALEV into areas where the site is tender, bruised, red, or hard to the touch.

Infusion Flow Rates

• Adjustment: Infusion rates may be adjusted in increments of 0.01 mL/hr (which is equivalent to approximately 1.7 mg of levodopa/hour).
  
• Alternative Flow Rates: The healthcare professional has the option to enable and pre-program the pump with 2 alternative continuous infusion rates (Low/High) that the patient may select to account for changes in functional demand (e.g., lowering the dosage at night or increasing the dose for prolonged intense activity) (see the Healthcare Professional Instructions for Use of VYAFUSER Pump).

Discarding VYALEV and Syringe

• Discard the vial after transfer of the product to the syringe. Discard the syringe and any unused VYALEV in the syringe after the product has been in the syringe for 24 hours.

2.4 Interruption of Therapy

Prescribing a backup oral carbidopa and levodopa product is recommended in the event that delivery of VYALEV is interrupted, which may result in underdosing. Sudden discontinuation or rapid dose reduction of VYALEV, without administration of alternative dopaminergic therapy, should be generally avoided [see Warnings and Precautions (5.5)]. 

Following interruptions of more than 1 hour, a new infusion set (tubing and cannula) should be used and rotated to a different infusion site. If the infusion has been interrupted for longer than 3 hours, the patient may also self-administer a loading dose, if enabled by their healthcare professional [see Dosage and Administration (2.2)].

5.1       Falling Asleep During Activities of Daily Living and Somnolence

Patients treated with levodopa (the active metabolite of VYALEV) 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 one 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 patients for drowsiness or sleepiness while using VYALEV, especially since some of the events occur well after the start of treatment. Prescribers should be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities. Patients who have already experienced somnolence or an episode of sudden sleep onset should not participate in these activities while taking VYALEV.

Before initiating treatment with VYALEV, advise patients about the potential to develop drowsiness and specifically ask about factors that may increase the risk for somnolence with VYALEV such as the use of concomitant sedating medications or the presence of sleep disorders. Consider discontinuing VYALEV in patients who report significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating). If VYALEV 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. There is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.

5.2       Hallucinations/Psychosis

There is an increased risk for hallucinations and psychosis in patients taking VYALEV. In Study 1 [see Clinical Studies (14)], hallucinations occurred in 12.2% of patients treated with VYALEV compared to 1.5% of patients treated with oral immediate-release carbidopa-levodopa. Psychosis occurred in 4.1% of patients treated with VYALEV compared to 1.5% of patients treated with oral immediate-release carbidopa-levodopa. Treatment with VYALEV was discontinued in 1 (1.4%) patient because of hallucinations.

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

Because of the risk of exacerbating psychosis, patients with a major psychotic disorder should not be treated with VYALEV. In addition, medications that antagonize the effects of dopamine used to treat psychosis may exacerbate the symptoms of PD and may decrease the effectiveness of VYALEV [see Drug Interactions (7.3)].

5.3       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 VYALEV, that increase central dopaminergic tone and that are generally used for the treatment of PD. 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 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 VYALEV. Consider reducing the dose or discontinuing VYALEV if a patient develops such urges.

5.4       Infusion Site Reactions and Infections

VYALEV can cause infusion site reactions and infections.

In Study 1, one or more infusion site reactions were reported in 62% of patients treated with VYALEV and 8% of patients who received placebo subcutaneous infusion. 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. In Study 1, 8% of patients treated with VYALEV and no patient who received placebo withdrew from treatment because of an infusion site reaction.

In Study 1, infusion site infections occurred in 28% of patients treated with VYALEV compared to 3% of patients who received placebo subcutaneous infusion. In Study 1, 5% of patients treated with VYALEV and 2% who received placebo withdrew from treatment because of an infusion site infection. The most frequent infusion site infection reported was cellulitis. If an infection is suspected at the infusion site, the cannula should be removed from the infusion site. 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 VYALEV [see Dosage and Administration (2.3, 2.4)].

5.5       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 VYALEV. If VYALEV is discontinued, the dose should be tapered to reduce the risk of hyperpyrexia and confusion [see Dosage and Administration (2.4)].

5.6       Dyskinesia

VYALEV may cause or exacerbate dyskinesias. In Study 1, dyskinesia occurred in 11% of patients treated with VYALEV compared to 6% of patients treated with oral immediate-release carbidopa-levodopa. The occurrence of dyskinesias may require a dosage reduction of VYALEV or other medications used to treat PD.

5.7       Cardiovascular Ischemic Events

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

5.8       Glaucoma

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

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.

In Study 1, a 12-week, active-controlled clinical trial, a total of 141 patients with advanced PD were enrolled [see Clinical Studies (14)]. Of these, 74 patients received VYALEV and 67 received oral immediate-release carbidopa-levodopa with placebo subcutaneous infusion.

Adverse reactions led to discontinuation of VYALEV in 22% of patients, which included hallucinations, infusion site reactions, and infusion site infections [see Warnings and Precautions (5.2, 5.5)]. Table 2 presents the adverse reactions that occurred in ≥3% of patients who received VYALEV and with a difference of >2% between the VYALEV and the oral immediate release carbidopa-levodopa groups in Study 1.  

7.1       Monoamine Oxidase (MAO) Inhibitors

Nonselective MAO Inhibitors

The use of nonselective MAO inhibitors (e.g., phenelzine and tranylcypromine) with VYALEV is contraindicated [see Contraindications (4)]. Discontinue use of any nonselective MAO inhibitors at least two weeks prior to initiating VYALEV.

Selective MAO Inhibitors

The use of selective MAO-B inhibitors (e.g., rasagiline and selegiline) with VYALEV may be associated with orthostatic hypotension. Monitor patients who are taking these drugs.

7.2       Antihypertensive Drugs

The concurrent use of VYALEV with antihypertensive medications can cause symptomatic postural hypotension. A dose reduction of the antihypertensive medication may be needed after starting or increasing the dosage of VYALEV.

7.3       Dopamine D2 Receptor Antagonists and Isoniazid

Dopamine D2 receptor antagonists (e.g., phenothiazines, butyrophenones, risperidone, metoclopramide, papaverine) and isoniazid may reduce the effectiveness of foslevodopa. Monitor patients for worsening Parkinson’s symptoms when patients are taking these medications with VYALEV.

8.1       Pregnancy

Risk Summary 

There are no data on the developmental risk associated with the use of VYALEV (foscarbidopa and foslevodopa) in pregnant women. Foscarbidopa is a prodrug of carbidopa, and foslevodopa is a prodrug of levodopa.  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 malformations 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

Foscarbidopa and Foslevodopa

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

Foscarbidopa is a prodrug of carbidopa, and foslevodopa is a prodrug of 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 VYALEV and any potential adverse effects on the breastfed infant from VYALEV or from the underlying maternal condition.

8.4       Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5       Geriatric Use

Clinical studies of VYALEV did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. 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.

12.1       Mechanism of Action

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

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 the 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 (e.g., nausea and vomiting) due to decarboxylation of levodopa; however, carbidopa does not decrease the adverse reactions due to the central effects of levodopa.

12.3       Pharmacokinetics

Absorption

VYALEV is administered directly into the subcutaneous space and is converted to carbidopa and levodopa by alkaline phosphatase. In a phase 1 study in healthy volunteers, carbidopa and levodopa were detectable in plasma within 30 minutes at the first pharmacokinetic (PK) collection point. In healthy volunteer subjects the steady state levodopa was achieved within 2 hours when VYALEV dosing was delivered as a loading dose followed by continuous infusion.

Healthy volunteers were administered VYALEV to different subcutaneous sites (i.e., abdomen, arm, and thigh) using a 3-way crossover design. PK analysis from this study showed that the 3 sites provided comparable carbidopa and levodopa exposure suggesting VYALEV absorption is similar at the different subcutaneous sites.

Effect of Food

VYALEV bypasses the gut, so consumption of food does not change absorption or systemic exposure of carbidopa/levodopa.

Distribution

Both foslevodopa and foscarbidopa have binding to plasma proteins between 24% to 26%.

Levodopa

Levodopa is distributed between erythrocytes and plasma in approximately 1:1 ratio. Levodopa binding to plasma proteins is< 10%. Levodopa is transported into the brain by the carrier mechanism for large neutral amino acids.

Carbidopa

Carbidopa is approximately 36% bound to plasma protein. Carbidopa does not cross the blood-brain barrier.

Metabolism and Excretion

The foscarbidopa and foslevodopa from VYALEV are converted by alkaline phosphatases into carbidopa and levodopa.

Levodopa

Levodopa is mainly eliminated via metabolism by the aromatic amino acid decarboxylase (AAAD) and the catechol-O-methyl-transferase (COMT) enzymes. Other routes of metabolism are transamination and oxidation. The decarboxylation of levodopa to dopamine by AAAD is the major enzymatic pathway when no enzyme inhibitor is co-administered. O-methylation of levodopa by COMT forms 3-O-methyldopa. When administered with carbidopa, the elimination half-life of levodopa is approximately 1.5 hours.

Carbidopa

Carbidopa is metabolized to two main metabolites (α-methyl-3-methoxy-4-hydroxyphenylpropionic acid and α-methyl-3,4-dihydroxyphenylpropionic acid). These 2 metabolites are primarily eliminated in the urine unchanged or as glucuronide conjugates. Unchanged carbidopa accounts for 30% of the total urinary excretion. The elimination half-life of carbidopa is approximately 2 hours.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

In rat, oral administration of carbidopa and levodopa for two years resulted in no evidence of carcinogenicity. VYALEV contains hydrazine, a degradation product of carbidopa. In published studies, hydrazine has been demonstrated to be carcinogenic in multiple animal species. Increases in liver (adenoma, carcinoma) and lung (adenoma, adenocarcinoma) tumors have been reported with oral administration of hydrazine in mouse, rat, and hamster.

Mutagenesis

Carbidopa was positive in the in vitro Ames test, in the presence and absence of metabolic activation, and the in vitro mouse lymphoma tk assay in the absence of metabolic activation but was negative in the in vivo mouse micronucleus assay.

In published studies, hydrazine was reported to be positive in in vitro genotoxicity (Ames, chromosomal aberration in mammalian cells, and mouse lymphoma tk) assays and in the in vivo mouse micronucleus assay.

Impairment of Fertility

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

16.1       How Supplied

VYALEV injection contains 120 mg foscarbidopa and 2,400 mg foslevodopa per 10 mL (12 mg foscarbidopa and 240 mg foslevodopa per mL) and is a colorless to yellow to brown (may have a purple or red tint), and clear to slightly opalescent solution. Each single-dose glass vial is filled with approximately 10 mL of solution and is fitted with a grey rubber stopper, aluminum crimp cap, and turquoise plastic flip-off cap.

The rubber stopper on the vial does not contain natural rubber latex.

Carton of 7 VYALEV vials: NDC 0074-0501-01

The VYAFUSER pump used to administer VYALEV (foscarbidopa and foslevodopa) is provided separately. 

16.2       Storage and Handling

• Keep the medication vials in the outer carton to protect the vials from breaking.
  
• Store VYALEV refrigerated at 2°C to 8°C (36°F to 46°F).
  
• VYALEV may be stored at room temperature up to a maximum of 30°C (86°F) for a single period of up to 28 days.
  • Once VYALEV has been stored at room temperature, do not return the product to the refrigerator. 
    
  • If stored at room temperature, discard VYALEV if not used within 28 days.
  
  
• Do not freeze. 
  
• Do not shake.