Vyalev

1 INDICATIONS AND USAGE VYALEV is indicated for the treatment of motor fluctuations in adults with advanced Parkinson’s disease (PD). VYALEV is a combination of foscarbidopa (an aromatic amino acid decarboxylation inhibitor) and foslevodopa (an aromatic amino acid) indicated for the treatment of motor fluctuations in adults with advanced Parkinson’s disease. ( 1 )

2 DOSAGE AND ADMINISTRATION Evaluate vitamin B6 levels prior to starting treatment with carbidopa/levodopa therapies. ( 2.1 ) For subcutaneous administration only, preferably in the abdomen, via the VYAFUSER pump. ( 2.2 , 2.3 , 2.4 ) See the Full Prescribing Information for calculation of the base continuous dosage, hourly infusion rate, optional loading dose, and extra dose. ( 2.3 ) The maximum recommended daily dosage of VYALEV is 3,525 mg of foslevodopa (approximately 2,500 mg levodopa). ( 2.3 ) 2.1 Management of Vitamin B6 Levels Evaluate vitamin B6 levels prior to initiating carbidopa/levodopa therapies, including VYALEV, periodically during treatment, and as clinically indicated [see Warnings and Precautions 5.7 ] . If vitamin B6 levels are low, supplement to sufficient levels per standard of care. Patients may initiate and continue treatment with VYALEV while supplementing vitamin B6. 2. 2 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. 3 Recommended Dosage VYALEV (foscarbidopa and foslevodopa) is administered as a subcutaneous infusion with the VYAFUSER pump [ see Dosage and Administration ( 2.4 ), 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 ( 2.4 ) 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 t…

5 WARNINGS AND PRECAUTIONS May cause falling asleep during activities of daily living. ( 5.1 ) Hallucinations/Psychosis: May respond to dose reduction of VYALEV. ( 5.2 ) Impulse Control Behaviors: Consider dose reductions or stopping VYALEV. ( 5.3 ) Infusion Site Reactions and Infections: Monitor for infusion site infections: Following aseptic techniques while using this medication and frequent rotation of the infusion site is recommended to reduce the risk. ( 5.4 ) Avoid sudden discontinuation or rapid dose reduction to reduce the risk of withdrawal-emergent hyperpyrexia and confusion. ( 5.5 ) May cause or exacerbate dyskinesia: Consider dose reduction of VYALEV. ( 5.6 ) 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 antagoniz…

4 CONTRAINDICATIONS VYALEV is contraindicated in patients who are currently taking a non-selective monoamine oxidase (MAO) inhibitor or have recently (within 2 weeks) taken a nonselective MAO inhibitor. Hypertension can occur if these drugs are used concurrently [see Drug Interactions ( 7.1 )] . VYALEV 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. ( 4 )

7 DRUG INTERACTIONS Selective MAO-B inhibitors: May cause orthostatic hypotension. ( 7.1 ) Antihypertensive drugs: May cause symptomatic postural hypotension. Dosage adjustment of the antihypertensive drug may be needed. ( 7.2 ) Dopamine D2 receptor antagonists and isoniazid may reduce the effectiveness of VYALEV. ( 7.3 ) 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.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed below and elsewhere in labeling: Falling Asleep During Activities of Daily Living and Somnolence [see Warnings and Precautions ( 5.1 ) ] Hallucinations/Psychosis [see Warnings and Precautions ( 5.2 ) ] Impulse Control/Compulsive Behaviors [see Warnings and Precautions ( 5.3 ) ] Infusion Site Reactions and Infections [see Warnings and Precautions ( 5.4 )] Withdrawal-Emergent Hyperpyrexia and Confusion [see Warnings and Precautions ( 5.5 ) ] Dyskinesia [see Warnings and Precautions ( 5.6 ) ] Vitamin B6 Deficiency and Seizures [see Warnings and Precautions ( 5.7 ) ] Cardiovascular Ischemic Events [see Warnings and Precautions ( 5.8 ) ] Glaucoma [see Warnings and Precautions ( 5.9 )] Most common adverse reactions for VYALEV (VYALEV incidence at least 10% and greater than oral carbidopa-levodopa incidence) were infusion/catheter site reactions, infusion/catheter site infections, hallucinations, and dyskinesia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc. at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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. Table 2. Adverse Reactions in Study 1 that Occurred in ≥3% of Patients with Advanced PD who Received VYALEV and 2% Difference from Active Control Adverse Reaction VYALEV (n = 74 ) % Oral immediate-release carbidopa-levodopa (n = 67 ) % Infusion/catheter site reaction a 62 8 Infusion/catheter site infection b 28 3 Hallucination 12 2 Dyskinesia 11 6 On and off phenomenon 8 0 Balance disorder 5 0 Constipation 5 0 Peripheral swelling 5 0 Agitation 4 2 Insomnia 4 2 Psychotic disorder c 4 2 Dyspnea 4 0 Infusion/catheter site reaction includes multiple related terms. Infusion site/catheter site infections includes multiple related terms. Psychotic disorder includes psychotic disorder, delusion, and paranoia.