PRESCRIBING INFORMATION (PI)

PRODUODOPA (foslevodopa and foscarbidopa) 240 mg/ml + 12 mg/ml solution for infusion

Refer to Summary of Product Characteristics (SmPC) before prescribing.

PRESENTATION: 1 ml contains 240 mg foslevodopa and 12 mg foscarbidopa. 10 ml contain 2400 mg foslevodopa and 120 mg foscarbidopa.
Foslevodopa and foscarbidopa are prodrugs equivalent to approximately 170 mg levodopa and 9 mg carbidopa per 1 ml.

INDICATION: Treatment of advanced levodopa-responsive Parkinson’s disease with severe motor fluctuations and hyperkinesia or dyskinesia when available combinations of Parkinson medicinal products have not given satisfactory results. 

DOSAGE AND ADMINISTRATION: Posology: Produodopa is administered as a continuous subcutaneous infusion, 24 hours per day. The recommended starting infusion rate of Produodopa is determined by converting the daytime levodopa intake to levodopa equivalents (LE) and then increasing it to account for a 24-hour administration (see Initiation of treatment). The dose may be adjusted to reach a clinical response that maximises the functional “On” time and minimises the number and duration of “Off” episodes and “On” episodes with troublesome dyskinesia. The maximum recommended daily dose of foslevodopa is 6000 mg (or 25 ml of Produodopa per day equivalent to approximately 4260 mg levodopa per day). Produodopa replaces levodopa-containing medications and catechol-O-methyl transferase (COMT)-inhibitors. If required, other classes of medicinal products for Parkinson's disease can be taken concurrently.
Initiation of treatment: Patients selected for treatment with Produodopa should be capable of understanding and using the delivery system themselves or with assistance from a caregiver. Patients should be trained on the proper use of Produodopa and the delivery system (pump, solution vial, vial adapter, syringe, infusion set, carrying accessory, rechargeable battery, and charger; see Method of administration) prior to initiating treatment with Produodopa and, as necessary, thereafter. Three steps are required to initiate treatment with Produodopa: Calculate the LE based on the levodopa-containing medications used during the patient’s awake time/ Determine the hourly infusion rate of Produodopa/ Determine the volume of the loading dose.
Step 1: Calculate the LE based on the levodopa-containing medications used during the patient’s awake time: The levodopa amount from all levodopa-containing formulations used during the awake time of the day (typically 16-hour/day) should be converted to LE using the appropriate dose multiplication factor from Table 1 in the SmPC and then summed. For this calculation, only consider levodopa and COMT inhibitors. Do not include rescue levodopa or any other anti-Parkinsonian medication or therapy, including medications taken outside of awake time (e.g., night-time dosing) in this calculation. If any COMT inhibitors are taken within a 24-hour period, regardless of the COMT inhibitor dose, a correction factor should be applied to the sum of LE as presented in Table 1 in the SmPC.
Step 2: Determine the hourly infusion rate of Produodopa: Refer to Table 2 in the SmPC for suggested Produodopa starting infusion rates based on the LE calculated in Step 1. The hourly infusion rate for Produodopa in Table 2 in the SmPC is based on a patient’s LE intake during a typical 16-hour awake time (LE₁₆). If the LE determined in Step 1 were based on an awake time either longer or shorter than 16 hours, the LE should be adjusted to a 16-hour period. To adjust to a 16-hour period, take the LE calculated in Step 1, divide by the number of hours the patient is typically awake, and then multiply by 16. Then refer to Table 2 in the SmPC for Produodopa suggested starting infusion rates. An alternative is to calculate the starting hourly infusion rate according to the formula given under Table 2, where X is the number of patient’s awake hours/day. The hourly infusion rate determined in this step should be entered as the Base infusion rate when programming the pump (refer to the pump instructions for use for details).
Step 3: Determine the volume of the loading dose: A loading dose can be administered immediately prior to commencing the hourly infusion to quickly achieve symptomatic control when starting Produodopa therapy in an "Off" state (or if the pump has been off for more than 3 hours). Loading doses can be administered either via the pump or using oral immediate-release carbidopa-levodopa tablets. Table 3 in the SmPC provides the recommended loading dose volume (ml) of Produodopa to be programmed into the pump (refer to the pump instructions for use for details) and the corresponding amount of immediate-release levodopa (mg), regardless of the peripheral inhibitor of the DOPA decarboxylase (e.g., carbidopa, benserazide) co-administered. In patients with a history of myocardial infarction who have residual atrial nodal or ventricular arrhythmias, cardiac function should be monitored with particular care during the period of initial dosage adjustments.
Method of Administration: Produodopa is administered subcutaneously, preferably in the abdomen, avoiding 5-cm radius area from the navel. Use aseptic technique when preparing and administering this product. The infusion set (cannula) can remain in place for up to 3 days when the medication is infused continuously. Rotate the infusion site and use a new infusion set at least every 3 days. It is recommended that new infusion sites be at least 2.5 cm from sites used within the previous 12 days. Produodopa should not be infused into areas where the site is tender, bruised, red, or hard to the touch. For administration of Produodopa only the Vyafuser pump should be used (refer to the pump instructions for use for details) using sterile, single-use infusion components (syringe, infusion set, and vial adapter) qualified for use. Patients should be trained on the proper use of Produodopa and the delivery system (pump, solution vial, vial adapter, syringe, infusion set, carrying accessory, rechargeable battery, and charger) prior to initiating treatment with Produodopa and, as necessary, thereafter. The medication vials are for single use only. Once the content of a vial is transferred into the syringe, the contents of the syringe should be administered within 24 hours. Used medication vials and syringes should be discarded according to local regulations. Syringes must be discarded, even if residual product remains, as instructed by the healthcare professional.
Sudden discontinuation or rapid dose reduction of Produodopa, without administration of alternative dopaminergic therapy should be generally avoided. Produodopa can be interrupted without further actions for brief periods of time. For interruptions longer 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, to quickly re-establish symptom control. If treatment is interrupted for a prolonged time (>24 hours) or permanently discontinued, the healthcare professional should determine appropriate alternative dopaminergic treatment (e.g., oral levodopa/carbidopa). Treatment with Produodopa may be resumed at any time following instructions as for initiation of Produodopa. The starting hourly infusion rate can be adjusted by the healthcare professional to achieve the optimal clinical response. The hourly infusion rate should be delivered continuously over the 24-hour daily infusion period. If desired, the healthcare professional can enable and program 2 alternative hourly infusion rates (Low/High). These must be enabled and pre-programmed by the healthcare professional and may be selected to account for changes in functional demand (refer to the pump instructions for use for details). All infusion rates may be adjusted in increments of 0.01 ml/hr (which is equivalent to approximately 1.7 mg of levodopa/hour) and should not exceed 1.04 ml/hr (or approximately 4260 mg levodopa per day [6000 mg of foslevodopa per day]). If required, the healthcare professional can enable and program a self-administered extra dose option to manage acute “Off” symptoms experienced during continuous infusion. The Extra Dose volume can be chosen from 5 options, see Table 4 in the SmPC for full information.
Special Populations: The pharmacokinetics of Produodopa has not been evaluated in any special population. Produodopa is intended for use in Parkinson’s disease patients who are already on a stable dose of oral levodopa. Elderly: The impact of age on the levodopa pharmacokinetics following Produodopa infusion was not specifically evaluated. Studies with levodopa suggest a modest reduction of levodopa clearance with increasing age. Paediatric: Safety in patients under 18 years has not been established and its use in patients below the age of 18 is not recommended. Renal/hepatic impairment: The pharmacokinetics of Produodopa in subjects with renal and/or hepatic impairment has not been established. Caution should be exercised in patients with End Stage Renal Disease on dialysis requiring treatment with Produodopa because of diminished ability of the kidneys to eliminate phosphate. 

CONTRAINDICATIONS: Hypersensitivity to ingredients, narrow-angle glaucoma, severe heart failure or cardiac arrhythmia, acute stroke. Conditions where adrenergics are contraindicated (e.g. pheochromocytoma, hyperthyroidism, Cushing’s syndrome). Non-selective MAO-inhibitors and selective MAO type A inhibitors are contraindicated and should be withdrawn at least two weeks before starting Produodopa. Because levodopa may activate malignant melanoma, Produodopa should not be used in patients with suspicious undiagnosed skin lesions or a history of melanoma.

SPECIAL WARNINGS AND PRECAUTIONS: Refer to SmPC for full details. Several warnings and precautions below are generic for levodopa and, therefore, also for Produodopa. Not recommended for drug-induced extrapyramidal reactions. Caution in severe pulmonary or cardiovascular disease, bronchial asthma, renal, hepatic or endocrine disease, or history of peptic ulcer disease or of convulsions, chronic wide-angle glaucoma. In patients with a history of myocardial infarction who have residual nodal or ventricular arrhythmias, cardiac function should be monitored with particular care during initial dose adjustments. Monitor all patients for development of mental changes, depression with suicidal tendencies and other serious mental changes, past or current psychosis should be treated with caution. Higher frequency of hallucinations can occur in patients treated with dopamine agonists and/or other dopaminergic treatments containing levodopa including Produodopa. Co-administration with antipsychotics with dopamine receptor blocking properties, particularly D2 receptor antagonists, should be carried out with caution. Produodopa may induce orthostatic hypotension, therefore, caution should be taken with products which may cause orthostatic hypotension. Levodopa has been associated with somnolence and episodes of sudden sleep onset in patients with Parkinson’s disease, and caution should, therefore, be exercised when driving and operating machines. A symptom complex resembling Neuroleptic Malignant Syndrome (NMS), including muscular rigidity, increased body temperature, mental changes (e.g., agitation, confusion, coma) and increased serum creatine phosphokinase, has been reported when anti-Parkinsonian medicinal products were withdrawn abruptly. Rhabdomyolysis secondary to Neuroleptic Malignant Syndrome (NMS) or severe dyskinesias have been observed rarely in patients with Parkinson’s disease. Therefore, patients should be carefully observed when the dose of levodopa/carbidopa combinations are abruptly reduced or discontinued, especially if the patient is receiving antipsychotics. Neither NMS nor rhabdomyolysis has been reported in association with Produodopa. Periodically evaluate hepatic, haematopoietic, cardiovascular and renal function during extended therapy. Increases in impulse control disorders have been reported and patients should be monitored and reviewed. Patients and providers are advised to monitor for melanomas on a regular basis when using Produodopa. Ideally, periodic skin examinations should be performed by appropriately qualified individuals. Dose may need to be adjusted downwards to avoid levodopa induced dyskinesia. Sudden or gradual worsening of bradykinesia may indicate an obstruction in the device and should be investigated. Produodopa contains hydrazine, a degradation product of foscarbidopa that can be genotoxic and possibly carcinogenic, clinical significance of exposure unknown. Before initiation of treatment, patients and caregivers should be warned of the potential risk of developing Dopamine Dysregulation Syndrome (DDS). Polyneuropathy has been reported in patients treated with levodopa/carbidopa containing product. Before starting therapy evaluate patients for history or signs of polyneuropathy and known risk factors, and periodically thereafter. Reduced ability to handle the delivery system can lead to complications, in such case assistance should be provided. Infusion site events have been reported in patients receiving Produodopa. Following aseptic techniques while using this medication and frequent rotation of the infusion site are recommended to reduce the risk. Careful monitoring of serious infusion site reactions and infusion site infections is recommended. Produodopa is high in sodium, to be considered especially in patients on a low salt diet. 

INTERACTIONS: No interaction studies have been performed with Produodopa. The following interactions are known from the generic combination of levodopa/carbidopa. Caution is needed in concomitant administration of Produodopa with the following medicinal products: antihypertensives, tricyclic antidepressants, dopamine receptor antagonists, benzodiazepines, isoniazid, phenytoin, papaverine, sympathomimetics (may increase cardiovascular adverse events related to levodopa), COMT inhibitors (e.g., tolcapone, entacapone, opicapone), amantadine (may increase levodopa related adverse events). An adjustment of the dose of Produodopa may be needed. Foscarbidopa has been identified as a potential inducer of CYP1A2 in vitro. Care should be taken when prescribing Produodopa in combination with sensitive CYP1A2 substrates (e.g., fluvoxamine, clozapine, caffeine, theophylline, duloxetine and melatonin). Produodopa may be administered concomitantly with the manufacturer’s recommended dose of a MAO inhibitor with selectivity for MAO type B (e.g., selegiline HCl). The dose of Produodopa may need to be reduced when a MAO inhibitor selective for type B is added.

FERTILITY, PREGNANCY AND LACTATION: Pregnancy: There are no data from the use of Produodopa in pregnant women. Studies of levodopa and carbidopa in animals have shown reproduction toxicity. Produodopa is not recommended during pregnancy and in women of childbearing potential not using contraception unless the benefit for the mother outweigh the possible risks to the foetus. Breastfeeding: There is insufficient information on the effects of Produodopa or their metabolites in newborns/infants. Breast-feeding should be discontinued during treatment with Produodopa. Fertility: In reproduction studies no effects on fertility were observed in rats receiving levodopa/carbidopa.

ABILITY TO DRIVE AND USE MACHINES: Produodopa can have a major influence on the ability to drive and use machines therefore caution should be exercised when driving and operating machines. Patients being treated with Produodopa and presenting with somnolence and/or sudden sleep episodes must be advised to refrain from driving or engaging in activities where impaired alertness may put them, or others, at risk of serious injury or death (e.g., operating machines) until such recurrent episodes and somnolence have resolved. 

UNDESIRABLE EFFECTS: See SmPC for full list of adverse reactions.
Very common (≥1/10): Infusion site infection, infusion site cellulitis, anxiety, depression, hallucination, infusion site erythema, infusion site reaction, infusion site nodule, infusion site oedema, infusion site pain, fall.
Common (≥1/100 to <1/10): Infusion site abscess, decreased appetite, confusional state, delusion, impulse control disorder, insomnia, paranoia, psychotic disorder, suicidal ideation, cognitive disorder, dizziness, dizziness postural, dyskinesia, dystonia, headache, hypoaesthesia, on and off phenomenon, paraesthesia, polyneuropathy, somnolence, syncope, hypertension, hypotension, orthostatic hypotension, dyspnoea, abdominal pain, constipation, diarrhoea, dry mouth, nausea, vomiting, pruritus, rash, muscle spasms, urinary incontinence, urinary retention, asthenia, fatigue, infusion site bruising, infusion site exfoliation, infusion site extravasation, infusion site haematoma, infusion site haemorrhage, infusion site induration, infusion site inflammation, infusion site irritation, infusion site mass, infusion site papule, infusion site pruritus, infusion site rash, infusion site swelling, malaise, oedema peripheral, vitamin B6 decreased, weight decreased.
Serious: infusion site events (infusion site erythema, infusion site celluitis, infusion site nodule, infusion site pain, infusion site oedema, infusion site reaction), fall, headache, delusion, psychotic disorder, paranoia, suicidal ideation, hypertension.
The following reactions were identified with Duodopa (levodopa/carbidopa intestinal gel) as drug-related events. These events were not considered adverse reactions for Produodopa. Very common: urinary tract infection; Common: anaemia, abnormal dreams, agitation, sleep attacks, sleep disorder, tremor, heart rate irregular, oropharyngeal pain, abdominal distension, dysgeusia, dyspepsia, dysphagia, flatulence, dermatitis contact, hyperhidrosis, neck pain, pain, amino acid level increased (methylmalonic acid increased), blood homocysteine level increased, vitamin B12 deficiency, weight increased. Serious: angle closure glaucoma, malignant melanoma, leukopenia, thrombocytopenia, completed suicide, suicide attempt, convulsion, optic ischaemic neuropathy, erythema, phlebitis.
Laboratory values: The following laboratory abnormalities have been reported with levodopa/carbidopa treatment and should, therefore, be acknowledged when treating patients with Produodopa: elevated urea nitrogen, alkaline phosphatases, S-AST, S-ALT, LDH, bilirubin, blood sugar, creatinine, uric acid and positive Coomb’s test, and lowered values of haemoglobin and haematocrit. Leucocytes, bacteria and blood in the urine have been reported.

OVERDOSE: In the event of an overdosage with Produodopa, the infusion should be stopped immediately. The treatment of an acute overdose of Produodopa is the same as that of an acute overdose of levodopa; however, pyridoxine has no effect on the reversal of the action of Produodopa. Electrocardiographic monitoring should be used, and the patient observed carefully for the development of cardiac arrhythmias; if necessary, an appropriate antiarrhythmic therapy should be given. Patients must also be monitored for hypotension. The possibility that the patient took other medicinal products together with Produodopa should be taken into consideration.

MARKETING AUTHORISATION NUMBERS / PRESENTATIONS / NHS LIST PRICE:
Great Britain (GB) PLGB 41042/0091, Northern Ireland (NI) PLNI 41042/0048; Produodopa 240 mg/ml + 12 mg/ml solution for infusion: 7 vials x 10 ml: £592.90.

LEGAL CLASSIFICATION: POM

MA HOLDER: Further information available from AbbVie Ltd, Maidenhead, SL6 4UB.

DATE OF REVISION: January 2024

DOCUMENT NUMBER: PDUO-UK-00002-C

 UK-DUOD-240029. Date of preparation: January 2024.