ABBREVIATED PRESCRIBING INFORMATION:

Produodopa® (foslevodopa/ foscarbidopa) 240 mg/ml + 12 mg/ml solution for infusion

Please refer to the Summary of Product Characteristics (SmPC) before prescribing.

PRESENTATION: Each 10 ml vial contains 2400 mg foslevodopa and 120 mg foscarbidopa. 1 ml contains 240 mg foslevodopa and 12 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, preferably in the abdomen, 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 (see Method of administration) prior to initiating treatment with Produodopa and, as necessary, thereafter. Three steps are required to initiate treatment with Produodopa: Step 1: Calculate the LE based on the levodopa-containing medications used during the patient’s awake time. Step 2: Determine the hourly infusion rate of Produodopa. Step 3: Determine the volume of the loading dose. Refer to Section 4.2 of the SmPC for further information. Method of administration: 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. 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. Refer to SmPC for details. 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 active substances or excipients, 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 must be discontinued at least two weeks before starting Produodopa. Produodopa should not be used in patients with suspicious undiagnosed skin lesions or a history of melanoma.

SPECIAL WARNINGS AND PRECAUTIONS: 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 atrial nodal or ventricular arrhythmias, cardiac function should be monitored with 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. Review of treatment recommended if symptoms develop. Co-administration of antipsychotics with dopamine receptor blocking properties should be carried out with caution. Produodopa may induce orthostatic hypotension, therefore, caution in co-administrating with products which may cause orthostatic hypotension. 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 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 dermatologists. 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 probably carcinogenic, clinical significance of exposure is 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 products. 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. Produodopa is high in sodium, to be considered 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: Produodopa is not recommended during pregnancy and in women of childbearing potential not using contraception unless the benefits for the mother outweigh the possible risks to the foetus. Breast-feeding should be discontinued during treatment with Produodopa. 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. May cause dizziness or orthostatic hypotension, therefore exercise caution. Refrain from driving/operating machinery if somnolence and/or sudden sleep episodes occur.

UNDESIRABLE EFFECTS: Very common (≥1/10): infusion site cellulitis, infusion site infection, 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. The following adverse reactions were identified with Duodopa (levodopa/carbidopa) intestinal gel as drug-related events; however, 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. 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. Refer to Section 4.8 of the SmPC for details of other side effects, and for further information.

LEGAL CATEGORY: POM (S1A).

MARKETING AUTHORISATION NUMBER: PA 1824/2/3 (7 x 10 ml vials).

MARKETING AUTHORISATION HOLDER: AbbVie Limited, Citywest Business Campus, Dublin 24, Ireland.

Further information is available on request from: AbbVie Limited, 14 Riverwalk, Citywest Business Campus, Dublin 24, Ireland. Adverse events should be reported. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, website: www.hpra.ie.

Date of Revision: February 2024. PI/2/3/003.