4.1. Therapeutic indications

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.

4.2. Posology and method of 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 (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.

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 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.

Table 1. Calculating the Levodopa Equivalents (LE)

Levodopa formulation

Dose multiplication factor

Immediate-release, including enteral suspension

1

Sustained-release, controlled-release or prolonged-releasea

0.75

If any COMT inhibitor is used, multiply sum of calculated LE from above by 1.33a

a The levodopa contained in combined LD/CD/COMT-inhibitor formulations count as immediate-release and needs to be added to the LE from all other sources of levodopa before the sum is multiplied for the COMT-inhibitors correction factor (i.e., do not apply COMT correction factor to single LE).

CD = carbidopa; LD = levodopa; COMT = catechol-O-methyl transferase; LE = levodopa equivalents.

Step 2: Determine the hourly infusion rate of Produodopa.

Refer to Table 2 for suggested Produodopa starting infusion rates based on the LE calculated in Step 1.

The hourly infusion rate for Produodopa in Table 2 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 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).

Table 2. Suggested Produodopa starting hourly infusion rate

LE16 (LE from all oral LD-containing medications taken over 16-hour awake time (mg))

Suggested Produodopa starting hourly infusion rate (ml/hr)a administered over 24 hours

< 400

0.15

400-499

0.15-0.17

500-599

0.17-0.20

600-699

0.20-0.24

700-799

0.24-0.27

800-899

0.27-0.30

900-999

0.30-0.34

1000-1099

0.34-0.37

1100-1199

0.37-0.40

1200-1299

0.40-0.44

1300-1399

0.44-0.47

1400-1499

0.47-0.51

1500-1599

0.51-0.54

1600-1699

0.54-0.57

1700-1799

0.57-0.61

1800-1899

0.61-0.64

1900-1999

0.64-0.68

2000-2099

0.68-0.71

2100-2199

0.71-0.74

2200-2299

0.74-0.78

2300-2399

0.78-0.81

2400-2499

0.81-0.84

2500-2599

0.84-0.88

2600-2699

0.88-0.91

2700-2799

0.91-0.94

2800-2899

0.94-0.98

2900-2999

0.98-1.01

3000-3099

1.01-1.04

>3100

1.04

a The hourly infusion rate can be calculated using the following formula, where X is the number of patient's awake hours used to determine the LE (e.g., X=16, in the table above).

Hourly infusion rate (ml/hr) = [(LE ∙ 0.92 ∙ 1.41) ∕ 240] ∕ X

Assumptions used to generate the “Suggested Produodopa starting hourly infusion rate”:

• Total daily LE over 16 hours are increased by 50% to account for 24-hour dosing

• Subcutaneous foslevodopa is 8% more bioavailable than enterally absorbed levodopa

• The molecular weight ratio between foslevodopa and levodopa is 1.41:1

• One millilitre of Produodopa contains 240 mg of foslevodopa and 12 mg of foscarbidopa

• Most patients with PD are treated with oral PD medications during their waking time (typically 16-hour/day treatment period); once the amount of foslevodopa needed over the 16-hour period has been calculated, it is divided by 240 mg to determine the number of millilitres needed over the 16-hour period, and then divided over 16 hours to establish the hourly infusion rate

LE = levodopa equivalents; LD = levodopa.

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 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.

Table 3. Determination of Produodopa volume recommended for the loading dose

Recommended loading dose volume (ml) to be programmed into the pump

Approximate corresponding levodopa amount (mg)

0.6

100

0.9-1.2

150-200

1.5-1.8

250-300

2.0

350

0.1 ml of Produodopa contains 24 mg foslevodopa (equivalent to approximately 17 mg of levodopa). The pump is capable of delivering a loading dose ranging from 0.1 ml to a maximum of 3.0 ml, in increments of 0.1 ml.

Optimisation and maintenance

The healthcare professional may adjust the starting hourly infusion rate to achieve the optimal clinical response for the patient. The hourly infusion rate should be delivered continuously over the 24-hour daily infusion period. If desired, the healthcare professional can program and enable 2 alternative hourly infusion rates (Low/High). 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]). The pump incorporates secure access to dose configuration to prevent patients from making changes to their pre-programmed flow rates or Extra Dose functionality.

Produodopa can be taken alone or, if necessary, with other concurrent medicinal products for Parkinson's disease, based on the judgement of the healthcare professional. A reduction in other concomitant medications for Parkinson's disease, followed by an adjustment in Produodopa dosage, may be considered during Produodopa infusion. The concomitant use of Produodopa with other levodopa-containing medications or with medicinal products that significantly regulate synaptic dopamine levels (such as COMT inhibitors) has not been studied.

Alternative flow rate

The pump also allows for 2 alternative infusion rate options to be programmed for patient use (Low/High). The alternative infusion rates must be enabled and pre-programmed by the healthcare professional and may be selected by patients to account for changes in functional demand, e.g., lowering the dosage at night-time or increasing the dose for prolonged intense activity (refer to the pump instructions for use for details).

Extra doses

If enabled by their healthcare professional, patients may self-administer an Extra Dose to manage acute “Off” symptoms experienced during continuous infusion. The Extra Dose volume can be chosen from 5 options (see Table 4). The Extra Dose feature is limited to no more than 1 extra dose per hour. If 5 or more extra doses are used by the patient during the 24-hour/day treatment period, a revision of the Base Infusion Rate should be considered. The ability to enable this function, as well as the minimum time required between extra doses, is determined by the healthcare professional and cannot be modified by the patient (refer to the pump instructions for use for details on programming the Extra Dose feature).

Table 4. Extra dose option for Produodopa

Produodopa volume (ml)

Levodopa equivalents (mg)

0.10

17

0.15

25.5

0.20

34

0.25

42.5

0.30

51

Method of administration

Produodopa is administered subcutaneously, preferably in the abdomen, avoiding a 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.

In a Pharmacokinetic crossover study, administration of Produodopa via the arm and thigh resulted in nearly equivalent exposure to the abdomen (see section 5.2 Absorption). Long-term safety and efficacy of administration to the arm and thigh have not been evaluated.

The medication should be stored and handled as described in section 6.4, Special precautions for storage. 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 (see section 6.6 Special precautions for disposal).

Interruption of therapy

Sudden discontinuation or rapid dose reduction of Produodopa, without administration of alternative dopaminergic therapy, should be generally avoided (see section 4.4).

Produodopa can be interrupted without further actions for brief periods of time, such as when the patient is taking a shower. 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 with Produodopa 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 (see section 4.2 Initiation of treatment).

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. Differences in exposure are not considered clinically significant because Produodopa is optimised once patients begin therapy. Therefore, covariate effects are not expected to impact clinical efficacy or safety. See section 5.2 for more information on the pharmacokinetics of levodopa and carbidopa in special populations.

4.3. Contraindications

Produodopa is contraindicated in patients with:

• hypersensitivity to the active substances or to any of the excipients listed in section 6.1

• narrow-angle glaucoma

• severe heart failure

• acute stroke

• severe cardiac arrhythmia

• non-selective MAO inhibitors and selective MAO type A inhibitors are contraindicated for use with Produodopa. These inhibitors must be discontinued at least two weeks prior to initiating therapy with Produodopa. 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) (see section 4.5).

• conditions in which medication with adrenergic activity are contraindicated, e.g., pheochromocytoma, hyperthyroidism and Cushing's syndrome.

Because levodopa may activate malignant melanoma, Produodopa should not be used in patients with suspicious undiagnosed skin lesions or a history of melanoma.

4.4. Special warnings and precautions for use

Special warnings and precautions for Produodopa

Several warnings and precautions below are generic for levodopa and, therefore, also for Produodopa.

• Produodopa is not recommended for the treatment of drug-induced extrapyramidal reactions.

• Produodopa therapy should be administered with caution to patients with severe cardiovascular or pulmonary disease, bronchial asthma, renal, hepatic, or endocrine disease, or history of peptic ulcer disease or of convulsions.

• 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.

• All patients treated with Produodopa should be monitored carefully for the development of mental changes, depression with suicidal tendencies, and other serious mental changes. Patients with 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 is recommended if such symptoms develop.

• Concomitant administration of antipsychotics with dopamine receptor-blocking properties, particularly D2 receptor antagonists, should be carried out with caution, and the patient should be carefully observed for loss of antiparkinsonian effect or worsening of parkinsonian symptoms (see section 4.5).

• Patients with chronic wide-angle glaucoma may be treated with Produodopa with caution, provided the intra-ocular pressure is well controlled and the patient is monitored carefully for changes in intra-ocular pressure during therapy.

• Produodopa may induce orthostatic hypotension. Therefore, Produodopa should be given cautiously to patients who are taking other medicinal products which may cause orthostatic hypotension (see section 4.5).

• 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 (see section 4.7).

• 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.

• Patients should be regularly monitored for the development of impulse control disorders. Patients and carers should be made aware that behavioural symptoms of impulse control disorders including pathologic gambling, increased libido and hypersexuality, compulsive spending or buying, binge-eating and compulsive-eating can occur in patients treated with dopamine agonists and/or other dopaminergic treatments containing levodopa including Produodopa. Review of treatment is recommended if such symptoms develop.

• Epidemiological studies have shown that patients with Parkinson's disease have a higher risk of developing melanoma than the general population. It is unclear whether the increased risk observed was due to Parkinson's disease or other factors, such as medicines used to treat Parkinson's disease. Therefore, patients and providers are advised to monitor for melanomas on a regular basis when using Produodopa for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).

• Dopamine Dysregulation Syndrome (DDS) is an addictive disorder resulting in excessive use of the product seen in some patients treated with levodopa/carbidopa. Before initiation of treatment, patients and caregivers should be warned of the potential risk of developing DDS.

• The dose of Produodopa may need to be adjusted downwards in order to avoid levodopa induced dyskinesias.

• Periodic evaluation of hepatic, haematopoietic, cardiovascular and renal function is recommended during extended therapy with Produodopa.

• Produodopa contains hydrazine, a degradation product of foscarbidopa, that can be genotoxic and probably carcinogenic. The median daily dose of Produodopa is approximately 2541 mg/day of foslevodopa and 127 mg/day of foscarbidopa. The maximum recommended daily dose is 6000 mg foslevodopa and 300 mg foscarbidopa. This includes hydrazine at up to a median exposure of 0.2 mg/day, with a maximum of 0.5 mg/day. The clinical significance of this hydrazine exposure is not known.

• Reduced ability to handle the delivery system can lead to complications. In such patients a caregiver (e.g., nurse, or close relative) should assist the patient.

• A sudden or gradual worsening of bradykinesia may indicate an obstruction in the device for whatever reason and needs to be explored.

• 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.

• Infusion site events (see section 4.8) 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. In clinical studies, few patients who reported infusion site reactions also experienced infusion site infections. Therefore, careful monitoring of serious infusion site reactions and infusion site infections is recommended.

Produodopa contains sodium

Produodopa contains 42.4 mg (approximately1.84 mmol) of sodium per ml, equivalent to 2.1% of the WHO recommended maximum daily dietary intake of sodium. The maximum daily dose of this medicine contains 54% of the WHO recommended maximum daily intake of sodium.

Produodopa is high in sodium. This should be considered especially in patients on a low salt diet.

4.5. Interaction with other medicinal products and other forms of interaction

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

Symptomatic postural hypotension has occurred when combinations of levodopa and a decarboxylase inhibitor are added to the treatment of patients already receiving anti-hypertensives. Dosage adjustment of the antihypertensive agent may be required.

Antidepressants

There have been rare reports of adverse reactions, including hypertension and dyskinesia, resulting from the concomitant administration of tricyclic antidepressants (e.g., amoxapine and trimipramine) and carbidopa/levodopa preparations.

COMT inhibitors (e.g., tolcapone, entacapone, opicapone)

Concomitant use of COMT (catechol-O-methyl transferase) inhibitors and Produodopa can increase the bioavailability of levodopa. The dose of Produodopa may need to be adjusted.

Other medicinal products

Dopamine receptor antagonists (some antipsychotics, e.g., phenothiazines, butyrophenones and risperidone and antiemetics, e.g., metoclopramide), benzodiazepines, isoniazid, phenytoin and papaverine can reduce the therapeutic effect of levodopa. Patients taking these medicinal products together with Produodopa should be observed carefully for loss of therapeutic response.

MAO inhibitors are contraindicated in patients taking Produodopa, with the exception of MAO-B selective inhibitors (for instance selegiline HCl). The dose of Produodopa may need to be reduced when a MAO inhibitor selective for type B is added.

Concomitant use of selegiline and levodopa/carbidopa has been associated with serious orthostatic hypotension.

Amantadine has synergistic effect with levodopa and may increase levodopa related adverse events. An adjustment of the dose of Produodopa may be needed.

Sympathomimetics (e.g., adrenergic drugs not limited to - salbutamol, phenylephrine, isoproterenol, dobutamine) may increase cardiovascular adverse events related to levodopa.

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). No clinical DDI studies have been conducted to assess the clinical relevance of this finding.

4.6. 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 (see section 5.3). 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.

Breastfeeding

Levodopa and possibly levodopa metabolites are excreted in human milk. There is evidence that lactation is suppressed during treatment with levodopa.

It is unknown whether carbidopa or its metabolites are excreted in human milk. Animal studies have shown excretion of carbidopa in breast milk.

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.

4.7. Effects on ability to drive and use machines

Produodopa can have a major influence on the ability to drive and use machines. Levodopa and carbidopa may cause dizziness and orthostatic hypotension. Therefore, caution should be exercised when driving or using 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 (see also section 4.4).

4.8. Undesirable effects

Summary of the safety profile

The most frequent adverse reactions (≥10%) reported in all Phase 3 studies in patients exposed to Produodopa were infusion site events (infusion site erythema, infusion site cellulitis, infusion site nodule, infusion site pain, infusion site oedema, infusion site reaction, and infusion site infection), hallucination, fall, and anxiety.

Tabulated list of adverse reactions

Adverse reactions reported in all Phase 3 studies in patients exposed to Produodopa (379 patients with total exposure of 414.3 person-years, 230 subjects exposed for ≥ 6 months, 204 subjects exposed for ≥ 12 months) or data from Duodopa Intestinal Gel based on treatment emergent frequencies, regardless of causality assigned are presented in Table 5, listed by MedDRA system organ class. Adverse reaction frequencies are based on the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); and very rare (<1/10 000).

Table 5. List of adverse reactions

System organ class

Frequency

Adverse reactions

Infections and infestations

Very common

Infusion site cellulitis

Infusion site infection

Urinary tract infectionb

Commona

Infusion site abscess

Blood and lymphatic system disorders

Common

Anaemiab

Uncommon

Leukopeniab

Thrombocytopeniab

Immune system disorders

Not known

Anaphylactic reactionb,e

Metabolism and nutrition disorders

Common

Decreased appetite

Psychiatric disorders

Very common

Anxiety

Depression

Hallucinationc

Common

Abnormal dreamsb

Agitationb

Confusional state

Delusion

Impulse control disorder Insomnia

Paranoia

Psychotic disorder

Sleep attacksb

Sleep disorderb

Suicidal ideation

Uncommon

Completed suicideb

Dementiab

Disorientationb

Dopamine dysregulation syndrome

Euphoric moodb

Fearb

Libido increasedb

Nightmareb

Suicide attemptb

Rare

Abnormal thinkingb

Nervous system disorders

Common

Cognitive disorder

Dizziness

Dizziness postural

Dyskinesia

Dystonia

Headache

Hypoaesthesia

On and off phenomenon

Paraesthesia

Polyneuropathyd

Somnolence

Syncope

Tremorb

Uncommon

Ataxiab

Convulsionb

Gait disturbanceb

Eye disorders

Uncommon

Angle closure glaucomab

Blepharospasmb

Diplopiab

Optic ischaemic neuropathyb

Vision blurredb

Cardiac disorders

Common

Heart rate irregularb

Uncommon

Palpitations

Vascular disorders

Common

Hypertension

Hypotension

Orthostatic hypotension

Uncommon

Phlebitisb

Respiratory, thoracic and mediastinal disorders

Common

Dyspnoea

Oropharyngeal painb

Uncommon

Dysphoniab

Rare

Respiration abnormalb

Gastrointestinal disorders

Common

Abdominal distensionb

Abdominal pain

Constipation

Diarrhoea

Dry mouth

Dysgeusiab

Dyspepsiab

Dysphagiab

Flatulenceb

Nausea

Vomiting

Uncommon

Salivary hypersecretionb

Rare

Bruxismb

Saliva discolourationb

Glossodyniab

Hiccupsb

Skin and subcutaneous tissue disorders

Common

Dermatitis contactb

Hyperhidrosisb

Pruritus

Rash

Uncommon

Alopeciab

Erythemab

Urticariab

Rare

Sweat discolourationb

Malignant melanomab

Musculoskeletal and connective tissue disorders

Common

Muscle spasms

Neck painb

Renal and urinary disorders

Common

Urinary incontinence

Urinary retention

Uncommon

Chromaturiab

Rare

Priapismb

General disorders and administration site conditions

Very common

Infusion site erythema

Infusion site reaction

Infusion site nodule

Infusion site oedema

Infusion site pain

Commona

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

Painb

Uncommon

Chest painb

Investigations

Common

Amino acid level increased (Methylmalonic acid increased)b

Blood homocysteine level increasedb

Vitamin B6 decreased

Vitamin B12 deficiencyb

Weight decreased

Weight increasedb

Injury, poisoning and procedural complications

Very common

Fall

a Common adverse reactions pertaining to infusion site events included if ≥2%.

b These adverse reactions were identified with Duodopa Intestinal Gel as drug-related events. However, these events were not considered adverse reactions for Produodopa.

c Hallucination includes hallucination, hallucination visual, hallucination auditory, hallucination olfactory, hallucinations tactile, and hallucinations mixed.

d Polyneuropathy includes neuropathy peripheral, polyneuropathy, decreased vibratory sense, peripheral sensory neuropathy, sensory disturbance, and sensory loss.

e Based on post-marketing data

Description of selected adverse reactions

Infusion site events

In the Phase 3 studies, the most common AEs related to Produodopa were infusion site reactions 77.6% (N=294) and infusion site infections 41.4% (N=157). Infusion site events including infusion site reactions and infections, commonly seen with subcutaneous infusions were observed with Produodopa in the clinical studies. The majority of the infusion site events were non-serious, were mild or moderate in severity, and resolved spontaneously or with treatment such as antibiotics and/or incision and drainage. Three subjects with infusion site infections had a complication of sepsis resulting in hospitalisation. Monitor for any skin changes at the infusion site that could indicate a potential infection, such as redness associated with warmth, swelling, pain, and discolouration when you apply pressure to it. Aseptic techniques should be followed while using this medication and consider rotating the infusion site more frequently than every 3rd day, using a new infusion set if you see these skin changes. It is recommended that new infusion sites be at least 2.5 cm from sites used within the previous 12 days.

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. Levodopa/carbidopa, and thus Produodopa, may cause a false positive result when a dipstick is used to test for urinary ketone; this reaction is not altered by boiling the urine sample. The use of glucose oxidase methods may give false negative results for glucosuria.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme.

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. 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.