PRODUODOPA Solution for infusion Ref.[116798] Active ingredients: Carbidopa Levodopa Levodopa and Carbidopa

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 (approximately 1.84 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.

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.

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.

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).

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:

^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 3^rd 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 HPRA Pharmacovigilance; website: www.hpra.ie.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.