DUODOPA Intestinal gel Ref.[116795] Active ingredients: Carbidopa Levodopa Levodopa and Carbidopa

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

• Duodopa is not recommended for the treatment of drug-induced extrapyramidal reactions.
• Duodopa 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 Duodopa 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.
• Concomitant administration of antipsychotics with dopamine receptor blocking properties, particularly D2 receptor antagonists should be carried out with caution, and the patient 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 Duodopa with caution, provided the intra-ocular pressure is well controlled and the patient is monitored carefully for changes in intra-ocular pressure.
• Duodopa may induce orthostatic hypotension. Therefore, Duodopa 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coma) and increased serum creatine phosphokinase, has been reported when anti-Parkinsonian medicinal products were withdrawn abruptly.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 Neuroleptic Malignant Syndrome 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 anti-psychotics. Neither NMS nor rhabdomyolysis has been reported in association with Duodopa.
• 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 Duodopa. 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 Duodopa for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g. dermatologists).
• If general anaesthesia is required, treatment with Duodopa may be continued for as long as the patient is permitted to take fluids and medicinal products by mouth. If therapy has to be stopped temporarily, Duodopa at the same dose as before may be restarted as soon as oral intake of fluid is allowed.
• The dose of Duodopa 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 Duodopa.
• Duodopa contains hydrazine, a degradation product of carbidopa that can be genotoxic and possibly carcinogenic. The average recommended daily dose of Duodopa is 100 ml, containing 2 g levodopa and 0.5 g carbidopa. The maximum recommended daily dose is 200 ml. This includes hydrazine at up to an average exposure of 4 mg/day, with a maximum of 8 mg/day. The clinical significance of this hydrazine exposure is not known.
• Previous surgery in the upper part of the abdomen may lead to difficulty in performing gastrostomy or jejunostomy.
• Reported complications in the clinical studies, and seen post-marketing, include abscess, bezoar, ileus, implant site erosion/ulcer, intestinal haemorrhage, intestinal ischaemia, intestinal obstruction, intestinal perforation, intussusception, pancreatitis, peritonitis, pneumonia (including aspiration pneumonia), pneumoperitoneum, post-operative wound infection and sepsis. Bezoars are retained concretions of indigestible material (such as vegetable or fruit non-digestible fibers) in the intestinal tract. Most bezoars reside in the stomach but bezoars may be encountered elsewhere in the intestinal tract. A bezoar around the tip of the jejunal tube may function as a lead point for intestinal obstruction or the formation of intussusception. Abdominal pain may be a symptom of the above listed complications. Some events may result in serious outcomes, such as surgery and/or death. Patients should be advised to notify their physician if they experience any of the symptoms associated with the above events.
• Reduced ability to handle the system (pump, tube connections) can lead to complications. In such patients a caregiver (e.g. nurse, assistant 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.
• 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 (see also section 4.8).
• Polyneuropathy has been reported in patients treated with levodopa/carbidopa intestinal gel. Before starting therapy evaluate patients for history or signs of polyneuropathy and known risk factors, and periodically thereafter.

No interaction studies have been performed with Duodopa. The following interactions are known from the generic combination of levodopa/carbidopa.

Caution is needed in concomitant administration of Duodopa 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 and carbidopa/levodopa preparations.

Anticholinergics

Anticholinergics may act synergistically with levodopa to decrease tremor. However, combined use may exacerbate abnormal involuntary movements. Anticholinergics may decrease the effects of levodopa by delaying its absorption. An adjustment of the dose of Duodopa may be needed.

COMT inhibitors (tolcapone, entacapone)

Concomitant use of COMT (Catechol-O-Methyl Transferase) inhibitors and Duodopa can increase the bioavailability of levodopa. The dose of Duodopa may need adjustment.

Other medicinal products

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

Duodopa can be taken concomitantly with the recommended dose of an MAO inhibitor, which is selective for MAO type B (for instance selegiline-HCl). The dose of levodopa may need to be reduced when an MAO inhibitor selective for type B is added.

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

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

Sympathicomimetics may increase cardiovascular adverse events related to levodopa.

Levodopa forms a chelate with iron in the gastrointestinal tract leading to reduced absorption of levodopa.

As levodopa is competitive with certain amino acids, the absorption of levodopa can be disturbed in patients who are on a protein rich diet.

The effect of administration of antacids and Duodopa on the bioavailability of levodopa has not been studied.

Pregnancy

There are no or limited amount of data from the use of levodopa/carbidopa in pregnant women. Studies in animals have shown reproduction toxicity (see section 5.3). Duodopa 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

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 levodopa/carbidopa or their metabolites in newborns/infants. Breast-feeding should be discontinued during treatment with Duodopa.

Fertility

No adverse reactions on fertility have been observed in preclinical studies with carbidopa or levodopa alone. Fertility studies in animals have not been conducted with the combination of levodopa and carbidopa.

Duodopa 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 Duodopa 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.

Drug-related undesirable effects that occur frequently with the Duodopa system include nausea and dyskinesia.

Device- and procedure related undesirable effects that occur frequently with the Duodopa system include abdominal pain, complications of device insertion, excessive granulation tissue, incision site erythema, postoperative wound infection, post procedural discharge, procedural pain, and procedural site reaction.

Most of these adverse reactions were reported early in the studies, subsequent to the percutaneous endoscopic gastrostomy procedure and occurred during the first 28 days.

Undesirable effects reported with Duodopa

The safety of Duodopa was compared to the standard oral formulation of levodopa/carbidopa (100 mg/25 mg) in a total of 71 advanced Parkinson's disease patients who participated in a randomized, double-blind, double-dummy, active controlled study of 12 weeks duration. Additional safety information was collected in an open-label, 12-month study in 354 patients with advanced Parkinson's disease and open-label extension studies.

An analysis was performed for patients who received Duodopa in all studies, regardless of the study design (double-blind or open-label) to allow for a summary of drug-related adverse reactions. Another analysis was performed for patients who received Duodopa or placebo gel through a PEG-J to allow for a summary of procedure-related and device-related adverse reactions in all studies, regardless of the study design (double-blind or open-label).

Drug-, Procedure- and device-related adverse reactions based on treatment emergent frequencies, regardless of causality assigned, in addition to adverse reactions identified during post-approval use of Duodopa are presented in Table 1.

Table 1. Adverse Reaction Data Derived From Clinical Trials and Post-marketing Experience:

Dislocation of the intestinal tube backwards into the stomach or an obstruction in the device leads to reappearance of the motor fluctuations.

The following additional adverse reactions (listed in MedDRA preferred terms) have been observed with oral levodopa/carbidopa and could occur with Duodopa:

Table 2. Adverse Reaction Observed with Oral Levodopa/Carbidopa:

Laboratory values: The following laboratory abnormalities have been reported with levodopa/carbidopa treatment and should, therefore, be acknowledged when treating patients with Duodopa: 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 Duodopa, 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.

Not applicable.