Duodopa: Indications, Dosage, Precautions, Adverse Effects
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Duodopa - Product Information

Manufacture: AbbVie
Country: Canada
Condition: Parkinson's Disease, Periodic Limb Movement Disorder, Restless Legs Syndrome
Class: Dopaminergic antiparkinsonism agents
Form: Cream, gel, liniment or balm, lotion, ointment, etc
Ingredients: levodopa, carbidopa, carmellose sodium, purified water

Summary product information

Route of AdministrationDosage
Form/Strength
Non-medicinal Ingredients

intestinal
infusion
gel/1 mL contains
20 mg levodopa and
5 mg carbidopa (monohydrate)
Carmellose sodium, purified water

Indications and clinical use

DUODOPA (levodopa/carbidopa intestinal gel) is indicated for the treatment of patients with advanced levodopa-responsive Parkinson’s disease:

  • who do not have satisfactory control of severe, debilitating motor fluctuations and hyper- /dyskinesia despite optimized treatment with available combinations of Parkinson’s medicinal products (see CLINICAL TRIALS), and
  • for whom the benefits of this treatment may outweigh the risks associated with the insertion and long-term use of the percutaneous endoscopic gastrostomy-jejunostomy (PEG-J) tube required for administration (see CONTRAINDICATIONS; WARNINGS AND PRECAUTIONS, Serious Warnings and Precautions, GeneralM, Peri-Operative Considerations, Gastrointestinal; ADVERSE REACTIONS).

Prior to insertion of the permanent percutaneous endoscopic gastrostomy jejunostomy (PEG-J) tube, a positive test of the clinical response to DUODOPA administered via a temporary nasojejunal (NJ) tube is recommended for all patients.

DUODOPA should only be prescribed by neurologists who are experienced in the treatment of patients with Parkinson’s disease, and who have completed the DUODOPA education program that includes training in: the criteria for selecting suitable patients; initiation and management with DUODOPA therapy via naso-intestinal infusion and percutaneous endoscopic gastrostomy; postprocedural care; and, the risks associated with the procedure and long-term use of the PEG-J.

Establishment of the transabdominal port should be performed by a gastroenterologist or other healthcare professional (e.g., radiologist, gastrosurgeon) experienced in the PEG placement procedure. Dose adjustments should be carried out in association with a neurological clinic staffed with healthcare professionals trained in the use of DUODOPA.

Geriatrics (> 65 years of age):

Of the total number of patients using the DUODOPA System in the clinical studies, more than half were 65 years of age or older. No overall differences in safety or effectiveness were observed between these patients and younger patients (see CLINICAL TRIALS).

Pediatrics (< 18 years of age):

The safety and efficacy of DUODOPA in patients under 18 years of age have not been evaluated and its use in patients below the age of 18 is not recommended.

Contraindications

Contraindications for Treatment with Levodopa

DUODOPA (levodopa/carbidopa intestinal gel) is contraindicated in patients with:

  • hypersensitivity to levodopa, carbidopa or to any ingredient in the formulation or component of the container. For a complete listing, see DOSAGE FORMS, COMPOSITION AND PACKAGING.
  • narrow-angle glaucoma.
  • clinical or laboratory evidence of uncompensated cardiovascular, cerebrovascular, endocrine, renal, hepatic, hematologic or pulmonary disease (including bronchial asthma).

Concomitant use of nonselective monoamine oxidase (MAO) inhibitors and selective MAO type A inhibitors with DUODOPA is contraindicated. Nonselective MAO inhibitors and selective MAO type A inhibitors must be discontinued at least 2 weeks prior to initiating therapy with DUODOPA (see DRUG INTERACTIONS, Drug-Drug Interactions).

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

DUODOPA should not be given when administration of a sympathomimetic amine is contraindicated (e.g., epinephrine, norepinephrine, isoproterenol) (see DRUG INTERACTIONS, Pharmacodynamic Interactions).

Contraindications for PEG Tube Placement

The placement of a PEG tube for DUODOPA treatment is contraindicated in patients with the following conditions:

  • Pathological changes of the gastric wall
  • Inability to bring the gastric wall and abdominal wall together
  • Blood coagulation disorders
  • Peritonitis
  • Acute pancreatitis
  • Paralytic ileus

Warnings and precautions

Serious Warnings and Precautions

Procedure- and Device-Related Complications

The morbidity and mortality associated with the procedure used for placing the percutaneous endoscopic gastrostomy-jejunostomy (PEG-J) and long-term use of PEG-J need to be balanced against the expected benefits of using DUODOPA (levodopa/carbidopa intestinal gel). See WARNINGS AND PRECAUTIONS, General Peri-Operative Considerations, Gastrointestinal, DUODOPA Treatment and Device- Related Complications and ADVERSE REACTIONS, Device-Related Adverse Events.

Sudden Onset of Sleep

Patients receiving treatment with levodopa and other dopaminergic agents have reported suddenly falling asleep while engaged in activities of daily living, including driving a car, which has sometimes resulted in accidents. Although some of the patients reported somnolence while on levodopa, others perceived that they had no warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event.

Physicians should alert patients of the reported cases of sudden onset of sleep, bearing in mind that these events were NOT limited to initiation of therapy. Patients should also be advised that sudden onset of sleep has occurred without warning signs and should be specifically asked about factors that may increase the risk with DUODOPA such as concomitant medications or the presence of sleep disorders. Given the reported cases of somnolence and sudden onset of sleep (not necessarily preceded by somnolence), physicians should caution patients about the risk of operating hazardous machinery, including driving motor vehicles, while taking DUODOPA. If drowsiness or sudden onset of sleep should occur, patients should be informed to immediately contact their physician.

Episodes of falling asleep while engaged in activities of daily living have also been reported in patients taking other dopaminergic agents, therefore, symptoms may not be alleviated by substituting these products.

While dose reduction clearly reduces the degree of somnolence, there is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.

Currently, the precise cause of this event is unknown. It is known that many Parkinson’s disease patients experience alterations in sleep architecture, which results in excessive daytime sleepiness or spontaneous dozing, and that dopaminergic agents can also induce sleepiness.

General

Patients and/or caregivers should be thoroughly assessed for physical and cognitive ability to operate the DUODOPA system, prior to insertion of the PEG-J tube.

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

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

Gastrointestinal

Patients with a history of upper gastrointestinal (GI) problems or problems with intestinal absorption were generally excluded from DUODOPA clinical trials. Previous surgery in the upper part of the abdomen may lead to difficulty in performing gastrostomy or jejunostomy.

DUODOPA Procedure- and Device-Related Complications

A commonly reported event in the clinical studies was abdominal pain associated with the PEG-J procedure. The peri-operative abdominal pain was mostly mild to moderate in severity and resolved in the first 4 weeks. Abdominal pain may also be a symptom of other procedure- and/or device-related complications reported in the clinical studies including bezoar, ileus, implant site erosion/ulcer, intestinal hemorrhage, intestinal ischemia, intestinal obstruction, intestinal perforation, pancreatitis, peritonitis, pneumoperitoneum and post-operative wound infection. Some of these adverse events have resulted in serious outcomes, including prolonged hospitalization, surgery and/or death. Patients should be instructed in the early recognition of abdominal pain and symptoms additional to abdominal pain that may indicate a serious complication related to the device and to seek immediate medical attention if they experience any of the symptoms (see ADVERSE REACTIONS, Device-Related Adverse Events).

A sudden deterioration in treatment response with recurring motor fluctuations should lead to the suspicion that the distal part of the tube has become displaced from the duodenum/proximal jejunum into the stomach. The location of the tube should be determined by X-ray and the end of the tube repositioned to the duodenum/jejunum. Patients should also be assessed for other potentially serious gastrointestinal complications that may occur with tube dislocation (e.g., perforation of intestine or adjacent anatomical structures).

Gastrostomy tube blockage and/or intestinal obstruction with bezoar formation, necessitating replacement of tubing and in rare cases surgery, have been reported with DUODOPA. Bezoars are retained concretions of undigested food material in the intestinal tract and consumption of fibrous food may be a risk factor for bezoar formation. Early symptoms include aggravation of Parkinson’s symptoms, reduced efficacy, abdominal pain, nausea and vomiting. In some cases gastric and intestinal ulcerations have been found.

Peri-Operative Considerations

Prior to surgical placement of a permanent PEG-J tube, patients and caregivers should be fully informed of the following:

The benefits and known risks associated with the placement of the PEG-J tube and use of the DUODOPA system, through educational material and discussions with healthcare professionals who are informed in the use of this product.

The majority of patients that underwent PEG-J insertion in DUODOPA clinical trials experienced procedure- and/or device-related adverse events, sometimes serious and/or life- threatening, mainly during the first month after PEG-J placement (see WARNINGS AND PRECAUTIONS, GastrointestinalM; ADVERSE REACTIONS, Device Related Adverse Events). Most of these adverse events were mild to moderate in severity, non-serious, reported within the first 28 days after the percutaneous endoscopic gastrostomy procedure and resolved in the same time period.

The PEG tube and J-tube will periodically require replacement. In DUODOPA clinical trials in which 395 patients had a PEG-J tube for a mean duration of 546 days, 14% (55/395) of patients required at least one PEG tube replacement and 43% (171/395) of patients required at least one J-tube replacement. Approximately half of the patients who had a J-tube replacement needed subsequent J-tube replacements.

Post-operative wound infections

Patients who are undergoing PEG-J tube placement are potentially at risk for postoperative peristomal infections. During the DUODOPA clinical trials 21% (83/395) of patients had postoperative wound infection adverse events. Antibiotic prophylaxis has been shown to markedly reduce the risk of peristomal infection, and is recommended for patients undergoing PEG-J placement for administration of DUODOPA. In the DUODOPA clinical trials 75% of patients received antibiotic prophylaxis.

Local infections around the stoma are treated conservatively (disinfectant) or with systemic antibiotics; 92% (46/50) of patients received antibiotics (mostly oral) for post-operative wound infections at some point during the open-label 12-month study including 354 patients with advanced Parkinson’s disease. Patients and caregivers should be instructed that daily cleansing/disinfecting of the wound is recommended for the first 10 days, with daily sterile (non-occlusive, gauze or foam) dressing change. Thereafter, daily cleansing with soap and water and a clean dressing change are recommended, with monitoring for signs of infection. Severe localized tenderness may indicate development of an abdominal wall abscess related to the stoma. Abscesses may resolve spontaneously but occasionally require surgical incision.

Leakage from the stoma site

Post procedural discharge was reported as an adverse event in DUODOPA clinical trials for 11% (43/395) of patients. Leakage of gastric or intestinal contents around the stoma site tube is a complication of PEG-J placement and can cause irritation, redness, and swelling. Management of gastric fluid leakage may include protecting the skin with a barrier cream that may reduce local skin irritation, and leaving the site open to air as much as possible. Use of a foam dressing may also help reduce local skin irritation.

Neurologic

DUODOPA should be administered cautiously to patients who have a history of seizures, conditions associated with seizure or who have a lowered seizure threshold.

Polyneuropathy

Polyneuropathy has been reported in patients treated with levodopa/carbidopa combinations, including DUODOPA. In patients treated with DUODOPA polyneuropathy adverse events were generally consistent with axonal polyneuropathy, manifested as sensory or sensorimotor neuropathies, with subacute or chronic onset. Reported symptoms mainly included numbness, tingling, decreased sensation, weakness, and pain in the legs, hands, feet, and extremities.Deficiencies in folic acid, vitamin B12 and vitamin B6 and elevated homocysteine were observed in the majority of patients (see ADVERSE REACTIONS, Post-Market Adverse Events).

Patients should be evaluated for a history of polyneuropathy and known risk factors (e.g., vitamin B12 and/or vitamin B6 deficiencies, diabetes mellitus, hypothyroidism) prior to initiating treatment with DUODOPA. For patients with pre-existing polyneuropathy the benefits of treatment with DUODOPA should be carefully weighed against the potential risks, including the potential for impaired mobility. For all patients, plasma concentrations of vitamin B12, vitamin B6, homocysteine, methylmalonic acid and folic acid should be obtained at baseline and at regular intervals during treatment with DUODOPA. Patients who develop symptoms of peripheral neuropathy and low plasma concentrations of vitamin B6 and/or vitamin B12, or elevated homocysteine or methylmalonic acid concentrations may benefit from vitamin supplementation. Physicians should carefully evaluate if a dose adjustment is warranted and assess the benefit/risk of continued treatment (see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests).

Neuroleptic Malignant Syndrome

DUODOPA must not be withdrawn abruptly. A symptom complex resembling Neuroleptic Malignant Syndrome (NMS), including muscular rigidity, elevated body temperature, mental changes (e.g. agitation, confusion), altered consciousness, autonomic instability and elevated serum creatine phosphokinase has been reported in association with rapid dose reduction, withdrawal of or changes in antiparkinsonian therapy. Therefore, patients should be carefully observed when the dose of levodopa/carbidopa is abruptly reduced or discontinued, especially if the patient is receiving antipsychotics. Should a combination of such symptoms occur, the patient should be kept under medical surveillance, hospitalized if necessary, and appropriate symptomatic treatment given. This may include resumption of therapy with DUODOPA after appropriate evaluation.

Psychomotor Performance

Levodopa and carbidopa may cause dizziness and symptomatic orthostatism. Therefore, caution should be exercised when driving or using machines during treatment with DUODOPA.

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 WARNINGS AND PRECAUTIONS, Serious Warnings and Precautions, Sudden onset of Sleep).

Psychiatric

Patients with past or current psychosis should be treated with caution.

Concomitant administration of antipsychotics with dopamine receptor blocking properties, particularly D2 receptor antagonists may reduce the therapeutic effects of levodopa and should be used with caution. Patients should be carefully observed for loss of antiparkinsonian effect or worsening of parkinsonian symptoms (see DRUG INTERACTIONS, Drug-Drug Interactions).

Impulse Control/Compulsive Behaviours

Patients and caregivers should be advised to adhere to dosage instructions given by the physician. Patients should be regularly monitored for the development of impulse control disorders. Patients and caregivers should be made aware that behavioral symptoms of impulse control disorders including pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating and compulsive eating have been reported in patients treated with dopamine agonists and/or other dopaminergic treatments for Parkinson’s disease, including DUODOPA. Safety data from various sources including literature, clinical trials, and post- market analysis have described an addictive pattern of dopamine replacement therapy, in which patients use doses in excess of those required to control their motor symptoms. Because patients may not recognize these behaviors as abnormal, it is important for physicians to specifically ask patients and caregivers to identify new behavior patterns. Review of treatment is recommended if such symptoms develop. These symptoms were generally reversible upon dose reduction or treatment discontinuation (see ADVERSE REACTIONS).

Depression

All patients treated with DUODOPA should be monitored carefully for the development of mental changes, depression with suicidal tendencies, and other serious mental changes.

Carcinogenicity

DUODOPA contains hydrazine, a degradation product of carbidopa that can be genotoxic and possibly carcinogenic (see TOXICOLOGY). The average daily dose of DUODOPA is 100 mL, containing 2 g levodopa and 0.5 g carbidopa. The usual maximum 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.

Cardiovascular

In patients with a history of myocardial infarction or who have atrial nodal or ventricular arrhythmias, cardiac function should be monitored with particular care during the period of initial dosage adjustments.

DUODOPA may induce orthostatic hypotension and should be given cautiously to patients who are taking other medicinal products which may cause orthostatic hypotension (see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests; DRUG INTERACTIONS, Drug-Drug Interactions).

Ophthalmologic

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 during therapy.

Skin

Melanoma

Epidemiological studies have shown that patients with Parkinson’s disease have a higher risk (2- to approximately 6-fold higher) 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 drugs used to treat Parkinson’s disease. Therefore, patients and healthcare providers are advised to monitor for melanomas frequently and on a regular basis when using DUODOPA for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).

Special Populations

Pregnant Women

There are no adequate or well controlled studies evaluating the use of levodopa/carbidopa in pregnant women. Levodopa and combinations of levodopa/carbidopa have caused visceral and skeletal malformations in rabbits (see TOXICOLOGY). The potential risk for humans is not known. Use of DUODOPA in women of child-bearing potential requires that the anticipated benefits of the drug be weighed against possible risks to mother and child.

Nursing Women

Levodopa is excreted in breast milk in significant quantities. There is evidence that lactation is suppressed during treatment with levodopa. Carbidopa is excreted in milk in animals but it is not known whether it is excreted in human breast milk. The safety of levodopa and carbidopa in the infant is not known. DUODOPA should not be used during breast-feeding.

Pediatrics (< 18 years of age)

The safety and efficacy of DUODOPA in patients under 18 years of age have not been evaluated and its use in patients below the age of 18 is not recommended.

Monitoring and Laboratory Tests

Periodic evaluation of hepatic, hematopoietic, cardiovascular and renal function is recommended during dosage optimization and during extended therapy with DUODOPA.

Blood pressure should be monitored in patients receiving antihypertensive medication (see WARNINGS AND PRECAUTIONS, Cardiovascular; DRUG INTERACTIONS, Drug-Drug Interactions).

Plasma concentrations of vitamin B12, vitamin B6, homocysteine, methylmalonic acid and folic acid should be obtained at baseline and at regular intervals during treatment with DUODOPA (see WARNINGS AND PRECAUTIONS, Neurologic, Polyneuropathy).

Adverse reactions

Adverse Drug Reaction Overview

Early Stage Clinical Development Program

DUODOPA was administered to a total of 46 patients in open label studies in which DUODOPA was compared to active treatments (oral levodopa products and/or other Parkinson drugs). The comparison of the safety of levodopa/carbidopa formulated as an intestinal gel versus oral levodopa products and, the characterization of the safety of long-term administration of DUODOPA via a PEG tube, was limited by: an overall small number of patients in the studies; a small subset of patients undergoing long-term treatment (6 months) following PEG tube placement (n=7); and, the use of a nasoduodenal tube for DUODOPA administration for short durations (3 weeks to 1 month) for most patients.

Phase III Clinical Development Program

DUODOPA was administered to a total of 416 patients in Phase III clinical trials.

The safety of DUODOPA was compared to the standard oral immediate release formulation of levodopa/carbidopa (100 mg/25 mg) in a total of 71 advanced Parkinson’s disease patients included in a randomized, double-blind, double-dummy, active controlled study with 12 weeks duration. The study data were from two identically-designed studies that were combined for analyses prior to breaking the study blind (total on DUODOPA n=37, total on oral levodopa/carbidopa n=34). Most patients in both treatment groups reported at least 1 treatment emergent adverse event (TEAE). The types of adverse events (procedure- and device-related adverse events and adverse events excluding procedure and device-related adverse events) were generally similar in both treatment groups and consistent with those reported in the safety data set for all Phase III studies. Several of the most frequently reported adverse events were reported more frequently in the DUODOPA group but, due to the numbers of patients in each treatment group, the significance of this observation is not known. A total of 3 of 71 patients (4.2%) discontinued the controlled studies prematurely due to treatment-emergent adverse events.

Additional safety information was collected in an open-label, 12-month study including 354 patients with advanced Parkinson’s disease and in open-label extension studies. In the open-label analysis set 92% of patients (379/412) reported at least 1 treatment-emergent adverse event, with 36.0% of patients (147/412) reporting at least 1 serious treatment-emergent adverse event. Forty- five of 412 patients (10.9%) discontinued treatment due to treatment-emergent adverse events.

The safety data presented in Table 1 and Table 2 represent the combined safety data, for patients receiving DUODOPA in all Phase III studies, regardless of study design (double-blind and open label). For treatment emergent adverse events, excluding procedure- and device-related adverse events, the reported frequencies are based on 416 patients that received DUODOPA through an NJ tube or PEG-J tube in the Phase III studies. The reported frequencies of all procedure- and device-related adverse events are based on 395 patients that received DUODOPA via a PEG-J tube in these studies.

Device

Device- or procedure-related adverse events were reported for 73.7% of patients (291/395) that received DUODOPA via a PEG-J tube in the Phase III clinical trials over an average PEG-J exposure of 546 days per patient (range 1 to 1276 days). The prevalence of any device- or procedure-associated event in clinical trials was highest between Day 1 and Day 28 (61.8%) and decreased over time.

Serious device- or procedure-related adverse events were reported for 13.9% of patients that received DUODOPA via a PEG-J tube, with the following adverse events being reported for at least 1% of patients: complication of device insertion (7.3%), abdominal pain (3.5%), peritonitis (2.8%), pneumoperitoneum (2.3%), device dislocation (1.5%), postoperative wound infection (1.5%), device occlusion (1.0%), and small intestine obstruction (1.0%). Overall, 3.5% of patients had at least 1 procedure- or device-related adverse event leading to treatment discontinuation. Complication of device insertion (2.3%) and abdominal pain (1.0%) were the only adverse events leading to treatment discontinuation for at least 1% of patients. Most of these adverse events were mild to moderate in severity, non-serious, reported within the first 28 days after the percutaneous endoscopic gastrostomy procedure, and resolved in the same time period.

Drug

Treatment emergent adverse events, excluding procedure- or device-related adverse events, were reported for 90.1% of patients (375/416) that received DUODOPA in clinical trials over an average exposure of 515 days (range 1 to 1284 days).

Serious treatment emergent adverse events, excluding procedure-or device-related adverse events, were reported for 30.1% of patients treated with DUODOPA. Pneumonia, hip fracture, polyneuropathy, Parkinson’s disease, weight decreased, urinary tract infection, fall and depression were serious treatment emergent adverse events reported for at least 1% of patients (each reported for less than 4% of patients). Pneumonia was the only treatment emergent adverse events leading to discontinuation of treatment for at least 1% of patients.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Device-related Adverse Events

Procedure-related and device-related adverse events reported in 395 patients who received DUODOPA via a PEG-J tube in all Phase III studies, regardless of the study design (double- blind or open-label) are presented in Table 1. Similar types of procedure- and device related adverse events were reported in the 12 week controlled clinical trial and the 12 month open label study.

Table 1. Procedure- and Device-Associated Adverse Events Reported in ≥ 1% of All Patients Who Received DUODOPA via PEG-J
System Organ Class
MedDRA 14.0 Preferred Term
PEG-J
N=395
n (%)
Gastrointestinal Disorders
Abdominal pain135 (34.2)
Pneumoperitoneum24 (6.1)
Abdominal discomfort17 (4.3)
Upper abdominal pain12 (3.0)
Peritonitis12 (3.0)
Small intestinal obstruction5 (1.3)
General Disorders and Administration Site Conditions
Complication of device insertion*156 (39.5)
Device dislocation10 (2.5)
Device occlusion6 (1.5)
Infections and Infestations
Postoperative wound infection83 (21.0)
Incision site cellulitis8 (2.0)
Post procedural infection7 (1.8)
Injury, Poisoning and Procedural Complications
Procedural pain100 (25.3)
Incision site erythema69 (17.5)
Procedural site reaction46 (11.6)
Post procedural discharge43 (10.9)
Incision site pain21 (5.3)
Post procedural hemorrhage13 (3.3)
Gastrointestinal stoma complication10 (2.5)
Post procedural discomfort6 (1.5)
Post procedural complication4 (1.0)
Postoperative ileus4 (1.0)
Skin and Subcutaneous Tissue Disorders
Excessive granulation tissue72 (18.2)
*Complication of device insertion was a commonly reported adverse event for both the nasojejunal (NJ) and the PEG-J. This adverse event was co-reported with 1 or more of the following adverse events for the NJ: oropharyngeal pain, abdominal distension, abdominal pain, abdominal discomfort, pain, throat irritation, gastrointestinal injury, esophageal hemorrhage, anxiety, dysphagia, and vomiting. For the PEG-J, this adverse event was co-reported with 1 or more of the following adverse events abdominal pain, abdominal discomfort, abdominal distension, flatulence, or pneumoperitoneum. Other adverse events that were co-reported with complication of device insertion included, abdominal pain upper, duodenal ulcer, duodenal ulcer hemorrhage, erosive duodenitis, gastritis erosive, gastrointestinal hemorrhage, peritonitis, and small intestine ulcer.

Management of Device-Related Adverse Events

  • Early recognition of symptoms that may indicate onset of serious adverse events related to the device (see WARNINGS AND PRECAUTIONS, Gastrointestinal, DUODOPA Procedure- and Device-Related Complications).
  • Gastrostomy tube blockage and/or intestinal obstruction with bezoar formation (see WARNINGS AND PRECAUTIONS, Gastrointestinal, DUODOPA Procedure- and Device-Related Complications).
  • Dislocation of the intestinal tube backwards into the stomach (see WARNINGS AND PRECAUTIONS, Gastrointestinal, DUODOPA Procedure- and Device-Related Complications).
  • Failure of the intestinal tube or pump resulting in motor complications (see DOSAGE AND ADMINISTRATION, Missed Dose).
  • The stoma usually heals without complications, but abdominal pain, infection and leakage of gastric fluid may occur (see WARNINGS AND PRECAUTIONS, Peri-Operative Considerations).
  • Complications with the devices are very common (≥ 1/10), e.g. connector leakage, dislocation of the intestinal tube. Patients should be instructed to contact their healthcare provider.
  • Occlusion, kinks or knots, of the intestinal tube lead to high pressure signals from the pump. Kinking or knotting may need readjustment of the tubing. Occlusions are usually remedied by flushing the tube with tap water. Patients should be instructed in the importance of daily flushing of the intestinal tubing with water, as a preventative measure against occlusions (see DOSAGE AND ADMINISTRATION, Recommended Dose and DOSAGE Adjustment).

Treatment Emergent Adverse Events, Excluding Procedure- and Device-Related Adverse Events

Treatment emergent adverse events, reported in patients who received DUODOPA in all Phase III studies, regardless of the study design (double-blind or open-label) are presented in Table 2. Adverse events are presented for patients that received doses of levodopa < 1250 mg/day, ≥ 1250 mg/day and any dose. In general, doses of levodopa ≥ 1250 mg/day were associated with a higher frequency of treatment emergent adverse events.

Table 2. Treatment Emergent Adverse Eventsa (Excluding Procedure- and Device-Associated Adverse Events) Reported in ≥ 2% of All Patients Who Received DUODOPA
System Organ Class
MedDRA 14.0 Preferred Term
DUODOPA
Low Dose
< 1,250 mg/day
N = 159
n (%)
DUODOPA
High Dose
> 1,250 mg/day
N = 257
n (%)
DUODOPA
Any Dose

N=416
n (%)
Blood and Lymphatic System Disorders
Anemia4 (2.5)7 (2.7)11 (2.6)
Gastrointestinal Disorders
Nausea31 (19.5)53 (20.6)84 (20.2)
Constipation24 (15.1)53 (20.6)77 (18.5)
Vomiting14 (8.8)26 (10.1)40 (9.6)
Diarrhoea11 (6.9)26 (10.1)37 (8.9)
Dyspepsia10 (6.3)21 (8.2)31 (7.5)
Abdominal distension10 (6.3)10 (3.9)20 (4.8)
Flatulence7 (4.4)11 (4.3)18 (4.3)
Gastritis3 (1.9)9 (3.5)12 (2.9)
Gastrooesophageal reflux disease3 (1.9)9 (3.5)12 (2.9)
Dysphagia3 (1.9)7 (2.7)10 (2.4)
Dry Mouth09 (3.5)9 (2.2)
General Disorders and Administration Site Conditions
Fatigue5 (3.1)14 (5.4)19 (4.6)
Pain6 (3.8)10 (3.9)16 (3.8)
Oedema peripheral4 (2.5)10 (3.9)14 (3.4)
Pyrexia6 (3.8)5 (1.9)11 (2.6)
Infections and Infestations
Urinary tract infection20 (12.6)35 (13.6)55 (13.2)
Pneumonia7 (4.4)14 (5.4)21 (5.0)
Upper respiratory tract infection5 (3.1)11 (4.3)16 (3.8)
Nasopharyngitis2 (1.3)7 (2.7)9 (2.2)
Injury, Poisoning and Procedural Complications
Fall22 (13.8)53 (20.6)75 (18.0)
Laceration5 (3.1)15 (5.8)20 (4.8)
Contusion6 (3.8)7 (2.7)13 (3.1)
Excoriation4 (2.5)8 (3.1)12 (2.9)
Hip fracture3 (1.9)6 (2.3)9 (2.2)
Investigations
Weight decreased9 (5.7)38 (14.8)47 (11.3)
Vitamin B6 decreased14 (8.8)23 (8.9)37 (8.9)
Blood homocysteine increased11 (6.9)22 (8.6)33 (7.9)
Metabolism and Nutrition Disorders
Decreased appetite5 (3.1)18 (7.0)23 (5.5)
Vitamin B6 deficiency4 (2.5)12 (4.7)16 (3.8)
Vitamin B12 deficiency2 (1.3)8 (3.1)10 (2.4)
Musculoskeletal and Connective Tissue Disorders
Back pain13 (8.2)27 (10.5)40 (9.6)
Arthralgia8 (5.0)17 (6.6)25 (6.0)
Pain in extremity7 (4.4)18 (7.0)25 (6.0)
Musculoskeletal pain5 (3.1)18 (7.0)23 (5.5)
Neck pain4 (2.5)11 (4.3)15 (3.6)
Muscle spasms2 (1.3)12 (4.7)14 (3.4)
Myalgia1 (0.6)11 (4.3)12 (2.9)
Musculoskeletal stiffness2 (1.3)8 (3.1)10 (2.4)
Neoplasms Benign, Malignant and Unspecified
Basal cell carcinoma2 (1.3)9 (3.5)11 (2.6)
Seborrhoeic keratosis2 (1.3)7 (2.7)9 (2.2)
Nervous System Disorders
Parkinsonв's disease9 (5.7)39 (15.2)48 (11.5)
Dyskinesia21 (13.2)26 (10.1)47 (11.3)
Headache11 (6.9)28 (10.9)39 (9.4)
Dizziness5 (3.1)19 (7.4)24 (5.8)
Dystonia6 (3.8)10 (3.9)16 (3.8)
Polyneuropathy2 (1.3)15 (5.8)17 (4.1)
Syncope3 (1.9)10 (3.9)13 (3.1)
Paraesthesia2 (1.3)10 (3.9)12 (2.9)
Freezing phenomenon0 (0.0)10 (3.9)10 (2.4)
Hypoaesthesia1 (0.6)9 (3.5)10 (2.4)
ON and OFF phenomenon3 (1.9)7 (2.7)10 (2.4)
Restless legs syndrome5 (3.1)4 (1.6)9 (2.2)
Psychiatric Disorders
Insomnia29 (18.2)56 (21.8)85 (20.4)
Anxiety14 (8.8)38 (14.8)52 (12.5)
Depression13 (8.2)34 (13.2)47 (11.3)
Sleep attacks8 (5.0)26 (10.1)34 (8.2)
Hallucination8 (5.0)19 (7.4)27 (6.5)
Confusional state3 (1.9)9 (3.5)12 (2.9)
Abnormal dreams4 (2.5)7 (2.7)11 (2.6)
Agitation2 (1.3)9 (3.5)11 (2.6)
Sleep disorder2 (1.3)9 (3.5)11 (2.6)
Renal and Urinary Disorders
Urinary retention2 (1.3)10 (3.9)12 (2.9)
Pollakiuria5 (3.1)5 (1.9)10 (2.4)
Nocturia0 (0.0)9 (3.5)9 (2.2)
Respiratory, Thoracic and Mediastinal Disorders
Oropharyngeal pain9 (5.7)20 (7.8)29 (7.0)
Dyspnoea7 (4.4)11 (4.3)18 (4.3)
Cough3 (1.9)8 (3.1)11 (2.6)
Skin and Subcutaneous Tissue Disorders
Hyperhidrosis3 (1.9)9 (3.5)12 (2.9)
Dermatitis contact3 (1.9)6 (2.3)9 (2.2)
Vascular Disorders
Orthostatic hypotension13 (8.2)29 (11.3)42 (10.1)
Hypertension8 (5.0)8 (3.1)16 (3.8)
Hypotension5 (3.1)5 (1.9)10 (2.4)
a. Treatment Emergent Adverse Events regardless of causality.

Less Common Clinical Trial Adverse Events (< 2%)

The following are medically significant adverse events reported in < 2% of all patients receiving DUODOPA.

Cardiac Disorders:atrial fibrillation, bradycardia
Gastrointestinal Disorders:bezoar, duodenal perforation, duodenal ulcer, gastric ulcer, ileus paralytic, intestinal infarction, intestinal ischaemia, intestinal obstruction, intestinal perforation, small intestina hemorrhage
General Disorders and Administration Site Conditions:asthenia, device occlusion, non-cardiac chest pain
Infections and Infestations:abdominal wall abscess, peritoneal abscess, post-operative abscess
Injury, Poisoning and Procedural Complications:post-operative fever
Investigations:blood creatine phosphokinase increased, vitamin B12 decreased
Metabolism and Nutrition Disorders:hypokalaemia , malnutrition
Nervous System Disorders:balance disorder, cognitive disorder, neuropathy peripheral, neuropathy, peripheral sensorimotor neuropathy, peripheral sensory, somnolence, sudden onset of sleep, tremor
Psychiatric disorders:depressed mood, impulse control disorder
Renal and Urinary Disorders:urinary incontinence
Respiratory, Thoracic and Mediastinal Disorders:pneumonia aspiration

Abnormal Hematologic and Clinical Chemistry Findings

The following laboratory abnormalities have been reported with levodopa/carbidopa treatment and should be considered when treating patients with DUODOPA: elevated blood urea nitrogen, alkaline phosphatases, aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT), alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT), lactate dehydrogenase (LDH), bilirubin, blood sugar, creatinine, uric acid and Coomb's test, and lowered values of hemoglobin and hematocrit.

Leucocytes, bacteria and blood in the urine have been reported.

Post-Market Adverse Events

Because these adverse events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Polyneuropathy has been reported in patients treated with levodopa/carbidopa combinations, including DUODOPA. In the majority of these patients, folic acid, vitamin B12 and vitamin B6 deficiencies and elevated homocysteine and methylmalonic acid have been observed Monitoring for changes in vitamin B12, vitamin B6, folic acid, homocysteine, and methylamlonic acid is recommended during treatment with DUODOPA (see WARNINGS AND PRECAUTIONS, Neurologic, Polyneuropathy).

The following additional adverse reactions have been identified during post-approval use of DUODOPA in Parkinson’s disease patients.

Blood and Lymphatic System Disorders:leukopenia, thrombocytopenia
Cardiac Disorders:heart rate irregular, palpitations
Eye Disorders:blepharospasm, optic ischemic neuropathy, diplopia, vision blurred
Gastrointestinal Disorders:bezoar, bruxism, colitis ischemic, dysgeusia, gastric perforation, gastrointestinal ischemia, gastrointestinal obstruction, gastrointestinal perforation, glossodynia, hiccups, ileus/paralytic ileus, intestinal fistula, large intestinal perforation, pancreatitis, peritoneal hemorrhage, salivary hypersecretion, small intestinal hemorrhage, small intestinal ischemia, small intestinal perforation, small intestinal ulcer
General Disorders and Administration Site Reactions:malaise
Infections and Infestations:abdominal abscess, sepsis, septic shock
Immune System Disorders:anaphylactic reaction
Metabolism and Nutritional Disorders:cachexia, increased weight
Neoplasms benign, malignant and unspecified:malignant melanoma (see WARNINGS AND PRECAUTIONS, Skin, Melanoma)
Nervous System Disorders:ataxia, cerebrovascular accident, convulsion, gait disturbance, somnolence
Psychiatric Disorders:abnormal thinking, completed suicide, dementia, disorientation, dopamine dysregulation syndrome, euphoric mood, fear, libido increased (see WARNINGS AND PRECAUTIONS, Psychiatric), nightmare, psychotic disorder, suicide attempt
Renal and Urinary Disorders:chromaturia, priapism, renal failure
Respiratory, Thoracic and Mediastinal Disorders:chest pain, dysphonia, pleural effusion, pneumonia aspiration, pulmonary embolism, respiration abnormal, respiratory arrest, respiratory disorder
Skin and Subcutaneous Tissue Disorders:alopecia, edema, erythema, pruritus, rash, urticaria
Vascular Disorders:phlebitis

The following additional adverse reactions have been observed with dopaminergic drugs and could occur with DUODOPA.

Blood and Lymphatic System Disorders:agranulocytosis, hemolytic anemia
Eye Disorders:Horner's syndrome, mydriasis, oculogyric crisis
Nervous System Disorders:Neuroleptic Malignant Syndrome (see WARNINGS AND PRECAUTIONS, Neurologic, Neuroleptic Malignant Syndrome), trismus
Skin and Subcutaneous Tissue Disorders:angioedema, Henoch-Schonlein purpura

Drug interactions

Overview

No specific pharmacokinetic studies have been conducted with DUODOPA (levodopa/carbidopa intestinal gel) and concomitant drugs. However, levodopa/carbidopa combinations have been used widely in clinical trials and clinical practice concomitantly with other drugs.

Drug-Drug Interactions

Table 3 represents established and other potentially significant drug interactions with levodopa/carbidopa combinations. Caution is needed when the following medicinal products are administered concomitantly with DUODOPA.

Table 3. Established or Potential Drug-Drug Interactions With Levodopa/Carbidopa Combinations
Concomitant Class or DrugRefEffectClinical comment
AntihypertensivesCPharmacodynamic interactionSymptomatic postural hypotension has occurred when combinations of levodopa and a decarboxylase inhibitor is added to the treatment of patients already receiving anti-hypertensives. DUODOPA should be administered cautiously and blood pressure should be monitored in patients receiving antihypertensive medication. Dosage adjustment of the antihypertensive agent may be required.
Catechol-O-Methyl Transferase (COMT) InhibitorsCT↓ levodopa clearanceThe dose of DUODOPA may need adjustment.
IronCT↓ levodopa bioavailabilityLevodopa may form a chelate with iron (drug-iron complex) in the gastrointestinal tract leading to reduced absorption of levodopa. Therefore, iron supplements and iron-containing multivitamins can decrease the bioavailability of levodopa.
Monoamine Oxidase (MAO) InhibitorsCTPharmacodynamic interactionNonselective monoamine oxidase (MAO) inhibitors and selective MAO A inhibitors are contraindicated for use with DUODOPA. These inhibitors must be discontinued at least 2 weeks prior to initiating therapy with DUODOPA. DUODOPA may be administered concomitantly with the recommended dose of selegiline-HCl, which is selective for MAO type B (see CONTRAINDICATIONS). Concomitant use of selegiline and levodopa-carbidopa has been associated with serious orthostatic hypotension.
Tricyclic AntidepressantsCPharmacodynamic interactionThere have been rare reports of adverse reactions, including hypertension and dyskinesia resulting from concomitant administration of tricyclic antidepressants and carbidopa/levodopa preparations.
Other Medicinal Products: Dopamine Receptor Antagonists (some antipsychotics, e.g., phenothiazines, butyrophenones and risperidone and antiemetics, e.g., metoclopromide), Benzodiazepines, Isoniazid, Phenytoin, PapaverineC, T↓ therapeutic effect of levodopaPatients taking these medicinal products together with DUODOPA should be observed carefully for loss of therapeutic response. See (WARNINGS AND PRECAUTIONS, Psychiatric and Neurologic, Neuroleptic Malignant Syndrome)
Legend: C = Case Study; CT = Clinical Trial; T = Theoretical

Pharmacodynamic Interactions

Sympathomimetics

DUODOPA should not be administered concomitantly with sympathomimetic agents (e.g., epinephrine, norepinephrine, isoproterenol or amphetamine), which stimulate the sympathetic nervous system as levodopa may potentiate cardiovascular effects (see CONTRAINDICATIONS). If concomitant administration is necessary, close surveillance of the cardiovascular system is essential, and the dose of the sympathomimetic agents may need to be reduced.

Drug-Food Interactions

Because levodopa competes with certain amino acids for transport across the intestinal wall, the absorption and therapeutic effects of levodopa can be reduced in patients who are on a protein rich diet.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

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.

Dosage and administration

Dosing Considerations

General

Periodic evaluation of hepatic, haematopoietic, cardiovascular and renal function is recommended during dosage optimization and during extended therapy with DUODOPA.

Mode of Administration

DUODOPA is a gel for continuous intestinal infusion. For long-term administration, the gel should be infused with a portable pump directly into the duodenum or upper jejunum by a permanent tube via percutaneous endoscopic gastrostomy (PEG) with an outer transabdominal tube and an inner intestinal tube. Alternatively, a radiological gastrojejunostomy may be considered if percutaneous endoscopic gastrostomy is not suitable for any reason.

Prior to duodenal/jejunal tube placement, it is recommended that all patients be treated short term using a nasojejunal tube (NJ). The dose should be adjusted to an optimal clinical response for the individual patient, which means maximizing the functional “On” time during the day by minimizing the number and duration of “Off” episodes (bradykinesia) and minimizing “On” time with disabling dyskinesia. The patient’s response and ability to tolerate the intestinal tubing and manage daily operation of the device system should be assessed prior to placement of the PEG-J tube (see DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment).

DUODOPA should be given initially as monotherapy. If required, other medicinal products for Parkinson’s disease can be taken concurrently. For administration of DUODOPA, only the CADD-Legacy DUODOPA pump should be used. A manual with instructions for using the portable pump is delivered together with the pump.

Treatment with DUODOPA using a permanent tube can be discontinued at any time by withdrawing the tube and letting the wound heal. Treatment should then continue with oral medicinal products including levodopa/carbidopa.

Recommended Dose and Dosage Adjustment

General

Levodopa given as DUODOPA has the same bioavailability as oral levodopa and therefore conversion from one form to another should be done in approximately a 1:1 ratio. The total dose/day of DUODOPA administered over approximately 16 hours is composed of three individually adjusted doses: the morning bolus dose, the continuous maintenance dose and extra bolus doses. During the nasojejunal test period the patient is supplied with and trained in the use of the portable pump, and the three DUODOPA dosing parameters are individualized for the patient. The patient can then independently control the infusion rates to suit their daily requirements, within parameters pre-set under the direction of their physician.

Each 100 mL cassette of DUODOPA contains 2000 mg levodopa/500 mg carbidopa. Some patients may require more than one cassette over a 16-hour period. The drug cassettes are for single use only and should not be used for longer than 16 hours even if some medicinal product remains. Patients should be instructed to not reuse an opened cassette.

By the end of the storage time, the gel might become slightly yellow. This does not influence the concentration of the drug or the treatment.

Morning Dose

The Morning Dose is an individualized daily loading dose administered to achieve a therapeutic dose level within 10 to 30 minutes.

Continuous Maintenance Dose

The Continuous Maintenance Dose (CMD) is administered after the Morning Dose and for the remainder of the 16-hour infusion period. The CMD is intended to provide continuous administration at a constant rate throughout the infusion period.

Extra Bolus Doses

Extra doses of DUODOPA can be used to assist in titration and during standard therapy to address immediate medical needs, such as the rapid deterioration of motor function (e.g., patient becomes hypokinetic). The extra dose feature is programmed by the healthcare professional and can be self-administered by the patient throughout the day. The pump includes a lockout feature to prevent inadvertent adjustments. The extra dose is customized for medication delivery to each patient. Refer to the pump manual for detailed instructions. If the need for use of the extra dose feature exceeds 5 doses/day, the physician should consider increasing the CMD.

After initial titration, additional adjustments of the dose settings may be performed over time.

Table 4. Determination of Daily Doses (Morning, Continuous and Extra)
Morning DoseContinuous Maintenance Dose (CMD)Extra Doses
GeneralUsually 5 to 10 mL, corresponding to 100 to 200 mg levodopa and will normally not exceed 15 mL (300 mg levodopa). The calculated Morning Dose should be increased by 3 mLa to compensate for the priming of the deadspace.May range from 1 to 10 mL/hour (20 to 200 mg levodopa/hour) and is usually 2 to 6 mL/hour (40 to 120 mg levodopa/hour).
In exceptional cases a higher dose may be needed.
Usually 0.5 to 2.0 mL. In rare cases, a higher dose may be needed.
If the need for Extra Doses exceeds 5 doses/day, the physician should consider increasing the maintenance dose.
Initiation of Treatment (Day 1)Patients should not be administered a full equivalent of their usual oral morning dose of levodopa/carbidopa. The Morning Dose of DUODOPA is to be based on a percentage of the patient's usual morning oral levodopa/carbidopa dose.

Morning Dose of Oral Levodopa/Carbidopa vs. Percent of Dose Given as DUODOPA
If the usual morning oral dose is:Give % DUODOPA:
0 to 200 mg80%
201 to 399 mg70%
≥ 400 mg60%
The CMD is adjustable in steps of 0.1 mL/hour (2 mg/hour).
Calculation: Previous day's dose minus morning dose = A mg
Divide A mg by 20 mg/mL = B mL
Divide B mL by 16 hours = C mL/hour
C x 0.9 = D mL/hour rate of infusion
May be given hourly, begin with 1 mL per dose.
Day 2 to End of Titration Period (titration generally takes 4 to 7 days)The morning dose may be adjusted as necessary based on the patient's response to the previous day's Morning Dose.Previous day's last infusion rate. The CMD is adjustable in steps of 0.1 mL/hour (2 mg/hour)May be given hourly, begin with 1 mL dose.
Stable Daily Dose PeriodOnce the effective Morning Dose has been established, no further adjustment should be made.Maintain previous day's last infusion rate.May be given every 2 hours as needed (usually set between 0.5 to 2 mL per use).
a.Amount may vary depending on tubing used.
End of Day

The PEG-J is to be disconnected from the infusion pump at bedtime and flushed with room temperature potable water. Patients should be instructed in the importance of daily flushing of intestinal tubing with water as a preventative measure against occlusions (see ADVERSE REACTIONS, Clinical Trial Adverse Drug Reactions, Management of Device-Related Adverse Events).

If medically justified, DUODOPA may be administered during the night (e.g., nocturnal akinesia).

Post-Infusion Night-Time Treatment

Patients should be given prescriptions for a supply of levodopa/carbidopa tablets. Following the discontinuation of the daily DUODOPA infusion, patients should administer their routine night- time dosage of oral levodopa/carbidopa tablets.

Monitoring of Treatment

A sudden deterioration in treatment response with recurring motor fluctuations should lead to the suspicion that the distal part of the tube has become displaced from the duodenum/jejunum into the stomach. The location of the tube should be determined by X-ray and the end of the tube repositioned to the duodenum/jejunum (see WARNINGS AND PRECAUTIONS,Gastrointestinal, DUODOPA Procedure- and Device-Related Complications).

Dose Adjustment for Renal and Hepatic Impairment

DUODOPA is contraindicated in patients with clinical or laboratory evidence of uncompensated hepatic or renal disease (see CONTRAINDICATIONS). There are no studies on the pharmacokinetics of carbidopa and levodopa in patients with hepatic or renal impairment. Dosing with DUODOPA is individualized by titration to optimal effect which corresponds to individually optimized levodopa and carbidopa plasma exposures. Therefore, potential effects of hepatic or renal impairment on levodopa and carbidopa exposure are indirectly accounted for in dose titration. Dose titration should be conducted with caution in patients with severe renal and hepatic impairment (see WARNINGS AND PRECAUTIONS, General).

Interruption of Therapy

Patients should be carefully observed when a sudden reduction of the dose is required or if it becomes necessary to discontinue treatment with DUODOPA, particularly if the patient is receiving antipsychotics. See (WARNINGS AND PRECAUTIONS, Psychiatric and Neurologic, Neuroleptic Malignant Syndrome).

In case of suspected or diagnosed dementia with a decreased confusion threshold, patient’s pump should be handled by the nursing staff or a care giver and the benefit/risk of continued treatment with DUODOPA should be re-assessed.

Missed Dose

If the pump malfunctions, and dosing is interrupted, resume dosing as per the instructions above. Failure of the intestinal tube or pump, resulting in motor complications (e.g., sustained bradykinesia), will require treatment with oral levodopa/carbidopa until the problem is resolved.

Administration

The cassette containing DUODOPA should be attached to the portable pump and the system connected to the nasojejunal tube or the transabdominal port/jejunal tube for administration just prior to use, according to the instructions provided in the pump instruction manual. The drug cassettes are for single use only and should not be used for longer than one day (up to 16 hours) even if some medicinal product remains. A cassette should not be re-used. By the end of the storage time (i.e., after 16 hours in use, or when approaching the expiration date) the gel might become slightly yellow. This does not influence the concentration of the drug or the treatment.

Substances other than DUODOPA (e.g., small tablet or food particles) should not be administered into the PEG-J tube due to the risk intestinal tube blockage by these substances.

Overdosage

For management of a suspected drug overdose, contact your regional Poison Control Centre.

The most prominent symptoms of an overdose with levodopa/carbidopa are dystonia and dyskinesia. Blepharospasm can be an early sign of overdose.

The treatment of an acute overdose of DUODOPA (levodopa/carbidopa intestinal gel) is in general the same as that of an acute overdose of levodopa; however, pyridoxine has no effect on the reversal of the action of DUODOPA. 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. The possibility that the patient took other medicinal products together with DUODOPA should be taken into consideration. To date experiences with dialysis have not been reported, therefore its value in the treatment of overdose is not known.

Action and clinical pharmacology

Mechanism of Action

Levodopa, a metabolic precursor of dopamine, is transported across the blood-brain barrier and relieves motor symptoms of Parkinson's disease following decarboxylation to dopamine in the brain. Carbidopa, which does not cross the blood-brain barrier, inhibits the peripheral decarboxylation of levodopa, resulting in a larger amount of unchanged levodopa being available for transport to the brain and transformation into dopamine. Combined therapy with levodopa and carbidopa reduces the amount of levodopa required for optimum therapeutic benefit and the incidence of levodopa side effects, such as nausea, vomiting and cardiac arrhythmias that are attributed to exposure to high levels of peripheral dopamine associated with large doses of levodopa.

The relatively short elimination half-life (∼1.5 hours) of levodopa and other factors, such as gastric emptying rate, contribute to variable plasma concentrations of levodopa following oral administration. Therapy with DUODOPA allows continuous infusion of levodopa/carbidopa directly into the proximal small intestine. With administration of levodopa/carbidopa directly into the proximal small intestine, gastric emptying rate, which is often erratic in Parkinson’s disease patients, has limited influence on the absorption rate. Upper intestinal infusion enables plasma concentrations of levodopa to be kept at a relatively constant level within the individual therapeutic window, eliminating end-of-dose and peak plasma concentrations associated with oral administration of levodopa (see DETAILED PHARMACOLOGY).

Pharmacodynamics

In patients with advanced, levodopa-responsive Parkinson's disease who do not have satisfactory control of severe, debilitating motor fluctuations and hyper-/dyskinesia despite optimized treatment with available combinations of Parkinson’s medicinal products, continuous delivery of levodopa via the DUODOPA system enables plasma concentrations of levodopa to be kept at a more constant level within the individual’s optimal therapeutic window, with less variability than orally administered levodopa formulations. Less variability in levodopa plasma concentrations is expected to provide continuous rather than intermittent stimulation of the dopaminergic receptors in the brain. Clinical trials with DUODOPA demonstrated that intraduodenal or intrajejunal delivery of levodopa/carbidopa resulted in less intraindividual variation in plasma levodopa concentrations, less motor fluctuations and dykinesias (see CLINICAL TRIALS).

Pharmacokinetics

Pharmacokinetic-Pharmacodynamic Relationship

The reduced fluctuations in levodopa plasma concentrations correlate with decreased fluctuations in treatment response. The levodopa dose needed varies considerably among patients with advanced Parkinson's disease and it is important that the dose is individually adjusted based on the clinical response. Development of tolerance over time has not been observed with DUODOPA. After a period of satisfactory treatment with DUODOPA, patients may find that a lower dose of levodopa will provide a satisfactory clinical response.

Absorption

DUODOPA is administered directly into the duodenum or jejunum. Levodopa is absorbed quickly and effectively from the intestine through a high capacity transport system for amino acids.

A cross-study population pharmacokinetic analysis suggested that DUODOPA has comparable levodopa bioavailability to the oral levodopa/carbidopa (100/25 mg overencapsulated tablets). The bioavailability estimate for levodopa from DUODOPA relative to oral levodopa/carbidopa immediate release tablets was 97%. The absolute bioavailability of levodopa from oral levodopa/carbidopa immediate release tablets is reported to be 84 to 99%.

The pharmacokinetics of levodopa and carbidopa with 16-hour intrajejunal infusion of DUODOPA was evaluated in a Phase I study in 18 patients with advanced Parkinson’s disease who had been on DUODOPA therapy for ≥ 30 days. Patients remained on their individualized DUODOPA doses. Intrajejunal administration of DUODOPA rapidly achieved therapeutic plasma levels of levodopa and maintained consistent levodopa levels over the course of a 16- hour infusion. Following termination of infusion, levodopa levels declined rapidly (Figure 1).


Figure 1 Plasma Concentration (Mean ± Standard Deviation) Versus Time Profile for Levodopa with DUODOPA 16-Hour Infusion

The pharmacokinetic parameters of levodopa and carbidopa with DUODOPA 16-hour infusion are presented in Table 5.

Table 5. Pharmacokinetic Parameters (Mean ± Standard Deviation) of Levodopa and Carbidopa
Analyte
Pharmacokinetic Parameters (units)Levodopa (N = 18)Carbidopa (N = 18)
Total DUODOPAВ Dose on Pharmacokinetic
Assessment Day (mg)
1580 ± 403395 ± 101
Tmax (h)2.9 ± 2.35.7 ± 5.2
Cmax (mcg/mL)4.21 ± 1.360.371 ± 0.149
Cmin a(mcg/mL)0.45 ± 0.280.10 ± 0.07
Cavg (mcg/mL)2.91 ± 0.840.22 ± 0.08
AUC0-16 (mcg•h/mL)46.5 ± 13.33.54 ± 1.33
t½ b (h)1.5 ± 0.19c--
a. Cmin values during the 16 hours of infusion were observed either at time 0 or 5 minutes after start of the infusion and were a result of drug washout prior to establishment of infusion.
b. Harmonic mean ± pseudo standard deviation.
c. N = 14.

The intra-subject variability in levodopa and carbidopa plasma concentrations starting from hour 2 to hour 16 following initiation of infusion was 13 and 19%, respectively.

In a 12-week, double-blind active-controlled, Phase III study, the intra-subject variability in levodopa and carbidopa plasma concentrations were much lower for patients treated with DUODOPA (21 and 25%, respectively) than in patients treated with oral levodopa/carbidopa 100/25 mg over-encapsulated tablets (67 and 39%, respectively).

Distribution

The volume of distribution for levodopa is 0.9 to 1.6 L/kg when given together with a decarboxylase inhibitor. The partitioning ratio for levodopa between erythocytes and plasma is approximately 1. Levodopa has negligible binding to plasma proteins.

Metabolism

Levodopa is metabolized by two major pathways (decarboxylation and O-methylation) and two minor pathways (transamination and oxidation).

Decarboxylation of levodopa to dopamine by aromatic amino acid decarboxylase (AAAD) is the predominant metabolic pathway for levodopa administered without an inhibitor of AAAD (e.g., carbidopa). The major metabolites of this pathway are homovanillic acid and dihydroxyphenylacetic acid.

When levodopa is co-administered with carbidopa the decarboxylase enzyme is inhibited so that metabolism via catechol-O-methyl-transferase (COMT) becomes the dominant metabolic pathway. COMT methylates levodopa to 3-O-methyldopa (3-OMD). The half-life of this metabolite is approximately ten times longer than that of levodopa, due to a significantly lower clearance. This results in a significantly higher plasma concentration of 3-OMD after chronic dosing.

Six metabolites of carbidopa have been identified in the urine of various species, including human. The 2 main metabolites of carbidopa are α-methyl-3-methoxy-4-hydroxyphenylpropionic acid and α-methyl-3,4-dihydroxyphenylpropionic acid. These 2 metabolites are primarily eliminated in the urine unchanged or as glucuronide conjugates.

Excretion

After intravenous administration of levodopa, together with carbidopa, the plasma clearance is 0.3 L/h/kg. The elimination half-life for levodopa is approximately 1 to 2 hours (in the presence of a dopa-decarboxylase inhibitor). Levodopa is eliminated completely through metabolism and the metabolites are excreted mainly in the urine.

The elimination half-life of carbidopa is approximately 2 hours. Unchanged carbidopa accounts for 30% of the total urinary excretion.

Special Populations and Conditions

No specific pharmacokinetic studies were conducted in special populations.

Storage and stability

Store DUODOPA in a refrigerator (2 to 8°C). The cassette should be kept in the outer carton in order to protect from light.

Special handling instructions

A cassette is only to be used for 16 hours once it is out of refrigeration. Cassettes are single use only. Do not reuse cassettes even if some intestinal gel remains.

Dosage forms, composition and packaging

DUODOPA (levodopa/carbidopa intestinal gel) is a gel for continuous intestinal infusion and is supplied in hard plastic cassettes for protection. Each cassette holds a reservoir bag containing 100 mL of gel with 2000 mg levodopa and 500 mg carbidopa monohydrate (20 mg/mL levodopa and 5 mg/mL carbidopa monohydrate). DUODOPA is available in cartons of 7 cassettes.

The gel is off-white to slightly yellow in colour.

Non-medicinal ingredients: carmellose sodium and purified water.