DUODOPA Dear Health Care Professional Letter

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November 2012

Dear Healthcare Professional,

AbbVie Corporation is pleased to announce that Health Canada has issued a marketing authorization with conditions under the Notice of Compliance with Conditions (NOC/c) policy to DUODOPA (levodopa/carbidopa intestinal gel), for use in the treatment of advanced levodopa-responsive Parkinson's disease when satisfactory control of severe, disabling motor fluctuations and hyper-/dyskinesia cannot be achieved with available combinations of Parkinson medicinal products.

Patients should be advised of the conditional nature of the marketing authorization for DUODOPA.

The marketing authorization with conditions of DUODOPA is based on promising results from small clinical trials that included patients with advanced Parkinson's disease, with duration of illness ranging from 2 to 31 years.  For the majority of patients, baseline Hoehn and Yahr scores ranged from 3 to 5 and satisfactory control of motor symptoms could not be achieved using combinations of available Parkinson's disease medications, including oral levodopa formulations.

The clinical trials showed that intraindividual plasma levodopa variance was reduced during DUODOPA treatment compared to optimized oral levodopa treatment.  In addition, patients generally performed faster and had less motor fluctuations during DUODOPA treatment than during optimized oral treatment.

Two additional identical clinical trials will be conducted to confirm the efficacy of DUODOPA for treatment of patients with advanced Parkinson's disease who have significant, persistent motor fluctuations and hyper-/dyskinesia, despite receiving optimized treatment with available oral therapies. In these 12 week, randomized, double-blind, double-dummy, placebo controlled trials patients will be allowed to continue treatment with all Parkinson's medications, except for those containing levodopa and apomorphine.

Pharmacology

Therapy with DUODOPA allows continuous infusion of levodopa/carbidopa directly into the duodenum or upper intestine. The principle behind constant levodopa infusion is to achieve continuous dopaminergic stimulation with an optimised dose that can be kept stable within the patient's individual therapeutic window. Gastric emptying must be bypassed to achieve this. Intravenous infusions and intraduodenal infusions of levodopa or levodopa/carbidopa have been shown to reduce fluctuations in plasma levodopa concentrations and to dramatically improve mobility compared to standard oral therapy.

Indications and Clinical Use

DUODOPA may be useful for treatment of advanced levodopa-responsive Parkinson's disease in which satisfactory control of severe, disabling motor fluctuations and hyper-/dyskinesia cannot be achieved with available combinations of Parkinson medicinal products.

DUODOPA is delivered by direct infusion to the upper small intestine (duodenum) by means of the portable, patient controlled CADD-Legacy DUODOPA pump, and requires insertion of a permanent access tube in the abdominal wall, by percutaneous endoscopic gastrostomy (PEG).

Prior to insertion of the permanent PEG tube, a positive test of the clinical response to DUODOPA administered via a temporary nasoduodenal tube is recommended for all patients.

DUODOPA should only be prescribed by neurologists who meet the following requirements:

1. experience in treating patients with Parkinson's disease, and
2. completion of the DUODOPA Education Program^{Footnote 1}.

Contraindications

Drug-related
DUODOPA (levodopa/carbidopa intestinal gel) is contraindicated in patients for whom other formulations [for example (e.g.), tablets] of levodopa/carbidopa are contraindicated.

PEG tube-related
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; and paralytic ileus.

Serious Warnings

Drug-related
In very rare cases, patients treated with levodopa have reported suddenly falling asleep while engaged in the activities of daily living. This sudden onset of sleep can occur without warning and is not limited to the initiation of therapy. It is important to caution patients about the risk of operating machinery, including driving motor vehicles, while taking DUODOPA.

PEG tube-related
Patients with a history of upper gastrointestinal problems or problems with intestinal absorption have not been systematically evaluated in trials with DUODOPA. A nasoduodenal test period is particularly important in such patients.

Serious complications may arise in connection with PEG-tube placement (e.g. acute bleeding and damage to the lining of the alimentary canal, associated with gastroscopy, peritonitis due to leakage of gastric fluid from the stoma and pneumonia). Although these complications are rare, it is important to discuss them with patients prior to surgery.

Adverse Reactions

Drug-related
The most commonly reported adverse drug reactions during clinical trials with DUODOPA were similar to those reported by patients on oral levodopa/carbidopa. Serious adverse events that have been reported with oral levodopa treatment include psychiatric disorders and cardiovascular effects.

Device-related
In addition to adverse events related to the use of levodopa/carbidopa, adverse events related to the device or surgical procedure are common, and can impact the patient's outcome.

• The most frequently reported complications related to the intestinal tube included dislocation, occlusion and kink/knot in tube.
  • Dislocation of the distal part of the tube from the duodenum into the stomach can lead to sudden deterioration of treatment response with recurring motor fluctuations.
  • An obstruction in the tube can lead to sudden or gradual worsening of bradykinesia.
• Complications related to the PEG tube included loose connectors and leakage.
• Adverse events related to the stoma, which may cause discomfort, included secretion from the stoma, infection, proud flesh around the stoma and pain.

In patients with a reduced ability to handle the pump and tube connections, a caregiver should provide assistance to prevent complications.

Dosage and Administration

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 is composed of three individually adjusted doses: the morning bolus dose, the continuous maintenance dose and extra bolus doses. During the 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 and programmed into the pump. The patient can then independently control the infusion rates to suit their daily requirements, within parameters pre-set under the direction of their physician.

Should you have any medical enquiries regarding DUODOPA or the DUODOPA Education Program, please contact our Medical Information Department at 1-800-699-9948.

The complete DUODOPA Product Monograph is available upon request or at
(Drug Product Database).

Linda Assouline, Ph.D.
Medical Director