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Duodopa^® Intestinal Gel

Availability

Duodopa^® is approved for use throughout the EU plus Switzerland, Norway, Croatia and Canada.

The availability of Duodopa^® treatment for the patients depends on the countries that Duodopa^® has been launched and to local funding restrictions. Currently Duodopa^® has been launched in:

• 
  Austria
• 
  Belgium
• 
  Denmark
• 
  Finland
• 
  France*
• 
  Germany
• 
  Ireland
• 
  Italy
• 
  Luxembourg
• 
  The Netherlands
• 
  Norway
• 
  Slovenia
• 
  Spain
• 
  Sweden
• 
  United Kingdom

* Under process

Availability - Formulation

Duodopa^® is a levodopa/carbidopa combination that comes in a white to slightly yellow gel form.

It is given inside the upper intestine via a small tube inserted directly into the first part of the small bowel, or duodenum.

The unique delivery system with a programmable pump allows the physician and patient to individually tune the delivery of active ingredients, suspended as stable gel from a cassette worn outside the body.

What Does It Contain?

• 1 ml contains 20 mg levodopa and 5 mg carbidopa (as monohydrate).
• 100 ml contains levodopa 2000 mg and carbidopa 500 mg (as monohydrate).

See also excipients.

Therapeutic Indication (Who Is It For?)

Treatment of advanced levodopa-responsive Parkinson's disease with severe motor fluctuations and hyper-/dyskinesia when available combinations of Parkinson medicinal products have not given satisfactory results.

A positive test of the clinical response to Duodopa^® administered via a temporary nasoduodenal tube is required before a permanent tube is inserted.

 

CADD Legacy Duodopa Pump

 

Contra-indications (When Not To Use)

Duodopa^® is contraindicated in patients with:

• hypersensitivity to levodopa, carbidopa or any of the excipients
• narrow-angle glaucoma
• severe liver and renal insufficiency
• severe heart failure
• severe cardiac arrhythmia
• acute stroke.

Non-selective MAO-inhibitors and selective MAO type A inhibitors must not be given concomitantly, and should be withdrawn at least two weeks before initiation of Duodopa.

Conditions in which adrenergics are contraindicated, e.g. pheochromocytoma, hyperthyroidism and Cushing's syndrome.

Special Warning & Precautions For Use

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 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.
• 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.
• 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.
• 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 also Effects on Ability to Drive & Use Machines).
• 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 was withdrawn abruptly. Rhabdomyolysis secondary to Neuroleptic Malignant Syndrome or severe dyskinesias has 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.
• 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.
• Previous surgery in the upper part of the abdomen may lead to difficulty in performing gastrostomy or jejunostomy,
• 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 (see section 4.2).
• A sudden or gradual worsening of bradykinesia may indicate an obstruction in the device for whatever reason and needs to be explored.

How To Take Duodopa^®

Duodopa® infusion therapy

Click on images to enlarge

Duodopa^® is a gel for continuous intestinal administration. For long-term administration, the gel should be administered with a portable pump directly into the duodenum by a permanent tube via percutaneous endoscopic gastrostomy 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. Establishment of the transabdominal port and dose adjustments should be carried out in association with a neurological clinic.

A temporary nasoduodenal tube should be used to find out if the patient responds favourably to this method of treatment and to adjust the dose before treatment with a permanent tube is started.

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 of OFF episodes and the time OFF (bradykinesia) and minimizing ON-time with disabling dyskinesia.

See recommendations under Dosage.

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 (CE 0473) 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.

Dosage

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.

• Morning dose
  
  The morning bolus dose is administered by the pump to rapidly achieve the therapeutic dose level (within 10-30 minutes). The dose should be based on the patient's previous morning intake of levodopa + the volume to fill the tubing. The total morning dose is usually 5-10 ml, corresponding to 100-200 mg levodopa. The total morning dose should not exceed 15 ml (300 mg levodopa).
• Continuous maintenance dose
  
  The maintenance dose is adjustable in steps of 2 mg/hour (0.1 ml/hour). The dose should be calculated according to the patient's previous daily intake of levodopa. When supplementary medicines are discontinued the Duodopa^® dose should be adjusted. The continuous maintenance dose is adjusted individually. It should be kept within a range of 1-10 ml/hour (20-200 mg levodopa/hour) and is usually 2-6 ml/hour (40-120 mg levodopa/hour). In exceptional cases a higher dose may be needed.
  
  Example: Daily intake of levodopa as Duodopa: 1640 mg/day Morning bolus dose: 140 mg = 7 ml (including the volume to fill the intestinal tube) Continuous maintenance dose: 1500 mg/day 1500 mg/day: 20 mg/ml = 75 ml Duodopa^® per day The intake is calculated over 16 hours: 75 ml/16 hours = 4.7 ml/hour.
  
• Extra bolus doses
  
  To be given as required if the patient becomes hypokinetic during the day. The extra dose should be adjusted individually, normally 0.5-2.0 ml. In rare cases a higher dose may be needed. If the need for extra bolus doses exceeds 5 per day the maintenance dose should be increased.
  
  After the initial dose setting, fine adjustments of the morning bolus dose, the maintenance dose and extra bolus doses should be carried out during a few weeks. If medically justified Duodopa^® may be administered during the night.

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 into the stomach. The location of the tube should be determined by X-ray and the end of the tube repositioned to the duodenum under radiological control.

Use in children and adolescents

• The safety in patients under 18 years of age has not been established.

Use in the elderly

• There is a wide experience in the use of levodopa/carbidopa in elderly patients. The recommendations set out above reflect the clinical data derived from this experience.

Use in renal/hepatic impairment

• No dose adjustment is necessary.

Interruption of the therapy

• Patients should be carefully observed in case of a sudden reduction of the dose or if it is necessary to discontinue treatment with Duodopa, particularly in the patient who is receiving antipsychotics. (see Special warnings and precautions for use).
• In the case of suspected or diagnosed dementia and lowered confusion threshold, the pump should be handled only by the nursing staff or a close relative who is experienced to do that. When the cassette is to be used it should be attached to the portable pump and the system connected to the nasoduodenal tube or the transabdominal port/duodenal tube for administration, according to the instructions given. 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. Do 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.

Interaction With Other Medicinal Products & Other Forms of Interaction

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 is 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. (See contra-indications for patients receiving monoamine oxidase inhibitors).
• 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.
• 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), Concomitant use of selegiline and levodopa-carbidopa has been associated with serious orthostatic hypotension.
  
  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.
  
  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 may form 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 and Lactation

Pregnancy

• There is insufficient data about the use of levodopa/carbidopa in pregnant women. Data from animal studies have shown reproduction toxicity (see Preclinical safety data).
• The potential human risk is not known. Duodopa^® should not be used during pregnancy unless the benefits for the mother outweigh the possible risks to the foetus.

Lactation

• Levodopa is secreted in the 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. While using Duodopa^® women should not breast feed.

Effects on Ability to Drive & Use Machines

Levodopa and carbidopa may cause dizziness and symptomatic orthostatism. 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 Special Warning & Precautions For Use).

Possible Undesirable Effects of Duodopa^®

Undesirable effects that occur frequently with levodopa/carbidopa are those due to central neuropharmacological activity of dopamine. These reactions can usually be diminished by levodopa dosage reduction.

Blood and lymphatic system disorders

• Rare (>1/10,000, <1/1,000): Leucopoenia, haemolytic and non-haemolytic anaemia, thrombocytopenia
• Very rare ( <1/10,000): Agranulocytosis

Metabolism and nutrition disorders

• Common (>1/100, < 1/10): Anorexia
• Uncommon (>1/1,000, <1/100): Loss of weight, increased weight

Psychiatric disorders

• Common (>1/100, < 1/10): Hallucinations, confusion, nightmares, sleepiness, fatigue, sleeplessness, depression with very rare suicide attempts, euphoria, dementia, psychotic episodes, feeling of stimulation
• Rare (>1/10,000, <1/1,000): Agitation, fear, reduced thinking capacity, disorientation, increased libido, numbness

Nervous system disorders

• Common (>1/100, < 1/10): Dyskinesias, choreatic movements and dystonia, “ON-OFF” episodes, dizziness
• Bradykinesia (“ON-OFF” episodes) may appear some months to years after the beginning of treatment with levodopa and is probably related to the progression of the disease. The adaptation of dose schedule and dose intervals may be required.
• Levodopa/carbidopa is associated with somnolence and has been associated very rarely with excessive daytime somnolence and sudden sleep onset episodes.
• Uncommon (>1/1,000, <1/100): Ataxia, increased tremor of the hands
• Rare (>1/10,000, <1/1,000): Neuroleptic malignant syndrome, paraesthesias, falling, walking defects, trismus, headache, convulsions

Eye disorders

• Rare (>1/10,000, <1/1,000): Blurred vision, blepharospasm, activation of a latent Horner's syndrome, double vision, dilated pupils, oculogyric crises
• A blepharospasm could be an early sign of overdose.

Cardiac disorders

• Common (>1/100, < 1/10): Palpitations, irregular heartbeat

Vascular disorders

• Common (>1/100, < 1/10): Orthostatic hypotension, inclination to faint, syncope
• Uncommon (>1/1,000, <1/100): Hypertension
• Rare (>1/10,000, <1/1,000): Phlebitis

Respiratory, thoracic and mediastinal disorders

• Uncommon (>1/1,000, <1/100): Hoarseness, chest pain
• Rare (>1/10,000, <1/1,000): Dyspnoea, abnormal breathing pattern

Gastrointestinal disorders

• Common (>1/100, < 1/10): Nausea, vomiting, dry mouth, bitter taste
• Uncommon (>1/1,000, <1/100): Constipation, diarrhoea, sialorrhoea, dysphagia, flatulence
• Rare (>1/10,000, <1/1,000): Dyspepsia, gastro-intestinal pain, dark saliva, bruxism, hiccups, gastrointestinal bleeding, burning sensation of the tongue, duodenal ulceration

Skin and subcutaneous tissue disorders

• Uncommon (>1/1,000, <1/100): Oedema
• Rare (>1/10,000, <1/1,000): Angioedema, urticaria, pruritus, facial redness, hair loss, exanthema, increased perspiration, dark perspiration fluid, malignant melanoma, Schönlein-Henoch purpura

Musculoskeletal, connective tissue and bone disorders

• Uncommon (>1/1,000, <1/100): Muscle spasms

Renal and urinary disorders

• Uncommon (>1/1,000, <1/100): Dark urine
• Rare (>1/10,000, <1/1,000): Urinary retention, urinary incontinence, priapism

General disorders and administration site conditions

• Uncommon (>1/1,000, <1/100): Weakness, malaise, flare ups

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 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.

The device: Complications with the device are very common ( >1/10). Dislocation of the intestinal tube backwards into the stomach leads to reappearance of motor fluctuations (due to erratic gastric emptying of Duodopa^® into the small intestines). Relocation of the tube is done using a guide-wire to steer the tube into the duodenum under fluoroscopy. Occlusion or kinking of the intestinal tube leads to high pressure beeps from the pump. Occlusions are usually remedied by flushing the tube with tap water; kinking may need readjustment of the tubing. Should complete failure of the intestinal tube or pump occur the patient must be treated with oral levodopa/carbidopa until the problem is solved. The stoma usually heals without complications. However, abdominal pain, infection and leakage of gastric fluid may occur shortly after surgery; it is rarely a problem long-term. Local infections around the stoma are treated conservatively (disinfectant); treatment with antibiotics is rarely needed.

Overdose

The treatment of an acute overdose of Duodopa^® 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 unknown.

Pharmacological Properties of Duodopa^®

Pharmacodynamic Properties

• Pharmacotherapeutic group: Anti-Parkinson drugs, levodopa and decarboxylase inhibitor ATC code N04BA02.
• Duodopa^® is a combination of levodopa and carbidopa (ratio 4:1) in a gel for continuous intestinal infusion in advanced Parkinson's disease with severe motor fluctuations and hyper-/dyskinesia
• Levodopa relieves symptoms of Parkinson's disease following decarboxylation to dopamine in the brain. Carbidopa, which does not cross the blood-brain barrier, inhibits the extracerebral decarboxylation of levodopa, which means that a larger amount of levodopa becomes available for transportation to the brain and transformation into dopamine. Without the simultaneous administration of carbidopa much larger amounts of levodopa would be required to achieve the desired effect.
• Intestinal therapy with Duodopa^® reduces the motor fluctuations and increase the ”on”-time for patients with advanced Parkinson's disease who have received tablet treatment with levodopa/decarboxylase inhibitor for many years. The motor fluctuations and hyper-/dyskinesias are reduced due to the fact that the plasma concentrations of levodopa are being kept at a steady level within the individual therapeutic window. Therapeutic effects on motor fluctuations and hyper-/dyskinesias are often achieved during the first treatment day.

Pharmacokinetic properties

• Absorption
  Duodopa^® is administered via an inserted tube directly into the duodenum. Levodopa is absorbed quickly and effectively from the intestine through a high capacity transport system for amino acids. Levodopa given as Duodopa^® has the same bioavailability as levodopa given as tablets (81-98 %). The variation in plasma concentration within an individual is considerably smaller for Duodopa^® due to the fact that it is given by continuous intestinal administration in which the gastric emptying rate has no influence on the absorption rate. With an initial high morning dose of Duodopa^® the therapeutic plasma level of levodopa is reached within 10-30 minutes.
• Distribution
  Levodopa is co-administered with carbidopa, a decarboxylase inhibitor, which increases the bioavailability and decreases clearance for levodopa. Clearance and volume of distribution for levodopa is 0.3 l/hour/kg and 0.9-1.6 l/kg, respectively, when given together with a decarboxylase inhibitor. The protein binding of levodopa in plasma is negligible.
• Metabolism and elimination
  The elimination half-life for levodopa is approximately 1-2 hours. Levodopa is eliminated completely through metabolism and the metabolites formed are excreted mainly in the urine. Four metabolic pathways are known, decarboxylation being predominant for levodopa administered without any enzyme inhibitor. 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.
• Pharmacokinetic-pharmacodynamic relationship
  The reduced fluctuations in the plasma concentration of levodopa reduce fluctuations in the treatment response. The levodopa dose needed varies considerably in 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^®. On the contrary, many patients, after a period of satisfactory treatment with Duodopa^®, may find that a lower dose of levodopa will provide a satisfactory clinical response.

Preclinical safety data

Animal studies with regard to the pharmacological safety and toxicity after repeated administration, mutagenicity studies and carcinogenicity investigations showed no particular risk for humans. In reproductive toxicity studies both levodopa and the combination of carbidopa/levodopa have caused visceral and skeletal malformations in rabbits.

Pharmaceutical Particulars of Duodopa^®

List of Excipients

• Carmellose sodium
• Purified water.

Incompatibilities

• Not applicable.

Shelf Life

• 15 weeks
• Chemical and physical in-use stability has been demonstrated for 16 hours at 40°C.

Special precautions for storage

• Store in a refrigerator (2ºC-8°C).
• Keep the cassette in the outer carton in order to protect from light.

Nature and contents of container

• Total amount of 100 ml in PVC bag inside a hard plastic cassette for protection.
• Carton with 7 cassettes.

Special precautions for disposal and other handling

• Empty/used cassettes should be returned to the pharmacy for destruction.

Product Information Downloads

Patient Information Leaflet

Duodopa^® Patient Information Leaflet

Case Studies

Case Studies are available for download : www.epda.eu.com/medinfo/duodopa

Life With The Duodopa^® Infusion Pump

How do I carry the pump? What does it feel like? Won’t people see it? Do I need special clothes?

At first glance, the infusion pump and its holder appear cumbersome, so it is natural that such issues crop up.

Wearing the pump, however, presents relatively few real drawbacks - the carrying system has been tested and refined so that the pump and related items, e.g. spare batteries, are comfortable to wear. Furthermore, several designs are available, e.g. shoulder holster or hip-bag.

For travel abroad, patients need a certificate stating in English that they are on medication and receiving continuous duodenal infusion with Duodopa^® via the pump. A special certificate for carrying the pump onboard a plane can also be issued if relevant. (Note that the pump can be used on airplanes.) In addition, most major airports provide a special check-in service to avoid long waits in a queue, as well as help when passing through security control with the pump. You should never hesitate to ask for advice or assistance.

Further reading

Life With The Duodopa^® Infusion Pump available for download at www.epda.eu.com/medifo/duodopa.

Living with Duodopa^® Video

Useful Links & References

• www.solvaypharmaceuticals.com
• www.duodopa.com

Further Information

Solvay Healthcare Limited
Mansbridge Road
West End
Southampton
SO18 3JD

Telephone:  +44 (0)2380 467 000
Facsimile:  +44 (0)2380 465 350
Customer Care direct line: +44 (0)1753 650 099
Medical Information e-mail: medinfo.shl@solvay.com
Medical Information facsimile: +44 (0)2380 465 350

Marketing Authorisation Holder

Solvay Pharmaceuticals GmbH
Hans-Boeckler-Allee 20
D-30173 Hannover
Germany

Telephone: +49 511 8570
Facsimile: +49 511 857 2294