Consumer medicine information

Duodopa

Levodopa; Carbidopa monohydrate

BRAND INFORMATION

Brand name

Duodopa

Active ingredient

Levodopa; Carbidopa monohydrate

Schedule

What is in this CMI

What Duodopa is used for
Before you use it
How to use it
While you are using it
Side effects
After using it
Product Description

This CMI answers some common questions about Duodopa intestinal gel.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Duodopa against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What Duodopa is used for

Duodopa intestinal gel is used to control severe involuntary movements of advanced Parkinson's disease.

Parkinson's disease is a condition where you lose control of your limbs and posture. Loss of control may be mild and can become severe.

Duodopa intestinal gel belongs to a group of medicines called Anti-Parkinson medications. These medicines work by increasing the amount of a chemical called dopamine which the brain requires to work properly. This helps you to gain control over your movements and posture again.

Duodopa may be used alone, or in combination with other medicines to treat your condition.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

There is no evidence that Duodopa is addictive.

This medicine is only available with a doctor's prescription.

Duodopa is not recommended for use in children under 18 years as its safety and effectiveness in that age group have not been established.

Before you use it

When you must not use it

Do not use Duodopa if you have an allergy to:

any medicine containing levodopa, carbidopa
any of the ingredients listed at the end of this leaflet.

Symptoms of an allergic reaction to Duodopa may include:

shortness of breath, wheezing or difficulty breathing
swelling of the face, lips, tongue or other part of the body
rash, itching or hives on the skin

Do not use Duodopa if you are taking a medicine called a monoamine oxidase inhibitor (MAOI) or have been taking it within the last 14 days. Duodopa can however be used with MAOIs which target MAO type B (e.g. Selegiline hydrochloride). Talk to your doctor or pharmacist if you have any questions. Taking Duodopa with, or within 14 days, of taking any other type of MAOI may cause a serious reaction with a sudden increase in body temperature, extremely high blood pressure and severe convulsions.

If you are taking or have recently taken antidepressant medicines and are unsure about whether you can use Duodopa, check with your doctor.

Do not use Duodopa if you have or have had, any of the following medical conditions:

an eye problem called 'narrow-angle glaucoma' which involves a change in vision and/or severe eye pain/headache
severe liver and kidney insufficiency
a tumour of the adrenal gland (pheochromocytoma)
hormonal problems such as too much cortisol (Cushing's syndrome) or your thyroid hormone levels are too high (hyperthyroidism)
any unusual skin lumps or moles which have not been examined by your doctor
melanoma (a type of skin cancer)

If you are unsure if any of the above conditions apply to you, ask your doctor.

Take special care with Duodopa

Before starting treatment with Duodopa tell your doctor about any medical problems that you have or have had, especially any of the following:

a heart attack, blocked blood vessels in your heart, or any other heart problems including an uneven heart beat (arrhythmia)
serious lung problems
bronchial asthma
depression with thoughts of suicide or any other mental problems
change in vision or severe eye pain/headache or if you have been diagnosed with an eye problem called 'wide-angle glaucoma'
stomach ulcer
a history of fits (convulsions)
surgery in your upper stomach area (upper abdominal surgery)
liver or kidney problems

Tell your doctor if you are pregnant, think you may be pregnant, or intend to become pregnant. Your doctor will discuss the risks and benefits of using it if you are pregnant.

Do not breastfeed while using this medicine. This medicine may pass into the breast milk and therefore there is the possibility that the breast-fed baby may be affected.

Do not take this medicine after the expiry date printed on the pack or if the packaging is damaged or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

Talk to your doctor about getting regular skin checks performed by a specialist, such as a dermatologist. It’s important that you regularly get your skin checked for any signs of melanoma.

Do not swim or bathe whilst being treated with Duodopa. The pump cannot be taken into water. The pump should not be disconnected to go swimming or bathing either, as doing so may cause your symptoms to worsen or you may find it harder to move without warning.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and Duodopa may interfere with each other. These include:

some medicines used to treat high blood pressure - such as antihypertensives
a medicine which may cause low blood pressure. This could cause something called 'orthostatic hypotension' - this can make you dizzy when standing up. Duodopa can make this worse. Always change positions slowly.
some medicines used to treat depression
some medicines used to treat mental (psychiatric) problems - such as phenothiazines, butyrophenones and risperidone
phenytoin, a medicine used to treat fits (convulsions)
benzodiazepines, medicines that act as relaxants and are used to treat problems relating to anxiety and sleeping disorders such as insomnia (difficulty in falling asleep)
papaverine, a medicine used to treat erectile dysfunction
metoclopramide, a medicine used to treat symptoms involving the stomach, including nausea, vomiting, heartburn and loss of appetite
isoniazid, a medicine used to treat tuberculosis
amantadine, entacapone and selegiline, other medicines used to treat Parkinson's disease
iron supplements or medications containing iron used to treat anaemia

These medicines may be affected by Duodopa or may affect how well the intestinal gel works. You may need different amounts of your medicine or you may need to take different medicines.

Your doctor or pharmacist has more information on medicines to be careful with or avoid while taking Duodopa.

If you have not told your doctor about any other medicines you are taking, tell him/her before you start using Duodopa.

How to use it

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the box, ask your doctor or pharmacist for help.

How much to use

The total amount of Duodopa used each day includes three individually adjusted doses: the morning bolus dose, the continuous maintenance dose, and extra bolus doses.

Usually, a larger morning dose (called the 'bolus dose') is given. This allows you to quickly get the right amount of medicine in your blood. After that dose, a steady ('maintenance') dose is given.

If needed, you may have extra doses - this will be decided by your doctor.

If you are prescribed Duodopa, your doctor or nurse will program the right dose amounts for you into your pump.

How to use it

Duodopa is a gel for continuous intestinal use. In long-term use the gel is normally pumped directly into the small intestine by a portable pump and a permanent tube.

A manual with instructions for using the portable pump is delivered together with the pump.

When to use it

Duodopa is for use daily, from the time you wake up in the morning till the time you go to bed.

How long to use it

Continue using your medicine for as long as your doctor tells you.

This medicine helps to control your condition, but does not cure it. It is important to keep using your medicine even if you feel well.

If you forget to use it

If you forget to use Duodopa, start using it as soon as you remember.

Start your pump, with your normal dose, as soon as possible.
Do not increase your dose to make up for a forgotten dose.

This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or nurse.

If you use too much (overdose)

If you have used too large a dose of the drug always contact a doctor or go to a hospital straight away. Take the medicine pack with you.

You may need urgent medical attention.

Symptoms of an overdose may include:

problems opening your eyes
muscle spasms you cannot control in your eyes, head, neck and body (dystonia)
movement you make without wanting to (dyskinesia)
unusual fast, slow or uneven heart beats (arrhythmia)
fits (convulsions)

While you are using it

Things you must do

If you are about to be started on any new medicine, tell your doctor, dentist or pharmacist that you are using Duodopa.

Tell any other doctors, dentists, and pharmacists who treat you that you are using Duodopa.

If you are going to have surgery or emergency treatment, tell the surgeon or anaesthetist that you are using Duodopa. It may affect other medicines used during surgery.

If you need to have any medical tests while you are using Duodopa, tell your doctor. Duodopa may affect the results of some tests.

Be sure to keep all of your doctor's appointments so that your progress can be checked. Your doctor will check your progress and may want to take some tests from time to time. This helps prevent unwanted side effects.

Things you must not do

Do not use Duodopa to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they seem to have the same condition as you.

Do not stop using your medicine or change your dose unless your doctor tells you to.

If you stop using it suddenly or change your dose, your condition may worsen or you may have unwanted side effects such as:

muscular rigidity
increased body temperature
mental change (agitation, confusion, coma)
movement you make without wanting to (dyskinesia)

If possible, your doctor will gradually reduce the amount you use each day before stopping the medicine completely.

Problems using the pump or tube

Should complete failure of the intestinal tube or pump occur, you must continue your treatment by starting oral levodopa/carbidopa until the problem is solved.

Tell your doctor if you notice any of the following symptoms:

you become less able to handle the pump and tube, your Parkinson's disease symptoms get worse or it is harder to move (bradykinesia)
you have pain in your stomach area or feel sick (nausea and/or vomiting)

Things to be careful of

Be careful driving or operating machinery until you know how Duodopa affects you.

As with other medicines, Duodopa may cause dizziness, light-headedness, tiredness, drowsiness, sudden sleep, blurred vision or other effects in some people. Make sure you know how you react to Duodopa before you drive a car, operate machinery, or do anything else that could be dangerous if you are dizzy, light-headed, or your vision is affected.

Do not drive or use any tools or machines until you feel fully awake again or you no longer feel lightheaded or dizzy.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Duodopa.

This medicine helps most people with advanced Parkinson's disease, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have. Many of the side effects can be relieved by adjusting the dose.

Tell your doctor if you notice any of the following and they worry you:

abnormal uncontrolled movements, including muscle twitching or spasms, which may or may not resemble your usual Parkinson's symptoms (dyskinesia)
dizziness, or light-headedness when standing quickly
neck pain
feeling sick (nausea/vomiting), loss of appetite, weight loss
discoloured saliva
dream abnormalities
drowsiness, tiredness or sudden sleep
trouble sleeping
slow movements, more difficulty in moving
twitching or spasm of the eyelids
any raw or red skin, thick scarring, sores, bleeding, discharge, pain or irritation at the site where the tube goes into your stomach
discomfort or swelling in the stomach
passing of wind (flatulence), diarrhoea
confusion, anxiety, abnormal dreams and feeling agitated
developing urges or cravings to behave in ways that are unusual for you (e.g. increased sex drive), unable to resist the impulse to do something of significant concern to you or others (e.g. desire to gamble, excessive spending or binge eating)

These are possible side effects of Duodopa and have normally been mild. They could also be an indication that the pump and tube may not be working properly.

Tell your doctor immediately if you notice any of the following:

abnormal changes to the colour of your urine (chromaturia)
any new dark pigmented skin lesions, or changes to a mole including growing bigger, bleeding, itching, or getting darker
pain, bleeding or swelling in the mouth or throat, difficulty swallowing
difficult or painful urination
changes in mood such as depression
signs of anaemia, such as tiredness, short of breath, and looking pale
signs of frequent or worrying infections such as fever, severe chills, sore throat or mouth ulcers
bruising or bleeding more easily than normal, nose bleeds
fainting
stomach aches, pain, cramping
skin rash, itchiness
numbness or tingling in the hands or feet
change in vision or severe eye pain/headache

These are serious side effects. You may need urgent medical attention. Serious side effects are generally rare.

Tell your doctor immediately or go to accident and emergency at your nearest hospital if you notice any of the following:

swelling of the face, lips, tongue or throat which may cause difficulty in swallowing or breathing
itchy swellings on the skin (hives or nettle rash)
bleeding from the back passage, black sticky bowel motions (stools), an urgency to pass stools, pain when passing stools or diarrhoea containing blood and mucus
severe stomach aches that may come and go, nausea and vomiting
vomiting blood or material that looks like coffee grounds
chest pain
fast or irregular heartbeats (palpitations)
muscle stiffness accompanied by fever
mental changes such as feeling very fearful or paranoid
developing unusual behaviours (e.g. seeing, hearing or feeling things that are not there - hallucinations)
shortness of breath

These are all serious side effects that need urgent medical attention. Serious side effects are generally rare.

Other side effects not listed above may also occur in some patients. Tell your doctor if you notice anything else that is making you feel unwell.

Some side effects can only be found when your doctor does tests from time to time to check your progress.

Do not be alarmed by this list of side effects. You may not experience any of them.

After using it

Storage

Keep your hard plastic cassettes of Duodopa intestinal gel in the refrigerator until it is time to use them.

Each cassette is for single use only and should not be used for longer than one day (up to 16 hours) even if some medicine is left.

Use before the expiry date printed on the carton.

Used cassettes should not be reused but returned to the nearest pharmacy.

Keep your gel in a cool dry place where the temperature stays between 2°C and 8°C (Refrigerate. Do not freeze).

Cassettes should be stored before use in the carton to protect from light.

Keep it where children cannot reach it.

Disposal

If your doctor tells you to stop using this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

Duodopa gel is a white to slightly yellow gel.

Duodopa gel is provided in 100 mL PVC (polyvinyl chloride) bags each inside individual hard plastic cassettes.

Duodopa gel is supplied in cartons of seven cassettes.

Ingredients

Active Ingredients:

levodopa
carbidopa monohydrate

Other Ingredients:

carmellose sodium
purified water

Duodopa does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Supplier

DUODOPA® is supplied in Australia by:

AbbVie Pty Ltd
241 O'Riordan Street
Mascot NSW 2020
Australia
Telephone: 1800 043 460

DUODOPA® is supplied in New Zealand by:

AbbVie Limited
6^th Floor, 156-158 Victoria Street
Wellington 6011
New Zealand
Telephone: 0800 900 030

®= Registered trademark

This leaflet was prepared in July 2019.

Australian Register Number: AUST R 133452

Version 8

Published by MIMS September 2019

BRAND INFORMATION

Brand name

Duodopa

Active ingredient

Levodopa; Carbidopa monohydrate

Schedule

1 Name of Medicine

Levodopa and carbidopa monohydrate.

2 Qualitative and Quantitative Composition

Each 1 mL of Duodopa gel contains levodopa 20 mg and carbidopa monohydrate 5 mg.
Each Duodopa 100 mL bag contains levodopa 2000 mg and carbidopa monohydrate 500 mg.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Duodopa gel is a white to slightly yellow gel for continuous intestinal infusion.

4 Clinical Particulars

4.1 Therapeutic Indications

For the treatment of advanced idiopathic Parkinson's disease with severe motor fluctuations despite optimised alternative pharmacological treatment.

4.2 Dose and Method of Administration

A temporary nasoduodenal/nasojejunal tube should be considered to determine if the patient responds favourably to this method of treatment before a permanent percutaneous endoscopic gastrostomy with jejunal (PEG-J) is placed. In cases where a physician considers this assessment is not necessary, the nasojejunal test phase may be waived and treatment initiated directly with placement of the PEG-J.
Duodopa is intended for continuous daytime 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, or via direct percutaneous endoscopic jejunostomy (PEJ) with a transabdominal tube. Alternatively a radiological gastrojejunostomy may be considered if PEG/direct PEJ is not suitable for any reason. Establishment of the transabdominal port and dose adjustments should be carried out in association with a neurological clinic.
The implantation placement target for the end of the tubing is the proximal small intestine past the Ligament of Treitz.
The dose should be adjusted to an optimal clinical response for the individual patient, which means maximising the functional "On" time during the day by minimising the number and duration of "Off" episodes (bradykinesia) and minimising "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 (PD) can be taken concurrently. For administration of Duodopa only the CADD-Legacy Duodopa pump should be used. Instructions for use of the portable pump are 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 medication including levodopa/carbidopa.

Dosage.

The total dose per day of Duodopa is composed of three individually adjusted doses: the morning bolus dose, the continuous maintenance dose and extra bolus doses. The medicine cassettes are for single use only and should not be administered for longer than 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 medicine or the treatment.

Morning dose.

The morning dose is an individualised daily loading dose administered for between 10 and 30 minutes to achieve a therapeutic dose level.

Continuous maintenance dose.

The Continuous Maintenance Dose (CMD) is administered after the Morning Dose and for the remainder of the 16-hour infusion period. When supplementary medicines are discontinued the Duodopa dose should be adjusted.

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. If the need for use of the extra dose feature exceeds five per day, the physician should increase the continuous maintenance dose. 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.
See Table 1.

Overnight break.

Continuous levodopa administration may lead to the development of tolerance and reduction of therapeutic effect. In addition, the Duodopa cassette must be discarded after it has been at room temperature for 16 hours. For these reasons, Duodopa infusion is normally stopped overnight. If medically justified, Duodopa may be administered continuously without an overnight break, but the cassette must be changed every 16 hours. Overnight breaks should be reinstituted if tolerance develops.

Prolonged interruption or cessation of 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 Section 4.4 Special Warnings and Precautions for Use).

Handling of the pump and cassette.

In the case of suspected or diagnosed dementia and lowered confusion threshold, the tube connections and patient's pump should be handled only by the nursing staff or an experienced caregiver.
When the cassette is to be used it should be attached to the portable pump and the system connected to the nasojejunal tube or the duodenal/jejunal tube for administration, according to the instructions given.

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.

Replacement therapy.

For convenience, patients receiving levodopa and carbidopa from tablets may instead wish to receive the combination intestinal gel.

Dosage adjustment in renal and hepatic impairment.

There are no studies on the pharmacokinetics of carbidopa and levodopa in patients with hepatic or renal impairment. Duodopa therapy should be administered cautiously to patients with severe renal or hepatic disease. Dosing with Duodopa is individualised by titration to optimal effect (which corresponds to individually optimised 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.

4.3 Contraindications

Duodopa is contraindicated in patients with hypersensitivity to levodopa, carbidopa, or any of the excipients.
Duodopa is contraindicated in patients with narrow-angle glaucoma.
Non-selective monoamine oxidase (MAO) inhibitors and selective MAO type A inhibitors are contraindicated for use with Duodopa. These inhibitors must be discontinued at least two weeks prior to initiating therapy with Duodopa. Duodopa may be administered concomitantly with the manufacturer's recommended dose of an MAO inhibitor with selectivity for MAO type B (e.g. selegiline hydrochloride) (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Conditions in which adrenergics are contraindicated, e.g. pheochromocytoma, hyperthyroidism and Cushing's syndrome.
Duodopa is also contraindicated in severe liver or renal insufficiency.
Because levodopa may activate a malignant melanoma, Duodopa should not be used in patients with suspicious undiagnosed skin lesions or a history of melanoma.

4.4 Special Warnings and Precautions for Use

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 a history of peptic ulcer disease.
As with levodopa, there is a possibility of upper gastrointestinal haemorrhage in patients with a history of peptic ulcer.
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 should be carefully observed for loss of anti-Parkinsonian effect or worsening of Parkinsonian symptoms (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
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.
Levodopa has been associated with daytime somnolence and episodes of sudden sleep onset in patients with Parkinson's disease and caution should therefore be exercised when driving and operating machines (see Section 4.7 Effects on Ability to Drive and 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 were withdrawn abruptly. Rhabdomyolysis secondary to Neuroleptic Malignant Syndrome or severe dyskinesias have been observed rarely in patients with Parkinson's disease. Therefore, patients should be carefully observed when the dose of levodopa/carbidopa combinations are abruptly reduced or discontinued, especially if the patient is receiving antipsychotics.
Epidemiological studies have shown that patients with Parkinson's disease have a higher risk of developing melanoma than the general population. It is unclear whether the increased risk observed was due to Parkinson's or other factors, such as medicines used to treat Parkinson's. Therefore, patients and providers are advised to monitor for melanomas on a regular basis when using Duodopa for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g. dermatologists).
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.
Reported complications in the clinical studies and observed post-marketing, include abscess, bezoar, ileus, implant site erosion/ulcer, intestinal haemorrhage, intestinal ischemia, intestinal obstruction, intestinal perforation, intussusception, pancreatitis, peritonitis, pneumonia (including aspiration pneumonia), pneumoperitoneum, post-operative wound infection and sepsis. Abdominal pain may be a symptom of the above listed complications. Some events may result in serious outcomes, such as surgery and/or death. Patients should be advised to notify their physician if they experience any of the symptoms associated with the above events.
Polyneuropathy has been reported in patients treated with levodopa/carbidopa intestinal gel. Before starting therapy evaluate patients for history or signs of polyneuropathy and known risk factors, and periodically thereafter.
Patients using Duodopa should be advised not to swim or bathe. The pump cannot be taken into the water. If the pump is disconnected to go swimming, bradykinesia may develop without warning and the patient could drown.

Compulsive behaviour.

There have been reports of patients experiencing intense urges to increased gambling, sexual urges, and shopping, eating, medication use and punding (repetitive purposeless activity), and the inability to control these urges while taking one or more of the medications that increase central dopaminergic tone and that are generally used for the treatment of Parkinson's disease, including Duodopa. Although it is not proven that the medications caused these events, these urges were reported to have stopped in some cases when the dose was reduced or the medication stopped. Prescribers should ask the patient about the development of new or increased gambling urges, increased sexual urges or other intense urges while taking Duodopa. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking Duodopa.

Hydrazine.

Duodopa contains hydrazine, a degradation product of carbidopa that can be genotoxic and possibly carcinogenic. In non-clinical studies, hydrazine showed notable systemic toxicity, including hepatotoxicity and CNS toxicity, and is genotoxic as well as carcinogenic. Liver and lung tumours have been reported in rodent studies following oral administration of hydrazine. In rats, estimated exposure (plasma AUC) at tumourigenic doses was a 5-fold multiple of the anticipated human exposure associated with a daily dose of one Duodopa cassette; the no-effect dose was associated with potential human exposure from one cassette. At higher Duodopa doses, these margins will be reduced. The clinical significance of this hydrazine exposure is not known.

Use in the elderly.

There is considerable experience in the use of levodopa/carbidopa in elderly patients (see Section 4.2 Dose and Method of Administration).

Paediatric use.

The safety of Duodopa in patients under 18 years of age has not been established, therefore its use in patients below the age of 18 is not recommended.

Effects on laboratory tests.

The following laboratory abnormalities have been reported with levodopa/carbidopa: Elevated serum urea, alkaline phosphatases, AST (GOT), ALT (GPT), LDH, bilirubin, creatinine, and uric acid; elevated blood sugar; positive Coombs test; reduced 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.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No interaction studies have been performed with Duodopa. The following interactions are known from the generic combination of levodopa/carbidopa.
Caution is needed in the concomitant administration of Duodopa with the following medicinal products:

Antihypertensives.

Symptomatic postural hypotension has occurred when combinations of levodopa and a decarboxylase inhibitor are added to the treatment of patients already receiving anti-hypertensives. Dosage adjustment of the antihypertensive agent may be required.

Antidepressants.

There have been rare reports of adverse reactions, including hypertension and dyskinesia, resulting from the concomitant administration of tricyclic antidepressants and levodopa/carbidopa preparations (see Section 4.3 Contraindications, MAO inhibitors).

Anticholinergics.

These may act synergistically with levodopa to decrease tremor.

COMT inhibitors.

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

Other medicinal products.

Dopamine receptor antagonists (some antipsychotics, e.g. phenothiazines, butyrophenones and risperidone and antiemetics, e.g. metoclopramide), benzodiazepines, isoniazid, phenytoin and papaverine can reduce the therapeutic effect of levodopa. Patients taking these medicinal products together with Duodopa, should be observed carefully for loss of therapeutic response.
Duodopa can be taken concomitantly with the recommended dose of an MAO inhibitor selective for MAO type B (e.g. selegiline HCl).
Concomitant use of selegiline and levodopa-carbidopa has been associated with serious orthostatic hypotension.
Amantadine has a synergistic effect with levodopa and may increase levodopa related adverse events. An adjustment of the dose of Duodopa may be needed.
The mechanism of action of amantadine in Parkinson's disease is thought to be due to direct and indirect effects on dopamine neurons. Amantadine has also been shown to be a weak, non-competitive NMDA-receptor antagonist. Therefore, amantadine does not directly interact with or affect the bioavailability of levodopa.
Levodopa forms a chelate with iron in the gastrointestinal tract leading to reduced absorption of levodopa.
As levodopa competes with certain amino acids for transport across the intestinal wall, the absorption of levodopa can be disturbed in patients who are on a protein rich diet.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Oral administration of combinations of levodopa and carbidopa to male and female rats prior to mating and during gestation had no adverse effects on fertility, reproductive performance or pup survival.
The immediate container for Duodopa is transparent PVC with di(2-ethylhexyl)phthalate (DEHP) as a plasticiser. Leaching of DEHP into the medicinal suspension is possible. DEHP has been shown to cause adverse effects on male reproductive organs in studies in laboratory animals. The effects on human fertility are unknown.
(Category B3)
There are no adequate or well controlled studies in pregnant women. Levodopa and combinations of carbidopa and levodopa, but not carbidopa alone, have caused visceral and skeletal malformations in rabbits. Carbidopa and combinations of levodopa and carbidopa were not teratogenic in mice. An oral combination of levodopa, carbidopa and entacapone was not teratogenic in rats and rabbits.
The effects of Duodopa on human pregnancy are unknown. Therefore, use of Duodopa in women of childbearing potential requires that the anticipated benefits of the medicine be weighed against possible hazards, should pregnancy occur.
Oral administration of combinations of levodopa and carbidopa to rats from late gestation to weaning had no adverse effects on reproductive performance or on pup growth and survival. It is not known whether levodopa and carbidopa are excreted in human milk. Because many medicines are excreted in human milk and because of the potential for serious adverse reactions in infants, Duodopa should not be used by breast-feeding mothers.

4.7 Effects on Ability to Drive and Use Machines

Levodopa and carbidopa may cause dizziness and orthostatic hypotension. Therefore, caution should be exercised when driving or using machines. Patients being treated with Duodopa and presenting with somnolence and/or sudden sleep episodes must be advised to refrain from driving or engaging in activities where impaired alertness may put them, or others, at risk of serious injury or death (e.g. operating machines) until such recurrent episodes and somnolence have resolved (see Section 4.4 Special Warnings and Precautions for Use).

4.8 Adverse Effects (Undesirable Effects)

Adverse reactions frequently observed with levodopa/carbidopa are those due to the central neuropharmacological activity of dopamine. These reactions can usually be diminished by levodopa dosage reduction.
Adverse effects that occur frequently with Duodopa include abdominal pain, complications of device insertion, dyskinesia, excessive granulation tissue, incision site erythema, nausea, postoperative wound infection, post procedural discharge, procedural pain, and procedural site reaction. Most of these adverse effects were reported early in studies, subsequent to the percutaneous endoscopic gastrostomy procedure, and occurred during the first 28 days.

Clinical trials.

The safety of Duodopa was assessed in the following studies:

NPP-003-00.

A double-blind, double-dummy, randomised trial which was terminated after the enrolment of 5 patients.

NPP-002-02.

A retrospective, open-label, medical records-based, safety analysis of 65 patients who had used developmental and/or final Duodopa formulations for up to 10.7 years (mean 4.1 years in the 52 patients who received Duodopa for 12 months or more). This analysis included all but one of the patients from the non-pivotal trials, plus an additional 44 patients who received Duodopa under a compassionate use program. It did not include the 24 patients from the pivotal trial, which was conducted at a later date.
There were no deaths in the pivotal trial. A total of 8 patients died while receiving Duodopa during the period covered by the retrospective safety analysis, NPP-002-02. Death was due to pneumonia (6 patients), myocardial infarction (1 patient) or stroke (1 patient). Pneumonia is a common cause of death in end-stage Parkinson's disease and none of the deaths were considered to be due to Duodopa or the delivery system.
In the pivotal trial, 3 patients had non-fatal serious adverse events: 2 during Duodopa treatment and 1 during conventional treatment. Of these, 1 serious event (insomnia and confusion during Duodopa use) was considered to be treatment-related. Non-fatal serious adverse events were reported in 2 patients during the period covered by the retrospective safety analysis, NPP-002-02: 1 patient developed a sub-diaphragmatic abscess following PEG surgery; 1 patient had episodic atrial fibrillation during levodopa/carbidopa treatment and during Duodopa therapy.
The safety of Duodopa was compared to the standard oral formulation of levodopa/carbidopa (100 mg/25 mg) in a total of 71 advanced Parkinson's disease patients who participated in a randomised, double-blind, double-dummy, active controlled study with 12 weeks duration. Additional safety information was collected in an open-label, 12-month study in 354 patients with advanced Parkinson's disease and open-label extension studies.
Drug-related adverse reactions in patients who received Duodopa in all studies, regardless of the study design (double-blind or open-label) are presented in Table 2.

Procedure-related and device-related adverse reactions.

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

The device.

Complication of device insertion was a commonly reported adverse reaction for both the nasojejunal tube (NJ) and the PEG-J. This adverse reaction was co-reported with one or more of the following adverse reactions for the NJ: oropharyngeal pain, abdominal distention, abdominal pain, abdominal discomfort, pain, throat irritation, gastrointestinal injury, oesophageal haemorrhage, anxiety, dysphagia, and vomiting. For the PEG-J, this adverse reaction was co-reported with one or more of the following adverse reactions: abdominal pain, abdominal discomfort, abdominal distension, flatulence, or pneumoperitoneum. Other non-serious adverse reactions that were co-reported with complication of device insertion included abdominal discomfort, abdominal pain upper, duodenal ulcer, duodenal ulcer haemorrhage, erosive duodenitis, gastritis erosive, gastrointestinal haemorrhage, peritonitis, pneumoperitoneum, small intestine ulcer.
Complications with the devices are very common (≥ 1/10), e.g. connector leakage, dislocation of the intestinal tube. Occlusion, kinking or knotting of the intestinal tube leads to high pressure signals from the pump. Occlusions are usually remedied by flushing the tube with tap water; kinking, knotting, or a tube displacement 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. Though abdominal pain, infection and leakage of gastric fluid may occur shortly after surgery, these are rarely long-term problems. Reported complications include perforation of adjacent anatomical structures, especially during PEG placement, and bleeding, wound infection (the most common complication) and peritonitis. Local infections around the stoma may be treated conservatively with a disinfectant as treatment with antibiotics is rarely needed. There have been isolated reports of bezoar formation (see Section 4.4 Special Warnings and Precautions for Use).
Dislocation of the intestinal tube backwards into the stomach or an obstruction in the device leads to reappearance of the motor fluctuations (due to erratic gastric emptying of Duodopa into the small intestines). Generally relocation of the tube can be done using a guide-wire to steer the tube into the duodenum under fluoroscopy.
Procedure-related and device-related adverse reactions in this analysis set are presented in Table 3.

Post-marketing experience.

Because these reactions 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 medicine exposure.
Polyneuropathy has been reported in patients treated with levodopa/carbidopa combinations, including Duodopa. In some of these patients, deficiencies of folic acid, vitamin B₁₂ and vitamin B₆ and elevated homocysteine have been observed; the etiology of these vitamin deficiencies is unclear. It is unknown whether there is a causal relationship between polyneuropathy and treatment with Duodopa or other levodopa/carbidopa combinations.
The following additional adverse reactions (presented in MedDRA preferred terms) have been identified during post-approval use of Duodopa in Parkinson's disease patients:

Blood and lymphatic system disorders.

Anaemia, leukopenia, thrombocytopenia.

Immune system disorders.

Anaphylactic reaction.

Metabolism and nutritional disorders.

Increased weight.

Psychiatric disorders.

Completed suicide, suicide attempt, nightmare, euphoric mood, dementia, fear, abnormal thinking, disorientation, libido increased (see Section 4.4 Special Warnings and Precautions for Use), hypoaesthesia.
Dopamine Dysregulation Syndrome (DDS) is a class effect described as an addictive disorder resulting in excessive use of the product seen in some patients treated with levodopa/carbidopa.

Nervous system disorders.

Ataxia, gait disturbance, convulsion.

Eye disorders.

Optic ischaemic neuropathy, vision blurred, blepharospasm, diplopia, angle closure glaucoma.

Cardiac disorders.

Palpitations, heart rate irregular.

Vascular disorders.

Hypertension, phlebitis.

Respiratory, thoracic and mediastinal disorders.

Dysphonia, chest pain, pneumonia (including aspiration pneumonia), respiration abnormal.

Gastrointestinal disorders.

Abscess, bezoar, colitis ischemic, gastric perforation, gastrointestinal ischaemia, gastrointestinal obstruction, gastrointestinal perforation, intussusception, sepsis, small intestinal haemorrhage, small intestinal ischaemia, small intestinal perforation, small intestinal ulcer, pancreatitis, dysgeusia, salivary hypersecretion, dysphagia, bruxism, hiccups, glossodynia.

Skin and subcutaneous tissue disorders.

Oedema, urticaria, pruritus, erythema, alopecia, rash, malignant melanoma (see Section 4.4 Special Warnings and Precautions for Use).

Renal and urinary disorders.

Chromaturia, urinary retention, urinary incontinence, priapism.

General disorders and administration site reactions.

Asthenia, malaise.
The following additional adverse reactions (listed in MedDRA preferred terms) have been observed with dopaminergic agents and could occur with Duodopa:

Blood and lymphatic system disorders.

Agranulocytosis, haemolytic anaemia.

Nervous system disorders.

Trismus, Neuroleptic Malignant Syndrome (see Section 4.4 Special Warnings and Precautions for Use).

Eye disorders.

Horner's syndrome, mydriasis, oculogyric crisis.

Gastrointestinal disorders.

Saliva discolouration.

Skin and subcutaneous tissue disorders.

Angioedema, Henoch-Schonlein purpura.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).
Most prominent clinical 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 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 Duodopa overdose is unknown.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Anti-Parkinson drugs, levodopa and decarboxylase inhibitor. ATC code: N04BA02.

Mechanism of action.

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 this combination gel reduces the motor fluctuations and increases 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.

Clinical trials.

Early stage clinical development program. Most patients in the Duodopa clinical studies were over 50 years of age (39-79). Each had illnesses for 4 to 31 years, levodopa treatment for 4 to 21 years or more, and had suffered motor fluctuations for 3 to 17 years in spite of many treatment variations with levodopa/carbidopa in combination with other anti-Parkinsonian medicines (COMT inhibitors, dopamine agonists, anticholinergics). Hoehn and Yahr disease stage "at worst" was 2-5 on a 5-point scale and the majority had a score of 3-5. In Study NPP-001-02 three patients had a Hoehn and Yahr score "at worst" of 2 and another 3 patients 2.5. So the patients matched the indication for treatment with Duodopa.
All studies were open label except NPP-003-00 which was discontinued due to design limitations. Blinded assessments of motor fluctuations and dyskinesias from video recordings were done in NPP-001-02.

Study NPP-001-02.

Designed as an open-label, 3 + 3 week, crossover study using video-scoring with blinded, third-party assessment of motor fluctuations and dyskinesia to compare Duodopa monotherapy with any conventional anti-Parkinsonian treatment combination in patients with PD and severe levodopa related motor complications.
Twenty-four patients were randomised into two treatment groups. In one patient group, conventional PD medication was administered for three weeks followed by three weeks with Duodopa as monotherapy by upper intestinal infusion via a nasoduodenal catheter while the other patient group received Duodopa monotherapy via nasoduodenal catheter for three weeks followed by three weeks of conventional PD medication.
Duodopa doses were individualised to each patient's need and dose adjustments were allowed throughout the study except on test days. Comparators: any anti-Parkinsonian medication available in Sweden. All patients were treated with levodopa, two-thirds received dopamine agonists, and approximately half received COMT inhibitors. For patients receiving Duodopa treatment, extra doses of 2-40 mg (0.1-2 mL) could be delivered via the CADD-Legacy Duodopa pump. Oral levodopa/carbidopa was allowed as needed at night for both treatment groups. See Table 4.
The study was open label for patients and investigators. Two independent neurologists, unaware of each patient's therapy, evaluated the video recordings. Each recording was assessed for symptoms of PD, dyskinesias, and treatment response.

The following secondary efficacy end-points were assessed in the intention-to-treat (ITT) and/or per protocol (PP) populations in the pivotal trial:

Wider TRS interval (ITT and PP).

The percentage of video recordings in the wider TRS interval of -1 to +2 was significantly greater with Duodopa than conventional treatment.

Percentage of time with dyskinesia (ITT and PP).

The percentage of time with moderate to severe dyskinesia (TRS +2 to +3) was low (6-8%) and did not differ significantly between treatments.

UPDRS (PP).

There was a significant between-treatment difference in favour of Duodopa for the UPDRS total score and for Parts I, II and IV subscores. The UPDRS part III subscore showed a non-significant trend in favour of Duodopa.

PDQ-39 and PDQ-8 (PP).

Duodopa was significantly better than conventional therapy in regard to the PDQ-39 summary index, the PD-8 summary index, and 7 of the 8 dimensions of the PDQ-39 (excluding 'Social Support').

15D (PP).

Quality of life, as measured by the 15D, was significantly better with Duodopa than conventional therapy.

Electronic diary (PP).

Duodopa was significantly better than conventional therapy in relation to responses to the morning question regarding ability to turn in bed, and the morning and daytime questions regarding difficulty walking, having been "Off", difficulty with chores and satisfaction with functioning. Duodopa was not significantly different to conventional therapy in regard to the responses to the morning question regarding overnight sleep, nor the morning and daytime questions regarding hyperkinesia, muscular cramps/spasms, and depression.
The efficacy of Duodopa was also assessed in the following non-pivotal studies:

NPP-001-99.

An open-label, randomised, 3+3 week crossover study in which 12 patients received Duodopa and controlled-release levodopa/carbidopa.

NPP-001-92.

An open-label study in which 7 patients who had been taking optimised oral levodopa/carbidopa were switched to a developmental Duodopa formulation for 6 months.
The efficacy findings in these studies were generally consistent with those of the pivotal trial, although confounded by various factors. For example, the assessments were not blinded and were not optimally timed to assess mobility fluctuations.
Adverse events related to Duodopa were consistent with those known to occur during oral levodopa/carbidopa treatment (see Section 4.8 Adverse Effects (Undesirable Effects)). Adverse events related to the delivery system and stoma were generally minor (see Section 4.8 Adverse Effects (Undesirable Effects)). There was no consistent pattern of laboratory, ECG, or vital sign abnormalities during Duodopa therapy.
Late stage clinical development program. This included two identically-designed Phase 3, 12-week, randomised, double-blind, double-dummy, active-controlled, parallel group, multicentre studies to evaluate the efficacy, safety, and tolerability of the Duodopa System. The studies were conducted with patients with advanced Parkinson's disease who were levodopa-responsive and had persistent motor fluctuations despite optimised treatment with oral levodopa/carbidopa and other available anti-Parkinson's disease medications. The two studies were combined prior to breaking the blind and a single analysis was conducted.
Patients were eligible for participation in the studies if their response to anti-Parkinson's disease medicine treatment was inadequate (i.e. they were experiencing ≥ 3 hours of "Off" time) and they demonstrated a clear responsiveness to treatment with levodopa. Seventy-one (71) patients enrolled in the study and 66 patients completed the treatment (3 patients discontinued treatment because of adverse events, 1 patient for lack of effect, and 1 patient for non-compliance).
Patients in this study had a mean age of 64.4 years and disease duration of 10.9 years.
Patients were randomised to 1 of 2 treatment arms:
1) Levodopa/carbidopa intestinal gel + placebo capsules; or
2) Placebo gel + levodopa/carbidopa capsules.
Duodopa or placebo gel was infused over 16 hours daily through a PEG-J tube using an ambulatory infusion pump. Patients in both treatment arms had a PEG-J device placement. Therefore, the primary difference between the treatment groups was the method of administration of levodopa/carbidopa (intestinal infusion versus oral capsule).
The primary outcome was a comparison between treatments in the change from baseline to week-12 in the total daily mean "Off" time based on Parkinson's Disease Diary data using last observation carried forward. The "Off" time was normalised to a 16-hour awake period based on a typical person's waking day and the daily infusion duration of 16 hours.
The primary efficacy endpoint, change in normalised "Off" time (baseline to endpoint) demonstrated a statistically significant least square (LS) mean difference of -1.91 hours (P = 0.0015) in favour of the Duodopa treatment group (LS mean change: -4.04 hours for Duodopa group and -2.14 hours for active control group) (Table 5).
This change in "Off" time was associated with a statistically significant LS mean difference from baseline in the average daily normalised "On" time without troublesome dyskinesia between the Duodopa treatment group and the active control group based on Parkinson's Disease Diary data. The baseline values were collected three days prior to randomisation and after 28 days of oral therapy standardisation.

Analyses also of other secondary efficacy endpoints, in order of the hierarchical testing procedure, demonstrated statistically significant results for Duodopa compared to oral levodopa/carbidopa for the Parkinson's Disease Questionnaire (PDQ-39) Summary Index, Clinical Global Impression (CGI-I) score, and Unified Parkinson's Disease Rating Scale (UPDRS) Part II score (Activities of Daily Living). The PDQ-39 Summary Index which showed a decrease from baseline of 10.9 points at week 12. Other secondary endpoints did not meet statistical significance based on the hierarchical testing procedure.
The primary end point results were supported by a Mixed Model Repeated Measures (MMRM) analysis, which examined the change from baseline to each post-baseline study visit. This analysis of "Off" time demonstrated a statistically significant greater improvement of the Duodopa group over the LC-oral group at Week 4, and that improvement was shown to be statistically significant at Weeks 8, 10, and 12 (Figure 1).

The mean daily dose for the Duodopa group was 1117.3 (SD 473.3) mg/day levodopa in the Duodopa group and 1350.6 (SD 617.9) mg/day levodopa in the active control group. For 36 (97.3%) patients on Duodopa the mean daily rescue medication dose was 139.8 (81.3) mg/day levodopa and 180.6 (156.2) mg/day levodopa for the active control group.
A Phase 3, open-label, single-arm, multicentre study was conducted to assess the long-term safety and tolerability of Duodopa over 12 months in 354 patients. The target population was levodopa-responsive patients with advanced Parkinson's disease and motor fluctuations despite optimised treatment with available Parkinson's disease medications. The average daily normalised "Off" time changed by -4.44 hours from Baseline to Endpoint (6.77 hours at Baseline and 2.32 hours at Endpoint).
During the study, the number of patients who discontinued due to all reasons were 30/354 (8.5%) patients during the NJ test period and 52/354 (14.7%) during the Post PEG long-term treatment period. The mean duration of treatment was 329 days.
A Phase 3b, open-label, randomised, multicentre study was conducted to assess the effect of Duodopa on dyskinesia compared with optimised medical treatment (OMT) over 12 weeks in patients with advanced Parkinson's disease who were levodopa-responsive and had persistent motor fluctuations that have not been controlled with OMT. Patients were eligible for participation in the study if they had a baseline Unified Dyskinesia Rating Scale (UDysRS) total score ≥ 30. Sixty-one (61) patients (28 on Duodopa intestinal gel and 33 on OMT) were treated in the study. The change from baseline to Week 12 in UDysRS total score demonstrated a statistically significant LS mean difference in favour of the Duodopa treatment group (Table 6). Analysis of all secondary efficacy endpoints, except UPDRS Part III (motor examination), demonstrated statistically significant results for Duodopa compared to the OMT group (Table 6).

5.2 Pharmacokinetic Properties

Absorption.

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 tablets), when the combination intestinal gel is administered directly into the jejunum. 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 84-99%.
In the Duodopa Phase 1 study, administration of Duodopa into the jejunum rapidly achieved therapeutic plasma levels of levodopa and maintained consistent levodopa levels over the course of infusion. Following termination of infusion, levodopa levels declined rapidly (Figure 2). The intra-subject variability in levodopa and carbidopa plasma concentrations starting from hour-2 to hour-16 following initiation of infusion was low (CV = 13% and 19%, respectively).

In the Duodopa double-blind, active-controlled, Phase 3 Study, the intra-subject variability in levodopa and carbidopa plasma concentrations were much lower for patients treated with Duodopa (CV=21% and 25%, respectively) than in patients treated with oral levodopa/carbidopa 100/25 mg tablets (Sinemet tablets over-encapsulated) (CV=67% and 39%, respectively).

Distribution.

Levodopa is co-administered with carbidopa, a decarboxylase inhibitor, which increases the bioavailability and decreases clearance for levodopa.
In patients on Duodopa with advanced Parkinson's disease, the model estimated the apparent steady-state volume of distribution (Vss/F) of levodopa was approximately 130 L for a 70 kg subject or ~1.9 L/kg, while the apparent clearance (CL/F) of levodopa, was 24.8 L/h when co-administered with carbidopa.
Levodopa has negligible binding to plasma proteins. Carbidopa does not cross the blood brain barrier.

Metabolism.

Levodopa is mainly eliminated via metabolism by the aromatic amino acid decarboxylase (AAAD) and the catechol-O-methyl-transferase (COMT) enzymes. Other routes of metabolism are transamination and oxidation. The decarboxylation of levodopa to dopamine by AAAD is the major enzymatic pathway when no enzyme inhibitor is co-administered. 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. O-methylation of levodopa by COMT forms 3-O-methyldopa. When administered with carbidopa, the elimination half-life of levodopa is approximately 1-2 hours. The elimination half-life of carbidopa is approximately 2 hours.
Carbidopa is metabolised to two main metabolites (α-methyl-3-methoxy-4-hydroxyphenylpropionic acid and α-methyl-3,4-dihydroxyphenylpropionic acid).

Excretion.

Unchanged carbidopa accounts for 30% of the total urinary excretion of radioactive labelled oral carbidopa.

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 this combination intestinal gel.

5.3 Preclinical Safety Data

Genotoxicity.

Carbidopa was positive in bacterial and mammalian gene mutation assays, but negative in an in vivo assay for clastogenicity. A combination of levodopa, carbidopa and entacapone was negative in a bacterial gene mutation assay and two in vivo assays for clastogenicity (see Section 4.4 Special Warnings and Precautions for Use, Hydrazine).

Carcinogenicity.

There was no evidence of carcinogenicity following daily oral administration of a combination of levodopa and carbidopa to rats for 106 weeks or following daily oral administration of carbidopa alone to rats for 96 weeks (see Section 4.4 Special Warnings and Precautions for Use, Hydrazine).

6 Pharmaceutical Particulars

6.1 List of Excipients

Carmellose sodium, purified water.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

Duodopa is stable for 24 months at -18°C (Deep freeze) and then for 15 weeks at 2°C to 8°C (Refrigerate. Do not freeze) i.e. after removal from the deep freeze.

6.4 Special Precautions for Storage

The product is only to be used for 16 hours once it is out of the refrigerator.
The cassettes should be stored before use in the outer carton to protect from light.

6.5 Nature and Contents of Container

Duodopa gel is provided in 100 mL PVC bags each inside a hard plastic cassette for protection. Each carton contains seven cassettes.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Levodopa is an aromatic amino acid, the metabolic pre-cursor to dopamine. Levodopa is also a white or slightly cream-coloured crystalline powder, slightly soluble in water, practically insoluble in alcohol and in ether. It is freely soluble in 1 M HCl and sparingly soluble in 0.1 M HCl, and is light and oxygen sensitive.
Carbidopa monohydrate is an inhibitor of aromatic amino acid decarboxylase. Carbidopa monohydrate is a white or yellowish-white powder, slightly soluble in water, very slightly soluble in alcohol, practically insoluble in methylene chloride. It dissolves in dilute solutions of mineral acids, and is light and oxygen sensitive.

Chemical structure.

Levodopa.

Mol. Wt: 197.2.
Molecular Formula: C₉H₁₁NO₄.
Chemical name: (2S)-2-amino-3-(3,4-dihydroxyphenyl) propanoic acid.

Carbidopa monohydrate.

Mol. Wt: 244.2.
Molecular Formula: C₁₀H₁₄N₂O₄.H₂O.
Chemical name: (2S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropanoic acid, monohydrate.

CAS number.

Levodopa: 59-92-7.
Carbidopa monohydrate: 38821-49-7.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription only medicine.

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