DUODOPA 20MG/ML + 5MG/ML INTESTINAL GEL

Active substance: LEVODOPA

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Duodopa 20 mg/ml + 5 mg/ml, intestinal gel

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
1 ml contains 20 mg levodopa and 5 mg carbidopa monohydrate.
100 ml contain 2000 mg levodopa and 500 mg carbidopa monohydrate.
For a full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Intestinal gel.
Off white to slightly yellow gel.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
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.

4.2

Posology and method of administration
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 or upper jejunum 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 may be used to determine if the patient responds
favourably to this method of treatment before a permanent PEG-J tube is placed. In
cases where the physician believes this assessment is not necessary, the NJ test phase

may be waived and treatment initiated directly with placement of the PEG-J. The
dose should be adjusted to an optimal clinical response for the individual patient,
which means maximizing the functional ON-time during the day by minimizing the
number and duration of OFF episodes (bradykinesia) and minimizing ON-time with
disabling dyskinesia. 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 1400 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
administered over approximately 16 hours. Please refer to Table 1 for instructions on
how to determine these individually adjusted doses on a patient by patient basis.
The drug cassettes are for single use only and should not be used 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 drug or the treatment.
Morning dose: The morning dose is an individualized daily loading dose administered
within 10 to 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. The CMD is intended to provide continuous administration at a constant rate
throughout the infusion period.

Extra bolus doses: The pump offers a feature to deliver extra doses to the patient.
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. The extra dose feature is programmed by the Health Care Provider and can
be self administered by the patient throughout the day. The pump includes a lockout
feature to prevent inadvertent adjustments. The extra dose is customized for
medication delivery to each patient (refer to the pump manual for detailed
instructions). If the need for use of the extra dose feature exceeds five per day, the
physician should consider increasing the continuous maintenance dose.
After initial titration, additional adjustments of the dose settings may be performed
over time.
If medically justified Duodopa may be administered during the night.
Table 1.

Determination of Daily Doses (Morning, Continuous and Extra)
Morning Dose

Continuous
Maintenance Dose
(CMD)

Extra Doses

Morning Dose

Initiation of
Treatment
(Day 1)

Extra Doses

Usually 5 to 10 mL,
corresponding to 100 to
200 mg levodopa and will
normally not exceed 15
mL (300 mg levodopa).
The calculated Morning
dose should be increased
by 3 mLa to compensate
for the priming of the
deadspace.

May range from 1 to 10
mL/hour (20 to 200 mg
levodopa/hour) and is
usually 2 to 6 mL/hour
(40 to 120 mg
levodopa/hour).

Usually 0.5 to 2.0
mL. In rare cases, a
higher dose may be
needed.

In exceptional cases a
higher dose may be
needed.

If the need for Extra
Doses exceeds five
per day, the
physician should
consider increasing
the maintenance
dose.

Patients should not be
administered a full
equivalent of their usual
oral morning dose of
levodopa/carbidopa. The
morning dose of Duodopa
is to be based on a
percentage of the patient's
usual morning oral
levodopa/carbidopa dose.

General

Continuous
Maintenance Dose
(CMD)

The CMD is adjustable
in steps of 0.1 mL/hour
(2 mg/hour).

May be given
hourly, begin with 1
mL dose.

Calculation:
Previous day’s dose
minus morning dose =
A mg,
Divide A mg by 20
mg/mL = B mL
Divide B mL by 16
hours = C mL/hour

Morning dose of oral
levodopa/carbidopa vs.
Percent of Dose Given
as Duodopa
If the usual
morning
oral dose is

Give %
Duodopa

0-200 mg

80%

201-399
mg

70%

400 mg

C x 0.9 = D mL/hour
rate of infusion

60%


Day 2 to end
of titration
period
(titration
generally
takes 4-7 days)

The morning dose may be
adjusted as necessary
based on the patient’s
response to the previous
day's morning dose.

Previous day's last
infusion rate.

Stable Daily
Dose Period

Once the effective
morning dose has been
established, no further

Maintain previous day's
last infusion rate.

The CMD is adjustable
in steps of 0.1 mL/hour
(2 mg/hour).

May be given
hourly, begin with 1
mL dose.

May be given every
2 hours as needed
(usually set

Morning Dose

Continuous
Maintenance Dose
(CMD)

adjustments should be
made.
a.

Extra Doses

between 0.5 to 2
mL per use).

Amount may vary depending on tubing used.

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.
Special Populations
Paediatric population
There is no relevant use of Duodopa in the paediatric population in the indication of
advanced levodopa-responsive Parkinson’s disease with severe motor fluctuations
and hyper-/dyskinesia.
Geriatric Population
There is a considerable experience in the use of levodopa/carbidopa in elderly
patients. Doses for all patients including geriatric population are individually adjusted
by titration.
Renal/hepatic impairment
There are no studies on the pharmacokinetics of carbidopa and levodopa in patients
with hepatic or renal impairment. Dosing with Duodopa is individualized by titration
to optimal effect (which corresponds to individually optimized levodopa and
carbidopa plasma exposures); therefore, potential effects of hepatic or renal
impairment on levodopa and carbidopa exposure are indirectly accounted for in dose
titration. Dose titration should be conducted with caution in patients with severe renal
and hepatic impairment.
Interruption of therapy
Patients should be carefully observed in case a sudden reduction of the dose is
required or if it becomes necessary to discontinue treatment with Duodopa,
particularly if the patient is receiving antipsychotics, see section 4.4.
In the case of suspected or diagnosed dementia with a decreased confusion threshold,
the pump of the patient should be handled only by the nursing staff or a caregiver..
When a cassette is about to be used, it should be attached to the portable pump and
the system connected to the nasoduodenal tube or duodenal/jejunal tube for
administration, according to the instructions given.

4.3

Contraindications
Duodopa is contraindicated in patients with:
• hypersensitivity to levodopa, carbidopa or to any of the excipients listed in
section 6.1.
• narrow-angle glaucoma
• Non-selective 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 HCl) (see section 4.5).
Because levodopa may activate 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
Several warnings and precautions below are generic for levodopa and, therefore, also
for Duodopa.
• Duodopa is not recommended for the treatment of drug-induced extrapyramidal
reactions.
• Duodopa therapy should be administered with caution to patients with severe
cardiovascular or pulmonary disease, bronchial asthma, renal, hepatic or endocrine
disease, or history of peptic ulcer disease or of convulsions.
• In patients with a history of myocardial infarction who have residual atrial nodal
or ventricular arrhythmias, cardiac function should be monitored with particular care
during the period of initial dosage adjustments.
• All patients treated with Duodopa should be monitored carefully for the
development of mental changes, depression with suicidal tendencies, and other
serious mental changes. Patients with past or current psychosis should be treated with
caution.
• Concomitant administration of antipsychotics with dopamine receptor blocking
properties, particularly D2 receptor antagonists should be carried out with caution, and
the patient carefully observed for loss of antiparkinsonian effect or worsening of
parkinsonian symptoms, see section 4.5.
• Patients with chronic wide-angle glaucoma may be treated with Duodopa with
caution, provided the intra-ocular pressure is well controlled and the patient is
monitored carefully for changes in intra-ocular pressure.
• Duodopa may induce orthostatic hypotension. Therefore Duodopa should be
given cautiously to patients who are taking other medicinal products which may cause
orthostatic hypotension, see section 4.5.
• Levodopa has been associated with somnolence and episodes of sudden sleep
onset in patients with Parkinson’s disease and caution should therefore be exercised
when driving and operating machines (see section 4.7).
• A symptom complex resembling Neuroleptic Malignant Syndrome (NMS),
including muscular rigidity, increased body temperature, mental changes (e.g.
agitation, confusion, coma) and increased serum creatine phosphokinase, has been
reported when anti-Parkinsonian medicinal products were withdrawn abruptly.
Rhabdomyolysis secondary to Neuroleptic Malignant Syndrome or severe dyskinesias
have been observed rarely in patients with Parkinson’s disease. Therefore, patients
should be carefully observed when the dose of levodopa/carbidopa combinations are
abruptly reduced or discontinued, especially if the patient is receiving anti-psychotics.
Neither NMS nor rhabdomyolysis has been reported in association with Duodopa.
• Patients should be regularly monitored for the development of impulse control
disorders. Patients and carers should be made aware that behavioural symptoms of
impulse control disorders including pathologic gambling, increased libido and
hypersexuality, compulsive spending or buying, binge eating and compulsive eating
can occur in patients treated with dopamine agonists and/or other dopaminergic
treatments containing levodopa including Duodopa. Review of treatment is
recommended if such symptoms develop.
• Epidemiological studies have shown that patients with Parkinson’s 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 drugs 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).
• If general anaesthesia is required, treatment with Duodopa may be continued for
as long as the patient is permitted to take fluids and medicinal products by mouth. If
therapy has to be stopped temporarily, Duodopa at the same dose as before may be
restarted as soon as oral intake of fluid is allowed.
• The dose of Duodopa may need to be adjusted downwards in order to avoid
levodopa induced dyskinesias.
• Periodic evaluation of hepatic, haematopoietic, cardiovascular and renal function
is recommended during extended therapy with Duodopa.
• Duodopa contains hydrazine, a degradation product of carbidopa that can be
genotoxic and possibly carcinogenic. The average recommended daily dose of
Duodopa is 100 ml, containing 2 g levodopa and 0.5 g carbidopa. The maximum
recommended daily dose is 200 ml. This includes hydrazine at up to an average
exposure of 4 mg/day, with a maximum of 8 mg/day. The clinical significance of this
hydrazine exposure is not known.
• Previous surgery in the upper part of the abdomen may lead to difficulty in
performing gastrostomy or jejunostomy
• Reported complications in the clinical studies include bezoar, ileus, implant site
erosion/ulcer, intestinal hemorrhage, intestinal ischemia, intestinal obstruction,
intestinal perforation, pancreatitis, peritonitis, pneumoperitoneum and post-operative
wound infection. Bezoars are retained concretions of undigested food material in the
intestinal tract. Most bezoars reside in the stomach but bezoars may be encountered
elsewhere in the intestinal tract. Abdominal pain may be a symptom of the above
listed complications. Some events may result in serious outcomes, such as surgery
and/or death. Patients should be advised to notify their physician if they experience
any of the symptoms associated with the above events.
• Reduced ability to handle the system (pump, tube connections) can lead to
complications. In such patients a caregiver (e.g. nurse, assistant nurse, or close
relative) should assist the patient.
• A sudden or gradual worsening of bradykinesia may indicate an obstruction in the
device for whatever reason and needs to be explored.

4.5

Interaction with other medicinal products and other forms of interaction
No interaction studies have been performed with Duodopa. The following
interactions are known from the generic combination of levodopa/carbidopa.
Caution is needed in concomitant administration of Duodopa with the following
medicinal products:
Antihypertensives
Symptomatic postural hypotension has occurred when combinations of levodopa and
a decarboxylase inhibitor are added to the treatment of patients already receiving antihypertensives. Dosage adjustment of the antihypertensive agent may be required.
Antidepressants
There have been rare reports of adverse reactions, including hypertension and
dyskinesia, resulting from the concomitant administration of tricyclic antidepressants
and carbidopa/levodopa preparations.

Anticholinergics
Anticholinergics may act synergistically with levodopa to decrease tremor. However,
combined use may exacerbate abnormal involuntary movements. Anticholinergics
may decrease the effects of levodopa by delaying its absorption. An adjustment of the
dose of Duodopa may be needed.
COMT inhibitors (tolcapone, entacapone)
Concomitant use of COMT (Catechol-O-Methyl Transferase) inhibitors and Duodopa
can increase the bioavailability of levodopa. The dose of Duodopa may need
adjustment.
Other medicinal products
Dopamine receptor antagonists (some antipsychotics, e.g. phenothiazines,
butyrophenons and risperidone and antiemetics, e.g. metoclopramide),
benzodiazepines, isoniazide, phenytoin and papaverine can reduce the therapeutic
effect of levodopa. Patients taking these medicinal products together with Duodopa
should be observed carefully for loss of therapeutic response.
Duodopa can be taken concomitantly with the recommended dose of an MAO
inhibitor, which is selective for MAO type B (for instance selegiline-HCl).
Concomitant use of selegiline and levodopa-carbidopa has been associated with
serious orthostatic hypotension.
Amantadine has synergic effect with levodopa and may increase levodopa related
adverse events. An adjustment of the dose of Duodopa may be needed.
Sympathicomimetics may increase cardiovascular adverse events related to levodopa.
Levodopa forms a chelate with iron in the gastrointestinal tract leading to reduced
absorption of levodopa.
As levodopa is competitive with certain amino acids, the absorption of levodopa can
be disturbed in patients who are on a protein rich diet.
The effect of administration of antacids and Duodopa on the bioavailability of
levodopa has not been studied.

4.6

Fertility, Pregnancy and lactation
Pregnancy
There are no or limited amount of data from the use of levodopa/carbidopa in
pregnant women. Studies in animals have shown reproduction toxicity(see section
5.3). Duodopa is not recommended during pregnancy and in women of childbearing
potential not using contraception unless the benefits for the mother outweigh the
possible risks to the foetus.

Breast-feeding
Levodopa and possibly levodopa metabolites are excreted in human milk. There is
evidence that lactation is suppressed during treatment with levodopa.
It is unknown whether carbidopa or its metabolites are excreted in human milk.
Animal studies have shown excretion of carbidopa in breast milk.
There is insufficient information on the effects of levodopa/carbidopa or their
metabolites in newborns/infants. Breast-feeding should be discontinued during
treatment with Duodopa.
Fertility
No adverse reactions on fertility have been observed in preclinical studies with
carbidopa or levodopa alone. Fertility studies in animals have not been conducted
with the combination of levodopa and carbidopa.

4.7

Effects on ability to drive and use machines
Duodopa has a moderate influence on the ability to drive and use machines.
Levodopa and carbidopa may cause dizziness and orthostatic hypotension. Therefore,
caution should be exercised when driving or using machines. Patients being treated
with Duodopa and presenting with somnolence and/or sudden sleep episodes must be
advised to refrain from driving or engaging in activities where impaired alertness may
put them, or others, at risk of serious injury or death (e.g. operating machines) until
such recurrent episodes and somnolence have resolved, see also section 4.4.

4.8

Undesirable effects
Drug-related undesirable effects that occur frequently with the Duodopa system
include nausea and dyskinesia.
Device- and procedure related undesirable effects that occur frequently with the
Duodopa system include abdominal pain, complications of device insertion, excessive
granulation tissue, incision site erythema, postoperative wound infection, post
procedural discharge, procedural pain, and procedural site reaction.
Most of these adverse reactions were reported early in the studies, subsequent to the
percutaneous endoscopic gastrostomy procedure and occurred during the first 28
days.
Undesirable effects reported with Duodopa
The safety of Duodopa was compared to the standard oral formulation of
levodopa/carbidopa (100 mg/25 mg) in a total of 71 advanced Parkinson's disease
patients who participated in a randomized, double-blind, double-dummy, active
controlled study of 12 weeks duration. Additional safety information was collected in
an open-label, 12-month study in 354 patients with advanced Parkinson's disease and
open-label extension studies.
An analysis was performed for patients who received Duodopa in all studies,
regardless of the study design (double-blind or open-label) to allow for a summary of
drug-related adverse reactions. Another analysis was performed for patients who

received Duodopa or placebo gel through a percutaneous endoscopic gastrostomy
with jejunal tube (PEG-J) to allow for a summary of procedure-related and devicerelated adverse reactions in all studies, regardless of the study design (double-blind or
open-label).
Drug-, Procedure- and device-related adverse reactions in addition to adverse
reactions identified during post-approval use of Duodopa are presented in Table 2.

Table 2.
Adverse Reaction Data Derived From Clinical Trials and Postmarketing Experience
Very
Common
( 1/10)

Common

Uncommon

Rare*

( 1/100 to < 1/10)

(>1/1,000 to <1/100)

(>1/10,000 to
<1/1,000)





MedDRA
System
Organ
Class

Frequency
Unknown
Postmarketing

Drug-Related Adverse Reactions
Anaemia,
Leukopenia

Blood and
lymphatic
system
disorders
Immune
System
Disorders
Metabolism
and
nutrition
disorders

Anaphylactic
reaction

Psychiatric
disorders

Nervous
system
disorders

Eye
disorders

Thrombocytopenia

Dyskinesia

Amino acid
level increased,
Blood
homocysteine
increased,
Decreased
appetite,
Vitamin B6
deficiency,
Vitamin B12
deficiency,
Weight
decreased
Abnormal
dreams,
Agitation,
Anxiety,
Confusional
state,
Depression,
Hallucination,
Insomnia,
Impulsive
behavior*,
Psychotic
disorder,
Sleep attacks,
Sleep disorder
Dizziness,
Dystonia,
Headache,
On and off
phenomenon,
Paraesthesia,
Parkinson’s
disease,
Polyneuropath
y,
Somnolence,
Syncope,
Tremor

Increased
weight

Disorientation,
Euphoric mood,
Hypoaesthesia,
Libido increased
(See Section
4.4)
Nightmare
Suicide Attempt

Abnormal
thinking,
Dementia,
Fear

Ataxia,
Gait disturbance

Convulsion

Blepharospasm,
Diplopia

Vision blurred

Completed
suicide

Optic
ischaemic

Very
Common
( 1/10)



Cardiac
disorders

Uncommon

Rare*

(>1/1,000 to <1/100)

(>1/10,000 to
<1/1,000)

Heart rate
irregular,
Palpitations
Hypotension,
Orthostatic
hypotension
Dyspnoea,
Oropharyngeal
pain

Vascular
disorders
Respiratory,
thoracic and
mediastinal
disorders
Gastrointestinal
disorders

Common
( 1/100 to < 1/10)



MedDRA
System
Organ
Class

Nausea

Abdominal
distension,
Constipation,
Diarrhoea,
Dry mouth,
Dysgeusia,
Dyspepsia,
Flatulence,
Vomiting
Dermatitis
contact,
Hyperhidrosis

Skin and
subcutaneo
us tissue
disorders
Musculoske
letal and
connective
tissue
disorders
Renal and
urinary
disorders

Fatigue,
Pain

Phlebitis

Chest pain,
Dysphonia,
Pneumonia
aspiration
Dysphagia,
Salivary
Hypersecretion

Respiration
abnormal

Alopecia,
Oedema,
Pruritus,
Rash

Erythema,
Malignant
melanoma (See
Section 4.4),
Urticaria

Urinary
incontinence,
Urinary
retention
Asthenia,
Malaise

Priapism

Bruxism,
Glossodynia,
Hiccups

Muscle
spasms,
Neck pain

General
disorders
and
administrati
on site
conditions
Injury,
poisoning
and
procedural
complicatio
ns

Hypertension

Frequency
Unknown
Postmarketing
neuropathy

Fall

Device- and Procedure-Related Adverse Reactions
Infections
and
infestations

Postoperative
wound
infection

Gastrointestinal
disorders

Abdominal
pain

Incision site
cellulitis,
Post procedural
infection
Abdominal
discomfort,
Abdominal

Postoperative
abscess

Bezoar (see
section 4.4),
Colitis

Gastric
perforation,
Gastro-

( 1/10)

Common

Uncommon

Rare*

(>1/1,000 to <1/100)

(>1/10,000 to
<1/1,000)

ischaemic,
Gastrointestinal
ischaemia,
Gastrointestinal
obstruction,
Pancreatitis,
Small intestinal
haemorrhage,
Small intestinal
ulcer





Skin and
subcutaneo
us tissue
disorders
General
disorders
and
administrati
on site
conditions
Injury,
poisoning
and
procedural
complicatio
ns

Very
Common

( 1/100 to < 1/10)

pain upper,
Peritonitis,
Pneumoperitoneum

MedDRA
System
Organ
Class

Frequency
Unknown
Postmarketing
intestinal
perforation,
Small
intestinal
ischaemia,
Small
intestinal
perforation

Excessive
granulation
tissue
Complications
of device
insertion***

Device
dislocation,
Device
occlusion

Incision site
erythema,
Post
procedural
discharge,
Procedural
pain,
Procedural
site reaction

Gastrointestina
l stoma
complication,
Incision site
pain,
Postoperative
Ileus,
Post procedural
complication,
Post procedural
discomfort,
Post procedural
haemorrhage

* Frequency derived from oral levodopa/carbidopa and also observed post-marketing with Duodopa
** Impulse control disorders: Pathological gambling, increased libido and hypersexuality, compulsive
spending or buying, binge eating and compulsive eating can occur in patients treated with dopamine
agonists and/or other dopaminergic treatments containing levodopa including Duodopa (see section
4.4. ‘Special warnings and precautions for use’).
*** Complication of device insertion was a commonly reported adverse reaction for both the NJ and
the PEG-J. This adverse reaction was co-reported with 1 or more of the following adverse reactions for
the NJ: oropharyngeal pain, abdominal distention, abdominal pain, abdominal discomfort, pain, throat
irritation, gastrointestinal injury, esophageal hemorrhage, anxiety, dysphagia, and vomiting. For the
PEG-J, this adverse reaction was co-reported with 1 or more of the following adverse reactions:
abdominal pain, abdominal discomfort, abdominal distension, flatulence, or pneumoperitoneum. Other
nonserious adverse reactions that were co-reported with complication of device insertion included
abdominal discomfort, abdominal pain upper, duodenal ulcer, duodenal ulcer hemorrhage, erosive
duodenitis, gastritis erosive, gastrointestinal haemorrhage, peritonitis, pneumoperitoneum, small
intestine ulcer.

Dislocation of the intestinal tube backwards into the stomach or an obstruction in the
device leads to reappearance of the motor fluctuations.
The following additional adverse reactions (listed in MedDRA preferred terms) have
been observed with oral levodopa/carbidopa and could occur with Duodopa:

Adverse Reaction Observed with Oral Levodopa/Carbidopa

MedDRA system organ class
Blood and lymphatic system
disorders
Nervous system disorders

Eye disorders

Skin and subcutaneous tissue
disorders

Rare
( 1/10,000 to <1/1,000)
Haemolytic anaemia



Table 3.

Very Rare
(>1/100,000 to,1/10,000)
Agranulocytosis

Trismus
Neuroleptic malignant syndrome
(see Section 4.4)
Horner’s syndrome
Mydriasis
Oculogyric crises
Angiooedema
Henoch-Schönlein purpura

Laboratory values: The following laboratory abnormalities have been reported with
levodopa/carbidopa treatment and should, therefore, be acknowledged when treating
patients with Duodopa: elevated urea nitrogen, alkaline phosphatases, S-AST, S-ALT,
LDH, bilirubin, blood sugar, creatinine, uric acid and positive Coomb’s test, and
lowered values of haemoglobin and haematocrit. Leucocytes, bacteria and blood in
the urine have been reported. Levodopa/carbidopa, and thus Duodopa, may cause a
false positive result when a dipstick is used to test for urinary ketone; this reaction is
not altered by boiling the urine sample. The use of glucose oxidase methods may give
false negative results for glucosuria.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is
important. It allows continued monitoring of the benefit/risk balance of the medicinal
product. Healthcare professionals are asked to report any suspected adverse reactions
via the national reporting system listed in Appendix V.
4.9

Overdose
Most prominent clinical symptoms of an overdose with levodopa/carbidopa are
dystonia and dyskinesia. Blepharospasms 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 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:
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 is a metabolic precursor of dopamine
that 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
infusion of individualized doses of Duodopa maintains plasma concentrations of
levodopa at steady levels within the individual therapeutic windows.
Pharmacodynamic Effects:
Intestinal therapy with Duodopa reduces the motor fluctuations and decreases the
“Off”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 Efficacy and Safety:The efficacy of Duodopa was confirmed in two
identically-designed Phase 3, 12-week, randomized, double-blind, double-dummy,
active-controlled, parallel group, multicenter studies to evaluate the efficacy, safety,
and tolerability of Duodopa against levodopa/carbidopa 100/25 mg tablets. The
studies were conducted with patients with advanced Parkinson's disease who were
levodopa-responsive and had persistent motor fluctuations despite optimized
treatment with oral levodopa carbidopa and other available anti-Parkinson's disease
medications and enrolled a total of 71 patients. The results of the two studies were
combined and a single analysis was conducted.
The primary efficacy endpoint, change in normalized "Off" time (baseline to
endpoint) based on Parkinson's Disease Diary© data using last observation carried
forward demonstrated a statistically significant least square (LS) mean difference of –
1.91 hours (P = 0.0015) in favor of the Duodopa treatment group (LS mean change: –
4.04 hours for Duodopa group and –2.14 hours for active control group) (Table 4).
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.
This change in “Off” time was associated with a statistically significant LS mean
difference from baseline in the average daily normalized "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 randomization and after 28 days of oral therapy standardization.
Table 4 Change from Baseline to Endpoint in "Off" Time and in "On" Time
Without Troublesome Dyskinesia

Treatment Group

N

"Off" time
Active Controla
Duodopa

31
35

"On" time without
troublesome
dyskinesia
Active Control
Duodopa

31
35

Endpoint
Baseline
(SD)
(hours)
Mean
(SD)
(hours)
Primary Measure
4.95
(2.04)
3.05
(2.52)
Secondary Measure

6.90 (2.06)
6.32 (1.72)

LS Mean
(SE) of
Change
(hours)
–2.14
(0.66)
–4.04
(0.65)

LS Mean
(SE) of
Differenc
e
(hours)

P value

–1.91 (0.57)

0.0015

9.92
(2.62
2.24 (0.76)
11.95
4.11 (0.75)
1.86 (0.65)
(2.67)
SD = standard deviation; SE = standard error
a.
Active control, oral levodopa/carbidopa 100/25 mg tablets
8.04 (2.09)
8.70 (2.01)

0.0059

Analyses 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 showed a decrease from baseline of 10.9 points at week 12. Other
secondary endpoints, UPDRS Part III score, EQ-5D Summary Index, and ZBI total
score, did not meet statistical significance based on the hierarchical testing procedure.
A Phase 3, open-label, single-arm, multicenter 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 optimized treatment with available Parkinson's disease
medications. The average daily normalized "Off" time changed by – 4.44 hours from
Baseline to Endpoint (6.77 hours at Baseline and 2.32 hours at Endpoint) with a
corresponding 4.8 hour increase in On time without dyskinesia.
Pediatric population
The safety of Duodopa in patients under 18 years of age has not been established and
its use in patients below the age of 18 is not recommended.

5.2

Pharmacokinetic properties
Absorption
Duodopa is administered via an inserted tube directly into the duodenum or jejunum.
Levodopa is absorbed quickly and effectively from the intestine through a high
capacity transport system for amino acids. The absolute bioavailability of levodopa

from oral levodopa/carbidopa immediate release tablets is reported to be 84-99%. A
cross-study population pharmacokinetic analysis suggested that Duodopa has
comparable levodopa bioavailability to the oral levodopa/carbidopa (100/25 mg)
tablets.
In a Phase 1 study, intrajejunal administration of Duodopa 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 (13% and 19%, respectively).

Levodopa Plasma Concentration (µg/mL)

Figure 1. Plasma Concentrations (mean ± standard deviation) versus Time
Profile of Levodopa with Duodopa 16-Hour Infusion

5

4

3

2

1

0
0

4

8

12

16

20

Time (hr)

In a 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 (21% and 25%, respectively) than in patients treated
with oral levodopa/carbidopa 100/25 mg over-encapsulated tablets (67% and 39%,
respectively).
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 partitioning ratio for
levodopa between erythrocytes and plasma is approximately 1. The protein binding of
levodopa in plasma is negligible (about 10%-30%). Levodopa is transported into the
brain by the carrier mechanism for large neutral amino acids.
Carbidopa is approximately 36% bound to plasma protein. Carbidopa does not cross
the blood-brain barrier.
Biotransformation and elimination

When administered with carbidopa, the elimination half-life for levodopa is
approximately 1.5 hours. Levodopa is eliminated completely through metabolism and
the metabolites formed are excreted mainly in the urine. Four metabolic pathways are
known, but 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-methyltransferase (COMT) becomes the dominant metabolic pathway. O-methylation of
levodopa by COMT forms 3-O-methyldopa.
Carbidopa is metabolized to two main metabolites ( -methyl-3-methoxy-4hydroxyphenylpropionic acid and -methyl-3,4-dihydroxyphenylpropionic acid).
These 2 metabolites are primarily eliminated in the urine unchanged or as glucuronide
conjugates. Unchanged carbidopa accounts for 30% of the total urinary excretion.
The elimination half-life of carbidopa is approximately 2 hours.

α

α

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.

5.3

Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies
of safety, pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential,
toxicity to reproduction. In reproductive toxicity studies both levodopa and the
combination of carbidopa/levodopa have caused visceral and skeletal malformations
in rabbits, see section 4.6.
Hydrazine is a degradation product of Carbidopa. In animal studies, hydrazine
showed notable systemic toxicity, particularly by inhalation exposure. These studies
reported that hydrazine is hepatotoxic, has CNS toxicities (although not described
after oral treatment), and is genotoxic as well as carcinogenic (see also section 4.4).
No evidence of carcinogenicity has been reported in animals at hydrazine plasma
exposures of greater than 4 times those observed in a clinical study at the usual
human daily dose of approximately one cassette. The clinical significance of this
hydrazine exposure is not known.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Carmellose sodium, purified water

6.2

Incompatibilities
Not applicable

6.3

Shelf life
Unopened: 15 weeks.
Once opened: Use immediately. The product is to be used for up to 16 hours once it
is out of the refrigerator. Discard any unused portion.

6.4

Special precautions for storage
Store in a refrigerator (2ºC-8°C).
Keep the cassette in the outer carton in order to protect from light.
For storage conditions after first opening of the medicinal product, see section 6.3.

6.5

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

6.6

Special precautions for disposal
Cassettes are for single use only.
Do not re-use an opened cassette.
Any unused medicinal product or waste material should be disposed of in accordance
with local requirements.
Empty/used cassettes should be returned to the pharmacy for destruction.

7

MARKETING AUTHORISATION HOLDER
AbbVie Ltd.,
Abbott House
Vanwall Business Park
Vanwall Road
Maidenhead
Berkshire
SL6 4XE

8

MARKETING AUTHORISATION NUMBER(S)
PL 41042/0001

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
14/11/2005 / 21/01/2009

10

DATE OF REVISION OF THE TEXT
14/05/2014

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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