Duodopa intestinal gel

Section 4.8

Inclusion of urinary tract infection as a very common AE

Section 4.8

Inclusion of urinary tract infection as a very common AE

Section 4.2 Posology and method of administration

The statement "In addition to daytime, if medically justified Duodopa may be administered during the night." has been amended to "Treatment is usually administered during the patient’s awake period. If medically justified, Duodopa may be administered for up to 24 hours."

Section 5.1 - Pharmacodynamic properties

• The following information has been added:

A Phase 3, open‑label, randomized, multicenter study was conducted to assess the effect of Duodopa on dyskinesia compared with optimized medical treatment (OMT) over 12 weeks in 61 patients. The target population was levodopa-responsive patients with advanced PD and motor fluctuations inadequately controlled with OMT and with a baseline Unified Dyskinesia Rating Scale (UDysRS) Total Score ≥30. The change from baseline to Week 12 in UDysRS total score (primary efficacy endpoint) demonstrated a statistically significant LS Mean difference (-15.05; P < 0.0001) in favour of the Duodopa treatment group compared with OMT group. Analysis of secondary efficacy endpoints using a fixed sequence testing procedure, demonstrated statistically significant results in favour of Duodopa compared with OMT for “On” time without troublesome dyskinesia as measured by PD diary, for Parkinson's Disease Questionnaire-8 (PDQ‑8) summary index, Clinical Global Impression Change (CGI‑C) score, UPDRS Part II score, and for “Off” time as measured by PD diary. The UPDRS Part III score did not meet statistical significance.

• Minor editorial update to Table 3

Section 10 - Date of Revision of the text

• Updated to 01/2021

Section 4.2 – Posology and method of administration

“CADD-legacy 1400 pump (CE 0473)” updated to “CADD-legacy 1400 pump (CE Marked)”

Section 4.4 – Special warnings and precautions for use

• The following have been added to Reported complications in the clinical studies, and seen post-marketing:
  
  Abscess, pneumonia (including aspiration pneumonia) and sepsis

Section 4.8 Undesirable effects

• The following have been added to Table 1 (Device and Procedure-Related Adverse Reactions)

• Sepsis (Frequency Unknown Postmarketing)
• Pneumonia/Aspiration pneumonia (system organ class: respiratory, thoracis and mediastinal disorders; frequency Common)
   

• Pneumonia  aspiration has been removed from Table 1 (Drug-Related Adverse Reactions)
   
• Table 2 – Frequency for “Very Rare” updated

Section 10 Date of Revision of the Text

• Updated to 10/2020

Minor editorial update (full stop missing on previous version)

Section 4.4  -  Special warnings and precautions for use

The following has been added:

• 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

Section 4.2 - Posology and method of administration

In use shelf-life for the Duodopa cassette has been updated from 16 hours to 24 hours.

The statement:

“The medicine cassettes are for single use only and should not be used for longer than 16 hours, even if some medicinal product remains.”

has been amended to:

“The medicine cassettes are for single use only and should not be used for longer than 24 hours, even if some medicinal product remains.”

Section 4.8 - Undesirable effects

The HPRA contact details for reporting adverse events has been updated as follows:

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 HPRA Pharmacovigilance; website: www.hpra.ie.

Section 6.3 Shelf life

In use shelf-life for the Duodopa cassette has been updated from 16 hours to 24 hours.

The statement:

“Once opened: Use immediately. The product is to be used for up to 16 hours once it is out of the refrigerator.”

has been amended to:

“Once opened: Use immediately. The product is to be used for up to 24 hours once it is out of the refrigerator.”

Section 10 - Date of Revision of the Text

Updated to July 2020

Section 4.4   Special warnings and precautions for use

The following bullet point has been added:

Dopamine Dysregulation Syndrome (DDS) is an addictive disorder resulting in excessive use of the product seen in some patients treated with levodopa/carbidopa. Before initiation of treatment, patients and caregivers should be warned of the potential risk of developing DDS (see also section 4.8).

 Section 4.8 Undesirable effects

The adverse reaction Dopamine dysregulation syndrome^d  has been added been added to Table 1; MedDRA System Organ Class: Psychiatric disorders,  (Frequency Unknown Post-marketing) , followed by the inclusion of the following footnote:

^d Dopamine Dysregulation Syndrome (DDS) is an addictive disorder seen in some patients treated with levodopa/ carbidopa. Affected patients show a compulsive pattern of dopaminergic drug misuse above doses adequate to control motor symptoms, which may in some cases result in severe dyskinesias (see also section 4.4).

Section 10 Date of Revision of text

Updated to December 2017

Section 1

“Duodopa, 20 mg/ml + 5 mg/ml, intestinal gel”  has been amended to “Duodopa 20 mg/ml + 5 mg/ml intestinal gel”

Section 2

“For a full list of excipients, see section 6.1.”   revised to “For the full list of excipients, see section 6.1.

Section 4.1

Amended to read:

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

Section 4.2

The below section amended to read:

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. In addition to daytime, if medically justified Duodopa may be administered during the night.

The drug  medicine 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 medicine or the treatment.

The statement “If medically justified Duodopa may be administered during the night.” has been deleted lower down in the section.

Section 4.3

The following bullet has been amended to read:

•       hypersensitivity to levodopa, carbidopa the active substances or to any of the excipients listed in section 6.1.

Section 4.4

The following bullet has been amended to read:

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 disease or other factors, such as drugs medicines used to treat Parkinson’s disease.

Section 4.8

Angle closure glaucoma has been added to Table 1 (uncommon).

Section 5.1

The below paragraph has been amended as follows:

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 (an index Parkinson’s disease-related quality of life), Clinical Global Impression (CGI-I) score, and Unified Parkinson's Disease Rating Scale (UPDRS) Part II score (ADL - Activities of Daily Living (ADL)). 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

Section 6.4

“Store in a refrigerator (2°C-8°C).” has been amended to read  

“Store and transport refrigerated (2°C-8°C).”

Section 10

Date of Revision of text has been amended to October 2017.

• The following has been updated:
  
  From 

Reported complications in the clinical studies, include bezoar, ileus, implant site erosion/ulcer, intestinal haemorrhage, intestinal ischaemia, 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.

To

• •       Reported complications in the clinical studies, and seen Post-marketing, include bezoar, ileus, implant site erosion/ulcer, intestinal haemorrhage, intestinal ischaemia, intestinal obstruction, intestinal perforation, intussusception, pancreatitis, peritonitis, pneumoperitoneum and post-operative wound infection. Bezoars are retained concretions of   undigested food indigestible material (such as vegetable or fruit non-digestible fibers) in the intestinal tract.  Most bezoars reside in the stomach but bezoars may be encountered elsewhere in the intestinal tract. A bezoar around the tip of the jejunal tube may function as a lead point for intestinal obstruction or the formation of intussusception. 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.
  
  
  Section 4.8 (Undesirable effects)
  

  • Intussusception added to the list of Device and Procedure Related Adverse Reactions
    

Update  to the  contact details in section 4.8 of the SmPC (from IMB to HPRA) for the reporting of suspected adverse reactions.

1) Section 4.1: Removal of the statement requiring the use of a nasoduodenal tube prior to insertion of permanent tube. This change is the consequence of change in Section 4.2.

2) Section 4.2:   Update the use of the nasoduodenal tube for the determination of patient response to Duodopa® prior to duodenal/jejunal tube placement from recommended to “based on physician judgement”.  Specify the pump model to be used with the cassettes. Include a dosing table, other dosing instructions and clarify tubing location.  Clarify the dosage recommendations in renally/hepatically impaired patients.

3) Section 4.3: Removing the contraindication severe liver and renal insufficiency. Non-selective MAO inhibitors and selective MAO type A inhibitors are contraindicated. Clarify that MAO Type B inhibitors may be administered concomitantly with Duodopa®.    Include a contraindication for use in patients with suspicious undiagnosed skin lesions or a history of melanoma.

4) Section 4.4:    Include the precaution that patients with Parkinson’s have a higher risk of developing melanoma than the general population. Removal of the specific precaution paragraph about bezoar and include it in a proposed precaution section about reported complications in the clinical studies that include bezoar, ileus, implant site erosion/ulcer, intestinal haemorrhage, intestinal ischemia, intestinal obstruction, intestinal perforation, pancreatitis, peritonitis, pneumoperitoneum and post-operative wound infection.

5) Section 4.5 this sentence is added:  The dose of levodopa may need to be reduced when an MAO inhibitor selective for type B is added.

6) Sections 4.6 and 4.7 are updated in line with the current QRD template.

7) Section 4.8    Include undesirable effects derived from clinical trials. Create a new table that includes ADRs derived from clinical trials and post-marketing. This table is divided in two sections; drug-related adverse reactions section, and device- and procedure-related adverse reactions section. Include a new table containing additional adverse reactions that have been observed with oral levodopa/carbidopa and could occur with Duodopa.

8) Section 5.1    Update the summary of pharmacodynamic to include the results of new studies using Duodopa® including a new Phase 1 study and a new Phase 3 study comparing Duodopa® to oral levodopa/carbidopa formulations.

9) Section 5.2    Update the summary of pharmacokinetic effects to include the results of new studies using Duodopa® including a new Phase 1 study and a new Phase 3 study comparing Duodopa® to oral levodopa/carbidopa formulations.

10) Section 5.3    Toxicity to reproduction is removed from the first paragraph.

•         Isolated reports have been received describing gastrostomy tube blockage and/or intestinal obstruction with bezoar formation, necessitating replacement of tubing and in rare cases surgery.  Early symptoms include aggravation of Parkinson’s symptoms, reduced efficacy, abdominal pain, nausea and vomiting.  In some cases, gastric and intestinal ulcerations have been found.  Bezoars are retained concretions of indigested food material in the intestinal tract.  Most bezoars are found in the stomach but bezoars may be encountered elsewhere in the intestinal tract.

The following text was added to section 4.8 :
There have been isolated reports of bezoar formation (see 4.4)

Section 4.2

From:

Morning bolus dose: 140 mg = 7 ml (including the volume to fill the intestinal tube)

To:

Morning bolus dose: 140 mg = 7 ml (excluding the volume to fill the intestinal tube)

Section 4.4

The following statement has been included;

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.

Section 4.8

The frequency sub headings have been updated.

Section 5.3

The following statement has been included;

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).

Section 7:

From:

Solvay Pharmaceuticals GmbH

Hans-Boeckler-Allee 20

D-30173 Hannover

Germany

To:

Abbott Products GmbH

Hans-Boeckler-Allee 20

D-30173 Hannover

Germany