Public Assessment Report Decentralised Procedure LAXAGOL powder by n1884

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									                         Public Assessment Report

                          Decentralised Procedure




                   LAXAGOL powder for oral solution



                                 PL 17507/0091



                              UK/H/1446/01/DC




                Auden Mckenzie (Pharma Division) Ltd.




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                                        Lay summary


The Medicines and Healthcare products Regulatory Agency (MHRA) granted Auden Mckenzie
(Pharma Division) Ltd. a Marketing Authorisation (licence) for the medicinal product LAXAGOL
powder for oral solution (Product Licence number: PL 17507/0091). This medicine is available
from pharmacies without prescription.

LAXAGOL powder for oral solution is a laxative for the treatment of constipation. LAXAGOL
helps you to have a normal bowel movement even if you have been constipated for a long time.
LAXAGOL also works when there is a build up of hard faeces in your bowel which may be the
result of long-term constipation (called faecal impaction). LAXAGOL contains macrogol 3350
which makes your faeces softer and easier to pass, giving you relief from constipation. The
electrolytes help to maintain your body’s normal levels of sodium, potassium and water while you
are being treated for constipation.

The data submitted in support of this application for LAXAGOL powder for oral solution raised no
clinically significant safety concerns and it was therefore judged that the benefits of using this
product outweigh the risks; hence a Marketing Authorisation has been granted.




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                                     TABLE OF CONTENTS


   Module 1: Information about decentralised procedure   Page 4

   Module 2: Summary of Product Characteristics          Page 5

   Module 3: Product Information Leaflets                Page 10

   Module 4: Labelling                                   Page 14

   Module 5: Scientific Discussion                       Page 17

               1 Introduction
               2 Quality aspects
               3 Non-clinical aspects
               4 Clinical aspects
               5 Overall conclusions




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                                          Module 1

                      Information about decentralised procedure

Name of the product in the Reference            LAXAGOL powder for oral solution
Member State
Type of application (Eudratrack details)        Level 1    Abridged
                                                Level 2    Initial
                                                Level 3    10.1
                                                Level 4    Chemical substance
                                                Level 5    Pharmacy
Name of the active substance                    Macrogol 3350
(INN)                                           Sodium Chloride
                                                Sodium Hydrogen Carbonate
                                                Potassium Chloride
Pharmacotherapeutic classification              Osmotically acting laxatives
(ATC code)                                      A06A D65
Pharmaceutical form and strength                Powder for solution for oral consumption,
                                                single-dose sachet, 13.8 g
Reference numbers for            the   Mutual   UK/H/1446/01/DC
Recognition Procedure
Reference Member State                          United Kingdom

Member States concerned                         Ireland

Date of start of the procedure                  5 December 2008

End date of decentralised procedure             6 August 2009

Marketing Authorisation Number                  PL 17507/0091

Name and address of the                         Auden Mckenzie (Pharma Division) Ltd.
authorisation holder                            Mckenzie House
                                                Bury Street
                                                Ruislip
                                                Middlesex HA4 7TL
                                                UK




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                                               Module 2

                            Summary of Product Characteristics

1     NAME OF THE MEDICINAL PRODUCT
      LAXAGOL powder for oral solution


2     QUALITATIVE AND QUANTITATIVE COMPOSITION
      Each sachet of LAXAGOL contains the following active ingredients:

      Macrogol 3350                                          13.125 g
      Sodium chloride                                        350.7 mg
      Sodium bicarbonate (Sodium hydrogen carbonate)         178.5 mg
      Potassium chloride                                     46.6 mg

      The content of electrolyte ions per sachet when made up to 125 ml of solution is as follows:

      Sodium                                           65 mmol/l
      Chloride                                         53 mmol/l
      Potassium                                        5.4 mmol/l
      Bicarbonate (Hydrogen carbonate)                 17 mmol/l

      For a full list of excipients, see Section 6.1


3     PHARMACEUTICAL FORM
      Powder for oral solution. Single-dose sachet containing a free flowing white powder.


4     CLINICAL PARTICULARS

4.1   Therapeutic indications
      For the treatment of chronic constipation. LAXAGOL is also effective in resolving faecal
      impaction, defined as refractory constipation with faecal loading of the rectum and/or colon.

4.2   Posology and method of administration
      Chronic constipation
      A course of treatment for constipation with LAXAGOL does not normally exceed 2 weeks,
      although this can be repeated if required.

      As for all laxatives, prolonged use is not usually recommended. Extended use may be
      necessary in the care of patients with severe chronic or resistant constipation, secondary to
      multiple sclerosis or Parkinson's Disease, or induced by regular constipating medication in
      particular opioids and antimuscarinics.




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      Adults, adolescents and the elderly: 1 –3 sachets daily in divided doses, according to
      individual response.

      For extended use, the dose can be adjusted down to 1 or 2 sachets daily.

      Children below 12 years old: Not recommended.

      Faecal impaction
      A course of treatment for faecal impaction with LAXAGOL does not normally exceed 3 days.

      Adults, adolescents and the elderly: 8 sachets daily, all of which should be consumed within
      a 6 hour period.

      Children below 12 years old: Not recommended.

      Patients with impaired cardiovascular function: For the treatment of faecal impaction the
      dose should be divided so that no more than 2 sachets are taken in any one hour.

      Patients with renal insufficiency: No dosage change is necessary for the treatment of
      constipation or faecal impaction.

      Administration
      Each sachet should be dissolved in 125 ml water. For use in faecal impaction 8 sachets may
      be dissolved in 1 litre of water.

4.3   Contraindications
      Intestinal perforation or obstruction due to structural or functional disorder of the gut wall,
      ileus, severe inflammatory conditions of the intestinal tract, such as Crohn's disease and
      ulcerative colitis and toxic megacolon.

      Hypersensitivity to the active ingredients or to any of the excipients.

4.4   Special warnings and precautions for use
      Diagnosis of impaction/faecal loading of the rectum should be confirmed by physical or
      radiological examination of the abdomen and rectum.

      Mild adverse drug reactions are possible as indicated in Section 4.8. If patients develop any
      symptoms indicating shifts of fluids/electrolytes (e.g. oedema, shortness of breath, increasing
      fatigue, dehydration, cardiac failure) LAXAGOL should be stopped immediately and
      electrolytes measured and any abnormality should be treated appropriately.

      LAXAGOL contains 0.68mmol (26mg) of potassium per sachet. This should be taken into
      consideration if more than one sachet is taken daily and for those patients that have reduced
      kidney function, or are on a controlled potassium diet.

      LAXAGOL contains 8.13mmol (187mg) of sodium per sachet. This should be taken into
      consideration for patients on a controlled sodium diet.

      The lemon flavouring used in LAXAGOL may contain sulphites. This may rarely cause
      severe hypersensitivity reactions and bronchospasm.




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4.5   Interaction with other medicinal products and other forms of interaction
      No clinical interactions with other medicinal products have been reported. Macrogol raises the
      solubility of medicinal products that are soluble in alcohol and relatively insoluble in water.
      There is therefore a theoretical possibility that the absorption of such medicinal products
      could be transiently reduced. Therefore, other medicines should not be taken orally for one
      hour before and one hour after taking LAXAGOL.

4.6   Pregnancy and lactation
      There is no experience of the use of LAXAGOL during pregnancy and lactation and it should
      only be used if considered essential by the physician.

4.7   Effects on ability to drive and use machines
      LAXAGOL has no influence on the ability to drive and use machines.

4.8   Undesirable effects
      Immune System Disorders:

      Allergic reactions are possible.

      Gastro-intestinal Disorders:

      Potential gastro-intestinal effects that may occur include abdominal distension and pain,
      borborygmi and nausea. Mild diarrhoea may also occur, but normally resolves after dose
      reduction.

4.9   Overdose
      Severe pain or distension can be treated by nasogastric aspiration. Extensive fluid loss by
      diarrhoea or vomiting may require correction of electrolyte disturbances.


5     PHARMACOLOGICAL PROPERTIES

5.1   Pharmacodynamic properties
      Pharmacotherapeutic group: Osmotically acting laxatives.

      ATC code: A06A D65

      Macrogol 3350 acts by virtue of its osmotic action in the gut, which induces a laxative effect.
      Macrogol 3350 increases the stool volume, which triggers colon motility via neuromuscular
      pathways. The physiological consequence is an improved propulsive colonic transportation of
      the softened stools and a facilitation of the defaecation. Electrolytes combined with macrogol
      3350 are exchanged across the intestinal barrier (mucosa) with serum electrolytes and
      excreted in faecal water without net gain or loss of sodium, potassium and water.

      For the indication of faecal impaction controlled comparative studies have not been
      performed with other treatments (e.g. enemas). In a non-comparative study in 27 adult
      patients, the listed combination of active substances cleared the faecal impaction in 12/27
      (44%) after 1 day's treatment; 23/27 (85%) after 2 days' treatment and 24/27 (89%) at the end
      of 3 days.

      Clinical studies using the listed active substances in the treatment of chronic constipation have
      shown that the dose needed to produce normal formed stools tends to reduce over time. Many


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      patients respond to between 1 and 2 sachets a day, but this dose should be adjusted depending
      on individual response.

5.2   Pharmacokinetic properties
      Macrogol 3350 is unchanged along the gut. It is virtually unabsorbed from the gastro-
      intestinal tract. Any macrogol 3350 that is absorbed is excreted via the urine.

5.3   Preclinical safety data
      Preclinical studies provide evidence that macrogol 3350 has no significant systemic toxicity
      potential, although no tests of its effects on reproduction or genotoxicity have been conducted.

      There are no long-term animal toxicity or carcinogenicity studies involving macrogol 3350,
      although there are toxicity studies using high levels of orally administered high molecular
      macrogols that provide evidence of safety at the recommended therapeutic dose.


6     PHARMACEUTICAL PARTICULARS

6.1   List of excipients
      Acesulfame potassium(E950)
      Lemon flavour

      (Lemon flavour contains the following constituents: nature-identical flavouring substances,
      flavouring preparations, natural flavouring substances, maltodextrin and starch modified).

6.2   Incompatibilities
      Not applicable.

6.3   Shelf life
      2 years.
      Reconstituted solution: 6 hours.

6.4   Special precautions for storage
      Sachet: Do not store above 25°C.
      Reconstituted solution: Store at 2 - 8°C (in a refrigerator and covered).

6.5   Nature and contents of container
      Sachet: laminate consisting of four layers: low density polyethylene, aluminium, low density
      polyethylene and paper.

      Pack sizes: boxes of 2, 8, 20, 30, 50 or 100 sachets.
      Not all pack sizes may be marketed.

6.6   Special precautions for disposal
      Any unused solution should be discarded within 6 hours.


7     MARKETING AUTHORISATION HOLDER
      Auden Mckenzie (Pharma Division) Ltd.
      Mckenzie House
      Bury Street
      Ruislip


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     Middlesex
     HA4 7TL
     UK


8    MARKETING AUTHORISATION NUMBER(S)
     PL 17507/0091


9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
     25/09/2009


10   DATE OF REVISION OF THE TEXT
     25/09/2009




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                                     Module 3

                           Product Information Leaflet




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                                     Module 4

                                     Labelling




Label:




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Carton:




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                                            Module 5

                      Scientific discussion during initial procedure

RECOMMENDATION
Based on the review of the data on quality, safety and efficacy, the Reference Member State (RMS)
considers that the application for LAXAGOL powder for oral solution in the treatment of chronic
constipation and in resolving faecal impaction is approvable.


EXECUTIVE SUMMARY

ABOUT THE PRODUCT
Macrogol 3350 acts by virtue of its osmotic action in the gut, which induces a laxative effect.
Macrogol 3350 increases the stool volume, which triggers colon motility via neuromuscular
pathways. The physiological consequence is an improved propulsive colonic transportation of the
softened stools and a facilitation of the defaecation. Electrolytes combined with macrogol 3350 are
exchanged across the intestinal barrier (mucosa) with serum electrolytes and excreted in faecal
water without net gain or loss of sodium, potassium and water.


GENERAL COMMENTS ON THE SUBMITTED DOSSIER
This is a Decentralised Procedure with the United Kingdom acting as the Reference Member State.
The application is submitted under article 10.1 of Directive 2001/83/EC, as amended, cross-
referring to the UK product Movicol (PL 00322/0070) licensed to Norgine Limited since 18
December 1995.

With UK as the Reference Member State in this Decentralized Procedure, Auden Mckenzie
(Pharma Division) Ltd. is applying for a Marketing Authorisation for LAXAGOL powder for oral
solution in Ireland.


GENERAL COMMENTS ON COMPLIANCE WITH GMP, GLP, GCP AND AGREED
ETHICAL PRINCIPLES.
The RMS has been assured that acceptable standards of GMP are in place for these product types at
all sites responsible for the manufacture and assembly of this product. For manufacturing sites
within the Community, the RMS has accepted copies of current manufacturer authorisations issued
by inspection services of the competent authorities as certification that acceptable standards of
GMP are in place at those sites.

For manufacturing sites located outside the Community, the RMS has accepted a copy of the
current GMP certificate of satisfactory inspection issued by the inspection services of the competent
authorities as certification that acceptable standards of GMP are in place at those non-Community
sites.

The RMS has been reassured that the submitted studies have been carried out in accordance with
GCP, and agreed ethical principles.




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SCIENTIFIC OVERVIEW AND DISCUSSION

QUALITY ASPECTS

Drug substance
The chemical-pharmaceutical documentation and Expert Report in relation to LAXAGOL powder
for oral solution are of sufficient quality in view of the present European regulatory requirements.
The active substances, Macrogol 3350, sodium chloride, sodium bicarbonate (sodium hydrogen
carbonate) and potassium chloride which are the subjects of Ph Eur monographs and are controlled
by current certificates of suitability. The drug substance specifications for the drug substances are
acceptable. Stability studies have been performed with the drug substance. No significant changes
in any parameters were observed. An adequate re-test period has been defined based on conducted
stability studies.

Drug Product
The development of the product has been described, the choice of excipients is justified and their
functions explained. The product specifications cover appropriate parameters for this dosage form.
Validations of the analytical methods have been presented. The batch analysis results show that the
finished products meet the specifications proposed. The conditions used in the stability studies are
according to the ICH stability guideline. The control tests and specifications for drug product are
adequately drawn up. The proposed shelf-life of 2 years is acceptable.


NON CLINICAL ASPECTS
The pharmacodynamic, pharmacokinetic and toxicological properties of the drug substances are
well known. As Macrogol 3350, sodium chloride, sodium bicarbonate and potassium chloride are
all well known active substances, no further new non-clinical data are required and the applicant has
provided none. An overview based on the literature is thus appropriate.

The non-clinical overview has been written by a qualified medical doctor with extensive drug safety
and clinical research experience. The overview, dated October 2008, refers to four references from
the published literature dated 1986 to 2007. The toxicological properties of the drug substances are
well known. The nonclinical overview is acceptable.


CLINICAL ASPECTS

Biowaiver
A bioequivalence study has not been performed. The Note for Guidance
CPMP/EWP/QWP/1401/98 states that if the product is an aqueous solution at the time of
administration, and contains an active substance in the same concentration as an oral solution
currently approved, no bioequivalence study is required providing the ingredients contained in it do
not affect gastrointestinal transit, absorption or in-vivo stability of the active.

Laxagol, once reconstituted, contains the same active ingredients in the same concentration as
Movicol, the only difference being flavouring which does not affect transit time, absorption or in-
vivo stability of the active. With regard to solubility, although Laxagol has to be dissolved in water
before administration, the resulting solution has been shown to be completely soluble (the accepted
definition of highly water soluble being when the amount contained in the highest dose strength of
an immediate release product is dissolved in 250ml of each of three buffers in the range 1 – 8 at
37°C). Solubility of Laxagol in 250ml of 0.1M HCl (pH1), pH 4 and pH 6.8 buffers has been tested


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for each of the actives contained in one sachet and each dissolved completely with minimal stirring;
it can therefore be considered highly water soluble.

In addition, a study was undertaken to show that the Laxagol product dissolved at the same speed as
the originator, Movicol. A sample of Movicol was dispensed into 125ml of potable water. This was
mixed for 10 seconds and then left to settle for 10 seconds. A few visible lumps remained after this
time so the solution was mixed for a further 10 seconds and allowed to settle for 10 seconds. After
this time, it was noted that the solution was clear and colourless with no visible lumps remaining. A
similar study was conducted using the developed product. It was found that this product dissolved
in exactly the same way as the brand. It can be confirmed that complete dissolution of both products
occurs in less than 1 minute.

Therefore, the absence of a bio-equivalence study is justified.

Pharmacodynamics
No new data have been submitted and none are required for this generic application.

Clinical efficacy
No new data have been submitted and none are required for this generic application.

Clinical safety
No new data have been submitted and none are required for this generic application.

Pharmacovigilance system
The RMS considers that the pharmacovigilance system as described by the applicant fulfils the
requirements and provides adequate evidence that the applicant has the services of a qualified
person responsible for pharmacovigilance and has the necessary means for the notification of any
adverse reaction suspected of occurring either in the Community or in a third country.

Risk Management Plan
LAXAGOL powder for oral solution is a generic product. As with the reference medicinal product,
no special important risks or potential risks have been identified which require additional risk
minimization activities other than the global pharmacovigilance system.

Product literature
All product literature (SPC, PIL and labelling) is satisfactory. The package leaflet was submitted to
the MHRA along with results of consultations with target patient groups ("user testing"), in
accordance with Article 59 of Council Directive 2001/83/EC. The results indicate that the package
leaflet is well-structured and organised, easy to understand and written in a comprehensive manner.
The test shows that the patients/users are able to act upon the information that it contains.


BENEFIT RISK ASSESSMENT
The application contains an adequate review of published clinical data and, for reasons discussed
above, the demonstration of bioequivalence compared to the originator Movicol is unnecessary.
Approval is recommended.




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