Talk:Cladribine

granulocyte colony-stimulating factor

This article says that “In patients with hairy cell leukemia, there is no benefit to using hormones such as filgrastim or Granulocyte macrophage colony-stimulating factor to raise white blood cell counts prophylactically,” with two citations, but I wonder whether that represents a truly neutral point of view.

The first citation points to an article that says there is no statistically significant difference in the number of patients who experience fevers, the number of days that the fevers last, or the number of patients admitted to the hospital between the filgrastim-treated group and the control group. It is good that a study with non-statistically-significant results is published; however, the article itself points out that “It is possible that the interpretation of results may have been weakened by the lack of a concurrent, randomized control group and by the fact that the number of study subjects and events were insufficient to detect subtle differences. These results could also have been influenced by there being more splenectomized patients among the historic controls and only patients in the filgrastim group had received prior cladribine therapy.” Although the lack of a statistically-significant result may mean that “the routine use of filgrastim as an adjunct to treatment with cladribine cannot be recommended for HCL patients” an alternative interpretation is simply that more study is needed.

The second citation points to an article whose abstract says that “GM-CSF protected from cladribine lymphotoxicity but did not improve neutropenia or febrile episodes,” but the full article requires payment, so I cannot see the extent to the data actually support the proposition that using GM-CSF is unnecessary. If this is another article with a statistically-insignificant result, then it would seem that Wikipedia is assuming that a statistically insignificant result is equivalent to no benefit, or is taking the position that no evidence of benefit is equivalent to evidence of no benefit. I do not think that it is the role of Wikipedia to take such positions. (But even if the article actually provides evidence that there is no benefit, we should also be mindful that verifiability and neutrality are two different policies, and an article can be fully verifiable with reliable sources and still be non-neutral.) Bwrs (talk) 00:44, 20 April 2013 (UTC)

This is what the sources say. Per WP:MEDRS, editors are not permitted to perform their own peer review to decide whether, in their personal opinion, the sources are justified in saying this. Per WP:DUE, if all the independent sources say this, then we should, too. (I'm sure that the manufacturer of this pricey drug would be happy to sell this drug to this tiny population anyway, but my PubMed search turns up nothing at all that supports prophylactic use, not even from the manufacturer.) WhatamIdoing (talk) 15:17, 20 April 2013 (UTC)

Factual Corrections

My name is Florian Schaub at Merck KGaA. My aim is to make some changes in this article, because we have identified some misleading information. I have provided clearly arranged suggestions that you can see below on the talk page. They all follow the same pattern:

• Current Version
  
• Suggested Revision (Suggested changes are bold)
  
• Reason
  
• Suggested Reference (if needed)
  

Please let me know if anyone has concerns.

_Current Text:
Routes of administration: Intravenous, subcutaneous, oral
Suggested Revision:
Routes of administration: Intravenous, subcutaneous (liquid), oral (tablets)
Reason:
Cladribine tablets (oral formulation) not currently available.

_Current Text:
Legal status:

• AU: S4 (Prescription only)
  
• CA: Rx-only
  
• UK: POM (Prescription only)
  
• US: Rx-only)
  

Suggested Revision:
Legal status (Leustatin):

• AU: S4 (Prescription only)
  
• CA: Rx-only
  
• UK: POM (Prescription only)
  
• US: Rx-only)
  

Reason:
Marketing of Leustatin has been discontinued in the US.
Suggested Additional Reference:
Drugs@FDA. Leustatin – Drug details. https://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails [Accessed 24 Jun 2016].

_Current Text:
Metabolism: Mostly via intracellular kinases; 15–18% if excreted unchanged
Suggested Revision:
Metabolism: Mostly via intracellular kinases; 15–18% is excreted unchanged
Reason:
Correction of typographical error; the reference reads “…is excreted unchanged”.
Suggested Additional Reference:
Litak Australian PI.

_Current Text:
Biological half-life: 5.4 hours (range 3–22 hours)
Suggested Revision:
Terminal elimination half-lifeBiological half-life: Approximately 10 hours after both intravenous infusion and subcutaneous bolus injection
Reason:
Changes suggested to match the Litak Australian PI.
Suggested Additional Reference:
Litak Australian PI.

_Current Text:
Formula: C₁₀H₁₂C1N₅O₃
Suggested Revision:
Formula: C₁₀H₁₂ClN₅O₃
Reason:
‘1’ corrected to ‘I’ [Cl for chlorine (lower case ‘L’)].
Suggested Additional Reference:
ChEMBL. Compound report card. https://www.ebi.ac.uk/chembldb/index.php/compound/inspect/CHEMBL1619 [Accessed 03 Jun 2016].

_Current Text:
Cladribine is a medication used to treat hairy cell leukemia (HCL, leukemic reticuloendotherliosis) and multiple sclerosis.
Suggested Revision:
Cladribine is a medication used to treat hairy cell leukemia (HCL; leukemic reticuloendotheliosis) and B-cell chronic lymphocytic leukemia. and multiple sclerosis.
Reason:
Correction of the spelling of ‘reticuloendotheliosis’.
Cladribine is not currently licensed for the treatment of multiple sclerosis, and is licensed for the treatment of B-cell chronic lymphocytic leukemia in the UK.
Suggested Additional Reference:
Litak EU SPC.
Leustat UK SPC.

_Current Text:
Its chemical name is 2-chlorodeoxyadenosine (2CDA).
Suggested Revision:
Its chemical name is 2-chloro-2’-deoxyadenosine (2CdA).

_Current Text:
As a purine analog, it is a synthetic anti-cancer agent that also suppresses the immune system. Chemically, it mimics the nucleoside adenosine and thus inhibits the enzyme adenosine deaminase, which interferes with the cell's ability to process DNA. It is easily destroyed by normal cells except for blood cells, with the result that it produces relatively few side effects and results in very little non-target cell loss.
Suggested Revision:
As a purine analog, it is a synthetic anti-cancerchemotherapy agent that targets lymphocytes. also and selectively suppresses the immune system. Chemically, it mimics the nucleoside adenosine and thus inhibits the enzyme adenosine deaminase, which interferes with the cell's ability to process DNA. It is easily destroyed by normal cells except for blood cells Cladribine is activated only by lymphocytes, and non-activated cladribine is removed quickly from all other cells. This means that there is, with the result that it produces relatively few side effects and results in very little non-target cell loss.
Reason:
Scientific clarification.
Clarification regarding the mechanism leading to little non-target cell loss.
Suggested Additional Reference:
Litak EU SPC. Leist TP, Weissert R. Clin Neuropharmacol 2011;34:28–35.

_Current Text:
Many people have mild rashes and many have nausea; the nausea generally does not lead to vomiting.
Suggested Revision:
At the dosage used to treat HCL in two clinical trials, 16% of people had rashes and 22% had nausea; the nausea generally did not lead to vomiting.
Reason:
Specific information on the actual percentage of patients affected by rashes and nausea is available in the Leustatin FDA PI. We have suggested giving specific values for the percentages of patients experiencing mild rashes and nausea. Please note that Leustatin marketing has now discontinued in the US.
Suggested Additional Reference:
Leustatin FDA PI for cladribine

_Current Text:
In 2010, a by mouth form of cladribine was studied for the treatment of multiple sclerosis. Russia was the first country to approve it for treatment multiple sclerosis on July 12, 2010. Other applications, including in Europe and North America, were initially rejected by drug regulatory agencies due to weak evidence of safety and efficacy. In June 2011, Merck withdrew all marketing application for cladribine tablets, and to stop selling it in Russia and Australia, where it had been approved.
Suggested Revision:
In 2010, a by mouth form of cladribine was studied for the treatment of multiple sclerosis. Russia was the first country to approve it for treatment of multiple sclerosis on July 12, 2010. It was also approved for the treatment of multiple sclerosis in Australia in September 2010. Other applications, including in Europe and North America, were initially rejected by drug regulatory agencies due to weak evidence of safety and efficacy. In June 2011, Merck withdrew all marketing applications for cladribine tablets, and to stop selling it cladribine tablets from the Russian and Australian markets, where it was approved. In addition, marketing authorization was withdrawn in Russia, but is still valid in Australia. Several clinical studies of the cladribine tablets formulation were allowed to complete and additional safety information was also collected in a long-term registry. In September 2015, Merck announced that it intends to submit cladribine tablets for the treatment of relapsing-remitting multiple sclerosis (RRMS) for registration in Europe.
Reason:
Correction of typographical error (missing word ‘of’ inserted). Corrective information to clarify the history of cladribine tablets.
Suggested Additional Reference:
Therapeutic Goods Administration. Movectro withdrawn. https://www.tga.gov.au/alert/movectro-withdrawn [Accessed 08 Jul 2016]. Merck. Merck intends to submit cladribine tablets to treat multiple sclerosis for registration in Europe. http://www.merckgroup.com/en/media/extNewsDetail.html?newsId=1C517A71C016A43BC1257EBC006B50C3&newsType=1 [Accessed 24 Jun 2016].

_Current Text:
Histiocytosis Association (http://www.histio.org)
Suggested Revision:
Histiocytosis Association. Erdheim-Chester disease. http://www.histio.org/page.aspx?pid=405#.V1BDvuTaHqk [Accessed 03 Jun 2016].
Reason:
Suggest revision to the specific source of information rather than the association’s home page.
Suggested Additional Reference:
Histiocytosis Association. Erdheim-Chester disease. http://www.histio.org/page.aspx?pid=405#.V1BDvuTaHqk [Accessed 03 Jun 2016].

--Florian Schaub at Merck KGaA (talk) 10:30, 19 July 2016 (UTC)

Start editing

I will start editing the article now. Before starting I want to withdraw the intended edit from 19th July 2016.

Suggested Revision:
In 2010, a by mouth form of cladribine was studied for the treatment of multiple sclerosis. Russia was the first country to approve it for treatment of multiple sclerosis on July 12, 2010. It was also approved for the treatment of multiple sclerosis in Australia in September 2010. Other applications, including in Europe and North America, were initially rejected by drug regulatory agencies due to weak evidence of safety and efficacy. In June 2011, Merck withdrew all marketing applications for cladribine tablets, and to stop selling it cladribine tablets from the Russian and Australian markets, where it was approved. In addition, marketing authorization was withdrawn in Russia, but is still valid in Australia. Several clinical studies of the cladribine tablets formulation were allowed to complete and additional safety information was also collected in a long-term registry. In September 2015, Merck announced that it intends to submit cladribine tablets for the treatment of relapsing-remitting multiple sclerosis (RRMS) for registration in Europe.
Reason:

--Florian Schaub at Merck KGaA (talk) 19:25, 19 August 2016 (UTC)

I rewrote most of this with better sources. Not sure what happened to the mechanism of action and chemistry sections; I'll see about restoring that. Wierd. Jytdog (talk) 04:49, 24 August 2016 (UTC)

More Factual Corrections

We have identified more misleading information that we announce below before editing them. We have provided them in the same way and same structure.

• Current Text
  
• Suggested Revision (Suggested changes are bold)
  
• Reason
  
• Suggested Reference (if needed)
  

Please let me know if anyone has concerns. Otherwise I will do the edits in two weeks.

1) Current Text:
The failure was a blow to Merck KGgA, leading to a reorganization, layoffs, and closing the Swiss facility where Serono had arisen.
Suggested Revision:
The failure was a blow to Merck KGaA, contributing leading to a reorganization, layoffs, and closing the Swiss facility where Serono had arisen.
Reason:
Other sources suggested that there were additional factors that may have contributed to the reorganization e.g. the European regulatory rejection of Erbitux and increased competition associated with Rebif in the MS market.
Suggested Additional Reference:
Firstword Pharma. Merck KGaA announces cost-cutting initiative, potential job cuts. http://www.firstwordpharma.com/node/954881?tsid=17#axzz4IAIZS6Ad [Accessed 23 Aug 2016].
Bloomberg. Merck KGaA to Close Merck Serono Site in Geneva, Cut Jobs. http://www.bloomberg.com/news/articles/2012-04-24/merck-kgaa-to-close-merck-serono-site-in-geneva-cut-jobs [Accessed 23 Aug 2016].

2) Current Text:
The concerns were that several cases of cancer had arisen, and the ratio of benefit to harm was not clear to regulators.
Suggested Revision:
The concerns were that several cases of cancer had arisen, and the ratio of benefit to harm was not clear to regulators. Subsequent to this, a meta-analysis of Phase III trials reported that there was no evidence for increased cancer risk in patients with multiple sclerosis taking cladribine tablets.
Reason:
Clarification that meta-analyses of Phase III trials have reported no increase in cancer incidence associated with cladribine tablets.
Suggested Additional Reference:
Multiple Sclerosis News Today. Potential MS drug cladribine reported to have no impact on cancer incidence. https://multiplesclerosisnewstoday.com/2015/10/09/potential-ms-drug-cladribine-reported-to-have-no-impact-on-cancer-incidence/ [Accessed 25 Aug 2016].
Pakpoor J et al. Neurology 2015; October 1 [Epub ahead of print]. doi: 10.1212/NXI.0000000000000158.

3) Current Text:
Cladribine is used for as a first and second-line treatment for symptomatic hairy cell leukemia and for B-cell chronic lymphocytic leukemia and is administered by intravenous infusion or by subcutaneous injection, depending on the formulation.
Suggested Revision:
No revision – additional reference suggested at the end of this sentence. Cladribine is used as a first and second-line treatment.
Reason:
The suggested additional reference is the Summary of Product Characteristics for Litak 2 mg/ml solution for injection, for which the recommended posology for hairy cell leukemia is subcutaneous bolus injection.
Out of the three currently referenced sources, one (reference 7) does not mention subcutaneous administration and another (reference 4) mentions that subcutaneous administration is not recommended but that there is data for its use in MS (unlicensed). Reference 6 is not open access.
Suggested Additional Reference:
[LITAK 2 mg/ml solution for injection] [EU] [Summary of Product Characteristics], June 2010. http://www.medicines.org.uk/emc/medicine/20597 [Accessed 23 Aug 2016].

Current Text:
In February 1991 Scripps began a collaboration with Johnson & Johnson to bring intravenous cladribine to market and by December of that year J&J had filed an NDA; cladrabine was approved by the FDA in 1993 for HCL as an orphan drug.
Suggested Revision:
In February 1991 Scripps began a collaboration with Johnson & Johnson to bring intravenous cladribine to market and by December of that year J&J had filed an NDA; cladribine cladrabine was approved by the FDA in 1993 for HCL as an orphan drug.
Reason:
Misspelling of cladribine and an additional reference to support cladribine’s orphan drug status.
Suggested Additional Reference:
U.S. Food and Drug Administration. List of orphan products designations and approvals. http://www.fda.gov/ohrms/dockets/dailys/00/mar00/030100/lst0094.pdf [Accessed 23 Aug 2016].

4) Current Text:
It used, often in combination with other cytotoxic agents, to treat various histiocytoses, including Erdheim–Chester disease and Langerhans cell histiocytosis
Suggested Revision:
…to treat various classes of histiocytosis histiocytoses…
Reason:
Histiocytosis is an umbrella term so does not need to be pluralized.

5) Current Text:
It used, often in combination with other cytotoxic agents, to treat various histiocytoses, including Erdheim–Chester disease and Langerhans cell histiocytosis
Suggested Revision:
Additional reference suggested for use of cladribine in Langerhans cell histiocytosis
Reason:
An additional reference is suggested as the current reference is not open access.
Suggested Additional Reference:
Histiocytosis Association. LCH in Adults. http://www.histio.org/page.aspx?pid=383 [Accessed 23 Aug 2016].

6) Current Text:
In 2015 Merck KGgA announced it would again seek regulatory approval with data from the completed clinical trials in hand
Suggested Revision:
No revision – additional reference suggested
Reason:
The suggested additional reference is the original Merck press release.
Suggested Additional Reference:
Merck Group. Merck Intends to Submit Cladribine Tablets to Treat Multiple Sclerosis for Registration in Europe. http://www.merckgroup.com/en/media/extNewsDetail.html?newsId=1C517A71C016A43BC1257EBC006B50C3&newsType=1 [Accessed 24 Aug 2016].

7) Current Text:
In 2015 Merck KGgA announced it would again seek regulatory approval with data from the completed clinical trials in hand, and in 2016 the EMA accepted its application for review.
Suggested Revision:
In 2015 Merck KGgA announced it would again seek regulatory approval with data from the completed clinical trials in hand. and in 2016 the EMA accepted its application for review. In July 2016, Merck announced that the European Medicines Agency (EMA) had accepted for review the Marketing Authorisation Application (MAA) of cladribine tablets for the treatment of relapsing-remitting multiple sclerosis (RRMS).
Reason:
Correction to specify that cladribine tablets are under review for the treatment of RRMS.
Suggested Additional Reference:
Merck. Merck receives European Medicines Agency acceptance for review of Marketing Authorization Application for cladribine tablets. http://www.merckgroup.com/en/media/extNewsDetail.html?newsId=57F6B32E5CD8E3AAC1257FF100307005&newsType=1 [Accessed 4 Aug 2016].

--Florian Schaub at Merck KGaA (talk) 13:05, 29 September 2016 (UTC)

Thanks for your note. Will take some time to evaluate all this. In the future please consider bringing stronger sources, and independent ones; press releases are not optimal. Jytdog (talk) 15:37, 29 September 2016 (UTC)

I numbered the items above.... when you provide references to journal articles, would you please provide the pubmed ID (PMID). For example the reference in Item 2 is PMID 26468472 and as you can see the WP software automatically converts that to a link to pubmed. much easier to deal with.

1)  Done

2)  Done

3)  Done Thanks for pointing out the error; I removed the subQ. a reference not being open access, is irrelevant. I removed PMID 19344416 as a ref, as it is a primary source that fails MEDRS.

4)  Done

5) that is not a MEDRS source. not done. per WP:MEDRS we need a literature review published in good quality journal or a statement by a major medical/scientific body.

6) not interested in using a press release; independent sources are highly preferred in WP

7) WP:NOTNEWS. We can add something when there is a decision

-- Jytdog (talk) 03:48, 30 September 2016 (UTC)

Announcement of Changes

My name is Florian Schaub from Merck KGaA. My aim is to make some changes in this article because we have found some misleading information. I've compiled the suggested changes which you can find herinafter. They all follow one pattern:

• Current text

• Suggested revision

• Reason

• Suggested reference

If someone has objections please let me know.

_Current text

Legal status:

AU: S4 (Prescription only) CA: Rx-only UK: POM (Prescription only)

_Suggested revision

Legal status (cladribine injection for intravenous infusion)1,2: prescription only

_Reason

Legal status referring to cladribine iv infusion specifically.

_Suggested reference

1. Leustat injection SmPC. https://www.medicines.org.uk/emc/medicine/6737. Accessed 16 October 2017.

2. Leustatin injection. http://www.janssen.com/australia/sites/www_janssen_com_australia/files/prod_files/live/leustatin_pi.pdf. Accessed 16 October 2017

_Current text

Chemically, it mimics the nucleoside adenosine and thus inhibits the enzyme adenosine deaminase, which interferes with the cell's ability to process DNA.

_Suggested revision

Cladribine is a nucleoside analogue of deoxyadenosine. A chlorine substitution in the purine ring protects cladribine from degradation by the enzyme adenosine deaminase. Subsequent phosphorylation of cladribine to its active triphosphate form, 2 chlorodeoxyadenosine triphosphate (CdATP), is particularly efficiently achieved in lymphocytes. CdATP leads to lymphocyte reduction by inducing cellular apoptosis and interfering with the cell's ability to process DNA.

_Reason

Correction to clarify the mode of action of cladribine

_Suggested reference

Sigal DS et al. Beyond hairy cell: the activity of cladribine in other hematologic malignancies. Blood 2010;116:2884–96.

_Current text

Cladribine is used for as a first and second-line treatment for symptomatic hairy cell leukemia and for B-cell chronic lymphocytic leukemia and is administered by intravenous infusion.[4][6]

_Suggested revision

Cladribine is used as first- and second-line treatment for symptomatic hairy cell leukemia and for B-cell chronic lymphocytic leukemia and is administered by subcutaneous injection or intravenous infusion.[4][6]

_Reason

Correction of grammar.

Can be given subcutaneously or by infusion.

_Suggested reference

Leustat injection [EU] [Summary of Product Characteristics], July 2014. https://www.medicines.org.uk/emc/medicine/6737 [Accessed 24/7/17]

_Current text

It used, often in combination with other cytotoxic agents, to treat various histiocytoses, including Erdheim–Chester disease[7] and Langerhans cell histiocytosis,[9]

_Suggested revision

It is used, often in combination with other cytotoxic agents, to treat various histiocytoses, including Erdheim–Chester disease[8] and Langerhans cell histiocytosis.[9]

_Reason

Correction of grammar.

An additional reference is suggested as the current reference is not open access.

_Suggested reference

Histiocytosis Association. LCH in Adults. http://www.histio.org/page.aspx?pid=383 [Accessed 27 July 2017].

_Current text

In February 1991 Scripps began a collaboration with Johnson & Johnson to bring intravenous cladribine to market and by December of that year J&J had filed an NDA; cladrabine was approved by the FDA in 1993 for HCL as an orphan drug,[10] and was approved in Europe later that year.[11]:2

_Suggested revision

In February 1991 Scripps began a collaboration with Johnson & Johnson to bring intravenous cladribine to market and by December of that year J&J had filed an NDA; cladribine was approved by the FDA in 1993 for HCL as an orphan drug,[10] and was approved in Europe later that year.[11,NEW]

_Reason

Misspelling of cladribine.

Additional reference to support cladribine’s orphan drug status.

_Suggested reference

U.S. Food and Drug Administration. List of orphan products designations and approvals. http://www.fda.gov/ohrms/dockets/dailys/00/mar00/030100/lst0094.pdf [Accessed 24 July 2017].

_Current text

A meta-analysis of data from clinical trials showed that cladiribine did not increase the risk of cancer at the doses used in the clinical trials.

_Suggested revision

A meta-analysis of data from Phase III clinical trials showed that oral cladribine tablets did not increase the risk of cancer in patients with MS.

_Reason

Misspelling of cladribine.

Clarification type of trials included in meta-analysis

_Suggested reference

Multiple Sclerosis News Today. Potential MS drug cladribine reported to have no impact on cancer incidence. https://multiplesclerosisnewstoday.com/2015/10/09/potential-ms-drug-cladribine-reported-to-have-no-impact-on-cancer-incidence/ [Accessed 25 July 2017].

_Current text

In 2015 Merck KGgA announced it would again seek regulatory approval with data from the completed clinical trials in hand,[23]

_Suggested revision

In 2015 Merck KGaA announced it would again seek regulatory approval with data from the completed clinical trials in hand,[23]

_Reason

Misspelling of KGaA

Additional suggested reference to be added; the suggested additional reference is the original Merck press release.

_Suggested reference

Merck Group. Merck Intends to Submit Cladribine Tablets to Treat Multiple Sclerosis for Registration in Europe. http://news.merck.de/EMD/CC/NewsRelease.nsf/0/1C517A71C016A43BC1257EBC006B50C3/$FILE/CladribineEng.pdf [Accessed 24 July 2017]

_Current text

, and in 2016 the EMA accepted its application for review.[25]

_Suggested revision

In July 2016, Merck Serono Europe announced that the European Medicines Agency (EMA) had accepted for review the Marketing Authorisation Application (MAA) of cladribine tablets for the treatment of relapsing-remitting multiple sclerosis (RRMS) [1]. On 23 June 2017, Merck Serono Europe announced that the Committee for Medicinal Products for Human Use (CHMP) of the EMA had issued a positive opinion for approval of Cladribine Tablets for the treatment of relapsing forms of MS (RMS) in patients with high disease activity [2]. On 25th August 2017, Merck Serono Europe announced that the European Commission (EC) granted marketing authorization for MAVENCLAD® 10 mg (Cladribine Tablets) for the treatment of highly active RMS in the 28 countries of the European Union (EU) in addition to Norway, Liechtenstein and Iceland [3].

_Reason

Correction to specify that cladribine tablets has received a positive CHMP opinion

_Suggested reference

1. Merck Group. Merck receives European Medicines Agency acceptance for review of Marketing Authorization Application for cladribine tablets. https://www.merckgroup.com/content/corporate/communications/mkgaa-global/en/news/marketing-authorization-application-for-cladribine-18-07-2016.html [Accessed 25 July 2017].

2. EMA Committee for Medicinal Products for Human Use (CHMP) Summary of opinion. http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/004230/WC500229786.pdf [Accessed 25 July 2017]

3. European Commission Grants Approval for Mavenclad (Cladribine Tablets) hhttp://ec.europa.eu/health/documents/community-register/2017/20170822138481/dec_138481_en.pdf [Accessed 01 September 2017]

--Florian Schaub at Merck KGaA (talk) 14:06, 18 October 2017 (UTC)

Start to edit the article

As nobody had any objections to my announcement of changes from the 18th October I will now start editing the article. --Florian Schaub at Merck KGaA (talk) 08:40, 7 November 2017 (UTC)

2021 Page factual update

My name is Samer Fahmy, I am reaching out on behalf of the Merck KGaA Neurology and Immunology Global Business Franchise Team, handling Cladribine tablets. Following my colleague Florian Schaub’s updates, we would like to add further detail to the current page, and are proposing some edits and restructuring.

Through these updates we aim to:

• Revise the text to fully align with the MAVENCLAD Summary of Product Characteristics
• Update with more recent information and clinical trial data
• Distinguish between outcomes for multiple sclerosis and hairy cell leukemia in terms of adverse effects, safety and efficacy
• Update and correctly reference the mechanism of action of cladribine, including an additional phosphorylation step
• Reposition the ‘Mechanism of action’ before ‘Adverse effects’, allowing readers to understand the mechanism of action and how this can cause certain side effects
• Provide additional information on medical uses for multiple forms of multiple sclerosis
• Separate the ‘History’ section to provide clearer flow and context to the two indications
• Reposition ‘Use in clinical practice’ above ‘Efficacy and safety’ to provide further context to clinical use

Please see below a list of the proposed revisions and associated rationale. Please let me know if anyone has any concerns.

Caption text

Section	Existing Text	Suggested revision	Justification	References
Introductory text	Cladribine, sold under the brand name Leustatin among others, is a medication used to treat hairy cell leukemia (HCL, leukemic reticuloendotheliosis), B-cell chronic lymphocytic leukemia and Relapsing-remitting Multiple Sclerosis (RRMS).[4][5] Its chemical name is 2-chloro-2'-deoxyadenosine (2CdA).	Cladribine, sold under the brand name Leustatin among others, is a medication used to treat hairy cell leukemia (HCL, leukemic reticuloendotheliosis) and B-cell chronic lymphocytic leukemia. Oral cladribine (Cladribine tablets), sold under the brand name MAVENCLAD, is indicated for the treatment of adult patients with highly active forms of relapsing-remitting multiple sclerosis (RRMS).	Updated to include the MAVENCLAD brand name and indication as per the MAVENCLAD Summary of Product Characteristics. A language to reflect the two different indications of two different products without overlap, since this is how the two products are approved. We suggest moving the chemical name to the paragraph below, outlining the mechanism of action.	European Medicines Agency - - Litak www.ema.europa.eu Leustat Injection. - Summary of Product Characteristics (SPC) - (eMC). www.medicines.org.uk MAVENCLAD® EU SmPC, February 2021
Introductory text	As a purine analog, it is a synthetic chemotherapy agent that targets lymphocytes and selectively suppresses the immune system. Chemically, it mimics the nucleoside adenosine. However, unlike adenosine it is relatively resistant to breakdown by the enzyme adenosine deaminase, which causes it to accumulate in cells and interfere with the cell's ability to process DNA. Cladribine is taken up by cells via a transporter. Once inside a cell cladribine is activated mostly in lymphocytes, when it is triphosphorylated by the enzyme deoxyadenosine kinase (dCK). Various phosphatases dephosphorylate cladribine. Activated, triphosphorylated, cladribine is incorporated into mitochondrial and nuclear DNA, which triggers apoptosis. Non-activated cladribine is removed quickly from all other cells. This means that there is very little non-target cell loss.	Cladribine (2-chloro-2'-deoxyadenosine [2-CdA]) is a purine analogue that selectively targets and suppresses lymphocytes implicated in the underlying pathogenesis of multiple sclerosis (MS) and B-cell leukaemia. Chemically, it mimics nucleoside adenosine. However, unlike adenosine it is relatively resistant to breakdown by the enzyme adenosine deaminase (ADA), which causes it to accumulate in targeted cells and interfere with the cell's ability to process DNA. Cladribine is taken up by cells via transporter proteins. Once inside a cell, cladribine undergoes phosphorylation by the enzyme deoxycytidine kinase (DCK) to produce mononucleotide 2-chlorodeoxyadenosine 5’monophosphate (2-CdAMP), which is subsequently phosphorylated to the tri-phosphorylated active compound 2-chlorodeoxyadenosine 5’triphosphate (2-CdATP). Activated cladribine is incorporated into cellular DNA, which triggers apoptosis. Accumulation of cladribine into cells is dependent on the ratio of 2-CdATP and 5'nucleotidase (5'-NT), which breaks down and inactivates the compound. This ratio differs between cell types, with high levels in T and B lymphocytes, resulting in selective targeting of these cells. In contrast, CdATP:5'NT is relatively low in other cell types, thus sparing numerous non-hematologic cells.	Text revised to reflect the changes made to the mechanism of action section and to include the additional phosphorylation step, providing further context and a clearer flow.	Leist, TP and Weissert, R. 2011;34(1): 28–35 Giovannoni G. Neurotherapeutics 2017;14:874–87
Medical uses	Cladribine is used for as a first and second-line treatment for symptomatic hairy cell leukemia and for B-cell chronic lymphocytic leukemia and is administered by intravenous or subcutaneous infusion.[5][7] Since 2017, cladribine is approved as an oral formulation (10 mg tablet) for the treatment of RRMS in Europe, UAE, Argentina, Chile, Canada and Australia. Marketing authorization for RRMS and SPMS in the US was obtained in March 2019.[8][9] Some investigators have used the parenteral formulation orally to treat patients with HCL. It is important to note that approximately 40% of oral cladribine is bioavailable orally. It used, often in combination with other cytotoxic agents, to treat various kinds of histiocytosis, including Erdheim–Chester disease[10] and Langerhans cell histiocytosis,[11] Cladribine may cause fetal harm when administered to a pregnant woman and is listed by the FDA as Pregnancy Category D; safety and efficacy in children has not been established.	Cladribine is used as a first and second-line treatment for symptomatic hairy cell leukemia and for B-cell chronic lymphocytic leukemia and is administered by intravenous or subcutaneous infusion. Some investigators have used the parenteral formulation orally to treat patients with HCL. It is important to note that approximately 40% of oral cladribine is bioavailable orally. It is used, often in combination with other cytotoxic agents, to treat various kinds of histiocytosis, including Erdheim–Chester disease and Langerhans cell histiocytosis. Following EMA approval of Cladribine tablets for the treatment of adult patients with highly active relapsing-remitting MS in 2017, it has since been approved in over 80 countries. In 2019, Cladribine tablets were approved by the FDA for the treatment of relapsing forms of multiple sclerosis, to include relapsing-remitting disease and active secondary progressive (SPMS) disease, in adult patients who have had an inadequate response to, or are unable to tolerate, an alternate drug indicated for the treatment of MS. Cladribine may cause fetal harm when administered to a pregnant woman and is listed by the FDA as Pregnancy Category D; safety and efficacy in children has not been established.	Provided additional and updated information (bold). Reordered text to improve flow and readability and detail both indications for the two different products without any perceivable overlap. Product labels in MS are well separated	Leustat Injection. - Summary of Product Characteristics (SPC) - (eMC). www.medicines.org.uk Drugs.com. Cladribine Pregnancy and Breastfeeding Warnings. https://www.drugs.com/pregnancy/cladribine.html Histiocytosis Association Erdheim-Chester Disease Archived 2019-06-06 at the Wayback Machine Page accessed Aug 20, 2016 Aricò M et al. Br J Haematol 2016;173(5):663–70 European Medicines Agency. MAVENCLAD. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/mavenclad U.S. Food and Drug Administration (FDA). FDA approves new oral treatment for multiple sclerosis. Available at: https://www.fda.gov/news-events/press-announcements/fda-approves-new-oral-treatment-multiple-sclerosis Merck group. Press release. Available at: https://www.merckgroup.com/en/news/actrims-2021-mavenclad-25-02-2021.html
Mechanism of action	As a purine analogue, it is taken up into rapidly proliferating cells like lymphocytes to be incorporated into DNA synthesis. Unlike adenosine, cladribine has a chlorine molecule at position 2, which renders it partially resistant to breakdown by adenosine deaminase (ADA). In cells it is phosphorylated into its toxic form, deoxyadenosine triphosphate, by the enzyme deoxycytidine kinase (DCK). This molecule is then incorporated into the DNA synthesis pathway, where it causes strand breakage. This is followed by the activation of transcription factor p53, the release of cytochrome c from mitochondria and eventual programmed cell death (apoptosis).[13] This process occurs over approximately 2 months, with a peak level of cell depletion 4–8 weeks after treatment[14] Within the lymphocyte pool, cladribine targets B cells more than T cells. Both HCL and B-cell chronic lymphocytic leukaemia are types of B cell blood cancers. In MS, its effectiveness may be due to its ability to effectively deplete B cells, in particular memory B cells[15] In the pivotal phase 3 clinical trial of oral cladribine in MS, CLARITY, cladribine selectively depleted 80% of peripheral B cells, compared to only 40-50% of total T cells.[16] More recently, cladribine has been shown to induce long term, selective suppression of certain subtypes of B cells, especially memory B cells.[17] Another family of enzymes, the 5´nucleotidase (5NCT) family, is also capable of dephosphorylating cladribine, making it inactive. The most important subtype of this group appears to be 5NCT1A, which is cytosolically active and specific for purine analogues. When DCK gene expression is expressed as a ratio with 5NCT1A, the cells with the highest ratios are B cells, especially germinal centre and naive B cells.[17] This again helps to explain which B cells are more vulnerable to cladribine-mediated apoptosis. Although cladribine is selective for B cells, the long term suppression of memory B cells, which may contribute to its effect in MS, is not explained by gene or protein expression. Instead, cladribine appears to deplete the entire B cell department. However, while naive B cells rapidly move from lymphoid organs, the memory B cell pool repopulates very slowly from the bone marrow.	As a purine analogue, cladribine (2-chloro-2'-deoxyadenosine [2-CdA]) is taken up into rapidly proliferating cells, including B and T lymphocytes, to be incorporated into DNA synthesis. Chemically, it mimics nucleoside adenosine. However, unlike adenosine, cladribine has a chlorine molecule at position 2, which renders it partially resistant to breakdown by ADA. This causes it to accumulate in cells and interfere with the targeted cell's ability to process DNA. Cladribine is taken up via specific nucleoside transporter proteins. Once inside a cell, cladribine undergoes phosphorylation by the enzyme deoxycytidine kinase (DCK) to produce mononucleotide 2-chlorodeoxyadenosine 5’monophosphate (2-CdAMP), which is subsequently phosphorylated to the tri-phosphorylated active compound, 2-chlorodeoxyadenosine 5’triphosphate (2-CdATP). Activated cladribine is incorporated into the DNA synthesis pathway, where it disrupts DNA repair and synthesis, resulting in an accumulation of DNA strand breaks. This is followed by the activation of transcription factor p53, the release of cytochrome c from mitochondria and eventual programmed cell death (apoptosis). This process occurs over approximately 2 months, with a peak level of cell depletion 4–8 weeks after treatment. Another family of enzymes, the 5´nucleotidase (5’-NT) family, is also capable of dephosphorylating cladribine, making it inactive. The most important subtypes of this group appear to be cytosolic 5’NT, c-5NCT1A and c-NT1B, which are cytosolically active and specific for purine analogues. Accumulation of cladribine into cells is dependent on the ratio of 2-CdATP and 5'-NT. This ratio differs between cell types, with high levels in T and B lymphocytes, making them particularly susceptible to cell death. The cells with the highest ratios are B cells, especially germinal centre and naive B cells. This helps to explain which B cells are more vulnerable to cladribine-mediated apoptosis. DCK is the rate limiting enzyme for conversion of the cladribine prodrug into its active triphosphate form, leading to the selective depletion of dividing and non-dividing T and B lymphocytes. In contrast, the CdATP:5'NT ratio is relatively low in other cell types, thus sparing numerous non-hematologic cells. In MS, cladribine’s effectiveness may be due to its ability to effectively deplete B cells, in particular memory B cells. In the pivotal phase 3 clinical trial of oral cladribine in MS, CLARITY, cladribine selectively depleted 80% of peripheral B cells, compared to only 40-45% of CD4+ T cells and 15-30% CD8+ T cells. More recently, cladribine has been shown to induce long term, selective suppression of certain subtypes of B cells, especially memory B cells. Although cladribine is selective for B cells, the long-term suppression of memory B cells, which may contribute to its effect in MS, is not explained by gene or protein expression. Instead, cladribine appears to deplete the entire B cell department. However, while naive B cells rapidly move from lymphoid organs, the memory B cell pool repopulates slowly from the bone marrow. Both HCL and B-cell chronic lymphocytic leukaemia are types of B cell blood cancers.	Text revised to provide further context to the mechanism of action of cladribine, include the additional phosphorylation step and provide a clearer flow. We suggest moving the mechanism of action section above ‘Adverse effects’, as it is important to understand the mechanism of action first, as this directly affects the side effects profile seen, for example lymphopenia	Leist, TP and Weissert, R. 2011;34(1):28–35 Giovannoni G. Neurotherapeutics 2017;14:874–87 Johnston, JB. Leukemia & Lymphoma 2011;52 Suppl 2:43–5 Beutler, E, et al. Leukemia & Lymphoma 1991;5(1):1–8 Ceronie, B J Neurol. 2018; 265(5): 1199–1209. Baker, D, et al. EBioMedicine 2017 16: 41–50 Baker D et al. Neurology: Neuroimmunology & Neuroinflammation 2017;4(4): e360
History	History	History in HCL	Suggest separating section into indications to provide clearer flow and context: ‘History in MS’ and ‘History in HCL’ History is currently also included in the 'Multiple sclerosis' section; however, it is more appropriate to include in a separate history section, as per HCL indication No other changes have been made to the current ‘History’ section	References remain unchanged
Adverse events	[Section title] Adverse events Injectable cladribine suppresses the body's ability to make new lymphocytes, natural killer cells and neutrophils (called myelosuppression); data from HCL studies showed that about 70% of people taking the drug had fewer white blood cells and about 30% developed infections and some of those progressed to septic shock; about 40% of people taking the drug had fewer red blood cells and became severely anemic; and about 10% of people had too few platelets.[7] At the dosage used to treat HCL in two clinical trials, 16% of people had rashes and 22% had nausea, the nausea generally did not lead to vomiting.[7] In comparison, in MS, cladribine is associated with a 6% rate of severe lymphocyte suppression (lymphopenia) (levels lower than 50% of normal). Other common side effects include headache (75%), sore throat (56%), common cold-like illness (42%) and nausea (39%)	[Section title] Safety profile of cladribine in HCL Injectable cladribine suppresses the body's ability to make new lymphocytes, natural killer cells and neutrophils (called myelosuppression); data from HCL studies showed that about 70% of people taking the drug had fewer white blood cells and about 30% developed infections and some of those progressed to septic shock; about 40% of people taking the drug had fewer red blood cells and became severely anemic; and about 10% of people had too few platelets.[7] At the dosage used to treat HCL in two clinical trials, 16% of people had rashes and 22% had nausea, the nausea generally did not lead to vomiting.[7] In comparison, in MS, cladribine is associated with a 6% rate of severe lymphocyte suppression (lymphopenia) (levels lower than 50% of normal). Other common side effects include headache (75%), sore throat (56%), common cold-like illness (42%) and nausea (39%)	As the side effects profile differs between indications, suggest separating into indications to ensure clear distinction between outcomes in MS and HCL: ‘Safety profile of cladribine in HCL’ and ‘Safety profile of Cladribine tablets in MS’. The current safety information provided on the use of cladribine in MS does not fully align with the reference – suggest deleting (indicated by italics). HCL content and associated references remains unchanged.	References remain unchanged
History	[Section title] Multiple sclerosis In the mid-1990s Beutler, in collaboration with Jack Sipe, a neurologist at Scripps, ran several clinical trials exploring the utility of cladribine in multiple sclerosis, based on the drug's immunosuppressive effects. Sipe's insight into MS, and Beutler's interest in MS due to his sister having it, led a very productive collaboration.[18]:17[22] Ortho-Clinical, a subsidiary of J&J, filed an NDA for cladribine for MS in 1997 but withdrew it in the late 1990s after discussion with the FDA proved that more clinical data would be needed.[23][24] Ivax acquired the rights for oral administration of cladribine to treat MS from Scripps in 2000,[25] and partnered with Serono in 2002.[24] Ivax was acquired by Teva in 2006,[26][27] and Merck KGaA acquired control of Serono's drug business in 2006.[28] An oral formulation of the drug with cyclodextrin was developed[29]:16 and Ivax and Serono, and then Merck KGaA conducted several clinical studies. Merck KGaA submitted an application to the European Medicines Agency in 2009, which was rejected in 2010, and an appeal was denied in 2011.[29]:4–5 Likewise Merck KGaA's NDA with the FDA rejected in 2011.[30] The concerns were that several cases of cancer had arisen, and the ratio of benefit to harm was not clear to regulators.[29]:54–55 The failures with the FDA and the EMA were a blow to Merck KGaA and were one of a series of events that led to a reorganization, layoffs, and closing the Swiss facility where Serono had arisen.[31][32] However, several MS clinical trials were still ongoing at the time of the rejections, and Merck KGaA committed to completing them.[30] A meta-analysis of data from clinical trials showed that cladiribine did not increase the risk of cancer at the doses used in the clinical trials.[33] In 2015, Merck KGaA announced it would again seek regulatory approval with data from the completed clinical trials in hand,[31] and in 2016 the EMA accepted its application for review.[34] On June 22, 2017, the EMA's Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorisation for the treatment of relapsing forms of multiple sclerosis.[35] Finally, after all these problems it was approved in Europe, in August 2017, for highly active RRMS.	[Section title] History in MS In the mid-1990s Beutler, in collaboration with Jack Sipe, a neurologist at Scripps Institute, ran several clinical trials exploring the utility of cladribine in multiple sclerosis, based on the drug's immunosuppressive effects. Sipe's insight into MS, and Beutler's interest in MS due to his sister having the disease, initiated a very productive collaboration. Ortho-Clinical, a subsidiary of J&J, filed an NDA for cladribine for MS in 1997 but withdrew it in the late 1990s after discussion with the FDA proved that more clinical data would be needed. Ivax acquired the rights for oral administration of cladribine to treat MS from Scripps in 2000 and partnered with Serono in 2002. Ivax was acquired by Teva in 2006, and Merck KGaA acquired control of Serono's drug business in 2006. An oral formulation of the drug with cyclodextrin was developed by Ivax and Serono, and then Merck KGaA conducted clinical trials. Merck KGaA submitted an application to the European Medicines Agency in 2009, which was rejected in 2010, and an appeal was denied in 2011. Likewise, Merck KGaA's NDA with the FDA rejected in 2011. The ratio of benefit to harm was not clear to regulators and further studies were requested to address concerns related to severe lymphopenia and cancer cases observed during pivotal trials. Phase II and III MS clinical trials were still ongoing at the time of the rejections, and Merck KGaA committed to completing them. A meta-analysis of data from clinical trials comparing the risk of cancer and other disease-modifying therapies showed that Cladribine tablets did not increase the risk of cancer at the doses used in the initial clinical trials. Based on the supporting data from the completed clinical trials that confirmed no increased risk of cancer, Merck announced it would again seek regulatory approval. In 2016, the EMA accepted its application for review. On June 22, 2017, the EMA's Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorisation for the treatment of relapsing forms of multiple sclerosis. Cladribine tablets were later approved in Europe, in August 2017, for highly active RRMS and has since been approved by the FDA for the treatment of relapsing-remitting and secondary progressive MS in the US.	Suggest separating section into indications to provide clearer flow and context: ‘History in MS’ and ‘History in HCL’ History is currently also included in the 'Multiple sclerosis' section; however, it is more appropriate to include in a separate history section, as per HCL. References remained unchanged	References remain unchanged
Use in clinical practice	[Section title] Use in clinical practice	[Section title] Use in MS in clinical practice As per the EU label, Cladribine tablets are indicated for the treatment of adult patients with highly active relapsing MS as defined by clinical or imaging features: (i) patients with 1 relapse in the previous year and at least 1 T1 Gd+ lesion or 9 or more T2 lesions, while on another disease-modifying therapies or (ii) patients with 2 or more relapses in the previous year, whether on disease-modifying treatment or not. There are two main approaches to MS treatment maintenance therapy – immunmodulation and immunsupression and alternatively, immune reconstitution therapy (IRT). Hypothesized to be an IRT, Cladribine tablets are administered intermittently as a short treatment course without continuous immunosuppression. In contrast to maintenance therapies, clinical efficacy extends beyond the dosing period. Cladribine tablets are administered as 2 courses separated by 1 year (a maximum of 20 days of treatment). The recommended cumulative dose is 3.5mg/kg body weight over 2 years, administered as one treatment course of 1.75 mg/kg per year. Each treatment course consists of 2 treatment weeks, one at the beginning of the first month and one at the beginning of the second month of the respective treatment year. Each treatment week consists of 4 or 5 days on which a patient receives 10 mg or 20 mg (1 or 2 tablets) as a single daily dose based on body weight. Before initiating treatment with Cladribine tablets, blood tests, MRI and infection screening must be performed. Due to an increased risk of herpes zoster with Cladribine tablets, it is recommended that patients who are antibody-negative for varicella zoster virus are vaccinated before starting treatment. Treatment should not be initiated within 4 to 6 weeks of receiving a live or attenuated live vaccine because of a risk of active infection. Vaccination with live or attenuated live vaccines should also be avoided during and after treatment but can be considered when lymphocyte counts have recovered to ≥1000 cells/mm3. Following completion of the 2 treatment courses, no further treatment or additional monitoring is required. The use of Cladribine tablets is contraindicated in pregnant women and women of childbearing potential must use effective contraception to prevent pregnancy during treatment and six months after receiving the last dose.	Suggest updating section title, as the current section only includes multiple sclerosis information. Suggest moving this section above efficacy and safety sections to provide further context to clinical use before the efficacy and safety outcomes are mentioned Text has been revised to fully align with the MAVENCLAD Summary of Product Characteristics	MAVENCLAD® EU SmPC, February 2021 Soelberg Sorensen P, Sellebjerg F. Ther Adv Neurol Disord 2019;12:1756286419836913 Giovannoni G. Curr Opin Neurol 2018;31(3):233–43 Baker D et al. Neurol Neuroimmunol Neuroinflamm 2017;4(4):e360
Efficacy	[Section title] Efficacy Cladribine is an effective treatment for relapsing remitting MS, with a reduction in the annual rate of relapses of 54.5%.[12] These effects may be sustained up to 4 years after initial treatment, even if no further doses are given.[37] Thus, cladribine is considered to be a highly effective immune reconstitution therapy in MS. Similar to alemtuzumab, cladribine is given as two courses approximately one year apart. Each course consists of a dose based on body weight, given over five days, in the first month, followed by a second dosing of another 4-5 tablets the following month[38] During this time and after the final dose patients are monitored for adverse effects and signs of relapse.	[Section title] Efficacy of Cladribine tablets in MS Clinical trial results have shown that Cladribine tablets can be an effective treatment for highly active relapsing forms of MS, with significant clinical benefits in relapse rate, disability progression and radiological measures. Compared with placebo, patients who received Cladribine tablets (3.5 mg/kg) in the CLARITY study had a 58% reduction in annualized relapse rate and 47% of patients showed no evidence of disease activity at 2 years. Clinical improvements can be observed at Week 24 of treatment, and benefits may be sustained up to 4 years, beyond the 2-year dosing period and recovery of total lymphocytes. Post-hoc analyses of clinical trial data showed that 89% of patients remained free from disability progression two years after treatment. Further analyses of a subgroup of patients in the CLARITY study who had very active MS showed there was a 67% reduction in relapse rates and an 82% reduction in disability progression in those treated with Cladribine tablets. Similarly, clinical improvements were seen in lesion burden on MRI scans in this population. Studies evaluating the treatment effects of Cladribine tablets across a spectrum of baseline demographics and disease characteristics showed that the relative risk of relapse was significantly reduced compared with placebo, irrespective of previous treatment experience. Furthermore, treatment with Cladribine tablets has been shown to significantly reduce the rate of brain atrophy in patients with highly active RRMS. This reduction correlated with a reduced risk in disability progression in a retrospective analysis. In clinical trials, higher cumulative doses of Cladribine tablets did not result in further improvement in efficacy nor did additional courses after the 2-year treatment period but was associated with a higher incidence of Grade 3 and Grade 4 lymphopenia.	Efficacy section has been renamed 'Efficacy of Cladribine tablets in MS' to reflect efficacy outcomes in multiple sclerosis Further information and more recent studies have been added to ensure the latest data is communicated. Missing information: current efficacy sections only mention relapse rate as an efficacy outcome; however, cladribine tablets have an effect on numerous disability measures including disability progression and brain atrophy.	Giovannoni G et al. Mult Scler 2018;24:1594-1604 Giovannoni G et al. N Engl J Med 2010;362:416-426 Giovannoni G et al. Lancet Neurol 2011;10:329-337 Schippling S et al. Poster presented at: 34th Congress of the European Committee for Treatment and Research in Multiple Sclerosis; October 10-12, 2018; Berlin, Germany. P549 Comi G et al. J Neurol. 2013;260(4):1136-1146 (and suppl) Comi G et al. Mult Scler Relat Disord. 2019;29:168-174 Giovannoni G et al. Poster presented at: 3rd Congress of the European Academy of Neurology; June 24-27, 2017; Amsterdam, the Netherlands. P0542 Giovannoni G et al. Poster presented at: 34th Congress of the European Committee for Treatment and Research in Multiple Sclerosis; October 10-12, 2018; Berlin, Germany. P894. Rammohan K et al. Mult Scler Relat Disord 2012;1(1):49-54
Safety	[Section title] Safety Compared to alemtuzumab, cladribine is associated with a lower rate of severe lymphopenia. It also appears to have a lower rate of common adverse events, especially mild to moderate infections[12][37] As cladribine is not a recombinant biological therapy, it is not associated with the development of antibodies against the drug, which might reduce the effectiveness of future doses. Also, unlike alemtuzumab, cladribine is not associated with secondary autoimmunity.[39] This is probably due to the fact cladribine more selectively targets B cells. Unlike alemtuzumab, cladribine is not associated with a rapid repopulation of the peripheral blood B cell pool, which then ´overshoots´ the original number by up to 30%.[40] Instead, B cells repopulate more slowly, reaching near normal total B cells numbers at 1 year. This phenomenon and the relative sparing of T cells, some of which might be important in regulating the system against other autoimmune reactions, is thought to explain the lack of secondary autoimmunity.	[Section title] Safety profile of Cladribine tablets in MS Cladribine tablets target the cells of the adaptive immune system with minimal impact on innate immune cells. Although the exact mechanism by which cladribine exerts its therapeutic effect is not fully elucidated, it is proposed to have a transient effect on B and T lymphocyte depletion, interrupting the cascade of immune events central to MS. As a result, a reduction in lymphocyte count (lymphopenia) may be reported following treatment. In clinical trials, lymphocyte levels above Grade 0 (≥1000 cells/mm3) and Grade 1 (<1000–800 cells/mm3) were maintained in most patients, with levels continuing to improve after the 2-year dosing period. Less than 1% of patients developed Grade 4 lymphopenia (<200 cells/mm3). It is important that patients with lymphocyte counts below 500 cells/mm3 are actively monitored for signs suggestive of infection and that anti-infective treatments are given to at-risk patients. Despite the initial reduction in lymphocyte counts following treatment, studies showed the overall risk of infection in patients receiving Cladribine tablets was comparable to those who received placebo, except for herpes zoster infection. Due to this increased risk, it is recommended that all patients are screened for varicella zoster virus and antibody-negative patients are vaccinated prior to receiving treatment. In an analysis of post-approval data, as of 2020, no new infection safety signals were observed in over 18,000 patients. Progressive multifocal leukoencephalopathy (PML) has been reported in patients with HCL treated with parenteral cladribine. However, in up to 10 years of follow-up of patients receiving Cladribine tablets for MS, no cases of PML have been observed; it is mandatory that baseline MRI is performed prior to initiating treatment. In clinical trials, malignancies were observed more frequently in patients treated with Cladribine tablets compared with patients who received placebo. Compared with a matched reference population from the Global Cancer Observatory (GLOBOCAN) database, Cladribine tablets had no increased risk of malignancy in long-term real-world evidence data.	Safety information has been renamed 'Safety profile of Cladribine tablets in MS' to ensure clear distinction between outcomes in MS and HCL. Text has been revised to provide further context to the side effect profile seen following administration of cladribine tablets. Further information and more recent studies have been added to ensure the latest data is communicated and aligned to the outcomes highlighted in the Summary of Product Characteristics	* MAVENCLAD® EU SmPC, February 2021 Comi G et al. Mult Scler Relat Disord 2019;29:168–74 Cook S et al. Mult Scler Relat Disord 2019;29:157–67 Giovannoni G, et al. ACTRIMS-ECTRIMS 2020 [A965] Cook S et al. AAN 2020; [P1656]
Pharmacokinetic data	Bioavailability 100% (i.v.); 37 to 51% (orally) Protein binding 25% (range 5-50%) Metabolism Mostly via intracellular kinases; 15-18% is excreted unchanged Elimination half-life Terminal elimination half-life: Approximately 10 hours after both intravenous infusion and subcutaneous bolus injection	Bioavailability 100% (i.v.); 37 to 51% (orally) Protein binding 25% (range 5-50%) Up to 20% (orally) Metabolism Mostly via intracellular kinases. Intravenous and subcutaneous bolus injection: 15-18% is excreted unchanged After oral administration, 25% (±21%) of dose is excreted unchanged in urine and 3.8% as a metabolite. Elimination half-life Approximately 10 hours after both intravenous infusion and subcutaneous bolus injection Ranging from 5.6 to 7.6 hours and 18.4 to 19.7 hours after oral administration, indicative of different elimination phases.	Text has been revised and separated to ensure correct information is presented and a clear distinction between MS and HCL is provided. Text that has been revised is bold.	"Cladribine". Drugs.com. 28 February 2020. Retrieved 4 March 2020. Liliemark, Jan (1997). "The Clinical Pharmacokinetics of Cladribine". Clinical Pharmacokinetics. 32 (2): 120–131. doi:10.2165/00003088-199732020-00003. PMID 9068927. S2CID 32926069. "PRODUCT INFORMATION LITAK© 2 mg/mL solution for injection"(PDF). TGA eBusiness Services. St Leonards, Australia: Orphan Australia Pty. Ltd. 10 May 2010. Retrieved 27 November 2014. Giovannoni G, et al. Neurotherapeutics 2017;14:874–887 Leist and Weissert. Clin Neuropharm 2011;34:28-35
Contents table	1. Medical uses 2. Adverse effects 3. Mechanism of Action 4. History 5. Multiple sclerosis 5.1. Efficacy 5.2. Safety 5.3. Use in clinical practice 6. Research directions 7. References 8. External links	1. Medical uses 2. Mechanism of Action 3. History in HCL 4. Safety profile of cladribine in HCL 5. History in MS 6. Use in MS in clinical practice 7. Efficacy of Cladribine tablets in MS 8. Safety profile of Cladribine tablets in MS 9. Research directions 10. References 11. External links	Update contents in line with suggested content revisions.	No references

SamerFahmy (talk) 14:56, 21 May 2021 (UTC)

Responses to Samer Fahmy's proposal above

@SamerFahmy, some of these sources are a bit on the old side. The ideal is to cite sources from the last five years, but for some things (e.g., rare diseases) we stretch a point and reach back for 10 years. Is there any chance that the older sources could be replaced with something fairly new? (For clarity, I don't want you to propose a worse source just to have a newer one. Also, review articles, textbooks and reputable reference works are fine, too, but the press release is unlikely to work. If you haven't seen it before, then Wikipedia:Identifying reliable sources (medicine) may be helpful.) WhatamIdoing (talk) 04:43, 15 June 2021 (UTC)

@WhatamIdoing, The new references incorporated as part of my updates are in bold, the only one older than 5 years is the Leist reference (2011). It is related to MoA and all recent publications are citing this one. It is usually a best practice to cite the original publication when developing new materials. Therefore, I would suggest citing this reference for the page update. As for the use of the press release, this is the only way I could reference the approval of Cladribine Tablets for treating MS in over 80 countries. Such information has not been be found in a clinical publication to date. Is this approach acceptable for you?

SamerFahmy (talk) 13:11, 16 June 2021 (UTC)

@SamerFahmy, Seems mostly fine to me. Appreciate the effort to describe the changes in detail. However, mentioning the approval "in over 80 countries" makes it sound like an advert, and if it has to reference a press release I'd leave it out until we have secondary sources that discuss how many countries it is approved in. - Rod57 (talk) 03:46, 4 July 2021 (UTC)