Safety in Lactation: Antimetabolites

23 September 2020Antineoplastic antimetabolites, whether used as monotherapy or in combination with other antineoplastics, are contra-indicated in breastfeeding (except where indicated below) because of their effects on…
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Refrigerated Storage


Injection, 10mg (1mg/ml)


Contact Janssen-Cilag Ltd in all cases where a deviation from the recommended storage conditions has occurred. Refer to the current BNF for company contact details

Please also refer to the manufacturer’s product literature for recommended storage information at

5 May 2020
London MI Service

LitakLipomed GMBh

Lipomed GMBh
2mg/ml injection

In the event of an inadvertent temperature excursion the following data may be used:

The extended stability tests performed by Lipomed, proved that Litak, in unopened vials, is stable at room temperature (25°C) for 2 years and at 30°C for 1 year.

Having unopened Litak vials at room temperature (25°C) for a short time does not affect the product quality. After interruption of the cold chain for a few hours or days, the product can still be used and put back in the fridge (between 2°C and 8°C) without changing the expiry date.

Please also refer to the manufacturer’s product literature for recommended storage information at

No, unless exposed to temperatures of 30°C, where the expiry date would be altered to 1 year.
Yes, if exposed to conditions described above.
12 June 2020
London MI Service

Lactation Safety Information

No published evidence of safety
Serious adverse effects reported in adults
16 September 2020

New Medicines

MavencladHighly active relapsing multiple sclerosis (MS) in adults


New formulation
Merck (formerly Merck Serono) / EMD in US
Merck (formerly Merck Serono) / EMD in US

Development and Regulatory status

September 2017
Nov 19NICE grants cladribine accelerated access for treating highly active MS. The Technology Appraisal Guidance (TAG), which is effective immediately, will soon state that the MS drug can be used as an option for treating highly active versions of the disease in adults without the requirement of a gadolinium-enhanced MRI scan. [31]
Apr 19Approved in US for the treatment of adults with relapsing-remitting disease (RRMS) and active secondary progressive disease (SPMS) [30]
Jul 18Re-submission accepted by the FDA [29].
Nov 17NHS England announce a deal with Merck to make cladribine routinely available on the NHS, allowing early access to the drug for patients. Patients and clinicians can access the treatment with immediate effect, and will not have to wait the usual 3 months after NICE publishes its final guidance to access cladribine [30].
Sep 17Launched in UK [29]
Aug 17Approved in EU [28].
Jun 17EU positive opinion for treatment of adult patients with highly active relapsing MS as defined by clinical or imaging features [27].
Jul 16Merck announces that the EMA has accepted the Marketing Authorisation Application for this indication. The submission includes data from three Phase III studies, CLARITY (NCT00213135), CLARITY EXTENSION (NCT00641537) and ORACLE MS (NCT00725985), and the Phase II ONWARD study (NCT00436826) [26].
Sep 15Merck announces it intends to submit a licence application for cladribine for treatment of relapsing MS to the EMA, following evaluation of new data and additional analyses of the compound’s benefit-risk profile. Merck has submitted a letter of intent to the EMA. [25].
Jun 11Merck have stated that due to U.S. drug regulators´ concerns about the risks of cladribine, any development or marketing plans for it are unlikely. Cladribine will also been withdrawn from Australia and Russia. Data from ongoing clinical trials are very unlikely to address the US FDA´s requirements. [24]
Mar 11Not approved in US; the FDA has issued a complete response letter requesting the Company provide an improved understanding of safety risks and the overall benefit-risk profile either through additional analyses or by additional studies [22].
Feb 11EU filing withdrawn [21].
Jan 11EMA has confirmed its previous negative opinion and adopted a final negative opinion, recommending that cladribine should not be granted a marketing authorisation [20].
Nov 10US FDA review date extended to 28th Feb 2011. [19]
Oct 10Merck is to ask the EU CHMP to review its negative opinion [18].
Sep 10The CHMP of the European Medicines Agency has adopted a negative opinion, recommending that cladribine should not be granted a marketing authorisation for MS. The decision is due to concerns over an increased number of pts developing cancer in trials with cladribine, which may indicate an increased risk of cancer over time and with increasing doses. The CHMP also noted that the benefits & the most appropriate dosage had not been fully established [17].
Sep 10Approved in Australia (trade name Movectro) [16]
Jul 10Approved in Russia for treatment of relapsing-remitting MS. [14]
Jul 10Granted a priority review in the US; the FDA decision on approval expected 4Q 2010 [15].
Jun 10Filing re-submitted in the US [13].
Mar 10Merck Serono are preparing a re-submission to the FDA (11).
Dec 09FDA will not consider the licence application for cladribine in relapsing-remitting MS, pending the availability of further data (10).
Oct 09Filed in the US. US launch anticipated Q2 2010; EU launch planned for Q4 2010 (9).
Sep 09US filing expected this month [8].
Jul 09Filed in EU. US filing expected soon [7].
Jan 09Submissions for EU and US licence planned for mid-2009 for relapsing-remitting MS based on positive results from CLARITY (5)
Dec 06PIII (oral) (1). Enrollment into PIII expected to be complete by end 06 (2). Fast track in US (3)


Cladribine is a small molecule that may interfere with the behaviour and the proliferation of certain white blood cells, particularly lymphocytes, thought to be involved in the pathological process of MS
NICE estimate the incidence and prevalence of MS equivalent to 3.5-6.6 per 100,000 people and 100-120 per 100,000, respectively, in England and Wales. About 80-90% of those newly diagnosed have RRMS.
Highly active relapsing multiple sclerosis (MS) in adults

Further information


Trial or other data

Mar 11In a post hoc & subgp analysis of CLARITY n=1,326) 1,192 pts were assessed for freedom from disease activity at 96 wks. Over 24 weeks, 266 (67%) of 395 patients in the cladribine 3.5 mg/kg gp & 283 (70%) of 406 in the cladribine 5.25 mg/kg gp were free from disease activity, vs. 145 (39%) of 373 in the placebo gp (odds ratio, 3.31 [95% CI 2.46 to 4.46] for the 3.5 mg/kg group; & 3.68 [2.73 to 4.97] for the 5.25 mg/kg gp; both p<0.0001). Over 48 wks, the corresponding figures were 208/384 (54%) & 222/396 (56%) vs. 86/360 (24%) [3.80 [2.77 to 5.22] for the 3.5 mg/kg gp; 4.13 [3.02 to 5.66] for the 5.25 mg/kg gp; both p<0.0001). Over 96 wks, the corresponding figures were 178/402 (44%) & 189/411 (46%) vs. 60/379 (16%) [4.28 [3.05 to 6.02] for the 3.5 mg/kg gp; 4.62 [3.29 to 6.48] for the 5.25 mg/kg gp; both p<0.0001) The effects of cladribine tablets on freedom from disease activity were statistically significant across all patient subgps [23].
Mar 11Top-line results from the CLARITY EXTENSION and ORACLE MS2 studies are expected by the end of 2011. Top-line results from the ONWARD3 study are expected in H1 2012 [22].
Apr 10new data were presented at the 62nd Annual Meeting of the American Academy of Neurology from pre-specified and post-hoc analyses of the PIII CLARITY Study. They show an: increase in the proportion of patients with disease activity-free status with cladribine (total dose of 3.5 mg/kg and 5.25 mg/kg) vs placebo over the entire 96-week study (43%, 44% and 16%, respectively) with statistically significant findings as early as 24 weeks (67%, 70% and 39%); reductions in annualized relapse rate (ARR) over 96 weeks across the spectrum of baseline demographics and disease characteristics relative to placebo; reduced consumption of healthcare resources, a decreased need for societal support, improvements in patient productivity, and reductions in total non-drug expenditure, relative to placebo; reduction in circulating CD4+ T cells relative to the total number of lymphocytes at the end of treatment periods compared to baseline, while the proportions of other lymphocyte subtypes (CD8+ T, B and natural killer cells) were preserved or increased relative to total lymphocytes [12].
Jan 10Results of the PIII CLARITY study published (Giovannoni G et al. A placebo-Controlled Trial of Oral Cladribine for Relapsing Multiple Sclerosis; available on; to be published in the February 4, 2010 printed issue of NEJM.).
Sep 09Further data from CLARITY presented at the European Committee for Treatment and Research in Multiple Sclerosis congress in Germany, indicated that 43 and 44% of patients treated with two different doses of cladribine had an absence of disease activity vs. 16% on placebo [8].
Apr 09Further results of the CLARITY study reported at the American Academy of Neurology meeting. There was a statistically significant relative reduction in the annualised relapse rate at 96 weeks (primary endpoint) with both the high-dose (54.5%) and low-dose (57.6%) regimens vs placebo. 78.9% and 79.7% of patients on high and low-dose cladribine remained relapse free vs 60.9% on placebo. Disability progression, defined as a sustained progression based on the baseline EDSS score, was significantly reduced by 33% and 31%, respectively, vs placebo. There was also a significant reduction in MRI activity, including T1 gadolinium lesions, active T2 lesions, and the composite of unique active lesions, with reductions of between 73% and 88% across these end points with treatment. Lymphopenia and leukopenia occurred more frequently in the cladribine-treated groups than the placebo group, 26.7% vs 1.8%, and 7.1% vs 0.5%, respectively. There were 4 malignancies, all in the cladribine groups (6).
Jan 09CLARITY met its 2-year primary efficacy endpoint in patients (N=1,326) with relapsing-remitting MS with a 58% RRR in annualised relapse rate in the low- and 55% in the high-dose treatment group vs placebo. Secondary endpoints were also met, including reduction of lesion activity as measured by MRI, proportion of subjects relapse-free and disability progression. Cladribine was given in two or four treatment courses in the first year, with each course consisting of once daily administration for four to five consecutive days, resulting in patients taking cladribine tablets for only 8 to 20 days during the year. In the second year, two treatment courses were administered to all patient groups. .Overall, the frequencies of adverse events were comparable in all 3 groups. Lymphopenia, an expected event based on the presumed mechanism of action of cladribine, occurred more frequently with active treatment. With the exception of lymphopenia, the most frequently reported adverse events in the 3 groups were headaches and nasopharyngitis. (4).
Dec 06CLARITY (CLAdRIbine Tablets Treating MS OrallY) PIII multi-centre, multi-national study, pt enrollment into this pivitol trial is planned to be completed by end 06 (2).

Evidence based evaluations