Table 5.
Pregnancy planning management and malignancy risk in patients being treated with cladribine tablets.
| Consensus recommendations | Strength of recommendation‡ | Level of consensus¶ |
|---|---|---|
| Q9a. How should pregnancy planning be managed in patients on cladribine tablets? (Level of evidence: very low) | ||
| Based on human experience with other substances inhibiting DNA synthesis, cladribine tablets could cause congenital malformations when administered during pregnancy. Studies in animals have shown reproductive toxicity. There is very limited pregnancy data from the clinical trial programme. | 8.5 (8.3) | 96.9% (31/32) |
| Cladribine tablets are contraindicated and should not be administered during pregnancy. Subsequent courses of cladribine tablets may be delayed during this time. | 9 (8.8) | 100% (32/32) |
| Breast-feeding is contraindicated during dosing with cladribine tablets and for 10 days after the last dose. | 9 (8.5) | 93.8% (30/32) |
| Before initiation of treatment both in year 1 and year 2, women of childbearing potential and males who could potentially father a child should be counselled regarding the potential for risk to the foetus and the need for effective contraception for at least 6 months after the last dose of cladribine tablets.* | 8 (8.4) | 100% (32/32) |
| Any unforeseen pregnancy within 6 months after the last dose of cladribine tablets is not necessarily an indication for a termination of the pregnancy. Any further administrations of cladribine tablets should, however, be discontinued immediately or delayed in this event. Patients should be counselled about potential risks to the foetus and referred to a high-risk pregnancy clinic. | 9 (8.5) | 96.9% (31/32) |
| *It is currently unknown whether cladribine may reduce the effectiveness of systemically acting hormonal contraceptives. Therefore, women using systemically acting hormonal contraceptives should add a barrier method during cladribine treatment and for at least 4 weeks after the last dose in each treatment year.24 | ||
| Q9b. Do cladribine tablets result in an increased risk of malignancy? (Level of evidence: moderate) | ||
| Cladribine tablets may increase the risk of malignancies, as seen with other high-efficacy DMDs. • There was a higher incidence of malignancies in clinical studies and long-term follow up of patients treated with a cumulative dose of 3.5 mg/kg cladribine tablets compared with placebo*; however, when compared with a matched reference population, there was no evidence for an increased risk.** |
8 (7.7) | 86.7% (26/30) |
| Clinicians should instruct patients to observe the standard guidelines for cancer screening.*** | 9 (8.5) | 100% (30/30) |
| Cladribine tablets are contraindicated in patients with an active malignancy. | 9 (8.2) | 90.0% (27/30) |
| *Included all studies that used cladribine tablets monotherapy, matching the recommended dose: CLARITY, CLARITY EXT and ORACLE-MS + follow-up in PREMIERE. **The rate of malignancies observed with cladribine tablets during the clinical development programme in MS was similar to the expected rate in the GLOBOCAN reference population [8.00 observed events in the monotherapy oral cohort versus 8.27 expected events, respectively; SIR: 0.97 (95% CI 0.44, 1.85)]. Non-melanoma skin cancer was excluded due to inconsistent reporting in GLOBOCAN. Data is adjusted for country of origin, age and gender.30 ***Physicians should direct patients to country-specific screening regimens, which may be found on cancer society or local health authority web sites. | ||
‡
median score on a 1–9 scale (mean score in brackets).
¶
percentage of votes with 7–9 on a 9-point scale.
CI, confidence interval; DMD, disease modifying drug; MS, multiple sclerosis; SIR, standardised incidence ratio.