Alimta® (pemetrexed): Prevention and Management of Skin Rash

Information from Summary of Product Characteristics

Skin reactions have been reported in patients not pre-treated with a corticosteroid. Pre-treatment with dexamethasone (or equivalent) can reduce the incidence and severity of skin reactions.¹

To reduce the incidence and severity of skin reactions, a corticosteroid should be given the day prior to, on the day of, and the day after pemetrexed administration. The corticosteroid should be equivalent to 4 mg of dexamethasone administered orally twice a day.¹

Management of Pemetrexed Skin Rash

Dose adjustments are recommended in the local labeling if a patient experiences grade 3 or 4 skin toxicity. Treatment may be delayed to allow sufficient time for recovery.²

If patients develop non-haematologic toxicities ≥ Grade 3 (excluding neurotoxicity), pemetrexed should be withheld until resolution to less than or equal to the patient’s pre-therapy value.¹

Table 1. Dose modification table for pemetrexed (as single agent or in combination) and cisplatin– Non-haematologic toxicities^1ab

	Dose of pemetrexed (mg/m2)	Dose for cisplatin (mg/m2)
Any Grade 3 or 4 toxicities except mucositis	75 % of previous dose	75 % of previous dose

^a National Cancer Institute Common Toxicity Criteria (CTC v2.0; NCI 1998)

^b Excluding neurotoxicity

Lilly does not recommend a specific approach to managing pemetrexed-associated rash beyond the guidance provided in the local labeling. Early clinical trial experience noted that the rash typically improved with dexamethasone treatment and resolved upon cessation of pemetrexed therapy.^3-5 Current protocols typically allow for the use of supportive care therapies in accordance with local standard practice.²

Prevention of Pemetrexed Skin Rash

Pretreatment with dexamethasone (or equivalent) reduces the incidence and severity of cutaneous reaction. In clinical trials, dexamethasone 4 mg was given by mouth BID the day before, the day of, and the day after pemetrexed administration.²

A small phase 1 study that evaluated 3 different steroid premedication regimens in patients who received pemetrexed for the treatment of advanced HNSCC found that it may be feasible to utilize a 20-mg IV dose of dexamethasone prior to the pemetrexed infusion on the day of treatment in situations in which the patient could not adhere to the oral dexamethasone premedication regimen.^2,6

A prospective study evaluated the efficacy of a single IV dose of dexamethasone administered before pemetrexed-based chemotherapy in preventing cutaneous toxicities. Seventy patients with advanced pulmonary adenocarcinoma received either 3 days of oral dexamethasone (4 mg, BID, starting the day before chemotherapy) or a single IV dose of 20 mg dexamethasone prior to pemetrexed. According to the emetogenic potential of the chemotherapy regimen used, 3 to 7 additional doses of oral dexamethasone were given after the administration of chemotherapy in both treatment arms. Patients who received the IV dexamethasone reported 10 episodes of skin rash during the total of 114 chemotherapy cycles (8.9%) while patients who received the standard oral dexamethasone reported 9 episodes of skin rash during the total of 154 cycles (5.8%; p=.35). No grade 3 or 4 skin rash was observed in the whole study population.⁷

Additional retrospective analyses investigated the preventive effect of dexamethasone on rash development with pemetrexed therapy^3,8,9 and alternative regimens of steroid premedication.^10-12

References

1. Alimta [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands

2. Data on file, Eli Lilly and Company and/or one of its subsidiaries.

3. Rusthoven JJ, Eisenhauer E, Butts C, et al. Multitargeted antifolate LY231514 as first-line chemotherapy for patients with advanced non-small-cell lung cancer: a phase II study. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 1999;17(4):1194. http://dx.doi.org/10.1200/jco.1999.17.4.1194

4. Thödtmann R, Depenbrock H, Dumez H, et al. Clinical and pharmacokinetic phase I study of multitargeted antifolate (LY231514) in combination with cisplatin. J Clin Oncol. 1999;17(10):3009-3016. http://dx.doi.org/10.1200/JCO.1999.17.10.3009

5. Clarke SJ, Abratt R, Goedhals L, et al. Phase II trial of pemetrexed disodium (ALIMTA^®, LY231514) in chemotherapy-naïve patients with advanced non-small-cell lung cancer. Ann Oncol. 2002;13(5):737-741. http://dx.doi.org/10.1093/annonc/mdf115

6. Coscio A, William WN Jr, Feng L, et al. Phase I study of pemetrexed in recurrent/metastatic head and neck squamous cell cancer (HNSCC) and to assess the need for steroid premedication [abstract]. J Clin Oncol. 2009;27(suppl 15):e17009. https://ascopubs.org/doi/abs/10.1200/jco.2009.27.15_suppl.e17009

7. Groleau A, Côté J. Comparison between two premedication regimens of dexamethasone before a pemetrexed-based chemotherapy: a single-center experience study [published online August 1, 2019]. J Oncol Pharm Pract. https://doi.org/10.1177/1078155219862040

8. Usui N, Kondo Y, Okamoto N, et al. Evaluation of the preventive effect of dexamethasone for rash in patients treated with pemetrexed [abstract]. Ann Oncol. 2014;25(suppl 5):v55. https://doi.org/10.1093/annonc/mdu435.49

9. Sakurada T, Kakiuchi S, Tajima S, et al. Pemetrexed-induced rash may be prevented by supplementary corticosteroids. Biol Pharm Bull. 2015;38(11):1752-1756. https://www.jstage.jst.go.jp/article/bpb/38/11/38_b15-00435/_pdf

10. Elsoueidi R, Lander MJ, Richa EM, Adane ED. Single-dose dexamethasone for the prevention of pemetrexed associated cutaneous adverse reactions. J Oncol Pharm Pract. 2016;22(2):271-274. https://doi.org/10.1177/1078155215583523

11. Usui N, Kondo Y, Ryota N, et al. Mandatory dexamethasone strictly monitored by pharmacists reduces the severity of pemetrexed-induced skin rash. Eur J Hosp Pharm. 2017;24:283-285. https://doi.org/10.1136/ejhpharm-2016-000957

12. Clark SK, Anselmo LM. Incidence of cutaneous reactions with pemetrexed: comparison of patients who received three days of oral dexamethasone twice daily to patients who did not. J Oncol Pharm Pract. 2019;25(7):1645-1650. https://doi.org/10.1177/1078155218804869

Glossary

BID = twice daily

HNSCC = head and neck squamous cell carcinoma 

IV = intravenous

Lilly = Eli Lilly and Company