|Year : 2021 | Volume
| Issue : 2 | Page : 183-186
Apremilast titration: Real-world indian experience
Abhishek De1, Aarti Sarda2, Dhiraj Dhoot3, Hanmant Barkate3
1 Department of Dermatology, Calcutta National Medical College, Kolkata, West Bengal, India
2 Department of Dermatology, Wizderm Skin and Hair Clinic, Kolkata, West Bengal, India
3 Global Medical Affairs, Glenmark Pharmaceuticals Ltd., Mumbai, Maharashtra, India
|Date of Submission||17-Sep-2020|
|Date of Decision||30-Nov-2020|
|Date of Acceptance||02-Dec-2020|
|Date of Web Publication||26-Aug-2021|
B D Sawant Marg, Chakala, Andheri (E), Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
Background: Apremilast is recommended to titrate in initial period to reduce adverse effects (AE). But inspite of that, in India; many dermatologists experienced a lot of AE resulting in discontinuation of therapy. As a result, many of them have adapted to titrate the dose in different ways. Objectives: To evaluate the AE profile and rate of discontinuation of apremilast during initial titration in different ways. Materials and Methods: A multicentre, retrospective data analysis was done at 121 dermatology clinics across India in the adult patients diagnosed with chronic plaque psoriasis and prescribed at least one dose of apremilast. Patient characteristics and data were obtained from medical records when available. Results: Out of 582 patients, 175 were prescribed apremilast starter pack in licensed dose (Group 1); 202 were prescribed starter pack in OD dosing (Group 2) for 13 days and 205 were prescribed 2 starter packs in OD dosing (Group 3) for 26 days. 45.14% had AE in Group 1 whereas 36.63% and 30.24% had in Group 2 & 3 respectively. Gastrointestinal upset, headache & nausea were most common. In Group 1, 17.71% of patients discontinued apremilast whereas 16.33% and 10.24% discontinued in Group 2 & 3 respectively. On comparison within group, Group 3 had significant difference over Group 1 (p value <0.05). Conclusion: It is concluded that slower titration of apremilast in initial phase leads to lesser AE profile and hence discontinuation of therapy and thus increasing adherence.
Keywords: Apremilast, Titration, Safety, Real world, India
|How to cite this article:|
De A, Sarda A, Dhoot D, Barkate H. Apremilast titration: Real-world indian experience. Clin Dermatol Rev 2021;5:183-6
| Introduction|| |
Apremilast, a phosphodiesterase 4 (PDE-4) inhibitor, has demonstrated a favorable safety profile for the management of psoriasis in randomized controlled trials, ESTEEM 1 and 2., The inhibition of PDE4 can elevate the intracellular level of cyclic adenosine monophosphate (cAMP) and subsequently modulate the inflammatory responses and maintain the immune balance.,, While apremilast is proven to be well tolerated with minimal risk of side effects, it may cause a few temporary and mild-to-moderate adverse events (AEs) such as diarrhea, nausea, and headache during the initiation of the therapy. Although several interventions are available for the management of adverse events, sometimes, dose adjustment and discontinuation of the therapy may be required. One of the approaches of dose adjustment is slower titration, and, hence, apremilast therapy is always initiated with a starter pack. In spite of using starter packs, many patients discontinue therapy on their own due to AE. As a result, many dermatologists adapted the strategy of slower titration of apremilast. Hence, we conducted this retrospective cohort analysis to evaluate the trends in the starter pack duration and analyze the safety data associated with it.
| Materials and Methods|| |
A multicentric, retrospective data analysis was done at 121 dermatology clinics across India after obtaining ethics committee approval (Om Institutional Ethics Committee; IEC registration: ECR/1168/Inst/GJ/2018). The data charts were identified by generating a list of all patients ever prescribed apremilast at all clinics, using the medical record database. Adult patients (age ≥18 years) diagnosed with chronic plaque psoriasis and prescribed at least one dose of apremilast were included. Patients who have received other antipsoriatic drugs along with apremilast were excluded. Different regimens of prescribing the apremilast starter pack and safety data (reported AEs) associated with them were recorded. If an AE was not re-recorded in the record at a follow-up visit up to 6 weeks, it was assumed that the AE had been resolved. Patients who discontinued the treatment due to AEs in different regimes were recorded in the study outcomes. Safety data and apremilast discontinuation of all regimes were compared. Fisher's exact test was used to compare the proportions between all regimes (IBM SPSS statistics version 20 Chicago Illinois USA). P < 0.05 was considered statistically significant.
| Results|| |
A total of 582 patients met the inclusion criteria and their baseline demographics is summarized in [Table 1]. A total of three different regimes of prescribing apremilast starter pack were identified through data analysis and named Groups I, II, and III. Group I patients were prescribed the apremilast starter pack in approved dosage, whereas Group II were prescribed all tablets of the apremilast starter pack in OD dosing. Group III were asked to use two starter packs, taking 10 mg OD after food for 8 days, followed by 20 mg OD after food for 8 days and thereafter 30 mg OD after food for 10 days, thus they took 26 days to complete their titration dose [Figure 1]. Of the 582 patients, 175 (30%) were in Group I, 202 (34.8%) in Group II, and 205 (35.2%) in Group III.
Safety outcomes in all groups are summarized in [Table 2]. In Group I, 45.14% reported AEs, whereas 36.63% reported AE in Group II (P = 0.11). However, there was a statistically significant difference (P < 0.05) with AE in Group III (30.24%) compared to Group I. Furthermore, the average number of reported AEs per patient was lower in Group III (1.14) compared to that in Group II (1.20) and Group I (1.34). Gastrointestinal (GI) upset was the most common AE reported in all groups, followed by headache and nausea. Although apremilast discontinuation trend was seen at all dosing of apremilast, half of the patients experienced AE at 30-mg apremilast dosing. As a result, 17.71% of the patients discontinued the therapy in Group I, 16.33% in Group II, and 10.24% in Group III [Figure 2]. There was no statistically significant difference between Group I and Group II (P = 0.7), but a statistically significant difference was seen between Group I and Group III (P < 0.05). There was no statistically significant difference between Group II and Group III in terms of AE (P = 0.17) and the discontinuation of apremilast (P = 0.08).
|Figure 2: Percentage of patients with adverse event and apremilast discontinuation in each group|
Click here to view
| Discussion|| |
While landmark clinical trials have examined the safety of apremilast over 52 weeks, this study examines the safety during titration period. In addition, most of the real-world studies as well examined the safety profile over the complete duration of the therapy. Apremilast is a PDE4 inhibitor, and inhibition of PDE4 can elevate the intracellular level of cAMP and subsequently modulate the inflammatory responses and maintain the immune balance. The cAMP-specific PDE4 is highly expressed in some specific organs such as brain, smooth muscles, keratinocytes, and GI tract, and hence nausea, emesis, GI effects, and other adverse effects have largely impeded the clinical application, which is attributed to PDE4 inhibition.,, Moreover, increasing evidence demonstrated higher expression of PDE4 in patients with inflammatory diseases than that of healthy individuals., Hence, more efforts and emphasis are required to minimize AE while maintaining balance of the efficacy.
Compared to earlier studies, where apremilast dosing began at the full dose, less AEs were reported in Phase II studies, where there was an upward titration of dosing over the initial 6 days of treatment. Hence, it is recommended to titrate the dose initially to lower down the AEs. However, in spite of that, a high number of AEs had been reported from landmark trials and real-world studies, leading to the discontinuation of the drug. In our study in Group I, 45.14% of the patients reported ≥1 AE compared to ESTEEM I and II where 68.9% of the patients receiving apremilast reported ≥1 AE. Although these AEs were mild-to-moderate in nature and resolved with the continuation of drug, most of the AEs occurred in the initial 2 weeks of dosing. Hence, dose titration is advised to reduce the AE In our study in Groups II and III, 36.63% and 30.24% of the patients reported AE, respectively, which suggests that a further slowdown of titration will help reduce AEs significantly. A similar trend was seen in AE per patient ratio, and the discontinuation of apremilast points toward better compliance and adherence by the patients.
To the best of our knowledge, the present study is the first real-world experience of analyzing the safety of apremilast during titration. Due to the retrospective design, the possibility of selection bias cannot be ruled out. Second, the duration of the present study was very less, which hampers overviewing of results to a larger population. In addition, this study does not address the clinical efficacy of apremilast. However, despite a relatively short study duration and nonmonitoring of clinical efficacy, this study offers important information regarding the response to different titration durations in real-world practice. Moreover, long-term efficacy of apremilast is well documented. Hence, future studies with a similar design and a larger sample size are required to evaluate the efficacy and to establish the concept in clinical practice.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initial s will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Papp K, Reich K, Leonardi CL, Kircik L, Chimenti S, Langley RG, et al
. Apremilast, an oral phosphodiesterase 4 (PDE4) inhibitor, in patients with moderate to severe plaque psoriasis: Results of a Phase III, randomized, controlled trial (Efficacy and safety trial evaluating the effects of apremilast in psoriasis [ESTEEM] 1). J Am Acad Dermatol 2015;73:37-49.
Paul C, Cather J, Gooderham M, Poulin Y, Mrowietz U, Ferrandiz C, et al
. Efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate-to-severe plaque psoriasis over 52 weeks: A Phase III, randomized controlled trial (ESTEEM 2). Br J Dermatol 2015;173:1387-99.
Schafer P. Apremilast mechanism of action and application to psoriasis and psoriatic arthritis. Biochem Pharmacol 2012;83:1583-90.
Schafer PH, Parton A, Capone L, Cedzik D, Brady H, Evans JF, et al
. Apremilast is a selective PDE4 inhibitor with regulatory effects on innate immunity. Cell Signal 2014;26:2016-29.
Maurice DH, Ke H, Ahmad F, Wang Y, Chung J, Manganiello VC, et al
. Advances in targeting cyclic nucleotide phosphodiesterases. Nat Rev Drug Discov 2014;13:290-314.
Dattola A, Del Duca E, Saraceno R, Gramiccia T, Bianchi L. Safety evaluation of apremilast for the treatment of psoriasis. Expert Opin Drug Saf 2017;16:381-5.
Langley A, Beecker J. Management of common side effects of apremilast. J Cutan Med Surg 2018;22:415-21.
Parasramani S, Thomas J, Budamakuntla L, Dhoot D, Barkate H. Real-world experience on the effectiveness and tolerability of apremilast in patients with plaque psoriasis in India. Indian J Drugs Dermatol 2019;5:83-8. [Full text]
Chiricozzi A, Caposiena D, Garofalo V, Cannizzaro MV, Chimenti S, Saraceno R. A new therapeutic for the treatment of moderate-to severe plaque psoriasis: Apremilast. Expert Rev Clin Immunol 2016;12:237-49.
Li H, Zuo J, Tang W. Phosphodiesterase-4 inhibitors for the treatment of inflammatory diseases. Front Pharmacol 2018;9:1048.
Dyke HJ, Montana JG. Update on the therapeutic potential of PDE4 inhibitors. Expert Opin Investig Drugs 2002;11:1-3.
Dietsch GN, Dipalma CR, Eyre RJ, Pham TQ, Poole KM, Pefaur NB, et al
. Characterization of the inflammatory response to a highly selective PDE4 inhibitor in the rat and the identification of biomarkers that correlate with toxicity. Toxicol Pathol 2006;34:39-51.
Schafer PH, Truzzi F, Parton A, Wu L, Kosek J, Zhang LH, et al
. Phosphodiesterase 4 in inflammatory diseases: Effects of apremilast in psoriatic blood and in dermal myofibroblasts through the PDE4/CD271 complex. Cell Signal 2016;28:753-63.
Busa S, Kavanaugh A. Drug safety evaluation of apremilast for treating psoriatic arthritis. Expert Opin Drug Saf 2015;14:979-85.
Young M, Roebuck HL. Apremilast, an oral phosphodiesterase 4 (PDE4) inhibitor: A novel treatment option for nurse practitioners treating patients with psoriatic disease. J Am Assoc Nurse Pract 2016;28:683-95.
[Figure 1], [Figure 2]
[Table 1], [Table 2]