繁体中文
设为首页
加入收藏
当前位置:药品说明书与价格首页 >> 上市新药 >> OTEZLA treatment initiation pack(apremilast 阿普斯特混合片)

OTEZLA treatment initiation pack(apremilast 阿普斯特混合片)

2015-04-20 02:05:47  作者:新特药房  来源:互联网  浏览次数:535  文字大小:【】【】【
简介:英文药名:OTEZLA(apremilast filmcoated tablets) 中文药名:阿普斯特片 生产厂家:Celgene公司药品介绍2015年1月27日,新基口服银屑病药物获欧盟委员会(ec)批准otezla用于2种自身免疫性疾病的治疗 ...

英文药名:OTEZLA(apremilast filmcoated tablets)

中文药名:阿普斯特片

生产厂家:Celgene公司
药品介绍
2015年1月27日,新基口服银屑病药物获欧盟委员会(ec)批准otezla用于2种自身免疫性疾病的治疗:用于对其他系统疗法包括环孢素、甲氨蝶呤或补骨脂素紫外线疗法治疗无响应、有禁忌或不耐受的中度至重度慢性斑块型银屑病成人患者的治疗;作为单药或联合其他疾病修饰抗风湿药物用于对先前dmard疗法响应不足或已经不能耐受的活动性银屑病关节炎成人患者的治疗。
otezla是一种首创的口服、选择性磷酸二酯酶4抑制剂。该药是过去20年中获批用于银屑病治疗的首个口服药物,也是过去15年中获批用于银屑病关节炎的首个口服药物。

30mgx 56粒
30mg x 168粒  
德国上市为盒式板装

Otezla 10mg, 20mg, 30mg treatment initiation pack(混合包装的27片)
1. Name of the medicinal product
Otezla 10 mg film-coated tablets
Otezla 20 mg film-coated tablets
Otezla 30 mg film-coated tablets
2. Qualitative and quantitative composition
Each film-coated tablet contains 10 mg of apremilast.
Each film-coated tablet contains 20 mg of apremilast.
Each film-coated tablet contains 30 mg of apremilast.
Excipient(s) with known effect:
Each film-coated tablet contains 57 mg of lactose (as lactose monohydrate).
Each film-coated tablet contains 114 mg of lactose (as lactose monohydrate).
Each film-coated tablet contains 171 mg of lactose (as lactose monohydrate).
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
Film-coated tablet (tablet).
Pink, diamond shaped 10 mg film-coated tablet of 8 mm length with “APR” engraved on one side and “10” on the opposite side.
Brown, diamond shaped 20 mg film-coated tablet of 10 mm length with “APR” engraved on one side and “20” on the opposite side.
Beige, diamond shaped 30 mg film-coated tablet of 12 mm length with “APR” engraved on one side and “30” on the opposite side.
4. Clinical particulars
4.1 Therapeutic indications
Psoriatic arthritis
Otezla, alone or in combination with Disease Modifying Antirheumatic Drugs (DMARDs), is indicated for the treatment of active psoriatic arthritis (PsA) in adult patients who have had an inadequate response or who have been intolerant to a prior DMARD therapy (see section 5.1).
Psoriasis
Otezla is indicated for the treatment of moderate to severe chronic plaque psoriasis in adult patients who failed to respond to or who have a contraindication to, or are intolerant to other systemic therapy including cyclosporine, methotrexate or psoralen and ultraviolet-A light (PUVA).
4.2 Posology and method of administration
Treatment with Otezla should be initiated by specialists experienced in the diagnosis and treatment of psoriasis or psoriatic arthritis.
Posology
The recommended dose of Otezla is 30 mg twice daily taken orally, morning and evening, approximately 12 hours apart, with no food restrictions. An initial titration schedule is required as shown below in Table 1. No re-titration is required after initial titration.
Table 1: Dose titration schedule

Day 1

Day2

Day 3

Day 4

Day 5

Day 6 & thereafter

AM

AM

PM

AM

PM

AM

PM

AM

PM

AM

PM

10 mg

10 mg

10 mg

10 mg

20 mg

20 mg

20 mg

20 mg

30 mg

30 mg

30 mg

If patients miss a dose, the next dose should be taken as soon as possible. If it is close to the time for their next dose, the missed dose should not be taken and the next dose should be taken at the regular time.
During pivotal trials the greatest improvement was observed within the first 24 weeks of treatment. If a patient shows no evidence of therapeutic benefit after 24 weeks, treatment should be reconsidered. The patient's response to treatment should be evaluated on a regular basis. Clinical experience beyond 52 weeks is not available (see section 5.1).
Special populations
Elderly patients
No dose adjustment is required for this patient population (see sections 4.8 and 5.2).
Patients with renal impairment
No dose adjustment is needed in patients with mild and moderate renal impairment. The dose of apremilast should be reduced to 30 mg once daily in patients with severe renal impairment (creatinine clearance of less than 30 mL per minute estimated by the Cockcroft-Gault equation). For initial dose titration in this group, it is recommended that Otezla be titrated using only the AM schedule listed in Table 1 and the PM doses be skipped (see section 5.2).
Patients with hepatic impairment
No dose adjustment is necessary for patients with hepatic impairment (see section 5.2).
Paediatric population
The safety and efficacy of apremilast in children aged 0 to 17 years have not been established. No data are available.
Method of administration
Otezla is for oral use. The film-coated tablets should be swallowed whole, and can be taken either with or without food.
4.3 Contraindications
Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.
Pregnancy (see section 4.6).
4.4 Special warnings and precautions for use
Patients with rare hereditary problems of galactose intolerance, lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Otezla should be dose reduced to 30 mg once daily in patients with severe renal impairment (see sections 4.2 and 5.2).
Patients who are underweight at the start of treatment should have their body weight monitored regularly. In the event of unexplained and clinically significant weight loss, these patients should be evaluated by a medical practitioner and discontinuation of treatment should be considered.
4.5 Interaction with other medicinal products and other forms of interaction
Co-administration of strong cytochrome P450 3A4 (CYP3A4) enzyme inducer, rifampicin, resulted in a reduction of systemic exposure of apremilast, which may result in a loss of efficacy of apremilast. Therefore, the use of strong CYP3A4 enzyme inducers (e.g. rifampicin, phenobarbital, carbamazepine, phenytoin and St. John's Wort) with apremilast is not recommended. Co-administration of apremilast with multiple doses of rifampicin resulted in a decrease in apremilast area-under-the-concentration time curve (AUC) and maximum serum concentration (Cmax) by approximately 72% and 43%, respectively. Apremilast exposure is decreased when administered concomitantly with strong inducers of CYP3A4 (e.g. rifampicin) and may result in reduced clinical response.
In clinical studies, apremilast has been administered concomitantly with topical therapy (including corticosteroids, coal tar shampoo and saliycyilic acid scalp preparations) and UVB phototherapy.
There was no clinically meaningful drug-drug interaction between ketoconazole and apremilast. Apremilast can be co-administered with a potent CYP3A4 inhibitor such as ketoconazole.
There was no pharmacokinetic drug-drug interaction between apremilast and methotrexate in psoriatic arthritis patients. Apremilast can be co-administered with methotrexate.
There was no pharmacokinetic drug-drug interaction between apremilast and oral contraceptives containing ethinyl estradiol and norgestimate. Apremilast can be co-administered with oral contraceptives.
4.6 Fertility, pregnancy and lactation
Women of childbearing potential
Pregnancy should be excluded before treatment can be initiated.Women of childbearing potential should use an effective method of contraception to prevent pregnancy during treatment.
Pregnancy
There are limited data about the use of apremilast in pregnant women.
Apremilast is contraindicated during pregnancy. Effects of apremilast on pregnancy included embryofetal loss in mice and monkeys, and reduced fetal weights and delayed ossification in mice at doses higher than the currently recommended highest human dose. No such effects were observed when exposure in animals was at 1.3-fold the clinical exposure (see section 5.3).
Breast-feeding
Apremilast was detected in milk of lactating mice (see section 5.3). It is not known whether apremilast, or its metabolites, are excreted in human milk. A risk to the breastfed infant cannot be excluded, therefore apremilast should not be used during breast-feeding.
Fertility
No fertility data is available in humans. In animal studies in mice, no adverse effects on fertility were observed in males at exposure levels 3-fold clinical exposure and in females at exposure levels 1-fold clinical exposure. For pre-clinical fertility data see section 5.3.
4.7 Effects on ability to drive and use machines
Apremilast has no influence on the ability to drive and use machines.
4.8 Undesirable effects
Summary of the safety profile
The most commonly reported adverse reactions in Phase III clinical studies have been gastrointestinal (GI) disorders including diarrhoea (15.7%) and nausea (13.9%). These GI adverse reactions were mostly mild to moderate in severity, with 0.3% of diarrhoea and 0.3% of nausea reported as being severe. These adverse reactions generally occurred within the first 2 weeks of treatment and usually resolved within 4 weeks. The other most commonly reported adverse reactions included upper respiratory tract infections (8.4%), headache (7.9%), and tension headache (7.2%). Overall, most adverse reactions were considered to be mild or moderate in severity.
The most common adverse reactions leading to discontinuation during the first 16 weeks of treatment were diarrhoea (1.7%), and nausea (1.5%). The overall incidence of serious adverse reactions was low and did not indicate any specific system organ involvement.
Hypersensitivity reactions were uncommonly observed in apremilast clinical studies (see section 4.3).
Tabulated list of adverse reactions
The adverse reactions observed in patients treated with apremilast are listed below by system organ class (SOC) and frequency for all adverse reactions. Within each SOC and frequency grouping, adverse reactions are presented in order of decreasing seriousness.
The adverse drug reactions were determined based on data from the apremilast clinical development programme. The frequencies of adverse drug reactions are those reported in the apremilast arms of the four Phase III studies in PsA (n = 1945) or the two Phase III studies in PSOR (n=1184) (highest frequency from either data pool is represented in Table 2).
Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000).
Table 2. Summary of adverse reactions in phase III psoriatic arthritis (PsA) and/or psoriasis (PSOR) clinical studies

System Organ Class

Frequency

Adverse reaction

Infections and infestations

Common

Bronchitis

Upper respiratory tract infection

Nasopharyngitis*

Immune system disorders

Uncommon

Hypersensitivity

Metabolism and nutrition disorders

Common

Decreased appetite*

Psychiatric disorders

Common

Insomnia

Nervous system disorders

Common

Migraine*

Tension headache*

Headache*

Respiratory, thoracic, and mediastinal disorders

Common

Cough

Gastrointestinal disorders

Very Common

Diarrhoea*

Nausea*

Common

Vomiting*

Dyspepsia

Frequent bowel movements

Upper abdominal pain *

Gastroesophageal reflux disease

Skin and subcutaneous tissue disorders

Uncommon

Rash

Musculoskeletal and connective tissue disorders

Common

Back pain*

General disorders and administrative site conditions

Common

Fatigue

Investigations

Uncommon

Weight decrease

At least one of these adverse reactions was reported as serious
Description of selected adverse reactions
Body weight loss
Patient weight was measured routinely in clinical studies. The mean observed weight loss in patients treated for up to 52 weeks with apremilast was 1.99 kg. A total of 14.3% of patients receiving apremilast had observed weight loss between 5-10% while 5.7% of the patients receiving apremilast had observed weight loss greater than 10%. None of these patients had overt clinical consequences resulting from weight loss. A total of 0.1% of patients treated with apremilast discontinued due to adverse reaction of weight decreased.
Please see additional warning in section 4.4 for patients who are underweight at beginning of treatment.
Depression
During the placebo-controlled period of the phase III clinical trials PSOR, 1.2% (14/1184) of patients treated with apremilast reported depression compared to 0.5% (2/418) treated with placebo. None of these reports of depression was serious or led to study discontinuation.
Special populations
Elderly patients
No overall differences were observed in the safety profile of elderly patients ≥ 65 years of age and younger adult patients < 65 years of age in the clinical studies.
Patients with hepatic impairment
The safety of apremilast was not evaluated in PsA or PSOR patients with hepatic impairment.
Patients with renal impairment
In the PsA or PSOR clinical studies, the safety profile observed in patients with mild renal impairment was comparable to patients with normal renal function. The safety of apremilast was not evaluated in PsA or PSOR patients with moderate or severe renal impairment in the clinical studies.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard (Freephone 0808 100 3352).
4.9 Overdose
Apremilast was studied in healthy subjects at a maximum total daily dose of 100 mg (given as 50 mg BID) for 4.5 days without evidence of dose limiting toxicities. In case of an overdose, it is recommended that the patient is monitored for any signs or symptoms of adverse effects and appropriate symptomatic treatment is instituted. In the event of overdose, symptomatic and supportive care is advised.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Immunosupressants, selective immunosuppressants, ATC code: L04AA32
Mechanism of action
Apremilast, an oral small-molecule inhibitor of phosphodiesterase 4 (PDE4), works intracellularly to modulate a network of pro-inflammatory and anti-inflammatory mediators. PDE4 is a cyclic adenosine monophosphate (cAMP)-specific PDE and the dominant PDE in inflammatory cells. PDE4 inhibition elevates intracellular cAMP levels, which in turn down-regulates the inflammatory response by modulating the expression of TNF-α, IL-23, IL-17 and other inflammatory cytokines. Cyclic AMP also modulates levels of anti-inflammatory cytokines such as IL-10.These pro- and anti-inflammatory mediators have been implicated in psoriatic arthritis and psoriasis.
Pharmacodynamics effects
In clinical studies in patients with psoriatic arthritis, apremilast significantly modulated, but did not fully inhibit, plasma protein levels of IL-1α, IL-6, IL-8, MCP-1, MIP-1β, MMP-3, and TNF-α. After 40 weeks of treatment with apremilast, there was a decrease in plasma protein levels of IL-17 and IL-23, and an increase in IL-10. In clinical trials in patients with psoriasis, apremilast decreased lesional skin epidermal thickness, inflammatory cell infiltration, and expression of pro-inflammatory genes, including those for inducible nitric oxide synthase (iNOS), IL-12/IL-23p40, IL-17A, IL-22 and IL-8.
Apremilast administered at doses of up to 50 mg BID did not prolong the QT interval in healthy subjects.
Clinical trials experience
Psoriatic Arthritis
The safety and efficacy of apremilast were evaluated in 3 multi-center, randomized, double-blind, placebo-controlled studies (Studies PALACE 1, PALACE 2, and PALACE 3) of similar design in adult patients with active PsA (≥ 3 swollen joints and ≥ 3 tender joints) despite prior treatment with small molecule or biologic DMARDs. A total of 1493 patients were randomised and treated with either placebo, apremilast 20 mg or apremilast 30 mg given orally twice daily.
Patients in these studies had a diagnosis of PsA for at least 6 months. One qualifying psoriatic skin lesion (at least 2 cm in diameter) was also required in PALACE 3. Apremilast was used as a monotherapy (34.8%) or in combination with stable doses of small molecule DMARDs (65.2%). Patients received apremilast in combination with one or more of the following: methotrexate (MTX, ≤ 25 mg/week, 54.5%), sulfasalazine (SSZ, ≤ 2 g/day, 9.0%), and leflunomide (LEF; ≤ 20 mg/day, 7.4%). Concomitant treatment with biologic DMARDs, including TNF blockers, was not allowed. Patients with each subtype of PsA were enrolled in the 3 studies, including symmetric polyarthritis (62.0%), asymmetric oligoarthritis (26.9%), distal interphalangeal (DIP) joint arthritis (6.2%), arthritis mutilans (2.7%), and predominant spondylitis (2.1%). Patients with pre-existing enthesopathy (63%) or pre-exisitng dactylitis (42%) were enrolled. A total of 76.4% of patients were previously treated with only small-molecule DMARDs and 22.4% of patients were previously treated with biologic DMARDs, which includes 7.8% who had a therapeutic failure with a prior biologic DMARD. The median duration of PsA disease was 5 years.
Based on the study design, patients whose tender and swollen joint counts had not improved by at least 20% were considered non-responders at Week 16. Placebo patients who were considered non-responders were re-randomized 1:1 in a blinded fashion to either apremilast 20 mg twice daily or 30 mg twice daily. At Week 24, all remaining placebo-treated patients were switched to either apremilast 20 or 30 mg BID.
The primary endpoint was the percentage of patients achieving American College of Rheumatology (ACR) 20 response at Week 16.
Treatment with apremilast resulted in significant improvements in the signs and symptoms of PsA, as assessed by the ACR 20 response criteria compared to placebo at Weeks 16. The proportion of patients with ACR 20/50/70(responses in Studies PALACE 1, PALACE 2 and PALACE 3, and the pooled data for studies PALACE 1, PALACE 2 and PALACE 3, for apremilast 30 mg twice daily at Week 16, are shown in Table 3. ACR 20/50/70 responses were maintained at Week 24.
Among patients who were initially randomized to apremilast 30 mg twice daily treatment, ACR 20/50/70 response rates were maintained through Week 52 in the pooled Studies PALACE 1, PALACE 2 and PALACE 3 (Figure 1).
Table 3. Proportion of patients with ACR responses in studies PALACE 1, PALACE 2 and PALACE 3 and pooled studies at Week 16

PALACE 1

PALACE 2

PALACE 3

POOLED

Na

Placebo

+/-

DMARDs

N=168

Apremilast

30 mg BID

+/-

DMARDs

N=168

Placebo

+/-

DMARDs

N=159

Apremilast

30 mg BID

+/-

DMARDs

N=162

Placebo

+/-

DMARDs

N=169

Apremilast

30 mg BID

+/-

DMARDs

N=167

Placebo

+/-

DMARDs

N=496

Apremilast

30 mg BID

+/-

DMARDs

N=497

ACR 20a

               

Week 16

19.0%

38.1%**

18.9%

32.1%*

18.3%

40.7%**

18.8%

37.0%**

ACR 50

               

Week 16

6.0%

16.1%*

5.0%

10.5%

8.3%

15.0%

6.5%

13.9%**

ACR 70

               

Week 16

1.2%

4.2%

0.6%

1.2%

2.4%

3.6%

1.4%

3.0%

p ≤ 0.01 for apremilast vs. placebo.
p ≤ 0.001 for apremilast vs. placebo
a N is the number of patients as randomized and treated.
Figure 1 Proportion of ACR 20/50/70 responders through Week 52 in the pooled analysis of studies PALACE 1, PALACE 2 and PALACE 3 (NRI*)


NRI: None responder imputation. Subjects who discontinued early prior to the time point and subjects who did not have sufficient data for a definitive determination of response status at the time point are counted as non-responders.
Among 497 patients initially randomized to apremilast 30 mg twice daily, 375 (75%) patients were still on this treatment on Week 52. In these patients, ACR 20/50/70 responses at Week 52 were of 57%, 25%, and 11% respectively.
Responses observed in the apremilast treated group were similar in patients receiving and not receiving concomitant DMARDs, including MTX. Patients previously treated with DMARDs or biologics who received apremilast achieved a greater ACR 20 response at Week 16 than patients receiving placebo.
Similar ACR responses were observed in patients with different PsA subtypes, including DIP. The number of patients with arthritis mutilans and predominant spondylitis subtypes was too small to allow meaningful assessment.
In PALACE 1, PALACE 2 and PALACE 3, improvements in Disease Activity Scale (DAS) 28 C-reactive protein (CRP) and in the proportion of patients achieving a modified PsA response criteria (PsARC) were greater in the apremilast group, compared to placebo at Week 16 (nominal p-value p< 0.0004, p-value ≤0.0017, respectively). These improvements were maintained at Week 24. Among patients who remained on the apremilast treatment to which they were randomized at study start, DAS28(CRP) score and PsARC response were maintained through Week 52.
At Weeks 16 and 24 improvements in parameters of peripheral activity characteristic of psoriatic arthritis (e.g. number of swollen joints, number of painful/tender joints, dactylitis and enthesitis) and in the skin manifestations of psoriasis were seen in the apremilast-treated patients. Among patients who remained on the apremilast treatment to which they were randomized at study start, these improvements were maintained through Week 52.
Physical function and health-related quality of life
Apremilast-treated patients demonstrated statistically significant improvement in physical function, as assessed by the disability index of the health assessment questionnaire (HAQ-DI) change from baseline, compared to placebo at Weeks 16 in PALACE 1, PALACE 2 and PALACE 3 and in the pooled studies (Table 4). Improvement in HAQ-DI scores was maintained at Week 24.
Among patients who were initially randomized to apremilast 30 mg twice daily treatment, the change from baseline in the HAQ-DI score at week 52 was -0.333 in the apremilast 30 mg twice daily group in a pooled analysis of the open label phase of studies PALACE 1, PALACE 2 and PALACE 3.
In studies PALACE 1, PALACE 2 and PALACE 3, significant improvements were demonstrated in health-related quality of life, as measured by the changes from baseline in the physical functioning (PF) domain of the Short Form Health Survey version 2 (SF-36v2), and in the Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-fatigue) scores in patients treated with apremilast compared to placebo at Weeks 16 and 24. Among patients who remained on the apremilast treatment, to which they were initially randomized at study start, improvement in physical function and FACIT- fatigue was maintained through Week 52.
Psoriasis
The safety and efficacy of apremilast were evaluated in two multicenter, randomized, double-blind, placebo-controlled studies (Studies ESTEEM 1 and ESTEEM 2) which enrolled a total of 1257 patients with moderate to severe plaque psoriasis who had a body surface area (BSA) involvement of ≥ 10%, Psoriasis Area and Severity Index (PASI) score ≥ 12, static Physician Global Assessment (sPGA) of ≥ 3 (moderate or severe), and who were candidates for phototherapy or systemic therapy.
These studies had a similar design through Week 32. In both studies, patients were randomized 2:1 to apremilast 30 mg BID or placebo for 16 weeks (placebo-controlled phase) and from Weeks 16-32, all patients received apremilast 30 mg BID (maintenance phase). During the Randomized Treatment Withdrawal Phase (Weeks 32-52), patients originally randomized to apremilast who achieved at least a 75% reduction in their PASI score (PASI-75) (ESTEEM 1) or a 50% reduction in their PASI score (PASI-50) (ESTEEM 2) were re-randomized at Week 32 to either placebo or apremilast 30 mg BID. Patients who were re-randomized to placebo and who lost PASI-75 response (ESTEEM 1) or lost 50% of the PASI improvement at Week 32 compared to baseline (ESTEEM 2) were retreated with apremilast 30 mg BID. Patients who did not achieve the designated PASI response by Week 32, or who were initially randomized to placebo, remained on apremilast until Week 52.The use of low potency topical corticosteroids on the face, axillae, and groin, coal tar shampoo and/or salicylic acid scalp preparations was permitted throughout the studies. In addition, at Week 32, subjects who did not achieve a PASI-75 response in ESTEEM 1, or a PASI-50 response in ESTEEM 2, were permitted to use topical psoriasis therapies and/or phototherapy in addition to apremilast 30 mg BID treatment.
In both studies, the primary endpoint was the proportion of patients who achieved PASI-75 at Week 16. The major secondary endpoint was the proportion of patients who achieved a sPGA score of clear (0) or almost clear (1) at Week 16.
The mean baseline PASI score was 19.07 (median 16.80), and the proportion of patients with sPGA score of 3 (moderate) and 4 (severe) at baseline was 70.0% and 29.8%, respectively with a mean baseline BSA involvement of 25.19% (median 21.0%). Approximately 30% of all patients had received prior phototherapy and 54% had received prior conventional systemic and/or biologic therapy for the treatment of psoriasis (including treatment failures), with 37% receiving prior conventional systemic therapy and 30% receiving prior biologic therapy. Approximately one-third of patients had not received prior phototherapy, conventional systemic or biologic therapy. A total of 18% of patients had a history of psoriatic arthritis.
The proportion of patients achieving PASI-50, -75 and -90 responses, and sPGA score of clear (0) or almost clear (1), are presented in Table 4 below. Treatment with apremilast resulted in significant improvement in moderate to severe plaque psoriasis as demonstrated by the proportion of patients with PASI-75 response at Week 16, compared to placebo. Clinical improvement measured by sPGA, PASI-50 and PASI-90 responses were also demonstrated at Week 16. In addition, apremilast demonstrated a treatment benefit across multiple manifestations of psoriasis including pruritus, nail disease, scalp involvement and quality of life measures.
Table 4. Clinical response at week 16 in studies ESTEEM 1 and ESTEEM 2 (FAS a, LOCFb)

ESTEEM 1

ESTEEM 2

 

Placebo

30 mg BID APR*

Placebo

30 mg BID APR*

N

282

562

137

274

PASIc 75, n (%)

15 (5.3)

186 (33.1)

8 (5.8)

79 (28.8)

sPGAd of Clear or

Almost Clear, n (%)

11 (3.9)

122 (21.7)

6 (4.4)

56 (20.4)

PASI 50, n (%)

48 (17.0)

330 (58.7)

27 (19.7)

152 (55.5)

PASI 90, n (%)

1 (0.4)

55 (9.8)

2 (1.5)

24 (8.8)

Percent Change BSAe (%)

mean± SD

- 6.9

± 38.95

- 47.8

± 38.48

- 6.1

± 47.57

-48.4

± 40.78

Change in Pruritus VASf (mm), mean± SD

- 7.3

± 27.08

- 31.5

± 32.43

- 12.2

± 30.94

- 33.5

±35.46

Change in DLQIg, mean± SD

- 2.1

± 5.69

- 6.6

± 6.66

-2.8

± 7.22

-6.7

± 6.95

Change in SF-36 MCS h, mean± SD

- 1.02

± 9.161

2.39

± 9.504

0.00 ±10.498

2.58

± 10.129

p< 0.0001 for apremilast vs placebo, except for ESTEEM 2 PASI 90 and Change in SF-36 MCS where p=0.0042 and p=0.0078, respectively.
a FAS = Full Analysis Set
b LOCF= Last Observation Carried forward
c PASI = Psoriasis Area and Severity Index
d sPGA = Static Physician Global Assessment
e BSA = Body Surface Area
f VAS = Visual Analog Scale; 0 = best, 100 = worst
g DLQI = Dermatology Life Quality Index; 0 = best, 30 = worst
h SF-36 MCS = Medical Outcome Study Short Form 36-Item Health Survey, Mental Component Summary
The clinical benefit of apremilast was demonstrated across multiple subgroups defined by baseline demographics and baseline clinical disease characteristics (including psoriasis disease duration and patients with a history of psoriatic arthritis). The clinical benefit of apremilast was also demonstrated regardless of prior psoriasis medication usage and response to prior psoriasis treatments. Similar response rates were observed across all weight ranges.
Response to apremilast was rapid, with significantly greater improvements in the signs and symptoms of psoriasis, including PASI, skin discomfort/pain and pruritus, compared to placebo by Week 2. In general, PASI responses were achieved by Week 16 and were maintained through Week 32.
In both studies, the mean percent improvement in PASI from baseline remained stable during the Randomized Treatment Withdrawal Phase for patients re-randomized to apremilast at Week 32 (Table 5).
Table 5. Persistence of effect among subjects randomized to APR 30 BID at Week 0 and re-randomized to APR 30 BID at Week 32 to Week 52

Time Point

ESTEEM 1

ESTEEM 2

Patients who achieved PASI-75 at Week 32

Patients who achieved PASI-50 at Week 32

Percent Change in PASI from baseline, mean (%) ± SDa

Week 16

-77.7 ± 20.30

-69.7 ± 24.23

Week 32

-88 ± 8.30

-76.7 ± 13.42

Week 52

-80.5 ± 12.60

-74.4 ± 18.91

Change in DLQI from baseline, mean± SDa

Week 16

-8.3 ± 6.26

-7.8 ± 6.41

Week 32

-8.9 ± 6.68

-7.7 ± 5.92

Week 52

-7.8 ± 5.75

-7.5 ± 6.27

Proportion of subjects with Scalp Psoriasis PGA (ScPGA) 0 or 1, n/N (%)b

Week 16

40/48 (83.3)

21/37 (56.8)

Week 32

39/48 (81.3)

27/37 (73.0)

Week 52

35/48 (72.9)

20/37 (54.1)

a Includes subjects re-randomized to APR 30 BID at Week 32 with a baseline value and a post-baseline value at the evaluated study week.
bN is based on subjects with moderate or greater scalp psoriasis at baseline who were re-randomized to APR 30 BID at Week 32. Subjects with missing data were counted as nonresponders.
In Study ESTEEM 1, approximately 61% of patients re-randomized to apremilast at Week 32 had a PASI-75 response at Week 52. Of the patients with at least a PASI-75 response who were re-randomized to placebo at Week 32 during a Randomized Treatment Withdrawal Phase, 11.7% were PASI-75 responders at Week 52. The median time to loss of PASI-75 response among the patients re-randomized to placebo was 5.1 weeks.
In Study ESTEEM 2, approximately 80.3% of patients re-randomized to apremilast at Week 32 had a PASI-50 response at Week 52. Of the patients with at least a PASI-50 response who were re-randomized to placebo at Week 32, 24.2% were PASI-50 responders at Week 52. The median time to loss of 50% of their Week 32 PASI improvement was 12.4 weeks.
After randomized withdrawal from therapy at Week 32, approximately 70% of patients in Study ESTEEM 1, and 65.6% of patients in Study ESTEEM 2, regained PASI-75 (ESTEEM 1) or PASI-50 (ESTEEM 2) responses after re-initiation of apremilast treatment. Due to the study design the duration of re-treatment was variable, and ranged from 2.6 to 22.1 weeks.
In Study ESTEEM 1, patients randomized to apremilast at the start of the study who did not achieve a PASI-75 response at Week 32 were permitted to use concomitant topical therapies and/or UVB phototherapy between Weeks 32 to 52. Of these patients, 12% achieved a PASI-75 response at Week 52 with apremilast plus topical and/or phototherapy treatment.
In Studies ESTEEM 1 and ESTEEM 2, significant improvements (reductions) in nail psoriasis, as measured by the mean percent change in Nail Psoriasis Severity Index (NAPSI) from baseline, were observed in patients receiving apremilast compared to placebo-treated patients at Week 16 (p< 0.0001 and p=0.0052, respectively). Further improvements in nail psoriasis were observed at Week 32 in patients continuously treated with apremilast.
In Studies ESTEEM 1 and ESTEEM 2, significant improvements in scalp psoriasis of at least moderate severity (≥3), measured by the proportion of patients achieving Scalp Psoriasis Physician's Global Assessment (ScPGA) of clear (0) or minimal (1) at Week 16, were observed in patients receiving apremilast compared to placebo-treated patients (p< 0.0001 for both studies).. The improvements were generally maintained in subjects who were re-randomized to Otezla at Week 32 through Week 52 (Table 5).
In Studies ESTEEM 1 and ESTEEM 2, significant improvements in quality of life as measured by the Dermatology Life Quality Index (DLQI) and the SF-36v2MCS were demonstrated in patients receiving apremilast compared with placebo-treated patients (Table 4). Improvements in DLQI were maintained through Week 52 in subjects who were re-randomized to apremilast at Week 32 (Table 5). In addition, in Study ESTEEM 1, significant improvement in the Work Limitations Questionnaire (WLQ-25) Index was achieved in patients receiving apremilast compared to placebo.
5.2 Pharmacokinetic properties
Absorption
Apremilast is well absorbed with an absolute oral bioavailability of approximately 73%, with peak plasma concentrations (Cmax) occurring at a median time (tmax) of approximately 2.5 hours. Apremilast pharmacokinetics are linear, with a dose-proportional increase in systemic exposure in the dose range of 10 to 100 mg daily. Accumulation is minimal when apremilast is administered once daily and approximately 53% in healthy subjects and 68% in patients with psoriasis when administered twice daily. Co-administration with food does not alter the bioavailability therefore, apremilast can be administered with or without food.
Distribution
Human plasma protein binding of apremilast is approximately 68%. The mean apparent volume of distribution (Vd) is 87 L, indicative of extravascular distribution.
Biotransformation
Apremilast is extensively metabolised by both CYP and non-CYP mediated pathways including oxidation, hydrolysis, and conjugation, suggesting inhibition of a single clearance pathway is not likely to cause a marked drug-drug interaction. Oxidative metabolism of apremilast is primarily mediated by CYP3A4, with minor contributions from CYP1A2 and CYP2A6. Apremilast is the major circulating component following oral administration. Apremilast undergoes extensive metabolism with only 3% and 7% of the administered parent compound recovered in urine and faeces, respectively. The major circulating inactive metabolite is the glucuronide conjugate of O-demethylated apremilast (M12). Consistent with apremilast being a substrate of CYP3A4, apremilast exposure is decreased when administered concomitantly with rifampicin, a strong inducer of CYP3A4.
In vitro, apremilast is not an inhibitor or inducer of cytochrome P450 enzymes. Hence, apremilast co-administered with substrates of CYP enzymes is unlikely to affect the clearance and exposure of active substances that are metabolised by CYP enzymes.
In vitro, apremilast is a substrate, and a weak inhibitor of P-glycoprotein (IC50>50µM), however clinically relevant drug interactions mediated via P-gp are not expected to occur.
In vitro, apremilast has little to no inhibitory effect (IC50>10µM) on Organic Anion Transporter (OAT)1 and OAT3, Organic Cation Transporter (OCT)2, Organic Anion Transporting Polypeptide (OATP)1B1 and OATP1B3, or breast cancer resistance protein (BCRP) and is not a substrate for these transporters. Hence, clinically relevant drug-drug interactions are unlikely when apremilast is co-administered with drugs that are substrates or inhibitors of these transporters.
Elimination
The plasma clearance of apremilast is on average about 10 L/hr in healthy subjects, with a terminal elimination half-life of approximately 9 hours. Following oral administration of radiolabelled apremilast, about 58% and 39% of the radioactivity is recovered in urine and faeces, respectively, with about 3% and 7% of the radioactive dose recovered as apremilast in urine and faeces, respectively.
Elderly patients
Apremilast was studied in young and elderly healthy subjects. The exposure in elderly subjects (65 to 85 years of age) is about 13% higher in AUC and about 6% higher in Cmax for apremilast than that in young subjects (18 to 55 years of age). There is limited pharmacokinetic data in subjects over 75 years of age in clinical trials. No dosage adjustment is necessary for elderly patients.
Renal impairment
There is no meaningful difference in the PK of apremilast between mild or moderate renal impaired subjects and matched healthy subjects (N=8 each). The results support that no dose adjustment is needed in patients with mild and moderate renal impairment. Reduce apremilast dose to 30 mg once daily in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2 or CLcr < 30 mL/min). In 8 subjects with severe renal impairment to whom a single dose of 30 mg apremilast was administered, the AUC and Cmax of apremilast increased by approximately 89% and 42%, respectively.
Hepatic impairment
The pharmacokinetics of apremilast and its major metabolite M12 are not affected by moderate or severe hepatic impairment. No dose adjustment is necessary for patients with hepatic impairment.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology and repeated dose toxicity. There is no evidencefor immunotoxic, dermal irritation, or phototoxic potential.
Fertility and early embryonic development
In a male mouse fertility study, apremilast at oral dosages of 1, 10, 25, and 50 mg/kg/day produced no effects on male fertility; the no observed adverse effect level (NOAEL) for male fertility was greater than 50 mg/kg/day 3-fold clinical exposure).
In a combined female mouse fertility and embryo-fetal developmental toxicity study with oral dosages of 10, 20, 40, and 80 mg/kg/day, a prolongation of oestrous cycles and increased time to mating were observed at 20 mg/kg/day and above; despite this, all mice mated and pregnancy rates were unaffected. The no observed effect level (NOEL) for female fertility was 10 mg/kg/day (1.0-fold clinical exposure).
Embryo-fetal development
In a combined female mouse fertility and embryo-fetal developmental toxicity study with oral dosages of 10, 20, 40, and 80 mg/kg/day, absolute and/or relative heart weights of maternal animals were increased at 20, 40, and 80 mg/kg/day. Increased numbers of early resorptions and reduced numbers of ossified tarsals were observed at 20, 40, and 80 mg/kg/day. Reduced fetal weights and retarded ossification of the supraoccipital bone of the skull were observed at 40 and 80 mg/kg/day. The maternal and developmental NOEL in the mouse was 10 mg/kg/day (1.3-fold clinical exposure).
In a monkey embryo-fetal developmental toxicity study, oral dosages of 20, 50, 200, and 1000 mg/kg/day resulted in a dose-related increase in prenatal loss (abortions) at dosages of 50 mg/kg/day and above; no test article-related effect in prenatal loss was observed at 20 mg/kg/day (1.4-fold clinical exposure).
Pre- and post-natal development
In a pre- and postnatal study, apremilast was administered orally to pregnant female mice at dosages of 10, 80 and 300 mg/kg/day from gestation day (GD) 6 to Day 20 of lactation. Reductions in maternal body weight and weight gain, and one death associated with difficulty in delivering pups were observed at 300 mg/kg/day. Physical signs of maternal toxicity associated with delivering pups were also observed in one mouse at each of 80 and 300 mg/kg/day. Increased peri- and postnatal pup deaths and reduced pup body weights during the first week of lactation were observed at ≥ 80 mg/kg/day (≥ 4.0-fold clinical exposure). There were no apremilast-related effects on duration of pregnancy, number of pregnant mice at the end of the gestation period, number of mice that delivered a litter, or any developmental effects in the pups beyond postnatal day 7. It is likely that pup developmental effects observed during the first week of the postnatal period were related to the apremilast-related pup toxicity (decreased pup weight and viability) and/or lack of maternal care (higher incidence of no milk in the stomach of pups). All developmental effects were observed during the first week of the postnatal period; no apremilast-related effects were seen during the remaining pre- and post-weaning periods, including sexual maturation, behavioural, mating, fertility and uterine parameters. The NOEL in the mouse for maternal toxicity and F1 generation was 10 mg/kg/day (1.3-fold clinical AUC).
Carcinogenicity studies
Carcinogenicity studies in mice and rats showed no evidence of carcinogenicity related to treatment with apremilast.
Genotoxicity studies
Apremilast is not genotoxic. Apremilast did not induce mutations in an Ames assay or chromosome aberrations in cultured human peripheral blood lymphocytes in the presence or absence of metabolic activation. Apremilast was not clastogenic in an in vivo mouse micronucleus assay at doses up to 2000 mg/kg/day.
Other studies
There is no evidence for immunotoxic, dermal irritation, or phototoxic potential.
6. Pharmaceutical particulars
6.1 List of excipients
Tablet core
Microcrystalline cellulose
Lactose monohydrate
Croscarmellose sodium
Magnesium stearate.
Film-coating
Polyvinyl alcohol
Titanium dioxide (E171)
Macrogol 3350
Talc
Iron oxide red (E172).
The 20 mg tablets also contain iron oxide yellow (E172).
The 30 mg tablets also contain iron oxide yellow (E172) and iron oxide black(E172).
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
21 months.
6.4 Special precautions for storage
Do not store above 30°C.
6.5 Nature and contents of container
The treatment initiation pack contains 27 film- coated tablets (4 x10 mg, 4x 20 mg, 19 x 30 mg).
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. Marketing authorisation holder
Celgene Europe Ltd.
1 Longwalk Road
Stockley Park
Uxbridge
UB11 1DB
United Kingdom
8. Marketing authorisation number(s)
EU/1/14/981/001
9. Date of first authorisation/renewal of the authorisation
15 January 2015
10. Date of revision of the text
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.
单包装资料附件:Otezla 30mg tablets(http://www.medicines.org.uk/emc/medicine/29792

10mg/20mg/30mg x27粒   
本品为德国上市为盒式板装
口服Oral OTEZLA (Apremilast)单药疗法显示对未用过DMARD的活动性银屑病关节炎患者有长期临床效益
OTEZLA组的起止点炎、指炎和躯体功能在第16周的改善有临床意义,最长维持至治疗第52周
PALACE 4是首个也是唯一探寻单一药物用于未用过DMARD治疗之患者的有效性和安全性的大样本、安慰剂对照随机研究
OTEZLA的长期安全性和耐受性特征与既往PALACE 研究一致
瑞士布德利 -- (美国商业资讯) -- Celgene Corporation (NASDAQ:CELG)的全资子公司Celgene International Sàrl今天发布了该公司的磷酸二酯酶4 (PDE4)选择性抑制剂口服制剂OTEZLA用于既往未用过延缓病程的抗风湿药(DMARDs)全身制剂或生物制剂的银屑病关节炎患者的III期试验的长期(52周)结果。这些结果在法国巴黎召开的欧洲抗风湿病联盟年会(EULAR 2014)上呈报。
明尼苏达州富兰克林风湿科和免疫科中心主任Alvin Wells, M.D., Ph.D.说:“医生需要多样化的选择来治疗银屑病关节炎,因为治疗是高度个体化的,部分患者可能不适用生物制剂或某些全身用药。这些有效性和安全性结果提示,OTEZLA单药疗法有望在启用DMARD治疗之前,作为一线用药用于活动性银屑病关节炎成人患者,还可能作为长期治疗的选择。”
52周起止点炎和指炎
有基础起止点炎(肌腱或韧带插入骨骼的部位发生炎症)或指炎(几根手指和脚趾发生炎症)的患者采用OTEZLA单药疗法治疗后的结果显示,银屑病关节炎的2个关键表现有长期改善。初始随机分至单药疗法且完成52周疗程的患者中,该结果在52周中得以维持。第52周时,《马斯特里赫特强直性脊柱炎起止点炎评分》(MASES)中位降幅为75.0%,接受 OTEZLA 30毫克每天2次的患者中,45.9%达到0分,即所评估的任何起止点炎部位均无疼痛。OTEZLA 30毫克每天2次组中,指炎数中位降幅也达到100%。 68.8%的患者达到指炎数为0,即无指炎体征。
52周躯体功能
PALACE 4研究的躯体功能分析结果显示,采用经过验证的评估工具进行衡量,OTEZLA单药疗法52周疗程可维持改善最长达52周。
采用OTEZLA单药疗法连续治疗52周的患者中,《健康评估问卷-残疾指数》(HAQ-DI)显示第16周的改善有临床意义,并维持至第52周,HAQ-DI是衡量躯体功能的关键工具,衡量患者在行使日常生活活动中的困难,例如穿衣、行走和进食困难。
采用OTEZLA单药疗法连续治疗52周的患者中,HAQ-DI结果得到《简明健康调查第2版躯体功能发挥》(SF-36 v2 PF)改善的进一步支持。
52周安全性和耐受性
PALACE 4长期(52周)安全性结果显示,与既往报道的24周安全性结果相比,OTEZLA未见新的安全性发现。安全性结果接近III期PALACE 1、2、3临床试验既往报道的结果。
多数不良事件(AEs) 的严重程度属轻度或中度,所致停药率低(所有暴露于OTEZLA的患者中为5.2%),最常报告的AE是恶心、腹泻、头痛和上呼吸道感染。恶心和腹泻的严重程度主要为轻度,最常见于治疗最初2周,常在一个月内缓解,尽管治疗仍在持续中,无需医疗干预。严重AE发生率低,各治疗组接近(OTEZLA 30毫克每天2次组为0.6%,安慰剂组为2.8%),不会随着OTEZLA暴露延长而升高。52周OTEZLA暴露期末的平均体重减轻量, OTEZLA30毫克每天2次组为1.19千克,OTEZLA 20毫克每天2次组为0.91千克。
这些数据未显示需要实验室监测,接近PALACE 1、2、3研究报道的其他OTEZLA数据。
关于PALACE
PALACE 4是III期、多中心、双盲、安慰剂对照、平行组研究,有2个活性治疗组,500多例未用过DMARD的患者按1:1:1比例随机接受OTEZLA 20毫克每天2次、30毫克每天2次或外观相同的安慰剂,疗程为24周,之后再接受活性治疗,最长达52周,再之后为长期安全性阶段,所有患者均接受治疗OTEZLA。
主要终点是第16周的美国风湿科学会20%改善(ACR20)修订版标准,次要终点包括银屑病关节炎的体征和症状的其他衡量指标、躯体功能和患者自诉的转归指标。
2014年3月21日,美国食品药品管理局(FDA)核准OTEZLA用于治疗活动性银屑病关节炎成人患者。银屑病关节炎/银屑病的联合上市授权申请(MAA)于2013年第四季度向欧洲卫生管理部门递交。
关于OTEZLA
OTEZLA是磷酸二酯酶4 (PDE4)的小分子抑制剂口服制剂,特定作用于单磷酸环腺苷酸(cAMP)。PDE4抑制可导致细胞内cAMP水平升高。
重要安全性信息
适应证
OTEZLA®(apremilast)适用于治疗活动性银屑病关节炎成人患者。
重要安全性信息
禁忌症
OTEZLA禁用于已知对apremilast或其剂型中任何成分超敏的患者。
警示和注意事项
抑郁症:OTEZLA治疗与抑郁不良反应增加有关。临床试验期间,1.0% (10/998)的OTEZLA治疗患者报告抑郁症或抑郁心境,相比之下,安慰剂组为0.8% (4/495);0.3% (4/1441) 的OTEZLA治疗患者因抑郁症或抑郁心境而停药,相比之下,安慰剂组没有患者停药(0/495)。OTEZLA组报告严重抑郁的患者为0.2% (3/1441),相比之下,安慰剂组没有患者报告严重抑郁(0/495)。OTEZLA组的0.2% (3/1441)患者可见自杀意念和行为,相比之下,安慰剂组没有自杀意念和行为(0/495)。安慰剂组有2例患者自杀,OTEZLA组没有患者自杀。
对于有抑郁史和/或自杀意念/行为的患者、或OTEZLA用药期间发生此类症状的患者,须慎重权衡OTEZLA治疗的风险和收益。须告知患者、照料者和家属,必须警惕抑郁、自杀意念或其他心境变化的出现和恶化,如果发生这些变化,必须与医疗保健提供者联系。
体重减轻:OTEZLA用药患者中10%报告体重减轻5-10%,安慰剂组为3.3%。应定期监测体重;评估无法解释或有临床意义的体重减轻,并考虑停用OTEZLA。
药物相互作用:OTEZLA与利福平(一种CYP450酶强诱导剂)合用时会降低apremilast暴露量;OTEZLA可能失效。不推荐OTEZLA与CYP450酶诱导剂(例如利福平、苯巴比妥、卡马西平、苯妥英)合用。
不良反应
(在5天剂量递增后)服用OTEZLA最长达16周的患者中,报告率至少为2%、且发生率比安慰剂组高至少1% 的不良反应(OTEZLA%,安慰剂%)有:腹泻(7.7, 1.6)、恶心(8.9, 3.1)、头痛(5.9, 2.2)、上呼吸道感染(3.9, 1.8)、呕吐(3.2, 0.4)、鼻咽炎(2.6, 1.6)、上腹痛(2.0, 0.2)。
特殊人群用药
妊娠和哺乳母亲:OTEZLA属于妊娠C类;尚未在妊娠女性中研究过。仅在潜在收益大于对胎儿的潜在风险时,方可用于妊娠期。Apremilast或其代谢产物是否存在于人类乳汁尚属未知。OTEZLA应慎用于哺乳女性。
肾功能损害:重度肾功能损害(肌酐清除率小于30毫升/分钟)患者应降低OTEZLA剂量;详细情况,参见完整处方信息的第二节“剂量与用法”。
关于银屑病关节炎
银屑病关节炎是一种令人痛苦的慢性炎性疾病,特点是关节疼痛、僵硬、肿胀、特定韧带和肌腱的炎症、躯体功能减退。据估计,世界各地有近3800万人罹患银屑病关节炎。银屑病关节炎可影响日常活动,有报道称可加重工作残疾。银屑病关节炎常见体征和症状包括关节疼痛、僵硬、肿胀。

责任编辑:admin


相关文章
阿普斯特片Otezla(Apremilast Tablets,オテズラ錠)
Otezla Filmtabl(apremilast)阿普斯特片
新型单克隆抗体Taltz(ixekizumab)获欧盟批准治疗斑块型银屑
OTEZLA filmcoated tablets(阿普斯特薄膜片)
Otezla Filmtabletten(Apremilast 阿普斯特薄膜包衣片/混合片)
阿普斯特片|OTEZLA(apremilast)Tablets
OTEZLA(apremilast Tablets)
瑞力芬片|Relifex(Nabumetone tablets)
美国FDA批准Otezla(apremilast)用于治疗银屑病关节炎
依那西普注射剂(ETANERCEPT,ENBREL)
 

最新文章

更多

· 艾地苯醌薄膜包衣片|Rax...
· BAVENCIO(avelumab inje...
· SILIQ(brodalumab)单剂...
· Emflaza(deflazacort t...
· SOLIQUA 100/33(insulin...
· YOSPRALA(aspirin/omepr...
· VIEKIRA XR TABLET(das...
· Xiidra(Lifitegrast Oph...
· LARTRUVO(olaratumab in...
· EXONDYS 51(eteplirsen ...

推荐文章

更多

· 艾地苯醌薄膜包衣片|Rax...
· BAVENCIO(avelumab inje...
· SILIQ(brodalumab)单剂...
· Emflaza(deflazacort t...
· SOLIQUA 100/33(insulin...
· YOSPRALA(aspirin/omepr...
· VIEKIRA XR TABLET(das...
· Xiidra(Lifitegrast Oph...
· LARTRUVO(olaratumab in...
· EXONDYS 51(eteplirsen ...

热点文章

更多