Alefacept
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| AHFS/Drugs.com | Monograph |
| MedlinePlus | a603011 |
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| Routes of administration | Intravenous,intramuscular |
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| Pharmacokineticdata | |
| Bioavailability | 63% (IM) |
| Eliminationhalf-life | ~270 hours |
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| Chemical and physical data | |
| Formula | C2306H3594N610O694S26 |
| Molar mass | 51801.25g·mol−1 |
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Alefaceptis agenetically engineeredimmunosuppressive drug.It was sold under the brand nameAmeviveinCanada,theUnited States,Israel,SwitzerlandandAustralia.In 2011, the manufacturers made a decision to cease promotion, manufacturing, distribution and sales of Amevive during a supply disruption. According to Astellas Pharma US, Inc.,[1]the decision to cease Amevive sales was neither the result of any specific safety concern nor the result of any FDA-mandated or voluntary product recall. On the other hand, usage of Amevive was associated with a certain risk of development systemic diseases such as malignancies. This drug was never approved for the European drug market.
Alefacept is used to controlinflammationin moderate to severepsoriasiswith plaque formation, where it interferes withlymphocyteactivation.[2]It is also being studied in the treatment ofcutaneous T-cell lymphomaandT-cellnon-Hodgkin lymphoma.[3]
Alefacept is afusion protein:it combines part of anantibodywith aproteinthat blocks the growth of some types of T cells.[3]
Mechanism of action
[edit]The mechanism of action involves dual mechanisms. Alefacept inhibits the activation ofCD4+andCD8+T cellsby interfering withCD2on the T cell membrane thereby blocking the costimulatory moleculeLFA-3/CD2 interaction. Another mechanism is inducingapoptosisof memory-effector T lymphocytes. If the T cells were to become activated they would stimulateproliferationofkeratinocytesresulting in the typical psoriatic symptoms. Therefore, alefacept leads to clinical improvement of moderate to severe psoriasis by blunting these reactions. Combinations of therapeutic modalities have been utilized to meet the challenge of difficult to treat psoriasis.[4]
Indications
[edit]Alefacept is indicated for the management of patients with moderate to severe chronic plaque psoriasis in adult patients who are candidates for systemic therapy orphototherapy.The concomitant use of low-potency topicalcorticosteroidswas permitted during the treatment phase with alefacept and does not seem to pose any additional risks.
The drug was approved based upon studies involving 1,869 patients altogether with plaques covering at least 10% of body surface. Either 7.5 mg IV or 15 mg IM once a week were applied. The long-term results (reduction of at least 75% in pretreatmentPASI scores) were 14% and 21%, respectively. Additional improvements ensuing after completion of the 12-week treatment phase or after completion of a second alefacept treatment were also seen. Often theremissionswere maintained for 7 to 12 months after end of treatment.
Contraindications and precautions
[edit]- Alefacept reducesCD4+T cellcounts and may worsen the clinical course ofHIV infections.It is therefore contraindicated in patients with HIV infections.
- Pretreatment CD4+and/orCD8+cellcounts below the accepted lower limit
- History of systemic malignancy
- Caution: Patients at high risk to develop a systemic malignancy
- Knownhypersensitivityto alefacept or to any other ingredient of the preparation
- Caution: There is little experience in geriatric patients (65 years of age or older); so far no differences to the younger age group have been noted.
Pregnancy and lactation
[edit]- Alefacept has been assigned to Pregnancy Category B in the US and to C in Australia.
- Lactation: It is not known if the drug is excreted into human milk. Either the drug orbreastfeedingshould be terminated, taking into account the importance of treatment to the mother.
Pediatric patients
[edit]No clinical experience exists in patients under 18 years of age. The drug should therefore not be used in pediatric patients.
Side effects
[edit]- Lymphopenia:Most common in clinical trials was a significant and dose-related reduction of CD4+ and CD8+ counts in 10 to 59% of patients. However, only 0 to 2% of patients experienced reductions below the accepted lower limit. Consequences of lymphopenia may be infections and/or treatment related malignancies (see below).
- Malignancies: In clinical studies among 1,869 patients 63 treatment-emerged malignancies in 43 patients were observed. Most of these werenonmelanomaandmelanomaskin cancers,othersolid tumors,andlymphomas.
- Infections: In clinical studies 0.9% of patients experienced significant infections compared to 0.2% in the placebo group. Among the infections were serious ones such assepsis,pneumonia,abscesses,wound infectionsandtoxic shock syndrome.
- Sensitivity reactions:Urticariaandangioedemawere observed. If ananaphylactic reactionshould occur symptomatic treatment should be initiated at once.
- Forming ofantibodiesto alefacept: About 3% of patients developed low-titer antibodies with unknown importance for the clinical efficiency of the drug. Long-term immune effects have not been well explored.
- Hepatic Toxicity: Postmarketing reports revealed asymptomatic increases intransaminases(ALTand/orAST),fatty liver degeneration,decompensation of preexistingliver cirrhosis,and acute treatment-relatedliver failure.It is not known if some or all of these manifestations are attributable to alefacept-therapy, but it is recommended to discontinue therapy as soon as any sign of liver toxicity develops.
- Different Common Side Effects: side effects such aspharyngitis,cough,dizziness,nausea,pruritus,myalgias,chills,and reactions at injection sites were observed quite frequently.
Interactions
[edit]- Patients currently undergoing immunosuppressive therapy (phototherapy, or concomitant application of other immunosuppressant agents) should not receive alefacept to avoid the risks of excessive immunosuppression. Studies concerning the combination withcyclosporineormethotrexateare conducted, but no results have been published so far.
- Live vaccines:The efficiency of concomitant application of livevaccineshas not been fully examined yet. However, the effect oftetanustoxoidwas well preserved in clinical trials.
Necessary laboratory examinations
[edit]- CD4+cell counts should be obtained before initiation of therapy and during the 12-week course of therapy in intervals of 2 weeks.
- It may be desirable to monitorliver function studies(AST and ALT) in patients at high risk to develop liver toxicity (e.g., preexisting hepatitis, or high daily consumption of alcohol).
Dosage regimens
[edit]The standard dosage regimen is the weekly application of either 7.5 mg IV or 15 mg IM for a course of 12 weeks. The benefits and risks of repeated courses have not been explored in sufficient detail. Therapy should be conducted under the supervision of a physician experienced in the use of immunosuppressant agents.
Withdrawal
[edit]Due to availability of better tolerated and more efficacious molecules for psoriasis, alefacept was withdrawn from use by its sponsor in 2011.[5]
Notes
[edit]- ^"Amevive (Alefacept) voluntarily discontinued in the U.S. | National Psoriasis Foundation".Archived fromthe originalon 2018-10-13.Retrieved2017-05-06.
- ^"New drugs".Australian Prescriber.27(101): 5. 2004. Archived fromthe originalon 2006-08-24.Retrieved2006-08-20.
- ^ab
This article incorporatespublic domain materialfromAlefacept.U.S. National Cancer Institute.
- ^Scheinfeld N (2005). "Therapy-resistant psoriasis treated with alefacept and subsequent narrow band ultraviolet B phototherapy with total clearing of psoriasis".Dermatol. Online J.11(2): 7.PMID16150215.
- ^"Alefacept",LiverTox: Clinical and Research Information on Drug-Induced Liver Injury,Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases, 2012,PMID31643667,retrieved2021-08-16
External links
[edit]- Koo J, Bagel J, Sweetser M, Ticho B (2006). "Alefacept in combination with ultraviolet B phototherapy for the treatment of chronic plaque psoriasis: results from an open-label, multicenter study".J Drugs Dermatol.5(7): 623–8.PMID16865867.
- Krell J (2006). "Use of alefacept and etanercept in 3 patients whose psoriasis failed to respond to etanercept".J Am Acad Dermatol.54(6): 1099–101.doi:10.1016/j.jaad.2005.08.032.PMID16713481.
- Parrish C, Sobera J, Robbins C, Cantrell W, Desmond R, Elewski B (2006). "Alefacept in the treatment of psoriatic nail disease: a proof of concept study".J Drugs Dermatol.5(4): 339–40.PMID16673801.
- AHFS Database online