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Alefacept

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Overview

Alefacept is a genetically engineered immunosuppressive drug sold under the brand name Amevive in Canada, the United States, and Australia. It is used to control inflammation in moderate to severe psoriasis with plaque formation, where it interferes with lymphocyte activation.[1]

Mode of Action

Mode of Action

The exact mode of action is very complicated, but is has been explored that alefacept inhibits the activation of CD2+, CD4+, and CD8+ T cells which in return stimulate hyperproliferation of keratinocyts resulting in the typical psoriatic symptoms. Therefore, alefacept leads to clinical improvement of moderate to severe psoriasis by blunting these reactions.

Drawbacks

Drawbacks

Due to safety issues (immunosuppression, risk of infections, malignancies, and allergies) the European Medicines Agency (EMEA) has so far rejected to approve alefacept.

Indications

Indications

Alefacept is indicated for the management of patients with moderate to severe chronic plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy. The concomitant use of low-potency topical corticosteroids was 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 pretreatment PASI 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 the remissions were maintained for 7 to 12 months after end of treatment.

Contraindications and Precautions

Contraindications and Precautions

  • Alefacept reduces CD4+ T cell counts and may worsen the clinical course of HIV infections. It is therefore contraindicated in patients with HIV infections.
  • Pretreatment CD4+ and/or CD8+ cell counts below the accepted lower limit
  • History of systemic malignancy
  • Caution: Patients at high risk to develop a systemic malignancy
  • Known hypersensitivity to 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

Pregnancy and Lactation

  • 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 or breastfeeding should be terminated, taking into account the importance of treatment to the mother.
Pediatric Patients

Pediatric Patients

No clinical experience exists in patients under 18 years of age. The drug should therefore not be used in pediatric patients.

Side effects

Side effects

  • 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 were nonmelanoma and melanoma skin cancers, other solid tumors, and lymphomas.
  • 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 as sepsis, pneumonia, abscesses, wound infections and toxic shock syndrome.
  • Sensitivity reactions: Urticaria and angioedema were observed. If an anaphylactic reaction should occur symptomatic treatment should be initiated at once.
  • Forming of antibodies to alefacept : About 3% of patients developed low-titer antibodies with unknown importance for the clinical efficiency of the drug. Longterm immune effects have not been well explored.
  • Hepatic Toxicity : Postmarketing reports revealed asymtomatic increases in transaminases (ALT and/or AST), fatty liver degeneration, decompensation of preexisting liver cirrhosis, and acute treatment-related liver 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 as pharyngitis, cough, dizziness, nausea, pruritus, myalgias, chills, and reactions at injection sites were observed quite frequently.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]


Overview

An adverse drug reaction (abbreviated ADR) or adverse drug event (abbreviated ADE) is an expression that describes the unwanted, negative consequences associated with the use of given medications. An ADR is a particular type of adverse effect. The meaning of this expression differs from the meaning of “side effect”, as this last expression might also imply that the effects can be beneficial.[1] The study of ADRs is the concern of the field known as pharmacovigilance.

Informing a patient that ARDs may be a sign that a drug is working may increase acceptance of a medication[2].

Classification

ADRs may be classified by cause and severity.

Cause

  • Type A: pharmacologically predictableddfd
  • Type B: bizarre and unpredictable (or idiosyncratic)
  • Type C: arising from chronic use
  • Type D: delayed reaction
  • Type E: end of dose reaction
  • Type F: failure of therapy

Types A and B were proposed in the 11970s,[3] and the other types were proposed subsequently when the first two proved insufficient to classify ADRs.[4]

Severity

The American Food and Drug Administration defines severe adverse event (SAE) as:[5]:

  • Death
  • Life-Threatening
  • Hospitalization (initial or prolonged)
  • Disability – significant, persistent, or permanent change, impairment, damage or disruption in the patient’s body function/structure, physical activities or quality of life.
  • Congenital Anomaly
  • – or –
  • Requires Intervention to Prevent Permanent Impairment or Damage

Overall Drug Risk

While no official scale exists yet to communicate overall drug risk, the iGuard Drug Risk Rating System is a five color rating scale similar to the Homeland Security Advisory System[6]:

  • Red (High Risk)
  • Orange (Elevated Risk)
  • Yellow (Guarded Risk)
  • Blue (General Risk)
  • Green (Low Risk)

Location

Adverse effects may be local, i.e. limited to a certain location, or systemic, where a medication has caused adverse effects throughout the systemic circulation.

For instance, some ocular antihypertensives cause systemic effects[7], although they are administered locally as eye drops, since a fraction escapes to the systemic circulation.

Mechanisms

As research better explains the biochemistry of drug use, less ADRs are Type B and more are Type A. Common mechanisms are:

  • Abnormal pharmacokinetics due to
    • genetic factors
    • comorbid disease states
  • Synergistic effects between either
    • a drug and a disease
    • two drugs

Abnormal pharmacokinetics

Comorbid disease states

Various diseases, especially those that cause renal or hepatic insufficiency, may alter drug metabolism. Resources are available that report changes in a drug’s metabolism due to disease states.[8]

Genetic factors

Main articles: Pharmacogenetics and Pharmacogenomics

Abnormal drug metabolism may be due to inherited factors of either Phase I oxidation or Phase II conjugation.[9][10] Pharmacogenomics is the study of the inherited basis for abnormal drug reactions.

Phase I reactions

Inheriting abnormal alleles of cytochrome P450can alter drug metabolism. Tables are available to check for drug interactions due to P450 interactions.[11].[12]

Inheriting abnormal butyrylcholinesterase (pseudocholinesterase) may affect metabolism of drugs such as succinylcholine[13]

Phase II reactions

Inheriting abnormal N-acetyltransferase which conjugated some drugs to facilitate excretion may affect the metabolism of drugs such as isoniazid, hydralazine, and procainamide.[13][12]

Inheriting abnormal thiopurine S-methyltransferase may affect the metabolism of the thiopurine drugs mercaptopurine and azathioprine.[12]

Interactions with other drugs

Main article: Drug interaction

The risk of drug interactions is increased with polypharmacy.

Protein binding

These interactions are usually transient and mild until a new steady state is achieved.[14][15] These are mainly for drugs without much first-pass liver metabolism. The prinicple plasma proteins for drug binding are:[16]

  1. albumin
  2. α1-acid glycoprotein
  3. lipoproteins

Some drug interactions with warfarin are due to changes in protein binding.[16]

Cytochrome P450

Patients have abnormal metabolism by cytochrome P450 due to either inheriting abnormal alleles or due to drug interactions. Tables are available to check for drug interactions due to P450 interactions.[17].

Synergistic effects

An example of synergism is two drugs that both prolong the QT interval.

Assessing causality

A simple scale is available at http://annals.org/cgi/content/full/140/10/795.[1]

Note that an ADR should not be labeled as ‘certain’ unless the ADR abates with dechallenge and recurs with rechallenge are true.

A more complicated scale is the Naranjo algorithm.

Publications reporting adverse drug reactions

Reporting standards

Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) recommends standard items to be included in publications[18][19].

Systematic reviews do not well search for or report adverse drug reactions[20][21]. This difficulty may in part be due to problematic reporting of adverse drug reactions in trials[22][22] incuding outcome reporting bias[23].

Searching for publications

Various search strategies have been developed to locate publications that report adverse drug reactions[24].

Monitoring bodies

Many countries have official bodies that monitor drug safety and reactions. On an international level, the WHO runs the Uppsala Monitoring Centre, and the European Union runs the European Medicines Agency (EMEA). In the United States, the Food and Drug Administration (FDA) is responsible for monitoring post-marketing studies.

Diagnosis

Physical Examination

Skin

Extremities
Face

See also

References

  1. ↑ 1.0 1.1 Nebeker JR, Barach P, Samore MH (2004). “Clarifying adverse drug events: a clinician’s guide to terminology, documentation, and reporting”. Ann. Intern. Med. 140 (10): 795–801. PMID 15148066.
  2. ↑ Leibowitz KA, Howe LC, Crum AJ (2021). “Changing mindsets about side effects”. BMJ Open. 11 (2): e040134. doi:10.1136/bmjopen-2020-040134. PMC 7849892 Check |pmc= value (help). PMID 33526496 Check |pmid= value (help).
  3. ↑ Rawlins MD, Thompson JW. Pathogenesis of adverse drug reactions. In: Davies DM, ed. Textbook of adverse drug reactions. Oxford: Oxford University Press, 1977:10.
  4. ↑ Aronson JK. Drug therapy. In: Haslett C, Chilvers ER, Boon NA, Colledge NR, Hunter JAA, eds. Davidson’s principles and practice of medicine 19th ed. Edinburgh: Elsevier Science, 2002:147-63. ISBN 0-44307-035-0.
  5. ↑ “MedWatch – What Is A Serious Adverse Event?”. Retrieved 2007-09-18.
  6. ↑ “‘Traffic-light’ medicine risk website to launch”. The Guardian. 2007-10-02. Check date values in: |date= (help)
  7. ↑ Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4. Page 146
  8. ↑ “Clinical Drug Use”. Retrieved 2007-09-18.
  9. ↑ Phillips KA, Veenstra DL, Oren E, Lee JK, Sadee W (2001). “Potential role of pharmacogenomics in reducing adverse drug reactions: a systematic review”. JAMA. 286 (18): 2270–9. PMID 11710893.
  10. ↑ Goldstein DB (2003). “Pharmacogenetics in the laboratory and the clinic”. N. Engl. J. Med. 348 (6): 553–6. doi:10.1056/NEJMe020173. PMID 12571264.
  11. ↑ “Drug-Interactions.com”. Retrieved 2007-09-18.
  12. ↑ 12.0 12.1 12.2 Weinshilboum R (2003). “Inheritance and drug response”. N. Engl. J. Med. 348 (6): 529–37. doi:10.1056/NEJMra020021. PMID 12571261.
  13. ↑ 13.0 13.1 Evans WE, McLeod HL (2003). “Pharmacogenomics–drug disposition, drug targets, and side effects”. N. Engl. J. Med. 348 (6): 538–49. doi:10.1056/NEJMra020526. PMID 12571262.
  14. ↑ DeVane CL (2002). “Clinical significance of drug binding, protein binding, and binding displacement drug interactions”. Psychopharmacology bulletin. 36 (3): 5–21. PMID 12473961.
  15. ↑ Benet LZ, Hoener BA (2002). “Changes in plasma protein binding have little clinical relevance”. Clin. Pharmacol. Ther. 71 (3): 115–21. doi:10.1067/mcp.2002.121829. PMID 11907485.OVID full text summary table at OVID
  16. ↑ 16.0 16.1 Sands CD, Chan ES, Welty TE (2002). “Revisiting the significance of warfarin protein-binding displacement interactions”. The Annals of pharmacotherapy. 36 (10): 1642–4. PMID 12369572.
  17. ↑ “Drug-Interactions.com”. Retrieved 2007-09-18.
  18. ↑ Zorzela L, Loke YK, Ioannidis JP, Golder S, Santaguida P, Altman DG; et al. (2016). “PRISMA harms checklist: improving harms reporting in systematic reviews”. BMJ. 352: i157. doi:10.1136/bmj.i157. PMID 26830668.
  19. ↑ PRISMA for reviews including harms outcomes. Available at http://prisma-statement.org/Extensions/Harms
  20. ↑ Golder S, Loke Y, McIntosh HM (2008). “Poor reporting and inadequate searches were apparent in systematic reviews of adverse effects”. J Clin Epidemiol. 61 (5): 440–8. doi:10.1016/j.jclinepi.2007.06.005. PMID 18394536.
  21. ↑ Zorzela L, Golder S, Liu Y, Pilkington K, Hartling L, Joffe A; et al. (2014). “Quality of reporting in systematic reviews of adverse events: systematic review”. BMJ. 348: f7668. doi:10.1136/bmj.f7668. PMC 3898583. PMID 24401468.
  22. ↑ 22.0 22.1 Barhli A, Joulia ML, Tournigand C, Kempf E (2021). “Adverse events reporting in phase 3 oncology clinical trials of checkpoint inhibitors: A systematic review”. Crit Rev Oncol Hematol. 157: 103162. doi:10.1016/j.critrevonc.2020.103162. PMID 33260049 Check |pmid= value (help).
  23. ↑ Saini P, Loke YK, Gamble C, Altman DG, Williamson PR, Kirkham JJ (2014). “Selective reporting bias of harm outcomes within studies: findings from a cohort of systematic reviews”. BMJ. 349: g6501. doi:10.1136/bmj.g6501. PMC 4240443. PMID 25416499.
  24. ↑ Golder S, Farrah K, Mierzwinski-Urban M, Wright K, Loke YK (2019). “The development of search filters for adverse effects of medical devices in medline and embase”. Health Info Libr J. 36 (3): 244–263. doi:10.1111/hir.12260. PMC 6853259 Check |pmc= value (help). PMID 31187590.
  25. ↑ 25.0 25.1 25.2 25.3 25.4 25.5 25.6 “Dermatology Atlas”.


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Interactions

Interactions

  • Patients currently undergoing immunosuppressive therapy (phototherapy, or concomitant application of other immunosuppressant agents) should not receive alefacept in order to avoid the risks of excessive immunosuppression. Studies concerning the combination with cyclosporine or methotrexate are conducted, but no results have been published so far.
  • Live vaccines : The efficiency of concomitant application of live vaccines has not been fully examined yet. However, the effect of tetanus toxoid was well preserved in clinical trials.
Necessary Laboratory Examinations

Necessary Laboratory Examinations

  • 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 monitor liver 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 Regimes

Dosage Regimes

The standard dosage regime 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.

Notes

Notes

  1. ↑ “New drugs“. Australian Prescriber. 27 (101): 5. 2004. Retrieved 2006-08-20.
External links
  • Koo J, Bagel J, Sweetser M, Ticho B. “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. PMID 16865867.
  • 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. PMID 16713481.
  • 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. PMID 16673801.
  • AHFS Database online

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