Table of Contents |
pt. I | General Aspects | |
1. | Introduction | 3 |
1.1. | Definitions | 4 |
1.1.1. | Drugs as Biological Derivative: Biomedicines | 5 |
1.2. | Adverse Events | 6 |
1.2.1. | Typology of Adverse Events | 7 |
1.2.2. | Classification of Adverse Events | 9 |
1.2.3. | Adverse Drug Events | 10 |
1.2.4. | Off-Label Observations | 11 |
1.2.5. | Postmarketing Surveillance | 11 |
1.2.6. | Adverse Events Analysis | 12 |
| References | 14 |
2. | Adverse Drug Events to Biomedicines | 15 |
| References | 24 |
3. | Systemic Syndromes with Biomedicines | 25 |
3.1. | Capillary/Vascular Leak Syndrome (CLS/VLS) | 25 |
3.2. | Cytokine Release Syndrome (CRS) | 31 |
3.3. | Infusion Reaction Syndrome (IRS) | 34 |
3.4. | Tumor Lysis Syndrome (TLS) | 34 |
3.5. | Systemic Inflammatory Response Syndrome (SIRS) | 36 |
3.6. | Macrophage Activating Syndrome (MAS) | 37 |
3.7. | Immune Reconstitution Inflammatory Syndrome (IRIS) | 38 |
| References | 45 |
pt. II | Monoclonal Antibodies | |
4. | Monoclonal Antibodies | 51 |
4.1. | Structure and Typology | 52 |
4.2. | Chimeric and Humanized mAb | 54 |
4.3. | Fully Humanized mAb | 54 |
4.4. | Nomenclature | 56 |
4.5. | Basic Structure, Targets and Mechanism of Action | 56 |
4.6. | Therapeutic Indications | 60 |
| References | 63 |
5. | Abciximab | 65 |
5.1. | Mechanism of Action | 65 |
5.2. | Adverse Events | 66 |
5.3. | Immunogenicity and Immune Thrombocytopenia | 67 |
5.4. | Off-Label Experience | 69 |
5.5. | Postmarketing Surveillance | 69 |
5.6. | Remarks | 70 |
| References | 70 |
6. | Adalimumab | 71 |
6.1. | Mechanism of Action | 72 |
6.2. | Immunogenicity | 74 |
6.3. | Adverse Events | 74 |
6.4. | Off-Label Experience | 78 |
6.5. | Postmarketing Surveillance | 79 |
6.6. | Remarks | 79 |
| References | 80 |
7. | Alemtuzumab | 81 |
7.1. | Mechanism of Action | 82 |
7.2. | Immunogenicity | 83 |
7.3. | Adverse Events | 83 |
7.4. | Off-Label Experience | 86 |
7.4.1. | Neoplastic Off-Label Experience | 86 |
7.4.2. | Non-Neoplastic Off-Label Experience | 88 |
7.5. | Postmarketing Surveillance | 92 |
7.6. | Remarks | 92 |
| References | 93 |
8. | Basiliximab | 97 |
8.1. | Mechanism of Action | 97 |
8.2. | Immunogenicity | 98 |
8.3. | Adverse Events | 99 |
8.4. | Off-Label Experience | 100 |
8.5. | Postmarketing Surveillance | 102 |
8.6. | Remarks | 102 |
| References | 103 |
9. | Belimumab | 105 |
9.1. | Mechanism of Action | 106 |
9.2. | Immunogenicity | 107 |
9.3. | Adverse Events | 107 |
9.4. | Off-Label Experience | 108 |
9.5. | Postmarketing Surveillance | 110 |
9.6. | Remarks | 110 |
| References | 111 |
10. | Bevacizumab | 113 |
10.1. | Mechanism of Action | 114 |
10.2. | Immunogenicity | 116 |
10.3. | Adverse Events | 116 |
10.4. | Off-Label Experience | 120 |
10.5. | AEs and Tumor Typology | 121 |
10.6. | The AMD Experience | 121 |
10.7. | Postmarketing Surveillance | 122 |
10.8. | Remarks | 123 |
| References | 124 |
11. | Brentuximab | 127 |
11.1. | Mechanism of Action | 128 |
11.2. | Immunogenicity | 129 |
11.3. | Adverse Events | 129 |
11.4. | Off-Label Experience | 130 |
11.5. | Postmarketing Surveillance | 131 |
11.6. | Remarks | 131 |
| References | 132 |
12. | Canakinumab | 135 |
12.1. | Mechanism of Action | 136 |
12.2. | Immunogenicity | 137 |
12.3. | Adverse Events | 137 |
12.4. | Off-Label Experience | 138 |
12.5. | Postmarketing Surveillance | 140 |
12.6. | Remarks | 140 |
| References | 141 |
13. | Catumaxomab | 143 |
13.1. | Mechanism of Action | 144 |
13.2. | Immunogenicity | 145 |
13.3. | Adverse Events | 145 |
13.4. | Postmarketing Surveillance | 146 |
13.5. | Remarks | 146 |
| References | 147 |
14. | Certolizumab | 149 |
14.1. | Mechanism of Action | 150 |
14.2. | Immunogenicity and Immunity | 151 |
14.3. | Adverse Events | 152 |
14.4. | Off-Label Experience | 154 |
14.5. | Postmarketing Surveillance | 155 |
14.6. | Remarks | 156 |
| References | 157 |
15. | Cetuximab | 159 |
15.1. | Mechanism of Action | 161 |
15.2. | Immunogenicity | 163 |
15.3. | Adverse Events | 164 |
15.3.1. | AEs in SCCHN | 165 |
15.3.2. | AEs in mCRC | 166 |
15.4. | Off-Label Experience | 168 |
15.5. | Postmarketing Surveillance | 169 |
15.6. | Remarks | 170 |
| References | 171 |
16. | Daclizumab | 173 |
16.1. | Mechanism of Action | 174 |
16.2. | Immunogenicity | 174 |
16.3. | Adverse Events | 175 |
16.4. | Off-Label Experience | 176 |
16.5. | Postmarketing Surveillance | 180 |
16.6. | Remarks | 180 |
| References | 181 |
17. | Denosumab | 183 |
17.1. | Mechanism of Action | 184 |
17.2. | Immunogenicity | 185 |
17.3. | Adverse Events | 186 |
17.4. | Off-Label Experience | 189 |
17.5. | Postmarketing Surveillance | 189 |
17.6. | Remarks | 190 |
| References | 192 |
18. | Eculizumab | 193 |
18.1. | Mechanism of Action | 194 |
18.2. | Immunogenicity | 195 |
18.3. | Adverse Events | 195 |
18.4. | Off-Label Experience | 196 |
18.5. | Postmarketing Surveillance | 198 |
18.6. | Remarks | 198 |
| References | 199 |
19. | Edrecolomab | 201 |
| References | 202 |
20. | Efalizumab | 203 |
20.1. | Mechanism of Action | 204 |
20.2. | Immunogenicity | 205 |
20.3. | Adverse Events | 206 |
20.4. | The PML Case and Postmarketing Surveillance | 208 |
20.5. | Remarks | 209 |
| References | 210 |
21. | Gemtuzumab | 211 |
21.1. | Mechanism of Action | 212 |
21.2. | Immunogenicity | 213 |
21.3. | Adverse Events | 213 |
21.4. | Postmarketing Surveillance | 215 |
21.5. | Remarks | 216 |
| References | 216 |
22. | Golimumab | 219 |
22.1. | Mechanism of Action | 220 |
22.2. | Immunogenicity | 221 |
22.3. | Adverse Events | 221 |
22.4. | Off-Label Experience | 224 |
22.5. | Postmarketing Surveillance | 225 |
22.6. | Remarks | 226 |
| References | 227 |
23. | Ibritumomab | 229 |
23.1. | Mechanism of Action | 230 |
23.2. | Immunogenicity | 231 |
23.3. | Adverse Events | 231 |
23.4. | Off-Label Experience | 233 |
23.5. | Postmarketing Surveillance | 234 |
23.6. | Remarks | 235 |
| References | 235 |
24. | Infliximab | 237 |
24.1. | Mechanism of Action | 238 |
24.2. | Immunogenicity and Related Events | 240 |
24.3. | Adverse Events | 241 |
24.3.1. | AEs Peculiarities | 243 |
24.4. | Off-Label Experience | 244 |
24.5. | Postmarketing Surveillance | 246 |
24.6. | Remarks | 246 |
| References | 248 |
25. | Ipilimumab | 251 |
25.1. | Mechanism of Action | 252 |
25.2. | Immunogenicity | 253 |
25.3. | Adverse Events | 254 |
25.4. | Off-Label Experience | 257 |
25.5. | Postmarketing Surveillance | 259 |
25.6. | Remarks | 259 |
| References | 260 |
26. | Muromonab | 263 |
| References | 265 |
27. | Natalizumab | 267 |
27.1. | Mechanism of Action | 268 |
27.2. | Immunogenicity | 269 |
27.3. | Adverse Events | 269 |
27.4. | Postmarketing Surveillance | 273 |
27.5. | Remarks | 273 |
| References | 274 |
28. | Nimotuzumab | 277 |
28.1. | Mechanism of Action | 278 |
28.2. | Adverse Events | 278 |
28.3. | Remarks | 279 |
| References | 280 |
29. | Ofatumumab | 281 |
29.1. | Mechanism of Action | 281 |
29.2. | Immunogenicity | 282 |
29.3. | Adverse Events | 283 |
29.4. | Off-Label Experience | 285 |
29.5. | Postmarketing Surveillance | 286 |
29.6. | Remarks | 287 |
| References | 288 |
30. | Omalizumab | 291 |
30.1. | Mechanism of Action | 292 |
30.2. | Immunogenicity | 293 |
30.3. | Adverse Events | 294 |
30.4. | Off-Label Experience | 295 |
30.5. | Unexpected Adverse Events | 297 |
30.6. | Postmarketing Surveillance | 297 |
30.7. | Remarks | 298 |
| References | 299 |
31. | Palivizumab | 301 |
31.1. | Mechanism of Action | 302 |
31.2. | Immunogenicity | 303 |
31.3. | Adverse Events | 304 |
31.4. | Off-Label Experience | 306 |
31.5. | Postmarketing Surveillance | 307 |
31.6. | The Motavizumab Experience | 308 |
31.7. | Remarks | 310 |
| References | 311 |
32. | Panitumumab | 313 |
32.1. | Mechanism of Action | 314 |
32.2. | Immunogenicity | 315 |
32.3. | Adverse Events | 316 |
32.4. | Off-Label Experience | 320 |
32.5. | Postmarketing Surveillance | 322 |
32.6. | Remarks | 322 |
| References | 324 |
33. | Pertuzumab | 327 |
33.1. | Mechanism of Action | 327 |
33.2. | Immunogenicity | 329 |
33.3. | Adverse Events | 329 |
33.4. | Off-Label Experience | 331 |
33.5. | Postmarketing Surveillance | 332 |
33.6. | Remarks | 333 |
| References | 333 |
34. | Ranibizumab | 335 |
34.1. | Mechanism of Action | 336 |
34.2. | Immunogenicity | 338 |
34.3. | Adverse Events | 339 |
34.3.1. | Ocular Adverse Events | 339 |
34.3.2. | Systemic Adverse Events | 340 |
34.4. | Off-Label Experience | 345 |
34.5. | Postmarketing Surveillance | 346 |
34.6. | Remarks | 346 |
| References | 348 |
35. | Rituximab | 351 |
35.1. | Mechanism of Action | 353 |
35.2. | Immunogenicity | 355 |
35.3. | Adverse Events | 355 |
35.4. | Off-Label Experience | 360 |
35.5. | Postmarketing Surveillance | 365 |
35.6. | Remarks | 365 |
| References | 367 |
36. | Tocilizumab | 369 |
36.1. | Mechanism of Action | 370 |
36.2. | Immunogenicity | 372 |
36.3. | Adverse Events | 373 |
36.4. | Off-Label Experience | 377 |
36.5. | Postmarketing Surveillance | 378 |
36.6. | Remarks | 379 |
| References | 380 |
37. | Tositumomab | 383 |
37.1. | Mechanism of Action | 384 |
37.2. | Immunogenicity | 386 |
37.3. | Adverse Events | 386 |
37.4. | Off-Label Experience | 389 |
37.5. | Postmarketing Surveillance | 389 |
37.6. | Remarks | 390 |
| References | 390 |
38. | Trastuzumab | 393 |
38.1. | Mechanism of Action | 394 |
38.2. | Immunogenicity | 397 |
38.3. | Adverse Events | 397 |
38.4. | Off-Label Experience | 402 |
38.5. | Postmarketing Surveillance | 403 |
38.6. | Remarks | 404 |
| References | 405 |
39. | Ustekinumab | 409 |
39.1. | Mechanism of Action | 410 |
39.2. | Immunogenicity | 411 |
39.3. | Adverse Events | 411 |
39.4. | Off-Label Experience | 417 |
39.5. | Postmarketing Surveillance | 418 |
39.6. | Remarks | 419 |
| References | 420 |
pt. III | Fusion Proteins | |
40. | Fusion Proteins | 425 |
| References | 428 |
41. | Abatacept | 429 |
41.1. | Mechanism of Action | 431 |
41.2. | Immunogenicity | 432 |
41.3. | Adverse Events | 433 |
41.4. | Off-Label Experience | 438 |
41.5. | Postmarketing Surveillance | 440 |
41.6. | Remarks | 440 |
| References | 442 |
42. | Aflibercept | 445 |
42.1. | Mechanism of Action | 447 |
42.2. | Immunogenicity | 449 |
42.3. | Adverse Events | 449 |
42.3.1. | Aflibercept (Eylea) | 450 |
42.3.2. | Aflibercept (Zaltrap; Ziv-Aflibercept) | 452 |
42.4. | Off-Label Experience | 453 |
42.4.1. | Aflibercept (Eylea) | 454 |
42.4.2. | Aflibercept (Zaltrap; Ziv-Aflibercept) | 455 |
42.5. | Postmarketing Surveillance | 458 |
42.6. | Remarks | 458 |
| References | 459 |
43. | Alefacept | 463 |
| References | 464 |
44. | Belatacept | 465 |
44.1. | Mechanism of Action | 466 |
44.2. | Immunogenicity | 467 |
44.3. | Adverse Events | 468 |
44.4. | Off-Label Experience and Postmarketing Surveillance | 470 |
44.5. | Remarks | 471 |
| References | 472 |
45. | Etanercept | 473 |
45.1. | Mechanism of Action | 475 |
45.2. | Immunogenicity | 478 |
45.3. | Adverse Events | 478 |
45.3.1. | Additional Adult Safety Profiles (Ps, PsA, AS) | 481 |
45.3.2. | Pediatric Additional Profiles (JIA, Ps, PsA) | 482 |
45.3.3. | Safety Profiles in Other Studies | 484 |
45.4. | Off-Label Experience | 487 |
45.5. | Postmarketing Surveillance | 489 |
45.6. | Remarks | 489 |
| References | 491 |
46. | Rilonacept | 495 |
46.1. | Mechanism of Action | 496 |
46.2. | Immunogenicity | 498 |
46.3. | Adverse Events | 498 |
46.4. | Experience in Gout Studies | 499 |
46.5. | Off-Label Experience | 500 |
46.6. | Postmarketing Surveillance | 501 |
46.7. | Remarks | 501 |
| References | 501 |
47. | Romiplostim | 503 |
47.1. | Mechanism of Action | 504 |
47.2. | Immunogenicity | 504 |
47.3. | Adverse Events | 505 |
47.4. | Off-Label Experience | 507 |
47.5. | Postmarketing Surveillance | 509 |
47.6. | Remarks | 510 |
| References | 511 |
pt. IV | Cytokines | |
48. | Cytokines | 515 |
| References | 521 |
49. | Interleukins | 523 |
49.1. | Interleukin-1 (IL-1) | 524 |
49.2. | Interleukin-2 (IL-2) | 526 |
| References | 529 |
50. | Denileukin-Diftitox | 531 |
50.1. | Mechanism of Action | 531 |
50.2. | Immunogenicity | 532 |
50.3. | Adverse Events | 533 |
50.4. | Off-Label Experience | 534 |
50.5. | Postmarketing Surveillance | 536 |
50.6. | Remarks | 536 |
| References | 537 |
51. | Anakinra | 539 |
51.1. | Mechanism of Action | 540 |
51.2. | Immunogenicity | 542 |
51.3. | Adverse Events | 542 |
51.4. | Off-Label Experience | 544 |
51.5. | Postmarketing Surveillance | 547 |
51.6. | Remarks | 547 |
| References | 549 |
52. | Interferons | 551 |
52.1. | Alpha Interferons | 552 |
52.2. | Beta Interferons | 555 |
52.3. | Gamma Interferon | 559 |
52.4. | Remarks | 560 |
| References | 562 |
53. | Hemopoietic Stimulatory Factors | 563 |
53.1. | Erythropoietins and Epoetins | 563 |
53.2. | Remarks | 569 |
| References | 570 |
54. | Myelopoietic Stimulatory Factors | 573 |
54.1. | Filgrastim, Pegfilgrastim, Sargramostim | 574 |
54.2. | Remarks | 578 |
| References | 578 |
55. | Thrombopoietic Stimulatory Factor | 579 |
55.1. | Interleukin-11 | 579 |
55.2. | Remarks | 581 |
| References | 581 |
56. | Pluripotent Growth Factors | 583 |
56.1. | Ancestim | 584 |
| References | 585 |
57. | Epidermal Growth Factors | 587 |
57.1. | Palifermin and Becaplermin | 588 |
| References | 590 |
pt. V | Overview | |
58. | Biomedicines as Adverse Event Inducers | 593 |
58.1. | General Safety Profile | 603 |
58.1.1. | Infusion Reactions and Injection Site Reactions | 603 |
58.1.2. | Infections | 604 |
58.1.3. | Hematological Events | 606 |
58.1.4. | Anti-Drug Antibody Response | 606 |
58.1.5. | Autoimmune Events | 607 |
58.1.6. | Cutaneous Reactions | 608 |
58.1.7. | Cardiotoxicity | 610 |
58.1.8. | Systemic Syndromes | 610 |
58.1.9. | Malignancies | 611 |
58.1.10. | Other AEs Typologies | 612 |
58.2. | Drug Class Analysis | 613 |
58.2.1. | TNF Inhibitors | 613 |
58.2.2. | T Lymphocyte Inhibitors | 614 |
58.2.3. | B Lymphocyte Inhibitors | 616 |
58.2.4. | VEGF Inhibitors | 617 |
58.2.5. | Cytokines | 617 |
58.2.6. | Interferons | 619 |
58.2.7. | Hemopoietic Stimulatory Factors | 619 |
58.2.8. | Epidermal Growth Factors | 620 |
| References | 622 |
59. | Conclusion and Perspectives | 625 |
| References | 632 |