Nilotinib/ 757 3. Silvani A, et al. Intra-arterial ACNU and versus in- 6. Mita MM, et al. A phase I, pharmacokinetic and biologic correl- (p.653). It has also been tried in the treatment of acute leukaemi- travenous with and BCNU in newly di- ative study of sodium (Genasense, G3139) and iri- as and other neoplastic disorders. agnosed patients with glioblastoma. Neurol Sci 2002; 23: notecan in patients with metastatic colorectal . Ann Oncol 219–24. 2006; 17: 313–21. The related compounds harringtonine, isoharringtonine, and de- 4. Weller M, et al. Neuro-Oncology Working Group 01 trial of 7. Bedikian AY, et al. Bcl-2 antisense (oblimersen sodium) plus oxyharringtonine have also been investigated. plus versus nimustine plus in patients with advanced melanoma: the Oblim- Adverse effects of omacetaxine mepesuccinate may include se- chemotherapy in addition to involved-field radiotherapy in the ersen Melanoma Study Group. J Clin Oncol 2006; 24: 4738–45. vere hypotension, cardiac arrhythmias, myelosuppression, gas- first-line treatment of malignant glioma. J Clin Oncol 2003; 21: 8. O’Brien S, et al. Randomized phase III trial of plus trointestinal disturbances, chest pain, headache, fatigue, alo- with or without oblimersen sodium (Bcl-2 3276–84. pecia, rashes, and hyperglycaemia. 5. Watanabe T, et al. Human interferon beta, nimustine hydrochlo- antisense) in patients with relapsed or refractory chronic lym- ride, and radiation therapy in the treatment of newly diagnosed phocytic leukemia. J Clin Oncol 2007; 25: 1114–20. Correction. ◊ References. ibid. 2008; 26: 820. malignant astrocytomas. J Neurooncol 2005; 72: 57–62. 1. Kantarjian HM, et al. Homoharringtonine and low-dose cytarab- ine in the management of late chronic-phase chronic myeloge- Preparations nous leukemia. J Clin Oncol 2000; 18: 3513–21. Proprietary Preparations (details are given in Part 3) 2. Kantarjian HM, et al. Homoharringtonine: history, current re- Ofatumumab (rINN) search, and future direction. Cancer 2001; 92: 1591–1605. Ger.: ACNU; Jpn: Nidran†; Neth.: ACNU†; Switz.: ACNU†. HuMax-CD20; Ofatumumabum. Immunoglobulin G1, anti-(hu- 3. O’Brien S, et al. Simultaneous homoharringtonine and interfer- on-alpha in the treatment of patients with chronic-phase chronic man CD20 (antigen))(human monoclonal HuMax-CD20 heavy myelogenous leukemia. Cancer 2002; 94: 2024–32. chain), disulfide with human monoclonal HuMax-CD20 κ-chain, 4. Tang J, et al. A homoharringtonine-based regimen for childhood Nolatrexed (rINN) dimer. acute myelogenous leukemia. Med Pediatr Oncol 2003; 41: 70–2. AG-337 (nolatrexed dihydrochloride); Nolatrexedum. 2-Amino- Офатумумаб 5. O’Brien S, et al. Results of triple therapy with interferon-alpha, 6-methyl-5-(4-pyridylthio)-4(3H)-quinazolinone. CAS — 679818-59-8. cytarabine, and homoharringtonine, and the impact of adding im- atinib to the treatment sequence in patients with Philadelphia Нолатрексед Profile chromosome-positive chronic myelogenous leukemia in early Ofatumumab is an anti-CD20 monoclonal antibody that is under C H N OS = 284.3. chronic phase. Cancer 2003; 98: 888–93. 14 12 4 investigation for the treatment of non-Hodgkin’s and 6. Luo CY, et al. Homoharringtonine: a new treatment option for CAS — 147149-76-6 (nolatrexed); 152946-68-4 (nola- chronic lymphocytic leukaemia. myeloid leukemia. Hematology 2004; 9: 259–70. trexed dihydrochloride). 7. Quintás-Cardama A, Cortes J. Homoharringtonine for the treat- ◊ References. ment of chronic myelogenous leukemia. Expert Opin Pharmaco- 1. Coiffier B, et al. Safety and efficacy of ofatumumab, a fully hu- ther 2008; 9: 1029–37. man monoclonal anti-CD20 antibody, in patients with relapsed 8. Quintás-Cardama A, Cortes J. Omacetaxine mepesuccinate - a or refractory B- chronic lymphocytic leukemia: a phase 1-2 semisynthetic formulation of the natural antitumoral alkaloid ho- H3C NH study. Blood 2008; 111: 1094–1100. moharringtonine, for chronic myelocytic leukemia and other my- 2. Hagenbeek A, et al. First clinical use of ofatumumab, a novel eloid malignancies. IDrugs 2008; 11: 356–72. NH2 fully human anti-CD20 monoclonal antibody in relapsed or re- N S N fractory follicular lymphoma: results of a phase 1/2 trial. Blood 2008; 111: 5486–95. O 3. Robak T. Ofatumumab, a human monoclonal antibody for lym- Oregovomab (USAN, rINN) phoid malignancies and autoimmune disorders. Curr Opin Mol Ther 2008; 10: 294–309. MAb-B43.13; Orégovomab; Oregovomabum. Immunoglobulin Profile G1, anti-(human CA125 (carbohydrate antigen)) (mouse mon- Nolatrexed is, like (p.766), a selective inhibitor of oclonal B43.13 γ1-chain), disulfide with mouse monoclonal thymidylate synthase. It has been investigated as an antimetabo- B43.13 κ-chain, dimer. (rINN) lite antineoplastic for the treatment of hepatocellular carcinoma, Ореговомаб although results of single-agent studies have been disappointing. Olaparibum. 4-[(3-{[4-(Cyclopropylcarbonyl)piperazin-1-yl]car- CAS — 213327-37-8. It is also under investigation in combination therapy for other bonyl}-4-fluorophenyl)methyl]phthalazin-1(2H)-one. solid tumours. Profile Олапариб Oregovomab is a murine monoclonal antibody that binds to CA- ◊ References. C24H23FN4O3 = 434.5. 125, an antigen that is overexpressed in the majority of ovarian CAS — 763113-22-0. 1. Mok TS, et al. A multi-centre randomized phase II study of nol- cancer patients, and stimulates an immune response to the tu- atrexed versus in treatment of Chinese patients with mour cells. It is under investigation for the treatment of ovarian advanced hepatocellular carcinoma. Cancer Chemother Phar- cancer. macol 1999; 44: 307–11. O 2. Hughes AN, et al. Clinical pharmacokinetic and in vitro combi- nation studies of nolatrexed dihydrochloride (AG337, Thymitaq) and . Br J Cancer 2000; 82: 1519–27. N 3. Estlin EJ, et al. A phase I study of nolatrexed dihydrochloride in Oxaliplatin (BAN, USAN, rINN) children with advanced cancer. Br J Cancer 2001; 84: 11–18. N N O N F JM-83; NSC-266046; l-OHP; Oksaliplatiini; Oksaliplatin; Oksalip- 4. Pivot X, et al. Result of two randomized trials comparing nola- H latina; Oxaliplatina; Oxaliplatine; Oxaliplatino; Oxaliplatinum; RP- trexed (Thymitaq) versus in patients with recurrent O head and neck cancer. Ann Oncol 2001; 12: 1595–9. 54780; SR-96669. [(1R,2R)-1,2-Cyclohexanediamine-N,N′]- 5. Jhawer M, et al. Phase II trial of nolatrexed dihydrochloride [oxalato(2-)-O,O′]platinum. [Thymitaq, AG 337] in patients with advanced hepatocellular Profile Olaparib is an antineoplastic that is under investigation for the Оксалиплатин carcinoma. Invest New Drugs 2007; 25: 85–94. C H N O Pt = 397.3. 6. Gish RG, et al. Phase III randomized controlled trial comparing treatment of ovarian cancer. 8 14 2 4 the survival of patients with unresectable hepatocellular carcino- CAS — 61825-94-3. ma treated with nolatrexed or doxorubicin. J Clin Oncol 2007; ATC — L01XA03. 25: 3069–75. ATC Vet — QL01XA03. Omacetaxine Mepesuccinate (pINN) CGX-635; HHT; Homoharringtonine; Mepesuccinato de oma- cetaxina; NSC-141633; Omacétaxine, Mépésuccinate d’; Oma- H2 Oblimersen Sodium (USAN, rINNM) cetaxini mepesuccinas. 1-[(1S,3aR,14bS)-2-Methoxy-1,5,6,- N O O G-3139; Natrii Oblimersenum; Oblimersén sódico; Oblimersen 8,9,14b-hexahydro-4H-cyclopenta[a][1,3]dioxolo[4,5-h]pyrro- Pt Sodique. lo[2,1-b][3]benzazepin-1-yl] 4-methyl (2R)-2-hydroxy-2-(4-hy- N droxy-4-methylpentyl)butanedioate. O O Натрий Облимерсен H2 Омацетаксин Мепесукцинат C172H204N62-Na17O91P17S17 = 6058.3. CAS — 190977-41-4. C29H39NO9 = 545.6. Pharmacopoeias. In Eur. (see p.vii). CAS — 26833-87-4. Ph. Eur. 6.2 (Oxaliplatin). A white or almost white, crystalline Profile powder. Slightly soluble in water; practically insoluble in dehy- Oblimersen sodium is an antisense oligonucleotide that blocks drated alcohol; very slightly soluble in methyl alcohol. the production of BCL-2, a mitochondrial that prevents O CH apoptosis. It is under investigation for the treatment of various 3 Incompatibility. Licensed product information states that malignant neoplasms, including leukaemias, lung cancer, and HO CH oxaliplatin should not be mixed with chloride-containing solu- 3 HO malignant melanoma. tions (including sodium chloride) or alkaline drugs or solutions. O In particular, oxaliplatin should not be mixed with or H C OCH3 ◊ References. 3 O any trometamol salts. While oxaliplatin may be infused through 1. Frankel SR. Oblimersen sodium (G3139 Bcl-2 antisense oligo- a Y-site with folinic acid (in glucose 5% solution), they may not nucleotide) therapy in Waldenstrom’s macroglobulinemia: a tar- O H be mixed in the same infusion bag, and folinic acid must not con- geted approach to enhance apoptosis. Semin Oncol 2003; 30: H tain trometamol as an excipient. The infusion line should be 300–304. O flushed with glucose 5% before giving any other medication. 2. Büchele T. Proapoptotische Therapie mit Oblimersen (bcl-2-An- N Oxaliplatin may degrade on contact with aluminium, and injec- tisense-Oligonukleotid)—Übersicht über präklinische und kli- tion equipment containing aluminium should not be used. nische Daten. Onkologie 2003; 26 (suppl 7): 60–9. O 3. Herbst RS, Frankel SR. Oblimersen sodium (Genasense bcl-2 Stability. UK licensed product information states that oxalipla- antisense oligonucleotide): a rational therapeutic to enhance ap- tin must be diluted in glucose 5% to give a concentration not less optosis in therapy of lung cancer. Clin Cancer Res 2004; 10 (sup- Pharmacopoeias. In Chin. than 200 micrograms/mL. From a microbiological point of view, pl): 4245s–4248s. Profile the infusion preparation should be used immediately; the infu- 4. Chi KN. Targeting Bcl-2 with oblimersen for patients with hor- Omacetaxine mepesuccinate is a semisynthetic formulation of sion should not be stored for longer than 24 hours at 2° to 8° mone refractory prostate cancer. World J Urol 2005; 23: 33–7. homoharringtonine, which is an alkaloid derived from the tree unless it has been prepared in controlled and validated aseptic 5. O’Brien SM, et al. Phase I to II multicenter study of oblimersen sodium, a Bcl-2 antisense oligonucleotide, in patients with ad- Cephalotaxus harringtonia, and related species. It is thought to conditions. Chemical and physical stability has been shown for vanced chronic lymphocytic leukemia. J Clin Oncol 2005; 23: induce apoptosis by inhibition of protein synthesis. It is under 48 hours at 2° to 8°, and for 24 hours at 25°. US licensed product 7697–7702. investigation for the treatment of chronic myeloid leukaemia information states that, after dilution in 250 to 500 mL of glucose The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii) 758 Antineoplastics 5%, oxaliplatin infusion solutions have a shelf-life of 6 hours at nous calcium gluconate and magnesium chloride infusions have 7. Brandi G, et al. Hypersensitivity reactions related to oxaliplatin room temperature (20° to 25°) and up to 24 hours when refriger- been used to prevent acute oxaliplatin neuropathy with good in- (OHP). Br J Cancer 2003; 89: 477–81. 8. Garufi C, et al. Skin testing and hypersensitivity reactions to ated (2° to 8°), and that protection from light is not required. itial results; similarly, intravenous calcium gluconate and magne- oxaliplatin. Ann Oncol 2003; 14: 497–8. A study1 found that oxaliplatin solutions at 700 micrograms/mL sium sulfate have been reported to dramatically improve oxalipl- 9. Lenz G, et al. Adverse reactions to oxaliplatin: a retrospective in polyolefin infusion bags of glucose 5% were chemically stable atin-associated neuropathy.4-6 However, a study designed to study of 25 patients treated in one institution. Anticancer Drugs for at least 30 days at both 3° to 7° and 20° to 24° without regard evaluate potential reduction of cumulative neurotoxicity associ- 2003; 14: 731–3. ated with oxaliplatin, using calcium and magnesium salts, was 10. Lim K-H, et al. Hypersensitivity reactions to oxaliplatin: a case to light. report and the success of a continuous infusional desensitization 1. André P, et al. Stability of oxaliplatin in infusion bags containing terminated after those patients receiving calcium and magnesium schedule. Anticancer Drugs 2004; 15: 605–7. 5% dextrose injection. Am J Health-Syst Pharm 2007; 64: reported a significantly lower response to chemotherapy (which 11. Gammon D, et al. Hypersensitivity reactions to oxaliplatin and 1950–4. consisted of oxaliplatin, folinic acid, fluorouracil, and bevacizu- the application of a desensitization protocol. Oncologist 2004; mab). Although these results need confirmation, the possibility 9: 546–9. Adverse Effects and Precautions that calcium and magnesium may reduce the activity of certain 12. Ng CVT. Hypersensitivity reactions to oxaliplatin in two Asian 7 patients. Ann Pharmacother 2005; 39: 1114–18. The adverse affects of oxaliplatin are similar to those of drugs in the treatment of colorectal cancer should be considered. 13. Mis L, et al. Successful desensitization to oxaliplatin. Ann 1. Extra JM, et al. Pharmacokinetics and safety profile of oxalipla- Pharmacother 2005; 39: 966–9. cisplatin (p.698) but nausea and vomiting, nephrotox- tin. Semin Oncol 1998; 25 (suppl 5): 13–22. icity, and myelosuppression, seem to be less marked. 2. Culy CR, et al. Oxaliplatin: a review of its pharmacological Interactions Raised liver enzyme values may occur. Neurotoxicity properties and clinical efficacy in metastatic colorectal cancer and its potential in other malignancies. Drugs 2000; 60: For reference to the effect of oxaliplatin on fluorour- can be dose-limiting. Peripheral neuropathy occurs in 895–924. acil, see Antineoplastics, p.723. 85 to 95% of patients given oxaliplatin; pain, function- 3. Cassidy J, Misset J-L. Oxaliplatin-related side effects: character- istics and management. Semin Oncol 2002; 29 (suppl 15): 11–20. al impairment, and loss of tendon reflexes may devel- 4. Gamelin L, et al. Prevention of oxaliplatin-related neurotoxicity Pharmacokinetics op. Pulmonary fibrosis, potentially fatal, has also been by calcium and magnesium infusions: a retrospective study of After intravenous doses, oxaliplatin is widely distribut- 161 patients receiving oxaliplatin combined with 5-fluorouracil reported. Extravasation of oxaliplatin can cause local and leucovorin for advanced colorectal cancer. Clin Cancer Res ed throughout the body. It binds irreversibly to red pain and inflammation; complications may sometimes 2004; 10: 4055–61. blood cells, which can prolong the half-life of the drug. be severe, including necrosis. 5. Cersosimo RJ. Oxaliplatin-associated neuropathy: a review. Ann Pharmacother 2005; 39: 128–35. The mean terminal half-life has been variously stated Neurological examinations should be carried out at 6. Gamelin L, et al. Neurotoxicité de l’oxaliplatine. Bull Cancer to be 273 hours and 391 hours. regular intervals during treatment and the dose should 2006; 93 (suppl 1): S17–S22. 7. Hochster HS, et al. Use of calcium and magnesium salts to re- Oxaliplatin is extensively metabolised to both inactive be reduced if symptoms are prolonged or severe. Reg- duce oxaliplatin-related neurotoxicity. J Clin Oncol 2007; 25: and active compounds and is predominantly excreted ular blood counts should be performed during treat- 4028–9. in the urine. ment and courses should not be repeated until blood GUILLAIN-BARRÉ SYNDROME. A patient with metastatic colon ◊ References. counts have recovered (see also Bone-marrow Depres- cancer developed Guillain-Barré syndrome after weekly treatment with oxaliplatin-based chemotherapy;1 he recov- 1. Lévi F, et al. Oxaliplatin: pharmacokinetics and chronopharma- sion, p.639). Oxaliplatin should not be given to patients cological aspects. Clin Pharmacokinet 2000; 38: 1–21. ered after treatment with intravenous immunoglobulin. with pre-existing sensory neuropathies or myelosup- 2. Graham MA, et al. Clinical pharmacokinetics of oxaliplatin: a 1. Christodoulou C, et al. Guillain-Barré syndrome in a patient with critical review. Clin Cancer Res 2000; 6: 1205–18. pression, nor to those with severe renal impairment. metastatic colon cancer receiving oxaliplatin-based chemothera- Renal function and toxicity should be carefully moni- py. Anticancer Drugs 2004; 15: 997–9. Uses and Administration tored in those with more moderate degrees of renal im- REVERSIBLE POSTERIOR LEUKOENCEPHALOPATHY SYNDROME. Oxaliplatin is a platinum-containing complex similar pairment. Reversible posterior leukoencephalopathy syndrome (RPLS) was diagnosed in a woman given oxaliplatin with bevacizum- to cisplatin (see p.698). It is given with fluorouracil and Patients are recommended to use appropriate contra- ab, and . She tolerated further therapy with beva- folinic acid in the treatment of metastatic colorectal ceptive measures during treatment and for 6 months af- cizumab and with no complications. The authors cancer and in the adjuvant treatment of stage III (Dukes ter stopping treatment for men and for 4 months for attributed the RPLS to oxaliplatin.1 C) colon cancer (p.665). The recommended dose is women. 1. Pinedo DM, et al. Reversible posterior leukoencephalopathy 2 by intravenous infusion over 2 to 6 hours, syndrome associated with oxaliplatin. J Clin Oncol 2007; 25: 85 mg/m Effects on the blood. Acute haemolysis, with1-4 and without5 5320–1. dissolved in 250 to 500 mL of glucose 5%. The dose anaemia, has been reported with the use of oxaliplatin. The reac- Extravasation. Although oxaliplatin was originally considered may be repeated at intervals of 2 weeks if toxicity per- tions were considered to be immune-mediated. Evan’s syndrome to be non-vesicant, there have been reports of extravasation caus- mits, reduced according to tolerance. In the adjuvant (immune-mediated thrombocytopenia and haemolytic anaemia) ing inflammation, sclerosis, or, in some cases, severe necrosis.1-4 setting, oxaliplatin is given for 12 cycles. After persist- 6 1,2 has also been reported. Some consider it to be a vesicant drug, although others state ent neurotoxicity or recovery from severe adverse ef- 1. Desrame J, et al. Oxaliplatin-induced haemolytic anaemia. Lan- oxaliplatin extravasation to be less harmful than that of more cet 1999; 354: 1179–80. classic vesicants.4 fects licensed product information recommends an in- 2. Garufi C, et al. Immunohemolytic anemia following oxaliplatin 2 For discussion of the management of extravasation, see under itial reduction to 65 mg/m in metastatic colorectal administration. Ann Oncol 2000; 11: 497. 2 3. Hofheinz R-D, et al. Two potential mechanisms of oxaliplatin- Treatment of the Adverse Effects of Antineoplastics, p.640. cancer, and to 75 mg/m when given as adjuvant treat- induced haemolytic anaemia in a single patient. Cancer Chem- 1. Baur M, et al. Extravasation of oxaliplatin (Eloxatin )–clinical ment. Oxaliplatin should always be given before fluor- other Pharmacol 2004; 53: 276–7. course. Onkologie 2000; 23: 468–71. opyrimidines. 4. Chen VMY, et al. An immediate hemolytic reaction induced by 2. Foo KF, et al. A case report of oxaliplatin extravasation. Ann repeated administration of oxaliplatin. Transfusion 2004; 44: Oncol 2003; 14: 961–2. Oxaliplatin is under investigation for the treatment of 838–43. 3. Kennedy JG, et al. Vesicant characteristics of oxapliplatin [sic] 5. Koutras AK, et al. Oxaliplatin-induced acute-onset thrombocy- following antecubital extravasation. Clin Oncol (R Coll Radiol) ovarian and lung cancer. A liposomal formulation of topenia, hemorrhage and hemolysis: a case report and review of 2003; 15: 237–9. oxaliplatin is in development. the literature. Oncology 2004; 67: 179–82. 4. Kretzschmar A, et al. Extravasations of oxaliplatin. J Clin Oncol 6. Earle CC, et al. Oxaliplatin-induced Evan’s syndrome. Br J Can- 2003; 21: 4068–9. ◊ References. cer 2001; 84: 441. 1. Culy CR, et al. Oxaliplatin: a review of its pharmacological Hypersensitivity. Hypersensitivity reactions, including anaph- properties and clinical efficacy in metastatic colorectal cancer Effects on the liver. The development of ascites, portal hyper- ylaxis, have been reported with oxaliplatin,1-13 usually after sev- and its potential in other malignancies. Drugs 2000; 60: tension, and hepatic lesions in a patient with colorectal cancer eral cycles of treatment. Symptoms include hypotension, tachy- 895–924. was considered to be due to oxaliplatin; metastatic or recurrent cardia, dyspnoea, burning sensations, pruritus, erythema, 2. Monnet I, et al. Oxaliplatin plus in advanced non- cancer had been originally suspected.1 1,2,7,8 small-cell lung cancer: final results of a multicenter phase II sweating, and dizziness. Rashes have also been study. Ann Oncol 2002; 13: 103–7. 1. Tisman G, et al. Oxaliplatin toxicity masquerading as recurrent reported5,6,12 as have fever and chills.9,10 While the mechanism 3. Louvet C, et al. Phase II study of oxaliplatin, fluorouracil, and colon cancer. J Clin Oncol 2004; 22: 3202–4. of hypersensitivity to oxaliplatin is not clear, it has been suggest- folinic acid in locally advanced or metastatic gastric cancer pa- Effects on the nervous system. Neurological toxicity is the ed that reactions are characterised by development of symptoms tients. J Clin Oncol 2002; 20: 4543–8. principal dose-limiting adverse effect with oxaliplatin.1-3 The during or shortly after the infusion, and are possibly due to a type 4. Simpson D, et al. Oxaliplatin: a review of its use in combination 7,10 therapy for advanced metastatic colorectal cancer. Drugs 2003; toxicity is biphasic: I IgE-mediated reaction. Idiosyncratic or infusional reactions, 63: 2127–56. • acute paraesthesias or dysaesthesias of the extremities, trig- which are delayed until hours after the infusion,6,10 are consid- 5. Winegarden JD, et al. A phase II study of oxaliplatin and pacli- gered or exacerbated by cold, are seen in 85 to 95% of patients ered to be associated with cytokine release.7,10 Cases have gener- taxel in patients with advanced non-small-cell lung cancer. Ann Oncol 2004; 15: 915–20. within hours of infusion, but are normally mild and resolve ally resolved on stopping oxaliplatin and giving appropriate 6. André T, et al. Oxaliplatin, fluorouracil, and leucovorin as adju- within hours or days. Some patients also have distressing treatment. vant treatment for colon cancer. N Engl J Med 2004; 350: laryngopharyngeal symptoms, such as difficulty in breathing Prophylaxis before further oxaliplatin therapy, with corticoster- 2343–51. or swallowing. oids and/or antihistamines, has shown variable efficacy.4-7,9,10 7. Chao Y, et al. Phase II study of weekly oxaliplatin and 24-h infusion of high-dose 5-fluorouracil and folinic acid in the treat- • with increasing cumulative dose, peripheral sensory symp- Desensitisation protocols using dilute solutions and longer infu- 10,11,13 ment of advanced gastric cancer. Br J Cancer 2004; 91: 453–8. toms increase in duration and intensity. Symptoms are some- sion times have been reported to be successful. 8. Pectasides D, et al. Oxaliplatin plus high-dose leucovorin and 5- times associated with pain and cramps, and may progress to Intradermal skin testing has been used to identify patients with fluorouracil (FOLFOX 4) in platinum-resistant and -pre- functional impairment (loss of fine sensorimotor coordina- suspected hypersensitivity to oxaliplatin; however, in some pa- treated ovarian cancer: a phase II study. Gynecol Oncol 2004; 95: 165–72. tion). Dosage reduction may be required, but in clinical prac- tients with negative skin tests, reactions have occurred upon re- 9. Keam SJ, et al. Oxaliplatin: in operable colorectal cancer. Drugs tice the onset of functional impairment often occurs after the challenge.6,8 2005; 65: 89–96. maximum response to therapy has been attained. Cumulative 1. Tournigand C, et al. Severe anaphylactic reactions to oxalipla- 10. Fu S, et al. Clinical application of oxaliplatin in epithelial ovar- neurotoxicity is reversible in most cases, and about 80% of tin. Eur J Cancer 1998; 34: 1297–8. ian cancer. Int J Gynecol Cancer 2006; 16: 1717–32. patients exhibit symptom regression within 4 to 6 months. 2. Médioni J, et al. Anaphylaxis after oxaliplatin. Ann Oncol 1999; 11. Kim GP, Erlichman C. Oxaliplatin in the treatment of colorectal 10: 610. cancer. Expert Opin Drug Metab Toxicol 2007; 3: 281–94. The incidence of neurotoxicity may be higher when oxaliplatin 3. Larzillière I, et al. Anaphylactic reaction to oxaliplatin: a case 12. Stordal B, et al. Oxaliplatin for the treatment of cisplatin-resist- is given with fluorouracil. There is some evidence that more pro- report. Am J Gastroenterol 1999; 94: 3387–8. ant cancer: a systematic review. Cancer Treat Rev 2007; 33: longed infusion of oxaliplatin can reduce acute toxicity, particu- 4. Stahl M, et al. Reaction after oxaliplatin—prevention with cor- 347–57. larly laryngopharyngeal symptoms. Antiepileptics such as car- ticosteroids? Ann Oncol 2001; 12: 874. Administration in renal impairment. The primary route of 5. Alliot C, et al. Severe anaphylactic reaction to oxaliplatin. Clin bamazepine (see Neuropathic Pain, p.477) or gabapentin have Oncol (R Coll Radiol) 2001; 13: 236. platinum elimination is renal, and clearance of platinum is de- been investigated in the management of oxaliplatin-induced neu- 6. Thomas RR, et al. Hypersensitivity and idiosyncratic reactions creased in patients with renal impairment. However, a study de- rotoxicity and glutathione has been tried for prevention. Intrave- to oxaliplatin. Cancer 2003; 97: 2301–7. termined that increased platinum exposure in patients with renal Oxaliplatin/Paclitaxel 759 impairment was not associated with increased oxaliplatin toxici- Peripheral neuropathy can also be severe, and occa- 2. Wasner G, et al. Clinical picture: nail changes secondary to do- ty. Dose reduction was not considered to be necessary in patients sionally dose-limiting. Hypersensitivity reactions, with cetaxel. Lancet 2001; 357: 910. with mild to moderate renal impairment (as defined by creatinine 3. Pavithran K, Doval DC. Nail changes due to . Br J Der- 1 flushing, rash, dyspnoea, hypotension, chest pain, and matol 2002; 146: 709–10. clearance of 20 mL/minute or more). UK licensed product in- 4. Leonard GD, Zujewski JA. Docetaxel-related skin, nail, and vas- formation concurs that no dose adjustment is necessary in mild angioedema may occur, and all patients should be giv- cular toxicity. Ann Pharmacother 2003; 37: 148. to moderate renal impairment, but contra-indicates the use of en initial premedication with corticosteroids, antihista- 5. Itoh M, et al. Taxane-induced scleroderma. Br J Dermatol 2007; oxaliplatin in severe renal impairment (defined as creatinine 156: 363–7. mines, and histamine H2-antagonists. Other adverse ef- clearance of less than 30 mL/minute), due to lack of data. fects include alopecia, arthralgia and myalgia, Hypersensitivity. Despite premedication with corticosteroids, 1. Takimoto CH, et al. Dose-escalating and pharmacological study gastrointestinal disturbances, mucositis, bradycardia antihistamines, and H2-antagonists, hypersensitivity reactions of oxaliplatin in adult cancer patients with impaired renal func- are common in patients given paclitaxel; up to about 40% of pa- tion: a National Cancer Institute organ dysfunction working and ECG changes, nail dystrophies, and elevation of group study. J Clin Oncol 2003; 21: 2664–72. tients may have a mild reaction and about 2% a severe reaction. liver enzyme values. Infections are common, as are in- Fatalities have been reported. There are rare reports of delayed Preparations jection site reactions; extravasation may result in tissue hypersensitivity reactions with paclitaxel; necrotic ulceration has Proprietary Preparations (details are given in Part 3) damage. Rare adverse events include hypertension, se- occurred, without evidence of extravasation.1 Some consider the Arg.: Crisapla; Dabenzol; Dacplat; Goxyral; Kebir; Metaplatin; Mitog; O-Plat; cause to be the polyoxyl castor oil diluent for paclitaxel, and do- Oxaltie; Platenk†; Platinostyl; Plusplatin; Uxalun; Xaliplat; Austral.: Eloxatin; vere thrombotic events, myocardial infarction, heart cetaxel has been suggested as a suitable alternative.2 However, Belg.: Eloxatin; Braz.: Eloxatin; Evoxali†; Ezulen; O-Plat; Uxalun; Chile: failure, severe cardiac conduction abnormalities, sei- hypersensitivity reactions have also occurred with docetaxel and Eloxatin; O-Plat; Cz.: Ebeoxal; Eloxatin; Oxiplat; Platox; Fr.: Eloxatine; Ger.: 3,4 Eloxatin; Hong Kong: Eloxatin; Hung.: Eloxatin; India: Dacotin; Indon.: zures, neuroencephalopathy, paralytic ileus, optic taxane cross-reactivity has been reported. Although the manu- Eloxatin; Ital.: Eloxatin; Malaysia: Eloxatin; Mex.: Eloxatin; Olipcis; Oxi- nerve disturbances, severe skin reactions, hepatic facturers of both drugs consider further use to be contra-indicat- tan; Riptam; Neth.: Eloxatin; NZ: Eloxatin; Philipp.: Eloxatin; Pol.: Eloxa- necrosis, and hepatic encephalopathy. There are rare ed after a severe reaction, strategies for continuation of treatment tin; Port.: Eloxatin; Rus.: Eloxatine (Элоксатин); Singapore: Eloxatin; and desensitisation have been described.5,6 Spain: Eloxatin; Swed.: Eloxatin; Switz.: Eloxatine; Thai.: Eloxatin; Oxalip; reports of interstitial pneumonia and other lung disor- Oxitan; Turk.: Eloxatin; UK: Eloxatin; USA: Eloxatin; Venez.: Eloxatin. Hypersensitivity reactions to paclitaxel-eluting stents have also ders. been reported;7 however, the incidence is low, and some consider Paclitaxel is not recommended in patients with severe- the polymer coating of the stent to be the likely cause.8 ly impaired hepatic function. The drug is formulated in 1. Beri R, et al. Severe dermatologic reactions at multiple sites after Paclitaxel (BAN, USAN, rINN) paclitaxel administration. Ann Pharmacother 2004; 38: 238–41. polyoxyl castor oil and should be avoided in patients 2. Bernstein BJ. Docetaxel as an alternative to paclitaxel after acute BMS-181339-01; NSC-125973; Paclitaxelum; Paklitakseeli; Pakli- hypersensitive to this substance. The formulation also hypersensitivity reactions. Ann Pharmacother 2000; 34: taksel; Paklitaxel; Taxol; Taxol A. (2S,5R,7S,10R,13S)-10,20-Bis(ac- 1332–5. contains alcohol, the CNS effects of which should be 3. Denman JP, et al. Hypersensitivity reaction (HSR) to docetaxel etoxy)-2-benzoyloxy-1,7-dihydroxy-9-oxo-5,20-epoxytax-11-en- considered. Blood counts should be monitored fre- after a previous HSR to paclitaxel. J Clin Oncol 2002; 20: 13-yl (3S)-3-benzoylamino-3-phenyl-D-lactate. quently. Continuous cardiac monitoring is needed in 2760–1. Паклитаксел 4. Karacan Ö, et al. Acute interstitial pneumopathy associated with patients who have had previous significant conduction docetaxel hypersensitivity. Onkologie 2004; 27: 563–5. C H NO = 853.9. 47 51 14 abnormalities when given paclitaxel. 5. Markman M, et al. Paclitaxel-associated hypersensitivity reac- CAS — 33069-62-4. tions: experience of the gynecologic oncology program of the ATC — L01CD01. Alcohol intoxication. Acute alcohol intoxication resulting Cleveland Clinic Cancer Center. J Clin Oncol 2000; 18: 102–5. ATC Vet — QL01CD01. from high-dose paclitaxel infusion has been reported;1 it was cal- 6. Feldweg AM, et al. Rapid desensitization for hypersensitivity re- 2 actions to paclitaxel and docetaxel: a new standard protocol used culated that the dose used (348 mg/m ) supplied 50 mL of alco- in 77 successful treatments. Gynecol Oncol 2005; 96: 824–9. hol, or the equivalent of about 3 drinks (half a bottle of wine). 7. Nebeker JR, et al. Hypersensitivity cases associated with drug- 1. Wilson DB, et al. Paclitaxel formulation as a cause of ethanol eluting coronary stents: a review of available cases from the Re- O intoxication. Ann Pharmacother 1997; 31: 873–5. search on Adverse Drug Events and Reports (RADAR) project. O J Am Coll Cardiol 2006; 47: 175–81. O OH Effects on the eyes. Optic neuritis has occurred with paclitax- 8. Azarbal B, Currier JW. Allergic reactions after the implantation CH H C 3 el. There is a report of glaucoma possibly related to the use of of drug-eluting stents: is it the pill or the polymer? J Am Coll 3 Cardiol 2006; 47: 182–3. H C CH3 docetaxel and paclitaxel in a patient also receiving corticoster- 3 oids.1 O NH O CH H Pregnancy. Paclitaxel has been shown to be fetotoxic in animal 3 1. Fabre-Guillevin E, et al. Taxane-induced glaucoma. Lancet studies, but although the use of potentially teratogenic drugs 1999; 354: 1181–2. would normally be avoided during pregnancy, the risk to the O O OH O O Effects on the heart. Infusion of paclitaxel has been associat- mother of inadequate treatment may outweigh whatever risks ex- OH CH3 ed with sinus bradycardia, atrial arrhythmias, ventricular tachy- ist of abnormality in the fetus. Paclitaxel has been used in the cardia, heart block, myocardial infarction, and sudden death.1,2 treatment of a patient who presented at 27 weeks of gestation O O Symptoms of heart failure have been reported.3 In another report with ovarian cancer. She had cytoreductive surgery and then ad- sudden death 7 days after paclitaxel treatment raised the question juvant chemotherapy consisting of 3 cycles of paclitaxel and cis- of whether paclitaxel might have had a delayed effect.4 There is platin given every 3 weeks. A healthy child was delivered by caesarean section at 37 weeks, and showed normal growth and NOTE. Paclitaxel was formerly referred to as taxol, but the use of some evidence of cellular damage to the myocardium of a patient 3 development at 30 months of age.1 this name is now limited, as Taxol is a trademark. with paclitaxel-associated cardiac symptoms. Licensed product information notes that severe cardiovascular events have been Anhydramnios has been associated with the use of trastuzumab In Eur. (see p.vii) and US. Pharmacopoeias. seen more frequently after the use of paclitaxel in patients with and paclitaxel, see Pregnancy, under Trastuzumab, p.783. Ph. Eur. 6.2 (Paclitaxel). Isolated from natural sources or pro- non-small cell lung cancer than in those with breast or ovarian 1. Sood AK, et al. Paclitaxel and platinum chemotherapy for ovar- duced by fermentation or by a semisynthetic process. A white or carcinoma. ian carcinoma during pregnancy. Gynecol Oncol 2001; 83: almost white, crystalline powder. Practically insoluble in water; 599–600. 1. Rowinsky EK, et al. Cardiac disturbances during the administra- freely soluble in dichloromethane; soluble in methyl alcohol. tion of taxol. J Clin Oncol 1991; 9: 1704–12. Store in airtight containers. Protect from light. 2. Arbuck SG, et al. A reassessment of cardiac toxicity associated Interactions USP 31 (Paclitaxel). A white to off-white powder. Insoluble in with Taxol. J Natl Cancer Inst Monogr 1993; 15: 117–30. For a general outline of antineoplastic drug interac- water; soluble in alcohol. Store in airtight containers at a temper- 3. Jekunen A, et al. Paclitaxel-induced myocardial damage detect- ature between 20° and 25°. Protect from light. ed by electron microscopy. Lancet 1994; 343: 727–8. tions, see p.642. Pretreatment with cisplatin may re- 4. Alagaratnam TT. Sudden death 7 days after paclitaxel infusion duce the clearance of paclitaxel, resulting in increased Incompatibility. The vehicle for paclitaxel injection, which for . Lancet 1993; 342: 1232–3. contains alcohol and polyoxl castor oil, was found to leach the toxicity, and when both drugs are given, paclitaxel plasticiser diethylhexyl phthalate from some plastic giving Effects on the musculoskeletal system. Gabapentin has should be given first. sets.1,2 Consequently, licensed product information recommends been reported to be of benefit in the management of taxane- induced arthralgia and myalgia.1,2 Antineoplastics. For reference to enhanced cardiotoxicity the use of non-PVC containers and giving sets. when paclitaxel was given with doxorubicin, see p.714. For the Paclitaxel was found to be compatible with doxorubicin for at 1. van Deventer H, Bernard S. Use of gabapentin to treat taxane- induced myalgias. J Clin Oncol 1999; 17: 434–5. pharmacokinetic changes reported when paclitaxel was given least 24 hours, but microcrystalline precipitation of paclitaxel oc- with , see p.728. 3 2. Nguyen VH, Lawrence HJ. Use of gabapentin in the prevention curred after 3 to 5 days. For mention of the incompatibility of of taxane-induced arthralgias and myalgias. J Clin Oncol 2004; Pretreatment with fluorouracil has been reported to inhibit pacl- paclitaxel and cisplatin see p.698. 22: 1767–9. itaxel’s cytotoxic action, possibly by preventing tumour cells 1. Trissel LA, et al. Compatibility of paclitaxel injection vehicle from entering the G -M phases of the .1 The effect also with intravenous administration and extension sets. Am J Hosp Effects on the respiratory system. Acute bilateral intersti- 2 Pharm 1994; 51: 2804–10. tial pneumonitis has been reported rarely in patients receiving occurred when the 2 drugs were given simultaneously, suggest- 2. Mazzo DJ, et al. Compatibility of docetaxel and paclitaxel in in- paclitaxel, despite premedication with corticosteroids and hista- ing that combination therapy might not be appropriate. travenous solutions with polyvinyl chloride infusion materials. mine antagonists.1 Symptoms resolved on treatment with Valspodar inhibits P-glycoprotein, and a pharmacokinetic study2 Am J Health-Syst Pharm 1997; 54: 566–9. parenteral corticosteroids. found that it decreased clearance of paclitaxel and prolonged the 3. Trissel LA, et al. Compatibility and stability of paclitaxel com- terminal half-life, increasing exposure to paclitaxel and myelo- bined with doxorubicin hydrochloride in infusion solutions. Ann 1. Khan A, et al. Paclitaxel-induced acute bilateral pneumonitis. Pharmacother 1998; 32: 1013–6. Ann Pharmacother 1997; 31: 1471–4. suppressive effects. The authors suggested that the dose of pacl- itaxel may need to be reduced by about 60%. Effects on the skin and nails. Nail changes, noted as pigmen- 1. Johnson KR, et al. 5-Fluorouracil interferes with paclitaxel cyto- Adverse Effects, Treatment, and Precau- tation or discoloration of the nail-bed, may occur with paclitaxel. toxicity against human solid tumor cells. Clin Cancer Res 1997; tions Onycholysis (separation of the nail from the nail-bed) has also 3: 1739–45. 1 For a general outline see Antineoplastics, p.635, p.639, been reported. Discoloration and onycholysis can also occur af- 2. Advani R, et al. A phase I trial of doxorubicin, paclitaxel, and ter docetaxel use, and there are reports of subungual hyperkera- valspodar (PSC 833), a modulator of multidrug resistance. Clin and p.641. tosis and haemorrhage.2-4 Cancer Res 2001; 7: 1221–9. Paclitaxel produces severe dose-limiting bone marrow Localised oedema evolving into skin sclerosis, mimicking sys- Antivirals. HIV-PROTEASE INHIBITORS. In a patient given vari- depression, the nadir of the white cell count usually oc- temic sclerosis, has been reported after taxane use. In most pa- ous antiretrovirals during paclitaxel treatment for Kaposi’s curring after about 11 days, with recovery usually by tients, the sclerosis developed mainly on the extremities, and es- sarcoma, pharmacokinetic parameters of paclitaxel were not day 15 to 21 after a dose. Myelosuppression may be pecially the lower extremities. Joint contracture may occur. The significantly different when compared with historical con- total cumulative dose of the taxane may contribute to the onset.5 trols.1 The first course of therapy combined paclitaxel with less frequent and less severe when infusions are given 1. Flory SM, et al. Onycholysis associated with weekly administra- lamivudine, stavudine, and the HIV-protease inhibitors riton- over 3 rather than 24 hours. tion of paclitaxel. Ann Pharmacother 1999; 33: 584–5. avir and saquinavir. In subsequent courses, paclitaxel was The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)