氟达拉滨药理

1、 FludarabineDRUG NAME: FludarabineSYNONYM(S): 9-B-D-arabinofuranosyl-2-fluoroadenine 5-monophosphate, FAMP,1 2,3131,312-fluoro-ara-A Monophosphate, 2-fluoro-ara-AMP, fludarabine phosphate, NSC-312887COMMON TRADE NAME(S): FLUDARAÒCLASSIFICATION: antimetabolite1Special pediatric considerations ar

2、e noted when applicable, otherwise adult provisions apply.MECHANISM OF ACTION:Fludarabine phosphate is a synthetic fluorinated analog of the purine nucleoside antiviral agent vidarabine (ara-A).1,41Unlike vidarabine, fludarabine phosphate is resistant to deamination by adenosine deaminase. Fludarabi

3、nephosphate is a water-soluble prodrug that is rapidly dephosphorylated to 2-fluoro-vidarabine (2F-ara-A). 2F-ara-A isactively transported into cells and is then rephosphorylated via deoxycytidine kinase to the active triphosphate1derivative 2F-ara-ATP. 2F-ara-ATP competitively inhibits DNA synthesi

4、s via inhibition of DNA polymerase,1,5ribonucleotide reductase, DNA primase, and DNA ligase. 2F-ara-ATP prevents elongation of DNA strands through1,2direct incorporation into DNA as a false nucleotide. Partial inhibition of RNA polymerase II and resultant reduction14in protein synthesis may also occ

5、ur. Cytotoxicity occurs primarily in the S-phase of cell division ; fludarabine is also4active against non-proliferating cells. Fludarabine has been shown to induce apoptosis in vitro.1,6PHARMACOKINETICS:IV and oral dosing provide similar systemic exposure 66Oral AbsorptionDistribution50-75%2,6,7; d

6、ose-independant, unaffected by food8widely distributed3cross blood brain barrier?volume of distribution3no information found283-98 L/m ; suggests significant degree of tissuebindingplasma protein bindingno in vivo information foundMetabolismExcretionrapidly and completely dephosphorylated in plasma

7、to 2-F-ara-A; pharmacokinetic data isbased on 2F-ara-Aactive metabolite(s)2F-ara-ATPinactive metabolite(s)2,92F-ara-A, 2-F-ara-adenosinediphosphateminor: 2F-ara-hypoxanthine, 2-fluoro-vidarabine40-60%, 23% as 2-fluoro-vidarabine within 24 hours;urine22renal elimination is dose-related: 24% at 25mg/m

8、 /d,3,1040-60% at higher dosesfecesno information foundterminal half life315-23 hchildren3,10: 10.5-19 h279 mL/min/m ; directly correlates with creatinineclearanceclearanceAdapted from standard reference unless specified otherwise. 1BC Cancer Agency Cancer Drug Manual©Developed: September 1994P

9、age 1 of 10FludarabineRevised: February 2007, 1 June 2013, 1 September 2013 FludarabineUSES:Primary uses:*Leukemia, chronic lymphocyticLeukemia, prolymphocytic*Lymphoma, non-HodgkinsOther uses:Conditioning regimen pre-allogeneic bone marrow transplant235Leukemia, acute myeloidLeukemia, hairy cell3,7

10、Lymphoma, cutaneous T-cell3,7Waldenstroms macroglobulinemia3,7*Health Canada approved indication SPECIAL PRECAUTIONS:Contraindicated in patients who have a history of hypersensitivity reactions to fludarabine or any components of theformulation, in renally impaired patients with a creatinine clearan

11、ce less than 30 mL/minute, and in patients with1decompensated hemolytic anemia.Caution:·Use fludarabine with caution in patients with severe impairment of bone marrow function, immunodeficiency, ora history of opportunistic infections.1·Potentially life-threatening transfusion-related graf

12、t-versus-host-disease can occur in patients with severelymphopenia; patients receiving fludarabine should receive irradiated blood products, effectively eliminating thisrisk.1··Concomitant therapy with corticosteroids and fludarabine increases the risk of infections with opportunistic7,113

13、pathogens such as Pneumocystis, Listeria, and cytomegalovirus ; the combination should be avoided.High doses of fludarabine (>96 mg/m /day for 5-7 days) have been associated with severe irreversible centralnervous system toxicity characterized by delayed progressive encephalopathy with seizures,

14、blindness,21,12 1paralysis, coma, and death ; severe neurotoxicity has rarely occurred at recommended doses.Hepatitis B (HBV) reactivation: All lymphoma patients should be tested for both HBsAg and HBcAb. If either test ispositive, such patients should be treated with lamivudine 100 mg/day orally, f

15、or the entire duration of chemotherapyand for six months afterwards. Such patients should also be monitored with frequent liver function tests and HBVDNA at least every two months. If the hepatitis B virus DNA level rises during this monitoring, management should bereviewed with an appropriate speci

16、alist with experience managing hepatitis and consideration given to halting13,14chemotherapy.Special populations: Because geriatric patients may have decreased renal function, and patients with renalimpairment may be at increased risk of fludarabine-induced toxicity, these patients should be monitor

17、ed and dosage1adjusted accordingly. Geriatric patients with advanced Rai stage chronic lymphocytic leukemia may require3substantial dosage reductions.Carcinogenicity: no information found3Mutagenicity: Not mutagenic in Ames test and mammalian in vitro mutation test. Fludarabine is clastogenic in1,3m

18、ammalian in vitro and in vivo chromosome tests.Fertility: No long term studies have been performed in men or women to determine the effect on fertility. Patients ofreproductive potential should use effective contraceptive methods during treatment and for a minimum of 6 months1following fludarabine t

19、herapy.2Pregnancy: FDA Pregnancy Category D. There is positive evidence of human fetal risk, but the benefits from usein pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or fora serious disease for which safer drugs cannot be used or are

20、ineffective).Breastfeeding is not recommended due to the potential secretion into breast milk.1BC Cancer Agency Cancer Drug Manual©Developed: September 1994Page 2 of 10FludarabineRevised: February 2007, 1 June 2013, 1 September 2013 FludarabineSIDE EFFECTS:The table includes adverse events that

21、 presented during drug treatment but may not necessarily have a causalrelationship with the drug. Because clinical trials are conducted under very specific conditions, the adverse eventrates observed may not reflect the rates observed in clinical practice. Adverse events are generally included if th

22、eywere reported in more than 1% of patients in the product monograph or pivotal trials, and/or determined to be15clinically important. When placebo-controlled trials are available, adverse events are included if the incidence is >5% higher in the treatment group.ORGAN SITESIDE EFFECTClinically im

23、portant side effects are in bold, italicsallergy/immunologyauditory/hearinganaphylaxis (<6%)3,4autoimmune reactions; Evans syndrome, pemphigus53hearing disturbances (<6%) ; loss, auditory hallucinationsblood/bone marrow/febrile neutropeniaanemia (35%, severe 7-24%)4,16,17autoimmune hemolytic a

24、nemia (<1-23%)4,5,17; has occurred after initial or subsequent3,7dosing,see paragraph following the Side Effects tableimmunosuppression ; lymphopenia, leukopenia (severe 28%)1611neutropenia (15-75%, severe 19-54%)3,11,17,18; dose-related, nadir day 13 (range 3-25), complete recovery typically occ

25、urs 5-7 weeks after treatment2,3autoimmune neutropenia5myelodysplastic syndrome (<0.1%); duration may be prolonged, up to 1 year2pancytopenia3,5; durations of 2 months to 1 year have been reported3thrombocytopenia (32%, severe 14-26%)16,17; nadir day 16 (range 2-32), completerecovery typically oc

26、curs 5-7 weeks after treatment2,3autoimmune thrombocytopenia5cardiovascular(arrhythmia)arrhythmia (<0.1%)cardiovascular (general)angina (<6%)3heart failure (<0.1%)pericardial effusioncoagulationthrombocytopenic purpura; idiopathic and thrombotic19chills (1%- >10%)2constitutional symptoms

27、fatigue (1%-38%)2,32fever (>10%) ; with iv,15 unrelated to infectionsweating (<13%)3sleep disorder (<3%)3dermatology/skinextravasation hazard: none20alopecia (1-10%, severe <1%)2,16,17,21pruritis (<5%)3,16rash (<15%)2,3,16reversible worsening or flare of pre-existing skin cancer le

28、sions22seborrhea (<5%)3Stevens-Johnson syndrome, toxic epidermal necrolysis (<0.1%)BC Cancer Agency Cancer Drug Manual©Developed: September 1994Page 3 of 10FludarabineRevised: February 2007, 1 June 2013, 1 September 2013 FludarabineORGAN SITESIDE EFFECTClinically important side effects ar

29、e in bold, italicsgastrointestinalemetogenic potential: rare23anorexia (<34%)3constipation (<5%)3dysphagia (<5%)3diarrhea (5%-38%, severe 1-5%)3,16,17; more frequent with oral formulation16intestinal pseudo-obstruction5mucositis (<5%) , stomatitis (<9%) , esophagitis (<5%)333nausea

30、 and vomiting (<39%, severe <1%)3,16,17,21; generally mild, more frequent with316oral formulation3taste alterations (<1%)2hemorrhageepistaxis (<5%)3gastrointestinal bleed (<13%)hemoptysis (<6%)3hemorrhage (<6%)3hepatobiliary/pancreasinfectionliver dysfunction (<6%)3pancreatit

31、is3infections (<77%, severe <35%)3,11; see paragraph following the Side Effects tablepneumonia (9-22%)2,3upper respiratory infections (2%-16%)5urinary tract infection (<15%)3edema (<19%)2,3lymphaticsmetabolic/laboratoryabnormal liver function tests (<6%)3,4abnormal renal function test

32、s (1%)4hyperglycemia (<6%)33hyperuricemia ; see syndromespancreatic enzyme level changes (<1%)osteoporosis (<6%)3musculoskeletalneurologyweakness (<65%)2,3cerebellar syndrome33cognitive disturbances ; agitation (<1%), confusion (<1%)coma (<0.1%)dizziness3depression3leukoencephal

33、opathy (<0.2%); higher incidence (36%) associated with high-dose,115onset typically 4-8 months after treatmentneurotoxicity (16%) ; onset typically 21-60 days after treatment,3,11 see paragraph21following the Side Effects tableBC Cancer Agency Cancer Drug Manual©Developed: September 1994Page

34、 4 of 10FludarabineRevised: February 2007, 1 June 2013, 1 September 2013 FludarabineORGAN SITESIDE EFFECTClinically important side effects are in bold, italicssensory neuropathy (<12%, severe <1%)2,3,17seizure (<0.1%)wrist drop3ocular/visualblindness (<0.1%)optic neuropathy (<0.1%), o

35、ptic neuritis (<0.1%)photophobia (<1%); primarily at higher doses2visual disturbances (<15%) ; blurred vision, diplopia (<1%)2dysuria3painheadache (1-10%)2,3myalgia (<16%),2,3 arthralgia (<6%)3pain not otherwise specified (<44%)2,3cough (<44%)3pulmonarydyspnea (<22%)33phar

36、yngitis (<9%), bronchitis and sinusitis (<5%)3pulmonary hypersensitivity reactions; pneumonitis, pulmonary infiltrates, fibrosis33(<5%) ; onset typically 3-28 days after the third or later treatment, see paragraphfollowing the Side Effects tablerenal/genitourinaryhemorrhagic cystitis (<0

37、.1%)renal failure (<1%)2urinary hesitancy (<5%)3syndromeshemophagocytic syndrome5tumour lysis syndrome (0.3%-10%)2,53Adapted from standard reference unless specified otherwise. 1Neurotoxicity: Severe and potentially irreversible or fatal neurotoxicity has occurred with fludarabine. While these

38、1,3effects typically occur with doses higher than those recommended, they have occurred at standard doses.Neurotoxicity generally occurs 21-60 days following fludarabine and may cause confusion, incontinence, seizures,1,321paralysis, vision changes, and coma. At regular doses, neurotoxicity is gener

39、ally mild and may be reversible,causing headache, somnolence, agitation, confusion, and paresthesias. Rarely, coma and seizures have occurred.1The mechanism by which fludarabine causes neurotoxicity is unknown. It is not known if the rate of drug3administration affects the risk of neurotoxicity; neu

40、rotoxicity has been reported with rapid IV injections and slow IV3infusions. If vision changes occur, discontinue fludarabine treatment.15Immunosuppression / opportunistic infections: Patients are at risk for opportunistic infections due to the T-cell1,11lymphopenia, particularly of CD4 cells, induc

41、ed by fludarabine.Lymphopenia develops within 2-3 months and thedecrease in CD4 cells may persist for years following treatment.11 In patients treated with fludarabine, up to 67% ofinfections are caused by opportunistic organisms. Delayed and/or severe opportunistic infections may occur,1111particul

42、arly after repeated cycles of fludarabine. Concomitant therapy with corticosteroids increases the risk of3opportunistic infections and the combination should be avoided. Routine anti-infective prophylaxis or immune3globulin use is not currently recommended but may be considered for high risk patient

43、s. If a serious infectionoccurs, fludarabine therapy should be interrupted but may be reinitiated following the resolution of the infection.Fludarabine-associated infections are caused by bacterial, fungal, and viral pathogens. Streptococcus and11Staphylococcus are the most common bacterial pathogen

44、s. Infections with gram-negative bacilli, Listeria, andBC Cancer Agency Cancer Drug Manual©Developed: September 1994Page 5 of 10FludarabineRevised: February 2007, 1 June 2013, 1 September 2013 Fludarabinerarely Mycobacteria infections have been reported.3,11 Invasive fungal infections have been

45、 caused by several3,11species including Pneumocystis, Candida, Aspergillus, and Cryptococcus.influenza, herpes, and hepatitis A and B viruses.5Infections by viral pathogens include3,5,11,24Herpes virus infections have occurred in up to 57% ofpatients receiving fludarabine. Herpes simplex reactivatio

46、n is the most common early viral infection.zoster virus (VZV) infections typically occur 7-8 months after fludarabine initiation.11Varicella5,11VZV ocular infections have5also been reported.Autoimmune hemolytic anemia: Serious and sometimes fatal autoimmune hemolytic anemia has occurred after3,5init

47、ial or subsequent dosing of fludarabine, in patients with or without a history of autoimmune hemolytic anemia or13a positive Coombs test, whose disease may or may not be in remission. The risk factor that predisposes patients3to the development of hemolytic anemia is not known. Patients undergoing t

48、reatment with fludarabine should bemonitored and treatment discontinued if hemolysis is detected. The transfusion of irradiated blood products and theadministration of corticosteroids are the most common treatment measures ; it is not known if corticosteroids arebeneficial in the management of fluda

49、rabine induced hemolytic anemia. Rituximab may be effective in managing the11325-27autoimmune thrombocytopenia and hemolytic anemia that results from fludarabine.Rechallenge with fludarabine3should be avoided.Pulmonary toxicities including respiratory distress and failure, pulmonary fibrosis and hem

50、orrhage, and interstitial3pneumonitis have been reported with fludarabine. Symptoms of cough, dyspnea, hypoxia, and pulmonary infiltrates3may be treated with corticosteroids; symptoms have recurred following cessation of the steroid.Respiratory3symptoms may resolve spontaneously. The exact mechanism

51、 of pulmonary toxicity is not known, though anunderlying disease process or previous exposure to agents that cause pulmonary toxicity may contribute to theincidence. Patients with chronic lymphocytic leukemia may be at greater risk of developing pulmonary toxicity.35Hyperuricemia may result from cel

52、l lysis by cytotoxic chemotherapy and may lead to electrolyte disturbances or28acute renal failure. It is most likely with highly proliferative tumours of massive burden, such as leukemias, high-grade lymphomas, and myeloproliferative diseases. The risk may be increased in patients with preexisting

53、renal29dysfunction, especially ureteral obstruction. Suggested prophylactic treatment for high-risk patients :·····aggressive hydration: 3 L/m²/24 hr with target urine output >100 ml/hif possible, discontinue drugs that cause hyperuricemia (e.g., thiazide diuretics)

54、or acidic urine (e.g., salicylates)monitor electrolytes, calcium, phosphate, renal function, LDH, and uric acid q6h x 24-48 hoursreplace electrolytes as requiredallopurinol 600 mg po initially, then 300 mg po q6h x6 doses, then 300 mg po daily x 5-7 daysUrine should be alkalinized only if the uric a

55、cid level is elevated, using sodium bicarbonate IV or PO titrated tomaintain urine pH>7. Rasburicase (FASTURTEC®) is a novel uricolytic agent that catalyzes the oxidation of uric30acid to a water-soluble metabolite, removing the need for alkalinization of the urine. It may be used for treatm

56、ent orprophylaxis of hyperuricemia; however, its place in therapy has not yet been established. Aluminium hydroxide (e.g.,AMPHOGEL®) may be added orally if phosphate becomes elevated. If aluminium hydroxide has been added,31discontinue sodium bicarbonate.INTERACTIONS:AGENTEFFECTMECHANISMMANAGEMENTcytarabine3,7decreases metabolism offludarabine to active 2F-ara- deoxycytidine kinase,cytarabine competes forclinical importance as yetunknownATP; cytarabine given firstappears to inhibit theantineoplastic effect offludarabine; fludarabinegiven first ap