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  • CLASSES

    Platinum Compounds

    BOXED WARNING

    Requires a specialized care setting, requires an experienced clinician

    Carboplatin therapy requires an experienced clinician in the management of cancer chemotherapy. Carboplatin administration requires a specialized care setting adequate for the appropriate management of carboplatin therapy and complications.

    Vomiting

    Vomiting occurs frequently with carboplatin therapy; ensure that patients are premedicated with appropriate antiemetic therapy prior to initiating therapy with carboplatin.

    DEA CLASS

    Rx

    DESCRIPTION

    Platinum alkylating antineoplastic agent; on a molar basis, carboplatin is 45 times less cytotoxic than cisplatin; as effective as cisplatin in ovarian, non-small cell and small cell lung cancers; not recommended for routine treatment of testicular or head and neck cancers.

    COMMON BRAND NAMES

    Paraplatin

    HOW SUPPLIED

    Carboplatin/Paraplatin Intravenous Inj Sol: 1mL, 10mg

    DOSAGE & INDICATIONS

    For the treatment of ovarian cancer.
    For the first-line treatment of ovarian cancer in combination with paclitaxel†.
    Intravenous dosage
    Adults

    AUC 5 to 7.5 IV on day 1 in combination with paclitaxel (175 to 185 mg/m2 IV over 3 hours on day 1), every 3 weeks for 6 cycles. In clinical trials, carboplatin combined with paclitaxel has been shown to be less toxic and produce similar efficacy to cisplatin combined with paclitaxel as first-line treatment of patients with advanced ovarian cancer. Additionally, carboplatin AUC 6 IV on day 1 in combination with paclitaxel (80 mg/m2 IV on days 1, 8, and 15), every 3 weeks for 6 cycles has been given. This dose-dense combination was compared to conventional carboplatin/paclitaxel in 631 patients with advanced ovarian cancer. Progression-free survival, the primary endpoint, was significantly higher in the dose-dense arm (28 months vs. 17.2 months, p = 0.0015).

    For the first-line treatment of ovarian cancer in combination with docetaxel†.
    Intravenous dosage
    Adults

    AUC 5 IV on day 1, immediately preceded by docetaxel (75 mg/m2 IV over 1 hour on day 1), repeated every 3 weeks for 6 cycles. In a phase III trial of 1077 patients, carboplatin combined with docetaxel was compared to carboplatin combined with paclitaxel. No significant differences in response rate, progression-free survival, or overall survival were observed between the 2 groups. Grades 2 to 4 neurosensory toxicity were significantly greater in the paclitaxel containing regimen (30% vs. 11%, p < 0.001) and grades 3 to 4 neutropenia were significantly higher in the docetaxel containing regimen (94% vs. 84%, p < 0.001).

    For the first-line treatment of or palliative treatment of recurrent advanced ovarian cancer.
    Intravenous dosage
    Adults

    For patients with previously untreated ovarian cancer, administer carboplatin 300 mg/m2 IV on day 1 in combination with cyclophosphamide (600 mg/m2 IV on day 1), repeated every 4 weeks for 6 cycles. For patients with recurrent ovarian cancer, administer single-agent carboplatin 360 mg/m2 IV (or AUC 5 to 6) on day 1, repeated every 4 weeks. Dosage adjustments should be made according to the lowest post-treatment platelet or neutrophil value as assessed by weekly blood counts.

    Intraperitoneal dosage†
    Adults

    200 to 650 mg/m2 intraperitoneally every 4 to 6 weeks has been studied. In 1 trial, 350 mg/m2 intraperitoneally with cyclophosphamide IV every 3 to 4 weeks resulted in similar response and survival rates as carboplatin 350 mg/m2 IV and cyclophosphamide IV with less myelotoxicity.

    For treatment of non-small cell lung cancer (NSCLC)†.
    For the treatment of advanced or metastatic NSCLC in combination with paclitaxel†.
    Intravenous dosage
    Adults

    Carboplatin AUC 6 IV in combination with paclitaxel (200 mg/m2) IV on day 1 given every 21 days produced an overall survival of 12.3 months in a phase 3 comparison of 4 chemotherapy doublets in advanced NSCLC. In another similar 4-arm phase 3 comparison, carboplatin AUC 6 IV on day 1 in combination with paclitaxel 225 mg/m2 IV on day 1 given every 21 days, produced an overall survival of 7.8 months, which was similar to the reference regimen of cisplatin and paclitaxel.

    For first-line treatment of inoperable, locally advanced or metastatic non-small cell lung cancer (NSCLC) in combination with gemcitabine†.
    Intravenous dosage
    Adults

    AUC 5 IV on day 1 in combination with gemcitabine 1,200 mg/m2 IV on days 1 and 8, every 21 days for 6 cycles. Alternatively, carboplatin AUC 5 IV on day 1 with gemcitabine 1,000 mg/m2 IV on days 1, 8 and 15, repeated every 28 days for 4 cycles or, carboplatin AUC 5 IV day 1 with gemcitabine 1,000 mg/m2 IV on days 1 and 8, repeated every 21 days for 4 cycles, have also been studied.

    For first-line treatment of unresectable, locally advanced or metastatic non-small cell lung cancer (NSCLC) in combination with docetaxel†.
    Intravenous dosage
    Adults

    AUC 6 IV in combination with docetaxel (75 mg/m2 IV) on day 1 given every 21 days for 4 to 6 cycles. In a phase 3 trial of 1,203 patients with unresectable locally advanced or metastatic NSCLC, docetaxel and platinum combinations (cisplatin or carboplatin) were compared with cisplatin/vinorelbine. No difference was observed between docetaxel/carboplatin and cisplatin/vinorelbine in overall survival, the primary endpoint. Grade 3 and 4 anemia and nausea/vomiting were significantly lower in both docetaxel containing arms. In addition, hospitalizations and treatment discontinuation secondary to toxicity were higher with cisplatin/vinorelbine. A separate phase 3 trial conducted in 422 patients with inoperable, locally advanced or metastatic NSCLC compared docetaxel/carboplatin to mitomycin C/cisplatin plus either ifosfamide or vinblastine. The primary endpoint, 1-year overall survival, was not significantly different between the treatment arms. Grade 3 and 4 neutropenia, infection, and mucositis were all significantly higher with docetaxel/carboplatin, while quality of life scores were significantly better.

    For the first-line treatment of stage IIIB or IV non-small cell lung cancer (NSCLC) in combination with pemetrexed†.
    Intravenous dosage
    Adults

    AUC 5 IV in combination with pemetrexed (500 mg/m2 IV) on day 1, repeated every 3 weeks for 4 cycles. In a phase 3 trial, 436 patients were randomized to pemetrexed/carboplatin or gemcitabine/carboplatin. No significant differences were observed for the primary endpoint, health-related quality of life, or the secondary endpoint, overall survival. Grade 3 or 4 toxicities were significantly worse in the gemcitabine/carboplatin arm.

    For the first-line treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who are not candidates for curative surgery or radiation in combination with nanoparticle albumin-bound paclitaxel†.
    NOTE: Nanoparticle albumin-bound paclitaxel is FDA approved in combination with carboplatin for the first-line treatment of locally advanced or metastatic NSCLC.
    Intravenous dosage
    Adults

    AUC 6 IV on day 1 in combination with nanoparticle albumin-bound (nab) paclitaxel (100 mg/m2 IV over 30 minutes on days 1, 8, and 15), repeated every 21 days; administer carboplatin immediately after the nab-paclitaxel infusion on day 1. Nab-paclitaxel plus carboplatin was noninferior to paclitaxel plus carboplatin in patients with previously untreated non-resectable stage IIIB or stage IV non-small cell lung cancer (NSCLC) in a multicenter, randomized, phase 3 trial (n = 1,052). The primary endpoint of overall response rate (ORR) assessed by independent radiologic review was significantly improved with nab-paclitaxel/carboplatin compared with solvent-based (sb) paclitaxel plus carboplatin (33% vs. 25%); all responding patients in the nab-paclitaxel arm had a partial response (PR) while 1 patient in the sb-paclitaxel arm achieved a complete response. In a subgroup analysis, the ORR was significantly improved with nab-paclitaxel plus carboplatin in patients with squamous cell histology (41% vs. 24%) but not nonsquamous cell histology (26% vs. 25%). Median progression-free survival (6.3 months vs. 5.8 months) and overall survival (12.1 months vs. 11.2 months) were nonsignificantly improved with nab-paclitaxel/carboplatin.

    For first-line treatment of metastatic, non-squamous, NSCLC, in combination with pemetrexed and pembrolizumab†.
    NOTE: Both pemetrexed and pembrolizumab are FDA-approved for this indication.
    Intravenous dosage
    Adults

    AUC 5 IV over 15 to 60 minutes on day 1, preceded by both pembrolizumab (200 mg IV over 30 minutes) and pemetrexed (500 mg/m2 IV over 10 minutes) on day 1, every 21 days for 4 cycles; administer pembrolizumab first, followed by pemetrexed, and then followed by carboplatin. After the initial dose, monitor the nadir ANC and platelet count to assess for possible pemetrexed dose reductions. Pembrolizumab therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Following completion of platinum-based therapy, pemetrexed (200 mg IV every 3 weeks) may be administered as maintenance therapy, alone or with pembrolizumab, until disease progression or unacceptable toxicity. To prevent or minimize toxicities, all patients should also receive the following concomitant medications: dexamethasone 4 mg PO twice daily for 3 consecutive days, beginning the day before each pemetrexed dose; folic acid 400 to 1,000 mcg PO daily beginning 7 days prior to the first pemetrexed dose and continuing until 21 days after the last pemetrexed dose; and vitamin B12 injection 1 mg IM one week prior to the first dose of pemetrexed and every 3 cycles (every 9 weeks) thereafter (do not substitute oral vitamin B12 for the IM injection). After the first vitamin B12 injection, subsequent injections may be given on the same day as pemetrexed treatment. In a multicenter, open-label, multi-cohort study (KEYNOTE-021), treatment with pemetrexed, carboplatin, and pembrolizumab significantly improved the overall response rate (ORR) compared with treatment with pemetrexed and carboplatin alone (55% vs. 29%) in patients with previously untreated, locally advanced or metastatic, non-squamous NSCLC, regardless of PD-L1 tumor expression; all responses were partial responses. Median progression-free survival (PFS) was also significantly improved (13 months vs. 8.9 months), and the duration of response was 6 months or longer in 93% versus 81% of patients, respectively. In an exploratory analysis of patients with PD-L1 tumor expression (TPS) less than 1%, the ORR was 57% in the pembrolizumab arm compared with 13% in patients who did not receive pembrolizumab. In patients with TPS 1% or more, the ORR was 54% in the pembrolizumab arm compared with 38% in patient who did not receive pembrolizumab.

    For treatment of head and neck cancer†.
    For the treatment of advanced-stage squamous cell carcinoma of the head and neck in combination with 5-fluorouracil and radiation therapy†.
    Intravenous dosage
    Adults

    70 mg/m2/day IV on days 1 through 4 in combination with 5-fluorouracil (5-FU) (600 mg/m2/day continuous IV infusion on days 1 through 4). Chemotherapy cycles were started on days 1, 22, and 43 and were administered concurrently with radiotherapy (RT). In a phase III trial, 226 patients with stage III or IV squamous cell carcinoma of the oropharynx (no evidence of distant metastasis) were randomized to receive RT alone or concomitantly with carboplatin/5-FU. Overall survival at 5 years was significantly improved in the chemoradiotherapy arm (22.4% vs. 15.8%, p = 0.05). The 5-year specific disease free survival rate (26.6% vs. 14.6%, p = 0.01) and locoregional control rate (47.6% vs. 24.7%, p = 0.002) were also significantly improved with chemoradiotherapy. Hematologic and skin toxicities were more common in chemoradiotherapy arm. In addition, grades 3 and 4 mucositis and poor nutritional status occurred more frequently with concomitant therapy. There were no significant differences in late toxic effects between the arms when assessed at 5 years.

    For the treatment of recurrent or metastatic squamous cell carcinoma of the head and neck in combination with 5-fluorouracil†.
    Intravenous dosage
    Adults

    300 mg/m2 IV on day 1 in combination with 5-fluorouracil (5-FU) (1,000 mg/m2/day continuous IV infusion over 96 hours on days 1 through 4); repeated every 4 weeks. In a phase III trial, 277 patients were randomized to receive carboplatin-5-FU, cisplatin-5-FU, or methotrexate (MTX). An increase in overall response rate was achieved with carboplatin-5-FU versus MTX, which was of borderline statistical significance (21% vs. 10%, p = 0.05). The overall response rate was numerically lower with carboplatin/5-FU compared to cisplatin-5-FU (21% vs. 32%).

    For the treatment of recurrent or metastatic squamous cell carcinoma of the head and neck in combination with 5-fluorouracil and cetuximab†.
    Intravenous dosage
    Adults

    AUC 5 IV on day 1 in combination with cetuximab (400 mg/m2 IV over 120 minutes on day 1, then on day 8, give 250 mg/m2 IV over 60 minutes weekly) and fluorouracil (1,000 mg/m2/day IV infusion over days 1 through 4). The treatment regimen was repeated every 3 weeks for 6 cycles. In a phase III trial, 442 patients were randomized to receive a platinum (cisplatin or carboplatin) and fluorouracil with or without cetuximab. Overall survival, the primary endpoint, was significantly greater with the addition of cetuximab (10.1 months vs. 7.4 months, p = 0.04). However, sepsis, hypomagnesemia, grade 3 skin reactions, and grade 3 or 4 infusion reactions occurred more frequently with the addition of cetuximab.

    For the treatment of advanced squamous cell carcinoma of the head and neck in combination with paclitaxel and radiotherapy†.
    Intravenous dosage
    Adults

    100 mg/m2 IV weekly in combination with paclitaxel (40 to 45 mg/m2 IV weekly). Chemotherapy was administered weekly prior to radiation therapy. In a clinical trial, 62 patients were administered carboplatin-paclitaxel concomitantly with radiation therapy. An overall survival of 33 months was achieved. A complete response (CR) occurred in 75% of patients; among patients with a CR, an overall survival of 49 months was achieved. At a follow-up of 30 months, a local control rate of 63% was observed.

    For treatment of testicular cancer†.
    For the treatment of testicular cancer in combination with etoposide and bleomycin†.
    Intravenous dosage
    Adults

    Carboplatin AUC 5 IV on day 1 in combination with etoposide (120 mg/m2/day IV on days 1 through 3) and bleomycin (30 international units on day 2), repeated every 21 days for 4 cycles has been used. In a randomized trial, the combination of carboplatin (AUC 5), etoposide, and bleomycin (CEB) was compared with the standard regimen of bleomycin, etoposide, and cisplatin (BEP) in patients with good-prognosis, metastatic testicular cancer. The combination containing carboplatin resulted in a significantly lower response rate than the cisplatin-containing regimen (87.3% vs. 94.4%, respectively).

    For the treatment of stage I seminoma†.
    Intravenous dosage
    Adults

    Single dose carboplatin IV (AUC 7 if measured by EDTA; 90% of that dose if measured by 24-hour urinary creatinine clearance) after resection. In a phase III trial of patients with stage I seminoma, no difference in relapse-free rates were observed between single dose carboplatin and adjuvant radiotherapy amongst the 1,447 patients who met the minimum follow-up requirement of 5 years. Contralateral germ-cell tumors occurred in only 2 patients randomized to receive carboplatin as compared to 15 patients randomized to receive radiotherapy.

    For the treatment of relapsed or refractory non-Hodgkin's lymphoma (NHL)† in combination with ifosfamide and etoposide.
    Intravenous dosage
    Adults

    Carboplatin AUC 5 IV on day 2 (Max: 800 mg), ifosfamide 5 g/m2 IV mixed with equal dose of mesna via continuous intravenous infusion over 24 hours beginning on day 2, and etoposide 100 mg/m2/day on days 1 through 3, every 2 weeks (ICE regimen) for 3 cycles, was developed to treated relapsed NHL and allow for adequate stem cell collection prior to transplant. Alternative dosage regimens have been used, including some in the outpatient setting.

    For stem cell transplant preparation†.
    For stem cell transplant preparation, in combination with ifosfamide and etoposide, prior to autologous stem cell transplant for the treatment of relapsed or refractory germ cell tumor†.
    Intravenous dosage
    Adults

    Ifosfamide 0 to 10 g/m2 IV in 4 divided doses on days -6 to -3, in combination with carboplatin 1,500 to 2,000 mg/m2 IV in 3 divided doses on days -6 to -4 (1,500 mg/m2) or in 4 divided doses on days -6 to -3 (more than 1,500 mg/m2), and etoposide 1,200 to 2,400 mg/m2 IV in 4 divided doses on days -6 to -3. Ifosfamide was administered on days -6 to -3 as a 22-hour infusion and mesna (each dose was 20% of the total dose/day of ifosfamide) was administered before the start of ifosfamide and every 6 hours after, including 2 doses after the final ifosfamide infusion. Each carboplatin dose was administered as a 1 hour infusion. Etoposide was administered undiluted through a central line.

    For stem cell mobilization in combination with ifosfamide and etoposide, in transplant eligible patients with non-Hodgkin's lymphoma.
    Intravenous dosage
    Adults

    Etoposide 100 mg/m2/day IV on days 1 to 3 in combination with carboplatin AUC 5 (Max dose: 800 mg) IV on day 2 and ifosfamide 5 g/m2 mixed with an equal dose of mesna administered via continuous IV infusion for 24 hours beginning day 2. Filgrastim was administered at 10 mcg/kg/day starting on day 5 until completion of leukapheresis.

    For the treatment of malignant glioma†.
    For the treatment of recurrent grade III malignant glioma in combination with teniposide†.
    Intravenous dosage
    Adults

    350 mg/m2 IV on day 1 in combination with teniposide 50 mg/m2/day IV on days 1, 2, and 3, every 28 days. Treatment has been studied up to a maximum of 10 cycles.

    For the treatment of previously untreated, low-grade malignant glioma in combination with vincristine†.
    Intravenous dosage
    Adolescents <= 16 years, Children, and Infants > 3 months

    175 mg/m2 IV once weekly on weeks 1 through 4 and 7 through 10 in combination with vincristine 1.5 mg/m2 IV (Max dose: 2 mg) once weekly on weeks 1 through 10 as induction therapy. Begin maintenance therapy on week 12 with carboplatin 175 mg/m2 IV once weekly for 4 weeks and vincristine 1.5 mg/m2 (Max dose: 2 mg) IV once weekly for 3 weeks repeated every 6 weeks for 8 cycles. Do not start maintenance therapy or the next cycle of maintenance therapy until the ANC is more than 1,000 cells/mm3 and the platelet count is more than 100,000 cells/mm3.

    For the treatment of recurrent high-grade malignant glioma†.
    Intravenous dosage
    Adults

    AUC 5 IV on day 1, every 28 days for 6 cycles. Alternately, carboplatin 350 to 400 mg/m2 IV on day 1, every 21 days for up to 8 cycles, has also been studied.

    For the first-line treatment of advanced transitional-cell bladder cancer†, in combination with paclitaxel.
    Intravenous dosage
    Adults

    AUC of 6 IV over 30 minutes on day 1 following paclitaxel 225 mg/m2 IV over 3 hours repeated every 21 days (CP regimen) for 6 cycles was compared with methotrexate 30 mg/m2 on days 1, 15, and 22, vinblastine 3 mg/m2 IV on days 2, 15, and 22, doxorubicin 30 mg/m2 on day 2, and cisplatin 70 mg/m2 on day 2 (MVAC regimen) in a randomized, phase III trial. In this study, the median overall survival (OS) times were 13.8 and 15.4 months with CP and MVAC, respectively (p = 0.75) in 85 patients (median follow-up of 32.5 months). This study was halted due to slow patient accrual and was therefore underpowered to detect a difference in the primary endpoint of OS. The progression-free survival time was 5.2 months in the CP arm and 8.7 months in the MVAC arm (p = 0.24). Grade 3 or higher toxicity reported less often with CP compared with MVAC included neutropenia (29% vs. 67%), anemia (5% vs. 38%), thrombocytopenia (10% vs. 21%), fatigue (10% vs. 24%), and dyspnea (2% vs. 14%); grade 3 sensory neuropathy occurred more often with CP (15% vs. 2%). Additionally, worst degree toxicity of grade 4 or higher occurred in fewer patients in the CP arm (15% vs. 33%) and there was 1 treatment-related death in each study arm.

    For the treatment of breast cancer†.
    For adjuvant treatment of patients with HER2 overexpressing node-positive or high-risk node negative breast cancer†, in combination with docetaxel and trastuzumab.
    NOTE: Trastuzumab is FDA approved for the treatment of HER2 overexpressing node-positive or high-risk node negative breast cancer in combination with carboplatin and docetaxel. Carboplatin is not FDA approved for the treatment of breast cancer.
    Intravenous dosage
    Adults

    Carboplatin AUC 6 IV with docetaxel (75 mg/m2 IV) on day 1 repeated every 3 weeks for a total of 6 cycles plus trastuzumab (8 mg/kg IV infusion on week 1, followed by 6 mg/kg IV infusion every 3 weeks for a total of 52 weeks) (TCH regimen). Interim analysis of a phase III trial comparing the TCH regimen versus doxorubicin, cyclophosphamide, docetaxel, and trastuzumab showed similar efficacy. The incidence of cardiac toxicity is significantly less with TCH.

    For the first-line treatment of metastatic breast cancer in combination with paclitaxel†.
    Intravenous dosage
    Adults

    Carboplatin AUC 6 IV on day 1 in combination with paclitaxel 175 mg/m2 IV over 3 hours on day 1, every 3 weeks for 6 cycles has been studied.

    For the front-line treatment of HER2-overexpressing metastatic breast cancer† in combination with paclitaxel and trastuzumab.
    Intravenous dosage
    Adults

    AUC 6 IV in combination with paclitaxel 175 mg/m2 IV beginning in week 1 repeated every 3 weeks for 6 cycles. Alternatively, carboplatin AUC 2 IV and paclitaxel 80 mg/m2 IV may be administered weekly for 3 weeks with a 1 week rest to complete 6 4-week cycles. Give both regimens with trastuzumab (4 mg/kg IV on week 1 then 2 mg/kg IV once/week starting week 2), continue trastuzumab until disease progression or unacceptable toxicity. A phase III trial of 196 patients with previously untreated HER2-overexpressing metastatic breast cancer examined trastuzumab and paclitaxel +/- carboplatin. The primary endpoint, overall response rate, was significantly increased with the addition of carboplatin (52% vs. 36%, p = 0.04). Progression-free survival was also superior in the carboplatin arm (10.7 months vs. 7.1 months, p = 0.03). Grade 4 neutropenia (36% vs. 12%, p = 0.0001) and grade 3 thrombocytopenia (9% vs. 1%) occurred more frequently in the carboplatin arm. A comparison of 2 parallel phase II studies revealed an increase in overall response rate, median time to disease progression, and overall survival with weekly administration of carboplatin/paclitaxel versus every 3 week administration.

    For the treatment of relapsed or refractory acute lymphocytic leukemia (ALL) in combination with ifosfamide, etoposide, and rituximab†.
    Intravenous dosage
    Adults 21 years or younger, Adolescents, and Children

    Carboplatin 635 mg/m2 IV on day 3 in combination with ifosfamide 3,000 mg/m2/day IV on days 3, 4, 5 (each dose mixed with mesna 600 mg/m2 IV, followed by mesna 600 mg/m2 IV over 15 minutes at 3, 6, 9, and 12 hours after the start of ifosfamide) and etoposide 100 mg/m2/day IV on days 3, 4, 5, repeated each cycle. Rituximab 375 mg/m2 IV was given on days 1 and 3 of cycles 1 and 2, and on day 3 only of cycle 3. Treatment was given up to a maximum of 3 cycles. Colony-stimulating factors were initiated on day 6 of each cycle and IT chemotherapy was also given as appropriate. Overall response rate was 60% and overall survival at 2 to 3 years was 37.5%.

    For the treatment of poor-risk relapsed Wilms' tumor in combination with etoposide and ifosfamide†.
    Intravenous dosage
    Adults <= 21 years, Adolescents, and Children

    Ifosfamide 1,800 mg/m2/day IV for 5 days (on days 0, 1, 2, 3, 4), carboplatin 400 mg/m2/day IV for 2 days (on day 0, 1) and etoposide 100 mg/m2/day IV for 5 days (on days 0, 1, 2, 3, 4), repeated every 21 days.

    For the treatment of intermediate-risk neuroblastoma in combination with etoposide, cyclophosphamide, and doxorubicin†.
    Intravenous dosage
    Infants and Children

    Carboplatin has been given in combination with etoposide, cyclophosphamide, and doxorubicin, in the following fashion. In Cycles 1 and 7: Carboplatin 560 mg/m2 IV on day 1 (18 mg/kg/day in children less than 12 kg) plus etoposide 120 mg/m2/day IV on days 1, 2, 3 (4 mg/kg/day in children less than 12 kg). Cycles 2 and 6: Carboplatin 560 mg/m2 IV on day 1 (18 mg/kg/day in children less than 12 kg) plus cyclophosphamide 1,000 mg/m2 IV on day 1 (33 mg/kg/day in children less than 12 kg), and doxorubicin 30 mg/m2 IV on day 1 (1 mg/kg/day in children less than 12 kg). Cycles 3 and 5: Cyclophosphamide 1,000 mg/m2 IV on day 1 (33 mg/kg/day in children less than 12 kg) plus etoposide 120 mg/m2/day IV on days 1, 2, 3 (4 mg/kg/day in children less than 12 kg). Cycle 4: Carboplatin 560 mg/m2 IV on day 1 (18 mg/kg/day in children less than 12 kg) plus etoposide 120 mg/m2/day IV on days 1, 2, 3 (4 mg/kg/day in children less than 12 kg), and doxorubicin 30 mg/m2 IV on day 1 (1 mg/kg/day in children less than 12 kg). Cycle 8: Cyclophosphamide 1,000 mg/m2 IV on day 1 (33 mg/kg/day in children less than 12 kg) plus doxorubicin 30 mg/m2 IV on day 1 (1 mg/kg/day in children less than 12 kg). All cycles given at 3 week intervals. Patients with favorable biologic features received 4 cycles; if incomplete response after 4 cycles, patients given an additional 4 cycles. Patients with unfavorable biologic features received 8 cycles. Infants younger than 60 days of age received granulocyte colony-stimulating factor after each cycle.

    For the first-line treatment of unresectable, advanced thymoma†, in combination with paclitaxel.
    Intravenous dosage
    Adults

    AUC of 6 IV over 30 minutes following paclitaxel 225 mg/m2 IV over 3 hours on day 1 repeated every 21 days for up to 6 cycles resulted in an objective response rate (ORR) of 42.9% (complete response rate, 14.3%; median duration of response, 16.9 months) in 21 patients with invasive, recurrent, or metastatic thymoma in a multicenter, phase II study. This ORR was less than the prespecified ORR of 60% that would warrant further study of this regimen. At a median follow-up of 59.4 months, the median progression-free survival time was 16.7 months and the median overall survival time was not reached. Serious toxicity reported in this study included grade 4 neutropenia and grade 3 sensory neuropathy.

    For the first-line treatment of unresectable, advanced thymic carcinoma†, in combination with paclitaxel.
    Intravenous dosage
    Adults

    AUC of 6 IV over 30 minutes following paclitaxel 225 mg/m2 IV over 3 hours on day 1 administered every 21 days for up to 6 cycles resulted in an objective response rate (ORR) of 21.7% (all partial responses; median duration of response, 4.5 months) in 23 patients with invasive, recurrent, or metastatic thymic carcinoma in a multicenter, phase II study. This ORR was less than the prespecified ORR of 45% that would warrant further study of this regimen. At a median follow-up of 63.8 months, the median progression-free survival and overall survival times were 5 and 20 months, respectively. Serious toxicity reported in this study included grade 4 neutropenia and grade 3 sensory neuropathy.

    For the treatment of small cell lung cancer (SCLC)†.
    For the treatment of extensive-stage SCLC, in combination with etoposide†.
    Intravenous dosage
    Adults

    AUC 5 IV on day 1 in combination with etoposide 80 mg/m2/day IV on days 1, 2, 3 per cycle every 3 to 4 weeks up to 4 courses.

    For the treatment of limited-stage SCLC, in combination with etoposide and radiation therapy†.
    Intravenous dosage
    Adults

    AUC 6 IV on day 1 in combination with etoposide 100 mg/m2/day IV on days 1, 2, 3, every 3 weeks for 6 courses. Hyperfractionated thoracic radiation therapy should be given concurrently with chemotherapy.

    For the treatment of relapsed SCLC in combination with paclitaxel†.
    Intravenous dosage
    Adults

    AUC 7 IV on day 1 in combination with paclitaxel 175 mg/m2 IV on day 1, every 3 weeks for 5 cycles.

    For the first-line treatment of extensive-stage SCLC, in combination with etoposide and atezolizumab†.
    Intravenous dosage
    Adults

    AUC 5 IV over 30 to 60 minutes on day 1, to be administered after completion of atezolizumab (1,200 mg IV over 60 minutes on day 1). After completion of both atezolizumab and carboplatin, administer etoposide (100 mg/m2 IV over 60 minutes on days 1, 2, and 3); repeat every 3 weeks for 4 cycles. If the first infusion of atezolizumab is tolerated, all subsequent infusions may be infused over 30 minutes. Upon completion of 4 cycles, continue atezolizumab 1,200 mg IV every 3 weeks until disease progression or unacceptable toxicity. In a randomized, double-blind, phase 3 clinical trial, the addition of atezolizumab to carboplatin plus etoposide (n = 201) significantly improved overall survival (12.3 months vs. 10.3 months) and progression-free survival (5.2 months vs. 4.3 months) compared with placebo. Survival at 1 year was 51.7% versus 38.2%, respectively. Treatment was well tolerated, with 56.5% of patients in the atezolizumab arm experiencing grade 3 or 4 adverse reactions compared with 56.1% of those in the placebo arm. Immune-related adverse reactions occurred in 39.9% versus 24.5% of patients, respectively.

    For the treatment of glioblastoma multiforme† after failing prior bevacizumab-based therapy, in combination with irinotecan and bevacizumab.
    Intravenous dosage
    Adults

    AUC 4 IV on day 1 in combination with irinotecan (enzyme-inducing antiepileptic drug: 340 mg/m2 IV on days 1 and 15; non-enzyme-inducing antiepileptic drug: 125 mg/m2 IV on days 1 and 15) and bevacizumab 10 mg/kg IV on days 1 and 15, every 28 days for up to 12 cycles.

    For the treatment of previously untreated, advanced, unresectable pleural malignant mesothelioma, in combination with pemetrexed†.
    Intravenous dosage
    Adults

    AUC 5 IV over 30 minutes on day 1; 30 minutes prior to carboplatin infusion on day 1, administer pemetrexed 500 mg/m2 IV over 10 minutes. Repeat every 21 days for up to 6 cycles, until disease progression or unacceptable toxicity. Premedicate pemetrexed with dexamethasone 4 mg by mouth twice daily for 3 days, beginning the day before pemetrexed administration to reduce cutaneous reactions. Additionally, supplement with folic acid (400 to 1,000 mcg by mouth daily) and vitamin B12 (1 mg IM every 3 months) beginning 7 days prior to the first dose of pemetrexed and continuing for 21 days after the last dose to reduce the severity and frequency of hematologic and GI toxicities; after the first dose, vitamin B12 may be given on the same day as pemetrexed. Do not substitute oral for IM vitamin B12.

    †Indicates off-label use

    MAXIMUM DOSAGE

    The suggested maximum tolerated dose (MTD) for carboplatin is dependent on performance status, other chemotherapy agents or radiation given in combination, and disease state. The dosing of carboplatin may vary from protocol to protocol. If questions arise, clinicians should consult the appropriate references to verify the dose.

    Adults

    Maximum dosage information is not available. For doses calculated using the Calvert formula with an estimated GFR, it is recommended to use a maximum GFR = 125 mL/min in the calculation.

    Geriatric

    Maximum dosage information is not available. For doses calculated using the Calvert formula with an estimated GFR, it is recommended to use a maximum GFR = 125 mL/min in the calculation.

    Adolescents

    Safety and efficacy have not been established. Maximum dosage information is not available. For doses calculated using the Calvert formula with an estimated GFR, it is recommended to use a maximum GFR = 125 mL/min in the calculation.

    Children

    Safety and efficacy have not been established. Maximum dosage information is not available. For doses calculated using the Calvert formula with an estimated GFR, it is recommended to use a maximum GFR = 125 mL/min in the calculation.

    Infants

    Safety and efficacy have not been established. Maximum dosage information is not available. For doses calculated using the Calvert formula with an estimated GFR, it is recommended to use a maximum GFR = 125 mL/min in the calculation.

    Neonates

    Safety and efficacy have not been established. Maximum dosage information is not available. For doses calculated using the Calvert formula with an estimated GFR, it is recommended to use a maximum GFR = 125 mL/min in the calculation.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No dosage adjustments are needed in patients with hepatic impairment.

    Renal Impairment

    NOTE: Recommendations are only available for the initial course of treatment for ovarian cancer with carboplatin as a single agent or with cyclophosphamide. Subsequent adjustments should be done base on the toxicity of the previous course.
    CrCl >= 60 ml/min: no dosage adjustment needed.
    CrCl 41—59 ml/min: give 250 mg/m2 on day 1 of the initial course for ovarian cancer.
    CrCl 16—40 ml/min: give 200 mg/m2 on day 1 of the initial course for ovarian cancer.
    CrCl <= 15 ml/min: Data too limited to permit a recommendation.
     
    Intermittent hemodialysis
    Multiple reports document the use of carboplatin in patients who are receiving concurrent hemodialysis. Most of the reports indicate that carboplatin is removed by hemodialysis. Studies indicate that anuric patients may receive carboplatin at initial doses not exceeding 150 mg/m2 IV followed by dialysis within 24—48 hours of treatment (written communication, Bristol-Myers Squibb Oncology/Immunology Division, September 1999).

    ADMINISTRATION

     
    CAUTION: Observe and exercise appropriate precautions for handling, preparing, and administering cytotoxic drugs.
    Aluminum needles or IV sets containing aluminum should not be used for carboplatin preparation or administration because aluminum reacts with carboplatin to form a precipitate, causing loss of potency.

    Injectable Administration

    Carboplatin is administered intravenously as an infusion.
    Routine hydration is not required with carboplatin therapy. Hydration should be considered in patients with renal impairment or in those receiving concurrent nephrotoxic agents.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Reconstitution of vials:
    Reconstitute carboplatin 50, 150, or 450 mg vials with 5, 15, or 45 mL, respectively, of sterile water for injection, 5% Dextrose for injection, or sodium chloride injection. The reconstituted vials should have a concentration of 10 mg/mL of carboplatin.
    Reconstituted vials are stable for 24 hours at room temperature (25 degrees C). Paraplatin multidose (10 mg/mL) vials are stable for up to 14 days following initial entry into the vial.
     
    Further dilution for infusion:
    Further dilute carboplatin solution (10 mg/mL) with 5% Dextrose injection or 0.9% Sodium Chloride injection to concentrations of 0.5—4 mg/mL.
    Carboplatin solutions further diluted with 5% Dextrose injection or 0.9% Sodium Chloride injection are stable for 8 hours at room temperature (25 degrees C). Since carboplatin solutions are preservative-free the manufacturer recommends discarding any unused carboplatin solution after 8 hours.
     
    Intermittent infusion:
    Infuse appropriate dose IV over 15 minutes to 1 hour.
     
    Continuous infusion:
    Infuse at a rate to allow administration of the entire dose over a 24 hour period.

    Other Administration Route(s)

    Intraperitoneal Administration:
    NOTE: Carboplatin is not approved by the FDA for intraperitoneal administration.
    Add carboplatin to a pre-warmed sterile 0.9% Sodium Chloride solution prior to instilling (i.e., body-temperature).
    Dilute carboplatin dosage in 2 liters 0.9% Sodium Chloride injection, instill and dwell for 2—4 hours, then drain by gravity as completely as possible.
    Carboplatin is administered via a Tenckhoff catheter or a percutaneously inserted peritoneal dialysis catheter.

    STORAGE

    Generic:
    - Protect from light
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Paraplatin:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Product is stable for up to 14 days at 77 degrees F following multiple uses
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store in carton until time of use

    CONTRAINDICATIONS / PRECAUTIONS

    Platinum compound hypersensitivity, serious hypersensitivity reactions or anaphylaxis

    Carboplatin is contraindicated in patients who exhibit platinum compound hypersensitivity. For example, patients who have worked with platinum in the electronics industry can develop sensitivity to platinum. There is an increased incidence of hypersensitivity reactions in patients previously exposed to platinum therapy. Serious hypersensitivity reactions or anaphylaxis may occur within minutes of carboplatin administration. Epinephrine, corticosteroids, and antihistamines have been utilized to treat these reactions.

    Anemia, bleeding, bone marrow suppression, coagulopathy, herpes infection, infection, neutropenia, radiation therapy, thrombocytopenia, varicella, viral infection

    Contraindications to carboplatin include patients with severe bone marrow suppression and significant bleeding; patients with acute leukemia may require treatment with carboplatin despite severe bone marrow suppression. Carboplatin-induced bone marrow suppression is dose-related and is dose limiting. Complete blood counts should be frequently monitored during carboplatin treatment and, when appropriate, until recovery is achieved. Single intermittent courses of carboplatin should not be repeated until leukocyte, neutrophil, and platelet counts have recovered. When used in combination with other myelosuppressive chemotherapy agents, the dose and administration of carboplatin must be carefully reviewed and adjusted to minimize additive effects. Carboplatin should be used cautiously in patients with coagulopathy, reduced renal function, or in those who have received previous cisplatin or myelosuppressive therapy such as chemotherapy or radiation therapy; these patients may require reduced dosages (i.e., lower target AUC values). Carboplatin is a radiation sensitizer and patients may experience severe myelosuppression or other toxicities with concurrent use. Patients with preexisting bone marrow suppression should be allowed to recover their counts prior to carboplatin administration. Severe thrombocytopenia (< 50,000/mm3) or neutropenia (< 500/mm3) following carboplatin treatment indicates the need for a dose reduction for subsequent courses. Anemia is cumulative; transfusions or use of red blood cell growth factors may be needed during carboplatin therapy, especially during prolonged treatment. Patients with an active infection should be treated prior to receiving carboplatin when possible. Patients with a history of varicella zoster, other herpes infection (e.g., herpes simplex), or other viral infection are at risk for reactivation of the infection when treated with chemotherapy.

    Anuria, dialysis, renal failure, renal impairment

    Due to extensive renal elimination, carboplatin dosage should be adjusted in patients with renal impairment or renal failure, including anuria, to avoid excessive myelosuppressive effects. Patients on dialysis have received carboplatin but at reduced doses. Previous therapy with nephrotoxic agents such as cisplatin or aminoglycosides may increase the incidence of nephrotoxicity. Hydration prior to treatment may lessen the nephrotoxic effects in patients with renal impairment or in those who are receiving nephrotoxic agents concurrently. Hydration should be given with high-dose carboplatin to decrease nephrotoxicity.

    Children, hearing impairment

    Carboplatin should be used with caution in patients with hearing impairment. Children are at increased risk of clinically apparent hearing loss, especially when receiving high-dose carboplatin. Concomitant use of other ototoxic agents (e.g., aminoglycosides) should be avoided.

    Peripheral neuropathy

    Patients over the age of 65 years and patients previously treated with cisplatin tend to be at increased risk of developing peripheral neuropathy during carboplatin therapy. Preexisting peripheral neuropathy due to cisplatin does not worsen in about 70% of patients receiving carboplatin.

    Pregnancy

    Carboplatin is classified as FDA pregnancy risk category D. Carboplatin is embryotoxic and teratogenic in animal models. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Females of childbearing potential should be advised to avoid becoming pregnant during treatment with carboplatin.

    Breast-feeding

    It is not known if carboplatin is excreted in breast milk. Women should stop breast-feeding while receiving carboplatin due to the potential harm to the infant.

    Requires a specialized care setting, requires an experienced clinician

    Carboplatin therapy requires an experienced clinician in the management of cancer chemotherapy. Carboplatin administration requires a specialized care setting adequate for the appropriate management of carboplatin therapy and complications.

    Geriatric

    Geriatric patients treated with cisplatin tend to be at increased risk of developing peripheral neuropathy during carboplatin therapy. Preexisting peripheral neuropathy due to cisplatin does not worsen in about 70% of patients receiving carboplatin. Poor performance status may increase the risk of other toxicities, such as bone marrow suppression. According to the Beers Criteria, carboplatin is considered a potentially inappropriate medication (PIM) in older adults and should be used cautiously because carboplatin can cause or exacerbate hyponatremia and SIADH and the elderly are at increased risk of developing these conditions. Sodium levels should be closely monitored when starting or changing dosages in older adults.

    Vomiting

    Vomiting occurs frequently with carboplatin therapy; ensure that patients are premedicated with appropriate antiemetic therapy prior to initiating therapy with carboplatin.

    ADVERSE REACTIONS

    Severe

    neutropenia / Delayed / 16.0-82.0
    leukopenia / Delayed / 15.0-71.0
    thrombocytopenia / Delayed / 25.0-33.0
    anemia / Delayed / 0-14.0
    bronchospasm / Rapid / 0-1.0
    visual impairment / Early / 0-1.0
    serious hypersensitivity reactions or anaphylaxis / Rapid / Incidence not known
    hearing loss / Delayed / Incidence not known
    new primary malignancy / Delayed / Incidence not known
    tissue necrosis / Early / Incidence not known
    hemolytic-uremic syndrome / Delayed / Incidence not known
    heart failure / Delayed / Incidence not known
    thromboembolism / Delayed / Incidence not known
    stroke / Early / Incidence not known

    Moderate

    hypomagnesemia / Delayed / 29.0-29.0
    hyponatremia / Delayed / 29.0-29.0
    hypocalcemia / Delayed / 22.0-22.0
    hypokalemia / Delayed / 20.0-20.0
    elevated hepatic enzymes / Delayed / 15.0-20.0
    bleeding / Early / 5.0-8.0
    constipation / Delayed / 6.0-6.0
    hyperbilirubinemia / Delayed / 5.0-5.0
    erythema / Early / 0-2.0
    hypotension / Rapid / 0-1.0
    bone marrow suppression / Delayed / Incidence not known
    stomatitis / Delayed / Incidence not known
    hypertension / Early / Incidence not known
    dehydration / Delayed / Incidence not known

    Mild

    nausea / Early / 10.0-93.0
    vomiting / Early / 65.0-83.0
    alopecia / Delayed / 3.0-49.0
    asthenia / Delayed / 11.0-41.0
    infection / Delayed / 5.0-16.0
    diarrhea / Early / 6.0-6.0
    rash / Early / 0-2.0
    pruritus / Rapid / 0-2.0
    urticaria / Rapid / 0-2.0
    dysgeusia / Early / 0-1.0
    anorexia / Delayed / Incidence not known
    injection site reaction / Rapid / Incidence not known

    DRUG INTERACTIONS

    Amikacin: (Moderate) Patients previously or currently treated with other potentially nephrotoxic agents, such as systemic aminoglycosides, can have a greater risk of developing carboplatin-induced nephrotoxicity. These patients may benefit from hydration prior to carboplatin therapy to lessen the incidence of nephrotoxicity. Monitor renal function closely.
    Aminoglycosides: (Moderate) Patients previously or currently treated with other potentially nephrotoxic agents, such as systemic aminoglycosides, can have a greater risk of developing carboplatin-induced nephrotoxicity. These patients may benefit from hydration prior to carboplatin therapy to lessen the incidence of nephrotoxicity. Monitor renal function closely.
    Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as carboplatin. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Capreomycin: (Major) Since capreomycin is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including carboplatin, may increase serum concentrations of either drug. Theoretically, the chronic coadministration of these drugs may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Monitor patients for changes in renal function if these drugs are coadministered.
    Carbamazepine: (Moderate) Myelosuppressive antineoplastic agents and radiation therapy possess hematologic toxicities similar to carbamazepine, and should be used concomitantly with caution. Dosage adjustments may be necessary. Monitor patient closely.
    Cisplatin: (Moderate) Patients previously treated with cisplatin can have a greater risk of developing carboplatin-induced myelosuppression or renal toxicity. Marrow suppression with carboplatin is usually more severe in patients with impaired kidney function. Both agents may cause neurotoxicity, and there may be a greater risk for cumulative neurotoxicity with sequential use. Patients previously treated with cisplatin may benefit from hydration prior to carboplatin therapy to lessen the incidence of nephrotoxicity. Monitor renal function and blood counts closely and monitor for other adverse effects.
    Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as carboplatin. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as carboplatin. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus.
    Colistimethate, Colistin, Polymyxin E: (Major) Both colistimethate sodium and carboplatin can cause nephrotoxicity. The coadministration of these drugs may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Monitor patients for changes in renal function if these drugs are coadministered.
    Daclizumab: (Minor) Concurrent use of carboplatin with other agents that cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as carboplatin. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as carboplatin. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as carboplatin. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as carboplatin. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as carboplatin. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as carboplatin. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus.
    Emtricitabine; Tenofovir alafenamide: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as carboplatin. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Emtricitabine; Tenofovir disoproxil fumarate: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as carboplatin. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus.
    Ethotoin: (Major) Patients receiving antineoplastic agents concurrently with hydantoins may be at risk for toxicity or loss of clinical efficacy and seizures; anticonvulsant therapy should be monitored closely during and after administration of antineoplastic agents. Concurrent therapy with phenytoin and carboplatin has been associated with subtherapeutic phenytoin serum concentrations and seizure activity. Phenytoin dosage increases of 20 to 100% have been required in some patients, depending on the chemotherapy administered.
    Fosphenytoin: (Major) Patients receiving antineoplastic agents concurrently with hydantoins may be at risk for toxicity or loss of clinical efficacy and seizures; anticonvulsant therapy should be monitored closely during and after administration of antineoplastic agents. Concurrent therapy with phenytoin and carboplatin has been associated with subtherapeutic phenytoin serum concentrations and seizure activity. Phenytoin dosage increases of 20 to 100% have been required in some patients, depending on the chemotherapy administered.
    Gentamicin: (Moderate) Patients previously or currently treated with other potentially nephrotoxic agents, such as systemic aminoglycosides, can have a greater risk of developing carboplatin-induced nephrotoxicity. These patients may benefit from hydration prior to carboplatin therapy to lessen the incidence of nephrotoxicity. Monitor renal function closely.
    Hydantoins: (Major) Patients receiving antineoplastic agents concurrently with hydantoins may be at risk for toxicity or loss of clinical efficacy and seizures; anticonvulsant therapy should be monitored closely during and after administration of antineoplastic agents. Concurrent therapy with phenytoin and carboplatin has been associated with subtherapeutic phenytoin serum concentrations and seizure activity. Phenytoin dosage increases of 20 to 100% have been required in some patients, depending on the chemotherapy administered.
    Kanamycin: (Moderate) Patients previously or currently treated with other potentially nephrotoxic agents, such as systemic aminoglycosides, can have a greater risk of developing carboplatin-induced nephrotoxicity. These patients may benefit from hydration prior to carboplatin therapy to lessen the incidence of nephrotoxicity. Monitor renal function closely.
    Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as carboplatin. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus.
    Mycophenolate: (Severe) Concurrent use of carboplatin with other agents that cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Paclitaxel: (Minor) In vitro studies have shown an increase in cytotoxicity with either the simultaneous or sequential administration of paclitaxel and carboplatin. It appears that paclitaxel followed by carboplatin is more cytotoxic. The pharmacokinetics of either agent is not affected by this sequence of administration.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Paromomycin: (Moderate) Patients previously or currently treated with other potentially nephrotoxic agents, such as systemic aminoglycosides, can have a greater risk of developing carboplatin-induced nephrotoxicity. These patients may benefit from hydration prior to carboplatin therapy to lessen the incidence of nephrotoxicity. Monitor renal function closely.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Phenytoin: (Major) Patients receiving antineoplastic agents concurrently with hydantoins may be at risk for toxicity or loss of clinical efficacy and seizures; anticonvulsant therapy should be monitored closely during and after administration of antineoplastic agents. Concurrent therapy with phenytoin and carboplatin has been associated with subtherapeutic phenytoin serum concentrations and seizure activity. Phenytoin dosage increases of 20 to 100% have been required in some patients, depending on the chemotherapy administered.
    Plazomicin: (Moderate) Patients previously or currently treated with other potentially nephrotoxic agents, such as systemic aminoglycosides, can have a greater risk of developing carboplatin-induced nephrotoxicity. These patients may benefit from hydration prior to carboplatin therapy to lessen the incidence of nephrotoxicity. Monitor renal function closely.
    Polymyxin B: (Major) Patients previously or currently treated with other potentially nephrotoxic agents, such as systemic polymyxins like Polymyxin B injection, can have a greater risk of developing carboplatin-induced nephrooxicity. These patients may benefit from hydration prior to carboplatin therapy to lessen the incidence of nephrotoxicity. Monitor renal function closely.
    Polymyxins: (Major) Both colistimethate sodium and carboplatin can cause nephrotoxicity. The coadministration of these drugs may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Monitor patients for changes in renal function if these drugs are coadministered.
    Sirolimus: (Minor) Concurrent use of carboplatin with other agents that cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Streptomycin: (Moderate) Patients previously or currently treated with other potentially nephrotoxic agents, such as systemic aminoglycosides, can have a greater risk of developing carboplatin-induced nephrotoxicity. These patients may benefit from hydration prior to carboplatin therapy to lessen the incidence of nephrotoxicity. Monitor renal function closely.
    Tacrolimus: (Moderate) Concurrent use of carboplatin with other agents that cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
    Tenofovir Alafenamide: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as carboplatin. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Tenofovir Alafenamide: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as carboplatin. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Tenofovir, PMPA: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as carboplatin. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus.
    Tobramycin: (Moderate) Patients previously or currently treated with other potentially nephrotoxic agents, such as systemic aminoglycosides, can have a greater risk of developing carboplatin-induced nephrotoxicity. These patients may benefit from hydration prior to carboplatin therapy to lessen the incidence of nephrotoxicity. Monitor renal function closely.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.

    PREGNANCY AND LACTATION

    Pregnancy

    Carboplatin is classified as FDA pregnancy risk category D. Carboplatin is embryotoxic and teratogenic in animal models. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Females of childbearing potential should be advised to avoid becoming pregnant during treatment with carboplatin.

    It is not known if carboplatin is excreted in breast milk. Women should stop breast-feeding while receiving carboplatin due to the potential harm to the infant.

    MECHANISM OF ACTION

    Carboplatin cytotoxic activity is similar to cisplatin as it binds with DNA to form intrastrand crosslinks and adducts that cause changes in the conformation of the DNA and affect DNA replication. Carboplatin readily crosses the cell membrane. Once inside the cell, the ring structure of carboplatin is hydroxylated by water to form the active moiety. This reaction occurs more slowly than the activation of cisplatin. Therefore, 4—6 times the amount of carboplatin is required to produce the same cytotoxic effects as cisplatin. Once in the active form, carboplatin functions similarly to cisplatin and binds with DNA, RNA, or other macromolecules at two sites to form interstrand and intrastrand links. Carboplatin forms irreversible covalent bonds which inhibit DNA replication, RNA transcription, and protein synthesis. Intrastrand crosslinks at the N7 position of guanine are the predominant binding sites. The maximal DNA crosslinks occur 18 hours after exposure to carboplatin compared to 6—12 hours for cisplatin. Carboplatin crosslinks have a slower removal rate than do cisplatin-induced crosslinks. This slower rate of onset and removal of carboplatin crosslinks is thought to be due to a slow rate of monofunctional adduct formation and/or a slower rate of conversion of monoadducts to crosslinks. While considered cell cycle non-specific, carboplatin cytotoxicity is increased with exposure during the S-phase and with increased infusion rates (24 hours versus 1 hour). Carboplatin causes cell cycle arrest in the G2-phase and then induces programmed cell death or apoptosis.

    PHARMACOKINETICS

    Carboplatin is primarily administered by IV infusion. The pharmacokinetics of carboplatin and cisplatin differ greatly. Very little protein binding occurs. Carboplatin distributes well into ascites and pleural fluid. CSF concentrations are approximately 30% of plasma concentrations. Carboplatin is not metabolized but undergoes spontaneous hydrolysis to form the active compound. The excretion of carboplatin is biphasic with half-lives of 90 and 180 minutes Carboplatin is excreted primarily by the kidneys via tubular filtration and secretion. Sixty-five percent of a dose can be recovered in the urine in the first 24 hours.
     
    The exposure to carboplatin or AUC is associated with myelosuppressive and cytotoxic effects. In general, carboplatin AUC of 4—7 is associated with acceptable myelosuppressive effects and efficacy. A carboplatin AUC of > 7 is associated with an increased incidence of severe myelosuppression with no added efficacy. Carboplatin bolus doses of 400—600 mg/m2 are associated with an AUC of 6—8 mg/mL x min in previously untreated patients with normal creatinine clearance. Several equations have been developed to individualize carboplatin dosing. The Calvert equation is the simplest equation and was approved by the FDA in 1995 for dosing of carboplatin. In the determination of this equation, creatinine clearance was determined using Cr-EDTA, which is thought to more accurately reflect glomerular filtration rate in patients with altered renal function than does a measured or a calculated creatinine clearance. Currently, Cr-EDTA is not available in the United States and creatinine clearance is determined using measured or calculated methods, which may not be as accurate. The Egorin equations use creatinine clearance and a relationship with platelet nadir to determine the carboplatin dosage. These equations also differentiate between previously treated and untreated patients to take into account the cumulative bone marrow toxicity of carboplatin. The dosing of carboplatin in many disease states is now almost entirely based upon AUC and not body surface area.

    Intravenous Route

    An IV dose of carboplatin distributes widely throughout the body tissues, and distribution is equal to the total body water.