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CARBOplatin

Pronunciation

Pronunciation

(KAR boe pla tin)

Index Terms

  • CBDCA
  • Paraplatin

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous:

Generic: 50 mg/5 mL (5 mL); 150 mg/15 mL (15 mL); 450 mg/45 mL (45 mL); 600 mg/60 mL (60 mL)

Solution, Intravenous [preservative free]:

Generic: 50 mg/5 mL (5 mL); 150 mg/15 mL (15 mL); 450 mg/45 mL (45 mL); 600 mg/60 mL (60 mL)

Pharmacologic Category

  • Antineoplastic Agent, Alkylating Agent
  • Antineoplastic Agent, Platinum Analog

Pharmacology

Carboplatin is a platinum compound alkylating agent which covalently binds to DNA; interferes with the function of DNA by producing interstrand DNA cross-links. Carboplatin is apparently not cell-cycle specific.

Distribution

Vd: 16 L (based on a dose of 300 to 500 mg/m2); into liver, kidney, skin, and tumor tissue

Metabolism

Minimally hepatic to aquated and hydroxylated compounds

Excretion

Urine (~70% as carboplatin within 24 hours; 3% to 5% as platinum within 1 to 4 days)

Half-Life Elimination

CrCl >60 mL/minute: Carboplatin: 2.6 to 5.9 hours (based on a dose of 300 to 500 mg/m2); Platinum (from carboplatin): ≥5 days

Protein Binding

Carboplatin: 0%; Platinum (from carboplatin): Irreversibly binds to plasma proteins

Special Populations: Renal Function Impairment

In patients with CrCl <60 mL/minute, the total body and renal clearance decreases as CrCl decreases.

Use: Labeled Indications

Ovarian cancer, advanced: Initial treatment of advanced ovarian cancer in combination with other established chemotherapy agents; palliative treatment of recurrent ovarian cancer after prior chemotherapy, including cisplatin-based treatment

Off Label Uses

Anal cancer (advanced)

Data from two small studies (one phase II and one retrospective) support the use of carboplatin (in combination with paclitaxel or paclitaxel and fluorouracil) for the treatment of advanced anal cancer [Hainsworth 2001], [Kim 2014]. Additional data may be necessary to further define the role of carboplatin in the treatment of this condition.

Bladder cancer

Data from two phase II studies support the use of carboplatin (in combination with gemcitabine or paclitaxel) in the treatment of advanced transitional cell urothelium cancer [Bamias 2006], [Vaughn 2002]. Additional trials may be necessary to further define the role of carboplatin in this condition.

Breast cancer (metastatic)

Data from two multicenter, randomized phase III studies support the use of carboplatin (in combination with docetaxel and trastuzumab or with paclitaxel and trastuzumab) in the treatment of HER-2 overexpressing metastatic breast cancer [Robert 2006], [Valero 2011]. Data from two earlier phase II studies also support the use of carboplatin in combination with docetaxel and trastuzumab [Peagram 2004].

Central nervous system tumors

Data from a multicenter study supports the use of carboplatin (in combination with vincristine) in the treatment of pediatric gliomas [Packer 1997].

Data from two studies support the use of carboplatin (in combination with etoposide for 2 cycles and then followed by cyclophosphamide, doxorubicin and vincristine) in the treatment of pediatric neuroblastoma [Rubie 1998], [Rubie 2001].

Cervical cancer (recurrent or metastatic)

Data from three studies support the use of carboplatin (in combination with paclitaxel or as a single agent) in the treatment of advanced/metastatic or recurrent cervical cancer [Pectasides 2009], [Tinker 2005], [Weiss 1990]. Additional trials may be necessary to further define the role of carboplatin in this condition.

Endometrial cancer

Data from two studies support the use of carboplatin (in combination with paclitaxel) in the treatment of advanced/metastatic or recurrent endometrial cancer [Pectasides 2008], [Secord 2007]. Additional trials may be necessary to further define the role of carboplatin in this condition.

Esophageal cancer

Data from a phase III trial supports the use of carboplatin (in combination with paclitaxel and radiation) as preoperative chemoradiotherapy for the treatment of esophageal or esophagogastric junction cancer [van Hagen 2012]. Data from two phase II studies also support the use of carboplatin (in combination with paclitaxel) in the treatment of esophageal cancer [El-Rayes 2004], [van Meerten 2006].

Gastric cancer

Data from a phase III trial supports the use of carboplatin (in combination with paclitaxel and radiation) as preoperative chemoradiotherapy for the treatment of esophageal or esophagogastric junction cancer [van Hagen 2012]. A small phase II study also suggests that carboplatin (in combination with paclitaxel) is an active and well-tolerated regimen in patients with advanced gastric cancer [Gadgeel 2003].

Head and neck cancer

Data from a phase III randomized study supports the use of carboplatin (in combination with fluorouracil) for the treatment of advanced squamous cell head and neck cancer [Forastiere 1992]. Data from a phase III randomized study supports the use of carboplatin (in combination with fluorouracil and cetuximab) as first-line treatment of recurrent or metastatic squamous cell head and neck cancer [Vermorken 2008]. Data from a phase II study supports the use of carboplatin (in combination with paclitaxel) in the treatment of advanced head and neck cancer [Clark 2001]. Data from a phase II study supports the use of carboplatin (in combination with cetuximab) in the treatment of recurrent or metastatic nasopharyngeal cancer [Chan 2005]. Data from randomized phase III trials support the use of weekly carboplatin (in combination with radiation) following induction chemotherapy with docetaxel, cisplatin, and fluorouracil (TPF) for the treatment of advanced head and neck cancer [Haddad 2013], [Posner 2007].

Hematopoietic stem cell transplant (adults)

Data from a retrospective study suggests that carboplatin (in combination with etoposide) followed by autologous stem cell transplant may be beneficial for the treatment of metastatic testicular cancer [Einhorn 2007]. Additional data may be necessary to further define the role of carboplatin in the treatment of this condition.

Hematopoietic stem cell transplant (pediatric)

Data from several studies in pediatric patients with malignant brain tumors supports the use of carboplatin (in combination with thiotepa or with thiotepa and topotecan) as part of a consolidation and/or conditioning regimen prior to autologous hematopoietic stem cell transplant [Cohen 2015], [Gilheeny 2010], [Kushner 2001]. Additional data may be necessary to further define the role of carboplatin in the treatment of this condition.

Hodgkin lymphoma (relapsed or refractory)

Data from a study of multimodality therapy in chemosensitive Hodgkin lymphoma supports the use of carboplatin (in combination with ifosfamide and etoposide, followed by autologous stem cell transplant) as salvage treatment of relapsed and refractory Hodgkin lymphoma [Moskowitz 2001]. Additional trials may be necessary to further define the role of carboplatin in this condition.

Malignant pleural mesothelioma

Data from two phase II studies support the use of carboplatin (in combination with pemetrexed) in the treatment of malignant pleural mesothelioma [Castagneto 2008], [Ceresoli 2006]. Additional trials may be necessary to further define the role of carboplatin in this condition.

Melanoma (advanced or metastatic)

Data from a retrospective review suggests that carboplatin (in combination with paclitaxel) may be beneficial as a second-line regimen for the treatment of advanced or metastatic melanoma [Rao 2006]. Additional data may be necessary to further define the role of carboplatin in this condition.

Merkel cell carcinoma

Data from a phase II study in patients with high-risk Merkel cell carcinoma of the skin suggests that synchronous radiation in combination with carboplatin and etoposide chemotherapy results in high levels of locoregional and distant control, as well as survival [Poulsen 2003]. Data from another small study supports the use of weekly carboplatin administered concurrently with radiation, followed by combination chemotherapy with carboplatin and etoposide after radiation completion for the treatment of Merkel cell carcinoma with high-risk features [Poulsen 2008]. Additional data may be necessary to further define the role of carboplatin in this condition.

Neuroendocrine tumors, advanced, atypical or poorly differentiated (nonpulmonary)

Clinical data and consensus guideline recommendations from the North American Neuroendocrine Tumor Society (NANETS) suggest that regimens active in the treatment of small cell lung cancer (eg, carboplatin and etoposide) may be effective for the management of atypical or poorly differentiated (nonpulmonary) neuroendocrine tumors [Skarlos 2001], [Sorbye 2013], [Strosberg 2010]. Additional data may be necessary to further define the role of carboplatin in this condition.

Non-Hodgkin lymphomas (relapsed or refractory)

Data from a small study supports the use of carboplatin (in combination with rituximab, ifosfamide and etoposide) as second-line therapy to induce a response in the treatment of relapsed or refractory diffuse large b-cell lymphoma (DLBCL) prior to autologous stem cell transplant [Kewalramani 2004]. Additional trials may be necessary to further define the role of carboplatin in this setting.

Non-small cell lung cancer

Data from a large randomized phase III study supports the use of carboplatin (in combination with paclitaxel and bevacizumab) in recurrent or advanced non-small cell lung cancer [Sandler 2006]. Data from a large randomized study supports the use of carboplatin (in combination with paclitaxel) in advanced non-small cell lung cancer [Schiller 2002]. Data from a subset analysis supports the use of carboplatin (in combination with paclitaxel) in elderly patients with advanced non-small cell lung cancer [Ramalingam 2008]. Data from a large randomized study supports the use of carboplatin (in combination with paclitaxel) in the adjuvant treatment of non-small cell lung cancer in patients with tumors ≥4 cm [Strauss 2008]. Data from a large randomized phase III study supports the use of carboplatin (in combination with or pemetrexed) as first-line therapy in advanced non-small cell lung cancer [Gronberg 2009]. Data from a randomized phase II study supports the use of carboplatin (in combination with radiation therapy and paclitaxel) in the treatment of locally advanced non-small cell lung cancer [Belani 2005]. Another large phase III study supports the use of carboplatin (in combination with bevacizumab and pemetrexed) for the treatment of advanced nonsquamous non-small cell lung cancer [Patel 2013].

Based on American Society of Clinical Oncology Guidelines, for Systemic Therapy for Stage IV Non-Small-Cell Lung Cancer, platinum (doublet) therapy is recommended as first-line therapy for stage IV non-small cell lung cancer in patients with a performance status of 1 or 0.

Retinoblastoma

Data from two small non-randomized trials support the use of carboplatin (in combination with vincristine or with etoposide and vincristine) for the treatment of retinoblastoma in pediatric patients [Friedman 2000], [Rodriguez-Galindo 2003]. Additional trials may be necessary to further define the role of carboplatin in this condition.

Sarcomas (Ewing sarcoma and osteosarcoma)

Data from a prospective clinical trial in patients (1 to 22 years of age) with recurrent/refractory sarcomas (including Ewing and osteosarcoma), supports the use of carboplatin (in combination with ifosfamide and etoposide) as reinduction therapy in the treatment of this condition [van Winkle 2005].

Small cell lung cancer

Data from a randomized phase III study supports the use of carboplatin (in combination with irinotecan) for the treatment of extensive stage small cell lung cancer [Hermes 2008]. Data from a phase 2 study also supports the use of carboplatin (in combination with irinotecan) for the treatment of extensive stage small cell lung cancer [Schmittel 2006].

Data from a randomized phase II study supports the use of carboplatin (in combination with etoposide and radiation therapy) for the treatment of limited stage small cell lung cancer [Skarlos 2001].

Based on American Society of Clinical Oncology Guidelines, for Treatment of Small-Cell Lung Cancer, platinum-based therapy in combination with either etoposide or irinotecan is recommended over other chemotherapy regimens for limited stage or extensive stage disease [Rudin 2015].

Testicular cancer

Data from a large randomized trial supports the use of carboplatin (as a one-time dose) as adjuvant treatment of stage I seminoma [Oliver 2011].

Data from a retrospective study suggests that carboplatin (in combination with etoposide) followed by autologous stem cell transplant may be beneficial for the treatment of metastatic testicular cancer [Einhorn 2007].

Thymic malignancies

Data from a phase II study supports the use of carboplatin (in combination with paclitaxel) in the treatment of advanced thymoma or thymic carcinoma [Lemma 2008]. Additional trials may be necessary to further define the role of carboplatin in this condition.

Thyroid cancer (anaplastic), advanced

Data from a randomized phase III trial supports the use of carboplatin (in combination with paclitaxel) for the treatment of advanced anaplastic thyroid cancer [Sosa 2014]. Additional data may be necessary to further define the role of carboplatin in the management of this condition.

The American Thyroid Association Guidelines for Management of Patients with Anaplastic Thyroid Cancer suggest that carboplatin (in combination with paclitaxel) may be used in the treatment of this condition [Smallridge 2012].

Unknown primary adenocarcinoma

Data from a multicenter phase II study supports the use of carboplatin (in combination with paclitaxel) in the treatment of unknown primary adenocarcinoma [Briasoulis 2000]. Data from a smaller phase II study also supports the use of carboplatin (in combination with docetaxel) in the management of unknown primary adenocarcinoma [Greco 2000]. Data from a prospective, multicenter, phase II study in patients with metastatic poorly differentiated neuroendocrine carcinoma (62% with unknown primary site) who had received no prior treatment demonstrated that carboplatin (in combination with paclitaxel and etoposide) is effective for the management of this condition [Hainsworth 2006].

Wilms tumor (pediatric)

Data from several small studies in pediatric patients supports the use of carboplatin (in combination with etoposide ± ifosfamide) for the treatment of poor-risk Wilms tumor [Abu-Ghosh 2002], [Daw 2009], [Pein 1994]. Additional data may be necessary to further define the role of carboplatin in the treatment of this condition.

Contraindications

History of severe allergic reaction to carboplatin, cisplatin, other platinum-containing formulations, mannitol, or any component of the formulation; should not be used in patients with severe bone marrow depression or significant bleeding

Dosing: Adult

Note: Doses for adults are commonly calculated by the target AUC using the Calvert formula, where Total dose (mg) = Target AUC x (GFR + 25). If estimating glomerular filtration rate (GFR) instead of a measured GFR, the Food and Drug Administration (FDA) recommends that clinicians consider capping estimated GFR at a maximum of 125 mL/minute to avoid potential toxicity. Carboplatin is associated with a moderate emetic potential in adult patients; antiemetics are recommended to prevent nausea and vomiting (Basch 2011; Roila 2016).

Ovarian cancer, advanced: Manufacturer’s labeling: IV: 360 mg/m2 every 4 weeks (as a single agent) or 300 mg/m2 every 4 weeks (in combination with cyclophosphamide) for 6 cycles or Target AUC 4 to 6 (single agent; in previously-treated patients)

Off-label dosing for advanced ovarian cancer: IV: Target AUC 5 to 7.5 every 3 weeks (in combination with paclitaxel) (Ozols 2003; Parmar 2003) or Target AUC 2 once weekly (in combination with weekly paclitaxel) for 18 consecutive weeks (Pignata 2014) or Target AUC 5 every 3 weeks (in combination with docetaxel) (Vasey 2004)

Off-label dosing for malignant germ cell tumor: IV: 400 mg/m2 on day 1 (in combination with etoposide) every 4 weeks for 3 cycles (Williams 2004)

Anal cancer, advanced (off-label use): IV: Target AUC 6 on days 1 and 22 every 6 weeks for up to 4 cycles (in combination with paclitaxel and fluorouracil) (Hainsworth 2001) or Target AUC 5 or 6 every 3 weeks (in combination with paclitaxel) (Kim 2014). Additional data may be necessary to further define the role of carboplatin in the treatment of this condition.

Bladder cancer (off-label use): IV: Target AUC 5 every 3 weeks (in combination with gemcitabine) (Bamias 2006) or Target AUC 6 every 3 weeks (in combination with paclitaxel) (Vaughn 2002)

Breast cancer, metastatic (off-label use): IV: Target AUC 6 every 3 weeks (in combination with trastuzumab and paclitaxel) (Robert 2006) or Target AUC 6 every 3 weeks (in combination with trastuzumab and docetaxel) (Pegram 2004; Valero 2011)

Cervical cancer, recurrent or metastatic (off-label use): IV: Target AUC 5 every 3 weeks (in combination with paclitaxel) (Pectasides 2009) or Target AUC 5 to 6 every 4 weeks (in combination with paclitaxel) (Tinker 2005) or 400 mg/m2 every 28 days (as a single agent) (Weiss 1990)

Endometrial cancer (off-label use): IV: Target AUC 5 every 3 weeks (in combination with paclitaxel) (Pectasides 2008) or Target AUC 2 on days 1, 8, and 15 every 28 days (in combination with paclitaxel) (Secord 2007)

Esophageal cancer (off-label use): IV: Target AUC 2 once weekly for 5 weeks (in combination with paclitaxel and radiation therapy) prior to surgery (van Hagen 2012; van Meerten 2006) or Target AUC 5 every 3 weeks (in combination with paclitaxel) (El-Rayes 2004)

Gastric cancer (off-label use): IV: Target AUC 2 once weekly for 5 weeks (in combination with paclitaxel and concurrent radiation) prior to surgery (van Hagen 2012) or Target AUC 5 to 6 every 3 weeks (in combination with paclitaxel) (Gadgeel 2003)

Head and neck cancer (off-label use): IV: Target AUC 5 every 3 weeks (in combination with cetuximab) (Chan 2005) or Target AUC 5 every 3 weeks (in combination with cetuximab and fluorouracil) (Vermorken 2008) or 300 mg/m2 every 4 weeks (in combination with fluorouracil) (Forastiere 1992) or Target AUC 6 every 3 weeks (in combination with paclitaxel) (Clark 2001) or Target AUC 1.5 weekly for 7 weeks (in combination with radiation, following 3 cycles of docetaxel, cisplatin, and fluorouracil [TPF] induction therapy [begin carboplatin/radiation therapy 3 to 8 weeks after the start of TPF cycle 3]) (Haddad 2013; Posner 2007)

Hematopoietic stem cell transplant (HSCT) for metastatic germ cell tumors: IV: 700 mg/m2/day for 3 days beginning 5 days prior to peripheral stem cell infusion (in combination with etoposide) for 2 cycles (Einhorn 2007). Additional data may be necessary to further define the role of carboplatin in the treatment of this condition.

Hodgkin lymphoma, relapsed or refractory (off-label use): IV: Target AUC 5 (maximum dose: 800 mg) for 2 cycles (in combination with ifosfamide and etoposide) (Moskowitz 2001)

Malignant pleural mesothelioma (off-label use): IV: Target AUC 5 every 3 weeks (in combination with pemetrexed) (Castagneto 2008; Ceresoli 2006)

Melanoma, advanced or metastatic (off-label use): IV: Target AUC 2 days on 1, 8, and 15 every 4 weeks (in combination with paclitaxel) (Rao 2006). Additional data may be necessary to further define the role of carboplatin in the treatment of this condition.

Merkel cell carcinoma (off-label use): IV: Target AUC 4.5 on day 1 of weeks 1, 4, 7, and 10 (in combination with etoposide and synchronous radiation therapy) (Poulsen 2003) or Target AUC 2 on day 1 weekly for up to 5 doses (administered concurrently with radiation), followed (beginning 3 weeks after radiation therapy) by carboplatin with a target AUC of 4.5 on day 1 (in combination with etoposide) every 3 weeks for 3 cycles (Poulsen 2008)

Neuroendocrine tumors, advanced, atypical or poorly differentiated (nonpulmonary) (off-label use): IV: Target AUC 6 every 3 weeks (in combination with etoposide) for 4 to 6 cycles (Skarlos 2001; Strosberg 2010).

Non-Hodgkin lymphomas, relapsed or refractory (off-label use): IV: Target AUC 5 (maximum dose: 800 mg) per cycle for 3 cycles (in combination with rituximab, ifosfamide and etoposide) (Kewalramani 2004)

Non-small cell lung cancer (off-label use): IV: Target AUC 6 every 3 to 4 weeks (in combination with paclitaxel) (Ramalingam 2008; Schiller 2002; Strauss 2008) or Target AUC 6 every 3 weeks (in combination with bevacizumab and paclitaxel) (Sandler 2006) or Target AUC 5 every 3 weeks (in combination with pemetrexed) (Gronberg 2009) or Target AUC 6 every 3 weeks (in combination with pemetrexed and bevacizumab) for up to 4 cycles followed by maintenance therapy (Patel 2013) or in combination with radiation therapy and paclitaxel (Belani 2005):

Target AUC 6 every 3 weeks for 2 cycles or

Target AUC 6 every 3 weeks for 2 cycles; then target AUC 2 weekly for 7 weeks or

Target AUC 2 every week for 7 weeks; then target AUC 6 every 3 weeks for 2 cycles

Sarcomas: Ewing sarcoma, osteosarcoma (off-label uses): IV: 400 mg/m2/day for 2 days every 21 days (in combination with ifosfamide and etoposide) (van Winkle 2005)

Small cell lung cancer (off-label use): IV: Target AUC 6 every 3 weeks (in combination with etoposide) (Skarlos 2001) or Target AUC 5 every 3 weeks (in combination with irinotecan) (Hermes 2008) or Target AUC 5 every 28 days (in combination with irinotecan) (Schmittel 2006)

Testicular cancer (off-label use): IV: Target AUC 7 as a one-time dose (Oliver 2011) or 700 mg/m2/day for 3 days beginning 5 days prior to peripheral stem cell infusion (in combination with etoposide) for 2 cycles (Einhorn 2007)

Thymic malignancies (off-label use): IV: Target AUC 5 every 3 weeks (in combination with paclitaxel) (Lemma 2008)

Thyroid cancer (anaplastic), advanced: IV: Target AUC 6 on day 1 every 3 weeks (in combination with paclitaxel) for 6 cycles (Smallridge 2012; Sosa 2014) or Target AUC 2 once weekly (in combination with weekly paclitaxel) (Smallridge 2012)

Unknown primary adenocarcinoma (off-label use): IV: Target AUC 6 every 3 weeks (in combination with paclitaxel) (Briasoulis 2000) or Target AUC 6 every 3 weeks (in combination with docetaxel) (Greco 2000) or Target AUC 6 every 3 weeks (in combination with paclitaxel and etoposide) (Hainsworth 2006)

Dosing: Geriatric

The Calvert formula should be used to calculate dosing for elderly patients. Refer to adult dosing.

Dosing: Pediatric

Carboplatin is associated with a high emetic potential in pediatric patients; antiemetics are recommended to prevent nausea and vomiting (Dupuis 2011).

Central nervous system tumors (off-label use):

Glioma: Infants ≥3 months, Children, and Adolescents: IV:

Induction: 175 mg/m2 weekly for 4 weeks every 6 weeks for 2 cycles, with a 2-week recovery period between courses (in combination with vincristine) (Packer 1997)

Maintenance: 175 mg/m2 weekly for 4 weeks (in combination with vincristine) for up to 12 cycles, with a 3-week recovery period between cycles (Packer 1997)

Neuroblastoma, localized and unresectable: IV: Children ≥10 kg: 200 mg/m2/day days 1, 2, and 3 every 21 days for 2 cycles (in combination with etoposide for 2 cycles then followed by cyclophosphamide, doxorubicin and vincristine) (Rubie 1998) or Children <1 year: 6.6 mg/kg/day days 1, 2, and 3 (in combination with etoposide for 2 cycles, then followed by cyclophosphamide, doxorubicin, and vincristine) (Rubie 2001)

Hematopoietic stem cell transplant (HSCT) (off-label use): IV:

Infants ≥6 months and Children ≤3 years: Consolidation regimen: 17 mg/kg over 2 hours on days 0 and 1 of a 21-day cycle for 3 cycles (in combination with thiotepa), followed by stem cell infusion at least 48 hours after the last thiotepa dose (Cohen 2015)

Children and Adolescents: Conditioning regimen: ~500 mg/m2/day for 3 consecutive days; dosing utilized pediatric Calvert formula with a target AUC 7 (in combination with thiotepa and topotecan) (Gilheeny 2010; Kushner 2001)

Retinoblastoma (off-label use):

Rodriguez-Galindo 2003: Infants and Children: IV:

GFR ≥50 mL/minute/m2: 560 mg/m2 in combination with vincristine every 21 days for 8 cycles

GFR < 50 mL/minute/m2: Dosing utilized modified Calvert formula with a target AUC 6.5 in combination with vincristine every 21 days for 8 cycles

Friedman 2000:

Infants and Children ≤3 years: IV: 18.6 mg/kg on day 0 every 28 days in combination with etoposide and vincristine for 6 cycles (VEC regimen)

Children >3 years: IV: 560 mg/m2 on day 0 every 28 days in combination with etoposide and vincristine for 6 cycles (VEC regimen)

Sarcomas: Ewing sarcoma, osteosarcoma (off-label uses): IV: 400 mg/m2/day for 2 days every 21 days (in combination with ifosfamide and etoposide) (van Winkle 2005)

Wilms tumor (off-label use): Children and Adolescents: IV: 160 mg/m2/day for 5 consecutive days every 21 days (in combination with etoposide) for 2 cycles (Pein 1994) or 400 mg/m2/day for 2 days (in combination with ifosfamide and etoposide) every 21 days (ICE regimen) (Abu-Ghosh 2002) or modified Calvert formula with a target AUC 6 for 1 day (in combination with ifosfamide and etoposide) every 21 days (ICE regimen) for 2 cycles, followed by vincristine, dactinomycin and doxorubicin (VAD regimen), surgery, radiation therapy, the VAD regimen and one more cycle of ICE for a total of 36 weeks of treatment (Daw 2009). Additional data may be necessary to further define the role of carboplatin in the treatment of this condition.

Dosing: Renal Impairment

Note: Dose determination with Calvert formula uses GFR and, therefore, inherently adjusts for renal dysfunction.

The manufacturer’s labeling recommends the following dosage adjustments for single-agent therapy: Adults:

Baseline CrCl 41 to 59 mL/minute: Initiate at 250 mg/m2 and adjust subsequent doses based on bone marrow toxicity

Baseline CrCl 16 to 40 mL/minute: Initiate at 200 mg/m2 and adjust subsequent doses based on bone marrow toxicity

Baseline CrCl ≤15 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling.

The following dosage adjustments have also been recommended:

Aronoff 2007:

Adults (Note: For dosing based on mg/m2):

GFR >50 mL/minute: No dosage adjustment is necessary

GFR 10 to 50 mL/minute: Administer 50% of the usual dose

GFR <10 mL/minute: Administer 25% of the usual dose

Hemodialysis: Administer 50% of the usual dose

Continuous ambulatory peritoneal dialysis (CAPD): Administer 25% of the usual dose

Continuous renal replacement therapy (CRRT): 200 mg/m2

Children:

GFR <50 mL/minute: Use Calvert formula incorporating patient’s GFR

Hemodialysis, peritoneal dialysis, continuous renal replacement therapy (CRRT): Use Calvert formula incorporating patient’s GFR

Janus 2010: Hemodialysis: Carboplatin dose (mg) = Target AUC x 25; administer on a nondialysis day, hemodialysis should occur between 12 to 24 hours after carboplatin dose

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling; however, carboplatin undergoes minimal hepatic metabolism therefore dosage adjustment may not be needed.

Dosing: Adjustment for Toxicity

Platelets <50,000 cells/mm3 or ANC <500 cells/mm3: Administer 75% of the usual dose

Dosing: Obesity

American Society of Clinical Oncology (ASCO) Guidelines for appropriate chemotherapy dosing in obese adults with cancer (excludes HSCT dosing): Dosing based on GFR should be considered in obese patients; GFR should not exceed 125 mL/minute (Griggs 2012).

American Society for Blood and Marrow Transplantation (ASBMT) practice guideline committee position statement on chemotherapy dosing in obesity: Utilize actual body weight (full weight) for calculation of body surface area (when applicable) in carboplatin dosing for hematopoietic stem cell transplant conditioning regimens in adults. Based on the literature, there is no consensus for carboplatin dosing based on AUC in transplant conditioning regimens or dosing adjustments during transplant for obese patients (Bubalo 2014).

Reconstitution

Solution for injection: Manufacturer’s labeling states solution can be further diluted to concentrations as low as 0.5 mg/mL in NS or D5W; however, most clinicians generally dilute dose in either 100 mL or 250 mL of NS or D5W.

Concentrations used for desensitization vary based on protocol.

Needles or IV administration sets that contain aluminum should not be used in the preparation or administration of carboplatin; aluminum can react with carboplatin resulting in precipitate formation and loss of potency.

Administration

Carboplatin is associated with a moderate emetic potential in adult patients and a high emetic potential in pediatric patients; antiemetics are recommended to prevent nausea and vomiting (Basch 2011; Dupuis 2011; Roila 2016).

Infuse over at least 15 minutes; usually infused over 15 to 60 minutes, although some protocols may require infusions up to 24 hours. When administered as a part of a combination chemotherapy regimen, sequence of administration may vary by regimen; refer to specific protocol for sequence recommendation.

Needles or IV administration sets that contain aluminum should not be used in the preparation or administration of carboplatin; aluminum can react with carboplatin resulting in precipitate formation and loss of potency.

Compatibility

See Trissel’s IV Compatibility Database

Storage

Store intact vials at room temperature at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from light. Further dilution to a concentration as low as 0.5 mg/mL is stable at room temperature (25°C) for 8 hours in NS or D5W. Stability has also been demonstrated for dilutions in D5W in PVC bags at room temperature for 9 days (Benaji 1994); however, the manufacturer recommends use within 8 hours due to lack of preservative. Multidose vials are stable for up to 14 or 15 days after opening when stored at 25°C (77°F) following multiple needle entries (refer to specific product labeling for stability information).

Drug Interactions

Aminoglycosides: May enhance the ototoxic effect of CARBOplatin. Especially with higher doses of carboplatin. Monitor therapy

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Bexarotene (Systemic): CARBOplatin may increase the serum concentration of Bexarotene (Systemic). Monitor therapy

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Fosphenytoin-Phenytoin: Platinum Derivatives may decrease the serum concentration of Fosphenytoin-Phenytoin. Monitor therapy

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Consider therapy modification

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

SORAfenib: May enhance the adverse/toxic effect of CARBOplatin. Management: Concurrent sorafenib with carboplatin and paclitaxel in patients with squamous cell lung cancer is contraindicated. Use in other settings is not specifically contraindicated but should be approached with added caution. Avoid combination

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Taxane Derivatives: Platinum Derivatives may enhance the myelosuppressive effect of Taxane Derivatives. Administer Taxane derivative before Platinum derivative when given as sequential infusions to limit toxicity. Consider therapy modification

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination

Topotecan: Platinum Derivatives may enhance the adverse/toxic effect of Topotecan. Consider therapy modification

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Adverse Reactions

Percentages reported with single-agent therapy.

>10%:

Central nervous system: Pain (23%)

Endocrine & metabolic: Hyponatremia (29% to 47%), hypomagnesemia (29% to 43%), hypocalcemia (22% to 31%), hypokalemia (20% to 28%)

Gastrointestinal: Vomiting (65% to 81%), abdominal pain (17%), nausea (without vomiting: 10% to 15%)

Hematologic & oncologic: Bone marrow depression (dose related and dose limiting; nadir at ~21 days with single-agent therapy), anemia (71% to 90%; grades 3/4: 21%), leukopenia (85%; grades 3/4: 15% to 26%), neutropenia (67%; grades 3/4: 16% to 21%), thrombocytopenia (62%; grades 3/4: 25% to 35%)

Hepatic: Increased serum alkaline phosphatase (24% to 37%), increased serum AST (15% to 19%)

Hypersensitivity: Hypersensitivity (2% to 16%)

Neuromuscular & skeletal: Weakness (11%)

Renal: Decreased creatinine clearance (27%), increased blood urea nitrogen (14% to 22%)

1% to 10%:

Central nervous system: Peripheral neuropathy (4% to 6%), neurotoxicity (5%)

Dermatologic: Alopecia (2% to 3%)

Gastrointestinal: Constipation (6%), diarrhea (6%), dysgeusia (1%), mucositis (≤1%), stomatitis (≤1%)

Hematologic & oncologic: Bleeding complications (5%), hemorrhage (5%)

Hepatic: Increased serum bilirubin (5%)

Infection: Infection (5%)

Ophthalmic: Visual disturbance (1%)

Otic: Ototoxicity (1%)

Renal: Increased serum creatinine (6% to 10%)

<1% (Limited to important or life-threatening): Anaphylaxis, anorexia, bronchospasm, cardiac failure, cerebrovascular accident, dehydration, embolism, erythema, febrile neutropenia, hemolytic anemia (acute), hemolytic-uremic syndrome, hypertension, hypotension, injection site reaction (pain, redness, swelling), limb ischemia (acute), malaise, metastases, pruritus, skin rash, tissue necrosis (associated with extravasation), urticaria, vision loss

ALERT: U.S. Boxed Warning

Experienced physician:

Carboplatin should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of therapy and complications is possible only when adequate treatment facilities are readily available.

Bone marrow suppression:

Bone marrow suppression is dose related and may be severe, resulting in infection or bleeding. Anemia may be cumulative and may require transfusion support.

Vomiting:

Vomiting is a frequent drug-related side effect.

Hypersensitivity reactions:

Anaphylactic-like reactions to carboplatin have been reported and may occur within minutes of carboplatin administration. Epinephrine, corticosteroids, and antihistamines have been employed to alleviate symptoms.

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: [US Boxed Warning]: Bone marrow suppression, which may be severe, is dose related; may result in infection (due to neutropenia) or bleeding (due to thrombocytopenia); anemia may require blood transfusion. Reduce dosage in patients with bone marrow suppression; cycles should be delayed until WBC and platelet counts have recovered. In patients receiving single agent carboplatin, the median nadir typically occurs at day 21. Patients who have received prior myelosuppressive therapy and patients with renal dysfunction are at increased risk for bone marrow suppression. Anemia is cumulative. Monitor blood counts closely.

• Gastrointestinal toxicity: [US Boxed Warning]: Vomiting may occur. Carboplatin is associated with a moderate emetic potential in adult patients and a high emetic potential in pediatric patients; antiemetics are recommended to prevent nausea and vomiting (Basch 2011; Dupuis 2011; Roila 2016). Nausea and vomiting may be more severe in patients who have received prior emetogenic therapy.

• Hypersensitivity/anaphylactoid reactions: [US Boxed Warning]: Anaphylactic-like reactions have been reported with carboplatin; may occur within minutes of administration. Epinephrine, corticosteroids and antihistamines have been used to treat symptoms. The risk of allergic reactions (including anaphylaxis) is increased in patients previously exposed to platinum therapy. Skin testing and desensitization protocols have been reported (Confina-Cohen 2005; Lee 2004; Markman 2003).

• Liver function abnormalities: High doses (>4 times the recommended dose) have resulted in severe abnormalities of liver function tests.

• Neurotoxicity: Although peripheral neuropathy occurs infrequently, the incidence of peripheral neuropathy is increased in patients >65 years and those who have previously received cisplatin treatment.

• Ototoxicity: Ototoxicity may occur when administered concomitantly with aminoglycosides. Clinically significant hearing loss has been reported to occur in pediatric patients when therapy was administered at higher than recommended doses in combination with other ototoxic agents (eg, aminoglycosides). In a study of children receiving carboplatin for the treatment of retinoblastoma, those <6 months of age at treatment initiation were more likely to experience ototoxicity; long-term audiology monitoring is recommended (Qaddoumi 2012).

• Renal toxicity: Carboplatin has a limited potential for nephrotoxicity unless administered concomitantly with aminoglycosides. Use caution with concomitant administration with aminoglycosides or other nephrotoxic medications.

• Vision loss: Loss of vision (usually reversible within weeks of discontinuing) has been reported with higher than recommended doses.

Disease-related concerns:

• Renal impairment: Use with caution in patients with renal impairment; patients with renal dysfunction are at increased risk for bone marrow suppression.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• Taxane derivatives: When administered as sequential infusions, taxane derivatives (docetaxel, paclitaxel) should be administered before the platinum derivatives (carboplatin, cisplatin) to limit myelosuppression and to enhance efficacy.

Special populations:

• Elderly: Patients >65 years are more likely to develop thrombocytopenia (severe) and peripheral neuropathy.

Other warnings/precautions:

• Dosing with Calvert formula: When calculating the carboplatin dose using the Calvert formula and an estimated glomerular filtration rate (GFR), the laboratory method used to measure serum creatinine may impact dosing. Compared to other methods, standardized isotope dilution mass spectrometry (IDMS) may underestimate serum creatinine values in patients with low creatinine values (eg, ≤0.7 mg/dL) and may overestimate GFR in patients with normal renal function. This may result in higher calculated carboplatin doses and increased toxicities. If using IDMS, the Food and Drug Administration (FDA) recommends that clinicians consider capping estimated GFR at a maximum of 125 mL/minute to avoid potential toxicity.

• Experienced physician: [US Boxed Warning]: Should be administered under the supervision of an experienced cancer chemotherapy physician.

Monitoring Parameters

CBC (with differential and platelet count), serum electrolytes, serum creatinine and BUN, creatinine clearance, liver function tests; audiology evaluations (children <6 months); signs/symptoms of hypersensitivity reactions

Pregnancy Risk Factor

D

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies. May cause fetal harm if administered during pregnancy. Women of childbearing potential should avoid becoming pregnant during treatment.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience abdominal pain, diarrhea, constipation, nausea or mouth sores. Have patient report immediately to prescriber signs of infection, signs of fluid and electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, severe dizziness, passing out, tachycardia, increased thirst, seizures, loss of strength and energy, lack of appetite, urinary retention or change in amount of urine passed, dry mouth, dry eyes, or nausea or vomiting), signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding), signs of electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting), vomiting; severe loss of strength and energy, pale skin, hearing impairment, burning or numbness feeling, blindness, or severe injection site redness, burning, edema, pain or irritation (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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