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CARBOPLATIN

VIEWS: 34 PAGES: 11

									                               CARB OPL ATI N
Class
This drug is a member of the following class(es):
       Antineoplastic Agent
       Platinum Coordination Complex

Synonyms
     Carboplatin
     CBDCA
IUPAC
      azanide; cyclobutane - 1,1 - dicarboxylic acid; platinum

Physicochemical Properties
     Molecular Weight - 371.26
     Molecular Formulae - C6H14N2O4Pt




Mechanism of Action
  • Carboplatin is a cisplatin analog with similar antineoplastic activity, but with a
     different adverse effect profile than cisplatin. Carboplatin has a
     carboxycyclobutane moiety replacing the chloride atoms on cisplatin. Both agents
     are cell cycle-nonspecific and share a similar mechanism of action.
  • The major antineoplastic mechanism of action for cisplatin and carboplatin is the
     production of crosslinks within and between strands of deoxyribonucleic acid
     (DNA). Normal DNA synthesis is inhibited by this disruption of cellular DNA
     conformation. The dicarboxylate group on carboplatin is much more stable than
     the chloride groups on cisplatin, and this may possibly affect the antitumor
     properties of the compound. In vitro and in vivo studies indicate that the
     differences in cytotoxicity between cisplatin and carboplatin may be related to the
     kinetics of their interaction with DNA.
  • Cisplatin breaks down to unstable hydrolysis products which are rapidly bound to
     plasma proteins and extensively filtered, with some active secretion, by the
     kidney, this high renal concentration is thought to be the major cause of
     nephrotoxicity. Carboplatin may be less nephrotoxic than cisplatin because
     carboplatin is more soluble and chemically stable and binds more slowly to
     plasma proteins. In vitro and in vivo studies indicate that the differences in
       cytotoxicity between cisplatin and carboplatin may be related to the kinetics of
       their interaction with DNA.

Dosing Information
a) Adult
1) Breast cancer - Optimal dosing and timing not yet defined.
2) Cancer of unknown origin - Optimal dosing and timing not yet defined.
3) Head and neck cancer - Optimal dosing and timing not yet defined.
4) Hodgkin's disease - Optimal dosing and timing not yet defined.
5) Malignant neoplasm of endometrium of corpus uteri - Optimal dosing and timing not
yet defined.
6) Malignant tumor of urinary bladder - Optimal dosing and timing not yet defined.
7) Non-small cell lung cancer - Optimal dosing and timing not yet defined.
8) Non-small cell lung cancer, first-line in combination with paclitaxel and bevacizumab
for advanced/metastatic non-squamous cell disease - paclitaxel 200 mg/m2 IV,
carboplatin (AUC of 6) IV, and bevacizumab 15 mg/kg IV, once every 3 weeks for 6
cycles, then bevacizumab alone until disease progression.
9) Ovarian cancer, Advanced (as initial treatment in combination with other approved
chemotherapy agents) - 300 mg/m2 on day 1 every 4 weeks for 6 cycles in combination
with cyclophosphamide 600 mg/m2 IV on day 1 every 4 weeks for 6 cycles.
10) Ovarian cancer, Advanced (palliative treatment of recurrent disease, including
patients previously treated with cisplatin) - 360 mg/m2 IV on day 1 every 4 weeks OR
dose based on the Calvert formula, with a target area under the curve (AUC) of 4-6
mg/mL x min dose (mg) = target (AUC) x (GFR + 25); area under the curve (AUC),
glomerular filtration rate (GFR).
11) Primary intracranial tumor - Optimal dosing and timing not yet defined.
12) Small cell carcinoma of lung - Optimal dosing and timing not yet defined.
13) Testicular cancer - Optimal dosing and timing not yet defined.

b) Pediatric
1) Safety and effectiveness in pediatric patients have not been established.
2) 175-600 mg/m2 IV has been used in various protocols.
       a) Non-Hodgkin's lymphoma - Optimal dosing and timing not yet defined.
       b) Retinoblastoma - Optimal dosing and timing not yet defined.

Contraindications
     a) hypersensitivity to cisplatin/platinum products or mannitol
     b) severe myelosuppression/significant bleeding

Serious Adverse Effects
     a) Electrolyte imbalance
     b) Immune hypersensitivity reaction
     c) Myelosuppression
     d) Peripheral neuropathy
     e) Visual disturbance
Clinical Applications
a) FDA Approved Indications
    1) Ovarian cancer, Advanced (as initial treatment in combination with other approved
    chemotherapy agents).
    2) Ovarian cancer, Advanced (palliative treatment of recurrent disease, including
    patients previously treated with cisplatin).
b) Non-FDA Approved Indications
    1) Breast cancer
    2) Cancer of unknown origin
    3) Head and neck cancer
    4) Hodgkin's disease
    5) Malignant neoplasm of endometrium of corpus uteri
    6) Malignant tumor of urinary bladder
    7) Non-Hodgkin's lymphoma
    8) Non-small cell lung cancer
    9) Non-small cell lung cancer, first-line in combination with paclitaxel and
    bevacizumab for advanced/metastatic non-squamous cell disease
    10) Primary intracranial tumor
    11) Retinoblastoma
    12) Small cell carcinoma of lung
    13) Testicular cancer

Storage and Stability
1. Carboplatin for injection should be protected from light and stored at controlled room
temperature, 15 to 30 degrees centigrade (59 to 86 degrees Fahrenheit).
2. Carboplatin Aqueous solution for injection should be protected from light and stored at
25 degrees Celsius (C) (77 degrees Fahrenheit (F)); excursions from 15 degrees C to 30
degrees C (59 to 86 degrees F) are permitted.
3. Carboplatin solutions, when prepared as directed, are stable for 8 hours at room
temperature (25 degrees Celsius) and have a pH of 5 to 7. Solutions should be discarded
after 8 hours as there is no antibacterial preservative in the formulation.

Pharmacokinetics - ADME
Distribution
Distribution Sites
   Protein Binding - not bound.
   • Carboplatin is not bound to plasma proteins, however, the platinum from
       degraded carboplatin irreversibly binds to plasma proteins and is slowly
       eliminated with an approximate half-life of 5 days.
   • Platinum protein binding may increase with time. Following carboplatin 20 to 320
       mg/m2, platinum protein binding increased from approximately 15 % to 40 %
       from beginning to the end of a 24-hour infusion.
   Other Distribution Sites
   Tissues
   • The concentration of platinum was higher in most tissues than in the plasma. The
       exceptions included fat, cerebrum, and cerebellum. The highest platinum
       concentrations were seen in the liver, kidney, skin, and tumors. Lung and liver
       tumors had higher platinum concentrations than did normal tissue at those sites.
   Peritoneum
   • Following intraperitoneal administration of carboplatin, the mean ratio of peak
       concentrations of carboplatin in intraperitoneal fluid and plasma ranged from 18
       to 24 fold greater in the peritoneal fluid.

Distribution Kinetics - Distribution Half-Life
   • Free platinum, approximately 83 to 96 minutes - Following the administration of
       intravenous carboplatin 20 to 1600 mg/m2 over 30 to 60 minutes to cancer
       patients.

Volume of Distribution - 16 to 17 liters.

Excretion
  Kidney - Renal Excretion (%)
  • Approximately 60 % to 80 %, as measured by total platinum.
  Other Excretion - Peritoneal
  • Carboplatin and total platinum have a peritoneal clearance of 7.2 to 21.8 mL/min
     following intraperitoneal administration of carboplatin.

Total Body Clearance
4.4 to 8.8 L/h in patients with a creatinine clearance of at least 60 mL/min.

Elimination Half-life
   Parent Compound
   • Intravenous, 1 to 6 hours.
   • The plasma concentration of carboplatin decays biexponentially, with an alpha
      half-life ranging from 1.1 to 2.0 hours with the beta half-life ranging from 2.6 to
      5.9 hours.
   • The elimination half-life of total platinum from the peritoneum following
      intraperitoneal administration of carboplatin ranges from 3.6 to 9.25 hours.
   • The elimination half-life of total platinum from plasma following intraperitoneal
      administration of carboplatin ranges from 6.7 to 7.7 days.
   Metabolites
   • Free platinum has an estimated plasma elimination half- life of 6 hours in cancer
      patients receiving carboplatin 170 to 1600 mg/m2 over 30 to 60 minutes.
   • The terminal half-life of free ultra-filterable nonprotein-bound platinum is 2 to 9
      times greater following administration of carboplatin than after cisplatin.
Extracorporeal Elimination
Hemodialysis
       Dialyzable: Yes
Peritoneal
       Dialyzable: No

Cautions
Black Box WARNING
   • 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 is dose related and may be severe, resulting in infection
       and/or bleeding. Anemia may be cumulative and may require transfusion support.
       Vomiting is another frequent drug-related side effect.
   • 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.

Precautions
   • Aluminum reacts with carboplatin to form an inactive precipitate; therefore,
     intravenous sets and needles containing aluminum which may come in contact
     with carboplatin should not be used.
   • Extravasation.
   • Patients over 65 years of age or those previously treated with cisplatin are at
     increased risk of developing carboplatin-induced peripheral neuropathy.
   • Prior aminoglycoside therapy may potentiate carboplatin-induced renal toxicity
   • Renal impairment.
   • Use proper procedures for handling and disposal of chemotherapy.

Teratogenicity/Effects in Pregnancy/Breastfeeding
  • U.S. Food and Drug Administration's Pregnancy Category: Category D (All
     Trimesters). There is positive evidence of human fetal risk, but the benefits from
     use in pregnant women may be acceptable despite the risk (e.g., if the drug is
     needed in a life-threatening situation or for a serious disease for which safer drugs
     cannot be used or are ineffective).
  • Australian Drug Evaluation Committee's (ADEC) Category: D. Drugs which have
     caused, are suspected to have caused, or may be expected to cause an increased
     incidence of human fetal malformations or irreversible damage. These drugs may
     also have adverse pharmacological effects. Accompanying texts should be
     consulted for further details.

Crosses Placenta: Unknown
Clinical Management
    • Teratogenic effects have been seen in animals, but not humans, associated with
       the use of carboplatin. In general, antineoplastic agents when given during the
       first trimester are believed to cause increases in the risk of congenital
       malformations, but when given during the second or third trimesters are believed
       to only increase the risk of growth retardation.
   •   Depending upon the nature of the malignancy, the progression of the disease and
       how advanced the gestation, chemotherapy can in some cases be deferred
       allowing fetal maturation to occur, and in some cases earlier-than-term delivery
       provides an acceptable compromise between maternal and fetal risk.
   •   Because apparently normal infants have been born despite having been exposed to
       virtually any antineoplastic agent or combination of agents, it should not be
       assumed that termination of pregnancy is necessary (unless it is in the best interest
       of the health of the mother), and the decision of the parents must take into account
       their desire to have children.

Breastfeeding
Thomson Lactation Rating: Infant risk cannot be ruled out. Available evidence and/or
expert consensus is inconclusive or is inadequate for determining infant risk when used
during breastfeeding. Weigh the potential benefits of drug treatment against potential
risks before prescribing this drug during breastfeeding.
Clinical Management
No reports describing the use of carboplatin during human lactation are available and the
effects on the nursing infant from exposure to the drug in milk are unknown. Breast-
feeding is not recommended due to potential risk to the infant.

Drug-Drug Interactions
Amikacin
  • Interaction Effect: ototoxicity
  • Summary: Concomitant administration of carboplatin and aminoglycoside
      antibiotics may increase the risk of ototoxicity.
  • Severity: moderate
  • Onset: delayed
  • Clinical Management: If clinically acceptable, an alternate antibiotic (a non-
      aminoglycoside) may be preferred.

Bacillus of Calmette and Guerin Vaccine, Live
   • Interaction Effect: an increased risk of infection by the live vaccine
   • Summary: Vaccination with a live vaccine in a patient immunocompromised by a
       chemotherapeutic agent has resulted in severe and fatal infections. Live virus and
       bacterial vaccines should not be administered to a patient receiving an
       immunosuppressive chemotherapeutic agent. At least three months should elapse
       between the discontinuation of chemotherapy and vaccination with a live vaccine.
   • Severity: major
   • Onset: delayed
   • Clinical Management: Patients receiving immunosuppressive chemotherapy
       should not be vaccinated with a live vaccine. In patients with leukemia in
       remission, allow at least three months between the end of chemotherapy and
       vaccination with a live vaccine.
Gentamicin
   • Interaction Effect: ototoxicity
   • Summary: Concomitant administration of carboplatin and aminoglycoside
      antibiotics may increase the risk of ototoxicity.
   • Severity: moderate
   • Onset: delayed
   • Clinical Management: If clinically acceptable, an alternate antibiotic (a non-
      aminoglycoside) may be preferred.

Kanamycin
   • Interaction Effect: ototoxicity
   • Summary: Concomitant administration of carboplatin and aminoglycoside
     antibiotics may increase the risk of ototoxicity.
   • Severity: moderate
   • Onset: delayed
   • Clinical Management: If clinically acceptable, an alternate antibiotic (a non-
     aminoglycoside) may be preferred.

Measles Virus Vaccine, Live
  • Interaction Effect: an increased risk of infection by the live vaccine
  • Summary: Vaccination with a live vaccine in a patient immunocompromised by a
      chemotherapeutic agent has resulted in severe and fatal. Live virus and bacterial
      vaccines should not be administered to a patient receiving an immunosuppressive
      chemotherapeutic agent. At least three months should elapse between the
      discontinuation of chemotherapy and vaccination with a live vaccine.
  • Severity: major
  • Onset: delayed
  • Clinical Management: Patients receiving immunosuppressive chemotherapy
      should not be vaccinated with a live vaccine. In patients with leukemia in
      remission, allow at least three months between the end of chemotherapy and
      vaccination with a live vaccine.

Mumps Virus Vaccine, Live
  • Interaction Effect: an increased risk of infection by the live vaccine
  • Summary: Vaccination with a live vaccine in a patient immunocompromised by a
     chemotherapeutic agent has resulted in severe and fatal infections. Live virus and
     bacterial vaccines should not be administered to a patient receiving an
     immunosuppressive chemotherapeutic agent. At least three months should elapse
     between the discontinuation of chemotherapy and vaccination with a live vaccine.
  • Severity: major
  • Onset: delayed
  • Clinical Management: Patients receiving immunosuppressive chemotherapy
     should not be vaccinated with a live vaccine. In patients with leukemia in
     remission, allow at least three months between the end of chemotherapy and
     vaccination with a live vaccine.
Netilmicin
   • Interaction Effect: ototoxicity
   • Summary: Concomitant administration of carboplatin and aminoglycoside
       antibiotics may increase the risk of ototoxicity.
   • Severity: moderate
   • Onset: delayed
   • Clinical Management: If clinically acceptable, an alternate antibiotic (a non-
       aminoglycoside) may be preferred.

Phenytoin
   • Interaction Effect: decreased phenytoin effectiveness
   • Summary: In case reports, the addition of antineoplastic drugs in patients
      maintained on phenytoin resulted in lower phenytoin concentrations. The decrease
      in phenytoin concentration is thought to be due to altered bioavailability, however
      increased phenytoin elimination has been reported with high dose methotrexate.
   • Severity: moderate
   • Onset: rapid
   • Clinical Management: Consider monitoring serum phenytoin levels during
      courses of chemotherapy; increased phenytoin dosage may be required. If the
      dose is adjusted, the level should again be checked after the course of
      chemotherapy is completed and the dose changed as necessary. Intravenous
      phenytoin may be useful in some situations.

Poliovirus Vaccine, Live
   • Interaction Effect: an increased risk of infection by the live vaccine
   • Summary: Vaccination with a live vaccine in a patient immunocompromised by a
       chemotherapeutic agent has resulted in severe and fatal infections. Live virus and
       bacterial vaccines should not be administered to a patient receiving an
       immunosuppressive chemotherapeutic agent. At least three months should elapse
       between the discontinuation of chemotherapy and vaccination with a live vaccine.
   • Severity: major
   • Onset: delayed
   • Clinical Management: Patients receiving immunosuppressive chemotherapy
       should not be vaccinated with a live vaccine. In patients with leukemia in
       remission, allow at least three months between the end of chemotherapy and
       vaccination with a live vaccine.

Rotavirus Vaccine, Live
   • Interaction Effect: an increased risk of infection by the live vaccine
   • Summary: Vaccination with a live vaccine in a patient immunocompromised by a
       chemotherapeutic agent has resulted in severe and fatal infections. The
       administration of the rotavirus vaccine is contraindicated in patients who are
       immunosuppressed due to chemotherapeutic agents.
   • Severity: contraindicated
   • Onset: delayed
   •   Clinical Management: Vaccination with rotavirus vaccine is contraindicated in
       patients receiving immunosuppressive chemotherapy.

Rubella Virus Vaccine, Live
   • Interaction Effect: an increased risk of infection by the live vaccine
   • Summary: Vaccination with a live vaccine in a patient immunocompromised by a
       chemotherapeutic agent has resulted in severe and fatal infections. Live virus and
       bacterial vaccines should not be administered to a patient receiving an
       immunosuppressive chemotherapeutic agent. At least three months should elapse
       between the discontinuation of chemotherapy and vaccination with a live vaccine.
   • Severity: major
   • Onset: delayed
   • Clinical Management: Patients receiving immunosuppressive chemotherapy
       should not be vaccinated with a live vaccine. In patients with leukemia in
       remission, allow at least three months between the end of chemotherapy and
       vaccination with a live vaccine.

Smallpox Vaccine
  • Interaction Effect: an increased risk of infection by the live vaccine
  • Summary: Live virus and bacterial vaccines should not be administered to a
      patient receiving an immunosuppressive chemotherapeutic agent. At least three
      months should elapse between the discontinuation of chemotherapy and
      vaccination with a live vaccine.
  • Severity: major
  • Onset: delayed
  • Clinical Management: Patients receiving immunosuppressive chemotherapy
      should not be vaccinated with a live vaccine. In patients with leukemia in
      remission, allow at least three months between the end of chemotherapy and
      vaccination with a live vaccine.

Streptomycin
    • Interaction Effect: ototoxicity
    • Summary: Concomitant administration of carboplatin and aminoglycoside
       antibiotics may increase the risk of ototoxicity.
    • Severity: moderate
    • Onset: delayed
    • Clinical Management: If clinically acceptable, an alternate antibiotic (a non-
       aminoglycoside) may be preferred.

Tobramycin
   • Interaction Effect: ototoxicity
   • Summary: Concomitant administration of carboplatin and aminoglycoside
      antibiotics may increase the risk of ototoxicity.
   • Severity: moderate
   • Onset: delayed
   •   Clinical Management: If clinically acceptable, an alternate antibiotic (a non-
       aminoglycoside) may be preferred.

Topotecan
   • Interaction Effect: severe myelosuppression
   • Summary: Concomitant administration of topotecan and carboplatin has resulted
      in severe myelosuppression, thereby necessitating a dose reduction. When
      combining topotecan with carboplatin a distinct sequence-dependent interaction
      on myelosuppression has been reported. Coadministration of carboplatin on day 1
      of topotecan dosing required lower doses of each agent compared to
      coadministration of day 5 of the topotecan dosing schedule.
   • Severity: major
   • Onset: delayed
   • Clinical Management: Treatment with carboplatin therapy followed by topotecan
      has been shown to induce more severe myelosuppression than topotecan followed
      by carboplatin. If concomitant use of these two agents is necessary, monitor the
      patient closely for toxicity, especially myelosuppression.

Typhoid Vaccine
   • Interaction Effect: an increased risk of infection by the live vaccine
   • Summary: Vaccination with a live vaccine in a patient immunocompromised by a
      chemotherapeutic agent has resulted in severe and fatal. Live virus and bacterial
      vaccines should not be administered to a patient receiving an immunosuppressive
      chemotherapeutic agent. At least three months should elapse between the
      discontinuation of chemotherapy and vaccination with a live vaccine.
   • Severity: major
   • Onset: delayed
   • Clinical Management: Patients receiving immunosuppressive chemotherapy
      should not be vaccinated with a live vaccine. In patients with leukemia in
      remission, allow at least three months between the end of chemotherapy and
      vaccination with a live vaccine

Varicella Virus Vaccine
   • Interaction Effect: an increased risk of infection by the live vaccine
   • Summary: Vaccination with a live vaccine in a patient immunocompromised by a
       chemotherapeutic agent has resulted in severe and fatal infections. Live virus and
       bacterial vaccines should not be administered to a patient receiving an
       immunosuppressive chemotherapeutic agent. At least three months should elapse
       between the discontinuation of chemotherapy and vaccination with a live vaccine.
   • Severity: major
   • Onset: delayed
   • Clinical Management: Patients receiving immunosuppressive chemotherapy
       should not be vaccinated with a live vaccine. In patients with leukemia in
       remission, allow at least three months between the end of chemotherapy and
       vaccination with a live vaccine.
Warfarin
  • Interaction Effect: increased risk for elevated INR and subsequent bleeding
  • Summary: An elevated INR, trace guaiac-positive black stools, and bruising at the
      site of blood draws occurred 16 days after a cycle of carboplatin and etoposide
      were reported in a male on warfarin. Monitor the INR (international normalized
      ratio) closely and monitor for signs of bleeding when warfarin is used
      concomitantly with etoposide and carboplatin. Warfarin dosage may require
      adjustment to maintain the desired level of anticoagulation.
  • Severity: major
  • Onset: delayed
  • Clinical Management: Monitor the INR (international normalized ratio) closely
      and monitor for signs of bleeding when warfarin is used concomitantly with
      etoposide and carboplatin. Warfarin dosage may require adjustment to maintain
      the desired level of anticoagulation.

Yellow Fever Vaccine
    • Interaction Effect: an increased risk of infection by the live vaccine
    • Summary: Vaccination with a live vaccine in a patient immunocompromised by a
       chemotherapeutic agent has resulted in severe and fatal infections. Live virus and
       bacterial vaccines should not be administered to a patient receiving an
       immunosuppressive chemotherapeutic agent. At least three months should elapse
       between the discontinuation of chemotherapy and vaccination with a live vaccine.
    • Severity: major
    • Onset: delayed
    • Clinical Management: Patients receiving immunosuppressive chemotherapy
       should not be vaccinated with a live vaccine. In patients with leukemia in
       remission, allow at least three months between the end of chemotherapy and
       vaccination with a live vaccine.

Intravenous Admixtures - Compatibility
Dextrose 5 % in Sodium chloride 0.9 % - Incompatible
        Carboplatin 1 mg/mL in Dextrose 5 % in Sodium chloride 0.9 %, 1 % carboplatin
decomposition reported in 6 hours and 5 % decomposition reported in 24 hours at 25
degrees C in a glass or polyvinylchloride container under fluorescent light; however, it
was recommended that this solution not be used for the dilution of carboplatin due to the
possibility of the lost carboplatin being converted to the more toxic cisplatin.

Sodium chloride 0.9 % - Incompatible
       Studies suggest that carboplatin when mixed with Sodium chloride degrades to
the more toxic cisplatin and therefore Sodium chloride should not be used as its diluent.

								
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