DESCRIPTION

Carboplatin injection is supplied as a sterile, pyrogen-free, 10 mg/mL aqueous solution of carboplatin, USP. It is available in multiuse vials containing 50 mg/5 mL, 150 mg/15 mL, 450 mg/45 mL and 600 mg/60 mL of carboplatin, USP. Inactive ingredients include water for injection, USP. The pH of the solution ranges from 5.0 to 7.0.

Carboplatin, USP is a platinum coordination compound. The chemical name for carboplatin, USP is platinum, diammine [1, 1- cyclobutanedicarboxylato (2- )-0, 0']-, (SP- 4-2), and carboplatin, USP has the following structural formula:

Carboplatin, USP is a crystalline powder. It is soluble in water at a rate of approximately 14 mg/mL, and the pH of a 1% solution is 5 to 7. It is virtually insoluble in ethanol, acetone, and dimethylacetamide.

CLINICAL PHARMACOLOGY

Carboplatin, like cisplatin, produces predominantly interstrand DNA cross-links rather than DNA protein cross-links. This effect is apparently cell-cycle nonspecific. The aquation of carboplatin, which is thought to produce the active species, occurs at a slower rate than in the case of cisplatin. Despite this difference, it appears that both carboplatin and cisplatin induce equal numbers of drug-DNA crosslinks, causing equivalent lesions and biological effects. The differences in potencies for carboplatin and cisplatin appear to be directly related to the difference in aquation rates.

In patients with creatinine clearances of about 60 mL/min or greater, plasma levels of intact carboplatin decay in a biphasic manner after a 30-minute intravenous infusion of 300 mg/m2 to 500 mg/m2 of carboplatin. The initial plasma half-life (alpha) was found to be 1.1 to 2 hours (n = 6), and the postdistribution plasma half-life (beta) was found to be 2.6 to 5.9 hours (n = 6). The total body clearance, apparent volume of distribution and mean residence time for carboplatin are 4.4 L/hour, 16 L and 3.5 hours, respectively. The Cmax values and areas under the plasma concentration versus time curves from 0 to infinity (AUC inf) increase linearly with dose, although the increase was slightly more than dose proportional. Carboplatin, therefore, exhibits linear pharmacokinetics over the dosing range studied (300 mg/m2 to 500 mg/m2).

Carboplatin is not bound to plasma proteins. No significant quantities of protein-free, ultrafilterable platinum-containing species other than carboplatin are present in plasma. However, platinum from carboplatin becomes irreversibly bound to plasma proteins and is slowly eliminated with a minimum half-life of 5 days.

The major route of elimination of carboplatin is renal excretion. Patients with creatinine clearances of approximately 60 mL/min or greater excrete 65% of the dose in the urine within 12 hours and 71% of the dose within 24 hours. All of the platinum in the 24-hour urine is present as carboplatin. Only 3% to 5% of the administered platinum is excreted in the urine between 24 and 96 hours. There are insufficient data to determine whether biliary excretion occurs.

In patients with creatinine clearances below 60 mL/min, the total body and renal clearances of carboplatin decrease as the creatinine clearance decreases. Carboplatin dosages should therefore be reduced in these patients (see DOSAGE AND ADMINISTRATION).

The primary determinant of carboplatin injection clearance is glomerular filtration rate (GFR) and this parameter of renal function is often decreased in elderly patients. Dosing formulas incorporating estimates of GFR (see DOSAGE AND ADMINISTRATION) to provide predictable carboplatin injection plasma AUCs should be used in elderly patients to minimize the risk of toxicity.

CLINICAL STUDIES

INDICATIONS

CONTRAINDICATIONS

Carboplatin injection is contraindicated in patients with a history of severe allergic reactions to cisplatin or other platinum-containing compounds.

Carboplatin injection should not be employed in patients with severe bone marrow depression or significant bleeding.

WARNINGS

Bone marrow suppression (leukopenia, neutropenia, and thrombocytopenia) is dose-dependent and is also the dose-limiting toxicity. Peripheral blood counts should be frequently monitored during carboplatin injection treatment and, when appropriate, until recovery is achieved. Median nadir occurs at day 21 in patients receiving single agent carboplatin. In general, single intermittent courses of carboplatin should not be repeated until leukocyte, neutrophil, and platelet counts have recovered.

Since anemia is cumulative, transfusions may be needed during treatment with carboplatin, particularly in patients receiving prolonged therapy.

Bone marrow suppression is increased in patients who have received prior therapy, especially regimens including cisplatin. Marrow suppression is also increased in patients with impaired kidney function. Initial carboplatin injection dosages in these patients should be appropriately reduced (see DOSAGE AND ADMINISTRATION) and blood counts should be carefully monitored between courses. The use of carboplatin in combination with other bone marrow suppressing therapies must be carefully managed with respect to dosage and timing in order to minimize additive effects.

Carboplatin has limited nephrotoxic potential, but concomitant treatment with aminoglycosides has resulted in increased renal and/or audiologic toxicity, and caution must be exercised when a patient receives both drugs. Clinically significant hearing loss has been reported to occur in pediatric patients when carboplatin was administered at higher than recommended doses in combination with other ototoxic agents.

Carboplatin can induce emesis, which can be more severe in patients previously receiving emetogenic therapy. The incidence and intensity of emesis have been reduced by using premedication with antiemetics. Although no conclusive efficacy data exist with the following schedules of carboplatin, lengthening the duration of single intravenous administration to 24 hours or dividing the total dose over five consecutive daily pulse doses has resulted in reduced emesis.

Although peripheral neurotoxicity is infrequent, its incidence is increased in patients older than 65 years and in patients previously treated with cisplatin. Pre-existing cisplatin-induced neurotoxicity does not worsen in about 70% of the patients receiving carboplatin as secondary treatment.

Loss of vision, which can be complete for light and colors, has been reported after the use of carboplatin with doses higher than those recommended in the package insert. Vision appears to recover totally or to a significant extent within weeks of stopping these high doses.

As in the case of other platinum-coordination compounds, allergic reactions to carboplatin have been reported. These may occur within minutes of administration and should be managed with appropriate supportive therapy. There is increased risk of allergic reactions including anaphylaxis in patients previously exposed to platinum therapy (see CONTRAINDICATIONS and ADVERSE REACTIONS, Allergic Reactions).

High dosages of carboplatin (more than 4 times the recommended dose) have resulted in severe abnormalities of liver function tests.

Carboplatin injection may cause fetal harm when administered to a pregnant woman. Carboplatin has been shown to be embryotoxic and teratogenic in rats. 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 receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.

PRECAUTIONS

General

Needles or intravenous administration sets containing aluminum parts that may come in contact with carboplatin injection should not be used for the preparation or administration of the drug. Aluminum can react with carboplatin causing precipitate formation and loss of potency.

Drug Interactions

The renal effects of nephrotoxic compounds may be potentiated by carboplatin.

Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenic potential of carboplatin has not been studied, but compounds with similar mechanisms of action and mutagenicity profiles have been reported to be carcinogenic. Carboplatin has been shown to be mutagenic both in vitro and in vivo. It has also been shown to be embryotoxic and teratogenic in rats receiving the drug during organogenesis. Secondary malignancies have been reported in association with multi-drug therapy.

Pregnancy

Pregnancy Category D

See WARNINGS.

Nursing Mothers

It is not known whether carboplatin is excreted in human milk. Because there is a possibility of toxicity in nursing infants secondary to carboplatin treatment of the mother, it is recommended that breastfeeding be discontinued if the mother is treated with carboplatin injection.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established (see WARNINGS "audiologic toxicity").

Geriatric Use

Of the 789 patients in initial treatment combination therapy studies (NCIC and SWOG), 395 patients were treated with carboplatin in combination with cyclophosphamide. Of these, 141 were over 65 years of age and 22 were 75 years or older. In these trials, age was not a prognostic factor for survival. In terms of safety, elderly patients treated with carboplatin were more likely to develop severe thrombocytopenia than younger patients. In a combined database of 1,942 patients (414 were ≥ 65 years of age) that received single agent carboplatin for different tumor types, a similar incidence of adverse events was seen in patients 65 years and older and in patients less than 65. Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Because renal function is often decreased in the elderly, renal function should be considered in the selection of carboplatin injection dosage (see DOSAGE AND ADMINISTRATION).

ADVERSE REACTIONS

For a comparison of toxicities when carboplatin or cisplatin was given in combination with cyclophosphamide, see CLINICAL STUDIES, use with cyclophosphamide for initial treatment of ovarian cancer, comparative toxicity.

ADVERSE EXPERIENCES IN PATIENTS WITH OVARIAN CANCER

*Use with Cyclophosphamide for Initial Treatment of Ovarian Cancer: Data are based on the experience of 393 patients with ovarian cancer (regardless of
baseline status) who received initial combination therapy with carboplatin and cyclophosphamide in two randomized controlled studies conducted by SWOG
and NCIC (see CLINICAL STUDIES).
Combination with cyclophosphamide as well as duration of treatment may be responsible for the differences that can be noted in the adverse experience table.
**Single Agent Use for the Secondary Treatment of Ovarian Cancer: Data are based on the experience of 553 patients with previously treated ovarian carcinoma
(regardless of baseline status) who received single agent carboplatin.
		First Line  Combination Therapy* Percent	Second Line Single Agent Therapy**  Percent
Bone Marrow
Thrombocytopenia	<100,000/mm3	66	62
	<50,000/mm3	33	35
Neutropenia	<2,000 cells/mm3	96	67
	<1,000 cells/mm3	82	21
Leukopenia	<4,000 cells/mm3	97	85
	<2,000 cells/mm3	71	26
Anemia	<11 g/dL	90	90
	<8g/dL	14	21
Infections		16	5
Bleeding		8	5
Transfusions		35	44
Gastrointestinal
Nausea and vomiting		93	92
Vomiting		83	81
Other GI side effects		46	21
Neurologic
Peripheral neuropathies		15	6
Ototoxicity		12	1
Other sensory side effects		5	1
Central neurotoxicity		26	5
Renal
Serum creatinine elevations		6	10
Blood urea elevations		17	22
Hepatic
Bilirubin elevations		5	5
SGOT elevations		20	19
Alkaline phosphatase elevations		29	37
Electrolytes loss
Sodium		10	47
Potassium		16	28
Calcium		16	31
Magnesium		61	43
Other side effects
Pain		44	23
Asthenia		41	11
Cardiovascular		19	6
Respiratory		10	6
Allergic		11	2
Genitourinary		10	2
Alopecia		49	2
Mucositis		8	1

In the narrative section that follows, the incidences of adverse events are based on data from 1,893 patients with various types of tumors who received carboplatin as single agent therapy.

OVERDOSAGE

There is no known antidote for carboplatin injection overdosage. The anticipated complications of overdosage would be secondary to bone marrow suppression and/or hepatic toxicity.

DOSAGE AND ADMINISTRATION

NOTE: Aluminum reacts with carboplatin causing precipitate formation and loss of potency, therefore, needles or intravenous sets containing aluminum parts that may come in contact with the drug must not be used for the preparation or administration of carboplatin injection.

PREPARATION OF INTRAVENOUS SOLUTIONS

Carboplatin injection is a premixed aqueous solution of 10 mg/mL carboplatin.

Carboplatin injection can be further diluted to concentrations as low as 0.5 mg/mL with 5% Dextrose in Water (D5W) or 0.9% Sodium Chloride Injection USP.

When prepared as directed, carboplatin injection is stable for 8 hours at room temperature (25°C). Since no antibacterial preservative is contained in the formulation, it is recommended that carboplatin injection be discarded 8 hours after dilution.

HOW SUPPLIED

Each mL of carboplatin injection contains 10 mg of carboplatin, USP in water for injection USP and is available as follows:

Contents	Size	NDC Number
50 mg	5 mL multidose vial	69097-239-35
150 mg	15 mL multidose vial	69097-241-38
450 mg	45 mL multidose vial	69097-242-41
600 mg	60 mL multidose vial	69097-243-43

STORAGE

Unopened vials of carboplatin injection are stable to the date indicated on the package when stored at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

PROTECT FROM LIGHT.

Carboplatin injection multidose vials maintain microbial, chemical, and physical stability for up to 14 days at 25°C following multiple needle entries.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Solutions for infusion should be discarded 8 hours after preparation.

HANDLING AND DISPOSAL

Caution should be exercised in handling and preparing carboplatin injection. Several guidelines on this subject have been published.1-4

To minimize the risk of dermal exposure, always wear impervious gloves when handling vials containing carboplatin injection. If carboplatin injection contacts the skin, immediately wash the skin thoroughly with soap and water. If carboplatin injection contacts mucous membranes, the membranes should be flushed immediately and thoroughly with water. More information is available in the references listed below.

REFERENCES

1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165.
2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling occupational exposure to hazardous drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html
3. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs.Am J Health-Syst Pharm. 2006;63:1172-1193.
4. Polovich M, White JM, Kelleher LO, eds. 2005. Chemotherapy and biotherapy guidelines and recommendations for practice. 2nd ed. Pittsburgh, PA: Oncology Nursing Society.

Manufactured by:

Cipla Limited

Verna Goa, INDIA

Manufactured for:

Cipla USA, Inc.

9100 S. Dadeland Blvd.,

Suite 1500 Miami, FL 33156

Revised: 1/2015

Patient Information

CARBOplatin Injection

(Aqueous Solution)

Rx Only

Read this entire leaflet carefully. Keep it for future reference.

This information will help you learn more about carboplatin injection. It cannot, however, cover all the possible warnings or side effects relating to carboplatin injection, and it does not list all of the benefits and risks of carboplatin injection. Your doctor should always be your first choice for detailed information about your medical condition and your treatment. Be sure to ask your doctor about any questions you may have.

What is cancer?

Under normal conditions, the cells in your body divide and grow in an orderly, controlled fashion. Cell division and growth are necessary for the human body to perform its functions and to repair itself. Cancer cells are different from normal cells because they are not able to control their own growth. The reasons for this abnormal growth are not yet fully understood.

A tumor is a mass of unhealthy cells that are dividing and growing fast and in an uncontrolled way. When a tumor invades surrounding healthy body tissue it is known as a malignant tumor. A malignant tumor can spread (metastasize) from its original location to other parts of the body.

What is carboplatin injection?

Carboplatin injection is a medicine that is used to treat cancer of the ovaries. It acts by interfering with the division of rapidly multiplying cells, particularly cancer cells.

Who should not take carboplatin injection?

Treatment with carboplatin injection is not recommended if you:

• are allergic to carboplatin or other platinum-containing products;
• have a weakened blood-forming system (bone marrow depression) or significant bleeding;
• are pregnant, intend to become pregnant, or are breastfeeding a baby.

How is carboplatin injection used?

Only a professional experienced in the use of cancer drugs should give you this medication. Carboplatin injection is given by dripping the medicine slowly and directly into a vein (intravenous infusion) for 15 minutes or longer. Your doctor will determine the dose of carboplatin for you based on your weight, height, and kidney function. Carboplatin injection may be given alone or with other drugs. Treatment is usually repeated every four weeks for a number of cycles.

Before and after carboplatin treatment, your doctor may give you medication to lessen the nausea and vomiting associated with this cancer treatment

What should you tell your doctor before starting treatment with carboplatin injection?

Discuss the benefits and risks of carboplatin injection with your doctor before beginning treatment.

Be sure to inform your doctor:

• If you are allergic to carboplatin or other platinum-containing products;
• If you are or intend to become pregnant, since carboplatin may harm the developing fetus. It is important to use effective birth control while you are being treated with carboplatin injection.
• If you are breastfeeding, since nursing infants may be exposed to carboplatin in this way;
• If you are taking other medicines, including all prescription and non-prescription (over-the-counter) drugs, since carboplatin may affect the action of other medicines;
• If you have any other medical problems, especially chicken pox (including recent exposure to adults or children with chicken pox), shingles, hearing problems, infection, or kidney disease, since treatment with carboplatin increases the risk and severity of these conditions.

What should I avoid while taking carboplatin injection?

If you are pregnant or think you might be pregnant, or if you are breastfeeding, let your doctor know right away.

Carboplatin may harm your developing fetus or breastfeeding baby. If you are a woman of childbearing age, you should use birth control to avoid getting pregnant while you are taking carboplatin.

You should avoid contact with adults and children who have infections, and tell your doctor right away if you show signs of infection such as cough, fever, and/or chills. Also, while you are being treated with carboplatin or after you stop treatment, first check with your doctor before getting any immunizations (vaccinations). Avoid contact with adults or children who have received oral polio vaccine since they can pass the polio virus to you.

What are the possible side effects of carboplatin injection?

Carboplatin injection may cause unwanted effects, particularly because carboplatin interferes with the growth of normal cells as well as cancer cells. For example, the occurrence of another cancer (secondary malignancy) has been reported in patients receiving cancer chemotherapy with multiple drugs. It is not always possible to tell whether such effects are caused by carboplatin, another drug you may be taking, or your illness. Because some of these effects may be serious, you will need close medical supervision during treatment with carboplatin injection.

The most serious side effects of carboplatin are:

• bleeding and reduced blood cells, including reduced red blood cells (anemia) and platelets (needed for proper blood clotting), which may be severe enough to require blood transfusion. You should tell your doctor right away if you notice any unusual bruising or bleeding, including black tarry stools or blood in the urine.
• infection – carboplatin can temporarily lower the number of white blood cells in your blood, increasing the risk of infection;
• life-threatening allergic reaction – during and after treatment the doctor or nurse will observe you carefully for signs of allergic reaction;
• kidney and liver problems;
• loss of hearing or ringing in the ears;

Contact your doctor right away if you experience any of these effects, or notice effects that worry you or are troublesome.

Of the less serious side effects associated with carboplatin treatment, the most common are nausea, vomiting, diarrhoea, loss of appetite, hair loss and numbness, tingling, burning, or pain in the hands and feet.

This medicine was prescribed for your particular condition. It must be given under close medical supervision by a doctor trained in the use of drugs for the treatment of cancer.

This summary does not include everything there is to know about carboplatin injection. Medicines are sometimes prescribed for purposes other than those listed in patient leaflets. If you have questions or concerns, or want more information about carboplatin injection, your physician and pharmacist have the complete prescribing information upon which this information is based. You may want to read it and discuss it with your doctor. Remember, no written summary can replace careful discussion with your doctor.

Manufactured by:

Cipla Limited

Verna Goa, INDIA

Manufactured for:

Cipla USA, Inc.

1560, Sawgrass Corporate Parkway,

Suite 130, Sunrise, FL 33323

Revised: 12/2018

CARBOplatin Injection

(Aqueous Solution)

50 mg/5 mL

CARBOplatin Injection

(Aqueous Solution)

150 mg/15 mL

CARBOplatin Injection

(Aqueous Solution)

450 mg/45 mL

CARBOplatin Injection

(Aqueous Solution)

600 mg/60 mL