CISPLATIN injection
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1. Patient Information
2. Manufactured By:

Patient Information ⮝

Nephrotoxicity

Inform patients that cisplatin injection can cause nephrotoxicity and that renal function and electrolyte monitoring during treatment is necessary. If indicated, inform patients about the use of electrolyte supplements[see Warnings and Precautions (5.1)].

Peripheral Neuropathy

Advise patients to report any new paresthesias to their healthcare provider[see Warnings and Precautions (5.2)].

Nausea and Vomiting

Advise patients concerning the use of antiemetics to prevent nausea and vomiting and to report persistent or severe symptoms to their healthcare provider[see Warnings and Precautions (5.3)].

Myelosuppression

Advise patients that cisplatin injection can reduce the absolute neutrophil count and the platelet count resulting in an increased risk of infection and bleeding and to contact their healthcare provider for new onset fever, symptoms of infection, or bleeding[see Warnings and Precautions (5.4)].

Ototoxicity

Advise patients to report any symptoms of hearing loss or vestibular dysfunction to their healthcare provider and that periodic monitoring of hearing may be performed[see Warnings and Precautions (5.6)].

Embryo-Fetal Toxicity

Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider if they are pregnant or become pregnant[see Warnings and Precautions5.9and Use in Specific Populations8.1)].

Advise females of reproductive potential to use effective contraception during treatment and for 14 months following the last dose of cisplatin injection[see Use in Specific Populations (8.3)].

Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 11 months following the last dose of cisplatin injection[see Use in Specific Populations (8.3)].

Lactation

Advise females not to breastfeed during treatment with cisplatin injection[seeUse in Specific Populations (8.2)].

Infertility

Inform patients that treatment with cisplatin injection may lead to permanent impairment of spermatogenesis, ovarian failure or premature menopause, and reduced fertility in both genders[see Use in Specific Populations (8.3)].

Alopecia

Inform patients that cisplatin injection can cause alopecia.

Manufactured By: ⮝

Intas Pharmaceuticals Limited,
Plot No. 5 to 14 Pharmez,
Nr. Village Matoda,
Bavla Road, Ta.- Sanand,
Dist. Ahmedabad - 382213,
India

For BluePoint Laboratories

51 0369 1 721039

Issued: April 2019

1. No Title 1572551565
2. Highlights Of Prescribing Information
3. See Full Prescribing Information For Complete Boxed Warning.
4. Indications And Usage
5. Dosage And Administration
6. Dosage Forms And Strengths
7. Contraindications
8. Warnings And Precautions
9. Adverse Reactions
10. Use In Specific Populations
11. Warning: Nephrotoxicity, Peripheral Neuropathy, Nausea And Vomiting And Myelosuppression.
12. 1 Indications And Usage
13. 2 Dosage And Administration
14. 3 Dosage Forms And Strengths
15. 4 Contraindications
16. 5 Warnings And Precautions
17. 6 Adverse Reactions
18. 7 Drug Interactions
19. 8 Use In Specific Populations
20. 10 Overdosage
21. 11 Description
22. 12 Clinical Pharmacology
23. 13 Nonclinical Toxicology
24. 15 References
25. 16 How Supplied/storage And Handling
26. Package/label Principal Display Panel
27. No Title 1572458211
28. Description
29. Clinical Pharmacology
30. Indications
31. Warnings
32. Precautions
33. Other Toxicities
34. Overdosage
35. Preparation Of Intravenous Solutions
36. Stability
37. How Supplied
38. References
39. Principal Display Panel
40. Serialization Image

No Title 1572551565 ⮝

WARNING

Cisplatin Injection 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 diagnostic and treatment facilities are readily available.

Cumulative renal toxicity associated with cisplatin is severe. Other major dose-related toxicities are myelosuppression, nausea, and vomiting.

Ototoxicity, which may be more pronounced in children, and is manifested by tinnitus, and/or loss of high frequency hearing and occasionally deafness, is significant.

Anaphylactic-like reactions to cisplatin have been reported. Facial edema, bronchoconstriction, tachycardia, and hypotension may occur within minutes of cisplatin administration. Epinephrine, corticosteroids, and antihistamines have been effectively employed to alleviate symptoms (see WARNINGS and ADVERSE REACTIONS sections).

Exercise caution to prevent inadvertent cisplatin overdose. Doses greater than 100 mg/m2/cycle once every 3 to 4 weeks are rarely used. Care must be taken to avoid inadvertent cisplatin overdose due to confusion with carboplatin or prescribing practices that fail to differentiate daily doses from total dose per cycle.

Highlights Of Prescribing Information ⮝

These highlights do not include all the information needed to use CISPLATIN INJECTION safely and effectively. See full prescribing information for CISPLATIN INJECTION.

CISPLATIN injection, for intravenous use

Initial U.S. Approval: 1978

See Full Prescribing Information For Complete Boxed Warning. ⮝

Nephrotoxicity: cisplatin injection can cause severe renal toxicity, including acute renal failure. Ensure adequate hydration. Consider dose reductions or alternative treatments in patients with renal impairment. ( 2.1, 5.1)

Peripheral Neuropathy: cisplatin injection can cause dose-related peripheral neuropathy. ( 5.2)

Nausea and Vomiting: cisplatin injection can cause severe nausea and vomiting. Premedicate with antiemetics. ( 2.1, 5.3)

Myelosuppression: cisplatin injection can cause severe myelosuppression with fatalities due to infections. Monitor blood counts and interrupt therapy accordingly. ( 5.4)

Indications And Usage ⮝

Cisplatin injection is a platinum-based drug indicated for the treatment of:

Advanced testicular cancer ( 1.1)

Advanced ovarian cancer ( 1.2)

Advanced bladder cancer ( 1.3)

Dosage And Administration ⮝

Administer pre-treatment hydration and pre- and post-treatment antiemetics. ( 2.1)

Cisplatin injection has been administered intravenously at:

5.

Advanced testicular cancer: 20 mg/m2 daily for 5 days per cycle ( 2.2)

6.

Advanced ovarian cancer: 75 mg/m2 to 100 mg/m2 per cycle once every 3 to 4 weeks ( 2.3)

7.

Advanced bladder cancer: 50 mg/m2 to 70 mg/m2 intravenously per cycle once every 3 to 4 weeks ( 2.4)

8.

Refer to current treatment guidelines for specific dosing information.

Administer by slow intravenous infusion. Avoid contact of cisplatin injection with aluminum parts. ( 2.6)

Dosage Forms And Strengths ⮝

Cisplatin injection is multiple-dose vials containing

50 mg/50 mL (1 mg/mL) ( 3)

100 mg/100 mL (1 mg/mL) ( 3)

Contraindications ⮝

Severe hypersensitivity to cisplatin ( 4)

Warnings And Precautions ⮝

Hypersensitivity reactions: Anaphylaxis and death may occur; monitor for and treat accordingly ( 5.5)

Ototoxicity: Cumulative toxicity may be severe particularly in pediatric patients; consider audiometric and vestibular function monitoring ( 5.6, 8.4)

Ocular toxicity: Optic neuritis, papilledema, and cortical blindness may occur ( 5.7)

Secondary leukemia: Secondary acute leukemia may occur ( 5.8)

Embryo-fetal toxicity: Can cause fetal harm. Advise of potential risk to a fetus and use of effective contraception. ( 5.9, 8.1, 8.3)

Adverse Reactions ⮝

Common adverse reactions are nephrotoxicity, peripheral neuropathy, nausea and vomiting, myelosuppression, and ototoxicity. ( 6)

To report SUSPECTED ADVERSE REACTIONS, contact Accord Healthcare Inc. at 1-866-941-7875 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Use In Specific Populations ⮝

Lactation: Advise not to breastfeed. ( 8.2)

Females and Males of Reproductive Potential: Verify pregnancy status prior to initiation of cisplatin injection. Can impair fertility. ( 8.3)

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 8/2019

Warning: Nephrotoxicity, Peripheral Neuropathy, Nausea And Vomiting And Myelosuppression. ⮝

Nephrotoxicity: cisplatin injection can cause severe renal toxicity, including acute renal failure. Severe renal toxicities are dose-related and cumulative. Ensure adequate hydration and monitor renal function and electrolytes. Consider dose reductions or alternative treatments in patients with renal impairment [see Dosage and Administration ( 2.1) and Warnings and Precautions ( 5.1)].

Peripheral Neuropathy: cisplatin injection can cause dose-related peripheral neuropathy that becomes more severe with repeated courses of the drug [see Warnings and Precautions ( 5.2)].

Nausea and Vomiting: cisplatin injection can cause severe nausea and vomiting. Use highly effective antiemetic premedication [see Dosage and Administration ( 2.1) and Warnings and Precautions ( 5.3)].

Myelosuppression: cisplatin injection can cause severe myelosuppression with fatalities due to infections. Monitor blood counts accordingly. Interruption of therapy may be required [see Warnings and Precautions ( 5.4)].

1 Indications And Usage  ⮝

1.1 Advanced Testicular Cancer

Cisplatin injection is indicated for the treatment of advanced testicular cancer.

1.2 Advanced Ovarian Cancer

Cisplatin injection is indicated for the treatment of advanced ovarian cancer.

1.3 Advanced Bladder Cancer

Cisplatin injection is indicated for the treatment of advanced bladder cancer.

2 Dosage And Administration  ⮝

2.1 Hydration and Anti-Emetic Treatment

Patients treated with cisplatin injection must receive appropriate pre-treatment hydration. Maintain adequate hydration and urinary output for 24 hours after cisplatin injection administration [see Warnings and Precautions ( 5.1)] . Administer pre-treatment and post-treatment antiemetics as appropriate [see Warnings and Precautions ( 5.7)] .

2.2 Advanced Testicular Cancer

Cisplatin injection has been administered at 20 mg/m 2 intravenously daily for 5 days per cycle. Other doses and combination regimens have been used.

2.3 Advanced Ovarian Cancer

Cisplatin injection has been administered at 75 mg/m 2 to 100 mg/m 2 intravenously per cycle once every 3 to 4 weeks on Day 1. Other doses and combination regimens have been used.

2.4 Advanced Bladder Cancer

Cisplatin injection has been administered at 50 mg/m 2 to 70 mg/m 2 intravenously per cycle once every 3 to 4 weeks. For heavily pretreated patients, an initial dose of 50 mg/m 2 per cycle repeated every 4 weeks is recommended. Other doses and combination in regimens have been used.

2.5 Dose Modifications

Consider alternative treatments or dose reductions for patients with impaired creatinine clearance, myelosuppression, or neuropathy. Consider permanent discontinuation for Grade 3-4 neuropathy. [See Warnings and Precautions ( 5.1)]

2.6 Preparation, Handling, and Administration

Do not use needles or intravenous sets containing aluminum parts that can come in contact with cisplatin injection during preparation or administration. Aluminum reacts with cisplatin injection, causing precipitate formation and a loss of potency.

Cisplatin injection is a cytotoxic drug. Follow applicable special handling and disposable procedures. 1

Instructions for Preparation

The aqueous solution should be used intravenously only and should be administered by IV infusion over a 6- to 8-hour period (see DOSAGE AND ADMINISTRATION).

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

NOTE TO PHARMACIST: Exercise caution to prevent inadvertent cisplatin overdosage. Please call prescriber if dose is greater than 100 mg/m 2 per cycle. Aluminum flip-off seal of vial have been imprinted with the following statement:
CALL DR. IF DOSE > 100 MG/M 2/CYCLE.

Administration

Administer cisplatin injection by slow intravenous infusion.

3 Dosage Forms And Strengths  ⮝

Cisplatin injection, is a clear, colorless to pale yellow, sterile aqueous solution available in sterilie multiple-dose vials containing

50 mg/50 mL (1 mg/mL)

100 mg/100 mL (1 mg/mL)

4 Contraindications  ⮝

Cisplatin injection is contraindicated in patients with severe hypersensitivity to cisplatin [see Warnings and Precautions ( 5.4)] .

5 Warnings And Precautions  ⮝

5.1 Nephrotoxicity

Cisplatin injection can cause dose-related nephrotoxicity, including acute renal failure that becomes more prolonged and severe with repeated courses of the drug. Renal toxicity typically begins during the second week after a dose of cisplatin injection. Patients with baseline renal impairment, geriatric patients, patients who are taking other nephrotoxic drugs, or patients who are not well hydrated may be more susceptible to nephrotoxicity [see Use in Specific Populations ( 8.5, 8.6)] .

Ensure adequate hydration before, during, and after cisplatin injection administration [see Dosage and Administration ( 2.1)] . Measure serum creatinine, blood urea nitrogen, creatinine clearance, and serum electrolytes including magnesium prior to initiating therapy, and as clinically indicated. Consider magnesium supplementation as clinically needed.

Consider alternative treatments or reduce the dose of cisplatin injection for patients with baseline renal impairment or who develop significant reductions in creatinine clearance during treatment with cisplatin injection according to clinical treatment guidelines [see Dosage and Administration( 2.5)].

5.2 Peripheral Neuropathy

Cisplatin injection can cause dose-related peripheral neuropathy that becomes more severe with repeated courses of the drug. Neurologic symptoms have been reported to occur after a single dose. Neuropathy can also have a delayed onset from 3 to 8 weeks after the last dose of cisplatin injection. Manifestations include paresthesias in a stocking-glove distribution, areflexia, and loss of proprioception and vibratory sensation. The neuropathy may progress further even after stopping treatment. Peripheral neuropathy may be irreversible in some patients.

Perform a neurological examination before initiating cisplatin injection, at appropriate intervals during therapy, and after completion of therapy. Consider discontinuation of cisplatin injection for patients who develop symptomatic peripheral neuropathy. Geriatric patients may be more susceptible to peripheral neuropathy [see Use in Specific Populations ( 8.5)] .

5.3 Nausea and Vomiting

Cisplatin injection is a highly emetogenic antineoplastic agent. Premedicate with anti-emetic agents [see Dosage and Administration ( 2.1)] . Without antiemetic therapy, marked nausea and vomiting occur in almost all patients treated with cisplatin injection and may be so severe that the drug must be discontinued. Nausea and vomiting may begin within 1 to 4 hours after treatment and last up to 72 hours. Maximal intensity occurs 48 to 72 hours after administration. Various degrees of vomiting, nausea, and/or anorexia may persist for up to 1 week after treatment. Delayed nausea and vomiting (begins or persists 24 hours or more after chemotherapy) has occurred in patients attaining complete emetic control on the day of cisplatin injection therapy. Consider the use of additional anti-emetics following infusion.

5.4 Myelosuppression

Myelosuppression suppression occurs in 25% to 30% of patients treated with cisplatin injection. Fever and infection have been reported in patients with neutropenia. Potential fatalities due to infection (secondary to myelosuppression) have been reported. Geriatric patients may be more susceptible to myelosuppression [see Use in Specific Populations ( 8.5)] .

Perform standard hematologic tests before initiating cisplatin injection, before each subsequent course, and as clinically indicated. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with cisplatin injection. For patients who develop severe myelosuppression during treatment with cisplatin injection, consider dose modifications and manage according to clinical treatment guidelines.

5.5 Hypersensitivity Reactions

Cisplatin injection can cause severe hypersensitivity reactions, including anaphylaxis and death. Manifestations have included facial edema, wheezing, tachycardia, and hypotension. Hypersensitivity reactions have occurred within minutes of administration to patients with prior exposure tocisplatin injection.

Monitor patients receiving cisplatin injection for possible hypersensitivity reactions. Ensure supportive equipment and medications are available to treat severe hypersensitivity reactions. Severe hypersensitivity reactions require immediate discontinuation of cisplatin injection and aggressive therapy. Patients with a history of severe hypersensitivity reactions should not be rechallenged with cisplatin injection [see Contraindications ( 4)] . Cross-reactivity between platinum-based antineoplastic agents has been reported. Cases of severe hypersensitivity reactions have recurred after rechallenging patients with a different platinum agent.

5.6 Ototoxicity

Cisplatin injection can cause ototoxicity, which is cumulative and may be severe. Consider audiometric and vestibular function monitoring.

Ototoxicity is manifested by tinnitus, hearing loss in the high frequency range (4,000 to 8,000 Hz) and/or decreased ability to hear normal conversational tones. Ototoxicity can occur during or after treatment and can be unilateral or bilateral. Deafness after the initial dose of cisplatin injection has been reported. Vestibular toxicity has also been reported.

Ototoxic effects can be more severe and detrimental in pediatric patients, particularly in patients less than 5 years of age. The prevalence of hearing loss in pediatric patients is estimated to be 40-60%. Additional risk factors for ototoxicity include simultaneous cranial irradiation, treatment with other ototoxic drugs and renal impairment. Consider audiometric and vestibular testing in all pediatric patients receiving cisplatin [see Use in Specific Populations ( 8.4)].

Genetic factors (e.g. variants in the thiopurine S-methyltransferase [TPMT] gene) may also contribute to the cisplatin-induced ototoxicity; although this association has not been consistent across populations and study designs.

5.7 Ocular Toxicity

Optic neuritis, papilledema, and cortical blindness have been reported in patients receiving standard recommended doses of cisplatin injection. Blurred vision and altered color perception have been reported after the use of regimens with higher doses and dose frequencies of cisplatin injection. The altered color perception manifests as a loss of color discrimination, particularly in the blue-yellow axis and irregular retinal pigmentation of the macular area on fundoscopic exam. Improvement and/or total recovery usually occurs after discontinuing cisplatin injection but can be delayed.

5.8 Secondary Malignancies

The development of acute leukemia secondary to the use of cisplatin injection has been reported. In these reports, cisplatin injection was generally given in combination with other leukemogenic agents.

5.9 Embryo-Fetal Toxicity

Based on human data, cisplatin injection can cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 14 months after the last dose of cisplatin injection. Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 11 months after the last dose of cisplatin injection [see Use in Specific Populations ( 8.1, 8.3)].

5.10 Injection Site Reactions

Injection site reactions can occur during the administration of cisplatin injection. Local soft tissue toxicity has been reported following extravasation of cisplatin injection. Severity of the local tissue toxicity appears to be related to the concentration of the cisplatin injection solution. Infusion of solutions with a cisplatin injection concentration greater than 0.5 mg/mL may result in tissue cellulitis, fibrosis, necrosis, pain, edema, and erythema.

Because of the possibility of extravasation, closely monitor the infusion site during drug administration.

6 Adverse Reactions  ⮝

The following adverse reactions are described in greater detail, in other sections:

Nephrotoxicity [see Warnings and Precautions ( 5.1)]

Peripheral Neuropathy [see Warnings and Precautions ( 5.2)]

Nausea and vomiting [see Warnings and Precautions ( 5.3)]

Myelosuppression [see Warnings and Precautions ( 5.4)]

Hypersensitivity reactions [see Warnings and Precautions ( 5.5)]

Ototoxicity [see Warnings and Precautions ( 5.6]

Ocular toxicity [see Warnings and Precautions ( 5.7)]

Secondary malignancies [see Warnings and Precautions ( 5.8)]

Injection site reactions [see Warnings and Precautions ( 5.10)]

Common adverse reactions are nephrotoxicity, peripheral neuropathy, nausea and vomiting myelosuppression, and ototoxicity. The following adverse reactions have been identified from clinical trials or post-marketing surveillance.

Blood and lymphatic system disorders: Coombs positive hemolytic anemia. hemolytic uremic syndrome, thrombotic thrombocytopenic purpura

Cardiovascular disorders: Venous thromboembolism, arterial thromboembolism, myocardial infarction, cerebrovascular accident, thrombotic microangiopathy, cerebral arteritis, pericardial effusion, cardiac failure, ventricular dysfunction, Raynaud s phenomenon

Eye disorders: Optic neuritis, papilledema, cortical blindness, blurred vision, color blindness, retinal pigmentation

Gastrointestinal disorders: Nausea, vomiting, anorexia, diarrhea, stomatitis, gastrointestinal perforation, pancreatitis, hiccups

General disorders: Asthenia, malaise

Hepatobiliary disorders: Elevations of aminotransferases, lactate dehydrogenase, and bilirubin; hepatic failure

Hypersensitivity: Anaphylaxis, facial edema, wheezing, tachycardia, and hypotension

Local Site Reactions: Tissue cellulitis, fibrosis, necrosis, pain, edema, and erythema

Metabolism and nutrition disorders: Hypomagnesemia, often requiring magnesium supplementation; hyperuricemia, other electrolyte abnormalities (hypocalcemia, hyponatremia, hypokalemia, and hypophosphatemia), Syndrome of Inappropriate Antidiuretic Hormone Excretion (SIADH), dehydration, tumor lysis syndrome, increased serum amylase

Musculoskeletal disorders: Muscle cramps (localized, painful, involuntary skeletal muscle contractions of sudden onset and short duration)

Nervous system disorders: Peripheral neuropathy, Encephalopathy, loss of motor function, loss of taste, leukoencephalopathy, reversible posterior leukoencephalopathy syndrome, progressive multifocal leukoencephalopathy, seizures, Lhermitte s sign, dorsal column myelopathy, autonomic neuropathy, seizures, involuntary skeletal muscle contractions, tetany (with hypocalcemia and hypomagnesemia)

Ototoxicity: Tinnitus, hearing loss, deafness, vestibular toxicity

Renal and urinary disorders: Nephrotoxicity including renal failure, renal electrolyte wasting, azotemia, decreased creatinine clearance

Respiratory disorders: pneumonitis/interstitial lung disease, pulmonary embolism

Skin and subcutaneous tissue disorders: Alopecia, rash

7 Drug Interactions  ⮝

The following drug interactions are described in other sections:

Nephrotoxic drugs [see Warnings and Precautions ( 5.1)]

Ototoxic drugs [see Warnings and Precautions ( 5.6)]

8 Use In Specific Populations  ⮝

8.1 Pregnancy

Risk Summary

Based on human data from published literature, cisplatin injection can cause fetal harm when administered to pregnant women. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Data demonstrates transplacental transfer of cisplatin. Exposure of pregnant women to cisplatin-containing chemotherapy has been associated with oligohydramnios, intrauterine growth restriction, and preterm birth. Cases of neonatal acute respiratory distress syndrome, cytopenias, and hearing loss have been reported. Cisplatin injection administration to animals during and after organogenesis resulted in teratogenicity. A published study in mice showed placental transfer of cisplatin increased with placenta maturation.

The background risk of major birth defects and miscarriage for the indicated populations are unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies.

8.2 Lactation

Risk Summary

Limited data from published literature report the presence of cisplatin in human milk in low amounts. Because of the potential for serious adverse reactions from cisplatin injection in a breastfed child and because of the potential for tumorigenicity shown for cisplatin injection, advise lactating women not to breastfeed during treatment with cisplatin injection.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiation of cisplatin injection.

Contraception

Females

Cisplatin injection can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1)] . Advise females of reproductive potential to use effective contraception during treatment and for 14 months following the last dose of cisplatin injection.

Males

Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 11 months after the last dose of cisplatin injection.

Infertility

Females

The use of cisplatin has been associated with cumulative dose-dependent ovarian failure, premature menopause, and reduced fertility.

Males

The use of cisplatin has been associated with a cumulative dose-dependent impairment of spermatogenesis (oligospermia, azoospermia; possibly irreversible) and reduced fertility.

8.4 Pediatric Use

Ototoxic effects may be more severe and detrimental in pediatric patients receiving cisplatin injection, particularly in patients less than 5 years of age. Consider audiometric and vestibular function monitoring in all patients receiving cisplatin injection. The prevalence of hearing loss in pediatric patients is particularly high and is estimated to be 40% to 60%.

Earlier detection of hearing loss can limit the potential impact of hearing impairment on a pediatric patient s cognitive and social development [see Warnings and Precautions ( 5.6)].

8.5 Geriatric Use

For the treatment of metastatic testicular tumors or advanced bladder cancer, clinical studies of cisplatin injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In four clinical trials of combination chemotherapy for advanced ovarian carcinoma, 1,484 patients received cisplatin either in combination with cyclophosphamide or with paclitaxel. Of these, 426 (29%) were older than 65 years. In these trials, age was not found to be a prognostic factor for survival. However, in a later secondary analysis for one of these trials, geriatric patients were found to have shorter survival compared with younger patients.

In all four trials, geriatric patients experienced more severe neutropenia than did younger patients. Higher incidences of severe thrombocytopenia and leukopenia were also seen in geriatric patients compared with younger patients, although not in all cisplatin-containing treatment arms. In the two trials where nonhematologic toxicity was evaluated according to age, geriatric patients had a numerically higher incidence of peripheral neuropathy than did younger patients. Other reported clinical experience suggests that geriatric patients may be more susceptible to nephrotoxicity, myelosuppression, and infectious complications than are younger patients [see Warnings and Precautions ( 5.1, 5.2, 5.4)].

Cisplatin is known to be substantially excreted by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and renal function should be monitored.

8.6 Use in Patients with Renal Impairment

Patients with baseline renal impairment may be more susceptible to nephrotoxicity [see Warnings and Precautions ( 5.1)] . Ensure adequate hydration before, during, and after cisplatin injection administration [see Dosage and Administration ( 2.1)]. Measure serum creatinine, blood urea nitrogen, creatinine clearance, and serum electrolytes prior to initiating therapy, and as clinically indicated. Consider alternative treatments or reduce the dose of cisplatin injection for patients with baseline renal impairment or who develop significant reductions in creatinine clearance during treatment with cisplatin injection according to clinical treatment guidelines [see Dosage and Administration ( 2.5)].

10 Overdosage  ⮝

Acute overdosage with cisplatin injection may result in renal failure, hepatic failure, hearing loss, ocular toxicity, myelosuppression, nausea and vomiting, and neuritis. In addition, death can occur following overdosage.

Management of overdosage should include general supportive measures to sustain the patient through any period of toxicity that may occur. Important measures include renal protection by intravenous hydration with or without the use of an osmotic diuretic. Hemodialysis is not effective because of the high degree of protein binding of cisplatin injection. Plasmapheresis has been used to treat cases of cisplatin injection overdosage, but the optimal treatment regimen has not been established.

For current information on the management of poisoning or overdosage, contact the National Poison Control Center at 1-800-222-1222 or www.poison.org.

11 Description  ⮝

Cisplatin injection, a platinum-based drug for intravenous use, is a clear, colorless to pale yellow, sterile aqueous solution. Each 50 mL or 100 mL amber vial of Cisplatin Injection contains: 1 mg/mL cisplatin, 9 mg/mL sodium chloride, hydrochloric acid and/or sodium hydroxide to adjust pH, and water for injection to a final volume of 50 mL or 100 mL, respectively. The pH range of Cisplatin Injection is 3.5 to 5.0.

Cisplatin, the active ingredient in Cisplatin injection, is a yellow to orange crystalline powder with the molecular formula Cl 2H 6N 2Pt and a molecular weight of 300.05. Cisplatin is a heavy metal complex containing a central atom of platinum surrounded by two chloride atoms and two ammonia molecules in the cis position. It is soluble in water or saline at 1 mg/mL and in dimethylformamide at 24 mg/mL. It has a melting point of 207 C.

The structural formula is:

12 Clinical Pharmacology  ⮝

12.1 Mechanism of Action

The main mechanism of the cytotoxic action involves the binding of cisplatin to genomic DNA in the cell nucleus to form interstrand and intrastrand cross-links. This interferes with normal transcription and/or DNA replication mechanisms and triggers cytotoxic processes that lead to cell death.

12.3 Pharmacokinetics

Distribution

Cisplatin dose not undergo the instantaneously and reversible binding to plasma protein that is characteristic of normal drug-protein binding. Platinum from cisplatin, but not cisplatin itself, becomes bound to several plasma proteins, including albumin, transferrin, and gamma globulin. Three hours after a bolus injection and 2 hours after the end of a 3 hour infusion, 90% of the plasma platinum is protein bound. The complexes between albumin and the platinum from cisplatin do not dissociate to a significant extent and are slowly eliminated with a minimum half-life of 5 days or more.

Following cisplatin doses of 20 mg/m 2 to 120 mg/m 2, platinum is present in tissues for as long as 180 days after the last administration. With the exception of intracerebral tumors, platinum concentrations in tumors are generally somewhat lower than the concentrations in the organ where the tumor is located. Hepatic metastases have the highest platinum concentrations, but these are similar to the platinum concentrations in normal liver. Maximum red blood cell concentrations of platinum are reached within 90 to 150 minutes after a 100 mg/m 2 dose of cisplatin and decline in a biphasic manner with a terminal half-life of 36 to 47 days.

Metabolism

The chlorine atoms of cisplatin are more subject to chemical displacement reactions by nucleophiles, such as water or sulfhydryl groups, than to enzyme-catalyzed metabolism. At physiological pH, the predominant molecular species are cisplatin and monohydroxymonochloro cis-diamine platinum (II) in nearly equal concentrations. The latter, combined with the possible direct displacement of the chlorine atoms by sulfhydryl groups of amino acids or proteins, accounts for the instability of cisplatin in biological matrices. The ratios of cisplatin to total free (ultrafilterable) platinum in the plasma vary considerably between patients and range from 0.5 to 1.1 after a dose of 100 mg/m 2.

Elimination

Over a dose range of 40 mg to 140 mg cisplatin per m 2 given as a bolus injection or as infusions varying in length from 1 hour to 24 hours, from 10% to about 40% of the administered platinum is excreted in the urine in 24 hours. Over 5 days following administration of 40 mg/m 2 to 100 mg/m 2 doses given as rapid, 2 to 3 hour or 6 to 8 hour infusions, a mean of 35% to 51% of the dosed platinum is excreted in the urine. Similar mean urinary recoveries of platinum of about 14% to 30% of the dose are found following 5 daily administrations of 20 mg/m 2 per day, 30 mg/m 2 per day, or 40 mg/m 2 per day. Only a small percentage of the administered platinum is excreted beyond 24 hours post-infusion and most of the platinum excreted in the urine in 24 hours is excreted within the first few hours.

The parent compound, cisplatin, is excreted in the urine and accounts for 13% to 17% of the dose excreted within 1 hour after administration of 50 mg/m 2. The mean renal clearance of cisplatin exceeds creatinine clearance and was 62 mL/min per m 2 and 50 mL/min per m 2 following administration of 100 mg/m 2 as 2 hour or 6 to 7 hour infusions, respectively.

Plasma concentrations of the parent compound, cisplatin, decrease monoexponentially with a half-life of about 20 to 30 minutes following bolus administrations of 50 mg/m 2 or 100 mg/m 2 doses. Monoexponential decreases and plasma half-lives of about 0.5 hour are also seen following 2 hour or 7 hour infusions of 100 mg/m 2. After the latter, the total body clearances and volumes of distribution at steady-state for cisplatin are about 15 Liters per hour per m 2 to 16 Liters per hour per m 2 and 11 Liters per m 2 to 12 Liters per m 2.

The renal clearance of free (ultrafilterable) platinum also exceeds the glomerular filtration rate, indicating that cisplatin or other platinum-containing molecules are actively secreted by the kidneys. The renal clearance of free platinum is nonlinear and variable and is dependent on dose, urine flow rate, and individual variability in the extent of active secretion and possible tubular reabsorption.

No significant relationships exist between the renal clearance of either free platinum or cisplatin and creatinine clearance.

13 Nonclinical Toxicology  ⮝

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenic effect of cisplatin injection was studied in BDIX rats. Cisplatin injection was administered three times a week at 1 mg/kg body weight intraperitoneally to 50 BDIX rats for 3 weeks. Four hundred fifty-five days after the first application, 33 animals died, 13 of them related to malignancies (12 leukemias and 1 renal fibrosarcoma) [see Warnings and Precautions ( 5.8)].

Cisplatin is mutagenic in the bacteria reverse mutation (Ames) test and produces chromosome aberrations in mammalian cells.

15 References  ⮝

1.

OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

16 How Supplied/storage And Handling  ⮝

How Supplied

Cisplatin injection

NDC 68001-283-24 Each multiple-dose amber vial contains 50 mg/50 mL (1 mg/mL) of cisplatin as a clear, colorless to pale yellow, sterile aqueous solution.
NDC 68001-283-33 Each multiple-dose amber vial contains 100 mg/100 mL (1 mg/mL) of cisplatin as a clear, colorless to pale yellow, sterile aqueous solution.

The above products are multiple dose vials packaged individually per shelf pack with NDC 68001-283-27 for 50mL and NDC 68001-283-32 for 100mL.

Storage

Store at 20 C to 25 C (68 F to 77 F); excursions permitted to 15 C to 30 C (59 F to 86 F) [see USP Controlled Room Temperature]. Do not refrigerate or freeze cisplatin solution since a precipitate or crystal will form.

If precipitate or crystal observed inside the vial, keep it at recommended storage condition till clear solution obtained. Protect unopened container from light.

The cisplatin remaining in the amber vial following initial entry is stable for 28 days protected from light or for 7 days under fluorescent room light.

Handling and Disposal

Cisplatin injection is a cytotoxic drug. Follow applicable special handling and disposal procedures. 1

Package/label Principal Display Panel  ⮝

Cisplatin Injection

50 mL Multiple Dose Vial (1 mg/mL)- Carton

50 mL Multiple Dose Vial (1 mg/mL)- Label

100 mL Multiple Dose Vial (1 mg/mL)- Carton

100 mL Multiple Dose Vial (1 mg/mL)- Label

CISPLATIN cisplatin injection

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:68001-283 Route of Administration INTRAVENOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CISPLATIN (UNII: Q20Q21Q62J) (CISPLATIN - UNII:Q20Q21Q62J) CISPLATIN 1 mg in 1 mL

Inactive Ingredients Ingredient Name Strength SODIUM CHLORIDE (UNII: 451W47IQ8X) HYDROCHLORIC ACID (UNII: QTT17582CB) SODIUM HYDROXIDE (UNII: 55X04QC32I)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:68001-283-27 1 in 1 CARTON 08/02/2016 1 NDC:68001-283-24 50 mL in 1 VIAL; Type 0: Not a Combination Product 2 NDC:68001-283-32 1 in 1 CARTON 08/02/2016 2 NDC:68001-283-33 100 mL in 1 VIAL; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA206774 08/02/2016

Labeler - BluePoint Laboratories (985523874)

Registrant - Accord Healthcare (604222237)

Establishment
Name	Address	ID/FEI	Business Operations
Intas Pharmaceuticals Limited		915837971	MANUFACTURE(68001-283) , ANALYSIS(68001-283)

Revised: 8/2019 Document Id: d3b55f3e-d3e7-4238-bcbe-b8cb1e3d0479 34391-3 Set id: a60c5173-6bc0-4c9d-9674-b3f4d68f79ba Version: 2 Effective Time: 20190821 BluePoint Laboratories

No Title 1572458211 ⮝

Rx only

Description ⮝

Cisplatin Injection infusion concentrate is a clear, colorless, sterile aqueous solution. Each 50 mL or 100 mL amber vial of Cisplatin Injection contains: 1 mg/mL cisplatin, 9 mg/mL sodium chloride, hydrochloric acid and/or sodium hydroxide to adjust pH, and water for injection to a final volume of 50 mL or 100 mL, respectively. The pH range of Cisplatin Injection is 3.8 to 5.9.

Cisplatin Injection infusion concentrate must be further diluted prior to administration (see DOSAGE AND ADMINISTRATION, All Patients).

The active ingredient, cisplatin, is a yellow to orange crystalline powder with the molecular formula PtCl2H6N2, and a molecular weight of 300.1. Cisplatin is a heavy metal complex containing a central atom of platinum surrounded by two chloride atoms and two ammonia molecules in the cis position. It is soluble in water or saline at 1 mg/mL and in dimethylformamide at 24 mg/mL. It has a melting point of 207 C.

Clinical Pharmacology ⮝

Plasma concentrations of the parent compound, cisplatin, decay monoexponentially with a half-life of about 20 to 30 minutes following bolus administrations of 50 or 100 mg/m2 doses. Monoexponential decay and plasma half-lives of about 0.5 hour are also seen following 2-hour or 7-hour infusions of 100 mg/m2. After the latter, the total-body clearances and volumes of distribution at steady-state for cisplatin are about 15 to 16 L/h/m2 and 11 to 12 L/m2.

Due to its unique chemical structure, the chlorine atoms of cisplatin are more subject to chemical displacement reactions by nucleophiles, such as water or sulfhydryl groups, than to enzyme-catalyzed metabolism. At physiological pH in the presence of 0.1M NaCl, the predominant molecular species are cisplatin and monohydroxymonochloro cis-diammine platinum (II) in nearly equal concentrations. The latter, combined with the possible direct displacement of the chlorine atoms by sulfhydryl groups of amino acids or proteins, accounts for the instability of cisplatin in biological matrices. The ratios of cisplatin to total free (ultrafilterable) platinum in the plasma vary considerably between patients and range from 0.5 to 1.1 after a dose of 100 mg/m2.

Cisplatin does not undergo the instantaneous and reversible binding to plasma proteins that is characteristic of normal drug-protein binding. However, the platinum from cisplatin, but not cisplatin itself, becomes bound to several plasma proteins, including albumin, transferrin, and gamma globulin. Three hours after a bolus injection and two hours after the end of a three-hour infusion, 90% of the plasma platinum is protein bound. The complexes between albumin and the platinum from cisplatin do not dissociate to a significant extent and are slowly eliminated with a minimum half-life of five days or more.

Following cisplatin doses of 20 to 120 mg/m2, the concentrations of platinum are highest in liver, prostate, and kidney; somewhat lower in bladder, muscle, testicle, pancreas, and spleen; and lowest in bowel, adrenal, heart, lung, cerebrum, and cerebellum. Platinum is present in tissues for as long as 180 days after the last administration. With the exception of intracerebral tumors, platinum concentrations in tumors are generally somewhat lower than the concentrations in the organ where the tumor is located. Different metastatic sites in the same patient may have different platinum concentrations. Hepatic metastases have the highest platinum concentrations, but these are similar to the platinum concentrations in normal liver. Maximum red blood cell concentrations of platinum are reached within 90 to 150 minutes after a 100 mg/m2 dose of cisplatin and decline in a biphasic manner with a terminal half-life of 36 to 47 days.

Over a dose range of 40 to 140 mg cisplatin/m2 given as a bolus injection or as infusions varying in length from 1 hour to 24 hours, from 10% to about 40% of the administered platinum is excreted in the urine in 24 hours. Over five days following administration of 40 to 100 mg/m2 doses given as rapid, 2- to 3-hour, or 6- to 8-hour infusions, a mean of 35% to 51% of the dosed platinum is excreted in the urine. Similar mean urinary recoveries of platinum of about 14% to 30% of the dose are found following five daily administrations of 20, 30, or 40 mg/m2/day. Only a small percentage of the administered platinum is excreted beyond 24 hours post-infusion and most of the platinum excreted in the urine in 24 hours is excreted within the first few hours. Platinum-containing species excreted in the urine are the same as those found following the incubation of cisplatin with urine from healthy subjects, except that the proportions are different.

The parent compound, cisplatin, is excreted in the urine and accounts for 13% to 17% of the dose excreted within one hour after administration of 50 mg/m2. The mean renal clearance of cisplatin exceeds creatinine clearance and is 62 and 50 mL/min/m2 following administration of 100 mg/m2 as 2-hour or 6- to 7-hour infusions, respectively.

The renal clearance of free (ultrafilterable) platinum also exceeds the glomerular filtration rate indicating that cisplatin or other platinum-containing molecules are actively secreted by the kidneys. The renal clearance of free platinum is nonlinear and variable and is dependent on dose, urine flow rate, and individual variability in the extent of active secretion and possible tubular reabsorption.

There is a potential for accumulation of ultrafilterable platinum plasma concentrations whenever cisplatin is administered on a daily basis but not when dosed on an intermittent basis.

No significant relationships exist between the renal clearance of either free platinum or cisplatin and creatinine clearance.

Although small amounts of platinum are present in the bile and large intestine after administration of cisplatin, the fecal excretion of platinum appears to be insignificant.

Indications ⮝

Cisplatin Injection is indicated as therapy to be employed as follows:

Metastatic Testicular Tumors

In established combination therapy with other approved chemotherapeutic agents in patients with metastatic testicular tumors who have already received appropriate surgical and/or radiotherapeutic procedures.

Metastatic Ovarian Tumors

In established combination therapy with other approved chemotherapeutic agents in patients with metastatic ovarian tumors who have already received appropriate surgical and/or radiotherapeutic procedures. An established combination consists of Cisplatin Injection and cyclophosphamide. Cisplatin Injection, as a single agent, is indicated as secondary therapy in patients with metastatic ovarian tumors refractory to standard chemotherapy who have not previously received Cisplatin Injection therapy.

Advanced Bladder Cancer

Cisplatin Injection is indicated as a single agent for patients with transitional cell bladder cancer which is no longer amenable to local treatments, such as surgery and/or radiotherapy.

Warnings ⮝

Cisplatin produces cumulative nephrotoxicity which is potentiated by aminoglycoside antibiotics. The serum creatinine, blood urea nitrogen (BUN), creatinine clearance, and magnesium, sodium, potassium, and calcium levels should be measured prior to initiating therapy, and prior to each subsequent course. At the recommended dosage, cisplatin should not be given more frequently than once every 3 to 4 weeks (see ADVERSE REACTIONS).

Elderly patients may be more susceptible to nephrotoxicity (see PRECAUTIONS, Geriatric Use).

There are reports of severe neuropathies in patients in whom regimens are employed using higher doses of cisplatin or greater dose frequencies than those recommended. These neuropathies may be irreversible and are seen as paresthesias in a stocking-glove distribution, areflexia, and loss of proprioception and vibratory sensation. Elderly patients may be more susceptible to peripheral neuropathy (see PRECAUTIONS, Geriatric Use).

Loss of motor function has also been reported.

Anaphylactic-like reactions to cisplatin have been reported. These reactions have occurred within minutes of administration to patients with prior exposure to cisplatin, and have been alleviated by administration of epinephrine, corticosteroids, and antihistamines.

Cisplatin can commonly cause ototoxicity which is cumulative and may be severe. Audiometric testing should be performed prior to initiating therapy and prior to each subsequent dose of drug (see ADVERSE REACTIONS).

All pediatric patients receiving cisplatin should have audiometric testing at baseline, prior to each subsequent dose of drug and for several years post therapy.

Cisplatin can cause fetal harm when administered to a pregnant woman. Cisplatin is mutagenic in bacteria and produces chromosome aberrations in animal cells in tissue culture. In mice cisplatin is teratogenic and embryotoxic. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Patients should be advised to avoid becoming pregnant.

The carcinogenic effect of cisplatin was studied in BD IX rats. Cisplatin was administered intraperitoneally (i.p.) to 50 BD IX rats for 3 weeks, 3 x 1 mg/kg body weight per week. Four hundred and fifty-five days after the first application, 33 animals died, 13 of them related to malignancies: 12 leukemias and 1 renal fibrosarcoma.

The development of acute leukemia coincident with the use of cisplatin has been reported. In these reports, cisplatin was generally given in combination with other leukemogenic agents.

Injection site reactions may occur during the administration of cisplatin (see ADVERSE REACTIONS). Given the possibility of extravasation, it is recommended to closely monitor the infusion site for possible infiltration during drug administration. A specific treatment for extravasation reactions is unknown at this time.

Precautions ⮝

Peripheral blood counts should be monitored weekly. Liver function should be monitored periodically. Neurologic examination should also be performed regularly (see ADVERSE REACTIONS).

Drug Interactions

Plasma levels of anticonvulsant agents may become subtherapeutic during cisplatin therapy.

In a randomized trial in advanced ovarian cancer, response duration was adversely affected when pyridoxine was used in combination with altretamine (hexamethylmelamine) and cisplatin.

Carcinogenesis, Mutagenesis, Impairment of Fertility

See WARNINGS.

Pregnancy

Pregnancy Category D

See WARNINGS.

Nursing Mothers

Cisplatin has been reported to be found in human milk; patients receiving cisplatin should not breastfeed.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

All children should have audiometric monitoring performed prior to initiation of therapy, prior to each subsequent dose, and for several years post therapy. Advanced testing methods may allow for earlier detection of hearing loss in an attempt to facilitate the rapid initiation of interventions that can limit the potential adverse impact of hearing impairment on a child s cognitive and social development.

Geriatric Use

Insufficient data are available from clinical trials of cisplatin in the treatment of metastatic testicular tumors or advanced bladder cancer to determine whether elderly patients respond differently than younger patients. In four clinical trials of combination chemotherapy for advanced ovarian carcinoma, 1484 patients received cisplatin either in combination with cyclophosphamide or paclitaxel. Of these, 426 (29%) were older than 65 years. In these trials, age was not found to be a prognostic factor for survival. However, in a later secondary analysis for one of these trials, elderly patients were found to have shorter survival compared with younger patients. In all four trials, elderly patients experienced more severe neutropenia than younger patients. Higher incidences of severe thrombocytopenia and leukopenia were also seen in elderly compared with younger patients, although not in all cisplatin-containing treatment arms. In the two trials where nonhematologic toxicity was evaluated according to age, elderly patients had a numerically higher incidence of peripheral neuropathy than younger patients. Other reported clinical experience suggests that elderly patients may be more susceptible to myelosuppression, infectious complications, and nephrotoxicity than younger patients.

Cisplatin is known to be substantially excreted by the kidney and is contraindicated in patients with pre-existing renal impairment. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and renal function should be monitored.

Other Toxicities ⮝

Vascular toxicities coincident with the use of cisplatin in combination with other antineoplastic agents have been reported. The events are clinically heterogeneous and may include myocardial infarction, cerebrovascular accident, thrombotic microangiopathy (hemolytic-uremic syndrome [HUS]), or cerebral arteritis. Various mechanisms have been proposed for these vascular complications. There are also reports of Raynaud s phenomenon occurring in patients treated with the combination of bleomycin, vinblastine with or without cisplatin. It has been suggested that hypomagnesemia developing coincident with the use of cisplatin may be an added, although not essential, factor associated with this event. However, it is currently unknown if the cause of Raynaud s phenomenon in these cases is the disease, underlying vascular compromise, bleomycin, vinblastine, hypomagnesemia, or a combination of any of these factors.

Serum Electrolyte Disturbances

Hypomagnesemia, hypocalcemia, hyponatremia, hypokalemia, and hypophosphatemia have been reported to occur in patients treated with cisplatin and are probably related to renal tubular damage. Tetany has been reported in those patients with hypocalcemia and hypomagnesemia. Generally, normal serum electrolyte levels are restored by administering supplemental electrolytes and discontinuing cisplatin.

Inappropriate antidiuretic hormone syndrome has also been reported.

Hyperuricemia

Hyperuricemia has been reported to occur at approximately the same frequency as the increases in BUN and serum creatinine.

It is more pronounced after doses greater than 50 mg/m2, and peak levels of uric acid generally occur between 3 to 5 days after the dose. Allopurinol therapy for hyperuricemia effectively reduces uric acid levels.

Neurotoxicity

See WARNINGS.

Neurotoxicity, usually characterized by peripheral neuropathies, has been reported. The neuropathies usually occur after prolonged therapy (4 to 7 months); however, neurologic symptoms have been reported to occur after a single dose. Although symptoms and signs of cisplatin neuropathy usually develop during treatment, symptoms of neuropathy may begin 3 to 8 weeks after the last dose of cisplatin. Cisplatin therapy should be discontinued when the symptoms are first observed. The neuropathy, however, may progress further even after stopping treatment. Preliminary evidence suggests peripheral neuropathy may be irreversible in some patients. Elderly patients may be more susceptible to peripheral neuropathy (see PRECAUTIONS, Geriatric Use).

Lhermitte s sign, dorsal column myelopathy, and autonomic neuropathy have also been reported.

Loss of taste, seizures, leukoencephalopathy, and reversible posterior leukoencephalopathy syndrome (RPLS) have also been reported.

Muscle cramps, defined as localized, painful, involuntary skeletal muscle contractions of sudden onset and short duration, have been reported and were usually associated in patients receiving a relatively high cumulative dose of cisplatin and with a relatively advanced symptomatic stage of peripheral neuropathy.

Ocular Toxicity

Optic neuritis, papilledema, and cerebral blindness have been reported in patients receiving standard recommended doses of cisplatin. Improvement and/or total recovery usually occurs after discontinuing cisplatin. Steroids with or without mannitol have been used; however, efficacy has not been established.

Blurred vision and altered color perception have been reported after the use of regimens with higher doses of cisplatin or greater dose frequencies than recommended in the package insert. The altered color perception manifests as a loss of color discrimination, particularly in the blue-yellow axis. The only finding on funduscopic exam is irregular retinal pigmentation of the macular area.

Anaphylactic-Like Reactions

Anaphylactic-like reactions have been reported in patients previously exposed to cisplatin. The reactions consist of facial edema, wheezing, tachycardia, and hypotension within a few minutes of drug administration. Reactions may be controlled by intravenous epinephrine with corticosteroids and/or antihistamines as indicated. Patients receiving cisplatin should be observed carefully for possible anaphylactic-like reactions and supportive equipment and medication should be available to treat such a complication.

Hepatotoxicity

Transient elevations of liver enzymes, especially SGOT, as well as bilirubin, have been reported to be associated with cisplatin administration at the recommended doses.

Other Events

Cardiac abnormalities, hiccups, elevated serum amylase, rash, alopecia, malaise, asthenia, and dehydration have been reported.

Local soft tissue toxicity has been reported following extravasation of cisplatin. Severity of the local tissue toxicity appears to be related to the concentration of the cisplatin solution. Infusion of solutions with a cisplatin concentration greater than 0.5 mg/mL may result in tissue cellulitis, fibrosis, necrosis, pain, edema, and erythema.

Overdosage ⮝

Caution should be exercised to prevent inadvertent overdosage with cisplatin. Acute overdosage with this drug may result in kidney failure, liver failure, deafness, ocular toxicity (including detachment of the retina), significant myelosuppression, intractable nausea and vomiting and/or neuritis. In addition, death can occur following overdosage.

No proven antidotes have been established for cisplatin overdosage. Hemodialysis, even when initiated four hours after the overdosage, appears to have little effect on removing platinum from the body because of cisplatin s rapid and high degree of protein binding. Management of overdosage should include general supportive measures to sustain the patient through any period of toxicity that may occur.

Preparation Of Intravenous Solutions ⮝

Preparation Precautions

Caution should be exercised in handling the aqueous solution. Procedures for proper handling and disposal of anticancer drugs should be utilized. Several guidelines on this subject have been published.1-4 To minimize the risk of dermal exposure, always wear impervious gloves when handling vials and IV sets containing cisplatin.

Skin reactions associated with accidental exposure to cisplatin may occur. The use of gloves is recommended. If cisplatin contacts the skin or mucosa, immediately and thoroughly wash the skin with soap and water and flush the mucosa with water. More information is available in the references listed below.

Instructions for Preparation

The aqueous solution should be used intravenously only and should be administered by IV infusion over a 6- to 8-hour period (see DOSAGE AND ADMINISTRATION).

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

NOTE TO PHARMACIST: Exercise caution to prevent inadvertent cisplatin overdosage. Please call prescriber if dose is greater than 100 mg/m2 per cycle. Aluminum and flip-off seal of vial have been imprinted with the following statement: CALL DR. IF DOSE > 100 MG/M2/CYCLE.

Stability ⮝

Cisplatin Injection is a sterile, multiple dose vial without preservatives.

Store at 20 to 25 C (68 to 77 F) [See USP Controlled Room Temperature]. Do not refrigerate. Protect unopened container from light.

The cisplatin remaining in the amber vial following initial entry is stable for 28 days protected from light or for 7 days under fluorescent room light.

How Supplied ⮝

Cisplatin Injection (1 mg/mL) is supplied as follows:

NDC 0143-9504-01 Each multiple dose vial contains 50 mg of cisplatin

NDC 0143-9505-01 Each multiple dose vial contains 100 mg of cisplatin

The above products are multiple dose vials packaged individually.

Store at 20 to 25 C (68 to 77 F) [See USP Controlled Room Temperature]. Do not refrigerate. Protect from light.

This container closure is not made with natural rubber latex.

To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp. at 1-877-845-0689, or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

For Product Inquiry call 1-877-845-0689

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
THYMOORGAN PHARMAZIE GmbH
Schiffgraben 23, 38690 Goslar, Germany

Distributed by
WEST-WARD
A Hikma Company
Eatontown, NJ 07724 USA

September 2017

127.207.007/01

Principal Display Panel ⮝

NDC 0143-9505-01 Rx only
CISplatin
INJECTION
100 mg/100 mL
(1 mg/mL)
CISplatin doses greater than 100 mg/m2
once every 3 to 4 weeks are rarely used.
See Package Insert.
FOR INTRAVENOUS USE
100 mL Multiple Dose Vial

NDC 0143-9505-01 Rx only
STOP!
VERIFY
DRUG NAME
& DOSE!
CISplatin
INJECTION
100 mg/100 mL
(1 mg/mL)
CISplatin doses greater than 100 mg/m2
once every 3 to 4 weeks are rarely used.
See Package Insert.
FOR INTRAVENOUS USE
1 x 100 mL Multiple Dose Vial

Serialization Image ⮝

CISPLATIN cisplatin injection

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0143-9504 Route of Administration INTRAVENOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CISPLATIN (UNII: Q20Q21Q62J) (CISPLATIN - UNII:Q20Q21Q62J) CISPLATIN 1 mg in 1 mL

Inactive Ingredients Ingredient Name Strength SODIUM CHLORIDE (UNII: 451W47IQ8X) 9 mg in 1 mL HYDROCHLORIC ACID (UNII: QTT17582CB) SODIUM HYDROXIDE (UNII: 55X04QC32I) WATER (UNII: 059QF0KO0R)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0143-9504-01 1 in 1 CARTON 11/07/2000 1 50 mL in 1 VIAL, MULTI-DOSE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA075036 11/07/2000

CISPLATIN cisplatin injection

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0143-9505 Route of Administration INTRAVENOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CISPLATIN (UNII: Q20Q21Q62J) (CISPLATIN - UNII:Q20Q21Q62J) CISPLATIN 1 mg in 1 mL

Inactive Ingredients Ingredient Name Strength SODIUM CHLORIDE (UNII: 451W47IQ8X) 9 mg in 1 mL HYDROCHLORIC ACID (UNII: QTT17582CB) SODIUM HYDROXIDE (UNII: 55X04QC32I) WATER (UNII: 059QF0KO0R)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0143-9505-01 1 in 1 CARTON 11/07/2000 1 100 mL in 1 VIAL, MULTI-DOSE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA075036 11/07/2000

Labeler - West-Ward Pharmaceuticals Corp (001230762)

Establishment
Name	Address	ID/FEI	Business Operations
THYMOORGAN GMBH PHARMAZIE		319029989	ANALYSIS(0143-9505, 0143-9504) , LABEL(0143-9505, 0143-9504) , MANUFACTURE(0143-9505, 0143-9504) , PACK(0143-9505, 0143-9504)

Revised: 11/2018 Document Id: 2c569ef0-588f-4828-8b2d-03a2120c9b4c 34391-3 Set id: 76aea034-6d58-4390-a164-36aa09c1f101 Version: 2 Effective Time: 20181102 West-Ward Pharmaceuticals Corp