Axycis Injection, Solution
FDA Label NDC 83831-158

• Nephrotoxicity: AXYCIS 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: AXYCIS 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: AXYCIS can cause severe nausea and vomiting. Administer pre-treatment and post-treatment antiemetics as clinically indicated [see Dosage and Administration (2.1) and Warnings and Precautions (5.3)].
• Myelosuppression: AXYCIS 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)].

AXYCIS is indicated for the treatment of advanced testicular cancer.

AXYCIS is indicated for the treatment of advanced ovarian cancer.

AXYCIS is indicated for the treatment of advanced bladder cancer.

Patients treated with AXYCIS must receive appropriate pre-treatment hydration. Maintain adequate hydration and urinary output for 24 hours after AXYCIS administration [see Warnings and Precautions (5.1)].

Administer pre-treatment and post-treatment antiemetics as appropriate [see Warnings and Precautions (5.3)].

To prevent inadvertent cisplatin overdosage, contact prescriber if dose ordered is greater than 100 mg/m² per cycle.

AXYCIS has been administered at 20 mg/m² intravenously daily for 5 days per cycle. Other doses and combination regimens have been used.

AXYCIS has been administered at 75 mg/m² to 100 mg/m² intravenously per cycle once every 3 to 4 weeks. Other doses and combination regimens have been used.

AXYCIS has been administered at 50 mg/m² to 70 mg/m² intravenously per cycle once every 3 to 4 weeks. For heavily pretreated patients, an initial dose of 50 mg/m² per cycle repeated every 4 weeks is recommended. Other doses and combination regimens have been used.

Preparation

AXYCIS is a hazardous drug. Follow applicable special handling and disposal procedures.¹

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

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard if the solution is discolored or contains particulate matter.

AXYCIS is supplied as a multiple-dose vial. After first use, store the partially used vial in the original carton at 20°C to 25°C (68°F to 77°F) to protect from light. Discard after 28 days. Do not refrigerate.

• Select the appropriate number of vial(s) based on the prescribed dose.
• Withdraw the calculated volume of AXYCIS from the vial.
• Dilute the calculated volume of AXYCIS in an infusion bag with one of the following diluents:

○     2 liters of 5% Dextrose in 0.45 % Sodium Chloride Injection, containing 37.5 g of mannitol.

○     2 liters of 5% Dextrose in 0.33% Sodium Chloride Injection, containing 37.5 g of mannitol.

• DO NOT dilute AXYCIS in solutions containing only 5% Dextrose Injection.
• After preparation, store the diluted solution:

○    at room temperature of 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature] for no more than 12 hours under fluorescent light, or

○    at room temperature of 20°C to 25°C (68°F to 77°F) for no more than 24 hours when protected from light.

• If not used immediately, discard diluted AXYCIS after 12 hours when stored under fluorescent light, and after 24 hours when protected from light.

Administration

Administer AXYCIS by slow intravenous infusion over a 6- to 8-hour period. AXYCIS SHOULD NOT BE GIVEN BY RAPID INTRAVENOUS INJECTION.

Injection: 50 mg/50 mL (1 mg/mL) available as colorless to yellowish clear liquid in multiple-dose amber glass vials.

AXYCIS is contraindicated in patients with severe hypersensitivity to cisplatin [see Warnings and Precautions (5.5)].

AXYCIS 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 AXYCIS. Patients with 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)].

Ensure adequate hydration before, during, and after AXYCIS 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 AXYCIS for patients with renal impairment or who develop significant reductions in creatinine clearance during treatment with AXYCIS according to clinical treatment guidelines.

AXYCIS can cause dose-related peripheral neuropathy that becomes more severe with repeated courses of the drug. Neurologic symptoms can occur after a single dose. Neuropathy can also have a delayed onset from 3 to 8 weeks after the last dose of AXYCIS. 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.

Prolonged treatment, treatment with other platinum-containing therapies, or use in combination with other drugs that cause peripheral neuropathy may increase the incidence or severity of peripheral neuropathy. Geriatric patients may be more susceptible to peripheral neuropathy [see Use in Specific Populations (8.5)].

Monitor for signs and symptoms of peripheral neuropathy. Withhold, reduce, or discontinue AXYCIS depending on the severity and persistence of peripheral neuropathy as clinically indicated.

AXYCIS is a highly emetogenic antineoplastic agent. Administer pre-treatment and post-treatment antiemetics as clinically indicated [see Dosage and Administration (2.1)]. Without antiemetic therapy, marked nausea and vomiting occur in almost all patients treated with cisplatin 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 therapy. Consider the use of additional antiemetics following infusion.

Monitor and manage patients with antiemetics or fluid replacement, as clinically indicated. Consider withholding or delaying AXYCIS if nausea or vomiting is severe or intolerable and is not responsive to antiemetics.

AXYCIS can cause myelosuppression. Myelosuppression occurs in 25% to 30% of patients treated with cisplatin, including febrile neutropenia and infection, and can be fatal. 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)].

Patients with impaired kidney function are at increased risk of severe myelosuppression and may require dosage modifications.

Monitor complete blood counts prior to each cycle and as clinically indicated. If myelosuppression occurs, modify AXYCIS dosage when required.

AXYCIS can cause severe hypersensitivity reactions, including anaphylaxis and death. Hypersensitivity reactions included facial edema, wheezing, tachycardia, and hypotension. These adverse reactions may occur within minutes of administration and during any cycle.

Monitor patients receiving AXYCIS for hypersensitivity reactions. Ensure supportive equipment and medications are available to treat severe hypersensitivity reactions. Severe hypersensitivity reactions require immediate discontinuation of AXYCIS and aggressive therapy. Do not rechallenge patients with a history of severe hypersensitivity reactions with AXYCIS [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.

AXYCIS can cause ototoxicity, which is cumulative and may be severe. Monitor for signs and symptoms of ototoxicity and 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, and vestibular toxicity. Ototoxicity can occur during or after treatment and can be unilateral or bilateral. Deafness after the initial dose of cisplatin has 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; this association has not been consistent across populations and study designs.

Consider permanent discontinuation of AXYCIS for patients who develop ototoxicity.

AXYCIS can cause ocular toxicity including optic neuritis, papilledema, and cortical blindness. Blurred vision and altered color perception have been reported after the use of regimens with higher doses and dose frequencies of cisplatin. 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 AXYCIS but can be delayed.

Monitor for signs and symptoms of ocular toxicity. Promptly refer patients to an eye care provider for any new or worsening ocular signs and symptoms. Interrupt, reduce the dose, or permanently discontinue AXYCIS based on severity.

Secondary acute leukemia has occurred with use of cisplatin.

Based on human data, AXYCIS 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 AXYCIS. Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 11 months after the last dose of AXYCIS [see Use in Specific Populations (8.1, 8.3)].

Injection site reactions can occur during the administration of AXYCIS. Local soft tissue toxicity has been reported following extravasation of AXYCIS. Severity of the local tissue toxicity appears to be related to the concentration of the AXYCIS 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.

Monitor patients for extravasation and advise patients to seek medical care for progression of symptoms.

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: Coombs-positive hemolytic anemia, hemolytic uremic syndrome, thrombotic thrombocytopenic purpura

Cardiac: Myocardial infarction, pericardial effusion, cardiac failure, ventricular dysfunction

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

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

General: Asthenia, malaise

Hepatobiliary: 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: Hypomagnesemia, hyperuricemia, hypocalcemia, hyponatremia, hypokalemia, and hypophosphatemia, Syndrome of Inappropriate Antidiuretic Hormone Excretion (SIADH), dehydration, tumor lysis syndrome, increased serum amylase

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

Nervous System: 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, involuntary skeletal muscle contractions, tetany (with hypocalcemia and hypomagnesemia)

Ototoxicity: Tinnitus, hearing loss, deafness, vestibular toxicity

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

Respiratory: Pneumonitis/interstitial lung disease, pulmonary embolism

Skin and Subcutaneous Tissue: Alopecia, rash

Vascular: Venous thromboembolism, arterial thromboembolism, cerebrovascular accident, thrombotic microangiopathy, cerebral arteritis, Raynaud's phenomenon

Avoid concomitant use with other products known to cause nephrotoxicity. 

Cisplatin can cause nephrotoxicity. Concomitant use of AXYCIS with other products that cause nephrotoxicity may result in a greater risk of nephrotoxicity [see Warnings and Precautions (5.1)].        

Risk Summary

Based on human data from published literature, AXYCIS can cause fetal harm when administered to pregnant women. 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 administration to animals during and after organogenesis resulted in teratogenicity. A published study in mice showed placental transfer of cisplatin increased with placenta maturation.

Advise pregnant women and females of reproductive potential of the potential risk to a fetus.

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.

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 in a breastfed child and because of the potential for tumorigenicity shown for cisplatin, advise lactating women not to breastfeed during treatment with AXYCIS.

AXYCIS can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy Testing

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

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment and for 14 months following the last dose of AXYCIS.

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 AXYCIS.

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.

The safety and effectiveness of AXYCIS in pediatric patients have not been established.

Ototoxic effects may be more severe and detrimental in pediatric patients receiving cisplatin, particularly in patients less than 5 years of age. Consider audiometric and vestibular function monitoring in all patients receiving AXYCIS. 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)].

For the treatment of metastatic testicular tumors or advanced bladder cancer, clinical studies of cisplatin 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)].

The signs and symptoms of overdose are similar to known adverse reactions of cisplatin but may be more severe. Acute overdosage with AXYCIS may result in renal failure, hepatic failure, hearing loss, ocular toxicity, myelosuppression, nausea and vomiting, and neuritis. In addition, death can occur following overdosage.

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. Plasmapheresis has been used to treat cases of cisplatin overdosage, but the optimal treatment regimen has not been established.

Closely monitor patients suspected of receiving an overdose, including signs and symptoms of the adverse reactions [see Warnings and Precautions (5)] and administer appropriate supportive treatment.

Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.

AXYCIS (cisplatin) injection is a platinum-based drug for intravenous use.  

Cisplatin is a yellow powder, or yellow or orange-yellow crystals with the molecular formula Cl₂H₆N₂Pt and a molecular weight of 300.05. Cisplatin, USP 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 slightly soluble in water, sparingly soluble in dimethylformamide and practically insoluble in ethanol (96 percent). It has a melting point of 270°C.

The structural formula is:

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AXYCIS is supplied as a sterile, colorless to yellowish clear liquid. Each mL of AXYCIS contains 1 mg Cisplatin, USP and 9 mg sodium chloride in water for injection. AXYCIS may contain hydrochloric acid for pH adjustment. The pH range of AXYCIS is 3.2 to 6.0.

Cisplatin is a platinum-based drug that binds to DNA and forms DNA cross-links. These crosslinks inhibit DNA replication and transcription and trigger cytotoxic processes that lead to cell death.

Cisplatin exposure-response relationships and the time course of pharmacodynamic response are unknown.

Distribution

Cisplatin steady-state apparent volume of distribution is 11 to 12 L/m².

Platinum plasma protein binding is about 90%. Platinum binds to several plasma proteins, including albumin, transferrin, and gamma globulin.

Platinum is present in tissues for as long as 180 days after the last administration.

Elimination

Cisplatin estimated elimination half-life is about 20 to 30 minutes. Platinum terminal half-life in red blood cells is 36 to 47 days.

Cisplatin mean apparent clearance is 15 to 16 L/hr/m² and its mean renal clearance is 50 to 62 mL/min/m².

Metabolism

The ratios of cisplatin to plasma ultrafiltrate range from 0.5 to 1.1 after a dose of 100 mg/m².

Excretion

After a single dose of 40 to 140 mg/m², about 10% to 40% of the administered platinum is excreted in the urine in 24 hours and about 35% to 51% is excreted within 5 days.

Cisplatin accounts for 13% to 17% of the dose excreted within 1 hour after administration of 50 mg/m².

The carcinogenic effect of cisplatin was studied in BDIX rats. Cisplatin 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.

• "OSHA Hazardous Drugs." OSHA. https://www.osha.gov/hazardous-drugs

How Supplied

AXYCIS™ (cisplatin) Injection is a colorless to yellowish clear liquid without preservatives, available in multiple-dose amber glass vials. Each vial contains 50 mg of Cisplatin, USP, and is individually packaged in a carton as follows:

Storage

Store in original carton at 20°C to 25°C (68°F to 77°F); excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Do not refrigerate. Retain in original carton to protect from light.

Handling and Disposal

AXYCIS is a hazardous drug. Follow applicable special handling and disposal procedures.¹

Nephrotoxicity

Inform patients that AXYCIS 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 numbness and tingling of the hands or feet or muscle weakness to their healthcare provider [see Warnings and Precautions (5.2)].

Nausea and Vomiting

Inform patients that they may experience nausea and vomiting, which may be severe. Advise on the use of antiemetics and to contact their healthcare provider for persistent or severe symptoms [see Warnings and Precautions (5.3)].

Myelosuppression

Inform patients that AXYCIS can cause myelosuppression. Advise patients to contact their healthcare provider for signs and symptoms of fever, infection, or bleeding [see Warnings and Precautions (5.4)].

Hypersensitivity Reactions

Instruct patients to report immediately if they experience any signs or symptoms of a hypersensitivity reaction during or following an infusion of AXYCIS [see Warnings and Precautions (5.5)].

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)].

Ocular Toxicity

Inform patients that AXYCIS can cause ocular toxicity. Instruct patients to immediately contact their healthcare provider for new or worsening ocular symptoms [see Warnings and Precautions (5.7)].

Secondary Malignancies

Inform patients that AXYCIS can increase the risk of secondary malignancies [see Warnings and Precautions (5.8)].

Embryo-Fetal Toxicity

• Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.9) and Use in Specific Populations (8.1))].
• Advise females of reproductive potential to use effective contraception during treatment with AXYCIS and for 14 months following the last dose [see Use in Specific Populations (8.3)].
• Advise male patients with female partners of reproductive potential to use effective contraception during treatment with AXYCIS and for 11 months following the last dose [see Use in Specific Populations (8.3)].

Lactation

Advise females not to breastfeed during treatment with AXYCIS [see Use in Specific Populations (8.2)].

Infertility

Advise males and females of reproductive potential that treatment with AXYCIS may impair fertility [see Use in Specific Populations (8.3)].

Injection Site Reactions

Inform patients of injection site reactions. Instruct patients to report immediately if they experience any signs or symptoms of extravasation [see Warnings and Precautions (5.10)].

Alopecia

Inform patients that AXYCIS can cause alopecia.

Manufactured for:

Avyxa Pharma, LLC

New Jersey 07054, USA

Made in China



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