Displanor (Concentrate) Instructions for Use

Marketing Authorization Holder

Actavis Group hf. (Iceland)

Manufactured By

S.C. Sindan-Pharma S.R.L. (Romania)

ATC Code

L01XA01 (Cisplatin)

Active Substance

Cisplatin (Rec.INN registered by WHO)

Dosage Forms

	Displanor	Concentrate for solution for infusion and intraperitoneal administration 10 mg/10 ml: vial 1 pc.
		Concentrate for solution for infusion and intraperitoneal administration 50 mg/50 ml: vial 1 pc.

Dosage Form, Packaging, and Composition

Concentrate for solution for infusion and intraperitoneal administration light yellow with a greenish tint, transparent.

Excipients : sodium chloride – 9 mg, hydrochloric acid (0.1 mol/l) – to pH4, water for injections – to 1 ml.

10 ml – glass bottles (1) – cardboard packs.

Concentrate for solution for infusion and intraperitoneal administration light yellow with a greenish tint, transparent.

Excipients : sodium chloride – 9 mg, hydrochloric acid (0.1 mol/l) – to pH4, water for injections – to 1 ml.

50 ml – glass bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agent, alkylating compound

Pharmacological Action

Displanor (Cisplatin) is an antineoplastic drug containing the heavy metal platinum.

Cisplatin has properties similar to those of bifunctional alkylating agents, forming interstrand and intrastrand cross-links in DNA, thereby disrupting its functions and inhibiting synthesis, which leads to cell death; the drug does not have cyclic or phase specificity. It suppresses protein and RNA synthesis to a lesser extent. It has immunosuppressive and radiosensitizing properties.

Platinum complexes with cis-arranged halogen atoms can form stable chelate complexes with purine and pyrimidine components of the nucleic acid molecule, thus forming bonds within one strand or parallel strands of the DNA double helix. The antineoplastic effect is partly facilitated by the immunosuppressive influence. The therapeutic effect persists for several days after administration.

Pharmacokinetics

After rapid intravenous infusion administration (15 min – 1 h), the maximum concentration of cisplatin is reached immediately. With intravenous infusion over 6-24 hours, the plasma concentration of the drug increases gradually during the infusion, reaching a maximum by the end of administration.

Cisplatin is characterized by extensive distribution in biological fluids of the body and in tissues; the highest concentrations are achieved in the kidneys, liver, and prostate. Cisplatin penetrates into breast milk. Cisplatin poorly penetrates into the cerebrospinal fluid.

Platinum released from cisplatin is rapidly bound to tissue and plasma proteins. Two hours after the end of a three-hour infusion, 90% of the platinum in the plasma is in a protein-bound state. Cisplatin has the ability to accumulate in the body and is detected in some tissues for up to six months after the last dose of the drug.

The biotransformation of cisplatin occurs through rapid non-enzymatic conversion to form inactive metabolites. Only protein-unbound Cisplatin, or its platinum-containing metabolites, have a cytotoxic effect.

After intravenous infusion, the half-life of cisplatin is about 30 minutes.

Cisplatin is excreted primarily by the kidneys. Cisplatin can be removed from the systemic circulation by dialysis, but only during the first 3 hours after drug administration.

Indications

Displanor, usually as part of combination chemotherapy regimens, is widely used in the treatment of the following solid tumors

• Germ cell tumors in men and women;
• Ovarian and testicular cancer;
• Lung cancer;
• Head and neck tumors.

In addition, Displanor has antineoplastic activity against the following types of tumors

• Cervical cancer;
• Bladder cancer;
• Osteosarcoma;
• Melanoma;
• Neuroblastoma;
• Esophageal cancer.

ICD codes

Dosage Regimen

Displanor can be used both as monotherapy and in combination with other cytostatics in various doses depending on the therapy regimen. When individually selecting the dose, one should be guided by data from specialized literature.

Displanor is administered intravenously as an infusion or, when indicated (intraperitoneal tumors), into the abdominal cavity.

Displanor as monotherapy or in combination with other chemotherapeutic drugs is usually administered at a dose of 50-100 mg/m² as an intravenous infusion every 3-4 weeks or 15-20 mg/m² intravenously by drip daily for 5 days every 3-4 weeks.

Hydration is performed to stimulate diuresis (up to 100 ml/h) and to maximally reduce the nephrotoxic effect of the drug. Before administration of Displanor, up to 2 liters of fluid (0.9% sodium chloride solution or 5% dextrose solution) are administered intravenously by drip. After the end of the drug infusion, an additional 400 ml of 0.9% sodium chloride solution or 5% dextrose solution is administered. Ample fluid intake and maintenance of diuresis must be observed for 24 hours. If intensive hydration to maintain adequate diuresis is insufficient, an osmotic diuretic (e.g., mannitol) can be administered.

Displanor is administered intravenously by drip at a rate not exceeding 1 mg/min. Prolonged infusions are carried out over 6-8-24 hours, provided there is sufficient diuresis before and during drug administration.

Displanor is dissolved in 2 liters of 0.9% sodium chloride solution.

Note: Since aluminum reacts with cisplatin and inactivates it, and also causes precipitate formation, it is very important not to use needles and other equipment containing aluminum when preparing and administering Displanor.

Adverse Reactions

From the urinary system: nephrotoxicity (is cumulative and is the main toxic factor limiting the dose of Displanor). Kidney damage, accompanied by damage to the renal tubules, may be first detected in the second week after dose administration and manifested by an increase in the concentration of creatinine, urea, uric acid in the blood serum and/or a decrease in creatinine clearance. Renal failure is usually mild or moderate and is reversible at usual doses of Displanor.

From the digestive system: nausea and vomiting, which usually begin within the first hour of therapy and continue for 24 hours or more, occur in 65% of patients. These side effects are only partially relieved by standard antiemetic drugs. The severity of these symptoms can be reduced by dividing the total dose calculated for the therapy cycle into smaller doses administered once daily for five days.

Other frequently observed adverse events from the gastrointestinal tract include abdominal pain, diarrhea, and constipation. Slight and transient increases in AST and ALT concentrations in the blood serum may occasionally be noted.

From the hematopoietic system: often – myelosuppression (in most cases it is mild or moderate, and is reversible when using usual doses). The lowest leukocyte and platelet counts are typically detected around 2 weeks; their baseline value is restored in most patients within 4 weeks. Anemia may also be observed.

From the hearing and balance system: unilateral or bilateral tinnitus, with or without hearing loss, is noted in approximately 10% of patients, usually this side effect is reversible. Damage to the hearing organ has been found to be dose-dependent and cumulative, and this side effect is more frequently observed in very young or elderly patients. There are reports of toxic effects of the drug on the vestibular apparatus.

From the nervous system: peripheral neuropathies occur infrequently. They are usually sensory in nature (e.g., paresthesia of the upper and lower extremities), but motor impairments (decreased reflexes and weakness in the lower extremities) can also occur. Autonomic neuropathy, seizures, slurred speech, loss of taste, and memory loss may also be noted. The development of Lhermitte’s syndrome (myelopathy of the spinal column and autonomic nervous system neuropathy) has been reported in the literature. Treatment should be discontinued at the first appearance of these symptoms.

Allergic reactions: allergic and anaphylactoid reactions are sometimes noted, manifested as facial redness and swelling, bronchospasm, shortness of breath, tachycardia, decreased blood pressure, and anaphylactic shock. These reactions can occur within minutes of starting cisplatin administration. In rare cases, urticaria and maculopapular skin rash may be observed.

From the organ of vision: in rare cases, optic neuritis, optic disc edema, cortical blindness are noted. Changes in color perception, especially in the yellow-blue part of the spectrum, may also be observed. The only change in the fundus may be uneven pigmentation of the retina in the macular area. These side effects are usually reversible and disappear after drug withdrawal.

From electrolyte balance: hypomagnesemia, hypocalcemia, and hypokalemia. Hypomagnesemia and/or hypocalcemia may clinically manifest as increased muscle sensitivity or cramps, tremor, carpopedal spasm (cramps in the hands and feet), and/or tetany. Hyponatremia due to the syndrome of inappropriate antidiuretic hormone secretion is possible.

From the cardiovascular system: myocardial infarction, stroke, cerebral arteritis, arrhythmias, bradycardia, tachycardia, thrombotic microangiopathy, orthostatic hypotension.

Other: hyperuricemia, slight alopecia, myalgia, fever, and platinum gum line.

There are reports of Raynaud’s syndrome occurring during therapy with a combination of bleomycin and vinblastine with or without cisplatin.

If the drug gets under the skin, phlebitis, inflammation of the subcutaneous tissue, and skin necrosis may develop.

Cases of impaired spermatogenesis and azoospermia have been noted.

Contraindications

• Impaired renal function (serum creatinine concentration more than 115 µmol/l);
• Bone marrow suppression;
• Heart failure;
• Pregnancy and breastfeeding period;
• Generalized infections;
• Hearing loss;
• Hypersensitivity to cisplatin or other platinum-containing compounds, as well as to any component of the drug.

With caution acute infectious diseases of viral (chickenpox, including recently suffered or recent contact with a patient, herpes zoster), fungal or bacterial origin; hyperuricemia (including manifested by gout and/or urate nephrourolithiasis), nephrourolithiasis, polyneuritis.

Special Precautions

Administration of Displanor should be carried out under the supervision of a physician experienced in the use of antineoplastic drugs.

Men and women of childbearing potential during treatment with Displanor should use reliable methods of contraception.

Patients undergoing treatment with Displanor should be periodically examined by a neurologist. If obvious symptoms of toxic effects on the central nervous system appear, therapy with Displanor should be discontinued.

Audiometry should be performed before starting therapy, and in cases where symptoms of damage to the hearing organ appear or clinical hearing impairment is detected, repeat audiometry is indicated. For clinically significant hearing impairment, dose adjustment or discontinuation of therapy may be required.

During treatment with Displanor, it is necessary to periodically perform a complete blood count with determination of leukocyte, platelet, and hemoglobin content. Functional kidney and liver function, as well as serum electrolyte concentrations, should also be monitored.

All standard instructions adopted for the use of cytotoxic drugs must be observed when using Displanor.

In case of anaphylactic or anaphylactoid reactions, administration should be stopped immediately and appropriate therapy initiated. In some cases, cross-allergic reactions have been reported with the administration of platinum salts.

If the drug gets into the eyes, they should be immediately rinsed with plenty of water or 0.9% sodium chloride solution. If the drug gets on the skin, the area of contact with the drug should be immediately rinsed with plenty of water. If the drug is inhaled or enters the mouth, a doctor should be consulted immediately.

The prepared cisplatin solution should be protected from light and stored at a temperature of 15-25°C (59-77°F) for 24 hours. The solution should not be placed in the refrigerator, as cooling may lead to precipitate formation. Unused solution should be destroyed.

Effect on ability to drive vehicles and operate machinery.

Cisplatin does not have a direct effect on the ability to drive vehicles and operate machinery. However, side effects from the central nervous system and sensory organs may reduce the speed of psychomotor reactions, which may affect the ability to drive vehicles and operate machinery.

Overdose

The main expected complications of overdose are impaired kidney and liver function, visual impairment (including retinal detachment) and hearing (deafness), severe myelosuppression, intractable vomiting and/or severe neuritis. Overdose can be fatal.

There is no known antidote for cisplatin. Treatment is symptomatic. A partial effect may be achieved with hemodialysis performed within the first three hours after overdose.

Drug Interactions

Simultaneous or sequential use of cisplatin with aminoglycoside antibiotics (gentamicin, kanamycin, streptomycin) or with other potentially nephrotoxic (e.g., amphotericin B) and ototoxic drugs (e.g., “loop” diuretics such as furosemide, clopamide, ethacrynic acid) may potentiate its nephrotoxic and ototoxic effects.

Cisplatin is known to impair the renal excretion of bleomycin and methotrexate (possibly due to cisplatin-induced nephrotoxicity) and enhance the toxicity of these drugs.

In patients receiving Cisplatin and anticonvulsant drugs, the serum concentration of the latter may decrease to subtherapeutic levels. Cisplatin may cause an increase in blood uric acid concentration. Therefore, in patients who are simultaneously taking medications for gout, such as allopurinol, colchicine, probenecid, or sulfinpyrazone, it may be necessary to adjust the dose of these drugs to control hyperuricemia and gout attacks.

Storage Conditions

Store out of reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 18 months. Do not use after the expiration date printed on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.