Cisplatin-mili

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CISPLATIN - MILI (CISPLATIN - MILI)

Composition:

Active substance: cisplatin;
1 ml of solution contains 0.5 mg of cisplatin;

Excipients: sodium chloride, water for injections.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: clear, colorless solution.

Pharmacotherapeutic group. Antineoplastic agents. Platinum compounds. Anticancer agent. ATC code L01X A01.

Pharmacological properties.

Pharmacodynamics.

Cisplatin (cis-diamminedichloroplatinum-II) is an inorganic compound containing the heavy metal platinum. Cisplatin binds to all DNA bases, particularly the N-7 atoms of guanine and adenine, and inhibits DNA synthesis by forming intra- and inter-strand cross-links (cross-links) within DNA strands. Protein and RNA synthesis are also suppressed, although to a lesser extent.

Although the antitumor effect of cisplatin is primarily associated with inhibition of DNA synthesis, other mechanisms of its antineoplastic action exist. In particular, cisplatin enhances tumor immunogenicity. The oncolytic effect of cisplatin is comparable to that of alkylating agents. Cisplatin also possesses immunosuppressive and antibacterial properties and increases sensitivity to radiation.

The action of cisplatin on cells is independent of the cell cycle phase.

Pharmacokinetics. After intravenous administration at doses of 20–120 mg/m² of body surface area, cisplatin rapidly distributes into all tissues. The highest concentrations of platinum are observed in the liver, prostate gland, and kidneys; somewhat lower levels are found in the urinary bladder, muscles, testes, pancreas, and spleen; and the lowest concentrations occur in the intestine, adrenal glands, heart, lungs, brain, including the cerebellum. Within 2 hours after administration, over 90% of the total cisplatin in blood plasma is protein-bound. This binding is likely irreversible. Protein-bound cisplatin lacks antitumor activity. The pharmacokinetics of cisplatin are nonlinear. Without enzymatic involvement, it is transformed into one or more metabolites. After bolus intravenous administration at doses of 50–100 mg/m² of body surface area, the elimination of cisplatin from plasma follows a biphasic pattern. The half-life during the first phase (distribution phase) ranges from 10 to 60 minutes, while during the second (terminal) phase, it lasts 2–5 days. The plasma half-life of cisplatin is prolonged in patients with impaired renal function. It may also theoretically be prolonged in patients with ascites due to extensive protein binding of cisplatin.

Due to significant binding of platinum to blood proteins, prolonged or incomplete elimination of cisplatin from the body is observed. Within 84–120 hours, 27–45% of the administered dose is excreted in urine. With prolonged infusions, the amount of cisplatin excreted in urine is higher. Fecal excretion is minimal, and only small amounts of platinum are detected in the gallbladder and large intestine.

Clinical Characteristics.

Indications.

• Advanced or metastatic testicular cancer;
• advanced or metastatic ovarian cancer;
• advanced or metastatic bladder cancer;
• advanced or metastatic squamous cell carcinoma of the head and neck;
• advanced or metastatic non-small cell lung cancer;
• advanced or metastatic small cell lung cancer;
• treatment of cervical tumors in combination with radiotherapy.

Cisplatin may be used either as monotherapy or in combination therapy.

The drug is indicated for the treatment of adults and children.

Contraindications.

• Hypersensitivity to cisplatin or to other platinum-containing agents or to any component of the drug in the patient's history.
• Impaired renal function (creatinine clearance < 60 mL/min).
• Dehydration (to prevent the development of severe renal dysfunction, pre- and post-hydration is required).
• Bone marrow suppression.
• Hearing impairment.
• Neuropathy caused by cisplatin therapy.
• Pregnancy and breastfeeding period.
• Concomitant use with yellow fever vaccine and prophylactic phenytoin therapy.

Special safety precautions.

As with handling any other cytotoxic agents, safety procedures must be followed when working with cisplatin: protective clothing (disposable gloves, masks, goggles, gowns, caps) must be worn; work should be performed under a fume hood whenever possible.

Contact of cisplatin solutions with skin and/or mucous membranes must be avoided. If contact occurs, the affected area should be washed thoroughly with large amounts of water and cream applied if irritation develops (skin reactions may occur in some individuals sensitive to platinum).

Pregnant healthcare workers should not handle cisplatin.

Unused solutions, instruments, and materials used during manipulation with cisplatin must be disposed of according to established procedures.

Dosing (dose calculation) of cisplatin should be performed with particular care.

Interaction with other medicinal products and other forms of interaction.

Myelosuppressive effects of cisplatin may be enhanced when used concomitantly with other agents that suppress bone marrow function or with radiotherapy.

Nephrotoxic effects of cisplatin may be enhanced when used concomitantly with antihypertensive agents containing furosemide, hydralazine, diazoxide, or propranolol.

Dosages of allopurinol, colchicine, probenecid, or sulfinpyrazone may need to be adjusted when used concomitantly, as cisplatin causes an increase in serum uric acid concentration.

Except for patients receiving cisplatin at doses exceeding 60 mg/m² body surface area and whose urine output does not exceed 1000 mL in 24 hours, forced diuresis using tubular diuretics should not be performed in patients, as this may lead to renal damage and increased ototoxicity.

Symptoms of cisplatin ototoxicity (e.g., dizziness, tinnitus) may be masked by concomitant use of thiamine preparations, buclizine, cyclizine, loxapine, meclizine, phenothiazines, thioxanthenes, or trimethobenzamides.

Nephrotoxic agents (e.g., cephalosporins, aminoglycosides) and ototoxic drugs (e.g., aminoglycosides) potentiate the toxic effects of cisplatin on the respective organs. Drugs primarily excreted via the kidneys (e.g., bleomycin and methotrexate) should be administered cautiously during or after cisplatin therapy, as cisplatin may reduce renal elimination.

When used in combination with cisplatin, increased protein excretion and enhanced nephrotoxicity have been observed. Ifosfamide also potentiates the ototoxic effects of cisplatin, although ifosfamide itself is not ototoxic.

It has been noted that the response to cisplatin therapy in patients with progressive ovarian cancer is worse when pyridoxine and hexamethylmelamine are used concomitantly.

It has been established that when paclitaxel is administered after cisplatin, its clearance may decrease by 33%, thereby potentially increasing neurotoxicity.

In several cases, combined therapy with cisplatin, bleomycin, and etoposide has been associated with decreased serum lithium concentration. Therefore, lithium levels should be monitored during treatment.

In patients with metastatic or advanced tumors, docetaxel in combination with cisplatin has caused more severe neurotoxic effects (dose-dependent and sensory) than either agent used as monotherapy at similar doses.

When cisplatin and cyclosporine are used concomitantly, excessive immunosuppression with risk of lymphoproliferative disorders should be considered.

Cisplatin may reduce phenytoin absorption, thereby reducing the efficacy of antiepileptic therapy.

Chelating agents, particularly penicillamine, may reduce the effectiveness of cisplatin treatment.

Live vaccines should not be administered during and for three months after completion of cisplatin therapy. Administration of the yellow fever vaccine is strictly contraindicated due to the risk of developing fatal systemic disease. Because of the risk of systemic illness, inactivated vaccines are recommended.

When oral anticoagulants are used concomitantly, regular monitoring of the international normalized ratio (INR) is recommended.

In patients receiving cisplatin and anticonvulsant drugs concomitantly, serum concentrations of the latter may decrease to subtherapeutic levels.

Special precautions for use.

Cisplatin reacts with aluminium, forming a black precipitate of platinum. Therefore, the use of aluminium-containing instruments (e.g., intravenous infusion sets, needles, catheters, syringes) should be avoided. For further details, see section "Incompatibilities".

Cisplatin therapy must be administered under the supervision of a qualified oncologist.

Cisplatin is characterized by cumulative ototoxic, nephrotoxic, and neurotoxic effects. Its toxicity may be enhanced when used concomitantly with other agents that exert toxic effects on these organs and systems.

Nephrotoxicity.

Cisplatin causes severe cumulative nephrotoxic effects. Cumulative and dose-dependent renal failure is the main dose-limiting toxicity of cisplatin. The most common manifestation is a decline in glomerular filtration rate, reflected by elevated serum creatinine levels and reduced effective renal plasma flow. Hyperuricemia and hyperalbuminemia may contribute to the development of nephrotoxicity. Before administering the next dose, normalization of renal function must be confirmed. To reduce nephrotoxicity, adequate hydration of the patient is required before, during, and after intravenous administration of cisplatin. A diuresis of 100 mL/hour or higher minimizes the nephrotoxic effect of cisplatin. Adequate diuresis can be achieved by pre-hydration with 2 L of appropriate solution administered intravenously or by similar hydration after cisplatin administration (administration of 2500 mL/m² over 24 hours is recommended). If active hydration is insufficient to maintain adequate diuresis, osmotic diuretics (e.g., mannitol) may be used.

Neuropathy.

Severe neuropathy has been reported. These complications may be irreversible and may manifest as paresthesia, areflexia, loss of proprioceptive sensation, and vibration sense. Cases of motor function loss have also been reported. Neurological examinations of patients should be performed regularly.

Ototoxicity.

Symptoms of ototoxicity may include tinnitus and/or hearing loss in the high-frequency range (4000 to 8000 Hz). In some cases, hearing loss may occur within the normal hearing range (250–2000 Hz). Hearing loss may be unilateral or bilateral and occurs more frequently and severely with repeated administration of the drug; however, isolated cases of deafness have been reported after the first dose of cisplatin. Deafness and vestibular dysfunction, possibly accompanied by systemic vertigo, may also occur. Prior or concurrent irradiation of the head region increases the risk of ototoxic complications, possibly related to peak plasma concentrations of cisplatin. However, only in isolated cases do patients lose the ability to communicate normally after cisplatin treatment. Complications may be more severe in children. It is not established whether cisplatin-induced ototoxicity is reversible. Audiograms should be performed before initiating cisplatin therapy and before each subsequent treatment cycle.

Before, during, and after cisplatin therapy, the following should be monitored:

• Renal function;
• Liver function;
• Hematopoietic system function (erythrocyte, leukocyte, and platelet counts);
• Serum electrolyte levels (calcium, sodium, potassium, magnesium).

Tests should be repeated weekly throughout the entire cisplatin treatment period.

The next treatment cycle should not be initiated until the following key parameters have normalized (in adults):

• Serum creatinine: ≤ 130 µmol/L (1.5 mg/dL);
• Urea: < 25 mg/dL;
• Leukocyte count: > 4.0 × 10⁹/L;
• Platelet count: > 100 × 10⁹/L;
• Audiogram: results within normal limits.

Particular caution is required when treating patients with pre-existing non-cisplatin-induced peripheral neuropathy, as well as patients with acute bacterial and viral infections.

Reactions at the injection site.

Due to the risk of extravasation, careful monitoring for infiltration at the infusion site is recommended during drug administration.

In case of extravasation:

• Immediately discontinue cisplatin infusion;
• Without removing the needle, aspirate the extravasate from the tissues and irrigate them with 0.9% sodium chloride solution (especially if the infusion solution contains cisplatin at a concentration higher than recommended).

Nausea and vomiting.

Nausea, vomiting, and diarrhea (usually within 1–4 hours after cisplatin administration) are commonly observed. These symptoms typically resolve within 24 hours in most patients. Milder nausea and anorexia may persist for up to 7 days after drug administration. Prophylactic use of antiemetics may help prevent or reduce the intensity of nausea and vomiting. Fluid loss due to vomiting or diarrhea must be compensated.

Myelosuppression and blood disorders.

Cisplatin causes dose-dependent, predominantly reversible leukopenia, thrombocytopenia, and anemia. Myelosuppression is cumulative. Isolated cases of Coombs-positive hemolytic anemia (reversible after therapy discontinuation) have been reported. Hemolysis possibly caused by cisplatin has also been reported. Severe bone marrow suppression (including agranulocytosis and/or aplastic anemia) may occur after high-dose cisplatin administration. Approximately 14 days after cisplatin administration, leukocyte counts may significantly decrease (to 1.5 × 10⁹/L or lower). The lowest platelet counts are observed around day 21 (in some patients, counts may fall to 50 × 10⁹/L or lower). Parameters typically normalize by approximately day 39.

Electrolyte disturbances.

Due to cisplatin-induced renal damage, reabsorption of certain cations in renal tubules is reduced, leading to electrolyte imbalances (hypomagnesemia, hypocalcemia, hyponatremia, hypophosphatemia, hypokalemia). Electrolyte monitoring is essential.

Allergic reactions.

As with other platinum-containing drugs, hypersensitivity reactions (including anaphylactic reactions) may occur during infusion. In such cases, the infusion must be stopped immediately, and appropriate symptomatic treatment initiated (antihistamines, adrenaline, and/or glucocorticoids). Cross-reactions, sometimes fatal, have been reported with all platinum compounds.

Potential carcinogenicity.

Cisplatin is theoretically carcinogenic (based on its mechanism of action), although there is no practical evidence of this. In isolated cases, acute leukemia has been observed during cisplatin therapy, generally associated also with other leukemogenic agents.

Mutagenicity, teratogenicity, embryotoxicity.

Cisplatin is a bacterial mutagen and causes chromosomal aberrations in animal cell cultures. Cisplatin exerts teratogenic and embryotoxic effects in mice.

Infections.

Particular caution is required when treating patients with acute bacterial and viral infections.

Fertility.

Cisplatin may cause temporary or permanent infertility. Therefore, men who wish to father children in the future should consider sperm cryopreservation prior to therapy initiation.

Use during pregnancy or breastfeeding.

Pregnancy. There is insufficient information on the use of cisplatin in pregnant women. Cisplatin may have toxic effects on the fetus and, based on its pharmacological properties, may cause severe fetal defects. Animal studies have demonstrated reproductive toxicity and transplacental carcinogenicity. Therefore, cisplatin should not be used during pregnancy unless there are life-threatening indications.

Both men and women of reproductive age receiving cisplatin should use effective contraception to prevent pregnancy during and for at least 6 months after treatment. Patients wishing to have children after therapy completion should consult a genetics specialist beforehand.

Breastfeeding. Cisplatin has been detected in breast milk; therefore, breastfeeding is contraindicated during cisplatin therapy.

Ability to influence reaction speed when driving or operating machinery.

No studies on the effect on the ability to drive or operate machinery have been conducted. However, the adverse reaction profile (e.g., nephrotoxicity) may negatively affect the ability to drive or operate machinery. Patients experiencing such effects (e.g., somnolence or vomiting) should not drive or operate machinery.

Method of Administration and Dosage

Cisplatin-Mili, concentrate for infusion solution, must be diluted before use.

Preparation of Infusion Solution

Cisplatin-Mili must be diluted under aseptic conditions prior to administration. Medical devices containing aluminum in parts that may come into contact with the drug (including intravenous infusion sets, needles, catheters, syringes) must not be used during preparation or administration of the infusion solution.

The required volume of concentrate, calculated according to the recommendations below, should be diluted in 1–2 L of 0.9% sodium chloride solution or in a mixture of 0.9% sodium chloride solution and 5% glucose solution in a 1:1 ratio (in such a solution, the concentration of sodium chloride is 0.45% and glucose is 2.5%).

If pre-infusion hydration is not feasible, the concentrate may also be diluted in a mixture of 0.9% sodium chloride solution and 5% mannitol solution in a 1:1 ratio (in such a solution, the concentration of sodium chloride is 0.45% and mannitol is 2.5%).

Infusion solutions containing cisplatin at a concentration of 0.1 mg/mL, prepared by diluting Cisplatin-Mili with 0.9% sodium chloride solution or with a 1:1 mixture of 0.9% sodium chloride and 5% glucose solution, are physically and chemically stable for 28 days. Solutions diluted with a 1:1 mixture of 0.9% sodium chloride and 5% mannitol are stable for 48 hours when stored protected from light at 2–8°C. From a microbiological standpoint, the infusion solution should be used immediately after preparation. If not used immediately, storage duration and conditions must be monitored by medical personnel or a physician. Generally, storage should not exceed 24 hours at 2–8°C, unless the solution was prepared under controlled and validated aseptic conditions.

Only clear, colorless solutions free from visible particulate matter should be used. The infusion solution is intended for single use only.

The diluted solution must be administered only by intravenous infusion.

Dosage for Adults and Children

Cisplatin dosage should be determined based on the specific pathology, expected patient response to therapy, and whether cisplatin is used as monotherapy or as part of combination chemotherapy. The dosage recommendations below apply to both adults and children.

For monotherapy, the following regimens are recommended:

• Single dose of 50–120 mg/m² body surface area administered every 3–4 weeks;
• Daily doses of 15–20 mg/m² body surface area administered for 5 consecutive days, repeated every 3–4 weeks.

Dosages should be lower when cisplatin is used in combination chemotherapy. The standard dose is 20 mg/m² or higher, administered once every 3–4 weeks.

The next treatment course may only be initiated after comprehensive assessment of the patient’s condition (see section "Special Precautions for Use").

Patients with Impaired Renal Function or Bone Marrow Suppression

Dosages must be appropriately reduced in patients with impaired renal function or suppressed bone marrow function.

Method of Administration

For intravenous infusion only.

The infusion solution must be administered solely by intravenous infusion over 6–8 hours. Adequate hydration must be provided for 2–12 hours before and for at least 6 hours after completion of cisplatin infusion to maintain sufficient diuresis during and after administration. Hydration is achieved by intravenous infusion of one of the following solutions: 0.9% sodium chloride solution or a 1:1 mixture of 0.9% sodium chloride and 5% glucose solution.

Hydration before cisplatin therapy: Intravenous infusion of one of the specified solutions at a rate of 100–200 mL/hour for 6–12 hours, with a total volume of at least 1 L.

Hydration after drug administration: Intravenous infusion of an additional 2 L of one of the specified solutions at a rate of 100–200 mL/hour over 6–12 hours. If urine output remains below 100–200 mL/hour despite hydration, forced diuresis may be required. For this, administer 37.5 mg of mannitol as a 10% solution (375 mL of 10% mannitol solution) intravenously, or use diuretics, provided renal function is normal. Mannitol or diuretics should also be administered when the cisplatin dose exceeds 60 mg/m² body surface area. Patients should be encouraged to drink large amounts of fluids for 24 hours after cisplatin infusion to ensure adequate urinary output.

Children

Before initiating the next treatment course in children, key parameters (serum creatinine, urea, leukocytes, platelets, audiogram) should be checked and confirmed to have returned to age-appropriate normal levels.

Overdose

Acute cisplatin overdose may lead to renal failure, hepatic failure, deafness, ophthalmotoxicity (including retinal detachment), severe bone marrow suppression, intractable nausea, vomiting, and/or neuropathy. Overdose can be fatal. Prompt and adequate hydration and osmotic diuresis immediately after overdose may reduce cisplatin toxicity.

In cases of significant overdose (≥ 200 mg/m² body surface area), cisplatin may cross the blood-brain barrier, resulting in direct effects on the respiratory center, potentially causing life-threatening respiratory disturbances and acid-base imbalance.

There is no specific antidote for cisplatin overdose. Even hemodialysis performed within 4 hours after overdose has minimal effect on removing cisplatin from the body, as cisplatin rapidly and tightly binds to proteins.

In cases of overdose, general supportive measures are indicated.

Side effects.

Adverse reactions depend on the dose of cisplatin and may have a cumulative nature.

Infections and infestations: sepsis, infections (sometimes infections complicated by fatal outcomes).

Renal and urinary system disorders: nephrotoxicity (has a cumulative effect); impaired kidney function; acute renal failure with tubular necrosis manifested by uremia or anuria; renal failure (can be reversible or irreversible); hyperuricemia (asymptomatic or with symptoms of gout); increased serum creatinine and urea concentrations. Hydration before and after cispllatin administration and a diuresis of 100 mL/hour or more reduce the risk of nephrotoxic damage. (See sections "Special precautions" and "Dosage and administration".)

Blood and lymphatic system disorders: leucopenia, thrombocytopenia, anemia, myelosuppression (has a cumulative effect), severe bone marrow function suppression including agranulocytosis and/or aplastic anemia (after high-dose cisplatin administration); Coombs-positive hemolytic anemia (reversible after completion of therapy), hemolysis (see section "Special precautions").

Benign, malignant, unspecified neoplasms: acute leukemia, secondary non-lymphoblastic leukemia. Cisplatin is theoretically carcinogenic (see section "Special precautions").

Gastrointestinal disorders: anorexia, nausea, vomiting, stomach pain, constipation, diarrhea, mucositis, metallic deposits on gums, hiccups (see section "Special precautions").

Hepatobiliary disorders: hepatotoxicity, impaired liver function (with elevated serum transaminase levels), increased levels of liver enzymes and blood bilirubin.

Metabolic and nutritional disorders: hypomagnesemia, hypocalcemia, hyponatremia, hypophosphatemia, hypokalemia (with muscle spasms and/or ECG changes), increased blood iron concentration, decreased albumin levels, hypercholesterolemia. Dehydration.

Ear and labyrinth disorders: ototoxicity (has a cumulative effect), hearing impairment in the high-frequency range (4000–8000 Hz) or in the normal hearing range (250–2000 Hz); tinnitus, deafness, vestibular dysfunction combined with systemic vertigo. (See section "Special precautions".)

Eye disorders: visual disturbances, color vision defects, vision loss, optic neuritis, blurred vision, retinal pigmentation, unilateral retrobulbar neuritis with loss of visual acuity, optic disc swelling with visual disturbances, cortical blindness. Ocular side effects may be reversible and vision may recover after discontinuation of treatment.

Nervous system disorders: neurotoxicity, peripheral neuropathy (usually bilateral and sensory), neuropathy (paresthesia, areflexia, loss of vibratory and proprioceptive sensation), loss of taste function, loss of tactile function, retrobulbar neuritis with vision loss and cerebral function disorders (confusion, slurred speech, cortical blindness, memory loss, paralysis), Lhermitte's sign, autonomic neuropathy and myelopathy of the spinal cord, severe brain damage (acute cerebrovascular complications, cerebral arteritis, carotid artery occlusion, encephalopathy, hemorrhagic stroke, ischemic stroke), seizures. If a patient develops any of the above-mentioned cerebral symptoms, cisplatin therapy must be discontinued immediately. Neurotoxic effects of cisplatin may be reversible; however, in some patients, impaired functions do not recover even after completion of cisplatin therapy. Neurotoxic effects of cisplatin may occur both after prolonged therapy and after administration of the first dose (see section "Special precautions").

Immune system disorders: immunosuppression, allergic reactions, anaphylactic reactions (manifested as rash, urticaria, erythema, pruritus), angioneurotic edema, arterial hypotension, tachycardia, dyspnea, bronchospasm, facial swelling, anaphylaxis. In such cases, treatment with antihistamines, epinephrine (adrenaline), and steroids may be required (see section "Special precautions").

Skin and subcutaneous tissue disorders: skin rashes, erythema, pruritus, alopecia.

Respiratory system disorders: dyspnea, bronchospasm, hoarseness, wheezing, pneumonia, respiratory failure.

Cardiac disorders: cardiac rhythm disturbances (bradycardia, tachycardia and other arrhythmias), ECG changes, cardiac arrest (very rare during cisplatin therapy in combination with other cytostatics), severe ischemic heart disease, impaired cardiac function, myocardial infarction.

Vascular disorders: arterial hypotension, vascular disorders (cerebral or coronary ischemia, impaired peripheral blood circulation similar to Raynaud's syndrome), thrombotic microangiopathy (hemolytic uremic syndrome), leukoencephalopathy, pulmonary artery embolism, thrombotic microangiopathy in combination with hemolytic uremic syndrome.

Endocrine disorders: increased serum amylase levels, inadequate antidiuretic hormone secretion.

General disorders and administration site conditions: weakness, chills, hyperthermia, asthenia, increased fatigue. After intravenous administration, local swelling and pain, erythema, skin ulcers, and phlebitis at the injection site may occur. Due to the risk of extravasation, careful monitoring of the infusion site for possible infiltration during drug administration is recommended (see section "Special precautions").

Reproductive system disorders: impaired spermatogenesis, ovulation disorders; painful gynecomastia, amenorrhea, azoospermia.

Shelf life. 2 years.

Storage conditions.

Store at a temperature not exceeding 25°C, in the original packaging, in a place inaccessible to children. Do not freeze.

Incompatibilities.

Cisplatin reacts with aluminum to form a black platinum precipitate. Therefore, instruments containing aluminum parts that may come into contact with the drug (including intravenous infusion sets, needles, catheters, syringes, etc.) must not be used during the preparation and administration of the infusion solution.

Cisplatin must not be mixed with any medicinal products except those specified in the section "Dosage and administration".

Cisplatin-Mili must not be diluted with 5% glucose solution or 5% mannitol solution, but only with mixtures of these solutions with 0.9% sodium chloride solution.

Antioxidants (e.g., sodium metabisulfite), bicarbonates (sodium bicarbonate), sulfates, fluorouracil, and paclitaxel may inactivate cisplatin in infusion systems.

Packaging. 1 vial per cardboard package.

Prescription status. Prescription only.

Manufacturer. Venus Remedies Limited.

Manufacturer's address and location of its operations.

Hill Top Industrial Estate, Jarmandjri, ERIPR Phase-I (Ext.), Battoli Kalan, Baddi, Solan District, Himachal Pradesh 173205, India.

Marketing Authorization Holder. Mili HealthCare Limited.

Address of the Marketing Authorization Holder.

2nd Floor, Office Premises, 4 Charterfield House, Castle Street, Taunton, Somerset, England, TA1 4AS, United Kingdom.