Paraplatin

Carboplatin.

Each vial contains: Active Substance: Carboplatin 150 mg.
Excipients/Inactive Ingredients: Water for injections.

Pharmacotherapeutic Group: Antineoplastic agent. ATC Code: L01XA02.
Pharmacology: Pharmacodynamics: Carboplatin has biochemical properties similar to the properties of cisplatin, thus producing predominantly interstrand DNA cross-links.
Pediatric Population: The safety and efficacy in children have not been established.
Pharmacokinetics: Following PARAPLATIN administration in humans, a linear relationship is observed between the dose and plasma concentrations of total and free ultrafilterable platinum. A similar linearity between dose and AUC/time curve for total platinum has been demonstrated. Repeated dosing during 4 consecutive days has not produced an accumulation of platinum in plasma. In humans, the administration of PARAPLATIN has led to terminal half-life values of free ultrafilterable platinum and carboplatin of approximately 6 and 1.5 hours, respectively.
During the initial phase, most of the free ultrafilterable platinum is present as carboplatin. No significant quantities of free, ultrafilterable, platinum-containing species other than carboplatin are present in plasma. Platinum from carboplatin becomes bound to plasma proteins and is slowly eliminated with a minimum half-life of 5 days. The terminal half-life of total platinum in plasma is 24 hours. In patients with creatinine clearance of 60 mL/min or greater receiving PARAPLATIN at doses ranging from 300 to 500 mg/m², the elimination curve exhibits a biphasic decrease with mean alpha and beta half-lives of 1.6 and 3.0 hours, respectively.
Therefore, at the dosages examined, carboplatin demonstrates linear, dose-independent pharmacokinetics in patients with creatinine clearance ≥60 mL/min. Approximately 87% of plasma platinum is protein bound within 24 hours following administration. PARAPLATIN is mainly excreted in the urine. Patients with creatinine clearance of approximately 60 mL/min or greater excrete 70% of the dose of carboplatin in the urine within 12 to 16 hours after administration. In patients with creatinine clearance below 60 mL/min, the total and renal clearances of carboplatin decrease as the creatinine clearance decreases. PARAPLATIN dosages should therefore be reduced in patients with creatinine clearance <60 mL/min (see Dosage & Administration).
Total body clearance and renal clearance of free ultrafilterable platinum are related to glomerular filtration rate and not to tubular secretion.
The variation in carboplatin clearance has been reported to be 3 to 4 times higher in pediatric patients. As for adult patients, data from literature suggest that renal function may contribute to changes in carboplatin clearance.
Toxicology: Preclinical Safety Data: Both in murine models and after xenograft transplantation of human tumors, the cytotoxic activity of carboplatin has shown to be comparable to the activity of cisplatin at a respective molar ratio of 4:1.
A comparative analysis of data from toxicity studies, following single and repeated multiple IV administration over several therapeutic courses, has revealed that at equal efficacy, carboplatin is less nephrotoxic (7.5 to 48 times), less ototoxic (8 times), less emetogenic (12 to 70 times), less lethal (8 to 12 times) and less neurotoxic than cisplatin. However, with reference to the latter toxicity, there is no valid animal model for predicting neurotoxicity in humans. LD₉₀ observed in CDF1 mice (males + females) and in Sprague-Dawley rats (males + females) is 545 mg/m² and 799 mg/m², respectively. The most significant toxicity of carboplatin following single and repeated doses to these animal species involves the hemopoietic system and is characterized by reversible anemia, neutropenia and thrombocytopenia.
Mutagenicity and Carcinogenicity: Carboplatin revealed to be a genotoxic/mutagenic substance in vivo and in vitro. In rats, which received carboplatin during organogenesis, embryotoxic and teratogenic effects were shown. The carcinogenic potential of carboplatin has not been investigated. Substances with similar mechanisms of action and similar mutagenicity have been described as carcinogenic.

PARAPLATIN is indicated for the treatment of advanced ovarian carcinoma of epithelial origin in: first-line therapy; second-line therapy, after treatment with other chemotherapeutic agents have failed.
PARAPLATIN is also indicated in the treatment of small cell carcinoma of the lung and squamous cell carcinoma of the head and neck.

Posology: PARAPLATIN should only be used by the intravenous (IV) route. The recommended dose of PARAPLATIN in previously untreated adult patients with normal renal function is 400 mg/m² as a single dose administered by slow IV infusion (15 to 60 minutes) (the Formula for Calculation of Carboplatin Dose as follows can be used as an alternative). PARAPLATIN SHOULD NOT BE ADMINISTERED BY RAPID IV INJECTION. Therapy should not be repeated again until four weeks have elapsed and/or until the neutrophil count is at least 2,000/mm³ and the platelet count is at least 100,000/mm³.
Reduction of the initial dosage by 20-25% is recommended for those patients who present with risk factors, such as prior myelosuppressive treatments or low performance status (ECOG-Zubrod 2-4 or Karnofsky below 80). At the beginning of treatment or in subsequent courses, a dosage adjustment may be required in patients aged 65 years or older, according to the physical status of the patient (see Precautions). Determination of the hematological nadir by weekly blood counts, during the initial courses of PARAPLATIN treatment, is recommended for future dosage adjustment (see Precautions).
Impaired Renal Function: Patients with creatinine clearance values below 60 mL/min are at increased risk of severe myelosuppression.
The onset of severe leukopenia, neutropenia or thrombocytopenia (incidence of about 25%) may be controlled using the following dosing schedule: 250 mg/m² IV on Day 1 in patients with creatinine clearance values of 41 to 59 mL/min at baseline; 200 mg/m² IV on Day 1 in patients with creatinine clearance values of 16 to 40 mL/min at baseline.
Insufficient data are available to determine the dosing schedule of PARAPLATIN in patients with creatinine clearance of 15 mL/min or less. The previously mentioned dosing recommendations apply to the initial course of PARAPLATIN treatment. Subsequent dosages should be adjusted according to the patient's tolerance and the desired myelosuppressive effect.
Combination Therapy: The optimal use of PARAPLATIN in combination with other myelosuppressive drugs requires dosage adjustments according to the polychemotherapy regimen adopted.
Pediatric Population: Insufficient data are available to allow dosing recommendations of PARAPLATIN in pediatric patients.
Formula for Calculation of Carboplatin Dose: Another approach for determining the initial dose of PARAPLATIN is the use of a mathematical formula based on a patient's renal function before starting chemotherapy with this drug. The use of this dosing formula, as compared to empirical dose calculation based on body surface area, allows adequate compensation for patient variations in pre-treatment renal function that might otherwise result in either underdosing (in patients with above average renal function) or overdosing (in the opposite case).
A simple formula for calculating the dose to be administered, based upon a patient's Glomerular Filtration Rate (GFR in mL/min) and PARAPLATIN target AUC (expressed in mg/mL/min), has been proposed by Calvert and is indicated as follows: Dose (mg): (target AUC) × (GFR + 25).
Note: With the Calvert formula, the total dose of PARAPLATIN is calculated in mg, not mg/m². (See table.)

Click on icon to see table/diagram/image

An overdose intensifies the toxic effects and can have fatal consequences as a result of the worsening of the thrombocytopenia and leukopenia. The experiences with dialysis are limited. There is no special specific antidote for PARAPLATIN.
At a very high dosage (up to 5-fold and more of the recommended dosage), there have been reports of serious liver and kidney function disorders as well as the loss of sight.

Hypersensitivity to carboplatin or other platinum-containing preparations, severe renal insufficiency (existing or diagnosed earlier), severe hepatic insufficiency, severe myelosuppression, tumor bleedings, marked hearing impairment, pregnancy, lactation.

Attention: Carboplatin is very hemotoxic and may only be used with the greatest care.
Hepatic and renal function; neurological symptoms: A full blood count, tests of kidney and liver function as well as checks of the neurologic status (see Adverse Reactions) should be performed regularly.
The treatment should be discontinued in the case of marked myelosuppression or severe renal or hepatic disorders (see Contraindications).
The creatinine clearance is the most sensitive parameter for the determination of the renal function in patients who are treated with PARAPLATIN and it is useful in order to correlate the excretion of the medicine with myelosuppression. The creatinine clearance is reduced during therapy in 27% of the patients who have a creatinine clearance of ≥60 mL/min at the start of treatment.
In the case of advanced renal insufficiency, the dosage and dosage interval must be adjusted to the glomerular filtration rate (see also Impaired Renal Function under Dosage & Administration).
Cases of Posterior Reversible Encephalopathy Syndrome (PRES) have been reported in patients receiving carboplatin, in most cases as part of combined chemotherapy. PRES is a rare, rapidly developing neurological disease that can include seizures, hypertension, confusion, blindness, and other visual and neurological disorders (see Adverse Reactions). PRES is usually reversible after discontinuation of treatment. The diagnosis of PRES is based on confirmation by imaging techniques, preferably MRI (magnetic resonance imaging).
Hematotoxicity: Myelosuppression is dose-dependent and dose-limiting. Myelosuppression resulting from monotherapy with PARAPLATIN at the recommended dosage is reversible and not cumulative. It may be particularly pronounced in patients with renal insufficiency, in patients who have received an intensive myelosuppressive treatment or cisplatin, as well as in persons whose general state of health is impaired. The initial doses in these patients should therefore be reduced (see also Dosage & Administration). Should suppression occur during the treatment with PARAPLATIN, peripheral blood analyses should be made frequently until recovery. The median of the nadir is 21 days in the case of patients who are treated with PARAPLATIN only and it is 15 days in patients who receive PARAPLATIN in combination. Within 28 days, the platelet count in 90% of patients rises again to over 100,000/mm³, the neutrophil count to over 2,000/mm³ in 74% of the patients and the leukocytes to over 4,000/mm³ in 67% of the patients. The preparation should not be re-administered until the leukocytes, granulocytes and platelets have returned to normal.
Hemolytic anemia with existing drug-induced serological antibodies has been reported in patients treated with carboplatin. This event can be fatal. In case of unexplained hemolysis, serological testing and discontinuation of treatment should be considered (see Adverse Reactions).
Ototoxicity: Auditory defects have been reported during carboplatin therapy. Ototoxicity may be more pronounced in children. Younger age, higher cumulative dose of chemotherapy, carboplatin conditioning for HCT, CNS tumors, renal insufficiency, and concomitant administration of other ototoxic drugs (e.g. aminoglycosides), radiation involving the ear ≥30 Gy or CNS radiation are considered as risk factors. Cases of hearing loss with a delayed onset have been reported in paediatric patients. A hearing test before starting treatment and a long-term audiometric follow-up with yearly (or if hearing loss is detected, more frequently) hearing tests is recommended in this population.
Electrolytes: There have been reports concerning early hyponatremia. The possibility of hyponatremia should not be ignored especially in patients with risk factors such as e.g. a concomitant diuretic therapy. The sodium levels could generally be normalised again by sodium replacement or by limiting water available.
Injection site reactions: Injection site reactions may occur during the administration of PARAPLATIN. 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.
Vaccinations: Concomitant use of PARAPLATIN with a live vaccine may potentiate the replication of the vaccine pathogen and/or may increase the adverse reaction of the vaccine pathogen because normal defense mechanisms may be suppressed by PARAPLATIN. Vaccination with a live vaccine in a patient being treated with PARAPLATIN may result in severe infection. The patient's antibody response to vaccines may be decreased. The use of live vaccines should be avoided and specialist advice should be sought. Killed or inactivated vaccines may be used, however, the response to such vaccines could be reduced (see Interactions).
Effects on Ability to Drive and Use Machines: There is no data available on the effects of PARAPLATIN on driving or using machines. Care should be taken when driving vehicles and operating machines, since undesirable effects such as sight impairment, vomiting and nausea may occur during the course of treatment.

Pregnancy: Carboplatin proved to be embryotoxic and mutagenic in organogenesis in rats.
No controlled studies have been conducted in pregnant women. PARAPLATIN should therefore not be used during pregnancy. Patients of child-bearing age should use reliable contraceptive measures and must be given advice both in this regard and regarding the risk presented by a pregnancy while they are being treated with PARAPLATIN.
Lactation: It is not known whether carboplatin is secreted into breast milk; during treatment with carboplatin, mothers should not breastfeed.
Fertility: Given the mutagenic potential of PARAPLATIN, an effective contraception is required for both male and female patients during treatment and up to six months after ending treatment. As PARAPLATIN may decrease male fertility, preservation of sperm may be considered for the purpose of later fatherhood (see Pharmacology: Toxicology: Preclinical Safety Data under Actions).

The following frequency definitions are used: "Very common" (≥1/10); "common" (≥1/100, <1/10); "uncommon" (≥1/1000, <1/100); "rare" (≥1/10,000, <1/1000); "very rare" (<1/10,000).
Infections and infestations: Common: Infectious complications (sometimes lethal).
Rare: Pneumonia.
Benign, malignant and unspecified neoplasms (including cysts and polyps): Secondary tumors have been reported in the context of treatments with cytostatic combinations, but the connection with carboplatin has not been clarified.
Blood and lymphatic system disorders: Very common: Anemia (71%), thrombopenia (25%), leukopenia (14%), neutropenia (18%).
Common: Haemorrhages (sometimes lethal).
Very rare: Febrile neutropenia, hemolytic-uremic syndrome, autoimmune hemolytic anemia.
Immune system disorders: Common: Allergic reactions such as exanthema, urticaria, erythema, fever without detectable cause, itching, anaphylactic reactions with bronchospasms and hypotension at the start of the treatment.
The risk of an allergic reaction (including anaphylaxis) is greater in patients who were previously treated with a platinum-containing substance.
Metabolism and nutrition disorders: Very common: Diminished serum levels of sodium (29%), potassium (20%), calcium (22%) and magnesium (29%). Combined chemotherapy did not lead to increased electrolyte losses. If necessary, electrolyte losses should be compensated.
Very rare: Tumor lysis syndrome.
Nervous system disorders: Common: Central nervous symptoms, peripheral neuropathy including paresthesias and weakness of the tendon reflexes, peripheral sensory disturbances such as visual disorders, impairment of taste.
The frequency of the neurological adverse effects seems to be increased in elderly patients (>65 years), during a combination therapy, in patients who have already received cisplatin or a long-term PARAPLATIN therapy, or during a long-lasting cumulative exposure.
Very rare: Posterior Reversible Encephalopathy Syndrome (PRES) in patients receiving carboplatin in combined chemotherapy (see Precautions).
Eye disorders: Very rare: Inflammation of the optic nerves with visual disorders including blindness in patients with renal insufficiency, who received doses higher than those recommended. Normalisation of sight or a significant improvement of the disorders occurred within weeks of the high doses being discontinued.
Ear and labyrinth disorders: Common: Ototoxicity. It initially affects higher frequencies (≥4 kHz); it can progress and involve speech frequencies (<4 kHz). In patients with hearing impairment due to cisplatin, a further deterioration of the hearing function can occur during treatment with carboplatin.
Cardiac disorders: Common: Cardiovascular disturbances.
Uncommon: Heart failure, thromboembolism, apoplexia, all of them sometimes lethal (correlation with carboplatin is not proven), high blood pressure.
Respiratory, thoracic and mediastinal disorders: Common: Dyspnoea, increased cough, pulmonary toxicity.
Gastrointestinal disorders: Very common: Abdominal pain (17%), nausea (15%), vomiting (65%; Grade 3/4: 20%). In general, nausea and vomiting did not occur after the first day. There are, however, cases of delayed vomiting. Patients who had been previously treated with cisplatin exhibited severe gastrointestinal adverse effects.
Common: Diarrhoea, constipation, mucositis.
Very rare: Loss of appetite, stomatitis.
Hepatobiliary disorders: Very common: Increase of SGOT (15%) and alkaline phosphatase (24%).
Common: Increase of bilirubin. In general, these changes are not pronounced and are reversible in 50% of the patients.
Skin and subcutaneous tissue disorders: Common: Skin reactions/skin change, alopecia.
Musculoskeletal, connective tissue and bone disorders: Uncommon: Arthralgia, myalgia.
Renal and urinary disorders: Very common: Creatinine clearance decrease (55%).
Common: Increase of uric acid, urinary incontinence, dysuria, increased urinary frequency, nocturia.
General disorders and administration site disorders: Common: Asthenia.
Rare: Attacks of fever without signs of an infection or an allergic reaction, malaise, dehydration.
Reactions at the application site such as redness, swelling, and pain have been reported during post-marketing surveillance. Necrosis, cellulitis, burning sensation, and rash associated with extravasation have also been reported.

The administration of nephrotoxic and/or ototoxic medications should be avoided as much as possible during treatment with PARAPLATIN (see Precautions).
The combination with myelosuppressive substances leads to the potentiation of myelotoxicity.
Aminoglycosides: Caution should be exercised when administering PARAPLATIN with aminoglycosides due to cumulative nephrotoxicity and ototoxicity, particularly in patients with renal failure.
Loop diuretics: Caution should be exercised when administering PARAPLATIN with loop diuretics due to cumulative nephrotoxicity and ototoxicity, particularly in patients with renal failure.
Vaccines: There is increased risk of fatal systemic vaccine disease with the concomitant use of live vaccines. Live vaccines are not recommended in immunosuppressed patients (see Precautions).

Special Precautions for Disposal and Other Handling: The ready-to-use solution may be further diluted with 5% dextrose in water or 0.9% sodium chloride injection, up to concentrations as low as 0.5 mg/mL. As with other antineoplastic medicinal products, PARAPLATIN should be handled with care.
Impermeable gloves should always be worn when handling vials that contain PARAPLATIN to minimize the risk of skin exposure. These precautions should be taken during all handling activities in hospitals, pharmacies, storage rooms and home healthcare settings, including during opening and inspection of packages, transport within a facility, as well as dose preparation and administration.
Incompatibilities: Needles and/or intravenous administration sets should not contain aluminum components that may come in contact with PARAPLATIN. Aluminum can react with the drug causing precipitate formation and loss of potency.

Store at room temperature at or below 25°C. Protect from light.
Special Precautions for Storage: Since no antibacterial preservative is contained in the current formulation, the administration of PARAPLATIN after eight hours from further dilution is not recommended.
Shelf Life: 2 years.

Cytotoxic Chemotherapy

L01XA02 - carboplatin ; Belongs to the class of platinum-containing antineoplastic agents. Used in the treatment of cancer.

P₁S₁S₃