COMBIPHAR

 

CARBOSIN TM
Carboplatin

 


CARBOSINTM
a widely used anti-cancer drug, carboplatin

CarbosinlTM is widely and successfully used to treat various tumors. The therapeutic value has been well demonstrated in ovarium cancer, testis carcinoma and small cell lung cancer (SCLC). CarbosinTM may also be valuable in the treatment of head and neck cancer.

CARBOSINTM
improved platinum analog

CarbosinTM in monotherapy or combination schedules is significantly less emetogenic than cisplatin. CarbosinTM is usually administered without forced diuresis or hydration.

CarbosinTM
powder for injection (PFI) and a ready to use solution (RTU)

CarbosinTM is available as a 10 mg/ml ready to use solution and as lyophilized powder for injection. Both presentations are available in a range of 150 and 500 mg.

CarbosinTM
excellent quality and purity

CarbosinTM both lyophilized powder for injection and the ready to use solution contain carboplatin of excellent quality and purity (see below).

 

Product information
Name and pharmaceutical form: CarbosinTM injection 10 mg/ml. Composition: CarbosinTM, injection 10 mg/ml containing 150 mg or 500 mg carboplatin (cis-diammine (1.1-cyclobutanedicarboxylato)platinum) and 250 mg or 500 mg, respectively, of mannitol. Pharmacological properties: Carboplatin is a platinum coordination complex. After dissociation of the cyclobutanedicarboxylate moiety and subsequent aquation of the molecule it interacts with DNA, producing predominantly interstrand cross-links. After intravenous administration of carboplatin plasma levels of intact drug decline in a biphasic manner, with an initial half-life of 1-2 hours (t1/2 α) and a terminal half-life (t1/2
b) of 3-6 hours. Plasma levels are correlated linearly with dose administered Unchanged carboplatin is virtually not bound to plasma proteins. However, irreversible protein binding of platinum from carboplatin increases gradually to about 87% after 24 hours, and is slowly eliminated (t1/2 5 days). Plasma clearance of unchanged drug occurs predominantly by renal excretion: about 70% of the total dose is excreted in 24 hours. In patients with impaired renal function (creatinine clearance <60 ml/min) carboplatin excretion decreases with decreasing creatinine clearance; lower dosages of carboplatin should be used in this patient group. Indications: Carboplatin is indicated for the palliative treatment of patients with advanced or recurrent ovarian carcinoma, including patients previously treated with cisplatin. Furthermore, carboplatin may be used for the treatment of small cell lung carcinoma, and carcinoma of the head and neck. Contra indications: Carboplatin is contraindicated in patients with a history of severe allergic reactions to platinum-containing compounds, or mannitol (in powder for injection), In patients with severe myelosuppression, or in patients with severe renal function disturbances (creatinine clearance < 20 ml/min.) Adverse effects; Bone marrow; Myelosuppression i s the major dose-limiting toxicity of carboplatin. Thrombocytopenia (platelets < 50,000/mm) is seen in most of the patients, with a nadir at about 3 weeks and full recovery at 4-5 weeks. Leukopenia (< 2,000/mm3 M3) is usually less pronounced, with a nadir at about 3 weeks and a somewhat slower recovery at 5 weeks. Anemia (hemoglobin < 2 mg/dl) is commonly seen, but usually not of a severe nature. Bone marrow depression is more severe in patients with impaired renal function, patients with an inadequate bone marrow reserve, or patients with poor performance status. Gastrointestinal: Nausea and vomiting are commonly seen, usually of mild to moderate degree, and in about 20% of patients severe. Nausea and vomiting usually cease within 24 hours after treatment. ' Neurotoxicity: Peripheral neuropathies have been observed in 5% of the patients, mild paresthesias occurring most frequently. The incidence and severity may be increased in patients previously treated with cisplatin. Clinical symptoms of ototoxicity, mostly tinnitus, occur in 1 % of patients. Nephrotoxicity: Development of abnormal renal function tests is uncommon with carboplatin, and preventive measures, such as hydration or forced diuresis are not necessary. Carboplatin treatment may result in a decrease in serum electrolytes, including sodium, potassium, magnesium and calcium, but these electrolyte abnormalities are rarely associated with clinical symptoms. Allergic reactions: Hype rsensitivity to carboplatin has been reported in 2% of the patients. These allergic reactions h ave been similar in nature and severity to those reported with other platinum-containing compounds, i.e., rash, urticaria, erythema and a pruritis. Miscellaneous: Abnormal liver function tests have been reported, but are generally mild to moderate. Pain, asthenia, alopecia and mucositis are rarely reported. Warnings and precautions: Bone marrow suppression (leukopenia, thrombocytopenia) is dose-dependent, and related to renal function. Peripheral blo counts should be monitored frequently during and after treatment, and renal function should be assessed. Dose reductions are generally necessary in patients with concomitant treatment with other myelosuppressive drugs, patients with inadequate bone marrow reserves due to previous treatments or bone metastases, patients with impaired renal function (creatinine clearance < 60 ml/min), patients with poor performance status and older patients. Carboplatin has limited nephrotoxic and ototoxic potential, but concomitant treatment with aminoglycosides or other nephrotoxic or ototoxic agents may result in an increased risk for renal or auditory toxicity. Emesis during carboplatin treatment can be effectively reduced by appropriate anti-emetic medication. Alternatively, emesis may be reduced by sustained administration schedules, e.g., dividing the total dose over 5 days or over a 24-hour i.v. infusion. The incidence of neurotoxicity may be increased in older patients, and patients previously treated with cisplatin. As in the case of other platinum coordination compounds, allergic reactions to carboplatin have been reported. These may occur within minutes of administration, and should be managed with appropriate supportive therapy, usually including adrenaline, corticosteroids and antihistaminics. Use during pregnancy and lactation. Safe use of carboplatin during pregnancy or lactation has not been established. Carboplatin has demonstrated embryotoxic and teratogenic effects in animals. Carboplatin has been shown to have a mutagenic potential in vitro and in vivo. Therefore, the use of carboplatin should be * avoided if possible during pregnancy. It is not known whether carboplatin is excreted in human milk. It is recommended that lactation is discontinued during carboplatin treatment. Interactions: Myelosuppression by carboplatin may be more severe with prior or concomitant treatment with other myelosuppressive drugs. Concomitant treatment with other nephrotoxic or ototoxic agents (e.g., aminoglycoside antibiotics) increases the risk of renal or auditory toxicity during carboplatin treatment. Dosage and method of administration: CarbosinTM, injection 10 mg/ml and CarbosinTM , powder for injection are intended for intravenous use. CarbosinTM , powder for injection 50 mg, 150 mg and 500 mg should be reconstituted with 5 ml, 15 ml or 50 ml, respectively, of water for injection, or glucose 5%. The recommended starting dose for previously untreated patients with normal kidney function is 400 mg/m2as a single i.v. dose, usually administered as a short term (15-60 min) infusion, once every four weeks. Reduction of the initial dose to 300-320 mg/m2 is recommended with concomitant myelosuppressive therapy, or other risk factors (see Warnings and precautions). Patients with impaired renal function: Patients with a creatinine clearance < 60 ml/min are at increased risk of severe myelopression. Recommended starting doses for these patients are: creatinine clearance 41-59 ml/min 250 mg/ml, and creatinine clearance 20-40 ml/min 200 mg/m2. Insufficient date are available for patients with a creatinine clearance below 20 ml/min, and treatment is not recommended in these cases. After the first course, dosage may be adjusted according to the patient's tolerance. Symptoms and treatment of overdosage: The anticipated complications of overdosage would be secondary to bone marrow suppression and/or hepatic toxicity. There is no known antidote for carboplatin, lncompatibilities: Contact with aluminium containing injection or infusion material should be avoided. Dilution with sodium chloride solution (0.9%) may have a negative effect on the stability of carboplatin, and is therefore not recommended. Storage and shelf-life: The unopened vials should be stored at controlled room temperature 15' to 25'C. Protect from light. Since no antibacterial preservative is contained in the formulation, it is recommended that carboplatin injection is discarded 8 hours after opening. Packaging: CarbosinTM , injection 10 mg/ml containing 150 mg or 500 mg carboplatin.

 

PLATOSIN
Cisplatin

 

General
Cisplatin, synthesised in 1845 (1), was discovered to be an agent with possible anti-tumour properties in 1965 (2). Since that time cisplatin has developed into a versatile anti-tumour drug. Cisplatin binds to DNA strands in the cell, thereby causing irreparable damage leading to cell death. The clinical break-through of cisplatin came with the paper of Einhorn and Donohue in testicular cancer (3). Since then, cisplatin appeared to be active in many more cancers.

Therapeutic indications
Cisplatin is given alone, but usually in combination with other cytostatic agents in the treatment of testicular cancer, ovarian cancer, bladder cancer and non-small cell lung cancer. it is also applied in numerous other tumours, such as breast-, cervix-, and head and neck cancer, osteosarcoma and melanoma. Cisplatin is one of the most frequently used cytostatics. Clinical research on cisplatin still offers novel results.

Dosage
The dosage of cisplatin varies according to the schedule applied, usually ranging from 50-100 Mg/M2 as a single intravenous administration, or 20 mg /M2 on each of 5 consecutive days. Some of the frequently used schedules for the various indications are depicted in the table.

Why Platosin
- Platosin is available in the most widely used dosage forms to meet the  customer's needs
- Platosin is preservative free.

Pharmaceutical forms
Platosin ready to use solution 10, 25 and 50 mg (0.5 mg/ml) Platosin ready to use solution 10, 25, 50 and 100 mg (1 mg/ml)

 

1. TRADE NAME OF THE MEDICINAL PRODUCT
Platosin
powder for injection.
Platosin
0.05%, injection.
Platosin
0.1%, injection.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Platosin
powder for injection contains respectively 10 mg, 25 mg and 50 mg of cisplatin. Platosin 0.05%, injection contains 0.5 mg/ml cisplatin. Platosin 0.1%, injection contains 1 mg/ml cisplatin.

3. PHARMACEUTICAL FORM
Powder for injection.
Injection.

4. CLINICAL PARTICULARS
4.1 Therapeutic indications

Platosin
is indicated for the treatment of advanced and metastatic testis carcinoma, advanced and metastatic ovarian carcinoma, and advanced and metastatic bladder carcinoma.
4.2 Posology and method of administration
Platosin
powder for injection 10 mg, 25 mg and 50 mg should be reconstituted with 10 ml, 25 ml and 50 ml of water for injections respectively. No aluminium containing infusion or injection material should be used for administration of Platosin Before administration of cisplatin intravenous hydration with at least 1 litre of 5% glucose/0.9% saline (1:1) is recommended. When urine flow is less than 100 ml per hour, 100-200 ml 15% mannitol may be administered. Subsequently the Platosin solution should be added to 2 litres 5% glucose/0.9% saline (1:1) and intravenously administered in 6-8 hours; after administration an adequate hydration and diuresis should be maintained during 24 hours. The next dose of Platosin should not be given until the renal function has returned to normal.
The usual dose of Platosin
is 50-100 mg/m2 as a single intravenous administration or 20 mg/m2 intravenously on each of 5 consecutive days. The dose may be adjusted, depending on combination with other cytostatics. A course can be administered once every 3-4 weeks, depending on results of blood tests, renal function tests and audiometric tests.
4.3 Contra-indications
Cisplatin should not be administered to patients with a history of severe allergic reactions to cisplatin or other platinumcontaining compounds and patients with renal function impairment, severe myelosuppression or hearing impairment.
4.4 Special warnings and special precautions for use
Existing renal insufficiency, disorders of hearing or bone marrow suppression may worsen by administration of cisplatin. Patients should have a normal renal function (creatinine clearance > 90 ml/min) prior to start of therapy with Platosin
Before administration, adequate hydration and diuresis should be ascertained. Appropriate antiemetic medication should be given, considering the severity of nausea and vomiting. Audiometric monitoring is recommended prior to and during therapy with cisplatin. Cisplatin is mutagenic in bacteria and causes chromosomal aberrations in animal cell cultures. Regarding the mechanism of action carcinogenicity is possible, but not proven. Anticonceptive therapy should be taken by both men and women, during cisplatin treatment, as well as during at least 3 months after treatment. After spillage of cisplatin the contaminated skin should be washed immediately with water and soap. Administration should be stopped immediately in case of extravasation. Subsequently 3-5 ml of blood should be obtained via the infusion needle. A plastic surgeon might be consulted, a corticosteroid injected in the effected area and a cold compress should be used during 12 hours. Generally cisplatin extravasation does not lead to serious problems.
4.5 Interaction with other medicaments and other forms of interaction
Patients receiving cisplatin should not be exposed to living vaccines. Partial or full protection can be achieved with a killed vaccine. Concomitant use of drugs with a potential ototoxic or nephrotoxic effect should be avoided or accurately monitored. The combination of cisplatin and aminoglycosides or cefalotine should be avoided. Furosemide could also potentiate nephrotoxicity. Pharmacodynamic interaction with vincaalkaloids could lead to increased neurotoxicity. Interaction with radiation during radiation therapy could also occur.
4.6 Pregnancy and lactation
Considering the pharmacological effect toxicity after treatment during pregnancy is possible. In animal experiments cisplatin was proven harmful.
4.7 Effects on ability to drive and use machines
Because of the frequent occurrence of nausea and vomiting precaution is advised in undertaking actions which require extra alertness, such as the use of machines and the participation in traffic.
4.8 Undesirable effects
Kidneys: The most serious sideeffect of cisplatin is nephrotoxicity. This is the main doselimiting factor. Renal damage is doserelated and cumulative; initially renal damage is reversible, but repeated cisplatin administration may cause irreversible renal function impairment. The risk of nephrotoxicity can be reduced by prehydration and careful monitoring. Nephrotoxicity is manifested by elevations in BUN, serum uric acid and creatinine, and a decrease in creatinine clearance.Electrolyte disturbances: Hypomagnesemia and hypocalcemia are frequently reported.
Gastrointestinal tract: Marked nausea and vomiting occur in almost all patients and usually start within a few hours after start of therapy. Nausea and vomiting may persist for 1-7 days after treatment. The symptoms may be so severe that discontinuation of therapy is indicated. Antiemetics or spreading of drug administration over several hours may cause less severe nausea and vomiting. Anorexia, stomatitis and mucositis have been reported during therapy of cisplatin. Increases of ASAT and ALAT are observed, but these are mild and temporary.
Ototoxicity: Ototoxicity has been observed in about 30% of patients treated with 50 mg/m2 of cisplatin, and is manifested as tinnitus and hearing loss in the high frequency range (4000 8000 Hz); hearing loss of frequencies in the speaking range occurs rarely. Hearing loss may be unilateral and is dose dependent. Hearing should be monitored carefully by audiometric tests. Ototoxicity may be more severe in children or in the elderly. Ototoxicity increases with cumulating dosage and is irreversible.
Myelotoxicity: Myelosuppression occurs in 25-30% of patients receiving cisplatin, but is usually not severe. The nadirs in platelet and leucocyte counts occur between day 18 and 23, but normal values have returned by day 39. At higher doses of cisplatin leucocytopenia and thrombocytopenia are more serious and may be accompanied by anemia.
Neurotoxicity: Cisplatin causes a bilateral, sensoric neuropathy, manifested by paresthesias, decreased vibratory sensation, tactile sense and decreased deeptendon reflexes. Fits, amnesia, tremor, loss of taste and orthostatic hypotension may occur. Optic neuritis, with temporary blindness has been reported a few times. Neurotoxicity is dose-dependent and may occur following single dose administration, but especially after prolonged treatment and it is often only slowly reversible. Neurotoxicity may progress after discontinuation of therapy.
Eye toxicity: Various grades of decrease of eye sight have rarely been reported during combination therapy with cisplatin.
Miscellaneous: Hyperuricemia may occur, especially in patients receiving higher doses of cisplatin. Treatment with allopurinol reduces uric acid plasma levels effectively. Disorders in cardiac function have been reported.
Anaphylactoid reactions are rare and usually seen directly after administration.
4.9 Overdose
Overdosage is associated with the usual adverse effects of a more severe kind. Myclosuppression should be treated with antibiotics and transfusions. Other adverse effects are treated symptomatic.

5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Cisplatin is a platinum coordination complex. After hydrolysis in the cell, substituting one or two chloride ligands by water or hydroxyl groups, the resulting molecule interacts with DNA, RNA and proteins. Cross-linking of DNA is probably the major mechanism of action.
5.2 Pharmacokinetic properties
Following intravenous administration cisplatin is rapidly distributed to all tissues; cisplatin does not penetrate the central nervous system to any appreciable extent. The highest concentrations are reached in liver, kidneys, bladder, muscle, skin, testes, prostate, pancreas and spleen. Following intravenous administration plasma elimination of filterable, free cisplatin is biphasic with an initial and terminal half-life of 10-20 minutes and 32-53 minutes respectively. Elimination of the total amount of cisplatin is triphasic with a half-life of 14 minutes, 274 minutes and 53 days respectively. 90% of cisplatin is bound to plasma proteins. Cisplatin is eliminated primarily via the urine: 27-43% of the administered dose is excreted in the urine during the first 5 days after administration. Cisplatin is also excreted in bile.
5.3 Preclinical safety data
Considering the mechanism of action, the product is mutagenic and in principle carcinogenic.

6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Powder for injection: mannitol, sodiumchloride. Injection: sodium chloride, water for injection.
6.2 Incompatibilities
Contact with aluminium containing material should be avoided. Cisplatin decomposes in media with low chloride content; the diluent used for administration should contain a chloride concentration at least equivalent to 0.45% sodium chloride.
6.3 Shelf life
If stored as indicated below, this medication can be used until the date stated on the packaging. The shelf life is 3 years for all three products. Platosin
contains no preservative. It is recommended to use reconstituted solutions within 8 hours. Reconstituted solutions and injection 1 mg/ml should not be stored in the refrigerator, because of risk of precipitation.
6.4 Special precautions for storage
Store at 15-25 C, protected from light.
6.5 Nature and contents of container
Brown glass vials for injection with butylrubber stopper. Platosin powder for injection 10 mg, 25 mg and 50 mg. Platosin 0.05%, injection 0.5 mg/ml, 20 ml, 50 ml and 100 ml. Platosin 0.1%, injection 1 mg/ml, 10 ml, 50 ml and 100 ml.

7. MARKETING AUTHORIZATION HOLDER
Pharmachemie B.V. P.O. Box 552 2003 RN Haarlem The Netherlands.

8. MARKETING AUTHORIZATION NUMBER
Registered in The Netherlands under RVG 09010, powder for injection. RVG 09263, injection 0.05%. RVG 15255, injection 0.1%.

9. DATE OF (PARTIAL) REVISION OF THE TEXT
January 1996

N Haarlem The Netherlands.

8. MARKETING AUTHORIZATION NUMBER
Registered in The Netherlands under RVG 09010, powder for injection. RVG 09263, injection 0.05%. RVG 15255, injection 0.1%.

9. DATE OF (PARTIAL) REVISION OF THE TEXT
January 1996