Grace Carboplatin 150 / 450

 

For the use only of a registered medical practitioner or a hospital or a laboratory

Rx

 

Grace Carboplatin Injection 150 mg

Grace Carboplatin Injection 450 mg

(Carboplatin Injection)

 

COMPOSITION

Grace Carboplatin Injection 150 mg

Each vial contains 150 mg of Carboplatin

Grace Carboplatin Injection 450 mg

Each vial contains 450 mg of Carboplatin

 

PHARMACEUTICAL FORM

Concentrate for solution for infusion.

 

THERAPEUTIC INDICATIONS

Grace Carboplatin Injection is indicated for the treatment of:

1. advanced ovarian carcinoma of epithelial origin in:

– first line therapy.

– second line therapy, after other treatments have failed.

2. small cell carcinoma of the lung.

 

POSOLOGYANDMETHOD OF ADMINISTRATION

Dosage and Administration:

Grace Carboplatin Injection should be used by the intravenous route only. The recommended dosage of Grace Carboplatin Injection in previously untreated adult patients with normal kidney function, i.e. creatinine clearance > 60 ml/min is 400 mg/m2 as a single short term IV dose administered by a 15 to 60 minutes infusion. Alternatively, the Calvert formula shown below may be used to determine dosage:

Dose(mg) = target AUC (mg/ml x min) x [GFR ml/min + 25]

 

 

Note: With the Calvert formula, the total dose of Carboplatin is calculated in mg, not mg/m².

     Therapy should not be repeated until four weeks after the previous Carboplatin course and/or until the neutrophil count is at least 2,000 cells/mm3 and the platelet count is at least 100,000 cells/mm².

     Initial dosage should be reduced by 20-25% in patients with risk factors such as previous myelosuppressive therapy and or poor performance status (ECOG-Zubrod 2-4 or Karnofsky below 80).

     Determination of haematologic nadir by weekly blood counts during initial courses is recommended for future dosage adjustment and scheduling of carboplatin.

     Needles or intravenous sets containing aluminium parts that may come in contact with carboplatin injection should not be used for preparation or admin istration. Aluminium reacts with carboplatin injection causing precipitate formation and/or loss of potency.

     The safety measures for dangerous substances are to be complied with preparation and administration. Preparation must be carried out by personnel who have been trained in the safe use while wearing protective gloves, face mask and protective clothes.

 

Impaired renal function:

     In patients with impaired renal function, dosage of carboplatin should be reduced (refer to Calvert formula) and haematological nadirs and renal function monitored.

     Patients with creatinine clearance below 60 ml/min are at increase risk of severe myelosuppression. The frequency of severe leukopenia, neutropenia, or thrombocytopenia has been maintained at about25% with the following dosage recommendations:

 

Baseline Creatinine Clearance lnitial                                                        Dose (Day 1)

                 41-59 ml/min                                                                        250 mg/m2I.V.

                16-40 ml/min                                                                        200 mg/m2I.V.

 

     Insufficient data exist on the use of carboplatin injection in patients with creatinine of 15 ml/minorless to permit are commendation for treatment.

     All of the above dosing recommendations apply to the initial course of treatment. Subsequent dosages should be adjusted according to the patient’s tolerance and to the acceptable level of myelosuppression.

 

Combination Therapy:

The optimal use of Carboplatin in combination with other myelosuppressive agents requires dosage adjustments according to the regimen and schedule to be adopted.

 

Elderiv:

In patients of more than 65 years of age, adjustment of the carboplatin dose to the general condition is necessary during the first and the subsequent therapeutic courses.

 

Paediatric population

There is insufficient information to support a dosage recommendation in the paediatric population.

 

Dilution and Reconstitution.

The product must be diluted prior to infusion.

 

CONTRAINDICATIONS

Grace Carboplatin Injection is contraindicated in:

– Hypersensitivity to the active substance(s) or to any of the excipients listed.

– patients with severe myelosuppression

– patients with pre-existing severe renal impairment (with creatinine clearance of ≤ 30 ml per minute) unless in the judgment of the physician and patient, the possible benefits of treatment outweigh the risks

– patients with bleeding tumors

– concomitant use with yellow fever vaccine

– patients with a history of severe allergic reaction or other platinum containing compounds.

Dosage adjustment may al low use in the presence of mild impairment.

 

WARNINGS AND PRECAUTIONS

Warnings:

Myelosuppression

     Myelosuppression as a result of Grace Carboplatin Injection treatment is closely related to the renal clearance of the drug. Therefore, in patients with abnormal renal function, or who are receiving concomitant therapy with nephrotoxic drugs, myelosuppression, especially thrombocytopenia, may be more severe and prolonged.

     The occurrence, severity and protraction of toxicity is likely to be greater in patients who have received extensive prior treatment with the drug for their disease or with cisplatin, have poor performance status and are advanced in years. Renal function parameters should be assessed prior to, during and after Grace Carboplatin Injection therapy Initial carboplatin dosages in these groups of patients should be appropriately reduced and the effects carefully monitored through frequent blood counts between courses. Myelosuppressive effects may be additive to those of concomitant chemotherapy.

     Peripheral blood counts (including platelets, white blood cells and haemoglobin) should be followed during and after therapy. Combination therapy with other myelosuppressive drugs may require modification of dosage/timing of schedules in order to minimize additive effects.

     Grace Carboplatin Injection courses should not, in general, be repeated more frequently than every 4 weeks in order to ensure that the nadir in blood counts has occurred and there has been recovery to a satisfactory level.

     Patients with severe and persistant myelosuppression are at high risk of infectious complications including fatal outcomes. If any of these events occurs, Grace Carboplatin Injection should be interrupted and dose modification or discontinuation should be considered.

 

Allergic reactions

     As with other platinum-based drugs, allergic reactions appearing most often during administration may occur and necessitate discontinuation of infusion. Patients should be observed carefully and an appropriate symptomatic treatment(including antihistamines, adrenaline and/or glucocorticoids) must also be initiated in such cases. Cross reactions, sometimes fatal, have been reported with all the platinum compounds.

     The vial stopper contains dry natural rubber (a derivative of latex), which may cause allergic reactions.

 

Renal Toxicity

In patients with impaired renal function, the effect of Grace Carboplatin Injection on the haemotopoietic system is more pronounced and longer-acting than in patients with normal renal function. In this risk group, therapy with Grace Carboplatin Injection must be performed with special caution.

 

Precautions:

     Grace Carboplatin Injection should only be administered under the supervision of a qualified physician who is experienced in the use of chemotherapeutic agents. Diagnostic and treatment facilities should be readily available for management of therapy and possible complications.

     Peripheral blood counts, renal and hepatic function tests should be monitored closely. Blood counts should be performed prior to commencement of Grace Carboplatin Injection therapy and at weekly intervals thereafter. The drug should be discontinued if abnormal depression of the bone marrow or abnormal renal or hepatic function is seen.

 

Haematologic Toxicity

Leukopenia, neutropenia, and thrombocytopenia are dose-dependent and dose-limiting. Peripheral blood counts should be monitored during Grace Carboplatin Injection treatment. This will monitor toxicity and help determine the nadir and recovery of haematological parameters and assist in subsequent dosage adjustments. Median day of nadir is day 21 in patients receiving single agent Grace Carboplatin Injection and day 15 in patients receiving Grace Carboplatin Injection in combination with other chemotherapeutic agents. In general, single intermittent courses of Grace Carboplatin Injection should not be repeated until leukocyte, neutrophil, and platelet counts have returned to normal. Lowest levels of platelets are generally seen between days 14 and21 of initial therapy. A greater reduction is seen in patients who previously received extensive myelosuppressive chemotherapy. Lowest levels of white cells occur generally between days 14 and 28 of initial therapy. If neutrophil levels fall below 2000 cells/mm3 or platelets are less than 100,000 cells/mm³ then postponement of Grace Carboplatin Injection therapy until bone barrow recovery is evident, should be considered. This recovery usually takes 5 to 6 weeks. Transfusions may be necessary and dosage reductions recommended for subsequent treatment.

 

Anaemia is frequent and cumulative, however rarely requires a transfusion

Haemolytic-uraemic syndrome (HUS)

     Haemolytic-uraemic syndrome (HUS) is a life-threatening side effect. Grace Carboplatin Injection should be discontinued at the firstsigns of any evidence of microangiopathic haemolytic anaemia, such as rapidly falling haemoglobin with concomitant thrombocytopenia, elevation of serum bilirubin, serum creatinine, blood urea nitrogen, or LDH. Renal failure may not be reversible with discontinuation of therapy and dialysis may be required.

     Haemolyticanaemia with the presence of serologic drug-induced antibodies has been reported in patients treated with Grace Carboplatin Injection. This event can be fatal.

     Acute promyelocytic leukaemia and myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) have been reported years after therapy with Grace Carboplatin Injection and other antineoplastic treatments.

 

Venoocclusive liver disease

Cases of hepatic venoocchusive disease (sinusoidal obstruction syndrome) have been reported, some of which were fatal. Patients should be monitored for signs and symptoms of abnormal liver function or portal hypertension which do not obviously result from liver metastases.

 

Tumour lysis syndrome (TLS)

In post marketing experience tumour lysis syndrome (TLS) has been reported in patients following the use of Grace Carboplatin Injection alone or in combination with other chemotherapeutic agents. Patient at high risk of TL.S, such as patients with high proliferative rate, high tumor burden, and high sensitivity to cytotoxic agents, should be monitored closely and appropriate precaution taken.

 

Renal toxicity

The incidence and severity of nephrotoxicity may increase in patients who have impaired kidney function before Grace Carboplatin Injection treatment. It is not clear whether an appropriate hydration programme might overcome such an effect but dosage reduction or discontinuation of therapy is required in the presence of severe alteration in renal function test. Impairment of renal function is more likely in patients who have previously experienced nephrotoxicity as a result of Cisplatin therapy.

 

Neurologic Toxicity

Although peripheral neurologic toxicity is generally common and mild, limited to paresthesia and decreases in osteotendinous reflexes, its frequency is increased in patients older than 65 years and/or in patients previously treated with cisplatin. Monitoring and neurological examinations should be carried out at regular intervals.

Visual disturbances, including loss of vision, have been reported after the use of Grace Carboplatin Injection in doses higher than those recommended in patients with renal impairment. Vision appears to recover totally or to a significant extent within weeks of stopping these high doses.

 

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

Cases of Reversible Posterior Leukoencephalopathy Syndrome (RPLS) have been reported in patients receiving Grace Carboplatin Injection in combination chemotherapy. RPLS is a rare, reversible (after treatment discontinuation), rapidly evolving neurological condition, which can include seizure, hypertension, headache, confusion, blindness, and other visual and neurological disturbances. Diagnosis of RPLS is based upon confirmation by brain imaging, preferably MRI (Magnetic Resonance lmaging)

 

Geriatric Use

In studies involving combination therapy with Grace Carboplatin Injection and cyclophosphamide, elderly patients treated with Grace Carboplatin Injection were more likely to develop severe thrombocytopenia than younger patients. Because renal function is often decreased in the elderly, renal function should be considered when determining dosage.

 

Other

     Auditory defects have been reported during Grace Carboplatin Injection therapy. Ototoxicity may be more pronounced in children and is more likely seen in patients previously treated with cisplatin.

     Cases of hearing loss with a delayed onset have been reported in pediatric patients. A long-term audiometric follow-up in this population is recommended.

     Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including Grace Carboplatin Injection may result in serious or fatal infections.

     Vaccination with a live vaccine should be avoided in patients receiving Grace Carboplatin Injection. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.

     Aluminium containing equipment should not be used during preparation and administration of Grace Carboplatin Injection.

 

DRUG INTERACTIONS:

     Grace Carboplatin Injection may interact with aluminium to form a black precipitate. Needles, syringes, catheters or IV administration sets that contain aluminium parts which may come into contact with Grace Carboplatin Injection, should not be used for the preparation or administration of the drug.

     Due to the increase of thrombotic risk in cases of tumoral diseases, the use of anticoagulative treatment is frequent. The high intra-individual variability of the coagulabilty during diseases, and the possibility of interaction between oral anticoagulants and anticancer chemotherapy, may require an increase in frequency of INR monitoring if a patient is treated with oral anticoagulants.

Concomitant use contraindicated

Yellow fever vaccine: risk of generalized disease mortal.

Concomitant use not recommended

– Live attenuated vaccines (except yellow fever): Risk of systemic, possible fatal disease. This is increased in subjects who are already immunosuppressed by their underlying disease. Use

inactivated vaccine where this exist (poliomyelitis).

– Phenytoin, fosphenytoin: Risk of exacerbation of convulsions (resulting from the decrease of phenytoin digestive absorption by the cytotoxic drug), risk of toxicity enhancement or loss of efficacy of the cytotoxic drug (due to increased hepatic metabolism by phenytoin).

Concomitant use to take into consideration

– Ciclosporin (and by extrapolation tacrolimus and sirolimus): Excessive immunosuppression with risk of lymphoproliferation.

– Concurrent therapy with nephrotoxic drugs or ototoxic drugs such as amino glycosides, vancomycin, capreomycin and diuretics, may increase or exacerbate toxicity, particularly in renal failure patients, due to Grace Carboplatin Injection induced changes in renal clearance.

– Loop diuretics: The concomitant use of Grace Carboplatin Injection with loop diuretic should be approached with caution due to the cumulative nephrotoxicity and ototoxicity.

Combination therapy with other myelosuppressive agents may require dose changes or rescheduling of doses in order to minimize the additive myelosuppressive effects

 

PREGNANCYAND LACTATION:

Pregnancy

     Grace Carboplatin Injection can cause foetal harm when administered to a pregnant woman. Grace Carboplatin Injection has been shown to be embryotoxic and teratogenic in rats receiving the drug during organogenesis. No controlled studies in pregnant women have been conducted.

     Safe use of Grace Carboplatin Injection in pregnancy has not been established. Both men and women receiving Grace Carboplatin Injection should be informed of the potential risk of adverse effects on reproduction. Women of chiidbearing potential should be advised to avoid becoming pregnant by using effective contraception and should be fully informed of the potential hazard to the foetus should they become pregnant during Grace Carboplatin Injection therapy. Grace Carboplatin Injection should not be used in pregnant women or women of childbearing potential who might become pregnant un less the potential benefits to the mother outweigh the possible risks to the foetus.

 

Breastfeeding

     It is not known whether Grace Carboplatin Injection is excreted in breast milk.

     To avoid possible harmful effects in the infant, breast-feeding must be stopped during Grace Carboplatin Injection therapy.

 

Fertility

     Gonadal suppression resulting in amenorrhoea or azospermia may occur in patients receiving antineoplastic therapy. These effects appear to be related to dose and length of therapy and may be irreversible. Prediction of the degree of testicular or ovarian functional impairment is complicated by the common use of combinations of several antineoplastics, which makes it difficult to assess the effects of individual agents.

     Men of sexually mature age treated with Grace Carboplatin Injection are advised not to father a child during treatment and up to 6 months afterwards. Male patients should seek advice about sperm preservation prior to initiation of the therapy because of the possibility of irreversible infertility due to therapy with Grace Carboplatin Injection.

 

SIDE EFFECTS

Like all medicines, this medicine can cause side effects, although not every body gets them. If any of the following happen, tell your doctor immediately:

– Abnormal bruising, bleeding, or signs of infection such as a sorethroat and high temperature.

– severe allergic reaction (anaphylaxis/anaphylactic reactions) – you may experience a sudden itchy rash (hives), swelling of the hands, feet, ankles, face, lips, mouth or throat (which may cause difficulty in swallowing or breathing), and you may feel you are going to faint

– muscle cramping, muscle weakness, confusion, visual loss or disturbances, irregular heartbeat kidney failure or abnormal blood test results (symptoms of tumorlysis syndrome which can be caused by the rapid breakdown of tumour cells)

 

These are serious side effects. You may need urgent medical attention.

 

Very common (may affect more than l in 10 people)

– Changes in your red and white blood cells and platelets (myelosuppression)

– Tiredness, shortness of breath and paleness caused by anaemia (a condition in which there is a decreased number of red blood cells)

– Increase in the level of urea in your blood.

– Abnormal liver enzyme levels.

– Feeling sick (nausea) or being sick (vomiting)

– Stomach pain and cramp

– Decrease in the level of sodium, potassium, calcium and magnesium in your blood.

– Decrease in renal creatinine clearance

– Common (may affect up to 1 in 10 people)

– Diarrhoea or constipation

– rash and/or itchy skin

– Ringing in the ears or changes in your hearing

– Hair loss Flu-like symptoms

– Signs of infection such as fever or sore throat

– symptoms of severe allergic reaction include sudden wheeziness or tightness of chest, swelling of the eyelids, face or lips, facial flushing, low blood pressure, rapid heartbeat, hives, shortness of breath, dizziness and anaphylactic shock

– tingling or numbness in your hands, feet, arms or legs.

– burning or prickling sensation

– decreased tendon reflex

– taste disturbance or loss of taste

– temporary worsening of eyesight or changes to your vision

– heart disorders

– tightness of the chest or wheezing

– interstitial lung disease (a group of lung disorders in which the deep lung tissues become inflamed)

– sore lips or mouth ulcers (mucous membrane disorders)

– pain or discomfort in your bones, joints, muscles, or surrounding structures(musculoskeletal disorder)

– problems with your kidneys or urine

– extreme tiredness/weakness (asthenia)

– increased level of bilirubin and creatinine in your blood

– increased level of uric acid in your blood which may lead to gout

 

Rare (may affect up to 1 in 1,000 people)

– temporary sight loss

– feeling unwell with high temperature due to low levels of white blood cells (febrile neutropenia)

 

Very rare (may affect up to 1 in 10,000 people)

– scarring of the lungs which causes shortness of breath and/or cough (pulmonary fibrosis)

 

Not known (frequency cannot be estimated from the available data)

– cancers caused by treatment with Grace Carboplatin Injection (secondary malignancies)

– haemolytic-uraemic syndrome (a disease characterised by acute renal failure)

– dry mouth, tiredness, and headache due to excessive loss of body water (dehydration)

– loss of appetite, anorexia

– stroke

– severely impaired liver function, damage or death of liver cells

– heart failure

– obstruction in blood vessel (embolism)

– changes in blood pressure (hypertension or hypotension)

– skin disorders such as hives, rash, skin redness (erythema), and itching

– swelling or soreness where the injection was given

– a group of symptoms such as headache, altered mental functioning, seizures and abnormal vision from blurriness to vision loss (symptoms of reversible posterior leukoencephalopathy

– syndrome, a rare neurological disorder)

– Pancreatitis

– sore or inflammation inside of the mouth (stomatitis)

– lung infection

Grace Carboplatin Injection may lead to problems with your blood, liver and kidneys. Your doctor will take blood samples to check for these problems

 

OVERDOSAGE

There is no known antidote for Grace Carboplatin Injection over dosage. No over dosage occurred during clinical trials. If necessary, however, the patient may need supportive treatment relating to myelosuppression, renal, hepatic and auditory function impairment. Reports of doses up to 1600mg/m2 indicate patients feeling extremely ill with diarrhoea and alopecia developing. Use of higher than recommended doses of Grace Carboplatin Injection has been associated with loss of vision.

 

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

Pharmacother apeutic group: Antineoplastic agents ATC code: LO1XA02

Grace Carboplatin Injection, like Cisplatin, interferes with DNA intra-strand and inter-strand crosslinks in cells exposed to the drug. DNA reactivity has been correlated with cytotoxicity.

 

Paediatric population

Safety and efficacy in children have not been established.

 

Pharmacokinetic properties

Absorption

After a 1-hour infusion (20-520mg/m2), plasma levels of total platinum and free (ultra filterable) platinum decay biphasically following first order kinetics. For free platinum, the initial phase (t alpha) half life is approximately 90 minutes and the later phase (t beta) half life approximately ó hours. All free platinum is in the form of Grace Carboplatin Injection in the first 4 hours after administration.

 

Distribution

Protein binding of Grace Carboplatin Injection reaches 85-89% within 24 hours of administration, although during the first 4 hours, only up to 29% of the dose is protein bound. Patients with poor renal function may require dosage adjustments due to altered pharmacokinetics of Grace Carboplatin Injection.

 

Elimination

     Grace Carboplatin Injection is excreted primarily by glomerular filtration in urine, with recovery of 65% of a dose within 24 hours. Most of the drug is excreted within the first 6 hours.

     Approximately 32% of a given dose of Grace Carboplatin Injection is excreted unchanged.

     Grace Carboplatin Injection clearance has been reported to vary by 3- to 4- fold in paediatric patients. As for adult patients, literature data suggest that renal function may contribute to the variation in Grace Carboplatin Injection clearance.

 

 

PHARMACEUTICAL PARTICULARS

List of Excipients:

 

Water for Injection

 

Shelf life: 24 months

 

Storage: Store below 30°C.

 

Nature and contents of container:

 

Grace Carboplatin Injection 150 mg: 15 mL filled in 20 mL USP type I amber tubular vials, stoppered with 20 mm grey bromo butyl stoppers and sealed with 20 mm flip off seal.

 

Grace Carboplatin Injection 450 mg: Filled in 50 mL USP type I amber tubular vials, stoppered with 20 mm bromo butyl stoppers and sealed with 20 mm flip off seal.

 

Manufactured By:

M/s Jodas Expoim Pvt. Ltd.,

Plot no. 55, Biotech Park, Phase-IIII

Karkapatla (v), Markook (M), Siddipet (D),

Telangana, Pin- 502279.

INDIA.

 

Product of:

Grace Biogen Pty Ltd.,

Page 15 of 24

Sydney, Australia.