Spalcarb 50 mg/150 mg/450 mg Solution

SPALCARB is indicated for the treatment of:

• 1. Advanced ovarian carcinoma of epithelial origin in:
• a.) First line therapy.
• b.) Second line therapy, after other treatments have failed.
• 2. Limited evidence in support of the following:
• a) Small cell carcinoma of the lung.
• b) The treatment of squamous cell carcinoma of the head and neck.

Posology

The recommended dosage of SPALCARB in previously untreated adult patients with normal kidney function is 400 mg/m2 as a single IV dose administered by a short term (15 to 60 minutes) infusion. Therapy should not be repeated until four weeks after the previous SPALCARB course and/or until the neutrophil count is at least 2 000 cells/mm3 and the platelet count is at least 100 000 cells/mm3. Reduction of the initial dosage by 20 to 25 % is recommended for those patients who present with risk factors such as prior myelosuppressive treatment and low performance status (ECOG- Zubrod 2 u2013 4 or Karnofsky below 80). For patients aged 65 and over, dosage adjustments, initially or subsequently, may be necessary, depending on the physical condition of the patient. Determination of the haematological nadir by weekly blood counts during the initial courses of treatment with SPALCARB is recommended for future dosage adjustment.

Special populations

Impaired Renal Function: The optimal use of SPALCARB in patients presenting with impaired renal function requires adequate dosage adjustment and frequent monitoring of both haematological nadirs and renal function. Patients with creatinine clearance values below 60 ml/min are at increased risk of severe myelosuppression. The frequency of severe leucopenia, neutropenia, or thrombocytopenia has been maintained at about 25 % with the following dosage recommendations: SPALCARB 250 mg/m2 IV on day 1 in patients with baseline creatinine clearance values between 41 u2013 59 ml/min. SPALCARB 200 mg/m2 IV on day 1 in patients with baseline creatinine clearance values between 16 u2013 40 ml/min. Insufficient data exist on the use of SPALCARB in patients with creatinine clearance of 15 ml/min or less to permit a recommendation for treatment. All of the above dosing recommendations apply to the initial course of treatment. Subsequent dosages should be adjusted according to the patientu2019s tolerance and to the acceptable level of myelosuppression.

Combination Therapy: The optimal use of SPALCARB in combination with other myelosuppressive medicines requires dosage adjustments according to the regimen and schedule to be adopted.

Elderly: Dosage adjustment, initially or subsequently, may be necessary dependent on the physical condition of the patient.

Paediatrics: Safety and efficacy in paediatrics have not been established.

Method of administration

SPALCARB should be used by the intravenous route only.

SPALCARB is contraindicated in:

• hypersensitivity to the active substance or to any of the excipients listed in 6.1
• patients with a history of severe hypersensitivity reactions to carboplatin or other platinum-containing compounds.
• patients with severe pre-existing renal impairment (creatinine clearance at or below 20 ml/min).
• severely myelosuppressed patients and/or in patients with localised tumoral bleeding.
• concomitant use with yellow fever vaccine (see section 4.5)
• Pregnancy and lactation.

Hypersensitivity reactions to carboplatin have been reported. These may occur within minutes of administration and should be managed with appropriate supportive therapy. There is an increased risk of allergic reactions, including anaphylaxis in patients previously exposed to platinum therapy (see section 4.3).

SPALCARB should be used only by a medical practitioner experienced with cancer chemotherapeutic medicines. Appropriate management of therapy and complications is possible only when adequate diagnostic and treatment facilities are readily available. Blood counts as well as renal and hepatic function tests must be done regularly and the medicines should be discontinued if abnormal depression of the bone marrow or abnormal renal or hepatic function is seen.

Haematological Toxicity: Myelosuppression (leucopenia, neutropenia and thrombocytopenia) is dose-dependent and dose limiting. Peripheral blood counts should be monitored frequently and until recovery is achieved. Median day of nadir is day 21 in patients receiving single medicine SPALCARB and day 15 in patients receiving SPALCARB in combination with other chemotherapeutic medicines. Single intermittent courses of SPALCARB should not be repeated until leucocyte, neutrophil and platelet counts have returned to normal. Transfusional support is frequently needed during treatment with SPALCARB, particularly in patients receiving prolonged therapy, since anaemia is cumulative. Myelosuppression is increased in patients with prior treatment (in particular with cisplatin) and/or impaired kidney function. Initial SPALCARB dosages in these groups of patients should be appropriately reduced (see section 4.2) and the effects carefully monitored through frequent blood counts between courses. SPALCARB combination therapy with other myelosuppressive forms of treatment must be planned very carefully with respect to dosages and timing in order to minimise additive effects.

Haemolytic-uremic syndrome (HUS): Haemolytic-uremic syndrome (HUS) is a life-threatening side effect. Carboplatin should be discontinued at the first signs of any evidence of micro-angiopathic 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.

Neurologic Toxicity: Although peripheral neurologic toxicity is mild, its incidence is increased in patients older than 65 years and/or in patients previously treated with platinum components. Visual disturbances, including loss of vision, have been reported less frequently after the use of carboplatin in doses higher than those recommended in patients with renal impairment.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Cases of Reversible Posterior Leukoencephalopathy Syndrome (RPLS) have been reported in patients receiving carboplatin 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 Imaging).

Venoocclusive liver disease: Cases of hepatic venoocclusive 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.

Other: Very high dosages of carboplatin (up to five times the single medicine recommended dose or more) have resulted in severe abnormalities in hepatic and renal function. SPALCARB carcinogenic potential has not been studied, but compounds with similar mechanisms of action and mutagenicity have been reported to be carcinogenic.

NOTE: SPALCARB interacts with aluminium to form a black precipitate and/or loss of potency. It is important not to use IV sets, needles, catheters or syringes containing aluminium parts while mixing or administering SPALCARB.

Elderly Use: In studies involving combination therapy with carboplatin and cyclophosphamide, elderly patients treated with carboplatin 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.

Paediatric Use: Safety and effectiveness in paediatric patients have not been systematically studied.

Carboplatin 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 carboplatin, should not be used for the preparation or administration of the medicine.

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 coagulability 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. (see section 4.3)

Concomitant use not recommended:

• Live attenuated vaccines (except yellow fever): Risk of systemic, possible fatal disease. This is increased in patients who are already immunosuppressed by their underlying disease. Use inactivated vaccine where this exists (poliomyelitis).
• Phenytoin, fosphenytoin: Risk of exacerbation of convulsions (resulting from the decrease of phenytoin digestive absorption by the cytotoxic medicine), risk of toxicity enhancement or loss of efficacy of the cytotoxic medicine (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 medicines or ototoxic medicines such as amino glycosides, vancomycin, capreomycin and diuretics, may increase or exacerbate toxicity, particularly in renal failure patients, due to Carboplatin induced changes in renal clearance.
• Loop diuretics: The concomitant use of carboplatin with loop diuretic should be approached with caution due to the cumulative nephrotoxicity and ototoxicity.
• Combination therapy with other myelosuppressive medicines may require dose changes or rescheduling of doses in order to minimize the additive myelosuppressive effects.
• Hearing loss has been reported to occur in paediatric patients when carboplatin was administered in combination with other ototoxic medicines.
• SPALCARB can induce nausea and vomiting, which can be more severe in previously treated patients (in particular in patients previously pre-treated with cisplatin).

Women of childbearing potential: It is recommended that patients with child-bearing or conceiving potential, who are receiving SPALCARB, exercise adequate contraception control.

Pregnancy: Pregnancy is a contraindication. SPALCARB has been shown to be an embryotoxin and mutagen (see section 4.3).

Breast-feeding: Safety in lactation has not been established. It is not known whether SPALCARB is excreted in breast milk (see section 4.3). To avoid possible harmful effects in the infant, breast-feeding must be stopped during carboplatin 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 medicines. Men of sexually mature age treated with SPALCARB 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 carboplatin.

No studies of the effects on the ability to drive and use machines have been performed. However, SPALCARB may cause nausea, vomiting, vision abnormalities and ototoxicity; therefore, patients should be warned of the potential effect of these events on the ability to drive or to use machines.

The following adverse reactions based on frequency have been reported in patients receiving single medicine carboplatin injection.

System Organ Class Frequency MedDRA Term

• Neoplasms, benign and malignant and unspecified (incl cysts and polyps) Unknown Treatment related secondary malignancy
• Infections and infestations Frequent Infections*
• Unknown Pneumonia
• Blood and lymphatic system disorders Frequent Thrombocytopenia, neutropenia, leukopenia, anaemia
• Frequent Haemorrhage*
• Unknown Bone marrow failure, febrile neutropenia, haemolytic-uraemic syndrome, haemolytic anaemia
• Immune system disorders Frequent Hypersensitivity, anaphylactoid type reaction
• Metabolism and nutrition disorders Unknown Dehydration, anorexia, hyponatraemia, Tumour lysis syndrome
• Nervous system disorders Frequent Paraesthesia, decrease of osteotendinous reflexes, sensory disturbance, dysgeusia
• Less frequent Peripheral neuropathy
• Unknown Cerebrovascular accident*, encephalopathy, Reversible Posterior Leukoencephalopathy Syndrome (RPLS)
• Eye disorders Frequent Visual disturbance (incl. rare cases of loss of vision)
• Ear and labyrinth disorders Frequent Ototoxicity
• Cardiac disorders Frequent Cardiovascular disorder*
• Unknown Cardiac failure*
• Vascular disorders Unknown Embolism*, hypertension, hypotension, venoocclusive disease (fatal)
• Respiratory, thoracic and mediastinal disorders Frequent Respiratory disorder, interstitial lung disease, bronchospasm
• Gastrointestinal disorders Frequent Vomiting, nausea, abdominal pain, diarrhoea, constipation, mucous membrane disorder
• Unknown Stomatitis, pancreatitis
• Skin and subcutaneous tissue disorders Frequent Alopecia, skin disorder
• Unknown Urticaria, rash, erythema, pruritus
• Musculoskeletal and connective tissue disorders Frequent Musculoskeletal disorder
• Renal and urinary disorders Frequent Urogenital disorder
• General disorders and administration site conditions Frequent Asthenia
• Unknown Injection site necrosis, injection site reaction, injection site extravasation, injection site erythema, malaise
• Investigations Frequent Creatinine renal clearance decreased, blood urea increased, blood alkaline phosphatase increased, aspartate aminotransferase increased, liver function test abnormal, blood sodium decreased, blood potassium decreased, blood calcium decreased, blood magnesium decreased.
• Blood bilirubin increased, blood creatinine increased, blood uric acid increased

* Fatal in <1%, fatal cardiovascular events in <1% included cardiac failure, embolism, and cerebrovascular accident combined.

Description of selected adverse reactions:

Blood and lymphatic system disorders: Myelosuppression is the dose-limiting toxicity of SPALCARB injection. In patients with normal baseline values, thrombocytopenia with platelet counts below 50,000/mm3 occurs in 25% of patients, neutropenia with granulocyte counts below 1,000/mm3 in 18% of patients, and leukopenia with WBC counts below 2,000/mm3 in 14% of patients. The nadir usually occurs on day 21. Myelosuppression can be worsened by combination of carboplatin injection with other myelosuppressive compounds or forms of treatment. Myelotoxicity is more severe in previously treated patients, in particular in patients previously treated with cisplatin and in patients with impaired kidney function. Patients with poor performance status have also experienced increased leukopenia and thrombocytopenia. These effects, although usually reversible, have resulted in infectious and hemorrhagic complications in patients given carboplatin injection, respectively. These complications have led to death in less than 1% of patients. Anaemia with haemoglobin values below 8 g/dL has been observed in patients with normal baseline values. The incidence of anaemia is increased with increasing exposure to SPALCARB injection.

Neoplasms, benign, malignant and unspecified (including cysts and polyps): Secondary acute malignancies after cytostatic combination therapies containing carboplatin have been reported.

Respiratory, thoracic and mediastinal disorders: Pulmonary fibrosis has been reported, manifested by tightness of the chest and dyspnoea. This should be considered if a pulmonary hypersensitivity state is excluded (see General disorders below).

Gastrointestinal disorders: Nausea and vomiting are commonly seen. Previously treated patients (in particular patients previously treated with cisplatin) appear to be more prone to vomiting. Nausea and vomiting are generally delayed until 6 to 12 hours after administration of SPALCARB, are readily controlled or prevented with antiemetics and disappear within 24 hours. Vomiting is more likely when SPALCARB injection is given in combination with other emetogenic compounds.

Nervous system disorders: Peripheral neuropathy (mainly paresthesias and decrease of osteotendinous reflexes) has occurred in patients administered SPALCARB injection. Patients older than 65 years and patients previously treated with cisplatin, as well as those receiving prolonged treatment with SPALCARB injection, appear to be at increased risk. Clinically significant-sensory disturbances (ie, visual disturbances and taste modifications) have occurred in patients. The overall frequency of neurologic side effects seems to be increased in patients receiving SPALCARB injection in combination. This may also be related to longer cumulative exposure. Parasthesias present prior to treatment, especially if caused by cisplatin, may persist or worsen during SPALCARB therapy.

Eye disorders: Visual disturbances, including sight loss, are usually associated with high dose therapy in renally impaired patients.

Ear and labyrinth disorders: A subclinical decrease in hearing acuity in the high frequency range (4000-8000 Hz), determined by audiogram, occurred in patients. Rare cases of hypoacusia have been reported. Tinnitus was also commonly reported. Hearing loss as a result of cisplatin therapy may give rise to persistent or worsening symptoms. At higher than recommended doses, in common with other ototoxic medicines, clinically significant hearing loss has been reported to occur in paediatric patients when carboplatin is administered.

Hepatobiliary disorders: Modification of liver function in patients with normal baseline values was observed, including elevation of total bilirubin, SGOT and alkaline phosphatase in patients. These modifications were generally mild and reversible in about one-half the patients. In a limited series of patients receiving very high dosages of carboplatin injection and autologous bone marrow transplantation, severe elevation of liver function tests has occurred. Cases of an acute, fulminant liver cell necrosis occurred after high-dose administration of carboplatin.

Renal and urinary disorders: When given in usual doses, development of abnormal renal function has been uncommon, despite the fact that carboplatin injection has been administered without high-volume fluid hydration and/or forced diuresis. Elevation of serum creatinine occurs in patients, elevation of blood urea nitrogen, and of uric acid in patients. These are usually mild and are reversible in about one-half the patients. Creatinine clearance has proven to be the most sensitive renal function measure in patients receiving SPALCARB injection. Patients who have a baseline value of 60 mL/min or greater, experience a reduction in creatinine clearance during SPALCARB injection therapy. Impairment of renal function is more likely in patients who have previously experienced nephrotoxicity as a result of cisplatin therapy.

Immune system disorders: Anaphylactic-type reactions, sometimes fatal, may occur in the minutes following injection of SPALCARB: facial oedema, dyspnoea, tachycardia, low blood pressure, urticaria, anaphylactic shock, bronchospasm. Fever with no apparent cause has also been reported.

Skin and subcutaneous tissue disorders: Erythematous rash, fever and pruritis have been observed. These were reactions similar to those seen after cisplatin therapy but in a few cases no cross-reactivity was present.

Investigations: Decreases in serum sodium, potassium, calcium, and magnesium occur in patients. In particular, cases of early hyponatraemia have been reported. The electrolyte losses are minor and mostly take a course without any clinical symptoms.

Cardiac disorders: Isolated cases of cardiovascular incidents (cardiac insufficiency, embolism) as well as isolated cases of cerebrovascular accidents have been reported.

Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reaction Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

There is no known antidote for SPALCARB overdosage. The anticipated complications of overdosage would be related to myelosuppression as well as impairment of hepatic and renal function. Use of higher than recommended doses of SPALCARB has been associated with loss of vision.