Accord Paclitaxel Injection

ACCORD PACLITAXEL is indicated for:

• The palliative treatment of stage 3 or 4 advanced local carcinoma of the ovary after surgical resection, in combination with cisplatin.
• The palliative management of metastatic carcinoma of the ovary after failure of first line or subsequent chemotherapy.
• The treatment of metastatic carcinoma of the breast after failure combination chemotherapy or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contra-indicated.
• First line therapy of advanced or metastatic breast cancer in combination with trastuzumab in patients who over-express HER-2 at a 2+ or 3+ level as determined by immunohistochemistry.
• Palliative treatment of advanced non-small cell lung cancer in patients who are not candidates for potentially curative surgery and/or radiation therapy.

Posology

Indication 1: Primary treatment of ovarian carcinoma: A combination regimen consisting of ACCORD PACLITAXEL 175 mg/m2 administered intravenously over 3 hours, followed by cisplatin 75 mg/m2 given every 3 weeks. Alternatively a combination regimen consisting of ACCORD PACLITAXEL 135 mg/m2 administered over 24 hours, followed by cisplatin 75 mg/m2, every 3 weeks. ACCORD PACLITAXEL should be administered before cisplatin.

Indication 2 and 3: Secondary treatment of ovarian carcinoma: ACCORD PACLITAXEL at a dose of 175 mg/m2 administered intravenously over 3 hours every 3 weeks has been shown to be effective in patients with metastatic carcinoma of the ovary or breast after the failure of first line or subsequent chemotherapy.

Indication 4: Combination, first-line therapy of advanced or metastatic breast cancer: In combination with trastuzumab, the recommended dose of ACCORD PACLITAXEL is 175 mg/m2 administered intravenously over a period of 3 hours, with a 3 week interval between courses. ACCORD PACLITAXEL infusion may be started the day following the first dose of trastuzumab or immediately after the subsequent dose of trastuzumab if the preceding dose of trastuzumab was well tolerated.

Indication 5: Palliative treatment of advanced non-small cell lung carcinoma: the recommended dose of ACCORD PACLITAXEL is 175 mg/m2 administered over a period of 3 hours; followed by a platinum compound, with a 3 week interval between courses. ACCORD PACLITAXEL should not be re-administered until the neutrophil count is at least 1 500/mm3 and the platelet count is at least 100 000/mm3. Patients who experience severe neutropenia (neutrophil count <500/mm3) or moderate to severe peripheral neuropathy should receive a dose reduction of 20 % for subsequent courses (see section 4.4).

The incidence and severity of neurotoxicity and haematological toxicity increases with dose. All patients must be premedicated prior to ACCORD PACLITAXEL administration to reduce the risk of severe hypersensitivity reactions. Such premedications may be corticosteroids, antihistamines, and H2 antagonists prior to ACCORD PACLITAXEL administration, e.g. dexamethasone 20 mg orally approximately 12 and 6 hours before ACCORD PACLITAXEL or 20 mg IV approximately 30-60 minutes prior to ACCORD PACLITAXEL, and cimetidine 300 mg or ranitidine 50 mg, IV 30 to 60 minutes before ACCORD PACLITAXEL. ACCORD PACLITAXEL should be administered through an in-line filter with a microporous membrane not greater than 0,22 u03bcm.

• ACCORD PACLITAXEL is contra-indicated in patients who have a history of severe hypersensitivity reactions to paclitaxel, or other medicines formulated with polyoxyethylated castor oil or to any of the excipients listed in section 6.1.
• ACCORD PACLITAXEL should not be used in patients with baseline neutrophils < 1500 /mm3.
• Pregnancy and lactation (see section 4.6).
• The safety and effectiveness of ACCORD PACLITAXEL in children has not been established.

ACCORD PACLITAXEL should be administered under the supervision of a medical practitioner experienced in the use of cancer chemotherapeutic medicines. Since severe hypersensitivity reactions may occur, appropriate supportive equipment should be available. ACCORD PACLITAXEL should be administered as a diluted infusion. ACCORD PACLITAXEL should be given before cisplatin when used in combination. Patients should be pre-treated with corticosteroids, antihistamines and H2 antagonists before receiving ACCORD PACLITAXEL.

Hypersensitivity reactions

Anaphylaxis and severe hypersensitivity reactions characterised by dyspnoea, flushing, chest pain and tachycardia and hypotension requiring treatment, angioedema and generalised urticaria have occurred in patients receiving ACCORD PACLITAXEL. These reactions are probably histamine-mediated. Rare fatal reactions have occurred in patients despite pre-treatment. In cases of severe hypersensitivity reactions, ACCORD PACLITAXEL infusion should be immediately discontinued, symptomatic therapy should be initiated and the patient should not be rechallenged with the agent. Minor hypersensitivity reactions such as flushing, skin reactions, and not requiring treatment do not require interruption of therapy.

Bone marrow suppression

Bone marrow suppression (primary neutropenia) is the principal dose-limiting toxicity. Frequent monitoring of blood counts should be instituted during ACCORD PACLITAXEL treatment. Patients should not be retreated until neutrophils recover to a level >1500/mm3 and platelets recover to a level >100 000/mm3. In cases of severe neutropenia (< 500 cells/mm3) during a course of ACCORD PACLITAXEL, a 20 % reduction in dose for subsequent courses of therapy is recommended. The incidence of neurotoxicity and the severity of neutropenia increase with dose within a regimen.

Cardiovascular

Severe cardiac conduction abnormalities have been reported. If patients develop significant conduction abnormalities during ACCORD PACLITAXEL administration, appropriate therapy should be administered and continuous cardiac monitoring should be performed during subsequent therapy with ACCORD PACLITAXEL. Severe cardiovascular events were observed more frequently in patients with non-small cell lung carcinoma than breast or ovarian carcinoma. Hypotension, hypertension and bradycardia have been observed during administration of ACCORD PACLITAXEL but generally do not require treatment. In severe cases, ACCORD PACLITAXEL infusions may need to be interrupted or discontinued at the discretion of the treating medical practitioner. Frequent vital sign monitoring, particularly during the first hour of ACCORD PACLITAXEL infusion, is recommended. Continuous cardiac monitoring is not required except for patients with serious conduction abnormalities. Cases of myocardial infarction have been reported. Congestive heart failure has been reported typically in patients who have received other chemotherapy, notably anthracyclines. Patients may experience severe cardiovascular events possibly related to ACCORD PACLITAXEL administration. Included are hypertension, venous thrombosis, ventricular tachycardia, and atrioventricular conduction block. ECG alterations are experienced by some patients. The most frequently reported ECG modification is non-specific repolarization abnormalities, sinus tachycardia and premature beats.

Paclitaxel clearance is not affected by cimetidine premedication. Cisplatin: The recommended regimen of ACCORD PACLITAXEL administration for the primary treatment of ovarian carcinoma is for ACCORD PACLITAXEL to be given before cisplatin. When ACCORD PACLITAXEL is given before cisplatin, the safety profile of ACCORD PACLITAXEL is consistent with that reported for single product use. When ACCORD PACLITAXEL was given after cisplatin, patients showed a more profound myelosuppression and an approximately 33 % decrease in paclitaxel clearance. Patients treated with paclitaxel and cisplatin may have an increased risk of renal failure as compared to cisplatin alone in gynaecological cancers.

Ketoconazole: Medications concomitantly administered with ACCORD PACLITAXEL (e.g. corticosteroids, antihistamines, and H2 antagonists) did not appear to interact adversely; however, possible interactions of ACCORD PACLITAXEL with concomitantly administered medications have not been formally investigated. Based on in vitro data, there is the possibility of the inhibition of ACCORD PACLITAXEL metabolism in patients treated with ketoconazole. As a result, caution should be exercised when treating patients with ACCORD PACLITAXEL when they are receiving ketoconazole as concomitant therapy.

Doxorubicin: Plasma levels of doxorubicin and doxorubicinol may be increased when ACCORD PACLITAXEL and doxorubicin are used in combination. Sequence effects characterised by more profound neutropenic and stomatitis episodes, have been observed with combination use of ACCORD PACLITAXEL and doxorubicin, when ACCORD PACLITAXEL was administered before doxorubicin and using longer than recommended infusion times.

Active substances metabolised in the liver: The metabolism of paclitaxel is catalysed by cytochrome P450 isoenzymes CYP2C8 and CYP3A4. In the absence of formal clinical interaction studies, caution should be exercised when administering ACCORD PACLITAXEL concomitantly with known substrates, inducers or inhibitors of these isoenzymes, e.g., ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, clopidogrel, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) because toxicity of paclitaxel may be increased due to higher paclitaxel exposure. Administering paclitaxel concomitantly with medicines known to induce either CYP2C8 or CYP3A4 (e.g. rifampicin, carbamazepine, phenytoin, efavirenz, nevirapine) is not recommended because efficacy may be compromised because of lower paclitaxel exposures.

PVC equipment: Contact of the undiluted concentrate with plasticised polyvinyl chloride (PVC) equipment or devices used to prepare solutions for infusion is not recommended. In order to minimise patient exposure to the plasticiser DEHP [di-(2-ethylhexyl) phthalate], which may be leached from PVC infusion bags or sets, diluted ACCORD PACLITAXEL solutions should preferably be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets. ACCORD PACLITAXEL should be administered through an in-line filter with a microporous membrane not greater than 0,22 microns. Use of filter devices such as IVEX-2 filters which incorporate short inlet and outlet PVC coated tubing has not resulted in significant leaching of DEHP.

Women of childbearing potential should be advised to avoid becoming pregnant during therapy with ACCORD PACLITAXEL and to inform the treating medical practitioner immediately should this occur. Female and male patients of fertile age, and/or their partners should use contraception for at least 6 months after treatment with paclitaxel.

Pregnancy: ACCORD PACLITAXEL should not be used during pregnancy. There is no information on the use of ACCORD PACLITAXEL in pregnant women. ACCORD PACLITAXEL may cause foetal harm when administered to pregnant women.

Breastfeeding: It is not known whether ACCORD PACLITAXEL is excreted in human milk. Breast feeding should be discontinued for the duration of ACCORD PACLITAXEL therapy.

Fertility: ACCORD PACLITAXEL has been shown to be embryotoxic, foetotoxic and to decrease fertility in animal studies. Male patients should seek advice regarding cryo-conservation of sperm prior to treatment with paclitaxel because of the possibility of infertility.

This medicine contains alcohol, which may impair the ability to drive or operate machines.

a. Summary of the safety profile

The frequency and severity of adverse events are generally similar between patients receiving ACCORD PACLITAXEL for the treatment of ovarian, breast or lung carcinoma.

b. Tabulated list of adverse reactions

System organ class Frequency Adverse reaction Infections and infestations Frequent Less Frequent Infection (mainly urinary tract and upper respiratory tract infections), with reported cases of fatal outcome Septic shock, pneumonia, peritonitis, sepsis, pseudomembranous colitis Blood and lymphatic system disorders Frequent Less Frequent Frequency unknown Myelosuppression, neutropenia, anaemia, thrombocytopenia, leukopenia, bleeding Febrile neutropenia, acute myeloid leukaemia, myelodysplastic syndrome Disseminated intravascular coagulation (DIC) Immune system disorders Frequent Less Frequent Minor hypersensitivity reactions (mainly flushing and rash) Significant hypersensitivity reactions requiring therapy (e.g. hypotension, angioedema, respiratory distress, generalised urticaria, oedema, back pain, chills, chest pain, tachycardia, abdominal pain, pain in extremity, diaphoresis, and hypertension), anaphylactic reactions (with fatal outcome), anaphylactic shock Bronchospasm Metabolism and nutrition disorders Less Frequent Frequency unknown Anorexia, dehydration Tumour lysis syndrome Psychiatric disorders Less Frequent Confusional state Nervous system disorders Frequent Less Frequent Neurotoxicity (mainly peripheral neuropathy; can persist beyond 6 months of paclitaxel discontinuation) Motor neuropathy (with resultant minor distal weakness), autonomic neuropathy (resulting in paralytic ileus and orthostatic hypotension), grand mal seizures, convulsions, encephalopathy, dizziness, headache, ataxia. Eye disorders Less Frequent Frequency unknown Reversible optic nerve and/or visual disturbances (scintillating scotomata), particularly in patients who have received higher doses than recommended Macular oedema, photopsia, vitreous floaters Ear and labyrinth disorders Less Frequent Hearing loss, tinnitus, vertigo, ototoxicity Cardiac disorders Frequent Abnormal ECG, bradycardia Less Frequent Cardiomyopathy, asymptomatic ventricular tachycardia, tachycardia with bigeminy, AV block and syncope, myocardial infarction, cardiac failure, atrial fibrillation, supraventricular tachycardia Vascular disorders Frequent Less Frequent Frequency unknown Hypotension, hypertension, thrombosis, thrombophlebitis Shock, Phlebitis Respiratory, thoracic and mediastinal disorders Less Frequent Dyspnoea, pleural effusion, respiratory failure, interstitial pneumonia, lung fibrosis, pulmonary embolism, cough Gastro-intestinal disorders Frequent Less Frequent Nausea, vomiting, diarrhoea, mucosal inflammation. Bowel obstruction, bowel perforation, ischaemic colitis, pancreatitis, mesenteric thrombosis, neutropenic colitis oesophagitis, constipation, ascites Hepato-biliary disorders Less Frequent Hepatic necrosis (with fatal outcome), hepatic encephalopathy (with fatal outcome) Skin and subcutaneous tissue disorders Frequent Alopecia, transient and mild nail and skin changes Less Frequent Frequency unknown Pruritus, rash, erythema, cellulitis, skin exfoliation, necrosis and fibrosis, radiation recall. Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, exfoliative dermatitis, urticaria, onycholysis (patients on therapy should wear sun protection on hands and feet). Palmar-plantar erythrodysesthesia syndrome Musculoskeletal, connective tissue and bone disorders Frequent Frequency unknown Arthralgia, myalgia Systemic lupus erythematosus, scleroderma General disorders and administration site conditions Frequent Less Frequent Mucosal inflammation, injection site reactions (including localised oedema, pain, erythema, induration, on occasion extravasations can result in cellulitis). Asthenia, malaise, pyrexia, oedema Investigations Frequent Less Frequent Severe elevation in AST (SGOT), severe elevation in alkaline phosphatase Severe elevation in bilirubin, increase in blood creatinine.

c. Description of selected adverse reactions

Unless otherwise noted, the following discussion refers to the overall safety database of 812 patients with solid tumours treated with single-agent ACCORD PACLITAXEL in clinical studies administered as one of two doses (135 or 175 mg/m2) and one of the two schedules (3 or 24 hours) in the metastatic setting. Haematological toxicities: Bone marrow suppression was the major dose-limiting toxicity of ACCORD PACLITAXEL. Neutropenia, the most important haematological toxicity, was dose and schedule dependent and was generally rapidly reversible. Even neutropenia (< 500 cells/ mm3) was more frequent with the 24-hour than with the 3-hour infusion; infusion duration had a greater impact on myelosuppression than dose. Neutropenia did not appear to increase with cumulative exposure and did not appear to be more frequent nor more severe for patients previously treated with radiation therapy. Infectious episodes occurred very commonly and were fatal in 1 % of all patients, and included sepsis, pneumonia and peritonitis. Urinary tract infections and upper respiratory tract infections were the most frequently reported infectious complications. The use of supportive therapy, including G-CSF, is recommended for patients who have experienced severe neutropenia. Twenty percent of the patients experienced a drop in their platelet count below 100 000 cells/mm3 at least once while on treatment; 7 % had a platelet count <50 000 cells/mm3 at the time of their worst nadir. Bleeding episodes were reported in 4 % of all courses and by 14 % of all patients but most of the haemorrhagic episodes were localised and the frequency of these events was unrelated to the ACCORD PACLITAXEL dose and schedule.

Neurologic: In general, the frequency and severity of neurologic manifestations were dose dependent in patients receiving single-agent ACCORD PACLITAXEL. The frequency of peripheral neuropathy increased with cumulative dose. Paraesthesia commonly occurs in the form of hyperaesthesia. Peripheral neuropathy was the cause of ACCORD PACLITAXEL discontinuation in 1 % of all patients. Sensory symptoms have usually improved or resolved within several months of ACCORD PACLITAXEL discontinuation. Pre-existing neuropathies resulting from prior therapies are not a contra-indication for ACCORD PACLITAXEL therapy. Infrequent reports in the literature of abnormal visual evoked potentials in patients have suggested persistent optic nerve damage.

Hypersensitivity reactions (HSR): All patients received premedication prior to ACCORD PACLITAXEL therapy. The frequency and severity of HSR were not affected by the dose or schedule of ACCORD PACLITAXEL administration. The most frequent symptoms observed during these severe reactions were dyspnoea, flushing, chest pain and tachycardia. Abdominal pain, pain in the extremities, diaphoresis and hypertension are also noted. Minor hypersensitivity reactions, mainly flushing and rash, did not require therapeutic intervention nor did they prevent continuation of ACCORD PACLITAXEL therapy.

Injection site reactions: During intravenous administration, injection site reactions were usually mild and consisted of localised oedema, pain, erythema, tenderness and indurations; on occasion, extravasations can result in cellulitis. Skin sloughing and/or peeling has been reported sometimes related to extravasations. Skin discolouration may also occur. These reactions have been observed more frequently with the 24-hour infusion than with the 3-hour infusion. In some cases, the onset of the injection site reaction either occurred during a prolonged infusion or was delayed by a week to 10 days.

Cardiovascular: Hypotension, during the first 3 hours of infusion, occurred in 12 % of all patients and 3 % of all courses administered. Bradycardia, during the first 3 hours of infusion, occurred in 3 % of all patients and 1 % of all courses. ECG alterations in the form of re-polarisation abnormalities like sinus tachycardia, sinus bradycardia, and premature beats have been observed in clinical studies. Severe cardiac conduction abnormalities have been reported in <1 % of patients during ACCORD PACLITAXEL therapy. If patients develop significant conduction abnormalities during ACCORD PACLITAXEL administration, appropriate therapy should be administered and continuous electrocardiographic monitoring should be performed during subsequent therapy with ACCORD PACLITAXEL.

Gastro-intestinal (GI) toxicity: mild to moderate nausea, vomiting, diarrhoea and mucositis (also reported as pharyngitis or cheilitis) were reported frequently by all patients. Mucositis was schedule dependent and occurred more frequently with the 24-hour than with the 3-hour infusion. Less frequent reports of neutropenic enterocolitis (typhilitis), despite the co-administration of G-CSF, were observed in patients treated with ACCORD PACLITAXEL alone and in combination with other chemotherapeutic agents.

ACCORD PACLITAXEL and cisplatin: Cross-study comparison of neurotoxicity suggests that when ACCORD PACLITAXEL is given in combination with cisplatin 75 mg/m2, the incidence of severe neurotoxicity is more common at an ACCORD PACLITAXEL dose of 175 mg/m2 given by 3-hour infusion (21 %) than at a dose of 135 mg/m2 given by 24-hour infusion (3 %). ACCORD PACLITAXEL and radiotherapy: radiation pneumonitis has been reported in patients receiving concurrent radiotherapy.

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 Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

There is no antidote for ACCORD PACLITAXEL overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, peripheral neurotoxicity and mucositis. Overdoses in paediatric patients may be associated with acute ethanol toxicity. In case of overdose, the patient should be closely monitored. Treatment should be directed at the primary anticipated toxicities. Treatment is symptomatic and supportive.