Apealea

Apealea should only be administered under the supervision of a qualified oncologist in units specialised in the administration of cytotoxic agents. It should not be interchanged with other paclitaxel formulations. Posology The recommended dose of Apealea is 250 mg/m2 body surface area (BSA) given as an intravenous infusion over 1 hour followed by carboplatin every three weeks for six cycles.

The recommended dose of carboplatin is AUC = 5–6 mg/mL×min. 5 × 109/L and platelets recover to ≥ 100 × 109/L. For Apealea, dose reductions of initially 50 mg/m2 and additionally 25 mg/m2 should be considered for subsequent courses (see Table 1).

In the case of febrile neutropenia or low platelet count (< 75 × 109/L), the dose of carboplatin should be reduced by 1 AUC unit in the treatment cycles following recovery. For appropriate use of carboplatin, the prescriber is advised to consult the prescribing information for carboplatin as well.

Medicinal product no longer authorised 3 Dose reductions or/and delays should be considered as a result of any clinically significant adverse reaction as presented in Table 1. Table 1. 5 × 109/L or platelet count < 100 × 109/L or febrile neutropenia Withhold treatment until recovery Standard dose: 250 Possible dose reductions: First dose level reduction: 200 Second dose level reduction: 175 Nervous system disorders grade ≥ 2 peripheral sensory neuropathy or grade ≥ 2 motor neuropathy Withhold treatment until recovery to < grade 2 Dose reduction: First dose level reduction: 200 Possible dose reduction: Second dose level reduction: 175 All other adverse reactions Any grade 4 toxicity Discontinue treatment Any grade 3 toxicity except nausea, vomiting and diarrhoea Withhold treatment until symptoms resolve to grade ≤ 1 Possible dose reductions: First dose level reduction: 200 Second dose level reduction: 175 a Grade of the adverse reaction is defined according to Common Terminology Criteria for Adverse Events (CTCAE).

b The dose of carboplatin should be reduced by 1 AUC unit for treatment cycles following the occurrence of febrile neutropenia or low platelet count (< 75 × 109/L). 5 × upper limit of normal (ULN) and aspartate aminotransferase (AST) ≤ 10 × ULN) may be treated with the same doses as patients with normal hepatic function.

5 to ≤ 5 × ULN and AST ≤ 10 × ULN), a 20% reduction in dose is recommended. 2). 2). Renal impairment Patients with mildly or moderately impaired renal function (glomerular filtration rate (GFR) 89−60 mL/min or GFR 59−30 mL/min, respectively) may be treated with Apealea without a dose modification.

Summary of the safety profile The most common clinically significant adverse reactions associated with the use of Apealea are neutropenia, gastrointestinal disorders, peripheral neuropathy, arthralgia/myalgia, and infusion site reactions.

Approximately 86% of patients experienced adverse reactions. Tabulated list of adverse reactions The frequency of undesirable effects listed in Table 2 is defined using the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to < 1/1 000), very rare (< 1/10 000), and not known (cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 2 lists adverse reactions associated with the administration of Apealea in combination with carboplatin observed in a clinical study (N = 391) and adverse reactions from post-marketing experience.

The latter ones may be attributed to paclitaxel regardless of the treatment regimen. Medicinal product no longer authorised 8 Table 2. Listing of adverse reactions System organ class Frequency Preferred term Infections and infestations Uncommon: Sepsis, abscess, pneumonia, influenza, respiratory tract infection viral, herpes simplex, infusion site cellulitis, tonsillitis, urinary tract infection, skin infection, cystitis Neoplasms benign, malignant and unspecified (incl.

cysts and polyps) Uncommon: Metastatic pain Blood and lymphatic system disorders Very common: Neutropeniaa Common: Febrile neutropeniaa, leukopeniaa, thrombocytopeniaa, granulocytopenia, anaemiaa Uncommon: Disseminated intravascular coagulationa, pancytopenia, haematotoxicity, coagulopathy Immune system disorders Common: Hypersensitivity Uncommon: Anaphylactic shock, drug hypersensitivity Metabolism and nutrition disorders Very common: Anorexia Uncommon: Hyponatraemia, hypokalaemia, hypomagnesaemia, dehydration, decreased appetite Psychiatric disorders Uncommon: Depression, insomnia, anxiety Nervous system disorders Very common: Peripheral sensory neuropathya,b, neuropathy peripherala,b Common: Hypoaesthesia, dizziness, paraesthesia, peripheral motor neuropathy, dysgeusia, headache Uncommon: Status epilepticus, coma, cerebrovascular accident, peripheral sensorimotor neuropathy, lethargy, hypotonia, neurotoxicity, polyneuropathy, polyneuropathy in malignant disease, burning sensation, somnolence, cognitive disorder, facial palsy, encephalopathy, hydrocephalus Eye disorders Uncommon: Vision blurred, eye irritation, ocular discomfort, lacrimation increased Ear and labyrinth disorders Uncommon: Vertigo, deafness, inner ear disorder, tinnitus Cardiac disorders Common: Angina pectoris, tachycardia Uncommon: Cardiac arrest, cardiac failure chronic, cyanosis, atrial fibrillation, sinus tachycardia, palpitations, sinus bradycardia Vascular disorders Common: Hypotension, flushing, phlebitis, vein pain, hyperaemia Uncommon: Circulatory collapse, venous thrombosis, vasculitis, thrombosis, hypertension, deep vein thrombosis, lymphoedema, phlebitis superficial, thrombophlebitis, blood pressure fluctuation, haemorrhage, angiopathy, hot flush, pallor Medicinal product no longer authorised 9 System organ class Frequency Preferred term Respiratory, thoracic and mediastinal disorders Common: Dyspnoea, nasal congestion Uncommon: Respiratory failure, epistaxis, cough, rhinorrhoea, oropharyngeal pain, pharyngeal disorder, asphyxia, bronchospasm, dysphonia, rhinitis allergic, allergic cough, oropharyngeal discomfort Gastrointestinal disorders Very common: Diarrhoeaa, nauseaa, vomitinga Common: Abdominal pain, constipation, abdominal pain upper, flatulence, dry mouth, stomatitis Uncommon: Abdominal distension, gastritis, abdominal discomfort, abdominal pain lower, dyspepsia, faecaloma, intestinal functional disorder, gingival bleeding, haematochezia, paraesthesia oral Hepatobiliary disorders Uncommon: Hepatitis, liver disorder Skin and subcutaneous tissue disorders Very common: Alopeciaa Common: Erythema, rash, pruritus, urticaria Uncommon: Angioedema, rash generalised, skin discolouration, hyperhidrosis, rash papular, dermatitis bullous, swelling face, pigmentation disorder, dry skin, cold sweat, livedo reticularis, nail disorder, pruritus allergic, skin disorder Not known: Palmar-plantar erythrodysesthesia syndromec Musculoskeletal and connective tissue disorders Very common: Arthralgiaa, myalgiaa Common: Back pain, bone pain, musculoskeletal pain, muscular weakness, pain in extremity Uncommon: Haemarthrosis, musculoskeletal discomfort, sensation of heaviness Renal and urinary disorders Uncommon: Azotaemia Reproductive system and breast disorders Uncommon: Vaginal haemorrhage, pelvic pain, breast pain General disorders and administration site conditions Very common: Astheniaa, fatiguea, infusion site reactiona,d Common: Oedema peripheral, pain, pyrexia, chest discomfort, hyperthermia, face oedema Uncommon: Death, multi-organ failure, oedema, administration site pain, catheter site haemorrhage, catheter site oedema, local swelling, generalised oedema, hernia, chest pain, influenza like illness, localised oedema, hypothermia, chills, feeling hot Investigations Uncommon: Alanine aminotransferase increased a See Description of selected adverse reactions.

Haematology Paclitaxel causes myelosuppression (primarily neutropenia). Neutropenia is a dose-dependent and dose-limiting adverse reaction. Therefore, frequent complete blood cell counts should be performed during treatment with Apealea.

In the pivotal study, about a third of the patients received granulocyte colony stimulating factor (GCSF) to treat neutropenia and clinicians should consider whether individual cases could benefit from GCSF. 5 × 109/L and platelets recover to ≥ 100 × 109/L.

Patients with low neutrophil count should be made aware of the increased risk of infections. The risk of myelosuppression is increased due to the combination use with carboplatin. 2). Medicinal product no longer authorised 5 Neuropathy Peripheral sensory neuropathy and peripheral neuropathy are very common adverse reactions.

2). Hepatic impairment Patients with hepatic impairment have not been studied with Apealea but may be at increased risk of toxicity, particularly from myelosuppression. 2) should therefore be performed with caution and they should be closely monitored with regard to increased liver impairment and myelosuppression.

Patients that have total bilirubin > 5 × ULN or AST > 10 × ULN should not be treated with paclitaxel. Gastrointestinal symptoms Gastrointestinal adverse reactions are very common. If patients experience nausea, vomiting and diarrhoea following the administration of Apealea, they may be treated with antiemetics and/or antidiarrhoeal agents.

Premedication may be considered in patients who have previously experienced gastrointestinal symptoms when being treated with cytotoxic medicinal products. Infusion-associated reactions Local reactions at the infusion site are very common during Apealea infusions.

The infusion site reactions observed include pain, phlebitis, discolouration, redness, oedema and rash. These reactions are more common on the first infusion and may be improved by slowing the rate of infusion. Patients who experience severe pain or other reactions to the infusion of Apealea are recommended to be considered for a central venous catheter.

4). 6). 5 × 109/L.