APEALEA Powder for solution for infusion Ref.[49913] Active ingredients: Paclitaxel

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. Patients should not be treated with subsequent cycles until neutrophils recover to ≥1.5 × 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. Dose recommendations for Apealea as well as for carboplatin in the case of myelosuppression should be followed (see section 4.2).

Neuropathy

Peripheral sensory neuropathy and peripheral neuropathy are very common adverse reactions. For CTCAE grade ≥2 sensory or motor neuropathy withhold treatment until resolution to < grade 2, followed by a dose reduction for all subsequent courses (see section 4.2).

Hepatic impairment

Patients with hepatic impairment have not been studied with Apealea but may be at increased risk of toxicity, particularly from myelosuppression. Administration in patients with hepatic impairment defined as total bilirubin >1 to ≤5 × ULN and AST ≤10 × ULN (see section 4.2) 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. Care should be taken to avoid accidental administration into the surrounding tissue during intravenous administration. If any sign of extravasal injection occurs, take immediate action: terminate the infusion, aspirate fluid from the catheter/cannula before the needle is withdrawn, infuse the affected area with sterile saline or lactated or acetated Ringer’s solution and closely monitor the area. To avoid accidental administration into the surrounding tissue and to ensure intravenous delivery of the complete dose, flush the infusion set and catheter/cannula before as well as after the administration.

Hypersensitivity

Most hypersensitivity reactions related to Apealea are mild to moderate and mainly occur as skin and subcutaneous tissue disorders, general disorders and administration site conditions, but serious hypersensitivity reactions including anaphylactic shock have been reported. Minor symptoms such as flushing or skin reactions do not require interruption of therapy. Moderate cases may require premedication with corticosteroids, antihistamines and/or H2 antagonists for the following treatment cycles. Severe reactions, such as hypotension requiring treatment, dyspnoea requiring bronchodilators, angioedema or generalised urticaria require immediate discontinuation of paclitaxel and initiation of symptomatic treatment. Patients experiencing severe reactions should not be re-challenged with paclitaxel. Patients should be observed closely during treatment, particularly those patients who previously suffered hypersensitivity reactions with any taxane formulation.

The true incidence, severity and time to onset of hypersensitivity reactions due to Apealea could not be established during clinical development due to the combination treatment with carboplatin. Delayed reactions related to paclitaxel occurring during or after infusion of carboplatin cannot be excluded.

Alopecia

Alopecia is a very common adverse reaction and occurs early in treatment. It can have a marked impact on the patients' self-image and quality of life and patients should be counselled about the likelihood of this adverse effect and on what measures might be available to mitigate it, for example the use of cold caps. In studies with Apealea, 45% of patients reported alopecia during therapy.

Cardiotoxicity

Heart failure has been observed in some patients receiving Apealea. In some of the cases, the patients had previously been exposed to cardiotoxic medicinal products such as doxorubicin or had underlying cardiac history. These patients should be vigilantly monitored by physicians for the occurrence of cardiac events.

Patients 65 years and older

There was no marked difference in overall tolerability between the 65–74 age group and younger patients. Limited data are available on use in patients ≥75 years. In view of this, and of the potential for frailty and co-morbidities, elderly patients should be carefully monitored.

Race

There are limited data on the use of Apealea in non-Caucasian patients. However, studies in breast cancer patients treated with paclitaxel-containing regimens indicate a possible increased risk of neuropathy in non-Caucasian patients (see section 4.2).

Excipients

When reconstituted, this medicinal product contains up to approximately 1.6 g sodium per dose (0.9 g/m² BSA; 3.6 mg per mL), equivalent to 80% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

No studies have been performed to evaluate drug-drug interactions between Apealea and other medicinal products.

The metabolism of paclitaxel is catalysed, in part, by cytochrome P450 isoenzymes CYP2C8 and CYP3A4 (see section 5.2). Therefore, caution should be exercised when administering paclitaxel concomitantly with medicines known to inhibit either CYP2C8 or CYP3A4 (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.

Apealea contains a mixture of two retinoic acid derivatives as excipients. In vitro studies using human microsomes have shown these derivatives to have inhibitory activity on CYP2B6, CYP2C8, CYP2C9, and to a lesser extent on CYP2D6. In the absence of in vivo studies addressing inhibition of CYP2B6 and CYP2C9, the concomitant use of Apealea and substances metabolised primarily by these CYP enzymes should be exercised with caution.

Apealea is indicated to be used in combination with carboplatin (see section 4.1). Apealea should be administered first, then carboplatin. Based on literature data, no clinically relevant pharmacokinetic interaction between paclitaxel and carboplatin is expected.

Clinically relevant pharmacokinetic interaction has been observed between paclitaxel and cisplatin. When paclitaxel is given before cisplatin, the safety profile of solvent-based paclitaxel is consistent with that reported for single-agent use. When solvent-based paclitaxel was given after cisplatin, patients showed a more profound myelosuppression and an approximately 20% decrease in paclitaxel clearance. A similar effect can be anticipated for Apealea (paclitaxel micellar). Patients treated with paclitaxel and cisplatin may have an increased risk of renal failure as compared to cisplatin alone in gynaecological cancers.

Women of childbearing potential/Contraception

Women of childbearing potential must use effective contraception during treatment and for six months afterwards.

Pregnancy

There are very limited data on the use of paclitaxel in pregnant women. Paclitaxel is suspected to cause serious birth defects when administered during pregnancy. Studies in animals have shown reproductive toxicity (see section 5.3). Paclitaxel should not be used during pregnancy unless the clinical condition requires this treatment.

Breast-feeding

Paclitaxel is excreted in human milk. Because of potential serious adverse reactions in children being breastfed, Apealea is contraindicated during lactation. Breast-feeding must be discontinued for the duration of therapy.

Fertility

Studies in animals being treated with paclitaxel have shown decreased fertility (see section 5.3).

Apealea has moderate influence on the ability to drive or use machines. Apealea may cause adverse reactions such as fatigue (very common) and dizziness (common) that may affect the ability to drive or use machinery. Patients should be advised not to drive or use machines if they feel tired or dizzy.

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.

Table 2. Listing of adverse reactions:

^a See Description of selected adverse reactions.
^b Can persist beyond 6 months of paclitaxel discontinuation.c
^c As reported in the post-marketing surveillance of paclitaxel.
^d Includes the following preferred terms: infusion site pain, infusion site phlebitis, infusion site reaction, infusion site discolouration, infusion site erythema, infusion site extravasation, infusion site inflammation, infusion site oedema, infusion site paraesthesia, infusion site irritation, and infusion site rash.

Description of selected adverse reactions

In the pivotal clinical study, patients were either treated with Apealea (paclitaxel micellar) at a dose of 250 mg/m² in combination with carboplatin or with solvent-based paclitaxel at a dose of 175 mg/m² in combination with carboplatin (N=391 in each arm). Overall, there were higher rates of serious adverse events with paclitaxel micellar (41%) than with solvent-based paclitaxel (27%). In both groups, the majority of the serious adverse events were haematological toxicities. There were no differences in Eastern Cooperative Oncology Group (ECOG) performance score between the two study groups at any time during or after treatment (mainly score 0 or 1).

Blood and lymphatic system disorders

Almost all patients treated with Apealea had neutropenia of some grade, 79% of the patients had grade 3 or 4. Neutropenia as a serious adverse reaction occurred in 29% of the patients and febrile neutropenia occurred in 3% of the patients. Neutropenia resolved to ≥1.5 × 10⁹/L before the next course of treatment. Almost all patients experienced anaemia, decreased platelet count and decreased white blood cell count of any grade during the treatment period (98%, 93% and 98%, respectively). Anaemia as serious adverse event occurred in 5% of the patients, thrombocytopenia and leukopenia in 3% and 6% of the patients, respectively.

In comparison to the patients receiving solvent-based paclitaxel, there were more patients in the group receiving paclitaxel micellar who experienced haematological toxicities with grade 3 and 4. Neutropenia occurred in 79% and 66%, leukopenia in 53% and 34%, thrombocytopenia in 18% and 10%, and anaemia in 24% and 14% of the patients in the treatment arms receiving either paclitaxel micellar or solvent-based paclitaxel, respectively.

Disseminated intravascular coagulation (DIC), often in association with sepsis or multi-organ failure, has been reported.

Gastrointestinal disorders

Nausea (38%), vomiting (22%) and diarrhoea (15%) were among the most commonly reported adverse reactions in the study.

Nervous system disorders

Peripheral neuropathies (including the preferred terms neuropathy peripheral, peripheral motor neuropathy, peripheral sensorimotor neuropathy, peripheral sensory neuropathy, polyneuropathy, and polyneuropathy in malignant disease) were reported in 29% of the patients and were mostly (98%) mild to moderate (CTCAE grade ≤2). The average time to onset was 53 days from the first dose. Peripheral sensory neuropathy represented the most common reaction and was reported in 16% of patients. Other associated reactions were reported in 10% of the patients and were mostly (98%) mild to moderate (CTCAE grade ≤2). Paraesthesia and hypoaesthesia were the most common ones. During the course of the pivotal study, 46% of the peripheral neuropathies as well as the majority (78%) of the associated reactions resolved. The dose-dependency of frequency and severity of neurotoxicity was not studied for Apealea, but has been observed for other paclitaxel formulations in other indications. Further, it has been demonstrated that peripheral neuropathies can persist beyond 6 months of paclitaxel discontinuation.

Hypersensitivity reactions

Most hypersensitivity reactions related to Apealea were mild to moderate (see section 4.4). The frequency of paclitaxel-related hypersensitivity reactions was similar in both groups (5% of the patients receiving paclitaxel micellar and 7% of the patients receiving solvent-based paclitaxel), whereas a higher frequency of carboplatin-related hypersensitivity reactions was observed in the group receiving paclitaxel micellar (12% vs 7%). As a result of the combined treatment, it is not possible to determine whether this observation is due to Apealea or to other factors, and delayed reactions related to paclitaxel cannot be excluded.

Skin and subcutaneous tissue disorders

Alopecia was observed in 45% of patients and was abrupt in onset. Pronounced hair loss of ≥50% is expected for the majority of patients who experience alopecia.

Musculoskeletal and connective tissue disorders

Arthralgia occurred in 19% of patients and myalgia in 10%.

General disorders and administration site conditions

Asthenia and fatigue were very common and occurred in 23% and 11% of patients, respectively. Infusion site reactions, such as pain, phlebitis, and erythema, were seen in 12% of patients (see section 4.4).

There were more reports of infusion site pain in the group receiving paclitaxel micellar as compared to the group treated with solvent-based paclitaxel (8% and 1%, respectively).

Additional experience from clinical studies

Apealea has been given as monotherapy in a total of 132 patients at doses ranging between 90 mg/m² in a 3-week regimen to weekly doses of 250 mg/m² for various indications. Based on the combined data from monotherapy studies, very common adverse reactions and those of special interest were the following: neutropenia (45%), fatigue (37%), leukopenia (33%), alopecia (30%), nausea (27%), infusion site reactiona (23%), peripheral sensory neuropathy (20%), diarrhoea (17%), asthenia (15%), pyrexia (12%), constipation (12%), arthralgia (12%), paraesthesia (11%), pain (11%), vomiting (9%), myalgia (9%), peripheral motor neuropathy (5%), neuropathy (5%), neuropathy peripheral (5%), thrombocytopenia (4%), febrile neutropenia (2%), sepsis (2%), tachycardia (2%), phlebitis (2%), thrombosis (2%).

^a Includes the following preferred terms: infusion site phlebitis, infusion site pain, injection site reaction, injection site inflammation, infusion site erythema, injection site extravasation, infusion site reaction, injection site oedema.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.