Biotalex

Biotalex monotherapy is indicated for the treatment of metastatic breast cancer in adult patients who have failed first-line treatment for metastatic disease and for whom standard, anthracycline containing therapy is not indicated.

Biotalex in combination with gemcitabine is indicated for the first-line treatment of adult patients with metastatic adenocarcinoma of the pancreas.

Biotalex in combination with carboplatin is indicated for the first-line treatment of non-small cell lung cancer in adult patients who are not candidates for potentially curative surgery and/or radiation therapy.

Ovarian carcinoma: in the first-line chemotherapy of ovarian cancer, Biotalex is indicated for the treatment of patients with advanced carcinoma of the ovary or with residual disease (> 1 cm) after initial laparotomy, in combination with cisplatin.

In the second-line chemotherapy of ovarian cancer, Biotalex is indicated for the treatment of metastatic carcinoma of the ovary after failure of standard, platinum containing therapy.

Breast carcinoma: in the adjuvant setting, Biotalex is indicated for the treatment of patients with node-positive breast carcinoma following anthracycline and cyclophosphamide (AC) therapy. Adjuvant treatment with Biotalex should be regarded as an alternative to extended AC therapy.

Biotalex is indicated for the initial treatment of locally advanced or metastatic breast cancer either in combination with an anthracycline in patients for whom anthracycline therapy is suitable, or in combination with trastuzumab, in patients who over-express HER-2 (human epidermal growth factor receptor 2) at a 3+ level as determined by immunohistochemistry and for whom an anthracycline is not suitable.

As a single agent, Biotalex is indicated for the treatment of metastatic carcinoma of the breast in patients who have failed, or are not candidates for standard, anthracycline containing therapy.

Advanced non-small cell lung carcinoma: Biotalex, in combination with cisplatin, is indicated for the treatment of non-small cell lung carcinoma (NSCLC) in patients who are not candidates for potentially curative surgery and/or radiation therapy.

AIDS-related Kaposi's sarcoma: Biotalex is indicated for the treatment of patients with advanced AIDS-related Kaposi's sarcoma (KS) who have failed prior liposomal anthracycline therapy.

Biotalex should only be administered under the supervision of a qualified oncologist in units specialised in the administration of cytotoxic agents. It should not be substituted for or with other paclitaxel formulations.

Posology

Breast cancer

The recommended dose of Biotalex is 260 mg/m² administered intravenously over 30 minutes every 3 weeks.

Dose adjustments during treatment of breast cancer

Patients who experience severe neutropenia (neutrophil count < 500 cells/mm³ for a week or longer) or severe sensory neuropathy during Biotalex therapy should have the dose reduced to 220 mg/m² for subsequent courses. Following recurrence of severe neutropenia or severe sensory neuropathy, additional dose reduction should be made to 180 mg/m². Biotalex should not be administered until neutrophil counts recover to >1500 cells/mm³. For Grade 3 sensory neuropathy, withhold treatment until resolution to Grade 1 or 2, followed by a dose reduction for all subsequent courses.

Pancreatic adenocarcinoma

The recommended dose of Biotalex in combination with gemcitabine is 125 mg/m² administered intravenously over 30 minutes on Days 1, 8 and 15 of each 28-day cycle. The concurrent recommended dose of gemcitabine is 1000 mg/m² administered intravenously over 30 minutes immediately after the completion of Biotalex administration on Days 1, 8 and 15 of each 28-day cycle.

Dose adjustments during treatment of pancreatic adenocarcinoma

Table 1: Dose level reductions for patients with pancreatic adenocarcinoma

Table 2: Dose modifications for neutropenia and/or thrombocytopenia at the start of a cycle or within a cycle for patients with pancreatic adenocarcinoma

Abbreviations: ANC=Absolute Neutrophil Count; WBC=white blood cell

Table 3: Dose modifications for other adverse drug reactions in patients with pancreatic adenocarcinoma

a. See Table 1 for dose level reductions

Non-small cell lung cancer:

The recommended dose of Biotalex is 100 mg/m² administered as an intravenous infusion over 30 minutes on Days 1, 8 and 15 of each 21-day cycle. The recommended dose of carboplatin is AUC = 6 mg-min/mL on Day 1 only of each 21-day cycle, beginning immediately after the end of Biotalex administration.

Dose adjustments during treatment of non-small cell lung cancer:

Biotalex should not be administered on Day 1 of a cycle until absolute neutrophil count (ANC) is >1500 cells/mm³ and platelet count is >100,000 cells/mm³. For each subsequent weekly dose of Biotalex, patients must have an ANC >500 cells/mm³ and platelets >50,000 cells/mm³ or the dose is to be withheld until counts recover. When counts recover, resume dosing the following week according to the criteria in Table 4. Reduce subsequent dose only if criteria in Table 4 are met.

Table 4: Dose reductions for haematologic toxicities in patients with non-small cell lung cancer

¹On Day 1 of the 21-day cycle reduce the dose of Biotalex and carboplatin simultaneously. On Days 8 or 15 of the 21-day cycle reduce the dose of Biotalex; reduce the dose of carboplatin in the subsequent cycle.

²Maximum of 7 days post scheduled Day 1 dose of next cycle.

For Grade 2 or 3 cutaneous toxicity, Grade 3 diarrhoea, or Grade 3 mucositis, interrupt treatment until the toxicity improves to ≤ Grade 1, then restart treatment according to the guidelines in Table 5. For > Grade 3 peripheral neuropathy, withhold treatment until resolution to ≤ Grade 1. Treatment may be resumed at the next lower dose level in subsequent cycles according to the guidelines in Table 5. For any other Grade 3 or 4 non-haematologic toxicity, interrupt treatment until the toxicity improves to ≤ Grade 2, then restart treatment according to the guidelines in Table 5.

Table 5: Dose reductions for non-haematologic toxicities in patients with non-small cell lung cancer

¹On Day 1 of the 21-day cycle reduce the dose of Biotalex and carboplatin simultaneously. On Days 8 or 15 of the 21-day cycle reduce the dose of Biotalex; reduce the dose of carboplatin in the subsequent cycle.

Special populations

Patients with hepatic impairment

For patients with mild hepatic impairment (total bilirubin > 1 to ≤ 1.5 x ULN and aspartate aminotransferase [AST] ≤ 10 x ULN), no dose adjustments are required, regardless of indication. Treat with same doses as patients with normal hepatic function.

For metastatic breast cancer patients and non-small cell lung cancer patients with moderate to severe hepatic impairment (total bilirubin > 1.5 to ≤ 5 x ULN and AST ≤ 10 x ULN), a 20% reduction in dose is recommended. The reduced dose may be escalated to the dose for patients with normal hepatic function if the patient is tolerating the treatment for at least two cycles.

For patients with metastatic adenocarcinoma of the pancreas that have moderate to severe hepatic impairment, there are insufficient data to permit dosage recommendations.

For patients with total bilirubin > 5 x ULN or AST > 10 x ULN, there are insufficient data to permit dosage recommendations regardless of indication.

Patients with renal impairment

Adjustment of the starting Biotalex dose is not required for patients with mild to moderate renal impairment (estimated creatinine clearance >30 to <90 ml/min). There are insufficient data available to recommend dose modifications of Biotalex in patients with severe renal impairment or end stage renal disease (estimated creatinine clearance <30 ml/min).

Older people

No additional dosage reductions, other than those for all patients, are recommended for patients 65 years and older.

Of the 229 patients in the randomized study who received Biotalex monotherapy for breast cancer, 13% were at least 65 years of age and < 2% were 75 years and older. No toxicities occurred notably more frequently among patients at least 65 years of age who received Biotalex. However, a subsequent analysis in 981 patients receiving Biotalex monotherapy for metastatic breast cancer, of which 15% were > 65 years old and 2% were > 75 years old, showed a higher incidence of epistaxis, diarrhoea, dehydration, fatigue and peripheral oedema in patients > 65 years.

Of the 421 patients with pancreatic adenocarcinoma in the randomized study who received Biotalex in combination with gemcitabine, 41% were 65 years and older and 10% were 75 years and older. In patients aged 75 years and older who received Biotalex and gemcitabine, there was a higher incidence of serious adverse reactions and adverse reactions that led to treatment discontinuation. Patients with pancreatic adenocarcinoma aged 75 years and older should be carefully assessed before treatment is considered.

Of the 514 patients with non-small cell lung cancer in the randomized study who received Biotalex in combination with carboplatin, 31% were 65 years or older and 3.5% were 75 years or older. Myelosuppression events, peripheral neuropathy events, and arthralgia were more frequent in patients 65 years or older compared to patients younger than 65 years of age. There is limited experience of Biotalex/carboplatin use in patients 75 years or older.

Pharmacokinetic/pharmacodynamic modelling using data from 125 patients with advanced solid tumours indicates that patients > 65 years of age may be more susceptible to development of neutropenia within the first treatment cycle.

Paediatric population

The safety and efficacy of Biotalex in children and adolescents aged 0-17 years has not been established. There is no relevant use of Biotalex in the paediatric population in the indication of metastatic breast cancer or pancreatic adenocarcinoma or non-small cell lung cancer.

Method of administration

Administer reconstituted Biotalex suspension intravenously using an infusion set incorporating a 15 µm filter. Following administration, it is recommended that the intravenous line be flushed with sodium chloride 9 mg/ml (0.9%) solution for injection to ensure administration of the complete dose.

Posology

Biotalex should only be administered under the supervision of a qualified oncologist in units specialised in the administration of cytotoxic agents.

All patients must be premedicated with corticosteroids, antihistamines, and H₂ antagonists prior to Biotalex 6 mg/ml, concentrate for solution for infusion, e.g.

*8-20 mg for KS patients

** or an equivalent antihistamine e.g. chlorpheniramine

First-line chemotherapy of ovarian carcinoma: although other dosage regimens are under investigation, a combination regimen of Biotalex and cisplatin is recommended. According to duration of infusion, two doses of Biotalex are recommended: Biotalex 175 mg/m² administered intravenously over 3 hours, followed by cisplatin at a dose of 75 mg/m² every three weeks or Biotalex 135 mg/m², in a 24-hour infusion, followed by cisplatin 75 mg/m², with a 3 week interval between courses.

Second-line chemotherapy of ovarian carcinoma: the recommended dose of Biotalex is 175 mg/m² administered over a period of 3 hours, with a 3 week interval between courses.

Adjuvant chemotherapy in breast carcinoma: the recommended dose of Biotalex is 175 mg/m² administered over a period of 3 hours every 3 weeks for four courses, following AC therapy.

First-line chemotherapy of breast carcinoma: when used in combination with doxorubicin (50 mg/m²), Biotalex should be administered 24 hours after doxorubicin. The recommended dose of Biotalex is 220 mg/m² administered intravenously over a period of 3 hours, with a 3-week interval between courses. When used in combination with trastuzumab, the recommended dose of Biotalex is 175 mg/m² administered intravenously over a period of 3 hours, with a 3-week interval between courses. Biotalex infusion may be started the day following the first dose of trastuzumab or immediately after the subsequent doses of trastuzumab if the preceding dose of trastuzumab was well tolerated (for detailed trastuzumab posology see the Summary of Product Characteristics of Herceptin®).

Second-line chemotherapy of breast carcinoma: the recommended dose of Biotalex is 175 mg/m² administered over a period of 3 hours, with a 3-week interval between courses.

The treatment of advanced non-small-cell lung carcinoma (NSCLC): the recommended dose of Biotalex is 175 mg/m² administered over a period of 3 hours, followed by cisplatin 80 mg/m², with a 3 week interval between courses.

The treatment of AIDS-related KS: the recommended dose of Biotalex is 100 mg/m² administered as a 3-hour intravenous infusion every two weeks.

Subsequent doses of Biotalex should be administered according to individual patient tolerance.

Biotalex should not be readministered until the neutrophil count is > 1,500/mm³ (> 1,000/mm³ for KS patients) and the platelet count is > 100,000/mm³ (> 75,000/mm³ for KS patients). Patients who experience severe neutropenia (neutrophil count < 500/mm³ for a week or longer) or severe peripheral neuropathy should receive a dose reduction of 20% for subsequent courses (25% for KS patients).

Patients with hepatic impaired: Inadequate data are available to recommend dosage alterations in patients with mild to moderate hepatic impairments. Patients with severe hepatic impairment should not be treated with Biotalex.

Paediatric population

Biotalex is not recommended for use in children below 18 years due to lack of data on safety and efficacy

Method of administration

Precautions to be taken before handling or administering the medicinal product

The concentrate for solution for infusion must be diluted before use and should only be administered intravenously.Biotalex should be administered intravenously through an in-line filter with a microporous membrane ≤0.22 μm.

Lactation.

Patients who have baseline neutrophil counts <1500 cells/mm³.

Biotalex should not be used in patients with baseline neutrophils < 1,500/mm³ (< 1,000/mm³ for KS patients) at the start of therapy.

Biotalex is contraindicated during lactation.

In KS, Biotalex is also contraindicated in patients with concurrent, serious, uncontrolled infections.

Biotalex is an albumin-bound nanoparticle formulation of paclitaxel, which may have substantially different pharmacological properties compared to other formulations of paclitaxel. It should not be substituted for or with other paclitaxel formulations.

Hypersensitivity

Rare occurrences of severe hypersensitivity reactions, including very rare events of anaphylactic reactions with fatal outcome, have been reported. If a hypersensitivity reaction occurs, the medicinal product should be discontinued immediately, symptomatic treatment should be initiated, and the patient should not be rechallenged with paclitaxel.

Haematology

Bone marrow suppression (primarily neutropenia) occurs frequently with Biotalex. Neutropenia is dose-dependent and a dose-limiting toxicity. Frequent monitoring of blood cell counts should be performed during Biotalex therapy. Patients should not be retreated with subsequent cycles of Biotalex until neutrophils recover to >1500 cells/mm³ and platelets recover to >100,000 cells/mm³.

Neuropathy

Sensory neuropathy occurs frequently with Biotalex, although development of severe symptoms is less common. The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose reduction. When Biotalex is used as monotherapy, if Grade 3 sensory neuropathy develops, treatment should be withheld until resolution to Grade 1 or 2 followed by a dose reduction for all subsequent courses of Biotalex is recommended. For combination use of Biotalex and gemcitabine, if Grade 3 or higher peripheral neuropathy develops, withhold Biotalex; continue treatment with gemcitabine at the same dose. Resume Biotalex at reduced dose when peripheral neuropathy improves to Grade 0 or 1. For combination use of Biotalex and carboplatin, if Grade 3 or higher peripheral neuropathy develops, treatment should be withheld until improvement to Grade 0 or 1 followed by a dose reduction for all subsequent courses of Biotalex and carboplatin.

Sepsis

Sepsis was reported at a rate of 5% in patients with or without neutropenia who received Biotalex in combination with gemcitabine. Complications due to the underlying pancreatic cancer, especially biliary obstruction or presence of biliary stent, were identified as significant contributing factors. If a patient becomes febrile (regardless of neutrophil count), initiate treatment with broad spectrum antibiotics. For febrile neutropenia, withhold Biotalex and gemcitabine until fever resolves and ANC > 1500 cells/mm³, then resume treatment at reduced dose levels.

Pneumonitis

Pneumonitis occurred in 1% of patients when Biotalex was used as monotherapy and in 4% of patients when Biotalex was used in combination with gemcitabine. Closely monitor all patients for signs and symptoms of pneumonitis. After ruling out infectious etiology and upon making a diagnosis of pneumonitis, permanently discontinue treatment with Biotalex and gemcitabine and promptly initiate appropriate treatment and supportive measures.

Hepatic impairment

Because the toxicity of paclitaxel can be increased with hepatic impairment, administration of Biotalex in patients with hepatic impairment should be performed with caution. Patients with hepatic impairment may be at increased risk of toxicity, particularly from myelosuppression; such patients should be closely monitored for development of profound myelosuppression.

Biotalex is not recommended in patients that have total bilirubin > 5 x ULN or AST > 10 x ULN. In addition, Biotalex is not recommended in patients with metastatic adenocarcinoma of the pancreas that have moderate to severe hepatic impairment (total bilirubin > 1.5 x ULN and AST ≤ 10 x ULN).

Cardiotoxicity

Rare reports of congestive heart failure and left ventricular dysfunction have been observed among individuals receiving Biotalex. Most of the individuals were previously exposed to cardiotoxic medicinal products such as anthracyclines, or had underlying cardiac history. Thus patients receiving Biotalex should be vigilantly monitored by physicians for the occurrence of cardiac events.

CNS metastases

The effectiveness and safety of Biotalex in patients with central nervous system (CNS) metastases has not been established. CNS metastases are generally not well controlled by systemic chemotherapy.

Gastrointestinal symptoms

If patients experience nausea, vomiting and diarrhoea following the administration of Biotalex, they may be treated with commonly used anti-emetics and constipating agents.

Patients 75 years and older

For patients of 75 years and older, no benefit for the combination treatment of Biotalex and gemcitabine in comparison to gemcitabine monotherapy has been demonstrated. In the very elderly (>75 years) who received Biotalex and gemcitabine, there was a higher incidence of serious adverse reactions and adverse reactions that led to treatment discontinuation including haematologic toxicities, peripheral neuropathy, decreased appetite and dehydration. Patients with pancreatic adenocarcinoma aged 75 years and older should be carefully assessed for their ability to tolerate Biotalex in combination with gemcitabine with special consideration to performance status, co-morbidities and increased risk of infections.

Other

Although limited data is available, no clear benefit in terms of prolonged overall survival has been demonstrated in pancreatic adenocarcinoma patients with normal CA 19-9 levels prior to start of treatment with Biotalex and gemcitabine.

Erlotinib should not be coadministered with Biotalex plus gemcitabine.

Excipients

When reconstituted, each ml of Biotalex concentrate contains 0.183 mmol sodium, which is 4.2 mg of sodium. To be taken into consideration by patients on a controlled sodium diet.

Biotalex should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. Since significant hypersensitivity reactions may occur, appropriate supportive equipment should be available.

Given the possibility of extravasation, close monitoring of the infusion site for possible infiltration during administration of the drug is recommended.

Patients must be pretreated with corticosteroids, antihistamines and H₂ antagonists.

Biotalex should be given before cisplatin when used in combination.

Significant hypersensitivity reactions characterised by dyspnoea and hypotension requiring treatment, angioedema and generalised urticaria have occurred in < 1% of patients receiving Biotalex after adequate premedication. These reactions are probably histamine-mediated. In the case of severe hypersensitivity reactions, Biotalex infusion should be discontinued immediately, symptomatic therapy should be initiated and the patient should not be rechallenged with the medicinal product.

Bone marrow suppression (primarily neutropenia) is the dose-limiting toxicity. Frequent monitoring of blood counts should be instituted. Patients should not be retreated until neutrophils recover to >1,500/mm³ (> 1,000/mm³ for KS patients) and platelets recover to >100,000/mm³ (> 75,000/mm³ for KS patients). In the KS clinical study, the majority of patients were receiving granulocyte colony stimulating factor (G-CSF).

Patients with hepatic impairment may be at increased risk of toxicity, particularly Grade 3-4 myelosuppression. There is no evidence that the toxicity of Biotalex is increased when given as a 3-hour infusion to patients with mildly abnormal liver function. When Biotalex is given as a longer infusion, increased myelosuppression may be seen in patients with moderate to severe hepatic impairment. Patients should be monitored closely for the development of profound myelosuppression. Inadequate data are available to recommend dosage alterations in patients with mild to moderate hepatic impairments.

No data are available for patients with severe baseline cholestasis. Patients with severe hepatic impairment must not be treated with Biotalex.

Severe cardiac conduction abnormalities have been reported rarely with single agent Biotalex. If patients develop significant cardiac conduction abnormalities during Biotalex administration, appropriate therapy should be administered and continuous cardiac monitoring should be performed during subsequent therapy with Biotalex. Hypotension, hypertension, and bradycardia have been observed during Biotalex administration; patients are usually asymptomatic and generally do not require treatment. Frequent vital sign monitoring, particularly during the first hour of Biotalex infusion, is recommended. Severe cardiovascular events were observed more frequently in patients with NSCLC than breast or ovarian carcinoma. A single case of heart failure related to Biotalex was seen in the AIDS-KS clinical study.

When Biotalex is used in combination with doxorubucin or trastuzumab for initial treatment of metastatic breast cancer, attention should be placed on the monitoring of cardiac function. When patients are candidates for treatment with Biotalex in these combinations, they should undergo baseline cardiac assessment including history, physical examination, ECG, echocardiogram, and/or MUGA scan. Cardiac function should be further monitored during treatment (e.g. every three months). Monitoring may help to identify patients who develop cardiac dysfunction and treating physicians should carefully assess the cumulative dose (mg/m²) of anthracycline administered when making decisions regarding frequency of ventricular function assessment. When testing indicates deterioration in cardiac function, even asymptomatic, treating physicians should carefully assess the clinical benefits of further therapy against the potential for producing cardiac damage, including potentially irreversible damage. If further treatment is administered, monitoring of cardiac function should be more frequent (e.g. every 1-2 cycles). For more details see Summary of Product Characteristics of Herceptin^® or doxorubicin.

Although the occurrence of peripheral neuropathy is frequent, the development of severe symptoms is rare. In severe cases, a dose reduction of 20% (25% for KS patients) for all subsequent courses of Biotalex is recommended. In NSCLC patients and in ovarian cancer patients treated in the first-line setting, the administration of Biotalex as a three hour infusion in combination with cisplatin, resulted in a greater incidence of severe neurotoxicity than both single agent Biotalex and cyclophosphamide followed by cisplatin.

Special care should be taken to avoid intra-arterial application of Biotalex, since in animal studies testing for local tolerance severe tissue reactions were observed after intra-arterial application.

Biotalex in combination with radiation of the lung, irrespective of their chronological order, may contribute to the development of interstitial pneumonitis.

Since Biotalex concentrate for solution for infusion contains anhydrous ethanol (391 mg/ml), consideration should be given to possible CNS and other effects.

Biotalex concentrate for solution for infusion contains Polyoxyl 35 Castor oil, which may cause severe allergic reactions.

Pseudomembranous colitis has been rarely reported including cases in patients who have not been concomitantly treated with antibiotics. This reaction should be considered in the differential diagnosis of cases of severe or persistent diarrhoea occurring during or shortly after treatment with Biotalex.

In KS patients, severe mucositis is rare. If severe reactions occur, the Biotalex dose should be reduced by 25%

Biotalex has shown to be teratogenic, embryotoxic and mutagenic in many experimental systems.

Therefore sexually active fertile female and male patients should use effective methods of contraception during treatment and up to six months after treatment for men and women. Hormonal contraception is contraindicated in hormone receptor positive tumors.

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

Biotalex has not been demonstrated to interfere with this ability. However, it should be noted that the formulation contains alcohol.

The ability to drive or to use machines may be decreased due to alcohol content of this medicinal product.

Summary of the safety profile

The most common clinically significant adverse reactions associated with the use of Biotalex have been neutropenia, peripheral neuropathy, arthralgia/myalgia and gastrointestinal disorders.

The frequencies of adverse reactions associated with the administration of Biotalex are listed in Table 6 (Biotalex as monotherapy) and Table 7 (Biotalex in combination with gemcitabine), and Table 9 (Biotalex in combination with carboplatin).

Frequencies are defined as: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1000 to <1/100), rare (>1/10,000 to <1/1000), very rare (<1/10,000). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Breast cancer (Biotalex administered as monotherapy)

Tabulated list of adverse reactions

Table 6 lists adverse reactions associated with the administration of Biotalex to patients from studies in which Biotalex has been administered as monotherapy at any dose in any indication (N = 789).

Table 6: Adverse reactions reported with Biotalex monotherapy at any dose in clinical studies

MedDRA = Medical Dictionary for Regulatory Activities.

SMQ = Standardized MedDRA Query; SMQ is a grouping of several MedDRA preferred terms to capture a medical concept.

¹ The frequency of hypersensitivity reactions is calculated based on one definitely related case in a population of 789 patients.

² As reported in the post-marketing surveillance of Biotalex.

³ The frequency of pneumonitis is calculated based on pooled data in 1310 patients in clinical trials receiving Biotalex monotherapy for breast cancer and for other indications using MedDRA SMQ Interstitial lung disease.

Description of selected adverse reactions

The following are the most common and clinically relevant adverse reactions related to 229 patients with metastatic breast cancer who were treated with 260 mg/m² Biotalex once every three weeks in the pivotal phase III clinical study.

Blood and lymphatic system disorders

Neutropenia was the most notable important haematological toxicity (reported in 79% of patients), and was rapidly reversible and dose dependent; leukopenia was reported in 71% of patients. Grade 4 neutropenia (< 500 cells/mm³) occurred in 9% of patients treated with Biotalex. Febrile neutropenia occurred in four patients on Biotalex. Anaemia (Hb < 10 g/dl) was observed in 46% of patients on Biotalex, and was severe (Hb < 8 g/dl) in three cases. Lymphopenia was observed in 45% of the patients.

Nervous system disorders

In general, the frequency and severity of neurotoxicity was dose-dependent in patients receiving Biotalex. Peripheral neuropathy (mostly Grade 1 or 2 sensory neuropathy) was observed in 68% of patients on Biotalex with 10% being Grade 3, and no cases of Grade 4.

Gastrointestinal disorders

Nausea occurred in 29% of the patients and diarrhoea in 25% of the patients.

Skin and subcutaneous tissue disorders

Alopecia was observed in >80% of the patients treated with Biotalex. The majority of alopecia events occurred less than one month after initiation of Biotalex. Pronounced hair loss >50% is expected for the majority of patients who experience alopecia.

Musculoskeletal and connective tissue disorders

Arthralgia occurred in 32% of patients on Biotalex and was severe in 6% of cases. Myalgia occurred in 24% of patients on Biotalex and was severe in 7% of cases. The symptoms were usually transient, typically occurred three days after Biotalex administration and resolved within a week.

General disorders and administration site conditions

Asthenia/Fatigue was reported in 40% of the patients.

Pancreatic adenocarcinoma (Biotalex administered in combination with gemcitabine)

Tabulated list of adverse reactions

Adverse reactions were assessed in 421 patients treated with Biotalex in combination with gemcitabine and 402 gemcitabine monotherapy-treated patients receiving first-line systemic treatment for metastatic adenocarcinoma of the pancreas in a phase III randomized, controlled, open-label trial. Table 7 lists adverse reactions assessed in patients with pancreatic adenocarcinoma treated with Biotalex in combination with gemcitabine.

Table 7: Adverse reactions reported with Biotalex in combination with gemcitabine (N =421)

MedDRA = Medical Dictionary for Regulatory Activities; SMQ = Standardized MedDRA Query (a grouping of several MedDRA preferred terms to capture a medical concept).

¹ Peripheral neuropathy evaluated using the SMQ (broad scope).

² Pneumonitis is evaluated using the SMQ interstitial lung disease (broad scope)

In this phase III randomized, controlled, open-label trial, adverse reactions resulting in death within 30 days of the last dose of study drug were reported for 4% of patients receiving Biotalex in combination with gemcitabine and for 4% of patients receiving gemcitabine monotherapy.

Description of selected adverse reactions

The following are the most common and important incidences of adverse reactions related to 421 patients with metastatic adenocarcinoma of the pancreas who were treated with 125 mg/m² Biotalex in combination with gemcitabine at a dose of 1000 mg/m² given on Days 1, 8 and 15 of each 28-day cycle in the phase III clinical study.

Blood and lymphatic system disorders

Table 8 provides the frequency and severity of haematologic laboratory-detected abnormalities for patients treated with Biotalex in combination with gemcitabine or with gemcitabine.

Table 8: Haematologic laboratory-detected abnormalities in pancreatic adenocarcinoma trial

^a 405 patients assessed in Biotalex/gemcitabine-treated group

^b 388 patients assessed in gemcitabine-treated group

^c 404 patients assessed in Biotalex/gemcitabine-treated group

Peripheral neuropathy

For patients treated with Biotalex in combination with gemcitabine, the median time to first occurrence of Grade 3 peripheral neuropathy was 140 days. The median time to improvement by at least 1 grade was 21 days, and the median time to improvement from Grade 3 peripheral neuropathy to Grade 0 or 1 was 29 days. Of the patients with treatment interrupted due to peripheral neuropathy, 44% (31/70 patients) were able to resume Biotalex at a reduced dose. No patients treated with Biotalex in combination with gemcitabine had Grade 4 peripheral neuropathy.

Sepsis

Sepsis was reported at a rate of 5% in patients with or without neutropenia who received Biotalex in combination with gemcitabine during the conduct of a trial in pancreatic adenocarcinoma. Complications due to the underlying pancreatic cancer, especially biliary obstruction or presence of biliary stent, were identified as significant contributing factors. If a patient becomes febrile (regardless of neutrophil count), initiate treatment with broad spectrum antibiotics. For febrile neutropenia, withhold Biotalex and gemcitabine until fever resolves and ANC > 1500 cells/mm³, then resume treatment at reduced dose levels.

Pneumonitis

Pneumonitis has been reported at a rate of 4% with the use of Biotalex in combination with gemcitabine. Of the 17 cases of pneumonitis reported in patients treated with Biotalex in combination with gemcitabine, 2 had a fatal outcome. Monitor patients closely for signs and symptoms of pneumonitis. After ruling out infectious etiology and upon making a diagnosis of pneumonitis, permanently discontinue treatment with Biotalex and gemcitabine and promptly initiate appropriate treatment and supportive measures.

Non-small cell lung cancer (Biotalex administered in combination with carboplatin)

Tabulated list of adverse reactions

Table 9 lists adverse reactions associated with the administration of Biotalex in combination with carboplatin.

Table 9: Adverse reactions reported with Biotalex in combination with carboplatin (N = 514)

MedDRA = Medical Dictionary for Regulatory Activities: SMQ = Standardized MedDRA Query

¹ Based on laboratory assessments: maximal degree of myelosuppression (treated population)

² Peripheral neuropathy is evaluated using the SMQ neuropathy (broad scope)

³ Pneumonitis is evaluated using the SMQ interstitial lung disease (broad scope)

For non-small cell lung cancer patients treated with Biotalex and carboplatin, the median time to first occurrence of Grade 3 treatment related peripheral neuropathy was 121 days, and the median time to improvement from Grade 3 treatment related peripheral neuropathy to Grade 1 was 38 days. No patients treated with Biotalex and carboplatin experienced Grade 4 peripheral neuropathy.

Anemia and thrombocytopenia were more commonly reported in the Biotalex arm than in the Taxol arm (54% versus 28% and 45% versus 27% respectively).

Patient-reported taxane toxicity was assessed using the 4 subscales of the Functional Assessment of Cancer Therapy (FACT)-Taxane questionnaire. Using repeated measure analysis, 3 of the 4 subscales (peripheral neuropathy, pain hands/feet, and hearing) favored Biotalex and carboplatin (p ≤ 0.002). For the other subscale (oedema), there was no difference in the treatment arms.

Post-marketing experience

Cranial nerve palsies, vocal cord paresis, and rare reports of severe hypersensitivity reactions have been reported during post-marketing surveillance of Biotalex.

There have been rare reports of reduced visual acuity due to cystoid macular oedema during treatment with Biotalex. Upon diagnosis of cystoid macular oedema, treatment with Biotalex should be discontinued.

There have been reports of tumour lysis syndrome during treatment with Biotalex.

In some patients previously exposed to capecitabine, reports of palmar-plantar erythrodysaesthesiae have been reported as part of the continuing surveillance of Biotalex. Because these events have been reported voluntarily during clinical practice, true estimates of frequency cannot be made and a causal relationship to the events has not been established.

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 Yellow Card Scheme at www.mhra.gov.uk/yellowcard (Freephone 0808 100 3352).

Unless otherwise noted, the following discussion refers to the overall safety database of 812 patients with solid tumours treated with single-agent Biotalex in clinical studies. As the KS population is very specific, a special chapter based on a clinical study with 107 patients, is presented at the end of this section.

The frequency and severity of adverse reactions, unless otherwise mentioned, are generally similar between patients receiving Biotalex for the treatment of ovarian carcinoma, breast carcinoma, or NSCLC. None of the observed toxicities were clearly influenced by age.

A significant hypersensitivity reaction with possible fatal outcome (defined as hypotension requiring therapy, angioedema, respiratory distress requiring bronchodilator therapy, or generalised urticaria) occurred in two (< 1%) patients. Thirty-four percent of patients (17% of all courses) experienced minor hypersensitivity reactions. These minor reactions, mainly flushing and rash, did not require therapeutic intervention nor did they prevent continuation of Biotalex therapy.

The most frequent significant adverse reaction was bone marrow suppression. Severe neutropenia (< 500 cells/mm³) occurred in 28% of patients, but was not associated with febrile episodes. Only 1% of patients experienced severe neutropenia for >7 days.

Thrombocytopenia was reported in 11% of patients. Three percent of patients had a platelet count nadir < 50,000/mm³ at least once while on study. Anaemia was observed in 64% of patients, but was severe (Hb < 5 mmol/l) in only 6% of patients. Incidence and severity of anaemia is related to baseline haemoglobin status.

Neurotoxicity, mainly peripheral neuropathy, appeared to be more frequent and severe with a 175 mg/m² 3-hour infusion (85% neurotoxicity, 15% severe) than with a 135 mg/m² 24-hour infusion (25% peripheral neuropathy, 3% severe) when Biotalex was combined with cisplatin. In NSCLC patients and in ovarian cancer patients treated with Biotalex over 3 hours followed by cisplatin, there is an apparent increase in the incidence of severe neurotoxicity. Peripheral neuropathy can occur following the first course and can worsen with increasing exposure to Biotalex. Peripheral neuropathy was the cause of Biotalex discontinuation in a few cases. Sensory symptoms have usually improved or resolved within several months of Biotalex discontinuation. Pre-existing neuropathies resulting from prior therapies are not a contraindication for Biotalex therapy.

Arthralgia or myalgia affected 60% of patients and was severe in 13% of patients.

Injection site reactions during intravenous administration may lead to localised oedema, pain, erythema, and induration; on occasion, extravasation can result in cellulitis. Skin sloughing and/or peeling has been reported, sometimes related to extravasation. Skin discoloration may also occur. Recurrence of skin reactions at a site of previous extravasation following administration of Biotalex at a different site, i.e. “recall”, has been reported rarely. A specific treatment for extravasation reactions is unknown at this time.

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.

Alopecia: Alopecia was observed in 87% of patients and was abrupt in onset. Pronounced hair loss of >50% is expected for the majority of patients who experience alopecia.

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

The table below lists adverse reactions associated with the administration of single agent Biotalex administered as a three hour infusion in the metastatic setting (812 patients treated in clinical studies) and as reported in the postmarketing surveillance* of Biotalex.

The frequency of adverse reactions listed below is defined using the following convention: very common (> 1/10); common (> 1/100, < 1/10); uncommon (> 1/1,000, < 1/100); rare (> 1/10,000, < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data)

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

*: as reported in the postmarketing surveillance

Breast cancer patients who received Biotalex in the adjuvant setting following AC experienced more neurosensory toxicity, hypersensitivity reactions, arthralgia/myalgia, anaemia, infection, fever, nausea/vomiting and diarrhoea than patients who received AC alone. However, the frequency of these events was consistent with the use of single agent Biotalex, as reported above.

Combination treatment

The following discussion refers to two major trials for the first-line chemotherapy of ovarian carcinoma (Biotalex + cisplatin: over 1050 patients); two phase III trials in the first line treatment of metastatic breast cancer: one investigating the combination with doxorubicin (Biotalex + doxorubicin: 267 patients), another one investigating the combination with trastuzumab (planned subgroup analysis Biotalex + trastuzumab: 188 patients) and two phase III trials for the treatment of advanced NSCLC (Biotalex + cisplatin: over 360 patients).

When administered as a three hour infusion for the first-line chemotherapy of ovarian cancer, neurotoxicity, arthralgia/myalgia, and hypersensitivity were reported as more frequent and severe by patients treated with Biotalex followed by cisplatin than patients treated with cyclophosphamide followed by cisplatin. Myelosuppression appeared to be less frequent and severe with Biotalex as a three hour infusion followed by cisplatin compared with cyclophosphamide followed by cisplatin.

For the first line chemotherapy of metastatic breast cancer, neutropenia, anaemia, peripheral neuropathy, arthralgia/myalgia, asthenia, fever, and diarrhoea were reported more frequently and with greater severity when Biotalex (220 mg/m²) was administered as a 3-hour infusion 24 hours following doxorubicin (50 mg/m²) when compared to standard FAC therapy (5-FU 500 mg/m², doxorubicin 50 mg/m², cyclophosphamide 500 mg/m²). Nausea and vomiting appeared to be less frequent and severe with the Biotalex (220 mg/m²) / doxorubicin (50 mg/m²) regimen as compared to the standard FAC regimen. The use of corticosteroids may have contributed to the lower frequency and severity of nausea and vomiting in the Biotalex/doxorubicin arm.

When Biotalex was administered as a 3-hour infusion in combination with trastuzumab for the first line treatment of patients with metastatic breast cancer, the following events (regardless of relationship to Biotalex or trastuzumab) were reported more frequently than with single agent Biotalex: heart failure (8% vs. 1%), infection (46% vs. 27%), chills (42% vs. 4%), fever (47% vs. 23%), cough (42% vs. 22%), rash (39% vs. 18%), arthralgia (37% vs. 21%), tachycardia (12% vs. 4%), diarrhoea (45% vs. 30%), hypertonia (11% vs. 3%), epistaxis (18% vs. 4%), acne (11% vs. 3%), herpes simplex (12% vs. 3%), accidental injury (13% vs. 3%), insomnia (25% vs. 13%), rhinitis (22% vs. 5%), sinusitis (21% vs. 7%), and injection site reaction (7% vs. 1%).

Some of these frequency differences may be due to the increased number and duration of treatments with Biotalex/trastuzumab combination vs. single agent Biotalex. Severe events were reported at similar rates for Biotalex /trastuzumab and single agent Biotalex.

When doxorubicin was administered in combination with Biotalex in metastatic breast cancer, cardiac contraction abnormalities (> 20% reduction of left ventricular ejection fraction) were observed in 15% of patients vs. 10% with standard FAC regimen. Congestive heart failure was observed in < 1% in both Biotalex/doxorubicin and standard FAC arms. Administration of trastuzumab in combination with Biotalex in patients previously treated with anthracyclines resulted in an increased frequency and severity of cardiac dysfunction in comparison with patients treated with Biotalex single agent (NYHA Class I/II 10% vs. 0%; NYHA Class III/IV 2% vs. 1%) and rarely has been associated with death (see trastuzumab Summary of Product Characteristics). In all but these rare cases, patients responded to appropriate medical treatment.

Radiation pneumonitis has been reported in patients receiving concurrent radiotherapy.

AIDS-related Kaposi's sarcoma

Except for haematologic and hepatic undesirable effects (see below), the frequency and severity of undesirable effects are generally similar between KS patients and patients treated with Biotalex monotherapy for other solid tumours, based on a clinical study including 107 patients.

Blood and the lymphatic system disorders : bone marrow suppression was the major dose-limiting toxicity. Neutropenia is the most important haematological toxicity. During the first course of treatment, severe neutropenia (< 500 cells/mm³) occurred in 20% of patients. During the entire treatment period, severe neutropenia was observed in 39% of patients. Neutropenia was present for > 7 days in 41% and for 30-35 days in 8% of patients. It resolved within 35 days in all patients who were followed. The incidence of Grade 4 neutropenia lasting >7 days was 22%.

Neutropenic fever related to Biotalex was reported in 14% of patients and in 1.3% of treatment cycles. There were 3 septic episodes (2.8%) during Biotalex administration related to the medicinal product that proved fatal.

Thrombocytopenia was observed in 50% of patients, and was severe (< 50,000 cells/mm³) in 9%. Only 14% experienced a drop in their platelet count < 75,000 cells/mm³, at least once while on treatment. Bleeding episodes related to Biotalex were reported in < 3% of patients, but the haemorrhagic episodes were localised.

Anaemia (Hb < 11 g/dL) was observed in 61% of patients and was severe (Hb < 8 g/dL) in 10%. Red cell transfusions were required in 21% of patients.

Hepato-biliary disorders : Among patients (> 50% on protease inhibitors) with normal baseline liver function, 28%, 43% and 44% had elevations in bilirubin, alkaline phosphatase and AST (SGOT), respectively. For each of these parameters, the increases were severe in 1% of cases.

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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard.

There is no known antidote for paclitaxel overdose. In the event of an overdose, the patient should be closely monitored. Treatment should be directed at the major anticipated toxicities, which are bone marrow suppression, mucositis and peripheral neuropathy.

There is no known antidote for Biotalex overdose. In case of overdose, the patient should be closely monitored. Treatment should be directed at the primary anticipated toxicities, which consist of bone marrow suppression, peripheral neurotoxicity and mucositis.

Paediatric population

Overdose in paediatric patients may be associated with acute ethanol toxicity.

Pharmacotherapeutic group: Antineoplastic agents, plant alkaloids and other natural products, taxanes, ATC Code: L01CD01

Mechanism of action

Paclitaxel is an antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilises microtubules by preventing depolymerisation. This stability results in the inhibition of the normal dynamic reorganisation of the microtubule network that is essential for vital interphase and mitotic cellular functions. In addition, paclitaxel induces abnormal arrays or “bundles” of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis.

Biotalex contains human serum albumin-paclitaxel nanoparticles of approximately 130 nm in size, where the paclitaxel is present in a non-crystalline, amorphous state. Upon intravenous administration, the nanoparticles dissociate rapidly into soluble, albumin bound paclitaxel complexes of approximately 10 nm in size. Albumin is known to mediate endothelial caveolar transcytosis of plasma constituents, and in vitro studies demonstrated that the presence of albumin in Biotalex enhances transport of paclitaxel across endothelial cells. It is hypothesised that this enhanced transendothelial caveolar transport is mediated by the gp-60 albumin receptor, and that there is enhanced accumulation of paclitaxel in the area of tumour due to the albumin-binding protein Secreted Protein Acidic Rich in Cysteine (SPARC).

Clinical efficacy and safety

Breast cancer

Data from 106 patients accrued in two single-arm open-label studies and from 454 patients treated in a randomised Phase III comparative study are available to support the use of Biotalex in metastatic breast cancer. This information is presented below.

Single-arm open-label studies

In one study, Biotalex was administered as a 30-minute infusion at a dose of 175 mg/m² to 43 patients with metastatic breast cancer. The second trial utilised a dose of 300 mg/m² as a 30 minute infusion in 63 patients with metastatic breast cancer. Patients were treated without steroid pre-treatment or planned G-CSF support. Cycles were administered at 3 week intervals. The response rates in all patients were 39.5% (95% CI: 24.9%-54.2%) and 47.6% (95% CI: 35.3%-60.0%), respectively. The median time to disease progression was 5.3 months (175 mg/m²; 95% CI: 4.6-6.2 months) and 6.1 months (300 mg/m²; 95% CI: 4.2-9.8 months).

Randomised comparative study

This multi-centre trial was conducted in patients with metastatic breast cancer, who were treated every 3 weeks with single-agent paclitaxel, either as solvent-based paclitaxel 175 mg/m² given as a 3-hour infusion with premedication to prevent hypersensitivity (N = 225), or as Biotalex 260 mg/m² given as a 30 minute infusion without premedication (N = 229).

Sixty-four percent of patients had impaired performance status (ECOG 1 or 2) at study entry; 79% had visceral metastases; and 76% had > 3 sites of metastases. Fourteen percent of the patients had not received prior chemotherapy; 27% had received chemotherapy in the adjuvant setting only, 40% in the metastatic setting only, and 19% in both metastatic and adjuvant settings. Fifty-nine percent received study medicinal product as second or greater than second-line therapy. Seventy-seven percent of the patients had been previously exposed to anthracyclines.

Results for overall response rate and time to disease progression, and progression-free survival and survival for patients receiving > 1^st-line therapy, are shown below.

*This data is based on Clinical Study Report: CA012-0 Addendum dated Final (23 March-2005)

^a Chi-squared test

^b Log-rank test

Two hundred and twenty nine patients treated with Biotalex in the randomized, controlled clinical trial were evaluated for safety. Neurotoxicity to paclitaxel was evaluated through improvement by one grade for patients experiencing Grade 3 peripheral neuropathy at any time during therapy. The natural course of peripheral neuropathy to resolution to baseline due to cumulative toxicity of Biotalex after > 6 courses of treatment was not evaluated and remains unknown.

Pancreatic adenocarcinoma

A multicenter, multinational, randomized, open-label study was conducted in 861 patients to compare Biotalex/gemcitabine versus gemcitabine monotherapy as first-line treatment in patients with metastatic adenocarcinoma of the pancreas. Biotalex was administered to patients (N = 431) as an intravenous infusion over 30-40 minutes at a dose of 125 mg/m² followed by gemcitabine as an intravenous infusion over 30-40 minutes at a dose of 1000 mg/m² given on Days 1, 8 and 15 of each 28-day cycle. In the comparator treatment arm, gemcitabine monotherapy was administered to patients (N = 430) in accordance with the recommended dose and regimen. Treatment was administered until disease progression or development of an unacceptable toxicity. Of the 431 patients with pancreatic adenocarcinoma who were randomized to receive Biotalex in combination with gemcitabine, the majority (93%) were white, 4% were black and 2% were Asian. 16% had a Karnofsky Performance Status of 100; 42% had a KPS of 90; 35% had a KPS of 80; 7% had a KPS of 70; and <1% of patients had a KPS of below 70. Patients with high cardiovascular risk, history of peripheral artery disease and/or of connective tissue disorders and/or interstitial lung disease were excluded from the study.

Patients received a median treatment duration of 3.9 months in the Biotalex/gemcitabine arm and 2.8 months in the gemcitabine arm. 32% of patients in the Biotalex/gemcitabine arm compared with 15% of patients in the gemcitabine arm received 6 or more months of treatment. For the treated population, the median relative dose intensity for gemcitabine was 75% in the Biotalex/gemcitabine arm and 85% in the gemcitabine arm. The median relative dose intensity of Biotalex was 81%. A higher median cumulative dose of gemcitabine was delivered in the Biotalex/gemcitabine arm (11400 mg/m²) when compared with the gemcitabine arm (9000 mg/m²).

The primary efficacy endpoint was overall survival (OS). The key secondary endpoints were progression-free survival (PFS) and overall response rate (ORR), both assessed by independent, central, blinded radiological review using RECIST guidelines (Version 1.0).

Table 11: Efficacy results from randomized study in patients with pancreatic adenocarcinoma (Intent-to-treat population)

CI = confidence interval, HR_A+G/G = hazard ratio of Biotalex+gemcitabine/gemcitabine, p_A+G/p_G=response rate ratio of Biotalex+gemcitabine/gemcitabine

^a stratified Cox proportional hazard model

^b stratified log-rank test, stratified by geographic region (North America versus others), KPS (70 to 80 versus 90 to 100), and presence of liver metastasis (yes versus no).

There was a statistically significant improvement in OS for patients treated with Biotalex/gemcitabine versus gemcitabine alone, with 1.8 months increase in median OS, 28% overall reduction in risk of death, 59% improvement in 1-year survival, and 125% improvement in 2-year survival rates.

Figure 1: Kaplan-Meier curve of overall survival (intent-to-treat population)

Treatment effects on OS favoured the Biotalex/gemcitabine arm across the majority of pre-specified subgroups (including gender, KPS, geographic region, primary location of pancreatic cancer, stage at diagnosis, presence of liver metastases, presence of peritoneal carcinomatosis, prior Whipple procedure, presence of biliary stent at baseline, presence of pulmonary metastases, and number of metastatic sites). For patients > 75 years of age in the Biotalex/gemcitabine and gemcitabine arms the survival Hazard Ratio (HR) was 1.08 (95% CI 0.653, 1. 797). For patients with normal baseline CA 19-9 levels the survival HR was 1.07 (95% CI 0.692, 1.661).

There was a statistically significant improvement in PFS for patients treated with Biotalex/gemcitabine versus gemcitabine alone, with 1.8 months increase in median PFS.

Non-small cell lung cancer

A multicenter, randomized, open-label study was conducted in 1052 chemotherapy-naive patients with Stage IIIb/IV non-small cell lung cancer. The study compared Biotalex in combination with carboplatin versus solvent-based paclitaxel in combination with carboplatin as first-line treatment in patients with advanced non-small cell lung cancer. Over 99% of patients had an ECOG (Eastern Cooperative Oncology Group) performance status of 0 or 1. Patients with pre-existing neuropathy of Grade > 2 or serious medical risk factors involving any of the major organ systems were excluded. Biotalex was administered to patients (N=521) as an intravenous infusion over 30 minutes at a dose of 100 mg/m² on Days 1, 8 and 15 of each 21-day cycle without any steroid premedication and without granulocyte colony stimulating factor prophylaxis. Beginning immediately after the end of Biotalex administration, carboplatin at a dose of AUC = 6 mg-min/mL was administered intravenously on Day 1 only of each 21-day cycle. Solvent-based paclitaxel was administered to patients (N=531) at a dose of 200 mg/m² as an intravenous infusion over 3 hours with standard premedication, immediately followed by carboplatin administered intravenously at AUC = 6 mg-min/mL. Each drug was administered on Day 1 of each 21-day cycle. In both study arms treatment was administered until disease progression or development of an unacceptable toxicity. Patients received a median of 6 cycles of treatment in both study arms.

The primary efficacy endpoint was overall response rate defined as the percentage of patients who achieved an objective confirmed complete response or partial response based on an independent, central, blinded radiological review using RECIST (Version 1.0). Patients in the Biotalex/carboplatin arm had a significantly higher overall response rate compared with patients in the control arm: 33% versus 25%, p = 0.005 (Table 12). There was a significant difference in overall response rate in the Biotalex/carboplatin arm compared to the control arm in patients with non-small cell lung cancer of squamous histology (N=450, 41% vs. 24%, p<0.001), however this difference did not translate into a difference in PFS or OS. There was no difference in ORR between the treatment arms in patients with non-squamous histology (N=602, 26% vs 25%, p=0.808).

Table 12: Overall response rate in randomized non-small cell lung cancer trial (intent-to-treat population)

CI = confidence interval; HR_A/T = hazard ratio of Biotalex/carboplatin to solvent-based paclitaxel/carboplatin; p_A/p_T = response rate ratio of Biotalex/carboplatin to solvent-based paclitaxel/carboplatin.

^a P-value is based on a chi-square test.

There was no statistically significant difference in progression-free survival (by blinded radiologist assessment) and overall survival between the two treatment arms. A non-inferiority analysis was conducted for PFS and OS, with a pre-specified non-inferiority margin of 15%. The non-inferiority criterion was met for both PFS and OS with the upper bound of the 95% confidence interval for the associated hazard ratios being less than 1.176 (Table 13).

Table 13: Non-inferiority analyses on progression-free survival and overall survival in randomized non-small cell lung cancer trial (intent-to-treat population)

CI = confidence interval; HR_A/T = hazard ratio of Biotalex/carboplatin to solvent-based paclitaxel/carboplatin; p_A/p_T = response rate ratio of Biotalex/carboplatin to solvent-based paclitaxel/carboplatin.

^a Per EMA methodological considerations for PFS endpoint, missing observations or initiation of subsequent new therapy were not used for censoring.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Biotalex in all subsets of the paediatric population in the treatment of metastatic breast cancer, pancreatic adenocarcinoma and non-small cell lung cancer (see section 4.2 for information on paediatric use).

Pharmacotherapeutic group: antineoplastic agents (taxanes), ATC code: L01C D01.

Biotalex is a antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilises microtubules by preventing depolymerization. This stability results in the inhibition of the normal dynamic reorganisation of the microtubule network that is essential for vital interphase and mitotic cellular functions. In addition, Biotalex induces abnormal arrays or bundles of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis.

Ovarian carcinoma

In the first-line chemotherapy of ovarian carcinoma, the safety and efficacy of Biotalex were evaluated in two major, randomised, controlled (vs. cyclophosphamide 750 mg/m² / cisplatin 75 mg/m²) trials. In the Intergroup trial (BMS CA139-209), over 650 patients with stage II_b-c, III or IV primary ovarian cancer received a maximum of 9 treatment courses of Biotalex (175 mg/m² over 3 hr) followed by cisplatin (75 mg/m²) or control. The second major trial (GOG-111/BMS CA139-022) evaluated a maximum of 6 courses of either Biotalex (135 mg/m² over 24 hrs) followed by cisplatin (75 mg/m²) or control in over 400 patients with stage III/IV primary ovarian cancer, with a > 1 cm residual disease after staging laparotomy, or with distant metastases. While the two different Biotalex posologies were not compared with each other directly, in both trials patients treated with Biotalex in combination with cisplatin had a significantly higher response rate, longer time to progression, and longer survival time when compared with standard therapy. Increased neurotoxicity, arthralgia/myalgia but reduced myelosuppression were observed in advanced ovarian cancer patients administered 3-hour infusion Biotalex/cisplatin as compared to patients who received cyclophosphamide/cisplatin.

Breast carcinoma

In the adjuvant treatment of breast carcinoma, 3121 patients with node positive breast carcinoma were treated with adjuvant Biotalex therapy or no chemotherapy following four courses of doxorubicin and cyclophosphamide (CALGB 9344, BMS CA 139-223). Median follow-up was 69 months. Overall, Biotalex patients had a significant reduction of 18% in the risk of disease recurrence relative to patients receiving AC alone (p = 0.0014), and a significant reduction of 19% in the risk of death (p = 0.0044) relative to patients receiving AC alone. Retrospective analyses show benefit in all patient subsets. In patients with hormone receptor negative/ unknown tumours, reduction in risk of disease recurrence was 28% (95%CI: 0.59-0.86). In the patient subgroup with hormone receptor positive tumours, the risk reduction of disease recurrence was 9% (95%CI: 0.78-1.07).

However, the design of the study did not investigate the effect of extended AC therapy beyond 4 cycles. It cannot be excluded on the basis of this study alone that the observed effects could be partly due to the difference in duration of chemotherapy between the two arms (AC 4 cycles; AC + Biotalex 8 cycles). Therefore, adjuvant treatment with Biotalex should be regarded as an alternative to extended AC therapy.

In a second large clinical study in adjuvant node positive breast cancer with a similar design, 3060 patients were randomized to receive or not four courses of Biotalex at a higher dose of 225 mg/m² following four courses of AC (NSABP B-28, BMS CA139-270). At a median follow-up of 64 months, Biotalex patients had a significant reduction of 17% in the risk of disease recurrence relative to patients who received AC alone (p = 0.006) ; Biotalex treatment was associated with a reduction in the risk of death of 7% (95%CI: 0.78-1.12). All subset analyses favored the Biotalex arm. In this study patients with hormone receptor positive tumour had a reduction in the risk of disease recurrence of 23% (95%CI: 0.6-0.92); in the patient subgroup with hormone receptor negative tumour the risk reduction of disease recurrence was 10% (95%CI: 0.7-1.11).

- In the first-line treatment of metastatic breast cancer, the efficacy and safety of Biotalex were evaluated in two pivotal, phase III, randomised, controlled open-label trials. In the first study (BMS CA139-278), the combination of bolus doxorubicin (50 mg/m²) followed after 24 hours by Biotalex (220 mg/m² by 3-hour infusion) (AT), was compared versus standard FAC regimen (5-FU 500 mg/m², doxorubicin 50 mg/m², cyclophosphamide 500 mg/m²), both administered every three weeks for eight courses. In this randomised study, 267 patients with metastatic breast cancer, who had either received no prior chemotherapy or only non-anthracycline chemotherapy in the adjuvant setting, were enrolled. Results showed a significant difference in time to progression for patients receiving AT compared to those receiving FAC (8.2 vs. 6.2 months; p= 0.029). The median survival was in favour of Biotalex/doxorubicin vs. FAC (23.0 vs. 18.3 months; p= 0.004). In the AT and FAC treatment arm 44% and 48% respectively received follow-up chemotherapy which included taxanes in 7% and 50% respectively. The overall response rate was also significantly higher in the AT arm compared to the FAC arm (68% vs. 55%). Complete responses were seen in 19% of the Biotalex/doxorubicin arm patients vs. 8% of the FAC arm patients. All efficacy results have been subsequently confirmed by a blinded independent review.

- In the second pivotal study, the efficacy and safety of the Biotalex and Herceptin^®combination was evaluated in a planned subgroup analysis (metastatic breast cancer patients who formerly received adjuvant anthracyclines) of the study HO648g. The efficacy of Herceptin^® in combination with Biotalex in patients who did not receive prior adjuvant anthracyclines has not been proven. The combination of trastuzumab (4 mg/kg loading dose then 2 mg/kg weekly) and Biotalex (175 mg/m²) 3-hour infusion, every three weeks was compared to single-agent Biotalex (175 mg/m²) 3-hour infusion, every three weeks in 188 patients with metastatic breast cancer overexpressing HER2 (2+ or 3+ as measured by immunohistochemistry), who had previously been treated with anthracyclines. Biotalex was administered every three weeks for at least six courses while trastuzumab was given weekly until disease progression. The study showed a significant benefit for the Biotalex/trastuzumab combination in terms of time to progression (6.9 vs. 3.0 months), response rate (41% vs. 17%), and duration of response (10.5 vs. 4.5 months) when compared to Biotalex alone. The most significant toxicity observed with the Biotalex/trastuzumab combination was cardiac dysfunction

Advanced non-small cell lung carcinoma

In the treatment of advanced NSCLC, Biotalex 175 mg/m² followed by cisplatin 80 mg/m² has been evaluated in two phase III trials (367 patients on Biotalex containing regimens). Both were randomised trials, one compared to treatment with cisplatin 100 mg/m², the other used teniposide 100 mg/m² followed by cisplatin 80 mg/m² as comparator (367 patients on comparator). Results in each trial were similar. For the primary outcome of mortality, there was no significant difference between the Biotalex containing regimen and the comparator (median survival times 8.1 and 9.5 months on Biotalex containing regimens, 8.6 and 9.9 months on comparators). Similarly, for progression-free survival there was no significant difference between treatments. There was a significant benefit in terms of clinical response rate. Quality of life results are suggestive of a benefit on Biotalex containing regimens in terms of appetite loss and provide clear evidence of the inferiority of Biotalex containing regimens in terms of peripheral neuropathy (p < 0.008).

AIDS-related Kaposi's sarcoma

In the treatment of AIDS-related KS, the efficacy and safety of Biotalex were investigated in a non-comparative study in patients with advanced KS, previously treated with systemic chemotherapy. The primary end-point was best tumour response. Of the 107 patients, 63 were considered resistant to liposomal anthracyclines. This subgroup is considered to constitute the core efficacy population. The overall success rate (complete/partial response) after 15 cycles of treatment was 57% (CI 44 - 70%) in liposomal anthracycline-resistant patients. Over 50% of the responses were apparent after the first 3 cycles. In liposomal anthracycline-resistant patients, the response rates were comparable for patients who had never received a protease inhibitor (55.6%) and those who received one at least 2 months prior to treatment with Biotalex (60.9%). The median time to progression in the core population was 468 days (95% CI 257-NE). Median survival could not be computed, but the lower 95% bound was 617 days in core patients.

The pharmacokinetics of total paclitaxel following 30- and 180-minute infusions of Biotalex at dose levels of 80 to 375 mg/m² were determined in clinical studies. The paclitaxel exposure (AUC) increased linearly from 2653 to 16736 ng.hr/ml following dosing from 80 to 300 mg/m².

In a study in patients with advanced solid tumours, the pharmacokinetic characteristics of paclitaxel following Biotalex administered intravenously at 260 mg/m² over 30 minutes were compared with those following 175 mg/m² of the solvent-based paclitaxel injection administered over 3 hours. Based on non-compartmental PK analysis, the plasma clearance of paclitaxel with Biotalex was larger (43%) than that following a solvent-based paclitaxel injection and its volume of distribution was also higher (53%). There were no differences in terminal half-lives.

In a repeat dose study with 12 patients receiving Biotalex administered intravenously at 260 mg/m², intrapatient variability in AUC was 19% (range = 3.21%-37.70%). There was no evidence for accumulation of paclitaxel with multiple treatment courses.

Distribution

Following Biotalex administration to patients with solid tumours, paclitaxel is evenly distributed into blood cells and plasma and is highly bound to plasma proteins (94%).

The protein binding of paclitaxel following Biotalex was evaluated by ultrafiltration in a within-patient comparison study. The fraction of free paclitaxel was significantly higher with Biotalex (6.2%) than with solvent-based paclitaxel (2.3%). This resulted in significantly higher exposure to unbound paclitaxel with Biotalex compared with solvent-based paclitaxel, even though the total exposure is comparable. This is possibly due to paclitaxel not being trapped in Cremophor EL micelles as with solvent-based paclitaxel. Based on the published literature, in vitro studies of binding to human serum proteins, (using paclitaxel at concentrations ranging from 0.1 to 50 µg/ml), indicate that the presence of cimetidine, ranitidine, dexamethasone, or diphenhydramine did not affect protein binding of paclitaxel.

Based on population pharmacokinetic analysis, the total volume of distribution is approximately 1741 L; the large volume of distribution indicates extensive extravascular distribution and/or tissue binding of paclitaxel.

Biotransformation and elimination

Based on the published literature, in vitro studies with human liver microsomes and tissue slices show that paclitaxel is metabolised primarily to 6α-hydroxypaclitaxel; and to two minor metabolites, 3'-p-hydroxypaclitaxel and 6α-3'-p-dihydroxypaclitaxel. The formation of these hydroxylated metabolites is catalysed by CYP2C8, CYP3A4, and both CYP2C8 and CYP3A4 isoenzymes, respectively.

In patients with metastatic breast cancer, after a 30-minute infusion of Biotalex at 260 mg/m², the mean value for cumulative urinary excretion of unchanged active substance accounted for 4% of the total administered dose with less than 1% as the metabolites 6α-hydroxypaclitaxel and 3'-p-hydroxypaclitaxel, indicating extensive non-renal clearance. Paclitaxel is principally eliminated by hepatic metabolism and biliary excretion.

At the clinical dose range of 80 to 300 mg/m², the mean plasma clearance of paclitaxel ranges from 13 to 30 L/h/m², and the mean terminal half-life ranges from 13 to 27 hours.

Hepatic impairment

The effect of hepatic impairment on population pharmacokinetics of Biotalex was studied in patients with advanced solid tumours. This analysis included patients with normal hepatic function (n=130), and pre-existing mild (n=8), moderate (n=7), or severe (n=5) hepatic impairment (according to NCI Organ Dysfunction Working Group criteria). The results show that mild hepatic impairment (total bilirubin >1 to ≤1.5 x ULN) has no clinically important effect on pharmacokinetics of paclitaxel. Patients with moderate (total bilirubin >1.5 to ≤3 x ULN) or severe (total bilirubin >3 to ≤5 x ULN) hepatic impairment have a 22% to 26% decrease in the maximum elimination rate of paclitaxel and approximately 20% increase in mean paclitaxel AUC compared with patients with normal hepatic function. Hepatic impairment has no effect on mean paclitaxel C_max. In addition, elimination of paclitaxel shows an inverse correlation with total bilirubin and a positive correlation with serum albumin.

Pharmacokinetic/pharmacodynamic modeling indicates that there is no correlation between hepatic function (as indicated by the baseline albumin or total bilirubin level) and neutropenia after adjusting for Biotalex exposure.

Pharmacokinetic data are not available for patients with total bilirubin >5 x ULN or for patients with metastatic adenocarcinoma of the pancreas.

Renal impairment

Population pharmacokinetic analysis included patients with normal renal function (n=65), and pre-existing mild (n=61), moderate (n=23), or severe (n=l) renal impairment (according to draft FDA guidance criteria 2010). Mild to moderate renal impairment (creatinine clearance >30 to <90 ml/min) has no clinically important effect on the maximum elimination rate and systemic exposure (AUC and C_max) of paclitaxel. Pharmacokinetic data are insufficient for patients with severe renal impairment and not available for patients with end stage kidney disease.

Older people

Population pharmacokinetic analysis for Biotalex included patients with ages ranging from 24 to 85 years old and shows that age does not significantly influence the maximum elimination rate and systemic exposure (AUC and C_max) of paclitaxel.

Pharmacokinetic/pharmacodynamic modelling using data from 125 patients with advanced solid tumours indicates that patients > 65 years of age may be more susceptible to development of neutropenia within the first treatment cycle, although the plasma paclitaxel exposure is not affected by age.

Other intrinsic factors

Population pharmacokinetic analyses for Biotalex indicate that gender, race (Asian vs. White), and type of solid tumours do not have a clinically important effect on systemic exposure (AUC and C_max) of paclitaxel. Patients weighing 50 kg had paclitaxel AUC approximately 25% lower than those weighing 75 kg. The clinical relevance of this finding is uncertain.

Following intravenous administration, Biotalex exhibits a biphasic decline in plasma concentrations. The pharmacokinetics of Biotalex were determined following 3 and 24 hour infusions at doses of 135 and 175 mg/m². Mean terminal half-life estimates ranged from 3.0 to 52.7 hours, and mean, non-compartmentally derived, values for total body clearance ranged from 11.6 to 24.0 l/hr/m²; total body clearance appeared to decrease with higher plasma concentrations of Biotalex. Mean steady-state volume of distribution ranged from 198 to 688 l/m², indicating extensive extravascular distribution and/or tissue binding. With the 3-hour infusion, increasing doses result in non-linear pharmacokinetics. For the 30% increase in dose from 135 mg/m² to 175 mg/m², the C_max and AUC_{→∞}values increased 75% and 81%, respectively.

Following an intravenous dose of 100 mg/ m² given as a 3-hour infusion to 19 KS patients, the mean C_max was 1,530 ng/ml (range 761 - 2,860 ng/ml) and the mean AUC 5,619 ng.hr/ml (range 2,609 - 9,428 ng.hr/ml). Clearance was 20.6 l/h/ m² (range 11-38) and the volume of distribution was 291 l/ m² (range 121-638). The terminal elimination half-life averaged 23.7 hours (range 12 - 33).

Intrapatient variability in systemic Biotalex exposure was minimal. There was no evidence for accumulation of Biotalex with multiple treatment courses.

In vitro studies of binding to human serum proteins indicate that 89-98% of medicinal product is bound. The presence of cimetidine, ranitidine, dexamethasone or diphenhydramine did not affect protein binding of Biotalex.

The disposition of Biotalex has not been fully elucidated in humans. Mean values for cumulative urinary recovery of unchanged drug have ranged from 1.3 to 12.6% of the dose, indicating extensive non-renal clearance. Hepatic metabolism and biliary clearance may be the principal mechanism for disposition of Biotalex. Biotalex appears to be metabolised primarily by cytochrome P450 enzymes. Following administration of a radiolabelled Biotalex, an average of 26, 2 and 6% of the radioactivity was excreted in the faeces as 6α-hydroxyBiotalex, 3'-p-hydroxyBiotalex, and 6α-3'-p-dihydroxy-Biotalex, respectively. The formation of these hydroxylated metabolites is catalysed by CYP2C8, CYP3A4, and both CYP2C8 and CYP3A4 respectively. The effect of renal or hepatic dysfunction on the disposition of Biotalex following a 3-hour infusion has not been investigated formally. Pharmacokinetic parameters obtained from one patient undergoing haemodialysis who received a 3-hour infusion of Biotalex 135 mg/m² were within the range of those defined in non-dialysis patients.

In clinical trials where Biotalex and doxorubicin were administered concomitantly, the distribution and elimination of doxorubicin and its metabolites were prolonged. Total plasma exposure to doxorubicin was 30% higher when Biotalex immediately followed doxorubicin than when there was a 24-hour interval between medicinal product.

For use of Biotalex in combination with other therapies, please consult the Summary of Product Characteristics of cisplatin, doxorubicin or trastuzumab for information on the use of these medicinal products.

Preparation and administration precautions

Paclitaxel is a cytotoxic anticancer medicinal product and, as with other potentially toxic compounds, caution should be exercised in handling Biotalex. The use of gloves, goggles and protective clothing is recommended. If the suspension contacts the skin, the skin should be washed immediately and thoroughly with soap and water. If it contacts mucous membranes, the membranes should be flushed thoroughly with water. Biotalex should only be prepared and administered by personnel appropriately trained in the handling of cytotoxic agents. Pregnant staff should not handle Biotalex.

Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during administration of the medicinal product. Limiting the infusion of Biotalex to 30 minutes, as directed, reduces the likelihood of infusion-related reactions.

Reconstitution and administration of the product

Biotalex is supplied as a sterile lyophilised powder for reconstitution before use. After reconstitution, each ml of suspension contains 5 mg of paclitaxel formulated as albumin bound nanoparticles.

100 mg vial: Using a sterile syringe, 20 ml of sodium chloride 9 mg/ml (0.9%) solution for infusion should slowly be injected into a vial of Biotalex over a minimum of 1 minute.

250 mg vial: Using a sterile syringe, 50 ml of sodium chloride 9 mg/ml (0.9%) solution for infusion should slowly be injected into a vial of Biotalex over a minimum of 1 minute.

The solution should be directed onto the inside wall of the vial. The solution should not be injected directly onto the powder as this will result in foaming.

Once the addition is complete, the vial should be allowed to stand for a minimum of 5 minutes to ensure proper wetting of the solid. Then, the vial should gently and slowly be swirled and/or inverted for at least 2 minutes until complete resuspension of any powder occurs. The generation of foam must be avoided. If foaming or clumping occurs, the solution must stand for at least 15 minutes until foam subsides.

The reconstituted suspension should be milky and homogenous without visible precipitates. Some settling of the reconstituted suspension may occur. If precipitates or settling are visible, the vial should be gently inverted again to ensure complete resuspension prior to use.

Inspect the suspension in the vial for particulate matter. Do not administer the reconstituted suspension if particulate matter is observed in the vial.

The exact total dosing volume of 5 mg/ml suspension required for the patient should be calculated and the appropriate amount of reconstituted Biotalex should be injected into an empty, sterile, PVC or non-PVC type intravenous bag.

The use of medical devices containing silicone oil as a lubricant (i.e. syringes and IV bags) to reconstitute and administer Biotalex may result in the formation of proteinaceous strands. Administer Biotalex using an infusion set incorporating a 15 µm filter to avoid administration of these strands. Use of a 15 µm filter removes strands and does not change the physical or chemical properties of the reconstituted product.

Use of filters with a pore size less than 15 µm may result in blockage of the filter.

The use of specialized di(2-ethylhexyl)phthalate (DEHP)-free solution containers or administration sets is not necessary to prepare or administer Biotalex infusions.

Following administration, it is recommended that the intravenous line be flushed with sodium chloride 9 mg/ml (0.9%) solution for injection to ensure administration of the complete dose.

Any unused product or waste material should be disposed of in accordance with local requirements.

Handling: as with all antineoplastic agents, caution should be exercised when handling Biotalex. Dilution should be carried out under aseptic conditions by trained personnel in a designated area. Adequate protective gloves should be worn. Precautions should be taken to avoid contact with the skin and mucous membranes. In the event of contact with the skin, the area should be washed with soap and water. Following topical exposure, tingling, burning and redness have been observed. In the event of contact with the mucous membranes, these should be flushed thoroughly with water. Upon inhalation, dyspnoea, chest pain, burning throat and nausea have been reported. If unopened vials are refrigerated, a precipitate may form that redissolves with little or no agitation upon reaching room temperature. Product quality is not affected. If the solution remains cloudy or if an insoluble precipitate is noted, the vial should be discarded. Following multiple needle entries and product withdrawals, the vials maintain microbial, chemical and physical stability for up to 28 days at 25°C. Other in-use storage times and conditions are the responsibility of the user. The Chemo-Dispensing Pin device or similar devices with spikes should not be used since they can cause the vial stopper to collapse, resulting in loss of sterile integrity.

Preparation for IV administration: prior to infusion, Biotalex concentrate for solution for infusion must be diluted using aseptic techniques in 0.9% Sodium Chloride Injection, or 5% Dextrose Injection, or 5% Dextrose and 0.9% Sodium Chloride Injection, or 5% Dextrose in Ringer's Injection, to a final concentration of 0.3 to 1.2 mg/ml.

Chemical and physical in-use stability of the solution prepared for infusion has been demonstrated at 5°C and at 25°C for 7 days when diluted in 5% Dextrose solution, and for 14 days when diluted in 0.9% Sodium Chloride Injection. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.

After dilution the solution is for single use only.

Upon preparation, solutions may show haziness, which is attributed to the formulation vehicle, and is not removed by filtration. Biotalex 6 mg/ml concentrate for solution for infusion should be administered through an in-line filter with a microporous membrane ≤0.22 μm. No significant losses in potency have been noted following simulated delivery of the solution through IV tubing containing an in-line filter.

There have been rare reports of precipitation during Biotalex infusions, usually towards the end of a 24 hour infusion period. Although the cause of this precipitation has not been elucidated, it is probably linked to the supersaturation of the diluted solution. To reduce the precipitation risk, Biotalex should be used as soon as possible after dilution, and excessive agitation, vibration or shaking should be avoided. The infusion sets should be flushed thoroughly before use. During infusion, the appearance of the solution should be regularly inspected and the infusion should be stopped if precipitation is present.

To minimise patient exposure to DEHP which may be leached from plasticised PVC infusion bags, sets, or other medical instruments, diluted Biotalex solutions should be stored in non-PVC bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets. Use of filter devices (e.g. IVEX-2) which incorporate short inlet and/or outlet plasticised PVC tubing has not resulted in significant leaching of DEHP.

Disposal: Any unused product or waste material should be disposed of in accordance with local requirements.

Protection instructions for preparation of Biotalex solution for infusion

1. Protective chamber should be used and protective gloves as well as protective gown should be worn. If there is no protective chamber available mouth cover and goggles should be used.

2. Pregnant women or women who may become pregnant, should not handle this product.

3. Opened containers, like injection vials and infusion bottles and used canules, syringes, catheters, tubes, and residuals of cytostatics should be considered as hazardous waste and undergo disposal according to local guidelines for the handling of HAZARDOUS WASTE.

4. Follow the instructions below in case of spillage: - protective clothing should be worn - broken glass should be collected and placed in the container for HAZARDOUS WASTE - contaminated surfaces should be flushed properly with copious amounts of cold water - the flushed surfaces should then be wiped thoroughly and the materials used for wiping should be disposed as HAZARDOUS WASTE

5. In the event of contact of Biotalex Concentrate for Solution for Infusion with the skin, the area should be rinsed with plenty of running water and then washed with soap and water. In case of contact with mucous membranes, wash the contacted area thoroughly with water. If you have any discomfort, contact a doctor.

6. In case of contact of Biotalex Concentrate for Solution for Infusion with eyes, wash them thoroughly with plenty of cold water. Contact an ophthalmologist immediately.