Vinflunine

A pharmacokinetic and tolerability phase I study in patients with altered liver functions test has been completed. Vinflunine pharmacokinetics was not modified in those patients, however based on hepatic biologic parameter modifications following vinflunine administration (gamma glutamyl transferases (GGT), transaminases, bilirubin), the dose recommendations are as follows:

• No dose adjustment is necessary in patients:
  • with a prothrombin time >70% NV (Normal Value) and presenting at least one of the following criteria: [ULN (Upper Limit of Normal) < bilirubin ≤ 1.5×ULN and/or 1.5xULN < transaminases ≤ 2.5×ULN and/or ULN < GGT ≤ 5×ULN].
  • with transaminases ≤ 2.5xULN (< 5xULN only in case of liver metastases).
• The recommended dose of vinflunine is 250 mg/m² given once every 3 weeks in patients with mild liver impairment (Child-Pugh grade A) or in patients with a prothrombin time ≥60% NV and 1.5×ULN < bilirubin ≤ 3×ULN and presenting at least one of the following criteria: [transaminases > ULN and/or GGT > 5×ULN].
• The recommended dose of vinflunine is 200 mg/m² given once every 3 weeks in patients with moderate liver impairment (Child-Pugh grade B) or in patients with a prothrombin time ≥50% NV and bilirubin > 3×ULN and transaminases > ULN and GGT > ULN.

Vinflunine has not been evaluated in patients with severe hepatic impairment (Child-Pugh grade C), or in patients with a prothrombin time <50% NV or with bilirubin >5xULN or with isolated transaminases >2.5xULN (≥5xULN only in case of liver metastases) or with GGT >15xULN.

In clinical studies, patients with CrCl (creatinine clearance) > 60 mL/min were included and treated at the recommended dose.

In patients with moderate renal impairment (40 mL/min ≤ CrCl ≤ 60 mL/min), the recommended dose is 280 mg/m² given once every 3 weeks.

In patients with severe renal impairment (20 mL/min ≤ CrCl < 40 mL/min) the recommended dose is 250 mg/m² every 3 weeks.

For further cycles, the dose should be adjusted in the event of toxicities, as shown in the table below.

Dose adjustments due to toxicity in renal impaired or elderly patients:

* National Cancer Institute, Common Toxicity Criteria Version 2.0 (NCI CTC v 2.0)
¹ NCI CTC Grade 2 constipation is defined as requiring laxatives, Grade 3 as an obstipation requiring manual evacuation or enema, Grade 4 as an obstruction or toxic megacolon. Mucositis Grade 2 is defined as “moderate”, Grade 3 as “severe” and Grade 4 as “life-threatening”.
² NCI CTC Grade 3 nausea is defined as no significant intake, requiring intravenous fluids. Grade 3 vomiting as ≥6 episodes in 24 hours over pretreatment; or need for intravenous fluids

In vitro studies showed that vinflunine is a P-gp-substrate like other vinca alkaloids, but with a lower affinity. Therefore, risks of clinically significant interactions should be unlikely.

A phase I study evaluating the effect of ketoconazole treatment (a potent CYP3A4 inhibitor) on vinflunine pharmacokinetics indicated that co-administration of ketoconazole (400 mg orally once daily for 8 days) resulted in a 30% and 50% increase in blood exposures to vinflunine and its metabolite 4Odeacetyl-vinflunine (DVFL), respectively.

Therefore the concomitant use of vinflunine and potent CYP3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole and grapefruit juice) or inducers (such as rifampicin and Hypericum perforatum (St John’s wort)) should be avoided since they may increase or decrease vinflunine and DVFL concentrations.

The concomitant use of opioids could enhance the risk of constipation.

Advice on conservation of sperm should be sought prior to treatment because of the possibility of irreversible infertility due to therapy with vinflunine.

No pharmacokinetic interaction was observed in patients when vinflunine was combined with doxorubicin. However, this combination was associated with a particularly high risk of haematological toxicity.

A pharmacokinetic interaction between vinflunine and pegylated/liposomal doxorubicin was observed, resulting in a 15% to 30% apparent increase in vinflunine exposure and a 2 to 3-fold apparent decrease of doxorubicin AUC, whereas for doxorubicinol, the concentrations of the metabolite were not affected. According to an in vitro study, such changes could be related to adsorption of vinflunine on the liposomes and a modified blood distribution of both compounds. Therefore, caution should be excercised when this type of combination is used.

A possible interaction with paclitaxel and docetaxel (CYP3 substrates) has been suggested from an in vitro study (slight inhibition of vinflunine metabolism). No specific clinical studies of vinflunine in combination with these compounds have been carried out yet.

The concomitant use of vinflunine with others QT/QTc interval prolonging medicinal products should be avoided.

Few QT interval prolongations have been observed after the administration of vinflunine. This effect may lead to an increased risk of ventricular arrhythmias although no ventricular arrhythmias were observed with vinflunine. Nevertheless, vinflunine should be used with caution in patients with increase of the proarrhythmic risk (e.g. congestive heart failure, known history of QT interval prolongation, hypokalaemia). The concomittant use of two or more QT/QTc interval prolonging substances is not recommended.

Special attention is recommended when vinflunine is administered to patients with prior history of myocardial infarction/ischaemia or angina pectoris. Ischaemic cardiac events may occur, especially in patients who have underlying cardiac disease. Thus, patients receiving vinflunine should be vigilantly monitored by physicians for the occurrence of cardiac events. Caution should be exercised in patients with a history of cardiac disease and the benefit/risk assessment should be carefully evaluated regularly. Discontinuation of vinflunine should be considered in patients who develop cardiac ischaemia.

Grade ≥ 3 constipation occurred in 15.3% of treated patients. NCI CTC Grade 3 constipation is defined as an obstipation requiring manual evacuation or enema, Grade 4 constipation as an obstruction or toxic megacolon. Constipation is reversible and can be prevented by special dietary measures such as oral hydration and fibre intake, and by administration of laxatives such as stimulant laxatives or faecal softners from day 1 to day 5 or 7 of the treatment cycle. Patients at high risk of constipation (concomitant treatment with opiates, peritoneal carcinomas, abdominal masses, prior major abdominal surgery) should be medicated with an osmotic laxative from day 1 to day 7 administered once a day in the morning before breakfast.

In case of Grade 2 constipation, defined as requiring laxatives, for 5 days or more or Grade ≥ 3 of any duration, the dose of vinflunine should be adjusted. In case of any Grade ≥ 3 gastrointestinal toxicity (except vomiting or nausea) or of mucositis (Grade 2 for 5 days or more or Grade ≥ 3 of any duration) dose adjustment is required. Grade 2 is defined as “moderate”, Grade 3 as “severe” and Grade 4 as “life-threatening”.

Severe hyponatraemia, including cases due to syndrome of inappropriate antidiuretic hormone secretion (SIADH), has been observed with the use of vinflunine. Therefore, regular monitoring of serum sodium levels is recommended during treatment with vinflunine.

Cases of posterior reversible encephalopathy syndrome (PRES) have been observed after administration of vinflunine.

The typical clinical symptoms are, with various degrees: neurological (headache, confusion, seizure, visual disorders), systemic (hypertension), and gastrointestinal (nausea, vomiting). Radiological signs are white matter abnormalities in the posterior regions of the brain. Blood pressure should be controlled in patients developing symptoms of PRES. To confirm the diagnosis, brain imaging is recommended.

Clinical and radiological features usually resolved rapidly without sequelae after treatment discontinuation.

Discontinuation of vinflunine should be considered in patients who develop neurological signs of PRES.

Neutropenia, leucopenia, anaemia and thrombocytopenia are frequent adverse reactions of vinflunine. Adequate monitoring of complete blood counts should be conducted to verify the ANC, platelet and haemoglobin values before each vinflunine infusion. Initiation of vinflunine is contraindicated in subjects with baseline ANC <1,500/mm³ or platelets <100,000/mm³. For subsequent administrations, vinflunine is contraindicated in subjects with baseline ANC <1,000/mm³ or platelets <100,000/mm³.

The recommended dose should be reduced in patients with haematological toxicity.

Dose delay or discontinuation due to toxicity

Table 1. Dose delay for subsequent cycles due to toxicity:

Dose adjustments due to toxicity

Table 2. Dose adjustments due to toxicity:

* National Cancer Institute, Common Toxicity Criteria Version 2.0 (NCI CTC v 2.0)
¹ NCI CTC Grade 2 constipation is defined as requiring laxatives, Grade 3 as an obstipation requiring manual evacuation or enema, Grade 4 as an obstruction or toxic megacolon. Mucositis Grade 2 is defined as “moderate”, Grade 3 as “severe” and Grade 4 as “life-threatening”.
² NCI CTC Grade 3 nausea is defined as no significant intake, requiring intravenous fluids. Grade 3 vomiting as ≥6 episodes in 24 hours over pretreatment; or need for intravenous fluids.

There are no data available on the use of vinflunine in pregnant women. Studies in animals have shown embryotoxicity and teratogenicity. On the basis of the results of animal studies and the pharmacological action of the medicinal product, there is a potential risk of embryonic and foetal abnormalities.

Vinflunine should therefore not be used during pregnancy, unless it is strictly necessary. If pregnancy occurs during treatment, the patient should be informed about the risk for the unborn child and be monitored carefully. The possibility of genetic counselling should be considered. Genetic counselling is also recommended for patients wishing to have children after therapy.

It is unknown whether vinflunine or its metabolites are excreted in human milk. Due to the possible very harmful effects on the infants, breast-feeding during treatment with vinflunine is contraindicated.

Contraception in males and females

Both male and female patients should take adequate contraceptive measures up to three months after the discontinuation of the therapy.

Fertility

Advice on conservation of sperm should be sought prior to treatment because of the possibility of irreversible infertility due to therapy with vinflunine.

Vinflunine may cause adverse reactions such as fatigue (very common) and dizziness (common) which may lead to a minor or moderate influence on the ability to drive and use machines. Patients should be advised not to drive or use machines if they experience any adverse reaction with a potential impact on the ability to perform these activities.

Summary of the safety profile

The most frequent treatment-related adverse reactions reported in the two phase II and one phase III trials in patients with transitional cell carcinoma of the urothelium (450 patients treated with vinflunine) were haematological disorders, mainly neutropenia and anaemia; gastrointestinal disorders, especially constipation, anorexia, nausea, stomatitis/mucositis, vomiting, abdominal pain and diarrhoea, and general disorders such as asthenia/fatigue.

Tabulated list of adverse reactions

Adverse reactions are listed below by System Organ Class, frequency and grade of severity (NCI CTC version 2.0). Frequency of adverse reactions 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); not known (cannot be estimated from available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Adverse reactions observed in patients with transitional cell carcinoma of the urothelium treated with vinflunine:

^a adverse reactions reported from post-marketing experience
^b frequency calculated on the basis of non-TCCU clinical trial

Adverse reactions in all indications

Adverse reactions occurring in patients with transitional cell carcinoma of the urothelium and in patients with other disease than this indication and potentially severe or adverse reactions that are a class effect of the vinca alkaloids are described below.

Blood and lymphatic system disorders

Grade ¾ neutropenia was observed in 43.8% of patients. Severe anaemia and thrombocytopenia were less common (respectively 8.8 and 3.1%). Febrile neutropenia defined as ANC <1,000/mm³ and fever ≥38.5°C of unknown origin without clinically microbiologically documented infection (NCI CTC version 2.0) was observed in 5.2% of patients. Infection with Grade ¾ neutropenia was observed in 2.8% of patients.

Overall 8 patients (0.6% of the treated population) died from infection as a complication occurring during neutropenia.

Gastrointestinal disorders

Constipation is a class effect of the vinca alkaloids: 11.8% of patients experienced severe constipation during treatment with vinflunine. Grade ¾ ileus reported in 1.9% of patients was reversible when managed by medical care. Constipation is managed by medical care.

Nervous system disorders

Sensory peripheral neuropathy is a class effect of the vinca alkaloids. Grade 3 was experienced by 0.6% patients. All resolved during the study. Rare cases of Posterior Reversible Encephalopathy Syndrome have been reported.

Cardiovascular disorders

Cardiac effects are a known class effect of the vinca alkaloids. Myocardial infarction or ischaemia were experienced by 0.5% of the patients and most of them had a pre-existing cardiovascular disease or risk factors. One patient died after myocardial infarction and another one due to a cardiopulmonary arrest.

Few QT interval prolongations have been observed after the administration of vinflunine.

Respiratory, thoracic and mediastinal disorders

Dyspnoea occurred in 3.2% of the patients but was rarely severe (Grade 3/4: 1.2%). Bronchospam was reported in one patient treated with vinflunine for a different setting from the indication.