Antineoplastic agent

Trabectedin

0.25 mg vial Each vial contains 0.25 mg of trabectedin. 1 mg vial Each vial contains 1 mg of trabectedin. 0.25 mg and 1 mg vials 1 ml of reconstituted solution contains 0.05 mg of trabectedin. Excipients: 0.25 mg vial Each vial contains 2 mg of potassium and 0.1 g of sucrose. 1 mg vial Each vial contains 8 mg of potassium and 0.4 g of sucrose. 0.25 mg and 1 mg vials

Powder for concentrate for solution for infusion. White to off-white powder.

Yondelis is indicated for the treatment of patients with advanced soft tissue sarcoma, after failure of anthracyclines and ifosfamide, or who are unsuited to receive these agents. Efficacy data are based mainly on liposarcoma and leiomyosarcoma patients.

Yondelis in combination with pegylated liposomal doxorubicin (PLD) is indicated for the treatment of patients with relapsed platinum-sensitive ovarian cancer.

Yondelis must be administered under the supervision of a physician experienced in the use of chemotherapy. Its use should be confined to qualified oncologists or other health professionals specialised in the administration of cytotoxic agents.

Posology

For the treatment of soft tissue sarcoma, the recommended dose is 1.5 mg/m² body surface area, administered as an intravenous infusion over 24 hours with a three-week interval between cycles.

For the treatment of ovarian cancer Yondelis is administered every three weeks as a 3-hour infusion at a dose of 1.1 mg/m², immediately after PLD 30 mg/m². To minimize the risk of PLD infusion reactions, the initial dose is administered at a rate no greater than 1 mg/minute. If no infusion reaction is observed, subsequent PLD infusions may be administered over a 1-hour period. (See also PLD Summary Product Characteristics for specific administration advice).

All patients must receive corticosteroids e.g. 20 mg of dexamethasone intravenously 30 minutes prior to PLD (in combination therapy) or Yondelis (in monotherapy); not only as anti-emetic prophylaxis, but also because it appears to provide hepatoprotective effects. Additional anti-emetics may be administered as needed.

The following criteria are required to allow treatment with Yondelis:

- Absolute neutrophil count (ANC)  1,500/mm³

- Platelet count  100,000/mm³

- Bilirubin  upper limit of normal (ULN)

- Alkaline phosphatase  2.5 x ULN (consider hepatic isoenzymes 5-nucleotidase or GGT, if the elevation could be osseous in origin).

- Albumin  25 g/l.

- Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST)  2.5 x ULN

- Creatinine clearance  30 ml/min (monotherapy), serum creatinine  1.5 mg/dl ( 132.6 μmol/l) or creatinine clearance  60 ml/min (combination therapy)

- Creatine phosphokinase (CPK)  2.5 x ULN

- Haemoglobin  9 g/dl

The same criteria as above must be met prior to re-treatment. Otherwise treatment must be delayed for up to 3 weeks until the criteria are met.

Additional monitoring of haematological parameters bilirubin, alkaline phosphatase, aminotransferases and CPK should occur weekly during the first two cycles of therapy, and at least once between treatments in subsequent cycles.

The same dose should be given for all cycles provided that no grade 3-4 toxicities are seen and that the patient fulfils the re-treatment criteria.

Dose adjustments during treatment

Prior to re-treatment, patients must fulfil the baseline criteria defined above. If any of the following events occur at any time between cycles, the dose must be reduced one level, according to table 1 below, for subsequent cycles:

- Neutropenia < 500/mm³ lasting for more than 5 days or associated with fever or infection

- Thrombocytopenia < 25,000/mm³

- Increase of bilirubin > ULN and/or alkaline phosphatase > 2.5 x ULN

- Increase of aminotransferases (AST or ALT) > 2.5 x ULN (monotherapy) or > 5 x ULN (combination therapy), which has not recovered by day 21

- Any other grade 3 or 4 adverse reactions (such as nausea, vomiting, fatigue)

Once a dose has been reduced because of toxicity, dose escalation in the subsequent cycles is not recommended. If any of these toxicities reappear in subsequent cycles in a patient exhibiting clinical benefit, the dose may be further reduced (see below). Colony stimulating factors can be administered for hematologic toxicity according to local standard practice.

Table 1 Dose modification table for Yondelis (as single agent for STS or in combination for ovarian cancer) and PLD

See the PLD SPC for more detailed information on PLD dose adjustments.

In the event that further dose reductions are necessary, treatment discontinuation should be considered.

Duration of treatment

In clinical trials, there were no pre-defined limits to the number of cycles administered. Treatment continued whilst clinical benefit was noted. Yondelis has been administered for 6 or more cycles in 29.5% and 52% of patients treated with the monotherapy and combination dose and schedule respectively. The monotherapy and combination regimens have been used for up to 38 and 21 cycles respectively. No cumulative toxicities have been observed in patients treated with multiple cycles.

Paediatric patients

The safety and efficacy of trabectedin in paediatric patients have not yet been established. Therefore, this medicinal product must not be used in children and adolescents until further data become available.

Elderly patients

No specific studies in elderly patients have been performed. Overall 20% of the 1164 patients in the integrated safety analysis of monotherapy clinical trials were over 65 years. Of the 333 patients with ovarian cancer who received trabectedin in combination with PLD, 24% were 65 years of age or older and 6% were over 75 years. No relevant differences in the safety profile were seen in this patient population. It seems that plasma clearance and distribution volume of trabectedin are not influenced by age. Therefore, dose adjustments based uniquely on age criteria are not routinely recommended.

Patients with impaired hepatic function

No studies with the proposed regimen have been conducted in patients with liver dysfunction. Thus, data are not available to recommend a lower starting dose in patients with hepatic impairment. However, special caution is advised and dose adjustments may be necessary in these patients since systemic exposure is probably increased and the risk of hepatotoxicity might be increased. Patients with elevated bilirubin must not be treated with Yondelis.

Patients with impaired renal function

Studies including patients with renal insufficiency (creatinine clearance < 30 ml/min for the monotherapy, and < 60 ml/min for the combination regimen) have not been conducted and therefore Yondelis must not be used in this patient population. Considering the pharmacokinetic characteristics of trabectedin, no dose adjustments are warranted in patients with mild or moderate renal impairment.

Method of administration

Administration through a central venous line is strongly recommended.

For instructions on reconstitution and dilution of the medicinal product before administration

Paediatric patients The safety and efficacy of trabectedin in paediatric patients have not yet been established. Therefore, this medicinal product must not be used in children and adolescents until further data become available.

No specific studies in elderly patients have been performed. Overall 20% of the 1164 patients in the integrated safety analysis were over 65 years. No relevant differences in the safety profile were seen in this patient population. It seems that plasma clearance and distribution volume of trabectedin are not influenced by age. Therefore, dose adjustments based uniquely on age criteria are not routinely recommended.

- Hypersensitivity to trabectedin or to any of the excipients

- Concurrent serious or uncontrolled infection

- Breast-feeding

- Combination with yellow fever vaccine

Hepatic impairment

Patients must meet specific criteria on hepatic function parameters to start treatment with Yondelis. Since systemic exposure to trabectedin is probably increased due to hepatic impairment and therefore the risk of hepatotoxicity might be increased, patients with clinically relevant liver diseases, such as active chronic hepatitis, must be closely monitored and the dose adjusted if needed. Patients with elevated bilirubin must not be treated with trabectedin.

Renal impairment

Creatinine clearance must be monitored prior to and during treatment. Yondelis monotherapy and combination regimens must not be used in patients with creatinine clearance < 30 ml/min and < 60 ml/min respectively.

Neutropenia and thrombocytopenia

Grades 3 or 4 neutropenia and thrombocytopenia associated with Yondelis therapy have been very commonly reported. A full blood cell count including differential and platelet count must be performed at baseline, weekly for the first two cycles and then once between cycles. Patients who develop fever should promptly seek medical attention. If this occurs, active supportive therapy should be started immediately.

Yondelis should not be administered to patients with baseline neutrophil counts of less than 1,500 cells/mm³ and platelets count of less than 100,000 cells/mm³. If severe neutropenia (ANC < 500 cells/mm³) lasting more than 5 days or associated with fever or infection occurs, dose reduction is recommended.

Nausea and vomiting

Anti-emetic prophylaxis with corticosteroids such as dexamethasone must be administered to all patients.

Rhabdomyolysis and severe CPK elevations ( > 5 x ULN)

Trabectedin must not be used in patients with CPK > 2.5 x ULN. Rhabdomyolysis has been uncommonly reported, usually in association with myelotoxicity, severe liver function test abnormalities and/or renal or multiorgan failure. Therefore, CPK should be closely monitored whenever a patient may be experiencing any of these toxicities or muscle weakness or muscle pain. If rhabdomyolysis occurs, supportive measures such as parenteral hydration, urine alkalinisation and dialysis should be promptly established, as indicated. Treatment with Yondelis should be discontinued until the patient fully recovers.

Caution should be taken if medicinal products associated with rhabdomyolysis (e.g. statins), are administered concomitantly with trabectedin, since the risk of rhabdomyolysis may be increased

Liver Function Test (LFT) abnormalities

Reversible acute increases in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) have been reported in most patients. Yondelis must not be used in patients with elevated bilirubin. Patients with increases in AST, ALT and alkaline phosphatase between cycles may necessitate dose reduction.

Injection site reactions

The use of central venous access is strongly recommended. Patients may develop a potentially severe injection site reaction when trabectedin is administered through a peripheral venous line.

Trabectedin extravasation may cause tissue necrosis requiring debridement. There is no specific antidote for extravasation of trabectedin. Extravasation should be managed by local standard practice.

Others

Co-administration of Yondelis with potent inhibitors of the enzyme CYP3A4 should be avoided. If this is not possible, close monitoring of toxicities are required and dose reductions of trabectedin should be considered.

Caution should be taken if medicinal products associated with hepatotoxicity are administered concomitantly with trabectedin, since the risk of hepatotoxicity may be increased.

Concomitant use of trabectedin with phenytoin may reduce phenytoin absorption leading to an exacerbation of convulsions. Combination of trabectedin with phenytoin or live attenuated vaccines is not recommended and with yellow fever vaccine is specifically contraindicated.

The concomitant use of trabectedin with alcohol must be avoided.

Men in fertile age and women of childbearing potential must use effective contraception during treatment and 3 months thereafter for women and immediately inform the treating physician if a pregnancy occurs, and 5 months after treatment for men.

This medicine contains potassium, less than 1 mmol (39 mg) per vial, i.e. essentially “potassium-free”.

See also PLD Summary of Product Characteristics for more detailed information on warnings and precautions.

Effects of other substances on trabectedin

In vivo interaction studies have not been performed. Since trabectedin is metabolised mainly by CYP3A4, co-administration of substances that inhibit this isoenzyme e.g. ketoconazole, fluconazole ritonavir, clarithromycin or aprepitant could decrease metabolism and increase trabectedin concentrations. If such combinations are needed, close monitoring of toxicities is required Likewise co-administration with potent inducers of this enzyme (e.g. rifampicin, phenorbarbital, Saint John's Wort) may decrease the systemic exposure to trabectedin.

Alcohol consumption must be avoided during treatment with trabectedin due to the hepatotoxicity of the medicinal product.

Preclinical data have demonstrated that trabectedin is a substrate to P-gp. Concomitant administration of inhibitors of P-gp, e.g. cyclosporine and verapamil, may alter trabectedin distribution and/or elimination. The relevance of this interaction e.g. CNS toxicity has not been established. Caution should be taken in such situations.

Unless otherwise specified, the following safety profile of Yondelis is based on the evaluation in clinical trials of patients treated with the recommended treatment regimens for both indications.

Most patients treated with Yondelis can be expected to have adverse reactions of any grade (91% in monotherapy and 99% in combination therapy) and less than one third serious adverse reactions of grade 3 or 4 severity (10% in monotherapy and 25% in combination therapy). The most common adverse reactions of any severity grade were neutropenia, nausea, vomiting, increases in AST/ALT, anemia, fatigue, thrombocytopenia, anorexia, and diarrhoea.

Fatal adverse reactions have occurred in 1.9% and 0.9% of patients treated with the monotherapy and combination regimens respectively. They were often the result of a combination of events including pancytopenia, febrile neutropenia, some of them with sepsis, hepatic involvement, renal or multiorgan failure and rhabdomyolysis.

Adverse reactions

The frequencies of the adverse reactions reported below are classified as very common ( 1/10), common ( 1/100 to < 1/10) and uncommon ( 1/1000 to < 1/100).

The table below displays the adverse reactions reported in  1% of patients treated with the soft tissue sarcoma recommended regimen (1.5 mg/m², 24 hour infusion every 3 weeks) according to the standard MedDRA system organ class. Both adverse reactions and laboratory values have been used to provide frequencies. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

* Derived from laboratory data

The table below provides the frequency and severity of undesirable effects considered possibly related to study drug and reported in  5% of patients with ovarian cancer randomised to receive Yondelis 1.1 mg/m²/PLD 30 mg/m² or PLD 50 mg/m² in the pivotal trial ET743-OVA-301. Both adverse reactions and laboratory values have been used. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

* Derived from laboratory data

The following reactions have been reported with a frequency below 5% in the combination arm, but are included here for their clinical relevance: neutropenic infection (< 1%), neutropenic sepsis (< 1%), pancytopenia (1.8%), bone marrow failure (1.5%), granulocytopenia (1.5%), dehydration, insomnia, peripheral sensory neuropathy, syncope, left ventricular dysfunction (< 1%), pulmonary embolism (1.2%), pulmonary edema (< 1%), cough, hepatotoxicity (< 1%), gamma-glutamyltransferase increased, bilirubin conjugated increased, musculoskeletal pain, myalgia, blood creatinine increased, oedema/peripheral oedema, catheter site reactions.

In the Yondelis+PLD arm, non-white (mainly Asian) patients had a higher incidence than white patients in grade 3 or 4 adverse reactions (96% versus 87%), and serious adverse reactions (44% versus 23% all grades). The differences were mainly observed in relation with neutropenia (93% versus 66%), anaemia (37% versus 14%) and thrombocytopenia (41% versus 19%). However, the incidences of clinical complications related to haematological toxicity such as severe infections or bleeding, or those leading to death or treatment termination, were similar in both subpopulations.

Most frequent adverse reactions

Blood and Lymphatic system disorders

Neutropenia: Neutropenia is the most common haematological toxicity. It followed a predictable pattern of rapid onset and reversibility, and was rarely associated with fever or infection. Neutrophil nadirs occurred at a median of 15 days and recovered within a week. The analysis per cycle performed in patients treated with the monotherapy regimen showed neutropenia of grade 3 and 4 in approximately 19% and 8% of cycles respectively. In this population febrile neutropenia occurred in 2% of patients and in < 1% of cycles.

Thrombocytopenia: Bleeding events associated to thrombocytopenia occurred in < 1% of patients treated with the monotherapy regimen. The analysis per cycle performed in these patients showed thrombocytopenia of grade 3 and 4 in approximately 3% and < 1% of cycles respectively.

Anaemia: Anaemia occurred in 93% and 94% of patients treated with the monotherapy and combination regimens respectively. The percentages of patients anaemic at baseline were 46% and 35% respectively. The analysis per cycle performed in patients treated with the monotherapy regimen showed anaemia of grade 3 and 4 in approximately 3% and 1% of cycles respectively.

Hepatobiliary disorders

AST/ALT increases: The median time to reach the peak values was 5 days for both AST and ALT. Most of the values had decreased to grade 1 or resolved by day 14-15. The analysis per cycle performed in patients treated with the monotherapy regimen showed grade 3 elevations of AST and ALT in 12% and 20% of cycles respectively. Grade 4 elevations of AST and ALT occurred in 1% and 2% of cycles respectively. Most transaminase elevations improved to grade 1 or to pre-retreatment levels within 15 days, and less than 2% of cycles had recovering times longer than 25 days. ALT and AST increases did not follow a cumulative pattern but showed a tendency towards less severe elevations over time.

Hyperbilirubinemia: Bilirubin peaks approximately a week after onset and resolves approximately two weeks after onset.

Liver function tests predicting severe toxicity (meeting Hy´s law) and clinical manifestations of severe hepatic injury were uncommon with a lower than 1% incidence of individual signs and symptoms including jaundice, hepatomegaly or liver pain. Mortality in the presence of hepatic injury occurred in less than 1% of patients in both regimens.

Other adverse reactions

CPK elevations and rhabdomyolysis: CPK elevations of any grade were observed in 23-26% of patients in both regimens. CPK increases in association with rhabdomyolysis were reported in less than 1% of patients.

Alopecia: Alopecia was reported in approximately 3% of patients treated with the monotherapy regimen, of which the majority was grade 1 alopecia.

Post-marketing experience

During post-marketing surveillance few cases of trabectedin extravasation with subsequent tissue necrosis requiring debridement have been reported

Pharma Mar

(POM)

23 November 2011