Consumer medicine information

Aplidin

Plitidepsin

BRAND INFORMATION

Brand name

Aplidin

Active ingredient

Plitidepsin

Schedule

What Is In This Leaflet

This leaflet answers some common questions about Aplidin powder for solution for infusion.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you being given Aplidin against the benefits they expect it will have for you.

If you have any concerns about being given this medicine, ask your doctor or pharmacist.

Keep this leaflet You may want to read it again.

What Aplidin Is Used For

Aplidin contains the active substance plitidepsin. It is a type of medicine used to treat multiple myeloma which is a cancer of plasma cells (a type of white blood cell).

Aplidin is given to patients that have received prior treatments for their multiple myeloma. It will be given to you together with dexamethasone, which is another medicine used to your condition.

Ask your doctor or nurse if you have any questions about why this medicine has been prescribed for you.

This medicine is only available with a prescription from a doctor experienced with chemotherapy treatment.

There is no evidence that this medicine is addictive.

Before you are given Aplidin

When you should not be given it

You should not be given this medicine if you have an allergy to:

plitidepsin
the excipient, PEG-35 castor oil
any of the other ingredients of this medicine, listed at the end of this leaflet.

If you think you may be allergic to Aplidin, ask your doctor for advice.

Some of the symptoms of an allergic reaction may include:

shortness of breath
wheezing or difficulty breathing
swelling of the face, lips, tongue or other parts of the body
rash, itching or hives on the skin.

Unless you are advised by your doctor that it is necessary to be given Aplidin, you should not be given this medicine if:

you are pregnant
you are breast-feeding
you are a child or adolescent
you have abnormal liver function

You should not be given this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering.

If you are not sure whether you should be given this medicine, talk to your doctor.

Before you are given it

This medicinal product contains 15% vol ethanol (alcohol), i.e. up to 2137.5 mg per dose, which is equivalent to 54 mL beer or 22.5 mL wine per dose. The ability to drive and use machines may be affected. Patients should not drive or operate machinery during therapy with Aplidin.

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Muscular symptoms:
Aplidin has been associated with muscle symptoms. Tell your doctor or nurse if you feel muscle weakness or muscular pain prior to starting treatment with Aplidin because this situation must be carefully assessed by your doctor before starting this therapy.

Tell your doctor if you:

Are pregnant or plan to become pregnant

Women treated with Aplidin should avoid becoming pregnant, as potential risks exist for the unborn child.
Men being treated with Aplidin should avoid fathering a child during treatment.
Effective contraception must be used during treatment and for 6 months after the treatment.
Only use Aplidin during pregnancy if your doctor tells you it is absolutely necessary.
If a pregnancy should occur, you must tell your doctor immediately. Genetic counselling is recommended, since Aplidin can cause genetic damage.
Your doctor can discuss with you the risks and benefits involved.

Are breast-feeding or plan to breastfeed

Aplidin must not be given to patients who are breast-feeding. Stop breast-feeding before starting treatment with Aplidin, and do not begin breast-feeding again until your doctor has told you it is safe to do so.
It is not known if Aplidin passes into breast milk.

Have any gastrointestinal problems

Diarrhoea, nausea or vomiting may occur with Aplidin.

Have any liver problems

Abnormal liver tests may occur with Aplidin.

Have heart problems, or have ever taken medicine for your heart

Aplidin may cause heart problems, including abnormal hearth rhythm.

Aplidin should not be used in children and adolescents because it has not been studied in this population.

Aplidin contains ethanol and may moderately affect your ability to drive and use machines.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

In particular, tell your doctor if you are using medicines containing any of the following active substances:

ketoconazole, itraconazole or voriconazole, used to treat fungal infections
rifampicin, telithromycin, clarithromycin, antibiotics used to treat bacterial infections
carbamazepine, phenytoin or phenobarbital used to treat epilepsy
St. John’s Wort (Hypericum perforatum) or nefazodone, used for depression or other conditions.

How Aplidin is given

Aplidin is given to you in the hospital or clinic 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 medicines.

How much is given

Aplidin is given in combination with dexamethasone, and the duration of each cycle of treatment is 28 days: Aplidin will be given to you on days 1 and 15 of each cycle, at the dose of 5 mg/m² of body surface area. Your doctor will determine the exact dose based on your height and weight. You will take dexamethasone on Day 1, 8, 15 and 22 of each cycle. So on days 1 and 15 you will receive the two medicines, first dexamethasone, and then Aplidin starting approximately one hour later. From day 23 to day 28 you will not receive either dexamethasone or Aplidin. Day 29 will be the first day of the next cycle of treatment.

How it is given

Before Aplidin is given to you, it will be reconstituted and diluted for intravenous use.

Aplidin will be given to you as an infusion (a drip) into a vein (intravenously) over a period of 3 hours.

If a peripheral venous line (an infusion into a blood vessel in your arm) is not possible, a central venous line (an infusion into a blood vessel in your chest or neck) will be used.

Before each infusion of Aplidin, you will be given other medicines to reduce the risk of nausea and vomiting, and allergic reactions.

How long it will be given for

The length of your whole treatment period will depend on your progress and how well you feel. Your doctor will tell you how long your treatment lasts. If you have any further questions on the use of this medicine, ask your doctor.

If too much is given (overdose)

As this medicine is being given by your doctor or nurse, it is unlikely that you will be given too much. In the unlikely event of an overdose, your doctor will monitor you for side effects treat any of your symptoms as required.

If you have any further questions on the use of this medicine, ask your doctor.

While You Are Being Given Aplidin

Things you must do

If you are about to be started on any new medicine, remind your doctor that you are being given Aplidin.

Tell any other doctors, dentists, and pharmacists who treat you that you are being given this medicine.

If you become pregnant while being given this medicine, tell your doctor immediately.

Things you must not do

If you experience side effects that impair your vision or balance, your ability to drive a car or operate machinery could be impaired.

Side Effects

All medicines may have some unwanted side effects, although not everybody gets them. Sometimes they are serious, most of the time they are not. Your doctor has weighed the risks of being given this medicine against the benefits they expect it will have for you.

Do not be alarmed by the following lists of side effects.

Tell your doctor as soon as possible if you do not feel well while you are taking Aplidin. You may need medical attention if you get some of the side effects.

Ask your doctor or pharmacist to answer any questions you may have.

Your doctor will perform certain checks periodically to test for side effects that may affect the blood, liver, kidneys, heart and muscle.

Tell your doctor if you notice any of the following side effects and they worry you:

Very common side effects (may affect more than 1 in 10 people):

Nausea (sickness), vomiting, diarrhoea
Fatigue (feel tired), oedema peripheral (swelling of the arms or legs)
Decreased appetite.
Myalgia (muscle pain)
Muscular weakness

The above list includes the most common side effects of your medicine.

This is not a complete list of side effects. For any unexpected effects while taking Aplidin, contact your doctor immediately.

Tell your doctor or nurse as soon as possible if you notice any of the following:

Fever
Aching muscles, muscle tenderness or weakness, not caused by exercise
Dark (brown/black/cola) coloured urine
Redness, pain or swelling at the injection site

Tell your doctor immediately or go to Accident and Emergency at your nearest hospital if you get any of the following side effects:

Symptoms of an allergic reaction which may include:

shortness of breath
wheezing or difficulty breathing
swelling of the face, lips, tongue, throat or other parts of the body
rash, itching or hives on the skin.

Symptoms of heart problems which may include:

faster than normal heart beat
irregular heart beats

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation.

Tell your doctor if you notice anything else that is making you feel unwell. Other side effects not listed above may also occur in some people.

You can report side effects to your doctor, or directly at www.tga.gov.au/reporting-problems.

After Being Given Aplidin

If you receive Aplidin and feel any of the symptoms mentioned above during the treatment, your doctor or nurse has to be informed. In case you suffer these symptoms, the Aplidin and/or dexamethasone dose may be omitted temporarily or reduced depending on the severity.

Allergic reactions to the infusion
Tell your doctor or nurse straight away if you feel unwell during infusion. Typical symptoms associated with allergic reactions are redness of the face or chest, itching, coughing, shortness of breath, chest discomfort, etc.Other symptoms may occur as well.

These side effects mostly occur during or after the infusion of the first dose. You will be monitored for signs of these effects during and after the infusion.

Depending on the seriousness of the allergic reactions, your infusion of Aplidin may be interrupted. You may require additional treatment to prevent complications and reduce your symptoms.

When the symptoms go away or improve, the infusion can be continued more slowly, and speeded up gradually if the symptoms do not recur. Your doctor may decide not to continue Aplidin treatment if you have a strong infusion reaction.

Your doctor may want to take additional precautions.

Storage

Aplidin will be stored in the pharmacy or the on the ward.

The medicine is kept in its original packaging in the refrigerator where the temperature stays between 2°C and 8°C.

Product Description

What it looks like

Aplidin is a powder for solution for intravenous infusion. Each carton contains 1 vial of powder (2 mg) and 1 ampoule of solvent (4 mL).

The powder is a white to off-white powder or solid cake. The solvent is a clear, slightly viscous liquid free of visible particles.

Ingredients

The active substance is plitidepsin.

The other ingredients are:

Powder
Mannitol

Solvent
PEG-35 castor oil
Ethanol
Water for injections

Sponsor

Specialised Therapeutics Pharma Pty Ltd
Level 2, 17 Cotham Road,
Kew, Victoria, 3101
Ph: 1300 798 820
Fax: 1800 798 829
www.stbiopharma.com

Australian Register Number

1 single pack containing 2 mg powder (1 vial) and 4 mL solvent (1 ampoule):
AUST R 291661

This leaflet was prepared by Specialised Therapeutics Pharma Pty Ltd

Last revised: 10 December 2018

Published by MIMS March 2019

BRAND INFORMATION

Brand name

Aplidin

Active ingredient

Plitidepsin

Schedule

1 Name of Medicine

Aplidin (plitidepsin) powder for solution for infusion.

2 Qualitative and Quantitative Composition

Each vial contains 2 mg of plitidepsin.
After reconstitution, each mL of reconstituted solution contains: 0.5 mg of plitidepsin, 158 mg of PEG-35 castor oil, and ethanol 0.15 mL/mL.

List of excipients.

For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Powder for solution for infusion. The powder is a white to off-white powder or solid cake.
The solvent is a clear, slightly viscous liquid free of visible particles.

4 Clinical Particulars

4.1 Therapeutic Indications

Aplidin, in combination with dexamethasone, is indicated for the treatment of patients with relapsed and refractory multiple myeloma who have received at least three prior treatment regimens, including both a proteasome inhibitor and an immunomodulator. Aplidin may be used after two prior lines of therapy if refractory and/or intolerant to both a proteasome inhibitor and an immunomodulator.

4.2 Dose and Method of Administration

Treatment must be initiated and administered under the supervision of a physician qualified and experienced in the use of chemotherapeutic agents.
Aplidin is administered in combination with dexamethasone. Pre-infusion medications should be administered to reduce the risk of infusion related reactions.
The recommended dose of Aplidin is 5 mg/m² according to Body Surface Area (BSA). Infusion must be performed through a pump device over three hours (fixed rate) on Day 1 and 15 every four weeks (q4wk).
The recommended dose of dexamethasone is 40 mg orally on Day 1, 8, 15 and 22 q4wk at least one hour before plitidepsin infusion (Day 1 and 15). For additional information concerning dexamethasone, see the corresponding Product Information.
Patients should be treated until disease progression or unacceptable toxicity.

Premedication for prevention of infusion reaction.

All patients must receive the following prophylactic medication 20-30 minutes before infusion of plitidepsin:
ondansetron 8 mg intravenously (i.v.) or equivalent (granisetron 3 mg intravenously preferred when available),
diphenhydramine hydrochloride 25 mg intravenously or equivalent, and
ranitidine 50 mg intravenously or equivalent.
Oral metoclopramide and/or extended oral ondansetron (or their equivalents) may be used at the physician's discretion.
If dexamethasone treatment is discontinued due to toxicity, dexamethasone at a lower dose (8 mg) must be given as premedication for plitidepsin treatment.

Management of infusion reaction.

Prophylaxis medication is mandatory at least 30 minutes prior to each plitidepsin infusion with dexamethasone or equivalent, antiemetics (setrons) and histamine receptor antagonists (H1 and H2 receptor antagonists).
In the event of severe/life threatening reactions (NCI-CTCAE v.4 grade ≥ 3) described as cardiovascular symptoms [hypertension ≥ 160/100 mmHg or tachycardia ≥ 120 bpm or hypotension (systolic pressure < 90 mmHg) requiring vasopressor therapy] or anaphylactic shock or respiratory symptoms (angioedema, generalised wheezing and/or respiratory distress) requiring oxygen therapy, the plitidepsin infusion must be interrupted. Immediate therapy with oxygen and bronchodilators should be considered if pulse oximetry indicates < 92% O₂ saturation at ambient air. Administer diphenhydramine 50 mg intravenously or equivalent, and hydrocortisone 100 mg up to a maximum of 300 mg intravenously, and add epinephrine (adrenaline) if clinically indicated. The infusion should not be restarted, and plitidepsin therapy must be discontinued.
In the event of mild to moderate/non-life threatening reactions (NCI-CTCAE v.4 grade ≤ 2) described as facial and/or trunk flushing, rash and/or pruritus and/or mild dyspnoea and/or coughing and/or chest discomfort, the infusion must be stopped immediately and vital signs and pulse oximetry must be continuously monitored. It should be determined if the premedication was administered appropriately and, if not, the premedication should be then properly given and the plitidepsin infusion can be re-started at least 30 minutes after.
If symptoms persist after interrupting the infusion, additional diphenhydramine at a dose of 50 mg intravenously or equivalent, and hydrocortisone 100 mg bolus intravenously or equivalent, should be administered.
Reassess symptoms and vital signs after 30 minutes, if normal or improving, then the infusion could be re-started at one third of the initial drip rate during the first hour. Signs and symptoms must be continuously monitored during infusion. Then the infusion rate could be increased according to tolerance. Any further infusions should be started at a reduced rate and should be given with prophylactic intravenous premedication, as above described. The patient should be monitored for symptoms during the first post-infusion hour. In these further infusions, dexamethasone will be administered intravenously (instead of orally). If no hypersensitivity reactions are observed, the rate of infusion to be applied could be set back to the initial one.
If there is no sign of improvement of symptoms after 30 minutes, repeat medication (H1 receptor antagonist and/or corticoids) until resolution, and plitidepsin therapy must be discontinued. See Table 1.

Method of administration.

Prior to administration, Aplidin must be reconstituted and further diluted by a healthcare professional.
Intravenous administration can be made through a peripheral venous line or a central venous line.
Infusion must be performed through a pump device over three hours (at a fixed rate).

Preparation for intravenous infusion.

Appropriate aseptic techniques must be used. Aplidin must be reconstituted and further diluted prior to administration.
Each vial of Aplidin is reconstituted with 4 mL of Aplidin solvent for reconstitution.

Instructions for reconstitution.

A syringe should be used to inject the 4 mL of solvent into the vial. Shake the vial until complete dissolution. The reconstituted concentrate results in a clear, colourless or slightly yellowish solution, free of visible particles.
This reconstituted concentrate contains 0.5 mg of plitidepsin per mL. lt requires further dilution and is for single-use only.

Instructions for dilution.

The reconstituted concentrate should be diluted with sodium chloride 9 mg/mL (0.9%) solution for infusion or glucose 50 mg/mL (5%) solution for infusion to a total volume of 500 mL for administration via a peripheral venous line or to a total volume of 250 mL for administration via a central venous line. The required volume of reconstituted concentrate to be diluted for an individual dose should be calculated (see Equation 1).

Instructions for administration.

Aplidin infusion solution should be administered with an infusion set and a sterile, non-pyrogenic, low-protein-binding filter (with a pore size of 0.2 micrometer) using an automated infusion pump.
A peripheral venous line or a central venous line for administration may be used.
Aplidin infusion is compatible with:
glass and polyolefin containers (polyethylene, polypropylene and mixtures);
PVC DEHP-free and polyolefin infusion sets (polyethylene, polypropylene and mixtures);
polyethersulfone and nylon in-line filters with pore sizes of 0.2 micrometer;
implantable venous access systems with titanium and plastic resin ports and with polyurethane or silicone intravenous catheters. Polyurethane intravenous catheters can be used as no adsorption has been observed under these circumstances.
The Aplidin solution for infusion should be administered within 6 hours of reconstitution if stored at room temperature and under ambient lighting. If storage is required prior to administration then solutions should be stored refrigerated and protected from light and should be used within 24 hours of reconstitution.
Aplidin is a cytotoxic anticancer medicinal product. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Criteria for treatment continuation, dose delay or interruption.

In order to receive the next planned dose of Aplidin, patients have to meet the criteria. See Table 2.

If the requirements for treatment continuation are unmet on Day 1 of the following cycle, the infusion of Aplidin will be withheld until recovery or for a maximum of 14 days. After this period, if the delay is due to toxicity assessed as related to plitidepsin, a dose decrease from 5.0 mg/m² to 4.0 mg/m² and then to 3.2 mg/m² is recommended. Further reductions might be performed according to clinical criteria.
If the requirements for treatment continuation are unmet on Day 15, the administration of plitidepsin will be omitted until recovery and restarted once re-treatment criteria are fulfilled. Patients requiring frequent dose omissions may have a dose reduction from 5.0 mg/m² to 4.0 mg/m² and then to 3.2 mg/m².
Dose reduction criteria for both medicinal products, plitidepsin and dexamethasone, are summarised in Table 3.

Special populations.

Paediatric population.

The safety and efficacy of Aplidin has not been studied in paediatric patients.

Elderly.

No age-related dose adjustment is required for plitidepsin.

Renal impairment.

No dose adjustment is necessary in patients with mild, moderate or severe renal impairment.
Caution is recommended in patients with severe renal impairment (GFR 15-29 mL/min), as experience in this population is limited. Patients with end stage renal impairment (GFR < 15 mL/min) have not been included in any clinical study with plitidepsin. There is no data on the safety and efficacy of plitidepsin in patients with end stage renal impairment.

Hepatic impairment.

Plitidepsin has not been formally studied in patients with impaired hepatic function. Patients with AST > 3 x ULN and/or bilirubin > ULN were not allowed to participate in most clinical studies with plitidepsin. Since most administered plitidepsin is eliminated by biliary excretion, patients with impaired hepatic function (AST > 3 x ULN and/or bilirubin > 1 × ULN) should not be treated with plitidepsin.

4.3 Contraindications

Hypersensitivity to the active substance, plitidepsin, or to the excipients PEG-35 castor oil or ethanol.

4.4 Special Warnings and Precautions for Use

Musculoskeletal and connective tissue disorders and investigations.

Myopathy including rhabdomyolysis.

Muscle weakness, myalgia and/or CPK elevation were frequently reported during treatment with plitidepsin plus dexamethasone. Isolated cases of rhabdomyolysis have also been observed. In order to minimise the risk of musculoskeletal events:
CPK should be monitored prior to each infusion (Day 1 and Day 15) from Cycle 1 to Cycle 4.
The treatment with plitidepsin should not be started in patients with grade > 2 myopathy or any clinical condition that causes significant and persistent elevation of CPK (i.e. > 2.5 x ULN in two different determinations performed one week apart). See Section 4.2 for dose recommendations.
If rhabdomyolysis occurs, plitidepsin treatment should be stopped. Supportive measures such as parenteral hydration, urine alkalinisation and dialysis should be promptly established. Caution should be taken if medicinal products associated with rhabdomyolysis (e.g. statins), are administered concomitantly with plitidepsin plus dexamethasone, since the risk of rhabdomyolysis may be increased.
The clinicians are recommended to report all severe and fatal musculoskeletal events.

Injection site reactions and hypersensitivity reactions.

Infusion reactions have been reported in patients who received plitidepsin. Symptoms may include, pain, catheter site phlebitis, infusion site reaction, injection site extravasation or thrombosis in device. These reactions can occur during or immediately after the administration of plitidepsin.
Treatment-related (or with unknown relationship) hypersensitivity reactions were reported in 6.6% of patients in Arm A (plitidepsin plus DXM) and in 5.4% of patients who crossed over from Arm B to Arm A. The frequency of grade ≥ 3 hypersensitivity reactions was 1.2% in Arm A and 2.7% in the crossover patients.
Premedication must be administered prior to plitidepsin to reduce the incidence of the reactions [see Section 4.2 Dose and Method of Administration, Management of infusion reaction].

Liver enzyme increase (ALT/AST).

Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) increases according to laboratory values were reported in 66.0% and 84.9% of patients, respectively, during treatment with plitidepsin. Most of them were grade 1 or 2. Transaminase increases occurred mostly during the first 2 cycles of treatment, and they were transient and reversible. Before plitidepsin plus dexamethasone administration, the patients must have total bilirubin ≤ 1.0 x ULN (or direct bilirubin ≤ 1.0 x ULN when total bilirubin is above the ULN) and AST/ALT ≤ 3.0 x ULN. AST and ALT measurements should be performed before the administration of plitidepsin.

Cardiac effects, including QT prolonged.

Cardiac effects such as bradycardia; electrocardiogram QT prolonged; sinus tachycardia; and orthostatic hypotension have been observed in patients treated with the combination plitidepsin plus dexamethasone in the phase III study. The causal relationship has not been established yet, since most of cardiovascular events reported had confounding factors, such as cardiovascular medical history or concomitant medications known to induce such cardiovascular effects.
Therefore, patients with risk factors for or existing heart disease should be closely monitored. Appropriate caution should be exercised when considering the treatment of such patients with plitidepsin plus dexamethasone, including periodic electrocardiogram monitoring.
Patients with symptomatic arrhythmia (excluding anaemia-related sinusal tachycardia grade ≤ 2) or any arrhythmia requiring ongoing treatment, and/or prolonged QT/QTc grade ≥ 2; or presence of unstable atrial fibrillation, should not be treated with plitidepsin plus dexamethasone.
It is recommended to monitor patients for clinical cardiac signs or symptoms. To include only patients with left ventricular ejection fraction (LVEF) by echocardiography above the lower limit of normal at baseline and to measure LVEF periodically during the treatment. LVEF assessment has to be performed every 12 weeks. If there is a decrease in LVEF, treatment should be interrupted until LVEF returns to normal values.

Other.

Since Aplidin contains ethanol (up to 2137.5 mg per dose), possible central nervous system and other effects might occur. Plitidepsin contains Polyoxyl 35 castor oil (Macrogolglycerol ricinoleate), which may cause severe allergic reactions.
Fertile female and male patients should use effective methods of contraception during treatment and for up to six months after treatment (see Section 4.6 Fertility, Pregnancy and Lactation).

Interactions.

Co-administration with strong CY3A4 inhibitors and inducers should be avoided since they may affect the plasma concentration of plitidepsin (see Section 4.5).
Co-administration with moderate CY3A4 inhibitors and inducers should be used cautiously, since an effect on plitidepsin exposure cannot be excluded (see Section 4.5).

Use in hepatic impairment.

As most plitidepsin is eliminated via the liver, patients with impaired hepatic function (AST > 3 x ULN and/or bilirubin > 1 × ULN) may be at risk of increased exposure to plitidepsin (see Section 4.2 Dose and Method of Administration; Section 5 Pharmacological Properties).

Use in the elderly.

No age-related dose adjustment is required for plitidepsin.

Paediatric use.

The safety and efficacy of Aplidin in the paediatric population has not been studied in MM.

Effects on laboratory tests.

No effects on laboratory test have been observed.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No interaction studies have been performed.

Effect of other medicinal products on Aplidin.

Interactions with CYP3A4 inhibitors.

In vitro studies indicate that CYP3A4 is the main enzyme involved in the metabolism of plitidepsin. Plitidepsin should not be administered with strong CYP3A4-enzyme inhibitors (e.g. grapefruit juice, clarithromycin, itraconazole, nefazodone, telithromycin, voriconazole). Strong CYP3A4 inhibitors should be discontinued at least 1 week prior to starting treatment and while on treatment with plitidepsin.
Moderate CYP3A4-enzyme inhibitors (e.g. aprepitant, diltiazem, erythromycin, fluconazole, verapamil) should be used cautiously, since an increase of plitidepsin exposure cannot be excluded.

Interactions with CYP3A4 inducers.

In order to avoid a loss of plitidepsin efficacy, plitidepsin should not be administered with strong CYP3A4-enzyme inducers such as anticonvulsants (phenytoin, phenobarbital or carbamazepine), rifampin, rifabutin and St. John's wort unless there are no therapeutic alternatives. The appropriate starting dose for patients taking these anticonvulsants or other strong inducers has not been defined. Consideration should be given to substituting with non-enzyme inducing therapies at least 2 weeks prior to initiation and while on treatment with plitidepsin therapy.
Moderate CYP3A4-enzyme inducers (e.g. bosentan, modafinil, nafcillin) should be used cautiously, since a reduction of plitidepsin exposure cannot be excluded.

Effect of Aplidin on other medicinal products.

No relevant inhibition of key CYP isozymes (1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4) or transporters (P-glycoprotein, OATP1B1, OATP1B3, BCRP, BSEP, MRP2, OAT1, OAT3 and OCT2) was observed with plitidepsin at therapeutic concentrations in vitro. Accordingly, pharmacokinetic drug-drug interactions caused by plitidepsin on co-administered substances are not expected.

Oral contraceptives.

Since dexamethasone is a moderate inducer of CYP3A4, efficacy of oral contraceptives may be reduced when administered concomitantly. Consequently, effective measures to avoid pregnancy must be taken.

Concomitant medication frequently used in malignancies.

In multiple myeloma patients, there is experience of co-administering plitidepsin and dexamethasone with antiemetics (i.e. serotonin antagonists such as ondansetron or granisetron, and metoclopramide), antihistamines (i.e. diphenhydramine), proton pump inhibitors (i.e. ranitidine) and bisphosphonates (i.e. zoledronate). Changes in the effects of these drugs have not been reported, but drug-drug interactions between plitidepsin plus dexamethasone and these drugs have not been formally investigated.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Studies in rats and dogs have shown that the compound may affect reproductive capacity. Impairment of male and female fertility, sperm degeneration and inhibition of ovulation were observed in animals treated with plitidepsin at doses yielding systemic exposure levels (plasma AUC) below that of patients at the recommended dose.
(Category D)
There is no human experience with plitidepsin during pregnancy.
Administration of a single intravenous dose of plitidepsin (0.6 mg/kg) to rats during gestation caused complete embryofetal lethality in all animals. Systemic exposure (plasma AUC) in animals at this dose was below that of patients at the recommended dose.
Aplidin should not be used during pregnancy unless the clinical benefit outweighs the potential risk to the fetus.
Women of childbearing potential must use effective contraception during and for up to 6 months after treatment.
Male patients must use effective contraception measures during and for up to 6 months after treatment if their partner is pregnant or of childbearing potential and is not using effective contraception.
It is unknown whether plitidepsin and/or its metabolites are excreted in human breast milk.
A risk to newborns/infants cannot be excluded.
Breast-feeding should be discontinued during treatment with plitidepsin.

4.7 Effects on Ability to Drive and Use Machines

Aplidin has moderate influence on the ability to drive and use machines. Fatigue/asthenia and somnolence have been reported in patients receiving plitidepsin. Furthermore, the plitidepsin formulation contains ethanol. The ability to drive and use machines may be affected. Therefore, patients who experience such events during therapy should not drive or operate machinery.

4.8 Adverse Effects (Undesirable Effects)

A total of 250 of 255 patients randomised in the ADMYRE study were treated (n=167 in P+DXM arm and n=83 in the DXM arm).
The most common adverse reactions were gastrointestinal disorders (nausea, 37.1% of patients; vomiting, 16.8%; diarrhoea, 14.4%); general disorders (fatigue, 36.5%; oedema peripheral, 12.0%); metabolism and nutrition disorders (decreased appetite, 12.6%); and musculoskeletal disorders (myalgia, 14.4%; muscular weakness, 9.6%). The most common grade ≥ 3 adverse reactions were fatigue (10.8%), myalgia (5.4%), muscular weakness (3.6%) and nausea (3.6%). See Table 4.

Tabulated list of adverse reactions.

The adverse reactions observed in patients with MM treated with plitidepsin are listed in Table 5, sorted by MedDRA System Organ Class (SOC), that fall below 1% frequency.
Within each SOC and frequency grouping, adverse reactions are presented in order of decreasing frequencies. Frequencies are defined using the following convention: Very common (≥ 1/10); common (≥ 1/100 to < 1/10); and uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000) and unknown (cannot be estimated from available data).

Description of selected adverse reactions.

Musculoskeletal and connective tissue disorders and investigations.

The most common musculoskeletal disorders reported as adverse reactions were myalgia (14.4% of patients) and muscular weakness (9.6%). CPK increase regardless of grade was reported in 44.5% of patients; this parameter was the most common grade 3/4 biochemical abnormality, reported in 20.0% of patients. The median onset of grade 3/4 CPK increase (day from first dose) was 48 days; the median number of cycles during which the patients experienced grade 3/4 CPK increase was 1 cycle, and the median time to recovery was 14.5 days. The treatment was withdrawn only in 0.5% of patients who experienced grade 3/4 CPK increase, while dose delay, dose reduction, dose omission and dose interruption occurred in 8.8%, 11.3%, 5.9% and 0.5%, respectively. The vast majority of patients (83.9%) who experienced CPK increase recovered. Adverse drug reactions of grade 3/4 rhabdomyolysis were reported in 1.2% of patients. See Section 4.4 Special Warnings and Precautions for Use for the management of myopathy occurring during treatment with plitidepsin.

Immune system and skin and subcutaneous tissue disorders.

Treatment-related (or with unknown relationship) hypersensitivity reactions were reported in 6.6% in Arm A (plitidepsin plus DXM), 5.4% in patients who crossed over from Arm B to Arm A. The frequency of grade ≥ 3 hypersensitivity reactions was 1.2% in Arm A and 2.7% in the crossover patients. Severe hypersensitivity reactions included an anaphylactic shock with grade 4 cardiac arrest, a grade 3 infusion-related reaction with hypoxia that led to treatment discontinuation, and a grade 3 rash requiring dose reduction. The majority of hypersensitivity reactions occurred in the first two cycles and, no change in severity was observed over time. Hypersensitivity reactions usually occurred on the day of plitidepsin plus dexamethasone infusion (median was the infusion day, range: 0-13 days); they were rapidly reversible (lasting one or two cycles); symptomatic treatment (corticosteroids, antihistamines and local treatment) was common, and no fatal outcome was reported.

Gastrointestinal disorders.

Nausea, vomiting and diarrhoea were very common reactions with the combination plitidepsin plus dexamethasone, occurring in 36.5%, 16.8% and 14.4% of patients, respectively. Few events were severe: grade ≥ 3 nausea was found in 3.6% of patients, grade ≥ 3 vomiting in 1.8% and grade ≥ 3 diarrhoea in 1.2%. The majority of these events were grade 1 or 2 and were reversible after symptomatic treatment. In case of diarrhoea, the clinicians are recommended to follow local guidelines on the symptomatic management of diarrhoea in patients administered chemotherapy.

Cardiac effects, including QT prolonged.

Liver enzyme increase (ALT/AST).

During the treatment with the combination plitidepsin plus dexamethasone, 84.9% and 66% of patients respectively reported ALT and AST increase. Grade 3/4 ALT and AST increase was respectively reported in 14.5% and 9.0% of patients who received plitidepsin plus dexamethasone. Grade 3/4 ALT increase occurred on Day 14 (range, 1-35 days) after dosing, with a median duration of 6 days (range, 1-16 days). Grade 3/4 AST appeared on Day 18 (range, 1-35 days) after dosing with a median duration of 6.5 days (range, 1-28 days). Grade 3/4 AST or ALT were more frequent in the first treatment cycle than in subsequent cycles. The median values for peak counts of ALT or AST from all patients, over 32 cycles, showed no evidence of cumulative toxicity.

Elderly population.

Myalgia, muscular weakness and hyperglycaemia were the most reported adverse drug reactions in patients aged ≥ 65 years treated with plitidepsin plus dexamethasone. Among patients who experienced hyperglycaemia, 80% had a previous medical history of diabetes mellitus. Myalgia and hyperglycaemia were reported as serious adverse drug reactions in 1.3% and 5.1% of elderly patients, respectively. No serious adverse drug reaction of muscular weakness was observed. None of these events led to treatment discontinuation or death.

Post-marketing experience.

Not applicable.

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after registration 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 at http://www.tga.gov.au/reporting-problems and to [email protected].

4.9 Overdose

In clinical trials there are no cases of accidental overdose. There is currently insufficient information to draw conclusions about the safety of doses higher than those evaluated in clinical studies. Grade 3/4 CPK increase and other muscular events are expected. There is no known antidote to plitidepsin.
For information on the management of overdose, contact the Poison Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Plitidepsin interacts with eukaryotic Elongation Factor 1A2 (eEF1A2), a protein that forms part of the cell's translation machinery and described to have oncogenic properties. eEF1A2 is overexpressed in various tumour cells, including some multiple myeloma cells. It is also expressed in brain, heart, pancreatic acinar and islet cells, endocrine cells of the gut, and skeletal muscle. Plitidepsin triggers the generation of early oxidative stress, which induces the sustained activation of MAPK signalling cascades that finally lead to apoptosis.

Pharmacodynamic effects.

Plitidepsin has been shown to exert in vitro antiproliferative effects against a range of human tumour cell lines (particularly against multiple myeloma (MM), leukaemia, lymphoma, pancreas, non-small cell lung cancer [NSCLC] and breast), as well as in vivo activity against experimental MM tumours. Enhanced antitumour activity was found for plitidepsin when combined with other agents, such as melphalan, dexamethasone, lenalidomide or bortezomib.

Clinical trials.

The efficacy of plitidepsin in combination with dexamethasone (P+DXM) was evaluated in a phase III multicentre, open-label, two-arm, randomised clinical trial, APL-C-001-09 (ADMYRE) that compared the efficacy of P+DXM versus dexamethasone (DXM) alone. Eligible subjects were patients with relapsed/refractory MM after at least three but not more than six prior therapeutic regimens for this disease (median of 4 prior lines of systemic therapy (range of 2 - 6 in the P+DXM)). The most common previous agents that patients received prior to entering the study were: bortezomib (98.4%), lenalidomide (97.6%), dexamethasone (97.6%), melphalan (87.8%), cyclophosphamide (74.5%), thalidomide (65.1%), doxorubicin (47.1%), vincristine (32.5%), and prednisone (23.9%). Other more novel anti-MM agents previously administered included: pomalidomide (13.3%), carfilzomib (3.9%), vorinostat (2.7%), elotuzumab (2.0%), and panobinostat (1.2%).
A total of 255 patients were enrolled in the study: 171 in Arm A (P+DXM) and 84 in Arm B (DXM). The median age of the whole population was 65 years (36-85 years). There were 51.8% of males enrolled and 48.2% of females.
Patients in the control arm (DXM alone, Arm B) with documented disease progression after a minimum of eight weeks from randomisation were offered crossover to the combination arm (P+DXM, Arm A). A total of 44% of patients crossed over from DXM to P+DXM arm.
Patients in the P+DXM arm (Arm A) received DXM 40 mg orally on Day 1, 8, 15 and 22 q4wk, at least one hour before plitidepsin infusion, plus plitidepsin 5 mg/m² intravenously over three hours on Day 1 and 15 q4wk. Patients in Arm B received DXM 40 mg orally on Day 1, 8, 15 and 22 q4wk.
The primary efficacy objective was the progression-free survival (PFS) calculated according to the 2008 International Myeloma Working Group (IMWG) criteria. Secondary efficacy endpoints included overall response rate (ORR) and overall survival (OS).

Progression-free survival.

In the primary efficacy analyses of all randomised patients, P+DXM showed statistically significant longer PFS compared to DXM in patients with relapsed/refractory MM, in both the blinded Independent Review Committee (IRC) assessment and the Investigator assessment.
The median PFS analysis from the blinded Independent Review Committee (IRC) was 2.6 months (95% CI, 1.9-3.0 months) in P+DXM arm and 1.7 months (95% CI, 1.1-2.0 months) in DXM arm (log-rank p=0.0054).
An updated analysis of PFS with confirmation of PD by IA at the censoring rate of 38.6% and 40.5% of patients in P+DXM and DXM arms, respectively, showed the following results: median PFS=3.8 months (95% CI, 2.9-5.6 months) in P+DXM arm, and median PFS=1.9 months (95% CI, 1.1-2.7 months) in DXM arm (log-rank p=0.0040) (HR=0.611; p=0.004).
A pre-planned sensitivity analysis of PFS requiring confirmation of PD was performed. There was a statistically significantly longer PFS with P+DXM (5 months) compared to DXM alone (2 months) (log-rank p=0.0005) and the relative risk of progression or death was reduced by 48.3% (HR=0.517; 95% CI: 0.354 - 0.756, p=0.0007). All other pre-planned supportive sensitivity analyses of PFS showed results consistent with the primary analysis with HRs ranging between 0.466 and 0.739.

Overall survival.

The study was not powered for the evaluation of the secondary end-point of OS. Final OS data was conducted with 195 events (76.5% of all the recruited patients). Median OS was 11.6 months in the P+DXM arm and 8.9 months in the DXM arm following the intention to treat principle (HR=0.797, 95% CI, 0.596-1.067). 37 (44%) of the patients in the control arm (Arm B) crossed over to the combination arm (Arm A); when crossover effect is mitigated, a statistically significant difference in favour of the combination arm (Arm A) was observed with a HR of 0.667 (log rank test p-value=0.0065), and median OS values of 11.6 months in the P+DXM arm and 6.7 months in the DXM arm. See Table 6 and Figure 1.

Response rate.

Overall response rate was higher in the P+DXM arm (9.9%) than in the DXM arm (1.2%) (p=0.0085).
Very good partial response (VGPR) were only observed in the combination arm.
In Arm A (P+DXM), median duration of response by the IRC in patients with response (VGPR, n=2; partial response [PR], n=15) was 12.0 months (95% CI, 2.8-23.2 months). In Arm B (DXM), only one patient had PR (duration of response was 1.8 months) (p=0.1015). Median duration of response as determined by investigator's assessment in responding patients was 5.1 months in P+DXM arm versus 0.9 months in DXM arm (p=0.0001). This includes patients with minor response (MR), partial response (PR) and VGPR.

5.2 Pharmacokinetic Properties

A population pharmacokinetic analysis was carried out in 303 patients with cancer, including 182 patients with relapsed/refractory MM. These patients received plitidepsin at doses of 2.0 to 5.0 mg/m² weekly or every two weeks.

Absorption.

Plitidepsin is dosed via an intravenous route and therefore is immediately and completely bioavailable.

Distribution.

The pharmacokinetics of plitidepsin is characterised by a 3-compartment model. Plitidepsin is distributed largely outside the blood volume, with a total volume of distribution in plasma of approximately 600 L. Blood cells are an important distribution compartment of plitidepsin. Partitioning equilibrium between blood cells and plasma is mostly reached during the infusion and the extent of partitioning can be considered linear up to the mean maximal concentration of the compound. In the blood, approximately 20% is present in plasma, and 80% in blood cells. In plasma, approximately 98% is bound to proteins, independent of concentration over the range of 100 to 500 nanogram/mL. Binding is mostly to albumin, with a lesser contribution by α₁-acid glycoprotein.

Metabolism.

In vitro studies indicate that plitidepsin undergoes metabolism in the liver and also the plasma. Experiments performed with human liver microsomes (both sexes) and recombinant CYP isoforms pointed to CYP3A4 as the main isoform involved in the phase I metabolism of plitidepsin, with smaller contributions by CYP2A6, CYP2E1 and CYP4A11. The contribution of phase II-mediated metabolism is negligible.
Plitidepsin experiences a moderate clearance in plasma from humans, suggesting the involvement of plasma esterases as an additional route of its metabolism. Owing to its distribution in blood cells, unchanged plitidepsin was the major circulating component (95% of radioactivity in the systemic circulation) in vivo in patients with cancer who received a single dose of [¹⁴C]-plitidepsin (2.2 mg). In plasma, the radioactivity measured was less explained by the parent compound as time after dosing increases, resulting in 30% of the administered dose, thus suggesting a gradual formation of metabolites. None of them was present at a relevant concentration relative to unchanged plitidepsin or total radioactivity in plasma.

Excretion.

Plitidepsin has a population estimated for plasma clearance of 5.4 L/h (coefficient of variation [CV] 46%), and a long terminal half-life of approximately 6 days. No significant accumulation of plitidepsin is observed on biweekly administration.
Plitidepsin is eliminated primarily by biliary excretion. The transport protein involved in the excretion is presently unknown, although preclinical in vitro studies indicate that plitidepsin is transported by P-glycoprotein (Pgp).

Linearity/non-linearity.

Studies in patients have demonstrated linear pharmacokinetics in the dose range of 2.0 to 5.0 mg/m².