Consumer medicine information

Folotyn

Pralatrexate

BRAND INFORMATION

Brand name

Folotyn

Active ingredient

Pralatrexate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Folotyn.

What is in this leaflet

This leaflet answers some common questions about FOLOTYN 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 taking FOLOTYN against the benefits they expect it will have for you.

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

Keep this leaflet with the medicine. You may need to read it again.

What FOLOTYN is used for

FOLOTYN solution for infusion contains pralatrexate. Pralatrexate is an anti-cancer (chemotherapy) medicine that belongs to a group of medicines called antifolates.

FOLOTYN is used to treat patients aged 18 years or older with peripheral T-cell lymphoma (PTCL) after previous treatments have not worked or have stopped working.

PTCL is a rare type of non-Hodgkin's lymphoma (a cancer of the lymphatic system). It occurs when T-cells, a type of white blood cell, multiply too quickly. PTCL may be found in the lymph nodes, skin, bone marrow, the liver, or spleen.

FOLOTYN works by slowing or stopping the growth of cancer cells.

Your doctor, however, may prescribe it for another purpose.

Ask your doctor if you have any questions about why it has been prescribed for you.

This medicine is only available with a doctor's prescription.

Before FOLOTYN is given

When you must not be given it

FOLOTYN solution for infusion should not be given to you if you are allergic to pralatrexate or any of the ingredients listed at the end of this leaflet.

FOLOTYN solution for infusion should not be given to you if you are breastfeeding. It is not known if FOLOTYN solution for infusion passes into breast milk, which may harm your baby. You and your doctor should decide whether you will be treated with FOLOTYN solution for infusion or whether you will breast feed your baby, but you should not do both.

Do not accept treatment with this medicine after the expiry date (EXP) printed on the pack. If it is given to you after the expiry date has passed, it may not work as well.

Before you begin your treatment

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

Tell your doctor if you have or have had any medical conditions, especially the following:

  • liver problems
  • kidney problems
  • extensive skin disease or a history of adverse skin reactions

FOLOTYN solution for infusion is not recommended if you have end stage kidney disease or are undergoing dialysis, unless the benefit outweighs the risk.

Females: Tell your doctor if you are pregnant or planning to become pregnant. FOLOTYN is not recommended for use during pregnancy. The effects of FOLOTYN in pregnant women are not known. FOLOTYN solution for infusion may harm the unborn baby.

Males: Tell your doctor if your partner intends to become pregnant while you are being treated with FOLOTYN or within 6 months after you have stopped treatment with FOLOTYN. FOLOTYN may cause birth defects if either the male or female is receiving treatment at the time of conception. A barrier method of birth control or abstinence is recommended to avoid pregnancy while being treated. Males should also use reliable contraceptive measures for 6 months after the end of treatment.

This medicine is not recommended to be used to treat a child of adolescent younger than 18 years of age. Safety and effectiveness in children and adolescents younger than 18 years of age has not been established.

If you have not told your doctor about any of the above, tell them before you are treated with FOLOTYN solution for infusion.

Taking other medicines

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

Some medicines and FOLOTYN solution for infusion may interfere with each other. These include:

  • other medicines used to treat cancer (e.g. carboplatin, cisplatin, oxaliplatin, etoposide and teniposide)
  • methotrexate, a medicine used to treat cancer, psoriasis and rheumatoid arthritis
  • cyclosporine, a medicine used to suppress the immune system
  • frusemide and other loop diuretics (also known as fluid and water tablets), medicines used to reduce swelling and lower blood pressure
  • ibuprofen and other non-steroidal anti-inflammatory drugs called NSAIDs used to relieve pain, swelling and inflammation
  • omeprazole and pantoprazole, medicines used to treat heartburn and stomach ulcers
  • penicillin, aminoglycosides, trimethoprim and sulfamethoxazole, antibiotics used to treat bacterial infections
  • probenecid, a medicine used to treat gout.

These medicines may be affected by FOLOTYN solution for infusion, may affect how well FOLOTYN works or may increase side effects. You may need to use different amounts of your medicines, or take different medicines.

Your doctor or pharmacist has more information on medicines to be careful with or avoid while being treated with this medicine.

How FOLOTYN is given

Taking premedication

Your doctor should advise you to take certain medicines or vitamin supplements before starting and while being given FOLOTYN to help minimise side effects.

Typically, you will be instructed to take folic acid by mouth for about 10 days before your first dose of FOLOTYN.

You should continue taking folic acid every day until your doctor tells you to stop.

Your doctor will also give you a vitamin B12 injection into the muscle before your first dose of FOLOTYN, and about every 8 to 10 weeks during treatment with FOLOTYN.

How much will be given

Your doctor will decide what dose of FOLOTYN you will receive. The dose given will be based on your body surface area, which your doctor will calculate from your height and weight. Your dose will also depend on how you react to the treatment.

You will usually be given FOLOTYN once a week for 6 weeks, with no treatment on the 7th week.

Several treatment cycles of FOLOTYN may be given depending on your response to treatment.

You will have regular blood tests during treatment to see if FOLOTYN is having any unwanted effects. Your doctor may change your dose or delay treatment based on the results of your blood tests and on your general condition.

Follow any instructions given to you by your doctor, nurse and pharmacist exactly.

How FOLOTYN is given

FOLOTYN solution for infusion will be administered to you under the supervision of a doctor or nurse experienced in treating cancer. It will be given as an infusion into your vein over 3 to 5 minutes. Each vial is for single use only.

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

If you have been given too much (overdose)

As FOLOTYN is given to you under the supervision of your doctor, it is very unlikely that you will receive too much.

However, if you experience severe side effects after being treated with FOLOTYN, tell your doctor immediately or go to Accident and Emergency at the nearest hospital.

While there is limited experience with overdose, symptoms may include more severe or prolonged mucous membrane inflammation (redness and sores in the lining of your mouth and may also affect your lips, throat, digestive tract and genitals) and decreased blood cell counts (unusual bruising or bleeding, increased risk of infections and unusual tiredness or weakness).

When seeking medical attention, take this leaflet with you to show the doctor. Also tell them about any other medicines which have been taken.

While you are being treated with FOLOTYN

Things you must do

Before you start on a new medicine, remind your doctor and pharmacist that you are receiving FOLOTYN solution for infusion.

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

If you are going to have surgery, tell your surgeon or anaesthetist that you are receiving this medicine.

Follow any specific instructions given to you by your doctor for vitamin supplementation with folic acid and vitamin B12 to help minimise side effects.

Use an effective method of birth control while you are being treated with FOLOTYN. Males should also use reliable contraceptive measures for 6 months after the end of treatment. A barrier method of birth control, such as a condom, should be used. Your doctor will tell you what forms of contraception are suitable and when it is safe to stop using contraception if you wish to do so.

If you or your partner becomes pregnant while being given this medicine or within 6 months after stopping treatment, tell your doctor immediately.

Keep all of your doctor's appointments so that your progress can be checked.

Tell your doctor if you are having any problems or difficulties while you are being treated with FOLOTYN solution for infusion.

Things you must not do

FOLOTYN solution for infusion must not be used to treat any other complaint, unless advised by your doctor.

It should not be administered to anyone else.

Do not inject FOLOTYN yourself. Always let your doctor or nurse do this.

Do not stop or change your treatment with FOLOTYN solution for infusion unless advised by your doctor.

Things to be careful of

Do not drive or operate machinery until you know how FOLOTYN solution for infusion affects you. FOLOTYN solution for infusion may cause fatigue, blurred vision, or dizziness. If you experience any of these side effects, do not drive or operate machinery.

Be aware of the following potential problems while being treated with FOLOTYN:

  • Low blood cell counts:
    FOLOTYN solution for infusion can affect your bone marrow and cause you to have low blood cell counts (platelets, white blood cells and red blood cells). Your doctor will do weekly blood tests and may decide to change the dose or stop your treatment.
  • Mucous membrane inflammation:
    FOLOTYN solution for infusion can cause redness and sores in the lining of your mouth and may also affect your lips, throat, digestive tract and genitals. Your doctor may change the dose or stop your treatment if this happens. You will be advised how to maintain nutrition and control the discomfort.
  • Skin reactions:
    You may experience severe skin reactions during treatment with FOLOTYN, especially if you have lymphoma in or under your skin. Skin reactions often occur when you first start treatment with FOLOTYN, but may increase in severity with continuing treatment. Your doctor may reduce the dose or stop your treatment if this happens.
  • Pneumonitis (swelling of the lungs):
    Symptoms may include coughing, difficulty breathing or wheezing.
  • Tumour lysis syndrome:
    Treatment with FOLOTYN may result in tumour lysis syndrome, caused by the breakdown products from dying cancer cells. Symptoms include nausea and vomiting, weakness and tiredness, changes to your heart beat and kidney problems.

Side effects

This medicine is to help treat PTCL, but it may have unwanted side effects in some people.

All medicines may have some unwanted side effects. Sometimes they are serious but often they are not. Your doctor has weighted the risks of the medicine against the expected benefits it will have for you.

Do not be alarmed by the list of possible side effects. You may not experience all of the side effects listed here.

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are being treated with FOLOTYN solution for infusion.

Other side effects that are not listed here may also occur in some people.

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

  • constipation, indigestion
  • loss of appetite, weight loss
  • pain in the stomach or abdomen
  • painful, stuff or swollen joints; pain or spasm of the muscles
  • pain in extremities
  • generalised pain in the back, neck or chest
  • effects on the eye, including irritation, itching, redness, increased tears, blurred vision
  • headaches
  • numbness, tingling or pins and needles sensation
  • dizziness
  • hair loss
  • hoarseness, sore throat coughing, difficulty or pain when swallowing
  • ringing sound in the ears
  • difficulty sleeping
  • anxiety.

Tell your doctor immediately if you notice any of the following:

  • inflammation, redness or sores of the mouth.
    Discomfort or pain can happen as early as a few days after treatment with FOLOTYN. Ask your doctor about how to reduce the risk of this and how to maintain your nutrition and control discomfort.
  • inflammation, redness or sores of the nose, genitals or anus (back passage)
  • thirst, dry mouth, flushed skin, darker coloured urine, fatigue, weakness or light-headedness.
    You may be dehydrated (insufficient fluid intake or fluid loss from the body). Follow your doctor's instructions to help prevent or treat dehydration.
  • unusual bleeding, such as nosebleeds, bruising under your skin or reddish/pinkish urine
  • any bleeding from the mouth, genitals or anus (back passage)
  • feeling weak, tired, getting tired easily, pale skin or shortness of breath
  • infections, e.g. fever, chills, cough, shortness of breath, pain or burning on urination.
    Fever is a common early sign of infection. Serious illness can occur if an infection is not treated straight away.
  • shingles or chicken pox
  • fungal infection in the mouth, throat, or vagina
  • severe skin reactions, e.g. itchiness, redness, rash, peeling or loss of skin, sores or blisters that may happen as early as a few days after treatment with FOLOTYN.
    If skin reactions are severe, they can lead to serious illness.
  • nausea, vomiting, diarrhoea
  • fast or irregular heart beats
  • yellow colouring of the skin and eyes
  • swelling of the legs and ankles.

The above list includes serious side effects that may require special attention.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at the nearest hospital:

  • you have an allergic reaction:
    shortness of breath, wheezing, shallow or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body; rash, itching or hives on the skin
  • chest pain when breathing, difficulty or fast breathing

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

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

Other side effects not listed above may also occur in some people. Some of these side effects (for example, abnormal blood cell counts) can only be found when your doctor does tests to check your progress.

When seeking medical attention, take this leaflet with you to show the doctor.

After being treated with FOLOTYN

Storage

If you are being given FOLOTYN solution for infusion in hospital, unopened vials will be stored in the pharmacy or on the ward.

FOLOTYN solution for infusion is stored in a refrigerator where the temperature stays between 2°C to 8°C and protected from light. It may be stored in the original carton for a single period at up to 30°C for 120 hours.

Disposal

Once opened, your doctor, nurse or pharmacist will discard any unused portion of this medicine.

Product description

What it looks like

FOLOTYN solution for infusion is available in glass vials containing a clear yellow solution. It is available in the following presentation:

20 mg in 1 mL.

FOLOTYN solution for infusion is supplied in packs containing 1 single-use vial with chlorobutyl stopper.

Ingredients

Active ingredients:

  • 20 mg in 1 mL solution for infusion contains 20 mg pralatrexate in every mL of solution.

Inactive ingredients:

  • sodium chloride
  • hydrochloric acid
  • sodium hydroxide
  • water for injections.

Manufacturer/Sponsor

FOLOTYN solution for infusion is made in Germany.

FOLOTYN solution for infusion is supplied in Australia by:

Mundipharma Pty Limited
ABN 87 081 322 509
10 Carrington Street
Sydney, NSW, 2000
Phone: 1800 188 009

® FOLOTYN is a registered trade mark owned by Acrotech Biopharma LLC and used by Mundipharma as Authorised User.

This leaflet was prepared in September 2022

Australian Registration Numbers for FOLOTYN solution for injection:

20 mg in 1mL: AUST R 192493

FOLOTYN-CMIv1-CCDSv2

Published by MIMS November 2022

BRAND INFORMATION

Brand name

Folotyn

Active ingredient

Pralatrexate

Schedule

S4

 

1 Name of Medicine

Pralatrexate.

2 Qualitative and Quantitative Composition

Pralatrexate is an off-white to yellow solid.
Each 1 mL of solution contains 20 mg of pralatrexate.

20 mg in 1 mL.

Each vial contains 20 mg of pralatrexate in 1 mL of solution.

40 mg in 2 mL*.

Each vial contains 40 mg of pralatrexate in 2 mL of solution.
* Not available.
The inactive ingredients in the solution for infusion are sodium chloride (approximately 6.3 mg in 1 mL of solution), a sufficient quantity of sodium hydroxide and hydrochloric acid if needed, to adjust and maintain the pH at 7.5-8.5, and water for injections.

3 Pharmaceutical Form

Pralatrexate solution for infusion is a preservative-free, sterile, isotonic, non-pyrogenic clear yellow aqueous parenteral solution.

4 Clinical Particulars

4.1 Therapeutic Indications

Folotyn is indicated for the treatment of adult patients with peripheral T-cell lymphoma (nodal, extranodal, and leukaemic/disseminated) who have progressed after at least one prior therapy.

4.2 Dose and Method of Administration

Treatment should only be administered under the supervision of a physician experienced in the use of anticancer chemotherapy. Folotyn vials contain no antimicrobial preservative and are for use in one patient on one occasion only.

Premedication regimen.

Patients should take low-dose (1.0-1.25 mg) oral folic acid on a daily basis. Folic acid should be initiated during the 10-day period preceding the first dose of Folotyn, and dosing should continue during the full course of therapy and for 30 days after the last dose of Folotyn. Patients should also receive a vitamin B12 (1 mg) intramuscular injection no more than 10 weeks prior to the first dose of Folotyn and every 8-10 weeks thereafter. Subsequent vitamin B12 injections may be given the same day as treatment with Folotyn. The premedication regimen should be strictly observed.

Dosage.

Adults.

The recommended starting dose of Folotyn is 30 mg/m2 administered as an intravenous infusion over 3-5 minutes, once weekly for six (6) weeks, followed by a one (1) week rest period (7-week treatment cycle), until progressive disease or unacceptable toxicity.

Monitoring.

Full blood cell counts and severity of mucositis should be monitored weekly for all patients receiving Folotyn. Serum chemistry tests, including renal and hepatic function, should be performed prior to the start of the first and fourth dose of a given cycle, or more often if required. Prior to initiating any dose of Folotyn, mucositis should be ≤ Grade 1, absolute neutrophil count (ANC) should be ≥ 1,000/microL, and platelet count should be ≥ 100,000/microL for the first dose and ≥ 50,000/microL for all subsequent doses.

Dose adjustments during treatment.

Doses may be omitted or reduced, based on patient tolerance. Omitted doses should not be made up at the end of the cycle. Once a dosage reduction occurs for toxicity, the dosing should not be re-escalated. For dose modifications and omissions, use the guidelines in Tables 1, 2 and 3.

Patients with hepatic impairment.

Folotyn has not been formally studied in patients with hepatic impairment, and caution is advised when administering pralatrexate to this patient group. Patients with the following laboratory values were excluded from the pralatrexate lymphoma clinical studies: total bilirubin > 1.5 mg/dL; aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 x upper limit of normal (ULN); and AST or ALT > 5 x ULN if documented hepatic involvement with lymphoma. Liver function test abnormalities have been observed after Folotyn administration and are usually not cause for modification of treatment. Persistent liver function test abnormalities may be indicators of liver toxicity and require evaluation. Liver function monitoring during treatment is recommended.

Patients with renal impairment.

Folotyn has not been formally studied in patients with moderate to severe renal impairment, and caution is advised when administering pralatrexate to patients with an estimated glomerular filtration rate [eGFR] of less than 60 mL/min. Avoid Folotyn use in patients with end stage renal disease, including those undergoing dialysis, unless the potential benefit justifies the risk. Approximately 34% of pralatrexate is excreted unchanged into urine. Renal function monitoring during treatment is recommended (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).

Third space fluid accumulation.

The effect of third space compartment fluid accumulation (e.g. pleural effusions, ascites, significant peripheral oedema) is unknown. In patients with clinically significant third space fluid, consideration should be given to draining the effusion prior to initiation of treatment with pralatrexate.

Elderly patients.

No overall differences in efficacy and safety were observed in patients based on age (< 65 years compared with ≥ 65 years). No dose adjustment is required in elderly patients with normal renal function (see Section 4.4 Special Warnings and Precautions for Use). In patients with age-related renal impairment, the dose should be reduced because of the possibility of increased pralatrexate plasma levels due to decreased renal clearance.

Paediatric patients.

Not recommended for children below 18 years.

Method of administration.

Folotyn is administered undiluted as an intravenous infusion over 3-5 minutes. The calculated dose of Folotyn should be aseptically withdrawn into a syringe and administered via the side port of a free flowing sodium chloride 9 mg/mL (0.9%) solution for injection intravenous line. Folotyn must not be administered by any other route of administration. A vial can be used in one patient on one occasion only as Folotyn contains no antimicrobial preservatives. Once the vial is opened, the solution should be used immediately.

Special precautions for handling.

Folotyn is a cytotoxic anticancer agent. Caution should be exercised in handling, preparing, and administering of the solution. The use of gloves and other protective clothing is recommended. If Folotyn comes in contact with the skin, immediately and thoroughly wash with soap and water. If Folotyn comes in contact with mucous membranes, flush thoroughly with water.
Folotyn is a clear, yellow solution. The vials should be inspected visually for particulate matter and discolouration prior to administration, and the solution should be clear and yellow. Vials showing particulate matter or discolouration should not be used. Folotyn vials contain no antimicrobial preservatives and are for use in one patient on one occasion only. After withdrawal of the dose, discard any unused portion left in the vial. Unused portions should not be saved for later administration.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients. Pregnancy or breast-feeding (see Section 4.4 Special Warnings and Precautions for Use).

4.4 Special Warnings and Precautions for Use

Folic acid and vitamin B12 supplementation.

Patients should be instructed to take folic acid and vitamin B12 to potentially reduce treatment-related haematological toxicity and mucosal inflammation (see Section 4.2 Dose and Method of Administration).

Bone marrow suppression.

Pralatrexate can suppress bone marrow function, manifested by thrombocytopenia, neutropenia, and anaemia. Folic acid and vitamin B12 supplementation is recommended to reduce the risk of haematological toxicity. Dose modifications are based on absolute neutrophil count (ANC) and platelet count prior to each dose (see Section 4.2 Dose and Method of Administration).

Mucosal inflammation.

Treatment with pralatrexate can cause mucosal inflammation. Monitor for mucosal inflammation weekly and if ≥ Grade 2 mucosal inflammation is observed, omit and/or reduce the dose (see Section 4.2 Dose and Method of Administration). Administer vitamin B12 and instruct the patient to take folic acid to reduce the risk of mucosal inflammation.

Dermatological reactions.

Folotyn can cause severe dermatological reactions, which may result in death. Dermatological reactions with Folotyn have ranged from alopecia (reported in 12% of patients in Study PDX-008), pruritus (7%) and rash (7%), to serious or fatal skin exfoliation, ulceration, toxic epidermal necrolysis.
There have been a small number of fatal dermatological reactions both within the clinical trials and post-marketing setting with pralatrexate. In most cases the reaction occurred after the first dose. In 5/6 cases, there was extensive skin involvement by PTCL.
Such reactions involve skin and subcutaneous sites of known lymphoma. The majority of these reactions are mild and self-limiting; however serious and potentially life-threatening events including skin exfoliation, ulceration and toxic epidermal necrolysis (TEN) have occurred, including fatal cases. Patients with extensive skin disease or a history of adverse skin reactions appear to be at highest risk of developing these severe reactions, with onset occurring early in the course of therapy in most cases. Skin reactions may be progressive and increase in severity with further treatment. Monitor patients with dermatological reactions closely, and if severe, discontinue Folotyn (see Section 4.2 Dose and Method of Administration, Table 2).

Pneumonitis.

Pneumonitis has been reported in patients treated with Folotyn. Across clinical studies, pneumonitis was reported in 9 patients (1.3%), including 7 patients with PTCL. Most cases were considered causally related to pralatrexate. In one case, it was considered to be an acute hypersensitivity reaction to pralatrexate.

Tumour lysis syndrome.

Tumour lysis syndrome has been reported in patients with lymphoma receiving pralatrexate. Patients should be monitored closely and treated for complications.

Sodium content.

Folotyn contains less than 1 mmol sodium (23 mg) per dose, i.e. is essentially 'sodium-free'.

Use in hepatic impairment.

Administration of pralatrexate to patients with hepatic impairment should only be done with caution and close monitoring of liver function and adverse events (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).

Use in renal impairment.

Administration of pralatrexate to patients with moderate to severe renal function impairment (estimated glomerular filtration rate [eGFR] < 60 mL/min) should only be done with caution and close monitoring of renal function and adverse events (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).

Use in the elderly.

No overall differences in efficacy and safety were observed in patients based on age (under 65 years compared with 65 years and over). No dose adjustment is required in elderly patients with normal renal function (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties). However, the decision whether to administer Folotyn to elderly patients should be made in the context of: concomitant disease, concomitant drug therapy or signs and symptoms of systemic toxicity.

Paediatric use.

No data are available in children aged 0 to 18 years, and the safety and efficacy of Folotyn has not yet been established in these patients.

Effects on laboratory tests.

Liver function test abnormalities have been observed after Folotyn administration and are usually not cause for modification of Folotyn treatment. Persistent liver function test abnormalities may be indicators of liver toxicity and require evaluation. Caution is advised when administering pralatrexate to patients with hepatic impairment. It is recommended that patients are monitored for liver function (see Section 4.4 Special Warnings and Precautions for Use).

4.5 Interactions with Other Medicines and Other Forms of Interactions

No formal interaction studies have been performed.

Cytochrome P450 interactions.

In vitro studies indicated that pralatrexate is not a substrate, inhibitor, or inducer of cytochrome P450 (CYP450) isoenzymes, and thus it has low potential for drug-drug interactions at CYP450 isoenzymes.

Uricosurics.

Concomitant use with probenecid should be avoided. The effect of co-administration of the uricosuric probenecid on pralatrexate pharmacokinetics was investigated in a Phase 1 clinical study. Co-administration of increasing doses of probenecid resulted in reduced clearance of pralatrexate and a commensurate increase in systemic exposure and reduced tolerability of pralatrexate. Monitor patients closely for systemic toxicity due to increased drug exposure.

Renal interactions.

Caution should be used in the concomitant administration of drugs that affect glomerular filtration and/or renal tubular secretion, because of the significant contribution of renal excretion to the overall clearance of pralatrexate (approximately 34% of unchanged pralatrexate is excreted renally). Such drugs include nonsteroidal anti-inflammatory drugs (NSAIDs), penicillins, omeprazole or pantoprazole, as they may result in reduced clearance of pralatrexate. Monitor patients closely for systemic toxicity due to increased drug exposure.
In addition, concomitant administration of nephrotoxic drugs (e.g. aminoglycosides, loop diuretics, platinum compounds, cyclosporine) could also potentially result in reduced clearance of pralatrexate and should be avoided in patients being treated with Folotyn.

Transporters.

In in vitro transporter studies, pralatrexate was a substrate for BCRP, OATP1B1, MRP2, MRP3 and OATP1B3. Pralatrexate was not a significant substrate for P-gp, OCT2, OAT1 or OAT3. Pralatrexate did not significantly inhibit P-gp, BCRP, OCT2, OAT1, OAT3, OATP1B1 and OATP1B3. Pralatrexate was a weak inhibitor of MRP2 (IC50 = 43.5 microM), and a potent inhibitor of MRP3 (IC50 < 0.3 microM). Since pralatrexate was found to be a potent inhibitor of MRP3, a liver transporter implicated in transport of etoposide, teniposide, and methotrexate caution is advised with concomitant use of these agents with pralatrexate.

Trimethoprim/sulfamethoxazole.

Trimethoprim/sulfamethoxazole has been reported in rare cases to increase bone marrow suppression in patients treated with methotrexate, presumably because of the increased antifolate effect. Caution should be exercised in the concomitant use of these agents with pralatrexate.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no human data on the effect of pralatrexate on fertility. No fertility studies have been performed in animals. Due to the potential of antifolates to irreversibly affect fertility, patients should be offered appropriate counselling.
(Category D)
There are no data from the use of pralatrexate in pregnant women. In pregnant rats and rabbits, pralatrexate administered IV during the period of organogenesis had a negative effect on fetal viability, manifested as an increase in post-implantation loss and a reduced number of live fetuses at greater than or equal to 0.06 mg/kg in rats and 1 mg/kg in rabbits. Total litter loss was seen at greater than or equal to 0.1 mg/kg in rats and 1 mg/kg in rabbits. Estimated exposures at these doses were below or slightly higher than the clinical exposure based on AUC. Retardation of fetal growth was also seen in rats at greater than or equal to 0.006 mg/kg. One rat fetus in the 0.06 mg/kg group had a syndactyly hindlimb or brachydactyly forelimbs.
Folotyn is not recommended during pregnancy or in women of childbearing potential, unless they are using reliable contraception. If pralatrexate is used during pregnancy or if the patient becomes pregnant while receiving pralatrexate, the possible risks to the foetus should be discussed with the patient.
Women of childbearing potential must use effective contraception during treatment with pralatrexate. Pralatrexate may have genetically damaging effects. Sexually mature males are advised not to father a child during treatment or up to six months thereafter. Barrier contraceptive measures or abstinence are recommended.
 Folotyn is contraindicated during breast-feeding (see Section 4.3 Contraindications).

4.7 Effects on Ability to Drive and Use Machines

There have been no studies relating to effects of pralatrexate treatment on the ability to drive or operate machinery. However, patients should be advised that they may experience fatigue, blurred vision or dizziness during treatment with Folotyn and should be advised against driving or operating machinery, if they experience any of these side effects.

4.8 Adverse Effects (Undesirable Effects)

The safety of pralatrexate was evaluated in 111 peripheral T-cell lymphoma (PTCL) patients in one single-arm pivotal clinical study, PDX-008, in which patients received 30 mg/m2 once weekly for 6 weeks in 7-week cycles. The median duration of treatment was 70 days, with a range of 1-696 days.
The most frequently reported adverse reactions included mucosal inflammation, myelosuppression (thrombocytopenia, neutropenia and anaemia), gastrointestinal symptoms (nausea, vomiting and constipation), fatigue, and epistaxis. The most serious adverse reactions included bone marrow suppression (thrombocytopenia, neutropenia and anaemia), mucosal inflammation, dermatological reactions (skin exfoliation and toxic epidermal necrolysis) and tumour lysis syndrome. Deaths, regardless of causality, from mucositis, febrile neutropenia, sepsis, and pancytopenia occurred in 1.2% of patients treated on all Folotyn trials at doses ranging from 30 to 325 mg/m2.
Adverse reactions reported in the trial that were at least possibly related to Folotyn are listed below by system organ class and frequency. The frequency key was as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100). Adverse effects are shown in order of decreasing seriousness within each frequency grouping.

Adverse drug reactions (from study PDX-008 in 111 PTCL patients).

Infections and infestations.

Common: sepsis, pneumonia1, bronchitis, urinary tract infection, cellulitis, herpes zoster, abscess1, infection1, herpes virus infection1, upper respiratory infection1, fungal infection1, folliculitis. Uncommon: Clostridium difficile colitis, cytomegalovirus colitis.

Neoplasms benign, malignant and unspecified (including cysts and polyps).

Uncommon: tumour lysis syndrome.

Blood and lymphatic system disorders.

Very common: neutropenia1, leukopenia1, thrombocytopenia1, anaemia1. Common: febrile neutropenia, pancytopenia, lymphopenia. Uncommon: haemolytic anaemia.

Metabolism and nutrition disorders.

Very common: anorexia1. Common: hyperkalaemia, hypokalaemia1, dehydration, hyperuricaemia1, hyperglycaemia1, hypomagnesaemia, hypophosphataemia. Uncommon: hypercalcaemia.

Psychiatric disorders.

Common: insomnia, anxiety.

Nervous system disorders.

Common: neuropathy peripheral1, headache, dizziness, paraesthesia1, hypoaesthesia. Uncommon: syncope, memory impairment.

Eye disorders.

Common: vision blurred, eye irritation1, lacrimation increased, ocular hyperaemia1, eye pruritus1. Uncommon: visual acuity reduced, uveitis, photopsia, eyelid ptosis, conjunctivitis.

Ear and labyrinth disorders.

Common: tinnitus. Uncommon: deafness, vertigo, hypoacusis.

Cardiac disorders.

Common: tachycardia1. Uncommon: cardio-respiratory arrest, cardiomegaly.

Vascular disorders.

Common: hypotension. Uncommon: venous thrombosis1.

Respiratory, thoracic and mediastinal disorders.

Very common: epistaxis. Common: pleural effusion, dyspnoea, cough1, pharyngolaryngeal pain, dysphonia. Uncommon: pneumonitis, pulmonary embolism, hypoxia, pulmonary congestion, pleuritic pain.

Gastrointestinal disorders.

Very common: mucosal inflammation1, vomiting, diarrhoea, nausea1, constipation. Common: abdominal pain1, odynophagia1, oral pain, dyspepsia1, rectal haemorrhage1, dry mouth1 . Uncommon: pancreatitis.

Hepatobiliary disorders.

Common: hepatosplenomegaly1, hyperbilirubinaemia1. Uncommon: cholangitis.

Skin and subcutaneous tissue disorders.

Very common: rash1. Common: skin ulcer1, skin lesion1, urticaria, pruritus1, skin haemorrhage1, periorbital oedema, erythema1, alopecia, blisters, dry skin. Uncommon: skin exfoliation, skin toxicity, night sweats.

Musculoskeletal and connective tissue disorders.

Very common: musculoskeletal pain1. Common: back pain, neck pain, arthralgia1, myalgia, muscle spasms, pain in extremity. Uncommon: costochondritis, joint swelling.

Renal and urinary disorders.

Uncommon: renal failure.

General disorders and administration site conditions.

Very common: pyrexia, peripheral oedema1, fatigue. Common: influenza-like illness, chest pain, chills, pain1, asthenia, face oedema. Uncommon: infusion-related reaction.

Investigations.

Very common: liver function test abnormal1 (elevated AST, ALT). Common: blood creatinine increased1, weight decreased. Uncommon: ejection fraction decreased.

Injury, poisoning, and procedural complications.

Common: contusion.
1 Closely-related adverse event terms were coded to the same lowest-level term in order to present the event in a uniform manner.

Description of selected adverse reactions.

Gastrointestinal disorders.

Mucosal inflammation occurred in 68% of patients, 18% with Grade 3 and 4% with Grade 4 reactions, classified in accordance with the National Cancer Institute-Common Terminology Criteria (NCI-CTC). Most patients for whom the dose was modified recovered to mucosal inflammation equal to, or below, Grade 1 (see Section 4.2 Dose and Method of Administration).

Blood disorders.

Myelosuppression was a very commonly observed adverse reaction.
Thrombocytopenia occurred in 40% of patients, 14% with Grade 3 and 17% with Grade 4 reactions. Platelet count recovery usually occurred after treatment was omitted or ceased. Bleeding complications (coincident with low platelet counts) were generally mild and predominantly presented clinically as epistaxis.
Neutropenia occurred in 24% of patients, 14% with Grade 3 reactions and 7% with Grade 4 reactions. Infection complications (coincident with low neutrophil counts) were mostly Grade 1-2 in severity.
Anaemia occurred in 32% of patients, 14% with Grade 3 and 2% with Grade 4 reactions. Other common hematologic Grade 3 and 4 haematologic reactions included febrile neutropenia, pancytopenia and leucopenia.

Other grade 3 and 4 adverse reactions.

Other common Grade 3 and 4 adverse reactions included skin ulcers, infections, anorexia, dyspnoea, vomiting, nausea, pain, and fatigue.

Investigations.

Elevated liver enzymes were the most frequently reported clinical chemistry laboratory abnormality. Clinically significant abnormalities were those ≥ Grade 2, per NI CTCAE and that represented a shift of ≥ 1 grade from the baseline value. Nineteen (17%) and 18 (16%) patients had increased AST and ALT values, respectively, that were considered clinically significant.

Post-marketing.

Toxic epidermal necrolysis (TEN), a clinically significant adverse reaction, was reported during post-approval use.
Serious adverse drug reactions including TEN and mucosal inflammation were reported in patients with end-stage renal disease undergoing dialysis who were administered Folotyn. Fatal events of serious skin reactions have been reported in patients in dialysis who received a dose of less than 30 mg/m2 per day.

Reporting suspected adverse effects.

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 www.tga.gov.au/reporting-problems.

4.9 Overdose

No specific information is available on the treatment of pralatrexate overdosage. General supportive measures should be instituted as deemed necessary. Based on the mechanism of action of pralatrexate, and clinical experience with other antifolates, prompt administration of leucovorin, adequate hydration and alkalinisation of the urine should be considered.
Experience with overdose of pralatrexate is very limited. However, doses of more than ten times the prescribed starting dose of pralatrexate for the indication of relapsed or refractory PTCL have been administered in solid tumour clinical studies with a similar adverse event profile. Anticipated symptoms of overdose might include increased severity and/or duration of mucosal inflammation and myelosuppression (primarily manifested by thrombocytopenia, leucopenia, neutropenia and anaemia).
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Pralatrexate is an antineoplastic folate analogue that is a substrate for reduced folate transporters, including reduced folate carrier 1 (RFC-1) and the enzyme folylpolyglutamyl synthetase (FPGS), resulting in internalisation and accumulation within tumour cells. Pralatrexate exerts anti-folate activity via the inhibition of dihydrofolate reductase (DHFR), resulting in a disruption of DNA synthesis and subsequent tumour cell death. In vitro testing indicates that pralatrexate exhibits cytotoxic activity across a number of human lymphoproliferative tumour cell types. Pralatrexate produced a significant reduction in tumour size in human tumour xenograft models.
The pharmacotherapeutic group for pralatrexate is "antineoplastic agents, antimetabolites, folic acid analogues". The ATC code is L01BA05.

Clinical trials.

The efficacy of Folotyn was evaluated in an open-label, single-arm, non-randomised, international study (PDX-008) that enrolled 115 patients with relapsed or refractory PTCL. One hundred and eleven patients were treated with Folotyn at 30 mg/m2 once weekly by intravenous infusion over 3-5 minutes for 6 weeks in 7-week cycles until disease progression or unacceptable toxicity. If methylmalonic acid level was > 200 nanoM and/or homocysteine > 10 microM, vitamin supplementation was given for ≥ 10 days prior to first dose of pralatrexate; otherwise, patients received concurrent folic acid (1-1.25 mg PO daily) and vitamin B12 (1 mg IM every 8-10 weeks). Vitamin supplementation continued for at least 1 month after discontinuation of pralatrexate.
Of the 111 patients treated, 109 patients were evaluable for efficacy. Evaluable patients had histologically confirmed PTCL, as confirmed by independent central review using the Revised European American Lymphoma (REAL) World Health Organization (WHO) disease classification, and relapsed or refractory disease after at least one prior treatment. Commoner subtypes included for study were PTCL-unspecified (n = 59), primary systemic anaplastic large cell lymphoma (n = 17), angioimmunoblastic T cell lymphoma (n = 13) and transformed mycosis fungoides (n = 12).
The primary efficacy endpoint was response rate (complete response, complete response unconfirmed and partial response) as assessed by independent central review using International Workshop Criteria (IWC). Response assessments were scheduled at the end of cycle 1 and then every other cycle (every 14 weeks). Duration of response was measured from the first day of documented response to disease progression or death. Response and disease progression were evaluated by independent central review using the IWC and by the local investigators. Overall survival and progression-free survival was estimated by the Kaplan-Meier method.
The median age of treated patients was 59.0 years (range 21-85); 68% were male and 32% were female. Patients had an Eastern Cooperative Oncology Group (ECOG) performance status at study entry of 0 (39%), 1 (44%), or 2 (17%). The median time from initial diagnosis to study entry was 15.6 months (range 0.8-322.3).
The median number of prior systemic therapies was 3 (range 1-12). In all treated evaluable patients (n = 109) the response rate was 29% (n = 32), with 12 of these patients achieving a complete response, as determined by independent central review using IWC. See Table 4.
Of the responders, 63% responded within cycle 1. The median time to first response was 45 days (range 37-349 days). Approximately two-thirds of patients (63%, n = 69) did not have evidence of response to their most recent prior therapy before entering the study. Of these 69 patients, 17 patients (25%) responded to pralatrexate per IWC. Approximately one-fourth of patients (24%, n = 26) did not have evidence of response to any previous therapy. Of these 26 patients, 5 patients (19%) responded to pralatrexate per IWC review.
The median progression-free survival for the efficacy analysis set was 3.5 months (95% confidence interval (CI), 1.7 to 4.8 months). The median overall survival was 14.5 months (95% CI, 10.6 to 22.5 months). Forty-seven patients (43%) were censored for overall survival because they were still alive at the time of the data cut-off date.
Response rate by histopathology was similar among the subtypes, with the possible exception of angioblastic T-cell lymphoma in which there was only 1 responder out of a limited number of patients (n = 13) with this histological subtype, for a responder rate for that subtype of 8%. The study was not designed to assess tumour responsiveness by histological subtype.
Four patients in PDX-008 achieved a response following treatment with pralatrexate, confirmed by independent central review. These patients were able to proceed to transplant as their subsequent therapy, and have achieved a prolonged response.

5.2 Pharmacokinetic Properties

Absorption.

Pralatrexate is administered by intravenous infusion, therefore absorption is not applicable. Maximum pralatrexate serum concentrations (Cmax) were generally observed at or shortly after the end of the infusion. The pharmacokinetics of pralatrexate administered as a single 30 mg/m2 dose by intravenous infusion over 3-5 minutes once weekly for 6 weeks in 7-week cycles was evaluated in 10 patients with peripheral T-cell lymphoma (PTCL). The mean Cmax value for pralatrexate was 5.8 microgram/mL. The mean total systemic exposure (AUC(0-∞)) was 268 microgram/mL.min.
The Cmax and AUC(0-∞) increased with the dose (dose range of 30-325 mg/m2, including pharmacokinetic data from high-dose solid tumour clinical studies). The pharmacokinetics of pralatrexate did not change significantly over the course of a single treatment cycle (6 doses) in 5 patients, and no accumulation of pralatrexate was observed. The potential for accumulation beyond a single cycle of treatment has not been assessed.

Distribution.

In the pivotal PDX-008 study in PTCL, pralatrexate diastereomers showed a steady-state volume of distribution of 105 L (S-diastereomer) and 37 L (R-diastereomer). In vitro studies indicated that pralatrexate is approximately 65% bound to human plasma proteins.

Metabolism.

In vitro studies using human hepatocytes, liver microsomes and S9 fractions, and recombinant human CYP450 isoenzymes showed that pralatrexate is not significantly metabolised by the phase I hepatic CYP450 isoenzymes or phase II hepatic glucuronidases. In vitro studies indicated that pralatrexate has low potential to induce or inhibit the activity of CYP450 isoenzymes.

Excretion.

The total systemic clearance of pralatrexate diastereomers was 417 mL/min (S-diastereomer) and 191 mL/min (R-diastereomer). The terminal elimination half-life of pralatrexate was 12-18 hours (coefficient of variance (CV) = 62-120%). The mean fraction of unchanged pralatrexate diastereomers excreted in urine following a pralatrexate dose of 30 mg/m2 administered as an IV infusion over 3-5 minutes was 31% (S-diastereomer) (CV = 47%) and 38% (R-diastereomer) (CV = 45%), respectively. Non-renal clearance accounts for the elimination of the remainder (approximately two-thirds) of the administered pralatrexate. The exact mechanism of the non-renal clearance is unknown.
A mass-balance study has not been completed in humans.

Special populations.

Renal impairment.

Limited pharmacokinetic data are available for patients with moderate renal impairment (eGFR < 60 mL/min) and no data are available for patients with severe renal impairment (eGFR < 30 mL/min). Approximately 34% of pralatrexate was excreted unchanged into urine following a single dose of 30 mg/m2 administered as an intravenous infusion over 3-5 minutes. Covariate analysis showed that pralatrexate clearance moderately decreased with decreasing creatinine clearance. Patients with moderate to severe renal function impairment may be at greater risk for increased exposure and toxicity. Monitor patients for renal function and systemic toxicity and adjust dosing accordingly. Avoid Folotyn use in patients with end stage renal disease including those undergoing dialysis unless the potential benefit justifies the potential risk.

Hepatic impairment.

No pharmacokinetic data are available for patients with hepatic impairment. Approximately two-thirds of pralatrexate is eliminated by non-renal clearance that may be largely via hepatobiliary excretion. For this reason, a risk for increased exposure in patients with hepatic impairment cannot be excluded.

Elderly.

Due to the contribution of renal excretion to overall clearance of pralatrexate, age-related decline in renal function may lead to a reduction in clearance and a commensurate increase in plasma exposure.

5.3 Preclinical Safety Data

Genotoxicity.

Pralatrexate was not mutagenic in the standard in vitro and in vivo mutagenicity assays, including Ames test, Chinese hamster ovary (CHO) cell chromosome aberration assay and mouse micronucleus assay. However, these tests may not reliably predict genotoxicity for this class of compound. Based on experience with other antifolates, an increased risk for genotoxicity from pralatrexate treatment cannot be excluded.

Carcinogenicity.

Carcinogenicity studies have not been performed with pralatrexate.

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

In the absence of compatibility studies, Folotyn must not be mixed with other medicines.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store in a refrigerator (2°C-8°C). Keep the vial in its outer carton to protect it from light. Unopened vials are stable if stored in the original carton for a single period at up to 30°C for 120 hours. Any vials left at 30°C for longer than 120 hours should be discarded. Folotyn should be used immediately after opening the vial and any unused portion should be discarded.

6.5 Nature and Contents of Container

Folotyn is supplied in a carton containing a clear glass, single-use vial with a chlorobutyl stopper covered with an aluminium flip-off seal.
Each 1 mL of solution contains 20 mg of pralatrexate. Two vial presentations are registered.

20 mg in 1 mL.

Each vial contains 20 mg of pralatrexate in 1 mL of solution. Pack size of 1 vial.

40 mg in 2 mL*.

Each vial contains 40 mg of pralatrexate in 2 mL of solution. Pack size of 1 vial.
* Not available.

6.6 Special Precautions for Disposal

Folotyn is a cytotoxic anticancer agent.
In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Pralatrexate is soluble in aqueous solutions at pH 6.5 or higher, and practically insoluble in chloroform and ethanol. The aqueous solubility of pralatrexate is U-shaped over a pH range of 1-7, and is controlled by the neutral species within this range. The intrinsic solubility of the neutral species was calculated as 132 microM or 63 microgram/mL. The lowest solubility is within the range of pH 3 to pH 6, which correlates with the measured pKa values of pralatrexate of 3.25 and 4.76 for the first two carboxylic acid groups, and 6.17 for the conjugate acid of the basic group. The partition coefficient (log P) is 0.025 (neutral) and 0.011 (monoanionic). Pralatrexate is a 1:1 mixture of R- and S-diastereomers at the C10 epimeric chiral centre, with a fixed chiral centre at C19.

Chemical structure.


CAS number.

146464-95-1.
Chemical name: N-(4-{1-[(2,4-diaminopteridin-6-yl)methyl]but-3-yn-1-yl}benzoyl)-L-glutamic acid.
Molecular formula: C23H23N7O5.
Molecular weight: 477.48.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes