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.

SUMMARY CMI

FOLOTYN®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I being given FOLOTYN?

FOLOTYN contains the active ingredient pralatrexate. FOLOTYN is used to treat patients over 18 years or older with peripheral T-cell lymphoma (PTLC) after previous treatments have not worked or have stopped working.

For more information, see Section 1. Why am I being given FOLOTYN? in the full CMI.

2. What should I know before FOLOTYN is given?

Do not use if you have ever had an allergic reaction to pralatrexate or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before FOLOTYN is given? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with FOLOTYN and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How is FOLOTYN given?

  • Your doctor will decide what dose of FOLOTYN you will receive.
  • FOLOTYN should only be given to you under the supervision of a doctor or nurse experienced in treating cancer.
  • Your doctor should advise you to take certain medicines or vitamin supplements before starting and while being given FOLOTYN to help minimise side effects.

More instructions can be found in Section 4. How is FOLOTYN given? in the full CMI.

5. What should I know while being given FOLOTYN?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using FOLOTYN.
  • 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.
Things you should not do
  • Do not inject FOLOTYN yourself. Always let your doctor or nurse do it.
  • Do not stop or change your treatment with FOLOTYN unless advised by your doctor.
Driving or using machines
  • Do not drive or operate machinery until you know how FOLOTYN solution for infusion affects you.
Looking after your medicine
  • Store FOLOTYN 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.

For more information, see Section 5. What should I know while being given FOLOTYN? in the full CMI.

6. Are there any side effects?

Side effects that require urgent medical attention: allergic reaction; chest pain when breathing, difficulty or fast breathing; redness or sores of the mouth, nose, genitals or anus; dehydration; fever; unusual bleeding; severe skin reactions; fast or irregular heartbeats, swelling of legs and ankles; nausea, vomiting; diarrhea.

Common side effects: constipation; indigestion; loss of appetite; weight loss; pain in the stomach or abdomen; painful, stiff or swollen joints, pain or spasm of the muscles; pain in extremities; generalized pain in the back, neck or chest; effects on the eye; 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.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

FOLOTYN®

Active ingredient: pralatrexate

Consumer Medicine Information (CMI)

This leaflet provides important information about using FOLOTYN. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using FOLOTYN.

Where to find information in this leaflet:

1. Why am I being given FOLOTYN?
2. What should I know before FOLOTYN is given?
3. What if I am taking other medicines?
4. How is FOLOTYN given?
5. What should I know while being given FOLOTYN?
6. Are there any side effects?
7. Product details

1. Why am I being given FOLOTYN?

FOLOTYN contains the active ingredient pralatrexate. FOLOTYN 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.

2. What should I know before FOLOTYN is given?

Warnings

Do not use FOLOTYN if:

  • you are allergic to pralatrexate, or any of the ingredients listed at the end of this leaflet.

Always check the ingredients to make sure you can use this medicine.

Check with your doctor if you:

  • have any other medical conditions, especially the following:
    - liver problems
    - kidney problems
    - extensive skin disease or a history of adverse skin reactions
    - have end stage kidney disease or are undergoing dialysis, unless the benefit outweighs the risk
    - take any medicines for any other condition.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Females: Check with your doctor if you are pregnant or intend to become pregnant. FOLOTYN is not recommended for use during pregnancy.

The effects of FOLOTYN in pregnant women are not known. FOLOTYN may harm the unborn baby.

FOLOTYN should not be given to you if you are breastfeeding.

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

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.

Children

This medicine is not recommended to be used to treat a child or adolescent younger than 18 years of age.

Safety and effectiveness in children and adolescents younger than 18 years of age has not been established.

3. What if I am taking other medicines?

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

Some medicines may interfere with FOLOTYN and affect how it works. 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.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect FOLOTYN.

4. How is FOLOTYN 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.

When will FOLOTYN be given

  • 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.

How FOLOTYN is given

FOLOTYN 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

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, you should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your 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).

5. What should I know while being given FOLOTYN?

Things you should do

  • Remind any doctor, dentist or pharmacist you visit that you are receiving FOLOTYN.
  • 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.

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.

Call your doctor straight away if:

  • You or your partner becomes pregnant while being given this medicine or within 6 months after stopping treatment.

Things you should not do

  • Do not inject FOLOTYN yourself. Always let your doctor or nurse do this.
  • Do not stop or change your treatment with FOLOTYN unless advised by your doctor.
  • FOLOTYN should not be used to treat any other complaint, unless advised by your doctor.
  • It should not be administered to anyone else.

Things to be careful of

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

  • Low blood cell counts: FOLOTYN 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 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 heartbeat and kidney problems.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how FOLOTYN affects you.

FOLOTYN may cause fatigue, blurred vision, or dizziness. If you experience any of these side effects, do not drive or operate machinery.

Looking after your medicine

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

FOLOTYN 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.

When to discard your medicine

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

Getting rid of any unwanted medicine

This medicine should not be used after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
Gastrointestinal:
  • Constipation, indigestion
  • Loss of appetite, weight loss
  • Pain in the stomach or abdomen.
Musculoskeletal:
  • Painful, stiff or swollen joints
  • Pain or spasm of the muscles.
Nervous system:
  • Pain in extremities
  • Generalized pain in the back, neck or chest
  • Headaches
  • Numbness, tingling or pins and needles sensation
  • Dizziness
  • Difficulty sleeping
  • Anxiety.
Eyes, Ears, and Throat:
  • Effects on the eye, including irritation, itching, redness, increased tears, blurred vision
  • Ringing sound in the ears
  • Hoarseness, sore throat, coughing, difficulty or pain when swallowing.
Hair loss		Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Mucosal inflammation:
  • Inflammation, redness or sores in the mouth
  • Inflammation, redness or sores in the nose, genitals or anus (back passage).
Dehydration:
  • Thirst, dry mouth, flushed skin, darker coloured urine, fatigue, weakness or light-headedness.
Infections:
  • Fever, chills
  • Cough
  • Shortness of beath
  • Pain or burning on urination
  • Fungal infection in the mouth, throat or vagina.
Low blood cell counts:
  • Unusual bleeding, such as nose bleeds
  • Any bleeding from the mouth, genitals or anus (back passage)
  • Bruising under your skin or reddish/pinkish urine
  • Feeling weak, tired, getting tired easily
  • Pale skin
  • Shortness of breath.
Severe skin reactions:
  • Itchiness
  • Redness
  • Rash
  • Peeling or loss of skin
  • Sores or blisters that may happen as early as a few days after treatment.
Liver:
  • Yellow colouring of the skin and eyes.
Heart problems:
  • Fast or irregular heartbeats
  • Swelling of the legs and ankles.
Nausea, vomiting
Diarrhea
Shingles or chicken pox		Call your doctor straight away if you notice any of these serious side effects.

Very serious side effects

Very serious side effectsWhat to do
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		Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may 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.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

What FOLOTYN contains

Active ingredient
(main ingredient)		Pralatrexate
Other ingredients
(inactive ingredients)		Sodium chloride
Hydrochloric acid
Sodium hydroxide
Water for injections.

Do not take this medicine if you are allergic to any of these ingredients.

What FOLOTYN looks like

FOLOTYN is available in glass vials containing a clear yellow solution. It is supplied in packs containing 1 single-use vial with chlorobutyl stopper.

It is available in a 20mg in 1 mL presentation (AUST R 192493). Note that a 40mg in 2mL (AUST R 192492) presentation is registered but not marketed.

Who distributes FOLOTYN

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

This leaflet was prepared in May 2024.

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

FOLOTYN-CMIv2-CCDSv2

Published by MIMS August 2024

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