Pharmacotherapeutic group:
Antineoplastic agents, antimetabolites

Therapeutic indications:
Folotyn is indicated in the treatment of adult patients with
peripheral Tcell lymphoma (nodal, extranodal and
leukaemic/disseminated) who have progressed and disease
progression after at least one prior treatment. The indication is
based on the response rate. No benefit in terms of progressionfree
survival or overall survival has been demonstrated.

Properties/Effects
ATC code: L01BA05

Mechanism of action
Pralatrexate is a folate antagonist which accumulates in tumour
cells by binding to folate transporter proteins, including Reduced
Folate-Carrier 1 (RFC-1), and as a substrate of folylpolyglutamyl
synthetase (FPGS), resulting in disruption of DNA synthesis and
subsequent tumour cell death via the inhibition of dihydrofolate
reductase (DHFR)
.

Pharmacodynamic effect
In vitro tests with various human lymphoma cells and in vivo
investigations with human xenograft tumour models showed
significant cytotoxicity and a reduction in tumour growth.

Clinical efficacy
In an open-label, uncontrolled, non-randomised study, 115
patients with peripheral T-cell lymphoma that progressed after at least one course of chemotherapy were treated with Folotyn 30 mg/m2 until the onset of disease progression or unacceptable toxicity. Of the 111 patients treated, 109 patients were evaluable
for efficacy.
The average age was 54 years and the median number of prior
therapies was three (1-12).
The primary efficacy endpoint was the overall response rate
(complete response (CR), complete response unconfirmed
(CRu) and partial response (PR)), as assessed in an independent
central review using the International Workshop Criteria
(IWC). This was 29% (CR+CRu 11%, PR 18%). The median
duration of response was 10.1 months.
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, 25% responded to
pralatrexate. Approximately a quarter of the patients (24%, n =
26) had not responded to any of the previous therapies. Of these 26 patients, 19% responded to pralatrexate.

Pharmacokinetics
Pralatrexate is a 1:1 racemic mixture of R- and S diastereomers
at the C10 chiral centre.

Absorption
The mean Cmax value for pralatrexate in PTCL patients is 5.8
μg/ml and the mean total systemic exposure (AUC(0-∞)) is 268
μg/ml∙min.

Distribution
In the pivotal study with PTCL patients, pralatrexate diastereomers
showed steady-state volumes of distribution of 105 l
(S-diastereomer) and 37 l (R-diastereomer) respectively.
The protein binding of pralatrexate is low (67%-86%).

Metabolism
Pralatrexate is not significantly metabolised by CYP450
isoenzymes or glucuronidases.

Elimination
The total systemic clearance of pralatrexate diastereomers is 417 ml/min. (S-diastereomer) and 191 ml/min. (R-diastereomer). The terminal elimination half-life of pralatrexate is 12 18 hours
(coefficient of variance (CV) = 62 120%). 31% of the
S-diastereomer and 38% of the R diastereomer are excreted in
urine. Elimination via the faeces has not been recorded.
Kinetics in specific patient groups
No investigations have been performed.

Preclinical data
Pralatrexate was not mutagenic in standard in vitro and in vivo
mutagenicity assays (Ames test, chromosome aberration assay
in Chinese hamster ovary (CHO) cells and mouse micronucleus
assay). However, these tests may not reliably predict
genotoxicity for this class of compounds. Based on experience
with other antifolates, an increased risk for genotoxicity from
pralatrexate treatment cannot be excluded.
Carcinogenicity studies have not been performed with
pralatrexate.
No fertility studies have been performed. In rats and rabbits,
pralatrexate was embryotoxic and foetotoxic at intravenous
doses. In rats, pralatrexate caused a dose-dependent decrease
in foetal viability, manifested as an increase in late, early and total resorptions. There was also a dose dependent increase in post implantation loss. In rabbits, the observed toxicity manifested itself as early and total resorptions, post implantation loss and a decrease in the total number of live foetuses.

Contraindications:
Hypersensitivity to the active substance, pregnancy or lactation,
treatment with probenecid.

Interactions:
In vitro studies indicate that pralatrexate is not a substrate,
inhibitor, or inducer of cytochrome P450 (CYP450) isoenzymes
and thus has low potential for drug drug interactions during
metabolism by CYP450 isoenzymes (see “Pharmacokinetics”).
The co-administration of increasing doses of probenecid resulted in reduced clearance of pralatrexate (see “Contraindications”).
Pralatrexate did not significantly inhibit P-glycoprotein (P-gp),
breast cancer resistant protein (BCRP), organic cation
transporter 2 (OCT2), or organic anion transporters 1, 3 and
P1B3 (OAT1, OAT3 and OATP1B3). Pralatrexate was a weak
inhibitor of organic anion transporter P1B1 (OATP1B1, 35%
inhibition at 100 μM) and multidrug resistance-associated protein 2 (MRP2; IC50 = 43.5 μM). Since pralatrexate was found to be a potent inhibitor of multidrug resistance-associated protein 3 (MRP3; IC50 < 0.3 μM), a liver transporter implicated in transport of etoposide, teniposide, and methotrexate, caution is advised with concomitant use of these agents with pralatrexate.

Warnings and precautions:
The pretreatment regimen of folic acid and vitamin B12 must be
strictly observed. The risk of myelosuppression and mucositis is
elevated without this treatment. The folic acid dosage may not be increased because this could impair the effect of the pralatrexate.
Patients should be asked at regular intervals about their
compliance. If they have failed to comply with instructions,
treatment should be stopped. The absolute neutrophil count
(ANC) should be ≥ 1,000/μl, the platelet count should be ≥
100,000/μl for the first dose and ≥ 50,000/μl for all subsequent
doses. Full blood cell counts should be monitored weekly for all
patients receiving pralatrexate. Serum chemistry tests, including renal and hepatic function, should be performed prior to the first and fourth dose of a given cycle, or more often if required.
Likewise, the mouth should be examined thoroughly before the
start of each dose of pralatrexate. Good oral hygiene (regular
mouthwashes, dental hygiene) should be maintained throughout treatment with pralatrexate.
If bone marrow suppression or mucositis occurs during treatment with pralatrexate, the dose should be adjusted in line with the platelet and neutrophil counts, fever and mucositis (see “Posology and method of administration”).
Regular inspection of the skin, and particularly areas affected by lymphoma, is essential during treatment. Serious and potentially life-threatening events, including exfoliative dermatitis,

skinnecrosis and toxic epidermal necrolysis (involving a fatal
outcome in some cases) have been observed. Most at risk are
patients with extensive skin involvement or a history of adverse
skin reactions. The first signs usually appear at an early stage of
treatment. The reactions may increase in severity with further
treatment. Treatment must be discontinued if severe
dermatological reactions (Grade 4) occur.
Caution should be used in the concomitant administration of
substances that are subject to renal tubular secretion (e.g.
NSAIDs, penicillins, omeprazole or pantoprazole), since these
my result in reduced clearance of pralatrexate.
Nephrotoxic medicinal products (e.g. aminoglycosides, loop
diuretics, platinum compounds, cyclosporine) should be avoided.
Etoposide, teniposide and methotrexate should not be
administered concurrently with pralatrexate because these
substances reduce the clearance of pralatrexate.
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 is therefore advised during the concomitant use of these medicinal products with pralatrexate.
Men and women of childbearing age must use an effective
method of contraception during treatment with pralatrexate.
Pralatrexate may have genetically damaging effects.
Male patients are advised not to father a child during treatment and for up to 6 months thereafter. A barrier method or abstinence are recommended 

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.

Pregnancy and Lactation:
Pregnancy
There are no data on the use of pralatrexate in pregnant women.
Studies in animals have shown reproductive toxicity (see
“Preclinical data”). Other antifolates of the same class have
caused teratogenic effects in humans. Folotyn should not be
used during pregnancy or in women of childbearing age who are not using contraception (see “Contraindications”). If the patient becomes pregnant while receiving pralatrexate, the patient should be informed of the possible risk to the foetus.
Lactation
Folotyn should not be used in breast-feeding mothers (see
“Contraindications”), alternatively, breast-feeding should be
stopped beforehand.
Driving and using machines:
Patients should be advised that they may experience fatigue,
blurred vision, or dizziness during treatment with Folotyn.
Patients should be advised against driving or using machines if
they experience any of these adverse reactions.

Dosage/Administration
Treatment should only be administered under the supervision of a physician experienced in the use of anticancer chemotherapy.
Folotyn is administered undiluted as an intravenous infusion over 3 5 minutes. The calculated dose 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.

Incompatibilities
In the absence of compatibility studies, this medicinal product
must not be mixed with other medicinal products.
The recommended dose of pralatrexate is 30 mg/m2,
administered as an intravenous infusion over 3 5 minutes, once
weekly over a period of 6 weeks, followed by a 1 week rest period
and repetition of the 7 week cycle until disease progression or
unacceptable toxicity occurs.

Pre-treatment regimen

1 mg vitamin B12 i.m. no more than 10 weeks prior to treatment and 1 mg folic acid daily for 10 days before the start of treatment.
As of the second dose, the i.m. vitamin B12 can be injected with
the pralatrexate (every 8-10 weeks). Oral treatment with folic acid at a dose of 1 mg per day should be continued during the full course of therapy, including during the treatment-free interval.
Blood test results
The absolute neutrophil count (ANC) should be ≥ 1,000/μl and
platelet count should be ≥ 100,000/μl for the first dose and
≥ 50,000/μl for all subsequent doses. Full blood cell counts
should be monitored weekly for all patients receiving
pralatrexate. 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.
The dose should be omitted in the event of thrombocytopenia of < 50,000/μl or neutropenia of 500-1000/μl that persists for 1
week; if it persists for 2 weeks, treatment should be continued at a reduced dose of 20 mg/m2. The dose should also be reduced to 20 mg/m2 in the event of the once-only recurrence of thrombocytopenia or neutropenia or in the event of neutropenic fever, and the use of G CSF or GM CSF is recommended.
Treatment should be discontinued if myelosuppression persists
for 3 weeks.
Mucositis
Prior to initiating pralatrexate treatment, mucositis should not
exceed Grade 1. Severity of mucositis should be monitored
weekly for all patients receiving pralatrexate. In the event of
Grade 2 mucositis, the dose should be omitted, and the existing
dose can be continued if it improves to Grade ≤ 1. However, if
Grade 2 mucositis returns or Grade 3 mucositis occurs, the dose
should be reduced to 20 mg/m2. Treatment should be
discontinued if Grade 4 occurs.

Other treatment-related toxicities

In the event of treatment-related Grade 3 toxicity, the dose should be omitted and continued at 20 mg/m2 upon recovery to ≤ Grade 2. Treatment should be discontinued in the event of Grade 4 toxicity.

Special dosage instructions
Renal and hepatic impairment
A third of the dose is excreted via the kidneys. Since no studies
have investigated patients with renal or hepatic impairment, no
recommended dosage can be given.
Elderly patients
No dose adjustment is required in elderly patients with normal
renal function.
Paediatric population
The safety and efficacy of Folotyn in paediatric patients have not been investigated. Patients under 18 years of age should not be treated with Folotyn.

Overdose
No information is available on the treatment of overdose of
Folotyn. The prompt administration of folinic acid, adequate
hydration and alkalinisation of the urine should be considered.

The most frequent adverse reactions were mucositis (68%,
Grade 3/4: 22%), thrombocytopenia (40%, Grade 3/4: 31%),
nausea (33%, Grade 3/4: 4%), anaemia (32%, Grade 3/4: 16%),
fatigue (30%, Grade 3/4: 6%), neutropenia (24%, Grade 3/4:
21%), epistaxis (23%, Grade 3/4: 0%), vomiting (21%, Grade 3/4:
2%) and constipation (21%, Grade 3/4: 0%).
The most serious adverse reactions were bone marrow
suppression (thrombocytopenia, neutropenia and anaemia),
mucositis, exfoliative dermatitis, toxic epidermal necrolysis and
tumour lysis syndrome.
Other common Grade 3/4 adverse reactions were skin ulcers,
infections, anorexia, dyspnoea, vomiting, nausea, pains and
fatigue.
Frequencies are defined as: very common (≥ 1/10), common (≥
1/100 to <1/10), uncommon (≥ 1/1,000 to <1/100), rare (≥
1/10,000 to <1/1,000), very rare (< 1/10,000), and not known
(cannot be estimated from available data).

Infections and infestations
Common: Sepsis, pneumonia, bronchitis, urinary tract infection,
cellulitis, herpes zoster, abscess, infection, herpes virus
infection, upper respiratory infection, fungal infection, folliculitis
Uncommon: Clostridium difficile colitis, cytomegalovirus colitis
Neoplasms
Uncommon: Tumour lysis syndrome
Blood and lymphatic system disorders
Very common: Neutropenia (24%), leukopenia (11%),
thrombocytopenia (40%), anaemia (32%)
Common: Febrile neutropenia, pancytopenia, lymphopenia
Uncommon: Haemolytic anaemia
Metabolism and nutrition disorders
Very common: Anorexia (12%)
Common: Hyperkalaemia, hypokalaemia, dehydration,
hyperuricaemia, hyperglycaemia, hypomagnesaemia,
hypophosphataemia, weight loss
Uncommon: Hypercalcaemia
Psychiatric disorders
Common: Insomnia, anxiety
Nervous system disorders
Common: peripheral neuropathy, headache, dizziness,
paraesthesia, hypoaesthesia
Uncommon: Syncope, memory impairment
Eye disorders
Common: blurred vision, eye irritation, increased lacrimation,
ocular hyperaemia, eye pruritus
Uncommon: Reduced visual acuity, uveitis, photopsia, eyelid
ptosis, conjunctivitis
Ear and labyrinth disorders
Common: Tinnitus
Uncommon: Deafness, vertigo, hypoacusis
Cardiac disorders
Common: Tachycardia
Uncommon: Cardiorespiratory arrest, cardiomegaly, ejection
fraction reduced
Vascular disorders
Common: Hypotension
Uncommon: Venous thrombosis
Respiratory, thoracic and mediastinal disorders
Very common: Epistaxis (23%)
Common: Pleural effusion, dyspnoea, cough, pharyngolaryngeal
pain, dysphonia
Uncommon: Pneumonitis, pulmonary embolism, hypoxia,
pulmonary congestion, pleuritic pain
Gastrointestinal disorders
Very common: Mucositis (68%), vomiting (21%), diarrhoea
(17%), nausea (33%), constipation (21%)
Common: Abdominal pain, odynophagia, oral pain, dyspepsia,
rectal haemorrhage, dry mouth
Uncommon: Pancreatitis
Hepatobiliary disorders
Very common: elevated liver enzymes (ASAT 17%, ALAT 16%)
Common: Hepatosplenomegaly, hyperbilirubinaemia
Uncommon: Cholangitis
Skin and subcutaneous tissue disorders
Very common: Rash (11%)
Common: Skin ulcers, urticaria, pruritus, skin haemorrhage,
periorbital oedema, erythema, alopecia, dry skin
Uncommon: Exfoliative dermatitis, toxic dermatitis, night sweats
Not known: Toxic epidermal necrolysis
Musculoskeletal and connective tissue disorders
Very common: Musculoskeletal pain (11%)
Common: Back pain, neck pain, arthralgia, myalgia, muscle spasms
Uncommon: Costochondritis, joint swelling
Renal and urinary disorders
Common: Elevated blood creatinine
Uncommon: Renal failure
General disorders and administration site conditions
Very common: Pyrexia (19%), peripheral oedema (18%), fatigue (30%)
Common: Influenza-like illness, chest pain, chills, pain, asthenia,
facial oedema
Uncommon: Infusion-related reaction

This medicinal product must not be used after the expiry date
(“EXP”) printed on the container.
The ready-to-use Folotyn solution for infusion contains no
preservatives and is intended for single use only. After
withdrawal of dose, discard any unused portion left in the vial.
Unused portions should not be saved for later administration.

Special precautions for storage
Store in the refrigerator (2-8°0C) out of the reach of children.
Keep the vial in the outer carton in order to protect from light.
Unopened vials may be removed from the refrigerator and
stored at up to 30°0C for a single period of up to 120 hours.

Instructions for handling
The rules for cytotoxic agents should be observed when
preparing and handling Folotyn.
Folotyn is a clear, yellow solution.
The vials should be inspected visually for particulate matter and
discolouration prior to administration. Vials exhibiting particulate matter or discolouration should not be used.