Jylamvo

Overdose

Symptoms of overdose

The symptoms following oral overdose predominantly affect the haematopoietic and gastrointestinal systems.

Symptoms include leucocytopenia, thrombocytopenia, anaemia, pancytopenia, neutropenia, myelosuppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration and bleeding.

Cases of overdose have been reported, sometimes fatal, due to erroneous daily intake instead of weekly intake of oral methotrexate. In these cases, symptoms that have been commonly reported are hematological and gastrointestinal reactions.

There are reports of deaths from sepsis, septic shock, renal failure and aplastic anaemia.

Therapeutic management of overdose

Calcium folinate is the specific antidote for neutralising the adverse toxic effects of methotrexate. In the event of accidental overdose, a dose of calcium folinate equal to or higher than the offending dose of methotrexate should be administered intravenously or intramuscularly within 1 hour, and dosing continued until serum level of methotrexate are below 10-7 mol/L.

In the event of a massive overdose, hydration and alkalinisation of the urine may be required to prevent precipitation of methotrexate and/or its metabolites in the renal tubules. Neither haemodialysis nor peritoneal dialysis has been shown to improve the elimination of methotrexate. Effective clearance of methotrexate is reported to be achieved with acute intermittent haemodialysis using a high-flux dialyser.

Shelf life

Unopened bottle

20 months.

After first opening

3 months.

Jylamvo price

Incompatibilities

Not applicable.

List of excipients

Macrogol 400

Glycerol

Orange flavour

Sucralose

Ethyl parahydroxybenzoate (E214)

Sodium methyl parahydroxybenzoate (E219)

Citric acid monohydrate

Tri-sodium citrate

Purified water

Undesirable effects

Summary of the safety profile

In general, the incidence and severity of side effects are considered to be dose-related.

In the antineoplastic treatment, myelosuppression and mucositis are the predominant dose-limiting toxic effects of methotrexate. The severity of these reactions depends on the dose, mode and duration of application of methotrexate. Mucositis generally appears about 3 to 7 days after methotrexate application, leucopenia and thrombocytopenia follow a few days later. In patients with unimpaired elimination mechanisms, myelosuppression and mucositis are generally reversible within 14 to 28 days.

Most serious adverse reactions of methotrexate include bone marrow suppression, pulmonary toxicity, hepatotoxicity, renal toxicity, neurotoxicity, thromboembolic events, anaphylactic shock and Stevens-Johnson syndrome.

Most frequently (very common) observed adverse reactions of methotrexate include gastrointestinal disorders (e.g. stomatitis, dyspepsia, abdominal pain, nausea, loss of appetite) and abnormal liver function tests (e.g. increased alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), bilirubin, alkaline phosphatase). Other frequently (common) occurring adverse reactions are leukopenia, anaemia, thrombopenia, headache, tiredness, drowsiness, pneumonia, interstitial alveolitis/pneumonitis often associated with eosinophilia, oral ulcers, diarrhoea, exanthema, erythema and pruritus.

The occurrence and severity of adverse reactions depend on dosage level and frequency of administration of methotrexate. However, as severe adverse reactions may occur even at low doses, it is essential for the treating physician to monitor patients closely.

Most adverse reactions are reversible if they are detected early. If such adverse reactions occur, the dose should either be reduced or treatment discontinued and appropriate countermeasures taken. Methotrexate therapy should only be resumed with particular caution, after careful consideration of the need for treatment and with increased vigilance for the possible recurrence of toxicity.

Tabulated list of adverse reactions

Frequencies in the table are defined according to the MedDRA convention:

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)

Not known (cannot be estimated from the available data)

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

1 can be reversible - see 4.4

2 Lymphoma/Lymphoproliferative disorders: there have been reports of individual cases of lymphoma and other lymphoproliferative disorders which subsided in a number of cases once treatment with methotrexate had been discontinued.

3 has been reported for methotrexate used in rheumatologic and related indications

4 see remarks on liver biopsy in section 4.4

Paediatric population

Frequency, type and severity of adverse reactions in children and adolescents are expected to be the same as in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the national reporting system listed below.

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: [email protected]

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

Preclinical safety data

Chronic toxicity

In chronic toxicity studies in mice, rats and dogs, toxic effects were seen in the form of gastrointestinal lesions, myelosuppression and hepatotoxicity.

Mutagenic and carcinogenic potential

Long-term studies in rats, mice and hamsters revealed no evidence of a tumorigenic potential of methotrexate. Methotrexate induces gene and chromosomal mutations in vitro and in vivo. There is a suspected mutagenic effect in humans.

Reproductive toxicology

Teratogenic effects have been observed in four species (rats, mice, rabbits, cats). In rhesus monkeys, no malformations comparable to those seen in humans occurred.

Pharmacotherapeutic group

Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic and immunomodulating agents, antimetabolites, folic acid analogues, ATC code: L01BA01

Mechanism of action

Methotrexate is a folic acid antagonist that, as an antimetabolite, belongs to the class of cytotoxic active substances. It acts by competitive inhibition of the enzyme dihydrofolate reductase and thus inhibits DNA synthesis.

It has not yet been possible to date to clarify whether the efficacy of methotrexate in the management of psoriasis, psoriatic arthritis and chronic polyarthritis is due either to an anti-inflammatory or immunosuppressive effect, or to what extent a methotrexate-induced increase in extracellular adenosine concentration at inflamed sites contributes to this effect.

Highly proliferating tissue such as malignant cells, bone marrow, foetal cells, skin epithelium and mucosa is generally more sensitive to this effect of methotrexate. Cell proliferation is usually greater in malignant tumours than in normal tissue and methotrexate can therefore exert a sustained effect on malignant growth without causing irreversible damage to normal tissue.

In psoriasis, cell proliferation of the epithelium is markedly increased compared with normal skin. This difference in cell proliferation rate is the starting point for the use of methotrexate in particularly severe, generalised, treatment-resistant psoriasis and psoriatic arthritis.

Pharmacokinetic properties

Absorption

After oral administration, methotrexate is absorbed from the gastrointestinal tract. When administered in low doses (7.5 mg/m2 to 80 mg/m2 body surface area), the mean bioavailability of methotrexate is approximately 70%, but considerable inter- and intra-individual variations are possible (25-100%). Peak serum concentrations are attained within 1-2 hours.

Data from a randomised trial in patients with juvenile rheumatoid arthritis (aged 2.8 to 15.1 years) indicated greater oral bioavailability of methotrexate in the fasting state. In children with JIA, the dose normalized area under the plasma concentration versus time-curve (AUC) of methotrexate increased with the age of the children and was lower than that found in adults. The dose normalized AUC of the metabolite 7-hydroxymethotrexate was not dependent on age.

Distribution

Methotrexate is approximately 50% bound to serum proteins. After distribution, it collects predominantly in the liver, kidneys and spleen in the form of polyglutamates, which can be retained for weeks or months.

The mean terminal half-life is 6-7 hours and demonstrates considerable variations (3-17 hours). The half-life may be prolonged up to four-fold in patients with a third distribution compartment (pleural effusion, ascites).

Biotransformation

Approximately 10% of the administered methotrexate dose is metabolised in the liver. The main metabolite is 7-hydroxymethotrexate.

Elimination

Excretion occurs predominantly in the unchanged form by glomerular filtration and active secretion in the proximal tubule via the kidneys.

Approximately 5-20% of methotrexate and 1-5% of 7-hydroxymethotrexate is eliminated in the bile. There is a pronounced enterohepatic circulation.

Elimination in patients with impaired renal function is markedly delayed. Impaired elimination in patients with hepatic impairment is not known at present.

Methotrexate crosses the placental barrier in rats and monkeys.

Date of revision of the text

22 May 2018

Marketing authorisation holder

Therakind Ltd

314 Regents Park Road

London

N3 2JX

United Kingdom

Special precautions for storage

Do not store above 25°C.

Keep the bottle tightly closed.

Nature and contents of container

75 ml amber type III glass bottle with tamper evident child-resistant closure (polypropylene with expanded polyethylene liner) containing 60 ml of oral solution.

Each pack contains one bottle, an LDPE bottle adaptor and a 10 ml white polypropylene dosing syringe (with major graduations at every 1 ml and minor graduations at every 0.25 ml).

Marketing authorisation number(s)

EU/1/17/1172/001

Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in females

Women must not get pregnant during methotrexate therapy, and effective contraception must be used during treatment with methotrexate and at least 6 months thereafter. Prior to initiating therapy, women of childbearing potential must be informed of the risk of malformations associated with methotrexate and any existing pregnancy must be excluded with certainty by taking appropriate measures, e.g. a pregnancy test. During treatment pregnancy tests should be repeated as clinically required (e.g. after any gap of contraception). Female patients of reproductive potential must be counselled regarding pregnancy prevention and planning.

Contraception in males

It is not known if methotrexate is present in semen. Methotrexate has been shown to be genotoxic in animal studies, such that the risk of genotoxic effects on sperm cells cannot completely be excluded. Limited clinical evidence does not indicate an increased risk of malformations or miscarriage following paternal exposure to low-dose methotrexate (less than 30 mg [15 ml]/week). For higher doses, there is insufficient data to estimate the risks of malformations or miscarriage following paternal exposure.

As precautionary measures, sexually active male patients or their female partners are recommended to use reliable contraception during treatment of the male patient and for at least 6 months after cessation of methotrexate. Men should not donate semen during therapy or for 6 months following discontinuation of methotrexate.

Pregnancy

Methotrexate is contraindicated during pregnancy in non-oncological indications. If pregnancy occurs during treatment with methotrexate and up to six months thereafter, medical advice should be given regarding the risk of harmful effects on the child associated with treatment and ultrasonography examinations should be performed to confirm normal foetal development. In animal studies, methotrexate has shown reproductive toxicity, especially during the first trimester. Methotrexate has been shown to be teratogenic to humans; it has been reported to cause foetal death, miscarriages and/or congenital abnormalities (e.g. craniofacial, cardiovascular, central nervous system and extremity-related).

Methotrexate is a powerful human teratogen, with an increased risk of spontaneous abortions, intrauterine growth restriction and congenital malformations in case of exposure during pregnancy.

- Spontaneous abortions have been reported in 42.5% of pregnant women exposed to low-dose methotrexate treatment (less than 30 mg [15 ml]/week), compared to a reported rate of 22.5% in disease-matched patients treated with drugs other than methotrexate.

- Major birth defects occurred in 6.6% of live births in women exposed to low-dose methotrexate treatment (less than 30 mg [15 ml]/week) during pregnancy, compared to approximately 4% of live births in disease-matched patients treated with drugs other than methotrexate.

Insufficient data is available for methotrexate exposure during pregnancy higher than 30 mg (15 ml)/week, but higher rates of spontaneous abortions and congenital malformations are expected, in particular at doses commonly used in oncologic indications

When methotrexate was discontinued prior to conception, normal pregnancies have been reported.

When used in oncological indications, methotrexate should not be administered during pregnancy in particular during the first trimester of pregnancy. In each individual case the benefit of treatment must be weighed up against the possible risk to the foetus. If the drug is used during pregnancy or if the patient becomes pregnant while taking methotrexate the patient should be informed of the potential risk to the foetus.

Breast-feeding

As methotrexate passes into breast milk and may cause toxicity in breast-fed children, treatment is contraindicated during the lactation period. If use during the lactation period should become necessary, breast-feeding is to be stopped prior to treatment.

Fertility

Methotrexate affects spermatogenesis and oogenesis and may decrease fertility. In humans, methotrexate has been reported to cause oligospermia, menstrual dysfunction and amenorrhoea. These effects appear to be reversible after discontinuation of therapy in most cases. In oncologic indications, women who are planning to become pregnant are advised to consult a genetic counselling centre, if possible, prior to therapy and men should seek advice about the possibility of sperm preservation before starting therapy as methotrexate can be genotoxic at higher doses.

Effects on ability to drive and use machines

Methotrexate has moderate influence on the ability to drive and use machines, since central nervous system disorders such as tiredness, dizzy spells or drowsiness can occur during treatment.

Special precautions for disposal and other handling

Safe handling

Anyone handling methotrexate should wash their hands before and after administering a dose. To decrease the risk of exposure, parents and care givers should wear disposable gloves when handling methotrexate.

Contact with the skin or mucous membrane must be avoided. If methotrexate comes into contact with skin or mucosa, it should be washed immediately and thoroughly with soap and water.

Spillages must be wiped immediately.

Women who are pregnant, planning to be or breast-feeding should not handle methotrexate.

Parents, care givers and patients should be advised to keep methotrexate out of the reach of children, preferably in a locked cupboard.

Accidental ingestion can be lethal for children.

Keep the bottle tightly closed to protect the integrity of the product and minimise the risk of accidental spillage.

The usual caution should be exercised in handling cytostatics.

Instructions for use of the syringe provided in the pack

1. Put on disposable gloves before handling.

2. Shake the bottle.

3. Remove the bottle cap and push the adaptor firmly into the top of the bottle.

4. Push the tip of the dosing syringe into the hole in the adaptor.

5. Turn the bottle upside down.

6. Pull the syringe plunger back SLOWLY so that the medicine is drawn from the bottle into the syringe until the WIDEST part of the white syringe plunger is lined up to the black syringe marking of the dose required. DO NOT measure to the narrow tip of the plunger. If there are air bubbles in the syringe, repeat until bubbles are eliminated.

7. Turn the bottle back the right way up and carefully remove the syringe from the adaptor, holding the syringe by the barrel rather than the plunger.

8. Confirm that the dose in the syringe is correct.

9. Ensure that the patient is sitting up or standing before giving the medicine.

10 Gently place the tip of the syringe into the patient's mouth and direct it to the inside of the cheek.

11. Slowly and gently push the plunger down to gently squirt the medicine into the inside of the cheek. DO NOT push down the plunger too hard or squirt the medicine to the back of the mouth or throat as this may cause choking. The plunger should be pushed back gently to the seated position until it clicks into place.

12. Remove the syringe from the patient's mouth.

13. Ask the patient to swallow the medicine and then to drink some water, making sure no medicine is left in the mouth.

14. Put the cap back on the bottle with the adaptor left in place. Ensure that the cap is tightly closed.

15. Wash the syringe immediately after use with fresh warm, soapy water and rinse well. The syringe should be held under water and the plunger drawn in and out several times until all traces of medicine are removed from inside the syringe including the tip. The plunger and barrel should then be separated and both washed thoroughly in the warm soapy water. They should then be rinsed thoroughly under COLD water and excess water shaken off before wiping dry with a clean paper towel. The plunger and barrel should be stored in a clean dry container with the medicine and reassembled before next use. All parts of the syringe should be completely dry before using it for the next dose.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements for cytotoxic products.

Date of first authorisation/renewal of the authorisation

Date of first authorisation: 29 March 2017

Interaction with other medicinal products and other forms of interaction

The risk of an interaction between NSAIDs and methotrexate should be considered in patients with a low methotrexate dose, particularly in the case of impaired kidney function. If combined treatment is required, the blood count and renal function should be monitored. Caution should be exercised if NSAIDs and methotrexate are administered within 24 hours, since in this case methotrexate plasma levels can rise and toxicity be increased as a result. Animal studies showed that the administration of NSAIDs including salicylic acid resulted in reduced tubular methotrexate secretion and accordingly potentiated its toxic effects. However, in clinical trials in which NSAIDs and salicylic acid were administered adjuvantly to patients with rheumatoid arthritis, no increase in adverse reactions was observed. Treatment of rheumatoid arthritis with such medicinal products can be continued during therapy with low-dose methotrexate, but only under close medical supervision.

Patients taking potentially hepatotoxic medicinal products during treatment with methotrexate (e.g. leflunomide, azathioprine, sulfasalazine and retinoids) should be monitored closely for increased hepatotoxicity. The consumption of alcohol should be avoided during treatment with methotrexate. Regular alcohol consumption and administration of additional hepatotoxic medicinal products increase the likelihood of hepatotoxic adverse reactions to methotrexate.

Administration of additional haematotoxic medicinal products (e.g. metamizole) increases the likelihood of severe haematotoxic adverse reactions to methotrexate.

Pharmacokinetic interactions between methotrexate, anticonvulsants (reduced serum methotrexate levels) and 5-fluoruracil (increased half-life of 5-fluoruracil) must be borne in mind.

Salicylates, phenylbutazone, diphenylhydantoin (= phenytoin), barbiturates, tranquillisers, oral contraceptives, tetracyclines, amidopyrine derivatives, sulphonamides, thiazide diuretics, oral hypoglycaemics, doxorubicin and p-aminobenzoic acid displace methotrexate from serum albumin binding and thus increase bioavailability and hence toxicity (indirect dose increase).

Probenecid and weak organic acids can also reduce the tubular secretion of methotrexate and thus likewise cause an indirect increase in dose.

Antibiotics such as penicillins, glycopeptides, sulphonamides, ciprofloxacin and cefalotin can in individual cases reduce the renal clearance of methotrexate, so that increased serum methotrexate concentrations can occur, accompanied by haematological and gastrointestinal toxicity.

Oral antibiotics such as tetracyclines, chloramphenicol and non-absorbable broad-spectrum antibiotics may reduce intestinal absorption of methotrexate or interfere with the enterohepatic circulation by inhibiting intestinal flora or suppressing bacterial metabolism.

In the event of (prior) treatment with medicinal products that can have adverse reactions on bone marrow (e.g. sulphonamides, trimethoprim/sulphamethoxazole, chloramphenicol, pyrimethamine), the possibility of haematopoietic disorders must be considered.

Concomitant therapy with medicinal products that can cause folic acid deficiency (e.g. sulphonamides, trimethoprim/sulphamethoxazole) can result in increased methotrexate toxicity. Accordingly, particular caution should be exercised in patients with pre-existing folic acid deficiency.

Conversely, co-administration of medicinal products containing folinic acid or vitamin preparations containing folic acid or derivatives may impair the efficacy of methotrexate.

The combination of methotrexate and sulfasalazine can enhance the effect of methotrexate, as sulfasalazine causes inhibition of folic acid synthesis. This can result in an increased risk of adverse reactions, although in several studies this was only observed in individual patients.

Ciclosporin may potentiate methotrexate efficacy and toxicity. There is a risk of excessive immunosuppression with risk of lymphoproliferation when the combination is used.

The use of nitrous oxide potentiates the effect of methotrexate on folate metabolism, yielding increased toxicity such as severe, unpredictable myelosuppression, stomatitis and neurotoxicity with intrathecal administration. Whilst this effect can be reduced by administering calcium folinate, the concomitant use should be avoided.

Co-administration of proton pump inhibitors such as omeprazole or pantoprazole can result in interactions: co-administration of methotrexate and omeprazole has resulted in delayed renal elimination of methotrexate. In one case in which methotrexate was combined with pantoprazole, renal elimination of the metabolite 7-hydroxymethotrexate was inhibited and myalgia and shivering occurred.

The application of procarbazine during high-dose methotrexate therapy increases the risk of impairment or renal function

Excessive consumption of caffeine- or theophylline-containing beverages (coffee, caffeinated beverages, black tea) should be avoided during methotrexate therapy as the effect of methotrexate may be reduced by the possible interaction between methotrexate and methylxanthines at the adenosine receptors.

Combination therapy with methotrexate and leflunomide may increase the risk for pancytopenia.

Particularly in the case of orthopaedic surgery where the risk of infection is high, combination therapy with methotrexate and immunomodulatory medicinal products must be used with caution.

Cholestyramine can increase the non-renal elimination of methotrexate by interfering with the enterohepatic circulation.

The possibility of delayed methotrexate clearance should be considered in combination with other cytostatic medicinal products.

Radiotherapy during the use of methotrexate can increase the risk for soft tissue or bone necrosis.

Methotrexate can reduce the clearance of theophylline. During concomitant therapy with methotrexate, therefore, serum theophylline levels should be monitored.

Combined administration of mercaptopurine and methotrexate can increase the bioavailability of mercaptopurine, possibly as a result of inhibition of the metabolism of mercaptopurine.

In view of its possible effects on the immune system, methotrexate can falsify vaccinal and test results (immunological procedures to assess the immune reaction). During methotrexate therapy, concurrent vaccination with live vaccines should be avoided.