Pfizer (Australia) Methotrexate Injection

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

WARNING: Important safety information is provided in a boxed warning in the full CMI. Read before using this medicine.

Pfizer Methotrexate Injection contains the active ingredient methotrexate. Pfizer Methotrexate Injection is used to treat certain types of cancers and severe psoriasis when the condition does not improve with other medicines.
For more information, see Section 1. Why am I using Pfizer Methotrexate Injection? in the full CMI.

Do not use if you have ever had an allergic reaction to Pfizer Methotrexate Injection 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 I use Pfizer Methotrexate Injection? in the full CMI.

Some medicines may interfere with Pfizer Methotrexate Injection 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.

• The dose of medicine given to you will depend on the condition being treated, your medical condition, your age, your size and how well your kidneys and liver are working. More instructions can be found in Section 4. How do I use Pfizer Methotrexate Injection? in the full CMI.

For more information, see Section 5. What should I know while using Pfizer Methotrexate Injection? in the full CMI.

Side effects include nausea, stomach pain, sore mouth (mouth ulcers, blisters), fatigue, generally feeling unwell, dizziness, drowsiness, blurred vision, sore eyes, ringing in ears and low numbers of blood cell counts. Pfizer Methotrexate Injection can cause serious side effects including severe allergic reaction; sore throat, fever, chills, achiness; severe skin rash with blistering; injection site reactions, persistent cough, pain or difficulty breathing, or becoming breathless; spitting or coughing blood; skin rash and fever with swollen glands; swelling of the hands, ankles or feet; yellowing of the skin and eyes; loss of coordination, ability to speak or understand speech, weakness and inability to move one side of the body or the whole body, convulsions or fits.
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.

Boxed Warnings

Methotrexate must be used only by physicians experienced in antimetabolite chemotherapy, or in the case of non-oncological conditions, by a specialist physician.
Patients should be fully informed of the risk of fatal or severe toxic reactions involved with the administration of methotrexate and should be under constant supervision of the physician.
Deaths have been reported with the use of methotrexate.
In the treatment of psoriasis, methotrexate should be restricted to severe, recalcitrant, disabling disease which is not adequately responsive to other forms of therapy, but only when the diagnosis has been established by biopsy and/or after appropriate consultation.
1. Methotrexate may produce marked depression of bone marrow, anaemia, aplastic anaemia, leucopenia, neutropenia, thrombocytopenia and bleeding.
2. Methotrexate may be hepatotoxic, particularly at high dosage or with prolonged therapy. Liver atrophy, necrosis, cirrhosis, fatty changes and periportal fibrosis have been reported. Since changes may occur without previous signs of gastrointestinal or haematological toxicity, it is imperative that hepatic function be determined prior to initiation of treatment and monitored regularly throughout therapy. Special caution is indicated in the presence of pre-existing liver damage or impaired hepatic function. Concomitant use of other drugs with hepatotoxic potential (including alcohol) should be avoided.
3. Malignant lymphomas, which may regress following withdrawal of methotrexate, may occur in patients receiving low dose methotrexate and, thus, may not require cytotoxic treatment. Discontinue methotrexate first and, if the lymphoma does not regress, appropriate treatment should be instituted.
4. Potentially fatal opportunistic infections, especially Pneumocystis jirovecii pneumonia, may occur with methotrexate therapy.
5. Vaccination with a live vaccine in patients receiving chemotherapeutic agents may result in severe and fatal infections.
6. Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.
7. Use in pregnancy: pregnancy category D. Methotrexate has caused fetal death and/or congenital abnormalities. Therefore, it is not recommended in women of childbearing potential unless there is appropriate medical evidence that the benefits can be expected to outweigh the considered risks. Pregnant psoriatic patients should not receive methotrexate. Women of childbearing potential should not be started on methotrexate until pregnancy is excluded and should be fully counselled on the serious risk to the fetus should they become pregnant while undergoing treatment.
Pregnancy should be avoided if either partner is receiving methotrexate, during and after cessation of therapy. Reliable contraception is recommended during and for at least three months after end of the treatment for males. For females, reliable contraception is recommended during and for at least six months after end of the treatment. The optimal time interval between the cessation of methotrexate treatment of either partner, and pregnancy, has not been clearly established.
8. Impaired renal function is usually a contraindication.
9. Diarrhoea and ulcerative stomatitis are frequent toxic effects and require interruption of therapy; otherwise, haemorrhage enteritis and death from intestinal perforation may occur.
10. Unexpectedly severe (sometimes fatal) marrow suppression, aplastic anaemia and gastrointestinal toxicity have been reported with concomitant administration of methotrexate (usually in high doses) along with nonsteroidal anti-inflammatory agents (NSAIDs).
11. Methotrexate induced lung disease including acute or chronic interstitial pneumonitis and pleural effusion is a potentially dangerous lesion, which may occur acutely at any time during therapy and which has been reported at low doses. It is not always fully reversible and fatalities have been reported. Pulmonary symptoms (especially a dry, nonproductive cough) may require interruption of treatment and careful investigation. Pulmonary lesions can occur at all dosages. Infections (including pneumonia) needs to be excluded. Patients should be closely monitored for pulmonary symptoms.
12. Methotrexate has been used in very high dosage followed by folinic acid (calcium folinate) rescue in the experimental treatment of certain neoplastic diseases. This procedure is investigational and hazardous. It should not be attempted outside of facilities where the necessary expertise and resources have been assembled. The recent published literature should be consulted.
13. Use only isotonic and preservative-free methotrexate for intrathecal administration. For more information, see Section 2 Qualitative and Quantitative Composition; Section 3 Pharmaceutical Form; Section 4.2 Dose and Method of Administration, Method of administration for more information.
14. Both the physician and the pharmacist should emphasise to the patient the importance of the weekly dosing regimen: mistaken daily use may cause serious and sometimes life-threatening or fatal toxicity.
15. Use in lactation. Women should be advised not to breastfeed while being treated with methotrexate.
16. Use in children. Aside from its established use in cancer chemotherapy; the safety and efficacy of using methotrexate in children has not been fully elucidated.
Because of its potential to cause severe toxicity, methotrexate therapy requires close supervision with particular caution to distinguish between daily and weekly dosage regimens. Weekly dosage prescriptions should specify a particular day of the week.
Methotrexate Injection (BP) products suitable for IV, IM or intrathecal use. Pfizer (Australia) Methotrexate 50 mg/2 mL injection BP, Pfizer (Australia) Methotrexate 500 mg/20 mL injection BP vial.
Methotrexate Injection (BP) Injection products suitable for IV use only. Not for intrathecal use as the solution is hypertonic: Pfizer (Australia) Methotrexate 1000 mg/10 mL injection BP vial (hypertonic).

1 Name of Medicine

Methotrexate.

2 Qualitative and Quantitative Composition

Each vial of Methotrexate Injection BP contains methotrexate 50 mg/2 mL, 500 mg/20 mL and 1000 mg/10 mL.
Sodium chloride is added to the 50 mg in 2 mL and 500 mg in 20 mL presentations to render them isotonic. Methotrexate Injection BP 1000 mg in 10 mL is hypertonic.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Solution for injection.
Methotrexate Injection BP is a sterile, preservative-free yellow to orange solution.

4 Clinical Particulars

4.9 Overdose

Signs and symptoms. In postmarketing experience, overdose with methotrexate has generally occurred with oral and intrathecal administration, although intravenous and intramuscular overdose has also been reported.
Discontinue methotrexate at the first sign of ulceration or bleeding, diarrhoea or marked depression of the haematopoietic system.
Symptoms commonly reported following oral overdose include those symptoms and signs reported at pharmacological doses, particularly haematological and gastrointestinal reactions. These signs and symptoms include leucopenia, thrombocytopenia, anaemia, pancytopenia, bone marrow suppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, gastrointestinal bleeding, anorexia, progressive weight loss and bloody diarrhoea. In some cases of overdose, no symptoms were reported. There have been reports of death following overdose. In these cases, events such as sepsis or septic shock, renal failure and aplastic anaemia were also reported.
Symptoms of intrathecal overdose are generally central nervous system (CNS) symptoms, including headache, nausea and vomiting, seizure or convulsion, and acute toxic encephalopathy. In some cases, no symptoms were reported. There have also been cases of fatal intrathecal overdose, in which cerebellar herniation associated with increased intracranial pressure and acute toxic encephalopathy were reported.
Treatment. Folinic acid (calcium folinate) neutralises effectively the immediate toxic effects of methotrexate. After an inadvertent overdosage of methotrexate, calcium folinate should be given as soon as possible and preferably started within 1 hour after the administration of methotrexate. As the time interval between methotrexate administration and folinic acid initiation increases, the effectiveness of folinic acid in counteracting toxicity decreases. Monitoring of the serum methotrexate concentration is essential in determining the optimal dose and duration of treatment with folinic acid.
Calcium folinate should be given at 10 mg/m² IV or IM every 6 hours until the serum methotrexate levels are below 10^-8 M. In the presence of gastric stasis or obstruction calcium folinate should be administered parenterally. Concomitant hydration (3 L/day) and urinary alkalinisation with sodium bicarbonate should be employed. The bicarbonate dose should be adjusted to maintain a urinary pH at 7 or greater. Serum samples should be assayed for creatinine levels and methotrexate levels at 24 hour intervals. If the 24 hour serum creatinine level has increased 50% over baseline or if the 24 hour methotrexate level is > 5 x 10^-6 M or the 48 hour methotrexate level is 9 x 10^-7 M or higher, the doses of calcium folinate should be increased to 100 mg/m² IV every 3 hours until the methotrexate level is < 10^-8 M. The infusion rate of calcium folinate should not exceed 16.0 mL (160 mg calcium folinate) per minute. Patients with significant third space accumulations should be considered high risk and closely monitored until serum methotrexate levels are < 10^-8 M regardless of their 24 hour serum concentration.
The above-mentioned statements on calcium folinate dosage do not apply with high dosage methotrexate therapy. The dosages of calcium folinate have varied in different studies and the published literature on high dosage methotrexate should be consulted.
In cases of massive overdose, hydration and urinary alkalinisation may be necessary to prevent the precipitation of methotrexate and/or its metabolites in the renal tubules. Neither standard haemodialysis nor peritoneal dialysis have been shown to significantly improve methotrexate elimination. Some clearance of methotrexate may be obtained by haemodialysis if the patient is totally anuric and no other therapeutic options are available. Effective clearance of methotrexate has been reported with acute, intermittent haemodialysis using a high flux dialysator.
Accidental intrathecal overdosage may require intensive systemic support, high dose systemic (intravenous) folinic acid, alkaline diuresis, and rapid CSF drainage and ventriculolumbar perfusion.
There are published case reports of intravenous and intrathecal carboxypeptidase G2 treatment to hasten clearance of methotrexate in cases of overdose.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.3 Preclinical Safety Data

Genotoxicity. Methotrexate is mutagenic in vivo and in vitro. There is evidence that methotrexate causes chromosomal damage to animal somatic cells and human bone marrow cells. In vitro, methotrexate caused chromosomal aberrations in Chinese hamster A(T1) C1-3 cells, induced morphological transformation in mouse C3H/10T_½ clone 8 cells and was associated with an increased incidence of large colony mutants at the tk locus in L5178Y/tk^± mouse lymphoma cells. In vivo, it caused an increased incidence of polychromatic erythrocytes in mice and a transient and reversible increase in chromosomal aberrations in human bone marrow cells. The clinical significance of these findings is uncertain.
Carcinogenicity. No controlled human data exist regarding the risk of neoplasia with methotrexate.
Methotrexate has been evaluated in a number of animal studies for carcinogenic potential with inconclusive results.
Cytotoxic drugs have been reported to be associated with an increased risk of development of secondary tumours in humans. Reports of lymphoma, including reversible lymphomas and tumour lysis syndrome have been documented in patients treated with methotrexate.
Malignant lymphomas may occur in patients receiving low dose methotrexate, in which case therapy must be discontinued. Failure of the lymphoma to show signs of spontaneous regression requires initiation of cytotoxic therapy.
Benefit should be weighed against this potential risk before using methotrexate alone or in combination with other drugs, especially in children or young adults.

6 Pharmaceutical Particulars

6.7 Physicochemical Properties

Methotrexate is a yellow or orange, crystalline powder, practically insoluble in water, alcohol, ether and ethylene chloride. It dissolves in dilute solutions of mineral acids and dilute solutions of alkali hydroxides and carbonates.
Chemical structure.
https://stagingapi.mims.com/au/public/v2/images/fullchemgif/CSMETREX.gif Chemical name: (S)-2-[4-[[(2,4-diaminopteridin- 6-yl) methyl]methylamino]benzoylamino] pentanedioic acid.
Molecular formula: C₂₀H₂₂N₈O₅.
Molecular weight: 454.4.
CAS number. 59-05-2.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes

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