Download 1. TRADE NAME OF THE MEDICINAL PRODUCT ABITREXATE 25

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1.
TRADE NAME OF THE MEDICINAL PRODUCT
ABITREXATE 25 mg/ml Solution for Injection
ABITREXATE 1g/10 ml (100 mg/ml) Solution for Injection
2.
QUALITATIVE AND QUANTITATIVE COMPOSITION
Composition
Abitrexate Injection 25 mg/ml Solution for Injection
Each 1 ml contains:
Active Ingredient
Methotrexate 25 mg
Other Ingredients
Sodium chloride, sodium hydroxide (for pH adjustment) hydrochloric acid (for pH adjustment), water for
injections.
Sodium content:
Each ml contains 1.93 mg sodium.
Abitrexate Injection 1g/10 ml (100 mg/ml) Solution for Injection
Each 1 ml contains:
Active Ingredient
Methotrexate 100 mg
Other Ingredients
Sodium hydroxide, hydrochloric acid (for pH adjustment), sodium hydroxide 1N (for pH adjustment),
water for injections.
Sodium content:
Each ml contains 10.11 mg sodium.
3.
PHARMACEUTICAL FORM
Solution for injection
4.
CLINICAL PARTICULARS
4.1 Therapeutic indications
Antineoplastic Chemotherapy
Treatment of gestational choriocarcinoma, chorioadenoma destruens and hydatidiform mole.
Palliation of acute lymphocytic leukemia. Abitrexate is also indicated in the treatment and
prophylaxis of meningeal leukemia.
Greatest effect has been observed in palliation of acute lymphoblastic (stem-cell) leukemias in
children. In combination with other anticancer agents, Abitrexate may be used for the induction of
remission, but is most commonly used in the maintenance of induced remissions.
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Abitrexate may be used alone, or in combination with other antineoplastic drugs, in the
management of breast cancer, epidermoid cancers of the head and neck, lung cancer (particularly
squamous cell and small cell types), bladder cancer and osteogenic cancer.
Abitrexate is effective in the treatment of the advanced stages (III and IV, Peter's Staging system)
of lymphosarcoma, particularly in children, and in advanced cases of mycosis fungoides.
Psoriasis
Because of the high risk attending its use, Abitrexate is indicated only in the symptomatic control
of severe recalcitrant, disabling psoriasis which is not adequately responsive to other forms of
therapy, and only when the diagnosis has been established, as by biopsy and/or after
dermatological consultation.
Rheumatoid Arthritis
Abitrexate can be used in the treatment of selected adults with severe rheumatoid arthritis, only
when the diagnosis has been well established according to rheumatological standards, with
inadequate response to other forms of antirheumatic therapy, including full dose NSAIDs and
usually a trial of at least one or more disease-modifying antirheumatic drugs.
4.2 Posology and method of administration
WARNINGS
The dose must be adjusted carefully depending on the body surface area if methotrexate is used
for the treatment of tumour diseases.
Fatal cases of intoxication have been reported after administration of incorrect calculated
doses. Health care professionals and patients should be fully informed about toxic effects.
Treatment should be initiated by or occur in consultation with a doctor with significant experience
in cytostatic treatment.
Abitrexate may be administered by intramuscular, intravenous (bolus injection or infusion),
intrathecal, intraventricular or intra-arterial.
For intrathecal administration, Abitrexate is administered as a 1 mg/ml solution, using an
appropriate sterile preservative-free medium such as Sodium Chloride Injection.
Dosages are based on the patient's bodyweight or surface area, except in the case of intrathecal or
intraventricular administration, when a maximum dose of 15 mg is recommended.
Dosage should be reduced in cases of hematological deficiency and hepatic or renal impairment.
When administered by infusion, Abitrexate should only be diluted with normal saline. Larger
doses (more than 100 mg) are usually administered by intravenous infusion over periods not
exceeding 24 hours. Part of the dose may be administered as an initial rapid intravenous injection.
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Abitrexate has been used with beneficial effects in a wide variety of neoplastic diseases, alone and
in combination with other cytotoxic agents, hormones, immunotherapy, radiotherapy or surgery.
Therefore, dosage schedules vary considerably depending on the clinical use, particularly when
intermittent high-dose regimens are followed by the administration of calcium leucovorin in order
to rescue normal cells from toxic effects. Dosage regimens for calcium leucovorin rescue are
discussed at the end of this section.
The following are some examples of the dosages of Abitrexate that have been used for particular
indications:
Choriocarcinoma and Other Trophoblastic Tumors
By the intramuscular route, in doses of 15-30 mg daily for a 5-day course. Such courses are
usually repeated 3-5 times as required, with rest periods of 1 or more weeks between courses, until
any toxic symptoms subside.
The effectiveness of therapy is ordinarily evaluated by 24-hour quantitative analysis of urinary
human chorionic gonadotrophin (HCG), which should return to normal or less than
50 IU/24 hours, usually after the 3rd or 4th course of treatment, and also usually followed by a
complete resolution of measurable lesions in 4-6 weeks. After the normalization of HCG, 1 or 2
courses of Abitrexate are usually recommended. Before each course of the drug, careful clinical
assessment is essential.
Higher doses of up to 60 mg i.m. every 48 hours may be administered for 4 doses, followed by
calcium leucovorin rescue. This course is repeated at 7-day intervals until levels of urinary HCG
return to normal. Not less than 4 courses of treatment are usually necessary. Patients with
complications, such as extensive metastases, may be treated with Abitrexate in cyclic combination
with other cytotoxic drugs.
Chorioadenoma Destruens and Hydatidiform Mole
Since hydatidiform mole may be followed by choriocarcinoma, prophylactic chemotherapy with
Abitrexate has been recommended.
Chorioadenoma destruens is considered to be an invasive form of hydatidiform mole. Abitrexate
is administered in these disease states in doses similar to those recommended for choriocarcinoma.
Lymphoblastic Leukemia
Daily administration of Abitrexate 3.3 mg/m2, in combination with prednisone 60 mg/m2, is
used as induction therapy in acute lymphatic (lymphoblastic) leukemia in children and young
adolescents.
Abitrexate alone, or in combination with other agents, appears to be a drug of choice for securing
maintenance of drug-induced remissions.
When remission is achieved and supportive care has produced general clinical improvement,
maintenance therapy is initiated with intramuscular methotrexate 30 mg/m2, twice weekly. It has
also been administered intravenously in doses of 2.5 mg/kg body weight, every 14 days. If relapse
does occur, reinduction of remission can again usually be obtained by repeating the initial
induction regimen.
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Meningeal Leukemia
Administer 12 mg/m2 intrathecally, or an empirical dose of 15 mg. Dilute methotrexate to a
concentration of 1 mg/ml using a sterile, preservative-free medium such as 0.9% Sodium Chloride
Injection. Administer at intervals of 2-5 days, and repeat until the CSF cell count returns to
normal. Then administer one additional dose.
Administration at intervals of less than 1 week may result in increased subacute toxicity. For
prophylaxis against meningeal leukemia, the dosage is the same as for treatment, except for the
intervals of administration.
The CSF volume is dependent on age, and not on body surface area (BSA). The CSF is at 40% of
the adult volume at birth and reaches the adult volume in several years.
Intrathecal methotrexate 12 mg/m2 (maximum 15 mg) has resulted in low CSF methotrexate
concentrations and reduced efficacy in children, and high concentrations and neurotoxicity in
adults. The following dosage regimen is based on age instead of BSA, and appears to result in
more consistent CSF methotrexate concentrations and less neurotoxicity.
Intrathecal Methotrexate Dosage According to Age.
Age (years)
Dose (mg)
Under 1
6
1
8
2
10
Over 3*
12
*equal or higher than 3 years of age.
Because the CSF volume and turnover may decrease with age, a dose reduction may be indicated
in elderly patients.
Lymphomas
In stage III, give methotrexate concomitantly with other antitumor agents.
Treatment in all stages generally consists of several courses with 7-10 day rest periods between
each course. Lymphosarcomas in stage III may respond to combined drug therapy with
methotrexate 0.625-2.5 mg/kg body weight/day.
Mycosis Fungoides
Although the usual treatment is by orally-administered methotrexate, methotrexate has also been
given intramuscularly in doses of 50 mg once a week, or 25 mg twice weekly.
Breast Cancer
Abitrexate in intravenous doses of 10-60 mg/m2 is commonly included in cyclical combination
regimens with other cytotoxic drugs in the treatment of advanced breast cancer.
Similar regimens have also been used as adjuvant therapy in early cases following mastectomy
and/or radiotherapy.
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Osteosarcoma
Effective therapy requires several cytotoxic chemotherapeutic agents. In addition to high-dose
methotrexate with leucovorin rescue, these agents may include doxorubicin, cisplatin and the
combination of bleomycin, cyclophosphamide and dactinomycin (BCD) in the doses and schedule
shown in the Table below.
The starting dose for high-dose methotrexate treatment is 12g/m2. If this is insufficient to
produce a peak serum concentration of 1,000 micromole per L (0.001 mol/l) at the end of
the methotrexate infusion, the dose may be increased to 15g/m2 in subsequent treatments. If the
patient is vomiting or unable to tolerate leucovorin orally, administer leucovorin I.V. or I.M. at the
same dose and schedule.
Chemotherapy Regimens for Osteosarcoma
DRUG*
DOSE*
TREATMENT WEEK
AFTER SURGERY
2
12 g/m IV as 4-hour 4,5,6,7,11,12,15,
16,29,30,44,45
infusion (starting dose)
Methotrexate
Leucovorin
Doxorubicin as
drug**
Doxorubicin**
Cisplatin**
a
Bleomycin**
Cyclophosphamide**
Dactinomycin**
15 mg orally every 6 hours
for 10 doses, starting 24
hours
after
start
of
methotrexate infusion
single 30mg/m2/day IV x 3 days 8,17
50 mg/m2IV
100 mg/m2 IV
20,23,33,36
20,23,33,36
15 units/m2 IV x 2 days
600 mg/m2 IV x 2 days
0.6 mg/m2 IV x 2 days
2,13,26,39,42
2,13,26,39,42
2,13,26,39,42
* Link MP, Goorin AM, Miseer AW et al. The effect of adjuvant chemotherapy on relapse-free
survival in patients with osteosarcoma of the extremity, N. Engl. J. Med. 1986;3 14(25):1600-6.
** See each respective monograph for more complete information.
Dosage modifications may be necessary because of drug-induced toxicity.
Bronchogenic Carcinoma
Intravenous infusions of 20-100 mg/m2 of Abitrexate have been included in cyclical combination
regimens for the treatment of advanced tumors. Higher doses of Abitrexate with calcium
leucovorin rescue may also be employed as sole treatment.
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Head and Neck Cancer
Intravenous infusions of 240-1,080 mg/m2 of Abitrexate with calcium leucovorin rescue may be
used both as preoperative adjuvant therapy and in the treatment of advanced tumors.
Intra-arterial infusions of Abitrexate are indicated for certain head and neck cancers, although this
route of administration is not used extensively.
Bladder Carcinoma
Intravenous injections or infusions of Abitrexate in doses up to 100 mg every 1-2 weeks may be
used in the treatment of bladder carcinoma. Diuretics and hydration are employed in an attempt to
reduce the excessive drug toxicity that may occur in patients with renal impairment.
Psoriasis
Patients should be fully informed of the potential risks involved, and should be under the constant
supervision of the treating physician.
The usual dose in cases of severe, uncontrolled psoriasis unresponsive to conventional therapy is
10-25 mg, administered intramuscularly or intravenously once a week and adjusted according to
the patient's response.
Rheumatoid Arthritis
Note: The following recommendation is based on clinical studies whose tabulated dosages,
as well as the references appear at the end of the paragraph.
Initially, 10 mg/week may be administered either intramuscularly or intravenously. The dosage
may be increased to 25 mg/week.
Duration of treatment varied in clinical studies from 6 weeks to 13 weeks. An intramuscular
dosage of 15 mg/week has been administered over a period of 6 months. An initial dosage of 10
mg/week IV, increased to a maximum of 50 mg/week IV has been administered over a period of 2
months.
Tabulated Summary of Dosages for the Use of Methotrexate (Parenteral) in Rheumatoid
Arthritis
STUDY
Herman (1)
Ahern (2)
Steinson (4)
DOSE
10 mg/m2, IV
15 mg , oral
15 mg, IV
30 mg/m2, oral
30 mg/m2, IV
30 mg/m2,, IM
7.5 mg-25 mg per week; IM/oral
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Campbell (3)
7
STUDY
Michaels (5)
Andersen (6)
Thompson (7)
Hoffmeister (8)
Weinstein (9)
Szanto (10)
Tishler (11)
Suarez-Almazor (12)
Rau (13)
DOSE
10 mg-50 mg per week, IV
10 mg per week, IM, increased up to 25 mg if required.
10 mg or 25 mg per week, IM
10 mg-15 mg per week, oral and IM
7.5 mg-25 mg per week, oral and IM
5 mg-15 mg per week oral/IM
12.5 mg (7.5 mg-15 mg) per week, oral/IM
10 mg per week IM
15 mg per week IM
References
1. Herman, R.A., Veng-Pedersen, P., Hoffman, J., Koehnke, R., and Furst, D.E.: Pharmacokinetics of Low-Dose
Methotrexate in Rheumatoid Arthritis Patients. J. Pharm. Sci. 78: 165-171, 1989. 2. Ahern, M., Booth, J., Loxton, A.,
McCarthy, P.M., Meffin, P., Kevant, S.: Methotrexate Kinetics in Rheumatoid Arthritis: Is there an Interaction with
Nonsteroidal Anti-Inflammatory Drugs. J. Rheumatol. 15: 1356-1360, 1988. 3. Campbell, M.A., Perrier, D.G., Dorr,
R. T., et. al.: Methotrexate Bioavailability .Cancer Treat. Rev. 69: 833-838, 1985. 4. Steinson, K., Weinstein, A.,
Korn, J., Abeles, M.: Low-Dose Methotrexate in Rheumatoid Arthritis. J. Rheumatol. 9: 860-866, 1982. 5. Michaels,
R. M., Nashel, D.J., Leonard, A., Sliwinski, A.J., Derbes, A. J.: Weekly Intravenous Methotrexate in the Treatment of
Rheumatoid Arthritis. Arthritis Rheum. 25: 339-341, 1982. 6. Andersen, P.A., West S.G., O'Dell, J. R., Via
C.S.,Claypool, R. G., Kotzin B. L. Weekly Pulse Methotrexate in Rheumatoid Arthritis. Clinical and Immunologic
Effects in a Randomized, Double-Blind Study. Ann. Intern. Med., 103: 489-496, 1985. 7. Thompson, R. N., Watts, C.,
Edelman, J., Russell, A. S.,: A Controlled Two-Center Trial of Parenteral Methotrexate Therapy for Refractory
Rheumatoid Arthritis. J. Rheumatol. 11: 760-763, 1984. 8. Hoffmeister, R. T., :Methotrexate in Rheumatoid Arthritis:
15 Years Experience. Am. J. Med. 75: 69-73, 1983. 9. Weinstein, A., Marlowe, S., Korn, J., Farouhan, F. Low-Dose
Methotrexate Treatment of Rheumatoid Arthritis. Long-Term Observations. Am. J. Med. 79: 331-337, 1985. 10.
Szanto, E., Low-Dose Methotrexate in Rheumatoid Arthritis: Effect and Tolerance. An Open Trial and a DoubleBlind Randomized Study. Scand. J. Rheumatol. 15: 97-102, 1986. 11. Tishler, M., Caspi, D., Rosenbach, T. O.,
Fishel, B., Wigler, I., Segal, R., Gazit, E., Yaron, M.: Methotrexate in Rheumatoid Arthritis; A Prospective Study in
Israeli Patients with immunogenetic Correlations. Ann. Rheum. Dis. 47: 654-659, 1988. 12. Suarz-Almazor M. E.,
Fitzgerald, A., Grace, M., Russell, A. S.: a Randomized Controlled Trial of Parenteral Methotrexate Compared with
Sodium Aurothiomalate (Myochrysine) in the Treatment of Rheumatoid Arthritis. J. Rheumatol. 15: 753-756, 1988.
13. Rau, R., Herborn, G., Kargen, T., Menninger, H., Elhardt, D.A Blinded Randomized Trial of Methotrexate and
Gold Sodium Aurothiomalate in Early Erosive Rheumatoid Arthritis. Arthritis Rheum. 32: S43, 1981 (Abstract).
Particular attention should be given to the appearance of liver toxicity by performing liver
function tests before initiating Abitrexate treatment, and repeating the tests at 2-4 month intervals
during therapy. Therapy should not be instituted, or should be discontinued, if any abnormality of
liver function tests or of a liver biopsy is present or develops during therapy. Such abnormalities
should return to normal within 2 weeks, after which, treatment may be recommended at the
discretion of the physician.
The use of Abitrexate may permit the return to conventional topical therapy which should be
encouraged.
Calcium Leucovorin Rescue
When administering high doses of methotrexate, the following guidelines for methotrexate
therapy with leucovorin rescue should be closely observed:
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 Methotrexate administration should be delayed until recovery if:
-the WBC count is less than 1500mm3
-the neutrophil count is less than 500mm3
-the platelet count is less than 75,000mm3
-the serum bilirubin level is more than 1.2 mg/dl
-the ALT level is more than 450 U
-mucositis is present, until there is evidence of healing
-persistent pleural effusion and ascite are present; drain dry prior to infusion
 Adequate renal function must be documented
 Serum creatinine must be normal and creatinine clearance must be more than 60 ml/min. before
the initiating of therapy.
 Serum creatinine must be measured prior to each subsequent course of therapy. If serum
creatinine has increased by 50% or more in comparison to a prior value, the creatinine clearance
must be measured and documented to be more than 60 ml/min. (even if the serum creatinine is
still within the normal range).
 Patients must be well hydrated, and must be treated with sodium bicarbonate for urinary
alkalinization. Administer 1,000 ml/m2 of intravenous fluid over 6 hours prior to initiating of the
methotrexate infusion. Continue hydration at 125 ml/m2/hour (3L/m2/day) during methotrexate
infusion, and for 2 days after the infusion has been completed.
 Alkalinize urine to maintain a pH above 7.0 during methotrexate infusion and leucovorin
calcium therapy by giving sodium bicarbonate orally or by incorporation into a separate i.v.
solution.
 Repeat serum creatinine and serum methotrexate 24 hours after starting methotrexate, and at
least once daily until the methotrexate level is below 5x10-8 mol/l (0.05 micromolar).
Leucovorin Rescue Schedules Following Treatment
with Higher Doses of Methotrexate
CLINICAL SITUATION
LABORATORY FINDINGS
Normal Methotrexate
Elimination
Serum methotrexate level approximately 10
micromolar at 24 hours after administration, 1
micromolar at 48 hours and less than 0.2
micromolar at 72 hours
Serum methotrexate level remaining above 0.2
micromolar at 72 hours and more than 0.05
micromolar at 96 hours after administration.
Delayed Late
Methotrexate Elimination
Delayed Early
Methotrexate Elimination
and/or Evidence of Acute
Renal Injury.
ABITREXATE Injection
Serum methotrexate level of equal or higher than
50 micromolar at 24 hours or equal or higher than
5 micromolar at 48 hours after administration, or
a 100% or greater increase in serum creatinine
level at 24 hours after methotrexate
administration (e.g. an increase from 0.5 mg/dl to
a level equal or higher than 1.0 mg/dl or more)
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LEUCOVORIN CALCIUM
DOSAGE AND DURATION
15 mg PO or IV every 6 hours
for 60 hours (10 doses starting
at 24 hours after start of
methotrexate infusion).
Continue 15 mg PO or IV
every 6 hours until
methotrexate level is less than
0.05 micromolar.
150 mg IV every 3 hours, until
methotrexate level is less than
1 micromolar; then 15 mg IV
every 3 hours, until
methotrexate level is less than
0.05 micromolar.
9
Patients who experience delayed/early methotrexate elimination are likely to develop irreversible
oliguric renal failure. In addition to appropriate leucovorin therapy, these patients require
continuing hydration and urinary alkalinization and close monitoring of fluid and electrolyte
status, until the serum methotrexate level has fallen to less than 0.05 micromolar and the renal
failure has resolved.
Some patients will have abnormalities in methotrexate elimination or abnormalities in renal
function following methotrexate administration which are significant, but less severe, than those
described in the Table. These abnormalities may, or may not be, associated with significant
clinical toxicity.
If significant clinical toxicity is observed, leucovorin rescue should be extended for an additional
24 hours (total of 14 doses over 84 hours) in subsequent courses of therapy.
When laboratory abnormalities or clinical toxicities are observed, the possibility that the patient is
taking other medications which interact with methotrexate should be considered.
Older People
Dose reduction should be considered in elderly patient due to reduced liver and kidney functin as
well as reserves which occur with increased age.
Hepatic Function Impairment
If the bilirubin is between 3-5, or AST more than 180, dosage should be reduced by 25%. If
bilirubin is more than 5, omit the dose.
Methotrexate should be administered with great caution, if at all, to patients with significant
current or previous liver disease, especially when caused by alcohol. Methotrexate is
contraindicated if bilirubin values are >5 mg/dl (85.5 μmol/L).
4.3 Contraindications
Methotrexate should not be used in pregnancy, and in patients in a poor state of nutrition.
Methotrexate is furthermore contraindicated in patients with serious renal (Creatinine clearance less
than 20 ml/min) severe liver disorders, bone marrow hypoplasia, leucopenia, thrombocytopenia,
anaemia, alcohol abuse, methotrexate hypersensitivity and lung toxicity due to methotrexate.
During methotrexate therapy no breastfeeding should be given.
Serious, acute or chronic infections such as tuberculosis and HIV.
Ulcers of the oral cavity and known active gastrointestinal ulcer disease.
Concurrent vaccination with live vaccines
4.4 Special warnings and special precautions for use
The cytostatic drug methotrexate may only be used under strict supervision of a physician who is
experienced in oncology. Treatment should take place in a hospital experienced in cancer
chemotherapy.
Fatal toxicity in association with intravenous and intrathecal administration due to dose
miscalculation has been reported. Particular caution should be exercised when calculating the dose.
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Because of the risk of severe toxic reactions (which can be fatal), methotrexate must only be used in
life-threatening neoplastic diseases. Deaths have been reported during treatment of malignancies
with methotrexate. The doctor should inform the patient of the risks of treatment and the patient
should be monitored constantly by the doctor.
Methotrexate has reportedly caused fetal death and/or congenital malformations. Treatment of
neoplastic diseases is not recommended in women of childbearing potential unless there are clear
medical indications that the benefits of treatment can be expected to outweigh the conceivable risks.
Methotrexate affects spermatogenesis and oogenesis during the period in which it is administered,
which can result in reduced fertility. These effects may be reversible on discontinuing treatment.
Tumor lysis syndrome
Like other cytotoxic agents, methotrexate can induce tumour lysis syndrome in patients with rapidly
growing tumours. Appropriate supportive treatment and pharmacological measures can prevent or
alleviate such complications.
Methotrexate and NSAIDs
Unexpected severe (including fatal) myelosuppression, aplastic anaemia and gastrointestinal toxicity
have been reported in connection with concomitant treatment with methotrexate (usually at a high
dose) and non-steroidal anti-inflammatory agents (NSAIDs).
Concomitant methotrexate treatment and radiotherapy can increase the risk of soft tissue necrosis
and osteonecrosis.
Intrathecal and intravenous administration of methotrexate can result in acute encephalitis and acute
encephalopathy, possibly with a fatal outcome. Patients with periventricular CNS lymphoma who
are given methotrexate intrathecally have reportedly developed cerebral herniation.
Methotrexate and pleural effusion/ascites
Methotrexate is eliminated slowly from collections of fluid (e.g. pleural effusion, ascites). This
results in a prolonged terminal half-life and unexpected toxicity. In patients with significant
collections of fluid, drainage of the fluid before treatment is started and monitoring of plasma
methotrexate levels are recommended.
If stomatitis, diarrhoea, haematemesis or black stool occurs, therapy with methotrexate should be
discontinued due to the danger of haemorrhagic enteritis or death from intestinal perforation or
dehydration.
Conditions in which there is folic acid deficiency can increase the risk of methotrexate toxicity.
In association with intrathecal administration or in high dose treatment, methotrexate must not be
mixed with solutions which contain preservatives.
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Solutions of methotrexate which contain the preservative benzyl alcohol are not recommended for
use in infants. Gasping syndrome with fatal outcome has been reported in infants following
intravenous treatment with solutions containing the preservative benzyl alcohol. Symptoms include
rapid onset of respiratory problems, hypotension, bradycardia and cardiovascular collapse.
Infection or immunological conditions
Methotrexate must be used with great care in connection with active infection and is usually
contraindicated in patients with manifest suppression of the immune response or where
immunodeficiency is demonstrated by laboratory tests.
Pneumonia (which in certain cases can lead to respiratory failure) can occur. Potentially fatal
opportunistic infections including Pneumocystis carinii pneumonia can occur in association with
methotrexate treatment. When a patient exhibits pulmonary symptoms, the possibility of
Pneumocystis carinii pneumonia should be considered.
Immunisation
Methotrexate may interfere with results of immunological tests Immunisation after a vaccination
may be less effective in association with methotrexate treatment. Particularly caution should be
exercised in the presence of inactive, chronic infections (e.g. herpes zoster, tuberculosis, hepatitis B
or C) due to possible activation. Immunisation with live viruses is not normally recommended.
Skin toxicity: Due to the risk of phototoxicity, the patient must avoid sunlight and solarium.
Monitoring treatment
Patients on methotrexate treatment must be closely monitored so that toxic effects can be detected
immediately. Analyses before treatment must include a full blood count with differential and platelet
counts, liver enzymes, testing for hepatitis B and C infections, renal function test and x-ray of the
lungs. Toxic effects of methotrexate can occur even with low doses and therefore it is important to
monitor treated patients carefully. Most undesirable effects are reversible if detected early.
After initiation of treatment or when there is a change in the dose, or during periods in which there is
an increased risk of elevated levels of methotrexate (e.g. in dehydration), monitoring should be
performed.
Bone marrow biopsy must be performed as necessary.
Serum methotrexate level monitoring can significantly reduce methotrexate toxicity and routine
monitoring of serum methotrexate level is necessary depending on dosage or therapy protocol.
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Leucopenia and thrombocytopenia occur usually 4 -14 days after administration of methotrexate.
In rare cases recurrence of leucopenia may occur 12 - 21 days after administration of methotrexate.
Methotrexate therapy should only be continued if the benefit outweighs the risk of severe
myelosuppression.
Haematopoietic suppression: Haematopoietic suppression induced by methotrexate may occur
abruptly and at apparently safe doses. In the event of any significant drop in leukocytes or platelets,
treatment must be discontinued immediately and appropriate supportive therapy instituted. Patients
must be instructed to report all signs and symptoms suggestive of infection. In patients
concomitantly taking haematotoxic medications (e.g. leflunomide), the blood count and platelets
should be closely monitored.
Liver function tests: Particular attention should be paid to the onset of liver toxicity. Treatment
should not be initiated or should be discontinued if there are any abnormalities in liver function tests
or liver biopsies, or if these develop during therapy. Such abnormalities should return to normal
within two weeks; after which, treatment may be resumed at the discretion of the doctor. Further
research is needed to establish whether serial liver chemistry tests or propeptide of type III collagen
can detect hepatotoxicity sufficiently. This assessment should differentiate between patients without
any risk factors and patients with risk factors, e.g. excessive prior alcohol consumption, persistent
elevation of liver enzymes, history of liver disease, family history of hereditary liver disorders,
diabetes mellitus, obesity and previous contact with hepatotoxic drugs or chemicals and prolonged
methotrexate treatment or cumulative doses of 1.5 g or more.
Screening for liver-related enzymes in serum: A transient rise in transaminase levels to twice or three
times the upper limit of normal has been reported with a frequency of 13 - 20%. In the event of a
constant increase in liver related enzymes, consideration should be given to reducing the dose or
discontinuing therapy.
Patients suffering from insulin-dependent diabetes should be carefully monitored because liver
cirrhosis and an increase in transaminase can occur.
Due to the potentially toxic effect on the liver, additional hepatotoxic medications should not be
given during treatment with methotrexate unless clearly necessary and alcohol consumption should
be avoided or greatly reduced. Closer monitoring of liver enzymes should be undertaken in patients
concomitantly taking other hepatotoxic medications (e.g. leflunomide). The same should also be
taken into consideration if haematotoxic medications are co-administered.
Malignant lymphomas may occur in patients receiving low-dose methotrexate; in which case,
methotrexate must be discontinued. If lymphomas should fail to regress spontaneously, initiation of
cytotoxic therapy is required.
Renal function: methotrexate treatment in patients with impaired renal function should be
monitored via renal function tests and urinalysis, since impaired renal function reduces the
elimination of methotrexate, which may result in severe adverse reactions.
ABITREXATE Injection
8. 3. 2015, RH
13
In cases of possible renal impairment (e.g. in elderly patients), close monitoring of renal function is
required. This is particularly applies to the co-administration of medicinal products which affect
methotrexate excretion cause kidney damage (e.g. non-steroidal anti-inflammatory drugs) or which
can potentially lead to haematopoietic disorder. Dehydration may also potentiate the toxicity of
methotrexate. Alkalinisation of the urine and increase a high diuresis is recommended.
Respiratory System: Acute or chronic interstitial pneumonitis, often associated with blood
eosinophilia, may occur and deaths have been reported. Symptoms typically include dyspnoea,
cough (especially a dry non-productive cough) and fever for which patients should be monitored at
each follow-up visit. Patients should be informed of the risk of pneumonitis and advised to contact
their doctor immediately should they develop persistent cough or dyspnoea.
Methotrexate should be withdrawn from patients with pulmonary symptoms and a thorough
investigation (including chest x-ray) should be made to exclude infection. If methotrexate induced
lung disease is suspected treatment with corticosteroids should be initiated and treatment with
methotrexate should not be restarted.
Pulmonary symptoms require a quick diagnosis and discontinuation of methotrexate therapy.
Pneumonitis can occur at all doses.
Vitamin preparations or other products containing folic acid, folinic acid or their derivatives may
decrease the effectiveness of methotrexate.
Children
Methotrexate should be used with caution in paediatric patients. Treatment should follow currently
published therapy protocols for children. Serious neurotoxicity, frequently manifested as generalised
or focal seizures has been reported with unexpectedly increased frequency among paediatric patients
with acute lymphoblastic leukaemia who were treated with intermediate-dose intravenous
2
methotrexate (1 g/m ). Symptomatic patients were commonly noted to have leukoencephalopathy
and/or microangiopathic calcifications on diagnostic imaging studies.
Elderly
Because of deterioration in liver and kidney function as well as reduced folic acid reserves, relatively
low doses should be considered in elderly patients. These patients must be closely monitored for
early signs of toxicity.
Sodium
Abitrexate solution or injection contains sodium as follows:
Abitrexate Injection 25 mg/ml Solution for Injection
Each ml contains 1.93 mg sodium.
Abitrexate Injection 1g/10 ml (100 mg/ml) Solution for Injection
Sodium content:
Each ml contains 10 mg sodium.
ABITREXATE Injection
8. 3. 2015, RH
14
This should be taken into consideration by patients on a controlled sodium diet.
Treatment of psoriasis and rheumatoid arthritis should only take place under strict supervision of a
physician experienced with dermatology and rheumatology.
During the use of methotrexate the following laboratory tests are generally advised: hemograms,
counting of the platelets and haematocrit; renal function tests and urine analysis; liver enzyme
determination; chest X-ray is recommended. During the treatment of psoriasis it is recommended to
repeat those tests regularly: monthly haematology, every 1-3 months liver and kidney function.
Usually during antineoplastic treatment a more frequent control procedure is applied. On treatment
initiation or a dose modification or during periods which an enhanced risk on increased methotrexate
blood levels (e.g. in case of dehydratation), a more frequent control is to be done.
A relationship between abnormal liver function tests and fibrosis or cirrhosis of the liver has not
been established. Transient deviation in liver function tests have often been observed after
methotrexate administration and usually do not lead to therapy modification. Permanent
abnormalities in liver function tests just prior to administration and/or serum albumin level decrease
may indicate serious liver toxicity and require further examination.
Lung function tests may be useful in case a methotrexate induced lung disease is suspected, in
particular when initial base line values are available.
Methotrexate should be used with extreme care in patients with infection, peptic ulcer, ulcerative
colitis, debility and in the very young or aged.
In case of severe leucopenia occurring during treatment bacterial infections could set in. When
infection occurs, discontinuation of methotrexate and adequate antibacterial therapy is indicated.
At the onset of nephrotoxicity also immediate discontinuation of therapy is indicated.
In case of severe bone marrow depression blood- or thrombocytes transfusion may be necessary.
Methotrexate induced lung disease is a potentially dangerous condition which may occur at any
moment during therapy with dosages higher than 7.5 mg weekly. The condition is not always
completely reversible. Pulmonary symptoms (in particular a dry, non-productive cough) may require
treatment interruption and thorough examination. In the treatment of methotrexate induced
(interstitial) pneumonitis after immediate discontinuation of therapy, corticosteroid treatment is
indicated. In case of the occurrence of lung toxicity re-initiation of therapy is contra-indicated.
Diarrhoea and ulcerative stomatitis require discontinuation of treatment because of the risk of
haemorrhagic enteritis and death by intestinal perforation.
ABITREXATE Injection
8. 3. 2015, RH
15
Special care should be taken in the treatment of patients with decreased renal function, and with
reduced doses, as the methotrexate elimination time is increased in renal dysfunction.
Thus far there are no indications for an increased risk of carcinogenicity in humans undergoing
prolonged therapy, such as psoriasis patients. The data on the carcinogenicity risk in case of use of
methotrexate by rheumatoid arthritis patients are limited.
While preparing methotrexate injections protective gloves, a mask and safety goggles should be
worn. The preparation of methotrexate, like the preparation of any cytostatic drug, has to take place
in a vertical laminar air flow hood. Spillage of methotrexate should be washed with ample water.
During methotrexate therapy and until at least three months after treatment with methotrexate
contraceptive precautions should be taken by female as well as male patients.
While in general a low dose of methotrexate is applied in the treatment of psoriasis and rheumatoid
arthritis, as compared to the doses used in antineoplastic therapy, intoxication and death may occur.
Patients should be fully informed on the risks of methotrexate therapy and should be instructed to
report any manifestation of toxicity immediately.
It is recommended to carry out a liver biopsy in psoriasis and rheumatoid arthritis patients after a
total cumulative dose of 1.5 g. Fibrosis of intermediate revering or any cirrhosis usually requires
discontinuation of therapy. Although mild changes usually are no reason to avoid or discontinue
methotrexate therapy, methotrexate should be used with care in patients.
The combined administration of methotrexate and other potentially hepatotoxic drugs and alcohol
should be avoided.
Malignant lymphomas may develop in patients, treated with low dose methotrexate. Spontaneous
remission may occur when methotrexate therapy is stopped; therefore, treatment with oncolytics is
not necessarily indicated. First, it is necessary to stop methotrexate treatment, when this adverse
event occurs. If remission fails to appear, an adequate treatment has to be started.
When concurrent administration of methotrexate and radiotherapy takes place there can be an
increased risk of necrosis of soft tissue (see section 4.8 ‘Undesirable effects’).
Periodic evaluation by specific cognitive tests to detect early signs of cognitive impairment is
advised in children.
ABITREXATE Injection
8. 3. 2015, RH
16
4.5 Interaction with other medicaments and other forms of interaction
Non steroidal anti-inflammatory drugs (NSAIDS) should not be administered prior to or
simultaneously with high dose methotrexate treatment (>10 mg methotrexate per week). Increased
serum levels of methotrexate have been reported at simultaneous administration of some NSAIDS
with high dose methotrexate resulting in death by serious haematologic or gastrointestinal toxicity.
NSAIDS, salicylates and other weak organic acids, like probenecid, can lower tubularly secretion of
methotrexate resulting in increased toxicity. Use of methotrexate with these drugs should be made
carefully under strict supervision. The potential toxicity of methotrexate is increased in particular at
simultaneous use of NSAIDS when also diuretics are used. In rheumatology, a combination therapy
of low-dose methotrexate and a NSAID is commonly used.
Methotrexate bound to serum proteins may be displaced by salicylates, NSAID's, sulphonamides,
phenytoin, tetracyclines, chloramphenicol, p-amino-benzoic acid, doxorubicin, bleomycin,
cyclophosphamide, aminoglycosides, allopurinol, vincristine, hydrocortisone, prednisone,
asparaginase and cytosine arabinoside, hereby increasing the fraction of free methotrexate in plasma.
Care should be taken in combining high dose methotrexate with potentially nephrotoxic therapy (e.g.
cisplatin).
Oral antibiotics (including tetracyclines, chloramphenicol and non-absorbable broad-spectrum
antibiotics) may influence the intestinal flora and inhibit methotrexate (re)absorption.
In isolated cases, trimethoprim/sulfamethoxazole has reportedly increased myelosuppression in
patients treated with methotrexate, probably due to reduced tubular secretion and/or an additive
antifolate effect
Interaction with therapeutic radiation may occur (see section 4.4 ‘Special warnings and special
precautions for use’ and section 4.8 ‘Undesirable effects). In combination with other cytostatic drugs
pharmacodynamic interactions may occur; resulting in increased therapeutic activity and increased
toxicity.
No vaccination with live virus vaccines should be performed in patients receiving methotrexate.
Partial or total protection can be obtained through inactivated vaccines.
Vitamin preparations containing folic acid or folic acid derivatives may decrease the effect of
systemically administered methotrexate. Preliminary human and animal studies have shown that
after intravenous administration of calcium folinate a small amount penetrates into the cerebrospinal
fluid, predominantly as 5-methyltetrahydrofolate, and this amount is a factor 1 to 3 lower than the
normal methotrexate concentration after intrathecal administration.
ABITREXATE Injection
8. 3. 2015, RH
17
Nevertheless high doses of calcium folinate may lower the effectivity of intrathecally administered
methotrexate. Folate deficiencies may increase methotrexate toxicity. In some cases a potentiation of
the
bone
marrow
suppression
in
patients
treated
with
methotrexate
by
trimethoprim/sulphamethoxazole was reported, probably by additional folic acid antagonism. The
combined use of methotrexate and sulphonamides is therefore strongly advised against.
Ciprofloxacin: Excretion of methotrexate possibly reduced (increased risk of toxicity).
Leflunomide: Methotrexate in combination with leflunomide can increase the risk of
pancytopenia.
Probenecid: Renal tubular transport is diminished by probenecid, and its use together with
methotrexate must be avoided.
Penicillins:Penicillins can reduce renal clearance of methotrexate. Haematological and
gastrointestinal toxicity have been observed in combination with high and low dose methotrexate.
Chemotherapeutic products: An increase in renal toxicity can be observed when high doses of
methotrexate are given in combination with potentially nephrotoxic chemotherapeutic agents (e.g.
cisplatin).
Cytarabine: Concomitant therapy with cytarabine and methotrexate can increase the risk of severe
neurological side effects ranging from headache to paralysis, coma and stroke-like episodes.
Hepatotoxic products: The risk of increased hepatotoxicity when methotrexate is administered
concurrently with other heptatotoxic products has not been studied. Hepatotoxicity has however
been reported in such cases. Patients receiving concomitant treatment with drugs with a known
hepatotoxic effect (e.g. leflunomide, azathioprine, sulfasalazine, retinoids) must be carefully
monitored for signs of any increase in hepatotoxicity.
Theophylline: Methotrexate can reduce clearance of theophylline. Theophylline levels must
therefore be monitored during concomitant treatment with methotrexate.
Mercaptopurine: Methotrexate increases plasma content of mercaptopurine. The combination of
methotrexate and mercaptopurine can therefore require dose adjustment.
Drugs with high plasma protein binding: Methotrexate is partially bound to serum albumin. Other
highly bound drugs such as salicylates, phenylbutazone, phenytoin and sulfonamides can increase
the toxicity of methotrexate by means of displacement.
Furosemide: Concomitant administration of furosemide and methotrexate can result in increased
levels of methotrexate due to competitive inhibition of tubular secretion.
ABITREXATE Injection
8. 3. 2015, RH
18
Proton pump inhibitors: Literature data indicate that co-administration of proton pump inhibitors
and methotrexate, especially at high dose, may result in elevated and prolonged plasma levels of
methotrexate and/or its metabolite, possibly leading to methotrexate toxicity.
4.6 Fertility, pregnancy and lactation
(see Contraindications)
Pregnancy
Methotrexate can cause foetal death, embryotoxicity, abortion or teratogenic effects when
administered to pregnant women. During pregnancy, especially in the first trimester, cytotoxic
drugs must only be given when strictly indicated, weighing the needs of the mother against the
risks to the foetus. Treatment with methotrexate during the first trimester has resulted in a high
risk of malformations (in particular cranial malformation and malformation of the extremities).
Breastfeeding
Methotrexate passes into breast milk in quantities such that there is a risk to the child even at
therapeutic doses. Breast feeding must therefore be discontinued during treatment with
methotrexate.
Fertility
Methotrexate may be genotoxic. Women of childbearing potential must not be treated with
methotrexate until pregnancy has been excluded. Since in men spermatogenesis can be affected by
methotrexate, pregnancy should be avoided if either partner is receiving methotrexate. The
optimum time interval between discontinuation of methotrexate therapy in either partner and
pregnancy has not been established. The recommended interval in published literature varies
between three months and one year. Both men and women receiving methotrexate should be
informed of the potential risk of adverse effects on reproduction. Women of childbearing potential
should be fully informed of the potential hazard to the fetus should they become pregnant during
methotrexate therapy.
4.7 Effect on ability to drive and use machines
Because methotrexate may cause blurred vision, paresis and hemiparesis, fatigue and dizziness, the
ability to drive and use machines may be adversely affected.
4.8 Undesirable effects
Conventional and high dose therapy
The frequency and degree of severity of undesirable effects depends on the dose administered, the
duration of exposure and method of administration, but side effects have been seen at all doses
and can occur at any time during treatment. Most undesirable effects are reversible when detected
at an early stage. When severe reactions occur, the dose should be reduced or treatment
discontinued and appropriate measures initiated. If treatment with methotrexate is resumed, this
should be done with caution after adequate consideration of the further need for the drug.
Increased vigilance with regard to any recurrence of toxicity is required.
ABITREXATE Injection
8. 3. 2015, RH
19
The most frequently reported undesirable effects include ulcerative stomatitis, leukopenia, nausea
and bloating. Other frequently reported undesirable effects are feeling unwell, unusual tiredness,
chills and fever, dizziness, reduced resistance to infections. Treatment with folinic acid during
high dose therapy can counteract or alleviate a number of undesirable effects. Temporary
discontinuation of therapy is recommended if there are signs of leukopenia.
Organ system class
Very common
(≥1/10)
Infections and
infestations
Common
Uncommon
(≥1/100 to <1/10) (≥1/1,000 to
<1/100)
Herpes zoster
Not known
(cannot be
estimated from the
available data)
Pericarditis,
pericardial
effusion,
pericardial
tamponade
leukocytopenia,
Pancytopenia,
thrombo-cytopenia agranulo-cytosis,
and anaemia
haematopoietic
disorders
Immune system
disorders
Anaphylactoid
reactions, allergic
vasculitis
Psychiatric disorders
ABITREXATE Injection
Very rare
(<1/10,000)
Sepsis,
opportunistic
infections (may be
fatal in some
cases), infections
caused by the
cytomegaly virus
Cardiac disorders
Blood and lymphatic
system disorders
Rare
(≥1/10,000 to
<1/1,000)
Megaloblastic
anaemia
Severe courses of Haemorrhage,
bone marrow
haematoma
depression aplastic
anaemia
Lymphadenopathy,
lymphoproliferative
disorders (partly
reversible)
eosinophilia and
neutropenia
Immunosuppression
hypogammaglobulinaemia
Insomnia,
cognitive
dysfunction
8. 3. 2015, RH
psychosis
20
Organ system class
Very common
(≥1/10)
Nervous system
disorders
Common
Uncommon
(≥1/100 to <1/10) (≥1/1,000 to
<1/100)
Rare
(≥1/10,000 to
<1/1,000)
Very rare
(<1/10,000)
Headache
fatigue
drowsiness
Severely impaired
vision
mood alterations
paresis, effect on
speech including
dysarthria and
aphasia,
myelopathy
Pain, muscular
asthenia or
paresthesia of the
extremities,
myasthenia,
changes in sense
of taste (metallic
taste), meningism
(paralysis,
vomiting), acute
aseptic meningitis
visual
disturbances,
blurred vision
Conjunctivitis
Retinopathy,
transient
blindness/loss of
vision, periorbital
oedema,
blepharitis,
epiphora,
photophobia
Vertigo
confusion
depression
seizures
convulsion
encephalo-pathy
Eye disorders
Neoplasms benign,
malignant and
unspecified (incl
cysts and polyps)
individual cases of
lymphoma which
abated in a
number of cases
once methotrexate
treatment had been
discontinued. In a
recent study, it
was not possible
to establish that
methotrexate
therapy increases
the incidence of
lymphomas
Vascular disorders
Vasculitis
ABITREXATE Injection
8. 3. 2015, RH
Not known
(cannot be
estimated from the
available data)
Tumour lysis
syndrome
hypotension
thrombo-embolic
events reactions
(incl. arterial
thrombosis,
cerebral
thrombosis,
thrombo-phlebitis,
deep vein
thrombosis, retinal
vein thrombosis,
pulmonary
embolism)
Cerebral oedema,
petechie
21
Organ system class
Very common
(≥1/10)
Respiratory, thoracic
and mediastinal
disorders
Gastrointestinal
disorders
Loss of appetite,
nausea, vomiting,
abdominal pain,
inflammation and
ulcerations of the
mucous membrane
of mouth and
throat (especially
during the first 2448 hours after
administration of
methotrexate).
Stomatitis,
dyspepsia
ABITREXATE Injection
Common
Uncommon
(≥1/100 to <1/10) (≥1/1,000 to
<1/100)
Rare
(≥1/10,000 to
<1/1,000)
Pulmonary
Pulmonary
complications due fibrosis
to interstitial
alveolitis /
pneumonitis and
related deaths
(independent of
dose and duration
of methotrexate
treatment).
Typical symptoms
may be: general
illness; dry,
irritating cough;
shortness of breath
progressing to rest
dyspnoea, chest
pain, fever. If such
complications are
suspected,
methotrexate
treatment must be
discontinued
immediately and
infections
(including
pneumonia) must
be excluded.
Pharyngitis,
Pneumocystis
Acute pulmonary
apnoea, bronchial carinii pneumonia, oedema
asthma
shortness of
breath, chronic
obstructive
pulmonary
disease. Infections
including
pneumonia have
also been
observed.
Pleural effusion
Diarrhoea
gastrointestinal
(especially during bleeding and
the first 24-48
ulcers, pancreatitis
hours after
administration of
methotrexate).
Gingivitis,
Haematemesis
Toxic megacolon
Enteritis, melaena (vomiting blood),
(bloody stools),
toxic megacolon
malabsorption
8. 3. 2015, RH
Very rare
(<1/10,000)
Not known
(cannot be
estimated from the
available data)
22
Organ system class
Very common
(≥1/10)
Common
Uncommon
(≥1/100 to <1/10) (≥1/1,000 to
<1/100)
Hepato-biliary
disorders
Increase in liverrelated enzymes
(ALAT, ASAT,
alkaline
phosphatase nd
bilirubin).
Rare
(≥1/10,000 to
<1/1,000)
Very rare
(<1/10,000)
Not known
(cannot be
estimated from the
available data)
Development of
Acute hepatitis
liver fattening,
and hepatotoxicity
fibrosis and
cirrhosis (occurs
frequently despite
regularly
monitored, normal
values of liver
enzymes); diabetic
metabolism; drop
of serum albumin.
Reactivation of
Metabolic disorder
chronic hepatitis,
acute liver
degeneration.
Furthermore,
herpes simplex
hepatitis and liver
insufficiency have
been observed
(also see the notes
regarding liver
biopsy in section
4.4).
Urticaria, photosensibility,
enhanced
pigmentation of
the skin, hair loss,
increase of
rheumatic
nodules, herpes
zoster, painful
lesions of psoriatic
plaque; severe
toxic reactions:
vasculitis,
herpetiform
eruption of the
skin, StevensJohnson
syndrome, toxic
epidermal
necrolysis (Lyell's
syndrome).
Increased
pigmentary
changes of nails,
acne, petechiae,
ecchymoses,
erythema
multiforme,
cutaneous
erythematous
eruptions.
Furunculosis,
Exfoliative
teleangiectasis,
dermatitis, skin
acute paronychia, necrosis,
Furthermore,
nocardiosis,
histoplasma and
cryptococcus
mycosis and
disseminated
herpes simplex
have been
reported.
Allergic vasculitis,
hidradenitis
Musculoskeletal
system, connective
tissue and bone
disorders
Osteoporosis,
Arthralgia,
myalgia
Stress fracture
Renal and urinary
disorders
Inflammation and
ulceration of the
urinary bladder
(possibly with
haematuria),
dysuria.
Renal failure,
Proteinuria
oliguria, anuria,
azotaemia, hyperuricaemia,
elevated serum
creatinine and
urea level
Skin and
subcutaneous tissue
disorders
ABITREXATE Injection
Exanthema,
erythema, itching
8. 3. 2015, RH
23
Organ system class
Very common
(≥1/10)
Common
Uncommon
(≥1/100 to <1/10) (≥1/1,000 to
<1/100)
Rare
(≥1/10,000 to
<1/1,000)
Very rare
(<1/10,000)
Reproductive system
and breast disorders
Inflammation and
ulceration of the
vagina
Loss of libido,
impotence,
oligospermia,
impaired
menstruation,
Vaginal discharge,
infertility,
gynaecomastia
General disorders
and administration
site conditions
Severe allergic
reactions
progressing to
anaphylactic
shock;
Fever, impaired
wound healing
Metabolism and
nutrition disorders
Not known
(cannot be
estimated from the
available data)
Diabetes Mellitus
The following undesirable effects have also been reported, but their frequency has not been
established: Pneumocystis carinii pneumonia, (including reversible cases), foetal death, damage to
the foetus, abortion.
Systemic organ toxicity
Lymphoma
Malignant lymphoma which can go into remission after discontinuation of the treatment with
methotrexate can occur in patients on low dose therapy, and may not therefore require any
cytotoxic treatment. Methotrexate should be discontinued first and appropriate treatment initiated
if the lymphoma does not regress.
Haematological
Methotrexate can suppress haematopoiesis and cause anaemia, aplastic anaemia, pancytopenia,
leukopenia, neutropenia and/or thrombocytopenia. Methotrexate must be administered with
caution to patients with malignancies and underlying factors affecting haematopoiesis. When
treating neoplastic conditions, treatment with methotrexate should only be given provided the
potential benefits outweigh the risk of myelosuppression.
Lungs
Lung disease caused by methotrexate, including acute or chronic interstitial pneumonitis, is a
potentially dangerous complication, which can occur at any time during the course of treatment.
This undesirable effect has been reported at low doses and is not always totally reversible. Deaths
have been reported.
ABITREXATE Injection
8. 3. 2015, RH
24
Signs of pulmonary involvement or symptoms such as dry non-productive cough, fever, chest
pains, dyspnoea, hypoxemia and infiltrate on x-ray of the lungs, or non-specific pneumonitis
which occurs in connection with methotrexate therapy, may indicate potentially serious damage
and requires discontinuation of treatment and careful investigation. Lung changes can occur at all
doses. The possibility of infection (including pneumonia) must be excluded.
Gastrointestinal
If vomiting, diarrhoea or stomatitis occur, with resulting dehydration, methotrexate therapy must
be discontinued until the patient has recovered. Haemorrhagic enteritis and deaths caused by
intestinal perforation can occur. Methotrexate must be used with great caution in patients with
peptic ulcers or ulcerative colitis. Stomatitis can be prevented or alleviated by folinic acid
mouthwashes.
Liver
Methotrexate involves a potential risk of acute hepatitis and chronic (fibrosis and cirrhosis)
hepatotoxicity. Chronic toxicity is potentially fatal and occurs commonly after long-term use (in
general after 2 years or more) and after a total cumulative dose greater than 1.5 g. In studies of
psoriasis patients hepatotoxicity was seen to be proportional to the cumulative dose and was
potentiated by alcoholism, overweight, diabetes and age.
Transient deterioration in liver enzyme values is frequently seen after methotrexate treatment and
does not usually necessitate adjustment of treatment. Existing abnormal liver values and/or
reduction in serum albumin can indicate severe hepatotoxicity.
Methotrexate has caused reactivation of hepatitis B infections and exacerbation of hepatitis C
infections, in some cases with fatal outcome. Some cases of hepatitis B reactivation have occurred
following discontinuation of methotrexate. Clinical and laboratory tests should be performed to
investigate any occurrence of liver disease in patients with prior hepatitis B or C infections. Based
on these investigations, treatment with methotrexate may prove unsuitable for certain patients.
In the event of impaired liver function, the undesirable effects of methotrexate (in particular
stomatitis) can be exacerbated.
Kidneys
Methotrexate can cause kidney damage which can result in acute renal failure. Renal function can
be exacerbated following high dose therapy to such an extent that the excretion of methotrexate is
inhibited, as a result of which systemic methotrexate toxicity can occur. In order to prevent renal
failure, alkalinisation of the urine and adequate fluid intake (at least 3 l/day) are recommended.
Measurement of serum methotrexate and renal function is recommended.
Skin
Serious, in some cases fatal skin reactions, including toxic epidermal necrolysis (Lyell's
syndrome), Stevens-Johnson syndrome and erythema multiforme have been reported within a few
days of oral, intramuscular, intravenous or intrathecal treatment with methotrexate in single or
repeat doses. Radiation dermatitis and sunburn can be accentuated after use of methotrexate.
ABITREXATE Injection
8. 3. 2015, RH
25
CNS
There are reports of leukoencephalopathy after intravenous treatment with methotrexate in
patients who have undergone craniospinal radiotherapy. Severe neurotoxicity, often manifested as
generalised or focal seizures have been reported with an unexpected increase in frequency in
children with acute lymphoblastic leukaemia treated with a moderately high dose of intravenous
methotrexate (1 g/m2). Symptomatic patients frequently had leukoencephalopathy and/or
microangiopathic calcifications in x-ray investigations.
Chronic leukoencephalopathy has also been reported in patients treated with repeated high doses
of methotrexate together with folinic acid, even without concomitant cranial radiotherapy.
Discontinuation of the methotrexate therapy did not always result in full recovery.
Leukoencephalopathy has also been reported in patients treated with methotrexate tablets.
One transient acute neurological syndrome has been observed in patients undergoing high dose
therapy. Manifestations of this neurological syndrome can include abnormal behaviour, focal
sensorimotor symptoms including transient blindness, and abnormal reflexes. The exact cause is
unclear.
Cases of neurological side effects ranging from headache to paralysis, coma and stroke-like
episodes have been reported, primarily in children and adolescents receiving concomitant
medication with cytarabine.
Intrathecal therapy
The subacute neurotoxicity is usually reversible after discontinuing methotrexate.
Organ system class
Common (>1/100)
Central and peripheral nervous system disorders
Headache, chemical arachnoiditis, subacute
neurotoxicity, necrotising demyelinating
leukoencephalopathy
Gastrointestinal disorders
Nausea and vomiting
General disorders and administration site conditions Fever
Chemical arachnoiditis, which can occur a few hours after intrathecal administration of
methotrexate is characterised by headache, back pain, stiff neck, vomiting, fever, meningism and
pleocytosis in the cerebrospinal fluid similar to that in bacterial meningitis. Arachnoiditis
generally disappears within a few days.
Subacute neurotoxicity, common after frequently repeated intrathecal administration, mainly
affects the motor functions in the brain or spinal cord. Paraparesis/paraplegia, with involvement of
one or more spinal nerve roots, tetraplegia, cerebellar dysfunction, cranial nerve paralysis and
epileptic seizures can occur.
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Necrotising demyelinating leukoencephalopathy can occur several months or years after starting
intrathecal therapy. The condition is characterised by progressive neurological deterioration with
insidious onset, confusion, irritability and somnolence. Ultimately severe dementia, dysarthria,
ataxia, spasticity, seizures and coma can occur. The condition can be fatal. Leukoencephalopathy
occurs primarily in patients who have received large quantities of intrathecal methotrexate in
combination with cranial radiotherapy and/or systemically administered methotrexate.
Signs of neurotoxicity (meningeal inflammation, transient or permanent paresis, encephalopathy)
must be followed up after intrathecal administration of methotrexate.
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 to the Ministry of Health
according
to
the
National
Regulation
by
using
an
online
form
(http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@m
oh.health.gov.il ) or by email ([email protected] ).
4.9
Overdose
Experience of overdose with the product has in general been associated with oral and intrathecal
treatment, although overdose in association with intravenous and intramuscular administration has
also been reported.
Reports of oral overdose have often been due to accidental daily instead of weekly ingestion.
Commonly reported symptoms following oral overdose include the symptoms and signs seen at
pharmacological doses, in particular haematological and gastrointestinal reactions such as
leukopenia, thrombocytopenia, anaemia, pancytopenia, neutropenia, myelosuppression, mucositis,
stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, gastrointestinal bleeding.
In certain cases no symptoms were reported. There are reports of deaths associated with overdose.
In these cases there were also reports of conditions involving sepsis or septic shock, renal failure
and aplastic anaemia.
The most common symptoms of intrathecal overdose are CNS symptoms including headache,
nausea and vomiting, seizures or convulsions and acute toxic encephalopathy. In certain cases, no
symptoms were reported. There have been reports of deaths following intrathecal overdose. In
these cases there were also reports of cerebellar herniation accompanying elevated intracranial
pressure and toxic encephalopathy.
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Recommended treatment
Antidote therapy: Folinic acid should be given parenterally at a dose at least the size of the
methotrexate dose and should wherever possible be administered within an hour. Folinic acid is
indicated to minimise toxicity and counter the effect of methotrexate overdose. Folinic acid
treatment should be initiated as soon as possible. The longer the interval between the
administration of methotrexate and the initiation of folinic acid, the less the effect of folinic acid
in suppressing the toxic effect. Monitoring of serum methotrexate concentrations is necessary to
be able to determine the optimum dose of folinic acid and the length of the treatment.
In the event of a major overdose, hydration and alkalinisation of the urine may be required to
prevent precipitation of methotrexate and/or its metabolites in the renal tubules. Neither standard
haemodialysis nor peritoneal dialysis have been shown to increase the elimination of
methotrexate. Acute intermittent haemodialysis with the use of highly permeable dialyser may be
attempted for methotrexate intoxication.
Intrathecal overdose may require intensive systemic supportive measures such as systemic
administration of high doses of folinic acid, alkaline diuresis, acute CSF drainage and ventricular
lumbar perfusion.
5.
PHARMACOLOGICAL PROPERTIES
5.1
Pharmacodynamic properties
Methotrexate belongs to the group of antimetabolites. It is a folic acid antagonist, which binds to
dihydrofolate reductase, an enzyme that reduces dihydrofolic acid to tetrahydrofolic acid. This
binding results in inhibition of the biosynthesis of thymine and purine. In high concentrations
methotrexate also prevents the influx of folate into the cell. Resistance to methotrexate may occur
due to a decreased transport of methotrexate through cell membranes and as result of an altered
affinity of the enzyme dihydrofolate reductase for methotrexate.
At very high concentrations (> 20 mol/l) methotrexate may penetrate cells not only through an
active transport mechanism but also by diffusion. This concept is the rationale for high-dose
methotrexate therapy.
5.2
Pharmacokinetic properties
Absorption
Methotrexate is usually completely absorbed after parental administration. After intramuscular
injection the peak blood level is reached after 30-60 min.
Distribution
After intravenous administration the initial volume of distribution is about 0.18 l/kg (18 % of the
body weight) and at equilibrium about 0.4-0.8 l/kg (40 - 80 % of the body weight). Methotrexate
slowly penetrates into third compartments as pleural effusions and ascites, where after 6 hours a
steady-state with the plasma concentration has been established. Methotrexate competes with
reduced folates for the carrier of the active cell membrane transport.
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At serum concentration higher than 100 M passive diffusion becomes the most important route to
achieve effective intracellular concentrations of methotrexate. In serum methotrexate is bound for
about 50% to proteins.
Methotrexate does not penetrate the blood-brain barrier in therapeutic concentrations after oral or
parental administration. In the cerebrospinal fluid high concentrations can be reached after
intrathecal administration.
Biotransformation
After absorption methotrexate is metabolized in the liver and intracellularly into polyglutamates
which can be re-converted into methotrexate by hydrolases. These polyglutamates act as inhibitors of
dihydrofolate reductase and thymidylate synthetase.
Small amounts of methotrexate polyglutamates may be present in tissue during prolonged periods of
time. The retention and the protracted action of these active metabolites varies between the different
cells, tissues and tumors. At normal dose, a small amount of methotrexate may be metabolized in the
liver into 7-hydroxymethotrexate. Cumulation of this inactive metabolite may be of importance in
the high dose treatment. The aqueous solubility of 7-hydroxymethotrexate is 3-5 times lower than
that of the original molecule. The half-life of methotrexate is about 3-10 hours in patients under
treatment for psoriasis and in case of antineoplastic therapy with low dosages (less than 30 mg/m2).
In patients on high dose methotrexate therapy the half-life is 8-15 hours.
Elimination
Elimination is predominantly by renal excretion and is dependent on dose and route of
administration. After intravenous administration 44-100% of the dose administered is excreted
unchanged within 24 hours into the urine.
Less than 10% of the dose administered is excreted via the bile. Enterohepatic recirculation of
methotrexate has been suggested. Renal excretion is by glomerular filtration and active tubular
excretion. Non-linear elimination is due to saturation of renal tubular re-absorption and has been
observed in psoriasis patients treated with doses of 7.5-30 mg. A decreased renal function and also
concomitant administration of drugs which also undergo tubular secretion (such as weak organic
acids) may increase considerably the serum methotrexate concentration. There is a good correlation
between methotrexate clearance and endogenous creatinine clearance. Methotrexate clearance varies
highly and is normally lowered at high dosages. It has been shown that a diminished clearance is one
of the most important factors responsible for methotrexate toxicity. Toxicity of methotrexate in
normal tissue is dependent rather on duration of exposition than on the peak concentration achieved.
In case a patient displays decreased elimination because of compromised kidney function, effusion
of the third compartment or by another reason, serum methotrexate concentration may remain
increased during prolonged periods of time.
The possibility of toxicity after administration of high dosages or in case of decreased elimination is
lowered by the administration of calcium folinate during the last phase of the methotrexate plasma
elimination. On the solubility methotrexate in the kidneys: at high dose therapy the probability of
precipitation is higher at pH <7. During the administration of high dose methotrexate
hyperhydratation and alkalinization of the urine is recommended to avoid renal toxicity.
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Pharmacokinetic monitoring of the serum methotrexate concentration may be useful to detect
patients with an increased risk on methotrexate toxicity and may facilitate calcium folinate dosing.
Guidelines to monitor serum methotrexate levels and to adapt the calcium folinate dose to lower the
risk of methotrexate toxicity are monitored under "Dosage and method of administration".
5.3
Preclinical safety data
Animal studies show that methotrexate impairs fertility and that it is embryotoxic, foetotoxic and
teratogenic. Methotrexate is mutagenic in vivo and in vitro, but the clinical significance is
unknown since rodent carcinogenicity studies have produced differing results. Chronic toxicity
studies in mice, rats and dogs showed toxic effects in the form of gastrointestinal lesions,
myelosuppression and hepatotoxicity.
6.
PHARMACEUTICAL PARTICULARS
6.1 List of excipients
See section 2. QUALITATIVE AND QUANTITATIVE COMPOSITION
6.2
Incompatibilities
Methotrexate should not be mixed in the infusion bottle with other drugs.
6.3
Special precautions for storage
Store in a dry place at room temperature (15-25°C) in a well closed packaging. Protect from light.
Do not use this medicine if the solution is not clear.
Abitrexate solution can be further diluted with 0.9% Sodium Chloride Injection or 5% Dextrose
Injection.
Abitrexate diluted solution stored between 15-250C and protected from light has a chemical and
physical in-use stability of 24 hours.
From a microbiological point of view, unless the method of dilution precludes the risk of microbial
contamination, the product should be used immediately. If not used immediately, in-use storage
times and conditions are the responsibility of the user.
6.4
Instructions for use/handling
Abitrexate solution is further diluted in normal saline and administered by IV injection or IV
infusion over periods not exceeding 24 hours. Abitrexate solution may be diluted with 0.9% Sodium
Chloride Injection or 5% Dextrose Injection. Part of the dose may be given as an initial bolus IV
injection. Any unused solution must be discarded.
Other drugs should not be mixed with Abitrexate in the same infusion container.
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6.6 Special precautions for disposal and other handling
Every form of contact with the fluid must be avoided. During preparation a strictly aseptic working
technique should be used; protective measures should include the use of gloves, mask, safety goggles
and protective clothing. Use of vertical laminar airflow (LAF) hood is recommended. If the solution
is spilled, rinse with plenty of water.
Gloves should be worn during administration. Waste-disposal procedures should take into account
the cytotoxic nature of this substance.
6.5
Presentation
Abitrexate 1g/10ml, packs of 1 vial
Abitrexate 5g/50ml, packs of 1 vial
Abitrexate 50 mg/2ml, packs of 1 vial
Abitrexate 100mg/4ml, packs of 1 vial
Abitrexate 200 mg/8ml, packs of 1 vial
Abitrexate 500 mg/20ml, packs of 1 vial
Abitrexate 1000 mg/40ml, packs of 1 vial
Not all packs may be marketed.
7.
PRODUCT REGISTRATION NO.:
Abitrexate 1g/10ml Vials: 100 38 24914 05
Abitrexate 25 mg/ml Vials: 048 96 23819 05
8.
MANUFACTURER
Pharmachemie BV,
Haarlem, Holland
9
LICENSE HOLDER
Salomon Levin & Elstein Ltd
P.O.Box 3696, Petach Tikva, 49133
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