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P&U METHOTREXATE® CSV

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

P&U METHOTREXATE® CSV

P&U METHOTREXATE® CSV 50 mg/2 mL INJECTION
P&U METHOTREXATE®CSV 500 mg/20 mL INJECTION

COMPOSITION:
Each 1 mL contains 25 mg methotrexate.

PHARMACOLOGICAL CLASSIFICATION:
A 26. Cytostatic agents

PHARMACOLOGICAL ACTION:
METHOTREXATE has as its principle mechanism of action the competitive inhibition of the enzyme, folic acid reductase. Folic acid must be reduced to tetrahydrofolic acid by this enzyme in the process of DNA synthesis and cellular replication. METHOTREXATE inhibits the reduction of folic acid and interferes with tissue-cell reproduction. Actively proliferating tissues such as malignant cells, bone marrow, foetal cells, dermal epithelium, buccal and intestinal mucosa and cells of the urinary bladder are in general more sensitive to this effect of METHOTREXATE.
Cellular proliferation in malignant tissue is greater than in most normal tissue and thus METHOTREXATE may impair malignant growth without irreversible damage to normal tissues.
In psoriasis, the rate of production of epithelial cells in the skin is greatly increased over normal skin. This differential in reproduction rates is the basis for the use of METHOTREXATE to control the psoriatic process.
Orally administered METHOTREXATE is absorbed rapidly in most, but not all patients, and reaches peak serum levels in 1-2 hours. After parenteral injection, peak serum levels are seen in about one-half of this period.
Approximately one-half of the absorbed METHOTREXATE is reversibly bound to serum protein but easily exchanges with body fluids and diffuses into the body tissue cells.
Excretion of single daily doses occurs through the kidneys in amounts from 55% to 88% or higher within 24 hours. Repeated daily doses result in more sustained serum levels and some retention of METHOTREXATE over each 24 hour period which may result in accumulation of the drug within the tissues.
The liver cells appear to retain certain amounts of the drug for prolonged periods even after a single therapeutic dose. METHOTREXATE is retained in the presence of impaired renal function and may increase rapidly in the serum and in the tissue cells under such conditions. METHOTREXATE does not penetrate the blood-cerebrospinal fluid barrier in therapeutic amounts when given orally or parenterally. High concentration of the drug may be attained by direct intrathecal administration when needed.

INDICATIONS:
Anti-neoplastic chemotherapy:
The management of acute lymphoblastic leukaemia in children and preventative treatment of leukemic meningitis. It is of established value in choriocarcinoma and related trophoblastic tumours of women. Many women with non-metastatic trophoblastic disease, hydatidiform mole, and chorioadenoma destruens have been treated successfully with METHOTREXATE. Beneficial effects are also observed in osteosarcoma and mycosis fungoides and when METHOTREXATE is used as part of the combination therapy of other non-Hodgkin's lymphomas and carcinomas of the breast, head and neck, lung, ovary and bladder.
High-dose METHOTREXATE, with leucovorin “rescue”, can cause substantial tumor regression in osteosarcoma and in combination therapy of leukemias and non-Hodgkin’s lymphomas.
Psoriasis chemotherapy (See “WARNINGS”):
Because of high risk attending its use, METHOTREXATE is only indicated in the symptomatic control of severe, recalcitrant, disabling psoriasis which is not adequately responsive to other forms of therapy, and then only when the diagnoses has been established by biopsy and/or after dermatologic consultation.

CONTRA-INDICATIONS:
Hypersensitivity to METHOTREXATE. Should not be given in pregnancy and during lactation. Psoriatic patients with severe renal and hepatic disorders, as well as pre-existing blood dyscrasias, such as bone marrow hypoplasia, leucopenia, thrombocytopenia or anemia.

WARNINGS:
METHOTREXATE must be prescribed only by physicians experienced in antimetabolite chemotherapy. Because of the possibility of fatal or severe toxic reactions the patient should be fully informed by the doctor of the risks involved and should be under constant supervision.
In the treatment of psoriasis, METHOTREXATE should be restricted to severe, disabling disease, which is not adequately responsive to other forms of therapy.
Deaths have been reported with the use of METHOTREXATE in the treatment of psoriasis.
Serious adverse reactions including deaths have been reported with concomitant administration of METHOTREXATE and non-steroidal anti-inflammatory medicines.
METHOTREXATE induced lung disease is a potentially dangerous lesion, which may occur acutely at any time during therapy. It has been reported at doses as low as 7.5 mg/week. It is not always fully reversible.
Pulmonary symptoms (especially a dry, non-productive cough) may require interruption of treatment and careful investigation.
With high doses, plasma concentrations of METHOTREXATE should be monitored to identify patients with delayed METHOTREXATE clearance. Urine pH determinations must also be done to minimize the risk of METHOTREXATE precipitation (pH should remain greater than 7).
METHOTREXATE should be used with great care in patients with hepatic or renal impairment and concomitant use of medicine that is hepatotoxic and nephrotoxic should be avoided.
It should be used cautiously in alcoholics or those with ulcerative disorders of the gastro-intestinal tract.
Because of the possibility of carcinogenicity and mutagenicity, patients of child bearing age or conceiving potential must exercise non-hormonal conception control.

DOSAGE AND DIRECTIONS FOR USE:
Anti-neoplastic chemotherapy:
P&U METHOTREXATE CSV® may be given by intramuscular, intravenous or intrathecal route. Initial treatment is usually undertaken with the patient under hospital care.
DISCARD ANY UNUSED PORTION.
The physician should in all cases be familiar with the current literature before choosing a specific dosage.
It is essential that examinations of blood tests, renal and liver functions be made before, during and after each course of treatment. Dosage must be adjusted according to each patient’s requirements and must be based on clinical response or severity of toxicity. If there is a severe fall in white cell or platelet counts, METHOTREXATE should be withdrawn.
High dosage therapy (see “WARNINGS”):
Diseases treated with very high doses, administered in the form of single-drug or combination therapy, include osteosarcoma. Calcium folinate protection is required to prevent toxic reactions.
High-dose METHOTREXATE administration should not be initiated unless folinic acid is physically present and ready to be administered, since rescue is critical. A variety of dosage schedules of folinic acid in combination with high-dose METHOTREXATE have been used. The prescriber should consult the medical literature in choosing a specific dosage. Folinic acid administration should be consecutive rather than simultaneous with METHOTREXATE so as not to interfere with METHOTREXATE’s antineoplastic effects (first dose usually 24 to 42 hours after starting METHOTREXATE).
In patients with aciduria, ascites, dehydration, gastro-intestinal obstruction, pleural or peritoneal effusions and renal function impairment it is recommended that the duration of folinic acid administration be based on the determination of plasma METHOTREXATE concentrations because excretion of METHOTREXATE is slowed and the length of time needed for plasma METHOTREXATE concentration to decrease to non-toxic levels is increased.
Leukemia:
Acute lymphoblastic leukemia:
Maintenance adult dosage: intramuscular, 15 to 30 mg/m² once or twice weekly with other agents such as mercaptopurine. Alternatively, 2,5 mg/kg of body weight may be given intavenously every 14 days.
Lymphoblastic leukemia (Prophylactically):
Similar doses as for meningeal leukemia are given, sometimes in combination with intrathecal cytarabine and hydrocortisone.
Meningeal leukemia:
Adult dosage, induction and prophylaxis: Intrathecal, 12 mg/m² to a maximum of 15 mg, whichever is less, once or twice weekly, until the cell count of the cerebrospinal fluid (CSF) returns to normal.
Paediatric dosage:
Under 1 year of age: Intrathecal, 6 mg/m² once or twice weekly
1 year of age: Intrathecal, 8 mg/m² once or twice weekly
2 years of age: Intrathecal, 10 mg/m² once or twice weekly
3 years of age: Intrathecal, 12 mg/m² once or twice weekly, until the cell count of the cerebrospinal fluid (CSF) returns to normal.
Choriocarcinoma, chorioadenoma destruens or hydatidiform mole:
Intramuscular, 15 to 30 mg daily for 5 days, at intervals of 1-2 weeks, for 3-5 courses; alternatively:
Intramuscular, 0,25 to 1 mg/kg body-weight up to a maximum of 60 mg every 48 hours for 4 doses, followed by folinic acid rescue, and repeated at intervals of 7 days. One to two doses are usually given after normalization of urinary human chorionic gonadotropin (HCG) concentrations. Combination chemotherapy may be necessary in patients with metastases.
Advanced lymphosarcoma:
Intravenous, 3 to 30 mg per kg, or about 90-900 mg per m² with folinic acid rescue when required.
Mycosis fungoides:
Intramuscular, 50 mg weekly as a single dose or 25 mg twice weekly.
Osteosarcoma:
Intravenous infusion (over 4 hours), 12-15 g per m² has been given experimentally, followed by folinic acid rescue.
Psoriasis: (See “WARNINGS”)
Intramuscular or intravenous, 10-25 mg weekly. Other more frequent regimens have been used but a weekly dosage appears to be less hepatotoxic.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
The most common adverse reactions include ulcerative stomatitis, leukopenia, nausea and abdominal distress. Others reported are malaise, undue fatigue, chills and fever, dizziness and decreased resistance to infection. In general, the incidence and severity of side-effects are considered to be dose-related.
Adverse reactions as reported for the various systems are as follows:
Bone marrow depression: Can occur abruptly, and leucopenia, thrombocytopenia, and anaemia may all occur. The nadir of the platelet and white-blood cell counts is usually around 5-10 days after a bolus dose, with recovery between about 14-28 days, but some sources suggest that leucocytes may exhibit an early fall and rise, followed by a second nadir and recovery, within this period. Megaloblastic anaemia has also been reported.
Gastro-intestinal toxicity: Ulceration of the mouth and gastro-intestinal disturbances are early signs of toxicity; stomatitis and diarrhoea are signs that treatment should be interrupted, otherwise haemorrhagic enteritis, intestinal perforation, and death may follow. Gingivitis and pharyngitis can also occur.
Hepatotoxicity: METHOTREXATE therapy is associated with liver damage, both acute (notably after high doses) and, more seriously, chronic (generally after long-term administration) hepatotoxicity. Hepatotoxicity, including liver atrophy, necrosis, fatty changes and periportal fibrosis occurred. Hepatic fibrosis and cirrhosis may develop without obvious signs of hepatotoxicity, and have led to eventual death.
Nephrotoxicity: Renal failure, azotemia, hyperuricemia, severe nephropathy and tubular necrosis are more frequent following high doses.
Hyperuricemia and uric acid nephropathy occur most commonly during initial treatment of patients with leukemia or lymphoma, as a result of rapid cell breakdown leading to elevated serum uric acid. With high-dose METHOTREXATE therapy, symptoms resembling uric acid nephropathy may also be due to renal tubular damage resulting from precipitation of METHOTREXATE or metabolites in urine.
Pulmonary toxicity: Reactions including life-threatening interstitial pneumonitis or pulmonary fibrosis.
Skin reactions: More frequent with high-dose therapy; erythematous rashes, bullae, skin ulceration and necrosis consistent with toxic epidermal necrolysis, desquamation, exacerbation of photosensitivity reactions and purpuric skin lesions due to vasculitis. Reactivation of sunburn or increased erythematous response to ultraviolet therapy has also been reported. Less frequently acne, boils, pale skin and skin rash or itching occurred.
Neurotoxicity: Leucoencephalopathy, demyelination, chemical arachnoiditis, and meningismus are associated particularly with intrathecal or prolonged high-dose administration and are more likely when cranial irradiation is also given. Increased cerebrospinal fluid pressure was also reported. Neurotoxicity may present as mild ataxia, seizures or perceptual disorders.
Other reactions: alopecia, osteoporosis, arthralgia, myalgia, ocular irritation, and precipitation of diabetes. METHOTREXATE may cause defective oogenesis and spermatogenesis, and fertility may be impaired. It is teratogenic, and it has been associated with foetal deaths.
METHOTREXATE should be used with great care in patients with hepatic or renal impairment. It should also be used cautiously in alcoholics or those with ulcerative disorders of the gastro-intestinal tract, and in the elderly and the very young.
Regular monitoring of renal and hepatic function is advisable. With high-dose regimens, plasma concentrations of METHOTREXATE should be monitored. Maintenance of an adequate flow of alkaline urine is essential. Pleural or ascitic effusions may act as a depot for METHOTREXATE and produce enhanced toxicity.
Interactions:
METHOTREXATE is bound in part to serum albumin after absorption, and toxicity may be increased because of displacement by certain drugs,or by a decrease in its renal excretion, e.g. if used concurrently with para-aminobenzoic acid, phenylbutazone and phenytoin.
Alcohol: Concomitant use of other drugs with hepatotoxic potential (including alcohol) should be avoided.
Antibacterial agents: The oral aminoglycosides neomycin and paromomycin have been reported to reduce the absorption of METHOTREXATE.
Various penicillins have been reported to decrease the clearance of METHOTREXATE quite markedly.
Tetracycline, sulphonamides, and co-trimoxazole may displace METHOTREXATE from binding sites and reduce renal clearance. Para-aminobenzoic acid has also beenimplicated.
Antineoplastics and immunosuppressants: Administration with other myelosuppressive or immunosuppressive agents might be expected to result in enhanced bone-marrow toxicity and immunosuppression. Nephrotoxic agents such as cisplatin could reduce METHOTREXATE excretion.
Enhanced toxicity has also been reported with concurrent use of cyclosporin and with sequential use of fluorouracil.
Antivirals: Homocysteine deficiency produced by vidarabine may be a risk when METHOTREXATE is also given.
Blood products: Great care should be exercised whenever packed red blood cells and METHOTREXATE are given concurrently as high serum-METHOTREXATE concentrations may result.
Etretinate: Increased risk of hepatotoxicity.
The administration of L-asparginase has been reported to antagonize the effect of METHOTREXATE.
Cholestyramine: METHOTREXATE was found to be bound to cholestyramine resulting in reduced serum concentrations of METHOTREXATE.
Nitrous oxide: Potentiation of the effects of METHOTREXATE on folate metabolism has been reported.
Non-steroidal anti-inflammatory agents (NSAIAs): Severe, and in some cases fatal, aggravation of METHOTREXATE toxicity has been reported when it was administered concomitantly with various NSAIAs including aspirin and other salicylates, azapropazone, diclofenac, indomethacin, ketoprofen and naproxen.
However, when METHOTREXATE is used in low doses in the treatment of psoriasis, combinations with NSAIAs need not be contra-indicated. Patients need to be appropriately monitored and cautioned to avoid “over-the-counter”analgesics.
Probenecid: 3 to 4 fold increases of serum-METHOTREXATE can result when given concomitantly.
Amiodarone administration to patients receiving METHOTREXATE treatment for psoriasis has induced ulcerated skin lesions.
PUVA: Concomitant use with METHOTREXATE in patients with psoriasis or mycosis fungoides may lead to a higher incidence of skin cancers.
Radiation: Radiation therapy has been reported to enhance METHOTREXATE-induced neutropenia.
Vaccines: Because normal defense mechanisms may be suppressed by METHOTREXATE therapy, the patient’s antibody response to vaccine may be decreased. Severe antigenic reactions may occur if a live vaccine is given concurrently.
Vitamins: Vitamin preparations containing folic acid or its derivatives may alter responses to METHOTREXATE.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
See "Side-effects and Special Precautions". Folinic acid neutralises the immediate toxic effects of METHOTREXATE on the bone marrow. It is given as calcium folinate by mouth, intramuscularly, by intravenous bolus injection, or by infusion. When overdosage is suspected the dose of calcium folinate should be at least as high as that of METHOTREXATE and should be administered within the first hour, if possible; further doses are given as required. When average doses of METHOTREXATE have an adverse effect, the equivalent of 6-12 mg of folinic acid may be given intramuscularly every 6 hours for 4 doses. Folinic acid is usually given in association with high-dose METHOTREXATE regimens to prevent damage to normal tissue.
An adequate flow of alkaline urine should be maintained following high doses of METHOTREXATE to prevent precipitation of METHOTREXATE or its metabolites in the renal tubules. Further treatment is symptomatic and supportive.

IDENTIFICATION:
A yellow to orange, clear solution.

PRESENTATION:
P&U METHOTREXATE CSV 50 mg/2 mL INJECTION: Single dose vials containing 2 mL solution.
P&U METHOTREXATE CSV 500 mg/20 mL INJECTION: Single dose vials containing 20 mL solution.

STORAGE INSTRUCTIONS:
Store below 25°C and protect from light.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBERS:
P&U METHOTREXATE CSV 50 mg/2 mL INJECTION: 30/26/0311
P&U METHOTREXATE CSV 500 mg/20 mL INJECTION: 29/26/0502

NAME AND BUSINESS ADDRESS OF APPLICANT:
Pharmacia South Africa (Pty) Ltd
Alphen West G
George Street
MIDRAND
1685

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
22 December 2000

New addition to this site: February 2005
Source: Pharmaceutical Industry
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