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Query : Methotrexate toxicity leads to immunosupression and bone marrow suppression. How long it tak

Methotrexate toxicity leads to immunosupression? – Yes


Methotrexate toxicity leads to bone marrow suppression. – Yes



At what dose it leads to toxicity ? – 15 mg


Your Explaination

It suppresses both bone marrow and immunosuppressant and need TDM for the patient.

by: Mr. Gopinath V Karnam

Descriptive Information:

Methotrexate toxicity leads to immunosupression? – Yes

Methotrexate toxicity leads to bone marrow suppression. – Yes At what dose it leads to toxicity ?

doses above 20 mg/m2 once weekly may be associated with an increased risk of toxicity Explaination

important Note

Methotrexate autoinjector is intended for once weekly subQ use only. Mistaken daily use has resulted in fatal toxicity. Use another formulation for alternative dosing regimens and routes of administration

Psoriasis (Severe), Recalcitrant, disabling

10 to 25 mg SUBQ once weekly; consider differences in bioavailability if switching from oral to subQ formulation; adjust dose gradually for optimal response, generally not exceeding 30 mg/wk; after optimal response, reduce to lowest possible drug dose and longest possible rest period, and consider return to conventional topical therapy

Rheumatoid arthritis (Severe), In patients with an insufficient response or intolerance to first-line therapy, including full-dose NSAIDs

initial, 7.5 mg SUBQ once weekly; individualize and adjust dose gradually for optimal response; at doses exceeding 20 mg/wk the incidence and severity of toxic reactions are increased; optimal duration of therapy is unknown; when switching from oral to subQ formulation consider differences in bioavailability

Methotrexate is an antimetabolite that interferes with DNA synthesis, repair, and cellular replication by inhibiting dihydrofolate reductase. In rheumatoid arthritis, the methotrexate mechanism of action is unknown, but it may have an effect on immune function [3][4]. Methotrexate controls the psoriasis process of increased proliferation in the rate of epithelial cell production in the skin .

Methotrexate is a folate antimetabolite that inhibits DNA synthesis, repair, and cellular replication. Methotrexate irreversibly binds to and inhibits dihydrofolate reductase, inhibiting the formation of reduced folates, and thymidylate synthetase, resulting in inhibition of purine and thymidylic acid synthesis, thus interfering with DNA synthesis, repair, and cellular replication. Methotrexate is cell cycle specific for the S phase of the cycle. Actively proliferative tissues are more susceptible to the effects of methotrexate.

Immunologic:

— immunization may be ineffective; immunization with live virus vaccines not recommended

— preexisting active infection necessitates additional caution as potentially fatal opportunistic infections, such as Pneumocystis jiroveci pneumonia, may occur

TOXICOLOGY: After an overdose, the effects of decreased DNA synthesis and cell death are noticed primarily in organ systems with rapidly dividing cells (eg, bone marrow, gastrointestinal tract).

The MOA in the treatment of rheumatoid arthritis is unknown, but may affect immune function. In psoriasis, methotrexate is thought to target rapidly proliferating epithelial cells in the skin.

In Crohn disease, it may have immune modulator and anti-inflammatory activity.

Methotrexate toxicities:

Nonhematologic toxicity: Diarrhea, stomatitis, or vomiting which may lead to dehydration: Discontinue until recovery

Hematologic toxicity:

Psoriasis, rheumatoid arthritis: Significant blood count decrease: Discontinue immediately.

Oncologic uses: Profound granulocytopenia and fever: Evaluate immediately; consider broad-spectrum parenteral antimicrobial coverage

Marked bone marrow depression may occur with resultant anemia, leukopenia, or thrombocytopenia. Unexpectedly severe (sometimes fatal) bone marrow suppression, aplastic anemia, and GI toxicity have been reported with concomitant administration of methotrexate (usually in high dosage) along with some nonsteroidal anti-inflammatory drugs (NSAIDs).

Bone marrow suppression: [US Boxed Warning]: Bone marrow suppression may occur (sometimes fatal), aplastic anemia has been reported; anemia, pancytopenia, leukopenia, neutropenia, and/or thrombocytopenia may occur. Use with caution in patients with preexisting bone marrow suppression. Discontinue treatment (immediately) in RA or psoriasis if a significant decrease in hematologic components is noted.

Patients may experience toxicity following therapeutic dosing, though toxicity may be ameliorated or even prevented with prompt therapy (eg, leucovorin). In children, intrathecal overdoses of less than 100 mg (less than a 15-fold overdose) usually do not develop significant CNS toxicity. Doses greater than 100 mg can cause severe morbidity. Intrathecal overdoses of greater than 500 mg have caused severe toxicity and are often fatal. In adults, inadvertent daily dosing instead of weekly dosing (orally) has been fatal; doses ranged from 60 mg over 16 days to 230 mg over 23 days. Together two children (3 and 4 years of age, respectively) ingested 2,025 mg of methotrexate and were given leucovorin. Both recovered with minimal adverse effect. THERAPEUTIC DOSE: Doses in adults vary widely depending on the indication. Acute lymphoid leukemia (ALL): Adults and children: Induction, 3.3 mg/m(2)/day IV in combination with prednisone 60 mg/m(2)/day. Maintenance, 30 mg/m(2)/week administered in 2 divided ORAL or IM doses; 2.5 mg/kg IV every 14 days has also been used. Advanced non-Hodgkin’s lymphoma: Adults: (Burkitt’s lymphoma, stages I and II): 10 to 25 mg/day orally for 4 to 8 days for several courses with a 7 to 10 day rest period; (stage III) in combination with other antineoplastic agents. (lymphosarcoma, stage III): 0.625 to 2.5 mg/kg/day in combination with other antineoplastics. HIGH-DOSE THERAPY: High doses range from 2.7 g/m(2) to 5 g/m(2). Administration of intravenous high-dose methotrexate occurs at different intervals in treatment and depends on the regimen being used. Juvenile rheumatoid arthritis: Children: 10 mg/m(2) orally once weekly. Meningeal leukemia: Adults: 12 mg intrathecally in intervals of 2 to 5 days; intervals of less than one week may increase subacute toxicity; until the cell count of the CSF returns to normal, and then 1 additional dose. Children: Varies by age: ranges from 6 mg for children less than 1 year of age to 12 mg for children 3 years or older intrathecally in intervals of 2 to 5 days; intervals of less than 1 week may increase subacute toxicity; until the cell count of the CSF returns to normal, and then 1 additional dose. Osteosarcoma: Adults: initial, 12 g/m(2) IV over 4 hours in combination with other chemotherapy agents (bleomycin, cisplatin, cyclophosphamide, dactinomycin, doxorubicin); if a peak serum methotrexate concentration of 1,000 micromolar (10 x (-3) mol/L) is not obtained, the dose can be increased to 15 g/m(2). Psoriasis: Adults: initial 10 to 25 mg/week orally/IM/IV or 2.5 mg every 12 hour for 3 doses; not to exceed 30 mg/week. Rheumatoid arthritis: Adults: 7.5 mg orally once weekly or 2.5 mg ORALLY every 12 hours for 3 doses once weekly OR 10 to 15 mg orally once weekly, increase by 5 mg/wk every 2 to 3 weeks, MAX 20 to 30 mg/wk (consensus-based).

By : Ms. Sahitya Kurapati


Methotrexate toxicity leads to immunosupression? – Yes

Methotrexate toxicity leads to bone marrow suppression. – Yes At what dose it leads to toxicity ? – minimum cumulative dose 10mg. Your Explaination

Pancytopenia is a rare but fatal complication.

It has been carefully re evaluated from clinical trials and case reports.

In fatal cases renal impairment was the most contributing factor.

Mean cumulative dose :675 mg (10-4800mg)

Minimum cumulative dose leading toxicity – 10 mg. Which indicates pancytopenia can occur at anytime during treatment!

There has been no evidence that bone marrow suppression is prevented by folic acid supplementation prophylaxis.

by : Ms. Rohini S P

#DrRohiniSP #DrSahityaKurapati #MrGopinathVKarnam

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