SNP PP Methotrexate Training Module ver 1.0

Methotrexate Policy Once a day is
Training Module not the way!

This training module will provide By Flynn Lew
pharmacologic background and policy review Pharm.D.
regarding Skilled Nursing Pharmacy’s
methotrexate program. Chief Compliance
Officer

Purpose

• This educational module will outline the
policy to ensure the safe prescribing,
administration, monitoring, communication, and
dispensing of regular WEEKLY oral methotrexate
(excluding use as part of a chemotherapy
regimen).

• This program was developed to manage and
reduce the risk of harm to patients of incorrect
administration of oral methotrexate, by
improving the communication of prescribing
decisions, dose changes and monitoring.

Introduction

• Methotrexate is a safe and
effective medication if taken at the
right dose and FREQUENCY with the
appropriate monitoring. However,
errors involving daily oral
administration have caused severe
harm and death.

• Since early 1996, harmful or fatal
errors with daily oral methotrexate
for nononcologic use have
repeatedly been reported to ISMP
(Institute for Safe Medication
Practices). Oral methotrexate has
been on the ISMP List of High-Alert
Medications since the inception of
the list in 2003.

Introduction

Methotrexate is a specific
antagonist of folic acid. It is classed
as a cytotoxic drug because, in high
doses, it inhibits the proliferation of
malignant cells and has teratogenic
properties and irritant effects to the
skin.

Introduction

When used correctly in lower non-cytotoxic weekly
dosage regimens it can be used as a safe and effective
disease-modifying drug indicated for the treatment of:

• Rheumatoid conditions
• Dermatological diseases such as psoriasis

For these conditions it is prescribed as a lower single
dose e.g. 5mg – 25mg ONCE A WEEK. Methotrexate
may also be used in neoplastic disease using much
higher doses according to a specific protocol.

Introduction

Blackbox Warnings

• METHOTREXATE SHOULD BE USED ONLY BY PHYSICIANS WHOSE KNOWLEDGE AND
EXPERIENCE INCLUDE THE USE OF ANTIMETABOLITE THERAPY BECAUSE OF THE POSSIBILITY
OF SERIOUS TOXIC REACTIONS (WHICH CAN BE FATAL):

• METHOTREXATE SHOULD BE USED ONLY IN LIFE THREATENING NEOPLASTIC DISEASES,
OR IN PATIENTS WITH PSORIASIS OR RHEUMATOID ARTHRITIS WITH SEVERE, RECALCITRANT,
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 MALIGNANCY, PSORIASIS, AND RHEUMATOID ARTHRITIS.

• PATIENTS SHOULD BE CLOSELY MONITORED FOR BONE MARROW, LIVER, LUNG AND
KIDNEY TOXICITIES.

• PATIENTS SHOULD BE INFORMED BY THEIR PHYSICIAN OF THE RISKS INVOLVED AND BE
UNDER A PHYSICIAN’S CARE THROUGHOUT THERAPY.

Introduction

1. Methotrexate has been reported to cause fetal death and/or congenital
anomalies. Therefore, it is not recommended for women of childbearing
potential unless there is clear medical evidence that the benefits can be
expected to outweigh the considered risks. Pregnant women with psoriasis or
rheumatoid arthritis should not receive methotrexate.

2. Methotrexate elimination is reduced in patients with impaired renal function,
ascites, or pleural effusions. Such patients require especially careful monitoring
for toxicity, and require dose reduction or, in some cases, discontinuation of
methotrexate administration.

3. Unexpectedly severe (sometimes fatal) bone marrow suppression, aplastic
anemia, and gastrointestinal toxicity have been reported with concomitant
administration of methotrexate (usually in high dosage) along with some non-
steroidal anti-inflammatory drugs (NSAIDs).

Introduction

4. Methotrexate causes hepatotoxicity, fibrosis and cirrhosis, but generally only
after prolonged use. Acutely, liver enzyme elevations are frequently seen. These
are usually transient and asymptomatic, and also do not appear predictive of
subsequent hepatic disease. Liver biopsy after sustained use often shows
histologic changes, and fibrosis and cirrhosis have been reported; these latter
lesions may not be preceded by symptoms or abnormal liver function tests in
the psoriasis population. For this reason, periodic liver biopsies are usually
recommended for psoriatic patients who are under long-term treatment.
Persistent abnormalities in liver function tests may precede appearance of
fibrosis or cirrhosis in the rheumatoid arthritis population.

5. Methotrexate-induced lung disease is a potentially dangerous lesion, which may
occur acutely at any time during therapy and which has been reported at doses
as low as 7.5 mg/week. It is not always fully reversible. Pulmonary symptoms
(especially a dry, nonproductive cough) may require interruption of treatment
and careful investigation.

6. Diarrhea and ulcerative stomatitis require interruption of therapy; otherwise,
hemorrhagic enteritis and death from intestinal perforation may occur.

7. Malignant lymphomas, which may regress following withdrawal of
methotrexate, may occur in patients receiving low-dose methotrexate and, thus,
may not require cytotoxic treatment. Discontinue methotrexate first and, if the
lymphoma does not regress, appropriate treatment should be instituted.

Introduction

8. Like other cytotoxic drugs, methotrexate may induce “tumor lysis syndrome” in
patients with rapidly growing tumors. Appropriate supportive and pharmacologic
measures may prevent or alleviate this complication.

9. Severe, occasionally fatal, skin reactions have been reported following single or
multiple doses of methotrexate. Reactions have occurred within days of oral,
intramuscular, intravenous, or intrathecal methotrexate administration. Recovery
has been reported with discontinuation of therapy.

10. Potentially fatal opportunistic infections, especially Pneumocystis
carinii pneumonia, may occur with methotrexate therapy.

11. Methotrexate given concomitantly with radiotherapy may increase the risk of soft
tissue necrosis and osteonecrosis.

Dosing

Rheumatoid Arthritis
• Starting dose is 7.5mg taken orally as one
dose ONCE WEEKLY or 2.5mg taken every
12 hours for 3 doses ONCE WEEKLY.
• The dose may be increased to 20mg ONCE
WEEKLY over time if needed.
• The benefits of treatment usually appear in
about 3 to 6 weeks after initiating therapy.

Dosing

Psoriasis The usual adult starting dose is 10mg to
• 25mg ONCE WEEKLY or 2.5mg orally every
12 hours for 3 doses ONCE WEEKLY.
•
The dose may be increased to 30mg ONCE
WEEKLY over time if needed.

Safe Dose Limits

• No more than three tablets (each taken 12
hours apart), or a total of 20 to 25 mg EACH
WEEK for treatment of psoriasis and
arthritis.

• Higher doses are used only if treating cancer

Contraindications Alcoholism, alcoholic liver
disease, or other chronic liver
disease.

Blood dyscrasias, such as
bone marrow hypoplasia,
leukopenia,
thrombocytopenia or
significant anemia,
immunodeficiency
syndromes.

Women of child bearing age.

Monitoring • Baseline Assessment:

• CBC

• CMP (for monitoring liver
enzymes and renal
function)

• Chest X-Ray

• During Therapy

• CBC monthly

• CMP every 1-2 months

• Monitor for: pulmonary
symptoms (dry, nonproductive
cough), diarrhea, skin reactions

Side Effects

• Minimal side effects occur with low doses to
treat psoriasis or rheumatoid arthritis

• Possible side effects include: nausea,
vomiting, drowsiness

• Low-dose methotrexate has been associated
with the rare development of cancerous
lymphomas (tumors in lymph nodes).

• Other side effects (typically seen when taking
high doses):
• Rash, excessive fatigue, mental
confusion, fever, chills, mouth sores,
shortness of breath, dry cough, rapid
heartbeat or palpitations, unusual
bleeding or bruising, black stools,
persistent GI distress, frequency of
urination.

Drug Interactions

Methotrexate Levels

• Some NSAIDs
• NSAIDs + salicylates
• Salicylates, phenylbutazone, phenytoin, and sulfonamides.
• Probenecid
• Tetracycline, chloramphenicol, penicillin's
• Hepatotoxin agents (azathioprine, retinoids, sulfasalazine).

Overdosage

• Leucovorin is indicated to diminish the toxicity and counteract the
effect of inadvertently administered overdosages of methotrexate.
Leucovorin administration should begin as promptly as possible.

• As the time interval between methotrexate administration and
leucovorin initiation increases, the effectiveness of leucovorin in
counteracting toxicity decreases.

• Monitoring of the serum methotrexate concentration is essential in
determining the optimal dose and duration of treatment with leucovorin.

• 1:1 ratio for leucovorin to inadvertent methotrexate overdose, within
1 hour.

• 15mg orally, IV, or IM q6hr and continue until methotrexate level has
fallen below 0.05 micromolar and the renal failure has resolved.

Best Practice

To prevent accidental daily dosing of oral methotrexate, Skilled Nursing Pharmacy,
has defaulted the computer order entry system to a weekly dosing regimen.

Clarify ALL
Daily Orders

Clarify all daily orders of the medication if
the patient does not have a documented
oncologic diagnosis. Pharmacists should
speak DIRECTLY with the prescriber to
determine the indication, verify the proper
dosing schedule, and recommend
appropriate patient monitoring.

Once a Day is
Not The Way!

• DO NOT TAKE METHOTREXATE EVERY
DAY!

• Fatal errors have happened when
methotrexate was prescribed, dispensed,
and/or taken daily instead of once or twice
a week. Treatment for rheumatoid arthritis
and psoriasis requires just one to three
doses (12 hours apart) taken each week.