LEUCOVORIN RESCUE SCHEDULES FOLLOWING TREATMENT WITH HIGHER DOSES OF METHOTREXATE
| Clinical Situation || Laboratory Findings ||
Leucovorin Dosage and Duration
|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.
15 mg PO, IM or IV q 6 hours for 60 hours (10 doses starting at 24 hours after start of methotrexate infusion).
|Delayed Late Methotrexate Elimination||
Serum methotrexate level remaining above 0.2 micromolar at 72 hours, and more than 0.05 micromolar at 96 hours after administration.
Continue 15 mg PO, IM or IV q 6 hours, until methotrexate level is less than 0.05 micromolar.
|Delayed Early Methotrexate Elimination and/or Evidence of Acute Renal Injury||
Serum methotrexate level of 50 micromolar or more at 24 hours, or 5 micromolar or more 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
150 mg IV q 3 hours, untilmethotrexate level is lessthan 1 micromolar; then15 mg IV q 3 hours, untilmethotrexate level is less than 0.05 micromolar.
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. (See PRECAUTIONS.)
PATIENTS SHOULD BE INFORMED BY THEIR PHYSICIAN OF THE RISKS INVOLVED AND BE UNDER A PHYSICIAN’S CARE THROUGHOUT THERAPY.
THE USE OF METHOTREXATE HIGH DOSE REGIMENS RECOMMENDED FOR OSTEOSARCOMA REQUIRES METICULOUS CARE. (See DOSAGE AND ADMINISTRATION.) HIGH DOSE REGIMENS FOR OTHER NEOPLASTIC DISEASES ARE INVESTIGATIONAL AND A THERAPEUTIC ADVANTAGE HAS NOT BEEN ESTABLISHED.
METHOTREXATE FORMULATIONS AND DILUENTS CONTAINING PRESERVATIVES MUST NOT BE USED FOR INTRATHECAL OR HIGH DOSE METHOTREXATE THERAPY.
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 (See CONTRAINDICATIONS).
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 nonsteroidal anti-inflammatory drugs (NSAIDs). (See PRECAUTIONS, Drug Interactions.)
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. (See PRECAUTIONS, Organ System Toxicity, Hepatic.)
5. Methotrexate-induced lung disease, including acute or chronic interstitial pneumonitis, is a potentially dangerous lesion, which may occur acutely at any time during therapy and has been reported at low doses. It is not always fully reversible and fatalities have been reported. Pulmonary symptoms (especially a dry, nonproductive cough) may require interruption of treatment and careful investigation.
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.
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. (See PRECAUTIONS, Organ System Toxicity, Skin.)
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.
GlucaGen [glucagon (rDNA origin) for injection] manufactured by Novo Nordisk A/S is produced by expression of recombinant DNA in a saccharomyces cerevisiae vector with subsequent purification.
For the treatment of hypoglycemia:
GlucaGen is used to treat severe hypoglycemic (low blood sugar) reactions which may occur in patients with diabetes treated with insulin.
Because GlucaGen depletes glycogen stores, the patient should be given supplemental carbohydrates as soon as he/she awakens and is able to swallow, especially children or adolescents.
Medical evaluation is recommended for all patients who experience severe hypoglycemia.
For use as a diagnostic aid:
GlucaGen is indicated for use during radiologic examinations to temporarily inhibit movement of the gastrointestinal tract. Glucagon is as effective for this examination as are the anticholinergic drugs. However, the addition of the anticholinergic agent may result in increased side effects. Because GlucaGen depletes glycogen stores, the patient should be given oral carbohydrates as soon as the procedure is completed.
Published Studies Related to Glucagen (Glucagon)
Acute effect on satiety, resting energy expenditure, respiratory quotient,
glucagon-like peptide-1, free fatty acids, and glycerol following consumption of
a combination of bioactive food ingredients in overweight subjects. 
following a standardized mixed meal with or without single consumption of a CBFI... CONCLUSION: CBFI may therefore be of great value in the treatment of overweight
Effects of LX4211, a dual sodium-dependent glucose cotransporters 1 and 2
inhibitor, on postprandial glucose, insulin, glucagon-like peptide 1, and peptide
tyrosine tyrosine in a dose-timing study in healthy subjects. 
and tolerability of LX4211 in healthy subjects were also assessed... CONCLUSIONS: This clinical study indicates that dosing of LX4211 immediately
The effect of the once-daily human glucagon-like peptide 1 analog liraglutide on the pharmacokinetics of acetaminophen. [2011.08]
INTRODUCTION: Acetaminophen is a commonly used analgesic and antipyretic drug, and is frequently used to study gastric emptying. Due to its high permeability and high solubility, acetaminophen can be used as a pharmacologic model for medications with similar characteristics. The objective of this study was to assess the effect of liraglutide on the pharmacokinetics (PK) of acetaminophen in patients with type 2 diabetes... CONCLUSION: The overall exposure of acetaminophen following a 1 g dose was comparable for subjects taking liraglutide or placebo, and the clinical impact of the lower C(max) and delay in absorption of acetaminophen was considered to be transient and small, and without clinical relevance. No adjustment for acetaminophen is recommended when used concomitantly with liraglutide.
Glutamine reduces postprandial glycemia and augments the glucagon-like peptide-1 response in type 2 diabetes patients. [2011.07]
Impaired glucagon-like peptide (GLP-1) secretion or response may contribute to ineffective insulin release in type 2 diabetes...
A pilot study to assess whether glucagon-like peptide-1 protects the heart from ischemic dysfunction and attenuates stunning after coronary balloon occlusion in humans. [2011.06]
CONCLUSIONS: In this pilot study, infusion of GLP-1 has been demonstrated to reduce ischemic LV dysfunction after supply ischemia during coronary balloon occlusion in humans and mitigates stunning. The findings require confirmation in a larger scale clinical trial. CLINICAL TRIAL REGISTRATION: URL: http://www.isrctn.org. Unique identifier: ISRCTN 77442023.
Clinical Trials Related to Glucagen (Glucagon)
Physiologic Response to Glucagon at Varying Insulin Levels [Recruiting]
The purpose of this research study is to test how different levels of insulin block the
effect of glucagon. Insulin is a hormone that lowers blood glucose. Glucagon raises blood
glucose. Both are natural hormones made by people without diabetes. Sensor-based blood
glucose control studies have been done by our research group using glucagon in small doses
to prevent hypoglycemia (low blood sugar). However, sometimes glucagon does not work to
raise blood sugar. The investigators believe this is because of too much insulin in the
body. This study will help determine how different levels of insulin in the body affect the
ability of glucagon to raise blood sugar.
Safety and Efficacy of a Novel Glucagon Formulation in Type 1 Diabetic Patients Following Insulin-induced Hypoglycemia [Recruiting]
Hypoglycemia is common in people with type 1 diabetes. Mild and moderate hypoglycaemia is
normally treated by consuming oral carbohydrates. During an episode of severe
hypoglycaemia however, the person with diabetes is unable to consume carbohydrates and
requires help from another person. The current standard treatment for severe hypoglycemia is
intravenous glucose or an injection of glucagon, which causes an increase of blood glucose,
which allows the person with diabetes to recover sufficiently to consume carbohydrate.
AMG Medical is investigating a novel formulation of glucagon which may be easier to
administer than the currently available glucagon formulations.
In this study, patients with Type 1 diabetes will receive injected insulin to reduce their
blood glucose, and will then receive one of three doses of the new glucagon formulation or a
dose of glucagon for injection, and their blood glucose will be measured for 3 hours.
The study hypothesis is that the new glucagon formulation will be as effective as the
current injected formulation at raising blood glucose levels within 15 minutes.
A Study of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamic Activity of Very Low Dose-Glucagon in Subjects With Type 1 Diabetes Mellitus [Completed]
The purpose of this study is to identify the safest dose of very low dose glucagon to prevent
hypoglycemia in patients with Type I diabetes who use insulin pumps and to measure the the
amount of glucagon in the blood and see how the body responds to the glucagon.
Influence of Glucagon Inhibition in Relation to the Anti-Diabetic Effect of Glucagon-Like Peptide-1 (GLP-1) in Patients With Type 2 Diabetes Mellitus [Active, not recruiting]
Incretinbased treatment of patients with type 2 diabetes mellitus (T2DM) has increasing
interest. The incretin glucagon-like peptide-1 (GLP-1) stimulates beta-cells to increased
secretion and production of insulin. Glucose sensitivity is enhanced, apoptosis inhibited -
progression in disease is potentially stopped. The alpha-cell is also influenced by GLP-1 as
infusion lowers plasmaglucose (PG) levels in patients with type 1 diabetes mellitus (T1DM)
(C-peptide negative) by inhibition of glucagon and thereby decreased hepatic
glucoseproduction (HGP). Further Vilsboll et al has proved normalization of the
glacgonostatic effect of glucose in patients with T2DM. As an attempt to elucidate
glucose-intolerance in patients with T2DM further Knop et al investigated the
glucagonresponse to both oral glucose tolerance test (OGTT) and a following iso-glycemic
clamp. He saw a sufficient suppression of glucagon when glucose was introduced intravenously
but the suppression of glucagon was attenuated and delayed when glucose was given orally.
The aim of this study is to elucidate the glucose intolerance further. Due to the complex
interactions and mutual feed-back regulation between the pancreatic hormones and the PG level
this protocol includes five days. All days include a euglycemic-clamp, patients with T2DM
(n=10) are clamped at their fasting PG as are healthy control subjects (n=10). During the
clamp either GLP-1 alone; GLP-1 in combination with somatostatin, insulin and glucagon; or
somatostatin, insulin and glucagon are infused and blood samples are drawn.
The design of the study makes it possible to isolate the effect of each hormone. Further we
will be able to enlighten the effect of GLP-1 on the increase in glucose turn-over it
The essential part in this design will be hormone concentrations and the response parameter
the amount of glucose (AUC) it takes to create the euglycemic-clamp.
The Effect of GLP-1 on the Inhibition of Glucagon Secretion [Recruiting]
Diabetes(both types) are recognized by high levels of glucagon in the circulation.
Glucagon is known to increase blood glucose, and might therefore contribute to the
respective diseases. Under some circumstances the gut hormone GLP-1 inhibits the glucagon
The investigators aim to identify the impact of GLP-1 on the glucagon secretion, at
increasing blood glucose levels in healthy subjects, in patients with type 2 diabetes, and
in patients with type 1 diabetes.
The investigators think that the effect of GLP-1 on the glucagon secretion might be
dependent of blood glucose levels.
Page last updated: 2014-11-30